NB000573

KI-NA-23132-EN-C
EUR 23132
The sequencing of the human genome and many other genomes heralded a new age in human biology, offering
unprecedented opportunities to improve human health and to stimulate industrial and economic activity. The global
understanding of the complete function of approximately 22 000 human genes constitutes a major challenge
for understanding normal and pathological situations. To tackle this challenge, the European Commission made
fundamental genomics research a priority in the Sixth Framework Programme for RTD (FP6) (2002-2006).
The European Commission has allocated approximately `594 million in FP6 to fundamental genomics research
activities with the overall aim of fostering the basic understanding of genomic information by developing the
knowledge base, tools and resources needed to decipher the function of genes and gene products relevant to
human health, and to explore their interactions with each other and with their environment.
The present publication provides a brief description of the goals, expected results, achievements and expected
impact of all the projects supported during FP6 in the fundamental genomics priority area in the following scientific
sub-areas: the development of tools and technologies for functional genomics; regulation of gene expression;
structural genomics and proteomics; comparative genomics and model organisms; population genetics and
biobanks; bioinformatics; multidisciplinary fundamental genomics research for understanding basic biological
processes in health and disease; and the emerging area of systems biology.
During FP6, the European Commission has supported several systems biology initiatives which paved the way for
further developing the genomics and systems biology programme in the Seventh Framework Programme for RTD
(FP7) (2007-2013). The introduction provides an overview of the FP6 research policies and the steps taken to
strengthen the European Research Area in each of the scientific sub-areas, as well as the FP7 vision in genomics
and systems biology collaborative research.
PROJECT SYNOPSES EUR 23132

FUNDAMENTAL GENOMICS RESEARCH EU-funded collaborative research projects
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From Fundamental Genomics

to Systems Biology:
UNDERSTANDING THE BOOK OF LIFE
Synopses of EU collaborative research projects funded in Fundamental

Genomics under the Sixth Framework Programme for the Thematic Priority
«Life Sciences, genomics and biotechnology for health»
FP6 and FP7 research policies in Fundamental Genomics and Systems Biology
edited by Christina Kyriakopoulou

Life Sciences, Genomics and Biotechnology for Health
2008 EU-funded collaborative research projects EUR 23132
Acknowledgements
This publication could have only been accomplished thanks to the essential contribution of the project coordinators and the
input of my colleagues in the Health Directorate. Thanks to my colleagues, scientific officers, in the Genomics and Systems
Biology unit: Christian Desaintes, Tomasz Dylag, Iiro Eerola, Sasa Jenko, Fred Marcus, Sandra Pinto Marques and Ioana
Siska. Thanks to the former colleagues of the fundamental genomics area Henriette Van Eijl, Indridi Benediktsson, Bill Baig
and Elena Bordini. My special thanks to Mrs Josefina Enfedaque, scientific officer on health communication activities for
her valuable input. Finally, my special gratitude to Patrik Kolar, Bernard Mulligan and Jacques Remacle for their continuous
support and valuable guidance.
Christina Kyriakopoulou
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Luxembourg: Office for Official Publications of the European Communities, 2008
ISBN 978-92-79-08004-3
DOI 10.2777/49314
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Contact details for the Genomics and Systems Biology unit
European Commission
Directorate F- Health
Unit F4- Genomics and Systems Biology
Dr Patrik Kolar, Head of Unit (patrik.kolar@ec.europa.eu)

Dr Bernard Mulligan, Deputy Head of Unit (Bernard.mulligan@ec.europa.eu)
Dr Jacques Remacle, Scientific officer (Jacques.remacle@ec.europa.eu)
Dr Christian Desaintes, Scientific officer (Christian.desaintes@ec.europa.eu)
Dr Tomasz Dylag, Scientific officer (tomasz.dylag@ec.europa.eu)
Dr Iiro Eerola, Scientific officer (iiro.eerola@ec.europa.eu)
Dr Sasa Jenko, Scientific officer (sasa.jenko@ec.europa.eu)
Dr Christina Kyriakopoulou, Scientific officer (christina.kyriakopoulou@ec.europa.eu)
Dr Beatrice Lucaroni, Scientific officer (beatrice.lucaroni@ec.europa.eu)
Dr Fred Marcus (fred.marcus@ec.europa.eu)
Dr Sandra Pinto Marques (Sandra.pinto-marques@ec.europa.eu)
Dr Ioana Siska (ioana.siska@ec.europa.eu)
Further information:
http://cordis.europa.eu/fp7/health/home_en.html
http://cordis.europa.eu/lifescihealth/genomics/home.htm
5
TABLE OF CONTENTS
Foreword 14
Abbreviations 15
Part A 16 Overview of FP6 and FP7 research policies in Fundamental Genomics and Systems Biology
Section 1 16 The importance of Fundamental Genomics research in the European Union’s Framework
Programmes for RTD
Section 2 19 Fundamental Genomics programme in FP6: sub-areas and their objectives
Section 3 20 Scientific Excellence and impact of European Fundamental Genomics Collaborative Research
Section 4 22 The way forward in FP7: From Fundamental Genomics to Systems Biology
Section 5 25 Content of the present publication
Section 6 27 EC’s financial contribution in Fundamental Genomics & Systems Biology
Collaborative Research
Section 7 27 Scientific sub-areas supported in the FP6 and FP7 in Fundamental Genomics and
Systems Biology
7.1 27 Tools and technologies for functional genomics

7.1.1 29 Tools and technologies for gene expression
7.1.2 31 Tools and technologies for proteomics
7.1.3 32 Tools and technologies for molecular imaging
7.1.4 33 Tools and technologies for gene integration and recombination
7.2 33 Regulation of gene expression
7.2.1 34 Transcriptional regulation
7.2.2 34 Epigenetic regulation
7.3 35 Structural Genomics and Structural Proteomics
7.4 40 Comparative Genomics and Model organisms
7.4.1 40 Mouse
7.4.2 42 Rat
7.4.3 43 Zebrafish
7.4.4 43 Other models
7.5 44 Population Genetics and Biobanks
7.6 48 Bioinformatics
7.7 51 Multidisciplinary functional genomics approaches to basic biological processes
7.7.1 53 Biological pathways and intracellular and extracellular signalling
7.7.2 54 Tissue and organ development, homeostasis and disease
7.7.3 56 Stem cell biology
7.7.4 57 RNA biology
7.7.5 57 Chronobiology
7.7.6 58 Biology of prokaryotes and other organisms
7.8 58 Systems Biology
Annexes 64 Basic facts and figures for Fundamental Genomics activity area
Annex I 64 Funding instruments-schemes in FP6 and FP7
Annex II 69 Development of the specific scientific topics for calls for proposals
in the FP6 Fundamental Genomics programme
Annex III 70 European Commission’s strategic workshops in different scientific areas
of fundamental genomics and systems biology
Annex IV 72 Evaluation process in the FP6 and FP7 Fundamental Genomics programme
Annex V 75 Evaluation criteria in FP6 and FP7
Annex VI 78 Basic facts and figures for Fundamental Genomics activity area in FP6
From Fundamental Genomics to Systems Biology: Understanding the Book of Life 7

Part B Synopses of projects funded in Fundamental Genomics in FP6
1. Tools and technologies for functional genomics

1.1 Tools and technologies for gene expression
MolTools 86 Advanced Molecular Tools for Array-Based Analyses of Genomes,

Transcriptomes, Proteomes and Cells
REGULATORY GENOMICS 90 Advanced Genomics Instruments, Technology and Methods for
Determination of Transcription Factor Binding Specificities: Applications
for Identification of Genes Predisposing to Colorectal Cancer
Tat machine 92 Functional genomic characterisation of the bacterial Tat complex as a nanomachine
for biopharmaceutical production and a target for novel anti-infectives
TransCode 94 Novel Tool for High-Throughput Characterisation
of Genomic Elements Regulating Gene Expression in Chordates
EMERALD 96 Empowering the Microarray-Based European Research Area
to Take a Lead in Development and Exploitation
Autoscreen 98 Autoscreen for Cell Based High-throughput and High-content
Gene Function Analysis and Drug Discovery Screens
TargetHerpes 100 Molecular intervention strategies targeting latent
and lytic herpesvirus infections
FGENTCARD 102 Functional GENomic diagnostic Tools
for Coronary Artery Disease
MODEST 104 Modular Devices for Ultrahigh-throughput and Small-volume Transfection
1.2 Tools and technologies for proteomics
INTERACTION PROTEOME 108 Functional Proteomics: Towards defining the

interaction proteome
NEUPROCF 112 Development of New Methodologies for Low
Abundance Proteomics: Application to Cystic Fibrosis
CAMP 114 Chemical Genomics by Activity Monitoring of Proteases
ProDac 116 Proteomics Data Collection
1.3 Tools and technologies for molecular imaging
MOLECULAR IMAGING 120 Integrated Technologies for In vivo Molecular Imaging

Tips4Cells 124 Scanning Probe Microscopy techniques for real time,
high resolution imaging and molecular recognition in
functional and structural genomics
COMPUTIS 126 Molecular Imaging in Tissue and Cells by Computer-
Assisted Innovative Multimode Mass Spectrometry
1.4 Tools and technologies for gene integration and recombination
GENINTEG 130 Controlled gene integration: a requisite for genome

analysis and gene therapy
PLASTOMICS 132 Mechanisms of transgene integration and expression
in crop plant plastids, underpinning a technology for
improving human health
TAGIP 134 Targeted Gene Integration in Plants: Vectors,
Mechanisms and Applications for Protein Production
MEGATOOLS 136 New tools for Functional Genomics based on
homologous recombination induced by double-strand
break and specific meganucleases
8 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

2. Regulation of gene expression
2.1 Transcription regulation
TRANS-REG 142 Transcription Complex Dynamics Controlling Specific

Gene Expression Programmes
X-TRA-NET 144 ChIP-Chip to Decipher Transcription Networks of RXR
and Partners
2.2 Epigenetic regulation
THE EPIGENOME 148 Epigenetic plasticity of the genome

HEROIC 152 High-Throughput Epigenetic Regulatory Organisation
in Chromatin
ChILL 156 Chromatin Immuno-linked ligation: A novel
generation of biotechnological tools for research
and diagnosis
SMARTER 158 Development of small modulators of gene activation
and repression by targeting epigenetic regulators
3. Structural Genomics and Proteomics
3DGENOME 164 3D Genome Structure and Function

BIOXHIT 166 Bio-Crystallography on a Highly Integrated
Technology Platform for European Structural Genomics
3D-EM 170 New Electron Microscopy Approaches for Studying
Protein Complexes and Cellular Supramolecular Architecture
GeneFun 174 )N 3ILICO Prediction of gene function
E-MeP 176 The European Membrane Protein Consortium
FSG-V-RNA 180 Functional and Structural Genomics of Viral RNA
VIZIER 182 Comparative structural genomics on viral enzymes
involved in replication
UPMAN 186 Understanding Protein Misfolding and Aggregation by NMR
NDDP 188 NMR Tools for Drug Design Validated on Phosphatases
3D repertoire 190 A Multidisciplinary Approach to Determine the
Structures of Protein Complexes in a Model Organism
FESP 194 Forum for European Structural Proteomics
E-MeP-Lab 196 E-MeP-Lab Training events in membrane protein
structural biology
HT3DEM 198 High throughput Three-dimensional Electron Microscopy
NMR-Life 200 Focusing NMR on the Machinery of Life
Extend-NMR 202 Extending NMR for Functional and Structural Genomics
IMPS 204 Innovative tools for membrane structural proteomics
SPINE2-COMPLEXES 206 From Receptor to Gene: Structures of Complexes from
Signalling Pathways linking Immunology,
Neurobiology and Cancer
OptiCryst 210 Optimisation of Protein Crystallisation for European
Structural Genomics
TEACH-SG 212 Training and Education in High Volume and High
Value Structural Genomics

4. Comparative Genomics and Model organisms
4.1 Mouse
EURExpress 218 A European Consortium to Generate a Web-Based

Gene Expression Atlas by RNA in situ Hybridisation
MUGEN 222 Integrated Functional Genomics in Mutant Mouse
Models as Tools to Investigate the Complexity of
Human Immunological Disease
PRIME 226 Priorities for mouse functional genomics research
across Europe: integrating and
strengthening research in Europe
FLPFLEX 228 A Flexible Toolkit for Controlling Gene Expression in
the Mouse
EUCOMM 230 The European Conditional Mouse Mutagenesis Programme
EUMODIC 234 The European Mouse Disease Clinic: A distributed
phenotyping resource for studying human disease
CASIMIR 238 Co-ordination And Sustainability of International
Mouse Informatics Resources
4.2 Rat
STAR 242 A SNP and Haplotype Map for the Rat

EURATools 244 European Rat Tools for Functional Genomics
Med-Rat 248 New Tools to Generate Transgenic and Knock-out
Mouse and Rat Models
4.3 Zebrafish
ZF-MODELS 252 Zebrafish Models for Human Development and Disease

ZF-TOOLS 256 High-throughput Tools for Biomedical Screens in Zebrafish
4.4 Other models
NemaGENETAG 260 Nematode Gene-Tagging Tools and Resources

TP Plants and Health 262 The European Technology Platform on Plant
Genomics and Biotechnology: Plants for healthy
lifestyles and for sustainable development
X-OMICS 264 Xenopus Comparative Genomics: Coordinating
Integrated and Comparative Functional Genomics for
Understanding Normal and Pathologic Development
5.Population Genetics and Biobanks
HUMGERI 270 Human Genomic Research Integration

MolPAGE 272 Molecular Phenotyping to Accelerate Genomic Epidemiology
GenOSept 276 Genetics of Sepsis in Europe
MICROSAT workshop 278 Microsatellites and VNTRs: workshop on
bioinformatics, genomics and functionality
EUHEALTHGEN 280 Harnessing the Potential of Human Population
Genetics Research to Improve the Quality of the EU Citizen
PHOEBE 282 Promoting harmonisation of epidemiological biobanks in Europe

EUROSPAN 284 EUROpean Special Populations Research Network:
Quantifying and Harnessing Genetic Variation for
Gene Discovery
DanuBiobank 286 The Danubian Biobank Initiative — Towards
Information-based Medicine
Impacts 288 Archive tissues: improving molecular medicine
research and clinical practice
EpiGenChlamydia 290 Contribution of molecular epidemiology and host-
pathogen genomics to understand Chlamydia
trachomatis disease
6. Bioinformatics
BioSapiens 296 A European Network for Integrated Genome Annotation

ATD 300 The Alternate Transcript Diversity Project
EMBRACE 302 A European Model for Bioinformatics Research and
Community Education
ENFIN 306 An Experimental Network for Functional Integration
EUROFUNGBASE 310 Strategy to build up and maintain an integrated
sustainable European fungal genomic database
required for innovative genomics research on
üĺLAMENTOUSĺFUNGI, important for biotechnology and
human health
7.Functional Genomics approaches for Basic biological processes

7.1 Biological pathways and signalling
MAIN 316 Targeting Cell Migration in Chronic Inflammation

WOUND 320 A multi-organism functional genomics approach to
study signalling pathways in epithelial fusion/wound healing
MitoCheck 322 Regulation of Mitosis by Phosphorylation-
A Combined Functional Genomics, Proteomics and
Chemical Biology Approach
SIGNALLING & TRAFFIC 326 Signalling and Membrane Trafficking in
Transformation and Differentiation
TransDeath 328 Programmed cell death across the eukaryotic kingdom
Peroxisomes 330 Integrated Project to decipher the biological function
of peroxisomes in health and disease
DNA Repair 334 DNA Damage Response and Repair Mechanisms
STEROLTALK 338 Functional Genomics of Complex Regulatory
Networks from Yeast to Human: Cross-Talk of Sterol
Homeostasis and Drug Metabolism
RUBICON 342 Role of Ubiquitin and Ubiquitin-like Modifiers in
Cellular Regulation
EndoTrack 346 Tracking the Endocytic Routes of Growth Factor
Receptor Complexes and their Modulatory Role on Signalling
AnEUploidy 350 AnEUploidy: understanding gene dosage imbalance
in human health using genetics, functional genomics
and systems biology

7.2 Tissue and organ development and homeostasis
NFG 356 Functional Genomics of the Adult and Developing Brain

LYMPHANGIOGENOMICS 358 Genome-Wide Discovery and Functional Analysis of
Novel Genes in Lymphangiogenesis
EuroHear 362 Advances in hearing science: from functional
genomics to therapies
MYORES 366 Multiorganismic Approach to Study Normal and
Aberrant Muscle Development, Function and Repair
EuReGene 370 European Renal Genome Project
EVI-GENORET 374 Functional genomics of the retina in health and disease
7.3 Stem cells
FunGenES 380 Functional Genomics in Engineered ES cells

Plurigenes 384 Pluripotency Associated Genes to Dedifferentiate
Neural Cells into Pluripotent Cells
ESTOOLS 386 Platforms for biomedical discovery with human ES cells
EuTRACC 390 European Transcriptome, Regulome & Cellular
Commitment Consortium
7.4 RNA biology
RIBOREG 396 Novel non-coding RNAs in differentiation and disease

FOSRAK 398 Function of small RNAs across kingdoms
Callimir 400 Studying the biological role of microRNAs in the
Dlk1-Gtl2 imprinted domain
Eurasnet 402 European Alternative Splicing Network of Excellence
BACRNAs 408 Non-coding RNAs in Bacterial Pathogenicity
RNABIO 410 Computational approaches to non-coding RNAs
Sirocco 412 Silencing RNAs: organisers and coordinators of
complexity in eukaryotic organisms
7.5 Chronobiology
EUCLOCK 418 Entrainment of the Circadian Clock

TEMPO 422 Temporal Genomics for Tailored Chronotherapeutics
7.6 Biology of prokaryotes and other organisms
BACELL HEALTH 426 Bacterial stress management relevant to infectious

disease and biopharmaceuticals
DIATOMICS 428 Understanding Diatom Biology by Functional
Genomics Approaches

8. Systems Biology
EUSYSBIO 434 The Take-off of European Systems Biology

SYMBIONIC 436 Towards European Neuronal Cell Simulation:
a European consortium to integrate the scientific
activities for the creation of a European Alliance
devoted to the complete in-silico model of Neuronal Cell
EMI-CD 438 European Modelling Initiative combating complex diseases
QUASI 440 Quantifying signal transduction
COMBIO 442 An integrative approach to cellular signalling and
control processes: Bringing computational biology to the bench
COSBICS 444 Computational Systems Biology of Cell Signalling
DIAMONDS 446 Dedicated Integration and Modelling of Novel Data
and Prior Knowledge to Enable Systems Biology
EU-US Workshop 448 Workshop on “Systems biology of DNA-damage-
induced stress responses”
ELIfe 450 The European Lipidomics Initiative: Shaping the life sciences
ESBIC-D 452 European Systems Biology Initiative for Combating
Complex Diseases
YSBN 454 Yeast Systems Biology Network
AMPKIN 456 Systems biology of the AMP-activated protein kinase pathway
RIBOSYS 458 Systems Biology of RNA Metabolism in Yeast
EuroBioFund 460 A Strategic Forum for the Dialogue and Coordination
of European Life Sciences, Funders and Performers
VALAPODYN 462 Validated Predictive Dynamic Model of Complex
Intracellular Pathways related to cell death and survival
AGRON-OMICS 464 Arabidopsis growth network integrating OMICS technologies
BaSysBio 468 Towards an understanding of dynamic transcriptional
regulation at global scale in bacteria: a systems
biology approach
BioBridge 472 Integrative Genomics and Chronic Disease
Phenotypes: modelling and simulation tools for clinicians
SYSBIOMED 474 Systems Biology for Medical Applications
SysProt 476 System-wide analysis and modelling of protein modification
Streptomics 478 Systems biology strategies and metabolome
engineering for the enhanced production of
recombinant proteins in Streptomyces
SYSCO 482 Systematic Functional analysis of Intracellular
Parasitism as a model of genomes conflict
Proust 484 The temporal dimension in functional genomics
Part C Indexes
PROJECTS ACRONYM INDEX 488
INSTITUTION AND
COORDINATOR INDEX 493
KEYWORDS INDEX 498

Foreword
The last decade has witnessed unprecedented advances in the life sciences. The sequenc-
ing of the human (2001) and other genomes has revolutionised biology, with genome
sequences becoming the ‘periodic table’ of biology. The global understanding of the com-
plete function of approximately 22 000 human genes constitutes a major challenge for
understanding normal and pathological situations. Therefore, to tackle this challenge, the
European Commission made fundamental genomics research into health and disease one
of the main action lines in the Life Sciences thematic priority under the Sixth Framework
Programme for RTD (FP6) (2002-2006).
The European Commission identified the importance of genomics quite early, and has played
a cohesive role in addressing the fragmentation of the genomics and post-genomics research
community in Europe by funding collaborative research projects via the EU Framework Pro-
grammes for RTD. The rationale for structuring and integrating fundamental genomics research
at European level to tackle fragmentation and research capacity gaps is based on its immense
potential contribution to the understanding of the processes underlying human disease, and
hence offering unprecedented opportunities to improve human health and stimulate industrial
and economic activity. This research requires a collaborative approach, is by nature highly
multidisciplinary, and needs expertise and critical mass that do not exist in a single laboratory.
Integrated multidisciplinary research and a strong interaction between high-throughput tech-
nology development and biology are vital in the fundamental genomics field for translating
genome data into practical applications.
The European Commission has allocated some `594 million over four years in FP6 for fun-
damental genomics research activities with the overall aim to foster the basic understanding
of genomic information by developing the knowledge base, tools and resources needed to
decipher the function of genes and gene products relevant to human health, and to explore
their interactions with each other and with their environment. The present publication provides
a brief description of the goals, expected results, achievements and expected impact of all
the projects supported during FP6 in the Fundamental Genomics priority area in the following
sub-areas: tools and technologies development for functional genomics; regulation of gene
expression; structural genomics and proteomics; comparative genomics and models organ-
isms; population genetics and biobanks; bioinformatics; and multidisciplinary fundamental
genomics research for understanding basic biological processes in health and disease and
the emerging area of systems biology. During FP6, the European Commission supported sev-
eral systems biology initiatives which paved the way for further developing the genomics
and systems biology programme in the Seventh Framework Programme for RTD (FP7) (2007-
2013). The introduction provides an overview on FP6 research policies and the steps taken to
strengthen the European Research Area in each of the scientific sub-areas, as well as the FP7
concept in genomics and systems biology collaborative research.
The European Commission via its Life Sciences and Health programme has been acting as
a catalyst for strengthening European excellence in genomics and systems biology research.
The path to scientific discovery and innovation is long and complex and we have realised
that further investment will continue to be necessary for this important area. We are proud of
the European scientists who collaborate in top-class research projects and we are certain that
these projects will lead to substantial advances in the understanding of the links between the
human genome and diseases, strengthen Europe’s position in this important field of research,
and eventually benefit society.
Manuel Hallen
Acting Director
Health Research

Abbreviations
AG (Advisory Group)
CA (Coordination Action)
CP (Collaborative Project)
CP-FP (Small-Medium Scale Focused Research Collaborative Project)
CP-IP (Large Scale Integrating Collaborative Project)
EC (European Commission)
ERA (European Research Area)
EU (European Union)
FG (functional genomics)
FP (EU’s Framework Programme)
FP5 (Fifth Framework Programme for RTD)
FP6 (Sixth Framework Programme for RTD)
FP7 (Seventh Framework Programme for RTD)
GDP (gross domestic product)
HTP (high-throughput)
INCO target countries (International Cooperation target countries)
IP (Integrated Project)
NoE (Network of Excellence)
RNA (ribonucleic acid)
RTD (Research and Technological Development)
SB (systems biology)
SG (structural genomics)
SME (small- to medium-sized enterprise)
SME-STREP (SME-Specific Targeted Research Project)
SP (structural proteomics)
SSA (Specific Support Action)
STREP (Specific Targeted Research Project)

Part A: Overview of FP6 and FP7 research policies
in Fundamental Genomics and Systems Biology
Section 1
The importance of fundamental genomics research in
the European Union’s framework programmes for RTD
Over the last 23 years, the European Union (EU), via the implementation of subsequent EU Framework Pro-
grammes (FPs) for supporting Research and Technological Development (RTD) activities in the European Union,
has funded European collaborative and multidisciplinary research projects. This multi-laboratory, multinational
collaboration represents the ‘reason of existence’ of the FPs for RTD, often essential for assembling critical mass,
tackling fragmentation and strengthening European excellence in important research areas. The expected impact
lies in enabling breakthroughs in important research areas in order to boost European biomedical and biotech
industry competitiveness, and ultimately to improve citizens’ quality of life.
A significant part of different FPs’ budgets is dedicated to supporting collaborative research in life sciences and
biomedical research. The overall budget of the Sixth Framework Programme for RTD (FP6) was `17.5 billion, of
which an important proportion of `2.5 billion was allocated to the thematic priority of ‘Life Sciences, Genom-
ics and Biotechnology for Health’ in the period 2002 - 2006. The overall budget of the Seventh Framework
Programme for RTD (FP7) is `50.5 billion; it will run for seven years, with approximately `6 billion dedicated
to health-related collaborative research support.
` billion
60

50
40
30

20

10
1984-1987 1987-1991 1990-1994 1994-1998 1998-2002 2002-2006 2007-2013

FP7
Fig. 1: Graphical representation of the budgets
of the EU Framework Programmes for RTD (FP1–FP7, 1984–2013)
The European Research Area (ERA) was launched in 2000 by the EU as a key concept in implementing the Lisbon
strategy to make the EU “the most dynamic and competitive knowledge-based economy” by 2010; this was later
followed by the goal to increase spending on R&D in the EU up to 3% of the gross domestic product (GDP), where
two thirds would originate from private investments. FP6 set the implementation of the ERA as its major objective
and addressed the fragmentation of EU research more intensively.

The ERA concept encompasses three interrelated aspects:
■ a European ‘internal market’ for research, where researchers, technology and knowledge can circulate freely;
■ effective European-level coordination of national and regional research activities, programmes and policies;
■ initiatives implemented and funded at European level.
The FP is the main financial instrument to implement the ERA at EU level, but it is clear that many other EU initia-
tives and particularly initiatives at national and regional level will have to be undertaken.
A New European Research Strategy
A joint effort by the EU and MS to address structural deficits in European research
Fragmentation
Under-resourcing
Unfavourable environment for research and innovation
European Research Area (ERA)
European Research Area
National
programmes
Open European
Coordination research policy
Framework
programme
European
organisations
Fig. 2: Graphical representation of the concept of ERA
The European Commission (EC) identified the importance of genomics quite early, and has played a cohesive
role in addressing the fragmentation of the genomics and post-genomics research community in Europe by fund-
ing collaborative research projects via the EU FPs for RTD. The rationale for structuring and integrating funda-
mental genomics research at European level to tackle fragmentation and research capacity gaps is based on
its immense potential contribution to the understanding of the processes underlying human disease, and hence
offering unprecedented opportunities to improve human health and stimulate industrial and economic activity.
This research is by nature highly multidisciplinary, requires a collaborative approach, and needs expertise and
critical mass not available in any single laboratory. Integrated multidisciplinary research and strong interaction
between high-throughput (HTP) technology development and biology is vital in the fundamental genomics field
for translating genome data into practical applications.

Why research at European level?
0OOLINGĺANDĺLEVERAGINGĺRESOURCES
Resources are pooled to achieve critical mass
Leverage effect on private investments
Interoperability and complementarity of big science
&OSTERINGĺHUMANĺCAPACITYĺANDĺEXCELLENCEĺINĺ34
Stimulate training and international mobility of researchers
Improve S&T capabilities
Stimulate competition in research
"ETTERĺINTEGRATIONĺOFĺ%UROPEANĺ2$
Create scientific base for pan-European policy challenges
Encourage coordination of national policies
Effective comparative research at EU-level
Efficient dissemination of research results
Fig. 3: The importance of European collaborative research
Between 1990 and 2002 (from the Third Framework Programme (FP3) through the Fifth Framework Programme
(FP5)), the EU invested in genomics research. This resulted in several major breakthroughs: the sequencing of the
first eukaryotic genome (yeast), the sequencing of the first plant genome (Arabidopsis thaliana), and the assem-
bling of the physical and genetic maps of the human genomes — important and necessary tools for the further
sequencing of the human genome.
During FP5 (1998–2002), the EC invested `120 million in genome research. In 2002, `39.4 million was pro-
vided to three large-scale research projects in genomics research for human health: GenomEUtwin, a major effort
in population genetics (see www.genomeutwin.org); EUMORPHIA, a large integrated project (IP) devoted to the
development and standardisation of mouse models phenotyping tools (see www.eumorphia.org); and SPINE, a
major structural proteomics effort that solved approximately 300 new protein structures (www.spineurope.org).
These three projects, the first of such scale in FP5 in the life sciences, played an important role in structuring the
research community in the respective areas.
The publication of the first complete sequence of the human genome in 2001, as well as the sequencing of many
other genomes, heralded a new age in modern biology and biomedicine, offering unprecedented opportunities
to improve human health and to stimulate industrial and economic activity. If science was looking for a milestone
to mark the entry into the 21st century, it seems that revealing the sequence of the letters of the ‘book of life’ was
the most important one. Researchers in the post-genomics era have doubled their efforts, with the major goal of
‘reading’ the ‘book of life’, and understanding its ‘syntax’ and ‘language’ by putting the ‘words’ (our genes and
their functions) in the correct order.
The three billion ‘letters’ that make up our genetic code contain all the information needed to turn a fertilised egg
into an adult human being. Thanks to the human genome project, we now know the sequence of letters constitut-
ing the approximately 22 000 human genes.
However, the global understanding of the complete function of our genome, including the function of approxi-
mately 22 000 human genes and the interactions amongst them and with the environment, still constitutes a
major challenge for the understanding of normal and pathological situations.
DNA and protein microarrays and other technologies for HTP molecular profiling have expanded our horizons
and have provided a context for the information on the human organism: there are approximately 20 000 to
25 000 protein-encoding genes, more than 100 000 transcript splice variants of those genes and perhaps 106
protein states of possible functional significance.

Early results in post-genomics research have already challenged established views about the nature of the ge-
nome. A surprising result of the human genome sequencing experiments was that only a very small proportion
(1.5%) of the entire genome encodes for proteins. It was once thought that a large proportion of our genome
was inactive ‘junk DNA’, but today we know that many of these genomic regions have turned out to be regula-
tory sequences, which are responsible for activating or silencing genes when necessary.
All the latest technological and knowledge breakthroughs and the accumulation of HTP novel data continue
to highlight how little we still know about the effect of genes on the development of healthy and diseased
phenotypes.
Therefore, to tackle these challenges, the EC made genomics and post-genomics research a research priority in
FP6 (2002–2006). Indeed, of the total `2 500 million allocated to the priority of ‘Life Sciences, Genomics and
Biotechnology for Health’, approximately `594 million was invested over four years in the FP6 Fundamental
Genomics programme. Investing substantially in this EU Fundamental Genomics programme area was also im-
portant in meeting the scientific community’s strong expectations, illustrated by the high number of expressions
of interest (550) submitted in this area during the 2002 launching of FP6.
Section 2
The Fundamental Genomics Programme in FP6:
sub-areas and their objectives
Functional genomics is the branch of genomics that determines the biological function of the genes and their
products using the development and application of global (genome-wide or systems-wide) experimental ap-
proaches (i.e. genomics, transcriptomics, proteomics, in silico functional prediction, etc.).
Life sciences R&D - chain
Biology: DNA, Analysis/

Tools/assays Applications
RNA, protein interpretation
sequences microarrays bioinformatics further research

variation NMR, spec comparative genomics diagnostics +
function genotyping structural genomics disease markers
cells siRNA target validation
systems model organisms drugs / therapies
imaging pharmacogenomics
Fundamental genomics
Fig. 4: Fundamental genomics research in the life sciences and biomedicine landscape
The EU FP6 Fundamental Genomics Programme identified its strategic objectives: to foster the basic understand-
ing of genomic information by developing the knowledge base, tools and resources needed to decipher the
function of genes and gene products relevant to human health, and to explore their interactions with each other
and with their environment.

Research in FP6 supported the following scientific sub-areas:
■ Gene expression and proteomics with the aim of enabling researchers to better decipher the functions
of genes and gene products, as well as to define the complex regulatory networks (biocomplexity) that
control fundamental biological processes. Research focused on developing high throughput tools and
approaches for monitoring gene expression and protein profiles and for determining protein functions
and protein interactions.
■ Structural genomics with the overall objective to enable researchers to determine, more effectively and at
a higher rate than currently feasible, the three-dimensional (3-D) structure of proteins and other macromolecules,
important for elucidating protein function and essential for drug design. Research focused on developing HTP
approaches for determining high-resolution 3-D structures of macromolecules.
■ Comparative genomics and population genetics with the goal of enabling researchers to use well-
characterised model organisms for predicting and testing gene function and to take full advantage of specific
population cohorts available in Europe, so as to determine the relationship between gene function and health
or disease. Research focused on developing model organisms and transgenic tools, and developing genetic
epidemiology tools and standardised genotyping protocols.
■ Bioinformatics with the aim of enabling researchers to access efficient tools for managing and interpreting
the ever-increasing quantities of genome data, and for making it available to the research community in
an accessible and usable form. Research focused on developing bioinformatics tools and resources for
data storage, mining and processing, and on developing computational biology approaches for in silico
prediction of gene function and for simulation of complex regulatory networks.
■ Multidisciplinary functional genomics approaches to basic biological processes with

the overall objective of enabling researchers to study fundamental biological processes by integrating the
above mentioned innovative approaches. Research will focus on elucidation of the mechanisms underlying
fundamental cellular processes, to identify the genes involved and to decipher their biological functions in
living organisms.
With the rise of the era of systems biology, which signalled a new approach in understanding biological processes,
the latter sub-area supported pilot projects applying systems biology approaches for understanding basic biological
processes in health and disease.
Although these areas represent different sections of the fundamental genomics programme during FP6, many
projects were found to be cross-cutting in nature, using multidisciplinary approaches. For this reason, the authors
decided to present the projects funded in fundamental genomics according to common scientific theme, rather than
to use the ‘artificial’ sections mentioned above: this is more comprehensible for the reader. The grouping of all the
projects funded in FP6 in scientific sub-areas is presented in Section 7, along with an introduction explaining which
EC Actions reinforce which areas, the steps taken towards the ERA and a set of representative project examples.
Section 3
Scientific excellence and impact of European
fundamental genomics collaborative research
The EC identified the importance of genomics quite early, and has played a cohesive role in addressing the frag-
mentation of the genomics and post-genomics research community in Europe by funding collaborative research
projects via the EU FPs for RTD. The rationale for structuring and integrating fundamental genomics research at the
European level to tackle fragmentation and research capacity gaps is based on its immense potential contribution

to the understanding of the processes underlying human disease, and hence offering unprecedented opportunities
to improve human health and stimulate industrial and economic activity. This research is by nature highly multidisci-
plinary, requires a collaborative approach, and needs expertise and access to methodologies, technologies, data,
facilities and critical mass not accessible in any one laboratory, in order to accelerate breakthrough discoveries.
Integrated multidisciplinary research and strong interaction between high-throughput (HTP) technology development
and biology is vital in the fundamental genomics field, for translating genome data into practical applications.
While it is still premature to predict the success of European projects supported under the Fundamental Genomics
programme under FP6, one may conclude that EU is funding top-class, ambitious and state-of-the-art projects, involv-
ing excellence in Europe (as exemplified by the seven European Nobel prize winners participating in projects in
fundamental genomics):
■ Harmut Michel: Nobel Prize Winner in Chemistry 1988 (project E-MEP)
■ Christiane Nüsslein-Volhard: Nobel Prize Winner in Physiology or Medicine 1995 (project ZF-MODELS)
■ Rolf Zinkernagel: Nobel Prize Winner in Physiology or Medicine 1996 (project MUGEN)
■ John E. Walker: Nobel Prize Winner in Chemistry 1997 (project E-MeP)
■ Tim Hunt: Nobel Prize Winner in Physiology or Medicine 2001 (project MITOCHECK)
■ Kurt Wüthrich: Nobel Prize Winner in Chemistry 2002 (project UPMAN)
■ Aaron Ceichanover: Nobel Prize Winner in Chemistry 2004 (project RUBICON)
The first FP6-funded projects started in 2004, some have already been finalised, others are still ongoing. It is al-
ready evident that many of these projects have already generated major discoveries on novel gene functions, and
resulted in high-level publications (see project websites for further details). Most importantly, these projects have
played an important role in integrating the research community in Europe, thereby increasing their visibility at na-
tional, European and international level. They have also substantially contributed towards reducing fragmentation
of research in Europe in their respective fields, thereby implementing the concept of the ERA and creating a real
multidisciplinary integrated programme of activities, as is illustrated with relevant figures in each sub-area’s activi-
ties description (see Section 7).
All the projects funded in the area of fundamental genomics have very ambitious objectives. To achieve these
objectives, it is necessary to apply a multidisciplinary transnational approach and to create the necessary critical
mass of researchers utilising a large set of different cutting-edge technologies. This multidisciplinary approach
is only possible at European level by networking the research capacities and excellence available in different
countries via the EU collaborative projects (CPs).
KI
KI LAU
CSIC
LAU
CNRS CNRS LU
EBI
LU
BIOZ
MPI-B
MPI-F CSIC MPI-B

EMBI
BIOZ EMBL
FEI
MPI-F
UOXF
UOXF
EBI Birkbeck
FEI
UU
Imperial
Birkbeck Imperial
UU
Fig. 5: The structuring effect and the added value of collaborative projects: an example
of active interactions between partners at the start point to the mid-term of a four year project

Section 4
The way forward in FP7:
from fundamental genomics to systems biology
The last decade has witnessed unprecedented advances in the life sciences. The rise of genomics after the se-
quencing of the human and other genomes has revolutionised biology, with genome sequences becoming the
‘periodic table’ of biology. The spectacular development of the field of functional genomics and other ‘-omics’
research has dramatically changed the research landscape in the life sciences.
Life sciences research is moving away from a reductionist approach towards a new paradigm shift and a systems
biology approach that attempts to understand biology in an integrative manner as large amounts of novel data
become available.
In this new era of biology, scientists combine data, produced by a multidisciplinary set of functional genomics
tools and technologies, into biological models with the power of computer science, mathematics or engineering
to understand the phenomena of life. Researchers are increasingly realising that complex organisms cannot eas-
ily be subdivided into individual, independent components. Rather, genes, proteins, cells and organs interact
with each other and the environment in numerous, complex ways.
Systems biology aims to shed new light on these interactions, which are vital for the holistic understanding of
many major diseases such as cancer and diabetes.
The FP7 programme (2007–2013) has already been launched and is expected to play an important role in devel-
oping the field of systems biology in Europe by supporting the necessary critical mass of multidisciplinary expertise
(‘-omics’, mathematics, physics, etc.) needed to produce the complex models underlying important biological proc-
esses. This will require modelling of complex systems involving networks of tens of thousands of genes, gene prod-
ucts and other molecules. By understanding these biological processes in their complexity, systems biology promises
to make real progress towards understanding, preventing and combatting major complex diseases.
Although the deciphering of the human genome sequence represents a major step towards understanding human
biology, many questions still remain unanswered, including the function of most of the genes. New large-scale
data-gathering initiatives (e.g. population genetics including biobanks, large-scale proteomics, etc.) will be es-
sential for generating new knowledge on gene functions and their interactions in complex regulatory networks in
health and disease for future systems biology approaches.
Furthermore, to catalyse progress in functional genomics and systems biology, it is important to develop new and
improve existing ‘-omics’ high-throughput (HTP) research tools. The tools will catalyse experimental progress by
enhancing the generation and acquisition of data by orders of magnitude, and by significantly increasing our
knowledge base to gain insight into the functioning of cells, tissues, organs and entire organisms.
Based on the continuation concept and building on the strong FP6 European collaborative activities that have tak-
en place, the priority area of fundamental genomics is evolving towards the systems biology era. The structure of
the Genomics and Systems Biology programme in FP7 (2007–2013) ) is subdivided in the following sub-areas:
■ High-throughput research
The objective of this activity is to develop new research tools for modern biology that will significantly enhance
data generation and improve data and specimen (biobanks) standardisation, acquisition and analysis. The focus
will be on new technologies for:

■ sequencing
■ gene expression
■ genotyping and phenotyping
■ structural genomics
■ bioinformatics
■ systems biology
■ other ‘-omics’ fields
Potential impact and European added value of high-throughput research initiatives
Functional genomics is a field of research offering many opportunities for technological innovation. New
tools and technologies will be essential to enhance our knowledge on gene functions in health and dis-
ease: increasing data output and considerably decreasing the cost for sample analysis will permit the
transfer of these technologies to the clinical environment. Developing new HTP research tools and technolo-
gies for collecting and processing vast amount of new and high-quality data will dramatically increase our
knowledge of complex biological processes.
The development of these new tools and technologies requires a large multidisciplinary and coordinated
effort, involving expertise in molecular biology, engineering, robotisation, electronics, material sciences and
physics. Only coordinated efforts at European level can harvest this diverse expertise with the common goal
of developing new cutting-edge technologies. Importantly, any technological innovation obtained through a
coordinated European effort greatly facilitates wider access to these new technologies in Europe.
In several technological areas (e.g. imaging, proteomics, structural genomics, transgenics), Europe is very
competitive and a wide range of direct medical applications have been or are being developed. The
integrated collaborative efforts launched in FP6 and future efforts in FP7 will reinforce this competitive posi-
tion. The development of groundbreaking technologies will support knowledge-based European competi-
tiveness and their applications are expected to have a great impact on biomedical and biotechnological
industry, including small to medium-sized enterprises (SMEs).
■ Integrating biological data and processes:

large-scale data gathering and systems biology
■ Large-scale data gathering
The objective is to use HTP technologies to generate data for elucidating the function of genes and gene products
and their interactions in complex networks. The focus will be on the following:
■ genomics
■ proteomics
■ population genetics
■ comparative genomics
■ functional genomics

Potential impact and European added value of large-scale data gathering initiatives
New large-scale and systematic data-gathering initiatives in functional genomics (e.g. on the human pro-
teome) will be essential for human biology in providing new knowledge on gene functions. Furthermore,
standardisation of approaches will be achieved by developing European norms to facilitate efficient data
interchange. The data will be freely available for the scientific community in Europe.
In the recent past, several large-scale European initiatives were proven to be successful. In FP6, several
new initiatives have been initiated, including, for example, the large-scale genome annotation programme,
the whole mouse genomes in situ hybridisation projects and several structural genomics efforts.
Many Member States have cutting-edge post-genomics infrastructures, capacities and expertise. However,
to launch new large-scale data-gathering initiatives, these will need to be networked in a well-coordinated
and integrated effort that will generate the necessary critical mass of scale and scope. They will offer pos-
sibilities to smaller Member States with more limited resources and capacities. Furthermore, considerable
economy of scale and resources can be achieved by networking these research capacities in a coordi-
nated and integrated way. This coordinated approach at European level has proven to be successful for
several large data-gathering initiatives: the sequencing of the first yeast and plant genomes, and more
recently, the determination of the 3-D structure of proteins important for human health, via the structural
genomics collaborative efforts.
These large-scale initiatives require a multidisciplinary approach involving different types of expertise.
One of the bottlenecks in the translational process is how to translate a massive amount of data into useful
knowledge that is directly applicable. For this purpose, it is important to closely associate the bioinfor-
matics communities with these initiatives, so as to develop the integrated databases necessary for wide
dissemination of results. Industry must be closely associated with these efforts, providing the required
technical innovation and assistance.
■ Systems biology
The focus will be on multidisciplinary research that will integrate a wide variety of biological data and will de-
velop and apply system approaches to understand and model biological processes.
Potential impact and European added value of systems biology initiatives
Solving biological problems in health and disease requires understanding of complex networks, involving
tens of thousands of genes, gene products and other molecules. To further our understanding of biologi-
cal phenomena, there is a need for quantitative approaches and systematic modelling, and analysis of
the enormous amounts of information gathered by HTP technologies. With such approaches, collectively
termed ‘systems biology’, we can gain new insight into the functioning of living systems, from the mo-
lecular levels to the organism and population levels. This research involves a wide variety of disciplines,
including modelling and simulation of the complex dynamic interactions. Eventually, systems biological
research will open the way towards predictive biology and medical applications, when sufficiently power-
ful models, fed with enormous amounts of data from different sources, become widely available.
Projects operating in this category will contribute to the ERA by combining dispersed forces from around Eu-
rope. Scientists working on a particular system system (e.g. a cell, an organ or a disease) in different locations
will be able to work together towards a thorough understanding of the systems. Enabling this type of research
to be carried out at European level will secure Europe’s place in an increasingly competitive field and so help
employment prospects, industrial development (including SMEs) and wealth creation. Exploiting biological
data in an integrated way is one of the most cost-effective means of supporting all life sciences, as well as
helping to achieve the Lisbon objectives with the move towards a dynamic knowledge-based society.
Such an interdisciplinary approach is difficult, if not impossible, to carry out in a single institute, company
or even a single country. This research can only be undertaken in a large consortium which ideally should
be multinational. The requirement for such varied expertise renders the area ideal for European pro-

grammes, where national strengths in different disciplines can be combined for the benefit of all. Europe-
wide collaboration best averts the duplication of efforts and is a strong starting point for joining or driving
international collaboration.
Under FP6, several projects are under way, that either work towards enabling system biology, or gather
data that are suitable for such approaches (examples are Biosapiens and Eurohear). Many researchers
currently working on various systems are moving into systems approaches and the trend is likely to con-
tinue in the coming decade. The genome era has enabled us to accumulate enormous quantities of data
on both our genome and that of other organisms. The amount of data is certain to increase exponentially
for the foreseeable future. Paradoxically, utilising this data is becoming feasible on the one hand, and
increasingly complex on the other. The high hopes for new drugs and other treatments from the genomic
data can only become reality if the potential is realised through approaches such as systems biology.
Multidisciplinary projects :
s "IOLOGY
s %NGINEERINGSCIENCESTECHDEV
s -ATHEMATICSMODELLING
s #OMPUTATIONALDATABASETOOLS
s #LINICALRESEARCHHUMANGENETICS
in a holistic approach to address complex

biological systems in health and disease
Fig. 6: The multidisciplinary nature of systems biology
Section 5
Content of the present publication
Although the sub-areas set out in Section 2 represent different sections of the fundamental genomics programme
in FP6, many projects were found to be cross-cutting in nature, involving multidisciplinary approaches. For
this reason, we thought the reader would find it clearer to present the list of projects funded in fundamental
genomics arranged according to common scientific theme rather ‘artificially’ distributed based on the action
lines mentioned above.
impact of all the projects supported during FP6 in the fundamental genomics priority area in the following scien-
tific sub-areas:
■ tools and technologies development for functional genomics
■ regulation of gene expression

■ structural genomics and proteomics
■ comparative genomics and models organisms
■ population genetics and biobanks
■ bioinformatics
■ multidisciplinary fundamental genomics research

for understanding basic biological processes in health and disease
■ the emerging area of systems biology.
For each of these sub-areas, an introductory section describes the importance and impact in the post-genomics
era of each field, including highlights from several projects and a short description of the activities implemented
in the FP7 first call for proposals. The introductory section also provides an overview of FP6 research policies and
the steps taken to strengthen the ERA in each of the scientific sub-areas, as well as the FP7 vision in genomics and
systems biology collaborative research. However, owing to space limitations in this publication, we could not
highlight all 130 projects funded in the fundamental genomics programme, in the introductory section. Naturally,
this by no means minimises the importance of the projects not cited.
Table 1: EC Funding of different thematic sub-areas in fundamental genomics

and systems biology collaborative research in FP6 and in FP7’s first call selected projects
Fundamental Genomics Research in FP6 (2002–2006)
Number of EC financial
Scientific sub-area projects contribution
(million `)
Tools and Technologies
20 68.0
for Functional Genomics
Regulation of Gene Expression 6 32.6
Structural Genomics
19 87.2
and Structural Proteomics
Comparative Genomics
15 82.4
and Model Organisms
Population Genetics and Biobanks 10 19.4
Bioinformatics 5 32.0
Multidisciplinary Approaches
32 219.4
for Basic Biological Processes
FP6 Pilot Projects on Systems Biology 23 53.0
4OTAL
Genomics and Systems Biology Research in FP7 (2007–2013) (first call)

Tools-Technologies for HTP research 3 35.7
Large-Scale Data Gathering 7 80.0
Systems Biology 4 45.8
4OTAL ĺ#0 )0

All the projects are highly multidisciplinary and include several areas of fundamental genomics in their research
plan. We thought it would be easier for the reader if we classified the projects using the respective scientific
themes they have in common. Having said that, there are several areas, like bioinformatics and databases,
which are an essential part of all the projects and particularly of all the projects funded in the area of multidisci-
plinary functional genomics, for understanding basic biological processes.
Section 6
EC financial contribution in fundamental genomics
and systems biology collaborative research
The EU FP6 thematic activity on ‘Life Sciences, Genomics and Biotechnology for Health’ has had a clear focus
in the post-genomics era, rising to the challenges following the sequencing of the human and other organisms’
genomes. More specifically, the Fundamental Genomics Research programme received support of approximately
`594 million under FP6 for a large number of collaborative projects (CPs) (small- to medium-scale (89) and large-
scale (41)), out of a total `2 500 million allocated to the priority of ‘Life Sciences, Genomics and Biotechnology
for Health’. The EC has committed approximately `635 million for 87 projects under Health research for the FP7
first call selected projects which started in the beginning of 2008. More specifically, in the Genomics and Systems
Biology area, 14 large-scale integrating projects were supported, constituting `161.5 million (for further details,
see Table 1). Specific explanatory notes on the definition of the funding instruments in FP6, namely Integrated
Projects (IPs), Networks of Excellence (NoE), Specific Targeted Research Projects (STREPs), Co-ordination Actions
(CAs) and Specific Support Actions (SSAs) are presented in Annex I of this publication.
Section 7
Scientific sub-areas supported in FP6 and FP7
in fundamental genomics and systems biology
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺFUNCTIONALĺGENOMICSĺ
All processes in biology and medicine reflect the flow of information from the genome of the organism to its
phenotype. Since the identification of the structure of the DNA molecule more than 50 years ago, progress in
understanding these processes has been driven by new technologies such as cloning, DNA sequencing, meas-
urements of ribonucleic acid (RNA) and protein, and use of robotics and microarrays. The genome sequencing
project has created a milestone for the deeper understanding of the function of the genes in a genome-wide, HTP
manner and set the challenges for the post-genomic era in the area known as functional genomics.
Functional genomics focuses on a series of dynamic aspects of cellular biology such as gene transcription,
translation and protein-protein interactions, including function-related aspects of the genome itself, such as muta-
tion analysis and the measurement of molecular activities. It utilises the development and application of global
(genome-wide or systems-wide) experimental approaches e.g. genomics, transcriptomics, proteomics, in silico
(in italics) functional prediction, etc.). HTP technologies are a hallmark of functional genomics experimentation,
with their capacity for collecting data on a genome-wide scale.

Functional genomics is a field of research offering many opportunities for technological innovation. These tech-
nologies have proven strategically important for both academia and industry. Developing new HTP research
tools and technologies for collecting and processing vast amounts of new and high-quality data will dramatically
increase our knowledge of complex biological processes.
Despite all the progress being made, there are a number of bottlenecks currently affecting functional genomics
research. The success of functional genomics lies in the development of novel tools to solve the practical limitations
it suffers today. It should also be noted that there is a high degree of fragmentation of technologies, resources and
expertise, which makes it difficult to exchange information and address the bottlenecks in a coordinated effort.
Such collaboration is particularly important in view of the speed with which these technologies are moving and
also because of their multidisciplinary nature. Another important issue is the tools standardisation aspect: this is
required to provide high-quality reproducible data and to enable valid exchange and comparison of experimental
data. In addition, due to the large quantity of data produced by these techniques, the development of sophisticated
bioinformatics tools is necessary to increase the power of the functional genomics technologies. Most importantly,
the development of new tools and technologies in functional genomics requires a large multidisciplinary and coor-
dinated effort involving expertise in molecular biology, engineering, robotisation, electronics, material sciences and
physics. Only coordinated efforts at European level can bring together this diverse expertise with common goals of
developing new cutting-edge technologies, and therefore the area is well suited for EU support.
FP6 activities
In order for Europe to keep its competitive position in the development of new and improved functional genom-
ics tools, a substantial number of projects have been supported in FP6 and several important actions have been
launched in the first three FP7 calls for proposals.
In summary, the fundamental genomics programme in FP6 supported projects that aimed to improve existing or
develop new tools and technologies for functional genomics research.
The projects addressing such technologies are grouped in four categories, namely:
■ technologies for gene expression
■ technologies for proteomics
■ technologies for molecular imaging
■ tools and technologies for gene integration
Plenty of other projects developing tools and technologies are presented in the different sub-areas of structural
genomics, model organisms, population genetics and bioinformatics in the following sections.
The FP6 European projects have been successful in bringing together the tools, the developers and the experi-
mentalists for developing the most appropriate state-of-the-art technology and for validating them in experi-
mental conditions. The HTP, high-precision technologies that are being established as a result of FP6-related
projects are expected to be of major importance to research, improving the competitiveness of Europe on the
world stage. Importantly, any technological innovation obtained through a coordinated European effort greatly
facilitates wider access to these new technologies in Europe and to the international scientific community. The
future applications of functional genomics technologies in health research are endless: cellular mechanisms
can be delineated, gene expression chips are already being used in early diagnosis, and proteins potentially
have enormous value as clinical biomarkers.
FP7 activities
The EC recognises the immense potential of the technologies in functional genomics for innovation and strength-
ening of European biotechnological and biomedical industry competitiveness. Therefore, FP7 has prioritised the

area of HTP research with a focus on new technologies for the following: sequencing, gene expression, genotyp-
ing and phenotyping, structural genomics, bioinformatics, systems biology and other ‘-omics’ fields.
During the FP7 first call for proposals, EC supported three large integrating projects launched in 2008, amount-
ing to `36 million overall, in the following subjects:
■ development of human genetic variation databases integration (Gen2Phen);
■ tools and technologies development for spatial and temporal proteomics (PROSPECTS);
■ on technologies for DNA sequencing and genotyping (READNA).
During the FP7 second call for proposals, a broad topic on SME-driven small-scale focused research CPs for
developing tools and technologies for HTP research was published. Several projects were selected for funding
amounting to approximately`30 million, covering areas on tools for gene expression, proteomics, sequencing,
phenotyping (currently under negotiation). The funding upper limit was `3 million EC contribution per project,
with 40% allocated to SMEs, which is expected to reinforce SMEs’ scientific and technological bases.
The EC, continuing its efforts in the functional genomics tools area, published the FP7 third call for
proposals in September 2008, with the aim of attracting proposals in the following areas:
■ computational tools for genome annotation and genotype/phenotype data integration

tools, which will enable integration of the vast amounts of functional genomics data, facilitate data mining
and catalyse progress in systems biology;
■ HTP tools and technologies to analyse samples in large-scale human biobanks, which will
deliver high-quality and standardised data and accelerate epidemiological studies and biomarker discovery;
■ tools, technologies and resources for the characterisation of protein functions, which will
help to overcome bottlenecks in the investigation of protein functions in cells, leading to a better under-
standing of biological processes in health and disease.
For the first time in EU CPs in health research, a two-stage selection process will be implemented, with proposal
topics that are broader in scope and that will invite a larger number of pre-proposals (of maximum 5 to 10 pag-
es) for the first stage. In this way, the scientific community will be consulted for their ideas on research projects,
aiming to keep Europe at the forefront of technology and resources development in HTP research.
Europe is very competitive in the development of several groundbreaking technologies for functional genomics,
and their applications are expected to have a great impact in biomedicine and in the biotechnology industry,
including SMEs. Only coordinated efforts at European level can gather this different expertise with the common
goal of developing new cutting-edge technologies. Therefore, the FP7 Health priority via its Genomics and Sys-
tems Biology programme will continue its support for catalyzing progress in this important area.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺGENEĺEXPRESSIONĺ ĺ
The ability to functionally explore the effect of genes on cellular phenotypes and signalling in a HTP fashion is of
fundamental importance in all fields of life sciences and biomedicine and has also attracted the attention of the
biotechnology and biomedical industries.
Developments in large-scale, high throughput technologies and robotics now allow researchers to simultaneously
profile vast numbers of different genes and gene products in parallel. Examples are DNA microarrays, where
many thousands of genes are spotted onto an area no bigger than a microscope slide, allowing researchers to
sample thousands of genes in parallel for expression analysis in health and disease.

The ability to monitor the activity of the genome by simultaneously measuring the expression of the transcribed
genes provides a broader view of the cellular response under specific conditions, such as a particular develop-
mental state, a specific cell type or a certain disease state. Studies in major diseases like cancer demonstrate
that genome-wide gene expression profiles could identify molecular profiles correlated to disease states; this
approach could have enormous potential for the development of novel diagnostic tools.
Recent years have seen the rapid growth of techniques for HTP analyses of genes, transcripts, proteins and cells
using microarrays, but current methods still capture only a small fraction of the information embodied in the
biological molecules. Methods are needed to detect nucleic acids and proteins in single cells, and in complex
samples even at the level of single molecules, to overcome the limitations imposed by techniques currently being
applied in heterogeneous populations of cells. The success of novel technologies will lie in breaking through
the practical limitations it suffers today, in terms of sensitivity, accuracy, and ‘noise’ levels. A great challenge
still remains the intensive interplay between tools developers and experimentalists, and between academy and
industry: collaborative and coordinated efforts at the European level are required to tackle this. In addition, the
optimisation of standardised HTP technologies to study gene expression will remain a requirement for the future,
as well as the development of ultra-precision technologies and devices.
FP6 activities
In summary, the FP6 projects funded in this sub-area may be classified into two categories:
1. Projects overcoming existing bottlenecks and developing tools and technologies

for the study of gene expression
With already existing array technologies serving as a starting point, the IP MolTools is developing a new
set of HTP methods with the aim of increasing sensitivity and precision, and enabling analyses at the level
of single DNA, RNA or protein level at a considerable lower cost. EMERALD aims to coordinate a discus-
sion on reproducibility, variability and comparability of microarray experiments at different platforms and to
overcome the limitations of microarray technologies in terms of reproducibility and sensitivity. The resolution
of these issues will facilitate the translation of microarray technology in a clinical setting. TRANSCODE
develops open source tools using bioinformatics and large-scale experimental approaches for the prediction
and verification of the functional role of regulatory elements controlling gene expression, and for the identifi-
cation of transcription factors (TFs) binding sites. AUTOSCREEN’s goal is the establishment of an innovative,
automated instrument for HTP and high-content screening that will permit the qualitative and quantitative
monitoring of cellular constituents (RNA, proteins, and metabolites) in living cells.
2. Projects developing tools for gene expression, which are applied to the study
of disease mechanisms
REGULATORY GENOMICS aims to develop novel tools and methods for the determination of tran-
scription factor binding specificity, and to apply these techniques for determination of the binding spe-
cificities of TFs linked to cancer. This information will subsequently be used for computational identifica-
tion of ‘regulatory’ SNPs (rSNPs) that are predicted to affect transcription factor binding. The principle
objective of the project MODEST is the development and use of modular devices as well as protocols
for highly efficient, small-volume ultra-HTP screenings of primary cells, in areas such as neurology and
liver metastasis, to accelerate basic research, target identification and drug validation. FGENTCARD’s
major goal is to develop methodologies that integrate functional genomics tools and genetic strategies
to address major unresolved questions concerning the molecular basis of common diseases with a focus
on coronary artery disease. TargetHerpes focuses on improving tools for producing novel antivirals.
These projects have already shown a clear added value in carrying out the work at an extremely cooperative
and integrated European level, by establishing tools with international visibility, that have been developed
through close collaboration of partners, both across European countries and via international cooperation.
FP7 future actions will continue to support projects developing tools for gene expression under the FP7 priority
sub-area for HTP research.

ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺPROTEOMICSĺ
The term proteome describes the full set of proteins encoded by the cell’s genome which are constantly changing,
reflecting the dynamic response of cells to their environment. Proteomics is the study of the proteome in a HTP
manner. In recent years, the term proteome has been expanding to include the study of all the protein isoforms,
their post-translational modifications, their interactions, and their structural analysis.
Following the technological development in genomics, the interest in the simultaneous analysis and measure-
ments of genome-wide protein levels will be of central importance in biological studies, since proteins are the
main regulators whose concentration and modification define the cells responses to the environment.
Proteomics complements other functional genomics approaches, including microarray-based expression profiles,
systematic phenotypic profiles at cell and organism level, systematic genetics and small-molecule-based arrays.
Additionally, proteomics is set to have a profound impact on clinical diagnosis and drug discovery via the detec-
tion of protein profiles associated with disease states, since most currently used drug targets are proteins.
Tremendous progress has been made in the past years in generating large-scale data sets for protein-protein
interactions, organelle composition, protein activity patterns and protein profiles in healthy and diseased situa-
tions. Moreover, large-scale data sets will be crucial for the emerging field of systems biology. But further techno-
logical improvements, coordination of European and international proteomics efforts, as well as open access to
results are needed for the field of proteomics to realise its full potential.
Proteomics advances would not be possible without the previous achievements of genomics, which provided the
‘blueprint’ of possible gene products that are the focus of proteomics studies. Unlike the challenges faced with the
human genome projects, proteomics faces inherent challenges which deal with problems of material limitations
and variability, sample sensitivity and degradation, low to high abundance, a plethora of post-translational modi-
fications and unlimited tissue, developmental and temporal, diseased state and drug responses variations. In
addition, over of the last years, vast amounts of heterogeneous data has been generated in proteomics research
as well as different bioinformatics software and formats, a fact that creates barriers for the direct comparison
and the sharing of data.
FP6 activities
To address the current challenges and the immense potential of the proteomics field, the majority of FP6-funded
projects were oriented towards improving throughput potential, sensitivity and accuracy of detection of the
proteomes, as well as the standardisation of data. INTERACTION PROTEOME, the largest effort established
at the European level, has objectives focused on the future of the functional proteomics field, via the develop-
ment of a broadly applicable platform of innovative methods for the analyses of protein-protein interactions.
A multidisciplinary approach has been established to address different aspects of protein-protein interaction
data: their validation by cell biology, biochemical and biophysical methods; the improvement of in silico (in
italics) methods for prediction of protein interactions; and ultimately the development of a new type of public
database for protein-protein interaction data.
The ProDac CA is contributing to the international proteome standards initiative for HTP proteomics by
implementing these standards in public repositories and data submission pipelines, and demonstrating the
practical use of improved, standardised proteomics data collection and analysis to the proteomics community.
NEUPROCF, a project with a more specific focus, is further developing and applying a set of proteomics tools
for the detection of low-abundance proteins to help the study of disease phenotype (i.e. cystic fibrosis). With the
project CAMP, the new emerging field of chemical genomics has also been addressed.
FP7 activities
Establishing how networks of proteins associate in time and space to generate function is an important goal in
post-genomics research. The formation of interaction networks is essential for cellular function and requires pro-
teins to be at the right place, at the right time and in the right concentration.

In view of the importance of spatial and temporal proteomics in the area of HTP tools development, at the FP7
first call for proposals the EC supported the project PROSPECTS, a large scale integrating project funded
with `12 million, to overcome current bottlenecks in the proteomics technologies. This multidisciplinary project
brings together the world leaders in proteomics to make a major advance, both by developing much more
powerful instrumentation and by applying novel proteomics methods that will quantitatively annotate the human
proteome with respect to protein localisation and dynamics. These technological developments will be applied
so as to gain unique insights into the molecular basis of multiple forms of human disease, specifically neurode-
generation and other diseases related to folding stress.
To keep Europe at the forefront of technology development in proteomics research, the EC, via its Health priority,
published the FP7 second call for proposals for SME-targeted focused CPs in HTP research. Several proteom-
ics projects have been selected for funding and are currently under negotiation. Continuing the efforts, the EC
published the FP7 third call for proposals in September 2008 with the aim of developing tools, technologies
and resources for the characterisation of protein functions, to be implemented via a bottom-up approach and a two-
stage selection procedure. In this way, the scientific community will be consulted for their ideas on research projects
developing state-of-the-art proteomics research.
Further advances in proteomics techniques will help overcome bottlenecks in the investigation of protein functions
in cells, leading to a better understanding of biological processes in health and disease, and fostering European
research excellence and technological innovation.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺMOLECULARĺIMAGINGĺ
Although we need to continue to sequence genomes and to indentify individual proteins involved in a given bio-
logical response, the ultimate challenge will be to utilise the enormous amount of data generated and to convert
this into a dynamic picture of the subcellular, cellular or whole organism level. In the dynamic cellular environ-
ment, proteins and other cellular components undergo many processes — all primarily designed to maintain
cellular function and homeostasis.
Most of the current knowledge on gene expression, regulation and delivery in mammalian systems results from in
vitro or ex vivo studies. It is worthwhile reflecting on the fact that study of a biological system over time is gener-
ally constructed from a series of data obtained from different specimens, which often fail to represent accurately
the true order of events in vivo. This situation, coupled with our inability to easily monitor multiple molecular
species simultaneously, seriously limits our ability to study cellular processes, keeping in mind that biology is
fundamentally dynamic.
Biomedical methods have elucidated many cellular pathways and continue to do so. However, the desire to capture
microsecond and nanosecond cellular changes and interactions in living cells in their natural environment, as well
as the need for high spatial and temporal specificity have led to the development of increasingly sophisticated imag-
ing technologies. These techniques are becoming more powerful with the contribution of computing power.
FP6 activities
The EC has supported FP6 collaborative projects (CPs), aiming at the development of new imaging technologies
for monitoring gene and protein expression in situ and in vivo (often in tissues or living cells and whole animals).
MOLECULAR IMAGING is an IP aiming to develop novel non-invasive imaging techniques that enable
monitoring of the dynamics of multiple molecules within living systems, and whole animals INĺVIVO.
The Tips4Cells focused project aims at further developing scanning probe microscopy (SPM); this is currently
the imaging method of choice for measuring intermolecular and intramolecular forces in biomolecules at the
single molecule level and for providing high-level information on structural details of biological samples in their
native environment. The COMPUTIS focused project is developing new and improved technologies for molecu-
lar imaging mass spectrometry (MIMS), enabling innovative methods of investigation in functional genomics,
proteomics and metabolomics, as well as investigation in cells and tissues.

High-resolution imaging of living cells and subcellular components is essential for functional and structural
genomics. Developments in this field are expected to transform our understanding of biology, making experimental
investigations much more efficient, speeding up research into life sciences. Multidisciplinary consortia established
in FP6, comprising physicists, mathematicians, biologists and chemists, addressing in vivo molecular imaging,
resulted in the formation of ‘centres of excellence’, enabling greater technological developments and commercial
opportunities. Imaging tools have potential for direct applicability in the biomedical sector; therefore partnerships
amongst academy, industry and the medical sector would facilitate the future transition from the laboratory and
a wider diffusion and application of these technologies.
ĺ4OOLSĺANDĺTECHNOLOGIESĺFORĺGENEĺINTEGRATIONĺANDĺRECOMBINATIONĺ
One of the most important goals in the post-genomics era is to systematically determine the function of all genes
and regulatory sequences within living cells. The so-called reverse genetics approaches rely on the targeted
integration of artificial gene constructs by homologous recombination to delete (knock-out) or alter (knock-in)
chromosomal sequences.
The modification of the cell’s genome by methods of gene targeting has traditionally been used in modern biol-
ogy for gene function analysis and for development of tools for gene therapy. Therefore, controlled gene integra-
tion and in particular targeted integration are key technologies for the exploitation of the full function of genomic
information. Targeted gene integration also fulfils a critical role in medical research, as it allows the establishment
of animal disease models for advancing research in disease pathogenesis and treatment.
Gene targeting allows researchers to precisely modify the genetic blueprint of living cells in vivo. The mechanism
of gene integration into the chromosomes of living cells is far less known, and can occur either randomly or be
targeted by homologous recombination.
In FP6, the EC supported several focused research projects developing tools for gene integration and the study of
the mechanisms of gene integration in different model organisms.
The GENINTEG project seeks to establish a greater understanding of the mechanism of gene targeting and devel-
op new generic tools for enhancing gene integration by applying an interdisciplinary and multi-organism compara-
tive approach. TAGIP is a focused project that aims to develop gene targeting via homologous recombination as a
routine technology in plants that will facilitate the cost-efficient and large-scale production of therapeutic proteins.
The PLASTOMICS project will define the mechanisms and improve the understanding of the genes and proteins
involved in several key stages of plastid transformation and foreign proteins expression. The focused project
MEGATOOLS studies meganuclease-induced recombination; this approach could provide a practical alterna-
tive to current approaches and represents an extremely powerful tool for gene alteration.
The clarification of gene function by transgenesis is important for our understanding of biological processes
and disease pathogenesis. Therefore, investment in further developing gene integration technology promises
advances not only in basic research, but also in drug development.
ĺ2EGULATIONĺOFĺGENEĺEXPRESSIONĺ ĺ
Research into regulation of gene expression will enable scientists to decipher the functions of genes and their
protein products, and acquire a clearer picture of the complex regulatory networks that control fundamental
biological processes.
The gene expression process is of fundamental importance for all living organisms. Regulation of gene expression
refers to cellular control of the quantity and the timing of changes to the appearance of the functional product of
the gene. Most genes reside in the chromosomes located in the cell nucleus and express themselves via proteins
synthesised in the cytoplasm. The genetic information is transcribed from DNA to RNA, and then translated from

RNA into protein, the so-called central dogma in biology. Any of the steps leading to the expression of a gene
may be modulated, from DNA or RNA transcription to the post-translational modification of a protein. Gene
regulation allows a cell to have control over its structure and function, which is the basis for cellular differentia-
tion, morphogenesis and the versatility and adaptability of any organism to its environment.
The sequence of an organism’s genome does not directly determine how the genome is used to build the organ-
ism. Buried deep in the primary code is a second regulatory code, which must also be deciphered.
To address the importance of the gene regulation in the post-genomics era, the majority of FP6-funded projects
were oriented towards the understanding of:
■ transcription regulation
■ epigenetic regulation.
The knowledge and methods developed within the FP6-funded projects will improve EU scientific competitive-
ness in the rapidly developing field of regulatory genomics, hopefully giving European scientists a head start
in the race to decipher the regulation of the genetic code.
ĺ4RANSCRIPTIONALĺREGULATIONĺ
Our genome consists of approximately 22 000 protein coding genes. However, only a fraction of these are used
in each cell. Which genes are expressed (i.e. govern the synthesis of new proteins) is controlled by the machinery
that copies DNA to mRNA in a process called transcription. In the gene expression pathway, the first regulated and
in most cases rate-limiting step is the process of transcription. This process, in turn, can be modulated by various
factors. A number of conceptual as well as mechanistic questions still need to be answered before we can attain a
complete picture of the principles employed by living organisms to control this process. One of the main gaps in our
knowledge is the limited insight we have regarding transcription regulation in the nuclear environment.
The goal of the TRANS-REG focused project is to obtain a comprehensive knowledge of the mechanism of
regulation of model genes during cell differentiation, cell proliferation and signal transduction. The consortium
is undertaking concerted efforts to develop and apply different molecular and cell biology approaches to study
the molecular characteristics.
The X-TRA-NET project develops and employs chromatin immunoprecipitation technology combined with sequenc-
ing to explore the complex transcriptional network of nuclear receptors signalling pathways and regulation. These
unique methods will be used to investigate the impact of binding site diversity on the mechanism of gene activation
with potential impact in the treatment of major diseases such as cancer, insulin resistance and atherosclerosis.
ĺ%PIGENETICĺREGULATIONĺ
The completion of the human genome has provided a wealth of information about our genetic wiring. Epige-
netics is defined as the study of the heritable changes in genome function that occur without a change in DNA
sequence. It seeks to determine how genome function is affected by mechanisms that regulate the ways the genes
are controlled. There are hundreds of different kinds of cells in our bodies. Although each one derives from the
same starting point, the features of a neuron are different from a liver cell. As cells develop, their fate is governed
by the selective use and silencing of genes. This process is subject to epigenetic factors where DNA methylation
plays an important role in all the phenomena where genes are switched on and off. Epigenetics also provides a
means by which genetic material can respond to changing environmental conditions.
Over recent years, the study of epigenetics (chromatin and/or DNA modifications not attributed to changes in
the DNA sequence but surviving across generations) has received increased attention due to its possible role in
pathogenesis and in a series of the organism’s phenotypic characteristics.

The huge interest in epigenetic regulation of gene expression has led to a number of excellent European-funded
initiatives. In the later stages of FP6, strong links were established between these projects, thereby developing a
European critical mass in this field.
The EPIGENOME project has established a network of excellence (NoE) providing a platform for the development
of the European epigenetic research. It seeks to promote the ERA in the field, not only by means of a strong research
programme, but also by integrating and disseminating the project’s activities, including an efficient communication
infrastructure to enable internal communication of geographically dispersed teams and to foster public dialogue.
The HEROIC project advances epigenetic research with HTP technology in the context of the whole genome
to help unravel the meaning of the epigenetic code. It performs research into gene regulatory systems at the
level of the chromatin structure and nuclear organisation, employing the most extensive multidisciplinary con-
sortium ever assembled at European level. Although the chromatin immunoprecipitation (ChIP) assay plays a
crucial role in deciphering patterns of epigenetic marks that govern gene transcription, it still suffers from low
resolution and low sensitivity. The CHILL project will overcome this by developing Chromatin Immuno-Linked
Ligation (ChILL) technology resulting in a better understanding of the epigenetic code. The SMARTER project
will help in the treatment of cancers by investigating the small molecules that target histone deacetylases and
by opening up new avenues of research.
Epigenetic research is anticipated to have far-reaching implications for medicine. Using a combination of ge-
nomic tools, researchers are trying to better understand processes like DNA methylation in order to use the
information for more effective early diagnosis of complex diseases (such as cancer) and to develop innovative
treatments directly targeting the molecules involved in these processes.
ĺ3TRUCTURALĺGENOMICSĺANDĺSTRUCTURALĺPROTEOMICSĺ ĺ
The way molecules such as proteins and ribonucleic acids (DNA and RNA) interact with one another and with
other molecules (such as drugs) is determined by their 3-D structure. Understanding the 3-D structure of these mac-
romolecules is critical for the understanding of their role in complex biological processes, and is essential for drug
design. Most molecular interactions can only take place as a result of the molecules’ chemical architecture, creating
active sites where they can link together with complementary molecules or interact as a part of cellular machinery,
in order to acquire the functional state required in a living organism. In proteins, these sites depend on the way the
long chains of amino acids of which they are constituted are intricately folded to give a final 3-D structure. Most
drugs target particular protein functions, either of proteins of human origin or of a specific pathogen, and the de-
velopment of new drugs relies heavily on knowledge of the targeted protein’s structure. Compounds with potential
pharmaceutical activity can be designed and tested to determine their potential by altering the protein structure.
Structural genomics researchers are using and developing a variety of techniques to study the 3D structure of mac-
romolecules ((X-Ray crystallography, nuclear magnetic resonance or NMR, 3-D Electron Microscopy). During, the
last decade, the major bottleneck in the technological developments described above, from the stage of sample
preparation to the analysis of structural data, has been the low-throughput outcome. The techniques did not permit
a sufficiently HTP analysis of samples and the determination of the structures of the thousands of macromolecules is
still to be solved. Research effort has therefore been focused on the automatisation of many stages in the procedures
to reduce bottlenecks and increase throughput.
The concept of structural genomics arose in the late 1990s in the US and Japan as a response of the success
of HTP sequencing methods applied to whole genomes. It was anticipated that similar HTP methods could be
applied to obtain 3-D structures of all the proteins. This vision led to the investment of substantial funds into large-
scale structural genomics projects in the US (between 2000 and 2005) and in Japan. Europe was slow to enter
the area of structural genomics and proteomics, and European investment in this area has been on a consider-
ably smaller scale.
In Europe, the first large collaborative initiative in implementing HTP approaches to structural biology was
launched in 2002 (pilot FP5 IP) with the project SPINE: Structural Proteomics in Europe (www.spineurope.org).
The challenge set for SPINE was to push forward cutting-edge technologies aimed at biomedically relevant tar-

gets, while at the same time generating a pan-European integrated effort directed towards biomedically oriented
structural proteomics. The project produced approximately 300 novel protein structures and also developed Eu-
ropean standards in protein crystal handling for X-ray crystallography studies. The success of the SPINE project,
and its catalytic effect on the area, led to a new generation of CPs.
FP6 activities
The effort in structural genomics and structural proteomics activity area was substantially increased in the EU’s
FP6 Programme for RTD (2002–2006), with objectives to enable researchers to determine, more effectively and
at a higher rate than was currently feasible, the 3-D structure of proteins and other macromolecules, which is
important for elucidating protein function and essential for drug design.
Whereas, in general, the projects elsewhere have tended towards a HTP approach, which would cover an
organism, an organelle or a category of proteins, most of the European projects are oriented towards technol-
ogy development or high-value targets, in most cases associated with diseases (drug targets, viral pathogens,
membrane receptors, signalling complexes involved in neuronal development and degeneration, immunology,
and cancer).
The FP6-funded projects in structural genomics and proteomics, whose objectives, results and potential impact
are presented in this publication, cover the three main technological disciplines (X-Ray crystallography, NMR,
and Electron Microscopy), which in many cases are integrated into the same consortium for the first time.
In summary, the FP6 projects can be classified into three categories:
1. Projects that are biologically focused and generate high-value 3-D structures
of proteins and complexes of fundamental and biomedical importance.
These projects aim at the following:
■ 3-D structure determination of viral pathogens

VIZIER: The aim of this IP is to gather knowledge on viral replication needed to develop new drugs to
prevent new viral outbreaks. RNA viruses include more than 350 different major human pathogens. The
project, unprecedented in size, has set out the sequence of the genomes of hundreds of viruses, defined
the proteins essential for replication, and through a major 3-D structural effort is identifying common sites
of these proteins that could be a target for new antivirals with a large spectrum of action. FSG-V-RNA
is a more targeted complementary project, which aims at developing and improving tools for the rapid
structural analysis of RNA and RNA-protein complexes in several RNA viruses.
■ 3-D structure determination of membrane proteins

E-MeP is an IP that aims at solving the bottlenecks that preclude the determination, at HTP, of high-
resolution structures of membrane proteins and membrane protein complexes; an integrated database
cataloguing E-MeP’s results, protocols and other pertinent data is being developed.
■ 3-D structures of components of important signalling pathways

SPINE-2-COMPLEXES is a second-generation SPINE project that aims at investigating signalling path-
ways from receptor to gene by combining the knowledge of genomes with HTP methods for structural
proteomics. The complexes under study are extremely important with respect to human health and are
drawn from the common theme of signalling pathways with targets from key areas of biology, including
cell cycle, neurobiology, cancer and immunology, as well as pathogen proteins that modulate or subvert
human signalling pathways.
■ 3-D structures of large complexes

3D-Repertoire aims at determining the structures of all amenable complexes from the budding yeast
at medium or high resolution by electron microscopy, X-ray crystallography, and in silico methods; these
structures will serve to integrate toponomic and dynamic analyses of protein complexes in a cell.

2. Projects that develop new and/or improving existing technologies and methods
as well as bioinformatics tools for structure determination of proteins and complexes.
These projects aim at the following:
■ New and improved tools for 3-D electron microscopy

3D-EM is bringing together European excellence in electron microscopy approaches for studying protein
complexes and cellular supramolecular architecture. This NoE addresses the development and improve-
ment of existing 3D-EM techniques, the standardisation of data processing, the integration of research
activities and the transfer of knowledge. HT3DEM is a more focused project aimed at developing an
innovative technological platform for HTP screening and analysis of native protein complexes and protein
crystals that will reduce processing time and cost.
■ New and improved tools for X-ray crystallography

BIOXHIT is mobilising both all European synchrotron facilities with beamlines equipped for macromolecu-
lar crystallography (either already in existence or planned for the future), and also most of the software
developers active in fields relevant to HTP structure determination. It aims to build a common platform for
European researchers in the field of biological crystallography. It focuses on the development of hardware
synchrotron technologies, HTP crystallisation technologies and standardisation of methodologies in syn-
chrotron data acquisition and treatment. This IP represents the greatest possible mobilisation of resources
at the European level, both in terms of infrastructure and scientific excellence.
Furthermore, the optimisation of methods for the production of proteins is important for retrieving suf-
ficient quantities for crystallisation purposes. OptiCryst is a focused project with the goal of improving
and automating methods for protein crystallisation and the objective of increasing speed and crystallisa-
tion success rates. IMPS aims at innovative techniques for expressing, stabilising, purifying and crystal-
lising membrane proteins.
■ New and improved tools for NMR structure determination

NDDP is a focused project that develops cutting-edge NMR techniques for the dynamic characterisation
of drug-receptor interactions to support structure-based drug design for phosphatases, a major class of
proteins for a broad range of medical applications. UPMAN is studying the structural states of proteins
from unfolded monomers to oligomers and fibrillar aggregates. A variety of NMR techniques coupled
with novel computational approaches are used in order to define the misfolded structures’ characteristics
and are then applied to representative samples of the various types of proteins that are associated with
misfolding diseases.
■ In silico tools for structure determination

Extend-NMR deals with the development of novel computational tools that extend the scope of NMR
and that make possible functional and structural studies of larger proteins and biomolecular complexes
which are not amenable to crystallisation. 'ENE&UN is developing improved bioinformatics tools for
reliably assigning function to genes, with an emphasis on in silico protein-protein interaction and 3-D
structure determination. The developed function prediction methods should improve the in silico func-
tional annotation of the genome.
3. Projects that network and coordinate research efforts in Europe,

as well as promoting high-level training. These projects aim at the following:
■ High-value training in structural genomics in Europe

E-MeP-Lab is an SSA, where for the first time Europe’s membrane protein structural biology community
will organise high-level training with advanced practical courses in the best-equipped laboratories in Eu-
rope. TEACH-SG is an SSA that provides a platform for training young scientists and those from smaller
laboratories and new EU Member States in the HTP technologies developed in the area of structural genom-
ics, by organising a series of workshops and meetings with hands-on training.
■ Networking and coordination in SG/SP

NMR-Life promotes the networking and coordination of NMR research in structural genomics via the
exchange of personnel and good practices, the organisation of meetings and the implementation of a vir-

tual laboratory. FESP is a CA that aims at a thorough assessment of the existing structural genomics and
structural proteomics projects and infrastructures at national, European and international levels. Its major
goal is to develop a strategy for structural genomics and structural proteomics in the broader context of
anticipated developments in biological research, resulting in recommendations for future European poli-
cies in this area.
In total, the EU investment in structural proteomics increased substantially in FP6, reaching

more than `90 million. Thanks in large part to EU-funded projects, in the last few years the structural
proteomics field has had good publicity and achieved international stature comparable to large-scale projects
in the US and Japan. While it is still premature to predict the success of the FP6 structural genomics projects,
we could say that these projects have played an important part in integrating the research community in Eu-
rope, thereby increasing visibility at national, European, and international level, and improving the capacity
to tackle ambitious challenges in research in a collaborative manner. By doing so, these projects are reducing
the fragmentation of research in Europe and are realising the concept of the ERA in structural genomics. In
figure 7, the steps towards the ERA in structural genomics are presented.
Interdisciplinary
Mature Field
Initiatives in Structural Genomics/Proteomics
VIZIER E-MeP
SPINE2-COMPLEXES
(RNA Viruses) (Membrane Signalling Pathways-
Biologically-Focused proteins)
Structures of complexes
Research FSG-V-RNA 3D-Repertoire
(viral RNA) (Large Complexes)
IMPS (tools for OptiCryst (Protein Extend-NMR HT-3DEM (high-

Membrane proteins) Crystallization) (NMR) throughput 3D-EM)
UPMAN (protein
Technological GeneFun (in silico
strucure prediction) misfolding-
Developments BIOXHIT aggregation) 3D-EM
(X-ray (Electron
3DGENOME Crystallography) NDDP (NMR- Microscopy)
1st call - 2002 (3D microscopy) phosphatases)
2nd call - 2003
3rd call - 2004 Coordination, Fora, FESP (Forum for NMR-Life E-Mep-Lab TEACH-SG
European Structural (coordination (Training in (Training in
4th call - 2005 Workshops, Training Proteomics) action) Membrane proteins) Structural Genomics)
IP, NoE
European FP5 foundations for European Structural Genomics:
STREP, CA, SSA
FP5 Pilot project SPINE (pilot IP 2002-2005)
Fig. 7: Steps to ERA in Structural Genomics and Structural Proteomics in FP6 (2002-2006)
FP7 activities
The future of the field relies on combining integrated structural biology with cell biology so that the atomic dissec-
tion of the cell can be reconstituted into a functional system (3-D cellular structural biology). FP7 will continue to
support projects aiming at developing new and/or improving existing tools and technologies for protein and pro-
tein-complex structure determination. Most importantly, in FP7, structural genomics projects will be implementing

large-scale data gathering initiatives, but will also participate in multidisciplinary systems biology approaches.
Understanding membrane protein function remains one of the research frontiers in cellular biology. Membrane
proteins constitute approximately one third of all human proteins and are important drug targets. However, in
the current literature, membrane protein structure determination represents only 0.3% of all the protein structures
existing in the public databases. To increase our knowledge in this important family of proteins, the EC set as a
priority the structure-function analysis of membrane transporters and channels for the identification of potential
drug target sites, in the FP7 first call for proposals in large-scale data gathering functional genomics initiatives.
The following two complementary large IPs were funded and started in the beginning of 2008.
EDICT: European Drug Initiative on Channels and Transporters

At a funding level of `12 million, this IP aims at characterising the structure-function of membrane superfamilies
in human and pathogenic microorganisms, covering a wide variety of human diseases. The main strength of
EDICT (where two of the partners are Nobel Prize winners) is its powerful HTP structural genomics pipeline. In ad-
dition, high-resolution images coupled with sophisticated computational methods will identify new drug targets.
NeuroCypres
At a funding level of `11 million, this IP focuses on channel proteins of the central and peripheral nervous system
involved in severe neurodegenerative diseases. Its main strength is its multidisciplinary approach with a focus on
biology for understanding the link between dysfunction and disease.
Figure 8 shows the runtime of current EU-funded CPs in structural genomics and structural proteomics between
2002 and 2008, including all FP6 and the FP7 first call funded projects.
This drastic change in investment implemented via the European FPs for RTD (FP5, FP6 and
FP7 first call for proposals), resulted in a major investment of approximately `120 million
allocated to Collaborative Structural Genomics projects between 2002 and 2008.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 FP
SPINE IP E13.7m FP5
BIOXHIT IP E10m FP6
3D-EM NoE E10m
3DGENOME STREP E2.2m
E-MeP IP E10.35m
VIZIER IP E13m
NDDP STREP E1m
UPMAN STREP E1.9m
GeneFun STREP E1.5m
FSG-V-RNA STREP E2.4m
3D-Repertoire IP E13m
Extend-NMR STREP E2m
HT3DEM STREP E1.8m
IMPS STREP E1.9m
OptiCryst STREP E2.3m
SPINE2-COMPLEXES IP E12m
FESP SSA E0.3m
E-MeP-Lab SSA E0.3m
NMR-Life CA E1.1m
TEACH-SG SSA E0.5m
EDICT IP E11.9m FP7

NeuroCypres IP E11.03m
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Fig. 8: Runtime of current EU-funded collaborative research projects in structural genomics and structural proteomics
(funding period started in 2004 for FP6 projects-most projects extend well beyond 2007; funding period started in 2008 for the FP7 first call projects)

ĺ#OMPARATIVEĺGENOMICSĺANDĺMODELĺORGANISMSĺ
Comparative genomics is the analysis and comparison of genomes from different species. The purpose is to gain
a better understanding on the genetic differences between species and to determine the function of the genes.
Researchers have learned a great deal about the function of human genes by examining their counterparts in
model organisms such as the mouse.
The sequencing of the human genome has revealed that our genetic material is composed of about 22 000 different
genes. Despite their morphological differences, model organisms and humans share a strong conservation of genes
as well as fundamental biological pathways. This extensive conservation has promoted the use of model organisms
as a means to study conserved processes.
However, just identifying a gene does not tell us much about its potential function in health and disease. To in-
vestigate this, it is necessary to mutate the gene in a model organism. Several model organisms are extensively
studied to understand particular biological phenomena, with the expectation that discoveries made in these
models will provide insight into the workings of other organisms. In particular, model organisms are widely used
to explore potential causes and treatments for human disease in instances where experimentation on humans
would be unfeasible or unethical.
FP6 activities
In FP6, substantial resources were invested in comparative genomics, in particular for research in rodent
models like the mouse and the rat, but also in other vertebrate models like the zebrafish and the frog. Projects
involving invertebrate models (e.g. nematodes, yeast, etc.) were been funded in FP6. Finally, bacterial and
plant functional genomics projects were also partially supported as cross-cutting activities with other FP6 fun-
damental genomics thematic areas.
ĺ-OUSEĺ
The identification of all the genes in mice and humans in the Human Genome Project has shown that about 99%
of the genes in mice have an equivalent gene (or homologue) in humans. This is important as, to date, around
5 000 diseases have been shown to be caused by an error in our genetic make-up (in our genes), for example
cystic fibrosis and Down’s syndrome. In several more complex diseases, such as diabetes, an error in the genetic
make-up is a contributory factor.
In addition, powerful conditional mutagenesis technology has been developed that currently can only be applied
in the mouse to specifically inactivate any gene in a time- and space-dependent manner. This approach allows
us to very precisely unravel the genetic networks underlying disease. All things considered, the mouse is one of
the model organism of choice for human disease research.
EUMORPHIA was the first major integrated research programme (funded at the end of FP5) on mouse re-
search that brought together a large consortium of 18 mouse research centres in 8 European countries. The
main goal of this large initiative was the development and standardisation of new approaches in phenotyping,
mutagenesis and informatics leading to improved characterisation of mouse models for the understanding of
human physiology and disease. The project delivered an extensive database of standardised phenotyping
protocols (EMPReSS) that is now widely used in many mouse laboratories across Europe (Brown S.D. et al.,
Nature Genetics, 2005, 11, 1113–20). Furthermore, this project has also played an important role in structur-
ing the research landscape in mouse research in Europe.
In FP6, building on the success of EUMORPHIA, several mouse large-scale functional genomics initiatives
(EUCOMM, EUMODIC, EUREXPRESS, and MUGEN) were funded that may be grouped as follows:

1. Projects that develop tools and resources for mouse functional genomics
EUCOMM integrates European skills, resources, and infrastructure to produce, in a systematic, HTP way,
mutations throughout the mouse genome. A collection of up to 20 000 mutated genes will be generated
in mouse embryonic stem (ES) cells using conditional gene trapping and gene targeting approaches. This
mutant resource will be of crucial importance for health research since it will allow scientists to dissect
gene functions within a living organism (in vivo) more accurately and to mimic human disease conditions
more closely. By networking their effort at the European level with the EUCOMM project, Europeans
researchers are playing a leading role in the International Mouse Knockout Consortium that was launched
recently (Collins F.S., Cell 2007, 128, 9–13; Qiu J., Nature 2006, 444, 814–816) and which joined
EUCOMM, KOMP (funded by the National Institutes of Health) and NorCOMM (funded by Genome
Canada). FLPFLEX is a more focused project aiming to develop flexible genomic insertion cassettes
carrying modifications to allow recombinase-mediated cassette exchange of effector genes of interest.
Molecular Imaging is another project (mentioned earlier in the functional genomics tools section) which
aims to develop non-invasive imaging tools for whole animals (mice) in vivo.
2. Projects that develop tools and technologies for large-scale

and HTP phenotyping studies
EUREXPRESS and EUMODIC are both focused on phenotyping. EUREXPRESS’s main goal will be to
deliver expression patterns for 20 000 mouse genes during embryonic development and in adult tissues.
EUMODIC will phenotype in depth, using the EMPReSS standardised protocols (about 650 mutant lines)
produced from the EUCOMM project. MUGEN is another FP6 major research initiative using functional
genomics tools to analyse more that 200 mouse mutant strains showing defects in the immune systems in a
standardised way.
3. Plenty of projects support biologically focused research, using mouse

as an essential model to understand diseases mechanisms
These projects cover a great variety of basic biological processes; several projects use predominantly
mouse as the animal model of choice.
MUGEN aims to structure and shape a world-class network of European scientific and technological
excellence in the field of murine models of human immunological diseases that will advance understanding
of the genetic basis of disease and enhance the innovation and translatability of research efforts.
The main objective of HEROIC is to make significant advances in the mechanistic questions of epigenetic
regulation, characterise the epigenetic modifications that occur, and then understand the implications for
gene expression in different cell types. The approach focuses on the use of HTP-enabling technologies on
predominantly primary and established mouse cell lines, particularly ES cells.
The majority of the projects funded under the areas on multidisciplinary approaches to basic biological
processes (see Part B,Chapter 7) are either using established mouse models or creating novel mouse models
to understand health diseases. One example is the FunGenES consortium, which addresses fundamental
issues of stem cell biology differentiation and functional genomics, pursuing an integrated strategy based
on cultured mouse ES cells. Another, the EUROHEAR IP develops novel mouse models to understand the
mechanisms of hearing deficiencies.
4. Projects that network and coordinate research efforts in Europe
Along with the research initiatives, the EC has financed two CA projects: PRIME and CASIMIR. The aim of
PRIME is to build on existing national and European mouse research programmes, resource centres and
infrastructures by focusing and integrating them, rather than establishing new programmes. The long-term
aim is to establish mechanisms to define future research policies and directions in a coordinated manner
across Europe. CASIMIR focuses on coordination and integration of databases set up in support of FP5
and FP6 projects containing experimental data, including sequences, and material resources such as
biological collections, relevant to the use of the mouse as a model organism for human disease.

Integrated European Mouse
-ATUREĺ&IELD
functional Genomics Programme
MUGEN EUROHEAR
FunGenES HEROIC
Biologically (mouse models
(mouse ES cells (Epigenetics in
(mouse models
Focused Research for immunological for hearing
differentiation) Mouse ES cells)
diseases) deficiencies)
EURExpress
EUMODIC
(high-throughput
Phenotyping in situ
(European mouse
Disease clinic)
hybridisation)
Molecular Imaging EUCOMM

Tools and Resources FLPFLEX
(in-vivo imaging (genome-wide
(transgenic tools)
technologies) mutagenesis)
1st call - 2002
2nd call - 2003
Coordination, Fora,
3rd call - 2004 PRIME CASIMIR
Workshops (Co-ordination of mouse functional (Co-ordination/integration
4 call - 2005
th
genomics programmes) of databases)
IP, NoE
FP5 foundations for European Mouse Functional Genomics
European
Pilot project
Programme: EUMORPHIA (pilot IP 2002-2005) on
STREP, CA, SSA standardised phenotyping protocols
Fig. 9 : Steps to ERA in mouse functional genomics research in FP6 (2002-2006)

In FP5 and FP6 the European Commission has invested substantially in mouse functional genomics.
All projects are very ambitious and highly complementary to each other, thereby creating an integrated European Research programme
in mouse functional genomics. By joining their forces at the European level via these collaborative projects,
Europe is now at the forefront of mouse functional genomics research at the international level.
ĺ2AT
Europe has a large community of researchers using the rat as a model. Indeed, over the last 50 years, the
rat has also intensively been used by physiologists to investigate molecular determinants of diseases such as
diabetes. The availability of the rat genome sequence (since December 2004) and genome-scale technologies,
along with the ability to clone fertile adult rats, has substantially advanced the potential for functional genom-
ics research in the rat model.
The EURATools IP draws together leading European researchers in rat genetics, pharmacology, toxicology, dis-
ease pathophysiology, and genome biology and informatics. The central aim of this project is the development
of integrated genome tools that will generate knowledge that can be translated into improvements in healthcare
for highly prevalent diseases in the EU. Besides scientific excellence, EURATools is expected to have a strong
European structuring effect in the rat research community.
In addition, two smaller-scale projects, MED-RAT and STAR, were also funded in FP6. These two projects are
complementary to the EURATools project: one is developing new tools to generate transgenic and knock-out rat
models (MED-RAT) while the other is generating a SNP and haplotype map for the rat model (STAR).

ĺ:EBRAüSHĺ
Zebrafish is a vertebrate model that offers numerous advantages compared to the rodent models. It is smaller in
size and less costly to grow and maintain. Many transgenic approaches are also possible in this animal, facilitat-
ing the study of genes highly conserved in vertebrates and having functions in health and diseases.
Furthermore, for developmental biologists, the zebrafish model offers additional advantages. Indeed, the devel-
opmental processes can be easily observed in the fish since the embryo develops outside the mother body and
is also fully transparent. ZF-MODELS IP aims to utilise the zebrafish model to harvest large datasets on gene
functions underlying development and disease. Fish with genetic disorders corresponding to human diseases are
produced by chemical mutagenesis (forward genetics) and targeted knock-out (reverse genetics) and are phe-
notypically characterised. These disease models will aid clinical researchers and the European pharmaceutical
industry in the development of new therapies. This project will also contribute to improving basic knowledge of
human development, since key genes involved in development are often reactivated in adult life in many con-
genital diseases and cancers.
Furthermore, the zebrafish embryo model also shows great potential to be incorporated into preclinical drug
screening pipelines. ZF-TOOLS aims to develop a case study for an anti-tumour drug screening system, based
on implantation of fluorescently labelled tumour cells into zebrafish embryos. This system allows for the powerful
combination of visual monitoring with HTP analysis of expression of marker genes with a predictive value for
tumour progression or for defence responses to developing tumours.
ĺ/THERĺMODELSĺ
The EC is also supporting functional genomics research projects in other model organisms including Xenopus
laevis (X-OMICS) and C. elegans nematode (NEMAGENETAG). Under the Systems Biology umbrella, the
EC is also supporting a large IP (AGRONOMICS) on leaf development in Arabidopsis thaliana and a large
IP (BaSysBio) in Bacillus subtilis. These projects are also cross-cutting in nature, relating to other FP6 thematic
priorities, in particular with Priority 2, related to Food Safety.
Importantly, an essential part of the thematic sub-area ‘Multidisciplinary functional genomics approaches to study
basic biological processes’ is devoted to model organism research used as tools to understand a particular basic
biological process. These projects are presented in a separate section in the current publication.
In conclusion, between 2002 and 2007, the EC’s FPs (FP5, FP6) provided more than `150
million for collaborative research projects on model organisms, such as mouse, rat,
zebrafish, plant, nematode worm and bacteria. These projects are playing an important role in
structuring the research landscape in Europe and creating the knowledge base to understand health and
disease. Furthermore, they are generating important and freely available data and/or animal resources that
will catalyse progress in biomedical research.
FP7 activities
In FP7, support of research on model organisms continues, and considering that FP6 funded several projects
in rodent models, we have proposed calls for proposals on establishing consortia on genome-wide association
studies in non-rodent mammalian models that develop diseases analogous to those seen in humans.
At the beginning of 2008, the EC launched the `12 million IP LUPA, which aims at elucidating the molecular
basis of common complex human disorders using the dog as a model system. This project brings together ex-
perts in genomics, the world’s leading scientists in complex trait genetic analysis, and interconnects the major
veterinary centres of Europe, utilising HTP molecular tools. It should also be emphasised that particular attention
is being paid to following strict national guidelines for animal welfare.

For the first two calls of the FP7, in the genomics and systems biology area, no specific topics related to large IPs in
rodent model organisms were proposed. This area, and in particular research in mouse, was well covered in FP6
and there was a need for the currently funded projects to reach the required maturity for novel evolving ideas.
A policy workshop was organised by the Genomics and Systems Biology unit in the Health Directorate in March
2007, in cooperation with other funding agencies, (including, the US National Institutes of Health and Genome
Canada), to explore the future research needs in the field of mouse functional genomics. The recommendations
of that workshop, which brought together the world-leaders in the field, also served as a foundation to reflect
on future FP7 activities in the area. In the FP7’s third call for proposals, published in September 2008, the EC
proposed a bottom-up approach, implementing (for the first time in the Health priority) a two-stage selection
procedure, to attract proposals on large-scale functional genomics efforts in multicellular model organisms. The
expected impact is to continue progressing in the understanding of the function of all human genes, their complex
interactions, and their role in disease.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 FP
EUMORPHIA IP E17.3m
EURExpress IP E10.8m
MUGEN NoE E11m
FLPFLEX STREP E1.7m
EUCOMM IP E10.3m
PRIME CA E0.8m
EUMODIC IP E12m
CASIMIR CA E1.3m
STAR STREP E2.4m
MED-RAT STREP E1.6m
EURATools IP E11m
ZF-MODELS IP E12m
ZF-TOOLS SME-STREP E1.7m
TP Plants SSA E0.56m
NEMAGENTAG SME-STREP E1.8m
X-OMICS CA E0.8m
LUPA IP E11.9m
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Fig. 10: Runtime of current EU-funded collaborative research projects in model organisms
ĺ0OPULATIONĺGENETICSĺANDĺBIOBANKSĺĺ
Common diseases of major public health importance are phenotypically complex, with many having a heritable
component. Population genetics approaches are used to characterise complex diseases and associated pathophysi-
ological states in respect to the genetic and environmental determinants involved. An important element of popu-
lation genetics research is the study of the genetic variations and/or mutations that are correlated to the healthy
and diseased phenotype. The estimated 22 000 protein-encoding genes are calculated to contain myriad possible
variations, called polymorphisms, which increase the complexity of our genes. The human genome comprises about
3 x 109 base pairs of DNA, and the extent of human genetic variation is such that no two humans, even identical
twins, will be genetically identical. The amount of genetic variation is about 0.1%, meaning that about 1 base pair
out of every 1 000 will be different between any 2 individuals. Some of these variations determine physical char-
acteristics, but others can determine the susceptibility to certain diseases, or the response to drug therapies.
Access to databases containing genotypic, clinical, and environmental and lifestyle information on individuals,
along with corresponding clinical samples/specimens (biobanks), are an essential component for population genet-
ics research. The systematic collections of genetic material and other relevant information on individuals, namely
biobank collections, make it easier for researchers — using HTP analytical tools for monitoring DNA variations
combined with powerful bioinformatics — to systematically search for links between gene variation and disease.

There has been relatively little success in finding genes for complex disease or complex traits, most likely due to
the expected small effect of individual genes on complex disease. Because of the complex relationship between
disease and genetic, environmental and lifestyle factors, population geneticists need access to very large num-
bers of samples to ensure that any patterns they observe are statistically significant. For this reason, population
studies increasingly necessitate international collaboration to ensure that large data sources can be shared. The
ethical, legal and social aspects of this type of research are also extremely important factors in ensuring that
individuals’ data are respected.
In several European countries, a multitude of national and regional population and disease-oriented biobanks
have been systematically collected for decades via the national healthcare systems, representing a unique
European strength. Significant advantage could be gained by pooling the resources already available or
under construction. This could give researchers access to greater cohort size and data sets, so that the re-
search outcome from associations’ studies between genotype, environment, and lifestyle at individual and
population level could lead to greater statistical significance and prediction. The lack of standardised and
quality-controlled protocols for data and sample collection, storage, retrieval, analysis and access, as well as
the diversity of national legal regulations, have created a great deal of fragmentation and created obstacles
for collaboration at European level. It would make an enormous difference if the protocols involved in human
population genetics research at national level could be harmonised to become representative and accessible
at European and international level.
Building the ERA in population genetics research via a coordinated and collaborative approach will address the
existing bottlenecks and would pave the way for advances in biomedicine and improvement of the public health.
The EC, recognising the power of population-based approaches in the study of genetic susceptibility for disease,
has funded a number of networking activities and collaborative research projects between 2002 and 2008.
In Europe, the first large collaborative initiative on genetic epidemiology on common diseases utilising samples
from large- and medium-sized population biobanks and involving cross-border transfer of data and samples was
launched in 2002 (pilot FP5 IP) with GenomEUtwin (www.genomeutwin.org). The main objective for Genom-
EUtwin was to perform genome-wide analyses of European twin and population cohorts with the aim of identify-
ing genes predisposing the carrier to common diseases. During the four-year period, the partners harmonised
and integrated the study cohorts’ data (a combined cohort of 850 000 twins and a cardiovascular diseases
cohort of 160 000 volunteers). Genome-wide studies have the potential to systematically identify the contribu-
tions of common genetic variants to human disease. This unique project has provided the basis for the detection
of small genetic infuences on common diseases, which may not be detected in small-scale family studies. Impor-
tantly, the project has developed an Ethics Manual defining policies for the transfer of data and samples between
countries. GenomEUtwin is a cornerstone of European genetic epidemiological research, because it paved the
way for harmonisation of collected data, easy access to available data by creating a unified database structure
and genome-wide analysis of the existing cohorts.
FP6 activities
The success of the GenomeEUtwin project, and its catalytic effect on the area, led to new CPs in FP6. These
projects are taking full advantage of specific population cohorts available in Europe for determining the re-
lationship between gene function and health or disease. These projects may be classified into the following
general categories.
1. Projects developing tools and technologies
These projects bring together the critical mass to catalyse the development of techniques and technologies
for population genetics research.
MOLPAGE is an IP that develops and validates a range of ‘-omics’ technology platform tools (metabo-
nomic, genomic, proteomic) for molecular phenotyping in large epidemiological studies. These tools will be
used for identification of biomarkers, prediction of disease, and risk determination or response to therapy.
The consortium develops and disseminates standards for the collection, processing and storage of biologi-

cal samples that are suitable for use in large sets of individuals, applicable to biological fluids and solid
tissue samples, and optimised for future ‘-omics’ platform analysis. The project is expected to significantly
contribute to the development of international scientific standards in molecular phenotyping.
2. Projects performing large and medium-scale epidemiological studies
All these projects perform large-scale studies on genetic epidemiology on common diseases and related
traits, utilising samples in large- and medium-sized biobanks and involving cross-border transfer of data
and samples.
The EUROSPAN focused project has the objective of quantifying genetic variation in established diseased
genes across population cohorts in Europe, with the goal of identifying novel disease variants. It will cre-
ate a large database of phenotypic and genotypic data from genetic isolated populations and will thus
improve European competitiveness in gene discovery.
GenOSept is a STREP which uses a multidisciplinary fundamental genomics approach to examine genetic
predisposition to sepsis by harmonising HTP genotyping and quality control between major European centres.
3. Projects for networking and coordination
The EC is also financing several CAs (such as PHOEBE and IMPACTS), as well as SSAs (such as DanuBiobank
and EUHealthGen). PHOEBE promotes harmonisation of epidemiological biobanks in Europe. IMPACTS
coordinates the standardisation of tissue archives. EUHealthGen organised a Wellcome Trust/EU EC con-
ference (‘From Biobanks to Biomarkers’) to enable dialogue on the potential of human population genetics
research. The aim of Danubiobank is to establish a biobank foundation for ageing disorders by networking
universities, teaching in hospitals, developing prevention programmes and clinics along the Danube River, via
the organisation of workshops and conferences.
On the whole, these projects have the following aims: to exchange information on research biobanks in
Europe and beyond; to standardise and harmonise existing protocols for the acquisition, management and
analysis of data and samples from different sources; to develop common quality assurance schemes; and
to standardise approaches to ethical and legal issues.
By networking existing national capacities, FP6-funded projects have provided the critical mass to catalyse the
development of techniques and technologies for population genetics and to conduct large epidemiological stud-
ies. Together, these projects will enable researchers to better understand the ways in which interactions between
genes and environmental factors are involved in the causes of common diseases and to determine the influence
of specific genetic variations on the development or severity of these diseases.
FP7 activities
The FP7 Health theme has several objectives, one of which is to integrate the vast amounts of genomics, epide-
miological and biological data with a view to translating this data into the understanding of major diseases and
the ultimate development of new preventive, diagnostic and therapeutic methods. That is why population genet-
ics and biobanks research aiming to develop tools and harmonisation principles is essential in FP7.
In the future, the integration of traditional population epidemiological genetic studies with HTP ‘-omics’ tools
(genomics, transcriptomics, and metabolomics) and bioinformatics as an essential component, is expected to
tremendously boost the field of population genetics.
With this in mind, in the FP7 first call for proposals under the HTP research activity area, the EC funded a large scale
integrating project to develop groundbreaking techniques for DNA sequencing and genotyping, which is expected
to increase the efficiency and cost of existing tools and lead to wider applicability in the clinical environment.
The READNA project, with `12 million of funding, focuses on next-generation nucleic analysis technologies and
devices. The tools developed should increase the sensitivity, rapidity and efficiency of existing tools for sequenc-

ing and genotyping, with a target of `1 000 for the sequence of a complete human genome, while at the same
time leading a revolution in cost-effective, non-invasive early screening of large cohorts for diseases.
In FP7’s first call for proposals, the large-scale data-gathering activity area supported two highly complementary
projects (started in 2008) for performing molecular epidemiological studies in existing well-characterised Euro-
pean population cohorts, with the objective of identifying candidate susceptibility genes to multifactorial diseases
by integrating genome-wide association studies and the advances of ‘-omics’ developments.
The ENGAGE project, with `12 million of funding, sets as its main objective the integration of the results from
many large-scale genetic studies underway in Europe and Australia, and the identification of novel disease-
and trait-susceptibility variants for multifactorial diseases. The scale is large, with more than 650 000 DNA
samples from various cohorts involved; the focus is primarily on cardiovascular and metabolic diseases, but
can be expanded to other common disorders.
The HYPERGENES project, with `10.2 million in funding, aims to dissect complex genetic traits using hyper-
tension as the disease model. The consortium will identify, by means of a whole genome association approach,
genes contributing to essential hypertension (EH) and to EH-associated target organ damage, utilising well-
characterised European cohorts. A combination of the most up-to-date methods of genomics, molecular genetics,
molecular epidemiology and bioinformatics, together with learning-based modelling of the data, is expected to
produce a disease model.
To keep Europe at the forefront of technology development in population genetics and biobanks research, the EC
published the third FP7 call for proposals in September 2008, via its Genomics and Systems Biology programme;
a bottom-up approach via a two-stage selection procedure was implemented for the first time in the Health priority.
In the activity area of HTP research, the scientific community is invited to submit proposals for large integrating
projects on the following topics:
■ The development of HTP tools and technologies to phenotype samples

in large-scale human biobanks.
The projects are expected to accelerate epidemiological studies and biomarker discovery by increasing
the molecular analysing capacity of biobanks, and will deliver high-quality and reproducible data set to
enable standardised approaches for large-scale biobanks.
In the activity area of large-scale data gathering initiatives, the FP7 third call for proposals invites proposals on
the following topics:
■ Characterisation of human genetic variation in Europe.
The projects should aim at characterising genetic variation in populations from different regions and ethnic
minorities in Europe, involving normal and/or disease phenotypes. A large-scale comparative study of ge-
netic variation in human populations in Europe is expected to facilitate ongoing and new epidemiological
studies, and fill in the information gaps on genetic variability in healthy and/or disease phenotypes.
■ Large-scale functional genomics efforts to identify molecular determinants of cancer.
The projects should implement multidisciplinary functional genomics approaches (e.g. sequencing, tran-
scriptomics and/or epigenetics) to characterise in detail a large number of human cancer tumour samples,
so as to identify molecular determinants that contribute to human oncogenesis. They should establish the
standards and norms on the manipulation and storage of tumours samples, thereby facilitating the compari-
son between different data sets.
Recognising the power of population-based approaches in the study of genetic susceptibility for disease, the
EC’s FPs for RTD provided more than `60 million to collaborative research projects in this
area between 2002 and 2008 (see fig.11 representing the steps towards the ERA in population genet-
ics research). In future calls, the Health theme will continue supporting this area, which will allow the EU to
develop and maintain a leading global position in genetic epidemiology and population genetics.

-ATUREĺ&IELD Integrated research in Population Genetics & Biobanks
ENGAGE HyperGenes
Genetic epidemiology GenOSept (genetic
(genetic epidemio- (genetic EUROSPAN
predisposition
of common diseases logy-Common epidemiology- (genetic variation)
sepsis)
diseases) hypertension)
MolPAGE READNA
(molecular (sequencing/genotyping
Technological Developments
phenotyping tools) technologies)
1st call - 2002

EUHEALTHGEN Impacts PHOEBE EpiGenChlamydia
2nd call - 2003
(impact of (Tissue archives (harmonisation of (host-pathogen
3rd call - 2004 Coordination, Fora, population genetics) standardisation) population biobanks) genomics)
4th call - 2005 Workshops Microsat DanubioBank HUMGERI
FP7 1st call - 2006 (workshop on (age-related (Human Genomics
microsatellites) biobanks) Integration)
IP, NoE
FP5 European FP5 foundations for Population Genetics:
STREP, CA, SSA Pilot project GenomEUtwin (pilot IP 2002-2005)
Fig. 11: Steps to ERA in Population Genetics and Biobanks in FP6 (2002-2006) and FP7 first call projects
ĺ"IOINFORMATICSĺ ĺ
As we move towards understanding biology at the systems level, access to large data sets of many different types
has become crucial. The data obtained from such technologies (such as genome-sequencing, microarrays, proteom-
ics and structural genomics) have provided ‘parts lists’ for many living organisms, and bioinformatics provides the
systematic cataloguing and interpretation of this data. Researchers are now focusing on how the individual compo-
nents fit together to build systems. The hope is that scientists will be able to translate their new insights into improving
quality of life. The functional genomics HTP revolution is generating a vast amount of data. There is an ongoing (and
growing) need to collect, store and curate all this information in ways that allow its efficient retrieval and exploita-
tion. By making these data available to the academic and industrial research communities in an accessible and
usable form, bioinformatics research ensures that the potential for genomics and health research is maximised.
FP6 activities
The FP6 objectives for the field of bioinformatics were to enable researchers to access efficient tools for manag-
ing and interpreting the ever-increasing quantities of genome data, and for making it available to the research
community in an accessible and usable form.
The foundations for meeting these challenges were laid in FP5, especially with the major large-scale IP TEM-
BLOR, which supported the development of major databases, including those for protein structure and sequence,
protein-protein interaction, gene expression and integration of this and other data. The capabilities established
and strengthened by TEMBLOR brought Europe to a level similar to that of other major world centres in the key
areas of life sciences research.
In FP6, an ERA has been established in bioinformatics, building on the foundations in FP5. This bioinformatics
ERA forms the basis for a wide range of applications for health research, and will be a key element in a future
ERA in systems biology, already under development in FP6 as well.

Three major NoE in bioinformatics were established in FP6, which constitute the core of the bioinformatics
ERA. All of them also involve the European Molecular Biology Laboratory and the European Bioinformatics
Institute (EMBL-EBI), which is a major core facility in Europe, and dozens of other major and smaller partners
in Europe and worldwide.
In bioinformatics, BIOSAPIENS has created a European Virtual Institute for Genome Annotation, bring-
ing together the best laboratories in Europe, including informaticians and experimentalists. The institute has
greatly improved bioinformatics research in Europe by providing a focus for annotation, and by organising
European meetings and workshops to encourage cooperation, rather than duplication of effort. The Institute
has established a permanent European School of Bioinformatics, to train bioinformaticians and to encourage
best practice in the exploitation of genome annotation data for biologists. The tools developed have already
been applied to gain important insights into the mechanisms of genetic mutation in major diseases such as
HIV/AIDS and Down’s syndrome.
The EMBRACE NoE integrates the major databases and software tools in bioinformatics in Europe by creating a
bioinformatics computer grid for easy and integrated data access, analysis and services. The integration efforts
are being driven by an expanding set of test problems representing key issues for bioinformatics service providers
and end-user biologists. As a result, groups throughout Europe will be able to use the EMBRACE service interfaces
for their own local or proprietary data and tools. ATD aims to understand the mechanisms that are responsible
for the formation of transcript isoforms on a genome-wide scale by creating a value added database of alternate
transcripts from human and model species.
Finally, ENFIN is connecting bioinformatics and wet-lab capabilities with a Europe-wide integration of computa-
tional approaches in systems biology. Computational work includes the development of a distributed database
infrastructure appropriate for small laboratories and development of analysis methods including Bayesian net-
works, metabolite flux modelling and correlations of protein modifications to pathways. ENFIN will deliver a
platform for database provision of diverse biological data, integrated analysis tools, guides for wet laboratory
utilisation, and ‘best practice’ guidelines for systems biology.
Furthermore, bioinformatics is included as an essential component by creating integrated databases in many

multidisciplinary functional genomics projects aiming to understand basic biological processes in health and dis-
ease (see next section). There are several characteristic project examples: MITOCHECK (which creates a publi-
cally accessible database for all the proteins involved in mammalian cell cycle), MYORES (a NoE on muscle
development in different model organisms, which implements a database for muscle research), EVI-GENORET
(which is creating a state-of-the-art relational database integrating functional genomics data and clinical disease
data for genes involved in retina development, degeneration and disease).
The development of computational biology and integrated bioinformatics databases of diverse ‘-omics’ data is an
essential component for the successful implementation of systems biology approaches. Several systems biology
projects funded in FP6 (see following section) are focused on the development of computational tools. There are
several characteristic examples: EMI-CD is developing a software platform connecting several modules neces-
sary for the in silico modelling of complex disease processes, while COMBIO combines a unique group of ex-
perimentalists, bioinformaticians and simulation groups in order to gain detailed understanding of key processes
like the P53-MDM2 regulatory network. Also, COSBICS is establishing and applying a novel computational
framework to investigate cellular signalling pathways and subsequent target gene expression. The DIAMONDS
project aims to demonstrate the power of a systems biology approach in the study of the regulatory network
structure of the most fundamental biological process in eukaryotes: the cell cycle, in different species.
FP7 activities
Continuing the efforts to strengthen the ERA in bioinformatics, in the FP7 first call for proposals under the HTP
research activity area, the EC funded a large scale integrating project to unify human and model organism ge-
netic variation databases; this is expected to achieve effective linkage between databases and would facilitate
analysis in population genetics studies.
The GEN2PHEN project, with `12 million level of funding, implements an integrated approach towards unifying

human- and model-organism genetic variation databases, in such a way that the resulting holistic view of genotype-
to-phenotype data can be blended with other biomedical databases via the central genome browser ENSEMBL.
The project will help to overcome existing access and usage barriers for genotype-to-phenotype relationships, by
providing an integrated informatics structure. It will further facilitate easy access to the stored information and as-
sociated resources through development of a Web portal knowledge centre.
To keep Europe at the forefront of bioinformatics developments, the EC, via its Genomics and Systems Biology
programme, published the third FP7 call for proposals in September 2008, implementing a bottom-up approach
via a two-stage selection procedure for the first time in the Health priority.
In the activity area of HTP research, the scientific community is invited to submit proposals for large IPs on the
following topic.
■ Computational tools for genome annotation and genotype/phenotype data integration.

The projects are expected to develop new computational tools and methods for genome/proteome annota-
tion to catalyse the progress of systems biology by describing, for example, molecular interactions, path-
ways and networks. The development of new computational tools for genome annotation and genotype/
phenotype data integration will enable integration of vast amounts of data generated on gene function
genomics to facilitate data mining and catalyse progress in systems biology.
In summary, between 2002 and 2008, the EC’s FPs for RTD provided approximately `75 mil-
lion to collaborative research projects in the area of bioinformatics. Before FP6, although there
was a strong European core at the European Bioinformatics Institute, there were a wide range of databases
and capabilities scattered across Europe with suboptimal access and interaction. By the end of FP6, databases,
services, analysis tools, and scientific research were strengthened locally and linked together at European level
to produce highly coordinated resources in support of biology and health-related research, a fact that has greatly
increased our understanding of the wealth of data being generated in Europe and the rest of the world.
Bioinformatics Databases,
-ATUREĺ&IELD
Computational tools for Systems Biology
COSBICS (modelling DIAMONDS (cell

ENFIN Cellular signalling) cycle modelling) COMBIO
Computational Biology (computational (P53 and spindle
tools for SB) EMI-CD modelling)
(Disease modelling)
Databases focused MYORES MITOCHECK EVI-GENORET

(muscle development (mammalian (retina development
on a biological theme network) cell cycle) & disease)
1st call - 2002
2nd call - 2003
3rd call - 2004 BioSapiens EMBRACE ATD GEN2PHEN
Classical Bioinformatics (Genome (Bioinformatics (Alternative (genotype/phenotype
4th call - 2005
and Databases Annotation) Grid) transcripts) Databases grid)
FP7 1st call - 2006
IP, NoE FP5 foundations for European Bioinformatics:

European
TEMBLOR (Cluster of 4 proposals) 2002-2004
FP5 Pilot project
STREP, CA, SSA Plus individual smaller projects
Fig. 12: Steps to ERA in Bioinformatics in FP6 (2002-2006) and FP7 first call projects

Extremely strong bases in the bioinformatics area have been established. However, just as existing fields are
showing an ‘explosion’ of data (as new fields are being established in the various ‘-omics’ disciplines such
as metabolomics, regulomics) and as these data and analysis tools are being linked together and used as the
driving force for systems biology analysis, so bioinformatics research also needs to grow.
The full potential of systems biology research has not yet been achieved in Europe, because basic databases and
research methods have not yet provided the entire basis needed to fully apply a systems approach. The approaches
planned in FP7 should allow us to overcome the future challenges in bioinformatics and computational biology.
ĺ-ULTIDISCIPLINARYĺFUNCTIONALĺGENOMICSĺAPPROACHESĺ
ĺ TOĺBASICĺBIOLOGICALĺPROCESSESĺ
The different approaches to functional genomics described in the earlier sections — gene expression, proteom-
ics, structural genomics, model organisms and population genetics and bioinformatics — provide researchers
with an extremely powerful multidisciplinary ‘toolbox’ which they can use to study and manipulate fundamental
biological processes.
By picking the most appropriate genomic tools, or combination of these tools, researchers are developing inno-
vative ways to study the basic understanding of cellular processes, by revealing the function and interactions of
cellular components in health and disease. The multidisciplinary approaches provide opportunities to view these
processes from different angles and gain new insights into the underlying cellular functions.
Diseases are often the result of important biological processes dysfunctioning, either because of external stimuli,
such as pathogens or environmental factors, or because of inherited or acquired gene mutations resulting in
incorrectly coded gene products unable to perform the appropriate cellular function. By understanding normal
cellular processes in organisms as diverse as micro-organisms, plants and animals, researchers will be able to
manipulate the cellular processes involved in disease, enabling therapeutic advances.
In FP6, this research sub-area funded projects implementing innovative and multidisciplinary approaches of func-
tional genomics to study basic biological processes in health and diseases. A series of large-and medium-scale
transnational projects were supported in FP6, where the main goal is to develop innovative ways to understand
basic biological processes such as transcription regulation, DNA repair, cell cycle, epigenetics, hearing and vision
processes, immune system, intra- and inter-cellular signalling, and developmental processes. The innovation is a
result of the integration of the most appropriate multidisciplinary functional genomics tools; in this way we can gain
new knowledge on the complexity of the underlying mechanisms of life that constitute the footprint of a physiologi-
cal and/or pathological situation.
In summary, the sub-area of multidisciplinary approaches to basic biological processes in FP6

supports projects that may be grouped into the following categories:
■ basic biological pathways in intracellular and extracellular signalling
■ tissue and organ development, homeostasis and diseases
■ stem cell biology
■ RNA biology
■ chronobiology
■ biology of prokaryotes and other organisms

Several projects aim to discover the genes involved in the regulation of fundamental processes such as cell cycle,
DNA repair (examples are MITOCHECK, DNA REPAIR, RUBICON). A series of projects, such as EVI-GENORET,
EUROHEAR and MYORES, provide new knowledge on the fundamental molecular and cellular biology of differ-
ent tissues/organs as well as their development and malfunction, with the ultimate goal of therapeutic advances.
Large-scale functional genomics initiatives were funded to shed light to fundamental questions in embryonic/
adult stem-cell research: how multipotent stem cells and early progenitors become committed to a single devel-
opmental pathway and then differentiate to the specific cell type (examples are FunGenes and ESTOOLS). The
exciting discoveries in RNA biology of the ‘second genome’ and the non-protein coding genes as organisers and
coordinators of the organism’s complexity are tackled by several projects (SIROCCO and RIBOREG), including
the increasing importance of post-transcriptional regulation of gene expression (EURASNET).
In FP6, between 2002 and 2006, the EC provided approximately `220 million to collabora-
tive research projects in the area of multidisciplinary approaches for fundamental biologi-
cal processes. All these European efforts have created the critical mass that will boost European excellence
in the respective fields by increasing integration and reducing fragmentation. It is important to mention that
even though the projects are focused on fundamental biology, for the first time several of them are integrating
basic biologists, clinical scientists and industry (including SMEs) where appropriate, to facilitate the transfer
of basic knowledge to clinical applications. Several projects are improving functional genomics tools for the
genome-wide understanding of gene function that would be applicable in all areas of cell biology. Training
courses in multidisciplinary expertise of the next generation of biologists has been implemented in several,
mostly large-scale projects. Importantly, the issues of setting up standard operational procedures on method-
ologies and data collection, and the creation of integrated bioinformatics databases have been addressed
— the latter being an essential element of collaborative effort in Europe.
In summary, the FP6 projects have already generated a comprehensive list and map of the multiple set of genes
and proteins related to a basic biological process in normal and/or pathological situations. Indeed, major
discoveries on novel gene functions have already been made that have resulted in high-level publications by
collaboration of various laboratories, previously working in isolation. Most importantly, these projects have
played an important role in integrating the research community in Europe, thereby increasing their visibility
Multidisciplinary Initiatives
-ATUREĺ&IELD
for understanding basic biological processes
Tissue/organ EuTracc
EUROHEAR EureGene (kidney ESTOOLS
Development and disease, (transcriptional
(Hearing process development (hES
regulation
Stem cell biology and deficiencies) and disease) differentiation)
in ES cells)
MAIN SIRROCO
Biological pathways
Chronic EndoTrack (Small
and signalling DNA Repair
inflammation (endocytosis) regulatory
RNAs)
1st call - 2002
2nd call - 2003
In silico tools, BIOSAPIENS
3rd call - 2004 EMBRACE
Integrated bioinformatics (Human Genome (Bioinformatics
4 call - 2005
th
databases Annotation) grid)
IP, NoE
Tools and technologics Basis for advances in post-genomics era: High-throughput
CA, STREP for ”-omics” Tools for Proteomics, transcriptomics, model organisms, imaging
Fig. 13: Steps to ERA in multidisciplinary functional genomics approaches

for understanding basic biological processes in FP6 (2002-2006)

at the national, European and international level. They have also substantially contributed towards reducing
fragmentation of research in Europe in their respective fields, thereby implementing the concept of the ERA and
creating a real multidisciplinary integrated programme of activities, as is illustrated in Fig. 13.
The FP6 investment constitutes the largest programme ever (in Europe and worldwide) that addresses fundamental
biology in such a multidisciplinary collaborative way, implementing state-of-the-art functional ‘-omics’ approaches.
However, it must be recognised that cellular components interact in subtle and complex ways, even in the simplest
organisms. The understanding of the enormous complexity of the interacting gene networks that are responsible for
most biological processes will require integrative and quantitative forms of analysis of diverse data. It is important to
emphasise that the ‘multidisciplinary approaches to basic biological processes’ action line, has already provided a
richness of large-scale ‘-omics’ data that constitutes the foundation for future systems biology initiatives in Europe.
ĺ"IOLOGICALĺPATHWAYSĺANDĺINTRACELLULARĺANDĺEXTRACELLULARĺSIGNALLINGĺĺ
Cellular signalling helps govern basic cellular activities and coordinates cellular function. A cell’s ability to re-
spond correctly to its surrounding environment is the basis of normal cellular growth and tissue homeostasis, as
well as development and repair. Dysfunctions of the transmission and process of signalling within the cell may
result in many diseases. An improved understanding of the basic biological pathways involved in intracellular
and extracellular signalling will lead to more effective therapies for these diseases.
In general, the FP6 projects funded in this broad sub-area could be classified into two groups: those focusing on
basic biological processes in healthy conditions, and others focusing on disease.
1. Projects applying multidisciplinary approaches

for understanding basic biological processes in healthy conditions
MITOCHECK involves research into the regulation of mitosis and into the mammalian cell cycle, ab-
normalities of which can contribute to cancer. The project applies cutting-edge technologies: the use of
RNA interference genome-wide screens to identify in a systematic manner (functional genomics) all genes
involved in mammalian cell-cycle, and proteomics approaches to identify novel protein complexes and
phosphorylation sites. A web-based database is created with such information as, the list of genes required
for mitosis, the sub-unit composition of mitotic complexes, and genome-wide RNAi screens phenotypic data
that will provide a valuable source of information to the whole cell biology community.
The RUBICON NoE focuses on the better understanding of post-translational modifications of proteins by
ubiquitination. It will establish the link to diseases such as infectious and inflammatory conditions, cancer,
and neurodegenerative disorders. This goal is achieved by applying multidisciplinary functional genomics
to elucidate the functions of genes and gene products, and by defining the regulatory networks controlling
ubiquitination.
The EndoTrack project aims at gaining conceptual advances into the signalling function of growth factors
from an unconventional perspective, namely by exploring the role of endocytic trafficking in the modula-
tion of signalling and gene expression regulation. It further aims to translate such basic knowledge into
novel opportunities for the development of a new generation of tools to combat diseases like cancer, and
cardiovascular, metabolic, and infectious and neurodegenerative diseases
The PEROXISOMES project, using cutting-edge proteomics tools, identifies and characterises the func-
tions of novel peroxisomal proteins and establishes a catalogue of peroxisomal proteins in human liver,
kidney and brain. The consortium will evaluate the role of peroxisomes as modulators or modifiers of dis-
eases of complex inheritance, such as cancer and neurodegenerative disorders.
TRANSDEATH will investigate the functional relationships between the different forms of programmed
cell death by using appropriate models. These mechanisms will then be used to understand corresponding
types of cell death in mammals, and particularly in humans.

SIGNALLING & TRAFFIC will establish the connections between signalling pathways and membrane
trafficking in the context of migrating, dividing and adhering mammalian cells. Through the study of
membrane traffic in the course of cell differentiation, dedifferentiation, and during mitosis, the project
explores how membrane traffic can influence signalling cascades.
2. Projects applying multidisciplinary approaches

for understanding basic biological processes in disease
The MAIN project is identifying and characterising the molecular mechanisms underlying chronic inflam-
matory responses and will produce cutting-edge technological approaches for use in cell migration. It
primarily studies the migration of leukocytes from the bloodstream into inflamed tissues, and their local ac-
tivation by inflammatory substances and pathogens. A bioinformatics database is being created, enabling
rapid data retrieval and analysis, and cross-correlation of functional genomic and functional proteomic
data, facilitating biological hypothesis-making and ‘systems’-level investigations.
Aneuploidy is the term used to describe the abnormal copy number of genomic elements. The ANEU-
PLOIDY project is studying the phenotypic consequences of gene dosage imbalance in humans at cellular
and organism level, by focusing on two prototype human model phenotypes: trisomy 21 and monosomy.
The project will allow the identification of genes and biological pathways potentially involved in new aneu-
ploidy syndromes.
The DNA REPAIR consortium is using an integrated multidisciplinary approach to improve understanding
of DNA damage response and repair systems in living organisms. Genomics tools are used to identify new
components of DNA damage response pathways. The project will extrapolate the findings from model
organisms to humans, by the investigation of cells from patients suffering from genome instability, cancer
predisposition and premature ageing syndromes.
WOUND will identify evolutionary conserved genes and major signalling pathways involved in epithelial
fusion and wound healing, using model systems.
The project STEROLTALK has undertaken a systematic post-genomic evaluation of cholesterol home-
ostasis and its cross-talk to drug metabolism and will contribute towards understanding the effects and
side-effects of hypolipidemic therapy and combined therapies.
All the projects described in this section have set very ambitious and technically challenging objectives which
clearly exceed the capacity of a single laboratory. The combination of a critical mass of excellent European
researchers with a readiness to develop new concepts and highly innovative methods as part of European con-
sortia has stimulated a European corporate identity in their respective fields and is expected to greatly reinforce
competitiveness. To overcome the duplication of efforts in the production of research tools and data, the majority
of the projects have established shared databases to include ‘-omics’ data which are shared between collabora-
tive laboratories. The availability of state-of-the-art HTP technologies is currently restricted to a relatively small
number of laboratories at larger institutions. All these projects have promoted access to advanced technology.
The development of these technologies, as well as the integration of industry and SMEs in most of the projects,
further facilitates the transfer of basic knowledge to future commercial applications.
ĺ4ISSUEĺANDĺORGANĺDEVELOPMENTĺHOMEOSTASISĺANDĺDISEASEĺ
FP6 has built a strong basis by funding several projects applying multidisciplinary ‘-omics’ approaches to under-
stand the molecular pathways and identify novel genes involved in tissue and organ development, degeneration
and disease. All projects apply functional genomics approaches and bring together multidisciplinary expertise
in the same consortium for the first time, and several of them are validating the knowledge produced for devel-
opment of gene and stem cell therapies. The focal point for most of these projects lies in fundamental research.
However, the involvement of clinical expertise, the use of disease population cohorts and industry (including
SME) involvement, promises rapid translation of the basic knowledge to clinical applications.

The LYMPHANGIOGENOMICS consortium brings together leading researchers established in the field
of lymphangiogenesis and provides fundamental insights into the molecular and cellular basis of the lym-
phatic diseases. The project promotes the development of therapies for the treatment of cancer, inflamma-
tory disease, tissue ischemia and lymph oedema, and has been one of the main drivers behind the recent
growth in the field of lymphatic biology.
The MYORES NoE integrates the work of European laboratories previously working in isolation. The
project aims at identifying the genetic determinants of muscle normal development, degeneration and dis-
ease, and at developing technologies for HTP screening in order to isolate novel molecules and rapidly test
their suitability for muscle function and repair in animal models. The creation of the MyoBase database as
a main integrating activity will become the main source of information in muscle biology.
The aim of EVI-GENORET is to understand the fundamental molecular and cellular biology of the retina,
of its development and of the way it is perturbed by genetic mutation, environmental factors and age.
The project integrates population genetics, clinical and experimental phenotyping, molecular genetics
approaches, and HTP transcriptomics and proteomics analysis for the pathophysiology of the retina. The
creation of a state-of-the-art bioinformatics database that will integrate diverse ‘-omics’ data with clinical
data it is expected to accelerate diagnosis, disease screening, drug target evaluation and the development
of new therapeutic strategies for inherited and age-related retinal diseases.
The EUROHEAR IP has two closely interrelated objectives: to provide fundamental knowledge on the
development and function of the inner ear and to identify the molecular effects underlying hereditary hear-
ing impairments, including presbycusis. The involvement of hearing-impaired individuals and their families
in research is essential for the understanding of normal and abnormal auditory function. The EUROHEAR
project demonstrates vigorous cross-disciplinary expertise with strong interaction between human and ani-
mal models geneticists, development of biophysical and bioimaging techniques combined with functional
genomics, as well as a sound inner-ear training programme for young European scientists.
EuReGene integrates European excellence in research relevant to renal development, pathophysiology

and genetics. The main objective is to discover genes responsible for renal development and disease.
The consortium involves the multidisciplinary expertise of leading scientists, including clinicians and SME
partners, and focuses on the development of novel technologies and discovery tools in functional ge-
nomics and their application to kidney research. Knowledge generated will be available to the scientific
community and to the stakeholders through freely accessible databases and repositories.
All of the above projects, representing an investment of more than `60 million, constitute the most coordinated
and integrated approach in Europe and internationally in the fields of kidney, inner ear, retina, muscle and lym-
phatic tissue health and disease.
All the above projects are developing standardisation of protocols, and several of them standard operating pro-
cedures facilitating the cross-comparison of results between geographically isolated laboratories. Several of them
are developing a strong bioinformatics database that for the first time will integrate diverse data existing in differ-
ent laboratories to be shared and analysed by members of the consortia in collaboration. An advantage in these
fields is access to large-scale population cohorts as well as access to HTP genomics and genetic platforms.
Given the genetic complexity of different organs and tissues, the cooperation between the European groups is
expected to be instrumental both in terms of resource sharing and complementary expertise. These consortia by
uniting their efforts, have created a structure unequalled elsewhere.
Disorders affecting normal organ and tissue function have an impact in the quality of life of large populations and
have a serious economic impact on the European economy. The knowledge produced will contribute strategies to
combat common and rare diseases as well as inherited and age-related diseases related to organ development
and degeneration, and to identify novel disease genes and novel targets for diagnosis and therapy.

ĺ3TEMĺCELLĺBIOLOGYĺ ĺ
The EU has supported stem cell research for a number of years in successive FPs. Stem cells have enormous po-
tential, not only in regenerative medicine for replacing damaged tissue in various diseases, but also for applica-
tions in drug discovery, toxicology and pharmacogenomics. Stem cell research is also crucial in understanding
the basic underlying processes that lead to serious pathological conditions.
In fundamental genomics and under the area in which multidisciplinary approaches are applied to basic biologi-
cal processes, the EC funds several projects with the aim of generating knowledge on the fundamental processes
governing stem cell differentiation in human and model organisms. If we can learn more about this fundamental
process, we might be able to reprogramme the body’s own cells, for example, to replace diseased or damaged
tissue. Various sources of stem cells are studied and compared, including ES cells, adult stem cells and induced
pluripotent stem (iPS) cells originating from somatic cells.
FUNGENES applies multidisciplinary approaches with an emphasis on microarray expression analysis to mouse
ES cells that are in a state of self-renewal or that have been induced to differentiate in various tissues of the three
major differentiation pathways. It delivers a gene expression atlas on the genetic pathways for cell differentiation
into heart cells (cardiomyocytes), nerve cells (neurons), smooth muscle cells, vascular endothelial cells, fat cells
(adipocytes), liver cells (hepatocytes) and insulin-producing cells of the pancreas. The data are analysed by meth-
ods of bioinformatics to produce new knowledge regarding genetic pathways, to identify novel genes that are
involved in different aspects of development, and lastly to validate the candidate genes by genetic engineering
of mouse ES cells. The project is expected to have an impact on future novel therapeutic strategies for diseases
including cancer, liver disease, diabetes and cardiovascular and neurodegenerative diseases.
ESTOOLS applies multidisciplinary genomic techniques and genetic tools to uncover the basic mechanisms con-
trolling the choice that human ES cells make between self-renewal and differentiation into the neuronal lineage, by
utilising 52 human ES cell lines. It will develop internationally agreed standardised protocols and tools for growing
and manipulating ES cell lines, and for monitoring their phenotypic, genetic and epigenetic stability. This knowl-
edge will be disseminated to the wider scientific community to make the best use of the existing stem cell lines, and
ultimately will allow the culture and exploitation of hES cells.It will also address the technology for deriving induced
Pluripotent Stem (iPS) cells and explore whether iPS cells have genetic, epigenetic and developmental properties
equivalent to human ES cells. If this technology can be established, and if the derived cells are indeed identical to
ES cells, then this approach may in the future reduce the need for working with embryo-derived stem cells.
A first step towards regenerative medicine involves finding a means to cause controlled dedifferentiation of
adult tissue. The project PLURIGENES investigates the controlled de-differentiation of adult tissue in order to
discover the function of genes controlling pluripotency and de-differentiation in the central nervous system, so
as to ultimately combat diseases such as brain injury and/or ageing. The project is based on the identification
of candidate pluripotency associated genes evolutionarily conserved between different model organisms. The
knowledge generated on self-renewal pathways (which are often deregulated in cancer stem cells) might also
lead to improved outcomes in the treatment of human tumours.
One of the big challenges for the next decade is to understand the regulatory network of TFs that control cel-
lular functions. EuTRACC determines the regulation of the genome by mapping the regulatory pathways and
networks of TFs (the ‘Regulome’) that control the activity of ES cells and the process of differentiation into neural
tissues and the blood system. The project utilises multidisciplinary approaches by applying genetics, proteomics
and genomics tools in the mouse mainly, which are complemented by functional assays in other model organ-
isms. The neural and hematopoietic tissue types were selected because of their well-characterised differentiation
pathways and their existing clinical applications.
Several of these projects cooperate closely with international efforts. ESTOOLS will play a significant role in the
development of standardised techniques for hES cells not only in Europe, but throughout the world, by working
together with the International Stem Cell initiative (ISCI), which addresses issues of standardisation of markers
and techniques for studying human ES cell lines. %542!## will collaborate with the International Regulome
Consortium (IRC), a worldwide consortium that will map the genetic regulatory nodes and networks that control
the function and lineage determination of embryonic and adult stem cells, with immense implications for devel-
opmental biology, disease and regenerative medicine.

ĺ2.!ĺBIOLOGYĺ ĺ
The flow of genetic information from DNA via mRNA to protein has been termed as the central dogma of molecular
biology. Early results in post-genomics research have already challenged established views about the nature of the
genome. A surprising result of the human genome sequencing experiments was that only a very small proportion
(1,5%) of the entire genome encodes for proteins. It was once thought that a large proportion of our genome was in-
active ‘junk DNA’, but today we know that many of these genomic regions are regulatory sequences responsible for
activating or silencing genes when necessary. A major surprise in the human and mouse genome sequences was
the discovery that humans do not have considerably more genes than other mammals. However, the mammalian
transcriptome is largely constituted of many non-protein coding transcripts (many more than the number of genes),
which might be associated with the level of cellular complexity in mammalian species. Many of these transcripts are
non-coding RNAs, while others are conserved across species and others are unique in species, yet their functions
in health and disease remain largely unknown.
The discovery of the RNA-interference mechanism that can degrade mRNA from a specific gene was reported
in 1998 and led to the 2006 Nobel Prize in Medicine and Physiology. This mechanism is activated by double-
stranded RNA which leads to degradation of the target mRNA so that the corresponding gene is silenced and no
protein is produced. RNA interference occurs in plants, animals, and humans and is already being widely used
in basic science as a method to study the function of genes and it may lead to novel therapies in the future. These
discoveries have revealed a previously unknown role for RNA as a silencer of gene expression, to its previously
understood role as a cellular messenger that directs protein synthesis.
The exciting discoveries in RNA biology and the non-protein coding RNAs as the ‘second genome’ are tackled
by several FP6 CPs (SIROCCO and RIBOREG are examples), including the increasing importance of post-tran-
scriptional regulation of gene expression (an example is EURASNET).
The SIROCCO project studies the role of non-protein coding genes as organisers and coordinators of the organ-
ism’s complexity. It investigates the role of small regulatory RNAs (sRNAs) in health and disease, with particular
emphasis on cancer, neurological diseases and developmental regulation, by using HTP technologies and bio-
informatics. It will determine the tissue and cell-type miRNA expression, optimise methods of sRNAs detection,
characterise the molecular machines responsible for both miRNA and siRNA biogenesis, and dissect sRNA
regulatory networks through the combination of multidisciplinary methods.
The RIBOREG project identifies novel non-coding RNA (ncRNA) genes linked to cell differentiation and disease
and analyse their mechanisms of action by developing a multidisciplinary approach integrating bioinformatics,
cell biology, genetics and genomic strategies. The BACRNAs project will identify non-coding RNAs involved
in bacterial pathogenicity and the identification of targets (virulence factors) controlled by ncRNAs involved in
virulence. RNABIO is an SSA: its main contribution was the organisation of an international workshop on com-
putational approaches to non-coding RNAs, with the main objectives of presenting and discussing the state of
RNA computational biology so as to identify needs and propose new developments.
The human genome contains a surprisingly low number of protein-coding genes — approximately 22 000. However,
the human proteome consists of approximately 100 000 protein isoforms. Part of the answer is alternative messenger
RNA (mRNA) splicing. The EURASNET NoE aims to develop an integrated approach to the study of alternative splic-
ing: it will provide durable structures that will change the way research in this field is carried out in Europe; establish
an ambitious, innovative and multidisciplinary programme of joint research activities with high impact; spread ex-
cellence within Europe; disseminate knowledge about alternative splicing in molecular biology and particularly in
medical communities; and foster public awareness of genomics and RNA research and their applications.
ĺ#HRONOBIOLOGYĺ
The circadian clock is a basic biological process that enables organisms to anticipate daily environmental
changes by adjusting behaviour, physiology and gene regulation. It impacts health and quality of life in
regulating sleep and well-being, in the consequences of shift work, in medical diagnosis and therapy, and in
age-related changes.

In EUCLOCK, European researchers join forces to investigate the circadian clock under entrainment. Utilising
the most advanced methods of functional genomics and phenomics, the team will compare genetic model
organisms and humans. Important findings such as the prerequisites for large-scale non-invasive research on
human entrainment as well as the first animal models for shift-work will be developed. These findings will en-
able the field of chronobiology to exploit the advantages of systems biology research on circadian timing, and
to perform and integrate findings at the level of the genome, the proteome, and the metabolome.
The general objective of TEMPO combines functional genomics, proteomics, cell signalling, systems biology and
pharmacokinetics, and will design mouse and in silico models to allow the prediction of optimal chronotherapeu-
tic delivery patterns for anti-cancer drugs.
ĺ"IOLOGYĺOFĺPROKARYOTESĺANDĺOTHERĺORGANISMS
The EC is also supporting multidisciplinary functional genomics research projects in prokaryotic organisms such
as bacteria and other organisms.
The BACELL HEALTH consortium aims to unravel the integrative cell stress-management systems and stress-
resistance processes required to sustain a bacterial cell when exposed to types of environmental signals. There
are also other projects using bacteria to understand the function of basic biological processes (like BaSysBio) and
applying systems approaches to understand transcriptional regulation.
DIATOMICS will make use of whole genome sequences from diatoms to provide information on gene function
and its relationship to ecology and evolution.
ĺ3YSTEMSĺ"IOLOGYĺ
Systems biology, now an emerging discipline, has gained popularity over the past few years. Each cell, organ
or tissue is a dynamic biological system. The cellular functions are controlled by many genes, proteins and sig-
nalling and metabolic processes. Technological and computational advances have enabled the acquisition and
analysis of large datasets obtained by diverse biological systems at multiple levels. Global measurements of
DNA have yielded data on sequence and genotype and information about chromatin structure. RNA measure-
ments have enabled genome-wide transcriptional profiling and information about alternative splicing and non-
coding RNAs. Proteomics approaches using mass spectrometry and more recently protein arrays have permitted
the global identification and quantification of proteins in their biological context. Furthermore, these technologies
have allowed the quantification of post-translational modifications and revealed dynamic protein-protein and
protein-DNA interactions. Great progress has also been made in measuring metabolic fluxes, and emerging
imaging technologies are providing important insights into biological function.
However, despite these advances, the link between complex biological networks and phenotype remains an
enormous challenge.
In order to gain deeper insights and ultimately a quantitative understanding of the complex and dynamic proc-
esses of living organisms (e.g. environmental adaptation, ageing, and immune defence) of the cells, it is neces-
sary to view the systems as a whole.
Systems biology promises to build up an integrated picture of the regulatory processes at all levels, from genome
to proteome, from organelles to cells and tissues, and the understanding of the whole organism, by integrating
functional data into a cohesive model. This stands in contrast to the standard reductionistic approaches of the
twentieth century, with biologists analysing functional information on organisms based on a single gene or a
single protein at a time.
There are two approaches proposed in systems biology. The top-down approach presupposes that it is not neces-
sary to know all the details of the ways in which cells work in order to make useful predictions about how organism

cells work. This method starts with a model of how the system works and then compares the model with information
from the real biological system. At the opposite end, stands the ‘bottom-up’ approach, which starts from the prop-
erties of individual molecules and builds models at increasingly higher scales. Therefore, the bottom-up approach
essentially requires complete information, including the dynamics of each step, to build a system model. When
complete, such a detailed model should be capable of describing exactly how the system works under any circum-
stance. The combination of the advantages of the above approaches leads to the so-called ‘middle-up’ approach.
The ultimate goal of biology is to understand biological systems in sufficient detail to enable accurate, quantita-
tive predictions about the behaviours of biological systems, including predictions of the effects of modifications
of the systems such as disease. The hope of the rapid translation of genomic information into novel drugs has
foundered on the reality that disease biology is complex. Systems biology aims ultimately to develop predictive
models of human disease. Currently, integration of ‘-omics’ data within the context of controlled gene expression
or drug perturbations of complex cell and animal models (and in the context of clinical data) is the basis for
systems biology efforts at a number of drug companies.
Such research has a strong multidisciplinary nature and the collaboration between different stakeholders, univer-
sity, research institutes, biotech companies and clinical centres is a prerequisite for success. The subject requires
collaboration between a broad spectrum of scientific disciplines including biology, physics, chemistry, computer
science and engineering. A collaborative approach is a prerequisite to achieving major breakthroughs.
FP6 activities
The EU is emerging as a major world player in the development of systems biology in Europe. An important fund-
ing effort has been initiated in FP6 through the support of collaborative research projects and through a number
of key studies and workshop events that have helped to integrate this emerging community.
In FP6, a number of systems biology projects predominantly initiated in 2005 have already demonstrated that
a systems approach can indeed work, to provide both a deeper understanding of biological processes and pre-
dictive potential for applications. These projects have major links to ongoing worldwide research programmes,
national programmes, and Europe-wide support and links (EMBL, EMBL-EBI).
Within FP6, the EC has already funded several pilot research projects paving the way toward systems biology.
These projects may be grouped into the following general categories:
1. Projects applying systems biology approaches in fundamental cellular

signalling pathways
Some of these projects (COMBIO, COSBICS and DIAMONDS) are already applying systems biology ap-
proaches to model cellular signalling pathways. Other projects (QUASI and AMPKIN) aim for a systematic
quantitative understanding of intracellular and extracellular signalling pathways of disease relevance, with
ultimate goals of building predictive pathway models. All of these projects demonstrate that the develop-
ment of computational biology and integrated bioinformatics databases of diverse ‘-omics’ data is an es-
sential component for the successful implementation of systems biology approaches.
COMBIO implements an integrative approach to cellular signalling by combining a unique group of

experimentalists, bioinformaticians and simulation groups in order to gain detailed understanding of key
processes, like the P53-MDM2 regulatory network. COSBICS establishes and applies a novel computa-
tional framework to investigate cellular signalling pathways and subsequent target gene expression.
The DIAMONDS project aims to demonstrate the power of a systems biology approach to study the
regulatory network structure of the most fundamental biological process in eukaryotes, the cell cycle, in
different species.
In the AMPKIN project, experimental and theoretical studies will be integrated to achieve an advanced under-
standing of the dynamic operation of the AMP-activated protein kinase signalling pathway. This pathway plays
a central role in monitoring the cellular energy status and controlling energy production and consumption.

In the last FP6 call, the EC also financed an integrated project (BaSysBio) which uses systems biol-
ogy approaches for the understanding of the dynamic transcriptional regulation in bacteria. It studies
the transcriptional regulation and metabolism in B. subtilis and B. anthracis, and the cellular transcrip-
tional responses in pathogenesis. The project AGRONOMICS applies integrative functional genomics
approaches to systematically investigate the components controlling growth processes in plant cells
(genome sequences, proteins and metabolites) and to explain quantitative growth phenotypes at the
molecular level. Finally, mathematical and statistical methods will be employed in order to model basic
plant processes. The aim is to investigate those further and test them in close collaboration with computer
scientists, statisticians and experimentalists.
2. Projects applying systems biology approaches

for understanding complex diseases phenotypes
EMI-CD, ESBIC-D and BioBridge are using systems biology approaches to gain new insight into highly
complex diseases, such as trisomy related illnesses (Down’s syndrome) and various cancers.
The main purpose of EMI-CD is to provide a software platform complex enough to cope with various ex-
perimental techniques, connecting several modules necessary for the in silico modelling of complex disease
processes such as cancer and diabetes.
VALAPODYN validates predictive dynamic models of complex intracellular pathways related to the cell
death and survival. It develops a new systems biology approach to model the dynamics of molecular inter-
action networks related to neurodegeneration. The ultimate goal is to select and validate drug targets for
human pathologies associated with neurodegeneration.
SysProt develops a new paradigm for the integration of proteomics data into systems biology. It will produce
quantitative proteomics data, and study post-translational protein modifications via the development of compu-
tational analysis, in order to gain understanding on the progression of complex diseases such as diabetes.
BioBridge focuses on the application of simulation techniques for integrated genomic, proteomic, metabo-
lomic and kinetic data analysis, in order to create models for understanding complex diseases at the systemic
level, with an emphasis on heart failure, chronic obstructive pulmonary disease and type II diabetes.
3. Projects aiming at coordination and networking in systems biology
To prepare the best research environment in Europe for systems biology, the EC is already supporting several
SSAs and CAs.
EUSYSBIO laid the foundations for the successful start of European systems biology research,
implementing networking activities and identifying the strengths and weaknesses in European systems
biology. SYMBIONIC is creating a broad European network of research institutions and industries with
interdisciplinary expertise in the systems biology field, which will be a driving force for future ambitious
initiatives in neuronal cell modelling.
ESBIC-D aims at organising a Europe-wide systems approach to combat complex diseases. The project
will network leading groups in the fields of cancer research, genomics, proteomics and computational biol-
ogy to strengthen the expertise and research infrastructure in Europe.
SYSBIOMED explores the potential application of SB to medical research in major disease areas (infec-
tious, neurodegenerative, metabolic and cardiovascular diseases and cancer), and its applications in drug
development. A series of workshops will be organised to promote European collaboration and to contribute
to the breaking down of barriers — between theoreticians, basic researchers and clinicians interested in
medical applications.
YSBN is a CA which focuses on defining standards, methods and concepts of systems biology using the
model organism S. cerevisiae.

It is worth mentioning that the EU-supported large-scale functional genomics initiatives in FP6 have produced a
richness of HTP ‘-omics’ data, which has provided new knowledge on basic biological processes such as the
mammalian cell cycle, tissue development and degeneration (muscle, retina, inner ear and kidney), human and
animal stem cell differentiation processes, organelle function, endocytosis and post-translational modifications.
These large initiatives will pave the way for future systems biology initiatives in Europe. An essential element in
future systems biology are the integrated bioinformatics and computational biology tools. In FP6, important fund-
ing has been provided in the area of bioinformatics, which will contribute to the ERA of systems biology.
-ATUREĺ&IELD ERA in Systems Biology
SysProt (systems BaSysBio

DIAMONDS ESBIC-D (SB for
analysis of protein (Bacterial Transcription
FP6 Pilot Systems (modelling cell cycle) complex diseases)
Modification) Regulation)
Biology Projects BioBridge
QUASI (MAPK- COMBIO COSBICS (modelling (SB for
kinase signalling) (P53 pathway) Cellular signalling) chronic diseases)
Fundamental genomics for MITOCHECK EUROHEAR ESTOOLS SIRROCO

basic Biological processes; (mammalian (Hearing process (hES (Small regulatory
cell cycle) and deficiencies) differentiation) RNAs)
“-omics” data gathering
1st call - 2002

2nd call - 2003 Integrated bioinformatics,
BIOSAPIENS EMBRACE ENFIN
3rd call - 2004 databases, (Human Genome (Bioinformatics (computational
4th call - 2005 Computational biology Annotation) grid) tools for SB)
IP, NoE
Experimental Tools and Tools for Proteomics, transcriptomics, structural genomics,
CA, STREP technologies for ”omics” population genetics, metabolomics, imaging
Fig. 14: Steps to ERA in Systems Biology in FP6 (2002-2006)
FP7 activities
The EU FP7 programme is already playing a major role in this important and rapidly expanding research field
by establishing multidisciplinary networks in Europe that will catalyse progress and excellence in this field. The
FP7 first call for proposals provided an important boost for large-scale European initiatives, by allocating
a total budget of `45 million to the following large scale integrating projects.
SYBILLA, a large scale integrating project, aims to understand at the systems level, how T-cells discriminate
foreign from auto-antigens and will address modelling of T-cell activation. The project will develop technologi-
cal and mathematical tools to generate and integrate high-density quantitative data describing T-cell activation
in health and disease, placing particular emphasis on multiple sclerosis. T-cell activation is a complex process,
relying on multiple layers of tightly controlled intracellular signalling modules, defects in which can cause severe
and chronic disorders such as autoimmune diseases.
The APOSYS project studies the basic cellular mechanisms of apoptosis. This multidisciplinary consortium brings
together and networks experimental biologists, biomathematicians, biostatisticians, computer scientists and clini-
cal scientists to examine cell death pathways in health and disease, with an emphasis on cancer and AIDS. It
complements the systems approach with a series of in silico, in vitro and in vivo model organisms and tissue

samples from patients suffering from cancer and AIDS. The project is expected to enhance our understanding of
clinical data and lead to the development of new diagnostic tools and drugs.
UNICELLSYS set as an overall objective the quantitative understanding of fundamental characteristics of eukaryotic
unicellular organism biology, using yeast as model organism. The project goes far beyond the state of the art in terms
of dynamic modelling of cellular subnetworks controlling complex biological processes such as control of cell growth
and proliferation. It is expected to deliver new knowledge on important biological processes relevant to human health
(cell growth and proliferation) but will also generate economic value in the form of new computational tools and ap-
proaches for systems biology that will be of general applicability to other systems in more complex organisms.
EuroSyStem is a large European effort that brings together elite European research teams to create a world-
leading programme in fundamental stem cell biology, with the main focus on the paradigmatic mammalian stem
cells: haematopoietic, epithelial, neural and embryonic. Cutting-edge multidisciplinary technologies such as
cytometry, transcriptomics, RNA interference, proteomics and single cell imaging, will be used to generate new
knowledge on stem cells differentiation in terms of cellular hierarchy, signalling, epigenetics, de-regulation, and
plasticity. An important bioinformatics and computational platform will be established to mine information and
subsequently to model these complex differentiation pathways.
From biological pathways in unicellular eukaryotic organisms to human cells and organs, there is a need to
combine, integrate and extend existing data sources and screen different heterogeneous data resources. These
large-scale projects on systems biology are expected to integrate dispersed capabilities and assemble the critical
mass necessary to enable systems approaches, as well as to secure European excellence and competitiveness
and the exploration of new directions for the field. The quantitative data delivered should serve as the basis from
which to design robust models with predictive value. They should produce new knowledge on basic biological
processes relevant to health and diseases.
Project Acronym 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 FP
EYSYSBIO SSA E0.5m FP6
SYMBIONIC SSA E0.2m
EMI-CD STREP E1.9m
QUASI STREP E1.9m
COMBIO STREP E2m
COSBICS STREP E1.7m
DIAMONDS STREP E2.5m
EU-US Workshop SSA E0.06m
ELife SSA E0.48m
ESBIC-D STREP E1.9m
YSBN CA E1.3m
AMPKIN STREP E2.1m
RIBOSYS STREP E2.4m
EUROBIOFUND SSA E0.9m
VALAPODYN SME-STREP E1.5m
AGRON-OMICS IP E12m
BaSysBio IP E12m
BioBridge SME-STREP E1.8m
SYSBIOMED SSA E0.36m
SysProt SME-STREP E2.1m
Streptromics SME-STREP E2.9m
SYSCO SME-STREP E1.8m
Proust SSA E1.5m
APOSYS IP E11.1m FP7
SYBILLA IP E11.1m
UNICELLSYS IP E11.03m
EuroSysStem IP E11.03m
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 FP
Fig. 15: Runtime of current EU-funded collaborative research projects in systems biology

In systems biology, not every research area requires a large collaborative effort. During the FP7 second call
for proposals, approximately 15 small-scale research projects were selected, and are cur-
rently under negotiation with a total of `45 million to be committed at the end of 2008 or be-
ginning of 2009. These projects may be categorised as follows: (i) projects aiming to enable systems biology
approaches for diseases like inflammatory response, cancer, neurological diseases, and bacterial infections; (ii)
projects applying systems biology for basic signalling pathways like DNA damage and repair, oxidative stress,
cellular organelle function, and stem cell differentiation; and (iii) support actions for tackling future challenges in
systems biology. All these projects are multidisciplinary and they are focused on collecting, analysing and apply-
ing quantitative data to enable systems biological approaches.
For an emerging and booming field like systems biology, it is rather difficult to identify which are the timely ideas
to investigate using an EU large-scale coordinated approach. The large-scale CPs will create the critical mass
of multidisciplinary expertise that is necessary for enabling complex systems approaches. Therefore, the EC via
its Genomics and Systems Biology programme published the FP7 third call for proposals in September 2008,
implementing a bottom-up approach via a two-stage selection procedure for the first time in the Health priority.
The scientific community is invited to submit proposals for large integrating projects on the following topic:
■ Systems biology approaches for basic biological processes relevant to health

and disease
The projects should focus on modelling important biological processes at any appropriate levels of system
complexity by generating and integrating quantitative data sets (e.g. transcriptomics, proteomics, metabo-
lomics, structural biology, RNAi screening, physiology and/or pathophysiology). These large multidiscipli-
nary efforts should integrate the critical mass of excellence in Europe that is necessary for generating and
validating the models using systems biology.
In summary, to face the challenges of the systems biology era, the EC’s FPs for RTD have al-
ready provided, between 2003 and 2008, more than `150 million for collaborative research
projects. With such substantial funding, the EU is emerging as a major world player in the development of
systems biology in Europe and will continue to do so in the future.
System Biology in FP7 & Health
SB: organisms
SB: tissues/organs
SB: Cells: Mammalian cells
SB: Cells: yeast/bacteria
SB: pathways
Biological processes: data gathering
Bioinformatics/ Data bases/software/computational biology

2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
FP6
FP7
Fig. 16: The future developments of systems biology in FP7

The FP6 fundamental genomics programme paved the way by supporting multidisciplinary projects collecting large amounts
of “-omics” data on basic biological processes, and by developing the bioinformatics and computation tools base.

Annexes
Basic facts and figures for
the Fundamental Genomics activity area
Annex I
Funding instruments and schemes in FP6 and FP7
Compared to FP5 (1998–2002), which mainly supported small and medium collaborative research projects, FP6
(2002–2006) has additionally offered more ambitious ‘new funding instruments’, namely IPs and networks of ex-
cellence (NoE). These two project types are more ambitious in size and scope than the research projects funded
previously by the EU. Both types of projects aim to stimulate and sustain world-class research in a specific area of
fundamental genomics and to improve the organisational aspects of European research in the specified topic. How-
ever, IPs and NoE have a different centre of gravity. With an IP the balance is towards achieving ambitious, clearly
defined scientific objectives; with a NoE the balance is shifted towards tackling the fragmentation of European
research in a specific field, so as to provide an improved organisational structure in which research can flourish.
It is clear that the ‘new instruments’ of FP6 have enabled European scientists to achieve a major critical mass in
very competitive areas of functional genomics and have really given European research a global profile.
For further information, see http://www.cordis.lu/fp6/instrument-ip/.
&UNDINGĺINSTRUMENTSĺINĺ&0
Integrated Projects (IPs)
IPs are large-scale projects aiming to support world-class objective-driven research, where the primary deliver-
able is generating new knowledge. In addition, by mobilising a critical mass of resources, IPs should also have
a structuring effect on European research (see Figure 17 for the graphical representation on the goals of an IP).
The activities integrated by an IP may cover the full research spectrum from basic to applied research, and
should contain:
■ objective-driven research;
■ technological development, innovation-related and demonstration components, as appropriate;
■ the effective management of knowledge and, when appropriate, its exploitation;
■ a training component, where appropriate.
All these activities should be integrated within a coherent management framework.
An IP should bring together a critical mass of research excellence and resources to achieve its ambitious objec-
tives. The European Community funding for an IP in the fundamental genomics programme ranges from `8 to
`13 million, their duration from 36 to 60 months, with an average of `11.2 million per project and 48 months
duration for the majority of the projects.

Integrated Projects
To integrate the critical mass of activities/resources needed for :

Addressing major societal needs
Increasing EU competitiveness
l aspects, science-society dialogu Predefined S/T

Ethica e results and
Training clear deliverables
RTD 4 RTD 5 Strong

RTD 3 Management RTD 1 management
structure
RTD 2
Demonstration
Implementation
Technol n
og y transfer, exploitatio Plan
Fig. 17: Graphical representation of the structure and the goals of an Integrated Project in FP6 (2002-2006)
Networks of Excellence (NoE)
NoE are large-scale projects with the goal of overcoming fragmentation in the European research landscape
and strengthening European excellence in a given area (see Figure 18 for a graphical representation of the
goals of a NoE). Their purpose is to reach a durable restructuring/shaping and integration of efforts and
institutions or parts of institutions (labs, departments, units, teams, etc.) in areas where this is necessary. The
success of a NoE is not measured only in terms of scientific results, but also by the extent to which the fabric for
researchers and research institutions in a given field has changed due to the project, and the extent to which
the existing capacities have become more competitive as a result of this change.
A NoE is implemented through a Joint Programme of Activities, which encompasses the following:
■ Integrating activities: These aim at structuring and shaping the way participants carry out research in
the topic (e.g. coordinated programming, sharing research facilities, tools and platforms, joint management
of the knowledge portfolio, schemes for increasing staff training and mobility, staff exchanges, shared
information and communication systems).
■ Jointly executed research: A world-class research programme is an obligatory part of the Joint
Programme of Activities or JPA (for example, to generate new knowledge in the research topic and to develop
new research tools and platforms for common use).
■ Activities for spreading excellence: An essential mission of a NoE is to spread excellence beyond
its boundaries. Typical examples of such activities would be the following: joint programmes for training
researchers and other key staff to ensure the sustainability of Europe’s excellence in the topic, communication
campaigns for disseminating results (and raising public awareness of science), and networking activities to
encourage knowledge transfer and innovation.
NoE should pursue ambitious goals and gather the critical mass needed to ensure their achievement. The Euro-
pean Community grant to a NoE in the fundamental genomics areas ranges from `10 to `12.5 million, their
duration from 48 to 60 months, with an average of `10.7 million per project and 60 months duration for the
majority of the projects.

Networks of Excellence
Governing Council Funding Bodies

European Commission Representatives
To structure the EU research potential

by integrating existing research capacities
Joint research activities
Integrating activities
Spreading of excellence (training)
Common management
Management
Group
Research team leader

Partner Organisation Representative
Fig.18: Graphical representation of the goals and the structure of a network of excellence in FP6 (2002-2006)
Specific Targeted Research Projects (STREPs)
STREPs are multi-partner research projects, with the goal to support research, technological development and
demonstration or innovation activities of a more limited scope and ambition than IPs. They are an evolved form of
the shared-cost RTD projects and demonstration projects used in FP5, and their main deliverables are to produce
new knowledge and improved tools and technologies in fundamental genomics.
The European Community financial support for a STREP in fundamental genomics ranges from `1.5 to `2.5 mil-
lion, their duration from 36 to 48 months, with an average of `2.1 million per project and 36 months duration
for the majority of the projects.
STREPs were also funded during the fourth call of FP6 with the specific goal of supporting projects for develop-
ing and/or improving tools and technologies development, and of encouraging SMEs’ research and innova-
tion efforts. The goal was that 30% of the EC contribution to be allocated to the SMEs. These projects are
entitled SME-STREPs in the current publication.
Co-ordination Actions (CAs)
CAs do not support research and development activities per se; they promote and support the networking and
coordination of research and innovation activities aiming at improved integration of European research. CAs are
a continuation of the concerted actions/thematic networks used in FP5, in a reinforced form.
A CA could contain activities such as:
■ the definition, organisation and management of joint or common initiatives;
■ the organisation of conferences and meetings;
■ the performance of studies and analyses;

■ the exchange of personnel;
■ the exchange and dissemination of ‘good practices’;
■ the setting up of information systems and expert groups;
■ specific training courses or seminars.
The European Community financial contribution for a CA in fundamental genomics ranges from `0.5 to `1.3
million, their duration from 24 to 48 months, with an average of `0.8 million and 36 months respectively.
Specific Support Actions (SSAs)
SSAs are more limited in scope than the accompanying measures of the previous FPs. They aim to:
■ promote and facilitate the dissemination, transfer, exploitation, assessment and/or broad take-up of
past and present programme results (over and above the standard diffusion and exploitation activities of
individual projects);
■ contribute to strategic objectives, notably regarding the ERA (e.g. pilot initiatives on benchmarking,
mapping, networking, etc.);
■ prepare future community RTD activities, (e.g. via prospective studies, exploratory measures, pilot ac-
tions, etc.).
The European Community funding contribution for an SSA in fundamental genomics ranges from `0.06 to `0.5
million, their duration from 12 to 36 months, with an average of `0.3 million and 24 months respectively.
&UNDINGĺSCHEMESĺINĺ&0ĺ
FP7 projects are all categorized with the general term collaborative projects.
Large scale collaborative Projects (Large scale integrating projects) (CP-IPs)
The large integrating projects could be considered an evolution of the IPs in FP6.
These projects will support objective-driven research projects aiming at developing new knowledge, new
technologies, products, demonstration activities or common resources for research, to improve European
competitiveness or to address major societal needs.
They include the following activities:
■ RTD — the core activities of the project;
■ demonstration, where applicable;
■ project management;
■ other activities such as dissemination of research results, etc.
The European Community funding contribution for CP-IPs in the Health theme should be more than `6 million
and maximum of `12 million. In the Genomics and Systems Biology programme during the implementation
of the FP7 first call for proposals, the funding ranges from `11 to `12 million, their duration from 48 to 60
months, with an average of `11.7 million and 48 months respectively.

Small or medium scale collaborative Projects
(Small-Medium Focused Research Projects) (CP-FPs)
These projects could be considered as a continuation of FP6 STREP projects and are research projects with
lower ambitions than IPs.
The European Community funding contribution for CP-FRPs in the Health theme should be `3 million to less
than `6 million. In the Genomics and Systems Biology programme during the implementation of the FP7
second call for proposals (with a September 2007 deadline), currently under negotiation, the funding ranges
from `2.5 to `2.99 million, their duration from 36 to 48 months, with an average of `2.7 million per project
and 36 months duration for the majority of the projects.
Coordination and Support Actions (CSAs)
These projects refer to Coordination and Support Actions (CSAs) and do not support research per se but
rather coordination activities with objectives similar to those of FP6.
The European Community funding contribution for CP-CSAs in the Health theme is generally in the range
of up to `1.5 million, although there is no upper limit. In the Genomics and Systems Biology programme
during the implementation of the FP7 second call for proposals (projects currently under negotiation), the
EC funding ranges from `0.5 to `2.7 million, and the duration from 24 to 36 months.

Annex II
Development of the specific scientific topics
for calls for proposals in the FP6 Fundamental
Genomics programme
At the beginning of FP6, a global expression of interest was established for the first time in the FP, and the most
innovative ideas for European collaborative research were selected. This concept has been applied in the whole
thematic area of Life Sciences, Genomics and Biotechnology for Health. In this section, we will concentrate on
the Fundamental Genomics activity area. The European scientific community has submitted 550 expressions of
interest, and these have been evaluated by eminent scientists both within and outside Europe. This high-level
evaluation process led to the strategic areas of research that defined the specific topic for calls for proposals,
mostly for the large-scale projects in the FP6 first, second and third call topics.
The rest of the calls have been developed by consulting the scientific community via EC’s strategic workshops
(see Annex III). The Scientific Advisory group was set up by the EC to provide input on the strategy and the imple-
mentation of the work programme in the Life Sciences theme in FP6: this group’s valuable advice is an important
source of consultation on the work programmes (for more information, please see http://cordis.europa.eu/fp6/
eags.htm and http://ec.europa.eu/research/fp7/index_en.cfm?pg=eag).
The EC also acknowledges the important role of the Member States’ recommendations in the final implementation
of the work programme.

Annex III
The EC organisation of strategic workshops
in different scientific areas of fundamental genomics
and systems biology
During FP6, the EC organised a number of successful workshops in collaboration with the scientific community,
to identify the challenges and the future developments in different areas of fundamental genomics, along with
new initiatives that have contributed to strategies in FP7. The following workshops were organised by the Unit of
Fundamental Genomics — this name was updated to the Genomics and Systems Biology Unit in FP7 (for further
information, see http://cordis.europa.eu/lifescihealth/genomics/home.htm).
■ Bioinformatics Structures for the Future, in March 2003, with the goal of setting a research agen-
da in the field for structuring European bioinformatics research;
■ Workshop on Mouse Genetics, in July 2003, with the aim of setting priorities for mouse functional
genomics research in Europe;
■ Computation Systems Biology: its Future in Europe, in September 2003, with the aim of defining
a research and policy agenda to promote the field of computational systems biology (CSB) in Europe;
■ Meeting on population genetics in Europe, in September 2003, in order to identify priorities for
research in population genetics and related areas;
■ Workshop on Structural Genomics, in October 2003, with the aim of identifying the strengths,
weaknesses and future opportunities for structural genomics in Europe;
■ Conference on European Structural Genomics & Proteomics Research combined with the
joint meeting of EU-funded projects, in October 2004, with the aim of creating synergies between the
projects by clustering and networking, of disseminating best practices and success stories to establish
gateways between disciplines; of debating and formulating a proposal on the current and future policies
needed for SG in Europe;
■ Functional Genomics Research: Future Perspectives in October 2004, with the aim of identifying
the future challenges and developments of the functional genomics field for future research policies actions,
in view of establishing genomics research for FP7;
■ Workshop on Systems Biology in December 2004, where European scientists identified key areas in
systems biology for development in the near future;
■ Conference on Funding Basic Research in Life Sciences: Exploring opportunities for Eu-
ropean synergies in December 2004, a joint effort of Directorate F (Life Science, Genomics And
Biotechnology for Health in FP6 & Directorate E (Food Quality And Safety);
■ EUROMOUSE conference: Understanding human disease through mouse genetics — The

European Dimension in October 2005, for creating synergies among projects using mouse as a model
organism and discussing priorities in mouse functional genomics;
■ Human genetic variation workshop in March 2006, exploring the need for a grid-linked set of
databases in this area;
■ Mouse functional genomics workshop in March 2007, concluding with recommendations for
international collaboration in the field of mouse as a model for human disease;

■ EU-US Task Force Workshop on Infrastructure Needs for Systems Biology in May 2007 (US),
with the aim of making recommendations for infrastructure support to enable systems biology research;
■ EU-US workshop on ‘How Systems Biology Could Advance Cancer Research’ in May 2008,
drawing up suggestions for international collaboration on systems biology of cancer.
For more information, including the published reports for some of the workshops, see http://cordis.europa.eu/
lifescihealth/genomics/home.htm. Information can also be found on the FP7 Health website, at http://cordis.
europa.eu/fp7/health/home_en.html.

Annex IV
Evaluation process in
the FP6 and FP7 Fundamental Genomics programme
The present section provides a short overview of the evaluation procedure in the thematic priority of Life Sciences,
and more specifically focuses in the area of Fundamental Genomics.
The procedure for evaluation of proposals is based entirely on the ‘Guidelines on proposal evaluation and project
selection procedures’, which can be found at: http://fp6.cordis.lu/lifescihealth/call_details.cfm?CALL_ID=148,
and which serves as the basis for the following brief presentation.
Role and code of conduct of evaluators
The EC appoints independent experts to assist in the evaluation of proposals. In general, independent experts
are expected to have skills and knowledge appropriate to the areas of activities in which they are asked to as-
sist. Details of potential independent experts are maintained in a central database. This database may be made
available, on request, to national authorities in the Member States and countries associated to the FPs. The names
of the independent experts assigned to individual proposals are not made public; however, at regular intervals,
the EC publishes the list of independent experts used per activity/research area, on the Internet.
The EC takes all reasonable steps to ensure that each expert is not faced with a conflict of interest in relation to
the proposals on which he/she is required to give an opinion. To this end, the EC requires experts to sign a dec-
laration that no such conflict of interest exists at the time of their appointment and that they undertake to inform
the EC if one should arise in the course of their duties. When so informed, the EC takes all necessary actions to
remove the conflict of interest. The experts are obliged to maintain the confidentiality of the information contained
within the proposals they evaluate and of the evaluation process and its outcomes and to act with strict impartial-
ity. A conflict of interest and confidentiality declaration will be signed by independent experts.
The proposal evaluation and project selection process
The overall evaluation and project selection process is summarised in the following diagram.
The evaluation procedure consists of the following steps:
Step 1: Briefing of the independent experts
All independent experts are briefed in writing and orally before the evaluation by representatives of the EC’s
service in charge of the call, in order to inform them of the general evaluation guidelines and the objectives
of the research area under consideration.
Step 2: Individual evaluation of proposals
The proposals are sent to the expert evaluators at their normal place of work. Each proposal is evaluated
against the applicable criteria relevant to each funding instrument independently by several experts who fill
in individual evaluation forms giving marks in each criterion and providing justification of marking. These
comments serve as input to the consensus discussion and related consensus report that takes place in Brussels.
The number of evaluators legally required is five for IPs/NoE and three for the other instruments. The EC has
established as a general practice the evaluation by a number of seven to nine evaluators for IPs/NoEs and
five for the other instruments, in order to further strengthen the quality of the evaluation procedure.
Written opinions from external reviewers are applied specifically for the large projects (IPs, NoE), where most
of the top European specialists in the field are involved in a given proposal. Therefore, to obtain an independ-
ent high-quality assessment, several specialists in the field, mainly from outside Europe, are invited to review

The Proposal Evaluation And Project Selection Process
Proposal
Eligibility
Individual Evaluation
Consensus
Ethical Issues
Thresholds
(OPTIONAL) Hearings
Panel
Ranking by EC
EC Rejection Decision Negotiation
Negotiation Result
Consultation of Programme
Committee if required
EC Funding Decision
and/or Rejection Decision
each proposal. The external reviewers are asked to provide their written opinion of the scientific quality of the
proposal. These written opinions are provided to the expert evaluators prior to the meeting of the consensus
group in Brussels, but after the expert evaluators have completed and forwarded to the EC services their in-
dividual assessment reports on the proposals assigned to them. Consideration of the written opinions of the
external reviewers makes up an important aspect of the consensus group’s discussions in Brussels.
Different consensus groups operate in parallel in different groups of closely related topics. The propos-
als passing the thresholds are reviewed by a final panel composed of several experts from each of the
several consensus groups. The final panel produces a ranking list of proposals in order to advise the EC
on which projects to select for funding.
Step 3: Consensus panels
Separate parallel consensus panels are convened in Brussels. The goal is that for each proposal all the
experts reach an agreement on a consensus mark for each of the blocks of evaluation criteria based on
the comprehensive discussion. They justify their marks with comments suitable for feedback to the pro-
posal coordinator. The discussion of the proposal continues until a consensus is achieved, i.e. a conclu-
sion with which all agree regarding the marks for each criterion and the accompanying comments. In the
event of persistent disagreement, the EC official supervising the evaluation of that proposal may bring in
up to three additional evaluators to examine the proposal.

In order to facilitate discussion among the experts, the EC officials act as moderators for the group and
assign an expert as ‘proposal rapporteur’. The proposal rapporteur introduces the proposal(s) assigned to
him/her and summarises the opinions of the external reviewers (in the case of IPs and NoE). The proposal
rapporteur is responsible for amalgamating the individual experts’ views, for initiating the discussion and
drafting the consensus report. The outcome of the consensus step is the consensus report signed by all inde-
pendent experts and the moderator. The moderating EC official is responsible for ensuring that the consen-
sus report faithfully reflects the consensus reached. For all proposals passing the thresholds, the consensus
group is asked to give an opinion on the appropriateness of the level of Community funding requested in
relation to the tasks and activities to be carried out.
Final evaluation panel
Immediately after completion of the consensus panels, an integrated final panel discussion is convened in Brus-
sels to examine and compare the consensus reports and marks of the independent consensus panels, to review
the proposals with respect to each other and, in specific cases (e.g. equal scores) to make recommendations on
a priority order of proposals. A panel rapporteur (who may also be the panel chairperson) is appointed to draft
the panel’s advice. An EC official may act as moderator of the panel. The role of the EC moderator is to ensure
fair and equal treatment of the proposals in the panel discussions. The outcome of the panel meeting is the panel
report recording the deliberations of the panel containing the following: an evaluation summary report (ESR) for
each proposal and a ranked list of proposals passing thresholds, along with a final mark and the panel recom-
mendations for priority order.
After the evaluation
At this stage, the EC services review the results of the evaluation by independent experts, make their assessment
of the proposals based on the advice from these experts and prepare the final evaluation results.
The EC services draw up a final ranked list of all the proposals evaluated and of those passed the required thresh-
olds. Due account is taken of the marks received and of any advice from the independent experts concerning the
priority order for proposals. The list of proposals to be retained for negotiation takes into account the budget avail-
able. Negotiation may cover any scientific, legal or financial aspects of the proposal, based on the comments of the
independent experts and on any other issue that was taken into consideration at the ranking stage. If negotiations
are successful, the EC may then enter into the contract with the coordinator and the other contractors.
Evaluation procedures in FP7
The procedure for evaluation of proposals is based entirely on the ‘Rules for submission and the related evalua-
tion, selection and award procedures’, which can be found at ftp://ftp.cordis.europa.eu/pub/fp7/docs/calls/
fp7-evrules_en_pdf.zip.
The basic structure of the procedure is similar to the one described in FP6, with some minor adaptations.
The evaluation criteria in FP7 have been consolidated to avoid repetition and the high level of complexity expe-
rienced during the FP6 evaluations.

Annex V
Evaluation criteria in FP6 and FP7
Evaluation criteria in FP6
The evaluation criteria applied for each funding instrument in FP6 are described below.
Each of the criteria may differ depending on the type of the funding instrument (described in Annex I). The evalu-
ation criteria are ranked as follows:
0: the proposal fails to address the issue under examination or cannot be judged against
the criterion due to missing or incomplete information;
1: poor;
2: fair;
3: good;
4: very good;
5: excellent.
Evaluation criteria for an Integrated Project (IP):
■ relevance (threshold score: 3), which means the extent to which

the proposed project addresses the objectives of the work programme/call;
■ potential impact (threshold score 3);
■ scientific & technological excellence (threshold score: 4);
■ quality of the consortium (threshold score: 3);
■ quality of the management (threshold score: 3);
■ mobilisation of resources (threshold score: 3).
The total score for an IP could be a maximum of 30 with threshold 24.
Evaluation criteria for a Network of Excellence (NoE):
■ relevance (threshold score: 3, which means the extent

to which the proposed project addresses the objectives
of the work programme/call);
■ potential impact (threshold score: 3);
■ excellence of the participants (threshold score: 3);
■ degree of integration & the joint programme of activities (threshold score: 4);
■ organisation and management (threshold score: 3).
The total score for a NoE could be a maximum of 25 with threshold 20.
Evaluation criteria for a Specific Targeted Research Project (STREP):
■ relevance (Threshold score: 3);

■ scientific and technological excellence (threshold score: 4);
■ quality of the management (threshold score: 3) ;
The total score for STREP could be a maximum of 30 with threshold 21.

Evaluation criteria for a Co-ordination Action (CA):

■ quality of the support action (threshold score: 4);
The total score for CA could be a maximum of 30 with threshold 21.
Evaluation criteria for a Specific Support Action (SSA):

■ quality of the co-ordination (threshold score: 3);
The total score for an SSA could be a maximum of 25 with threshold 17.5.
Evaluation criteria in FP7
Evaluation criteria for Collaborative Projects (CPs)
■ Scientific and/or technological excellence (relevant to the topics addressed by the call) (threshold score: 3).
Under this criterion, the following aspects will be evaluated: soundness of concept and quality of objec-
tives; progress beyond the state of the art; and quality and effectiveness of the S/T methodology and
associated work plan. The relevance of a proposal is considered in relation to the topic(s) of the work
programme open in a given call, and to the objectives of a call. When a proposal is partially relevant
Table 2: Quality of funded projects in the Fundamental Genomics area: an overview of the average total scores of the funded projects

Average normalised
Range of total score
Funding instrument score in funded
in funded projects
projects*
)0 p p
.O% p p
342%0ĺINCLUDINGĺ3-% 342%0 p p
#! p p
33! p p
Genomics and Systems Biology Research -FP7 (2007–2013) (first call)
#0 )0 p
p
* The total score is divided by the number of the criteria per funding instrument, in order to have a normalised score
comparison between different types of projects.
** The number of criteria has been reduced to 3 in FP7, and hence the maximum score is 15.

because it only marginally addresses the topic(s) of the call, or if only part of the proposal addresses the
topic(s), this condition is reflected in the scoring of the first criterion.
■ Quality and efficiency of the implementation and the management (threshold score: 3). under this criterion
the following aspects will be evaluated: appropriateness of the management structure and procedures;
quality and relevant experience of the individual participants; quality of the consortium as a whole (includ-
ing complementarity and balance); and appropriateness of the allocation and justification of the resources
to be committed (budget, staff, equipment).
■ Potential impact through the development, dissemination and use of project results (threshold score: 3). Under
this criterion, the following aspects will be evaluated: contribution, at European and/or international level, to
the expected impacts listed in the work programme under relevant topic/activity; appropriateness of measures
for the dissemination and/or exploitation of project results, and management of intellectual property.
Impact is considered in relation to the expected impact listed in the work programme. The total score for a CP
could be a maximum of 15 with threshold 10.
Table 3: Number of proposals evaluated, proposals funded and success rates in all the calls for proposals in FP6
in the Fundamental Genomics activity area, including the first call of FP7

Number of Number of Average
Call* proposals proposals percentage of
evaluated funded success rate**
&IRSTĺCALLĺAPPLICATIONSĺ

DEADLINEĺ
3ECONDĺCALLĺAPPLICATIONSĺ

DEADLINEĺ
4HIRDĺCALLĺAPPLICATIONSĺ

DEADLINEĺ
&OURTHĺCALLĺAPPLICATIONSĺ

DEADLINEĺ
All FP6 calls
&IRSTĺCALLĺAPPLICATIONSĺ

DEADLINEĺ
* Four calls for proposals with an overall budget of `594 million were open in the Fundamental Genomics programme
in FP6 during 2002 and 2005. Some 441 proposals were evaluated and 127 projects were selected for funding, with
an overall average success rate of 29%.
** The average success rate represents the success rate for all types of funding instruments. If we would calculate the
success rate, separately for IPs/NoEs, STREPs/CAs and SSAs, which had different budget allocations, one would
note a variation on the success rate. The average percentage per call is calculated by dividing the total number of
proposals funded in all funding instruments by the total number of proposals evaluated.
*** In FP7, the success rate generally concerns the large IPs for the first call. On the whole, the average success rate for the
Health theme ranges from 15% to 17% and could vary considerably in some areas, in relation to the higher number
of applications received.

Annex VI
Basic facts and figures for
the Fundamental Genomics activity area
Table 4: Number of funded proposals per funding instrument and total budget allocated per funding instrument
Total EC Percentage
Funding Number of financial budget spent/
instrument funded projects contribution type of funding
(million `) instrument
)0
.O%
342%0ĺINCLUDINGĺ

3-% 342%0
3-% 342%0ĺONLY
#!
33!
Total FP6 130 594.1 100

#0 )0

Table 5: Average funding level, average number of partners and average duration per funding instrument,
in FP6 in the Fundamental Genomics activity area, including the first call of FP7
Average EC Average
Average duration
Funding contribution* number of
(months)/
instrument (million `/ partners**/
instrument
instrument) instrument
)0 ĺp ĺp ĺMAJORITYĺ
ĺMAJORITYĺĺWITHĺONEĺ
.O% ĺp
LASTINGĺ
342%0ĺINCLUDINGĺ
ĺp ĺp ĺMAJORITYĺ
3-% 342%0
3-% 342%0ĺONLY
#! ĺp ĺp
33! ĺp ĺp

#0 )0
* The budget is indicative and is calculated based on the maximum EC contribution at the start of the project; it does not
relate to the final spent by the project for projects not finalised.
** A partner is an independent legal entity, which might include several independent scientific groups belonging to the same
legal entity; partners (independent legal entities) are calculated based on information including amendments of the FP6
projects until the end of 2007.

Table 6: Distribution of partners and percentage of EC contribution per activity type of partner
Percentage EC
Activity type of Number partners/
contribution/activity
partners* activity type of partners
type of partners
(%
2%3
).$ĺ
/4(
3-%

4OTAL
* HES: higher education; RES: research institutes; IND: industry; OTH: other (for example, international organisations).
The number of partners has been calculated based on information which includes amendments of the FP6 projects until
the end of 2007. Figures do not include calculation of inclusion or termination of partners — with these included,
numbers may vary.
** The total EC contribution allocated to SMEs in the fundamental genomics area constitutes approximately 7% of the total
EC contribution during FP6 (2002–2006), with an allocated budget of more than `40 million; SME participation
constitutes 84% of the number of industrial activity partners.

Table 7: Distribution of partners and percentage of EC contribution among different groups of countries
Percentage EC
Number of partners/
Countries contribution/country
country group
group
EU-25*
(New Member States)
Candidate countries**
Associated countries
Third countries***
4OTAL
* During FP6, the EU comprised 25 Member States; Bulgaria and Romania became Member States in 2007.
The new Member States (from May 2004) are the Czech Republic, Estonia, Cyprus, Latvia, Lithuania, Hungary, Malta,
Poland, Slovenia, Slovakia.
The associated countries are Switzerland, Israel, Iceland, Norway, and Lichtenstein
** Candidate countries for accession in EU during FP6 were Bulgaria, Romania, Croatia and Turkey; Bulgaria and Roma-
nia were candidate countries and are therefore included in this group in the FP6 statistics for the Fundamental Genomics
programme.
*** Third countries. The FP6 programme was open for participation to the International Cooperation target group countries,
which may be found in the relevant FP6 work programmes Annexes. Other third countries, for example industrialised
countries like the US, Canada, Australia and Japan may participate on a case-to-case basis if during the evaluation their
participation is considered essential for implementing the objectives of the respective project; generally speaking, in FP6 the
industrialised countries did not receive EC contributions.
Table 8: Distribution of non-EU-25 partners in FP6 Fundamental Genomics projects

Candidate countries Associated countries Third countries
Bulgaria (1) )CELANDĺ !RGENTINAĺ
Croatia (2) )SRAELĺ Australia (2)
Turkey (1) .ORWAYĺ Canada (5)
3WITZERLANDĺ China (1)
Gambia (1)
Japan (1)
Lebanon (1)
Russia (4)
South Africa (2)
Tunisia (2)
US (5)
4OTALĺ 4OTALĺ 4OTALĺ

1. TOOLS AND
TECHNOLOGIES FOR
FUNCTIONAL GENOMICS
1.1
TOOLS & TECHNOLOGIES
FOR GENE EXPRESSION
MolTools
REGULATORY GENOMICS
Tat machine
TransCode
EMERALD
AutoScreen
TargetHerpes
FGENTCARD
MODEST
MolTools
www.moltools.org
Project Type: State-of-the-Art:

Integrated Project
Contract number: The recording of complete genome sequences now for the first time, provides opportunities to
characterise comprehensively the flow of information from genetic variation at the DNA level,
LSHG-CT-2003-503155
over messages expressed as RNA and to their protein products, and to functions of the cell.
Starting date: By eavesdropping on these processes, it will be possible to identify genetic variations underly-
1st January 2004 ing malignancy, diabetes and other common diseases, and to monitor and ultimately explain
Duration: molecular processes involved in these and other important conditions.
42 months
EC Funding: Recent years have seen rapid growth of techniques for high-throughput analyses of genes,
transcripts, proteins and cells using microarrays, but current methods still capture only a small
`9 000 000
fraction of the information embodied in the molecules. This project brings together leading
European laboratories and one American lab involved in the development of molecular tools,
to study the molecules that make up our genomes and all their products. Our purpose is to
build an infrastructure to develop a next-generation toolbox for large-scale molecular analy-
ses. The suite of microarray-based technologies developed in the course of this project will
be of strategic value throughout biological research, and for the biotech and pharmaceutical
industries. Gradually the techniques should also become available to clinical medicine to
guide diagnosis and therapy, and in agriculture and environmental monitoring.
Scientific/Technological Objectives:
A series of interrelated research problems are being dealt with in collaboration between
partners in academia and in biotechnology companies. The partners provide the comple-
mentary expertise required to establish an individualised genome analysis technology by
achieving the following objectives:
sDEVELOP EVOLVE AND APPLY METHODS FOR $.! ANALYSIS FOR SEQUENCING GENOTYPING
and haplotyping, and the elucidation of duplications
sESTABLISHMETHODSFORHIGH SENSITIVITYHIGH THROUGHPUTANDLOW COSTGENEEXPRESSION
profiling
sESTABLISH TECHNOLOGIES FOR HIGHLY SPECIlC PROTEIN ANALYSIS IN A MANNER THAT CAN BE
read out on microarrays
sDEVELOPAFAMILYOFTECHNIQUESTHATWILLENABLEULTRA SENSITIVEANALYSESOFPROTEINSAND
nucleic acids in the complexity of biological samples
sENABLE PARALLEL ANALYSES OF THE FUNCTIONAL CONSEQUENCES OF A VARIETY OF MOLECULAR
alterations in cells by establishing technologies for cell array studies.
Expected Results:
The ambitious plan for the MolTools project is to have developed, by 2007, a next-gen-
eration toolbox for large-scale molecular analyses on arrays and in cells, with the ability
to detect even single molecules. The tools will increase throughput and decrease costs for
analyses of genomes, transcriptomes, proteomes and functional cells. Important progress
towards these goals has been made during the course of the project.
Regarding the development of techniques for single-molecule detection and for the analy-
sis of single cells, Uppsala and Aarhus Universities, in a joint project, have developed

Advanced Molecular Tools
for Array-Based Analyses of Genomes,
An image of serum analyses on

arrays made of 700 antibodies
a method for in situ genotyping, visualising single nucleotide allelic variations in single
molecules, directly in cells and tissues, using a combination of padlock probes and rolling
circle replication. An article was published in Nature Methods on how the technology was
applied to genotyping mitochondria in individual cells. Since then, the technology has been
further refined and now permits analysis of nuclear single-copy genes in fixed cell prepara-
tions. The Uppsala lab has published a paper describing a related technology that allows
individual and interacting pairs of protein molecules to be detected in cells.
Progress has also been made on working towards

establishing methods for high-sensitivity, high-
throughput and low-cost gene expression profiling.
Very often the molecular characterisation of clini-
cal samples is complicated and limited due to the
available amount of samples. During the MolTools
project, the so-called TAcKLE technique has been de-
veloped at DKFZ. This method generates amplified, In situ genotyping single-nucle-
antisense-orientated fluorescent representations of otide variation in single mito-
initial mRNA for the sensitive parallel detection of chondrial genomes. Larsson et al.
transcripts on oligonucleotide arrays.. Nature Meth., 1. 227-232 2004
Potential Impact:
The MolTools project brings together some of Europe’s leading groups developing technolo-
gies for molecular medicine to overcome fragmentation, create synergy and speed up the
development process. The high-throughput, high-precision technologies established in this
programme are expected to be of decisive importance in many forms of molecular biologi-
cal research, and the programme can therefore provide leverage in academic research,
increasing competitiveness in the European Research Area in a global context. The project
also addresses one of Europe’s main challenges in biotechnology: translating technological
innovations into commercially successful products, thereby increasing competitiveness of
the European biotech industry.

MolTools
MolTools participants have strong

records of developing techniques,
which are now used by companies
such as Affymetrix, Agilent, Ap-
plied Biosystems, GE Healthcare,
BiopsyTec, Biotage, Bruker Dal-
tonics, DynaMetrix, Epigenomics,
GPC-Biotech, Hybaid, Integragen,
Lynx, Micro Discovery, Molecular
Staging, Mosaic Technologies,
PEPperPRINT, Prot@gen, PSF AG
and Scienion. By strengthening
the interactions between research
groups in this consortium, we
hope to provide a critical mass
that will stimulate the transfer of
inventions from academia to es-
tablished industries, and that will
also promote the establishment
of new companies. During the
course of MolTools, one new com-
pany, Olink, has been established
in Sweden and another will soon
The MolTools be founded in Denmark.
consortium at the
2004 annual meeting
in Berlin, Germany
Keywords: genomics, proteomics, diagnostics

Advanced Molecular Tools for Array-Based Analyses of Genomes,
Partners
Project Coordinator: Dr. Michael Taussig
Prof. Ulf Landegren The Babraham Institute
Uppsala University Technology Research Group
Department of Genetics and Pathology Cambridge, UK
Dag Hammarskjoldsvag 20
P. O. Box 256 Prof. Arvydas Janulaitis
75185 Uppsala, Sweden Fermentas UAB
ulf.landegren@genpat.uu.se Vilnius, Lithuania
Project Manager: Dr. Ove Ohman

Dr. Carolina Rydin Amic AB
Uppsala University Uppsala, Sweden
Department of Genetics and Pathology
75185 Uppsala, Sweden Prof. Anthony Brookes
molecular.medicine@genpat.uu.se University of Leicester
Department of Genetics
Prof. Delores Cahill Leicester, UK
University College of Dublin in Ireland
Centre for Genomics and Bioinformatics Prof. Marc Zabeau
Dublin, Ireland Methexis Genomics
Ghent, Belgium
Prof. Ivo Gut
Centre National de Génotypage Dr. Michael Dahms
Evry, France Febit AG
Technology Department
Dr. Jorg Hoheisel Mannheim, Germany
Deutsches Krebsforschungszentrum
Functional Genome Analysis
Heidelberg, Germany
Prof. Olli Kallioniemi

VTT Technical Research Centre of Finland
Medical Biotechnology
Turku, Finland
Dr. Jorn Koch

University of Aarhus
Institute of Pathology
Aarhus, Denmark
Prof. Hans Lehrach

Max-Planck-Institute for Molecular Genetics
Dept of Vertebrate Genomics
Berlin, Germany
Prof. Andres Metspalu

Estonian Biocentre
Laboratory of Gene Technology
Tartu, Estonia
Prof. Edwin Southern

Oxford Gene Technology (Operations) Ltd
Oxford, UK

REGULATORY GENOMICS
http://research.med.helsinki.fi/regulatorygenomics

Specific Targeted
Research Project Determination of the sequence of the human genome, and knowledge of the genetic code
through which mRNA is translated have allowed rapid progress in the identification of
Contract number:
mammalian proteins. However, less is known about the molecular mechanisms that control
LSHG-CT-2004-512142 expression of human genes, and about the variations in gene expression that underlie many
Starting date: pathological states, including cancer. This is caused, in part, by lack of information about
1st September 2004 the second genetic code – binding specificities of transcription factors (TFs). Deciphering
Duration: this regulatory code is critical for cancer research, as little is known about the mechanisms
48 months by which the known genetic defects induce the transcriptional programmes that control cell
proliferation, survival and angiogenesis. In addition, changes in binding of transcription
EC Funding:
factors caused by single nucleotide polymorphisms (SNPs) are likely to be a major factor in
`2 200 000 many quantitative trait conditions, including familial predisposition to cancer.
We aim to develop novel genomics tools and methods for the determination of transcription
factor binding specificity. These tools will be used for the identification of regulatory SNPs
that predispose to colorectal cancer, and for characterisation of downstream target genes
that are common to multiple oncogenic TFs.
The specific aims are:
1. to develop novel high-throughput multiwell-plate and DNA chip-based methods for
determination of TF binding specificity
2. to determine experimentally the binding specificities of known cancer-associated TFs
3. to predict computationally, and to verify experimentally, elements that are regulated
by these TFs in genes that are essential for cell proliferation
4. to develop an SNP genotyping chip composed of SNPs that affect the function of TF-
binding sites conserved in mammalian species
5. to use this chip for the genotyping of patients with hereditary cancer predisposition,
as well as controls in three European populations, for identification of regulatory
SNPs associated with cancer.
Expected results
This project aims to understand the basic principles involved in growth regulation by on-
cogenic TFs, and is expected to have a major impact on understanding cancer. Identifi-
cation of SNPs associated with low penetrance cancer predisposition would be a major
breakthrough in the effort to understand inheritance of quantitative trait loci, and will have
implications on healthcare at the population level.
The methods developed within the project¹ have already allowed genome-scale prediction
of regulatory elements in the human genome, and the methods developed should make
feasible the analysis of DNA-binding specificities of all TFs, and consequently significantly
improve our understanding of the regulation of gene expression.
¹ Hallikas O, Palin K, Sinjushina N, Rautiainen R, Partanen J, Ukkonen E and Taipale J: Genome-wide Prediction of Mammalian
Enhancers Based on Analysis of Transcription Factor Binding Affinity. Cell. 124:47-59, 2006.

Advanced Genomics Instruments,
Technology and Methods for Determination
of Transcription Factor Binding Specificities:
Applications for Identification of Genes
Predisposing to Colorectal Cancer
Potential impact
We expect that the project will lead to the identification of genes that associate with color-
ectal cancer. This will have direct implications on diagnosis and treatment of a cancer type
that affects more than 200 000 Europeans each year.
Methods, tools and instrumentation for advanced genomics developed within the proposed
project will improve EU scientific competitiveness in the rapidly developing field of regula-
tory genomics, and will allow EU scientists to be in a very good starting position to decipher
the genetic code controlling regulation of gene expression.
Keywords:
genomics, molecular genetics, cancer, transcription factors
Partners
Project Coordinator:
Prof. Jussi Taipale
University of Helsinki
Faculty of Medicine
Genome-Scale Biology Research Programme
Yliopistonkatu 4
00014 Helsinki, Finland
jussi.taipale@helsinki.fi
Dr. Jörg Hoheisel

Functional genome Analysis
Heidelberg, Germany
Dr. Markus Beier

Febit Biotech GmbH
Heidelberg, Germany
Prof. Torben Ørntoft

Aarhus University Hospital, Skejby Sygehus
Molecular Diagnostic Laboratory
Department of Clinical Biochemistry
Aarhus N, Denmark
Prof. Jan Lubinski

Pomeranian Medical University
International Hereditary Cancer Center
Szczecin, Poland

Tat machine
www.tatmachine.net
State-of-the-Art:
Project Type: Bacterial protein secretion is a fundamental biological process that is of the utmost relevance
Specific Targeted to human health. On the one hand, it can be exploited to enhance health through the bio-
Research Project technological production of biopharmaceuticals. On the other hand, secreted bacterial toxins
and virulence factors represent a major threat to health. The twin-arginine translocation (Tat)
Contract number: machinery represents a recently discovered, but highly conserved, system for bacterial protein
LSHG-CT-2004-005257 secretion. This multi-sub-unit nanomachine can transport fully folded proteins, and thus has im-
Starting date: mense potential for biopharmaceutical production in the bacterial species already being used
1st November 2004 for this purpose, including "ACILLUS, %SCHERICHIA coli and 3TREPTOMYCES. Moreover, it has been
demonstrated that critical virulence factors are secreted via Tat in important pathogens, such as
Duration: 0SEUDOMONASĺAERUGINOSA and E. coli O157.
48 months
EC Funding:
`2 000 000
The goal of the multidisciplinary Tat machine consortium is to carry out the functional ge-
nomic characterisation of the Tat nanomachine, for both biotechnological and biomedical
purposes. It has two specific objectives: firstly, to eliminate the current bottlenecks in the Tat
nanomachine that limit biopharmaceutical production in "ACILLUS, %ĺCOLI and 3TREPTOMYCES,
and secondly, to characterise the structure and function of Tat nanomachines in a few selected
Gram-positive and Gram-negative bacteria, including major pathogens. To achieve these
goals, the full potential of bioinformatics, comparative and structural genomics and proteom-
ics will be exploited. The Tat machine consortium has a proven track record in the application
of these cutting-edge technologies.
The consortium’s principal technological objective is to generate a platform for the secretion
of a wide range of heterologous proteins, in particular those of therapeutic value, based on
the Tat machinery. Its principal scientific objective is to obtain a clear picture of the ‘global’
role of Tat in a range of pathogenic and non-pathogenic organisms, and to obtain detailed
information on the Tat structure that will lay the foundations for the future design of specific
inhibitors. It is already clear that the Tat system is vital to the pathogenesis of a range of
bacteria. Some bacteria export major virulence factors by this pathway, and disruption of the
Tat pathway impairs the viability of others. Because Tat sub-units are also unique in structural
terms, and completely absent from mammals, the Tat machine represents a superb target for
novel anti-infectives.
Expected Results:
The consortium aims to produce the following results: (1) A detailed structure of Tat complexes
from representative Gram-negative and Gram-positive species. This is an ambitious target.
The project is geared to the efficient delivery of a wide range of Tat complexes, to partners
with track records in the elucidation of membrane protein structures; (2) Development of super-
secreting strains of B. subtilis and S. coelicolor that are capable of exporting heterologous
proteins with high efficiency. These strains will fill major gaps in the present repertoire of bac-
terial vehicles for protein production; (3) Understanding of the overall role of Tat in a limited
series of pathogenic bacteria, including identification of specific virulence determinants that
employ this export pathway; (4) In-depth understanding of the Tat translocation mechanism.
This will be achieved through a combined biochemical/genetic analysis of the Tat transloca-
tion process, and the results will benefit all the elements of this project, mentioned above.
Potential Impact:
The expected deliverables of the Tat machine project include knowledge of a fundamental
biological system, the Tat nanomachine, which is of vital relevance to human health. The

Functional genomic characterisation of the
bacterial Tat complex as a nanomachine
for biopharmaceutical production and a
target for novel anti-infectives
results will serve to reinforce efforts to design anti-infectives and to produce novel biophar-
maceuticals. In addition, the consortium will add to the stock of highly trained young Euro-
pean scientists working in this area, and will disseminate knowledge via scientific books
and journals, scientific meetings and practical training courses. These deliverables will be
achieved through multidisciplinary research involving biochemistry, proteomics, functional
genomics, structural genomics and comparative genomics approaches, in combination with
robust project management.
Keywords: anti-infectives, biopharmaceuticals, human health, nanomachines,

twin-arginine translocation, Bacillus, E. coli, Staphylococcus, Spe-
cific Targeted, Research Projecttomyces, Mycobacterium, bioinfor-
matics, structural genomics, drug targets
Partners
Project Coordinator: Dr. Long-Fei Wu
Prof. Jan Maarten van Dijl Centre National de la Recherche Scientifique (CNRS)
University Medical Center Groningen Laboratoire de Chimie Bacterienne UPR 9043
Department of Medical Microbiology Marseille, France
Hanzeplein 1
P. O. Box 30001 Prof. Michael Hecker
9700 RB Groningen, The Netherlands Ernst-Moritz-Arndt-Universität
j.m.van.dijl@med.umcg.nl Institute for Microbiology and Molecular Biology
Greifswald, Germany
Project Manager:
Dr. Sierd Bron Prof. Werner Kühlbrandt
University of Groningen and Max-Planck-Institute for Biophysics
University Medical Center Groningen Structural Biology
Kerklaan 30 Frankfurt, Germany
9751 NN Haren, The Netherlands
s.bron@rug.nl Prof. So Iwata
Imperial College of Science
Prof. Colin Robinson Centre for Structural Biology
University of Warwick Division of Molecular Biosciences
Department of Biological Sciences London, UK
Coventry, UK
Prof. Roland Freudl
Prof. Oscar Kuipers Jülich Research Institute
University of Groningen Jülich, Germany
Groningen Biomolecular Sciences and
Biotechnology Institute
Molecular Genetics
Groningen, The Netherlands
Prof. Marc Kolkman

Genencor International
Microbial and Molecular Screening
Leiden, The Netherlands
Prof. Matthias Müller

Universität Freiburg
Institute for Biochemistry and Molecular Biology
Freiburg, Germany
Dr. Tracy Palmer

University of Dundee
College of Life Sciences
Division of Molecular & Environmental Microbiology
Dundee, UK

TransCode
http://transcode.tigem.it/
State-of-the-Art:
Project Type: The aim of this project is to develop open source tools enabling the identification of regula-
Specific Targeted tory elements controlling gene expression. In particular it is focused on elements which con-
Research Project trol the expression of transcription factors, which in turn control expression of all other genes
Contract number: in the genome. This field has undergone a rapid expansion since the sequencing of several
chordate genomes, which enabled researchers to identify elements through the discipline
LSHG-CT-2004-511990 of comparative genomics, i.e. a comparison of sequenced genomes in search of conserved
Starting date: elements, which are likely to harbour functional elements. The great challenge is identifying
1st January 2005 effectively the elements that do not encode well-understood protein-coding genes but tend
Duration: to act as regulators of expression. Recent advances have identified several such elements
but they are likely to be the tip of the iceberg. TransCode aims to unravel many more such
39 months
elements as well as some of the fundamental properties that characterise them.
EC Funding:
`1 000 000
The project aims to perform medium-scale studies on conserved non-coding elements across
several chordate organisms, as well as tackling fundamental questions related to transcription
factor binding. The project will study a dozen transcription factor gene families and investi-
gate in-depth for the presence of regulatory elements within the family across organisms. The
following analyses will be performed on each gene family:
s IDENTIlCATION OF CONSERVED SEQUENCE ELEMENTS VIA A @GLOBAL LOCAL APPROACH WHICH
aims to identify elements which have remained conserved in position within a phylum
and elements that have ‘shuffled’, i.e. changed position during evolution, when com-
paring sequences across different phyla
s PREDICTIONOFREGULATORYANDTRANSCRIPTIONPOTENTIALOFCONSERVEDELEMENTSBYIMPROV-
ing current algorithms with knowledge derived from the project
s LARGE SCALEVERIlCATIONOFENHANCERACTIVITYBYCO INJECTIONINZEBRAlSHEMBRYOS
s medium-scale verification of activity in mammalian cell-lines as well as Ciona embryos
s MEDIUM SCALEVERIlCATIONOFSELECTEDELEMENTSIN%3CELLSPERFORMINGDIVERSE%3DIF-
ferentiation assays and knock-out of transcription factors (TFs) in differentiated cells, to
identify TFs involved in enhancer activity
s SMALL SCALEVERIlCATIONOFSELECTEDELEMENTSUSINGSTABLETRANSGENICMICE
s DEVELOPMENTOFAPUBLICLYAVAILABLERESOURCEPROVIDINGALLDATAOBTAINEDin silico, in
vitro and in vivo
s ANALYSISOF$.!BINDINGAFlNITYFORASELECTEDNUMBEROFTRANSCRIPTIONFACTORS
s DEVELOPMENTOFNOVELALGORITHMSRESULTINGFROMDATAOBTAINEDASABOVE
This project represents a large-scale pluri-disciplinary effort to decipher the grammar of chor-
date regulatory sequences, and will have a strong impact by building tools and resources that
will enable devising more sophisticated hypothesis regarding regulatory networks, especially
those of TFs which are involved in fundamental biological processes.
Expected Results:
The project has completed its first year and has successfully completed the in silico analysis
of selected transcription factor gene families, as well as the development of a central reposi-
tory for both in silico and in vivo data that is being collected. The repository is available at
the website (http://transcode.tigem.it/). It collates the in silico analyses so far performed,
which indicate the sequence elements predicted to have functional potential based on pub-
lished algorithms, as well as algorithms developed by project members. Some elements
have undergone testing and for those tested in vivo results are also integrated, indicating
those which have acted as enhancers or repressors and those which have yielded no results.

Novel Tool for High-Throughput
Characterisation of Genomic Elements
Regulating Gene Expression in Chordates
In the long term, the project
aims to collate this data on a
larger scale and with more
in-depth information regard-
ing the transcription factors
responsible for the function of
each element and their mode
of action and interactions.
Potential
Impact:
Throughout our project we are contributing widely to the creation, refinement and good use
of standards. We are using open source software and XML data transfers, and generating
novel tools and experimental protocols that will set new standards in both dry and wet
areas of biology, which will help others to explore further the language of gene regulation.
The identification of regulatory modules that are responsible for well-defined expression
patterns will be very useful in gene therapy, thus having a direct impact on health issues.
Finally we are reinforcing European competitiveness by carrying out a transnational and
co-operative project of international visibility via a tight collaboration of partners across
four European countries.
Keywords: comparative genomics, conserved non-genic sequences,

bioinformatics algorithms, gene expression regulation
Partners
Dr. Sandro Banfi
Fondazione Telethon
Telethon Institute of Genetics and Medicine
Molecular Biology Unit
Via G. Saliceto, 50
00161 Rome, Italy
banfi@tigem.it
Dr. Patrick Lemaire

Université de la Méditerranée
Centre National de la Recherche Prof. Graziano Pesole
Scientifique (CNRS) Università di Milano
Marseille, France Dipartimento di Scienze
Biomolecolari e
Dr. Cristian Brocchieri Biotecnologie
University of Cambridge Milan, Italy
Department of Oncology
Cambridge, UK Dr. Elia Stupka
CBM Scrl – Consorzio
Dr. Ferenc Muller per il Centro di
Forschungszentrum Karlsruhe Biomedicina Molecolare
Institute of Toxicology and Genetics Bioinformatic Unit
Eggenstein-Leopoldshafen, Germany Trieste, Italy

EMERALD
State-of-the-Art:
Project Type: Data quality and meta-data (documentation) are the key to all microarray implementations,
Co-ordination Action ensuring that maximum information is extracted from the data. The microarray community
Contract number: has long realised the importance of structured documentation accompanying microarray
LSHG-CT-2006-037689 data. To this end, a ‘grassroots movement‘, now the Microarray Gene Expression Data
(MGED) Society, established guidelines for experimental description (Minimum Information
Starting date: About a Microarray Experiment, MIAME) and description of a structured data exchange
1st November 2006 model (Microarray Gene Expression Markup Language, MAGE-ML). MGED initiatives have
Duration: mainly focused on data context, and only recently has this focus expanded to include data
36 months content. Quality and coherence of microarray data compendia (for example in ArrayEx-
EC Funding: press) are major determinants of information extraction and model-building. EMERALD is
designed to structure and organise these efforts at a European level, in close association
`1 300 000 with MGED and the External RNA Controls Consortium (ERCC).
The EMERALD consortium aims to establish and disseminate quality metrics (QC), micro-
array standards and best laboratory practices (QA) throughout the European microarray
community, in order to improve the quality of microarray data.
Its specific objectives are as follows:
1. To investigate existing microarray data resources in ArrayExpress, preparing
a full inventory of these and deriving fair and meaningful QC from them;
2. To develop a normalisation and transformation ontology for the description of
data pre-processing information;
3. To bring together all major players in the European microarray community;
4. To structure communication and information exchange within this community;
5. To obtain microarray community agreement on QA;
6. To assess microarray standards for QC. An analysis of QC relevant to vari-
ous data production protocols and available hybridisation standards (spikes,
reference RNAs) will in turn facilitate the development of QA for high data
quality;
7. Key microarray laboratory volunteers to validate QA/QC;
8. To validate the benefits of QA/QC in data compendium modelling;
9. To disseminate microarray standards and best practices to the microarray
community, through a user community website and information exchange and
support networks, and to provide training in their proper implementation;
10. To extrapolate and apply these standards to developing technologies.
Intensity representation on an
Affymetrix array (spatial plot).
The false colours represent the Expected Results:
spatial intensity distribution
of the array. The colour scale The main result of EMERALD will be a quality metrics system for microarray data, accompanied
by ontologies for documentation of microarray meta-data. The project will also generate hy-
was chosen proportional to the
bridisation standards and, in general, integrate European efforts towards laboratory standard-
intensity ranks. This graphical
isation in this area. Recent scientific publications have shown that microarray data produced
representation highlights
under a series of standardisation constraints show improved significance and sensitivity.
problems that result from EMERALD will bring together the main research and innovation operators involved in the devel-
the experimentation such as opment of microarray standards and quality metrics, with stakeholders in the data production
fingerprints, artifactual intensity process (core facilities, companies, technology innovators), data mining (computational and
gradient or dye specific failures systems biology research teams) and data information (toxicology, clinical diagnostics, prog-
for instance. nostics, etc). The coordination and amalgamation of the activities and interests of these diverse
stakeholders will strengthen the European microarray community, consolidating an essential
component of data-driven systems biology.

Empowering the Microarray-Based
European Research Area to Take
a Lead in Development and Exploitation
Potential Impact:
Data-driven modelling approaches that depend on data quality and coherence are es-
sential to systems biology. EMERALD aims to bring about the implementation of QA/QC,
especially in the building of high quality, compendium-style data repositories. The Seventh
Framework Programme (FP7) is expected to place an emphasis on the development of new
biological research tools that will significantly improve the acquisition and analysis of data,
with a view to enhancing our understanding of complex biological systems. FP7 research
will include the development of technologies related to sequencing, gene expression, geno-
typing and systems biology. EMERALD will contribute to these research goals by improving
large scale data gathering.
Keywords: microarray technology, quality control, quality assurance, systems

biology, data modelling, technology development
Partners
Project Coordinator: Dr. Laszlo Puskas
Prof. Martin Kuiper Biological Research Centre of
Ghent University/Flanders Interuniversity Institute the Hungarian Academy of Sciences
for Biotechnology Laboratory for Functional Genomics
Department of Plant Systems Biology Szeged, Hungary
Computational Biology group
Ghent, Belgium Prof. Ulf Landegren
martin.kuiper@psb.ugent.be Uppsala University
Prof. Arne Sandvik Rudbeck Laboratory
Norwegian University of Science and Technology Uppsala, Sweden.
Norwegian Microarray Consortium
Trondheim, Norway
Dr. Alvis Brazma

European Molecular Biology Laboratory
European Bioinformatics Institute (EBI)
Hinxton, UK
Dr. Carole Foy

Microarray Standardisation LGC Ltd
Teddington, UK
Prof. Joaquin Dopazo

Centro de Investigación Príncipe Felipe
Department of Bioinformatics
Valencia, Spain
Dr. Heinz Schimmel,

Joint Research Centre of the European Commission
Institute for Reference Materials and Measurements
Geel, Belgium

Autoscreen
State-of-the-Art:
Project Type: As more and more genomes are being sequenced, efficient methods to elucidate the func-
SME- Specific Targeted tions of the many unknown genes need to be developed. Such methods will be an essential
Research Project prerequisite for turning biology from a qualitative, mostly descriptive, to a quantitative,
ultimately predictive, science. Although quantitative tools such as DNA microarrays for
Contract number: transcriptome analysis have been available for some years, they have not yet been used to
LSHG-CT-2007-037897 their full potential due to the overwhelming complexity.
Starting date: Cells are built from thousands of different proteins that are expressed, both temporally and
1st January 2007 spatially, over an extremely wide dynamic range. Proteins and other cellular components
are regulated through variations of their location, their activity and their state of modifica-
Duration: tion. Although DNA microarrays have proved to be important tools for gene discovery on
60 months the tissue level, and, moreover, hold great promise for diagnostic applications, they have
EC Funding: major shortcomings in their lack of cellular resolution. In order to obtain qualitative and
quantitative data on cellular pathways, new equipment needs to be developed.
`3 217 280
The overall objective of the AUTOSCREEN project is the establishment of an innovative and
automated screening instrument for high-throughput and high-content screens. This instru-
ment will allow standardised, robust, automated and ultrasensitive high-resolution analysis
of RNAs and proteins at cellular and subcellular resolution.
The main goal of the project is to develop an innovative screening platform suitable for high-
throughput and high-content cell-based assays and to demonstrate its suitability for high-res-
olution in situ techniques. This instrument, named AUTOSCREEN, will not only provide the
basis for intelligent and efficient high-content screens, but will also be designed for low cost
genetic, medical, chemical and pharmaceutical screens. It will constitute a significant com-
petitive advantage for the European pharmaceutical and agro biotechnological industry.
Expected Results:
The main expected result of the project is the generation of an innovative screening instru-
ment, named AUTOSCREEN. This instrument, which will consist of the modular iMIC imag-
ing microscopy platform as a future microscopy standard, will integrate ultra-sensitive CCD-
technology and novel software concepts that allow an adaptive, i.e. result-based, shaping
of the ongoing experiment. An ultra-sensitive fluorescence-based scanning device for single-
molecule measurements and a fully automated plate feeder station for automated sample
handling and tracking will increase the flexibility and wide utility of AUTOSCREEN. This
system will be tested in a large number of applications for performance and excellence.
The project is expected to permit the qualitative and quantitative monitoring of cellular con-
stituents (RNA, proteins, and metabolites) in living cells at the highest possible cellular and
subcellular resolution and with maximal sensitivity and specificity. This will allow quantify-
ing protein expression and monitoring its subcellular localisation, its state of modification
and its association with other proteins and ligands. Furthermore, it will allow measuring of
the change of these processes over time.
Potential Impact:
AUTOSCREEN will have a strategic impact on functional genomic, biotechnological and bio-
medical research by permitting qualitative and quantitative monitoring of cellular constituents
in cells at the highest possible cellular and subcellular resolution and with maximal sensitivity
and specificity. This will allow, for example, quantifying protein expression, monitoring of sub-
cellular protein localisation and state of modification, and characterisation of the toponome.

Autoscreen
for Cell Based High-throughput
and High-content Gene Function Analysis
and Drug Discovery Screens
The demonstration of the wide applicability of AUTOSCREEN to the quantitative monitoring
of biological processes, within living cells, at highest currently possible resolution and with
sensitivity to the limit set by the laws of physics, will have a significant impact on biomedical
research in general. By combining interdisciplinary activities from academic and industrial
sources and by interfacing biological research with nanotechnology, computing and engi-
neering, the team expects to create an important tool for biomedical research. Moreover,
AUTOSCREEN-based assays will allow the monitoring of cellular networks and incorporate in
vivo protein interaction assays and features like protein concentration and kinetic parameters.
Thus, available information on gene expression networks will not only be useful for identifying
points of the network affected by the drugs and for simulations of cellular processes, but will
also allow the assessment of drug side reactions at an early stage and facilitate the design of
novel, less toxic compounds.
The project will reveal new, faster and better possibilities to determine gene functions and
regulatory networks in a much shorter period of time. The implementation of these technolo-
gies will lead to a higher competitiveness of European biomedical SMEs, in the sense that the
instrumentation to be developed and assembled in this project will enable many European
SMEs to efficiently perform their screens. The estimated low cost of this instrument is expected
to be of great benefit for SMEs as it will promote their market success.
Keywords: imaging, screening, genomics, proteomics, drug screening, high-

throughput technologies
Partners
Prof. Dr. Klaus Palme
University of Freiburg
Institute for Biology II
Faculty of Biology
Center for Applied Biosciences
Fahnenbergplatz
79085 Freiburg, Germany
klaus.palme@biologie.uni-freiburg.de
Dr. Stefanie Klemm

TILL ID GmbH
Gräfelfing, Germany
Dr. Martin Oheim
Dr. Andras Filep Institut National de la Santé
Manz Kft et de la Recherche Médicale
Debrecen, Hungary (INSERM)
Neurophysiology and
Dr. Alois Sonnleitner New Microscopies Laboratory
Upper Austrian Research GmbH Paris, France
Linz, Austria
Dr. Hartmann Harz
Dr. Colin Coates Ludwig-Maximilians-Universität
Andor Technology Plc BioImaging Zentrum
Belfast, UK Planegg, Germany
Dr. Carmen Plasencia Dr. Benedetto Ruperti

Aromics SL University of Padova
Barcelona, Spain Legnaro, Italy

TargetHerpes
www.targetherpes.org
State-of-the-Art:
Project Type: Herpes viruses cause many serious and life-threatening diseases, especially in immuno-
SME- Specific Targeted compromised patients, such as transplant recipients and HIV-infected individuals. Even in
Research Project healthy ones, herpesviruses can result in serious diseases. For example, the herpes simplex
Contract number: virus (HSV) remains one of the most common sexually transmitted diseases, while human
cytomegalovirus (HCMV) is a leading cause of birth defects, and human herpes virus 8
LSHG-CT-2006-037517 (HHV-8) causes a number of cancers. At present, the options for antiviral therapy are lim-
Starting date: ited, and owing to toxicity, the current anti-herpesvirus drugs cannot be administered to
1st January 2007 pregnant women. There is a continuing need to develop new treatments, because drug-
Duration: resistant viruses are constantly evolving.
36 months
A principal characteristic of herpesvirus infections, is that after primary infection (usually
EC Funding: in childhood), the viruses establish a latent state that remains for life. Up to 90 percent of
`2 351 818 the population may be latently infected with one or more herpes viruses. The social and
psychological consequences of the herpesvirus infections are severe.
The major objective of TargetHerpes is to define novel drug targets and to identify new
strategies, for the control of herpesvirus infections. These targets and strategies will help, in
the long term, to provide the next generation of antiviral compounds, Specifically, TargetH-
erpes will perform the following actions: (i) develop peptide inhibitors that interfere with
virus entry; (ii) generate synthetic peptides that enable antibody-dependent cellular cytolysis
against herpesviruses; (iii) define, investigate and apply RNA silencing reagents that block
the expression of viral genes that enhance herpesvirus replication; (iv) define, investigate
and apply RNA silencing reagents that interfere with proviral host genes; (v) identify viral
and cellular genes involved in herpesvirus-mediated oncogenesis, and define RNA silenc-
ing reagents and peptide inhibitors; and (vi) develop approaches to inhibit the reactivation
of HSV from latency.
This programme of work will provide innovative technologies for the identification and de-
velopment of future products targeted at preventive and therapeutic interventions for human
herpesvirus diseases. Moreover, these strategies will likely be transferable to many other
persistent infections.
Expected Results:
The TargetHerpes project is divided into six experimental work packages (WPs). The aim of
WP1 is the development of peptide molecules that will inhibit the functions of herpesvirus
glycoproteins and elucidate their roles in entry of the virus particles into cells. Preliminary
work has provided proof-of-principle that mimetic peptides to HSV gH inhibit infection.
Such peptides targeting HSV glycoproteins will be suitable for future animal experimenta-
tion and translational research by partners PRIMM and IBA. WP2 will generate synthetic
peptides that enable IgG antibodies to execute cell-mediated cytolysis against HSV and
HCMV. Such peptides will be evaluated for their individual potency in vitro, then bioac-
tive peptides will be evaluated with regard to safety and harmlessness to cells, as well as
optimal stability in cultured cell systems. WP3, WP4, WP5 and WP6 will identify suitable
molecular targets for antiviral intervention by RNAi.
These targets will include important herpes virus gene products that have known or sus-
pected roles in promoting viral replication directly or indirectly. In case of WP5, siRNAs
Molecular intervention strategies targeting
latent and lytic herpesvirus infections
targeted at viral genes will be selected based on their capacity to interfere with HHV-8 me-
diated cell transformation and immortalization. WP6 expects to identify the cellular interac-
tion partners of ICP0 (the viral protein that is necessary for HSV to reactivate from latency),
and to define those elements that are required for its activity.
Potential Impact:
TargetHerpes will identify novel strategies, leading to the development of new approaches
to inhibit replication of, or pathogenesis caused by, HSV, HCMV and HHV-8. Due to the
conservation of genes and replication strategies within herpesviruses, the approaches dis-
covered will be applicable to other human herpesviruses as well. For example, treatments
that target HSV-1 are highly likely to be effective against HSV-2 and may be adapted to
counteract varicella zoster virus (VZV). Similarly, treatments that are effective against HHV-8
may also be applicable to Epstein-Barr virus (EBV). Given the figures on the health burden
and costs of herpesvirus infections, the potential impact of a successful outcome of the Tar-
getHerpes project is considerable.
Keywords:
herpesvirus; chemiotherapeutics; herpes simplex virus; human cytomegalovirus; human her-
pesvirus 8; fusion; glycoproteins; siRNA; innate immunity; host response; IFN
Partners
Prof. Gabriella Campadelli-Fiume
University of Bologna
Centro Interdipartimentale Galvani (CIG)
via S. Giacomo 12
I-40126 Bologna, Italy
gabriella.campadelli@unibo.it
Dr. Michael Nevels
Dr. Roger Everett University of Regensburg
Medical Research Council Institute for Medical
Virology Unit Microbiology and Hygiene
Glasgow, UK Faculty of Medicine,
Molecular Virology Unit
Prof. Hartmut Hengel Regensburg, Germany
University of Duesseldorf
Institute for Virology Dr. Angela Pontillo
Düsseldorf, Germany PRIMM Srl
Milan, Italy
Dr. Joachim Bertram
IBA GmbH Dr. Ivan Rossi
Göttingen, Germany BioDec Srl
Bologna, Italy
Dr. Frank Neipel
University of Erlangen Wolfgang Laepple-Boettiger
Institut fuer Klinische ARTTIC S.A.
und Molekulare Virologie Office Mannheim
Erlangen, Germany Schifferstadt, Germany
FGENTCARD
www.fgentcard.eu
State-of-the-Art:
Project Type: The general aim of FGENTCARD is to apply functional genomic and genotyping technolo-
SME-Specific Targeted gies along with the knowledge arising from mammalian genome annotations, in order to
Research Project define novel diagnostic tools for risk factors of Coronary Artery Disease (CAD) (glucose
Contract number: intolerance, insulin resistance, hypertension, dyslipidaemia and obesity). FGENTCARD,
supported by available functional genomic technologies, will tackle these increasingly fre-
LSHG-CT-2006-037683 quent and prevalent inherited diseases. The project will ultimately generate fundamental
Starting date: knowledge on the impact of functional genomics to identify disease biomarkers and test
1st January 2007 their use for disease prediction. The consortium is interested in focusing on CAD because
Duration: of its frequency and prevalence in the general population, the strong impact on human
36 months health and the burden of related healthcare costs. Pathological elements of CAD have been
shown to have complex etiology and pathogenesis that influence an individual’s relative
EC Funding: risk of developing these diseases. The genetic input is complex, and involves combinations
`3 000 000 of multiple genes that contribute to susceptibility or resistance to CAD risk factors. In order
to take advantage of high density multimodal phenotyping, the consortium is preparing an
innovative infrastructure of both the techniques and materials that provide strategic support
for CAD quantitative genetics in rodent models and humans.
One of the major objectives of the FGENTCARD is to identify biomarkers associated with
CAD risk factors, by means of network biology that can be used as disease prediction tools in
clinical studies and as targets for developing novel and more efficient drugs.
FGENTCARD is objective-driven research which develops along the following lines:
1) Characterization of CAD phenotypes, using classical physiological and biochemical
methods in a large cohort of patients and in animal models;
2) Generation of functional genomic quantitative trait datasets using plasma and urine
metabonomic profiling in animal models and humans, plasma proteomic profiling in
animal models and humans and tissue transcriptomic, proteomic and metabonomic
profiling in animal models;
3) Genetic studies which aim at testing the association between plasma biomarkers and
CAD risk factors in humans, at testing the inheritance of plasma, urine and organ
biomarkers in animal models and at identifying underlying gene variants in animal
models and humans.
Close interactions with external international groups investigating related disorders in other
models and human cohorts will provide resources for extension and validation of CAD biomar-
kers. In addition, interactions with other EC funded programmes of research, including MOL-
TOOLS and MOLPAGE, will maximize the scientific and technical outputs of FGENTCARD.
Expected Results:
The consortium plans to deliver the following specific results:
1) Multimodal phenotyping in a novel collection of 5,000 CAD patients, and in mouse
and rat models of spontaneous and experimentally-induced pathologies relevant to
CAD risk factors;
2) A series of integrated functional genomic datasets defining biomarkers associated
with CAD risk factors, through quantitative genetic studies in experimental crosses
derived from animal models and further genetic association and linkage studies in
humans;
3) CAD susceptibility loci and genes providing chromosomal targets for positional clon-
ing experiments and entry points to the development of novel drugs designed for
specific protein and metabolite disease biomarkers;
Functional GENomic diagnostic Tools
for Coronary Artery Disease
4) A set of standard operation procedures (SOPs) for the characterization of novel CAD
quantitative biomarkers, applicable to genetic and clinical studies in other cohorts of
patients and controls.
5) Data analysis using bioinformatics and statistical genetic tools developed in experi-
mental populations and human cohorts, which will further strengthen the impact of
comparative genomics in biomedical research.
Potential Impact:
FGENTCARD brings together a comprehensive set of specific expertise in functional ge-
nomic technologies (metabonomics, proteomics, transcriptomics), genotyping methods and
statistical genetics in rodent models and humans. This multidisciplinary approach is neces-
sary when undertaking an integrated functional genomic approach that addresses genetic
variation, in the context of CAD risk factors.
Overall, the potential wealth of information that can be obtained on gene expression, from
transcription to protein effects, is enormous. It represents novel challenges in quantitative
genetics, and ultimately, significant advances for disease diagnosis and prevention as well.
An important goal of this research in CAD patients and animal models lies in disease gene
identification. Knowledge of the effects of genetic variations on metabolic processes and
metabotype regulation will have a major impact in the field of polypharmacology, on the
development of novel drugs designed to affect multiple targets simultaneously.
Keywords: metabonomics, quantitative genetics, diagnostics, coronary artery,

cardiovascular disease
Partners
Dr. Dominique Gauguier Dr. Ulla Grove Sidelmann
University of Oxford NovoNordisk A/S
Wellcome Trust Centre Malov, Denmark
for Human Genetics
Roosevelt Drive Dr. Jorg Hager
Oxford, OX3 7BN, UK IntegraGen SA
gdomi@well.ox.ac.uk Evry, France
Prof. Mark Lathrop, Dr. Ivo G. Gut Dr. Frank Bonner

Centre National de Génotypage (CNG) Metabometrix Ltd
Evry, France London, UK
Prof. Jeremy K. Nicholson

Imperial College
Faculty of Medicine
Chemical and Molecular Systems Biology
London, UK
Dr. Pierre Zalloua

Lebanese American University
School of Medicine
Department of Internal Medicine
Beirut, Lebanon
MODEST
State-of-the-Art:
Project Type: The pharmaceutical industry is highly interested in using primary cells instead of cell lines
SME- Specific Targeted for cell-based screening campaigns in drug development since primary cells are freshly
Research Project isolated from the organism’s tissue, and have not gone through any transformations, which
Contract number: is the prerequisite for the unlimited growth of conventional cell lines. With more predictive
screens in terms of both the relevance of a target and the pharmaco-kinetics/-dynamics of a
LSHG-CT-2007-037291 drug compound, it becomes much easier to make adequate decisions as to which targets or
Starting date: compounds to focus on for further development. While conventional transfection methods,
1st April 2007 such as lipofection or electroporation, usually yield satisfactory results for standard cell lines,
Duration: many other cell lines — as well as most primary cells — are difficult or even impossible to
36 months transfect with these methods. Viral vectors - as an alternative for DNA delivery - work well
in some cases, but are labour-intensive, not versatile, and remain connected with significant
EC Funding: safety issues. As a consequence, most primary cells are considered non-transfectable. This
`2 755 356 represents a tremendous disadvantage in highly relevant research areas, as primary cells
are the ones that most closely resemble the situation of the living organism.
Besides the delivery of DNA, RNA or small molecules to primary cells, throughput of trans-
fection experiments is of extreme importance. The emerging RNA interference (RNAi) tech-
nology, continued growth of (drug) compound libraries, and the increasing number of po-
tential targets to be screened, have resulted in the high pressure to increase the throughput
of screening to higher formats, the so-called ultrahigh-throughput screening (uHTS). How-
ever, cell-based assays still use the 96- or occasionally the 384-well format and screening
of millions of compounds may take months instead of days.
The principle objective of the MODEST project is the development and use of an ultrahigh-
throughput device for nucleofection (uHTN device) as well as protocols for highly efficient,
small volume ultrahigh-throughput screenings of primary cells, mainly in the areas of immunol-
ogy, neurology and liver metastasis with the aim of accelerating basic research, target identi-
fication and validation as well as drug development.
These uHTN device will represent a major breakthrough, since it would allow high-throughput
screenings in efficiently transfected and differentiated networks of primary cells. In addition,
the concept of disposable modular multi-well plates for transfection is perfectly suited for pre-
plating substances, for storage and for later use, thus allowing flexible approaches, e.g. for
high-throughput screening campaigns.
Application of these tools is planned in order to investigate medically highly relevant disor-
ders. On the basis of the 96-well Nucleofector, which was launched by “amaxa” in 2006,
the Consortium will develop ultrahigh-throughput devices. In parallel, protocols for cultivating,
differentiation, nucleofection and functional screens of primary cells in very small volumes will
be elaborated on and, furthermore, adapted to the devices.
Development of automated cell Expected Results:

manipulation in the 384-well
Development of uHTS device is the main objective of this project. These devices will be dis-
format will add an important tool
tributed by the coordinator, “amaxa”. In order to efficiently commercialise this platform with-
for biomedical research and drug
in a well-balanced marketing and sales strategy, the coordinator will combine a top-notch
development.
sales force in key markets and alliances with quality strategic and distribution partners. The
commercialisation strategy aims to optimise short- and medium-term revenues, secure broad
market access and share, and provide crucial market feedback to the company.
Modular Devices for Ultrahigh-throughput
and Small-volume Transfection
The scientific knowledge of the MODEST project shall be published in premium peer-re-
viewed journals, and scientists involved in the project will present their data at national and
international conferences.
Potential Impact:
The partners of MODEST will employ the results of the project to service pharmaceutical
customers who repeatedly have expressed the urgent need for devices, protocols and as-
says for primary cells or differentiated human neuronal stem cells in target discovery and
validation. The results of the project will give the partners a clear competitive advantage.
The use of primary cells in preclinical R&D will positively impact attrition rates and reduce
the significant time and capital involved in drug development. The proximity to European
pharmaceutical research and the size of the international pharmaceutical research market
strengthen the logic for the creation and implementation of the MODEST project.
Keywords:
nucleofection, primary cells, hard-to-transfect cell lines, RNAi, siRNA, ultra high throughput
transfection, adult stem cells, neuronal cells, apoptosis, lead, gene silencing/knockdown,
screening
Partners
Dr. Birgit Nelsen-Salz
Amaxa AG
Nattermannallee 1
50935 Cologne, Germany
Birgit.nelsen-salz@amaxa.com
Dr. Alexander Scheffold

Deutsches Rheuma Forschungszentrum
Berlin, Germany
Dr. Joerg Poetzsch

RNAx GmbH
Berlin, Germany
Dr. Kaia Palm

Protobios Ltd.
Tallin, Estonia
Helmut Loibl
FOTEC Forschungs- und Technologietransfer GmbH
Wiener Neustadt, Austria
Josef Anton Pallanits

HTP High Tech Electronics GmbH
Neudoerfl, Austria
Dr. Naiara Telleria Thomas Schaumann

Dominion Pharmakine S. L. Prevas AB
Derio, Spain Västerås, Sweden
1.2
TOOLS & TECHNOLOGIES FOR
PROTEOMICS
INTERACTION PROTEOME
NEUPROCF
CAMP
ProDac
www.interaction-proteome.org
Project Type:
State-of-the-Art:
Integrated Project The main objective of the INTERACTION PROTEOME project is the establishment of a broad-
Contract number: ly applicable platform of routine methods for the analysis of protein interaction networks
in biomedical research. A multidisciplinary approach will address different aspects of the
LSHG-CT-2003-505520
generation of protein-interaction data, their validation by cell biological, biochemical and
Starting date: biophysical methods, their collection in a new type of public database and their exploitation
1st January 2004 and use for in silico simulations of protein-interaction networks.
Duration:
66 months These goals represent substantial state-of-the-art advances in these technologies. The innova-
tions generated in INTERACTION PROTEOME will thus provide the basis for an efficient
EC Funding: analysis and systems modelling of fundamental biological processes in health and disease.
`11 999 527
More specifically, INTERACTION PROTEOME will develop novel technologies, including a
high-end mass spectrometer with an extremely large dynamic range, high-density peptide ar-
rays and improved visualisation technology for light and electron microscopy. These technolo-
gies will be validated through model systems of great relevance to medicine and biotechnol-
ogy. In order to cope with the massive increase in experimental data on protein interactions
obtained by using the novel technologies, extensive bioinformatics support will be a key
element in facilitating this work. In particular, the efficient integration of disparate data sets
represents a vital challenge in proteomics and functional genomics.
Within the context of interaction data already included within the scientific literature written
by a community of ‘traditional biologists’, the analysis of the newly discovered interactions
will represent an essential prerequisite for the success of the consortium. For this purpose,
the consortium includes the creation of the only European protein-interactions database,
called MINT.
The aim of INTERACTION PRO-
TEOME is to establish Europe as the
international scientific leader in the
field of functional proteomics, and in
particular in the analysis of protein-
protein interactions. One of the major
Localisation of proteins within a objectives includes the establishment
cell: Protein complexes (coloured) of a broadly applicable platform of
are depicted at various levels of routine methods for the analysis of
resolution in their cellular context protein interaction networks.
(background). This technology
enables the visualisation of the The interaction partners of more
3-dimensional architecture and than 100 relevant protein domains
supramolecular structure of cells. and more than 3,000 peptides will
be characterised using these novel
technologies, while the data obtained during the project will be collected in an improved
version of the European MINT database. At the same time, novel bioinformatics tools for
the prediction of protein interactions and their relation to post-translational modifications
will be created. In addition, software for in silico modelling of protein interactions will be
developed and validated with the projects’ model systems.
Functional Proteomics:
Towards defining the interaction proteome
Expected Results:
The aim of INTERACTION PROTEOME is to establish ground-
breaking technology for the analysis of protein-protein inter- Visualisation of the cytoskeleton
actions. During the first two years of the project, major goals of a Dictyostelium cell. Colours
have already been achieved. were subjectively attributed
to mark the actin filaments
In terms of technology, a major breakthrough by INTERAC- (reddish); other macromolecular
TION PROTEOME was the development of a novel mass complexes, mostly ribosomes
spectrometer, the LTQ-Orbitrap, and its introduction to the (green); and membranes (blue).
market in June 2005 by the project partner Thermo Electron
(Bremen). The Orbitrap is the first fundamentally new mass analyser in more than 20 years.
Compared to a state-of-the-art high performance mass spectrometer (LTQ-FT), the Orbitrap
exhibits a 10-fold increase in sensitivity along with a four-fold extension of the dynamic
range. Based on highly accurate mass determination combined with high resolution and
sensitivity, the novel instrument not only allows for routine analysis with high-throughput,
but also for straight forward analysis of peptide mixtures without chemical or enzymatic
modifications.
From a methodological point of view, the Orbitrap is the ideal instrument for the two novel
“2D-Gel-free” proteomics approaches developed within the project, namely the “SILAC”
(Stable Isotopic Labelling by Amino acids in Cell culture) technology developed by the team
of Matthias Mann at the University of Odense/Max Planck Institute of Biochemistry, Mar-
tinsried, and the “COFRADIC” (COmbined FRActional DIagonal Chromatography) created
by the team of J. Vandekerckhove from Flanders Interuniversity Institute of Biotechnology,
Ghent. Both technologies have been successfully applied to a number of the project’s model
systems, including, among others, the analysis of protein processing in apoptosis by COF-
RADIC, as well as the analysis of Chaperone-dependent protein folding and of signalling
(de)differentiating stem cells by SILAC.
In the first two years of its existence, INTERACTION PROTEOME has published over 30
peer-reviewed publications in internationally renowned journals. During the project’s mid-
term review in December 2005, external experts evaluated INTERACTION PROTEOME
as a clear “showcase project for EU research”. By the end of year four of the project, the
number of publications issued has risen up to 120.
Potential Impact: Protein folding by the Chap-

erone machinery: an unfolded
substrate protein is inserted into
the barrel-shaped GroEL cage,
which is subsequently locked
with the GroES lid. Folding
proceeds within the secluded
chaperonin cage, which finally
releases either correctly folded
functional protein (upper), or
an incompletely folded protein
which may undergo either an-
other folding cycle or degrada-
tion in the cytosol.
The technology and

methodology produced
in INTERACTION PRO-
TEOME will facilitate
a large-scale analysis
of protein interactions
in various fields of bio-
medicine. The interdis-
ciplinary collaboration
within the project will
support the development
Clusters of phosphorylation sites of coherent standards in
assigned according to the tempo- methodology and data
ral profiles of their modulation formats, foster further
after EGF stimulation of the cells. horizontal integration
Prominent members are indicated of research centres and
above each cluster. facilitate the exchange
and comparison of data
obtained in different laboratories. Although this coherence will initially be observed only
within the consortium, its scientific success will promote the spreading of its standards to
European proteomics centres outside the partnership. The active contribution of individual
partners to various other networks at national and international level will also facilitate the
dissemination of standards and promote the coherence of the proteomics field in Europe.
In terms of human resources, the impact of INTERACTION PROTEOME in the many ex-
panding areas of biomedicine will be considerable. Young scientists involved in the project
will acquire multidisciplinary skills, including training in bioinformatics, and will thus rep-
resent a valuable resource for the growing biomedical and biotechnological industry. In
addition, highly qualified technical personnel in this novel interdisciplinary research field
will become available through the project. Finally, administrative staff involved in the
management of this large EU project will gain experience for future careers as managers
of international projects.
Keywords: protein-protein interaction, signalling network, proteome
Phototaxis in Halobacterium
salinarum. A) Halobacteria are
repelled by blue light (left) and
attracted by orange light (right).
B) Components of the halobacte-
rial signal transduction chain
modulating clockwise (CW) and
counterclockwise (CCW) rotation
of the flagellar motor.
Functional Proteomics: Towards defining the interaction proteome
Partners
Project Coordinator: Prof. Luis Serrano
Prof. F. Ulrich Hartl Centre De Regulació Genómica (CRG)
Max-Planck-Institute of Biochemistry Systems Biology Research unit
Department of Cellular Biochemistry Barcelona, Spain
Am Klopferspitz 18
82152 Martinsried, Germany Dr. Philippe Bastiaens
uhartl@biochem.mpg.de European Molecular Biology Laboratory (EMBL)
(EMBL)-Heidelberg
Project Manager: Cell Biology and Cell Biophysics Programme
Dr. Anne Katrin Werenskiold Heidelberg, Germany
Max-Planck-Institute of Biochemistry
EU Project Acquisition & Management Dr. Mike Schutkowski
Am Klopferspitz 18 JT Peptide Technologies
82152 Martinsried, Germany Berlin, Germany
proteome@biochem.mpg.de
Prof. Wolfgang Baumeister, Prof. Dieter Oesterhelt,

Prof. Matthias Mann
Max-Planck -Institute of Biochemistry
Martinsried, Germany
Prof. Joel Vandekerckhove

Flanders Interuniversity Institute of Biotechnology
Department of Medical Protein Research
Ghent, Belgium
Prof. Gianni Cesareni

University of Rome Tor Vergata
Department of Biology
Laboratory of Molecular Genetics
Rome, Italy
Prof. Søren Brunak

Technical University of Denmark
Center for Biological Sequence Analysis
Lyngby, Denmark
Dr. Raymond Wagner

FEI Electron Optics BV
Eindhoven, The Netherlands
Prof. Walter Kolch

Beatson Institute for Cancer Research
Signalling & Proteomics Laboratory
Glasgow, UK
Dr. Marius Ueffing

GSF - National Research Center
for Environment and Health
Institute of Human Genetics
Neuherberg, Germany
Dr. Reinhold Pesch

ThermoElectron (Bremen) GmbH
Bremen, Germany
NEUPROCF
State-of-the-Art:
Project Type: In the search for new diagnostic and prognostic biomarkers for the development of new
Specific Targeted drugs for cystic fibrosis (CF), the identification of new low- and medium-abundance pro-
Research Project teins involved in its pathophysiology is a very promising field. The characterisation of such
markers requires the development of several high performance techniques and the crea-
Contract number:
tion of standards for these new approaches. Several ways will be explored to bring new
LSHG-CT-2004-512044 knowledge to the CF community, applying and developing state-of-the-art mass spectrom-
Starting date: etry, chromatography and electrophoresis methods to the inflammation mechanisms in CF,
1st July 2005 interaction between proteins, mainly the cystic fibrosis transmembrane regulator (CFTR),
Duration: and other molecules, like DNA, other proteins or lipids. In addition to the biomarkers, this
should bring a better understanding of CF pathophysiology with regard to transepithelial
36 months ion transport, inflammatory processes and the identification of factors responsible for the
EC Funding: different CF phenotypes.
`2 355 000
The aim is to identify new low abundance protein biomarkers in serum. In the meantime,
the project will generate new basic knowledge for inflammation, protein-, lipid- and DNA-
interaction in all fields related to scientific fields, such as cancer, neurodegenerative dis-
eases and asthma that are considered as priorities for EC science.
Another strategic impact concerns prognostic biomarkers: the phenotype of CF is quite vari-
able, even in patients bearing the most frequent mutation delta F508. To tackle the prob-
lems posed by this disease and to try to decipher the underlying mechanisms, large-scale
studies at the protein level would certainly accelerate discoveries, in particular by detecting
low abundance proteins. This will imply new standard protocols for sample collection and
technologies by:
sDEVELOPING AND APPLYING HIGHLY SENSITIVE METHODS FOR PROTEIN IDENTIlCATION BY -3
which will be useful for the proteomic community;
sDEVELOPINGANDAPPLYINGHIGHLYSENSITIVEMETHODSFORTHEIDENTIlCATIONANDQUANTIl-
cation of lipid molecules which interact with CF-related proteins;
sAPPLYINGTHESETECHNOLOGIESTOIDENTIFY#& ASSOCIATEDPROTEINSANDLIPIDSINVOLVEDIN
pathogenesis of CF;
sINTEGRATINGTHEDATAINACOMPREHENSIVEDATABASEUSEFULFOR#&RESEARCH
Expected Results:
Methodological improvements in mass spectrometry, to be patented if applicable, will
maintain the very high level of skills in this field in Europe, and open new lipidomic-DNA-
proteomic approaches.
Here is a list of expected results:
sSTRENGTHENINGOFLINKSISSUEDFROMPREVIOUSCOLLABORATIONS
sSTANDARDPROTOCOLSFORTHECOLLECTIONOFPATIENTSAMPLESFORANALYSIS
sIMPROVEDSENSITIVITYOF-3METHODS
sNEWKEYPROTEINSWHICHCANBETARGETEDFORFUTUREDRUGDISCOVERY
sNEWKEYPROTEINSWHICHCANBEUSEDINFUTUREDIAGNOSTICSANDTHERAPY MONITORINGOF
CF patients;
sNEWSOFTWAREFORPROTEOMICANALYSIS
Potential Impact:
Through the NEUPROCF results and the ability to monitor low- and medium-abundance CF
biomarkers, the objective is to give a better prognostic of the disease severity. The treat-
Development of New Methodologies
for Low Abundance Proteomics:
Application to Cystic Fibrosis
ments could be then adapted, being lighter for
a less severe affection, hence improving the pa-
tient’s quality of life.
In addition, the input of knowledge on the

mechanisms underlying CF phenotypes in a da-
One of the NEUPROCF strategies
tabase could prove to be a decisive asset in
the perspective of transferring the knowledge to identify biomarkers: high
to biotech or pharmaceutical groups, together resolution MS/MS analysis
with standard protocols for sample collection peptide map.
and high-tech technology. © Dr. M. Dadlez (IBB-MS)
Keywords: low abundance proteins, proteomics, cystic fibrosis
Partners
Project Coordinator: Dr. Dorota Sands Dr. Josef Vogt
Dr. Aleksander Edelman Institute of Mother and Child Universitätsklinikum Ulm
Institut National de la Santé et CF Centre Department of Anaesthesiology
de la Recherche Médicale Warsaw, Poland Ulm, Germany
Faculte de Medecine Necker Inserm U467
156, rue de Vaugirard Dr. Lena Hjelte Prof. Margarida Amara
75730 Paris, France Karolinska Institutet Fundacao da Faculdade de
edelman@necker.fr Huddinge University Hospital Ciencias de Universidade de Lisboa
Stockholm Cystic Fibrosis Center Department of Chemistry and
Dr. Michal Dadlez Stockholm, Sweden Biochemistry - Laboratory of
Polish Academy of Sciences Molecular Genetics
Department of Bioinformatics Lisbon, Portugal
Warsaw, Poland
Dr. Peter Bergsten

Uppsala University
Department of Medical Cell Biology
Uppsala, Sweden Dr. Laure-Emmanuelle Benhamou
INSERM - Transfert
Prof. Jasminka Godovac-Zimmermann European Projects Management
University College London Saint-Beauzire, France
Department of Medicine Rayne Institute
London, UK Dr. Michael Cahill
ProteoSys Ag
Dr. Robert Dormer Mainz, Germany
University of Wales
Department of Medical Biochemistry
& Immunology School of Medicine
Cardiff, United Kingdom
Prof. Gérard Lenoir

Assistance Publique - Hopitaux de
ParisHôpital Necker Department
of Pediatrics
Paris, France
CAMP
http://camp.bioinfo.cipf.es
State-of-the-Art:
Project Type: Proteases are key molecules in biological systems. They modify numerous proteins by hydro-
Specific Targeted lytic cleavage, thus controlling and executing many physiological processes. Their intricate
Research Project networks require rigorous regulation to prevent fortuitous proteolysis. Where this regulation
Contract number: fails, proteases trigger pathologies such as neurodegeneration, inflammation, and cancer.
Many therapeutic approaches are directed towards proteases or their natural inhibitors, and
LSHG-CT-2006-018830
are already leading to drugs for life threatening diseases. However, the tight regulation of
Starting date: proteases by posttranslational modifications makes current functional genomics technologies
1st January 2006 unsuitable for fully establishing biological relevance. The project “Chemical Genomics by Ac-
Duration: tivity Monitoring of Proteases” (CAMP) will lay the groundwork for the study and understand-
36 months ing of proteases through activity labelling and functional imaging in cells. Specifically, CAMP
will investigate the substrate specificity of proteases by using large peptide libraries, derive
EC Funding: fluorescent labelling molecules from the sequence information gathered, and use these mol-
`2 700 000 ecules to investigate proteolytic activities in cellular environments. Given the estimated number
of 600 proteases to 1100 proteases in the human genome, the team’s selected set constitutes
a significant representation and will establish the feasibility of the project’s approach to ad-
dress the protease proteome. CAMP’s proteases will serve as prototypes to develop novel
protease-specific technologies and probes for studying expression and folding, the activity
state of proteases and their endogenous interaction partners in vitro and in vivo. The gathered
information will be annotated in a public repository. The team expects the derived insights of
CAMP to foster high-throughput approaches and research, leading to new avenues in drug
discovery, using integrated data on the protease proteome.
The CAMP project will develop and integrate novel technologies in the areas of recombinant
protein production, High Throughput (HT) structure determination and bioinformatics, together
with the development of specific chemical tools for functional annotation, INĺVIVO localization
and characterization. Ultimately, CAMP will provide the following: information on synthetic
peptide substrates of proteases; chemical probes as tools to investigate the physiological role
of proteases in cellular environment; identification of physiological substrates of proteases
providing information about protease signalling pathways, essential for understanding bio-
logical roles in health and disease, and an assessment of the tools developed in the project;
and novel crystal structures of proteases in the activated form (either alone or in complex with
inhibitors), as well as in the zymogen state. The team has selected a total of 45 targets from
the cysteine proteases (papain-like lysosomal proteases and caspases) and metalloproteases
(carboxypeptidases, matrix metalloproteases and ADAM-TS metalloproteases) to develop,
Structure of the LCI-CPA2 complex implement and demonstrate the feasibility of the team’s proteomics-oriented approaches for
proteases. The aim of CAMP is to establish the interdisciplinary core infrastructure and tech-
nologies that will be required for a subsequent full-scale protease proteomics approach. The
team’s choice of protease targets has been based on two criteria: implication in important
physiological processes, as well as novelty with respect to function.
Expected Results:
Besides the proteomics-focused technological aims, CAMP focuses on a selected and medi-
cally highly relevant subset of human proteases. The team further expects to substantially
increase the current knowledge (at the level of genomic annotation) of four selected clans of
proteases, encompassing 45 prototypic representatives. Many of them are critically involved
in medical problems and pathologies, such as those related to hormone and neuropeptide
processing and maturation (i.e.N/E carboxypeptidases), inflammation and joint diseases
Structure of Caspase 2 (cathepsins, caspases, ADAM-TSs), stroke and cardiovascular arteriosclerosis (caspases,
TAFI, MMPs, ADAM-TSs) andcancer (cathepsins, caspases, MMPs).
Chemical Genomics
by Activity Monitoring of Proteases
Potential Impact:
The data resulting from CAMP will promote and stimulate novel applied research based on
the enzyme targets, which have been poorly interconnected or neglected so far owing to
the lack of an integrated and generally available platform for protease-specific proteomics.
Within the present project, the selected proteases will be used as a training set to develop
such proteomics technologies. Proteases have been recognized as valid drug targets, and
many inhibitors of proteases have been designed that resulted in drugs, e.g. to treat HIV infec-
tions, thrombosis, or hypertension. Therefore, a significant expansion of knowledge on these
enzymes and on molecules controlling them (such as natural or artificial inhibitors) will have a
direct impact on the landscape of biomedical sciences and technologies in Europe. The results
and technologies of CAMP should facilitate the efficient generation of structural and functional
data for this set at a full proteomic scale. Furthermore, the tools developed in CAMP should
facilitate the future application of the developed technologies to other hydrolytic enzymes. By Complex between TIMP-1 and
developing and integrating family-specific technologies for high-throughput expression, bio- the catalytic domain of MMP-3
chemistry, inhibitor design and structural proteomics, CAMP aims to enable a future functional
and structural annotation of the entire protease proteome.
Keywords: chemogenomics, chemoproteomics, functional probing, proteolytic

enzymes
Partners
Prof. Francesc Xavier Aviles
Universitat Autonoma de Barcelona
Institut de Biotecnologia i de Biomedicina
Protein Engineering and Enzymology Unit
08193 Bellaterra (Barcelona), Spain
francescxavier.aviles@uab.es
Dr. Matthias Wilmanns

(EMBL) – Hamburg unit
German Synchrotron Research Center
Hamburg, Germany
Prof. Boris Turk

J. Stefan Institute Proteolysis
Research Group
Department of Biochemistry and
Molecular Biology
Ljubljana, Slovenia
Dr. Ulrich Wendt
Prof. Markus G. Gruetter Sanofi-Aventis
University of Zurich Deutschland GmbH
Department of Biochemistry Valorisation & Innovation
of the University of Zurich Frankfurt, Germany
Zurich, Switzerland
Prof. Dr. Wolfram Bode
Dr. Ernst Meinjohanns Max-Planck Institute of
Arpida AS Biochemistry
Copenhagen, Denmark Martinsried, Germany
ProDac
www.fp6-prodac.eu
State-of-the-Art:
Project Type: Based on the work of the Human Proteomics Organisation (HUPO), the Proteomics Standards
Co-ordination Action Initiative (PSI) and the experience of the HUPO Brain Proteome Project (HUPO BPP), ProDaC
Contract number: aims to develop and implement international standards for the representation of high-per-
LSHG-CT-2006-036814 formance proteomics data. The main focus of the project is standardised data collection as
well as standardised data analysis of protein identification by mass spectrometry. In total, 12
Starting date: core partners (European Bioinformatics groups and proteomics laboratories) and 31 associ-
1st November 2006 ated partners (non-EU laboratories, both academic and commercial) will participate in the
Duration: 30-month project. Data providers from experienced European proteomics laboratories will
30 months provide appropriate data, derived from state-of-the-art proteomics technologies, for proof of
EC Funding: concept; moreover, they will utilise the newly developed software tools. The project will be
supported by a number of high-ranking scientific journals, which will be actively involved in
`1 000 000 the standards’ development, including the defining of mandatory supplementary information
for submitting articles.
In phase one, all ProDaC partners will contribute to the finalisation of the analysisXML
standard for the representation of protein identifications; they will also contribute to the PSI
GPS modules for the overall representation of a proteomics experiment, in particular
the sample description, sample handling, and separation modules.
In phase two, ProDaC core partners will establish submission pipelines from experimental
data providers and data analysis centres to the PRIDE proteomics repository.
In phase three, the strategies developed will be implemented by a much broader group of
project participants, building on the previous project experience, and supported by dedi-
cated technical advisors. At the end of phase three, it is expected that the PSI proteomics
standards will be adopted by major European and worldwide proteomics data providers.
To demonstrate the immediate benefit of central data collection to data producers, we will
extend PRIDE functionality to allow for the comparison of submitted, but nonetheless pri-
vate data in pre-publication status, to other, publicly available datasets. Through the data
exchange between proteomics repositories, the scope of proteomics data integration into
sequence databases will reach out to other repositories, such as Proteios, ProteinScape, and
PeptideAtlas; ultimately, this may improve or validate (or both), or even sequence databases
themselves.
Expected Results:
ProDaC expects that the following results will be produced:
1. PSI standards finalised and tested;
2. Implementation of mzData and analysisXML capabilities in ProteinScape;
3. PROTEIOS, Phenyx and Mascot and PRIDE (and conversion of existing data);
4. Identification of relevant proteomics tools used in the consortium, and of develop-
ment needs to ensure functional data submission pipelines from data producers to
PSI-compatible repositories;
5. Tools for compiling raw data into standard file formats (mzData and analysisXML);
6. Evaluation of existing data storage solutions at the participants’ sites;
7. Elaboration, testing and optimising of the data submission pipeline;
8. Elaboration and testing of submitted supplementary data sets for publications;
9. Collection of data packages;
10. Establishing of a steering committee and the network structure;
11. Implementation of the intranet and other communication platforms;
12. Coordination of software implementation
Proteomics Data Collection
Potential Impact:
Systematic coordination in the ProDaC context may boost proteomics data standardisation
and collection on a global level, and may significantly reduce the timeframe in which these
aims could otherwise be achieved, to boot. Moreover, the European core component of the
ProDaC proposal will help to retain Europe’s strong position in the field of proteomics, while
the significant global participation of associated partners will ensure broad acceptance of
the project in the global proteomics community.
The ProDaC consortium comprises commercial and open source proteomics tool providers
who will implement PSI standards in their products, thus minimising the effort necessary for
data conversion and submission. Moreover, the participation of scientific publishers in Pro-
DaC will ensure that the developed standards, tools and repositories meet the requirements
of the publication process, and will in turn, promote the application of these standards on
behalf of their authors, thus increasing the transparency, quality and public value of pro-
teomics publications.
Keywords: proteomics, databases, standardisation
Partners
Project Coordinator: Dr. Frederique Lisacek Prof. Herbert Thiele
Prof. Helmut E. Meyer Swiss Institute of Bioinformatics Bruker Daltonics GmbH
Ruhr-Universitaet Bochum Proteome Informatics Group Bremen, Germany
Medizinisches Proteom-Center Geneva, Switzerland
Universitätsstrasse 150 Dr. John Cottrell
44801 Bochum, Germany Matrix Science
helmut.e.meyer@ruhr-uni-bochum.de London, UK
Dr. Rolf Apweiler

European Molecular Biology
Laboratory (EMBL)
European Bioinfomatics Institute (EBI) Dr. Jari Häkkinen
Hinxton, UK Lund University
Department of Theoretical
Prof. Rudi Aebersold Physics
Federal Institute of Technology Lund, Sweden
ETH Zurich
Zurich, Switzerland Dr. Simon Hubbert
Manchester University
Prof. Joel Vandekerckhove School of Biological
University of Ghent Sciences
Department of Medical Manchester, UK
Protein Research
Ghent, Belgium Dr. Pierre-Alain Binz
Genebio
Prof. Michael J. Dunn Geneva, Switzerland
University College Dublin
Conway Institute of Biomolecular Martin Blüggel
and Biomedical Research Protagen AG
Dublin, Ireland Dortmund, Germany
1.3
FOR MOLECULAR IMAGING
MOLECULAR IMAGING
Tips4Cells
COMPUTIS
MOLECULAR IMAGING
www.molimg.gr

Integrated Project
Contract number: Advances in molecular biology have provided considerable information concerning the
sequence, structure and function of genes. This has opened new perspectives for the un-
LSHG-CT-2003-503259
derstanding of fundamental biological processes underlying human disease and for the
Starting date: development of innovative diagnostic, prognostic and therapeutic tools. Strategies for ge-
1st January 2004 nomic research and therapeutic interventions at the genetic level will benefit from increased
Duration: capability to monitor in vivo the effects of genetic manipulations in cells and living organ-
60 months isms. Ironically, although biology is fundamentally dynamic, most of the current knowledge
EC Funding: on gene expression, regulation and delivery in mammalian systems relies on results from
in vitro or ex vivo studies. This, coupled with our inability to easily monitor multiple molecu-
`11 000 000
lar species simultaneously, seriously limits our ability to study a wide range of biological
processes. Furthermore, since empirical descriptions of the evolution of systems over time
are generally constructed from a series of data ob-
tained from different specimens, they often fail to
represent the true order of events accurately. Ad-
ditionally, these invasive techniques tend to be time
consuming and labour intensive, often leading to
distortion or even destruction of native properties.
Thus the current capacity to extract biological in-
formation in intact microenvironments of living sys-
tems is severely limited. MOLECULAR IMAGING
Single-molecule fluorescence close aims at developing new tools that will enable moni-
to an absorbing nanostructure. toring the dynamics of multiple molecules within
The emission rate is strongly living systems and will transform our understand-
modified by the local-field ing of biology, making experimental investigations
enhancement and the non- much more efficient and accelerate the progress in
radiative coupling with the object. life sciences.
The goal of the Molecular Imaging Integrated Project is to generate and apply novel ad-
vanced technology for non-invasive imaging of biomolecular function in living systems rang-
ing from single cells to whole animals. The main areas for technological innovation are:
s THEGENERATIONOFNEWBIOSENSORSENABLINGNOVELWAYSOFFUNCTIONALCONTRAST
s IMPROVINGTHERESOLUTIONOFMICROSCOPICANDTOMOGRAPHICIMAGINGSYSTEMS
s CREATINGNEWMULTIMODALIMAGINGSETUPSWHICHCOMBINEDIFFERENTCONTRASTMODES
Different imaging scales involved

in the MOLECULAR IMAGING
Integrated Project
Integrated Technologies
for In vivo Molecular Imaging
We will combine multidisciplinary research in biology, bioorganic chemistry, theoretical

physics and biomedical optics with the objective of developing novel imaging tools that will
enhance genomic and post genomic research, and biotechnological capabilities in Europe.
It is expected that our combined effort will provide spectacular new opportunities for phe-
notyping functional (molecular) analysis in cells and animal models.
Expected Results:
The expected results are:
s THEDEVELOPMENTOFINVERSEMETHODSANDBASICTHEORYOFLIGHTTRANSPORTFORIMPROVED
3D tomographic approaches
s THEDEVELOPMENTOFBASICTHEORYFORNANOSCALEPHENOMENAANDAPPLICATIONFORIM-
proved microscopic molecular imaging techniques
s THE DEVELOPMENT OF ORGAN SPECIlC IMAGING BIOTECHNOLOGIES AND NOVEL mUORESCENT
probes and biosensors
s THE ASSESSMENT OF THE ABOVE TECHNIQUES IN SPECIlC BIOLOGICAL SYSTEMS SO THAT THEY
become available to a variety of end-users in the scientific community.
The development of such tools will offer multilevel information, (spatial, temporal and rela-
tive) so that reliable and complex conclusions can be reached faster. This proposal aims to
coordinate the development of functional in vivo imaging capabilities in order to address
fundamental biological questions. This will be achieved by partnering high-resolution im-
aging with post-genomic molecular technology. Much of the technology and techniques to
be developed under this integrated project will be directly applicable to high-throughput
screening and genomic and proteomic microanalysis.
Non-invasive phenotyping will drastically reduce the number of sacrificed animals neces-
sary for accurately addressing biological problems and will:
sINCREASETHEQUALITYANDCOMPREHENSIVENESSOFDATACOLLECTEDFROMEACHANIMAL
sCUTDOWNTHEINVASIVEPROCEDURESTOTHEANIMALS
sCUTDOWNTHETIMEOFPHENOTYPINGPOSITIVEANIMALS
sFORMTHEBASISFORHUMANUSEINTHEFUTURE
a) b)
a) Visualisation of the intestinal

lymphatic system
b) Flow chart of the different

subprojects and work packages
MOLECULAR IMAGING
Potential Impact:
The proposed consortium of physicists,
mathematicians, biologists and chemists
offers a unique opportunity to address the
challenge of in vivo molecular imaging in
a concentrated but Europe-wide effort. We
believe that this project will lead to the for-
mation of centres of excellence in the near
future that will attract scientists to join those
countries and institutions that are able to
provide this technology. Such research cen-
Interaction between
tres would promote the commercialisation
disciplines in the
of this technology in partnership with high-
MOLECULAR IMAGING
end industry to make it widely available
Integrated Project
and widely deployed in the near future.
This will create many new jobs for highly educated scientific and technical personnel. Spe-
cific innovation aspects include:
a) New probes. These will be engineered, taking into account the natural absorbance
properties of tissue and will be suitable for imaging in organs and animals.
b) Simultaneous spatially and temporally resolved detection of multiple physiological
events.
c) Novel theoretical tools to model light propagation and atomic-scale interactions.
d) New optical instruments with improved depth detection that allows the identification
of fluorescent organs or structures within the animal body non-invasively in vivo.
e) New optical instruments that allow the localisation of individual cells and their distribu-
tion and migration within organs.
f) Novel multimodal nanometric imaging setups that will allow follow up of atomic inter-
actions in vivo.
Keywords: genetic engineering, applied optics, molecular chemistry, tomogra-

phy, microscopy, fluorescence, inverse problem, functional genom-
ics, phenotyping
Partners
Prof. Eleftherios Economou
Foundation for Research and Technology – Hellas
Fluorescence molecular Institute of Electronic Structure and Laser (IESL)
tomography (FMT) imaging Institute of molecular biology and biotechnology (IMBB)
of T-cell regulation. (A) FMT P.O Box 1385, Vassilika Vouton
setup where the specimen 71 110 Heraklion, Crete
rotates along an axis, an economou@admin.forth.gr
excitation source (Ar+ laser) is
scanned over the surface and Prof. Stefan Andersson-Engels
excitation and emission images Lund University
are collected using appropriate Department of Physics
filters. (B) 3D reconstruction of Lund, Sweden
GFP concentration in the spleen
for GFP-tagged T-cells in a F5 Prof. Simon Arridge
mouse. This figure indicates the University College London
potential that FMT has to image Department of Computer Science
biological processes in vivo. London, UK
Integrated Technologies for In vivo Molecular Imaging
Prof. Dr. Christoph Bremer Dr. Oliver Dorn Dr. Jens Stein
University of Münster Universidad Carlos III de Madrid University of Bern
Department of Clinical Radiology Department of Mathematics Theodor Kocher Institute
Münster, Germany Madrid, Spain Bern, Switzerland
Prof. Remi Carminati Prof. Frank Grosveld Dr. James Sharpe

Centrale Recherche SA Erasmus Medical Centre Rotterdam Centre for Genomic
Laboratoire EM2C Department of Cell Biology Regulation (CRG)
Paris, France Rotterdam, The Netherlands Barcelona, Spain
Prof. Juan Jose Saenz Prof. Carlos Martinez, Dr. Miguel Torres
Universidad Autonoma de Madrid Prof. M. Nieto-Vesperinas, Prof. N. Garcia CNIC Fundación Centro
Departamento de Fisica de Consejo Superior de Investigaciones Nacional de Investigaciones
la Materia Condensada Científicas Cardiovasculares Carlos III
Madrid, Spain Madrid, Spain Madrid, Spain
Prof. Maria Carmo-Fonseca Prof. Cristoph Cremer

Institute of Molecular Medicine Ruprecht-Karls-Universitat Heidelberg
Laboratory of Cell Biology Kirchhoff-Institute for Physics
Lisbon, Portugal Heidelberg, Germany
Dr. Paul French Dr. Martin Ingle

Imperial College of Science Photek Ltd
Technology and Medicine St Leonards-on-Sea, UK
Physics Department
London, UK
Prof. Theodorus Gadella

University of Amsterdam
Swammerdam Institute for Life Sciences
Amsterdam, The Netherlands
Dr Dimitris Kioussis
Medical Research Council
Division of Moleculer Immunology, Dr. Patrick Courtney
National Institute for Medical Research Perkinelmer Life and
London, UK Analytical Science
Cambridge, UK
Dr. Carsten Schultz
European Molecular Biology Dr. Levin Shimon
Laboratory (EMBL) Lenslet Labs Ltd
Gene Expression Programme Ramat-Gan, Israel
Heidelberg, Germany
Dr. Paul Wynn
Prof. Vahid Sandoghdar Kentech Instruments Ltd
Swiss Federal Institute of Didcot, UK
Technology (ETH)
Department of Chemistry
Zurich, Switzerland
Dr. Konstantin Lukyanov

Russian Academy of Sciences
Institute of Bioorganic Chemistry
Moscow, Russia
Tips4Cells
www.tips4cells.org

Specific Targeted
Research Project High resolution imaging of living cells and subcellular components is essential for func-
tional and structural genomics. Scanning Probe Microscopy (SPM) is currently the imaging
Contract number:
method of choice, because it yields the greatest number of structural details of biological
LSHG-CT-2005-512101 samples in their native, aqueous environment and at ambient conditions. Due to the high lat-
Starting date: eral resolution and sensitive force detection capability of SPM, it is now possible to measure
1st February 2005 intermolecular and intramolecular forces in biomolecules at the single molecule level. This,
Duration: in turn, has made it possible to examine the physiological consequences of the interaction
36 months of a single ligand molecule with its cognate receptor. The Tips4Cells consortium proposes
to develop SPM still further. New technologies, such as faster scanning force microscopy
EC Funding:
(SFM) at lower forces, improved tip chemistry and integration of optical imaging techniques
`1 713 000 will be used to analyse ligand-receptor interactions in the plasma membrane and in down-
stream signalling events in living cells, and to study the structure, transport and dynamics of
nuclear pore complexes (NPC) in functional nuclei.
The general goal of the consortium is to develop new SPM technologies for functional and
structural genomics. More specifically, its goals are as follows:
1) To develop new SFM hardware, including fast scanning hardware (scanner, mini-
ature cantilevers) and electronics (high speed data acquisition, Q control);
2) To develop molecular recognition force microscopy (MRFM), via the intermediary
development of the following: (i) Chemically functionalised tips/beads; (ii) The chem-
istry of the drugs that are put on those tips/beads; (iii) Imaging and spectroscopy
modes for recognition (pulsed force mode and recognition mode);
3) To integrate optical techniques into SFM, to improve detection of signalling after
administering a chemical to a cell, by approaching it with a functionalised tip;
4) To validate the new technologies in the study of cell biology systems, such as the non-
genomic effects of steroids (e.g. aldosterone), the Wnt signalling pathway and the
structure, transport and dynamics of NPC in functional nuclei.
Expected Results:
The consortium expects to achieve higher data acquisition rates through faster electron-
ics, and faster sensors with higher force sensitivity through miniaturised cantilevers. Faster
scanners will move more rapidly around the surfaces to be scanned, allowing for frame
rates above 100 images per second. The consortium also expects to improve the speed
of MRFM. More general functionalisation protocols will allow a wider range of chemicals
to be attached to SFM tips. Through the use of linkers between tip and molecule that are
optimised in length, a higher resolution will be achieved in molecular recognition imaging.
Genomics knowledge will be advanced through high resolution imaging and docking site
identification, the development of new tools for biomolecular analysis of drugs for orphan
receptors, the introduction of new chemistries for drugs on tips, and new substitutes for map-
ping receptor distribution in living cells. The commercialisation of novel imaging platforms
will be managed by the consortium’s SME partners, thereby bringing these techniques
within reach of a broad range of researchers.
Scanning Probe Microscopy techniques
for real time, high resolution imaging
and molecular recognition in functional
and structural genomics
Potential Impact:
The project will generate improved research tools and insights in SPM. It is anticipated that
the breakthroughs in nanoscience and technology will serve to stimulate industry, generating
employment opportunities. The SMEs involved in Tips4cells specialise in hardware develop-
ment, and will clearly benefit from the commercial opportunities generated by the research.
The multinational, multidisciplinary nature of the consortium will facilitate broad dissemina-
tion of new knowledge, both across Europe and across academia and industry. The consor-
tium will also foster novel collaborations between research institutes and industry.
Keywords: scanning force microscopy, imaging techniques, high resolution,

molecular recognition
Partners
Dr. Tjerk Oosterkamp
Leiden Institute of Physics
Leiden University
Niels Bohrweg 2
2333 CA Leiden, The Netherlands
oosterkamp@physics.leidenuniv.nl
Dr. Peter Hinterdorfer

University of Linz
Institute of Biophysics
Linz, Austria
Prof. Michael Horton

University College London
Department of Medicine Dr. Torsten Jähnke
London, UK JPK Instruments AG
Berlin, Germany
Dr. Ziv Reich
Weizmann Institute of Science Dr. Gertjan van Baarle
Department of Biological Chemistry Leiden Probe Microscopy
Rehovot, Israel Leiden, The Netherlands
Prof. Mervyn Miles Dr. Gerald Kada

University of Bristol Agilent Technologies
H.H. Wills Physics Laboratory Österreich GmbH
Bristol, UK Austria
Prof. Hans Oberleithner

University Hospital Münster
Department of Physics
Institut für Physiologie II
Münster, Germany
COMPUTIS
State-of-the-Art:
Project Type:
Specific Targeted Significant improvements in desorption and ionisation techniques, such as SIMS (secondary
Research Project ion mass spectrometry) or MALDI-MS (matrix-assisted laser desorption ionisation – mass
spectrometry ) associated with TOF-MS (time of flight – mass spectrometers), offer levels of
Contract number:
sensitivity and mass accuracy which allow detection, and analysis of large organic mol-
LSHG-CT-2005-518194 ecules like peptides or proteins with very small sample amounts.
Starting date: Recent developments showed the possibility of extrapolating these techniques to produce
1st January 2006 actual molecular images of flat samples with a full mass spectrometry at each pixel down
Duration: to micrometric scales.
42 months The growing interest of this approach and its high potential will lead to the development,
optimisation, combination and correlation of these SIMS and MALDI-MS techniques.
EC Funding:
`2 200 000
This project aims to develop new and improved technologies for molecular imaging mass
spectrometry (MIMS), enabling innovative methods of investigation in functional genomics,
proteomics and metabolomics, as well as investigation in cells and tissues.
It is the goal of the project to develop, optimise, combine, correlate and apply methods of
mass spectrometric molecular imaging, especially various specialised methods of SIMS and
MALDI associated with various types of mass spectrometers.
The three principal objectives of the project are:
sINNOVATIVE-3IMAGINGINSTRUMENTATIONTHROUGHTHEDEVELOPMENTANDAPPLICATIONOF
novel desorption, ionisation and detection techniques
sREALISATIONOFADVANCEDDIAGNOSTICMETHODSFORIDENTIFYINGDISEASECLASSIlCATIONBY
the study of molecular images
sMONITORINGOFTHERAPEUTICEFFECTSONEXPRESSIONPATTERNSOFDAMAGEDANDABNORMAL
cells or tissue growth.
This project will provide innovative analytical capabilities for mapping a variety of biologi-
cal compounds directly at the tissue or cell level by superposing information from different
sources in the same image.
MIMS needs further development to make it routinely accessible to users. Application of
these methods to analytical problems requires appropriate instrumentation, sample prepa-
ration methodology, and computerisation with high performance massive data acquisition
and processing.
Expected Results:
The objectives of the project will be achieved by significant improvements in desorption
and ionisation techniques, leading to a new protocol of sample preparation for better
matrix deposition control. Instrumentation developments include the setup of UV confocal
microscopy integrated into the MALDI imaging instrument and the adaptation of new ion
guns favouring secondary ion emission for SIMS analysis. Dedicated software tools will
be implemented for high performance data acquisition and processing with, in particular,
the realisation of the superposition of data from different analytical sources in the same
image. The project will conclude with definition, implementation and testing of new analyti-
cal concepts, as well as criteria for diagnostics of chosen pathologies or diseases, and the
development of an industrial concept. In addition, a validation phase through the applica-
Molecular Imaging in Tissue and Cells
by Computer-Assisted Innovative
Multimode Mass Spectrometry
tion of MIMS to the three selected biological problems is imperative for the acceptance of
the methodology.
Potential Impact:
MIMS techniques connected with proteomics and bioinformatics pave the way to in situ in-
spection of cell and tissue physiology. They could be extended towards pathophysiological
inspections of human tissues performed at the molecular level on a large-scale.
Imaging MS eliminates the need to know in advance about the specific proteins that may have
changed in a comparative study. So, these new analytical methods will be performed ideally
with almost no a priori knowledge about markers and gene products expressed in normal
and pathological specimens. Improved image acquisition, image processing and connectiv-
ity with existing biological databases will have a critical impact for applications in human
healthcare.
Keywords: bioanalytical chemistry, mass spectrometry, massive data processing and

information treatment
Partners
Dr Haan Serge, Dr Robbe Marie-France
Commissariat à l’Energie Atomique CEA)
LIST/DETECS
Centre de Saclay, Bat. 451
P.O. Box 91191 Cedex
Gif-sur-Yvette, France
serge.haan@cea.fr
marie.france.robbe@cea.fr
Prof. Bernhard Spengler

Justus Liebig University
Institute of Inorganic and Dr. Ronald Schut
Analytical Chemistry PCC UvA BV
Giessen, Germany Amsterdam, The Netherlands
Prof. Ronald MA Heeren Dr. Fedor Svinartchouk

Stichting FOM (Fundamenteel Généthon
Onderzoek der Materie) Département Recherche
AMOLF et Développement
Amsterdam, The Netherlands Evry, France
Dr. Olivier Laprevote Dr. Markus Stoeckli

Centre National de la Recherche Novartis Pharma AG
Scientifique (CNRS) Discovery Technologies
Institute de Chimie des Substances Analytical and
Naturelles (ICSN) Imaging Sciences
Gif-sur-Yvette, France Basel, Switzerland
1.4
FOR GENE INTEGRATION AND
RECOMBINATION
GENINTEG
PLASTOMICS
TAGIP
MEGATOOLS
GENINTEG
State-of-the-Art:
Project Type: Despite the enormous potential of using transgenesis for gene function analysis and gene
Specific Targeted therapy, little is known about the mechanism of gene integration in eukaryotic cells. Trans-
Research Project gene integration into the chromosomes of living cells can occur either randomly or targeted
by homologous recombination. The latter type of integration is the most useful, because it
Contract number: allows precisely sequences to be precisely deleted or modified at defined chromosomal po-
LSHG-CT-2003-503303 sitions. The GENINTEG consortium was formed to study gene integration by recombination
Starting date: in a number of different model organisms. As DNA repair is conserved during evolution, a
1st January 2004 comparative genomics approach was proposed to discover evolutionary conserved princi-
ples of gene integration.
Duration:
48 months
EC Funding: Scientific/Technological Objectives:
`1 846 561 The main objective is to understand and enhance gene integration through interdiscipli-
nary and comparative genome analysis in different model organisms. As DNA structure
and DNA repair are conserved during evolution, the gained knowledge and resources
will improve gene integration across plant and animal species and facilitate large-scale
gene function analysis and transgene expression for biotech and medical applications.
Other objectives are: (1) better insight into the genetics, the regulation and the mechanism
of homologous recombination; (2) new protocols to increase targeted gene integration in
primary cells and cell lines either by modification of gene constructs or the gene delivery
mode; (3) adaptation of existing site specific recombination system for safe and stable gene
expression and long range chromosome engineering; (4) use of improved gene integration
for gene function analysis; (5) exploitation of the generated knowledge and resources for
commercial application through the protection of intellectual property and product develop-
ment; (6) new protocols for transgenesis of whole organisms.
Expected Results:
Controlled gene integration and in particular targeted integration has to be considered
a key technology for exploiting the wealth of recently obtained genome information. This
is due to the fact that traditional transgenesis can only add bits of poorly controlled infor-
mation to the genome, whereas targeted integration can be used to modify the genome
precisely at any chosen position. The proposed work will therefore significantly reinforce
genome research and support many of the activities envisioned for funding within FP6. Al-
though successfully employed in yeast and murine embryonic stem cells, a major stumbling
block for the widespread use of targeted integration is the tendency of most eukaryotic cells
to insert transfected DNA at random chromosomal positions. More efficient gene targeting
will expedite reverse genetics in a variety of cells and organisms enabling truly comparative
genome function analysis across species boundaries. Targeted gene integration also fulfills
a critical role for medical research, as it allows the experimental verification of the findings
of human genetics and the establishment of animal disease models for further detailed re-
search of pathogenesis and treatment.
Potential Impact:
To realize the full potential of transgenesis for genome research, biotechnology and medical
applications, only a concerted European initiative can bring together and focus the avail-
able expertise in academia and industry. The GENINTEG consortium has recruited some
of the best laboratories working on gene integration and also balances the work among
different species to allow for a truly comparative genomics approach.
The availability of genome sequences helps traditional genetics approaches and it pro-
motes reverse genetics as a means to modify the genotype in precisely defined terms.
Controlled gene integration:
a requisite for genome analysis
and gene therapy
The clarification of gene function by transgenesis is paramount to our understanding of
biological processes and disease pathogenesis. Consequently, investment in further devel-
opment of controlled gene integration technology promises rich returns not only for basic
research, but also for drug development.
Keywords: gene, homologous recombination, transformation, biotechnology,

genomic function, transgenes, site-specific, integration
Partners
Prof. Dr. Jean-Marie Buerstedde
GSF-Forschungszentrum fur Umwelt und Gesundheit GmbH
Institute of Molecular Radiation Biology
Ingolstädter Landstraße 1
85764 Neuherberg, Germany
buerstedde@gsf.de
Dr. William Brown

University of Nottingham
Queen’s Medical Centre
Institute of Genetics
Nottingham, UK
Prof. Ann Depicker

Flanders Interuniversity Institute for Biotechnology (VIB)
Ghent University Technologiepark
Department of Plant Systems Biology
Ghent, Belgium
Dr. Francis Fabre

Commissariat à l’Energie Atomique (CEA)
Fontenay-aux-Roses, France
Prof. Dr. Martin Fussenegger

Cistronics Cell Technology GmbH
Zurich, Switzerland
Dr. Andrzej M. Kierzek

University of Surrey
School of Biomedical and Molecular Sciences
Guildford, UK
Dr. Bernd Reiss

Max Planck Society for the Advancement of Science
Max-Planck Institute for Plant Breeding Research MPIZ
Cologne, Germany
Prof. Dr. Walter Schaffner

University of Zurich-Irchel
Institute of Molecular Biology
Zurich, Switzerland
PLASTOMICS
State-of-the-Art:
Project Type: Plastid transformation is the most precise method of integrating foreign genes in plants. It
Specific Targeted offers the possibility of cheap and large-scale production for therapeutic proteins, such as
Research Project hormones and vaccines, and also for food of improved nutritional quality. Plastid transfor-
mation and high level expression of foreign proteins in chloroplasts in tobacco leaves is well
Contract number: established. However, the commercial success of plastid transformation as a production
LSHG-CT-2003-503238 platform, depends mainly on the successful high level expression in non-green plastids (such
Starting date: as chromoplasts and amyloplasts), using crops that are amenable to processing.
1st February 2004
Duration:
42 months
Scientific/Technological objectives:
EC Funding: The aim of the project was to define the mechanisms and to improve the understanding of
`2 384 000 the genes and proteins involved in several key stages of plastid transformation and foreign
gene expression, in different plastid types, in tobacco, tomato and potato. Genomics and
proteomics approaches were used to identify genes and proteins involved in several proc-
esses: 1) transgene integration and marker gene excision via homologous recombination;
2) regulated gene expression in chloroplasts, chromoplasts and amyloplasts; 3) protein
degradation in different plastid types.
The project was divided into 3 work packages (WPs). WP1 relates to transgene integra-
tion and marker excision. WP2 relates to regulated plastid gene expression. WP3 relates
to protein degradation in different plastid types. WP3 aimed to identify the proteolysis
systems in plastids that may limit the expression of transgenes in plastids. It also aimed to
develop cleavable protein-fusion systems that may protect foreign proteins from proteolysis
and simplify protein purification.
Expected results:
WP1’s achievements are as follows:
1. Identification (using database searches) of genes encoding putative components of the
plastid recombination system in higher plants and isolation of tobacco cDNAs encod-
ing some of these plastid recombination proteins.
2. Characterization of transgenic tobacco plants with altered expression of genes encod-
ing plastid recombination proteins to examine the effects on transgene integration and
marker excision
3. Optimization of plastid transformation vectors, with different amounts of flanking plastid
DNA, and with foreign genes of different length, orientation and control sequences.
4. Proof-of-concept of an novel system of automatic marker excision, using transformation
vectors with the selectable marker gene located outside the plastid sequences flanking
the transgene.
1. Determination of the complete nucleotide sequences of the plastid genomes of tomato
and potato.
2. Use of DNA microarrays and macroarrays for examining transcripts of all plastid genes
and open reading frames in tomato fruits and in potato tubers.
3. Characterization of nuclear-encoded RNA polymerases (NEP) and identification of
NEP-transcribed plastid genes.
4. Production of improved plastid transformation vectors, with altered sequences in the
vicinity of the translation initiation codon.
1. Identification by database searches of genes and cDNAs encoding components of
plastid proteolysis systems in tobacco, tomato and potato, and production of trans-
genic tobacco with alteration of levels of ClpC.
2. Production and introduction of gene constructs into the tobacco plastid genome for
three cleavable protein-fusion systems.
Mechanisms of transgene integration
and expression in crop plant plastids,
underpinning a technology
for improving human health
Potential impact:
The PLASTOMICS team expects the project to result in
improved understanding of processes involved in plastid
transformation, and in improved efficiency of plastid trans-
formation and transgene expression in tomato and potato.
This has the potential to impact significantly on the area of
plant biotechnology applied to human health, through the
production of protein products of benefit to human health
and food, with better nutritional value.
Keywords: gene integration, gene expression,

protein degradation, plastid trans-
formation, proteomics, plant models
Partners
Prof. John Gray Prof. Philip Dix
University of Cambridge National University of
Department of Plant Sciences Ireland Maynooth
Downing Street Biology Department
CB2 3EA Cambridge, UK Maynooth, Co Kildare, Ireland
jcg2@mole.bio.cam.ac.ak
Dr. Anil Day

Victoria University of Manchester
School of Biological Sciences
Manchester, UK
Prof. Zach Adam Prof. Tony Kavanagh

Hebrew University of Jerusalem Trinity College Dublin
Department of Agricultural Botany Smurfit Institute
Jerusalem, Israel Department of Genetics
Dublin, Ireland
Prof. Ralph Bock
Max-Planck Institute of Dr. Stefan Herz
Molecular Plant Physiology Icon Genetics AG
Golm, Germany Research Centre Freising
Munich, Germany
Dr. Janusz Bujnicki
International Institute of Dr Silva Lerbs-Mache
Molecular and Cell Biology Université Joseph Fourier Grenoble 1
Laboratory of Bioinformatics Laboratoire Plastes et
Warsaw, Poland Differenciation Cellulaire
Grenoble, France
Dr Teodoro Cardi
Consiglio Nazionale Delle Ricerche
CNR-IGV, Institute of Plant Genetics
Research Division Portici
Rome, Italy
TAGIP
www.eurotagip.com
State-of-the-Art:
Project Type: Plants can be considered as natural, solar energy powered, and environmentally friendly
Specific Targeted protein factories that can be genetically improved for the production of proteins with thera-
Research Project peutic value. It is crucial that the production of target proteins is well controlled in terms of
Contract number: high and steady yield, and tissue-specific deposition allowing for easy harvest, extraction
and purification. However, current transgenesis technologies are not accurate enough to
LSHG-CT-2005-018785 secure a protein production scheme that demands such high reliability and precision.
Starting date: Random chromosomal integration of transgenic inserts often causes unpredictable misregula-
1st December 2005 tion of their transcription, including complete gene silencing. Therefore, the abilities to modify
Duration: the plant genome in a precise manner and/or control the chromatin environment of transgen-
ic inserts, are arguably the most important missing technologies in the toolkit of plant biolo-
36 months
gists. DNA integration, via homologous recombination (Gene Targeting, or GT) has proved
EC Funding: to be a powerful technology in many species. In particular, it enables not only targeted gene
`1 980 972 disruption or replacement of an endogenous locus by a modified or different gene, but also
expression of a new protein in the genomic context of the native gene. GT enables a precise
alteration of genomes, from single nucleotide modifications to gene replacement or knockout.
It is an invaluable tool for functional genomics as well as for biotechnology. Despite its success
in other organisms, GT has not yet become a routine technique in plants, owing to the natu-
rally low frequencies of homologous, as compared to non-homologous, DNA integration.
New findings, several of which originate from the TAGIP partners, as well as advances in
functional genomics, suggest that the precise engineering of plant genomes structure by GT,
via DNA integration at any locus or at specific sites, has recently become a realistic goal.
Achieving this goal will involve the following activities: 1) gaining fundamental knowledge
in the field of genome maintenance/modifications via DNA recombination; 2) applying this
knowledge to develop new technologies for precise engineering of plant genomes in the
model organism Arabidopsis and in selected crop plants; and 3) using this knowledge for
the production of proteins of high value in the most suitable crop.
There are three specific objectives:
1) Stimulation of GT via reduction of non-homologous DNA recombination pathways;
2) Enhancing the rate of GT in Arabidopsis via over-expression of GT-related proteins;
3) Testing for synergistic interactions between partner proteins, to stimulate GT.
Expected Results:
The exploitable products expected from this project include a technological platform for GT
in crops and a technological platform for protein production in plants (based on GT). This
project will speed up the acceptance of new GM corn in Europe. The Biogemma consor-
tium, which includes key EU players for crop improvement, guarantees the preservation of
EU Plant Biotech and Seed Business company competitiveness. This will ensure that in the
future era of GM crops in Europe, EU companies will not have to pay large royalties to US
competitors, to gain access to GT technologies necessary for the registration of GM traits.
Potential Impact:
Industry competitiveness and societal problems:
An important aspect of this project is that in the EU, public reluctance to consume GMO
products has slowed down progress in agricultural biotechnology, while in other countries
(such as the USA, China, Japan), this Agro-biotech revolution is taking place. A technol-
Targeted Gene Integration in Plants:
Vectors, Mechanisms and
Applications for Protein Production
ogy such as GT, enables precise and controlled alteration of the Size Markers
genome. A B kDa
124
The European added-value: 79
One reason to carry out this work at European level is that research 48
38
in DNA recombination in plants is far more advanced in Europe 25
than in the USA, and it should be further supported to maintain 18
this competitive edge. The proposed TAGIP project brings together 13
leading groups in the field of DNA recombination in plants, thus 11
further increasing the competitiveness of the EU in this field.
Innovation aspects:
One single protein, Poly Phenol
At a technological level, the project plans to turn GT into a routine tool in plants. This technol-
ogy has a very high potential economic impact in the Agro-biotech industry, as well as on Oxydase (PPO), consitutes 60%
the pharma industry via “molecular farming” for protein production in plants. At a scientific of the proteins in trichomes (leaf
level, the mechanism whereby GT occurs is still poorly understood in higher eukaryotes. The hairs) of tomato. Trichome are
team will test several genes, working at different levels of the DNA recombination process thus ideally suited for protein
(initiation, invasion, strand exchange, heteroduplex formation and resolution), for their effect
production and purification. One
on GT. of the goals of TAGIP is to replace
PPO by a gene of interest for
Keywords: high and specific expression and

homologous recombination, gene targeting, protein production, for simple purification.
model organisms, Arabidopsis, genome structure and mainte-
nance, functional genomics, plant technologies
Partners
Prof. Avi Levy Prof. Jerzy Paszkowski
Weizmann Institute of Science University of Geneva
Faculty of Biochemistry Département de Biologie
Department of Plant Sciences Végétale
Herzl St. 2 Geneva, Switzerland
7600 Rehovot, Israel
avi.levy@weizmann.ac.il Dr. Pascual Perez
Biogemma SAS Les Crezaux
Dr. Charles White Aubière, France
Centre National de la Recherche
Scientifique (CNRS) Dr. Hagai Karch
UMR47, Université Blaise Pascal Evogene Ltd
Aubière, France Rehovot, Israel
Prof. Holger Puchta Prof. Barbara Hohn

University of Karlsruhe Novartis Forschungsstiftung
Botanical Institute Zweigniederlassung
Karlsruhe, Germany Friedrich Miescher
Institute for Biomedical
Dr. Karel J. Angelis Research
Institute of Experimental Basel, Switzerland
Botany ASCR
Molecular Farming and Dr. Pnina Dan
DNA Repair Laboratory OSM-Dan Ltd
Prague, Czech Republic Rehovot, Israel
MEGATOOLS
www.cellectis.com/megatools
Project Type:
State-of-the-Art:
SME- Specific Targeted The genome sequence programmes have contributed a huge amount of information, and
Research Project created many possibilities. An exhaustive catalogue of genes is now available for many
organisms, but the real meaning of this information remains to be deciphered. Thus, the
Contract number:
success of functional genomics definitively lies in the development of novel tools breaking
LSHG-CT-2006-037226 through the practical limits it suffers today. Meganucleases-induced recombination could
Starting date: provide a practical alternative to current approaches. Meganucleases are, by definition,
1st October 2006 sequence-specific endonucleases with large (>14 bp) recognition sites. However, the inacti-
Duration: vation or modification of any and all known genes, or genomic sequence, depends on the
availability of Meganucleases that cleave within or in the vicinity of each gene sequences.
36 months This issue would be addressed if it was possible to rapidly engineer the specificity of natural
EC Funding: Meganucleases.
`1 999 962
The first objective of the project is to provide the means to modify a large number of se-
quence in rodent genomes. The second is to develop the tools to engineer a large number
of rodent genes, for functional genomic purposes. Since meganuclease-induced recombina-
tion represents an extremely powerful tool for gene alteration, we will focus on the genera-
tion of four kinds of results:
1) A large collection of novel meganucleases. This collection of novel proteins should

greatly enhance the repertoire of natural meganucleases and thus allow for the target-
ing of a large number of genes in organisms whose genome has been sequenced,
with a strong focus on rodent genomes.
2) The means to exponentially increase this collection. The collection of novel meganucle-
ases should provide a unique database of characterised DNA binders. Structural and
statistical studies should reveal the laws governing these interactions, and this data
Purpose of MEGATOOLS could in turn be used in a predictive way, for the design of novel meganucleases.
and strategy for meganuclease 3) The methods, procedures and quality standards to make these meganucleases widely
engineering usable as research tools.
4) A refined method to use these mega-
nucleases in cells. The focus will be
on mouse cells for functional genom-
ics, providing a direct validation.
Expected Results:
1) Protein engineering: Partner 1 has
established the basis of a combina-
torial process to assemble functional
engineered meganucleases. We ex-
pect this combinatorial strategy to
provide a functional meganuclease
for most chosen gene.
2) Computational biology: The FoldX al-
gorithm can successfully predict the
effect of protein mutation on the spe-
cificity of protein-DNA recognition
specificities. Subsequent versions of
New tools for Functional Genomics
based on homologous recombination
induced by double-strand break
and specific meganucleases
FoldX should allow for more efficient design of meganucleases combinatorial process.
3) Structural Biology: A continuous flow of novel structures that will contribute to the
computational steps is expected.
4) Standardisation of protein storage and use: An efficient purification and characterisa-
tion process for each engineered protein is expected.
5) Validation of the general approach: The whole approach should eventually be vali-
dated by the use of engineered meganucleases on real chromosomal targets in rodent
cells. A general, standard protocol for rodent cells is expected.
Potential Impact:
The possibility of correcting errors in a genome through targeted homologous recombina-
tion or modifying at will any DNA sequence is clearly enormously attractive to the scientific
community. Although it is clearly valuable to understand how genomic information is trans-
lated into function, rational modification of the DNA sequence of an organism has been
limited by the time consuming process it requires, despite the development of new tools for
the construction of targeting vectors. Thus, the possibility of having new tools that will al-
low targeting of any DNA sequence for insertion, deletion or repair could introduce a new
revolution in the field of functional genomics and could also bring a new paradigm and a
new momentum to human gene therapy.
Keywords:
genome engineering, protein engineering, meganucleases, gene targeting, homologous
recombination, functional genomics, tools and technologies
Partners
Dr. Frédéric Pâques
CELLECTIS SA
102 Route de Noisy
92 235 Romainville Cedex, France
paques@cellectis.com
Prof. Guillermo Montoya Blanco

Centro Nacional de Investigaciones Oncologicas (CNIO)
Structural Biology
Macromolecular Cristolography Group
Madrid, Spain
Prof. Luis Serrano

Centro de Regulacio Genomica
System Biology Laboratory
Barcelona, Spain
Dr. Arvydas Lubys

Fermentas UAB
Vilnius, Lithuania
2. REGULATION OF
GENE EXPRESSION
2.1
TRANSCRIPTION
REGULATION
TRANS-REG
X-TRA-NET
TRANS-REG
www.imbb.forth.gr/people/talianidis/strep.htm
Project Type:
State-of-the-Art:
Specific Targeted In the pathways of gene expression, the first regulated and, in most cases, rate-limiting step
Research Project is the process of transcription. Despite the detailed picture that is emerging, a great number
of conceptual as well as mechanistic questions still need to be resolved. One of the main
Contract number: gaps in our knowledge is the limited insights we have on transcription regulation in the nu-
LSHG-CT-2003-502950 clear environment. The general goal of the project is to obtain a comprehensive knowledge
Starting date: on the mechanism of regulation of model genes during cell differentiation, cell proliferation
and signal transduction. The consortium will undertake concerted efforts to develop and
1st April 2004 apply fluorescent imaging techniques, coupled with genetic, proteomic and conventional
Duration: molecular and cell biology approaches to study the molecular characteristics and functions
36 months of individual multiprotein complexes, and their dynamic interplay in the context of unique
EC Funding: chromatin structures in living cells.
`1 860 000
The objectives of this project are:
s ANALYSIS OF THE SPATIAL DISTRIBUTION OF THE DIFFERENT COMPLEXES IN THE NUCLEUS COLO-
calisation studies by indirect immunofluorescence assays in vivo and in situ protein-
protein interaction studies by FRET (fluorescence resonance energy transfer)
s ANALYSISOFTHESUBNUCLEARDISTRIBUTIONOFTHECOMPONENTSOFCOMPLEXESINRELATIONTO
known nuclear structures under different conditions
s BIOCHEMICALANALYSISUSING#HROMATINIMMUNOPRECIPITATION#HIP ASSAYSOFTHETIME
course of assembly of complexes on model genes induced during cell differentiation,
cell proliferation and signal transduction
s in situ analysis by FLIP (fluorescence loss in photobleaching) and FRAP (fluorescence
recovery after photobleaching) of the time course of assembly of complexes on a
model gene and its relationship with transcription initiation
s ANALYSIS OF THE DYNAMIC REDISTRIBUTION OF GENES BETWEEN NUCLEAR TERRITORIES CORRE-
sponding to euchromatin and heterochromatin during gene activation/ repression
s ANALYSISOFPOSTTRANSLATIONALMODIlCATIONSOFTHECOMPONENTSOFCOMPLEXESANDTHEIR
role in subnuclear targeting
s GENETIC AND PROTEOMIC ANALYSIS IN YEAST drosophila and mice, and cross-species
comparisons of the individual complex components.
Expected Results:
The successful execution of the project is expected to result in:
1. new knowledge on the in situ dynamics of the RNA polymerase-II machinery
2. new knowledge on the molecular mechanism of transcription regulation that leads to
pathway-specific gene expression programmes
3. development of new technologies and research tools.
The results of the first 18-month period resulted in 4 joint publications and 27 individual
publications in high impact scientific journals. These and other results of the research can
be found on the project’s website.
Potential Impact:
The consortium is developing and applying state-of-the-art in vivo imaging techniques based
on FRET, with improved spatial and temporal resolution and mathematical tools to extract
three-dimensional information from two-dimensional spatial images. Development of high
sensitivity and quantitative assays for chromatin immunoprecipitation is also an important
deliverable of the project. While the work focus is on transcription complexes, we be-
Transcription Complex Dynamics
Controlling Specific Gene
Expression Programmes
lieve that the technologies and
the research tools generated
in parallel will be useful for a
broader range of biological
applications.
The project combines and ex-
pands individual activities with
a more comprehensive collab-
oration.
Keywords:
Localization of TBP and TBP2
gene expression, transcription, (TBP-related factor 3) during
RNA polymerase-II, transcrip-
mouse folliculogenesis. TBP and
tion regulation, transcription
factors, complex-complex in- TBP2 exhibit different localization
teractions, signal transduction pattern. TBP expression is absent
in the oocyte but present in
surrounding follicular cells. TBP2
is detected exclusively in oocytes.
Partners
Prof. Iannis Talianidis Dr. Marc Timmers
Foundation for Research and Technology – Hellas University Medical Centre – Utrecht
Institute of Molecular Biology and Biotechnology Laboratory for Physiological Chemistry
Vassilika Vouton P.O. Box 1527 Utrecht, The Netherlands
71110 Heraklion, Greece
talianid@imbb.forth.gr Dr. Laszlo Tora
Institut de Génétique et de
Prof. Imre Boros Biologie Moléculaire et Cellulaire
University of Szeged Illkirch, France
Faculty of Science
Department of Genetics and Molecular Biology
Szeged, Hungary
Dr. Annick Harel-Bellan

Centre National de la Recherche Scientifique (CNRS)
Institut André Lwoff
Villejuif, France
Prof. Dr. Michael Meisterernst

GSF-Forschungszentrum für Umwelt
und Gesundheit
National Department of Gene Expression
Munich, Germany
Dr. Alexander Pintzas

National Hellenic Research Foundation
Institute of Biological Research and
Biotechnology
Athens, Greece
X-TRA-NET
http://rxrnet.dk/

Specific Targeted
Research Project The majority of nuclear receptors signal as heterodimers with the promiscuous retinoid X
receptors (RXRs). Heterodimerisation introduces several key regulatory features to the RXR
Contract number:
family, as it specifies response element recognition and allows dual ligand input in an HD-
LSHG-CT-2005-018882 specific manner. Together these features allow the large family of RXR heterodimerising
Starting date: nuclear receptors to establish a plethora of cognate ligand-dependent gene networks that
1st September 2005 regulate major aspects of cell and organ function during embryogenesis and in the adult.
Duration: Importantly, nuclear receptors are “druggable” and play central roles in major diseases
42 months like cancer, diabetes and atherosclerosis. Hitherto, heterodimer target gene regulation has
only been investigated by a gene-by-gene approach. Thus, key aspects of this regulatory
EC Funding:
network, such as the identity of primary targets and their response dynamics, sharing of
`1 950 000 targets by different heterodimers, nuclear receptor subtype and ligand dependency, are
entirely unknown.
The main objective of X-TRA-NET is to develop and employ chromatin-immunoprecipitation
(ChIP) in combination high throughput sequencing (ChIP-seq) to explore the complex transcrip-
tional network of RXR and its partners. X-TRA-NET will use this combination to investigate the
impact of position and binding site diversity on the mechanisms of RXR target gene activation.
The complex interplay between cellular context, target site diversity and receptor subtype
specificity will also be addressed. Furthermore, the genome-wide ChIP analyses will be used
to investigate how treatment of cell culture and animal models with different ligands targeting
the heterodimerization partner, or RXR itself, differentially affects recruitment of the NRs and
their associated co-factors to target sites. Thus, X-TRA-NET aims to provide the first “proof of
concept” for the use of genome-wide ChIP technology in NR ligand profiling. This would rep-
resent a major leap forward in NR pharmacogenomics by providing the missing link between
in vitro ligand binding studies and testing these putative drugs in animals.
Expected Results:
Global RXR target site profiles will be generated by ChIP-seq. These analyses will allow us
to gain insight into several aspects of the RXR transcriptional network. These will include:
1) the impact of position and binding site diversity on the composition, kinetics and
spatio-temporal action of transcription-factor/co-factor complexes recruited
2) molecular mechanisms underlying nuclear receptor subtype specific action
3) molecular mechanisms of RXR agonists
4) molecular mechanisms of selective nuclear receptor modulators, thereby providing
proof of concept that the ChIP-seq approach is suitable nuclear receptor profiling.
Potential Impact:
The ChIP-seq approach pioneered by X-TRA-NET will serve as a model to tackle other
transcription factor families. In addition, due to the central role of nuclear recepors in a
number of major diseases, the new insight into the nuclear receptor field would significantly
improve our understanding of the molecular mechanisms of the etiology and treatment of
major diseases like cancer, insulin resistance and atherosclerosis. In addition, proof of con-
ChIP-Chip to Decipher
Transcription Networks of RXR and Partners
cept that ChIP-seq technology can be used in nuclear receptor drug discovery will provide
companies with hitherto unsurpassed insight into the molecular mechanisms underlying the
physiological effects of their drugs. Thus X-TRA-NET is likely to increase competitiveness of
European biotechnology and pharmaceutical companies.
Keywords:
chromatin-IP, nuclear receptors, global target site array, ligand specific effects, co-factors,
pharmacogenomics, transcription factors, high-throughput techniques, ChIP-chip
Partners
Project Coordinator: Dr. Dean Hum
Prof. Susanne Mandrup GENFIT
University of Southern Denmark Loos, France
Molecular Biology
Campusvej 55
5230 Odense M, Denmark
s.mandrup@bmb.sdu.dk
Prof. Hendrik G. Stunnenberg

Stichting Katholieke Universiteit
Deptartment of Molecular Biology
Nijmegen, The Netherlands
Dr. Hinrich Gronemeyer

Centre Européen de Recherche en Biologie
et Médecine - Groupement d’Intérêt
Economique
Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC)
Illkirch, France
Prof. Bart Staels

Université de Lille 2 - Droit et Santé
Department of Atherosclerosis
Institut Pasteur de Lille
Lille, France
2.2
EPIGENETIC
REGULATION
THE EPIGENOME
HEROIC
ChILL
SMARTER
THE EPIGENOME
www.epigenome-noe.net
Project Type:
State-of-the-Art:
Network of Excellence In this “post-genomic” era, advances in epigenetic research represent a new frontier that is
Contract number: predicted to yield novel insights into gene regulation, cell differentiation, stem cell plastic-
ity, development, human diseases, cancer, infertility and ageing. According to an impor-
LSHG-CT-2004-503433
tant emerging concept, there is an “epigenetic code”, which greatly extends the potential
Starting date: information of the genetic code. Based on this concept, one genome can generate many
1st June 2004 “epigenomes”, as the fertilised egg progresses through development and translates its infor-
Duration: mation into a multitude of cell fates.
60 months In general, epigenetic research covers many topics that are of key interest to the public and
scientists alike, such as embryonic and adult stem cells. Epigenetic research is therefore
EC Funding: anticipated to have far-reaching implications for medicine and for the understanding of the
`12 500 000 basic processes of cell fate determination. The developments of research in this field will
therefore undoubtedly impact academic and industrial research communities and will form
an important knowledge-base for policymakers and public bodies that contribute to the
socio-economic future of our “post-genomic” society.
Europe has many world-leading laboratories in epigenetic research. The Network of Excel-
lence (NoE) project EPIGENOME, proposes to follow a progressively expanding strategy.
In the initial phase of the project, 25 teams with a proven record as leaders in their field
will combine their expertise and resources and will constitute the “virtual core centre” of
the project.
During the course of the project, 22 additional “junior” researchers (newly established
teams, or NETs) will be supported and integrated via the NET programme, which will pro-
vide them with access to a world class epigenetic research platform.
The EPIGENOME NoE aims at reinforcing existing synergies to build a strong base for sci-
entific excellence. Furthermore, it seeks to promote the ERA not only by means of a strong
research programme, but also by integrating and disseminating the project’s activities,
including an efficient communication infrastructure to enable internal communication of
geographically dispersed teams and to foster a dialogue with the public.
The NoE comprises around 25 of the leading European research groups to study epigenetic
mechanisms. Together, they constitute the critical mass for an internationally competitive
research programme. This programme is structured into 8 research topics to build on the
current strengths of the NoE. Within this framework, the 8 sub-programmes will address a
number of the ‘big questions’ in epigenetic research, thereby providing a coordinate ap-
proach to establish a research force of world-class standard.
There are 8 sub-programes:
1. Chromatin modification 5. Transcriptional memory
2. Nuclear dynamics 6. Assembly & nuclear organisation
3. Non-coding RNA & gene silencing 7. Cell fate & disease
4. X-inactivation & imprinting 8. Epigenomic maps
The major advantage of the NoE is that the common theme of chromatin modifications
will ideally interconnect most of the projects carried out by the individual members. Thus,
although there are progressively increasing layers of experimental approaches in different
organisms to study the complex mechanisms of epigenetic control in regulating information
of the chromatin template, all 8 research topics can be integrated into a logical platform,
central to the unravelling of the many questions that will lead to a deeper understanding of
stem cell plasticity and disease.
Epigenetic plasticity of the genome
Based on the resources and expertises provided by this NoE, and
fostered by the numerous collaborations even broader initiatives can
be envisaged. These can include large-scale profiling for decipher-
ing the epigenetic plasticity of the genetic information by genome-
wide microarray analyses. The availability of genomic micro-arrays
in genetically tractable organisms, together with the expertises of
ChIP-on-chip technology and modification-specific histone antibod-
ies places this NoE in a strong position to analyse the differences
between stem cells versus committed cells and to map epigenetic
transitions along entire chromosomes (chromosome landscaping).
With respect to model organisms, THE EPIGENOME represents a
multidisciplinary project covering S.cerevisiae, S.pombe, plants,
Drosophila, mouse and human. It integrates high-end genetic, bio-
chemical, cytological and micro-array approaches for a functional
analysis of epigenetic control.
The strength of this NoE is in its focus on molecular mechanisms
rather than on descriptive analyses. In addition, thanks to the ex-
pertise of the NoE members, some of the most important questions
in modern epigenetic research may be addressed. The implications
of epigenetic research are far-reaching and range from agriculture
to human biology and disease, including our understanding of stem
cells, cancer and ageing.
Genomes vs Epigenomes
The programme of EPIGENOME NoE rests on 5 pillars, namely, a joint research pro-
gramme that is directed towards elucidating epigenetic mechanisms; a Newly Established
Team (NET) programme to integrate ‘junior’ scientists into the NoE; measures ensuring
network development and durability; communication platforms to address the needs of both
scientific exchange, and public consulting and a management structure that will underpin
the network.
Expected Results:
Research into epigenetics represents the new frontier for addressing many questions that,
despite a vast resource of existing genetic data, still remain unanswered. The importance
of the “epigenetic code” concept explains why it is essential to have a better understanding
of the processes of cell fate determination: better knowledge means better understanding of
disease and development, and will therefore, improve intervention strategies for multifacto-
rial disease.
The recent discoveries related to an epigenetic “histone code” and the function of the RNAi
machinery in epigenetic silencing only serve to highlight the emerging new concepts in
epigenetic research. In this sense, the creation of a NoE will not only provide an important
nucleation point for durable structure research, but will also overcome the problem of frag-
mentation by promoting the longer-term aims of scientific progress, and by contributing to
an expanding and dynamic community.
Our increasing understanding of epigenetic control should therefore foster the development
of innovative strategies for therapeutic intervention based on regulatory pathways of epi-
genetic mechanisms.
Epigenetics covers many topics of key interest to the general public, including embryonic
and adult stem cells, their medical use and the cloning of whole animals. Advances in epi-
genetic research are expected to have far-reaching implications for medicine and human
health. By acknowledging its responsibility towards the public, the NoE is committed to
ensuring the dissemination of knowledge regarding epigenetic research and its societal im-
plications. With these measures the NoE aims to provide a benchmark for a new European
partnership between science and society.
THE EPIGENOME
THE EPIGENOME group
Potential Impact: Partners

In defining a coordinated joint programme
Prof. Thomas Jenuwein
of activities (JPA), this NoE will assimilate ex-
Research Institute for Molecular Pathology (IMP)
isting synergies for building a structure that Dr. Bohr-Gasse 7
can feed three important needs: advance 1030 Vienna, Austria
scientific discoveries, integrate European thomas.jenuwein@imp.univie.ac.at
research and establish an open dialogue.
The project’s main objectives will contribute Dr. Denise Barlow
to the long-lasting determination of a co- Research Center for Molecular Medicine
herent European Research Area (ERA) on Vienna, Austria
epigenetic research. In the short term, THE
EPIGENOME aims at constituting a frame- Prof. Ingrid Grummt
work for important discoveries in Europe, Deutsches Krebsforschungszentrum Heidelberg
thus establishing the NoE as an internation- Division Molecular Biology of the Cell II / A030
ally competitive research force. As a con- Heidelberg, Germany
sequence, the NoE will provide a platform
for the development of epigenetic research, Prof. Jörn Walter
benefiting not only the NET members, but Universität des Saarlands
also the wider scientific community Department of Genetics
A major goal of THE EPIGENOME is to Saarbrücken, Germany
support post-doctoral research, thereby al-
lowing the team to gain visibility at interna- Prof. Peter Becker, Philipp Korber
tional meetings and to disseminate their re- Ludwig-Maximilians-Universität
sults. The NoE organises annual meetings,
Adolf-Butenandt-Institut Molekularbiologie
Munich, Germany
workshops and the ‘Alan Wolffe’ Epigenet-
ics Conference, which provides a venue to Prof. Gunter Reuter
effectively showcase the NoE’s excellence. Martin-Luther-Universität Halle-Wittenberg
The EPIGENOME also promotes initiatives Institut fur Genetik
for dialogue and disseminates information to Halle, Germany
the public via organised events, the media,
and the World Wide Web. This will help the Prof. Frank Grosveld, Peter Verrijzer
public keep pace with new developments Erasmus Medical Center
in knowledge, technology and innovation, Rotterdam, The Netherlands
and facilitate a greater acceptance of sci-
entific endeavours. As a consequence, the Prof. Robin Allshire, Dr. Adrian Bird, Dr. Irina Stancheva
public could have a more informed role in University of Edinburgh
scientific governance, particularly on impor- Wellcome Trust Centre for Cell Biology
tant issues for society, which also raise ethi- Edinburgh, United Kingdom
cal questions.
Prof. Wendy Bickmore, Prof. Neil Brockdorff
Prof. Amanda Fisher
Keywords: The Medical Research Council
Faculty of Medicine
chromatin modification, RNA silencing, epi- MRC Clinical Sciences Center
genetic code, cell fate determination, repro- Lymphocyte Development Group
gramming
Edinburgh, United Kingdom
Epigenetic plasticity of the genome
Prof. Bryan Turner Dr. Fred van Leeuwen, Dr. Bas van Steensel
The University of Birmingham Het Nederlands Kanker Instituut
School of Medicine Amsterdam, The Netherlands
Department of Anatomy
Birmingham, UK Dr. Valerio Orlando
Fondazione Telethon
Dr. Wolf Reik, Dr. Patrick Varga-Weisz Dulbecco Telethon Institute
Dr.Miguel Constancia Naples, Italy
The Babraham Institute
Developmental Genetics & Imprinting Laboratory Prof. Susan Gasser, Dr. Antoine Peters
Cambridge, United Kingdom Dr. Dirk Schübeler
Friedrich Miescher Institute for Biomedical Research
Prof. Azim Surani Basel, Switzerland
The University of Cambridge
Gurdon Institute Dr. Ana Losada, Dr. Oskar Fernandez-Capetillo
Cambridge, United Kingdom Centro Nacional de Investigaciones Oncológicas
Madrid, Spain
Prof. Peter Meyer
The University of Leeds Dr. Ortrun Mittelsten Scheid
Leeds, UK Gregor Mendel-Institut
Vienna, Austria
Dr. Genevieve Almouzni, Dr. Edith Heard
Centre National de la Recherche Scientifique (CNRS) Dr. Leonie Ringrose
Institut Curie Institute of Molecular Biotechnology
Paris, France Vienna, Austria
Prof. Philip Avner Dr. Deborah Bourc’his

Centre National de la Recherche Scientifique (CNRS) Institut National de la Santé et de la Recherche
Institut Pasteur Médicale (INSERM)
Paris, France Institut Jacques Monod
Paris, France
Prof. Jerzy Paszkowski
Université de Genève Dr. Wolfgang Fischle
Geneva, Switzerland Max Planck Institute for Biophysical Chemistry
Goettingen, Germany
Prof. Ueli Grossniklaus
Universität Zürich Dr. Robert Schneider
Institute of Plant Biology Max Planck Institute of Immunobiology
Department of Plant Developmental Biology Freiburg, Germany
Zurich, Switzerland
Prof. Renato Paro
Dr. Asifa Akhtar, Dr. Andreas Ladurner Eidgenössische Technische
European Molecular Biology Laboratory (EMBL) Hochschule Zürich
Heidelberg, Germany Basel, Switzerland
Dr. Karl Ekwall

Karolinska Institutet
University College Södertörn
Stockholm, Sweden
Dr. Vincent Colot

Plant Genomics Research Unit
Institut National de la Recherche Agronomique (INRA)
Evry, France
Dr. Giacomo Cavalli

Institut de Génétique Humaine
Montpellier, France
The complete list of the 22 newly established groups integrated might not appear due to space limitations;
see project web site for updated information
HEROIC

Integrated Project
Contract number: At last the completed genetic code of many organisms gives science the chance to under-
stand how genes build organisms. Unfortunately, like all truly great codes, simply decoding
LSHG-CT-2004-018883
the letters does not explain how life is manifest, since buried deep in the primary genetic
Starting date: code is a second regulatory code, which we need to decipher to understand how the ge-
1st November 2005 nome works. This regulatory code is encrypted in chromatin and 3D nuclear organisation,
Duration: and functions to regulate the accessibility of the primary genetic information. We know
52 months that there is linear genome organisation and that genes subject to similar regulatory con-
EC Funding: trols are adjacent to each other. What we do not yet know is the extent of these ‘genome
domains’ – if domains operate between different chromosomes, or how domains are set
`12 000 000
up and maintained. Answers to these questions will depend upon global and long-range
genome strategies that need the development of high-throughput technologies. HEROIC will
take a two-pronged approach. First, it will develop global biochemical and high-throughput
genomic tools and screens that will identify novel gene regulators and determine when
and where transcription factors, histone modifying enzymes and chromatin remodelling
proteins interact with the primary genetic code. Then well-characterised progenitor-differ-
entiation systems, such as pluripotent mouse ES cells and paradigm silencing models from
genomic imprinting and X-inactivation, will be studied using high-throughput ChIP-on-chip,
chromosome interaction and whole genome nuclear localisation assays to provide basic
information on linear and 3D genome organisation. HEROIC will provide knowledge that
contributes to a functional understanding of gene regulation in a genome context. It will
inject epigenetic research with high-throughput technology on a genome-wide scale, thus
making a wider contribution to understanding the primary genetic code that will eventually
allow society the full benefit expected from its decryption.
The main objective of HEROIC is to make significant advances in the mechanistic ques-
tions of epigenetic regulation, characterise the epigenetic modifications that occur, and
then understand the implications for gene expression in different cell types. The approach
focuses on the use of high-throughput enabling technologies on predominantly primary and
established mouse cell lines, particularly ES cells.
To characterise the epigenome, high-throughput bisulphite sequencing, advanced mass

spectrometry applied to histone post-translational modifications, ChIP-on-chip, and three
dimensional interaction mapping and profiling DNA replication timing across the genome
will be applied to ES cells, mutated ES cells and macrophages differentiated from these ES
cell lines. This will allow a comparison of pluripotent to differentiated aspects and changes
of the epigenome in a model case. As a complement, aspects of the epigenome will be
mapped in the haematopoietic compartment in the mouse.
Expected Results:
The histone code
HEROIC aims to unravel the meaning of the epigenetic code. This requires comprehensive
documentation of coding combinations, the hierarchies and cross signalling within the code
and understanding what the code means.
High-Throughput Epigenetic Regulatory
Organisation in Chromatin
Whole genome epigenetic and

transcription factor profiling
HEROIC will screen whole ge-
nome tile path arrays to identify
and compile a definitive set of
non-coding regulatory elements
for the mouse genome yielding
a TRR microarray. HEROIC will
screen high-density oligonu-
cleotide arrays at nucleosome
resolution to study the epige-
netic response of cells in cul-
ture to short-term treatment with
hormones in relevant regions of
the genome. It will use the TRR
microarrays to profile changes
in gene expression and chro-
matin structure that underlie the
Overview of
reprogramming of differentiated
HEROIC’s scientific goals
B-lymphocytes towards the my-
eloid lineage by the enforced expression of the transcription factor CEBP.
In-depth DNA methylation and epigenetic profiling of mouse Chromosome 17

HEROIC aims to provide a comprehensive map of epigenetic layers of chromosome 17
ranging from histone marks, factors that read, write and interpret the marks, DNA meth-
ylation and parental imprinting to understand how transcription networks and epigenetic
information contribute to the formation of specialised cell types in multicellular organisms.
HEROIC will focus on two fundamental areas: pluripotency and lineage restriction.
The epigenetic dimension of global genome structure and nuclear organisation

HEROIC addresses epigenetic aspects of nuclear architecture and its relevance to cell com-
mitment and memory by exploiting well-defined cellular systems to examine how gene
regulation is affected by global genome structure and nuclear organisation.
Bioinformatics
HEROIC will accumulate all epigenetic data generated as well as public data. The accumu-
lated datasets will be analysed for currently unknown patterns of epigenetic states.
Potential Impact:
s+NOWLEDGEBASE
The main impact of the HEROIC IP will be research into gene regulatory systems at
the level of chromatin structure and nuclear organisation, with high-throughput tech-
nology approaches in the context of the whole genome. Never before has such an
extensive multidisciplinary consortium been assembled at European level.
s,INKAGEOFTECHNOLOGYPLATFORMS
The yield of cumulative joint research carried out in this IP will stimulate competitive-
ness within Europe and between other developed countries, such as the US and
Canada. HEROIC will also act as a focal point within Europe for the development of
novel technology applied to chromatin and nuclear organisation studies.
HEROIC
s4RAININGANDDEMONSTRATION
The undertaking of proactive training will contribute to extending the widespread use
of the technology employed by consortium members to address other research ques-
tions.
s+NOWLEDGEDISSEMINATION
HEEROIC aims to disseminate actively but also protect research results where com-
mercial exploitation is a possibility. Dissemination will occur in the form of joint publi-
cations and within the network through conferences and workshops.
s!CADEMIC SOCIALRESPONSIBILITY
Researchers of HEROIC will be called upon as expert voices in discussions within
Europe on topics such as stem cell therapy, novel genetic and epigenetic diagnostic
screening methods and gene therapies involving RNAi.
Keywords: epigenetics, chromatin, gene regulation, high-throughput techniques
©Shutterstock, 2007
High-Throughput Epigenetic Regulatory Organisation in Chromatin
Partners
Project Coordinator: Prof. Matthias Merkenschlager
Prof. Henk Stunnenberg Medical Research Council
Stichting Katholieke Universiteit MRC Clinical Sciences Centre
Department of Molecular Biology Lymphocyte Development Group
Geert Grooteplein 28 London, UK
6500 HB Nijmegan, The Netherlands
h.stunnenberg@ncmls.ru.nl Dr. Miguel Beato
Centre de Regulació Genòmica
Project Manager: Department of Chromatin & Gene Expression
Dr. Adrian Cohen Barcelona, Spain
Scientific Manager
Nijmegen Centre for Molecular Life Sciences (NCMLS) Dr. Edith Heard
P.O. Box 9101 Institut Curie Paris
6500 HB Nijmegen, The Netherlands Nuclear Dynamics and Plasticity of the Genome
Paris, France
Prof. Denise Barlow
CeMM - Forschungszentrum für Dr. Kurt Berlin
Molekulare Medizin GmbH Epigenomics AG
Institute of Microbiology and Genetics Science Department
Vienna, Austria Berlin, Germany
Prof. Rolf Ohlsson

Uppsala University
Department of Development & Genetics
Uppsala, Sweden
Dr. Matthias Mann

Max-Planck Society for the Advancement of Sciences
Proteomics and Signal Transduction
Martinsreid, Germany
Prof. Francis Stewart

Technische Universität Dresden
Biotec and Genomics
Dresden, Germany
Dr. Stephan Beck, Dr. Dave Vetrie

Genome Research Ltd
Wellcome Trust Sanger Institute,
Immunogenomics Laboratory
Cambridge, UK
Dr. Ewan Birney

European Molecular Biology Laboratory (EMBL)
Hinxton, UK
Didier Allaer
Diagenode SA
Science Department
Liege, Belgium
ChILL
State-of-the-Art:
Project Type: The sequence of an organism’s genome does not directly determine how the genome is
SME- Specific Targeted used to build the organism. A second, more complex regulatory code - the epigenetic code
Research Project - is encrypted in the chromatin structure and the 3D nuclear organisation of chromosomes.
Contract number: Epigenetic information is encoded in DNA modifications (namely methylation), chromatin
composition and modification, and nuclear topology, or the dynamic organisation of the
LSHG-CT-2006-037462 genome within the nucleus.
Starting date: Epigenetic information not only provides the first cue to allow a cell to interpret the genome,
1st October 2006 it can also be heritably transmitted through cell division to maintain cellular identity. Moreo-
Duration: ver, while many heritable disorders in humans are caused by DNA sequence changes (mu-
36 months tations) that abolish gene expression, a number of diseases are caused by inappropriate
gene silencing brought about by epigenetic modifications. Indeed, most cancers involve the
EC Funding: epigenetic silencing of genes that normally control cell proliferation. The principal forms of
`1 800 480 epigenetic modification are DNA and histone methylation.
A challenge that is central to modern biology is the identification of the spatial and tempo-
ral dynamics of epigenetic factors in a number of physiological situations. The Chromatin
Immuno-Precipitation (ChIP) assay has played a pivotal role in deciphering patterns of
epigenetic marks that govern gene transcription. Besides ‘classical’ ChIP, several similar
techniques have been described in the literature. Recently, new technologies designed to
improve on the existing ChIP and native ChIP (NChIP) technologies, have emerged.
In addition, low resolution and reproducibility problems are often encountered. These se-
vere limitations of the ChIP method are overcome by the Chromatin Immuno-Linked Ligation
(ChILL) method, , which could provide the foundation for a new generation of biotechnology
tools and methods.
The objective of this project is to develop and validate a new technology which has the
potential to replace the various ChIP technologies, and to transform the way the molecular
analysis of chromatin is performed. The ChILL technique has been patented by one of the
partners of this project, leaving the consortium free to operate with regard to intellectual
property rights. The ChILL method is based on specific ligations which occur between DNA
stretches under diluted conditions. In this environment, ligation partners can only interact if
they are in close proximity.
This proximity is created by new oligonucleotide-antibody conjugates (nucleoproteic probes,
or oligo-ab), which physically place the target DNA in contact with the oligonucleotide re-
porter sequences. The ligation products are then amplified by the polymerase chain reac-
tion and analysed with real-time instruments and/or classical gel electrophoresis.
Due to the ligation step taking place under diluted conditions, the ChILL method will gen-
erate data comparable to those obtained with ChIP, but with increased sensitivity and a
simpler protocol that omits the tedious immuno-precipitation step. As a proof of principle,
the ChILL method has already been shown to be at least 100 times more sensitive than the
regular ChIP assay.
ChILL will not only facilitate analysis of very small samples, such as early embryos or diag-
nostic samples from patients, but will also radically improve the resolution of the epigenetic
marks. In addition, strong detergents used in the ChILL assay open up the chromatin struc-
ture, rendering it more accessible to antibodies than in conventional ChIP assays.
Another major advantage of ChILL will be its ability to interrogate several parameters in a
single sample. For this purpose, a variant of ChILL called combinatorial ChILL will be devel-
oped. This will represent a major breakthrough, because it will mean that several epigenetic
marks can be collected from a single tube, making it easier to build up what might be called
an “epigenetic profile” of the biological material in question.
Chromatin Immuno-linked ligation:
A novel generation of biotechnological
tools for research and diagnosis
Expected Results:
The Chromatin Immuno-Precipitation (ChIP) assay plays an absolutely pivotal role in deci-
phering patterns of epigenetic marks that govern gene transcription. While the ChIP assay
is a versatile tool, it suffers from low resolution and low sensitivity. These strong limitations
of the ChIP method are overcome by the Chromatin Immuno-Linked Ligation (ChILL) meth-
od. ChILL will not only facilitate analysis of very small sample sizes, such as early embryos
or diagnostic samples from patients suffering from a range of diseases, but also radically
improve the resolution of the epigenetic marks. The ChILL approach also offers opportuni-
ties to examine simultaneous co localization of two or more factors on the same chromatin
template, and the epigenetic marks will be resolved in unprecedented detail.
The expected results of the program would be to make ChILL technology accessible to all
European research laboratories via validated procedures, reagents or kits. We also ex-
pected to launch diagnostic kits using ChILL technology for the diagnosis of diseases linked
to epigenetic disorders.
Potential Impact:
The first impact of ChILL will be a better understanding of the epigenetic code. Of course,
the commercial impact of the ChILL method might consequently also be very important for
Diagenode with the possible development of tools for the research or diagnostic market.
Keywords:
chromatin remodeling, transcription regulation, epigenetics, ChIP assay, histones,
DNA methylation
Partners
Didier Allaer
Diagenode SA
Avenue de L’Hopital, 1 Tour Giga B34
4000 (Sart Tilman) Liège, Belgium
didier.allaer@diagenode.com
Dr. François Fuks
Prof. Dr. Rolf I. Ohlsson Free University of
Uppsala University Brussels
Development and Faculty of Medicine
Genetics Evolution Center Laboratory of
Uppsala, Sweden Molecular Virology
Brussels, Belgium
Prof. Dr. Henk G. Stunnenberg
Radbout University Nijmegen Dr. Duncan Clark
Department of Molecular Biology GeneSys Ltd
Nijmegen, The Netherlands Camberley, UK
SMARTER
State-of-the-Art:
Project Type: The identity of a given cell within a metazoan organism is primarily defined by the expression
SME-Specific Targeted pattern of its genes. The activation and repression of genes is tightly regulated by the con-
Research Project certed action of transcription factors that recognise and bind specific DNA sequences within
Contract number: regulatory regions. Work done over the last 20 years established this basic regulatory mecha-
nism of gene activation and repression, while recent experiments have exposed an additional
LSHG-CT-2006-037415 layer of regulation involving modifications of DNA and bound histones. These modifications
Starting date: are involved in cellular inheritance of transcriptional states through cell division and develop-
1st December 2006 ment, and as they are not coupled to DNA sequence, are referred to as epigenetic.
Duration:
Many factors that impact on epigenetic phenomena are clearly distinct from basic transcrip-
48 months
tion factors and are involved in regulating chromatin structure. Modulation of chromatin
EC Funding: structure is frequently achieved by intrinsic enzymatic activities that either mark particular
`2 499 999 regions within the genome for activity or repression, or use the hydrolysis of ATP to remodel
nucleosomal arrays. This alteration of gene expression patterns in response to external and
internal signals has a major influence on stem cell differentiation, the maintenance of tissue
integrity, and the adaptation of organisms to environmental changes.
Recently, small molecules that target histone deacetylases (HDAC) have been used in the
treatment of cancer, opening up new avenues in therapeutic research. However, small
molecules targeting epigenetic regulators have so far not been the major focus of drug
discovery efforts.
The SMARTER project aims to develop such compounds, and this is also the primary mis-
sion of Chroma Therapeutics, the SME participating in the consortium. The interaction be-
tween leading European chromatin labs and Chroma is expected to greatly strengthen the
company’s knowledge base, and thus, have a powerful impact on its ability to enter drug
candidates for clinical trials.
The SMARTER project has the following goals:
1) Identification of small molecule inhibitors that target various histone-modifying en-
zymes (SMARTERs);
2) Validation of these inhibitors through in vivo analysis of histone modification states;
3) Establishment of histone modification states as standard readouts for drugs that target
epigenetic modifiers;
4) Improvement of known epigenetic modulators through medicinal chemistry;
5) Identification of target genes that are regulated by the SMARTER molecules and
6) Application of the SMARTER molecules in standard animal model systems to verify
their activity in living organisms.
Expected Results:
After 48 months, SMARTER will provide:
1) SMARTER molecules that are selective for specific histone deacetylases and two ad-
ditional targets, with high potency;
2) An assay system for new epigenetic modifiers that is applicable to high throughput
screen for small molecule inhibitors;
3) Definition of SMARTER effects on histone modification patterns and kinetic analysis
of effects on chromatin;
4) Identification of one or several bona fide target genes for direct SMARTER effects;
Development of small modulators
of gene activation and repression
by targeting epigenetic regulators
5) Establishment of one or several SMARTER molecules for one or several targets that
show an in vivo effect in mice;
6) Demonstration of global and gene-specific effects of SMARTERs on the epigenetic
pattern of lymphomas in a model of radiation-induced lymphomagenesis, with a
view to investigating the chemotherapeutic potential of SMARTERs.
Potential Impact:
The SMARTER project is specifically designed to increase the knowledge base of Chroma
Therapeutics, a SME located in the UK. Chroma will profit from the collaboration, because
the consortium will greatly facilitate the analysis of SMARTER molecules that have been and
will be discovered by the company. The project will also allow Chroma to direct improve-
ment of the small molecules through medicinal chemistry, and to test them rapidly in various
biological systems. Being a SME-targeted STREP, the project will contribute significantly to
the Lisbon objective of Europe becoming the most competitive knowledge-based economy
in the world by 2015.
The knowledge gained through this project will be disseminated and translated into new
therapies and clinical practice. SMARTER will have a strategic impact on European R&D
through facilitating the generation of small molecules that are cell-permeable and that dura-
bly change chromatin modification states. In order to fully understand how the eukaryotic
genome in general and the human genome in particular operate, knowledge about their
DNA sequence, epigenetic control systems and dynamic structure in relation to gene ex-
pression must be integrated.
Keywords: epigenetics, small molecules, gene regulation
Partners
Prof. Axel Imhof
Ludwig Maximilians University of Munich
Adolf-Butenandt Institute
Histone Modifications Group
Protein Analysis Core Facility
Schillerstr. 44
80336 Munich, Germany
imhof@lmu.de
Dr. Scott Cuthill

Chroma Therapeutics Ltd
Oxford, UK
Dr. Dirk Schübeler

Friedrich Miescher Institute for
Biomedical Research
Basel, Switzerland Prof. Tony Kouzarides
University of Cambridge
Dr. Manuel Esteller The Wellcome Trust
Spanish National Cancer Centre Cancer Research
Cancer Epigenetics Laboratory UK Gurdon Institute
Madrid, Spain Cambridge, UK
3. STRUCTURAL GENOMICS
& STRUCTURAL
PROTEOMICS
3.
STRUCTURAL
GENOMICS
3DGENOME FESP
BIOXHIT E-MeP-Lab
3D-EM HT3DEM
GeneFun NMR-Life
E-MeP Extend-NMR
FSG-V-RNA IMPS
VIZIER SPINE2-COMPLEXES
UPMAN OptiCryst
NDDP TEACH-SG
3D repertoire
3DGENOME
http://3dgenome.uva.sara.nl/3dg.html
Project Type:
State-of-the-Art:
Specific Targeted
Research project Understanding the molecular mechanisms that underlie the orchestration of many thousands
of genes in higher eukaryotes is a key target in modern biomedical research. Our knowl-
Contract number:
edge about gene regulation at the single gene is rapidly expanding. However, understand-
LSHG-CT-2003-503441 ing of the coordination of gene regulation, for example during cell differentiation and dis-
Starting date: ease, is still remarkably limited. There is considerable evidence that the three-dimensional
1st December 2003 folding of the DNA chain, packaged as chromatin, plays an important role in gene control.
Duration: The 3DGENOME project has the ambition to force a breakthrough in our understanding of
the relationship between the functioning of the human genome and its 3D structure inside
42 months the cell nucleus. To this end we analyse the 3D folding of the human genome inside its natu-
EC Funding: ral environment, i.e. the cell nucleus, and relate this to its transcriptional activity. This study
`2 173 803 combines 3D light microscopy with genome-wide information about gene activity.
The 3DGENOME project is based on the systematic and large-scale combination of two
main technologies:
sHIGH THROUGHPUTmUORESCENTin situ hybridisation (FISH) followed by 3D light microscopy
sDATAANALYSISTHATRELATES$STRUCTURALINFORMATIONTOTHEHUMANTRANSCRIPTOMEMAP
A major challenge is created by the large cell-to-cell variation of 3D chromatin structure in
otherwise identical (cultured) human cells. Novel methods are developed to identify signifi-
cant structural features that stand out against this ‘noisy’ background. At the same time it is
essential to quantify and characterise this cell-to-cell variation precisely. Results will tell which
aspects of chromatin structure are important for genome function and which are not.
An integral part of this approach is the development of novel high-throughput 3D imag-
ing routines in combination with automated 3D image processing and quantitative image
analysis. Specific aspects of 3D chromatin structure will be analysed by high-resolution light
microscopy, including 4Pi microscopy.
Most of the work is carried out with primary human cells and cell lines. In addition, Dro-
sophila is used as a system in which specific changes can be made in the genome, after
which the effect of 3D chromatin structure can be analysed.
Expected Results:
The 3DGENOME project is unveiling the link between the folding of the chromatin/chromo-
some fibre inside the interphase nucleus and the functional (primarily transcriptional) proper-
ties of the human genome. It builds on the human transcriptome, which shows genes of high
transcriptional activity in a limited number of gene-dense clusters in the genome. Results of
these studies will give new insight into how the eukaryotic genome in general, and the human
genome in particular, operates inside the living cell. This project will lay the groundwork for
understanding how, beyond the regulation at the individual gene level, a large-scale chromatin
structure affects the complex gene regulation networks in normal and deceased cells.
Potential Impact:
1. Fundamental insight into the relationship between gene regulation and 3D struc-
ture of the eukaryotic genome. To understand fully how the eukaryotic genome in
general, and the human genome in particular, operate, knowledge about its DNA
sequence, its epigenetic control systems and its dynamic 3D structure in relation to
gene expression must be integrated.
3D Genome Structure and Function
2. High resolution 3D microscopy and related software tools 3DGENOME will bring
forth new developments on the areas of high-resolution 3D light microscopy, 3D im-
age processing and quantitative analysis of acquired images. Furthermore, we will
develop methods to quantitatively compare and statistically analyse 3D structures
and distribution in biological specimens.
Keywords: 3D structure, fluorescent in situ hybridization, gene expression, high

throughput imaging analysis
Partners
Project Coordinator: Dr. Hans van der Voort
Prof. Roeland Van Driel Scientific Volume Imaging BV
Universiteit van Amsterdam Hilversum, The Netherlands
Science Faculty
Swammerdam Institute for Life Sciences
Kruislaan 318
1098 SM Amsterdam, The Netherlands
van.driel@science.uva.nl
Prof. Dr. Thomas Cremer

Ludwig-Maximilians-Universität München (LMU)
Department of Biology II
Martinsried/Munich, Germany
Prof. Dr. Christoph Cremer

Angewandte Optik und
Informationsverarbeitung
Kirchhoff Institut für Physik
Heidelberg, Germany
Prof. Dr. Roland Eils

Deutsches Krebsforschungszentrum (DKFZ)
Division of Theoretical Bioinformatics
Heidelberg, Germany
Prof. Dr. Giacomo Cavalli

Centre National de la Recherche Scientifique (CNRS)-IHG
Montpellier, France
Prof. Dr. Rogier Versteeg

University of Amsterdam
Academisch Medisch Centrum
Prof. Dr. Stanislav Kozubek

Academy of Sciences of the Czech Republic
Institute of Biophysics
Brno, Czech Republic
BIOXHIT
www.bioxhit.org

Integrated Project
Contract number: The recently acquired knowledge pertaining to numerous genome sequences provides a
unique opportunity to quantitatively decipher the roles of biological molecules in complex
LSHG-CT-2003-503420
processes within cells, organs and organisms. An essential step in accomplishing this task
Starting date: is to determine their atomic structures; this permits a more comprehensive description of the
1st January 2004 roles of molecules in living systems, in the context of both health and disease. The acquisi-
Duration: tion of structural information on biological macromolecules on a genomic scale lies at the
54 months core of Structural Genomics (SG).
EC Funding:
At present, the only techniques appropriate for determining three-dimensional (3D) struc-
`9 993 849
tures of biological macromolecules in atomic detail, and at a rate appropriate for SG, are
biological X-ray crystallography (biocrystallography) and NMR-spectroscopy. Biocrystal-
lography has been responsible for roughly 85% of all biomolecular structures (and for 95%
of all the smallest proteins) deposited in the Protein Data Bank (http://www.rcsb.org/pdb)
and the Molecular Structural Database (http://www.ebi.ac.uk/msd).
Biocrystallography has undergone a tremendous transitional period over the past decade.
Formerly, determining a macromolecular crystal structure required years; today it would
typically require a few weeks, if not days. And crucially, the potential for further improve-
ment is far from exhausted. Furthermore, recent technological advances have made a wide
range of new biological problems responsive to crystallographic study. Although obtaining
large amounts of a protein in soluble form is still in many cases an important issue, bioc-
rystallography is in principle applicable to the complete spectrum of biological macromol-
ecules, derived from all organisms (from eubacteria and archeae, to human organisms),
and of all sizes (from small domains to gigantic ribosome or virus particles).
BOIXHIT Group
The central objective of the BIOXHIT project entails tackling the challenge posed by the
Structural Genomics initiatives already underway in the USA and in Japan, and to de-
velop, assemble, standardise and provide a highly integrated technology platform for High
Throughput Structural Biology. This goal will be attained as a result of coordinated efforts
with the present and future European synchrotron radiation facilities, and a team of inter-
nationally recognised European leaders in hardware and software development, directly
associated with high-throughput methodologies.
Bio-Crystallography on
a Highly Integrated Technology Platform
for European Structural Genomics
Biocrystallography is the method of choice, and synchrotron radiation the principal source
of X-rays, for data acquisition. This technology encompasses the components necessary to
produce an efficient pipeline linking crystallisation to completed 3D-structure determination.
It will operate with minimal user intervention, and will be fully accessible to the wider life
sciences research community.
Expected Results:
BIOXHIT aims to deliver the following results:
s!N EXTENSION OF THE LIMITS OF CURRENT CRYSTALLISATION TECHNOLOGIES TOWARDS THE USE OF
smaller crystallisation drops, with less protein consumption;
s(IGHERQUALITYCRYSTALSFOR8 RAYDIFFRACTIONANDENHANCEDSTABILITYOFCRYSTALSINTHE
X-ray beam;
s!DVANCED SYNCHROTRON BEAMLINE TECHNOLOGIES DEVELOPED FOR STANDARD AUTOMATED
and easy-to-operate beamlines, providing high-quality stable X-rays, that are auto-
matically delivered to the sample;
s)MPROVEDMEANSOFRELIABLEAUTOMATEDHANDLINGANDCHARACTERISATIONOFTHECRYSTAL
in order to optimally plan the actual diffraction experiment;
s!STRUCTUREDETERMINATIONPIPELINECONSOLIDATEDFROMTHEBOTTOMUPSOASTOENSURE
the success of the experiment at the earliest possible stage, and to allow direct feed-
back for data collection and crystallisation;
s!LOGISTICSARCHITECTURETHATCANACCOMMODATEMAXIMUMAUTOMATION
s%FlCIENTDATAMANAGEMENTANDFULLPROJECTTRACKINGINCLUDINGTHEPOSSIBILITYOFREMOTE
control;
s%FlCIENTBIOINFORMATICSSOFTWAREARCHITECTURETHATISDEVELOPEDTOLINKTHESTEPSMEN-
tioned above, and high-level training in new hardware;
s3OFTWARETECHNOLOGIESANDHIGH LEVELTRAININGTHATAREPROVIDEDTORESEARCHERSBOTH
within and external to the BIOXHIT consortium.
Potential Impact:
BIOXHIT provides a substantial component in scientific as well as technical innovation. The
task of building such integrated platforms entails numerous developments in instrumentation
and in hardware automation. Instances of this are the complete tracking of crystal samples
during synchrotron experiments, and interaction with the project information management
systems of the users; the automated handling of crystal samples by robots, their automatic
recognition and centring on the goniometric hardware; and their automated screening.
The BIOXHIT project activities include innovative developments in many of these directions,
(as exemplified in the mini-kappa goniometer and its control software), and therefore pro-
vide access to new categories of data collection strategies hitherto inaccessible. Another
prominent feature of BIOXHIT is the assembly of a computational crystallographic pipeline,
which aims at automating the sequence of steps involved in determining macromolecular
crystal structures. This requires a dramatic paradigm shift in X-ray crystallographic meth-
odology, as compared to the old paradigm, whereby the successive steps of structure de-
termination were performed by crystallographers running computer programs interactively
through graphical interfaces, to a new pipeline operating with little or no human interven-
tion. The immediate demand for such integration will be met by connecting these programs,
BIOXHIT
BIOXHIT: Integration and Activity Areas
Standardisation Sample Core hardware Core software Diffraction Logistics / remote

preparation developments developments Experiment operation / integration
and
manipulation
1 2 3 4 5
The BIOXHIT project: Relationship Crystallisation Synchrotron Beamline end- Data processing and Databases and
between activity areas, partner technologies technologies stations and data structure determination networking
collection
contributions, workpackages
and sections. Each link defines a
contribution of a Partner to a WP.
thus emulating the actions of a crystallographer by the execution of suitable scripts. The
complexity of this approach should not be underestimated; it will serve to deliver a first
generation of integrated structure determination pipelines.
BIOXHIT ultimately proposes to achieve a genuine integration of all of the processes into
a single, seamless computational scheme that will be structured around a conceptual uni-
fication of the structure determination process. This demands a radical rethinking of X-ray
crystallographic methods, and a profound reorganisation of their software implementation
around the modern techniques of object-oriented programming. In return, it will deliver a
markedly powerful second generation of integrated pipelines, as well as considerably im-
proved software for general use. The combination of hardware and software innovations
will in turn render new phasing techniques accessible, such as routine phasing by means of
anomalous dispersion from sulphur and phosphorus.
The number of scientists from the structural biology community subsequently becoming new
users of the synchrotron facilities has increased rapidly during recent years. Synchrotron
radiation centres have had long experience in training users, but training of the increasing
number of new users represents a challenge that would be impossible to meet by the hard-
ware core-facilities alone. These efforts will be amplified throughout the BIOXHIT project
lifetime. A number of Training, Implementation and Dissemination TID-centres will be estab-
lished outside the participating laboratories as the vital tools for the dissemination of the
developed know-how.
Keywords: synchrotrons, hardware and software pipeline, protein crystallisa-

tion, X-ray crystallography, robotics, automation techniques, stand-
ardisation, technology platform, structural genomics
Partners
Project Coordinator: Project Research Director:
Dr. Victor Lamzin Dr. Manfred Weiss
European Molecular Biology Laboratory (EMBL) European Molecular Biology Laboratory (EMBL)
Outstation Hamburg Outstation Hamburg
Macromolecular Crystallography Macromolecular Crystallography
22603 Hamburg, Germany 22603 Hamburg, Germany
victor@embl-hamburg.de msweiss@embl-hamburg.de
Bio-Crystallography on a Highly Integrated Technology Platform
Project Manager: Prof. George Sheldrick Dr. J. Juanhuix

Natalie Sebastian Georg-August-Universität Göttingen Campus Universitat
European Molecular Biology Göttingen, Germany Autònoma de Barcelona
Laboratory (EMBL) Consorci Laboratori de
Outstation Hamburg Dr. Andrew Thompson Llum de Sincrotó
c/o DESY Societe Civile Synchrotron SOLEIL Barcelona, Spain
Notkestr. 85, building 25A Gif-sur-Yvette, France
22603 Hamburg, Germany Dr. Edgar Weckert
natalie.sebastian@embl-hamburg.de Dr. Thomas Schneider Deutsches Elektronen
Fondazione Italiana per Synchrotron
Dr. Raimond Ravelli la Ricerca sul Cancro Hamburg, Germany
(since 2008 replaced by Dr. Andrew McCarthy) Milan, Italy
European Molecular Biology Laboratory (EMBL) (Since 2007 at the project Dr. Gábor Mihály Lamm
Outstation Grenoble coordinator’s site) EMBLEM Enterprise
Grenoble, France Management
Dr. Marjolein Thunnissen Technology Transfer GmbH
Dr. Kim Henrick Lund University Heidelberg, Germany
European Molecular Biology Laboratory (EMBL) Department of Molecular Biophysics
European Bioinformatics Institute (EBI) Lund, Sweden Dr. Kristina Djinovic-Carugo
Hinxton, UK University of Vienna
Prof. Sine Larsen Insittute for Biomolecular
Dr. Sean McSweeney University of Copenhagen Structural Chemistry
European Synchrotron Facility Department of Chemistry Vienna, Austria
Grenoble, France Copenhagen, Denmark
Dr. C. Schulze-Briese Dr. Elizabeth Duke, Dr. Colin Nave

Swiss Light Source (SLS) Diamond Light Source Ltd
Villigen, Switzerland Didcot, UK
Dr. Gerard Bricogne

Global Phasing Ltd
Cambridge, UK
Dr. Anastassis Perrakis

Het Nederlands Kanker Instituut Antoni
van Leeuwenhoekziekenhuis
Dr. Roberto Pugliese

ELETTRA Trieste
Sincrotrone Trieste S.C.P.A.
Trieste, Italy
Prof. Keith Sanderson Wilson

University of York
Structural Biology Laboratory
York, UK
Dr. Uwe Mueller

Freie Universität Berlin
Proteinstrukturfabrik c/o BESSY GmbH
Berlin, Germany
Dr. Peter John Briggs

Council of the Central Laboratory
of Research Councils
Warrington, UK
3D-EM
www.3dem-noe.org

Network of Excellence
Contract number: Currently, the primary challenge for biological research lies in understanding the cellular
function in molecular detail, based on genomic and proteomic information. Detailed knowl-
LSHG-CT-2004-502828
edge of the structure of macromolecules and macromolecular complexes, and also of the
Starting date: interaction networks that underlie cellular function, allow for progress in the study of biologi-
1st March 2004 cal processes in health and disease. This project will specify potential targets for therapeutic
Duration: intervention, as well as identify pharmaceutical lead structures.
60 months
EC Funding: Three-dimensional (3D) visualization is the best way to appreciate the complex interactions
of macromolecules, such as proteins. Visual techniques, especially electron microscopy (EM),
`10 000 000
can complement and extend quantitative data obtained using other methods in this field.
EM is a powerful tool that derives 3D structural information from biological specimens. The
specific EM technologies provide 3D projections in a wide spectrum of resolutions ranging
from atomic to cellular. Electron crystallography is applied when studying symmetric 2D
crystals of molecules, such as membrane proteins, showing the same structure and orienta-
tion. Single particle analysis enables the 3D reconstruction of noncrystalline and asymmet-
ric assemblies. The application of electron tomography reveals macromolecular interactions
in native cellular contexts. A near physiological preservation of small cells and viruses is
achieved by rapid freezing in vitreous ice.
The sectioning of these vitreous samples and subsequent cryo-electron tomography, as well
as the 3D reconstruction based on low contrast 2D images, represent technical challenges.
European laboratories and companies are taking the lead in different EM techniques, and
also in their related aspects, like that of image processing. Such interdisciplinary coopera-
tion is required to standardise, develop, improve and combine EM techniques.
The 3D determination of macromolecular structures, such as proteins, will play an essential
role in future life-science research. The 3D-EM network was initiated so as to create a forum
for internationally recognised European manufacturers and institutions, in various fields of
3D structural research. The activities of the network focus on 3D imaging of macromolecules
and molecular machines, as well as cells and cell organelles.
The main objectives of 3D-EM are the following:

1) Improvement and development: 3D-EM improves existing techniques, and also de-
velops novel techniques necessary for 3D visualization of macromolecules and their
functions within cells.
2) Provision of training: The European Molecular Biology Organization (EMBO) annu-

ally offers a continually oversubscribed training course on cryo-EM. A novel course
programme has been established in close collaboration with EMBO. 3D-EM experts
train advanced students and scientists in specific EM techniques, data analysis and
image processing. The courses provide hands-on training, as well as lectures and
seminars concerning the theoretical background of EM methods. Basic skills in state-
of-the-art EM technologies will increase, since new knowledge is included in the ad-
vanced training courses. The training programme, access to central registration and
further details are available on the Internet (http://www.3dem-noe-training.org/).
New Electron Microscopy Approaches
for Studying Protein Complexes
and Cellular Supramolecular Architecture
3) Exchange of knowledge: Expertise gained in EM techniques, especially the inno-

vative cryo-electron microscopy of vitreous sections (CEMOVIS), is disseminated to
scientists both within and external to 3D-EM. In addition to the course programme,
workshops have also been organised, intended to promote discussion and the aware-
ness of new developments in electron microscopy.
4) Standardisation: the processing and comparison of data obtained with the different
EM methods are extremely time-consuming. Standards for 3D image reconstruction
must be identified, developed and tested. An EM data base and an optimal stand-
ard software platform (based on these standards), will be established. User-friendly
interfaces, operating between electron crystallography, single particle analysis and
electron tomography, will reduce processing time. Knowledge and excellence are
spread via collaborations, training courses, scientific meetings and publications.
The results achieved by 3D-EM have been presented at numerous conferences and work-
shops. Furthermore, they have been published in over 65 scientific articles in peer-reviewed
journals, and are listed in detail on the project web page, mentioned above.
Expected Results:
Towards the end of its second year, 3D-EM was reviewed by external experts. These advi-
sors rated the overall project performance as excellent. Over the full project duration, the
following results are expected:
1) Improvement of methods and technologies related to electron microscopy, e.g. speci-

men preparation and image processing
2) Integration of software packages and tools with instrumentation? User-friendly, uni-

versal interfaces between electron crystallography, single particle analysis and elec-
tron tomography
3) Development and use of standards for 3D image reconstruction Expansion of the

network in the direction of Eastern Europe
Setting 3D-EM guidelines for software development and data exchange some highlights of
the current results are:
s!TWO LEVELTRAININGPROGRAMMEINSTRUCTURALBIOLOGYHASBEENDESIGNED-ORETHAN
240 participants, beginners and advanced, were trained in 21 courses
Scientists from several European labs have already been trained in the technology devel-
oped by CEMOVIS. The outstanding results achieved thus far include the development of
several software tools, packages and algorithms, such as the TOM Toolbox and the IPLT
(Image processing library & toolbox) programme.
3D-EM
Potential Impact:
In the field of electron microscopic technologies, 3D-EM provides a platform for the joint
solution of issues. A standardised comparison and exchange of experimental data obtained
with differing EM methods, will facilitate these efforts and contribute to the understanding
of cellular function in molecular detail.
The close cooperation of individuals, respectively grounded in academic and applied re-
search, guarantees an immediate transfer of knowledge and experience from the field of
basic research to industrial application. In addition, the added benefit of improved tools
or instrumentation, suitable for research requirements, strengthens the market position of
European companies.
A growing market for structural biology in Europe generates novel employment opportuni-
ties in this sector, associated with the need for experienced personnel. In collaboration with
the European Molecular Biology Organization (EMBO), 3D-EM created a novel training
programme covering specific aspects of electron microscopy, applicable to both beginners
and experienced scientists.
3D-EM trains and supports groups with experience in electron microscopy to bring them
to the state-of-the-art in terms of methodology and equipment. This strategy will generate a
network of electron microscopy centres across Europe. The network defines future needs for
research, standardisation and instrumentation.
Keywords:
3D electron microscopy, protein complexes, cryoelectron microscopy, electron tomography,
single particle, electron microscopy techniques, imaging, structural biology
Training Program
WP 1
Co-ordination
Electron Single Particle
Electron Tomography Crystallography Analysis
and Network
WPs: 4, 5, 6, 8, 13 WP 7 WPs: 9, 10, 11 Management
WP 12
Setting 3D-EM Guidelines

WPs: 2, 3
New Electron Microscopy Approaches for Studying Protein Complexes
and Cellular Supramolecular Architecture
Partners Prof. Stephen Fuller

University of Oxford
Project Coordinator: Division of Structural Biology
Prof. Andreas Engel Oxford, UK
University of Basel
M.E. Miller Institute for Structural Biology Prof. Marin van Heel
Biozentrum Imperial College
Klingelbergstrasse 70 Centre for Biomolecular Electron Microscopy
CH-4056 Basel, Switzerland Centre for Structural Biology
andreas.engel@unibas.ch London, UK
Project Manager: Prof. Helen Saibil

Dr. Urs Müller Birkbeck University of London
University of Basel Department of Crystallography
M.E. Miller Institute for Structural Biology London, UK
Biozentrum
Klingelbergstrasse 70 Prof. Jacques Dubochet
CH-4056 Basel, Switzerland University of Lausanne
u.mueller@unibas.ch Laboratory of Ultrastructural Analysis
Lausanne, Switzerland
Prof. Wolfgang Baumeister
Max-Planck Institute of Biochemistry Dr. Nicolas Boisset † , Dr. Slavica Jonic
Department of Molecular Structural Biology (MPIB) Université Pierre et Marie Curie
Martinsried, Germany Paris, France
Prof. Werner Kühlbrandt Prof. A.J. (Bram) Koster

Max-Planck Institute of Biophysics Leiden University Medical Center
Frankfurt am Main, Germany Department of Molecular Cell Biology
Electron Microscopy Division
Prof. Jose Carrascosa Leiden, The Netherlands
Consejo Superior de Investigaciones Cientificas
Centro Nacional de Biotecnologia (CNB) Prof. Christian Spahn
Madrid, Spain Charité – Universitätsmedizin Berlin
Institut für Medizinische Physik
Dr. Kim Henrick und Biophysik
European Molecular Biology Laboratory (EMBL) Berlin, Germany
European BioInformatics Institute (EBI)
Hinxton, UK Dr. Sergio Marco
Centre de Recherche Laboratoire
Dr. Achilleas Frangakis Raymond Latarjet
European Molecular Biology Laboratory (EMBL) Institut Curie
Heidelberg, Germany Centre Universitaire d’Orsay
Orsay, France
Dr. Werner Hax
FEI Company
Eindhoven, The Netherlands
Prof. Bertil Daneholt, Prof. Hans Hebert,

Prof. Oleg Shupliakov, Prof. Ulf Skoglund
Medical Nobel Institute
Stockholm, Sweden
Prof. Nicolas Boisset † , Dr. Eric Larquet

Paris, France
Prof. Arie Verkleij

University of Utrecht
Faculty of Biology
Utrecht, The Netherlands
GeneFun
www.genefun.org
State-of-the-Art:
Project Type: Deciphering the information on genome sequences in terms of the biological function of genes
Specific Targeted and proteins is a major challenge of the post-genomic era. Most function assignments for new-
ly sequenced genomes are performed using bioinformatics tools that infer the function of a
Research project
gene on the basis of sequence similarity with other genes of known function. This approach is,
Contract number: however, error-prone. Continuing to use it without clearly defining the limits of its applicability
LSHG-CT-2004-503567 would lead to an unmanageable propagation of errors. On the other hand, various novel
Starting date: bodies of data are being generated. These provide information on the physical and functional
1st March 2004 interactions between genes and proteins, and on whole networks and processes. In parallel,
structural genomics efforts are providing much better coverage of proteins structures and in-
Duration: teractions. This novel data offers an unprecedented opportunity for incorporating higher-level
52 months functional features into the annotation pipeline, and the GeneFun project addressed these
EC Funding: important aspects. To limit error propagation, criteria will be developed for evaluating the reli-
`1 500 000 ability of the annotations currently available in databases, and derived reliability scores will
be incorporated into standard annotation pipelines. To incorporate higher-level features into
functional annotations, the project will combine sequence and structure information in order
to identify non-linear functional features (eg. interaction sites), and will also integrate avail-
able and newly developed methods for inferring function from information on protein domain
architecture, protein-protein interaction, genomic context, etc.
The main objective of the GeneFun project is to develop improved methods for reliably assign-
ing function to genes. To that end it will pursue the following specific scientific and technical
objectives: (1) Quantifying error rates (error baseline) for classical sequence similarity-based
functional annotations from the analysis of meaningful descriptions of protein families and
sub-families, and functional annotations currently available; (2) Developing automatic pro-
cedures for deriving detailed functional descriptors for individual protein families by map-
ping sequence family information onto the experimental or modelled 3D structure, then using
this information to improve functional annotation from sequence; (3) Combining objective 1
and objective 2, in order to enable more efficient and reliable prediction of function from
sequence; (4) Exploiting information on domain architecture to infer context-based function-
al properties, including domain and protein interactions; (5) Developing new methods for
identifying protein-protein interactions by combining information on sequence families, 3D
structure, domain and genome architecture; (6) Benchmarking existing and newly developed
methods for the prediction of interactions, which use context-based approaches, combine
information on sequences families and 3D structure, and analyse various data sets on protein-
protein interactions (obtained through experiments and automatic analyses of published lit-
erature); (7) Integrating sequence similarity-based and context-based prediction methods, and
applying them to verify and improve available annotations of eukaryotic genes and to infer
function for the still important number of non-annotated regions of these genes; (8) Performing
experimental validation of the predicted function and other related features, for a selected
set of proteins of strategic importance for evaluating the performance of the various function
prediction algorithms. Methods and data produced in this project will be made available to
the scientific community through the Internet. This will include a web server for assessing ho-
mology-based annotation reliability, a downloadable protocol for performing the assessment,
and a comprehensive set of protein family trees with structure-annotated functional groups.
Other tools will include an automated system for predicting enzyme function, sites for specific
high affinity recognition, and interaction partners for peptide-binding modules.
Expected Results:
The expected results of the GeneFun project are as follows: (1) improved procedures for
inferring function on the basis of sequence similarity; (2) a set of procedures for predicting
)N 3ILICO Prediction of gene function
non-linear functional features from sequence and 3D structure in a more automated way; (3)
benchmarked procedures for predicting context-based functional features. Major efforts will
be devoted to devising protocols that optimally combine the results from several methods.
In particular, web-based servers for the individual and combined procedures will be devel-
oped and made available to the scientific community. The community will be introduced to
these new tools through open workshops and training sessions.
Potential Impact:
The developed function prediction methods should make a significant contribution towards
improving the in silico annotation of gene function, and thereby have an important impact
on the entire life-science sector, which heavily depends on these annotations.
Keywords: Function prediction, protein structure, protein-protein interactions,

interaction networks, structural genomics
Partners
Project Coordinator: Prof. Cheryl Arrowsmith Prof. Luis Serrano
Prof. Shoshana Wodak Ontario Cancer Institute Center for Genomic Regulation (CRG)
Université Libre de Bruxelles University Health Network Systems Biology Laboratory
Service de Conformation de Toronto, Canada Barcelona, Spain
Macromolecules
Biolgiques et Bioinformatique
Biologie Moleculaire
Avenue F Roosevelt CP 194/6
B-1050 Brussels, Belgium Dr. Christian Blaschke
shoshana.wodak@rogers.com Alma Bioinformatics Sl
Madrid, Spain
Dr. Alfonso Valencia
Centro Nacional de Investigaciones
Oncologicas
Madrid, Spain
Dr. Arne Elofsson

Stockholm University
Stockholm Bioinformatics Center
Stockholm, Sweden
Prof Peer Bork

Heidelberg Outstation
Heidelberg, Germany
Dr. Chen Ceasar. Prof. Daniel Fischer

Ben-Gurion University
Department of Computer Science
Beer Sheva, Israel
Dr. Leszek Rychlewski

BioInfoBank Institute
Poznan, Poland
E-MeP
www.e-mep.org

Integrated Project
Contract number: E-MeP’s research platform focuses on developing and implementing new technologies to
solve the bottlenecks that preclude the determination, at high throughput, of high-resolution
LSHG-CT-2004-504601
structures of membrane proteins and membrane protein complexes. This has been achieved
Starting date: by integrating the activities of many of the world leaders in membrane protein structural
1st May 2004 biology. The E-MeP consortium focuses on developing methods and exchanges laboratory
Duration: and in silico tools, with the aim of solving the structures of membrane proteins, which com-
60 months prise more than 30% of known proteomes.
EC Funding:
Specifically, the heterologous production, purification and crystallisation of a library of
`10 347 066
bioinformatically-selected membrane proteins are being streamlined by elucidating the pa-
rameters responsible for success and failure at each of these key stages. In the process, new
technologies are being developed and commercialised, to overcome existing bottlenecks
peculiar to membrane protein structural genomics, which cannot be solved using existing
methods. A mobilisation of European expertise to address this timely issue, will ultimately
contribute to understanding membrane protein-related human diseases.
E-MeP has several scientific objectives, including the following:
s4OSELECTMEMBRANEPROTEIN-0 TARGETSPROKARYOTICEUKARYOTIC
s4OPRODUCETHESEPROTEINSINUPTOSIXDIFFERENTHOSTSYSTEMSWITHTHEOBJECTIVEOFOB-
taining milligram quantities;
s4OREFOLDORSOLUBILISEATLEAST-0S
s4ODELIVERUPTOPURIlEDPROTEINSSUITABLEFORCRYSTALLISATIONTRIALS
s4OGENERATEUPTONEW$STRUCTURESOF-0S
s4ODEVELOPANINTEGRATEDDATABASECATALOGUING% -E0SRESULTSPROTOCOLSANDOTHER
pertinent data.
Crystal Structure of a Divalent

Metal Ion Transporter CorA at 2.9
Angstrom Resolution.
The European Membrane
Protein Consortium
There are also several specific technological objectives, namely:

s4ODEVISEASPARSEMATRIXOFOPTIMISEDSCREENINGANDEXPRESSIONSYSTEMS
s4OSTANDARDISE% -E0SREFOLDINGTECHNOLOGIES
s4OSTANDARDISE% -E0SSOLUBILISATIONTECHNOLOGIES
s4ODEVISEAPANELOFPURIlCATIONTECHNIQUES
s4ODEVISEASPARSEMATRIXOF-0CRYSTALLISATIONCONDITIONS
s4O IMPLEMENT HIGH THROUGHPUT FORMATSWHEREVER FEASIBLE SO AS TO GENERATE AN -0
structural genomics platform. Overall, the aim is to build a European Membrane Pro-
tein Structural Genomics Research Area.
Expected Results:
The resolution of membrane protein (MP) structures is important for health. The findings of
E-MeP will contribute to scientific communities’ understanding of key biological processes,
and will also serve as templates for structure-based drug design.
Potential Impact:
An increase in the number of membrane protein (MP) structures will help to understand many
basic phenomena underlying the cellular functions essential to human health, and may lead
Structure of a LTC4 synthase;

2.15 Å. Published in Nature,
2007, 448: 613-616
E-MeP
directly to products with both societal impact and commercial value. E-MeP will contribute
to important social requirements related to health, because structural genomics, together
with functional genomics, transcriptomics and proteomics, will open up new routes to fight
disease and will explore new dimensions in biotechnology and bio-nanotechnology.
Keywords:
membrane proteins, protein production, X-ray crystallography, structure determination, 3D
structure, structural genomics
Partners
Dr. Roslyn Bill
Aston University
Department of Life and Health Sciences
Aston Triangle
Birmingham B4 7ET, UK
r.m.bill@aston.ac.uk
Project Manager:
Eric Bourguignon
Aston University
Aston Triangle
Birmingham, BA 7ET, UK
e.bourguignon@aston.ac.uk
Prof. So Iwata, Prof. Naomi Chayen

Imperial College of Science, Technology and Medicine
Division of Molecular Biosciences
and Division of Biomedical Sciences –
Biological Structure and Function Section
London, UK
Prof. Peter Henderson, Prof. John Findlay

The University of Leeds
Astbury Centre for Structural – Molecular Biology
and Faculty of Biological Sciences
Institute of Membrane and Systems Biology
Leeds, UK
Sir John Walker, Dr. Edmund R. S. Kunji

Dunn Human Nutrition Unit
Cambridge, UK
Dr. Franc Pattus

et Médicine (CERBM)
Groupement d’intérêt économique
Illkirch, France
The European Membrane Protein Consortium
Prof. Christian Cambillau Prof. Lars-Oliver Essen

Université de la Mediterranée Phillipps-Universität Marburg
Architecture et Fonction Department of Chemistry
des Macromolecules Biologiques, Marburg, Germany
UMR 6098, CNRS-Université Aix-Marseille I & II
Marseille, France Prof. Pär Nordlund
Karolinska Institute
Dr. Etienne L’Hermite Medical Biochemistry and Biophysics
BioXtal SA Stockholm, Sweden
Mundolsheim, France
Prof. Richard Neutze
Prof. Hartmut Michel Gothenburg University
Max-Planck-Institut für Biophysik Department of Chemistry
Molecular Membrane Biology Biochemistry & Biophysics
Frankfurt am Main, Germany Gothenburg, Sweden
Prof. Richard Cogdell

University of Glasgow
Institute of Biomedical & Life Sciences -
Division of Biochemistry & Molecular Biology
Glasgow, UK
Prof. Paula Booth

University of Bristol
Department of Biochemistry
Bristol, UK
Dr. Nicolas Le Novère

Hinxton, UK
Prof. Horst Vogel

Ecole Polytechnique Fédérale de Lausanne
Laboratoire de Chimie Physique des Polymères
et Membranes (LCPPM)
Institut des Sciences et Ingénierie Chimiques (ISIC)
Prof. Arnold Driessen, Prof. Bert Poolman

University of Groningen
Groningen Biomolecular Sciences and
Biotechnology Institute
Kerklaan, The Netherlands
Prof. Rainer Rudolph

Martin-Luther-Universität Halle-Wittenberg
Institut fur Biotechnologie
Halle, Germany
Prof. Wim de Grip

Stichting Katolieke Universiteit
University Medical Centre Nijmegen
FSG-V-RNA
www.fsgvrna.nmr.ru.nl
State-of-the-Art:
Project Type: We will develop and improve tools and approaches to facilitate the generation of new
Specific Targeted knowledge in functional and structural genomics of viral RNAs. The project exploits avail-
Research project able RNA sequence data but will also expand our knowledge of viral RNA sequence ele-
ments and their variations.
Contract number:
The biomedical importance of RNA as a research target is stressed by the fact that viral
LSHG-CT-2004-503455 infections are global public health problems. The outcomes of the project can initiate the de-
Starting date: velopment of novel drugs that target viral RNA molecules and thus have strong implications
1st July 2004 for public health. The innovative tools developed will open the way for efficient analysis of
Duration: a wide range of RNA-based processes extending far beyond the analysis of viral RNAs.
51 months
EC Funding: Scientific/Technological Objectives:
`2 400 000
RNA is a central molecule in all living organisms. They can adopt a wide variety of confor-
mations ranging from single-stranded to complex tertiary structures tightly associated with
their functions. To understand the function of RNAs, and to act on these functions with small
molecules, it is essential to expand our knowledge of the structure of these molecules and of
their interactions. A multidisciplinary research approach is taken in the project to address
this need, by integrating the research facilities of a number of leading European labs as
well as an SME.
The main objectives of the consortium are:
1. to develop new methods and tools for rapid and efficient structure determination of (large)
RNA and (large) RNA-protein complexes and RNA ligand screening, including:
a) new and streamlined methods for site-specific and segmental 2H, 13C, 15N isotope
labelling of RNAs via in-vitro and/or in-vivo methods
b) to establish, experimentally and theoretically, chemical shift-structure relationships
(CSRs) for 1H, 13C, 15N, 31P of RNAs
c) to implement these (CSRs) and other easily accessible NMR parameters, such as
RDCs and CSAs, in efficient NMR structure calculation protocols
d) to implement scanning probe microscopy (SPM) tools for morphology and interactions.
2. to apply these methods on key viral RNA targets (from HBV, HCV and HIV), which are
currently considered major public health threats. The efforts will be three-fold:
a) characterise the RNA sequences involved
b) perform structural analysis on key RNA elements and/or reconstituted viral RNA and
RNA-protein assemblies either by NMR or SPM for the larger objects
c) produce and identify new antiviral compounds (small molecules, siRNA, modified
oligonucleotides) capable of binding these RNAs. These compounds could provide
the basis for developing new viral agents.
Expected Results:
Novel tools will be developed and implemented, which will provide improved methods for
structural analysis of RNA and RNA-protein complexes. The molecular details obtained by
applying these tools to viral and other important RNA molecules will provide a basis for
the identification and screening of small molecule inhibitors that target key RNA structures.
The unique combination of technological platforms available within the consortium will
add new fundamental knowledge on HCV translation and HBV replication by generating
novel three-dimensional data on the corresponding RNAs and RNA-protein complexes. This
will provide an opportunity to correlate RNA 3D structure with function, and to make the
HCV, HBV and HIV RNA elements and their protein complexes new targets for the rational
design of drug leads. The results of the project will allow a comparative analysis of small
compounds targeting viral RNA elements and antiviral RNAs.
Functional and Structural Genomics
of Viral RNA
Potential Impact:
New and optimised research tools for the structure/function analysis of RNA and RNA-
based processes will be generated. The potential of these tools in correlating structure and
function of RNA molecules and the identification of inhibitors will enhance basic research
on RNA splicing, translation and the recently discovered essential mechanisms for the post-
transcriptional regulation of gene expression that involve non-coding RNAs. These tools are
also expected to enhance our understanding of viral RNAs significantly and to further the
development of new antiviral drugs. The consortium allows the setting up a multidisciplinary
research-project that addresses biomedical questions in a unique way that extends beyond
current research programmes.
Keywords: labelling, synthesis, NMR, screening, function, RNA structure, ge-

nomics, RNA viruses, RNA, RNAi, HBV, HIV, HCV
Partners
Project Coordinator: Prof. Michael Nassal Dr. Karin Kidd-Ljunggren
Prof. Sybren Wijmenga Universitätsklinikum Freiburg Lund University
Radboud University Nijmegen Department of Internal Medicine Department of Medical Microbiology,
IMM/Faculty of Science Laboratory of Molecular Biology Dermatology and Infectious Diseases
Mathematics and Informatics University Hospital Freiburg Lund, Sweden
Toemooiveld 1 Freiburg, Germany
6525 ED Nijmegen, The Netherlands Dr. Richard Blaauw
s.wijmenga@science.ru.nl Chiralix B.V.
Project Manager:
Susanna Bicknell
Radboud University Nijmegen
Faculty of Science
Finance and Economic Affairs
S.Bicknell@science.ru.nl
Prof. Dr. Michael Sattler

Helmholtz Zentrum München
German Research Center
for Environmental Health
And Lehrstuhl Biomolekulare
NMR-Spektroskopie
Department Chemie
Technische Universität München
Garching, Germany
Prof. Frédéric Dardel

Scientifique (CNRS)
Laboratory of Crystallography and
Biological NMR
Paris, France
Prof. Vladimir Sklenar

Masaryk University
National Center for Biomolecular Research
Brno, Czech Republic
VIZIER
www.vizier-europe.org

Integrated Project
Contract number: This project aims to have a significant impact on the identification of potential new drug
targets against RNA viruses through comprehensive structural characterisation of a diverse
LSHG-CT-2004-511960
set of viruses. RNA viruses include more than 350 different major human pathogens and
Starting date: most of the etiological agents of emerging diseases: viruses of gastroenteritis (1 million
1st November 2004 deaths annually), measles (45 million cases and 0.6 million deaths annually), influenza
Duration: (100 million cases annually), dengue fever (300 million cases annually), enteroviruses and
48 months encephalitis (several million cases of meningitis annually), and hepatitis C virus (170 million
EC Funding: infected people in the world).
`12 905 986
The SARS outbreak has dramatically demonstrated how high the economic cost of an epi-
demic caused by an emerging virus could be. This possibility is growing every day as
many governments are being forced to make costly arrangements to cope with the threat of
bio-terrorism, which lists some deadly RNA viruses in its arsenal. To meet these challenges,
science needs to look for new therapeutic and prophylactic substances active against RNA
viruses since those currently available are scarce and of low potency. The common strate-
gies used for the development of antiviral drugs are mainly based on the knowledge ac-
cumulated through studies of virus genetics and structure. Yet, genomic and structural char-
acterisation of RNA viruses was not accepted as a priority until very recently. The VIZIER
project proposes to fill the existing gap between the necessary scientific characterisation of
emerging viruses and pre-clinical drug design.
To address society’s needs, scientists need to anticipate potential threats and be ready
should they arise. The participants of the VIZIER project have created a team that brings
together the leading authorities on RNA viruses in the EU and other countries as well as
many leading European structural biologists. This team includes three partners with P4
facilities, as well as leaders in the field of structural genomics. The development of proto-
cols for high-throughput (HTP) protein production means that a concerted programme of
structure determination is now appropriate and feasible. The VIZIER consortium will char-
acterise RNA viruses that do not include a DNA stage in their replicative cycle. These virus
classes employ profoundly different replicative mechanisms driven by poorly characterised
replication machineries. Although virus-specific, they are the most conserved and essential
viral components and thus the most attractive targets for antiviral therapy. In the framework
of this project the core enzymes/proteins of the replication machinery, carefully selected
among 300 different RNA viruses, including strains of medical interest, will be character-
ised. One unique feature of VIZIER, compared to other structural genomics projects, is the
integration of major structural effort within a broad multidisciplinary study, having virology
upstream and target validation (candidate drug design) downstream. As a result, the im-
plementation plan of the VIZIER project is structured into five interacting scientific sections:
(1) bioinformatics, for genome annotation, target selection and data integration (2) virus
production and genome sequencing (3) HTP protein production (4) HTP crystallisation and
structural determination (5) target validation to assess the function of enzymes and design
strategies for virus inhibition (6) training, implementation and dissemination. This organisa-
tion will allow in record time the full characterisation of a viral target that can quickly be
Crystal structure of the 3C used to design drugs, either by the pharmaceutical industry through the VIZIER industrial
proteinase of coxsackievirus B3 platform or by any research and development institution.
Comparative structural genomics
on viral enzymes involved in replication
Expected Results:
VIZIER will produce an unprecedented wealth of data on replicases of RNA viruses with a
window into the antiviral drug development. A representative set of RNA-based viruses that
belong to three major classes which are profoundly different in their replicative strategies,
will be characterised by a concerted and multidisciplinary effort unparalleled to date. At
the end of this programme, the percentage of sequenced genomes of RNA virus species that
infect vertebrates will virtually double from 30% to 55%. As a case example, the genomic
characterisation of Flavivirus (ssRNA+) and Arenavirus (ssRNA-) genera, which include a
large number of human pathogens, will be systematically executed. A dramatic advance
is expected in the number and diversity of 3D structures of the replicative subunits, now
in the one-digit range. VIZIER will aim to identify lead molecules inhibiting the replicative
enzymes, but will not enter into the broad field of drug development. Offers of cooperation
will be made on a contractual basis to the pharmaceutical and biotechnology industries
for further drug development, and through the VIZIER industrial platform, which connects
upfront scientific results to the pharmaceutical industry.
Potential Impact:
With no equivalent integrated programme in the world, the VIZIER project will undoubt-
edly have a profound impact on the field of structural genomics of emerging viruses. In
particular, it is expected that VIZIER will contribute very significantly to the sequencing of
new viruses (viral genomics) as well as to the deposition of new crystal structures of viral
proteins in the Protein Data Bank. These viral proteins can then be considered as targets for
drug design. There is expected to be considerable scientific impact on drug design through
concepts and methods implemented up to the design stage. Indeed, current drug discov-
ery still often relies on screening compounds in a blind manner. Thousands or millions of
compounds are screened on infected cells or purified enzymes, and ‘hits’ are selected. This
is followed by confirmation of the inhibitor activity and basic toxicology studies, which is
a frequently tedious and uncertain phase for a project. It is widely believed that structural
biology is capable of speeding up the whole process. HTP crystallography, coupled with
a strong validation section such as that proposed in VIZIER, will undoubtedly reinforce this
trend by leading the field. Indeed, the concept of finding a drug and its target together with
the putative bottlenecks in further improvement can prove to be scientifically challenging,
innovative, and promising.
VIZIER will develop new products, technologies and strategies. The products are RNA virus
genomic sequences, soluble viral protein domains, their 3D structures, assigned protein
functions, and inhibitors or ligands for selected protein targets (drug leads). All these prod-
ucts will have a substantial impact on our (currently limited) understanding of the RNA viral
replication machinery. They will also identify entirely new targets for the development of
specific drugs, with a high level of detail. Collectively such information is seen as being of
strong strategic value, not only for the health issues described, but also for the development
of industrial enterprises. Although diverse DNA-based cellular and viral parasites are also
responsible for a large fraction of human infections, none of them are so poorly controlled
by drugs as the RNA viruses. Consequently, drug development against RNA viruses, the
ultimate goal of the VIZIER project, is becoming a top priority for global health-care pro-
grammes.
VIZIER
Keywords: RNA viruses, genomics, structural genomics, antiviral drugs, crys-

tal structure, bioinformatics, protein production, high-throughput,
screening
3D Structure Drug-design
Partners
Dr. Bruno Canard
Laboratoire Architecture et Fonction des
Macromolecules Biologiques UMR 6098
Marseille, France
bruno.canard@afmb.univ-mrs.fr
Dr. Andrei M Leontovich

Moscow State University
A N Belozersky Institute of Physico-Chemical Biology
Department of Mathematical Methods in Biology
Genebee Group
Moscow, Russia
Prof. Miguel Coll

Consejo Superior De Investigaciones Cientificas
Instituto De Biologia Molecular De Barcelona
Madrid, Spain
Prof. Johan Neyts

Katholieke Unversiteit Leuven
Department of Microbiology and Immunology
Division of Virology and Chemotherapy
Leuven, Belgium
Dr. Etienne L’Hermite

BioXtal SA
Mundolsheim, France
Comparative structural genomics on viral enzymes involved in replication
Dr. Paul Tucker Dr. Boris Klempa

European Molecular Biology Laboratory (EMBL) Slovak Academy of Sciences
Hamburg Outstation Institute Of Zoology
Hamburg, Germany Bratislava, Slovakia
Dr. Segolene Arnoux Dr. Jacques Rohayem

Alma Consulting Group Sas Technische Universität Dresden
Innovation Department Institut für Virologie - The Calcilab Medical Faculty
Houlbec Cocherel, France Carl Gustav Carus
Dresden, Germany
Dr. Herve Bourhy
Institut Pasteur Prof. Rolf Hilgenfeld
Laboratoire de la Rage Universität Lübeck
Paris, France Institute of Biochemistry
Lübeck, Germany
Dr. Gerard Bricogne,
Global Phasing Ltd Prof. Paolo La Colla
Cambridge, UK Università Degli Studi di Cagliari
Dipartimento di Scienze E Tecnologie Biomediche
Prof. Dave Stuart Cagliari, Italy
Wellcome Trust Centre for Human Genetics Prof. Par Nordlund
Division of Structural Biology Stockholm University
Oxford, UK Department of Biochemistry and Biophysics
Stockholm, Sweden
Prof. Martino Bolognesi
National Institute for the Physics of Matter - Genova Dr. Eric Leroy, Dr. Jean Paul Gonzales
Udr Genova Institut de recherche pour le développement
Genoa, Italy Paris, France
Prof. Andrea Mattevi Dr. Stephan Günther

University of Pavia Bernhard-Nocht-Institute (BNI)
Department of Genetics and Microbiology Centers for Disease Control and Prevention
Laboratory of Biocrystallography Hamburg, Germany
Pavia, Italy
Dr. Gerhard Puerstinger
Prof. Alwyn T. Jones Universität Innsbruck
Uppsala Universitet Innrain 52a
Uppsala, Sweden Institut für Pharmazie
Innsbruck, Austria
Dr. Alexander Gorbalenya
Leiden University Medical Center
Department of Medical Microbiology
Prof. Ernest Gould

Natural Environment Research Council
CEH Oxford
Polaris House
Swindon, UK
Dr. Helene Norder

Swedish Institute for Infectious Disease Control
Virological Department, Hepatitis Section
Solna, Sweden
UPMAN
http://schwalbe.org.chemie.uni-frankfurt.de/upman
State-of-the-Art:
Project Type: To gain biological function, polypeptide chains generally need to fold into specific 3D
Specific Targeted structures – their native states. Aberrant folding of proteins can lead to a range of other
Research project scenarios, including the development of highly organised and intractable aggregates that
Contract number: are deposited inside or outside cells. Such misfolding events are at the origins of a range
of neurological and systemic diseases that increasingly compromise the quality and ex-
LSHG-CT-2004-512052 pectancy of life and the health resources of advanced societies. The focus of this applica-
Starting date: tion is the development of novel methods to study the structural states of proteins that are
1st November 2004 particularly relevant to understanding protein misfolding and aggregation. In most of these
Duration: states, polypeptide chains acquire structures that differ substantially from those of the native
proteins, which are accessible from conventional approaches of structural biology or from
42 months
structural genomics procedures.
EC Funding:
`1 900 000
In this STREP, a range of complementary NMR approaches will be developed. These ap-
proaches include a variety of NMR techniques, which will be coupled with novel computa-
tional approaches able to define even the disorganised ensembles characteristic of some of
the most interesting and biologically relevant species. These techniques will then be applied
to representative examples of the various types of proteins that are associated with misfold-
ing diseases. These range from native unfolded species (such as a-synuclein associated with
Parkinson’s disease) and partially unfolded intermediates (such as forms of superoxide dis-
mutase associated with motor neuron disease), to the precursors of aggregation prone frag-
ments (such as the Alzheimer precursor protein) and the prion proteins, which are uniquely
associated with transmissible conditions. One of the major aims of this project is to provide
a novel unified view of the conformational behaviour of protein molecules, which will have
a broad significance for understanding important aspects of functional genomics, includ-
ing the fundamental links between genetic mutations and disease, and the mechanisms by
which normally soluble proteins can sporadically misfold, giving rise to a wide range of
disorders associated with diet, medical and agricultural practices and ageing.
NMR is able to provide both dynamic and structural information about proteins in a variety
of different states at atomic resolution. It has the potential for probing residual structure, the
size of aggregating molecules and variation in the internal dynamical properties based on
diffusion-weighted NMR spectroscopy, heteronuclear relaxation measurements, paramag-
netic enhancement of relaxation induced by paramagnetic spin labels, and residual dipolar
couplings.
Expected Results:
Fundamental Research, Structural Studies:
1) Structure of protein-folding intermediates
2) Time course of the folding process
3) Structure of protein aggregates
4) New technologies to characterise protein folding and aggregation at atomic resolution
5) Common factors underlying the development of protein-folding diseases.
Potential Impact:
By generating structural information about prefibrillar states that are currently assumed to be
the most toxic states of protein folding diseases, this STREP research project would help to
develop pharmaceutical products against some of the most debilitating conditions in mod-
Understanding Protein Misfolding
and Aggregation by NMR
ern society. However, in contrast to many other major diseases, the
fundamental mechanism of protein misfolding and aggregation is
less well studied. Therefore, studies aiming at providing a structural
basis for protein misfolding and aggregation are not only at the
forefront of innovative research but are also important assets for the
Life Science and Health priority area of the European Commission.
Keywords: mutation genetics, protein deposition

disorders, molecular evolution
Partners
Project Coordinator: Dr. Ago Samoson
Prof. Harald Schwalbe National Institute of Chemical
Johann Wolfgang Goethe-Universität Physics and Biophysics
Center for Biomolecular Magnetic Resonance Tallinn, Estonia
Institute for Organic Chemistry and Chemical Biology The different states a protein
Marie-Curie-Atr. 11 Prof. Kurt Wüthrich molecule can attain
60439 Frankfurt am Main, Germany ETH Zurich
schwalbe@nmr.uni-frankfurt.de Institute of Molecular
Biology and Biophysics
Prof. Lucia Banci Zurich, Switzerland
University of Florence
Polo Scientifico Dr. Jesús Zurdo
Centro Risonanze Magnetiche (CERM) Zyentia Ltd
Sesto Fiorentino, Italy Babraham Research Campus
Cambridge, UK
Prof. Rolf Boelens
Utrecht University
Bijvoet Center for Biomolecular Research
NMR Spectroscopy Research Group
Prof. Chris Dobson

The University Chemical Laboratory
Cambridge, UK
Prof. Astrid Gräslund

Stockholm University
The Arrhenius Laboratories for Natural Sciences
Department of Biochemistry and Biophysics
Stockholm, Sweden
Prof. Flemming Martin Poulsen

University of Copenhagen
Department of Molecular Biology
Structural Biology
and NMR Laboratory
Copenhagen, Denmark
NDDP
www.projects.bijvoet-center.nl/nddp
Project Type:
State-of-the-Art:
Specific Targeted The instruments for drug discovery include high-throughput synthesis and subsequent screen-
Research Project ing, biological assays, molecular biology, computational modelling, electron microscopy,
X-ray crystallography, and NMR spectroscopy. Only NMR and X-ray diffraction provide
Contract number:
high-resolution information about the protein-ligand interactions at atomic resolution.
LSHG-CT-2004-512077
Starting date: While the technology for high-throughput X-ray crystallography of protein-ligand complexes
1st November 2004 has been optimised such that it is now routinely used in all major pharmaceutical compa-
Duration: nies, this is not the case for NMR spectroscopy, despite its tremendous potential, relative
to and complementary to X-ray crystallography. NMR can provide both structural and dy-
42 months namic information on the protein-ligand complex at atomic resolution, information that is
EC Funding: highly desirable for efficient drug design. Potentially, NMR can provide such information
`1 000 000 very rapidly and without the constraints of co-crystallization.
This structure-based drug design will use cutting-edge nuclear magnetic resonance (NMR)
techniques. The NDDP project will speed up drug design efforts for typical drug targets and
will shorten the lead time for new drugs.
Fast, reliable and robust NMR techniques will be developed by the team, for an exact
structural and dynamic characterisation of drug-receptor interactions at atomic resolution,
thus enabling and/or improving the directed development of drugs by demonstrating the
maximum desired interaction characteristics in a relatively short time.
Protocols for obtaining the NMR parameters needed for the characterisation of proteins,
inhibitors and protein-inhibitor complexes will be developed, starting from known X-ray
structures. These parameters will establish a tight connection between NMR and X-ray tech-
nology, enabling the optimal exploitation
of the complementary strengths of the two
techniques.The NMR technologies to be
developed will be complemented by new,
fast computer modelling approaches for
protein-inhibitor complexes, and also by
specific advanced tailored protein expres-
sion methods.
X-ray structures of unknown phosphatases

will be determined, and these structures will
be used as molecular models to provide a
highly detailed picture of the proteins in
question. Knowing the X-ray structure of the
protein target, the NDDP consortium will
be able to provide a streamlined protocol
Schematic project presentation.
for the rapid identification of its protein-lig-
The NDDP project aims to de-
and complexes. Such a protocol will boost
velop an efficient screening pro- the impact of NMR technology on structure-
tocol using high-field NMR and based drug discovery. It is the intention of
advanced modelling techniques this consortium to provide the means to de-
that allows to dock lead targets termine protein-ligand complexes, with a
to pharmaceutical receptors such turnaround of three structures per high-field
as phosphatases. instrument per week.
NMR Tools for Drug Design
Validated on Phosphatases
Expected Results:
In order to show the potential impact of NMR techniques on drug development, NMR pro-
tocols will be developed and tested using phosphatases, a major class of drug targets for
a broad range of medical indications. The majority of cellular functions depend on phos-
phorylation by kinases and dephosphorylation by phosphatases. High eukaryotes encode
approximately 500 protein kinase and 100 protein phosphatase schemes, corresponding
to three percent of their genome. While the importance of kinases in cellular regulation has
led to substantial drug design activities, the importance of phosphatases has only recently
become appreciated.
Potential Impact:
Protein phosphatases regulate insulin signalling, cell growth and the cell cycle. The inhibi-
tion of phosphatases is therefore relevant NDDP to the treatment of diabetes, obesity and
various types of cancer, for instance. The availability of the human genome provides re-
searchers with access to a wide variety of phosphatases, and allows systematic drug design
using sophisticated techniques to identify potential inhibitors.
Keywords: NMR spectroscopy, phosphatases, drug design, structural genomics

Partners
Prof. Rolf Boelens Prof. Egon Ogris
Utrecht University University of Vienna
Bijvoet Center for Biomolecular Research Department of Medical Biochemistry
Faculty of Sciences Vienna, Austria
Heidelberglaan 8
3584 CS Utrecht, The Netherlands Dr. Wolfgang Stirner
r.boelens@uu.nl Synthacon GmbH
Frankfurt am Main, Germany
Prof. Harald Schwalbe
Johann Wolfgang Goethe-Universität
Center for Biomolecular Magnetic Resonance
Institute for Organic Chemistry and
Chemical Biology
Prof. Ivano Bertini

Consorzio Interuniversitario di Risonanze Magnetiche
di Metalloproteine Paramagnetiche
Magnetic Resonance Centre (CERM)
Sesto Fiorentino, Italy
Prof. David Barford

Institute of Cancer Research Section of
Structural Biology
Chester Beatty Laboratories
London, UK
3D repertoire
www.3drepertoire.org
State-of-the-Art:
Project Type:
Integrated Project The major current initiatives in structural biology can be divided into two general types. Re-
Contract number: searchers are channelling their efforts into structural genomics, with the aim of determining
structures for all individual protein structures in an organism or system. At the same time,
LSHG-CT-2005-512028
efforts have been intensified to obtain structures of individual large complexes. Despite all
Starting date: the efforts that have been made, an initiative aimed at the structural resolution of all protein
1st February 2005 complexes in a living organism, has not yet been formulated. Such an initiative, if combined
Duration: with other EU-oriented initiatives such as BIO-XHIT or SPINE, would give Europe the edge over
54 months all non-European competitors.
EC Funding:
Recent proteomics studies with the budding yeast Saccharomyces cerevisiae have indicated
`12 997 641
that the number of complexes that exist, transiently at least, in a cell, has been largely underes-
timated. The techniques of isolation and purification that are traditionally used in biochemistry
often include many steps, and due to this, the most robust and abundant complexes tend to be
selected. This is especially true as many complexes are transient, occurring, for example, only
during a certain stage of the cell cycle, or in the presence of a specific co-factor, such as GTP,
calcium or phosphorylated subunits. More recent technologies, including the Tandem Affinity
Purification (TAP), which has been developed at the EMBL and commercialised by the Euro-
pean company Cellzome, allow purification of weaker complexes. There are also a number
of means to identify both new components of complexes, or entirely new assemblies, through
the use of other sources of protein interaction data (experimental and in silico). Such methods
are currently being developed by members of the consortium project 3D Repertoire.
Large-scale proteomic approaches suggest that single proteins interact, on average, with
seven other proteins. Even if this is an overestimation, it is clear that many more complex struc-
tures are needed, in order to complete the structural view of the cell. Analysis of proteins in the
context of complexes has the advantage of revealing new protein folds, to help complete the
known repertoire in nature, as well as adding to the set of protein-protein interaction surfaces.
The latter advantage cannot emerge from an analysis of single proteins or domains. The aim
of 3D-Repertoire is to determine the structures of all amenable complexes in a cell at medium
or high resolution, which will later serve to integrate toponomic and dynamic analyses of
protein complexes in a cell.
3D Repertoire will develop novel approaches and technologies for the expression and
isolation of protein complexes, as well as for the analysis of their constituents by mass
spectrometry. New methods for the production of yeast protein complexes will be tested
and validated, to become part of the standard technology for the production of protein
complexes from any source of biochemical characterisation and structural analysis. In par-
ticular, 3D-Repertoire will focus on the development of combined Free Flow Electrophoresis
(FFE) separation techniques, specifically for the separation of protein complexes, and on the
development and production of a prototype instrument. The performance of the prototype-
instrument and the underlying separation techniques will be tested in the case of the enrich-
ment and isolation of complexes of interest. 3D-Repertoire will develop new tools for faster
and more accurate image processing in single particle electron cryomicroscopy, which
should help to speed up 3D structure determination at increasingly higher resolution.
A Multidisciplinary Approach
to Determine the Structures of Protein
Complexes in a Model Organism
The instrumentation of electron microscopes will be improved to allow for automated data
collection. Improved sample preparation techniques will also be developed to make even
the most difficult complexes accessible to structural studies by cryo-EM. Furthermore, 3D
Repertoire will develop X-ray crystallography and electron microscopy technologies, par-
ticularly suited for the structural analysis of large macromolecular assemblies. In particular,
automated crystal screening procedures to detect optimally diffracting crystals and to im-
prove initial crystal diffraction by systematically applying shrinking, annealing or derivatisa-
tion protocols will be developed.
Moreover, major technological advances are expected in the automation of single-particle

electron microscopy data collection, which will considerably speed up data acquisition.
Special emphasis will be placed on the development of technologies at the interface be-
tween X-ray crystallography and electron microscopy, where improved docking procedures
and validation of these fits are required, to allow such hybrid approaches to become stand-
ard procedure in structural biology. In addition, the collaboration of a leading laboratory
in electron tomography will stimulate the development of new technologies suited to the
analysis of protein complexes within the cell. It will provide a unique platform for the subcel-
lular localisation of protein complexes.
Expected Results: The RNA Polymerase III:

protein purification and
The project’s deliverables include a series of high and medium resolution structures of the composition (left), negatively
yeast complexes as well as improved protocols and vectors, for expression and purification stained particles (middle)
of large complexes. Furthermore, the partners aim to develop software to automatically and cryo-EM structure (right).
build protein complexes using structural information regarding the complex components, or
related proteins as well as innovative software to automatically fit modelled complexes into
low resolution structures. Within the 3D Repertoire consortium, partners will create a data-
base resource containing structural, functional and experimental information on all protein
complexes of S. cerevisiae, as well as on homologues in other organisms. Finally, training
in new protein expression, and purification and software technologies, will be provided to
researchers both within and outside the 3D-Repertoire consortium.
Potential Impact:
The era of post-genomic research is characterised by the necessity to develop high through-
put procedures, in order to exploit the vast amount of information generated by the large
number of genome projects. This is of particular relevance for the health sector, where the
effective identification of functional protein-protein interactions in multiprotein complexes,
e.g. in cell signalling, provides the basis for the development of novel diagnostics and
therapeutics. Recently, some 50 biologists and officials from government-funding agencies
met at the NIH campus in Bethesda, Maryland, to explore the interdisciplinary science and
organisation of the emerging field of structural proteomics. This field aims to discover mac-
romolecular complexes and characterise their three-dimensional structures and functional
mechanisms, in space and time.
The goal of structural proteomics may appear daunting, but the consensus is that the pre-
dictable outcome is well worth the effort invested, especially given the importance of mo-
lecular machines and functional networks in biology and medicine. Identification of assem-
blies and transient complexes combined with their structural and functional characterisation
3D repertoire
will allow us to understand, control, design and change the functioning of larger biological
systems, and to contribute to drug target discovery, lead discovery, and lead optimisation
for treatment of human disease.
To maintain Europe’s international competitiveness in this field, it is essential to promote

interdisciplinary cooperation of the continent’s most innovative research centres. Europe
playing a leading role in the structure genomics field will also yield economic benefits, since
the number of drugs developed or improved using 3D structures is growing every year. In
addition, it will allow Europe to be well positioned for the next challenge in biology, namely
the quantitative understanding of the cell.
3D Repertoire will contribute to rendering this task feasible, through the establishment of
suitable technological platforms. The project’s main contribution comprises large data sets
and material for protein complexes, which will be produced for biomedically relevant com-
ponents of the cell.
Keywords: protein complexes, 3D-electron microscopy, electron tomography,

X-ray crystallography, structural genomics, yeast, bioinformatics
Partners
Project Coordinator: Prof. Herman van Tilbeurgh
Prof. Luis Serrano Institut de Biochimie et de Biophysique
Centre de Regulació Genòmica (CRG) Moléculaire et Cellulaire (IBBMC)
Systems Biology Laboratory Centre National de la Recherche
Dr. Aiguader 88 Scientifique (CNRS) UMR8619
08003 Barcelona, Spain Université Paris-Sud
luis.serrano@crg.es Orsay, France
Project Manager: Prof. Bertrand Séraphin

Dr. Michela Bertero Centre National de la Recherche
Centre de Regulació Genòmica (CRG) Scientifique (CNRS)
Dr. Aiguader 88 Center for Molecular Genetics
08003 Barcelona, Spain Gif-sur-Yvette, France
michela.bertero@crg.es
Prof. Patrick Cramer
Prof. Alfred Wittinghofer, Dr. Susanne Eschenburg Ludwig-Maximilians-Universität München
Max-Planck Institute for Molecular Physiology Gene Center Munich
Dortmund, Germany Department of Chemistry and Biochemistry
Munich, Germany
Prof. Wolfgang Baumeister, Dr. Stephan Nickel,
Prof. Elena Conti Dr. Anastassis Perrakis, Dr. Titia Sixma
Max-Planck Institute of Biochemistry Netherlands Cancer Institute
Abteilung Molekulare Strukturbiologie Molecular Carcinogenesis
Martinsried, Germany Amsterdam, The Netherlands
Dr. Holger Stark Dr. Andrea Musacchio

Max-Planck Institute for Biophysical Chemistry European Institute of Oncology
Research Group 3D Electron Cryo-Microscopy Milan, Italy
Goettingen, Germany
Dr. Guillermo Montoya, Dr. Jeronimo Bravo
Spanish National Cancer Research Centre
Madrid, Spain
A Multidisciplinary Approach to Determine the Structures
of Protein Complexes in a Model Organism
Prof. Helen Saibil Dr. Matthias Wilmanns

Birkbeck College London European Molecular
Department of Crystallography Biology Laboratory (EMBL)
Bloomsbury Centre for Structural Biology Hamburg Oustation
London, UK Hamburg, Germany
Prof. Jose L. Carrascosa Dr. Patrick Aloy

Centro Nacional de Biotecnologia Institute for Research in
Madrid, Spain Biomedicine
Barcelona, Spain
Prof. Miquel Coll
Institute for Research in Biomedicine Dr. Andrzej Dziembowski
(IRB Barcelona) Warsaw University
Barcelona, Spain Institute of Genetics
and Biotechnology
Prof. Hanah Margalit Warsaw, Poland
The Hebrew University
Faculty of Medicine Dr. Michael Sattler
The Institute of Microbiology Helmholtz Zentrum Muenchen (HMGU)
Jerusalem, Israel Neuherberg, Germany
Prof. Carol Robinson Dr. Francisco Blanco

University of Cambridge Centro de Investigación Cooperativa en Biociencias
Churchill College CICBioGUNE
Cambridge, UK Bilbao, Spain
Dr. Gordana Apic

Cambridge Cell Networks Ltd
St. John’s Innovation Centre
Cambridge, UK
Dr. Hervé Ginisty

GTP Technology
Immeuble Biostep
Labège, France
Dr. Joan Aymami

Crystax Ltd
Barcelona, Spain
Dr. Rob Russell, Dr. Elena Conti, Dr. Bettina Boettcher,

Dr. Klaus Scheffzeck, Dr. Dietrich Suck, Dr. Peer Bork,
Dr. Anne-Claude Gavin, Dr. Christoph Mueller
European Molecular
Biology Laboratory (EMBL)
Heidelberg Outstation
Heidelberg, Germany
(*Dr. Sattler moved to GSF as of 01/10/2007)
Dr. Darren Hart

European Molecular
Biology Laboratory (EMBL)
Grenoble Outstation
Grenoble, France
FESP
www.ec-fesp.org

Specific Support Action
Contract number: The main goal of the project is to perform a thorough assessment of the existing structural
genomics (SG) and structural proteomics (SP) projects throughout the world. This will in-
LSSG-CT-2005-018750
clude the assessment of the existing infrastructures in Europe relevant to SG and SP, and
Starting date: their comparison with those active in the rest of the world. The requirements, in terms of
1st July 2005 thematic areas and infrastructures, will also be evaluated. This SSA will result in staged pub-
Duration: lications, a complete register of the structural genomics and structural proteomics projects
30 months worldwide, and a position paper on strategic plans for a European policy in the area of
EC Funding: structural genomics and proteomics.
`300 000
The objectives are:
1) an assessment of the existing infrastructures relevant to SG and SP projects in Europe
in comparison with the rest of the world, and the evaluation of EU requirements,
especially for new EU members
2) an assessment and analysis of existing SG and SP projects at national and EU levels
and worldwide, and a comparison with respect to their strategic objectives, organi-
sation, budgetary aspects, their outcomes (i.e. structures determined, contribution to
data banks, etc.) and their impact on academia and industry
hAChe-FAS-II 3) an assessment of industrial needs for SG and SP and of their impact on health and
the economy in the EU
4) establishing of a database resource to serve as a complete
register of structural genomics and structural proteomics
projects worldwide
5) drafting a series of staged publications based on the as-
sessment and compilation of a position paper that will in-
clude an assessment of SG and SP activities in the EU, and
a strategic road map to guide future directions of structural
genomics and structural proteomics initiatives in Europe.
Nuclear pore particle
Expected Results:
A database will be established and it will
serve as a complete register of the structural
genomics/proteomics projects worldwide.
A position paper will be compiled which will
include an assessment of structural genom-
ics/proteomics, and the infrastructures and
activities in Europe and the rest of the world.
A strategic road map will be prepared to
guide future directions of SG and SP initia-
tives in the EU.
3EEĺHTTPWWWEC FESPORG&%30REPORTHTML
NMR Structure
Forum for European Structural Proteomics
Potential Impact:
1) The open discussion that we plan to stimulate and
direct within the SG/SP European community
should raise the awareness of structural biology
centres among high-throughput SG/SP research-
ers in healthcare and academia, and in big phar-
macological and biotech companies throughout
the EU.
2) The staged documents, based on our assessments
and discussions with a wide spectrum of scientists and national scientific officers
worldwide, should help the EC in formulating policies for future scientific calls in Life
Sciences, in general, and in SG/SP in particular.
3) The position paper will provide guidelines for an overall strategic direction that the EC
can consider adopting for future directions for European research in the SG/SP area.
Keywords: structural proteomics, structural genomics, research policies
Partners
Prof. Joel L. Sussman
Weizmann Institute of Science
Department of Structural Biology
Herzel Street P.O. Box 26
Joel.Sussman@weizmann.ac.il
Project Manager:
Bracha Vaknin
Israel Structural Proteomics Center
Department of Structural Biology
100 Herzel Street
P.O. Box 26
ispc@weizmann.ac.il
Prof. Gunter Schneider
Prof. Lucia Banci Karolinska Institutet
University of Florence Division of Molecular
Centro Risonanze Structural Biology
Magnetiche (CERM) Department of Medical
Sesto Fiorentino, Italy Biochemistry and Biophysics
Stockholm, Sweden
Prof. Udo Heinemann
Max-Delbrück-Center for Prof. Wolfgang Baumeister
Molecular Medicine Max-Planck Institut für Biochemie
Department of Crystallography Abteilung Molekulare Strukturbiologie
Berlin, Germany Martinsried, Germany
E-MeP-Lab
www.e-mep.org/?rub=lab

Contract number: E-MeP is an EC funded FP6 integrated project. Its research will develop new technologies to
solve the bottlenecks that preclude the determination, at high throughput, of high-resolution
LSHG-CT-2005-512011
structures of membrane proteins and their complexes. This will be achieved by integrat-
Starting date: ing the activities of world leaders in membrane protein structural biology. E-MeP-Lab is a
1st July 2005 proposal for a Specific Support Action to exploit this confluence of talent. For the first time,
Duration: Europe’s membrane protein structural biology community will converge as teachers and
48 months demonstrators in a Master Class and five Advanced Practical Courses in the best equipped
EC Funding: laboratories in their fields in Europe. This research field is important because membrane
proteins comprise the major target area of study within modern structural genomics. Moreo-
`250 000
ver, the field of membrane protein study involves approximately 70 percent of human pa-
tients that qualify for therapeutic intervention.
E-MeP-Lab’s objectives are to:
1) Increase the pool of appropriately skilled young researchers in membrane protein
structural genomics;
2) Provide access for all European researchers to training programmes;
3) Integrate with other Structural Genomics programmes to facilitate a coherent Euro-
pean Structural genomics strategy on membrane and soluble proteins.
Expected Results:
In addition to working with researchers from European member states, the project aims
to harness the considerable scientific talent in the new Member States to ensure their full
participation within the European Structural Genomics community, through the provision of
ring-fenced funding. Together with an analysis provided by an expert in gender and mobil-
ity issues, this will provide an excellent opportunity to evaluate the potential impact of an
increase in scientific mobility and more equal gender participation. Thus, achievement of
balanced growth in the wider ERA will be achieved with a particular focus on the transfer
of knowledge in the structural genomics of membrane proteins.
E-MeP-Lab Training workshop
E-MeP-Lab Training events in
membrane protein structural biology
Potential Impact:
By providing training to eliminate bottlenecks that preclude the structural determination of
membrane proteins and membrane protein complexes to atomic resolution, the E-MeP-Lab
project addresses this issue head-on. Intelligent, structure-based drug design will short-cir-
cuit current brute force random screening of drugs and will therefore save pharmaceutical
companies time and money. Even in the absence of structures, the provision of the skill set to
produce functional eukaryotic membrane proteins for targeted drug screening by high-tech
SMEs will be an important outcome from E-MeP-Lab. This will give Europe a competitive
edge in the pharmaceutical and biotechnology markets.
Keywords: structural proteomics, structural genomics, research policies
Partners
Dr. Roslyn Bill
Aston University
Aston Triangle
Birmingham, B4 7ET, UK
r.m.bill@aston.ac.uk
Project Manager:
Eric Bourguignon
Aston University
Aston Triangle
e.bourguignon@aston.ac.uk
Prof. Peter Henderson

University of Leeds
Astbury Centre for Structural - Molecular Biology
Leeds, UK
HT3DEM
www.ht3dem.org
State-of-the-Art:
Project Type: Membrane proteins, unlike soluble proteins, are generally not easily amenable to 3D crys-
Specific Targeted tallization. The most regular organization of a membrane protein amenable to crystallogra-
Research project phy is a 2D crystal (2DX). It comprises only a single layer of the regularly packed protein,
Contract number: which is reconstituted in a lipid bilayer. Electrons must be used for the diffraction analyses.
The availability of membrane proteins suitable for electron crystallography is of high impor-
LSHG-CT-2005-018811 tance for rational drug design since about 70% of all drug targets are membrane proteins.
Starting date: The potential of this approach has long been recognized, and the first structure of a human
1st October 2005 channel protein, aquaporin-1, has been solved to a 3.8 Å resolution. An innovative technol-
Duration: ogy platform for high throughput screening and analysis of native protein complexes and
protein crystals by EM would reduce processing time and cost and greatly increase the
42 months
probability of obtaining high quality 2D crystals of membrane proteins.
EC Funding:
`1 802 501
The objective of the HT3DEM project is to develop an automated pipeline for sample prepa-
ration and analysis by electron microscopy. The novel hardware and software under devel-
opment includes: (1) a 2D crystallisation robot: Membrane protein reconstitution is critically
dependent on lipid mixtures, lipid-to-protein ratio and cofactors such as divalent cations,
ionic strength and pH. Such a multi-parameter optimisation for each protein investigated
can only be satisfyingly screened using a high-throughput approach; (2) a sample prepa-
ration robot. This robot is designed to prepare negatively stained samples from cytosolic
fractions or 2D crystallisation experiments. The robot will be compatible with the 96 well
plate format and the autoloader of the EM; (3) An automated grid loader (AutoLoader)
and a cassette revolver fitting on the EM and the corresponding software are in develop-
ment. These robots will enable the automatic loading of up to 96 samples and thus be fully
compatible with the sample preparation robot; (4) development of software for instrumental
control and screening acquisition schemes. Automatic acquisition and screening software,
involving novel developments and improvement of existing routines will allow a first quality
assessment and the selection of suitable sample areas for further in-depth investigations; (5)
development of a versatile, self-learning image analysis and pattern recognition system for
the automated identification of interesting sample areas and directing the pertinent image
acquisition at different magnifications; (6) design of a versatile, user friendly database to
allow storage and analysis of all pertinent experimental data.
Expected Results:
1) A fully integrated high throughput system for screening and analysis of native protein
complexes and protein crystals by electron microscopy is expected. Good progress
has been achieved in all parts of the project.
2) 2D-Cryrsallisation Robot: The alpha version of the robot (96 well plate) has been
working reliably for a few months. Proteins have already been processed to yield
high quality crystals. (Picture).
3) Sample Preparation Robot: A first version of a robot has been used with encouraging
Regions Of Interest (ROI) results. New developments to improve the automated staining are in progress.
identification at medium 4) Autoloader and Cassette Revolver: Both robots are in a well advanced state of devel-
magnification: after an edge opment and will be ready in six to nine months.
detection of the membranes (B), 5) Software for instrumental control and screening acquisition: The software to control
the ROI (red squares) are placed the automatic grid loading hardware (AutoLoader) has been tested and will be inte-
around the detected edges. Then, grated as soon as the EM is ready. The software design of the screening and acquisi-
a selection process retains the tion process suitable for crystalline objects and particles is well advanced.
more significant ones (C). 6) Image analysis and pattern recognition software for crystal detection and analysis
High throughput Three-dimensional
Electron Microscopy
has been developed for low, medium and high
magnification.
7) Database: A first version of the database is
ready for data entry. The statistical analysis of
data is in development.
Potential Impact:
The development of a versatile platform enabling the
automated screening and analysis of various types of
samples by electron microscopy closes a gap in the gen-
eral use of this technology. It will speed up the structural Alpha version of the 2D-crystal-
analysis of several classes of fundamentally important specimens, such as macromolecular lisation robot at Partner BIOZ
complexes, and, most importantly, membrane proteins. 2D crystals can provide 3D structural (Right). High quality crystals of
information of membrane proteins in their native environment by EM analysis and on surface
Aeromonas hydrophila Aerolysin
properties by AFM analysis, including molecular interactions. This development thus fits in
obtained with the cy-clodextrin
with the European effort to advance leadership in electron microscopy and with the enhance-
method. Scale bars represent
ment of European competitiveness in the field of structural genomics. In the greater context,
the project will also aid competitiveness in life sciences and the European pharma industry. 100 nm. (Left)(Prof. Gisou van
der Goot and Ioan Iacovache are
acknowledged for kindly provid-
Keywords: high throughput, three-dimensional electron microscopy, ing us with Aero-lysin).
membrane proteins, 2D crystallisation
Partners
Prof. Andreas Engel
University of Basel
M E Mueller Institute for Structural Biology
Biozentrum
Nadelberg 6
4054 Basel, Switzerland
andreas.engel@unibas.ch
Project Manager:
Dr. Urs Mueller
University of Basel
M E Mueller Institute for Dr. Werner Hax, Dr. Marc Storms
Structural Biology FEI Electron Optics BV
Biozentrum Eindoven, The Netherlands
Nadelberg 6
4054 Basel, Switzerland Dr. Bart van der Schoot
u.mueller@unibas.ch Seyonic SA
Neuchatel, Switzerland
Prof. Wolfgang Baumeister
Max-Planck Institute of Prof. Jean-Philippe Urban
Biochemistry Université de Haute Alsace
Department of Molecular Faculté des Sciences et
Structural Biology Techniques
Martinsried, Germany Mulhouse, France
NMR-Life
www.postgenomicnmr.net
State-of-the-Art:
Project Type: Structural genomics originally aimed at the full structural coverage of the proteome. In the
Co-ordination Action meantime, the investigation of the whole network of interacting proteins produced by a
Contract number: living organism (the ‘interactome’), and of how these interactions are being modulated by
LSHG-CT-2005-018758 changing concentrations of small molecules, has become an emerging field of research
providing information on the biochemical processes which occur through protein-protein
Starting date: and protein-DNA/RNA interactions. NMR spectroscopy is particularly suited for the study
1st December 2005 of weak and/or transient intermolecular interactions.
Duration: The present project will implement coordination activities focused on the scientific areas of
39 months protein-protein, protein-DNA/RNA, and protein-ligand interactions, and membrane pro-
teins. These scientific areas share common technical and methodological aspects, which
EC Funding:
represent crucial issues for the development of the whole field of biological NMR. The
`1 070 000 project will contribute to standardising and disseminating best practices.
Coordination activities will be developed to achieve the following main goals:
s FOSTERCROSS FERTILISATIONBETWEENTHEFOURDIFFERENTSCIENTIlCAREASONWHICHTHISPROJECT
focuses, mainly through the common vertical aspects
s CONTRIBUTE TO THE DEVELOPMENT AND DISSEMINATION OF COMMON GOOD PRACTICES AND
methodological approaches
s FOSTERTHETRANSFEROFKNOWLEDGEAMONGDIFFERENTRESEARCHTEAMSTHEREBYENHANCING
the spreading of innovative methods and tools
s IMPLEMENTACOMMONREFERENCEPOINTFORTHE%UROPEAN.-2COMMUNITYONTHE)NTER-
net by maintaining a common virtual laboratory
s JOINTLYIDENTIFYBOTTLENECKSANDPOSSIBLEBREAKTHROUGHSINTHElELDOFBIOLOGICAL.-2
The above coordination activities will be crucial in guaranteeing that on-going research and
methodological innovation in Europe, such as the development of new software tools, are
carried out by promptly tackling the needs of the European scientific community. This will
be achieved by guaranteeing the awareness of the potential stakeholders, and by avoiding
both the duplication and exclusion of efforts (as much as possible), which may later become
bottlenecks for the evolution of the whole field of biological NMR.
Expected Results:
Actions to be taken within the project are planned by the managing committee (MC) on a
yearly basis. Actions will involve:
s ORGANISATIONOFEXPERTGROUPSFORFOCUSEDSTUDIES
s ORGANISATIONOFMEETINGS
s PREPARATION OF DOCUMENTS DESCRIBING STATE OF THE ART DEVELOPMENTS RECENT INNOVA-
tions of high potential impact, unprecedented scientific challenges and opportunities,
proposition of new standards, etc.
s EXCHANGESOFPERSONNEL
s ACTIVITIES TO ENHANCE THE SPREADING AND DISSEMINATION OF GOOD PRACTICES SUCH AS
demonstrations or road shows presenting new advances, etc.
s IMPLEMENTATIONANDMAINTENANCEOFAVIRTUALLABORATORY
These actions are complemented by an annual meeting involving all participants in the
project, organised by the coordinator in collaboration with all MC members.
Endothelin-1 bound to
Potential Impact:
Endothelin-B receptor The impact of this Coordination Action is that it brings together scientists, creating a com-
Focusing NMR on the Machinery of Life
mon reference basis in terms of experimental approaches, data elaboration and analysis
through exchanges of good practices and/or by sharing procedures and results. The
coordination of research activities is important when making breakthroughs or advanc-
ing technologies achieved by the various scientists in the field, by avoiding needless
duplication of efforts, thus enhancing and allowing the extensive scientific productivity of
European researchers. This will help reinforce the European lead in the field of biologi-
cal NMR, and the interaction with pharmacological and biotech companies will lead to
industrial applications.
Keywords: protein interactions, protein ligand interactions, membrane pro-

teins, immobilised proteins, NMR NMR Structure of the yeast
Atx1: Copper(I): Ccc2a adduct
Partners
Project Coordinator: Prof. Hartmunt Oschkinat Prof. Ernest D. Laue
Prof. Ivano Bertini Leibniz-Institut für Molekulare University of Cambridge
Consorzio Interuniversitario Pharmakologie (FMP) Cambridge, UK
di Risonanze Magnetiche di Berlin, Germany
Metalloproteine Paramagnetiche, Prof. Iain Campbell
Magnetic Resonance Center (CERM) Prof. Geoffrey Bodenhausen University of Oxford
Via Luigi Sacconi, 6 Ecole Normale Supérieure de Paris Department of Biochemistry
50019 Sesto Fiorentino, Italy Département de chimie Oxford, UK Structure of a protein:
bertini@cerm.unifi.it Laboratoire de Resonance single-stranded DNA complex
Magnetique Biomoleculaire
Project Manager: Paris, France
Kathleen McGreevy
Consorzio Interuniversitario di
Risonanze Magnetiche di
Metalloproteine Paramagnetiche,
Magnetic Resonance Center (CERM)
Via Luigi Sacconi, 6
50019 Sesto Fiorentino, Italy
mcgreevy@cerm.unifi.it Prof. Flemming Martin Poulsen
Dr. Michael Sattler Structural Biology and
GSF – National Research Center NMR Laboratory
for Environment and Health the Institute of
Lehrstuhl Biomolekulare Molecular Biology
NMR-Spektroskopie Copenhagen, Denmark
Department Chemie
Technische Universität München Prof. Vladimir Sklenar
Garching, Germany Masaryk University
National Center for
Prof. Rolf Boelens Biomolecular Research
Utrecht University Brno, Czech Republic
Bijvoet Center for Biomolecular Research
NMR Spectroscopy Research Group
Prof. Harald Schwalbe

Johann Wolfgang Goethe-Universität
Center for Biomolecular Magnetic Resonance
Institute for Organic Chemistry and Chemical Biology
Extend-NMR
www.ccpn.ac.uk/ccpn/projects/extendnmr/extend-nmr-project-information
Project Type:
State-of-the-Art:
Specific Targeted In comparison with better-established methods like X-ray crystallography, computational
Research project tools for the extraction of information from NMR spectra of large proteins and complexes,
and its analysis and interpretation, are much less well developed. As a result, the full power
Contract number:
of the method cannot be exploited at present. Novel tools that allow the identification of
LSHG-CT-2005-018988 signals in crowded NMR spectra of larger proteins and complexes, and their quantification,
Starting date: are urgently needed. The resulting information will, in turn, provide the starting point for the
1st January 2006 development of novel algorithms that facilitate structure determination of protein complexes
Duration: in situations where NMR can play a key role; for example, where one or more components
are only partly structured, or for solid-state studies of membrane proteins.
42 months
EC Funding:
`2 000 000 Scientific/Technological Objectives:
The objectives of the project are:
1. the development of novel computational tools that allow rapid assignment of NMR
spectra for studies of interactions and dynamics by making optimal use of existing (in
particular structural) information, i.e. the NMR equivalent of molecular replacement
in X-ray crystallography,
2. extending the scope of NMR spectroscopy by developing novel tools that allow the
calculation of structures without the need for prior spectral assignment,
3. the development of improved tools for the identification and quantification of signals
from NMR data.
These three objectives will be facilitated by the development and implementation of a series
of computational algorithms involving Bayesian analysis, maximum entropy reconstruction,
multi-dimensional decomposition, principle component analysis, and statistical and expert
system-based analysis tools. These algorithms will be implemented within a common soft-
ware framework developed by the CCPN project, so that they can be flexibly employed
in the development of the different tools. We will develop novel tools for the validation of
structures and experimental results and mine databases for NMR and structural information
crucial to the aims of the project.
Expected Results:
The expected result is the development of
a highly integrated set of computational
tools, which will extend the scope of NMR
spectroscopy and allow researchers to
carry out studies flexibly in functional and
structural genomics, as well as NMR-based
drug design.
Potential Impact:
An integrated system allowing the extrac-
tion of information from raw NMR data
and the direct calculation of the final 3D
structure, without the need for assignment
of that information to specific atoms in the
Extending NMR for Functional
and Structural Genomics
molecule, would be highly desirable and make a significant impact in NMR programmes
of functional/structural genomics. In a similar vein, a method that allowed one to obtain
assignments with the aid of a structure of a homologous protein would be extremely useful
for functional studies. The development of novel algorithms will therefore greatly stimu-
late the use and usefulness of NMR in functional/structural genomics, having a crucial
impact on increasing the potential of NMR for studies in biology and medicine in the
post-genomic era.
Keywords: nuclear magnetic resonance, NMR, structural genomics, functional

genomics, biomolecular complexes, spectrum assignment, structure
calculation, high-throughput techniques
Partners
Project Coordinator: Dr. Hans-Robert Kalbitzer
Professor Ernest D. Laue University of Regensburg
University of Cambridge Institute of Biophysics
80 Tennis Court Road Regensburg, Germany
Cambridge, CB2 1GA, UK
e.d.laue@bioc.cam.ac.uk Dr. Bruno Guigas
Bruker BioSpin GmbH
Project Manager: Magnet Division
Charles Shannon Karlsruhe, Germany
Research Services Division
16 Mill Lane Dr. Alexandre Bonvin
Cambridge, CB2 1SB, UK Utrecht University
charles.shannon@rsd.cam.ac.uk NMR Research Group
Bijvoet Center for
Dr. Kim Henrick Biomolecular Research
European Molecular Biology Utrecht, The Netherlands
Laboratory (EMBL)
European Bioinformatics Institute (EBI),
Hinxton, UK
Dr. Michael Nilges

Centre National de la Recherche Scientifique (CNRS) -
Institut Pasteur
Unité de Recherche Associeé (URA)
Unité de Bioinformatique Structurale,
Paris, France
Dr. Gert Vriend

Radboud University Nijmegen Medical Centre
Nijmegen Centre for Molecular Life Sciences (NCMLS)
Centre for Molecular and Biomolecular Informatics (CMBI)
Dr. Martin Billeter

Gothenburg University
Biochemistry and Biophysics
Gothenburg, Sweden
IMPS
State-of-the-Art:
Project Type: The objective of IMPS is to explore innovative approaches to membrane protein (MP) over-
Specific Targeted expression, stabilization and crystallography. Establishing the structure of MPs is of major
importance in basic life sciences as well as drug development. Yet fewer than 1% of protein
Research project structures currently available correspond to MPs, most of them devoid of pharmacological
Contract number: interest. The reason for the paucity of crystallographic structures can be traced mainly to the
LSHG-CT-2005-513770 following factors: (1) most MPs purified from natural sources are in short supply, hence the
Starting date: need for overexpression; (2) most MPs become unstable once extracted from their natural
membrane environment, hence the need for improved handling conditions; (3) MPs do not
1st January 2006 crystallize easily, hence the need for alternative crystallization approaches to improving
Duration: crystal quality and for specialized methods to deal with microcrystals. IMPS is an integrated
36 months attempt to develop novel, original ways of circumventing these three bottlenecks.
EC Funding:
MPs play key roles in innumerable biological processes. Even though their genes are now
accessible, solving their structure remains time-consuming and most often unsuccessful. Given
their physiological and biomedical importance, this constitutes a major problem in basic life
sciences as well as public health care. Tools have been developed to overexpress, solubilize,
stabilize, purify and crystallize MPs, and they are currently being used in large-scale initiatives
for structure determination. Unfortunately, most MPs resist one or more of these steps.
The objective of IMPS is to develop imaginative, broad-range tools for membrane structural
proteomics. The project brings together experts in chemistry, biochemistry, molecular genetics,
electron microscopy and X-ray crystallography, and aims at developing original, innovative
tools to attack each of these stumbling blocks. A strong core of crystallographers with dem-
onstrated expertise in MP structure determination will apply these novel techniques to a rep-
resentative test set of MPs. The approaches to be developed include original overexpression
systems (insect photoreceptor cells and the chloroplast), unconventional surfactants (amphip-
athic polymers, fluorinated surfactants, novel detergents and additives) and unconventional
crystallization systems (lipid cubic phase crystallization, other non-detergent environments,
molecular scaffolding). As the project progresses, some of these objectives are being adapted,
extended, or, in some cases, superseded by alternative novel approaches that have yielded
particularly promising results. These novel methodologies will be made available to the scien-
tific community through a distributed technological platform including workshops, hands-on
training, and dissemination of the new molecules, whose large-scale synthesis and distribution
will be carried out by a participant SME. The circulation of scientists between IMPS laborato-
ries and the organization of workshops ensures the rapid spread of know-how.
Expected Results:
The general philosophy of the project has been outlined above. The resources and experi-
ence brought by the eight partners and four associated laboratories are highly complemen-
tary. Thirteen MPs have been selected either as models for technological development and/
or as pharmacologically important targets. At the onset of the project, some proteins were
already available in mg amounts, either from natural sources or following overexpression,
while others were at the stage of setting up overexpression systems. As methodologies de-
velop, new proteins are being chosen to further explore their domain of applicability, a rule
of the game being the sharing among IMPS laboratories of plasmids, novel molecules and
know-how. The main results to be expected are the following:
1) validation and dissemination of the most promising of the novel approaches to MP
overexpression, stabilization and crystallization;
2) solving, or making significant steps towards solving, the structure of some of the tar-
get MPs;
3) training the members of IMPS and other laboratories and creating the basis for col-
laborations extending beyond the end of the project.
Innovative tools
for membrane structural proteomics
Potential Impact:
Solving the structure of MPs that constitute important pharmacological targets is currently a
high-risk endeavor, calling for long-term work-intensive investments. Providing new tools to-
wards this goal will speed up structure resolution and cut down on its cost, which can have
a significant economic impact in a field where research investments represent hundreds of
millions of dollars. Most of the innovative approaches developed by IMPS partners origi-
nated in Europe. IMPS provides an opportunity to consolidate the leadership that European
laboratories currently hold in these new developments and speed up their optimization
and the definition of their field of applicability. Once validated, the novel methods will be
disseminated throughout European laboratories, thanks, in particular, to workshops and
collaborations involving both IMPS and external laboratories.
Keywords: membrane proteins, overexpression, crystallization, stabilization,

novel surfactants, microcrystallography, lipid cubic phases, am-
phipols, Drosophila, yeast
Partners
Project Coordinator: Prof. Kaspar Hegetschweiler
Dr. Jean-Luc Popot Universität des Saarlandes
Centre National de la Recherche Scientifique (CNRS)/ Fakultaet 8 Chemie Pharmazie
Université Paris-7 UMR 7099 Biowissenschaften
Institut de Biologie Physico-Chimique Werkstoffwissenschaften
13, rue Pierre-et-Marie-Curie Saarbrücken, Germany
75005 Paris, France
jean-luc.popot@ibpc.fr Dr. Gebhard Schertler
MRC-LMB
Prof. Eva Pebay-Peyroula Medical Research Council
Centre National de la Recherche Scientifique (CNRS) Cambridge, UK
CEA/Université Joseph Fourier
Institut de Biologie Structurale
Grenoble, France
Dr. Isabelle Mus-Veteau
Université de Nice-Sophia Antipolis
Nice, France
Prof. Irmgard Sinning
Ruprecht-Karls-Universität
Heidelberg, Germany
Prof. Bernard Pucci

Université d’Avignon et des Pays du Vaucluse
Avignon, France
Prof. Wolfram Welte

Universität Konstanz, F R G
Mathematisch-Naturwissenschaftliche Sektion
Fachbereich Biologie
Lehrstuhl Biophysik
Konstanz, Germany
Dr. Jean-Pierre Salles

Targeting System Pharma
Eguilles, France
SPINE2-COMPLEXES
www.spine2.eu

Integrated Project
Contract number: SPINE2-COMPLEXES builds on the technological developments in structural genomics/pro-
teomics of the last decade and aims to break new territory in this field. The concept of struc-
LSHG-CT-2005-031220
tural genomics arose in the USA at the end of the 1990s, as a response to the availability
Starting date: of whole genome information, and also as a response to the success of high throughput
1st July 2006 (HTP) methods in genome sequencing. At that time, it was foreseen that similar HTP methods
Duration: could be applied to obtain 3-D structures of all the proteins (the proteome) of an organism,
42 months thus generating an efficient way of filling in the gaps in observed fold-space. This vision led
EC Funding: to the investment of immense sums of money into large-scale structural genomics projects.
Instances of this are noted both in Japan, e.g. the massive RIKEN project, (http://www.rsgi.
`12 000 000
riken.go.jp/), and in the USA, e.g. nine multi-million dollar projects funded by the NIH/
NIGMS Protein Structure Initiative, costing around $270 million and stretching over a 5
year period, ending in June 2005 (http://www.nigms.nih.gov/psi/ ).
These projects were characterised by the following elements: the concentration of resources
into a small number of large centres, the development of novel, automated technologies per-
mitting a high-throughput, a pipeline approach to structure determination, a focus on novel
folds as the major target criterion, and immediate public deposition of structural data.
Europe has been slower off the mark in implementing structural genomics. The Protein
Structure Factory in Berlin, Germany (http://www.proteinstrukturfabrik.de/) first made the
move, followed by the OPPF in Oxford, England (http://www.oppf.ox.ac.uk/), and the
Genopoles in France (notably Gif, Marseille and Strasbourg, http://rng.cnrg.fr/). How-
ever, it was not until October 2002 that the first Europe-wide project began. This was a
three-year project funded by the EU FP5 programme called SPINE: Structural Proteomics
in Europe (http://www.spineurope.org). SPINE, a second generation structural genomics
project, made some radical departures from previously funded initiatives, and has benefited
from the experience and developments in technology arising from previous findings in this
field. SPINE2-COMPLEXES plans to push developments beyond the previous limits.
SPINE2-COMPLEXES’ aim is to investigate challenging biological systems by combining
knowledge of genomes with HTP methods for structural proteomics. The project targets
the development and application of HTP methods, for an efficient determination of atomic
resolution structures of protein-protein and protein-ligand complexes. These complexes,
which are extremely important with respect to human health, are drawn from the common
theme of signalling pathways from receptor to gene.
Overall, the success of SPINE2-COMPLEXES will be assessed on the scientific impact of
its output.
The project work is divided into 3 sections:

Section 1 involves 3-D structure determination of complexes within the target focus of
signalling pathways from receptor to gene. This is the major section of SPINE2-COM-
PLEXES, both in terms of allocation of manpower, and in terms of scientific impor-
tance. Targets are drawn from key areas of biology, including cell cycle, neurobiol-
ogy, cancer and immunology, as well as pathogen proteins that modulate or subvert
human signalling pathways. This section has been subdivided into a set of WPs which
From Receptor to Gene:
Structures of Complexes from Signalling
Pathways linking Immunology,
Neurobiology and Cancer
bring together Partners working in specific areas. Since the apparently diverse cel-
lular processes often involve the same components and pathways, this will provide
wide opportunities for inter-Partner synergies.
Section 2 involves the development of technologies addressing the difficult problems

associated with the production of human protein complexes in quantities sufficient
for structural studies, and also with the provision of an interdisciplinary approach
for determining protein complex structures. This will build on and extend the HTP
protein expression and crystallisation technologies initiated and implemented within
the SPINE project.
Section 3 deals with the dissemination and organization of the emerging data and
knowledge, through a series of training session and symposia on an annual basis.
Expected Results:
To date, the SPINE2-COMPLEXES project has made progress in several areas, as detailed
below:
1) Significant progress has been made towards the development of protein complex-
specific target tracking software, to enable the rigorous capture, storage and analysis
of protein expression and structure determination data. This tracking software will be
PIMS compatible and will utilise a similar interface for data acquisition and retrieval.
2) A SPINE2-COMPLEXES website (http://www.spine2.eu) has been set up and will be
further developed over the next months, after which it will form the centre of the consor-
tium communication strategy.
3) A planned timetable of training workshops, demonstrating the state-of-the-art technolo-
gies relevant to protein structure determination, will be implemented in the first twelve-
month reporting period of the project.
4) All Partners have started work on the structure determination of their nominated protein
components. These component proteins have been identified as members of the cell
signalling pathways, which in turn, form the biological focus of the project. Some pro-
tein structures are expected to be delivered in the first twelve-month reporting period.
Potential Impact:
SPINE2-COMPLEXES has several deliverables, and they are as follows: 1) high value 3D
structures of complexes of fundamental and biomedical importance; 2) novel methods for
the production, characterisation and structure determination of eukaryotic proteins and
complexes; 3) new bioinformatics tools; and 4) an interactive and co-ordinated Europe-
wide network of laboratories engaged in training and research in structural proteomics.
These deliverables will ensure the profound impact of this project both in Europe and be-
yond. SPINE2-COMPLEXES intends to further develop and streamline the high through-
put technologies, so as to tackle not only individual proteins, but also more challenging
protein/protein and protein/nucleic acid complexes. The success of the consortium will
demand technological innovation, resulting in new and/or improved HTP procedures at
all stages, from cloning, expression and purification, through biophysical and biochemical
characterization of individual proteins and complexes, to crystallization, data collection,
and solution of their structures, as well as solution of smaller protein structures by NMR, and
electron microscopy (EM) studies on complexes.
SPINE2-COMPLEXES
The SPINE2-COMPLEXES project goes far beyond the capacities of individual laboratories,
which work in isolation, lacking both the infrastructure and the critical mass to tackle such
a far-reaching and ambitious project. At European level, the added value of the project will
find expression in several ways. Firstly, consortium members will be able to take advantage
of infrastructures and expertise, especially in protein production, bioinformatics and LIMS,
NMR and synchrotron facilities that are offered by consortium partners. The training and
mobility programme of SPINE2-COMPLEXES will facilitate interactions and dissemination.
Secondly, major emphasis will be placed on Internal Networking. This will utilize a website,
with adjunct internal databases, linked to LIMS systems in the member laboratories.
Keywords: crystallography, protein expression, nanodrop technology, protein

complexes, ligand interfaces, signalling pathways, protein structure,
structural genomics, high-throughput techniques
Partners
Prof. David Stuart Prof. Joel Sussmann
Wellcome Trust Centre for Human Genetics Weizmann Institute of Science
Division of Structural Biology The Israel Structural Proteomics Center
Roosevelt Drive, Headington Department of Structural Biology
Oxford, OX3 7BN, UK Rehovot, Israel
dave@strubi.ox.ac.uk
Dr. Stephen Cusack
Project Manager: European Molecular Biology Laboratory (EMBL)
Dr. Susan Daenke Grenoble Outstation
Scientific Program Manager Grenoble, France
European Projects
Wellcome Trust Centre for Human Genetics Dr. Matthias Wilmanns
Roosevelt Drive, Headington European Molecular Biology Laboratory (EMBL)
Oxford, OX3 7BN, UK Hamburg Outstation
susan@mail.strubi.ox.ac.uk Hamburg, Germany
Dr. Dino Moras

Centre Européen de Recherche en Biologie et
en Médecine – Groupement d’Intérêt Économique
UPR9004/CERBM G.I.E.
Illkirch, France
From Receptor to Gene: Structures of Complexes from Signalling Pathways
linking Immunology, Neurobiology and Cancer
Prof. Gunter Schneider Dr. Beata Vertessy

Karolinska Institutet Hungarian Academy of Sciences
Department of Medical Biochemistry and Biophysics Metabolism and Repair Department
Stockholm, Sweden Institute of Enzymology
Budapest, Hungary
Prof. Keith Wilson
University of York Dr. Jan Dohnalek
Department of Chemistry Ustav makromolekularnii chemie
Structural Biology Laboratory Akademie ved Ceske republiky
York, UK Department of Structure Analysis
Group of Analysis of Molecular Structure
Dr. Rolf Boelens Prague, Czech Republic
University of Utrecht
Bijvoet Center for Biomolecular Research Prof. Maria Armenia Carrondo
NMR Spectroscopy Instituto de Technolgie Quimica e Biologica
Utrecht, The Netherlands Protein crystallography laboratory
Oeiras, Portugal
Prof. Titia Sixma
Netherlands Cancer Institute (NKI) Dr. Renos Savva
Division of Molecular Carcinogenesis Domainex Limited
Amsterdam, The Netherlands Birkbeck College, University of London
Rosalend Franklin Laboratory
Prof. Ivano Bertini London, UK
Magnetic Resonance Center (CERM)
SestoFiorentino (FI), Italy
Prof. Sine Larsen

European Synchrotron Radiation Facility
(Installation Européenne de
Rayonnement Synchrotron)
Grenoble, France
Prof. Udo Heinemann

Max-Delbruck-Center for Molecular Medicine
Department of Crystallography
Berlin, Germany
Prof. Miquel Coll

Consejo Superior de Investigaciones Científicas
Institut de Biologia Molecular de Barcelona
Barcelona, Spain
Dr. Yves Bourne

Institute de Biologie Structurale et Microbiologie
Architecture et Fonction des
Macromolecules Biologiques
Marseille, France
Dr. Herman van Tilbeurgh

Université Paris-Sud
IBBMC-Institut de Biochemie et de
Biophysique Moleculaire et Cellulaire
Scientifique (CNRS) UMR 8619
Orsay, France
OptiCryst
www.opticryst.org

SME- Specific Targeted
Research Project The wealth of information obtained by Structural Genomics has allowed protein structure-
based drug design to complement screening and combinatorial chemistry to provide more
Contract number:
efficient drug development. Ultimately, this approach will reduce the time of production
LSHG-CT-2006-037793 cycles and therefore cost per drug.
Starting date:
1st December 2006 Structural Genomics has coincided with the era of high-throughput, resulting in major ad-
Duration: vances in the automation of protein preparation and X-ray crystallographic analysis, and in
36 months automating and miniaturising crystallisation trials (thousands per day). Despite this, the suc-
cess rate in going from cloned gene to high-resolution protein structure is still relatively low
EC Funding:
in all current Structural Genomics projects, with a major bottleneck situation from purified
`2 270 000 protein to diffracting crystals. This problem clearly needs to be addressed. This can be done
through the production of a design that will offer new and improved optimisation methods,
in order to turn crystal leads into useful diffracting crystals.
The key objective of the OptiCryst project is to address the critical post-protein production
bottleneck area in the field of Structural Genomics. To date, this area has been consistently
ignored by initiatives worldwide. We propose to enhance the state-of-the-art in protein
crystal optimisation by increasing the success rate of the production of diffraction-quality
crystals from the current rate of 21 percent to at least 40 percent.
Expected Results:
Moving away from current approaches, and applying methods based on understanding the
fundamental principles of crystallisation, the OptiCryst project will focus on designing tech-
niques to actively control the crystallisation environment as the project progresses through
its stages.
Potential Impact:
Structural Genomics is a key discipline in post-genomic biology, and today the pressure to
produce diffraction-quality crystals that can yield new protein structures is greater than ever.
As a result, the science of crystallisation is becoming a rapidly developing field and it is
gathering new momentum. The work being carried out by the Opticryst project will go a sig-
nificantly long way towards addressing the outstanding needs within that research area.
Masterclass Opticryst 2007
Optimisation of Protein Crystallisation
Keywords:
protein crystallization, phase diagrams, nucleation, robotics, high throughput, structural
genomics
Partners
Project Coordinator: Dr. Marcus J. Swann
Dr. Roslyn Bill Fairfield Scientific Ltd
Aston University Crewe, UK
Aston Triangle Prof. Juan Manuel Garcia-Ruiz
Birmingham, B4 7ET, UK Consejo Superior de Investigaciones
r.m.bill@aston.ac.uk Cientificas (CSIC)
Laboratorio de Estudios Cristalograficos
Project Manager: Armilla, Spain
Eric Bourguignon
Aston University Prof. Christian Betzel
Department of Life and Health Sciences PLS Design GmbH
Aston Triangle Hamburg, Germany
e.bourguignon@aston.ac.uk Prof. Lena Gustafson
Gothia Yeast Solutions AB
Prof. Naomi Chayen Gothenburg, Sweden
Imperial College of Science, Technology and Medicine
Biomedical Sciences
Biological Structure and Function
London, UK
Dr. Patrick Shaw Stewart

Douglas Instruments Ltd
Hungerford, UK
Dr. Flip Hoedemaeker

Key Drug Prototyping
Dr. Anthony Savill

Molecular Dimensions Ltd
Newmarket, UK
Dr. Rafael Rubio Cruz

Triana Science & Technology
Armilla, Spain
Prof. Rolf Hilgenfeld

University of Lübeck
Institute of Biochemistry
Lübeck, Germany
TEACH-SG
www.teach-sg.eu
State-of-the-Art:
Project Type: Since 2002, momentum has been gathering in European structural genomics. EU funding for
Specific Support Action six major projects, along with other initiatives in Europe (SGC, PSF, OPPF, Genopoles and
Contract number: PSB) has provided a broad base to build a comprehensive and competitive European structural
genomics research effort. These early programmes have excelled in the development and im-
LSSG-CT-2004-503468 plementation of automated, computational and high throughput methods for protein structure
Starting date: determination in a number of organisms. The challenge is to broadcast this knowledge to Eu-
1st January 2007 ropean laboratories as the scientific and strategic goals of structural genomics are expanded
Duration: and refined to address important issues for human health. TEACH-SG provides a focus for
30 months training in all the main methodological areas of structural genomics, bringing together exper-
tise from each programme to provide an integrated skill resource for researchers in the field.
EC Funding:
`490 000
The principal objective of TEACH-SG is to institute a programme to train and educate the
next generation of biomedical and computational scientists in the methods and technologies
of high throughput and high value structural proteomics. TEACH-SG will provide training in
several formats:
1) Practical workshops on state-of-the-art structural genomics/proteomics methodology.
2) Networking meetings bringing together several projects under the European struc-
tural genomics umbrella, TEACH-SG, will host joint meetings with representatives
from other structural genomics programmes.
3) Unrestricted web-based training information: All workshop and conference pro-
grammes will be published on a dedicated TEACH-SG website.
4) European Structural Genomics Newsletter: As part of the information dissemination,
a newsletter will be established
5) Visits from world-class scientific researchers in SG.
Expected results:
TEACH-SG will provide a platform for training young scientists and those from smaller labo-
ratories and new EU member states in the technologies developed in Structural Genomics,
particularly in high throughput techniques. Training will be provided in: i) bioinformatics
approaches to target selection and data handling; ii) high throughput automated methods
in cloning and protein expression in prokaryotic and eukaryotic systems; iii) automated
protein characterization iv) high volume crystallogenesis and evaluation; v) computational
structural determination methods. The programme of networking meetings will have a spe-
cific Structural Genomics/Proteomics theme, presenting recent technological and methodo-
logical advances in the field with the aim of fostering a constructive dialog between devel-
opers of similar or complementary technologies.
Potential impact:
TEACH-SG will provide essential focus for training in all the main methodological areas
of high throughput structural biology, bringing together expertise from each programme to
provide integrated skills resource for researchers. Productive associations with the commer-
cial and industrial sector will also identify and support the transfer of developmental work
into the highly focused area of new drug design. TEACH-SG will provide a scale of training
and opportunity that is not always met with a limited budget available within a multidi-
mensional but largely research-driven programme. TEACH-SG will be able to concentrate
on providing these resources, particularly practical hands-on experience of emerging and
fast-moving technologies and will be in an excellent position to monitor the impact of this
programme in subsequent years.
Training and Education in High Volume
and High Value Structural Genomics
Keywords:
structural proteomics, training, work-
shops, website, networking, crystal-
lography, structure determination
Partners
Project Coordinator: Prof. Keith Wilson Dr. Maria Armenia Carrondo
Prof. David Stuart University of York Instituto de Technolgie Quimica e Biologica
University of Oxford Department of Chemistry Protein crystallography laboratory
Wellcome Trust Centre for Structural Biology Laboratory Oeiras, Portugal
Human Genetics York, UK
Division of Structural Biology Prof. Miquel Coll
Roosevelt Drive Dr. Anastassis Perrakis Institute for Research in
Headington, OX3 7BN, UK Netherlands Cancer Institute (NKI) Biomedicine (IRB Barcelona)
dave@strubi.ox.ac.uk Division of Molecular Carcinogenesis Barcelona, Spain
Project Manager: Prof. Lucia Banci
Dr. Susan Daenke University of Florence
University of Oxford Polo Scientifico
Wellcome Trust Centre for Centro Risonanze
Human Genetics Magnetiche (CERM)
Roosevelt Drive Sesto Fiorentino, Italy
Headington, OX3 7BN, UK
susan@mail.strubi.ox.ac.uk Dr. Beata Vertessy
Hungarian Academy of Sciences
Prof. Joel L. Sussman Metabolism and Repair Department
Weizmann Institute of Science Institute of Enzymology
Department of Structural Biology Budapest, Hungary
Faculty of Chemistry
Rehovot, Israel Dr. Jan Dohnalek
Ustav makromolekularnii
Dr. Stephen Cusack chemie Akademie ved
European Molecular Biology Ceske republiky
Laboratory (EMBL) Department of Structure Analysis
Grenoble Outstation Group of Analysis of Molecular
Grenoble, France Structure
Prague, Czech Republic
Prof. Dino Moras
Centre Européen de Recherche
en Biologie et en Médecine –
Groupement d’Intérêt Economique
UPR9004/CERBM G.I.E.
Illkirch, France
4. COMPARATIVE
GENOMICS
& MODEL ORGANISMS
4.1
MOUSE
EURExpress
MUGEN
PRIME
FLPFLEX
EUCOMM
EUMODIC
CASIMIR
EURExpress
www.eurexpress.org/ee/

Integrated Project
Contract number: This EURExpress integrated project responds to the priority topic “Global in situ gene ex-
pression analysis in rodent models and human tissues”. EURExpress integrates European
LSHG-CT-2004-512003
skills, efforts, resources and information in the field of systematic gene expression analysis.
Starting date: Expression data of approximately 20 000 genes will be generated by RNA in situ hybridi-
1st January 2005 sation (ISH) on E14.5 wild type murine embryos which will result in detailed description
Duration: (at a cellular level) of gene expression patterns. A ‘transcriptome atlas’ will be generated
48 months using a newly developed automated RNA ISH system. Automated scanning microscopes
EC Funding: will collect image data which will be electronically sent out in a digital format for annota-
tion. The latter will be performed using a web-based ‘virtual’ microscope and entered in
`10 800 000
a hierarchical database designed to hold large amounts of image data and display them
in a user-friendly format. For a subset of genes, mainly those directly involved in human
diseases, expression data will also be generated by using human and murine tissue arrays.
This will offer the opportunity to compare human and mouse expression patterns in adult
tissues. This project builds up a strong European concentration of skills in gene expression
analysis and mouse genomics. It will allow integration with existing European projects,
such as mouse mutagenesis and mouse phenotyping projects, which critically depend on
detailed information on gene expression patterns. Integration of the efforts of several Eu-
ropean laboratories will result in the standardisation of methods to generate, collect and
display gene expression data. Furthermore, technological expertise will be disseminated
by training and exchange programmes. All expression data will be made readily avail-
able to the scientific community via the EURExpress web-linked database, advancing our
knowledge of gene function and having a significant impact on the identification of gene
expression markers of disease processes.
The scientific and technological objectives of this grant proposal are:
sTORETRIEVEFROMPUBLICSEQUENCEDATABASESCHROMOSOMESPECIlCTRANSCRIPTMAPSTHAT
represent the major source for the transcriptome atlas. Additional priorities include
disease genes and genes subject to alternative splicing
sTOOBTAINTHEEXPRESSIONPATTERNBY)3(ONEMBRYOS
of approximately 20 000 genes
sTOINTEGRATEANDVALIDATETHEEXPRESSIONPATTERNANALYSISPERFORMEDINMOUSEANDHU-
man tissues using tissue microarray analysis with medically relevant genes
sTOESTABLISHANONLINE%UROPEANDATABASEOFGENEEXPRESSION
sTOINTEGRATETHE%52%XPRESSDATABASEWITHOTHERBIOINFORMATICSRESOURCES
sTOTRAINYOUNGRESEARCHERSINTHElELDOFGENEEXPRESSIONANDBIOINFORMATICS
sTOBUILDATASKFORCEOFRESEARCHERSFOCUSEDONGENEEXPRESSIONANALYSISIN%UROPE
and synergistically integrate with other European mouse functional genomics efforts
such as EUMORPHIA.
Expected Results:
EURExpress proposes a transcriptome-wide acquisition of expression patterns chiefly by
means of in situ hybridisation (ISH) with non-radioactive probes and will use this data to
establish a web-linked, interactive digital transcriptome atlas of embryonic mouse. In addi-
A European Consortium to Generate
a Web-Based Gene Expression Atlas
by RNA in situ Hybridisation
Template
Clone Selection Generation
EURExpress
Transcriptome
Atals
Tracking
Database
AUTOMATED in situ
Image Annotation
Automated Microscopy
Work Flow. In Situ

Hybridization (ISH)
tion to generating large sets of embryonic expression data in mouse, EURExpress will take
a detailed look at expression in human tissues. Over >1000 disease-related genes will
be analysed using tissue microarrays containing several hundred mouse and adult human
tissues. A publicly accessible transcriptome atlas database will be created to store and
retrieve all image, experimental and annotation data.
The consortium will undertake an integrated approach to create a web-based gene expres-
sion atlas by RNA in situ hybridisation.
The direct results at the end of the project will be:
The establishment of a tracking database that will allow monitoring and integrating data
flow. This database will be accessible across the project, facilitating the management of
data production.
The establishment of high-throughput ISH technology in Europe.

Eurexpress will contribute to setting up a structure in which scientists can be trained in the
field of gene expression and database management.
The generation and management of approximately 20 000 murine templates.
The implementation of simple search interfaces to the transcriptome database and of an
initial set of programmatic interfaces to other bio-informatics resources to support functional
genomics analyses.
High-resolution expression data throughout brain development for a subset of brain-specific
genes.
EURExpress
left: Saggittal section of an

E14.5 embryo showing the
expression pattern of Fgfb3
(Fibroblast binding protein 3) in
the developing CNS.
middle: Expression of an
uncharacterized gene in the CNS,
in the sympathetic ganglion and
in the dorsal root ganglia
right: Example of a gene (Otx2)

with strong expression in the
developing retina
The gene expression data for approximately 20 000 genes.

The generation of ISH data for tissue microarray sections.
The implementation of user interfaces, which will provide public access to EURExpress data
and will facilitate its application in functional genomics.
The generation of a web-based gene expression atlas.
Potential Impact:
The era of ‘post-genomic research’ is characterised by the requirement of high-throughput
procedures to exploit the vast amount of information generated in genome projects. High-
resolution analysis of gene expression can be performed by RNA in situ hybridisation,
which allows definition of gene expression with great accuracy. Europe is not only at the
leading edge in studies in mammalian genetics and the use of mouse models to elucidate
the genetic bases of disease, but has undertaken the lead in a number of new research
and development areas in the field of mouse functional genomics. EURExpress intends to
add to this European effort by creating an atlas of mouse gene expression in the form of
a searchable database that will be available to the scientific community. The expression
pattern of a gene in a multicellular organism is a basic feature of the biological function of
any gene. The mouse is strategic for this type of study because the mouse genome encodes
an experimentally tractable organism and has emerged as a pre-eminent organism for the
study of human diseases and gene function. More than 98% of human genes are present
in the mouse.
The potential impact on the study of human development and disease is enormous:
sITWILLHELPINIDENTIFYINGGENESWHOSEMUTATIONSLEADTOWELLCHARACTERISEDDISEASE
phenotypes
sITWILLHELPINIDENTIFYINGDOWNSTREAMMARKERSTOCHARACTERISEDISEASEPHENOTYPETO
evaluate disease prognosis and to measure therapeutic benefits.
Keywords:
RNA in situ hybridisation, mouse, gene expression analysis, functional genomics, transcrip-
tome atlas, automated RNA ISH system, web-based virtual microscope, web-linked gene
expression database
A European Consortium to Generate a Web-Based Gene Expression Atlas
by RNA in situ Hybridisation
Partners
Project Coordinator: Dr. Uwe Radelof
Prof. Andrea Ballabio RZPD German Resource Center for Genome Research
Fondazione Telethon Berlin, Germany
TIGEM-Telethon Institute of Genetics and Medicine
Via Pietro Castellino 111
80131 Naples, Italy
ballabio@tigem.it
Prof. Gregor Eichele

Max-Planck Institute of Biophysical Chemistry
Göttingen, Germany
Dr. Marie-Laure Yaspo

Max-Planck Institute for Molecular Genetics
Berlin, Germany
Dr. Duncan Davidson

MRC Human Genetics Unit
Edinburgh, UK
Prof. Stylianos Antonarakis

University of Geneva
Faculty of Medicine/ Division of Medical Genetics
Geneva, Switzerland
Prof. Salvador Martinez Perez

Universidad Miguel Hernandez
Instituto de Neurociencias -Laboratorio de
Embriología Experimental
Alicante, Spain
Dr. Pascal Dolle

Centre Européen pour la Recherche en Biologie
et Médecine
Mouse Clinic Institute
Illkirch, France
Dr. David Tannahill

Wellcome Trust Sanger Institute
Wellcome Trust Genome Campus
Hinxton, UK
Prof. Pier Paolo Di Fiore

IFOM, The FIRC Institute for Molecular Oncology
Milan, Italy
Dr. Stefan Kruse

Orgarat GmbH
Essen, Germany
Dr. Paolo Sarmientos

PRIMM Srl
Milan, Italy
MUGEN
www.mugen-noe.org

Integrated Project
Contract number: Immunological diseases are complex diseases. They encompass a wide variety of disor-
ders, affecting a steadily increasing proportion of people living in modern societies. During
LSHG-CT-2004-005203
the past decade, dramatic advances have been made in understanding the mechanisms
Starting date: regulating the immune system, its pathological processes and the processes of immune de-
1st January 2005 viation. Central to this was the ability of studying individual genes in the immune system of
Duration: live animals using gene-targeting technologies. At the same time, this allowed the develop-
60 months ment of models of immune diseases.
EC Funding:
Life Sciences have entered the post-genomic era. A surprisingly small number of 30 000
`11 000 000
or less genes comprise our genome. Thus, it is feasible to apply technologies such as DNA
microarrays and proteomics to analyse almost all genes and proteins simultaneously. This
provides the unprecedented opportunity to map genes and gene networks systematically.
By applying functional genomics to models for immunological diseases, gene-networks can
be mapped and genes underpinning immune deviations and diseases can be identified.
This will unlock a huge potential for generating novel diagnostic tools and identifying novel
pharmacological targets. The next major contribution to our understanding of the immune
system is expected to come from a systematic coordinated application of functional genom-
ics approaches to animal models for immune disorders or processes.
MUGEN aims to structure and shape a world-class network of European scientific and tech-
nological excellence in the field of murine models of human immunological diseases that
will advance understanding of the genetic basis of disease and enhance the innovation and
translatability of research efforts. The network is pursuing three parallel approaches:
sAJOINTPROGRAMMEOFACTIVITIESHASBEENFORMULATEDTHATISDESIGNEDTOMAKEMAXI-
mum use of the common resources to identify new target genes for immune processes
and diseases
sTECHNOLOGICAL CORE UNITS ARE BEING ESTABLISHED WHICH ARE CENTRES OF TECHNOLOGICAL
expertise able to provide all MUGEN participants with the services necessary for an
efficient application of post-genomic protocols
sAWEB BASED-5'%.KNOWLEDGEENVIRONMENT-+% ISBEINGCREATEDWHICHISA
relational database for the integration and management of knowledge and informa-
tion in the area of immunological research.
Expected Results:
MUGEN aims to bridge the gaps in immunological research by assembling, coordinating
and exploiting the animal model resources of its participants, and employing a unifying
functional genomics approach to efficiently predict and validate dominant gene function with
pathogenic relevance for human immunological disease. In the first phase, the project is as-
similating expertise in key areas of immunological research that can be divided roughly into
the three categories: basic immunological processes, immunological diseases and immuno-
genetics. Following this assimilation, a selective functional genomics strategy will lead to the
identification of putative genetic networks in human immunological diseases. A comparative
analysis of the data produced by the first phase will allow us to decide on key genetic targets
Integrated Functional Genomics
in Mutant Mouse Models as Tools
to Investigate the Complexity of
Human Immunological Disease
for immune diseases. Integrating

functional genomic platforms will
be implemented to validate the
genetic targets in animal model
systems and allow for the devel-
opment of biotechnological prod-
ucts targeting pathological proc-
esses. This will produce new basic
knowledge on immune processes
and additional targets for human
immunological diseases.
Through the integration of this

knowledge into the MKE, the re- TNFRI positive
sults from this network will help Follicular Dendritic Cells
formulate new concepts for clinical
applications. Besides the scientific
and technological components, the
network is keen on spreading its
scientific and technological excel-
lence. The primary objective is to
promote training-through-research
to a new generation of scientists.
MUGEN also wants to create an
impact on the public awareness of
the pan-European dimension of re-
search efforts into immunological
problems.
MUGEN is dedicated to extending

TNFRI deficient
every effort to promote the exploi-
Follicular Dendritic Cells
tation, dissemination and commu-
nication of its scientific and tech-
nological excellence to key stakeholders in the area of immunological diseases, including
physicians, patients, policy-makers, the industry, academia and the public at large.
Potential Impact:
Immune pathologies encompass a wide variety of disorders with epidemiological relevance,
hence the discovery of therapeutic targets is a major priority in European health policies.
Previous work in immunological research resulted in independent knowledge, complemen-
tary expertise and resources. The benefit of the consortium lies in the integration of labora-
tories that are expert in the modelling of immunological processes or disease, state-of-the-art
technologies in genome research and functional genomics, with the aim of enhancing our
understanding of mechanisms in immunity and disease.
The coordinated application of functional genomics approaches to existing mouse models

and the integration of the research results into a common knowledge environment is expect-
ed to have a significant impact on our understanding of pathways and gene networks un-
derlying immunological diseases. With the notion that the major drug candidates in clinical
MUGEN
development were either predicted or validated in mouse models, this approach promises to
add significantly to future diagnostic and treatment options of immune related diseases.
Thus, the successful implementation of the network will have a major structural impact for
biomedical research in Europe, which will persist well after the end of the duration of the
project. MUGEN’s achievements and deliverables are expected to benefit research beyond
its borders and will therefore be of broad scientific and socioeconomic value.
Keywords:
functional biology, molecular genetics, animal immunology, targeted mutagenesis, animal
models, molecular pathways, exploratory drug discovery, functional genomics
Project Flyer
This is the first project flyer
describing participation and
activities throughout the first
Joint Programme of Activities,
running from month 1-18.
© BSRC Al. Fleming
Partners
Project Coordinator: Prof. Paola Ricciardi-Castagnoli
Dr. George Kollias University of Milano-Bicocca
Biomedical Sciences Research Center Department of Biotechnology and Bioscience
34 Al. Fleming Street Milan, Italy
16672 Vari, Greece
g.kollias@fleming.gr Prof. Maries Van Den Broek, Prof. Rolf Zinkernagel
University of Zurich
Prof. James Disanto Institute of Experimental Immunology
Institut Pasteur Zurich, Switzerland
Unité des Cytokines et Developpement Lymphoide
Paris, France Dr. Werner Müller
GBF Gesellschaft für Biotechnologishe Forschung mbH
Dr. Günter Haemmerling Department of Experimental Immunology
Deutsches Krebsforschungszentrum (DKFZ) Braunschweig, Germany
Molekulare Immunologie
Heidelberg, Germany Prof. Anton Berns
Netherlands Cancer Institute
Prof. Bernard Malissen Antoni van Leeuwenhoek Hospital
Centre National de la Recherche Scientifique (CNRS), Division of Molecular Genetics
Delegation Provence Amsterdam, The Netherlands
Marseille, France
Integrated Functional Genomics in Mutant Mouse Models as Tools to
Investigate the Complexity of Human Immunological Disease
Prof. Alvis Brazma Dr. François Romagne

European Molecular Biology Laboratory (EMBL) Innate Pharma SAS
European Bioinformatics Institute (EBI) Marseille, France
Microarray Informatics Team
Outstation Hinxton Dr. Martin Bachmann
Hinxton, UK Cytos Biotechnology AG
Zurich-Schlieren, Switzerland
Prof. Lars Fugger, Prof. Dimitris Kioussis
Medical Research Council Jesper Zeuthen
Human Immunology Unit Biomedical Venture, Bankinvest Group
Oxford, UK Copenhagen, Denmark
Prof. Rikard Holmdahl Dr. Alberto Mantovani

Lunds Universitet – Medical Inflammation Research Instituto Clinico Humanitas
Department of Cell and Molecular Biology Rozzano, Italy
Lund, Sweden
Dr. Bjorn Lowenadler
Prof. Paola Ricciardi-Castagnoli Biovitrum AB
Genopolis Consortium Gothenburg, Sweden
University of Milano-Bicocca
Department of Bioscience and Biotechnology/U4 Dr. Manolis Pasparakis
Milan, Italy University of Cologne
Dr. Antonio Lanzavecchia Department for Mouse Genetics and Inflammation
Institute for Research in Biomedicine Cologne, Germany
Bellinzona, Switzerland
Dr. Lefteris Zacharia
Prof. Klaus Pfeffer BioMedCode Hellas SA
Heinrich-Heine-Universitat Düsseldorf Vari, Athens, Greece
Institut für Medizinische Mikrobiologie
Düsseldorf, Germany
Prof. Andreas Radbruch

Deutsches Rheuma-Forschungszentrum
Berlin, Germany
Prof. Glauco Tocchini-Valentini

Consiglio Nazionale delle Richerche
Istituto di Biologia Cellulare
Rome, Italy
Prof. Jurg Tschopp

University of Lausanne
Epalinges, Switzerland
Dr. Klaus Rajewsky

The CBR Institute for Biomedical Research Inc
Harvard Medical School
Boston, USA
Dr. Andreas Persidis

Biovista – A. Persidis & Sia O.E.
Elliniko, Athens, Greece
PRIME
www.prime-eu.org
State-of-the-Art:
Project Type: At present, the genetic make-up or genome of the mouse is familiar to scientists. The next chal-
Coordination Action lenge for biomedical science is to determine the function of these genes, and the manner in
Contract number: which their alterations can cause disease. This is what is referred to as functional genomics.
LSHG-CT-2005-005283
The mouse model plays a pivotal role in the investigation of human diseases and their diagno-
Starting date: sis and treatment. Most EU member states perform research into mouse functional genomics.
1st June 2005 This research is funded at two levels: nationally, and by the European Commission. Mouse
Duration: functional genomics research in Europe would benefit significantly from a pan-European ap-
48 months proach, which would integrate both national and EU programmes. Greater interaction be-
EC Funding: tween research scientists and national policymakers would in fact allow for research priorities
to be formulated.
`799 417
The European Commission provides support for infrastructures, such as the development
of databases of anatomy, or the European Mutant Mouse Archive (EMMA). Collaboration
amongst policy makers within the member states may promote the development of new strate-
gies, which would secure funding to support these essential infrastructures.
In delivering a new coordinating action to improve the structure and integration of Euro-
pean mouse functional genomics, we propose 3 phases for PRIME, namely:
1. Benchmarking, mapping and assessment of European activities committed to mouse

functional genomics;
2. Exploring methods for convergence of policy, communality of research and commu-
nication;
3. Extending and consolidating the new coordination activities.
The aim is to ensure that Europe delivers research of outstanding quality, by employing more
integrated approaches and by more effectively harnessing existing resources (both biologi-
cal and informational); the development of new resource and infrastructure opportunities
will likewise further this cause. Achieving these goals will allow us to more advantageously
compete for funding, utilise available opportunities, and ultimately acquire financial back-
ing from both national and European sources.
Networking meetings will be held, with the intention of determining how far Europe is
already integrated in terms of research policy, and how the means for achieving such
convergence might be enhanced. It is also important to assess how communication and
informational resources can assist in this matter. Following networking meetings, dialogue
between expert groups of scientists and policy makers will establish new means for im-
proved convergence of policy, communality of research and communication. The following
key areas will be addressed:
Convergence of research policy

1. Initiation of dialogue between key research funders and policy makers;
2. Exploration of research policies and mechanisms of research support.
Communality of research currency

1. Determination of current resource centres (including infrastructures), inclusive of those
under development, and those requiring assistance;
2. Determination of informatics currently used to keep records, and provide access to
these resource centres;
Priorities for mouse functional genomics
research across Europe: integrating and
strengthening research in Europe
3. Determination of areas with standard protocols
in place, and areas lacking such protocols;
4. Determination of the presence and absence of
quality control.
Improved communication
1. Determination of websites and databases cur-
rently available, and of means to improve
their inter-communication;
2. Exploration of training needs, and means to
fund training;
3. Determination of available expertise at indi-
vidual institutes within the project, and poten-
tial for training provision.
Potential Impact:
The Eumorphia programme of mouse phenotyping delivered pan-European standards for
a mouse phenotyping platform (www.empress.har.mrc.ac.uk). PRIME will investigate stand-
ardisation in other areas of mouse functional genomics, by investigating means of produc-
ing common and standardised information systems for mouse resources, as well as improv-
ing integration and common data standards.
PRIME will find ways to avoid duplication in research, by facilitating interaction between
research groups working in common research areas; improve access to resources and da-
tabases, ensuring that data can be shared and avoiding duplication; and work to common
standards and protocols, allowing data to be directly compared by laboratories, reducing
the need to duplicate the research. In addition, the project will genuinely benefit the cause
of animal welfare, by reducing the number of animals used for research purposes.
Keywords: mouse functional genomics, animal models, integrating research,

resources, infrastructures, research policies
Partners
Project Coordinator: Prof. Johan Auwerx
Prof. Steve Brown Institut Clinique de la Souris
Medical Research Council Illkirch, France
Mammalian Genetics Unit
MRC Harwell Prof. Philip Avner
Oxfordshire, OX11 0RD, UK Institut Pasteur
s.brown@har.mrc.ac.uk Paris, France
Prof. Martin Hrabé de Angelis

GSF-National Research Center for
Environment and Health GmbH
Institute of Experimental Genetics
Neuherberg, Germany
Prof. Andrea Ballabio

TIGEM, Telethon Institute of Genetic Medicine
Naples, Italy
FLPFLEX

Specific Targeted
Research Project The aim of FLPFLEX is to develop a novel genetic approach to the manipulation of gene
expression in the mouse in order to dissect complex genetic pathways and to provide
Contract number:
more accurate models of human disease. Most major human diseases are caused by small
LSHG-CT-2005-513769 cumulative changes in cell function that are often related to inherited susceptibility to differ-
Starting date: ent diseases. Recapitulating these multiple genetic susceptibilities in an animal model has
1st July 2005 remained a major challenge to modern medical research. The FLFPLEX system engages the
Duration: cell’s own gene regulatory circuits to capture subtle gene expression patterns, and at the
42 months same time provides a means to target different small changes to specific genes, allowing
rapid assessment of the effect of gene mutations that cause human disease. This novel tech-
EC Funding:
nology provides powerful and adaptable tools for designing increasingly complex genetic
`1 698 000 models of human physiology and pathology.
The project will develop readout vector technologies, establish the FLPFLEX cell library and
develop flexible genomic insertion cassettes carrying modifications to allow recombinase-
mediated cassette exchange of effector genes of interest. The FLPFLEX vector carrying a mul-
tifunctional tag will be randomly incorporated into the genome of embryonic stem (ES) cells.
The team will also sequence and identify 10 000 FLPFLEX cassette integration sites using
mouse genomic information. Fifty FLPFLEX clones will be selected for further characterisation
and focused studies in vivo. Different effector genes will be introduced in selected FLPFLEX
cell clones. The consortium will engage and refine the FLPFLEX system in a series of proof-of-
concept experiments that focus on genes whose disease relevance is well documented, but
mutations which have yet to be modelled in the mouse
Expected Results:
Once proven, the system can be scaled to produce the desired change in virtually any
gene of clinical interest. The project also intends to provide an efficient mechanism for gen-
erating, characterising and disseminating these models. FLPFLEX is strategically designed
to provide an efficient mechanism for generating, characterising and disseminating these
models. Information and reagents generated will be disseminated on a publicly accessible
database.
Potential Impact:
These studies will be correlated with work in related EU-funded projects on mouse gene ex-
pression patterns and mutagenesis and the models will be disseminated to the international
scientific community for further analysis and testing, broadening the knowledge base of
gene expression in mice for future testing.
Keywords:
medical genetics, molecular genetics, genetic engineering, animal models
A Flexible Toolkit for Controlling
Gene Expression in the Mouse
a The transgene has the same
pattern of expression of the
endogenous SPNR gene, as
visualized by in situ hybridization
with both SPNR and GFP probes
and by direct GFP fluorescence
b (a) Diagram of direct (Bgeo) and

flipped (hygro-GFP) insertions in
the third intron of the SPNR locus
(b) Sagittal sections of whole
embryos at 13.5 d.p.c. of
heterozygous SPNR +/GFP
mice, hybridized with a DIG-
labeled probe of the endogenous
SPNR gene and the GFP gene,
indicate a specific signal in the
telencephalon, mesencephalon
and spinal cord. Direct GFP
visualization of the adjacent
sections shows the same pattern
of expression of the transgene.
Partners
Prof. Nadia Rosenthal
Mouse Biology Unit
Monterotondo Outstation
Campus “A Buzzati-Traverso”
Via Ramarini 32
00016 Monterotondo, Italy
rosenthal@embl-monterotondo.it

TIGEM, Telethon Institute of Genetics and Medicine
Rome, Italy
Prof. Dr. Wolgang Wurst

Helmholtz-Zentrum Muenchen
German Research Center for Environmental Health
Institute of Developmental Genetics
Neuherberg, Germany
Prof. Riccardo Cortese

(Partner until project month 24)
Istituto Di Ricerca Di Biologia Molecolare P Angeletti
Pomezia, Italy
Dr. Hansjorg Hauser

Helmholz Center for Infection Research
Braunschweig, Germany
EUCOMM
www.eucomm.org

Integrated Project
Contract number: The EUCOMM project responds to the most important topic defined by Priority 1, Life
Sciences and Biotechnology for Health, Genome-wide Mutagenesis in Mouse. EUCOMM
LSHM-CT-2005-018931
integrates European skills, efforts, resources and infrastructure to produce, in a systematic
Starting date: high-throughput way, mutations throughout the mouse genome. A collection of up to 20
1st January 2006 000 mutated genes will be generated in mouse embryonic stem (ES) cells using conditional
Duration: gene trapping and gene targeting approaches. This library will enable mouse mutants to
48 months be established worldwide in a standardised and cost-effective manner, making mouse mu-
EC Funding: tants available to a much wider biomedical research community than has been previously
possible. For a subset of genes relevant for human disease, mutant mice will be estab-
`13 000 000
lished, archived and analysed. This will offer an opportunity to decipher molecular disease
mechanisms and, in some cases, provide a foundation for the development of diagnostic,
prognostic and therapeutic strategies. This project is built on exceptionally strong European
expertise in mouse molecular genetics, genomics and bioinformatics, and enables automa-
tion of targeting vector production and professional dissemination of material. EUCOMM
fosters integration with existing European consortia which address mouse gene expression
analysis, mutant phenotyping, imaging and archiving. Progress of all of these projects will
be enhanced by EUCOMM mouse mutants. All targeting vectors, mutant ES cells, mouse
resources and standard operating procedures generated by EUCOMM are displayed to the
scientific community via the EUCOMM web-linked database, other EU consortia databases
and the Ensembl browser, and distributed by two professional distribution units. Taken to-
gether, EUCOMM will make a major contribution to the analysis of gene function. Finally,
EUCOMM resources will represent major opportunities for exploitation by SMEs and the
pharmaceutical industry.
EUCOMM presents a work plan for a pan-European effort in mouse mutagenesis that builds
on existing resources in mutagenesis, gene expression analysis, phenotyping, archiving
and bioinformatics to move towards a comprehensive annotation of gene function in the
mouse genome. EUCOMM aims at making a significant contribution to the international
effort to establish a library of condi-
tionally mutated mouse ES cells which
are available to the scientific com-
munity. An ES cell library containing
up to 20 000 independently mutated
genes will be created using condi-
tional gene trapping and conditional
gene targeting approaches. From the
mutant ES cell resource, by EUCO-
MM itself, up to 320 mutant mouse
lines will be established focusing on
disease-relevant gene mutations. EU-
COMM’s mutant ES cells, vectors and
mouse models are publicly accessible
via an interactive website, and mate-
rial is disseminated via two profes-
Chimeric mice © GSF - IDG sional distributing units.
Photo: Ralf Kuehn
The European Conditional Mouse
Mutagenesis Programme
Schematic presentation of
EUCOMM organisation
Expected Results:
The expected EUCOMM results after the end of the funding period will be:
sTHE ESTABLISHMENT AND DISTRIBUTION OF UP TO CONDITIONAL GENE TRAP AND
conditional gene targeting
mutations in mouse ES
cells, including mutations
associated with human
disease
sTHE ESTABLISHMENT AND
archiving of up to 320
mutant mouse lines
sTHEESTABLISHMENTOFUPTO
20 ligand-inducible Cre-
recombinase expressing
transgenic mouse lines
which differ in their
expression characteristics
sTHE ESTABLISHMENT OF
an online database to Mouse embryonic stem (ES) cell
disseminate EUCOMM colonies ©GSF - IDG
material worldwide Photo: Ralf Kuehn
EUCOMM
sTHEINTEGRATIONOFTHE%5#/--DATABASEWITHOTHERBIOINFORMATICSRESOURCES
sTHETRAININGOFTECHNICALSTAFFSTUDENTSANDPOST DOCS
sTHEGENERATIONOFA%UROPEANMOUSEMUTAGENESISPLATFORMANDFORUMANDTHESYNERGISTIC
integration of EURExpress, FLPFLEX, EMAGE, PRIME, FunGenES, EUMODIC, EMMA,
and others.
Potential Impact:
EUCOMM’s repository of conditionally mutated ES cells will allow the establishment of
sophisticated mouse models for a wide range of human diseases including neurological
and psychiatric diseases, cardiovascular diseases, cancer and diseases related to ageing
processes. EUCOMM’s deliverables will also be very useful for target identification and
validation in the development process of human disease diagnostics and therapeutics, im-
plemented by companies. EUCOMM will secure intellectual property rights and the benefit
for the European industry, especially SMEs, in exploiting the respective results. Altogether,
EUCOMM will have a great impact on societal needs as well as on the strengthening of the
European biotech industry.
Furthermore, EUCOMM will contribute to the establishment of a European Research Area:
1) EUCOMM’s repository of conditionally mutated mouse ES cells will allow the estab-
lishment of mouse models in a systematic, standardised, and non-redundant manner
across the European scientific community, thus helping to overcome fragmentation of
research efforts.
2) EUCOMM will establish a close interaction with several other EU research consortia,
including the integration of all the projects’ databases, thereby supporting the estab-
lishment of a European Research Area in web area terms. In addition, EUCOMM
co-operates with complementary mouse functional genomics initiatives at the global
level (KOMP, TIGM in the United States, and NorCOMM in Canada) in the frame-
work of the International Knockout Mouse Consortium (IKMC).
Keywords: functional analysis of the mouse genome, mouse disease models,

conditionally mutated mouse ES cell library
Cell culture robot

(HAMILTON MICROLAB STAR)
Detail of a HAMILTON MICROLAB
STAR, showing the independently
spreadable channels and a
96-channel pipetting head in
the background. ©Hamilton Life
Science Robotics allowed the use
of the picture for this purpose.
Photo: Alexander Starcevic
The European Conditional Mouse Mutagenesis Programme
Partners
Prof. Wolfgang Wurst Prof. Nadia Rosenthal
Helmholtz Zentrum München, German Research Center European Molecular Biology Laboratory (EMBL)
for Environmental Health GmbH EMBL Monterotondo Outstation
Institute of Developmental Genetics Mouse Biology Unit
Ingolstaedter Landstrasse 1 Monterotondo, Italy
wurst@helmholtz-muenchen.de Prof. Steve Brown
Project Co-Coordinator: Mammalian Genetics Unit
Prof. Allan Bradley Harwell, UK
Genome Research Ltd
Wellcome Trust Sanger Institute Prof. Glauco Tocchini-Valentini
Wellcome Trust Genome Campus Consiglio Nazionale delle Ricerche
Hinxton, CB10 1SA, UK Istituto di Biologia Cellulare (CNR-IBC)
abradley@sanger.ac.uk Monterotondo Scalo, Italy
Project Manager:
Dr. Cornelia Kaloff
Helmholtz Zentrum München, German Research Center
for Environmental Health GmbH
Ingolstaedter Landstrasse 1
cornelia.kaloff@helmholtz-muenchen.de

Helmholtz Zentrum München,
German Research Center for Environmental
Health (GmbH)
Neuherberg, Germany
Prof. Harald von Melchner

University Hospital of the Johann Wolfgang
Goethe University Frankfurt
Department of Haematology
Prof. Patricia Ruiz

Charité Universitaetsmedizin Berlin
Center for Cardiovascular Research
Berlin, Germany

Technische Universitaet Dresden
Department of Biotec, Genomics
Dresden, Germany
Prof. Johan Auwerx

et Médecine - Groupement d’Intérêt Economique
Institut Clinique de la Souris
Illkirch, France
EUMODIC
www.eumodic.org

Integrated Project
Contract number: The major challenge for genetics in the 21st century is the determination of the function of
all the proteins encoded by the human genome and, moreover, the role of these proteins in
LSHG-CT-2006-037188
disease. Model organisms will be the key to this endeavour as the EUMODIC team are able
Starting date: to manipulate the genes and investigate the consequences for the organism. The EUMODIC
1st February 2007 (http://www.eumodic.eu) consortium is made up of 18 laboratories across Europe and in-
Duration: cludes leading experts in the field of mouse functional genomics and phenotyping who have
48 months a track record of successful collaborative research in the FP5 EUMORPHIA project.
EC Funding:
The mouse occupies a unique position in determining the genetics of disease for a number
`11 999 832
of reasons. Firstly, it demonstrates a remarkably similar development, physiology and bio-
chemistry to the human. Secondly, mouse geneticists have developed a very extensive ge-
netic toolkit that enables defined targeted alteration of genes in the mouse genome. Thirdly,
previous research has revealed the complete sequence of the mouse genome.
As a first step towards a functional annotation of the mouse genome, EUMODIC will under-
take a primary phenotype assessment of up to 650 mouse mutant lines. In addition, a number
of these mutant lines will be subject to a more in-depth secondary phenotype assessment.
The EUMODIC project will provide the tools to determine the function of the genes, by pass-
ing the mice through a series of screens that will fully identify the characteristics (or pheno-
type) of a mouse that has had its genes altered. These screens are designed to identify a
broad range of characteristics to determine the function of the gene. The screens will give
reproducible results so information from different groups of mice with different alterations to
their genes can be compared.
The EUMODIC consortium will build on the findings of the EUMORPHIA project, which
delivered a comprehensive database EMPReSS (European Mouse Phenotyping Resource
of Standardised Screens) of Standard Operating Procedures (SOPs) that can be used to
determine the phenotype of a mouse (http://www.empress.har.mrc.ac.uk). EUMODIC has
developed a selection of screens, EMPReSSslim, which is structured for comprehensive,
primary, high-throughput phenotyping of large numbers of mice. Primary phenotype assess-
ment using EMPReSSslim will be undertaken in four large-scale phenotyping centres. They
are: GSF (Germany), ICS (France), MRC Harwell (UK) and the Sanger Institute (UK). Pheno-
type data from these mice will be made publicly available to the wider scientific community
via the EuroPhenome database (http://www.europhenome.eu).
Mutant lines will be made available from another EU initiative, the EUCOMM (European
Conditional Mouse Mutagenesis) project which aims to produce conditional mutations in
20,000 mouse genes (www.eucomm.org). EUMODIC will undertake a comprehensive pri-
mary phenotype assessment of up to 650 mouse mutant lines generated by the EUCOMM
consortium in the null configuration.. A distributed network of centres with in-depth expertise
in phenotyping domains will undertake more complex, secondary phenotyping screens and
apply them to a subset of the mice which have shown interesting phenotypes in the primary
screen. Phenome data on the mouse lines will be disseminated to the wider biomedical sci-
ences community via the EuroPhenome database (www.europhenome.eu). EUMODIC will
The European Mouse Disease Clinic:
A distributed phenotyping resource
for studying human disease
also undertake further refinement of a number of phe-

notyping approaches to speed mouse phenotyping.
Overall, EUMODIC is a first step towards tackling the

need for large-scale phenotyping in the mouse and the
comprehensive study of mammalian gene function and
its role in disease.
Expected Results:
The aim of the EUMODIC project is to generate com-
prehensive phenotype data covering most body sys-
tems on a large number of mouse mutants.
Moreover, EUMODIC plans a major discovery phase of the programme where many of the
most interesting mutants will undergo more detailed secondary phenotyping. The secondary
data recovered will add considerable value to the primary phenome data on many of the
mutant lines. Each virtual centre will deliver a set capacity to analyse a number of mutant
lines for one or more secondary screens. In addition, EUMODIC may direct particular lines
of high interest directly to the secondary phenotyping centres, depending on a variety of
factors such as the putative functional domains of the relevant gene, its expression patterns
or interactions with other genes of known function.
Potential Impact:
One of the key objectives of the LifeSciHealth priority has been to translate genomic in-
formation into an improved understanding of the role of genes in disease. Research on
the determination of the gene function has been supported by the availability of complete
sequences of both human and a number of model organism genomes. The provision of well
annotated complete sequences of the mouse genome is an important starting-point for the
determination of the function of mammalian genes and the role they play in disease.
With the extensive toolkit that is available to generate mutants, this team is now in a position
to generate mutations for all of the genes in the mouse genome and to examine the pheno-
typic outcome for each mutant allele. The information provided would bolster and underpin
many of the projects in both human and mouse genetics that are at the core of European
funding and objectives of the LifeSciHealth Priority. The EUMODIC project will ensure that
Europe will remain competitive in the development of phenotyping tools and approaches.
The EUMODIC project is crucial for increasing momentum in the key goals of mouse func-
tional genomics by applying phenotyping platforms to the mouse mutant resources that are
being developed. Moreover, the proposed links with disease genetics groups across Europe
in the selection of mutants to be phenotyped will underpin the competitiveness of European
functional genomics programmes.
Identifying the genetic bases for human disease is a fundamental goal of biomedical sci-
ences programmes. The investigation of gene function through mouse mutagenesis and
phenotyping is a central element in achieving this goal and we can expect that the iden-
tification of the many disease models that will arise from the EUMODIC programme will
EUMODIC
considerably inform our understanding of disease genetics. The EUCOMM programme

will be complemented by a major effort in the US to develop a knock-out mouse mutant re-
source (the KOMP initiative). A large-scale gene trap initiative has been recently announced
(NorCOMM) in Canada as well. An international Complex Trait Consortium (CTC) is also
progressing with the generation of recombinant inbred mice strains which would comple-
ment the mutants created on both sides of the Atlantic.
Keywords:
phenotyping, mouse disease models, animal models, human disease models
Partners
Prof. Steve Brown
MRC Harwell
Harwell, OX11 0RD, UK
s.brown@har.mrc.ac.uk
Prof Johan Auwerx

Centre Européen de Recherche en
Biologie et en Médecine GIE
Institut Clinique de la Souris
Illkirch, France
Prof. Dr. Martin Hrabé de Angelis

German Research Center for
Environmental Health
Neuherberg, Germany
Prof. Karen Steel

Hinxton, UK
Dr. Werner Mueller

Helmholtz-Zentrum für
Infektionsforschung GmbH
Helmholtz Centre for Infection Research

Consiglio Nazionale delle Ricerche
Istituto di Biologia Celluare
Monterotondo Scalo, Italy
Prof. Ludwig Neyses

University of Manchester
Heart Failure Group
Manchester, UK
The European Mouse Disease Clinic:
A distributed phenotyping resource for studying human disease
Prof. Nadia Rosenthal Prof. George Kollias

European Molecular Laboratory (EMBL) Alexander Fleming Biomedical
EMBL Monterotondo Outstation Sciences Research Center
Mouse Biology Unit Vari, Greece
Monterotondo, Italy
Prof. Mariano Barbacid

Centro Nacional de Investigaciones Oncológicas (CNIO)
Spanish National Cancer Research Centre
Madrid, Spain
Dr. Jacqueline Marvel

Ecole normale supérieure de Lyon
Ani.Rhône-Alpes
DR2 Centre National de la Recherche
Lyon, France
Prof. Karen B. Avraham

Tel Aviv University
Sackler School of Medicine
Department of Human Molecular Genetics
and Biochemistry
Tel Aviv, Israel
Prof. Fatima Bosch

Universitat Autònoma de Barcelona
Center of animal biotechnology and genetic
therapy (CBATG)
Bellaterra, Spain
Prof. Walter Wahli

Université de Lausanne
Centre Integratif de Génomique
Le Génopode
Dr. Yann Herault

Centre National de Recherche Scientifique (CNRS)
Institut de Transgenose,
Laboratoire d’Immunologie et Embryologie
Moléculaires (IEM)
Orléans, France
Dr. Paul Schofield

Department of Physiology,
Development and Neuroscience
Cambridge, UK

Telethon Insitute of Genetic and
Medicine (TIGEM)
Naples, Italy
CASIMIR
www.casimir.org.uk
State-of-the-Art:
Project Type: In Europe, much of the current effort in functional genomics, as well as knowledge of the
Co-ordination Action biology of human disease, is underpinned by a scattered collection of databases. Failure
Contract number: to sustain and integrate these databases will ultimately damage Europe’s competitiveness in
these areas of research. CASIMIR is designed to coordinate and integrate databases that
LSHG-CT-2006-037811
have been set up in support of the Fifth, Sixth and Seventh Framework Programmes for the
Starting date: storage of experimental data, including sequences; and of material resources, such as bio-
1st February 2007 logical collections, that are relevant to the mouse as a model for human disease. Ensuring
Duration: that databases are inter-operable will generate enormous synergy in the provision, integra-
36 months tion and analysis of data, significantly enhancing the value of research.
EC Funding:
CASIMIR will deliver a series of scientific meetings, reports and papers addressing the cur-
rent state of databases supporting mouse functional genomics in Europe, and will recom-
mend a feasible and widely applicable model for their inter-operability and sustainability. It
will also address the mobilisation of national resources, where databases are funded solely
or partly by Member States. The consortium’s specific objectives are set out below:
1) Standardisation of data representation and its semantics;
2) Standardisation of data transfer and database-querying protocols;
3) Creation of the modes of database use that are required by the community, and
provision of appropriate interfaces;
4) Dissemination of information regarding the existence of, and means of accessing,
databases throughout Europe;
5) Consideration of legal issues surrounding the deposition of data in public databases.
Failure to address these issues could damage European research in future, if data resources
remain fragmented. CASIMIR will also, therefore, address three aspects of the sustainability
of databases and informatics infrastructures: (1) Scientific sustainability, as measured by
the willingness of scientists to use them and to deposit their data in them, for the benefit of
the whole scientific community; (2) Financial sustainability, measured mainly in terms of the
provision of curators, database developers and informaticians; (3) Technical sustainability,
i.e. the need to accommodate innovations in database and (semantic) web technologies,
to keep databases compatible with evolving worldwide standards, once they have been
established.
Expected Results:
In the first phase of the project, which will last nine months, the consortium will gather
information concerning interested parties with a stake in informatics infrastructures and da-
tabases, beyond the consortium itself, and establish a presence on the world wide web, in
order to inform the community of its existence and to invite external views. It will make use
of reports from an existing European project known as PRIME, to obtain information about
the current state-of-the-art, in mouse databases in Europe.
In the second phase of the project, the consortium will prepare a set of recommendations
for data standards and semantics, together with reports on strategies for financial sustain-
ability and an assessment of the impact of legal considerations on data deposition. An
annual public meeting will be held, which, along with scientific publications, will contribute
towards the dissemination of the project’s findings.
Co-ordination And Sustainability of
International Mouse Informatics Resources
Potential Impact:
CASIMIR will produce a coherent strategy for the technical integration and scientific sus-
tainability of the database infrastructure required for mouse functional genomics and re-
lated investigations into human disease. It will lay the foundations for a coherent and sus-
tainable informatics infrastructure, which will produce added value for both the European
Commission and for funding agencies of the EU Member States. In doing so, it will support
the following activities: (1) The functional analysis of mammalian genes; (2) The develop-
ment of animal models of human disorders; (3) The development of widely applicable
resources for the understanding of gene function and the dissection of genetic networks,
which, in turn, will aid comparison of conserved and species-specific functions between
various model organisms and man.
Europe currently has a competitive edge over the rest of the world, in terms of academic
and industrial research using the mouse as a model. If that advantage is to be retained,
a coherent strategy must be settled for maintaining and developing the existing database
infrastructure. To this end, CASIMIR will drive integration, the free flow of information and
ultimately, innovation in the health sciences.
Keywords: bioinformatics, databases, mouse, animal models

Partners
Dr. Paul Schofield Prof. Glauco Tocchini-Valentini
University of Cambridge Istituto di Biologia Cellulare
Department of Physiology Consiglio Nazionale della Ricerche
Development and Neuroscience Monterotondo Scalo, Italy
Downing Street
Cambridge, UK Dr. Tom Weaver
ps@mole.bio.cam.ac.uk Geneservice Ltd
Cambridge, UK
Dr. John Hancock
Harwell, UK Prof. Nadia Rosenthal
Dr. Duncan Davidson Laboratory (EMBL)
Medical Research Council EMBL Monterotondo Oustation
Human Genetics Unit Mouse Biology Unit,
Edinburgh, UK Monterotondo, Italy
Prof. Rudi Balling Dr. Ewan Birney

Helmholtz-Zentrum für European Molecular Biology
Infektionsforschung Laboratory (EMBL)
Braunschweig, Germany European Bioinformatics Institute (EBI)
Hinxton, UK
Helmholtz Zentrum München Prof. George Kollias
German Research Center for Institute of Immunology
Environmental Health (GmbH) Biomedical Sciences Research
Institute of Experimental Genetics Centre ‘Alexander Fleming’
Neuherberg, Germany Vari, Greece
4.2 RAT
STAR
EURATools
Med-Rat
STAR
www.mdc-berlin.de

Specific Targeted
Research Project The rat is an important model organism for systems biology, providing the most relevant
models of common multifactorial human disease, and is by far the leading model species
Contract number:
in pharmacology and toxicology. Decades of exquisite phenotyping and detailed analysis
LSHG-CT-2004-005235 of crosses of inbred rats have resulted in initial localisation of hundreds of loci involved in
Starting date: complex disease and quantitative phenotypes, but with very few eventual gene identifica-
1st January 2005 tions to date. A clear understanding of the origin and structure of the genetic variation in the
Duration: rat will provide a missing key piece of this puzzle. The proposed SNP-based haplotype map
24 months provides a valuable tool for functional genomics, specifically by focusing positional cloning
of QTLs through the reduction of regions obtained through linkage analysis, the selection of
EC Funding:
ideal strain combinations for further reduction of critical regions, and the use of correlation
`2 400 000 across many inbred strains to identify very short gene-harbouring regions.
Taking advantage of the access to novel gene functions promised by mouse and rat QTL
studies, there is a need for new innovative and straightforward approaches that provide
strategic support for QTL research in the rat in Europe. The proposed haplotype map will
be represented to the genetics community to facilitate QTL gene identification. The develop-
ment of a set of 150 000 high-quality candidate SNPs is a prerequisite for the construction
of a detailed haplotype map across the rat genome. Ancestral segments of rats representing
the most commonly used rat strains in life science will be used to identify very short genomic
regions, which are most likely to harbour the corresponding disease genes. A clear under-
standing of the haplotype structure and origin of genetic variation in these strains will be a
key progress in biology and will have deep impact on understanding disease development
and health.
Expected Results:
STAR will lead a comparative molecular analysis across many disease relevant strains. It
will provide essential tools that will be immediately useful to focus positional cloning of QTLs
through the reduction of regions obtained through linkage analysis via identification of seg-
ments shared by the strains used for the cross, and the selection of ideal strain combinations
for further reduction of critical regions through simple intercross/backcross experiments.
Also, the use of correlation between phenotype and ancestral sequence origin across many
inbred strains will help to identify the very short genomic regions most likely to harbour
responsible genes.
The research will be objective-driven and carried out in the following steps:
1. identification of sufficiently large sets of sequence variation throughout the rat ge-
nome within transcribed sequences and within genomic sequences
2. establishment of a haplotype map
3. display of results to integrate into existing databases.
A SNP and Haplotype Map for the Rat
Potential Impact:
STAR’s focus is to gather fundamental knowledge and basic tools for functional genomics
by conducting research on sequence variation across the rat genome to define the ancestral
haplotype blocks. It has strong innovative aspects and will contribute towards strengthen-
ing the competitive position of European research, but it has also a potentially very signifi-
cant societal impact in the mid to longer term regarding the improvement of healthcare.
The STAR consortium will internally generate standard operational procedures for defining
haplotype blocks and widely applicable genotyping panels, which will provide a valuable
basis for the creation of standards in SNP typing and validation.
Keywords: rat model, SNP, haplotype map, genetic variation, positional clon-
ing, phenotyping
Partners
Project Coordinator: Dr. Richard Reinhardt
Dr. Norbert Hübner Max-Planck-Institute for Molecular Genetics
Max-Delbrück-Center for Molecular Medicine High Throughput Technology and Service Unit
Experimental Genetics of Cardiovascular Diseases Berlin, Germany
Robert-Rössle-Strasse 10
13092 Berlin, Germany Dr. Roderic Guigó
nhuebner@mdc-berlin.de Centre de Regulació Genòmica
Research Group on Biomedical
Dr. Ivo Glynne Gut Informatics (GRIB-IMIM)
Consortium National de Recherche Barcelona, Spain
en Génomique (CNRG)
Technology Department
Evry, France
Dr. Dominique Gauguier

Wellcome Trust Centre for Human Genetics
Oxford, UK
Dr. Ewan Birney

Hinxton, UK
Dr. Roderic Guigó

Institut Municipal d’Assitència Sanitaria
Genome Bioinformatics Research Lab
Barcelona, Spain
Dr. Edwin Cuppen

Hubrecht Laboratory
Netherlands Institute for Developmental Biology
Functional Genomics Group
EURATools
www.euratools.eu

Integrated Project
Contract number: The EURATools Consortium will address fundamental issues of genetic and phenotypic varia-
tion in mammalian biology. The project will be carried out in an integrated manner by using a
LSHG-CT-2005-019015
number of innovative approaches. EURATools methodology is credited with making it possible
Starting date: to anticipate that progress will be clearly demonstrable against the state-of-the-art.
1st March 2006
Duration: The use of whole-genome scans to identify Quantitative Trait Locus (QTL) is a powerful way to
48 months investigate the genetic basis of susceptibility to complex human diseases. Although QTL map-
EC Funding: ping has become easier with the availability of many genetic markers, identifying the genes
that underlie the QTL that are associated with common phenotypes has proved to be a chal-
`11 000 000
lenge. The new genome data generated by EURATools will build on, and markedly improve,
the recently assembled draft rat genome sequence, thus improving gene models as well as the
utility of the sequence for rat genetics.
Genome projects are, by

nature, highly collabora-
tive, as it is unusual for
any single centre (or even
a single country) to em-
bark on genome projects
alone. This makes the
EURATools proposal very
suited to EU funding, and
will place the EU in an
extremely competitive po-
Optimisation of nuclear transfer sition. Collaborative work
techniques for standardised with the USA, Canada
creation of cloned rats and Japan will give the
EU a strong place in ne-
gotiations on future resources and initiatives in these countries, and will build on the signifi-
cant investment already made by the EU in the area of rat biology and genetics.
Moreover, the advancement in knowledge and associated reagents and resources will con-
tribute significantly to the scientific communities’ understanding of the genetic programmes
that underpin multifactorial diseases. Progress in this area will play a key role in providing the
essential tools for the development of future strategies. The main goals of these strategies are
to identify susceptibility genes for epidemiologically important disorders; to optimise strate-
gies for new drug design; and to identify new targets for therapies for treatment of common
human diseases.
The main scientific and technological objectives of the EURATools project are the following:
1) Development of high-throughput genomic tools for annotation and identification of
complex trait disease genes in the rat;
2) Optimization and facilitation of germline modification procedures, refinement and
adaptation of nuclear transfer protocols;
European Rat Tools
for Functional Genomics
3) Provision of a resource for depos-

iting, exchanging, preserving and
distributing inbred, congenic and
mutant rat strains, mapping of mul-
tiple physiological phenotypes;
4) Coordination of genome sequence,
gene models, mapping resources
and expression data, development Computerised measurement
of data mining resources and train- of blood pressure by radio
ing of bioinformatics expertise; telemetry in conscious, free-
5) Definition of genes and regulatory moving rats
pathways underlying control of
gene expression and protein abundance in relation to disease phenotypes, integra-
tion of expression profiling and linkage analysis;
6) Positional cloning of genes in minimal congenic strains representing cardiovascular
and inflammatory diseases as models for human diseases, dissection of the complex-
ity of pathway controls.
Expected Results:
After 4 years, the EURATools programme plans to deliver the positional cloning of several rat
complex trait genes. Presently, two have been definitively identified, but several more have
tantalising results based on very small, minimal
congenic regions and strong positional candidates.
Given the development of proposed genome re-
sources and tools, the development of this is likely
to accelerate to such an extent that the team could
anticipate entering an exponential phase of QTL
gene discovery and characterisation.
Based on past successful progress and existing ex-

pertise of EURATools Partners in the field of nuclear
transfer and oocyte biology; achieving robust pro-
tocols for rat cloning and homologous recombina-
tion by the end of the project is anticipated. Results
from the project would potentially give rise to a
quantum leap in the research on rat genetics and
would lead to mechanistic experiments of test hy-
potheses that, through observational phenotyping
experiments in the rat, have arisen in hundreds of
laboratories world-wide over the past 50 years.
EURATools programme plans to offer very signifi-

cant opportunities for translating investment in ba-
sic scientific discovery to improvements in health
and opportunities for wealth generation. The tools
to be put in place under these proposals will pro-
vide the stimulus for an exciting period of discovery Development of a rat congenic
in biomedical science and translational research. strain for genetic analysis
of rat arthritis
EURATools
Potential Impact:
The project has strong innovative aspects that will contribute to strengthening the competi-
tive position of European research. Specifically, EURATools will merge European research
resources and, most importantly, will use and consolidate common tools and protocols that
will allow genomics data to be effectively used to understand the biology of the genome
for a large number of inbred strains. The Consortium will also develop a collection of novel
molecular tools to mark and select disease specific inbred strains.
EURATools has a potentially significant societal impact regarding the improvement of health-
care. Its integrative and multidisciplinary approach will considerably contribute to the re-
structuring and strengthening of European
R&D activities. Comparative and functional
genomics studies are likely to provide data
for annotating the human genome sequence,
Nuclear donor cell for building better animal models, for assist-
in the pipette prior to transfer ing in the development of new therapeutic
– a preparation for rat cloning agents, and for understanding gene regula-
tion. As the genomic sequence is annotated
with more and more function, it will become increasingly easy to formulate testable hypoth-
eses for common diseases. In addition, the project will have a broad stimulating effect on
gene target validation and drug development in pharmaceutical industries.
Keywords:
complex traits, drug development, disease mechanisms, informatics, gene targeting
Partners
Project Coordinator: Dr. Laurence Game
Prof. Timothy J. Aitman Medical Research Council
Medical Research Council Microarray Centre
Physiological Genomics and Medicine London, UK
MRC Clinical Sciences Centre
Hammersmith Hospital Prof. Norbert Hübner, Prof. Michael Bader
Du Cane Road Max-Delbrück-Centrum für
London, W12 0NN, UK Molekulare Medizin (MDC)
t.aitman@csc.mrc.ac.uk Berlin, Germany
Project Manager: Prof. John Mullins, Sir Ian Wilmut

Dr. Erik Werner University of Edinburgh (UEDIN)
Medical Research Council Edinburgh, UK
Physiological Genomics and Medicine
MRC Clinical Sciences Centre Dr. Michal Pravenec, Dr. Vladimír Landa,
Hammersmith Campus Prof. Vladimír Kren
Du Cane Road Czech Academy of Sciences (CAS)
London, W12 0NN, UK Prague, Czech Republic
erik.werner@csc.mrc.ac.uk
Dr. Ewan Birney, Dr. Xosé M. Fernández
Hinxton, UK
European Rat Tools for Functional Genomics
Prof. Anna F Dominiczak, Prof. Walter Kolch Dr. Alexandre Fraichard

University of Glasgow (UGL) genOway SA
Glasgow, UK Lyon, France
Prof. Rikard Holmdahl Prof. Roland Wolf

Lund University CXR Biosciences Ltd. (CXR)
Medical Inflammation Research Dundee Technopole
Lund, Sweden Dundee, UK
Prof. Claude Szpirer

Université Libre de Bruxelles
Institut de Biologie et
de Medecine Moleculaires (IBMM)
Brussels, Belgium
Prof. Mark Lathrop, Dr. Ivo Gut,

Dr. Jean Weissenbach
Commissariat à l’Energie Atomique
Centre National de Séquençage (CNS),
Centre National de Génotypage (CNG)
Evry, France
Prof. Dominique Gauguier

Prof. Jonathan Flint
Wellcome Trust Centre for Human Genetics
Oxford, UK
Prof. Alberto Fernández-Teruel

Universitat Autònoma de Barcelona
Dept. of Psychiatry and Forensic Medicine
Bellaterra (Cerdanyola del Vallès), Spain
Prof. Tomas Olsson

Neuroimmunology Unit
Center for Molecular Medicine (CMM)
Stockholm, Sweden
Prof. Qi Zhou
Chinese Academy of Sciences (IOZ CAS)
Institute of Zoology
State Key Lab of Reproductive Biology
Beijing, Peoples Republic of China
Dr. Richard Reinhardt

Max-Planck-Institute for
Molecular Genetics (MPIMG)
Berlin, Germany
Prof. Jean-Paul Renard

Institut National de la Recherche Agronomique (INRA)
Unité de Biologie du Développement
Jouy en Josas, France
Med-Rat
State-of-the-Art:
Project Type: The post-genomic era offers opportunities to improve the quality of life in Europe. Whilst
Specific Targeted projects involving mice and human genome have revealed the basic genomic information,
Research Project complex modelling systems are now required to transfer knowledge into functional biology
Contract number: and medicine. Transgenic (TG) animal models play an important role in the attempt to dis-
cover the genetic basis of human disease. In particular, there is a need for animal models
LSHG-CT-2006-518240 instead of cell culture because of the complexity of the biological processes that form the ba-
Starting date: sis of most diseases. To date, most information on genomics has been generated through the
1st March 2006 mouse model. However, the potential of this is limited because the anatomy and physiology
Duration: of mice are not always adequate for studying human disease. In addition, the sophisticated
36 months techniques used for the mouse model have, through the procedure of nuclear replacement,
now become available for studies in non-murine species.
EC Funding:
`1 575 000 The MED-RAT project aims to exploit these advances, and, by generating transgenic models
in other species, bridge the gap between mouse models and treatment of human diseases.
Many species have metabolism and organs more similar to humans than to mice. However,
the lack of stable stem cell lines in animal species other than mice has impeded the use of
refined genetic tools for specific targeted genetic models.
The aim of the MED-RAT project is to establish Europe as a leader in animal models for compar-
ative functional genetic research by 2008. The establishment of transgenic laboratory animal
models will reveal the correlation between the genetic code and the biological functions and
this approach will potentially clarify the genetic base of many diseases including Alzheimer’s,
cardiovascular diseases, diabetes and cancer.
As part of the 6th Framework Programme, the primary objective of MED-RAT is to produce a
technological platform for the generation of novel targeted genetic animal models, thus provid-
ing a powerful tool for European functional genomics with great potential for medical research.
Additional objectives include: 1) validating the nuclear replacement as a technical platform to
produce transgenic mouse models; 2) clarifying the role of mitochondrial inheritance in nuclear
replacement; 3) improving gene targeting methods in somatic cells cultures; 4) developing an
improved system for banking and distributing the newly generated model animals.
Expected Results:
The examples reported above demonstrate the need to understand gene function differences
in various species. The aim of MED-RAT is to create models in rats with targeted genetic modi-
fications. This will result in the creation of new models to compare the functional genomics
of rats with those of mice. The application of
these conclusions will create new or improved
methods for somatic cell gene targeting, gam-
ete and embryo cryopreservation, and new
knowledge on the role of mitochondria in nu-
clear replacement, Activation of mitochondrial
and ribosomal RNA genes following nuclear
replacement will altogether contribute to the
creation of a novel technological platform.
The safety and reliability of this platform will
be validated in the mouse model, by apply-
ing an already existing state-of-the-art mouse
Mouse clones geno- and phenotyping system.
New Tools to Generate Transgenic
and Knock-out Mouse and Rat Models
Potential Impact:
The development of novel and more efficient animal nuclear replacement techniques for
mammalian animal models in mouse and rat with targeted genetic modifications, is crucial
for the generation of precisely defined transgene conditions and defined genomic back-
grounds. This is an important prerequisite for the standardised and reproducible appraisal
of transgene-induced phenotypic variations. The parallel animal nuclear replacement and
phenotype studies within this consortium will allow the standardisation of animal nuclear
replacement procedures and result in interpretation. Development and dissemination of ani-
mal models are fundamental for making them accessible for the wider scientific community.
A separate work package focuses on the cryopreservation of gametes of newly generated
animal models in mouse and rat. Banking of such gametes and their international exchange
will allow the laboratories involved to study a standardized genetic background model.
Forecasts in different countries point out that in 2020, close to 40 percent of the population
will be older than 65 years. The ageing population is prone to various diseases, causing
immense social and economic problems. Gene medicines will be effective in primary pre-
vention and in the treatment of chronic diseases as they interfere with their molecular cause,
and will thus provide better treatment at lower cost.
Keywords: gene targeting, somatic cell, nuclear replacement, mouse, rat, com-
parative functional genomics, animal models
Partners
Dr. Andras Dinnyes
Agricultural Biotechnology Center
Genetic Reprogramming Group
Szent-Gyorgyi A. u. 4
2100 Godollo, Hungary
dinnyes@abc.hu
Project Manager:
Nora Burgmann
Agricultural Biotechnology Center
Genetic Reprogramming Group
Szent-Gyorgyi A. u. 4
2100 Godollo, Hungary Prof. Poul Maddox-Hyttel
burgmann@abc.hu University of Copenhagen
Department of Basic Animal
Dr. Johannes Beckers and Veterinary Sciences
Helmholtz Zentrum München Frederiksberg, Denmark
Deutsches Forschungszentrum
für Gesundheit und Umwelt Prof. Keith Campbell
(HMGU) (former GSF) University of Nottingham
Neuherberg, Germany Division of Animal Physiology
School of Biosciences
Prof. Mathias Müller Nottingham, UK
University of Veterinary Medicine
Institute of Animal Breeding Dr. Andras Dinnyes
and Genetics BioTalentum Ltd
Vienna, Austria Godollo, Hungary
4.3
ZEBRAFISH
ZF-MODELS
ZF-TOOLS
ZF-MODELS
www.zf-models.org

Integrated Project
Contract number: In recent years, model organisms have played an increasingly important role in genome
research, both in addressing basic biological questions and in making the best possible use
LSHG-CT-2003-503496
of sequence information for human health (drug design and diagnostics). While Drosophila
Starting date: and #AENORHABDITIS have yielded valuable information, many aspects of human develop-
1st January 2004 ment and gene regulation require a vertebrate model. In this context, the zebrafish has
Duration: several unique advantages, such as transparent, easily accessible embryos, simple breed-
60 months ing and a short generation time. It has therefore become the pre-eminent, non-mammalian
EC Funding: vertebrate model organism, complementing the most widely used mammalian organism,
the mouse.
`12 000 000
Zebrafish mutants have been characterised, that affect a large number of developmental
processes, such as early embryogenesis, organ formation and simple behaviour. The func-
tions of most zebrafish genes have been shown to be conserved in other vertebrate groups,
and a large proportion of the known zebrafish mutations are candidates for human disease
genes. The importance of the zebrafish for functional genomics is illustrated by the recent
establishment of several SMEs that focus on zebrafish research. To provide a systematic
basis for the cloning of zebrafish mutations, increasingly powerful genomic tools have been
developed, both in Europe and in the USA. The Fishman lab in Boston, for example, has
produced 4,000 microsatellite markers, while the zebrafish genomics group currently led
by Robert Geisler, in Tübingen, Germany, has mapped several hundred mutations and cre-
ated a radiation hybrid map for the zebrafish.
The ZF-MODELS consortium will produce new insights into how genes control development
and ageing in vertebrates, insights that could potentially lead to the development of new
or improved therapies for human diseases. Its targets include common pathologies such as
cancer, neurodegenerative diseases, muscular dystrophies and eye diseases, as well as
resistance to infections, the process of wound-healing and behavioural disorders.
Zebrafish development
Zebrafish Models
for Human Development and Disease
The specific, scientific objectives of the project can be described as follows: (1) Two large-
scale mutagenesis projects, offering scientists the opportunity to examine zebrafish carrying
genetic mutations. The first such screen, organised by the Max-Planck Institute for Develop-
mental Biology, was initiated in January 2005; the second, organised by the University of
Freiburg, got underway in mid-2005. In contrast to previous zebrafish mutagenesis screens,
the ZF-MODELS project places an emphasis on the genes relevant to human disease, and
on mutations affecting the adult as well as the developing fish; (2) Analysis of gene expres-
sion patterns. Thousands of fish are being generated, in which the expression of green
fluorescent protein is under the control of enhancer sequences of specific genes (enhancer
detection screening). Under blue light, the tissues of these fish light up where the gene in
question is being expressed. Three-dimensional patterns of gene expression will also be
analysed during development, on a large scale, using in situ hybridisation; (3) Expression
profiling and proteomics. The activity (expression) of tens of thousands of zebrafish genes
is being analysed on gene chips (microarrays), in an effort to discover how genes regulate
each other’s activity during normal development, and how this regulation is disturbed in mu-
tants. In addition, proteins expressed in normal and mutant zebrafish are being analysed,
to elucidate how protein expression is affected.
Expected Results:
The expected results of the ZF-MODELS project are as follows: (1) Disease models. Fish with
genetic disorders corresponding to human diseases will be produced by chemical muta-
genesis (forward genetics) and targeted knockout (reverse genetics), and characterised by
the consortium. These disease models will aid clinical researchers and the European phar-
maceutical industry in developing new therapies; (2) Drug targets. The vast majority of ze-
brafish genes are orthologues to human genes, over half of which have yet to be assigned
a function in the Human Genome Project. ZF-MODELS will discover novel candidate genes
for regulatory pathways by their expression patterns and mutant phenotypes. These genes
will be made available to the European pharmaceutical industry for evaluation as potential
drug targets, in small molecule screens, for instance; (3) Analysis of regulatory pathways.
The consortium will elucidate previously unknown pathways of gene regulation that are
relevant to human development. This information will be obtained by expression profiling
Zebrafish adult
ZF-MODELS
and proteomics, in combination with more traditional approaches in developmental genet-

ics, such as phenotypic and functional analysis of mutants. Improving basic knowledge of
human development is central to understanding the causes of many congenital diseases
and cancers.
Potential Impact:
ZF-MODELS will provide new tools and large data sets for functional genomics of the ze-
brafish, allowing European researchers to access genomic data from the ongoing sequenc-
ing project in novel ways. There are currently estimated to be nearly 300 research groups
using zebrafish data and screening methods, of which almost 200 are located in the USA.
The American research groups are focusing on the development and deployment of new
functional genomics tools, in anticipation of sequencing information to be generated by the
UK’s Wellcome Trust Sanger Institute. It is important that European groups also have the
tools to use this resource, in order to compete on an international level, and to strengthen
the European science base in comparative genomics, and its applications in understanding
the basis of human diseases.
The geographical distribution of zebrafish research groups in Europe reflects past invest-
ments in research as well as the historical development of the field. One of ZF-MODELS’
main goals is to spread expertise and to encourage the use of the zebrafish as a non-mam-
malian vertebrate model in groups emerging beyond the traditional centres of strength — in
particular, in groups in EU Candidate States, which lack the large-scale facilities required
for genome sequencing and high-throughput functional genomics, but which could benefit
greatly from use of the zebrafish model, in addressing their specific research questions.
The ZF-MODELS consortium will therefore encourage the participation of researchers from
emerging groups across the EU and the Candidate States in its training programmes and
workshops. Arrangements will be made for the training of technicians, and advice will be
offered on means of setting up new laboratories and screening facilities. There will also
be opportunities for emerging groups to join the consortium — opportunities that will be
announced publicly as and when they rise, through mailing lists, websites and international
meetings, as well as through direct contact with those emerging European groups known
to the consortium. With its strong focus on human disease, ZF-MODELS expects to advance
basic, early clinical and translational research.
Keywords:
functional genomics, model organisms, animal models, disease mechanisms, drug targets,
bioinformatics, zebrafish, human development
Partners
Project Coordinator: Carl-Philipp Heisenberg
Dr. Robert Geisler Max Planck Institut of Molecular Cell
Max Planck Institute for Developmental Biology Biology and Genetics
Department of Genetics Dresden, Germany
Tübingen, Germany
robert.geisler@tuebingen.mpg.de Dr. Matthias Hammerschmidt
Max-Planck-Institut für Immunbiologie
Prof. Christiane Nüsslein-Volhard Freiburg, Germany
Max Planck Institute for Developmental Biology
Tübingen, Germany
Zebrafish Models for Human Development and Disease
Prof. Jane Rogers Dr. Philippe Herbomel

Genome Research Ltd Institut Pasteur
Wellcome Trust Sanger Institute Département de Biologie du Développement
Cambridge, UK Unité Macrophages et Développement de l’Immunité
Paris, France
Dr. Christine Thisse
Centre Européen de Recherche en Biologie Prof. Herman Spaink
et en Médecine (CERBM) Leiden University
Institut de Génétique et de Biologie Moléculaire Institute of Biology
et Cellulaire (IGBMC) Leiden, The Netherlands
Illkirch, France
Prof. Uwe Strähle
Prof. Ronald H. A. Plasterk Forschungszentrum Karlsruhe GmbH
Hubrecht Laboratory Institut für Toxikologie und Genetik
Netherlands Institute for Developmental Biology Karlsruhe, Germany
Dr. Michael Brand
Prof. Philip W. Ingham Technische Universitaet Dresden
The University of Sheffield BIOTEChnologisches Zentrum
Centre for Developmental Genetics Dresden, Germany
Sheffield, UK
Prof. Stephan C. F. Neuhauss
Prof. Stephen Wilson Universität Zürich
University College London Institute of Zoology
Department of Anatomy and Developmental Biology Zurich, Switzerland
London, UK
Dr. Frédéric Rosa

Institut National de la Santé et de la Recherche
Médicale (INSERM)
U368 INSERM: “Biologie Moléculaire du
Developpement”
Paris, France
Prof. Wolfgang Driever

Albert-Ludwigs-Universität Freiburg
Laboratory of Developmental Biology
Freiburg, Germany
Dr. Thomas Becker

University of Bergen
Sars Centre for Marine Biology
Bergen, Norway
Dr. Francesco Argenton

Universita’ degli Studi di Padova
Dipartimento di Biología
Padova, Italy
Dr. Laure Bally-Cuif

GSF-Research Center for Environment and Health
Neuherberg, Germany
ZF-TOOLS
State-of-the-Art:
Project Type: Human disease research and drug development rely heavily on the use of animal models.
SME- Specific Targeted Among these, the mouse model is the most intensively studied. However, over the last dec-
Research Project ade the zebrafish has emerged as an attractive alternative model and has progressively
Contract number: gained importance. This is due to the fact that the zebrafish offers exciting novel research
opportunities because of the optical transparency of its embryos and its amenability to
LSHG-CT-2006-037220 genetics. To date, the value of zebrafish in pharmacological studies has not yet been exten-
Starting date: sively explored and exploited. However, findings emphasise the potential of using zebrafish
1st January 2007 in several phases of drug discovery processes and in toxicological screens.
Duration:
36 months
EC Funding:
`1 739 000 The ZF-TOOLS project comprises the coordinated effort of three research laboratories and
three SMEs aimed at achieving the following two main objectives: Firstly, a genomic-based
marker discovery for biomedical screens in zebrafish and, secondly, the use of high-through-
put marker analysis and tumour cell implants for the identification of tumour growth and
metastasis factors and organismal defence factors.
More specifically, the project aims to develop a case study for an anti-tumour drug screen-
ing system, based on the implantation of fluorescently labelled tumour cells into zebrafish
embryos. This innovative tumour cell implantation system is currently being developed by
one of the SME partners and has the major advantage that it does not involve the use of
transgenic animals. Growth and metastasis properties of implanted tumour cells can be ef-
ficiently monitored by fluorescence microscopy during the development of the transparent
zebrafish embryos. This system resembles the natural situation of tumour growth, as the
tumour cells are derived from zebrafish cell cultures of embryonic origin and implanted
back into zebrafish embryos. It is envisaged that a powerful screening system can arise by
combining high-throughput marker analysis with the possibility to visualise tumour growth
and metastasis in an optically transparent vertebrate model organism.
However, for the realisation of this complex screening system, the identification of relevant
disease marker genes in zebrafish represents a crucial step. In ZF-TOOLS, different ge-
nomics approaches will be used to discover novel markers, which will be suitable for ap-
plication in the ZF-TOOLS tumour screening system and will also have a broader utility for
disease research in the zebrafish model.
Expected Results:
The strategic aim of ZF-TOOLS is the development of a zebrafish embryo screening system
as an innovative genomics tool. This system will be employed for high-throughput effective-
ness testing of pharmaceutical compounds that have the potential to influence disease proc-
esses, including tumour growth, metastasis and immune defence responses. This zebrafish
screening tool offers some unique features that make it very attractive in comparison with
existing tools.
In order to establish the zebrafish screening tools, the project will undertake a multidiscipli-
nary functional genomics approach which integrates different global expression profiling
techniques and bioinformatics. Based on this approach, the ZF-TOOLS project expects to
achieve the following results:
1) Knowledge of tumour growth and metastasis factors and organismal defence factors;
2) High-throughput tools for quantitative analysis of disease marker sets;
Transparent zebrafish embryo 3) A collection of constitutive and inducible, oncogenic and non-oncogenic reporter
High-throughput Tools
for Biomedical Screens in Zebrafish
cell lines useful for basic disease research and for application in screening
systems;
4) Case study results of a novel anti-tumour drug screening system, based on the
implantation of fluorescently labelled tumour cells into zebrafish embryos.
Potential Impact:
The ZF-TOOLS project aims to reinforce European competitiveness by generating
strategic knowledge thanks to its multidisciplinary research approach. The developed
tools and technology will be exploited for basic research on vertebrate disease and
for strategic research and service activities on behalf of three high-tech SMEs.
The lack of basic knowledge of disease marker genes is the current bottleneck for
biomedical research in zebrafish and for genomics-based compound screens in this
model organism. The ZF-TOOLS project uses multidisciplinary functional genomics
approaches to discover novel disease markers. The expected identification of factors
important for tumour growth and metastasis and organismal defence responses will
generate fundamental knowledge relevant to human health and will open the door to
the establishment of zebrafish-based biomedical research and screening tools.
Tumour screening system
Keywords: zebrafish, animal models, zebrafish embryo model, oncogenic cell

implants, anti-tumor drug discovery, reporter cell lines, tumor mark-
ers, immune response markers, expression profiling, screens, high-
throughput techniques
Partners
Dr. Annemarie H. Meijer
Leiden University
Institute of Biology
Molecular Cell Biology
Wassenaarseweg 64
2333 AL Leiden, The Netherlands
a.h.meijer@biology.leidenuniv.nl
Prof. Dr. Herman P. Spaink

ZF-screens BV
Dr. Nicholas Simon Foulkes

Forschungszentrum Karlsruhe GmbH
Institute for Toxicology and Genetics
Eggenstein-Leopoldshafen, Germany
Dr. Bas Reichert

BaseClear BV
Leiden, The Netherlands Dr. Mátyás Mink
Szeged University
Dr. Tamás Forrai Department of Genetics
Zenon Bio Ltd and Molecular Biology
Szeged, Hungary Szeged, Hungary
4.4 OTHER
MODELS
NemaGENETAG
TP Plants and Health
X-OMICS
NemaGENETAG
http://elegans.imbb.forth.gr/nemagenetag
Project Type:
State-of-the-Art:
Specific Targeted The nematode Caenorhabditis elegans is a widely appreciated, powerful platform on
Research Project which to study important biological mechanisms related to human health. Numerous human
disease genes have homologues in C. elegans, and essential aspects of mammalian cell
Contract number:
biology, neurobiology and development are faithfully recapitulated in this worm. We aim to
LSHG-CT-2003-503334 develop cutting-edge tools and resources that will facilitate the modelling of human patholo-
Starting date: gies in C. elegans, and advance our understanding of animal development and physiology.
1st January 2004 The final product of our focused project – a comprehensive collection of transposon-tagged
Duration: alleles – together with the acquisition of efficient transposon-based tools for mutagenesis
and transgenesis in C. elegans, should be of great value to the European and international
36 months scientific community.
EC Funding:
`1 782 474
Our initiative has three clear objectives.
1. Optimisation/automation of the Mos1-based system for large-scale mutagenesis.
The Mos1 system has already been established as an efficient tool for gene tagging
in C. elegans. We will further characterise this system in terms of insertion bias and
mutagenicity. Through such detailed characterisation, we will seek to optimise Mos1
tools and reagents for high-throughput screenings.
2. Development of novel transposon-based systems for mutagenesis, transgenesis and
genome engineering in C. elegans.
Development of other transposon systems is important for two reasons. First, all trans-
posons have preferential insertion sites in genomes. Second, transposons can be
used to introduce foreign sequences into the host genome and can accommodate
exogenous DNA, but the frequency of transposition decreases exponentially with
the size of the insert. We plan to develop alternative transposon systems in C. el-
egans based on the well-characterised and widely used Minos transposable element.
Transposon insertions represent an entry point to further manipulate the locus where
they were inserted. We aim to develop and optimise transposon-based tools for
transgene-instructed gene conversion as an alternative to homologous recombination
techniques that are not available in C. elegans.
3. Construction of an ordered library of transposon-tagged alleles covering at least
85% of the C. elegans gene complement.
Our aim is to use the tools and technologies described above to generate a compre-
hensive collection of transposon-tagged nematode genes. Such a mutant collection
will provide an extremely valuable resource because it will accelerate our under-
standing of gene function, which is a major challenge in biology.
Expected Results:
The expected results of our activities are categorised into two major types.
Research results:
1. Optimisation/automation of Mos1 transposon-based technologies
2. Development of alternative systems for mutagenesis and transgenesis in C. elegans
based on the Minos transposon
3. Generation of a comprehensive, ordered library of tagged nematode genes
4. Case-studies/evaluation of the resource.
Technological development, innovation and demonstration-related results:
5. Platform technology development/deployment.
Nematode Gene-Tagging Tools
and Resources
Potential Impact:
The massive amount of raw data generated
by genome sequencing projects worldwide
presents the scientific community with the stag-
gering task of making sense of the information.
Upon completion of our programme, we will
have generated a comprehensive resource,
highly valuable for functional genomics as well
as for individual case studies. This resource, to-
gether with the acquisition of cutting-edge func-
tional genomics tools, will transform the field
of nematode functional genomics and allow
straightforward modelling of human patholo-
gies in C. elegans, in addition to greatly accel-
erating research on important biological areas,
ultimately interfacing with approaches aiming
to improve human health and quality of life.
Keywords: nematode, Caenorhabditis elegans, functional genomics, trans- Procedure for generation
of transposon-insertion
poson-mediated mutagenesis, transposable elements, transpo-
mutants
son-tagged mutants, gene knock-out, heterologous transposition
Partners
Dr. Nektarios Tavernarakis
Foundation for Research and Technology – Hellas
Institute of Molecular Biology and Biotechnology
Vassilika Vouton
P.O. Box 1385
71110 Heraklion, Greece
tavernarakis@imbb.forth.gr
Dr. Jean-Louis Bessereau

Institut National de la Santé
et de la Recherche Médicale (INSERM)
Paris, France
Dr. Jonathan Ewbank

Institut National de la Santé et
de la Recherche Médicale (INSERM)
Centre d’Immunologie de Marseille-Luminy
Marseille, France
Dr. Johan Geysen

MAIA Scientific
Geel, Belgium
Dr. Laurent Segalat
Prof. Patricia Kuwabara Centre National de la
University of Bristol Recherche Scientifique
Department of Biochemistry Université Claude Bernard
Bristol, UK Lyon, France
TP Plants and Health

Contract number: In the 1970s and 80s plant science had a solid research base in Europe, but European
plant biotechnology activities have declined over the past decade. The Eurobarometer sur-
LSSB-CT-2004-512149
vey “Europeans and Biotechnology” in 2002 showed that most Europeans are in favour of
Starting date: biotechnology if it is related to medical research, but many remain sceptical of agricultural
1st June 2004 and food-related biotechnology. The academic sector and plant biotechnology industry has
Duration: severely curtailed biotechnology field research programmes in the EU in favour of third
32 months country trials. Also, at European universities the number of students interested in pursuing
EC Funding: careers in plant science, genomics and biotechnology has declined. This was recognised
as a matter of concern by the 2003 EU Council with a recommendation that the matter be
`555 840
addressed.
The key objectives of the TP Plants and Health project were to:
s DEVELOP%UROPEANPLANTSCIENCEGENOMICSANDBIOTECHNOLOGYRESEARCHPOLICYOPTIONS
sADDRESSTHEDECLINEINPLANTSCIENCERESEARCH
sDEALCONSTRUCTIVELYWITHSOCIETYSCONCERNSABOUTPLANTBIOTECHNOLOGY
sDEVELOPALONGTERMSTRATEGICPLANFOR%UROPEANPLANTGENOMICSANDBIOTECHNOLOGY
until 2025;
sARTICULATEANACTIONPLANFOR%UROPEANPLANTGENOMICSANDBIOTECHNOLOGYUNTIL
based on the long term strategic plan;
sPROVIDE%UROPEANCITIZENSWITHTHECHOICEOFAHEALTHIERLIFESTYLETHROUGHSUPPORTING
the development of plants and products offering a healthy, balanced diet.
Expected Results:
The project’s main result will be publication of the Plant Genomics and Biotechnology Action
Plan in 2010. Other results will be: 1) a common vision for plant genomics and biotechnol-
ogy research in the EU and a discussion of this amongst policy makers to develop coherent
©Shutterstock, 2007
The European Technology Platform
on Plant Genomics and Biotechnology:
Plants for healthy lifestyles
and for sustainable development
research policy measures; 2) an increased interaction between the public and private plant
genomics and biotechnology research sectors with the aim of stimulating knowledge to be
turned into innovation leading to increased productivity and competitiveness in Europe; 3)
a more balanced public debate recognising plant genomics, biotechnology, classical agri-
cultural practices and organic farming all as natural and valid components of both research
and application.
Potential Impact:
The publications of TP Plants and Health will be used in meetings and consultations with
different stakeholders including academic institutions, industry, farmers, consumers, etc).
The project will also have a long-term impact on policy makers at European level (European
Commission and European Parliament) and at national level (Member State consultations
and several meetings organised by individual countries, for example by the UK during its
EU-presidency). This will continue and increase in the future, creating an impact on science
and research policy at European level (the European Commission’s
proposal for FP7) and at national level (ERA-PG, 1st National Research Programmes).
Keywords:
European technology platform, policy recommendations, genomics, plant models, stake-
holder forum
Partners
Dr. Karin Metzlaff
European Plant Science Organisation
Technologiepark 927
Ghent, Belgium
karin.metzlaff@psb.ugent.be
Simon Barber
EUROPABIO
The European Association of Bioindustries
Plant Biotechnology Unit
Brussels, Belgium
X-OMICS
State-of-the-Art:
Project Type:
Co-ordination Action Elucidation of the function of the 25 000 genes in the human genome will be significant-
Contract number: ly accelerated by exploiting comparative genomic approaches in an integrative manner.
The international community will soon have access to the complete genome sequence of
LSHG-CT-2004-512065
several organisms, already validated as excellent experimental models of developmental
Starting date: biology. European scientists need to coordinate an efficient interfacing in their strengths
1st January 2005 in comparative bioinformatics and functional genomic approaches. Comparisons across
Duration: several vertebrate and invertebrate systems allow us, by bioinformatics analysis, to identify
48 months sequenced-conserved orthologous genes with important biological roles which will most
EC Funding: likely have conserved functions in mammals, including humans. The aim of the proposal is
to organise the coordination of the research of several recognised European laboratories
`800 000
using the amphibian Xenopus as a model to identify vertebrate genes of medical and de-
velopmental interest.
Our overall aim is to strengthen the coordination in functional genomics research in the
EU in order to understand the genetic basis of human pathologies better. We will apply a
comprehensive comparative functional genomics strategy, based on the amphibian Xeno-
pus model organism, with the goal of identifying and assessing the function for conserved
genes during early and late development. This objective will be reached through a strong
coordination between European experts in several scientific areas: bioinformatics, genom-
ics and developmental genetics, using the vertebrate amphibian models Xenopus laevis and
Xenopus tropicalis. The consortium will coordinate the ‘vertical’ studies from in silico defini-
tion of orthologous genes (comparisons across all available genomic models) down to gene
expression and function studies. Analyses of many genes by high-throughput techniques will
be followed by in-depth analysis of gene sets selected for their importance in human health.
This project will be integrative through the generation of interactive databases linked to
mouse and human electronic resources. More precisely, the objectives of the coordination
action in Xenopus genomics are to coordinate:
sTHE IDENTIlCATION AND THE RELATIONSHIPS OF ORTHOLOGY BETWEEN ALL AMPHIBIAN GENES
identified by genomic sequencing and those of other model organisms: Drosophila,
Ciona, zebrafish, chick, mouse and human
sTHE DESCRIPTION OF THE EXPRESSION PROlLE DURING DEVELOPMENT OF THE AMPHIBIAN FOR
thousands of orthologous genes
sTHEDESCRIPTIONOFTHEPHENOTYPESOFGAINANDLOSSOFFUNCTIONOFSELECTEDORTHOLOGOUS
genes playing a role in development and differentiation
sWHEREPOSSIBLETHEESTABLISHMENTOFMODELSFORHUMANDEVELOPMENTALDISORDERSINTHE
amphibian
sTODISSEMINATETHERESULTSTOTHESCIENTIlCANDMEDICALCOMMUNITYVIA)NTERNETTOOLSAS
well as general and specialised meetings and workshops.
Expected Results:
The first and central aspect of this project is to coordinate the use of integrated tools which
means that we go beyond the classical way of doing our science, and use and develop
tools for functional genomics. The functionally characterised genes will permit development of
databases directly providing comparative information between all model organisms includ-
ing man. They will also provide seamless integration with downstream applications, such as
Xenopus Comparative Genomics:
Coordinating Integrated and Comparative
Functional Genomics for Understanding
Normal and Pathologic Development
high-throughput screening of drug candidates and provide information for developing animal
models of human diseases. Another side-product of our action is the dissemination of the im-
provements of biotechnological techniques made by some of us for modulating gene function
in Xenopus. The end result of X-OMICS will be the disposal of comparative functional genom-
ics data as alternative and complementary information with other organisms.
Potential Impact:
Novel gene functions and technological development resulting from Xenopus genomics will
give fuel to innovation activities and help in understanding human development and diseas-
es. X-OMICS will facilitate efficient comparative genomics, the generation and comparison
across species of gene expression data, the improvement of techniques for gene expression
analysis, the development of accessible gene expression and function databases, compatible
with human databases and the expansion of bioinformatic tools.
Moreover, the in-depth functional analyses carried out within the consortium framework will
link genomic data to development and to several human diseases, thereby guaranteeing the
medical impact of the project.
Keywords: vertebrate models, Xenopus, zebrafish, mouse, systematic high-

throughput gene expression studies, conserved genes, functional
in vivo studies, bioinformatics, genomics, developmental genetics,
interactive databases
Partners
Dr. Andre Mazabraud
UMR 8080 Développement et Evolution
Rue Michel-Ange 3
75794 Orsay, France
andre.mazabraud@ibaic.u-psud.fr
Dr. Nancy Papalopulu

Wellcome Trust Cancer Research
Cancer Gurdon Institute
Cambridge, UK Dr. Tim Mohun
Dr. Eric Bellefroid The National Institute for
Université Libre de Bruxelles Medical Research
IBMM Laboratory of Molecular Division of Development Biology
Embryology London, UK
Brussels, Belgium
Prof. Tomas Pieler
Prof. Christoph Niehrs University of Göttingen,
Deutsches Krebsforschungszentrum Center of Molecular Biology
Department of Molecular Department of
Embryology Developmental Biochemistry
Heidelberg, Germany Goettingen, Germany
5. POPULATION GENETICS
& BIOBANKS
5.
POPULATION GENETICS
& BIOBANKS
HUMGERI
MolPAGE
GENOSEPT
MICROSAT workshop
EUHEALTHGEN
PHOEBE
EUROSPAN
DanuBiobank
Impacts
EpiGenChlamydia
HUMGERI
www.humangenom.hu

Contract number: The morbidity and mortality statistics of the Hungarian population are among the worst in
Europe and it is assumed that genetic as well as epigenetic factors play a significant role in
LSSG-CT-2003-503405
this phenomenon. Genomic research is very likely to provide a new framework to approach
Starting date: this problem. However, Hungarian genomic research is in its infancy, rather fragmented
1st April 2004 and unfocused. The main objective of the project is to obtain specific support for changing
Duration: this unfortunate situation. A consortium of Genomic Research for Human Health in Hungary
30 months has been formed, which starts organising genomic research within this action by pulling
EC Funding: together all the related activities in the country and providing an umbrella for medically
orientated genomic research.
`285 000
Based on studies and comparisons of European human genome projects, the objectives of
this action are:
s THECOLLECTIONOFALLINFORMATIONONGENETICANDGENOMICRESEARCHASWELLASDIAG-
nostic works carried out in Hungary and making it available to the public and of-
ficials of the healthcare system.
s THEFORMATIONOFASTABLEBIOINFORMATICSBACKGROUNDFORGENOMICACTIVITIES
1) explore and integrate existing, genome-specific bioinformatics resources of the
members of the consortium
2) develop a common website for the consortium including links to local activities
of the partners, to their national and international collaborations, and to other
genome research networks
3) organise an international workshop with experts from several existing European
genome research networks with the purpose of integrating the activities of the
consortium with European partners.
s THEDEVELOPMENTOFABIOBANKINGSYSTEM
1) collect and provide information about the various, existing human tissue and
DNA/RNA collections, their content and medical background or research project,
and rules for access
2) establish a nationwide quality assurance system for collecting, handling, storing
and documenting human biological samples in Hungary
3) establish the framework for sample collections from large volunteer cohorts, and
move towards a centralised national biobank.
s THE ESTABLISHMENT OF A NETWORK OF (UNGARIAN 3-%S RELATED TO HUMAN GENOMICS
projects. Establish an, as yet, non-existing, integrated, non-profit network of biotech-
nology orientated, primarily Hungarian-based SMEs.
s THE CLARIlCATION OF ETHICAL AND LEGAL ASPECTS OF GENOMIC RESEARCH 4HE (UNGARIAN
legal framework of R&D activity, the existing official network and procedure of the
ethical assessment of research protocols, and in particular genomic research pro-
grammes have to conform to high European standards and regulations.
Expected Results:
s /VERVIEW OF THE AVAILABLE BIOINFORMATICS INFRASTRUCTURES WITHIN THE CONSORTIUM AND
proposition on the required computing environment
Human Genomic Research Integration
s !DOPTED #ODE OF %THICS FUNCTIONING %THICS !DVISORY #OMMITTEE %THICS 7ORKING
Group
s #OMMON WEBSITE WWWBIOBANKHU FOR THE CONSORTIUM WITH DIFFERENT FUNCTIONING
sub-domains and partner pages (SME partnering, bioethics, genetic tests, projects,
etc.)
s #OMPARATIVESTUDYONGENOMICRESEARCHIN(UNGARYAND%UROPE
s !GREEMENTBETWEENINTERNATIONALPARTNERSANDTHECONSORTIUM
s .#%'#ONFERENCE.ATURE#ONFERENCEON%NVIRONMENTALAND'ENETIC)NTERACTIONS
in Disease Development)
s %XISTING BIOBANK INFORMATION GOOD BIOBANKING PRACTICE GUIDELINES AND HEALTH
questionnaires are on the website. There is a standard database and information
management system for Hungarian biobanks.
s 3TRATEGICINITIATIVESFORSPECIlCHUMANGENOMEPROJECTSIN(UNGARY
s %THICAL AND LEGAL ASPECTS OF BIOBANKING SUGGESTIONS FOR RESEARCHERS AND FOR
legislation.
Potential Impact: Partners

s 4HE AVAILABILITY OF "IOBANK (UNGARY Project Coordinator:
will stimulate: Dr. László Fésüs
a) further uncovering of inherited University of Debrecen
risk factors and identify candidate Medical and Health Science Center
genes/SNPs for major disease Department of Biochemistry and
groups Molecular Biology
b) identification of genetic features/ Egyetem Ter 1
markers unique to the Middle 4032 Debrecen, Hungary
European region fesus@indi.biochem.dote.hu
c) characterisation of the
MHC (HLA) gene pool in
Hungary
s "Y ESTABLISHING AN 3-% NET-
work, the EC will have access to all of
the potential facets of the Hungarian
genome-related SMEs.
s 4HE DISSEMINATION OF INFORMATION TO-
wards neighbouring candidate coun-
tries will help integration of the region
into the ERA.
s 3UCCESSOFTHIS33!WILLPROVIDETHECRU-
cial impact on decision-makers to start
a new funding system, providing the
appropriate framework for a long-term
genomic programme in Hungary.
Keywords:
human genomics, research policies
MolPAGE
www.molpage.org
State-of-the-Art:
Project Type: It is widely recognised that large-scale phenotyping studies are required in order to identify
Integrated Project biomarkers that will translate from bench to bedside. More specifically, such studies are
Contract number: necessary for an examination of the influence of many environmental and genetic deter-
LSHG-CT-2004-512066 minants of disease. Because of the molecular heterogeneity that contributes to most of the
major common disease phenotypes studied in large populations, these studies must aim to
Starting date: analyse large numbers of cases and controls.
1st October 2004
Duration: Currently, a number of biobank efforts are being carried out, not exclusively in the UK,
48 months but worldwide. These efforts will soon produce an unprecedented number of samples for
EC Funding: molecular phenotyping. As a consequence, epidemiologists, clinical trial workers and ex-
perimental scientists will potentially soon be presented with numerous opportunities for
`12 000 000 the molecular phenotyping of large numbers of biological samples obtained from these
biobank cohorts, patients or animal models.
Although the development of genotyping technologies for the analysis of DNA markers
has, to a degree, matured enough to allow for their use on an epidemiological scale, it is
not yet clear how the application of post-genomic technologies such as metabonomics and
proteomics, (where standardisation of procedures and high throughput approaches are less
well established), will be tackled.
The MolPAGE (Molecular Phenotyping to Accelerate Genomic Epidemiology) project aims

to design a programme to bridge this gap. The four-year project MolPAGE brings together
a consortium of 18 leading academic institutions, and biotechnology and pharmaceutical
companies, with expertise from a wide variety of ‘omics’ technologies and computational
methods, as well as from the biology of metabolic disease.
The consortium partners are working to upscale and optimise a range of genomic, metabo-
nomic and proteomic tools. In addition, the consortium is seeking to develop novel technical
data analysis and integration protocols, to facilitate biomarker discovery and validation
studies conducted on an epidemiological scale (“genomic epidemiology”).
Post-genomic technologies deriving from the project will be applied to biomarker discovery
and typing in metabolic diseases such as diabetes and its associated vascular complica-
tions, which constitute major causes of ill health and premature death, and which are reach-
ing epidemic proportions in Europe and worldwide.
A major goal of the MolPAGE consortium, is to develop and upscale a range of ‘omic’
technology platform tools (metabonomic, genomic, proteomic), and to apply these identify-
ing biomarkers in predicting disease, determining risk and relating to disease activity or
response to therapy.
The programme is divided into three component parts. Firstly, the project aims to evaluate
sample collection and storage methodologies, understand sources of technical and biologi-
cal variation and explore issues of analyte stability, so as to inform ongoing and future
endeavours in biobanking and biomarker discovery.
Secondly, MolPAGE seeks to develop, upscale and validate tools that will allow molecular
phenotyping at an epidemiologic scale. This includes the capacity to undertake analysis of
(a) small molecules (metabonomics); (b) mRNA (transcript profiling); (c) proteins and pep-
tides; (d) DNA methylation patterns; and (e) genome sequence variation.
Molecular Phenotyping
to Accelerate Genomic Epidemiology
The third part of the project entails the development of bioinformatic tools and statistical
methods to support the storage, interrogation and analysis of the large complex data sets
produced. The analysis of longitudinal cohorts from Biobank projects will be used for the
validation (and large-scale phenotyping) of risk biomarkers. A number of technologies in-
ternal to the consortium will be utilised for these tasks.
The MolPAGE project is using two separate approaches to biomarker discovery and valida-
tion, namely a genome wide, systematic methodology (for example, transcriptomics, NMR
and MS based metabonomics, and ms based proteomics) and a limited analysis which uses
sets of candidate biomarkers (methylation, affinity arrays, and tissue arrays).
The MolPAGE consortium, which is coordinated by the University of Oxford, comprises 18

partners from 5 SMEs, 2 international pharmaceutical organisations and 11 public bodies.
The project is organized into work packages (WPs); from an operational point of view,
these work packages fall into four main areas: sample-related (1); technology-related (2);
informatics and analysis (3); and training and management (4).
Expected Results:
The MolPAGE project will significantly contribute to the development of international sci-
entific standards in molecular phenotyping. During the project the consortium will de-
velop, establish and disseminate standards for the collection, processing and storage of
biological samples that are firstly, suitable for use in large sets of individuals, secondly,
applicable to blood, urine and solid tissue samples, and thirdly, optimised for future
‘omic’ platform analysis of DNA, RNA, protein and other biological analytes.
Another crucial aspect of the project is the development of standardised data handling
and analysis methods, which will be applicable to future molecular phenotyping efforts
performed on an epidemiological scale. The consortium has released an open source
version of our novel web-based sample management system (http://passim.sourceforge.
net) for use by other projects. Furthermore, by the end of the project, the consortium will
have completed the development of a data warehouse, optimised for the submission, stor-
age and integration of both raw and analysed data from a wide range of the MolPAGE
technology platforms.
Similarly MolPAGE is actively working to improve the statistical tools available for analy-
sis of many of these types of data, and to develop approaches for deriving an integrated
view of the transcriptional, proteomic and metabonomic changes which associate with
and/or predict disease. Towards MolPAGE standard setting goals, the consortium and
the EU co-hosted an international workshop on ‘Standards and Norms in Population
Genomics’, to establish a roadmap for developments standard setting and obtaining ac-
ceptance by the wider scientific community.
Significant efforts to upscale the enabling metabonomic and proteomic technology plat-
forms were made in the first two years of the project; these efforts will continue on a select-
ed subset of the most promising technology platforms for the remainder of the project.
A medium-term goal of the MolPAGE consortium was to apply the methods developed in
the initial phase, to proof-of-principle biomarker discovery efforts. These studies are now
underway, focused on metabolic and cardiovascular disease in samples from MolPAGE
and from selected European longitudinal cohort projects. By the end of the funding pe-
riod, we propose to make our recommendations regarding the most suitable technology
platforms for application to molecular phenotyping of biobank samples, in a broad range
of disease areas.
MolPAGE
Potential
Impact:
With MolPAGE’s initial
focus on biomarker dis-
covery and validation in
metabolic disease (type 2
diabetes and cardiovas-
cular disease), the team
will be addressing a ma-
jor public health problem
in the EU community — a
problem of considerable
health and economic pro-
portions even now, and
one expected to escalate
in the decades to come.
The methodology to be
developed, however, will
have applications in eve-
ry form of common human
Differential gene
disease, including cancer,
expression analysis of adipose
inflammatory diseases
tissue RNA comparing obese
and degenerative diseas-
and lean subjects from es. The involvement of five
a rat model of diabetes. industrial partners in the
consortium, has provided the power necessary for the distribution of the project’s results
and experience, to corporate institutions. These corporate institutions are capable of con-
verting the knowledge generated by the project into new drug opportunities and treatment
modalities, which will benefit patient groups worldwide, and increase the competitiveness
of the EU-based pharmaceutical industry.
This project will therefore influence economic development in the EU in several distinct
ways. By establishing successful technology platforms, we expect to stimulate the technol-
ogy and diagnostic section of the health-care related economy. In addition, by addressing
the single largest causes of ill health and premature death, and through their direct health
benefits as well as indirectly through facilitating discovery in the pharmaceutical sector,
these studies have the potential to enhance economic development.
Keywords: phenotyping, epidemiology, molecular phenotyping, genomics
Molecular Phenotyping to Accelerate Genomic Epidemiology
Partners
Joint Project Coordinators: Prof. Vladimir Stich Prof. Tim Spector
Prof. John Bell Charles University Kings College London
University of Oxford Department of Sports Medicine Twin Research Unit
Richard Doll Building, Roosevelt Drive Prague, Czech Republic London, UK
Headington, Oxford, OX3 7DG, UK
regius@medical-sciences-office.oxford.ac.uk Dr. Alvis Brazma Dr. Dominique Langin
European Molecular Biology Institut National de la Santé
Prof. Mark McCarthy Laboratory (EMBL) et de la Recherche Médicale
University of Oxford European Bioinformatics (INSERM)
Oxford Centre for Diabetes Institute (EBI) Obesity Research Unit
Endocrinology and Metabolism (OCDEM) Microarray Group Toulouse, France
Churchill Hospital Site Hinxton, UK
Old Road, Headington Dr. Fredrik Ponten
Oxford, OX3 7LJ, UK Dr. Juris Viksna Uppsala University
mark.mccarthy@drl.ox.ac.uk Institute of Mathematics Department of Genetics and
and Computer Science Pathology
Project Manager: Riga, Latvia Human Proteome Research
Dr. Maxine Allen Uppsala, Sweden
University of Oxford Prof. Jeremy Nicholson
Oxford Centre for Diabetes Imperial College London Dr. Hanno Langen
Endocrinology and Metabolism (OCDEM) Department of Biological Chemistry F. Hoffman-La Roche AG
Churchill Hospital Site London, UK Protemics Initiative
Old Road, Headington Basel, Switzerland
Oxford, OX3 7LJ, UK Prof. Luisa Bernardinelli
maxine.allen@drl.ox.ac.uk University of Pavia
Department of Health Sciences
Prof. Peter Donnelly, Prof. Lon Cardon Pavia, Italy
Oxford, UK Dr. Stephan Hoffman
Gyros AB
Prof. Sir Edwin Southern Uppsala, Sweden
Oxford Gene Technology
Oxford, UK
Dr. Ivo Gut

Centre National de Genotypage (CNG)
Evry, France
Dr. Kurt Berlin

Epigenomics AG
Berlin, Germany
Dr. Rainer Voegeli

Digilab BioVisioN GmbH
Hannover, Germany
Dr. Esper Boel

Novo Nordisk A/S
Novo Alle, Denmark
Prof. Mathias Uhlen

KTH Biotechnology
Royal Institute of Technology
AlbaNova University Center
Stockholm, Sweden
Dr. Thomas Bergman

Affibody AB
Bromma, Sweden
GenOSept
https://www.genosept.eu
State-of-the-Art:
Project Type: GenOSept is a STREP which uses a multidisciplinary fundamental genomics approach (gene
Specific Targeted expression, structural genomics and population genetics) to examine genetic predisposition
Research Project to sepsis. Sepsis (a life-threatening infection) is a major public health problem throughout
Europe. In the USA, in 1995, it cost $17 billion to treat 751 000 patients with severe sep-
Contract number:
sis, of whom 28.6% died. The Centre for Disease Control suggests that sepsis-attributable
LSHG-CT-2004-512155 mortality rates are rising. We hypothesise that susceptibility to expensive new treatments
Starting date: and fatal outcomes from severe sepsis are, in part, genetically determined.
1st January 2005 The GenOSept project will test this hypothesis. It will standardise protocols for genotyping,
facilitate application of new knowledge in functional and structural genomics, harmonise
Duration:
high-throughput genotyping and quality control between major European centres, and con-
48 months tribute to reducing sepsis-related mortality in European healthcare.
EC Funding:
Genetic predisposition for the incidence and outcome of sepsis has been recognised and
suggested as a possible powerful tool for future risk stratification and even as inclusion cri-
teria for therapeutic trials. GenOSept also contains a module which links patterns of gene
expression with patterns of genomic variation in corresponding genes.
Genomic variants may influence the individual phenotype including gene expression levels
and patterns, as well as protein levels and protein structure. A possible result is that future
intensive care physicians may have access to readily available genetic risk patterns includ-
ing pharmacogenetics of their patients which not only allows for better risk stratification, but
may also help tailor individual patient care and drug therapy.
The major milestones of GenOSept are:
s CONSENSUSDElNITIONSANDTHESETTINGUPOFANINCLUSIONANDEXCLUSIONCRITERIADATA-
base;
s COLLECTIONOFBLOODSAMPLESFROMABOUTPATIENTSALLOVER%UROPE
s BLOODGENOTYPINGANDGENETICTESTING
s IDENTIlCATIONOFRELEVANTCANDIDATEGENESANDTHEIRGENOMICVARIATIONS
s GENETIC EPIDEMIOLOGY STUDY TO BE PERFORMED IN %UROPEAN INTENSIVE CARE UNITS
(ICUs);
s DElNITIONOFADIAGNOSTIC3.0SET
Expected Results:
The expected results of GenOSept are that it will:
s CONTRIBUTETOUNRAVELLINGTHEGENETICPREDISPOSITIONOFSEPSIS
s DElNENOVELCANDIDATEGENESBYGENEEXPRESSIONSTUDIES
s INCLUDEGENESDIRECTINGPATHWAYSOFTHEHOSTIMMUNERESPONSETOINFECTIONANDIN-
flammation, and of programmed cell death.
The novel genes identified by expression studies will add to a set of candidate genes used
in a subsequent epidemiologic study which will:
s STANDARDISEPROTOCOLSFORGENOTYPINGTOFACILITATEAPPLICATIONOFNEWKNOWLEDGEIN
functional and structural genomics;
s HARMONISESTANDARDSFOR%UROPEANHIGH THROUGHPUTGENOTYPINGANDQUALITYCONTROL
by coordinating major European genotyping centres;
s DELIVERDATAONGENDER RELATEDMORTALITYANDMORBIDITY
First project achievement: the diseases to be included in the study were refined and four will
be examined. The inclusion and exclusion criteria database have been developed.
Potential Impact:
The GenOSept findings will contribute to reducing sepsis-mortality and morbidity in Euro-
Genetics of Sepsis in Europe
pean ICUs. The project will link fundamental genomics to sepsis, a major European public
health issue. The application of gene expression studies and structural genome analysis
detecting genomic variation will generate novel data on relevant genes as well as novel
genomic variations involved in the genetic predisposition of incidence and outcome from
sepsis. The evaluation and use of novel techniques, including the gene chip technology and
the establishment of a European network of clinical and laboratory groups working in the
field of critical care medicine, will strengthen European biotech industry.
Keywords: intensive care medicine, sepsis, mortality, epidemiology, genetic

testing, genetic predisposition
Partners
Project Coordinator: Dr. Yoram Weiss Dr. Vladimir Sramek
Prof. Julian Bion, Dr. Nathalie Mathy Hadassah Medical Organisation Masaryk University
European Society of Intensive Department of Anaesthesia Brno Medical Faculty
Care Medicine and Critical Care Medicine St Ann’s University Hospital
Research Activities Jerusalem, Israel Department of Anaesthesiology
40 avenue Joseph Wybran and Intensive Care
1070 Brussels, Belgium Prof. Dr. Stefan Russwurm Brno, Czech Republic
public@esicm.org SIRS-Lab GmbH
R&D Department Dr. Ilona Bobek
Prof. Dr. Frank Stüber Jena, Germany National Medical Center
Rheinische Friedrich-Wilhelms- Department of Anaesthesia
Universität Bonn Prof. Marion Schneider and Intensive Care
Klinik und Poliklinik für A University Ulm Medical Faculty Budapest, Hungary
nästhesiologie und spezielle Sektion Experimentelle
Intensivmedizin Universitätsklinikum Anästhesiologie Dr. Silver Sarapuu
Bonn, Germany Universitätsklinikum Ulm Tartu University Clinics
Ulm, Germany Intensive Care Unit
Prof. Jean-Daniel Chiche Tartu, Estonia
Institut National de la Santé et Prof. Konrad Reinhart
de la Recherche Médicale (INSERM) Klinikum der Friedrich-
Institut Cochin- Réanimation médicale Schiller-Universität Jena
Paris, France Department for
Anaesthesiology and
Prof. Adrian Hill Intensive Care Medicine
University of Oxford Jena, Germany
Wellcome Trust Centre for
Human Genetics
Oxford, UK
Prof. Vito Marco Ranieri

Universita degli Studi di Torino
Sezione di Anestesiologica e
Rianimazione
Turin, Italy
Prof. Jordi Rello

University Rovira & Virgili
Hospital Universitari Joan XXIII
Critical Care Department
Tarragona, Spain
Prof. Thomas Meitinger

Neuherberg, Germany
MICROSAT workshop
www.microsatellites.org

Contract number: Tandem repeats are repeat sequences in the human genome. They occur in all genomes,
including bacteria, yeast, plants and humans. Tandem repeats have been widely used in
LSSG-CT-2004-013019
linkage analysis in many organisms, where they are used as non-functional markers for
Starting date: inheritance of genetic loci. They have also been implicated in human disease, with micros-
1st January 2005 atellites such as CAG triplet repeats causing a variety of neurological disorders and higher
Duration: order motifs such as the insulin gene VNTR influencing complex diseases such as diabetes.
24 months VNTRs affect gene expression and are useful for genetic fine mapping of complex disease
EC Funding: loci; for example they were used to identify the neuregulin 1 gene which predisposes to
schizophrenia. However, despite their clear importance, in recent years far more emphasis
`112 000
has been placed on single nucleotide polymorphisms (SNPs) than tandem repeats because
of the unproven perception that SNPs are the major cause of complex diseases. The SNP
Consortium Ltd is a non-profit foundation that was developed for the purpose of provid-
ing public genomic data. Its mission is to develop up to 300,000 SNPs distributed evenly
throughout the human genome and to make the information related to these SNPs available
to the public.
1) To stimulate international cooperation in functional genomics in Europe by bringing
together researchers to examine microsatellite and variable number of tandem re-
peat (VNTR) markers in human and non-human genetics and genomics.
2) To promote and facilitate international co-operation in microsatellite research by net-
working scientists for a research consortium.
3) To develop microsatellite and VNTR markers as tools for genomic and genetic analy-
sis with the potential to develop long term research funding and be a catalyst for
cooperation, especially with SMEs and third world countries.
4) To develop web-based resources to facilitate the use of microsatellite markers in ge-
nomic and genetic analysis.
Expected Results:
The consortium ran two workshops, one in the UK at the Institute of Psychiatry and one in
Hungary at the Hungarian Academy of Sciences (Institute of Enzymology) to train research-
ers to use microsatellites in genomic and genetic analysis, which will lead to self-financing
workshops in future years. The first workshop established the consortium and the second
provided training in the field and allowed the dissemination of research findings and trans-
fer of knowledge and technologies which developed as a result of the first workshop. SMEs
participated directly in two workshops and were encouraged to develop technology that
can be commercially exploited. Researchers from China and Brazil played a direct role in
the consortium, and training and knowledge were transferred to other developing nations
in addition to European states. The fist self-funded microsatellite workshop will be held in
Colorado in February 2009.
Microsatellites and VNTRs: workshop on
bioinformatics, genomics and functionality
Potential Impact:
Microsat-SSA was focused on stimulating research into microsatellites and VNTRs as basic
tools for genome research, and as candidate polymorphisms for human and animal dis-
ease. A team working in a neglected area of genomics will have a significant impact on
genetic and genomics, including the areas of human and animal disease, by increasing
the variety of tools available to the scientists. This will improve our understanding of the
basic biology of the genome, as well as the ability to locate disease-causing genes and the
underlying variants, and to understand population genetics from a different perspective.
Microsat-SSA will contribute to economic competitiveness by promoting the involvement
of SMEs in activities related to microsatellite markers, including the provision of contract
genotyping and other intellectual property related research services.
Keywords:
microsatellite, VNTR, tandem repeat, population, genetics, mapping, association, compar-
ative, linkage
Partners
Prof. David Collier
King’s College, University of London
Department of Social
Genetic and Developmental Psychiatry
Institute of Psychiatry
De Crespigny Park
London, SE5 8AF, UK
d.collier@iop.kcl.ac.uk
EUHEALTHGEN

Contract number: Member and Associated States across the European Research Area are supporting re-
search on population genetics in order to build upon the significant investments made in
LSHG-CT-2005-518144
sequencing the human genome. Significant added value can be obtained if the objectives
Starting date: and protocols involved in human population genetics research at a national level can be
1st September 2005 harmonised to become representative of the entire EU population. The EU would thereby
Duration: develop and maintain a leading global position in genetic epidemiology and population
12 months genetics. Project coordination will be by a steering committee, which will meet twice dur-
EC Funding: ing the planning phase of the proposed conference. It will then meet twice following the
conference to agree the report and to lay the foundations for implementing the developed
`245 000
strategy. The conference will be held at the Wellcome Trust Conference Centre, Cambridge,
United Kingdom on 21-23 September 2005.
EUHEALTHGEN has been established to:
sPROMOTE COMMUNICATION BETWEEN MAJOR BIOBANK AND LONGITUDINAL COHORT INITIATIVES
across the ERA and restrict fragmentation
sSERVEASAPOWERHOUSEFORTHESTRATEGICPLANNINGOFTHELARGE SCALERESEARCHANDDA-
tabase infrastructure needed for major population genetic studies in Europe
sENHANCEEFFECTIVESHARINGANDDISSEMINATIONOFRESEARCHINFORMATIONANDMATERIALS
sPROMOTECOMMONLEARNINGEXPERIENCESANDSTANDARDISEMETHODOLOGIES
sPROMOTEPOPULATIONGENETICSRESEARCHFORTHEBENElTOFTHE%5CITIZEN
sSTIMULATEECONOMICGROWTHANDENHANCEINDUSTRIALCOMPETITIVENESS
sINTEGRATEETHICALLEGALANDSOCIALISSUES
sINVOLVEACCESSIONANDASSOCIATEDCANDIDATECOUNTRIES
sPROMOTEPOSITIVECOMMUNICATIONOFTHEBENElTSOFEDUCATINGTHEGENERALPUBLICHEALTH-
care professionals, policy-makers and funders about human population genetics
sIDENTIFYGOALSANDPRIORITISEAPPROACHESACROSSTHE%UROPEANNETWORK
sPROMOTETHEUPTAKEOFBESTPRACTICEINHUMANPOPULATIONGENETICSRESEARCHANDTHE
adoption of a joined-up and fully integrated strategy from basic research, through
clinical studies to the treatment of individual patients
sPROMOTE THE ANTICIPATED PARADIGM SHIFT IN HEALTHCARE FROM DISEASE DIAGNOSIS AND
treatment to the identification of personal disease risk and the development of appro-
priate personalised prevention strategies.
Expected Results:
Some of the expected results are:
sTOFURTHERPROMOTETHEDEVELOPMENTANDUSEOFBOTHHIGH THROUGHPUT$.!SEQUENC-
ing technology and proteomic analysis for clinical research, thereby enhancing data
generation, standardisation, acquisition and analysis
sFACILITATETHEDETECTIONDIAGNOSISMONITORINGANDPREVENTIONOFDISEASE
sGENERATEABETTERUNDERSTANDINGOFHUMANGENETICVARIATIONINPREDICTINGDISEASEAND
so achieve the better targeting of limited health resources
sPROVIDEINNOVATIVEAPPROACHESTOTHERAPEUTICINTERVENTIONSANDTECHNOLOGIES
Harnessing the Potential
of Human Population Genetics Research
to Improve the Quality of the EU Citizen
sLEADTOTHECREATIONOFADDITIONALPOPULATIONBIOBANKSGENERATINGANDGIVINGACCESS
to the large data sets needed to integrate biological data with clinical need thus pro-
moting translational research for improved human health
sFACILITATEABETTERUNDERSTANDINGOFBOTHCLINICALDECISION MAKINGANDPOLICY MAKING
in this area and help improve the efficiency of translating the outcomes of clinical
research into clinical practice.
Potential Impact:
Human population genetics will play an important role in analysing the complex inter-
actions that occur in determining susceptibility and cause of the priority disease areas.
However, for this to be realised it will be necessary to ensure that the biobanks operating
across Europe are compatible so that validated reagents, samples and information can be
exchanged in a safe and ethically acceptable way. This provides further justification for the
main aim of EUEALTHGEN, namely to develop a forward-looking strategy for translating
the outputs of population genetics research into clinically useful and health enhancing initia-
tives, whilst improving EU industrial competitiveness in this area.
Keywords: health sciences, population genetics, biobanks, human genetics

Partners
Project Coordinator
Dr. Alan Doyle
The Wellcome Trust
Department of Biomedical Resources
and Functional Genomics
215 Euston Road
London, NW1 2BE, UK
a.doyle@wellcome.ac.uk
PHOEBE
www.phoebe-eu.org
State-of-the-Art:
Project Type: This coordination action aims to help create a harmonised network of population-based
Co-ordination Action biobanks across Europe and Canada. The main purpose is to maximize the use of Europe’s
population-based biobanks in the study of complex disease etiology.
Contract number:
LSHG-CT-2006-518148
Starting date: Scientific/Technological Objectives:
1st March 2006 The objectives can be categorized accord- of flexible communication engines sup-
Duration: ing to the following harmonization areas: porting reliable, efficient and secure
Epidemiology: communication between biobanks
36 months sIDENTIFY AND DESCRIBE LARGE POPULA- Genotyping:
EC Funding: tion-based biobanks and longitudinal sCREATEANOPERATIONALINFRASTRUCTUREFOR
`800 870 cohort studies in Europe the evaluation of large-scale genotyp-
sEMPHASISESTUDIESTHATCANCONTRIBUTE ing efforts in population cohorts,
to coordinated investigations of the ge- Phenotypes and environmental exposures:
netic and environmental determinants sLAYTHEGROUNDWORKFORAHARMONISED
of complex diseases approach to the assessment of a range
Isolated populations: of complex phenotypes and life-style
sIDENTIFYNEWBIOBANKINGOPPORTUNITIES exposures
in Europe, with a focus on genetically Ethical, legal and governance issues:
isolated populations s establish ethical, legal and governance
sESTABLISH STANDARD CRITERIA FOR THE SE- criteria consistent with the international
lection and collection of data and norms and European practices that will
samples from these populations enable data and sample sharing for re-
Biobank information management: search purposes
sREVIEWCURRENTBESTPRACTICEFOR"IOBANK Statistics:
Information Management Systems sINTEGRATECOLLECTED%UROPEANAND#A-
sEXPLORE ISSUES OF HARMONISATION RELAT- nadian expertise related to statistical
ed to the management of large and challenges
complex databases for biobanks sEXPLORETHESTATISTICALMETHODOLOGYUN-
sFOCUS ON EFlCIENT TECHNOLOGIES HIGH derpinning the design, analysis and
level programming and development harmonization of population-based
biobanks.
Expected Results:
s DATABASELISTINGOFCOMPLETEDONGOINGANDPLANNEDPOPULATION BASEDBIOBANKSANDLARGE
cohorts in Europe, and information on the accessibility of data and status of the studies;
s REPORT ON ISSUES SPECIlC TO STUDIES OF %UROPEAN POPULATION BASED BIOBANKS IN GENETIC
isolates;
s REPORTONTHECOMPLETEINVENTORYOFLARGE%UROPEANBIOBANKPROJECTSTHEIRINFORMATION
and storage strategy and report on standards in European biobanks;
s ESTABLISHMENTOFANONLINEINFORMATIONCENTREONMAJORGENOTYPINGEFFORTSIN%UROPEAN
population biobanks, genotyping quality and cost reports, a web-based SNP selection
tool, and procedures for collection and storage of genotyping data;
s REPORTONACONCISE@MINIMUMDATASETREPRESENTINGACOREASSESSMENTPROTOCOLFORALL
phenotypes and exposures for future European biobanks;
s REPORT ON THE POSSIBILITY FOR AN INTERNATIONALLY CONSISTENT SOCIO ETHICAL AND GOVERNANCE
platform;
s REPORTONFORMALSTRATEGIESFORMETA ANALYSISINTHEGENETICEPIDEMIOLOGICALSETTING
Potential Impact:
s#OMMUNICATION WITHIN AND BETWEEN MAJOR BIOBANKING INITIATIVES WILL HELP TO OVER-
come existing fragmentation of European population genomic research.
s%FFECTIVE SHARING AND SYNTHESIS OF INFORMATION WILL ADDRESS THE NEED FOR VERY LARGE
sample sizes, and will help to promote collaborative international genetic epidemio-
logical research.
Promoting harmonisation
of epidemiological biobanks in Europe
Keywords: epidemiology, genetic epidemiology, biobanks, population-based co-
horts, complex disease, isolated populations, bioethics, phenotyping,
genotyping, GenomEUtwin, COGENE, P3G, data management
Partners
Project Coordinator: Prof. Dorret Boomsma Prof. Milan Macek
Dr. Jennifer Harris Vrije Universiteit Charles University Prague
Norwegian Institute of Public Health Department of Biological Institute of Biology and Medical
Division of Epidemiology Psychology Genetics - Cystic Fibrosis Centre
Oslo, Norway Amsterdam, The Netherlands Prague, Czech Republic
jennifer.harris@fhi.no
Prof. Anne Cambon-Thomsen Prof. Pagona Lagiou
Prof. George Davey-Smith INSERM U 558 University of Athens
University of Bristol Faculté de Médecine Medical School
Department of Social Medicine Toulouse, France Department of Hygiene
Bristol, UK and Epidemiology
Prof. Bartha Maria Knoppers Athens, Greece
Prof. Max Bauer Université de Montreal
University of Bonn Faculté de Droit, Centre de Prof. Paul Elliott
Institute of Medical Biometry Recherche en Droit Public Imperial College of Science
Informatics and Epidemiology Montreal, Canada Technology and Medicine
Bonn, Germany Department of Epidemiology
Prof. Paul Burton and Public Health
Prof. Paolo Gasparini University of Leicester London, UK
Universita degli Studi di Trieste Department Epidemiology
Facolta di Medicina e Chirurgia and Public Health
Trieste, Italy Leicester, UK
Prof. Jaume Bertranpetit
Universitat Pompeu Fabra
Department de Ciencies
Experimentals i de la Salut
Barcelona, Spain
Prof. Jan-Eric Litton
Karolinska Institutet Prof.. Cornelia van Duijn
Department of Medical Erasmus Medical Center
Epidemiology and Biostatistics Department of Epidemiology
Stockholm, Sweden and Biostatistics
Rotterdam, The Netherlands
Andy Harris
UK Biobank Ltd Prof. Andres Metspalu
Manchester Incubator Building University of Tartu, IMCB
Manchester, UK Estonian Biocentre
Tartu, Estonia
Prof. Leena Peltonen
National Public Health Institute
Department of Molecular Medicine
Helsinki, Finland
Dr. Thomas J. Hudson
McGill University
McGill University and Quebec
Innovation Centre
Montreal, Canada
EUROSPAN
State-of-the-Art:
Project Type: This project will study five special populations throughout Europe which represent a unique
Specific Targeted resource for genomic research. It will quantify genetic variation in genes known to be involved
Research Project in health and disease and will harness this variation to identify novel variants. The project will
Contract number: build on the achievements of substantial existing investment in these special populations and
will pool expertise across Europe in phenotyping, genotyping, statistical genetics and social
LSHG-CT-2006-018947 and ethical aspects of genomic research. A common database of health and disease-related
Starting date: phenotypes will be established and cores of expertise established in the major project areas.
1st March 2006 This will create the largest database of phenotypic and genotypic data from genetic isolate
Duration: populations and will thus improve European competitiveness in gene discovery. The project
will also provide the platform for the evaluation of a novel gene discovery approach (hybrid
36 months
identity profiling) which has been developed by a European SME.
EC Funding:
`2 400 000
The objectives regarding genetic variation in established disease genes are:
sTOASSESSGENETICVARIATIONINMORETHANHUMANDISEASEGENESACROSSlVESPECIAL
(genetic isolate) populations in five European countries and in three outbred European
populations
sTODEVELOPADATABASEOFACORESETOFPHENOTYPEDATAGATHEREDWITHCOMMONMETH-
ods across five special populations
s TOSTUDYTHERELATIONSHIPBETWEENGENETICVARIATIONINTHEABOVEGENESANDAPPROXIMATE-
ly 40 QTs influenced by these genes across five diverse environmental backgrounds.
The objectives regarding employing genetic variation to identify novel genetic variants are:
sTOCARRYOUTWHOLEGENOMELINKAGESCANSINCOMPLEXPEDIGREESTOIDENTIFYNEWGE-
netic loci underlying traits (QTs) of public health importance in Europe and to employ
cross population mapping and high density SNP association approaches to fine-map
these loci
sTOEVALUATEANOVELMETHODOF)"$MAPPINGOF14,QUANTITATIVETRAITLOCI BYIDENTIFY-
ing shared chromosomal regions that show IBD sharing by genome hybrid identity
profiling (HIP)
sTOEVALUATETHEAPPROACHOFGENETICASSOCIATIONUSINGTHRESHOLD SELECTEDEXTREME14
values and high-density chip genotyping
sTODEVELOPSTATISTICALGENETICSMETHODSFORTHEANALYSISOFCOMPLEXPEDIGREEDATAIN
these special populations
sTO INVESTIGATE RELEVANT SOCIAL AND ETHICAL ASPECTS OF GENOMIC RESEARCH IN ORDER TO
develop a statement of best practice for interaction with study populations in terms of
consent, sharing of benefits, and communication with individuals and communities
sTO ADOPT A PROACTIVE APPROACH IN WHICH CHANGE TO STUDY PROCEDURES WILL BE INTRO-
duced in response to research findings, where this is appropriate.
Expected Results:
New Knowledge:
s'ENETICVARIATIONSINDISEASE RELATEDGENESACROSSlVEDIVERSESPECIALPOPULA-
tions and three outbred populations in Europe will be described.
s4HERELATIONSHIPBETWEENGENETICVARIATIONSINTHESEGENESANDHEALTH AND DIS-
ease-related phenotypes (QTs) will be described.
s!PEDIGREE BASEDGENOME WIDELINKAGESTUDYONAPPROXIMATELYINDIVIDUALSTO
identify new genetic loci related to these QTs will be performed.
EUROpean Special Populations Research
Network: Quantifying and Harnessing
Genetic Variation for Gene Discovery
Tools:
s4HEUTILITYOFTHEGENOMEHYBRIDIDENTITYPROlLINGMETHODWILLBEASSESSED
s4HE STRATEGY OF GENETIC ASSOCIATION BY HIGH DENSITY GENOTYPING OF INDIVIDUALS WITH
extreme QT values will also be assessed.
s !NALYTICMETHODSFORPEDIGREE BASEDGENOME WIDELINAGEANALYSISWILLBEDEVELOPED
Resources:
s4HEFOLLOWINGWILLBEESTABLISHEDCORESOFEXPERTISEINMICRO SATELLITEANDHIGH THROUGH-
put SNP genotyping and statistical genetics; ethical and social aspects of genomic
research; phenotyping to serve the project partners.
Pulse wave
Potential Impact:
EUROSPAN will give new information on genetic variations in traits underlying conditions of
public health importance in Europe and how this is related to disease risk. The project will
result in greater efficiency of effort, application of state-of-the art methods, pooling of intellec-
tual resources to tackle scientific problems and, ultimately, more internationally competitive
research. The approach draws on genetic diversity across Europe and is distinct from exist-
ing investments in national biobanks and international twin studies. The social and ethical
issues raised, explored and resolved before and during the research process will have wider
relevance for genetic epidemiology and the meaning of research participation.
Keywords: genomics, genetic variation, gene discovery, quantitative traits,

endophenotypes, genetic isolate
Partners
Prof. Harry Campbell Prof. Igor Rudan
University of Edinburgh University of Zagreb
Public Health Sciences Deptarment of Medical Statistics
Teviot Place Epidemiology and
Edinburgh, EH8 9AG, UK Medical Informatics
harry.campbell@ed.ac.uk Zagreb, Croatia
Prof. Alan Wright Dr. Jorg Hager

Medical Research Council IntegraGen SA
Human Genetics Unit Evry, France
Edinburgh, UK
Dr. Peter Pramstaller
Prof. Cornelia Van Duijn EURAC - European Academy
Erasmus Medical Center of Bolzano
Epidemiology & Biostatistics Department of Genetic Medicine
Rotterdam, The Netherlands Bolzano, Italy
Prof. Ulf Gyllensten

University of Uppsala
Uppsala, Sweden
Prof. Thomas Meitinger

GSF - Forschungszentrum für Umwelt und Gesundheit
Munich-Neuherberg, Germany
DanuBiobank

Contract number: Public healthcare systems in Europe are facing the challenge of a rapidly ageing population
which is susceptible to a wide variety of ageing-related disorders, such as heart disease
LSSG-CT-2006-018822
and strokes, and metabolic disorders such as diabetes. People over 65 use 3 to 5 times
Starting date: more healthcare facilities than young people, and even though death rates from heart dis-
1st January 2006 ease and strokes have decreased in recent years, these illnesses are making an increasing
Duration: financial demand on health services. Setting up a comprehensive healthcare strategy for
24 months dealing with this problem is imperative.
EC Funding:
`480 000
The aim of Danubiobank is to establish a biobank foundation in molecular medicine for
ageing disorders in order to identify risk factors in population studies. Large clinical trials
of new medications can then take place. The project aims to connect universities, teaching
hospitals, prevention programmes and clinics along the Danube River and in neighbouring
areas. Danubiobank will study the field of ageing disorders, focusing mainly on diabetes-
related endpoints including vascular disease and neuro-degenerative disorders. The project
also aims to integrate biobanking into local and regional health care systems’ e-health
structures and IT-based strategies along the Danube.
Expected Results:
The formulation of regional networks will help to realise a biobank model providing access
to the latest information and data concerning ageing-related disorders. Scientific meetings,
networking, policy meetings and the publication of papers will bring attention to this field
and encourage scientists and researchers to establish working alliances. A series of work-
shops and a concluding conference will be organised to this effect. An interactive website
will also be available with access for the general public. The project team hopes that other
consortia will grow out of Danubiobank and will undertake research activities with national
or international funding. The project also hopes to collaborate with self-help communities
such as Weight Watchers, and public health groups.
Potential Impact:
The project’s aim is to impact positively on the treatment of ageing-related disorders in
European health services through the biobank foundation and through its networks of
researchers disseminating information through workshops, meetings, research and poli-
cymaking activities.
Keywords:
metabolic disorder, ageing disorder, biobank, vascular disease, neuro-degenerative disorder
The Danubian Biobank Initiative —
Towards Information-based Medicine
Partners
Prof. Gerd Schmitz
University Hospital Regensburg
Institute of Clinical Chemistry and Laboratory Medicine
Franz-Josef-Straub-Allee 11
93053 Regensburg, Germany
gerd.schmitz@klinik.uni-regensburg.de
Prof. Oswald Wagner

Medical University of Vienna
Clinical Institute for Medical and Chemical
Laboratory Diagnostics
Vienna, Austria
Prof. Gyorgy Keri

Semmelweis University Budapest
Cooperative Research Center
Rational Drug Design Laboratories
Budapest, Hungary
Dr. Jaroslav Hubacek

Institute for Clinical and Experimental Medicine
Prof. Iwar Klimeš

Slovak Academy of Sciences
Institute of Experimental Endocrinology
Diabetes and Nutrition Group
Bratislava, Slovakia
Dr. Vita Dolzan

University of Ljubljana
Faculty of Medicine
Institute for Biochemistry
Ljubljana, Slovenia
Prof. Wolfgang König, Prof. Bernhard Boehm

University of Ulm
Ulm, Germany
Dr. Jaako Tuomilehto, Prof. Michael Brainin

Danube University Krems
Krems, Austria
Impacts
www.impactsnetwork.eu
State-of-the-Art:
Project Type: Today, most of the molecular research is carried out on cell culture and animal models, but it is
Co-ordination Action possible also to apply it directly to human clinical tissues. A very important tool for translational
Contract number: research is represented by the large number of human archive tissues (AT) that are stored in
hospitals all over Europe. Tissue specimens removed from patients for diagnosis or surgical
LSHG-CT-2007-037211 therapy are fixed and paraffin-embedded in order to obtain a conclusive diagnosis. After a
Starting date: few sections are cut, the tissues are stored in archives for many decades. For each hospital an
1st February 2007 average of between 10 000 and 30 000 tissue samples are collected each year. We already
Duration: have the technology that allows a molecular research at DNA and RNA level on fixed and
paraffin embedded tissues, and new possibilities for proteomics analysis are emerging. In
24 months Europe, many laboratories are working with archive tissues at molecular level. DNA genomic
EC Funding: analysis is already widely spread in research and diagnostics (lymphomas and leukaemia etc).
`600 000 Less diffused and validated are the techniques for studying DNA methylation, comparative ge-
nomic hybridization (CGH) or single nucleotide polymorphisms (SNP) in archive tissues. Many
laboratories also perform analysis at RNA level in order to detect RNA virus persistence or to
study gene expression for functional genomics or micro-RNAs.
The project is capable of overcoming some of the major obstacles and limitations in the devel-
opment of clinical molecular medicine, obstacles created by insufficient expertise at clinical
level in the use of molecular methods and the collection of appropriate clinical materials. The
objectives of IMPACTS are:
1) to analyse the present knowledge and use of molecular analysis in archive human tis-
sues in Europe and to propose methods of validation and standardisation;
2) to explore the range of technical availability and reproducibility of these new methods
for research in functional genomics and clinical application;
3) to establish a more organised European research effort. There are uncommon protocols
for some of the molecular analysis in AT and every laboratory has its own experience.
4) to compare methods and results by organising meetings and inter-laboratory compari-
sons for a proposal of method validation and standardisation.
Expected Results:
1) organisation of meetings
2) publication of technical guidelines
3) definition of future research proposals on archive tissues
4) standardised protocols and guidelines diffusion
5) validation of new tissue fixation procedures with better molecular preservation
6) proposal of bioethics guidelines for human archive tissue multicentric research
7) guidelines for archive tissue multicentric collection
8) proteomic analysis protocols in archive tissues for research and clinical applications
Potential Impact:
This project will make a positive impact on the health of European citizens. Among the pro-
ponents of the project are the scientists who first developed this type of molecular analysis.
IMPACTS aims to integrate this expertise with others for the final goal of better management
of research. The project will also have an impact on research and development in European
industry. Collaboration with pharmaceutical and biotechnological enterprises may stimulate
industrial activities with evident economic advantages. Preparing technological innovation is
a basic aim of IMPACTS with the development of new procedures (new fixatives, standard-
ised molecular methods and diagnostic kits) and suggestion of new devices for molecular
analysis. The project has also developed a network of laboratories and pathology archives
with a very large number of tissues to validate new methods and clinical biomarkers.
Archive tissues: improving molecular
medicine research and clinical practice
Keywords: pathological anatomy, ethics in health sciences, molecular biology,
molecular medicine, functional genomics, personalised medicine,
biobanks
Partners
Project Coordinator: Prof. Aldo Scarpa Dr. Serena Bonin
Prof. Giorgio Stanta University of Verona International Centre for Genetic
University of Trieste Department of Pathology Engineering and Biotechnology
Department of Clinical Verona, Italy Molecular Histopathology
Morphological and Laboratory
Technological Sciences Prof. Gianni Bussolati Trieste, Italy
c/o Ospedale di Cattinara University of Torino
Strada di Fiume 447 Department of Biomedical Prof. Samuel Navarro
34149 Trieste Sciences and Human Oncology University of Valencia
and Turin, Italy Department of Pathology
International Centre for Genetic Valencia, Spain
Engineering and Biotechnology Marco Bellini
Molecular Histopathology Laboratory Milestone Srl Prof. Elias Campo
Padriciano 99 Sorisole- Bergamo, Italy Hospital Clinico Provincial
34012 Trieste, Italy de Barcelona
stanta@icgeb.org Prof. Mladen Belicza Department of Pathology
University Hospital Barcelona, Spain
Prof. J.H.J.M. Van Krieken “Sestre milosrdnice”
Radboud University University Department of Prof. Gerald Hoefler
Nijmegen Medical Centre Pathology “Ljudevit Jurak” Medical University of Graz
PO Box 9010 Zagreb, Croatia Institute for Pathology
6500 GL Nijmegen, The Netherlands Graz, Austria
Prof. Nina Gale
Prof. Fatima Carneiro University of Ljubljana Prof. Jaime Prat
University of Porto Institute of Pathology Hospital de la Santa Creu
Institute of Molecular Pathology Ljubljana, Slovenia i Sant Pau
and Immunology Barcelona, Spain
Porto, Portugal Prof. Pierre Bedossa
Prof. Fred Bosman Scientifique (CNRS)
University of Lausanne UMR 8149 - Université Paris V
Lausanne, Switzerland Hôpital Beaujon
Clichy, France
Prof. Generoso Bevilacqua
University of Pisa Prof. Maciej Zabel
Department of Oncology Medical University of Wroclaw
Pisa, Italy Department of Histology
and Embryology
Prof. Gregor Mikuz Wroclaw, Poland
Medical University Innsbruck
Institute of Pathology Prof. Helmut Popper
Innsbruck, Austria Medical University of Graz
Institute for Pathology
Prof. Heinz Hoefler Graz, Austria
Technical University Munich
Institute of Pathology Prof. Thomas Kirchner
Munich, Germany Ludwig-Maximilians-
Universitaet München
Prof. Manfred Dietel Department of Pathology
Charite – Universitatsmedizin Berlin Munich, Germany
Institut for Pathologie CCM
Berlin, Germany
EpiGenChlamydia
www.epigenchlamydia.eu
State-of-the-Art:
Project Type: The preliminary findings of members of EpiGenChlamydia estimate that there is a 40 per-
Co-ordination Action cent genetic predisposition to Chlamydia trachomatis (CT) infections. To allow full exploita-
Contract number: tion of this knowledge, it is essential to know which part of a person’s genetic make-up pre-
LSHG-CT-2007-037637 disposes them to CT infections. Therefore, genomic analysis on a large number of unrelated
Starting date: individuals needs to be performed.
1st July 2007
As no single entity has access to all the information, nor the necessary expertise to process
Duration: all samples and data, a collaborative effort is required. This Coordination Action gives the
24 months consortium the opportunity to thoroughly define the requirements for successful collabora-
EC Funding: tions on this issue.
`450 000
1) To provide state-of-the-art reports on the epidemiology of both ocular and sexually
transmitted CT infections;
2) To define and provide an approach based on the host-pathogen interaction for large-
scale genetic typing;
3) To generate a validated and integrated large biobank and efficient data warehouse;
4) To integrate ongoing immunogenetic CT research lines in three European centres in
which several participants are involved;
5) To apply for research grants;
6) To disseminate the EpiGenChlamydia consortium’s activities.
Expected Results:
1) A validated central biobank;
2) Validated data warehouses;
3) A validated EpiGenChlamydia website for the data warehouse;
4) Research integration;
5) Enhanced collaboration between partners and potential new partners;
6) Dissemination of results;
7) Media coverage, including publications and meetings. Reports and reviews will be
produced to keep the partners, the EC and the general public aware of the consor-
tium’s achievements.
Potential Impact:
By the end of this CA, an integrated network of all key players for the genetic epidemiologi-
cal study to determine the genetic predisposition to CT infection will have been formed.
The collective knowledge acquired in this CA will allow for the development of tools for the
early detection of a predisposition to CT infection and diagnostics to detect CT infections
indicative of non-regular treatment (persistent infections).
Keywords: genetic epidemiology and standardisation, SNP-Chip, Chlamydia

trachomatis, screening-cohorts, sample collections, host factors, bac-
terial factors, environmental factors, datawarehouse development
Contribution of molecular epidemiology
and host-pathogen genomics to understand
Chlamydia trachomatis disease
Partners
Project Coordinator: Dr. Ansumana Sillah Dr. Jan van Bergen
Dr. Servaas A. Morré The Gambia International STI AIDS
VU University Medical Center Centre for Eye Health Amsterdam, The Netherlands
Immunogenetics of Infectious Diseases Ministry of Health
Department of Pathology Banjul, Gambia Prof. Jolande Land
Laboratory of Immunogenetics University of Maastricht
De Boelelaan 1117 Dr. Björn Herrmann Maastricht, The Netherlands
1081 HV Amsterdam, The Netherlands Swedish Institute of Infectious
samorretravel@yahoo.co.uk Disease Control Dr. Marianne van der Sande
Section of Sexually Transmitted National Institute of Public
Prof. Chris Meijer, Prof. Salvador Peña, Infections Health and the Environment
Bart Crusius Uppsala, Sweden Department of Infectious
VU University Medical Center Diseases Epidemiology
Department of Pathology Dr. Björn Buan, Dr. Inger Bakken Bilthoven, The Netherlands
Amsterdam, The Netherlands Stiftelsen for Industriell og Teknisk
Forskning ved Norges Tekniske Prof. Joseph Igietseme
Prof. David Mabey, Prof. Robin Bailey Hogskole Morehouse School of Medicine
University of London Trondheim, Norway Atlanta, USA
School of Hygiene and Tropical Medicine
London, UK Prof. Lars Ostergaard, Prof. Paul Savelkoul
Dr. Berit Andersen Microbiome Ltd
Dr. Ioannis Ragoussis, Richard Mott, Aahus University Hospital Houten, The Netherlands
Prof. Michael Parker, Department of Clinical
Prof. Dominic Kwiatkowski Microbiology Prof. Cathy Ison,
University of Oxford Arhus, Denmark Dr. Mary Macintosh
Wellcome Trust Centre for Human Genetics Health Protection Agency
Oxford, UK Dr. Tjaco Ossewaarde Centre for Infection
Erasmus University Sexually Transmitted Bacterial
Prof. Jorma Paavonen Department of Medical Reference Laboratory
University of Helsinki Molecular Microbiology London, UK
University Hospital Rotterdam, The Netherlands
Department of Obstetrics and
Gynaecology Dr. Yvonne Pannekoek
Helsinki, Finland Academic Medical Centre
Department of Medical
Dr. Helj-Marja Surcel Microbiology
National Public Health Institute Amsterdam, The Netherlands
Helsinki, Finland
Dr. Han Fennema, Dr. Henry de Vries

Municipal Health Service
Dr. James Ito, Dr. Joe Lyons

City of Hope National Medical Center
and Beckman Research Institute
Department of Infectious Diseases
Duarte, California, USA
Dr. Jean-Francois Schemann

L’Institut de Recherche pour le
Developpement (IRD)
Paris, France
6. BIOINFORMATICS
6.
BIOINFORMATICS
BIOSAPIENS
ATD
EMBRACE
ENFIN
EUROFUNGBASE
BioSapiens
www.biosapiens.info

Contract number: The genome projects have revealed for the first time the “blue-print” of life. The first draft of
the human sequence was published in 2001, and there are now over 100 completed and
LSHG-CT-2003-503265
70 draft genome sequences in the public domain. This explosion in genomic information
Starting date: has been achieved in a remarkably short period of time, and the flood of new sequence
1st January 2004 data is likely to continue for the next decade. However, DNA sequence is merely a string
Duration: of letters; it must be interpreted in terms of the RNA and proteins that it encodes and the
60 months promoter and regulatory regions that control transcription and translation.
EC Funding:
Annotation can be described as the process of “defining the biological role of a molecule
`12 000 000
in all its complexity” and mapping this knowledge onto the relevant gene products encoded
by genomes. This involves both experimental and computational approaches and, indeed,
absolutely requires their integration. The BioSapiens network provides the necessary exper-
tise and European infrastructure to allow distributed annotation, from both computational
and experimental laboratories. These expert annotations will be made available to every-
one over the web. To date, European scientists have been very active in the field of genome
and protein annotation, with Ensembl and SWISS-PROT being the primary resources in use
worldwide. Many of the tools used in genome and protein sequence and structure annota-
tion, prediction and validation, as well as in pathway analysis were developed in Europe.
Many of the secondary resources derived from protein sequences and structures are also
European.
However, the groups that develop the methods for improving genome annotation are widely
distributed throughout Europe and the best methods are often not incorporated into publicly
available genome annotations. Furthermore, these methods are continually changing and
improving, so keeping up to date becomes problematic. The fragmentation of currently
available resources for genome annotation means that only a few bioinformatics experts
know where to look for them. Consequently, most experimentalists cannot access all the
best information about a genome. This problem will only get worse as annotation methods
become more sophisticated and more bioinformatics laboratories are established to handle
all the new data.
The objective of the BIOSAPIENS Network of Excellence is to provide a large-scale, con-
certed effort to annotate genome data by laboratories distributed around Europe, using
both informatics tools and input from experimentalists. The Network will create a European
Virtual Institute for Genome Annotation, bringing together many of the best laboratories in
Europe. The institute will help to improve bioinformatics research in Europe, by providing a
focus for annotation and through the organisation of European meetings and workshops to
encourage cooperation, rather than duplication of effort.
An important aspect of the network activities is to try and achieve closer integration be-
tween experimentalists and bioinformaticians, through a directed programme of genome
analysis, focused on specific biological problems. The annotations generated by the Insti-
tute will be available in the public domain and easily accessible on the web. This will be
achieved initially through a distributed annotation system (DAS), which will evolve to take
advantage of new developments in the GRID. European scientists have traditionally been
A European Network
for Integrated Genome Annotation
BIOSAPIENS School
very active in the field of protein and genome annotation, and Ensembl and SWISS-PROT
(now part of UniProt) are the primary resources in use worldwide.
Many of the tools used in genome and protein sequence and structure annotation, predic-
tion and validation, and pathway analysis have been developed in Europe. The BioSapiens
NoE will further increase European competitiveness, through new discoveries, increased
integration, expert training and improved tools and services, and enhance Europe’s role in
the academic and industrial exploitation of genomics.
A further objective of the Network of Excellence is the establishment of a permanent Euro-

pean School of Bioinformatics, to train bioinformaticians and to encourage best practice in
the exploitation of genome annotation data for biologists. The courses and meetings will be
open to all scientists throughout Europe, and available at all levels, from basic courses for
experimentalists to more advanced training for experts.
Expected Results:
Some of the main results expected from the project will be the development of an integrated
approach to genome annotation from gene to function, and the establishment of an inte-
grated and distributed website for Genome Annotation. The team expects a stimulation
of cooperation between experimental scientists and computational biologists for genome
annotation, in the form of meetings and joint collaborations. Experimental validation of
predictions made in silico will form part of these col-
laborations. The team will also focus on the develop-
ment of improved computational methods for annota-
tion through cooperation: new methods will be made
available via the web. Annotations from new methods
will be available on the BioSapiens website.
Potential Impact:
The BioSapiens Network of Excellence will have an
impact on the establishment of a European research
structure that will support the coordination of bioinfor-
BIOSAPIENS
DNA Proteome Functional

Annotation Annotation Annotation
uProtein Families
uGene Definition (alternative splicing) uSequence & Structure to Function
uProtein Structure & Modelling
uRegulators & Promoters uMembrane Proteins & Ligands

uProtein-Protein Complexes
uExpression uPost Translation Modification
uPathways and Networks
uVariation (haplotypes & SNP’s) & Localisation
matics research activities across different sub-areas, and across different areas of medical
and biotechnological application. It will promote the development of the required level of
critical mass, which is essential if Europe should be able to compete with the major invest-
ments made in this area in the USA, Canada and Japan.
The integration between the groups in the BioSapiens Network of Excellence will have a
lasting impact on the European bioinformatics infrastructure, and on the sharing of human
resources, infrastructure databases and tools. Through cutting-edge research, high-level
training, and vigorous European interaction, the BioSapiens Network of Excellence will
make a substantial contribution to improving Europe’s knowledge base, and increase the
potential for creating new industries, new knowledge, and new employment.
The exploitation of the biological informa-

tion enabled by the BioSapiens Network
of Excellence will in some cases be rela-
Partners
tively direct: e.g., improved health-care Project Coordinator:
through better drugs, new vaccines, and Prof. Janet Thornton
personalised medicines for individuals
and sub-populations, and by improved Wellcome Trust Genome Campus
understanding of diet and health. Hinxton, CB10 1SD, UK.
thornton@ebi.ac.uk
Project Manager:
Dr. Kerstin Nyberg
Hinxton, CB10 1SD, UK
knyberg@ebi.ac.uk
Prof. Peer Bork

European Molecular Biology Laboratory,(EMBL)
Heidelberg, Germany
Prof. Dmitrij Frishman

Helmholz Zentrum
Neuherberg, Germany
Keywords: Prof; Jacques van Helden

Université Libre de Bruxelles,
genome annotation,
Service de Conformation de Macromolécules
Biologiques et Bioinformatique
data integration, databases Brussels, Belgium
A European Network for Integrated Genome Annotation
Prof. Alfonso Valencia Prof. Esko Ukkonen Dr; Leszek Rychlewski

Spanish National Cancer Research University of Helsinki BioInfo Bank Institute
Centre (CNIO) Department of Computer Science Bioinformatics Laboratory
Madrid, Spain Helsinki, Finland Poznan, Poland
Dr. Roderic Guigo Prof. Stylianos Antonarakis Prof. Martin Vingron

Centre for Genomic Regulation University of Geneva Max-Planck Institute for
Barcelona, Spain Division of Medical Genetics Molecular Genetics
Geneva, Switzerland Berlin, Germany
Dr. Tim Hubbard
Genome Research Ltd Prof. László Patthy Dr. Vincent Schachter
Wellcome Trust Sanger Institute Institute of Enzymology Genoscope
Hinxton, UK Biological Research Center Evry, France
Prof. Thomas Lengauer Budapest, Hungary Prof. Rita Casadio
Max-Planck Institute for Informatics University of Bologna
Saarbrücken, Germany Dietmar Schomburg Department of Biology
Technical University of Braunschweig Bologna, Italy
Prof. Michal Linial Department of Bioinformatics and
Hebrew University of Jerusalem Biochemistry Dr. Christos Ouzounis
Department of Biological Chemistry Braunschweig, Germany Institute of Agrobiotechnology
Jerusalem, Israel Centre for Research and
Antoine Danchin Technology Hellas (CERTH)
Prof. Anna Tramontano Institut Pasteur Thessaloniki, Greece
University of Rome ‘La Sapienza’ Department Structure and Dynamics
Department of Biochemical Sciences of Genomes
Rome, Italy Paris, France
Prof. Gunnar von Heijne

University of Stockholm
and Biophysics
Stockholm, Sweden
Dr. Richard Mott

Wellcome Trust Centre for
Human Genetics
Oxford, UK
Prof. Christine Orengo, Prof. David Jones

Molecular Biology
London, UK
Prof. Gert Vriend

Radboud University
Nijmegen Medical Centre
Centre for Molecular and
Biomolecular Informatics
Dr. Anne-Lise Veuthey

Swiss Institute of Bioinformatics
Geneva, Switzerland
Prof. Søren Brunak

Center for Biological Sequence
Analysis (CBS)
Lyngby, Denmark
ATD
www.atdproject.org
State-of-the-Art:
Project Type: A single human gene can produce a variety of alternative transcripts (ATs or mRNA iso-
Specific Targeted forms), which differ in terms of their transcription initiation, splicing or polyadenylation pat-
Research Project terns. Expression of alternative transcripts has been observed to be specific to tissue-type
Contract number: or developmental stage. Disruptions in AT expression have serious consequences for an
organism and are associated with numerous diseases, including cancer, multiple sclerosis,
LSHG-CT-2003-503329 heart failure and neurodegenerative disorders.
Starting date:
1st March 2004 The ATD project aims to understand the mechanisms responsible for the formation of dif-
Duration: ferent ATs. It is anticipated that studies in the field of ATs will develop into a significant
research area, with direct applications for pharmaceutical industries. These applications
36 months
are inclusive of disease diagnosis or prognosis of risk patients, as well as identification of
EC Funding: new drug targets.
`2 000 000
The ATD project is a collaborative multi-disciplinary project.
It aims to comprehensively characterise alternative tran-
script (AT) forms throughout the human genome, and also
to assess the differential expression of these forms in time
and space, in normal and disease-related tissues. This is ac-
companied by adequate quality control procedures, such
as research for evolutionary proof through comparative se-
quence data analysis, between human and mouse. Further
characterisation of the AT is implemented through activities
such as identification of regulatory patterns, and deriva-
tion of expression states (i.e. expression specificity in terms
of association with diseases, developmental stages, or tis-
sue-specificity). The project also aims to develop standard
vocabularies and models that will represent gene structures
and their expression patterns.
The validity of the bioinformatics prediction of disease-

specific ATs is being examined through the execution of
RT-PCR experiments on selected tissues. The AT discovery
effort is accompanied by database integration, and also by
dissemination to the scientific community.
Expected Results:
The principal end results being targeted are as follows:
s4HECREATIONOFAUNIlED!4$DATABASEINTEGRATINGVARIOUSINFORMATIONLEVELSSUCHAS
gene, feature variants, transcript variants, annotations, derived expression states, pro-
tein functionalities, results of experimental validations and associations with diseases.
Fully developed query interfaces and toolboxes are available in the database, which
is accessible at: http://www.ebi.ac.uk/atd/;
s4HEDElNITIONOFSTANDARDSTOREPRESENTGENESTRUCTURESANDVARIANTSANDTHECREATION
of vocabularies for the representation of annotations;
s4HECONlRMATIONOFDIFFERENTIALLYEXPRESSED!4SINHEALTHYANDDISEASEDTISSUESFROM
human and mouse;
s4HEPREDICTIONOFTHEREGULATORYMOTIFSINVOLVEDINALTERNATETRANSCRIPTFORMATION
The Alternate Transcript Diversity Project
Potential Impact:
Alternative transcription has such a strong impact on gene products, that any disruption of
ATs is potentially linked to fatal diseases. Diseases that have been linked to AT disruption
include cancer, multiple sclerosis, heart failure and neurodegenerative diseases; ATD has
the capacity to facilitate and support those areas.
Traditional molecular biology approaches founded on a “one gene at a time” basis, are no
longer practical when detecting new disease-specific ATs. There is currently a need for the
execution of genome-wide AT detection, followed by high-throughput analysis of transcript
expression. It is predicted that these studies on alternative transcripts will develop into a
major research area, with direct applications for pharmaceutical industries.
Keywords: transcriptome, gene expression regulation, splicing, diagnosis,

disease markers, microarrays, basic biological processes, transcript
Partners
Project Coordinator: Prof. Magnus von Knebel Doeberitz
Prof. Daniel Gautheret University of Heidelberg
ERM-0206 TAGC Department of Applied Tumor Biology
Institut National de la Santé et de la Heidelberg, Germany
Recherche Médicale (INSERM)
75654 Marseille, France Dr. Christiane Dascher-Nadel
daniel.gautheret@u-psud.fr Inserm Transfert SA
European Project Management Department
Prof. Peer Bork Marseille, France
Structural and Computational Biology Unit Prof. Jens Reich
Heidelberg, Germany Max-Delbruck-Centrum für
Molekulare Medizin Berlin-Buch
Dr. Eleanor Whitfield Bioinformatics Unit
European Molecular Biology Laboratory (EMBL) Berlin-Buch, Germany
Hinxton, UK
Prof. Winston Hide

University of the Western Cape
South African National Bioinformatics Institute
Cape Town, South Africa
Dr Roderic Guigo
Centre de Regualci Genmica
Bioinformatics and Genomics Unit
Barcelona, Spain
Dr. Jaak Vilo

Estonian Biocenter
Bioinformatics Group
Tartu, Estonia
EMBRACE
www.embracegrid.info

Contract number: The EMBRACE project addresses the need for integration of data and analysis resources for
biological and biomolecular information. The many publicly available collections of biomo-
LHSG-CT-2004-512092
lecular information do a reasonable job for a given domain. Software tools to organise and
Starting date: analyse this information are available both from the public domain, and commercially. In
1st February 2005 principle, cross-references in these databases allow inter-database navigation; however, the
Duration: links are sparse and coarse-grained, and their exploitation requires biological knowledge
60 months and expert programming. As a result, every serious bioinformatics centre is burdened not
EC Funding: only with the task of maintaining local data and software, but also of supporting users in the
substantial task of exploring the natural biological connections between data. This requires
`8 280 000
considerable human effort. Current trends in systems biology demand greatly improved
connections between different domains of knowledge, and the weaknesses in information
integration are becoming an intolerable hindrance. This network will address these weak-
nesses by enabling data providers and tool builders to standardise their data access and
software tools, using the new grid computing technologies that are ideally adapted to the
task. The use of these standard methods will allow data resources to be essentially self-
describing, allowing software to work out the structure of the data, in large part automati-
cally. Apart from facilitating widespread integration of software and data, this will make
the interacting systems easy to update; for example, it will reflect changes to the internal
representation of the data.
The objective of the EMBRACE Network of Excellence is to draw together a wide group
of experts throughout Europe who are involved in the use of information technology in the
biomolecular sciences. The EMBRACE network will optimize informatics and information ex-
ploitation by pure and applied biological scientists, in both the academic and commercial
sectors. The result will be highly integrated access to a broad range of biomolecular data
and software packages. Groups in the network are involved in the following activities:
1) collection, curation and provision of biomolecular information;
2) development of tools and programming interfaces to exploit that information; and
3) tracking and exploiting advances in information technology, with a view to applying
them in bioinformatics training and also to reaching out to groups who can benefit
from the work of the network.
A European Model
for Bioinformatics Research
and Community Education
These groups work together to enable highly functional interactive access to a wide range
of biomolecular data (sequence, structure, annotation, etc.), and tools with which to ex-
ploit the data. This naturally includes many core databases and tools available from the
European Bioinformatics Institute (EBI), but, crucially, the methods used will support the
integration of dispersed, autonomous information. As a result, groups throughout Europe
will be expected to integrate their own local or proprietary databases and tools into the
collaborative “information space” which constitutes the EMBRACEgrid — a ‘data grid’
allowing integrated exploitation of data, analogous to a ‘compute grid’, which enables
unified exploitation of dispersed computer resources. EMBRACEgrid will serve as a com-
prehensive virtual information source: virtual in the sense that it will have no single physi-
cal location, being rather a dispersed set of tightly coupled resources. EMBRACEgrid will
be a permanent product of the project.
Expected Results:
The results expected are as follows:
1) Standardized application programming interfaces (APIs) with all the core biological
databases at the EBI, as well as with several wide-ranging sources of other information
distributed throughout Europe.
2) Software tools that exploit the data through the new APIs, to provide a working
environment in which to access and analyze the data, and also to facilitate the
development of further tools in a consistent programming environment.
3) Technological standards for finding and describing the data and application services
mentioned above.
4) Training and outreach to enable biologists to get the best out of the resulting tools
and data, and bioinformaticians to develop ever better tools, in the knowledge that
they are firmly connected to all the data.
Potential Impact:
There is currently a great deal of investment in post-genomics projects. About once a week
the sequence of an entire species becomes available. Transcriptomics and proteomics
projects are producing data avalanche after data avalanche. Each time that (bio)informati-
cians have dealt with the data flow of one type of project, two new types of high throughput
experiment have been developed. All this data is finding its way to the biosciences, and
fields such as pharma, health, food and agriculture are all likely to undergo major revolu-
tions, that are expected to improve the quality of life for all, from infants to the elderly. This
project sits in the context of existing integration projects such as Integr8 and BioMart. These
projects, and information resources like Ensembl will exploit the standards developed in
EMBRACE to provide common interfaces to data and tools across Europe, targeted to the
needs of experimental research.
Keywords: bioinformatics, standards, web services, integration
EMBRACE
Partners
Dr. Graham Cameron
Laboratory (EMBL)
cameron@ebi.ac.uk
Project Manager:
Dr. Kerstin Nyberg
Laboratory (EMBL)
knyberg@ebi.ac.uk
Dr. Andreas Gisel

Institute of Biomedical Technologies
Section Bari
Consiglio Nazionale della Ricerche (CNR)
Bari, Italy
Prof. Terri Attwood

Manchester, UK
Marco Pagni
Swiss Institute of Bioinformatics
Dr. Erik Bongcam-Rudloff

Swedish University of Agricultural Sciences
Linnaeus Centre for Bioinformatics
Uppsala, Sweden
Dr. Vincent Breton, Dr Christophe Blanchet

Clermont-Ferrand and Lyon, France
Prof. Søren Brunak

Analysis (CBS)
BioCentrum-DTU
Lyngby, Denmark
Jose-Maria Carazo Garcia

Spanish National Research Council (CSIC)
Madrid, Spain
A European Model for Bioinformatics Research and Community Education
Prof. Arne Elofsson

University of Stockholm
Stockholm Bioinformatics Centre
Stockholm, Sweden
Dr. Daniel Kahn

INRIA-UCBL
Institut National de la Recherche
Agronomique (INRA)
Toulouse, France
Dr. Ralf Herwig

Max-Planck Institute for
Molecular Genetics
Department of Vertebrate Genomics
Berlin, Germany
Dr. Eija Korpelainen

CSC – Scientific Computing Ltd
Espoo, Finland
Prof. Christine Orengo

and Molecular Biology
London, UK
Dr. Yitzhak Pilpel

Department of Molecular
Genetics/Biochemistry
Rehovot, Israel
Dr. Gert Vriend

Radboud University
Centre for Molecular and
Biomolecular Informatics
Prof. Alfonso Valencia

Instituto Nacional De Tecnica
Aeroespacial (Centro De
Astrobiologia)
Laboratory of Bionformatics
CAB
Madrid, Spain
Prof. Inge Jonassen

Bergen Center for
Computational Science
Bergen, Norway
ENFIN
www.enfin.org

Contract number: Despite the progress made in bioinformatics methods and databases to date, even the best
experimental laboratories use only a small number of computational tools in their work, and
LSHG-CT-2005-518254
they rarely exploit the potential of multiple datasets. The ENFIN network will transform the
Starting date: way computational analysis is used in the laboratory. The infrastructure will be entirely open,
15 November 2005 in the same way that genome information is accessible to all.
Duration:
60 months To achieve its goals, the network will encourage close internal collaboration between experi-
EC Funding: mental and computational research groups, and will have a specific consumables budget for
testing predictions experimentally. The computational work includes the development of a
`8 967 500
distributed database infrastructure appropriate for small laboratories, and the development of
analysis methods, including Bayesian networks, metabolite flux modelling and correlations of
protein modifications to pathways.
The experimental techniques used to test this system include mass spectroscopy, synthetic
peptide biochemistry and RNA interference knockdown. Where appropriate, the network has
chosen experimental areas related to intracellular signalling, associated with the cell cycle.
ENFIN’s network’s specific objectives can be summarised as follows:
1) Development of the ENFIN Core (EnCORE), by taking a number of pre-existing

database packages and providing a unified installation which can be used in
laboratories worldwide;
2) Curation of appropriate pathway knowledge and hypotheses;
3) Development and management of new experimental data standards;
4) Discrete function prediction;
5) Network reconstruction;
6) Systems level modelling. (Objectives 4, 5 and 6 comprise the ENFIN analysis
layer. Cycling between computational predictions and experimental validation
feedback will be used, to improve the accuracy of bioinformatics tools for predict-
ing biological features in this layer);
7) Critical assessment and integration, i.e. bringing together groups across the analy-
sis layer, both to critically assess the methods and also to uncover new synergies
between computational and experimental groups;
8) Provision of graduate level training, coordinated with the European School of Bio-
informatics, so as to arrange a short course for graduate level students;
9) Documentation from a wet laboratory perspective, enabling the consortium to de-
velop a multi-authored resource, which is kept as current as possible through direct
editing by appropriate researchers within the network;
10) Facilitating SME outreach, to raise awareness of ENFIN in the biotechnology com-
munity, and to increase the understanding of SMEs’ needs.
An Experimental Network
for Functional Integration
Expected Results:
EnCore, the network, will develop a set of existing databases for the storage and integra-
tion of public and local data, such as microarray data, protein-protein interaction data and
pathway information. This core will be available by all nodes of the ENFIN network, and
will form the backbone for the communication of datasets.
The ENFIN analysis layer will work with EnCore as a series of computer programs to pro-
vide analysis of the data stored in EnCore. Interaction between experimental and computa-
tional researchers is crucial in the development of these programs. There will be a critical
assessment of the computational tools using experimental information as a challenge.
A truly multidisciplinary set of investigators will be gathered across Europe, spanning ex-
perimental research in mitogenic signalling through to algorithm development in machine-
learning techniques. ENFIN will use a variety of experimental techniques to test and inform
computational work. This work will also provide insights into cancer, since the bulk of the
network’s experimental research concerns regulation of the cell cycle. These biological
results will prove the effectiveness of the network’s products and provide insights that could
be used to enhance human health.
ENFIN’s products will be disseminated, not principally as scientific results, but rather as a
technical solution for how to coordinate computational and experimental work. The produc-
tive interactions between computational and experimental researchers will be as important
as the technical programming aspect of the work. Through its dissemination programme,
ENFIN will reach the post-doctoral student in the lab, the SME researcher, and biological
and bioinformatics graduate students. The project will pass on developments in bioinfor-
Systems Modeling Methods
ENFIN
matics best practice and software deployment to core biological labs, and will benefit from
feedback on their use.
Potential Impact:
The main tangible benefit of ENFIN will be the development of a set of scientific procedures
for understanding multi-component systems using computational techniques. The ENFIN
infrastructure will be distributed firstly to all the network’s partners, and then to various iden-
tified collaborators and other interested laboratories. Local installation of ENFIN will allow
on-site processing of information, access to public archived data as well as local informa-
tion, access to specific, designed analysis methods which have been tested experimentally,
and access to documentation written from the wet laboratory perspective.
ENFIN will have an impact on the understanding of complex human diseases such as can-
cer and diabetes. The systems-level vision of ENFIN is applicable to many other complex
diseases and biological processes in other fields. As well as mammalian cells, systems
biology could potentially impact the understanding of many pathogenic organisms - both
eubacteria and eukaryotes.
In addition to the network’s research being fully integrated with that of leading molecular
biology laboratories, it will organise a public, highly visible conference to explicitly test the
outputs of systems biology predictions. The scientific approach taken by ENFIN will be of
great interest to many industrial groups. Through the industry programme at the European
Bioinformatics Institute (EBI), whose members include all the main life science companies,
the network will be able to educate these industrial partners in new approaches.
Keywords:
systems biology, functional genomics, pathways, computational predictions
Partners
Project Coordinator: Dr. Jan Ellenberg
Prof. Ewan Birney European Molecular Biology Laboratory (EMBL)
European Molecular Biology Laboratory (EMBL) Heidelberg, Germany
Wellcome Trust Genome Campus Dr. Henning Hermjakob
Hinxton, CB10 1SD, UK European Molecular Biology Laboratory (EMBL)
birney@ebi.ac.uk European Bioinformatics Institute (EBI)
Hinxton, UK
Project Manager
Dr. Pascal Kahlem Prof. Geoffrey J. Barton
European Molecular Biology Laboratory (EMBL) University of Dundee
European Bioinformatics Institute (EBI) Division of Biological Chemistry and
Wellcome Trust Genome Campus Molecular Microbiology
Hinxton, CB10 1SD, UK School of Life Sciences
pkahlem@ebi.ac.uk Dundee, UK
Prof. Søren Brunak

Centre for Biological Sequence Analysis
Lyngby, Denmark
An Experimental Network for Functional Integration
Prof. Gianni Cesareni Dr. Jaak Vilo

University of Rome Tor Vergata OÜ QureTec
Department of Biology Tartu, Estonia
Rome, Italy Ioannis Xenarios
Serono Pharmaceutical Research Institute
Dr. John Hancock Geneva, Switzerland
Mammalian Genetics Unit Prof. Alfonso Valencia
Harwell, UK Spanish National Cancer Research Centre (CNIO)
S-CompBio
Prof. Carl-Henrik Heldin Structural Biology and Biocomputing Programme
Ludwig Institute for Cancer Research Madrid, Spain
Uppsala, Sweden
Dr. Jaap Heringa
Dr. Edda Klipp, Dr. James Adjaye Centre for Integrative Bioinformatics VU
Max-Planck Institute for Molecular Genetics Amsterdam, The Netherlands
Berlin, Germany
Prof. Erich Nigg

Max-Planck Institute of Biochemistry
Department of Cell Biology
Prof.Tomi Mäkelä
University of Helsinki
Faculty of Medicine
Molecular and Cancer Biology Research Program
Helnsinki, Finland
Prof. Christine Orengo

Molecular Biology
London, UK
Dr. Christos Ouzounis

National Center for Research and Technology
Institute of Agrobiotechnology
Thessaloniki Greece
Dr. Dietmar Schomburg

Technical University Braunschweig
Bioinformatics & Biochemistry
Dr. Vincent Schachter

Consortium national de recherche
en Genomique (Genoscope)
Evry, France
Dr. Eran Segal

Department of Computer Science and
Applied Mathematics
Rehovot, Israel
EUROFUNGBASE
www.eurofung.net

Co-ordination Action
Contract number: The biotechnology industries that exploit filamentous fungi are strong within Europe. Large
companies and SMEs have participated in EUROFUNG projects within FP4 and FP5, and
LSSG-CT-2005-018964
this is a major strength. Similarly, European research into the pathogenesis of A. fumiga-
Starting date: tus is strong. On the other hand, genomic resources for filamentous fungi have not been
1st November 2005 a strong European feature. The sequencing efforts have been carried out largely outside
Duration: Europe (in the USA and Japan) although Europe has made modest contributions to sequenc-
36 months ing of fungal genomes and ESTs. Genome sequence information has only recently become
EC Funding: publicly available for the fungi to be used within this project. There are no gene arrays
currently available for any of these fungal species that cover the entire genome, although
`486 000
partial genome coverage has been achieved on slides in some cases. The international
Aspergillus Genomes Research Policy Committee, which was founded in 2004, concluded
that fabrication of A. nidulans microarrays is a top community priority
There is no bioinformatics resource available that makes it possible to store and inter-
connect transcriptomic and proteomic data, for filamentous fungi. The current state of the
art for yeast-based data repositories is that platforms have been developed and will serve
as the model for the filamentous fungi. Integration of the yeast data will provide the model
for the fungal equivalent. European scientists within the consortium are international lead-
ers in many areas of science that will exploit the filamentous fungal genome sequence
information.
The EUROFUNGBASE project is a Coordination Action. The objectives of the project are
to develop the tools and technologies necessary, so as to enable innovative functional
genomic research of hyphal fungi. In that context it is also essential, as a community, to
develop a strategy to set up and maintain a sustainable database.
The project focuses on several filamentous fungi for different reasons. Aspergillus nidulans
has a long record of use as a fungal model organism. Aspergillus niger, Trichoderma
reesei and Penicillium chrysogenum are important cell factories used for the production of
enzymes and metabolites including compounds such as β-lactams with benefits to human
health. The human pathogen Aspergillus fumigatus not only serves as a model pathogen,
but is becoming more and more of a serious threat to human health.
This new genomics information will thus be beneficial to Europe’s biotechnology industries,
and will help to improve the prevention and treatment of fungal disease.
Expected results:
The main results expected from this project are set out below:
s ! CONTRIBUTION TO THE MANUAL ANNOTATION OF IMPORTANT FUNGAL GENOMES THROUGH AN-
notation jamborees.
s 4HEREALISATIONOFANINTEGRATEDSUSTAINABLEFUNGALGENOMICDATABASETHROUGHCOL-
laboration with bioinformatics centres, and incorporation of the consortium’s data.
s 4HEREALISATIONOFAFUNGALGENOMICSKNOWLEDGEBASEFORTHE%52/&5.'"!3%COM-
munity and the European fungal biotech industry through meetings, workshops and
web-based information.
Strategy to build up and maintain an integrated
sustainable European fungal genomic database
required for innovative genomics research on
üLAMENTOUSĺFUNGI, important for
biotechnology and human health
s )NTENSIlEDCOLLABORATIONBETWEENTHEMEMBERSOFTHENETWORKINCLUDINGTHEPARTICI-
pating industries, thus strengthening infrastructure for high quality fungal genomics
research in Europe and determining joint research targets for the future.
s )NDIVIDUALISEDTRAININGFORTHENEXTGENERATIONOFYOUNGSCIENTISTSINFUNGALGENOMICS
and biotechnological research.
Potential impact:
Enlarging and maintaining genomic databases is of paramount importance in order to
further develop systems biology for model organisms, including relevant filamentous fungi.
Therefore, bioinformatics tools must become progressively more sophisticated, to allow for
the interpretation of the enormous amounts of data that already have been generated, and
are increasing every day. In the end, not only the EUROFUNGBASE community but also
other research communities will profit from the effort put in to maintaining a sustainable
database. The EUROFUNGBASE project will illustrate the impact described above.
Keywords: fungal pathogenicity, fungal health applications, genomic databases

Partners
Prof. Cees van den Hondel
Leiden University
Clusius Laboratory
Wassenaarseweg 64
2333 AL Leiden, The Netherlands
c.a.m.van.den.hondel@biology.leidenuniv.nl
Dr. Dave Ussery

Lyngby, Denmark
Prof. Steve Oliver,

Dr. Geoffrey Robson
University of Manchester,
Manchester, UK
7. FUNCTIONAL GENOMICS
APPROACHES FOR BASIC
BIOLOGICAL PROCESSES
7.1
BIOLOGICAL PATHWAYS
AND SIGNALLING
MAIN
WOUND
MITOCHECK
SIGNALLING & TRAFFIC
TransDeath
PEROXISOMES
DNA REPAIR
STEROLTALK
RUBICON
EndoTrack
AnEUploidy
MAIN
http://main-noe.org

Contract number: Chronic inflammation is a systemic disorder resulting from the dysregulation of multiple,
mechanistically unrelated higher order biological processes. This consortium will promote
LSHG-CT-2003-502935
the integration of multi-disciplinary research groups to achieve a thorough understanding of
Starting date: directed inflammatory cell migration towards
1st January 2004 and across injured tissues. To achieve its
Duration: goals, the MAIN consortium will be based on
48 months four developmental research programmes,
EC Funding: three support facilities and one core facility.
The research programmes are tightly inter-
`10 000 000
connected in a logical sequence of highly
integrated activities. The tool development
programme (TDP) will develop technologi-
cal tools that are instrumental in making ad-
vancements in the field of cell migration. The
target identification programme (TIP) will
identify signalling pathways and/or molecu-
lar networks involved in defined aspects of
inflammatory cell migration. The target vali-
dation programme (TVP) will validate targets
emerging from the TIP by testing them across
in vitro and in vivo models, different inducing
stimuli and manipulating conditions. The TVP
combines the products of the TDP and the TIP
to provide a unified explanation on how mul-
tiple ‘inputs’ received by inflammatory cells
result in spatially and temporally coordinated
‘outputs’, affecting the migratory behaviour
TNF-a stimulated HUVECs of such cells. The drug development pro-
and T-lymphoblast, 12 min gramme (DDP) will transfer selected targets
coincubation. The projection into a pipeline of drug development, through
of a z-stack of 8 images. the SMEs of the consortium. The support fa-
Acknowledgement: Jaime Millan cilities (imaging, microarrays and proteom-
ics) and the bioinformatics core will provide
technological and bio-computational support
to the programmes. To spread excellence through education and training, MAIN will imple-
ment a training and education programme (TEP), with practical courses and workshops for
graduate students and technicians.
The scientific goal of MAIN is to identify and characterise the molecular mechanisms under-
lying chronic inflammatory responses, with emphasis on a crucial step in such responses,
namely the transmigration of leukocytes (white blood cells) from the bloodstream into in-
flamed tissues and their local activation by inflammatory substances and pathogens. MAIN
has gathered over 150 researchers and graduate students from 13 research institutes and
two biotechnology companies of five EU Member States, and Switzerland and Israel. The
international dimension of MAIN is emphasised by the strong connection between MAIN
TARGETINGCELLMIGRATIONINCHRONICINFLAMMATION
Targeting Cell Migration

in Chronic Inflammation
scientists and the US Cell Migration Consortium’s (CMC) goal of exploring the complex
mechanisms underlying cell migration in embryonic development, wound healing and can-
cer. MAIN and CMC share information/technology platforms and will develop a coordi-
nated agenda of scientific events to communicate their scientific achievements to a wider
scientific audience and the public.
Expected Results:
Bioinformatic databases on the website: integrated suite of MAIN’s resources, bioinformat-
ics software tools, application databases enabling rapid data retrieval/analysis and cross-
correlation of functional genomic/proteomic data facilitating biological hypothesis-making
and ‘systems’ level investigations. It includes MAIN’s deliverables (public access) detail-
ing work packages, publications, patents, training, meetings and workshops, experimental
tools (main members’ access only)including a database of antibody, cell lines, peptides,
plasmids, vectors, cDNA and transgenic organisms.
Tutorials (the cell migration and inflammation section of website) explain the process to a
non-expert public audience.
‘Deciphering the Cell Migration Code’:

students meeting held 30 April-3 May
2005, Switzerland. The format was a
combination of poster presentations,
20 student presentations and guest
speakers/partners from the MAIN con-
sortium. It was a unique opportunity to
meet other students from the consor-
tium, encouraging mobility and ena-
bling an exchange of scientific/tech-
nology transfer expertise between the
consortium members via their young Endothelial cell
scientists. junctions delineated in
a mouse cremasteric
MAIN published papers: Prof. B. Mo- venule by the use of an
ser: ‘Follicular B Helper T Cells in An- anti-PECAM-1 mAb
tibody Responses and Autoimmunity’
and ‘Professional Antigen-Presentation
Function by Human gamma-delta T
Cells’, (Nature Reviews Immunology
November 2005/Science Express 2
June 2005); Prof. R. Alon: ‘How do
rolling immune cells use their integrins
to arrest on inflamed blood vessels?’
and ‘Immune Cell Migration in Inflam-
mation: present and future therapeutic Tracking of leucocyte
targets’, Nature Immunology May/De- (white) transmigration
cember 2005. through IL-1β-
stimulated cremasteric
venules immunostained
with an anti-PECAM-1
mAb (red)
MAIN
Potential Impact:
The bioinformatics core facility will or-
ganise/disseminate MAIN’s informa-
tion inside and outside its boundaries.
It is hoped that the TDP will produce
cutting-edge technological approaches
for widespread use in the cell migration
research community and refine existing
technologies to make them appropriate
for use in the cell migration field. The TIP
will promote identification and charac-
Inflamed mouse cremasteric terisation of signalling pathways and/or
venule stained for pericytes molecular networks involved in defined
(a-SMA; red) and neutrophils aspects of inflammatory cell migration,
(MRP-14; green) achieved by the implementation of joint
research projects. The TVP aims at com-
bining the TDP and TIP results to provide
a unified explanation of how multiple
‘inputs’ received by inflammatory cells
result in spatially and temporally co-
ordinated ‘outputs’, as applied to cell
migration and related biological proc-
esses occurring in chronically inflamed
tissues. The TVP aims to identify the most
Inflamed mouse cremasteric promising targets for further analysis/
venule stained for pericytes potential use in drug development. The
(a-SMA; red), neutrophils DDP will focus on selected target path-
(MRP-14; green) and monocytes ways/networks emerging from the TVP
(CX3CR1; green) and will transfer them into a pipeline of
drug development, using biotechnologi-
cal/pharmaceutical SMEs participating in the network. The TEP aims to develop PhDs with
top quality, up-to-date education in biotechnology/technology transfer. Training in different
European institutions will encourage mobility and enable an exchange of scientific/technol-
ogy transfer expertise.
Keywords: general pathology, immunology, medicine, cell migration, inflamma-

tion, signal transduction
Targeting Cell Migration in Chronic Inflammation
Partners
Project Coordinator: Prof. Ronen Alon Dr. Daniele D’Ambrosio
Prof. Ruggero Pardi Weizmann Institute of Science BIOXELL SpA
Fondazione Centro San Raffaele Del Monte Tabor Department of Immunology Research Department
Department of Molecular Biology and Rehovot, Israel Milan, Italy
Functional Genomics
Via Olgettina 58 Prof. Dorian Haskard Dr Françoise Cailler
20132 Milan, Italy Imperial College London Endocube SAS
pardi.ruggero@hsr.it National Heart and Lung Institute Proloque Biotech
London, UK Labege, France
Prof. Francisco Sanchez-Madrid
Universidad Autonoma de Madrid Dr. Matthias P. Wymann Dr. Marco Baccanti
Hospital De La Princesa University of Basel Science Park Raf SpA
Departamento De Medicina Department of Clinical & Biotechnology Transfer
Madrid, Spain Biological Sciences Centre
Basel, Switzerland Milan, Italy
Prof. Anne Ridley
King’s College London Dr. Jean-Philippe Girard
Randall Division of Cell & Institut de Pharmacologie et
Molecular Biophysics de Biologie (IPBS)-
London, UK Centre National de la
Recherche Scientifique (CNRS)
Prof. Dietmar Vestweber UMR 5089
Max-Planck-Institute of Department of Cancer Biology
Molecular Biomedicine Toulouse, France
Department of Cell Biology
Muenster, Germany
Dr. Jochen Wittbrodt

Laboratory (EMBL)
Heidelberg, Germany
Dr. Christina Caschetto

IFOM-Istituto FIRC di Oncologia Molecolare
Institute for Molecular Oncology
Milan, Italy
Prof. Antonio Lanzavecchia

Institute for Research in Biomedicine
Immune Regulation Laboratory
Bellinzona, Switzerland
Dr. Marlene Wolf

University of Bern
Theodor-Kocher Institute
Bern, Switzerland
Prof. Fritz Krombach

Ludwig-Maximilians-Universität München
Institute for Surgical Research
Munich, Germany
WOUND
http://pdg.cnb.uam.es/bioinfogp/wound

Specific Targeted
Research Project Understanding the properties of the signalling mechanisms involved in epithelial fusion and
wound healing is of central importance for basic science and in clinical applications. A func-
Contract number:
tional genomics approach has been chosen to unravel the signalling pathways involved in
LSHG-CT-2003-503447 these processes. It can provide direct information on the coordination of the cell communica-
Starting date: tion systems directing these events and on the molecules and cellular activities that implement
1st January 2004 them. Thus, the wealth of information and resources generated by efforts in genomics can
Duration: be directly translated into understanding the functioning of cells and tissues in vivo and to
48 months clinical applications. To achieve these goals, a multiorganism approach will be developed
to analyse the control of gene expression during wound healing and related morphogenetic
EC Funding:
programmes. The result will be a truly comparable genomic description of a basic biological
`1 870 321 mechanism conserved throughout evolution. It is important to emphasise that this multiorgan-
ism analysis will be performed in organisms which have had their genomes sequenced.
Wound healing disorders are major health problems that demand the development of effective
therapeutics. This, however, requires a thorough understanding of the molecular mechanisms
underlying healing. The goal of this project is to identify evolutionary conserved genes and
major signalling pathways that orchestrate the healing process, and to use model systems to
help define their function. Previous studies demonstrated a strong conservation of the genes
involved in murine and human wound repair and epithelial movement and fusion in Dro-
sophila and C. elegans. Therefore, we are performing a multi-organism functional genomics
approach to identify genes that are under- or over-expressed during wound healing or that
are required during epithelial morphogenesis. Our first objective is to identify genes regulat-
ed in more than one system. The second objective is to analyse their expression in situations
of impaired fusion/repair. The third objective is to use invertebrate models and monocultures
and organotypic mammalian culture systems to examine the function of the most highly
conserved genes. Finally, for a few selected genes, transgenic/knockout mouse studies and
studies using skin-humanised mice shall be performed to identify their in vivo function in re-
pair. The ultimate goal
is to identify and inves-
The process of dorsal closure tigate selected genes as
initiales at 10 hours after targets for the develop-
egg laying and is completed ment of innovative ther-
after 13 hours apeutics.
Expected Results:
The objective of this project is to define the conserved acting elements of the biomolecular
networks involved in epithelial fusion/wound healing, to analyse their functions and to
explore their use as targets for the development of innovative therapeutics. Major specific
goals as identified below will be tackled in a logical sequential fashion. Each of them cor-
responds to independent subprojects with recognised deliverables:
1) To identify the common pathways directing epithelial fusion both during morphogen-
esis and in the process of wound healing.
2) To identify those conserved genes whose expression is altered in models of impaired
epithelial fusion and wound healing.
A multi-organism functional genomics
approach to study signalling pathways
in epithelial fusion/wound healing
3) The functional characterisation of the relevant genes/pathways in different organ-

isms by defining the expression pattern of selected genes and interfering with their
function.
4) Translational research and preclinical studies.
Potential Impact:
In most cases, skin wounds heal without obvious problems. However, wound repair in the
postnatal mammalian organism does not lead to perfect regeneration, but to the formation
of a scar that lacks the elasticity of the normal dermis and all appendages. Therefore, pa-
tients with large wounds, for example. extended burn wounds, suffer from severe cosmetic
and functional impairments. The identification of genes that are regulated in different wound
healing models in Drosophila,ĺ#%LEGANS, mice and men using GeneChip hybridisation ap-
proaches will help to define major conserved signalling pathways that are important for the
healing response. In the long run, this project will help to define new therapeutic targets to
alleviate and eventually perhaps cure major wound healing disorders and thus improve the
quality of life for the patients concerned.
Keywords: wound healing, morphogenesis, skin, signalling pathways, con-

served genes.
Partners
Dr. Enrique Martin-Blanco Dr. Osvaldo Podhajcer
Consejo Superior de Investigaciones Cientificas (CSIC) Gene Therapy Laboratory
Instituto de Biologia Buenos Aires, Argentina
Molecular de Barcelona
C/ Josep Samitier 1-5
08028 Barcelona, Spain
embbmc@cid.csic.es
Prof. Sabine Werner

Swiss Federal Institute of Technology
Department of Biology, Institute of Cell Biology
Zurich, Switzerland
Dr. Petra Boukamp

Genetics of Skin Carcinogenesis
Heidelberg, Germany
Dr. Michel Labouesse

Institut de Génétique et de Biologie Moléculaire
et Cellulaire (IGBMC)
Illkirch Graffenstaden, France
Dr. Jose Luis Jorcano

Centro de Investigaciones Energeticas y
Medioambientales
Epithelial Damage, Repair and Tissue
Engineering Department
Madrid, Spain
MitoCheck
www.mitocheck.org

Integrated Project
Contract number: The proliferation of cells depends on the duplication and segregation of their genomes. The
latter is an immensely complex process that remains poorly understood at a molecular level.
LSHG-CT-2004-503464
Mistakes during mitosis contribute to cancer, whereas mistakes during meiosis, causing
Starting date: aneuploidy, are the leading cause of infertility and mental retardation.
1st April 2004
Duration: During mitosis, sister DNA molecules are dragged towards opposite poles of the cell due
48 months to their prior attachment to microtubules with opposite orientations (bi-orientation). Bi-orien-
EC Funding: tation involves dissolution of the nuclear membrane, changes in chromosome organisation
and reorganisation of the spindle apparatus. How mitotic cells coordinate these disparate
`8 578 177
but interlocking processes is poorly understood.
Protein kinases like Cdk1 have fundamental roles during cell division. However, Cdk1’s
actual function remains mysterious despite recognition of its importance with a Nobel Prize.
The same is true for other mitotic kinases, such as Plk1 and Aurora A and B. We need to
know which set of proteins are phosphorylated, what their functions are, and how phospho-
rylation changes their activity. Identification of kinase substrates has been hampered by dif-
ficulties in mapping phosphorylation sites, in experimentally controlling protein kinase activ-
ity, and in evaluating the physiological consequences of defined phosphorylation sites. The
premise behind MitoCheck is that all three hurdles can be overcome by new technologies,
namely the use of RNA interference to identify in systematic (functional genomics) manner
potential substrates, iTAP-tagging to purify protein complexes, small molecules to inhibit
specific kinases in a controlled fashion and mass spectrometry to identify phosphorylation
sites on complex subunits. As the concept behind MitoCheck’s project could be applied to
other areas, the projects outcomes have the potential to impact on European cell biology
far beyond the cell cycle community.
The main objective for the MitoCheck team is to understand how mitotic kinases orchestrate
the many events of mitosis.
MitoCheck is carrying out genome-wide RNAi screens in human cells to systematically

search for potential substrates of mitotic kinases. A genome-wide collection of synthetic
small interfering RNAs (siRNAs) is introduced into human cells to deplete the entire 22, 000
human genes one- by- one. The behaviour of the cells after transfection is then recorded by
live cell video microscopy. Genes whose depletion causes mitosis to go awry are crucial
for mitosis.
Regulation of Mitosis by Phosphorylation-
A Combined Functional Genomics,
Proteomics and Chemical Biology Approach
A subset of the proteins crucial for mitosis is currently being tagged with green fluorescent
protein (GFP) and with an affinity purification tag. The GFP tag will allow visualisation of the
subcellular localisation of these proteins during cell cycle, whereas the affinity tag will en-
able the identification of binding partners of these proteins via affinity purification followed
by mass spectrometry. Since the phosphorylation state of these proteins and their binding
partners are thought to be crucial for their function during mitosis, much of MitoCheck’s
efforts will be devoted to identifying the mitosis-specific phosphorylation sites on them by
mass spectrometry and the mitotic kinases responsible for these phosphorylation events.
Some mitotic kinases are over-expressed in human tumours. One important objective of Mi-
toCheck is to develop assays to systematically evaluate the clinical utility of mitotic kinases
as diagnostic or prognostic markers.
Expected Results:
1) A list of mammalian proteins that have important roles during mitosis: This list will be
compiled based on knowledge in the published literature, knowledge obtained in the
MitoCheck labs and, most importantly, data from our genome-wide RNAi screens.
2) Subunit composition of the mitotic protein complexes and their mitosis-specific phos-
phorylation sites: MitoCheck will employ mass spectrometry methods to identify the
binding partners of the selected mitotic proteins, and to map the mitosis-specific phos-
phorylation sites on them. We will further link particular mitotic kinases with specific
phosphorylation sites.
3) Expression profiles of mitotic kinases in tumour samples and the potential of the mi-
totic kinases as diagnostic or prognostic markers in clinical oncology
4) A web-based database: This database will contain important information such as a

list of genes required for mitosis, subunit composition of mitotic complexes and their
phosphorylation sites. Furthermore, the dataset from the genome-wide RNAi screens
will also be displayed in the future. This dataset includes a wide range of cellular
phenotypes, mitotic and non-mitotic. The MitoCheck database will therefore be a
unique and highly valuable source of information, not only for the cell cycle field but
also for many other areas in the life sciences.
Potential Impact:
In order to gain insight into how cell division is controlled by phosphorylation, MitoCheck
is developing a variety of genomic, proteomic and chemical approaches. Besides cell
division, protein phosphorylation is also essential in many other biological processes such as
Normal rat kidney cells in

different stages of cell division
stained for chromosomes (blue)
microtubules (green) and actin
(red). (Courtesy of Dr. Jan
Ellenberg, EMBL/Heidelberg)
© Dr. Jan Ellenberg, EMBL/
Heidelberg
MITOCHECK
signal transduction, gene expression and

cellular differentiation. Abnormalities in
protein phosphorylation pathways can
contribute to human diseases such as
cancer. The technologies MitoCheck is
establishing will therefore have an impact
on other research areas, far beyond cell
cycle field.
Although MitoCheck focuses on basic

research, it will also foster innovations
in applied research. In some cases it
may lead to new commercial products.
For example, MitoCheck is developing
biological assays for measuring both
the amount and the activity of protein
kinases in human biopsy material. These
methods may be useful as diagnostic
and prognostic assays in cancer therapy, where novel “biomarker” assays are urgently
needed to tailor therapies to the specific needs of patients.
The potential impact of MitoCheck in the area of product development is reflected by

the participation of both a small biotech company (Gene Bridges GmbH) and a large
company (Leica Microsystems CMS GmbH). Leica is one of the world’s leading bio-
optical manufacturers. It is expected that novel software tools developed by Leica as part
of the MitoCheck project will be introduced to the market soon.
Last, but not least, a unique strength of MitoCheck is its integration of leading experts from
many disciplines ranging from optical engineering to high throughput genomics, from
chemical biology to protein crystallography, and from bioinformatics to human pathology.
This unusual diversity of expertise helps to foster innovation in technology development. It also
creates opportunities for basic research that may lead to unforeseen important discoveries.
Regulation of Mitosis by Phosphorylation -
A Combined Functional Genomics, Proteomics and Chemical Biology Approach
Keywords: mitosis, phosphorylation, RNAi, mass spectrometry, chemical

inhibitors, cancer, chemical biology, proteomics, functional genomics,
regulation, cell cycle
Partners
Project Coordinator: Prof. Tim Hunt
Dr. Jan-Michael Peters Cell Cycle Control Laboratory
Forschungsinstitut für Molekulare Pathologie GmbH Clare Hall Laboratories, Cancer Research UK
Dr. Bohrgasse 7 South Mimms, UK
1030 Vienna, Austria
peters@imp.univie.ac.at Dr. Kai Stoeber
Project Manager: Wolfson Institute for Biomedical Research
Dr. Yan Sun London, UK
Forschungsinstitut für Molekulare Pathologie GmbH
Dr. Bohrgasse 7 Dr. Richard Durbin
1030 Vienna, Austria Wellcome Trust Sanger Institute
sun@imp.univie.ac.at Hinxton, UK
Dr. Jan Ellenberg

Gene Expression and Cell Biology
Biophysics Programmes
Heidelberg, Germany
Prof. Dr. Roland Eils

Theoretical Bioinformatics
Heidelberg, Germany
Frank Sieckmann
Leica Microsystems CMS GmbH
Mannheim, Germany
Prof. Dr. Tony Hyman

Max Planck Institute of Molecular Cell Biology
and Genetics (CBG)
Dresden, Germany
Gary Stevens
Gene Bridges GmbH
Heidelberg, Germany
Dr. Andrea Musacchio

European Institute of Oncology
Department of Experimental Oncology
Milan, Italy
Dr. Ariane Abrieu

Centre de Recherche de Biochimie
Macromoléculaire (CRBM)
Montpellier, France
SIGNALLING & TRAFFIC
www.signallingtraffic.com
State-of-the-art:
Project Type: Intracellular communication in eukaryotes is largely achieved by the trafficking of mem-
Specific Targeted branes carrying membrane-bound and/or intravesicular signalling molecules. Inside cells,
Research Project vesicles circulate from one intracellular compartment to another thus facilitating vectorial
transport of signals. Between cells, membrane anchored and secreted soluble molecules
Contract number: mediate extracellular signalling. Exocytosis and endocytosis of receptors control the re-
LSHG-CT-2004-503228 sponse of sensitive cells to extracellular signals. The routes of membrane trafficking are
Starting date: controlled by cell signalling pathways but the underlying molecular machinery is scarcely
1st May 2004 characterised. Moreover, membrane trafficking has been studied mainly in differentiated
cells and rarely in cells changing phenotype during differentiation or dedifferentiation. Such
Duration:
drastic phenotypic changes occur during development when cells mature to differentiated
43 months cells as complex as neurons, and during malignant transformation.
EC Funding:
`1 600 000
The goal of this STREP is to establish the connections between signalling pathways and mem-
brane trafficking in the context of migrating, dividing and adhering mammalian cells. Through
the study of membrane traffic in the course of cell differentiation, dedifferentiation, and dur-
ing mitosis, we aim to unravel how important signalling pathways remodel the intracellular
trafficking routes and conversely, how membrane traffic can influence signalling cascades.
We will take advantage of several cellular models including neurons differentiating in culture
and cancer cells dividing and migrating. We will investigate proteins that play central roles
in membrane trafficking and secretion such as rabs, SNAREs and their partners. We will
focus on the trafficking of signalling molecules including cell-cell and cell-substrate adhesion
molecules, growth factors and their receptors, and also investigate the role of glycosylation.
Through these approaches we will define the connections between Signalling and Traffic.
Using modern cell biological approaches, the SIGNALLING & TRAFFIC consortium will study
several cellular models, including neurons differentiating and establishing contacts in culture,
and cancer cells dividing and migrating. It will investigate proteins that play central roles in
membrane trafficking and secretion — such as Rabs, SNAREs and their partners — some of
which have already been linked to cancer and brain related diseases. It will also focus on the
trafficking of signalling molecules, including cell-cell and cell-substrate adhesion molecules,
growth factors and their receptors.
In the case of cancer, the goal is to shift the therapeutic emphasis (at least for some tumours)
from surgical to pharmacological interventions, thereby reducing hospitalisation costs as well
as the financial, psychological and physical burden on patients and their families. In the case
of neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases and neuropa-
thies, there is an urgent need to identify effective therapies. This will depend on advances in
knowledge concerning the physiopathological links between gene defects and symptoms.
The project’s results will be disseminated through congresses, workshops and publications,
and in classes in the partners’ universities. Its website will represent the hub of a communica-
tion network, intended to attract both students working in relevant academic fields, and the
general public.
Expected Results:
A number of results have already been reported by members of the consortium: (1) Tetanus
neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and cell adhe-
sion; (2) Expression of the cell adhesion molecule L1 augments cell motility, invasiveness
and tumour growth in vivo; (3) Recycling of pro-transforming growth factor alpha regulates
the activation of the epidermal growth factor receptor (EGFR), opening up the possibility
that defects in trafficking may contribute to the development of tumours; (4) Two different
Signalling and Membrane Trafficking
in Transformation and Differentiation
pathways exist for the internalisation of the EGFR; (5) The Rab6A’ GTPase enzyme is re-
quired for the metaphase/anaphase transition in mitosis; (6) Crosstalk exists between the
actin-remodelling signalling pathway, activated by platelet-derived growth factor stimula-
tion of cells, and endocytosis.
Potential Impact:
The intention of SIGNALLING & TRAFFIC is to open up new avenues in the development of
molecular diagnostic and therapeutic tools for diseases demonstrating a membrane trafficking
and/or signalling component. This will be relevant to a range of pathologies, from cancer
and proliferative non-neoplastic diseases, to neurodegenerative diseases and neuropathies.
Cancer and brain-related diseases are major causes of death in Europe and they represent
a large socioeconomic burden and an increasing challenge in Europe’s increasingly ageing
population. SIGNALLING & TRAFFIC is designed to develop new therapies and new diag-
nostic tools, ultimately leading to improvements in health and quality of life for the European
population.
Keywords: Signalling, membrane trafficking, cell division, cell migration,

cell adhesion
Partners
Project Coordinator: Dr. Bruno Goud Dr Jonathan Dando
Prof. Thierry Galli Centre National de la Inserm-Transfert
Institut Jacques Monod Recherche Scientifique (CNRS) Dept International and European Affairs
Team ‘Avenir’ INSERM Institut Curie Paris, France
2 Place Jussieu UMR 144
75005 Paris, France Paris, France
thierry@tgalli.net
Prof. Peter Altevogt

German Cancer Research Centre
Tumour Immunology Programme
Heidelberg, Germany
Dr. Joaquín Arribas

University Hospital Research Institute
Medical Oncology Research Programme Prof. Jacqueline Trotter
Barcelona, Spain Johannes
Gutenberg-Universität
Dr. Júlia Costa Interdisciplinary Centre
Instituto de Tecnologia Química for Neurosciences
e Biológica Mainz, Germany
Laboratory of Glycobiology
Oeiras, Portugal Dr. Letizia Lanzetti
Institute for Cancer
Prof. Pier Paolo Di Fiore Research and Treatment
FIRC Institute of Molecular Oncology Division of Molecular
Foundation Angiogenesis
Milan, Italy Turin, Italy
TransDeath
State-of-the-art:
Project Type: Apoptosis is controlled by multiple pathways, which include extrinsic signalling via death
Specific Targeted receptors, and by intrinsic pathways involving the mitochondria and endoplasmatic reticu-
Research Project lum. These inputs activate proteolytic caspase cascades and subsequent cell death. Pro- and
anti-apoptotic Bcl-2 family members are important in controlling mitochondrial signals, in-
Contract number:
cluding cytochrome c, whose association with the downstream regulator Apaf-1 and pro-
LSHG-CT-2004-511983 caspase-9 forms the apoptosome that mediates caspase activation. Although homologs of
Starting date: the apoptotic machinery are not found in plants and lower eukaryotes, comparative phylo-
1st December 2004 genetic analysis of the domains conserved in these proteins indicates that they existed in the
common ancestor of animals, plants, and fungi. These ancient domains were, and in some
Duration:
cases still are, components of ancestral signalling pathways for responses to pathogens and
36 months stresses, including starvation and DNA damage.
EC Funding: A goal of the Transdeath program is to understand the mechanistic relations between extant
`2 500 000 PCD programmes in different organisms. For example, plant leaves senesce at the end of
growth seasons. How is this developmental form of PCD related to the more rapid PCD
induced during the plant hypersensitive response to pathogens?
Transdeath aims to define (phenomenologically and molecularly) dis-
tinct types of cell death by using models appropriate for each type of
death. A main focus of the project is the research on the less studied cell
death types, which are caspase-independent and non-apoptotic. These
mechanisms will then be used to understand corresponding types of cell
death in mammals, in particular humans.
The general lines of inquiry followed in the WorkPackages (WPs) in-
clude: analysing distinct types of cell death in their respective optimal
model(s); comparing cell death types within and between these models;
and extending the study to corresponding cell death types in humans.
The project has five scientific WPs. WP1 (Bioinformatics & Database)
identifies genes of interest for experimental WPs, and provides a hub
for data used to develop gene-silencing experiments. WP2 (Apopto-
sis) uses phylogenetic comparison to elucidate apoptotic functions of
proteins involved in human diseases. WP3 (Autophagic PCD) aims to
identify and analyse phylogenetically conserved pathways, subcellular
events, and molecular mechanisms involved in autophagic/vacuolar
cell death by using the most amenable models.
Death in the mold – Top - during
fruiting body development in the WP4 (Necrosis & other PCD) analyses necrotic/non-apoptotic cell death using methodolo-
social amoeba Dictyostelium, cells gies in diverse model systems. This strategy permits the analysis of aspects of non-apoptotic
of the stalk under programmed cell death from different angles and in organisms of increasing complexity. This vertical
cell death. Bottom - cultured cells approach has the potential to reveal points of convergence for the underlying mechanisms
can be induced to die and are that would otherwise go unnoticed.
used to study this process.
Expected Results:
The Transdeath project will potentially provide cutting-edge tools and resources for the
European and international scientific community, and additionally nucleate a larger pan-
European network of laboratories aimed at exploiting these tools and resources to model
human diseases and to address gene function. Both of these objectives are immediately
relevant to the improvement of human health and quality of life.
Programmed cell death
across the eukaryotic kingdom
The partners are expected to identify all well-conserved and poorly-conserved eukaryotic
homologs of cell death genes, and construct phylogenetic trees for all families. Further-
more, the team will identify potentially missing family members, and establish a function-
ing, basic web platform for data exchange between partners.
Potential Impact:
The results of Transdeath will be useful to the scientific community at large by making
diverse PCD genes and models attractive and accessible platforms to study genes and
biological phenomena of particular importance to biomedicine. These developments will
bridge the gap between development and progress in the United States with European Death Suppressor Screen –
research on PCD in model organisms and biomedicine.
A mutant, transgenic plant in
The project will signify a major achievement in terms of consolidating the fragmented which death can be chemically-
European PCD research base, strengthening the European model organism research com- induced was used to screen
munity and laboratories, and providing new opportunities for European biomedical and ~3 million progeny for secondary
biotechnology interests to acquire intellectual property. mutations that suppress death.
The corresponding genes encoding
death activators are now being
Keywords: apoptosis, bioinformatics, cancer identified.
Partners
Prof. John Mundy
Institute of Molecular Biology
Norregade 10
1017 Copenhagen, Denmark
mundy@adm.ku.dk
mundy@my.molbio.ku.dk
Prof. Kai-Uwe Fröhlich Dr. Nektarios Tavernarakis

University of Graz Foundation for Research
Institute of Molecular Biosciences and Technology Hellas
Graz, Austria Institute of Molecular
Biology and Biotechnology
Dr. Corinne Clavé Heraklion, Greece
Scientifique (CNRS) IBGC-UMR 5095 Prof. Adi Kimchi
Unit with U. Bordeaux 2 Weizmann Institute
Bordeaux, France of Science
Rehovot, Israel
Dr. Pierre Golstein
Centre National de la Recherche Prof. Roberto Testi
Scientifique (CNRS) CIML-UMR 6102 University of Rome
Unit with INSERM & U. Aix-Marseille II ‘Tor Vergata’
Marseille, France Department of
Experimental Medicine
Dr. Guido Kroemer Rome, Italy
Scientifique (CNRS) IGR-UMR 8125 Prof. Jonathan Jones
Unit with INSERM & U. Paris XI The Sainsbury Laboratory
Paris, France Norwich, UK
Peroxisomes
www.peroxisome.eu

Integrated Project
Contract number: Peroxisomes are single, membrane-bound organelles that are present in virtually all eu-
karyotic cells. In mammals, the size, number and protein content of peroxisomes vary
LSHG-CT-2004-512018
significantly, depending on the cell and tissue type as well as on the developmental and
Starting date: physiological stage in question. Consequently, peroxisomes are considered to be multi-
1st January 2005 purpose organelles.
Duration:
48 months In humans, impairments of these multiple functions lead to different peroxisomal disorders
EC Funding: which can be divided into two groups. The first of these are peroxisome biogenesis disor-
ders (PBDs), which are caused by a generalised or multiple loss of peroxisomal function due
`8 000 000
to a defect in the formation of the organelle. Many PBDs were named before their associa-
tion with the organelle was recognised. These include Zellweger syndrome (ZS), neonatal
adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondrodysplasia punc-
tata. The second group of disorders is caused by a single peroxisomal enzyme deficiency.
Although they are essential for life, the various functions and dynamics of peroxisomes in
health and disease are poorly understood. Most inherited peroxisomal disorders in humans
have a low incidence, but collectively they represent an enormous burden on affected
individuals, their families and society. At present, the number and nature of peroxisomal
matrix proteins are unknown. Each year, several novel peroxisomal matrix proteins are dis-
covered, and the number of metabolic pathways known to exist within peroxisomes, grows.
Evidence is now emerging that peroxisomes play a role in modulating diseases of complex
inheritance, such as arteriosclerosis, cancer and Alzheimer’s disease (AD).
Using cutting edge proteomics tools, the Peroxisomes consortium will identify and charac-
terise the functions of novel peroxisomal proteins, and establish a catalogue of peroxiso-
mal matrix proteins in human liver, kidney and brain. In parallel, it will characterise and
catalogue the mouse peroxisomal proteome in liver, kidney and brain, in order to gain a
deeper understanding of species differences - the basis for a more accurate interpretation
of existing mouse models of peroxisomal diseases.
The consortium will also evaluate the role of peroxisomes as modulators or modifiers of
diseases of complex inheritance, such as AD and cancer. Tissue microarray analysis, cDNA
chip and quantitative RT-PCR analysis will be used to verify the results, with the final goal of
developing improved diagnostic and prognostic tools for these disorders.
Many of the functions affected by peroxisomal disorders are related to processes which
take place at the peroxisomal membrane. A complete catalogue of peroxisomal membrane
proteins in mouse and man will contribute to our understanding of what kind of metabolites
are transported across this membrane, how peroxisomes import proteins and lipids, and
how the organelles divide and are transmitted to a new cell. The distinction between matrix
and membrane-localised proteins is based mainly on technical considerations. As mem-
brane proteins are notoriously under-represented in conventional proteomic approaches,
the consortium will apply state-of-the-art techniques for membrane isolation.
Integrated Project
to decipher the biological function
of peroxisomes in health and disease
Expected Results:
Almost all peroxisomal diseases are as-
sociated with childhood pathology. Most
of them are incurable, and lead to death
before the first decade. The Peroxisomes
consortium’s fundamental studies on the
role of peroxisomes, should shed light on
the pathogenesis of these devastating dis-
eases, and may lead to novel treatment
regimens for them. It is clear that the ex- Plasmalogen-deficient knockout
pertise brought together by this proposal mouse showing eye defects
will drive significant advances in this and cataract
area. The consortium will also create and
apply novel tools, including peroxisomal
membrane anchor proteins for affinity
purification of peroxisomes from different
sources and tissues, transgenic animals
permitting the regulated inactivation of
peroxisomal function in distinct tissues
only, and an automated tissue microar-
rayer. Finally, by means of this joint ef-
fort, it should be possible to decipher the Peroxisomes visualised as
molecular mechanisms of so far unchar- dark granules by catalase
acterised peroxisomal disorders, thereby immunostaining in human fetal
creating novel diagnostic and therapeutic renal cortex
opportunities.
Potential Impact:
The motivation for this project was
the realisation that peroxisomes have
remained an ill-defined subcellular
organelle for years, even though they Peroxisomes visualised as
are known to be essential for life, as is dark granules by catalase
clearly demonstrated by the devastating immunostaining in human
consequences of the absence of fetal liver
peroxisomes in patients affected by ZS.
Lack of knowledge about peroxisomes
is a serious obstacle to determining their
true significance in health and disease,
and to designing effective diagnostic and
therapeutic strategies for such diseases.
Some peroxisomal disorders, such as

ZS, have a rapid, lethal course, causing Cytochemical incubation for
death in the first year. Patients with other catalase activity in mouse
types of peroxisomal disorders, however, renal cortex (proximal tubule)
may survive for long periods with severe revealing peroxisomes as
electron-dense organelles
PEROXISOMES
handicaps which require chronic

treatment and care, often in special
institutions for mentally retarded
people. This is obviously costly to
society, but it also imposes an enormous
emotional and psychological burden
on the families affected. Clearly,
increasing knowledge about the
biological role of peroxisomes could
reduce that burden, if it leads to
therapeutic advances. Moreover,
A molecular model of part many patients with a likely defect of
of the structure of the (3R)- peroxisomal function currently remain
hydroxyacyl-CoA dehydrogenase undiagnosed. If this project leads
of human peroxisomal MFE-2 to improvement in the diagnosis of
showing two residues, Val218 peroxisomal disorders, such patients
and Trp273, whose mutation to will benefit from a more rapid and
other residues causes dysfunction more accurate diagnosis, which will
of the enzyme in humans in turn mean they can then be treated
appropriately.
Keywords:
peroxisome, genomics, proteomics,
human diseases, diagnosis, therapy,
mouse models
Fluorescent image of peroxisomes
Morphometry of peroxisomes
in normal mouse liver
Integrated Project to decipher the biological
function of peroxisomes in health and disease
Partners
Project Coordinator: Prof. Kalervo Hiltunen
Prof. Johannes Berger University of Oulu
Centre for Brain Research Biocenter Oulu and Department
Medical University of Vienna of Biochemistry
Spitalgasse 23 Oulu, Finland
johannes.berger@meduniwien.ac.at Prof. Stefan Alexson
Prof. Ron Wanders, Dr. Antoine van Kampen Department of Medical Laboratory
Academic Medical Centre Sciences and Technology
Amsterdam, The Netherlands Stockholm, Sweden
Prof. Myriam Baes Prof. Gerald Hoefler

Catholic University of Leuven Medical University Graz
Laboratory of Clinical Chemistry Institute for Pathological Anatomy
Leuven, Belgium Graz, Austria
Prof. Ralf Erdmann, Prof. Helmut Meyer Prof. Marc Espeel

Ruhr-Universität Bochum University of Gent
Bochum, Germany Department of Anatomy, Embryology
Histology and Medical Physics
Prof. Wilhelm Just Ghent, Belgium
Universität Heidelberg
Biochemie-Zentrum der
Universität Heidelberg
Heidelberg, Germany
Prof. Andreas Hartig

University of Vienna
Vienna, Austria
Prof. Norbert Latruffe

Université de Bourgogne
Laboratoire de Biologie
Moléculaire et Cellulaire
Dijon, France
Prof. Klaus-Armin Nave

Experimental Medicine
Department of Neurogenetics
Göttingen, Germany
Dr. Annamaria Cimini

University of L’Aquila
Department of Basic and
Applied Biology
Coppito, Italy
Prof. Jorge E. Azevedo

IBMC-University of Porto
Instituto de Biologia Molecular e Celular
Porto, Portugal
DNA Repair
www.dna-repair.nl

Integrated Project
Contract number: Understanding the pleiotropic effects of the time-dependent erosion of the genome, and
the complexity of cellular responses to DNA damage, requires a comprehensive, multi-
LSHG-CT-2005-512113
disciplinary approach ranging from molecule to patient. At the level of structural biology
Starting date: and biochemistry, the DNA Repair consortium will analyse individual components and path-
1st May 2005 ways, to identify new components and clarify reaction mechanisms. The interplay between
Duration: pathways and crosstalk with other cellular processes will be explored using biochemical
48 months and cellular assays.
EC Funding:
To better understand the function and impact of DNA damage response and repair systems
`11 500 000
in living organisms, the DNA Repair consortium will take full advantage of its unique and
extensive collection of models (mutant yeast cells and mice), to engineer and analyse new
mutants whose genome stability is impaired. The latest genomic and proteomic technolo-
gies will be exploited to identify novel genes involved in genome surveillance. Bioinformat-
ics, high throughput gene expression analysis and proteomics will be used to identify the
putative functions of these genes and their proteins.
Similar global genome analytical tools

will be used to identify interactions with,
and effects on, other cellular processes.
The ‘druggability’ of potential targets, in
Figure 1. DNA repair proteins at the context of anti-cancer therapies, will
work. Treatment of cells with be tested in collaboration with SMEs.
ionising radiation can result in Through its existing contacts with clini-
cell death because the irradiation cians, the consortium will continue to ana-
introduces breaks in the DNA. lyse patients with previously identified de-
DNA repair proteins counteract fects in DNA damage response and repair
the lethal effect of irradiation mechanisms, and will also screen patients
by restoring the integrity of the for new disorders.
DNA. After irradiation the DNA
repair proteins are organised into
clusters, called foci, at sites of Scientific/
repair. This dynamic relocalisation
can be visualised in living cells Technological
by fusing DNA repair proteins to
a naturally fluorescent protein. Objectives:
The cells in the image have been
irradiated and foci containing the The study of the vast problem of DNA
repair protein become visible. damage requires an integrated, multidis-
ciplinary approach. European research
teams have played a prominent role in increasing understanding of individual pathways
involved in this phenomenon, but many challenges remain, including the following: (1) Un-
derstanding the complex interplay between the various genome stability systems, and plac-
ing the pathways which have already been described into an integrated cellular context;
(2) Gaining insight into the clinical impact of the systems, both individually and collectively,
from the cellular level to that of intact organisms and the human population; (3) Translat-
ing this knowledge into practical applications in the form of improved diagnosis, effective
therapy and prevention or postponement of diseases associated with the functional decline
of the genome.
DNA Damage Response
and Repair Mechanisms
Figure 2. Accumulation of the

Mre11 DNA repair complex
Expected at sites of DNA double-strand
breaks (DSBs). The left panel
Results: shows a cell immunostained for
the Mre11 complex (in green)
DNA Repair expects to produce at DSBs. The linear arrangement
the following results: of the DSBs is caused by the
1) A detailed understand- passage of an α-particle through
ing of the biochemical the cell (DNA shown in blue).
mechanism of DNA The length of the linear track is
repair and checkpoint about 10 μm. The panel on the
pathways; right shows the archtitecture
2) Insight into the cellular functioning and consequences of defects in one of the ge- of the Mre11 DNA complex as
nome surveillance pathways; determined by Atomic Force
3) Identification of new components of DNA damage response pathways; Microscopy. The arms protruding
4) Extrapolation of findings from model organisms to humans. The expected results from the globular domain are 50
will be accomplished firstly by the investigation of patients and cells from patients nm in length.
suffering from genome instability, cancer predisposition and premature ageing syn-
dromes, and secondly by an extensive comparison of mouse mutants with these
human conditions.
Potential Impact:
Our DNA is constantly under attack from physical and chemical agents that compromise
its integrity and represent a threat to genomic stability, potentially resulting in cancer and
other health problems. A large number of chemical compounds in food have a potentially
harmful influence on human genetic make-up, especially under conditions in which the DNA
repair capacity is sub-optimal.
The proposed research will be im-

portant for assessing potential risks
posed by environmental hazards
(such as food components and envi-
ronmental pollutants). A better under-
standing of genome-wide responses
to genotoxins, in relation to the DNA
repair status of an organism, will en-
able the evaluation of possible risks
to consumer health and contribute to Figure 3. Chromosomal
the eventual elimination of identified aberrations, associated with
toxins. carcinogenesis, induced by
interstrand crosslink (ICL)-
The consortium’s genomics and inducing agents. In the absence
proteomics approaches could also of the Ercc1/Xpf DNA repair
be applied to the assessment of the protein ICLs cause numerous
health risks of such compounds for chromosomal aberrations, most
specific sub-groups who carry subtle notably fusion of chromatids.
mutations in DNA repair genes, and Shown is a metaphase spread of
for the ageing population. an Ercc1/Xpf deficient Chinese
ovary hamster cell line.
DNA REPAIR
Keywords:
genome (in)stability, cancer, ageing, molecular biology, genomics, proteomics, human dis-
ease, DNA damage, DNA repair mechanisms
Partners
Prof. Jan Hoeijmakers
Erasmus Universitair Medisch
Centrum Rotterdam
Dept. of Cell Biology and Genetics
‘s Gravendijkwal 230
3015 CE Rotterdam, The Netherlands
j.hoeijmakers@erasmusmc.nl
Project Manager:
Dr. Rini de Crom
Erasmus Universitair Medisch
Centrum Rotterdam
Dept. of Cell Biology and Genetics
‘s Gravendijkwal 230
3015 CE Rotterdam, The Netherlands
dna.repair@erasmusmc.nl
m.decrom@erasmusmc.nl
Prof. Roland Kanaar, Dr. Wim Vermeulen

Dr. G.T.J. van der Horst
Erasmus Universitair Medisch Centrum Rotterdam
Department of Cell Biology and Genetics
Dr. Stephen West, Dr. Jesper Q. Svejstrup

Cancer Research UK
Genetic Recombination Laboratory
London, UK
Prof. Jiri Bartek, Dr. Jiri Lukas

Danish Cancer Society
Institute of Cancer Biology and
Centre for Genotoxic Stress Research
Copenhagen, Denmark
Prof. Karl-Peter Hopfner

University of Munich
Gene Centre
Munich, Germany
Prof. Stephen P. Jackson

Wellcome Trust/Cancer Research
UK Gurdon Institute
Cambridge, UK
DNA Damage Response and Repair Mechanisms
Prof. Josef Jiricny Dr. Graeme C. M. Smith, Dr. Mark O’Connor

University of Zürich KuDOS Pharmaceuticals Ltd
Institute of Molecular Cancer Research Cambridge, UK
Zurich, Switzerland
Prof. Alan R. Lehmann,

Prof. Anthony M. Carr, Dr. Penelope A. Jeggo
University of Sussex
Genome Damage and Stability Centre
Brighton, UK
Prof. Hans E. Krokan

Norwegian University of Science
and Technology
Dept. of Cancer Research and
Molecular Medicine
Trondheim, Norway
Prof. Leon H. F. Mullenders

Department of Toxicogenetics
Prof. Marco Foiani

Istituto FIRC di Oncologia Molecolare
(FIRC: Fondazione Italiana per
la Ricerca sul Cancro)
Milan, Italy
Prof. Paolo Plevani

University of Milano
Dipartimento di Scienze Biomolecolari
e Biotecnologie
Milan, Italy
Prof. Magnar Bjørås

Rikshospitalet Oslo
Institute of Medical Microbiology
Oslo, Norway
Prof. Noel Lowndes

University of Ireland
Genome Stability Laboratory
Galway, Ireland
Prof. Jean-Marc Egly

et de la Recherche
Médicale (INSERM)
Université Louise Pasteur
Illkirch, France
STEROLTALK
www.steroltalk.net

Specific Targeted
Research Project Cardiovascular diseases remain one of the major causes of mortality in the developed
world. Dependence between cholesterol levels and mortality and the positive influence of
Contract number:
cholesterol lowering effects are clearly established. Even if statins are still considered as
LSHG-CT-2004-512096 relatively safe drugs, considerable attention is payed to the statin-based risk of muscular
Starting date: adverse drug reactions (ADR). Considering that 5-10% of population in developed societies
1st September 2005 is treated with statins, this represents an important health risk problem. Drugs are gener-
Duration: ally metabolized by the cytochrome P450 (CYP) system. Once bound to nuclear receptors,
36 months drugs modulate the expression of the responsive CYPs, which represents the basis of ADR:
a modulated metabolism of xenobiotics (and enobiotics) that are metabolized by the same
EC Funding:
CYP. Statins are often used in combination with other medications since patients with hyper-
`2 200 000 lipidemia frequently have other medical problems. 60% of statin-related rhabdomyolysis is
attributed to ADR. Post-genomic approaches applied in Steroltalk offer venues to approach
such complex physiological questions that have a great impact on human therapy.
The STEROLTALK multidisciplinary

functional genomics approaches
and models. Human primary
hepatocytes and normal, hyperli-
pidemic and nuclear receptor PXR
and CAR knockout mice were
treated with known and novel
drugs. Transcriptome, limited
proteome and sterol metabolome
have been measured and data
incorporated into the in silico
model, together with the human-
ized yeast data and literature
information. The model is able to
simulate cholesterol homeostasis
and the cholesterol lowering
effect of statins as well as novel
chemical entities. This gives an
insight into the mechanism of
hypolipidemics action.
The vision of STEROLTALK is to develop a global approach by combining dedicated func-
tional genomic tools, three model organisms and in silico modelling, for the discovery of
new drug targets, new chemical entities and therapeutic strategies. Regulatory networks in
human, mouse and S. cerevisiae will be assessed through integrative analysis of transcrip-
Functional Genomics of
Complex Regulatory Networks from
Yeast to Human: Cross-Talk of Sterol
Homeostasis and Drug Metabolism
tome, proteome, metabolome and by yeast engineering. For the first time this will allow
the deciphering of multi-level response of cholesterol homeostasis to known and candidate
drugs, and its modulation in pathologies. Typical investigation targets will be mouse livers
and primary human hepatocytes. The first task of our project is to develop original tools for
functional genomic analyses of drug-modulated responses of STEROLTALK genes, proteins
and metabolites in biological models. Tools include a dedicated microarray, an antibody
set, siRNA knockouts, humanised yeast and a database. Deposited analytical data will be
evaluated by numerous bioinformatic approaches, to assist in building relevant in silico
models with predictive values, ready for implementation in novel drug discovery strate-
gies. These models will allow, for the first time, the identification of potential cholesterol
homeostasis-related targets that will be validated in vivo in biological models by the original
STEROLTALK tools.
Expected Results:
The project STEROLTALK will for the first time undertake a systematic post-genomic evalu-
ation of the cholesterol homeostasis and its cross-talk to drug metabolism and contribute
to understanding the effects/side effects of the hypolipidemic therapy and the combined
therapies. Original functional genomics tools will be developed with focus on the genes,
enzymes and metabolites that are involved in cholesterol homeostasis and in drug me-
tabolism. The Steroltalk tools include dedicated mouse and human Steroltalk microarrays
containing genes of the cholesterol homeostasis and the entire CYP and nuclear receptor
gene families, a structured Steroltalk database, a set of novel Steroltalk antibodies raised
against membrane-bound choelsterogenic enzymes, humanized yeast strains synthetizing
cholesterol, representing novel drug screening tools and predictive in silico models. The
novel tools will be used in combination with commercial tools, to experimentally determine
the cross-talk between cholesterol homeostasis and drug metabolism in drug-treated human
primary hepatocytes and in livers of normal, hyperlipidemic and nuclear receptor-knockout
mice, at the level of transcriptome, proteome and metabolome.
The original tools developed within the STEROLTALK

project. The Steroltalk microarray exists in the human
and mouse version, containing 300 gene of each species.
The Steroltalk database contains protocols used within
the consortium as well as data. It is restricted to access
by Steroltalk partners through a safe web portal. The
Steroltalk antibody set consists of over 20 antibodies.
Some are commercial, some original and raised against
the membrane proteins of the cholesterol homeostasis
and drug metabolism network. The prototype Steroltalk
protein chips and protein maps are under development.
Several humanized yeast strains have been developed
by yeast engineering, synthetizing cholesterol and being
evaluated as novel hypolipidemic drug screening tools.
The first set of data regarding the Steroltalk
transcriptome, limited proteome and sterol metabolome
is available for drug treated mice and human primary
hepatocytes. Novel findings regarding statin and original
hypolipidemics action have been acquired and drug
discovery strategies discussed
STEROLTALK
These data will be interpreted, and when appropriate, also included into in silico models.
The Steroltalk tools and experimental data will together with mathematical models aid in
determining novel correlations and in resolving unknown molecular mechanisms of the cho-
lesterol homeostasis/drug metabolism network.
Potential Impact:
STEROLTALK will compare the effects of clinically approved ‘safe’ statins with novel, non-sta-
tin hypolipidemics, at the levels of transcriptome, proteome and metabolome. This will have
a high impact on understanding the multi-level effects and potential side effects of drugs.
This innovative functional genomic approach, which involves development of original and
dedicated tools, will reinforce the competitiveness in developing new and, for humans, safe
hypolipidemics.
Keywords:
functional genomics, medical pathway modelling, yeast engineering, improved human
health
Functional Genomics of Complex Regulatory Networks from Yeast to Human:
Cross-Talk of Sterol Homeostasis and Drug Metabolism
Partners
Prof. Rita Bernhardt
Saarland University
Campus, Building B2.2
66123 Saarbrücken, Germany
ritabern@mx.uni-saarland.de
Prof. Damjana Rozman

University of Ljubljana
Department of Electrical Engineering
Ljubljana, Slovenia
Dr. Denis Pompon

Centre National de la
Recherche Scientifique
CNRS-CGM
Gif-sur-Yvette, France
Prof. Steven Kelly

University of Wales, Swansea
School of Medicine
Swansea, Wales
Prof. Ingemar Björkhem

Division of Clinical Chemistry
Stockholm, Sweden
Prof. Urs Meyer

University of Basel
Biozentrum
Basel, Switzerland
Dr. Patrick Maurel

de la Recherche Médicale (INSERM)
U632
Montpellier, France
Dr. Katalin Monostory

Chemical Research Center
Budapest, Hungary
Dr. Drago Kuzman

Lek Pharmaceuticals d.d.
Ljubljana, Slovenia
Dr. Andrej Gustin

CREA storitve in svetovanje, d.o.o.
Ljubljana, Slovenia
RUBICON
www.rubicon-net.org

Contract number: Numerous cellular proteins are post-translationally modified by a conjugation of ubiquitin
and ubiquitin-like (UbL) proteins. Among them are cell cycle regulators, tumour suppressors,
LSHG-CT-2005-018683
growth regulators, transcriptional activators and inhibitors, signalling proteins and regula-
Starting date: tory enzymes in key metabolic, replicative and quality control/stress pathways. Membrane
1st January 2006 proteins, which include cell surface receptors, ion channels and ER proteins, are also tar-
Duration: geted by the system. Finally, mutated and denatured/misfolded proteins are specifically
60 months recognized and efficiently removed.
EC Funding:
With this diverse repertoire of substrates it is not surprising that the system regulates a
`12 000 000
broad array of cellular processes inclusive of the following: cell cycle and division, differ-
entiation and development, signal transduction, regulation of transcription, modulation of
the immune and inflammatory responses, intracellular trafficking of proteins, biogenesis of
organelles, morphogenesis of neuronal networks and axon guidance, modulation of cell
surface receptors, ion channels and the secretory pathway, DNA repair, long-term memory,
circadian rhythms, and the cellular stress response and quality control machineries.
Aberrations of the system are implicated in the pathogenesis of human diseases, seen in
many malignancies, neurodegenerative disorders and pathologies of the inflammatory and
immune response. Consequently, a great deal of effort has been channelled into the de-
velopment of drugs, which target the different components of the system, namely enzymes,
substrates and modifiers. One of these drugs is already on the market, while others are in
the pipeline. Within this context, a better understanding of the underlying mechanisms in-
volved in this complex post-translational modifying system has important biological, clinical
and therapeutic implications.
Overview of the RUBICON project
Role of Ubiquitin and
Ubiquitin-like Modifiers
in Cellular Regulation
Malfunctions of the ubiquitin and ubiquitin-related systems are strictly connected to the
pathogenesis of numerous diseases, including cancer and inflammation. Insights into the
role of ubiquitin-dependent pathways in disease development, may ultimately lead to the
identification of novel therapeutic targets. A striking instance of this is the recent finding, on
behalf of network members, of the central role of ubiquitin in DNA repair in yeast, a finding
that impacts crucially on cancer research. This discovery highlights the potential importance
of basic research in the understanding of disease-related processes.
Moreover, the understanding of functional genomics and protein-protein interactions is an

essential prerequisite for rational structure-driven drug design. This is expected to have
an impact on future drug discovery processes, on the competitiveness of pharmaceutical
industries and, ultimately, on the health of the world population. Improved information on
altered signalling pathways and on modifications in the target structure is essential for the
acceleration of the development of a drug. In this sense, it is expected that network research
will lead to patent applications relevant to medical research and, ultimately, to the develop-
ment of new drugs and therapeutic procedures in clinics.
The RUBICON project aims to foster translational research, by bringing together basic sci-
entists, clinicians and biotech SMEs. They will form a communication network that will pro-
vide the industry with new therapeutic avenues, which can be investigated and exploited in
a mutually beneficial manner.
Expected Results:
The RUBICON consortium will substantially enhance the competitiveness of basic European
research on ubiquitin and ubiquitin-like molecules, and explore their role in the regulation
of basic cellular processes. Moreover, the project will promote translational research on
the system’s involvement in human diseases; by acting as a catalyst, it will also encourage
progress, and facilitate further coordination of biotech research enterprises, within this key
area of biomedicine.
The European contribution to the ubiquitin field has been both pioneering and substantial,
and Europe is currently home to some of this field’s world-leading scientific groups. For
many years, research funding for this field has been provided at a national level, and de-
spite the high degree of specialisation, it has resulted in poor dissemination of the acquired
knowledge to new and relevant research areas. RUBICON will overcome this apparent
fragmentation and further the combined efforts of European laboratories, by establishing
collaborative multi-centre research projects.
The “virtual core facilities” of RUBICON will allow all laboratories to access and employ
highly specialised, cutting-edge technology on demand, thus accelerating scientific progress.
The rapid dissemination of such sophisticated methodology is greatly hampered by the high
start-up and maintenance costs, and the lack of specifically trained technical personnel. In
addition, RUBICON will support pre-existing technical platforms created through national
funding, making them available for use on behalf all the partners. RUBICON, through the
development, collection and dissemination of commonly required research tools, will coor-
dinate research activities, eliminate a duplication of effort, and allow for the faster and more
RUBICON
economic use of resources in ubiquitin research. RUBICON will generate new knowledge,
which will be published in specialist journals and presented at international meetings, thus
ensuring the dissemination of the project’s findings to the scientific community. The website,
press releases, media events and seminars in schools will be instrumental in transmitting
discoveries to the general public.
Potential Impact:
RUBICON is expected to have a lasting impact on European research. The training of
research workers in networked laboratories will foster a rich source of young and talented
people, who will enter the academic and industrial spheres where they will continue con-
ducting research and teaching in this area. Collectively, these multi-disciplinary researchers
will contribute to the ongoing effort to make Europe the global leader in this field.
Moreover, interaction with researchers from countries in Eastern Europe, coupled with the
training of young scientists from these countries, will have a long-standing impact on the
European scientific community. As a result, not only will these countries be able to rapidly
attain the highest international standards, but the position of Europe as a competitive par-
ticipant in global science will also be strengthened.
Finally, RUBICON will form research collaborations with SMEs and large pharmaceutical
companies in Europe. An improved understanding of the complementary needs of basic sci-
ence and biomedical companies, will facilitate affiliations and encourage the development
of new drugs for the treatment of human diseases.
Keyword: ubiquitin
Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation
Partners
Project Coordinator: Prof. Martin Scheffner Prof. Yinon Ben-Neriah
Prof. Maria Masucci Universitat Konstanz Hebrew University of Jerusalem
Karolinska Institutet Konstanz, Germany Jerusalem, Israel
Department of Cell and Molecular Biology
Nobels vag 16 Dr. Thomas Sommer Dr Hans Langedijk
17177 Stockholm, Sweden Max-Delbrueck-Centrum Pepscan Systems
maria.masucci@ki.se fuer Molekulare Medizin Lelystad, The Netherlands
Berlin, Germany
Prof. Rene Bernards Dr Henk Viëtor
Netherlands Cancer Institute Prof. Dieter H. Wolf Drug Discovery Factory BV
Antoni van Leeuwenhoek Hospital Universität Stuttgart Abcoude, The Netherlands
Division of Molecular Carcinogenesis Institute of Biochemistry
Amsterdam, The Netherlands Stuttgart, Germany Dr Dominique Thomas
Cytomics Systems SA
Prof. Ger Strous Prof. Pier Paolo Di Fiore Gif-Sur-Yvette, France
Utrecht University Medical Center IFOM Fondazione Istituto Firc
Department of Cell Biology di Oncologia Molecolare Dr Paul Sheppard
Division of Biomedical Genetics Milan, Italy Affiniti Research Products Ltd
Utrecht, The Netherlands (trading as BIOMOL
Prof. Aaron Ciechanover International LP)
Dr Colin Gordon TECHNION - Israel Institute Exeter-Devon, UK
Medical Research Council of Technology
Human Genetics Unit Haifa, Israel Dr Yuval Reiss
Edinburgh, UK Proteologics Ltd
Rehovot, Istrael
Prof. Ronald T. Hay
Dundee, UK
Prof. Ronald Thomas

Dundee, UK
Dr. Anne De Jean

Institut Pasteur
Unité de Recherche Organisation
Nucléaire et Oncogenèse
Paris, France
Dr. Pascal Genschik

Institut de Biologie Moléculaire des
Plantes (IBMP) du CNRS UPR 2357
Strasbourg, France
Prof. Stefan Jentsch

Max-Planck Institute for Biochemistry
Prof. Frauke Melchior

Bereich Humanmedizin der
Georg-August-Universitaet Göttingen
Stiftung Oeffentlichen Rechts
Göttingen, Germany
EndoTrack

Integrated Project
Contract number: Endocytic trafficking plays a more active role in the regulation of polypeptide growth factor
(GF) signalling than was previously recognised. Despite great progress in the description of
LSHG-CT-2006-019050
the endocytic routes and their molecular regulation, the scientific community is far from pos-
Starting date: sessing a complete understanding of the endocytic trafficking of GF receptor (GFR) complexes
1st February 2006 and to what extent their signalling activity requires, and is modulated by, these routes. The
Duration: EndoTrack project aims to fill this gap by gaining a basic understanding of the relationship
48 months between the endocytic transport and signalling activity of GFRs.
EC Funding:
EndoTrack combines leading European interdisciplinary research teams to pursue the follow-
`11 000 000
ing aims:
1) Define the trafficking routes of various GFR complexes in cultured cells with an unprec-
edented degree of precision, combining high-throughput microscopy with automated
image analysis and electrochemiluminescence technology.
2) Define the molecular machinery responsible for this transport using proteomics and
functional genomics approaches, and generate proof of concept that trafficking con-
tributes to GF signalling activity in cultured cells;
3) Integrate the information from cultured cells with in vivo studies in animal model sys-
tems, in particular Drosophila, zebrafish, Xenopus and mouse;
4) Test the relevance of the modulation of endocytic trafficking on signal transduction in
disease model systems;
5) Within four years, the use of knockdown approaches, reporter cell lines and animals,
combined with target validation proprietary technology from biotech SMEs, will pro-
vide a new generation of assays to measure GFR trafficking and signalling. These
assays will lead to the identification of novel key regulatory components and hence,
to a new generation of diagnostic markers and potential targets for modulation of GF
signalling in the treatment of human diseases. EndoTrack’s translational research will
thus strengthen the innovation potential of the European biotech and pharmaceutical
industries.
EndoTrack has twin objectives. The first is to fill a gap in basic knowledge by providing
new insights into how cells transduce extracellular stimuli in the form of polypeptide GFs
to changes in gene expression, exploiting the enormous potential of the spatio-temporal
regulation provided by the endocytic pathway. The second is to develop new concepts that
will lead in future to novel opportunities for therapeutic intervention in human disease. The
results of EndoTrack will be relevant to the treatment of many diseases that are currently ei-
ther incurable or can only be treated inadequately, such as cancer and neurodegenerative
and cardiovascular disorders.
The EndoTrack project is aimed at gaining conceptual advance into the signalling function
of GFs from an unconventional perspective, namely by exploring the role of endocytic traf-
ficking in the modulation of GF signalling. It further aims to translate such basic knowledge
into novel opportunities for the development of a new generation of tools to combat dis-
eases like cancer, cardiovascular, metabolic, infectious and neurodegenerative diseases. To
achieve this ambitious goal, a multidisciplinary action plan carried out by a consortium of
academic groups and SMEs will define the intracellular routes of GFR complexes, identify
Tracking the Endocytic Routes
of Growth Factor Receptor Complexes
and their Modulatory Role on Signalling
selective regulators of trafficking, and provide mechanistic insights into the contribution of
endocytic trafficking to the signalling outcome. The plan will use in vitro, ex-vivo and in vivo
systems. These efforts should result in the proof of principle that it is possible to qualitatively
and quantitatively modify the signal transduction output of a variety of GFs via the modula-
tion of endocytic routes, with predictable consequences at the patho-physiological level.
Expected Results:
After 48 months, EndoTrack will provide:
1) A new generation of cell-based assays tracking the endocytic routes of GFR com-
plexes and the position of signalling components downstream of the GFRs along
these routes;
2) A comprehensive description of the machinery that regulates GFR trafficking along
these endocytic routes;
3) Proof of principle that modulation of trafficking can modulate the signalling output of
GFs;
4) Proof of principle that trafficking modulators are novel potential therapeutic targets
for the treatment of various human diseases.
Schematic diagram of the

endocytic pathway. Various
internalization routes and
internal endocytic compartments
are depicted. The continuous
lines represent experimentally
characterized trafficking routes;
the dashed lines illustrate the
postulated or cell-type specific
transport steps. GEEC, GPI-
anchored protein enriched early
endosomal compartment.
EndoTrack
Potential Impact:
The societal impact of EndoTrack lies in the opportunity it provides to alter the textbook
model of how cytoplasmic cascades transduce proliferation and differentiation signals from
the plasma membrane to the cell nucleus. The current models barely acknowledge the im-
portance of endocytic trafficking routes, and when they do address them, they ignore their
complexity at the subcellular level. Taking advantage of this opportunity implies gaining
novel mechanistic insights into the regulation of signalling pathways, and how these are
integrated in a multi-GF environment with the fundamental principles of cellular organisa-
tion and its overall significance in embryogenesis. Besides enhancing basic knowledge,
advances in this area will also have implications for the treatment of severe diseases result-
ing from dysfunction of signal transduction and gene expression.
The economic impact of the project will be most evident in the middle and long term.
EndoTrack itself will not carry out screening of small molecule libraries to identify novel
potential drug candidates in disease model systems. Nevertheless, by defining new mecha-
nistic principles, it will conduct the groundwork necessary for the development of novel
opportunities for intervention. Specifically, these opportunities are based on the following
deliverables:
1) Development of new cell-based, multi-parameter assays that can be scaled up for
high-throughput screening and will consequently be amenable to the screening of
chemical libraries;
2) Identification of a large number of novel key signalling regulators that can serve as
potential drug targets.
3) The generation of new cellular and animal models systems that recapitulate different
aspects of human disease.
4) Proof of principle for the value of intervention via trafficking regulators to modulate
signalling functions required for normal development and which are altered in hu-
man diseases. Altogether, at the end of the funding period, EndoTrack will deliver not
only new knowledge but also an entirely novel technology platform with the potential
to provide higher efficiency of drug development, hence improved cost effectiveness
of health care and increased competitiveness of European biotech companies.
Knocking down gene expression

of the kinase EEF2K in HeLa
cells via siRNA oligonucleotides
deregulated clathrin-mediated
endocytosis and led to
a different phenotype.
Keywords:
high-throughput screen, high-throughput techniques, cancer metastasis, receptor trafficking,
signalling, endocytosis
Tracking the Endocytic Routes of Growth Factor Receptor Complexes and
their Modulatory Role on Signalling
Partners
Project Coordinator: Prof. Michael Brand
Prof. Marino Zerial Technische Universität Dresden
Max-Planck Institute of Molecular Biotechnology Center
Cell Biology and Genetics Dresden, Germany
Pfotenhauerstr. 108
01307 Dresden, Germany Prof. John Heath
zerial@mpi-cbg.de University of Birmingham
School of Biosciences
Project Manager Birmingham, UK
Dr. Jutta Tatzel
Max-Planck Institute of Molecular Prof. Jim Smith
Cell Biology and Genetics University of Cambridge
Pfotenhauerstr. 108 Wellcome Trust/Cancer Research
01307 Dresden, Germany UK Gurdon Institute
tatzel@mpi-cbg.de Cambridge, UK
Prof. Carl-Phillipp Heisenberg Dr. Carol Murphy

Max-Planck Institute of Molecular Foundation for Research &
Cell Biology and Genetics Technology-Hellas
Dresden, Germany Biomedical Research Institute
University of Ioannina,
Prof. Danny Huylebroeck Ioannina, Greece
Flanders Interuniversity Institute
for Biotechnology (VIB) Dr. Jérôme Pansanel
Department of Molecular and Imaxio SA
Developmental Genetics Lyon, France
Katholieke Universiteit Leuven
Leuven, Belgium
Prof. Carl-Henrik Heldin

Uppsala University
Ludwig Institute for Cancer Research
Uppsala, Sweden
Prof. Christof Niehrs

Department of Molecular Embryology
Heidelberg, Germany
Dr. Marta Miaczynska

International Institute of Molecular
and Cell Biology
Warsaw, Poland
Dr. Ruediger Klein

Max-Planck Institute of Neurobiology
Dr. Jean-Paul Vincent

National Institute for Medical Research
London, UK
AnEUploidy
www.aneuploidy.eu

Integrated Project
Contract number: AnEUploidy is the term used to describe the abnormal copy number of genomic elements
(i.e. when one chromosome set is incomplete). This predisposition is one of the most com-
LSHG-CT-2006-037627
mon causes of morbidity and mortality in human populations. The importance of AnEU-
Starting date: ploidy is often neglected, because its effects only materialise in the embryonic and fetal
1st December 2006 periods. The prototype of extra genomic material is trisomy 21 (Down syndrome), and some
Duration: common microdeletion syndromes are the models of monosomies.
48 months
EC Funding: It is likely that numerous other unknown pathologic conditions (including common pheno-
types) are attributable to segmental aneuploidies. In addition, an extensive variability of the
`12 000 000
copy number of numerous genomic regions has been found to be polymorphic in human
populations. Aneuploidy is related to gene expression perturbation and abnormalities, but
the molecular pathogenesis of the numerous aneuploid disorders is largely unknown.
The project has the ambitious goal of contributing to the understanding of the molecular
basis and pathogenetic mechanisms of aneuploidies. The project proposes to use experi-
mental strategies that will incorporate and take advantage of recent achievements within
this field of research. The project incorporates the following areas of existing research:
1) human genome sequencing,

2) comparative genome analysis,
3) genome variation,
4) mouse transgenesis,
5) technological platforms for transcriptome and genotypic analysis,
6) bioinformatics tools, and
7) systems biology.
The overall goal of this integrated project is to understand the molecular mechanisms of gene
dosage imbalance (aneuploidy) in human
health using genetics, functional genomics
and systems biology. The project will focus
on the following 2 models of aneuploidy:
1) trisomy 21 as the prototype for supernu-
merary copies of a genomic segment, and
2) monosomy for 7q11.23 (Williams-Beuren
syndrome) as one prototype of haploinsuf-
ficiency for a genomic segment.
In terms of looking at specific objectives, the

phenotype of heart defect in the monosomy
22q11 (VCFS) will be used. Furthermore,
certain novel emerging syndromes of aneu-
ploidy and Copy Number Variation (CNV)
will be also used as experimental and dis-
covery models.
Karyotype
AnEUploidy: understanding gene dosage
imbalance in human health using genetics,
functional genomics and systems biology
The specific aims are as follows:

1. To study the phenotypic consequences of gene dosage imbalance in humans at the
cellular and organism level, by focusing on two prototype human model phenotypes:
trisomy 21 (T21, Down syndrome; DS) and the monosomy model Williams Beuren
syndrome (WBS at 7q11.23). We hypothesise that it is feasible to identify a small
number of genes, or even single genes, that are responsible for a given phenotype.
2. To identify and characterise novel microaneuploidy syndromes. Clinically well-de-

fined entities will be used as a starting point for high-resolution analysis of copy
number. In addition, patients with specific syndromes will be selected and screened
for gene dosage alterations, using ultra high-resolution microarrays. The project will
allow the identification of genes and biological pathways potentially involved in new
aneuploidy syndromes. Furthermore, a catalogue of copy number variants (CNVs)
and segmental duplications (SDs) of the human genome will be established in Euro-
peans.
3. To exploit the unique advantages of the mouse embryonic stem (ES) cell as an ex-
perimental paradigm, so as to identify the effects of gene dosage imbalance on the
global transcriptome and proteome. The effects of dosage imbalance on the ability
of pluripotent ES cells to differentiate into lineages that are relevant to human aneu-
ploidy phenotypes, will also be investigated.
The project will focus on two regions of the human genome, which are subject to
gene dosage imbalance: HSA21 and 7q11.23, respectively involved in DS and
WBS. Global transcriptome and proteomics analysis of the cell lines will be per-
formed through specific platforms, and systematic analysis and integration of tran-
scriptome and proteomics data will be carried out.
4. To use a large number of mouse models of aneuploidy
Expected Results:
The AnEUploidy project will result in the identification of genes involved in Down Syn-
drome, Congenital Heart Defect, and of ma-
jor dysregulated pathways in human cells
of Down Syndrome and Williams Beuren
Syndrome patients; functional genomics and
systems biology analysis in Lymphoblastoid
cell lines and isogenic lines will be applied
to this end.
AnEUploidy will also identify new aneuploi-

dy syndromes, assess their clinical signifi-
cance, and develop appropriate diagnostic
methods. In addition, emerging aneuploidy
syndromes will be characterised at a mo-
lecular level, so as to identify key dosage
imbalanced genes. This project will gener-
ate a comprehensive ES-cell line resource
of single-gene and segmental overexpres-
Down Syndrome Karyotype
AnEUploidy
sion, comprising the large

majority of genes within
HSA21 and WBS regions.
Microarray analysis, fol-
lowed by systems biology
analysis, will allow the con-
sequences of dosage im-
balance leading to the pa-
thology of these disorders
to be revealed. The new
mouse models for T21,
HSA22q11.2 deletion syn-
drome and WBS, generat-
ed during this project, will
elucidate the contribution of
different genomic segments
to the complex phenotypes
present in these aneuploi-
dies syndromes.
The AnEUploidy project represents a complementary approach to the identification of

genes involved in Down Syndrome Congenital Heart Defect, and to the identification of
new aneuploidy syndromes. AnEUploidy will result in the characterisation of the functional
role of conserved non-genic sequences, micro-RNAs and HSA21 transcription factors, and
an exposition of their contribution to disease, in the context of dosage imbalance.
Potential Impact:
AnEUploidy has major clinical implications, and countless patients with their support networks
of families and carers, are suffering from its consequences; the results of the project’s outcome
will go some way towards supporting the work undertaken in this field. The impact of the
AnEUploidy project can be summarised as follows:
1. The results of this research could lead to the identification of novel targets for therapeu-
tic interventions.
2. This proposal could ultimately result in diagnostic tests of novel disorders, the identifica-
tion of diagnostic markers, or the improvement of exciting methodologies.
3. All of the above will contribute to the overall improvement of health in Europe. It
should not escape our attention that disorders of aneuploidy in Europe are relatively
more common than in many other countries, owing to the reduction of morbidity and
mortality stemming from infectious diseases, and also because of the increased mean
maternal age (which is a result of better educational and professional opportunities for
women).
Furthermore, the individual component symptoms of trisomy 21, for example, are indistin-
guishable from those of other serious diseases; therefore, research on the mechanisms of those
components will benefit not only aneuploidies, but also memory decline, mental retardation,
autism, epilepsy, diabetes, muscle hypotonia, infertility, immune system deficiencies, leuke-
mias, neoplasias and a very important aspect of the understanding of Alzheimer’s disease.
Keywords: Aneuploidy, gene dosage imbalance, trisomy, monosomy, gene

expression, transcriptome, copy number polymorphisms, mouse
transgenesis
AnEUploidy: understanding gene dosage imbalance in human health using
genetics, functional genomics and systems biology
Partners
Project Coordinator: Dr. Marie-Laure Yaspo Prof. Joachim Klose
Prof. Stylianos Antonarakis Max-Planck Institute Charite-Universitatsmedizin Berlin
University of Geneva of Molecular Genetics Institute for Human Genetics
Faculty of Medicine Chromosome 21 Berlin, Germany
Department of Genetic Medicine Gene expression and regulation
and Development Berlin, Germany Prof. Andrea Ballabio
1, Rue Michel Servet Telethon Institute of Genetics
1211 Geneva, Switzerland Prof. Jiri Forejt and Medicine
Stylianos.Antonarakis@medecine.unige.ch Academy of Sciences Naples, Italy
of the Czech Republic
Project Manager: Institute of Molecular Genetics Prof. Alexandre Reymond
Dr. Jérôme Wuarin Mouse Molecular Genetics University of Lausanne
University of Geneva Medical School Prague, Czech Republic Center for Integrative Genomics
Department of Genetic Medicine Lausanne, Switzerland
and Development Dr Luis Perez Jurado
Jerome.Wuarin@medecine.unige.ch Universitat Pompeu Fabra Dr. Henri Bléhaut
Unitat de Genètica Institut Jérôme Lejeune
Dr. Yann Herault Departament de Ciències Paris, France
Centre National de la Recherche Experimentals
Scientifique (CNRS) Barcelona, Spain Dr. Fabrice Trovero
Immunologie et embryologie moleculaire Key-Obs SA
Institut de Transgenose Prof. Han G. Brunner Paris, France
Orleans, France Radboud Universiteit
Prof. Yoram Groner Human Genetics
Weizman Institute Nijmegen, The Netherlands
Biomedical Research
Department of Molecular Genetics
Rehovot, Israel
Dr. Maria del Mar Dierssen

Centre de Regulacio Genomica (CRG)
Barcelona, Spain
Dr. Jean Maurice Delabar

Université Paris 7
Paris, France
Dr Dean Nizetic
Barts & the London School
of Medicine and Dentistry
Institute of Cell and Molecular Science
London, UK
Dr. Victor Tibulewicz

National Institute for Medical
Research (NIMR)
Immune cell biology
Infection and immunity
London, UK
7.2
TISSUE AND
ORGAN DEVELOPMENT,
HOMEOSTASIS AND DISEASE
NFG
LYMPHANGIOGENOMICS
EuroHear
MYORES
EuReGene
EVI-GENORET
NFG
State-of-the-Art:
Project Type: Neurons are not all the same — many thousands of different classes of neurons, defined by
Specific Targeted a variety of criteria such as morphology, patterns of connectivity, and expression of particular
neurotransmitters and receptors, serve as the cellular building blocks of the brain. Each of
Research Project
these neuronal types has a specific physiological role in brain function. Neurological and
Contract number: psychiatric diseases target particular neurons or neural circuits. The brain is a natural mosaic
LSHG-CT-2003-503221 of a large variety of different cell types and a combined approach is necessary in order to
Starting date: describe them fully. Northern blot analysis, RT_PCR amplifications and cDNA microarraya-
1st January 2004 nalysis allow rapid testing of many genes, but lack spatial resolution. One promising alterna-
tive is to tag individual genes in transgenic animals using a marker such a green fluorescent
Duration: protein (GFP), thereby revealing their pattern of expression in vivo. Not only does this tech-
48 months nique reveal cell morphologies with high resolution, it also allows particular cell types to be
EC Funding: harvested for molecular analysis. The complexity of brain cell types and circuits is reflected
`1 849 600 in the complexity of gene expression patterns in the brain. It is not yet known how many cell
types are in the brain, but it seems likely that a classification of neuronal types based on gene
expression, will reveal many more neuronal subtypes than can be recognized with traditional
electrophysiological and morphological methods. Therefore, a proper classification cannot
be obtained through the exclusive use of anatomy and electrophysiology.
The most efficient approach is to start mapping transcription factors for individual neurons:
they may provide powerful markers for adult cell types and neural development. It is likely that
a specific combination of transcription factors will determine many cellular properties, both
morphological and electrophysiological, i.e. excitability, connectivity and synaptic properties.
A cellular list for the nervous system is a powerful resource, not only for understanding the
development of the nervous system, but also for understanding brain functions.
There will be three milestones involved in this process:
1) Objective one focuses on delivering the first cDNA chips; developing the technique
of single cell gene profiling; in part WKP 1 and 2 of the project are transferred to the
electrophysiological laboratories.
2) This objective will ascertain whether preliminary experiments of gene expression
profiling have been performed in specific parts of the project; whether specific tasks
have been carried out; and lastly, whether the technique for the selective ablation of
specific neuronal populations is working.
3) At this point, NFG will further assess whether the characterisation of sensory, cortical
and hippocampal neurons combining gene profiling, electrophysiology and mor-
phology has been effectively obtained, and if real advancements towards the main
objectives of the project have occurred.
Expected Results:
Functional genomics tools will be developed. This technological development consists of the
construction of cDNA arrays, and of the optimisation of the procedure to harvest mRNA
from single neurons, and for global amplification of single cell cDNA.
Using the tools developed within the project it will be possible to examine the gene expres-
sion profile from single neurons identified either by their morphological or their electrophysi-
ological characteristics. Such data enable the identification of gene abundantly expressed
in particular classes of neurons, which can be used as markers. Having identified these
markers, transgenic mice will be constructed using BAC technology, in order to specifi-
cally label particular cell types with a fluorescent label, whose expression will be identical
Functional Genomics of the Adult
and Developing Brain
to the cell-specific marker. When specific neuronal populations have been marked with a
fluorescent label, they are selected by FACS, and can also be tagged with a toxin whose
expression is driven by a promoter specific to the identified neuron of interest, allowing
selective ablation of that neuronal population. This technological development is carried
out in a coordinated way in Cambridge, Trieste and Tokyo, and additional groups are per-
forming the electrophysiological experiments of the present project. Part of the NFG project
is dedicated to understanding the relation of sensory transduction and gene expression in
olfactory sensory neurons and photoreceptors.
Potential Impact:
NFG plans to answer questions relating to basic functional properties of the genome in
olfactory sensory neurons and photoreceptors. The project’s findings will impact our knowl-
edge of the links between gene expression and sensory adaptation. Furthermore, it will
improve our understanding of existing and potentially new cell types in the cortex, based
on expression patterns using cortical neurons. Finally, NFG’s research into the hippocam-
pus will be aimed at elucidating the links between gene expression in identified neurons,
and changes in their electrical and functional properties during the major changes associ-
ated with mammalian development. These developments are expected to further enhance
research efforts in the area of brain function, and potentially establish a clear European
advantage in this field.
Keywords: functional genomics, genetics, DNA chips, development, brain

Partners
Prof. Anna Menini Dr. Simona Capsoni
SISSA (Scuola Internazionale LLG (Lay Line Genomics)
Superiore di Studi Avanzati / Rome, Italy
International School for Advanced Studies)
Neurobiology Sector
via Beirut 2-4
34014 Trieste, Italy
menini@sissa.it
Prof. Hugh Robinson, Dr. Frederick Livesey

Cambridge, UK
Dr. Richard Miles

0224 Cortex et Epilepsie
Paris, France
Dr. Piero Carninci

RIKEN (The Institute for the Physical
and Chemical Research)
Wako, Saitama, Japan
LYMPHANGIOGENOMICS
www.lymphomic.org

Integrated Project
Contract number: The lymphatic vasculature is essential for the maintenance of fluid balance in the body, for
immune defence and for the uptake of dietary fat. Absent or damaged lymphatic vessels
LSHG-CT-2004-503573
may lead to lymphoedema, a chronic and disfiguring swelling of the extremities which
Starting date: sometimes necessitates the amputation of affected limbs. In addition, lymphatic vessels
1st May 2004 promote metastatic spread of cancer cells to distant organs, a leading cause of death in
Duration: patients with cancer and a major obstacle to the design of effective cancer therapies. The
60 months lymphatic vessels were identified hundreds of years ago, yet their development and func-
EC Funding: tion, and the molecular mechanisms underlying their role in disease processes is in effect,
poorly understood.
`9 000 000
The aim of this project is to discover novel genes that are important for lymphatic vascular
versus blood vascular development and function, and to study the functional role and thera-
peutic potential of their gene products in lymphangiogenesis, using state-of-the-art technolo-
gies. The methods planned by the consortium include large-scale knockout and knockdown
of the mouse genome, embryonic stem (ES) cell technology, knockdown of zebrafish genes
by morpholino-antisense technology and positional cloning of disease susceptibility genes
involved in lymphangiogenesis.
Although historically it has been somewhat neglected, the field of lymphatic biology has ex-
perienced a dramatic growth in the last year, this, due for the large part, to the availability
of enhanced techniques and tools and a greatly improved understanding of basic aspects of
lymphatic physiology. The LYMPHANGIOGENOMICS project has been an essential driver
of this development. Lymphatic biologists, physiologists, biomedical engineers and physi-
cians have a great need for a forum in which to collaborate and discuss developments, so
as to determine the future direction of research within this field. The project brings together
the leading laboratories working in lymphangiogenesis. The project has been brought into
action, in an effort to understand, at the molecular level, the mechanism of growth of lym-
phatic vessels and the key molecules in the lymphatic differentiation programme.
Expected Results:
The project’s research outcomes may hold significant therapeutic potential for the two
foremost causes of morbidity and mortality in Europe: cancer and vascular diseases. The
project will provide fundamental insights into the molecular and cellular basis of lymphang-
iogenesis and thereby enabling scientists to develop therapies that suppress (e.g. for the
treatment of cancer and inflammatory diseases), or stimulate the growth of lymphatic vessels
(e.g. for the treatment of tissue ischaemia and lymphoedema).
The consortium’s many and greatly significant achievements to date include the following:
(1) Several new target candidate genes have been identified, some of which have been
validated in Xenopus and Zebrafish models; (2) The new amphibian genetic system, as
developed and validated for the analysis of lymphatic vascular development, has been
made available to the consortium for semi-high throughput functional lymphangiogenomics;
(3) Immortalised cell lines have been developed from primary lymphatic endothelial cells;
Genome-Wide Discovery
and Functional Analysis of Novel Genes
in Lymphangiogenesis
Images by: Tuomas Tammela,
(4) Several neural molecules that provide Fig. 1
Molecular/Cancer Biology Laboratory,
guidance cues in the lymphatic vessel
University of Helsinki, Finland.
development have been discovered. A
great advance was the identification of a
role for vascular endothelial growth fac-
Fig.1. Lymphatic vessels in red
tor C (VEGFC) in the regulation of neural
are shown encircling a very small
progenitor cells; (5) Protocols have been
tumor (0.1 mm in diameter) that
optimised for the isolation of multipotent
is grown in the mouse ear.
adult progenitor cells from mouse and rat
The tumor secretes growth
bone marrow, for the study of lymphatic
factors that promote the
endothelial cell (LEC) differentiation ; (6)
growth of lymphatic vessels
Striking new results on the trans-differen-
into the tumor. Individual
tiation of macrophage-like cells into lym-
tumor cells gain entry into the
phatic endothelium; (7) New vascular
lymphatic vessels, and use them
malformation mutants have been identi-
as routes for spreading to nearby
fied, including a novel VEGFR-3 receptor
lymph nodes.
mutation in a sporadic lymphoedema; (8)
Different monoclonal antibodies directed
to human LECs have been obtained, in Fig. 2
some cases from a human antibody phage
display library; (9) A web-accessible da-
tabase, QRISP, that provides a platform
for integrated bioinformatics analysis of
consortium and public expression data,
has been implemented and is now fully Fig.2. Lymphatic vessels
operational; (10) An extensive database (green) and blood vessels (red)
of blood vascular and lymphatic endothe- intermingle in the mouse ear
lial transcriptomes has been compiled; skin. The lympahtic vessels are
(11) A company, Lymphatix Ltd, has been blind-ended vessels that take
established and has started to develop up fluid, large molecules and
VEGFC and VEGFD for the therapy of cells, which leak out of the blood
lymphoedema and tissue ischaemia. vessels and return them back to
the blood circulation via larger
lymphatic vessels.
Potential Impact:
Fig. 3
While the focus of this project is on pro- Fig.3. A high magnification
viding new insights into the pathophysiol- microscopic image of a small
ogy and biology of lymphangiogenesis, lymphatic vessel (green) that has
its broad scope and multidisciplinary na- been stimulated with a growth
ture mean that it will also have a positive factor protein called VEGF-C.
impact on the wider scientific community Note the very thin projections
and on society in general. This statement of lymphatic endothelial cells
is supported by evidence of the central sprouting from the vessel.
role that lymphangiogenesis plays in hu- VEGF-C does not affect the
man disease. It is estimated that in Europe nearby blood vessels (red), which
alone, three to five million people are af- indicates that it can be used to
fected by secondary lymphoedema (due specifically grow new lymphatic
to radiation therapy, cancer, surgery or vessels for example in patients
infections). This number increases when suffering from lack or impairment
one considers the role of the lymphatic of lymphatic vessel function.
LYMPHANGIOGENOMICS
system and blood vessels in the spread of inflammatory and infectious diseases (e.g. tuber-
culosis and filariasis). If one also takes into account the millions of people who suffer from
metastatic spread of cancer via the lymphatic vasculature, it becomes clear that the inte-
grated project described here stands to have a profound impact on the burden of human
disease in Europe. Novel therapies for cancer, inflammatory diseases, lymphoedema and
tissue ischaemia will also be developed.
Keywords:
vascular diseases, cancer, inflammatory diseases, vascular biology, molecular
biology, stem cells, lymphoedema, genomics, lymphangiogenesis
Genome-Wide Discovery and Functional Analysis of
Novel Genes in Lymphangiogenesis
Partners
Project Coordinator: Prof. Peter Carmeliet
Prof. Kari Alitalo Flanders Interuniversity Institute
University of Helsinki for Biotechnology (VIB)
Faculty of Medicine Centre for Transgene Technology and Gene Therapy
Biomedicum Helsinki Leuven, Belgium
Molecular Cancer Biology Program
Haartmaninkatu 8 Prof. Hellmut Agustin
P.O. Box 63 Deutsches Krebsforschungszentrum
00014 Helsinki, Finland Vascular Medicine
kari.alitalo@helsinki.fi Heidelberg, Germany
Project Manager : Prof. Seppo Yla-Herttuala

Dr. Pirjo Laakkonen University of Kuopio
University of Helsinki A.I. Virtanen Institute
Molecular Cancer Biology Program Kuopio, Finland
pirjo.laakkonen@helsinki.fi
Dr. Per Lindahl
Dr. Anne Eichmann Gothenburg University
Institut National de la Santé et Institute of Medical Biochemistry
de la Recherche Médicale (INSERM) U36 Göteburg, Sweden
Paris, France
Dr. Jyrki Ingman
Prof. Christer Betsholtz Lymphatix Oy
Karolinska Institutet Helsinki, Finland
Department of Medical Biochemistry
and Biophysics Dr. Bernhard Barleon
Stockholm, Sweden RELIATech GmbH
Prof. Dontscho Kerjaschki
Medical University Vienna
Clinical Institute of Pathology
Vienna, Austria
Prof. Elisabetta Dejana

FIRC Institute of Molecular Oncology
Milan, Italy
Prof. Gerhard Christofori

University of Basel
Institute of Biochemistry and Genetics
Basel, Switzerland
Prof. Lena Claesson-Welsh

Uppsala University
Rudbeck Laboratory
Uppsala, Sweden
Prof. Miikka Vikkula

Christian de Duve Institute of Cellular Pathology
Laboratory of Human Molecular Genetics
Brussels, Belgium
EuroHear
www.eurohear.org
State-of-the-Art:
Project Type: Hearing impairment is the most common human sensory deficit, affecting more than 10 per-
Integrated Project cent of the European population (40 million people). This causes a considerable social and
Contract number: economic burden to those afflicted and to society, but early identification and intervention
LSHG-CT-2004-512063 has proved to be cost-effective. Seventy percent of human hearing impairment is genetic
in origin and classified as non-syndromic hereditary hearing impairment, meaning it has
Starting date: only one symptom. The remaining 30 percent of human hearing impairments have other
1st December 2004 symptoms and are therefore described as syndromic.
Duration:
60 months Hearing impairment is the most common birth defect in humans. Of the non-syndromic,
prelingual cases, about 80 percent are due to recessive inheritance, with the majority of
EC Funding:
parents hearing normally. About 20 percent are due to dominant inheritance, with at least
`12 500 000 one of the parents found to be hearing-impaired. Whereas single gene defects probably
account for over half of cases of childhood deafness, no such quantitative data exists for the
proportion of hearing impairment in adults that may be due to hereditary causes.
Over 45 genes responsible for isolated (nosyndromic) hearing impairment in humans are
known, but at least as many as this still need to be identified. The involvement of hearing-im-
paired individuals and their families in research made these breakthroughs possible, and their
ongoing support will be the key to future success in understanding the molecular basis of audi-
tory function. Moreover, as a result of their participation, molecular diagnostics have been de-
veloped and the quality of genetic counselling has been dramatically improved. The ultimate
goal of this research is the development of new ways of treating hearing impairment.
The Eurohear project, comprised of 25 research teams, is building on their work on genetic
and molecular mechanisms underlying hearing impairment.
EuroHear aims to identify the molecules that play a critical role in the inner ear, and more
specifically in the cochlea or the auditory sensory organ. The project has three closely re-
lated objectives:
1) To identify the genes underlying sensorineural hearing impairment, in turn enabling

research on these molecular mechanisms involved in the development and function-
ing of the inner ear. The consortium proposes to identify the human and mouse
genes that underlie early and late onset forms of hearing impairment - both those
that are monogenic and those that are multifactorial in origin. Special emphasis will
be placed on late-onset forms of hearing impairment (age-related hearing loss) and
more specifically on the sensorineural form, presbycusis, since these are better tar-
gets than congenital hearing impairment for preventive and curative therapies.
2) To understand the mechanisms underlying normal and impaired hearing. EuroHear

will not only address the hair bundle, the ribbon synapse of the hair cells and outer
Hair bundles hair cell electromotility mechanisms, it will also investigate the cochlear ion channels,
transporters and gap junctions that contribute to potassium homeostasis.
3) To develop tools for preventing and treating hearing impairment. This includes test-
ing candidate drugs in vivo, developing high throughput screening of organotypic
cochlear cultures for testing of drugs, and in-depth exploration of three possible
therapeutic approaches (gene therapy, cell transplantation, and therapy based on
the use of inner ear progenitor/stem cells, especially hair cell progenitors). Experi-
mental evidence show that pharmacological compounds can significantly reduce the
progression of hearing impairment and this approach could lead to more efficient
Advances in hearing science:
from functional genomics to therapies
treatment strategies. Recent observations on cell and gene therapy, as well as the
discovery of inner ear progenitor cells, suggest entirely new methods for treating the
inner ear deficits. Within the next five years, EuroHear expects to realise some of
these methods.
EuroHear has a strong, cross-disciplinary training programme whose objective is to create

a network of scientific expertise on the development and function of the inner ear and hear-
ing impairment. The training programme aims to provide high-standard, multi-curricular in-
ner ear training courses in Europe to favour the growth of a generation of young European
scientists with multi-disciplinary research
training.
Expected Results:
So far, Eurohear has made a significant
advance with the identification of several
novel genes and their mutations respon-
sible for different forms of deafness. This
was made possible by the active involve-
ment of hearing-impaired patients and
their families. Some of these results are:
1) Mouse mutants are an invaluable

resource for studying the mecha-
nisms of hearing and deafness.
The consortium has been work-
ing on 21 mutant mice. Loci for
14 mutants have been mapped
and genes for 13 mutants have
been cloned;
2) Human deafness: 13 novel genes
causative for isolated or syndro-
mic forms have been discovered
by EuroHear; The ear consists of external,
3) Dysfunction of the hair cell’s ribbon synapse has been shown by the project to be middle, and inner structures.
the cause of human hereditary deafness. This finding is a major breakthrough in the The eardrum and the three tiny
understanding of how auditory information is relayed to the central nervous system, bones conduct sound from the
and reveals that cochlear implants are likely to be successful in the “treatment” of eardrum to the cochlea.
children diagnosed with mutations in the Otoferlin gene;
4) The amplification of low level sound signals by a motile protein localised in the
membranes of hair cells is crucial for proper hearing. Eurohear’s research has re-
cently identified unique regions within the sequence of this protein that are essential
for its function as a cellular motor;
5) Mutations in the gene encoding connexin 26, a gap junction required for intercel-
lular communication within the ear, are the major cause of deafness in human
beings. Work carried out in the consortium has now identified two genes that are
downregulated as a consequence of the loss of connexin 26, and are likely thera-
peutic targets for intervention;
6) Eurohear is also seeking tools for prevention and cure. Promising observations in
cell and gene therapy, as well as the recent discovery of progenitor cells (stem
cells) in the inner ear, suggest new ways to treat the inner ear in the future. Tests
have been initiated using several new in vitro models for drug screening, and novel
methods for stimulating the regeneration of the replacement of inner ear cells are
being actively explored.
EuroHear
Other expected results of EuroHear include a

standardisation of investigative protocols, the Partners
provision of access to large-scale platforms Project Coordinator:
for genetics and genomic analysis, and the Prof. Christine Petit
development and diffusion of physiological Institut National de la Santé et
and biophysical techniques of relevance for de la Recherche Médicale (INSERM)
functional investigations of the inner ear. UMRS 587- Institut Pasteur
Unité de Génétique et Physiologie de l’Audition
Potential Impact: 25 rue du Dr Roux
75724 Paris, France
Sensory cells of the cochlea cpetit@pasteur.fr
This research has direct implications for pa-
tients. For example, it will lead to improve- Project co-Coordinator:
ments in presymptomatic diagnosis, which Prof. Karen Avraham
in the case of Usher syndrome type 1 (deaf- University of Tel Aviv
ness associated with blindness) will allow cli- Department of Human Molecular Genetics
nicians to provide hearing-impaired children and Biochemistry, Sackler School of Medicine
with cochlear implants at the best possible Ramat Aviv
stage, i.e. when they are young and before 39040 Tel Aviv, Israel
they lose their sight. It will allow the diagno- karena@post.tau.ac.il
sis of a predisposition to a form of hearing
impairment that is induced by aminoglyco- Project Manager:
sides, so that the treatment of affected in- Laurent Charvin
dividuals with this class of antibiotics can INSERM Transfert
be avoided. It will also enable clinicians to 7 rue Watt
predict, on the basis of information about a 75013 Paris, France
patient’s underlying genetic defect, whether laurent.charvin@inserm-transfert.fr
or not a cochlear implant will be successful.
Prof. Jonathan Ashmore
In the case of late onset hearing impairment, University College London
molecular diagnosis will allow susceptible Department of Physiology
individuals to make informed career choices London, UK
in order to avoid excessive noise exposure.
Obviously, the effective treatment of hearing Prof. Stephen Brown
impairment will significantly improve quality Medical Research Council
of life for deaf or hard-of-hearing individu- Mammalian Genetics Unit
als. Among the molecular mechanisms that Oxfordshire, UK
contribute to hearing impairment, those that
involve potassium homeostasis could be- Prof. Cor W. R. J. Cremers
come a therapeutic target within a reason- University Medical Centre Nijmegen (UMCN)
able timeframe. Otorhinolaryngology
Keywords: Prof. Dominik Oliver
Philipps-Universität Marburg
hearing impairment, inner ear, synapse, Institut für Physiologie und Pathophysiologie
K+ homeostasis, hair bundle, therapy, cell Marburg, Germany
physiology, functional genomics
Prof. Jonathon Howard
Max Planck Society for the Advancement of Science
Max-Planck Institute of Molecular Cell Biology
and Genetics
Dresden, Germany
Prof. Thomas Jentsch

Max-Delbrück-Centrum für Molekulare Medizin
Metabolic Diseases, Genetics
Genomics and Bioinformatics
Berlin, Germany
Advances in hearing science: from functional genomics to therapies
Prof. Guy P. Richardson, Prof. Corné Kros Prof. E. Sylvester Vizi

University of Sussex Institute of Experimental Medicine
School of Life Sciences Hungarian Academy of Sciences
Brighton, UK Department of Pharmacology
Budapest, Hungary
Prof. Christian Kubisch
University Hospital of the University of Cologne Dr. Christian Vieider
Institut of Human Genetics ACREO AB
Cologne, Germany MicroTechnology Department
Stockholm, Sweden
Prof. Mark Lathrop
Consortium National De Recherche En Dr. Jörg Hager
Genomique (CNRG) IntegraGen SA
Centre National de Génotypage Research & Development
Evry, France Evry, France
Prof. Fabio Mammano Stéphane Silvente
Istituto Veneto Di Medicina Molecolare (VIMM) Affichem
Centro Di Ricerca Della Fondazione Per Research and Development
La Ricerca Biomedical Toulouse, France
Padova, Italy
Prof. Hammadi Ayadi
Prof. Felipe Moreno University of Sfax
Fundación para la Investigación Biomédica del Faculty of Medicine of Sfax
Hospital Universitario Ramón y Cajal Human Molecular Genetics Laboratory
Unidad De Genetica Molecular Sfax, Tunisia
Madrid, Spain
Prof. Klaus Willecke
Prof. Tobias Moser University of Bonn
Bereich Humanmedizin Georg August Institute of Genetics
Universität Göttingen Bonn, Germany
Department of Otorhinolaryngology
Göttingen, Germany
Dr. Ulla Pirvola

University Of Helsinki
lnstitute of Biotechnology
Helsinki, Finland
Dr. Pascal Martin

lnstitut Curie, Division de Recherche
Laboratoire Physico-Chimie ‘Curie’ (UMR 168)
Paris, France
Prof. Karen P. Steel

Genome Research Ltd
Cambridge, UK
Prof. Mats Ulfendahl

Department of Clinical Neuroscience
Center for Hearing and Communication Research
Stockholm, Sweden
Prof.Guy Van Camp

University of Antwerp
Department of Medical Genetics
Antwerp, Belgium
MYORES
www.myores.org
State-of-the-Art:
Project Type: In Europe, over 300,000 people are affected by muscular dystrophies leading to decreased
Network of Excellence mobility and loss of independence. This has severe consequences at both a personal and
Contract number: economic level. The aim of this proposal is to understand how these muscular defects can
LSHG-CT-2004-511978 be repaired.
Starting date: To date, the genetic mechanisms responsible for the emergence of these diseases have only
1st January 2005 been identified for some of the most common muscular dystrophies, such as Duchenne or
Duration: Limb Girdle dystrophies, and it is still necessary to identify the genetic determinants for a
60 months number of other myopathies. In addition to identifying the genetic determinants of muscle
EC Funding: diseases, it is crucial to acquire a profound understanding of the molecular and physi-
opathological mechanisms associated with aberrant gene function in order to be able to
`12 000 000 design efficient therapies.
Inherited diseases are not the sole pathologies associated with muscle dysfunction: the bed-
ridden and the elderly suffer from muscle degeneration too, which has huge implications
for the economy, particularly with the latter group as life expectancy continues to rise in
Europe. For these reasons as well as the large economical burden that these diseases place
on our societies it is an urgent matter to find cures for muscle pathologies. Since a number
of avenues are explored by various laboratories in isolation around Europe it is becoming
clear that the integration of European potential in this domain is an important step in de-
signing successful therapies. To address efficiently the problem posed by muscular diseases,
three fundamental rules must be followed: i) breadth of investigations in order not to miss
important routes of research; ii) clear and focused research to provide patients with fast
relief; iii) rapid transfer of new information to health providers.
All aspects of muscle differentiation will be investigated in this project and this will be
translated into the mechanisms of repair in the adult. Fundamental to the advancement of
our knowledge is the recent demonstration that throughout evolution many of the molecular
mechanisms regulating muscle differentiation have been highly conserved. As molecular
pathways can be easily assessed in invertebrates, the European Muscle Development Net-
work (MYORES) will exploit this advantage and rapidly extend the knowledge gained in
these systems to determine gene function in higher vertebrates. This is a unique aspect of
the proposal and places the consortium at the international forefront of understanding gene
function during normal muscle development and disease.
MYORES aims to target various aspects of muscle disease by bringing together European
specialists in muscle development and function. This integrated approach is aimed at pro-
viding a critical mass of researchers with complementary expertise who will be able to
tackle more difficult problems and make more key advancements than when working alone.
Satellite cell (in blue) and The MYORES participants will utilize different animal models to investigate various aspects
muscle cell nuclei of muscle development, from myogenic induction morphogenesis to terminal differentiation.
This is complemented by teams with expertise in muscle protein structure, muscle disease
and degeneration and tissue engineering as well as human therapy or bio-computing. In
addition, the MYORES project will maximise the scientific and commercial potential of Eu-
ropean research in muscle biology by: i) promoting the sharing of data and research tools;
ii) enhancing exchanges of personnel between laboratories and through the organisation
of training programmes; iii) developing and implementing an integrated multiorganismic
approach to accelerate investigations and improve understanding of normal muscle devel-
opment, function and pathological dysfunction.
Multiorganismic Approach
to Study Normal and Aberrant Muscle
Development, Function and Repair
The overall objectives of the project are:
1) To integrate internationally recognised European specialists working on various as-
pects of muscle biology and pathology in a number of model organisms.
2) To coordinate research on well-defined aims and obtain a critical mass of researchers
who will be able to make significant scientific advancements.
3) To create state-of-the-art technical platforms and resources.
4) To organise the rapid transfer and application of knowledge acquired in genetically
amenable organisms into specific applications for human muscle diseases.
5) To publicise scientific actions broadly and, through education, attract a younger gen-
eration of scientists into this essential field of research.
6) To contribute to reducing the incidence and impact of muscle diseases on the European
population and help the European healthcare sector to compete internationally. Further-
more, MYORES is working to restructure the field of muscle biology, providing added
value by strengthening the impact of European research.
In achieving its objectives, MYORES further aims to coordinate the efficient transfer of knowl-
edge and information from research projects to regulatory bodies and industrial sectors.
Expected Results:
A fundamental aspect of the MYORES network is the extensive use of recently developed
technologies of high-throughput screening to isolate novel molecules and to rapidly test
their relevance in the various aspects of muscle function and repair in a number of animal
models. Special emphasis will be put on the interaction, coordination and efficient transfer
of knowledge between experimental models and clinical demands to ensure that the infor-
mation obtained is fully exploited.
As a result of this collaborative effort, we expect to gain broad insight into the regulatory
interactions and cellular pathways that underlie normal and aberrant muscle formation and
function. Hopefully, this will lead to designing new therapeutic approaches for muscular
diseases and muscle weakening in humans.
We expect isolation of about 100 novel genes expressed during the various steps of myo-
genesis in invertebrates and/or vertebrates. The function of about 30 novel genes will be
determined. The network expects to publish at least one collaborative publication per RP in
the second year of funding and at least two co-signed publications per RP in the next years
of funding. Thus, by the end of the funding period MYORES plans to publish about 40 pub-
lications, co-signed by at least two of the network’s participants. An Internet resource will
be developed that will be used by MYORES participants and by the scientific community.
The first release of MyoBase is expected during the second year of funding to augment
exchanges between scientists working in the muscle biology field in Europe. This will result
in an increase in competitiveness of European research in this field. MYORES members will
also contribute to the designing of novel therapeutic strategies and to the generation of
diagnostic tools. Drosophila transgenesis platform
An important aspect of the project is to transfer efficiently the knowledge present within the created in Clermont-Ferrand and
MYORES network to young researchers and doctors, and to this effect MYORES is organ- supervised by INSERM for gain
izing summer schools and workshops to provide technical training and up-to-date knowl- and loss of function of autologous
edge in the field of mycology. In 2006, one summer school dedicated to various aspects of and heterologous genes in vivo
muscle biology took place in Spain with 20 students from MYORES laboratories attending.
Moreover, in house training and mobility programmes have been initiated allowing techni-
cal training for young researchers in collaborating laboratories within the network.
Potential Impact:
The MYORES network will create the necessary framework to accelerate the pace of muscle
research, and generate, much more efficiently, the important advances in our understand-
MYORES
ing of muscle patholo- Project Sub-Coordinator:

wupA/Tpnl ArgK
gies and in defining Prof. Christophe Marcelle
cures or treatments for Centre National de la Recherche Scientifique (CNRS)
Drosophilia
human muscle diseases. LGPD UMR6545

EC funding will promote Université de la Méditerranée
the development of par- Developmental Biology Institute of Marseille
ticipating groups and im- LGPD, Campus de Lumigny
prove their contribution 13288 Marseille, France
to the EC as a whole, by marcelle@lgpd.univ-mrs.fr
Ciona
allowing cross-discipline
and cross-border links Project Manager:
to be established and Anton Ottavi
fostered. Shared use of INSERM Transfert SA
research infrastructures Hôpital du Vinatier
and development of
Zebrafish
Bat. 452b
mutual specialisation is 95 Bd Pinel
expected to result from 69500 Paris, France
jointly undertaken par- anton.ottavi@inserm-transfert.fr
ticipant activities. These
will further strengthen Dr. Dominique Daegelen, Dr. Pascale Maire,
Example of identified ortholog both the participants’ expertise and the
muscle-specific genes from European knowledge base, and will have Dr. Bénédicte Chazaud, Dr. Frédéric Relaix
Drosophila, Ciona and Zebrafish. an important impact on the job market by Institut National de la Santé et de
la Recherche Médicale (INSERM)
attracting young researchers to the field of Paris, France
muscle biology. The MYORES network has
been structured to extend previously exist- Dr. Patrick Lemaire, Dr. Laurent Ségalat,
ing smaller scale collaborations. Both short- Dr. Josiane Fontaine-Perus, Dr. Delphine Duprez
term and long-term projects are designed to Centre National de la Recherche Scientifique (CNRS)
provide important information and research
Paris, France
tools for the academic and industrial sec-
tors, and patient associations. An impor-
Dr. Anne-Gaëlle Boricky, Prof. Phil Ingham
tant MYORES deliverable for the scientific
University of Sheffield
community will be the MyoBase database.
Centre for Developmental Genetics
The intention is that this regularly updated
Department of Biomedical Science
database will become the main source of
Sheffield, UK
information in muscle biology and represent
a durable contribution to the network, which
will have far-reaching impacts on the entire
Prof. Beate Brand Saberi, Prof. Bodo Christ
scientific community.
Universitatklinikum Freiburg
Institut fur Anatomie und Zellbiologie II
Freiburg, Germany
Keywords: Dr. Baljinder Mankoo, Dr. Mathias Gautel,
degenerative diseases, developmental biol- Dr. Simon Hughes, Dr. Susanne Dietrich,
ogy, molecular biology, myogenic specifica- Dr. Philippa Francis-West, Dr. Peter Zammit
tion, muscle differentiation, diversification of King’s College London
muscle fibres, muscle patterning, myoblasts Randall Centre for Molecular Cell Biology
fusion, functions of muscle-specific proteins, GKT School of Biomedical Sciences
muscle stem cells, muscle regeneration London, UK
Dr. Andrea Munsterberg

University of East Anglia
Partners School of Biological Sciences
Project Coordinator: Cell and Developmental Biology
Dr. Krzysztof Jagla Norfolk, UK
Institut National de la Santé et de
la Recherche Médicale (INSERM) U384 Dr. Michael Victor Taylor
28 place Henri Dunant University of Wales, Cardiff
63000 Clermont-Ferrand, France Cardiff School of Biosciences
christophe.jagla@u-clermont1.fr Cardiff, UK
Multiorganismic Approach to Study Normal and Aberrant Muscle
Development, Function and Repair
Prof. Margaret Buckingham, Dr. Chava Kalcheim, Yann Dantal

Dr. Shahragim Tajbakhsh Dr. Orna Halevy Soluscience SA
Institut Pasteur Hebrew University of Jerusalem Biopôle Clermont-Limagne
Département de Biologie du Développement Department of Anatomy and Cell Biology St. Beauzire, France
Paris, France Jerusalem, Israel
Dr. Peter Currie
Dr. Eileen Furlong Prof. John Sparrow, Victor Chang Cardiac
European Molecular Biology Dr. Belinda Bullard Research Institute
Laboratory (EMBL) University of York Darlinghurst, Australia
Developmental Biology and Department of Biology
Gene Expression Programmes York, UK Dr. Thierry Toursel
Heidelberg, Germany Association Française
Dr. Vincent Mouly contre les Myopathies (AFM)
Prof. Nadia Rosenthal Université Pierre et Marie Curie Direction Recherche et
European Molecular Biology UMR 7000, Cytosquelette et Développement des
Laboratory (EMBL) Développement Therapeutiques
Mouse Biology unit Paris, France Evry, France
Monterotondo,Italy
Prof. Thomas Braun Dr. Jonathan Beauchamp
Prof. Bernard Thisse Max-Planck Institute for Physiological Royal Holloway and
Centre Européen de Recherche en and Clinical Research Bedford New College
Biologie et en Médecine (CERBM) W.G. Kerckhoff-Institut School of Biological Sciences
Institut de Génétique et de Biologie Bad Nauheim, Germany Egham, UK
Moléculaire et Cellulaire
Illkirch, France Prof. Peter Rigby Prof. John Squire
Institute of Cancer Research University of Bristol
Prof. Hans Henning Arnold Royal Cancer Hospital Department of Physiology
Technical University Braunschweig Section of Gene Function and Bristol, UK
Cell and Molecular Biology/Biosciences Regulation, Chester Beatty Laboratories
Biochemistry and Biotechnology London, UK
Prof. Stefano Schiaffino

Universita degli Studi di Padova
Dipartimento di Scienze Biomediche
Sperimentali
Padova, Italy
Dr. Tomas Soukup

Institute of Physiology, Academy of
Sciences of the Czech Republic
Department of Functional Morphology
Prof. Renate Renkawitz-Pohl

Philipps-Universitat Marburg
Developmental of Developmental Biology
Marburg, Germany
Prof. Carmen Birchmeier

Max-Delbruck-Centrum fur
Molekulare Medizin
Signaltransduction and
Developmental Biology Group
Berlin, Germany
Prof. Alberto Ferrus, Dr. Mar Ruiz-Gomez

Consejo Superior de
Investigaciones Cientificas
Instituto Cajal
Madrid, Spain
EuReGene

Integrated Project
Contract number: Diseases of the kidney represent a major cause of morbidity and mortality in Europe. The
elderly are disproportionately affected, but renal disease is also a condition that severely
LSHG-CT-2004-005085
affects children. An estimated 4.5 million Europeans suffer from renal disorders. The annual
Starting date: death rate in patients with renal failure is 20%.
1st January 2005
Duration: The focus of the European Renal Genome Project (EuReGene) is to challenge kidney dis-
48 months eases. Elucidation of human and other genomes heralds a new era in biomedical research,
EC Funding: offering unprecedented opportunities to understand disease processes and to identify strate-
gies, so as to improve health. The project embraces these opportunities and plans to imple-
`10 500 000
ment an interdisciplinary research programme. EuReGene integrates European excellence
in research relevant to renal development, pathophysiology and genetics. The goal is to
discover the genes responsible for renal development and disease, and to examine their
proteins and their actions. To this end, a consortium has been established, comprising
leading scientists, clinicians and SME partners that will focus on the development of novel
technologies and discovery tools in functional genomics, and their application to kidney
research. Moreover, we will look to comparative genomic studies in many systems that pro-
vide utilitarian models, ranging from zebrafish to Xenopus, and from mice and rats to man.
The studies will be performed at different levels, including the gene, the cell, the organ and
the organism. Ultimately, identification of disease genes will lead to a better understanding
of renal disease processes, to improved diagnosis and to new concepts in therapy. The
programme will establish a paradigm for an integrated post-genomic approach to analyse
renal disease-related developments that may be transferred to other organ systems or dis-
ease entities, in the future.
EuReGene will pursue objectives in four areas:
1. Functional genomics technologies: EuReGene will develop new high throughput gene
expression analysis methods; renal organ cultures to study gene function; databases
for tools, methodologies and results; and kidney atlas for spatio-temporal description
of renal mechanisms.
2. Renal development: EuReGene will develop new cell lines for the study of develop-
mental programmes, as well as detailed gene expression maps of developing an
adult kidney; and identify genes involved in nephrogenesis/differentiation.
3. Pathophysiology: EuReGene will develop new mouse and rat models; study regula-
tory networks in cell differentiation, injury and repair and cellular transport; and
identify new targets for therapeutic intervention in renal diseases.
4. Complex genetics: EuReGene will establish new ENU models in zebrafish and mice;
map modifier QTLs for proteinuria and progressive renal injury in rats, and for
glomerulosclerosis and renal stone disease in mice; and identify modifiers in diabetic
nephropathy in mice.
Expected Results:
The project’s integrated research approach will have a fundamental impact on the current
understanding of renal development and disease in humans. At the end of the project
(which has a 4-year duration) the following measurable results will be delivered:
European Renal Genome Project
Elizabeth Robertson, Enyu Imai, Mathias Brandis, Nine Knoers
EU Commission Advisory Board Alastair Kent, Steve Hebert, Luigi Baroni, Karl-Heinz Wilbers
Project Management
General Office
Project coordinator Iwan Meij,
Assembly Steering Committee
Thomas Willnow Dorothee Saar
Panel “Training”
Dominik Müller,
Nick Hastie Andreas Schedl Erik Christensen Corinne Antignac Carsten Wagner,
Andreas Schedl,
Topic 1 Topic 2 Topic 3 Topic 4 Raj Thakker,
Seppo Vainio,
Genome Renal Patho- Complex Friedrich Luft
Technologies Development physiology Genetics
Jamie Davies Andreas Schedl Pierre Verroust Roger Cox Panel “Exploitation, IPR”
Topic coordinators Gregor Eichele André Brändli Olivier Devuyst Corinne Antignac ReceptIcon,
MDC Berlin Thomas Willnow Dominik Müller Ascenion,
Friedrich Luft
Duncan Davidson Thomas Willnow
MRC Edinburgh Jamie Davies Nick Hastie
University Nice Andreas Schedl
Panel “Ethics, Gender”
Necker Hospital, Paris Corinne Antignac
UCL Brussels Olivier Devuyst Pierre Courtoy Ariela Benigni,
ETH Zürich André Brändli Mathias Kretzler,
MRC Harwell
Raj Thakker,
Roger Cox
Friedrich Luft,
Mario Negri Inst. Bergamo Giuseppe Remuzzi Rikke Nielsen
University Paris Pierre Verroust
University Zurich Heini Murer
MPI Hannover Gregor Eichele
University Oulu Steffen Ohlmeier Seppo Vainio
University Hamburg Thomas Jentsch
Aarhus University Erik Christensen
University Oxford Raj Thakker
LMU Münich Mathias Kretzler
ReceptIcon Anders Nykjaer
EuReGene management structure
1. Methods for high throughput in situ expression analysis at organ level

2. Methods for 3D reconstruction of expression maps at organ level
3. Bioinformatic tools to integrate data from various genomic approaches into an kid-
ney atlas of spatio-temporal relationships of developmental/pathophysiological proc-
esses at organ level
4. A comprehensive kidney atlas of renal developmental and pathophysiological proc-
esses (as data and as 3D image reconstructions)
5. Novel discovery tools including zebrafish, Xenopus, mouse and rat models (knock-
outs, knockdowns, transgenics, GFP reporter lines, Cre lines), as well as new cell and
organ cultures
6. Repositories (models, cell lines, biopsies, DNA) and databases (expression maps)
that are accessible throughout the scientific community
7. A list of candidate genes responsible for (i) developmental, (ii) complex genetic and
(iii) acquired renal diseases (diabetic nephropathy, glomerulosclerosis, nephrotoxic-
ity, proteinuria, end-organ damage) representing major new targets for diagnosis,
drug development, and therapeutic intervention
8. A patent portfolio that protects the intellectual property rights of the EuReGene con-
sortium, and forms the basis for commercial exploitation and funding beyond the FP6
period
9. Websites that inform stakeholders (patient advocacy groups, health care providers,
scientists) of latest developments in renal disease research.
Potential Impact:
EuReGene’s integrated approach will have a profound impact on the current understanding
of renal development and disease, and will contribute to fundamental knowledge produc-
tion, and novel concepts for improving health. It will focus on innovative aspects of tech-
nology development such as animal models, organ cultures and imaging techniques. The
burden of renal disease is vast in terms of financial cost, as well as in increased mortality
EuReGene
Graphic representation
of the four interrelated topics
within EuReGene
and medical and psychological morbidity of patients and their families. Through the iden-
tification of the mechanisms underlying disease processes, EuReGene will have a major
impact on lifting the societal and economic burdens caused by renal disease. It will also
address the ongoing problem of fragmented research activities that hampers efficient medi-
cal research in Europe.
Keywords:
animal models, transgenic animals, mouse, zebrafish, Xenopus, organogenesis, kidney
diseases, transcriptome analysis, cardiovascular diseases, renal pathogenesis, complex
genetics, QTL mapping, solute carrier
Expression of Slc12a1
in adult kidney visu-
alised by ISH on a 10
micron paraffin section
using optimised meth-
ods for automated ISH
European Renal Genome Project
Partners
Project Coordinator: Prof. André Brändli
Thomas Willnow Swiss Federal Institut of Technology ETHZ
Max-Delbrück-Center for Molecular Medicine Institute of Pharmaceutical Sciences
Cardiovascular Research Centre Department of Chemistry and Applied Biosciences
Department of Cardiovascular Research Zürich, Switzerland
Lipids and Experimental Gene Therapy
Robert Roesslestrasse 10 Dr. Giuseppe Remuzzi, Dr. Ariela Benigni
13125 Berlin, Germany Mario Negri Institute for Pharmacological Research
willnow@mdc-berlin.de Negri Bergamo Laboratories
Bergamo, Italy
Project Manager:
Dr. Iwan C. Meij Prof. Jürg Biber, Prof. Carsten Wagner
Max-Delbrück-Center for Molecular Medicine University of Zürich
Cardiovascular Research Centre Institute for Physiology
Robert Roesslestrasse 10 Zürich, Switzerland
13125 Berlin, Germany
i.meij@mdc-berlin.de Prof. Gregor Eichele
Max-Planck Institute of Biophysical Chemistry
Prof. Friedrich Luft, Dr. Dominik Müller Genes and Behaviour Organisation
Prof. Thomas Jentsch Göttingen, Germany
Max-Delbrück-Center for Molecular Medicine
Berlin, Germany Prof. Seppo Vainio
University of Oulu
Prof. Nick Hastie, Dr. Duncan Davidson Biocenter Oulu
MRC Human Genetics Unit Department of Biochemistry
Western General Hospital Oulu, Finland
Edinburgh, UK
Prof. Erik Ilsø Christensen, Dr. Anders Nykjaer
Dr. Jamie Davies Aarhus University
University of Edinburgh Aarhus C, Denmark
Centre for Integrative Physiology
Edinburgh, UK Prof. Raj Thakker
Dr. Roger Cox Nuffield Department of Clinical Medicine
Medical Research Council Harwell Oxford Centre for Diabetes
MRC Mammalian Genetics Unit Endocrinology and Metabolism
Diabetes, QTL and Modifier Loci Group Churchill Hospital
Oxfordshire, UK Oxford, UK
Prof. Andreas Schedl

Médicale (INSERM) U 470
Université Nice - Sophia Antipolis - Centre de Biochimie
Nice, France
Prof. Corinne Antignac, Prof. Pierre Verroust

Médicale (INSERM) U 574 & 538
Necker Hospital, & Faculté de Médecine Saint-Antoine
Paris, France
Prof. Pierre Courtoy, Dr. Olivier Devuyst

Université Catholique de Louvain (UCL)
Faculté de médecine
Brussels, Belgium
EVI-GENORET
www.evi-genoret.org

Integrated Project
Contract number: About 90 percent of all the information humans use in order to interact in society, is received
through their eyes. But despite major clinical and therapeutic achievements in ophthalmol-
LSHG-CT-2005-512036
ogy, the number of people suffering from serious eye problems is growing. This paradox
Starting date: reflects the fact that we have yet to find ways of stemming and repairing the damage
1st April 2005 caused by diseases that affect the retina, such as Inherited Retinal Degenerations (IRD) and
Duration: Age-Related-Macular Degeneration (ARMD). Furthermore, visual handicaps are a particular
48 months problem in a society in which visual communication is ever increasing.
EC Funding:
The retina — the part of the eye that converts light into sight — is a highly complex system
`10 000 000
that accommodates both numerous tissue-specific and ubiquitously expressed developmen-
tal and pathologic pathways. The number of genes identified in IRDs has steadily increased.
Over the past 20 years, a massive accumulation of knowledge has led to the recognition
of more than 180 mapped loci and the identification of about 120 genes. The most com-
mon form of visual impairment of people above 60, with 12.5 million people affected in
Europe, is ARMD, caused by mostly unknown genetic factors. Preventing blindness from IRD
and ARMD requires understanding of the genetic and cellular interactions controlling retinal
development, maintenance and function. Understanding complex diseases of the retina is
not only challenging, but it also offers a major incentive to use the knowledge that can be
gathered by using state-of-the-art functional genomics technologies in order to generate a
more comprehensive analysis of retinal degenerations.
In the EVI-GENORET project, 25 academic and industrial partners have formed five interact-
ing components — phenotyping, development, genetics, functional genomics and therapy
— to establish working platforms and share tools and knowledge in the field of the retina
within and outside the academic community.
Development
of standards and information
networking system
Functional genomics of the retina
in health and disease
The aim of EVI-GENORET is to build on the current understanding of the fundamental mo-
lecular and cellular biology of the retina. The project will help to prevent blindness caused
by IRD and ARMD by aiming its work at pursuing a greater understanding of the genetic
and cellular interactions that control retinal development, maintenance and function. The
consortium plans to overcome the lack of critical knowledge in single EU countries by struc-
turing retinal research from leading scientists throughout Europe in order to offer a source
of expertise for those involved in that research field.
Further focus is on: (1) Obtaining and integrating the information on gene function through
numerous human, animal and in vitro models of retinal degeneration available as well as
data from studies during development; (2) Standardising and analysing this information
(databases, bioinformatics, transcriptome, proteome and expression studies); (3) Valida-
tion of the information (bioinformatics and functional assays); (4) Generating conceptual
and biological models of genes, gene networks and pathways relevant to major functions
involved and/or impaired in retinal health and disease; (5) Designing novel cell-based and
genomic-based therapies that will potentially benefit patients but also validate the pathways
and targets identified, using the above-described approaches.
Expected Results: Cross-secion of the retina

(microphotograph)
The project has already provided some significant results towards the above objectives, and Acknowledgement:
these are listed as follows: (1) Harmonisation of Standard Operating Procedure and devel- Dr. O. Goureau, INSERM PARIS
opment of the relational EVI-GENORET database. The EVI-GENORET database is a Euro-
pean database devoted to fundamental and clinical scientists, as well as patients and aims
at the centralization, sharing, exploitation and dissemination of the data and knowledge
related to retinal health and disease. The database integrates heterogeneous data encom-
passing population genetics, experimental phenotyping of human and animals, molecular
genetics, high throughput functional genomics. Its design is specifically oriented towards
the harmonization, standardization and interoperability of retinal data, protocols and clini-
cal practices allowing the establishment of an effective networking systems at the European
level; (2) Identification of several novel candidate genes involved in retinal degeneration
by DNA chips and proteomic analysis in dominant retinitis pigmentosa (RP) and in a severe
inherited retinal disease in children(3) Retinoid dehydrogenases/reductases (RDH) catalyse
key oxidation reduction reactions in the visual cycle that converts vitamin A , the chromo-
phore of the rod and cone photoreceptors; that the consortium has shown that mutations in
RDH12, encoding a retinal dehydrogenase, result in severe and early-onset autosomal re-
cessive retinal dystrophy (arRD) (4) development of vectors as potential gene therapy tools.
Fundus photograph of the human
The project has already initiated a gene therapy clinical trial in a specific form of IRD.
eye Acknowledgement: Dr. S.
Mohand-Saïd, INSERM, PARIS
Potential Impact:
EVI-GENORET will increase the scientific community’s understanding of
the function of the retina, its cellular components, and molecular princi-
ples as well as the mechanisms of retinal degeneration. The project aims
is to develop and validate innovative therapeutic approaches.
This is a unique opportunity to implement a structured project, gathering

the most active and experienced professional research teams on retin-
opathies and basic retinal biology. The team expects will to deciphering
EVI-GENORET
the mechanisms underlying retinal diseases, and setting up functional assays which will con-
tribute to advance practical development of therapeutics. EVI-GENORET has great potential
for breakthroughs at each of the many incremental steps towards integrated system biology
as well as in the outcome measures. Thus, with the potential impact on public health, it will
convince basic and applied scientists of the importance of such concerted effort.
The goal, at the completion of the project, is to help integrate a broad and in depth under-
standing of the function and interactions of major cells and gene networks, thereby propos-
ing functional models. The unique knowledge base on molecular networks thus generated
will facilitate identification and validation of novel therapeutic targets of broad interest.
Developing stem cell culture methods and new approaches to gene and drug delivery
mechanisms is expected to provide novel tools for future therapeutic interventions after test-
ing in this privileged organ.
Keywords:
vision, gene expression, retinal developement, photoreceptors, age-related macular degen-
eration (AMD), retinal dystrophies, animal dystrophies, animal mutants, genotype-pheno-
type-correlation
Partners
Project Coordinator: Prof. Shomi Bhattacharya, Prof. Alan Bird, Dr. Robin Ali,
Prof. Jose-Alain Sahel Dr. John Greenwood, Dr. Stephen Moss
Institut National de la Santé et de la Recherche University College London
Médicale (INSERM) U592 Institute of Ophthalmology
Laboratoire de Physiopathologie Cellulaire et London, UK
Moleculaire de la Retine
Institut de la Vision Prof. Eberhart Zrenner, Dr. Mathias Seeliger,
CHNO des Quinze-vingts, Dr. Frank Schuettauf, Dr. Bernd Wissinger,
17 rue Moreau, Dr. Ulrich Schrayermeyer
75012 Paris, France Eberhard-Karls-Universitaet Tuebingen
j-sahel@quinze-vingts.fr University Eye Hospital
Tuebingen, Germany
Project Scientific Manager:
Dr. Olivier Lorentz Prof. José Cunha-Vaz
INSERM Transfert SA Aibili - Associação Para Investigação Biomédica E
7, rue Watt Inovação Em Luz E Imagem
75013 Paris, France CNTM - Centro De Novas Tecnologias Para A Medicina
olivier.lorentz@st-antoine.inserm.fr Azinhaga De Santa Comba - Celas
Coimbra, Portugal
Project Administrative Manager:
Dr. Thomas Wheeler-Schilling Dr. Sandro Banfi
European Vision Institute EEIG Telethon Institute of Genetics and Medicine
Brussels, Belgium Naples, Italy
Prof. Jose-Alain Sahel, Dr. Thierry Leveillard, Dr. Ronald Roepman, Dr. Frans Cremers
Dr. Serge Picaud, Dr. Olivier Goureau,
The University Medical Centre Nijmegen
Dr. Josseline Kaplan, Dr. Christian Hamel,
Department of Human Genetics
Dr. Francine Behar-Cohen, Dr.Frédéric Mascarelli,
Dr. Ségolène Aymé Nijmegen, The Netherlands
Médicale (INSERM) Dr. Theodorus Van Veen, Dr. Per Ekstroem,
Laboratoire de Physiopathologie Cellulaire et Dr. Maria-Theréza Perez
Moléculaire de la Rétine Lund University
Paris, France Department of Ophthalmology
Wallenberg Retina Center
Lund, Sweden
Functional genomics of the retina in health and disease
Prof. Angelo Luigi Vescovi Dr. Pascal Dolle, Dr. Olivier Poch
University of Milano Bicocca Centre Européen pour la Recherche en Biologie et
Dipartimento Di Biotecnologie E Bioscienze Btbs Médecine-Groupement D’Intérêt Economique
Milan, Italy (CERBM-GIE)
Institut de Génétique et de Biologie Moléculaire et
Prof. Veronica Van Heyningen, Prof. Alan Wright Cellulaire (IGBMC)
Medical Research Council Illkirch, France
MRC Human Genetics Unit
Edinburgh, UK Dr. Kader Thiam
Genoway
Dr. Marius Ueffing Lyon, France
GSF-Forschungszentrum Fuer Umwelt Und
Gesundheit Gmbh Dr. Carmen Ayuso
Institute of Human Genetics Fundacion Jimenez Diaz UTE
Neuherberg, Germany Department of Medical Genetics
Madrid, Spain
Prof. Andreas Gal
University Hospital Hamburg-Eppendorf Dr. Smaragda Kamakari
Institute of Human Genetics National and Kapodistrian University of Athens
Hamburg, Germany School of Medicine, Laboratory of Biology
Athens, Greece
Dr. Christian Grimm
University of Zurich Dr. Valeria Marigo
Department of Ophthalmology Università di Modena e Reggio Emilia
University Hospital Dipartimento di Scienze Biomediche
Lab For Retinal Cell Biology Modena, Italy
Zurich, Switzerland
Prof. Frank G Holz, Hendrik Scholl

University of Bonn
Department of Ophthalmology
Faculty of Medicine
Bonn, Germany
Prof. Peter Humphries

The Provost, Fellows and Scholars of
The College of The Holy and Undivided Trinity
of Queen Elizabeth
Ocular Genetics Unit
Dublin, Ireland
Dr. Christina Fasser

Retina International
Zurich, Switzerland
Dr. Frank Mueller

Research Centre Juelich Gmbh
Institute for Biological Information Processing
Juelich, Germany
Dr. Geraoid Tuohy

Genable Tehnologies Ltd
Smurfit Institute of Genetics
Trinity College Dublin
Dublin, Ireland
Prof. Usha Chakravarthy

Queens University Belfast
Ophthalmology and Vision Science
Belfast, UK
7.3 STEM
CELLS
FunGenES
PLURIGENES
ESTOOLS
EuTRACC
FunGenES
www.fungenes.org

Integrated Project
Contract number: Current knowledge of the genetic mechanisms regulating pluripotency and differentiation is
limited. While many of the conditions that facilitate lineage commitment and differentiation
LSHG-CT-2003-503494
are known, an in-depth understanding of the underlying genetic programmes is lacking.
Starting date: FunGenES aims to systematically identify genes that are involved in different aspects of
1st March 2004 development, such as maintenance of pluripotency, formation of the three germ layers and
Duration: further differentiation into somatic lineages. An approach of this scale has not previously
46 months been attempted, and therefore there is considerable potential for advancing the field.
EC Funding:
The FunGenES consortium addresses fundamental issues of stem cell biology and functional
`8 500 000
genomics, pursuing an integrated strategy based on cultured mouse embryonic stem (ES)
cells. Traditionally, studies in developmental genetics have used a variety of animal models.
These studies are time-consuming and their results cannot be directly compared, due to the
heterogeneity of methods and species used. In contrast, the FunGenES approach using
cultured murine ES cells, offers a standardised, well-characterised, in vitro model of pluripo-
tency and differentiation.
FunGenES will identify the gene subsets that are active at different stages of ES cell differen-
tiation. Its major objective is to produce a gene expression atlas covering the development
of ES cells into all three germ layers (ectoderm, mesoderm and endoderm) and the various
somatic cell types.
More specifically, the consortium has several objectives, inclusive of the following: (1) De-
veloping a detailed understanding of ES cell self-renewal, differentiation and lineage com-
mitment, and identifying potential novel target genes for therapeutic intervention; (2) Deriv-
ing new molecular and cellular tools for characterising gene function in tissue-specific cell
populations; (3) Developing new ES cell-based methods for high throughput screening of
small candidate molecules for therapeutic applications in human diseases.
Expected Results:
FunGenES expects to deliver the following results:
1) A phenotypic and expression profile atlas of cell lineage commitment from the pluripo-
tent state (ES cells) to the three major germ lineages. Based on the information in this
atlas, the intention is to develop a detailed understanding of the following items: (i)
The genetic mechanisms and extrinsic and intrinsic signalling cascades responsible
for ES cell proliferation and self-renewal; (ii) The molecular basis of pluripotency; (iii)
The processes determining fate from precursors to differentiated cells; (iv) The mecha-
nism of mesodermal commitment, and identification of master genes, extrinsic and
intrinsic signalling cascades and transcription factors involved in the determination
of cardiac cells, endothelial cells, adipocytes, osteoblasts and haematopoietic cells;
(v) The mechanism of ectodermal commitment and identification of master genes,
extrinsic and intrinsic signalling cascades and transcription factors involved in the
determination of neurons and glial cells; (vi) The mechanism of endodermal commit-
ment and identification of master genes, extrinsic and intrinsic signalling cascades
Functional Genomics
in Engineered ES cells
and transcription factors involved in determination of hepatocytes and insulin produc-

ing β-cells.
2) Determination of gene expression patterns at landmark differentiation points in ES-
derived somatic cell lineages.
3) Engineered ES cell lines, including physiological information on the behaviour of
these cells.
4) A set of standard operating procedures, to be used for the following purposes: (i)
Use of ES cell models and differentiation protocols; (ii) Technical tools (RNA prepa-
ration, standard formatted chips for gene expression analysis, bacterial artificial
chromosome methods, endoribonuclease-prepared small interfering RNA methods);
(iii) Data analysis using bioinformatics and cluster gene analysis.
Potential Impact:
New knowledge about the genetic pathways that underlie the differentiation of ES cells to
somatic cells will contribute to novel therapeutic strategies for human diseases that are char-
acterised by the irreversible loss of functional cells. Potential clinical applications include
tissue and cell transplantation, and new therapies for diseases such as cancer, liver disease,
diabetes and cardiovascular and neurodegenerative diseases.
Murine ES cells represent a valuable tool for understanding developmental processes and
for screening for embryo-toxicology without the use of animals. They are therefore expected
to have a major impact on drug development, considering that the high failure rate in this
process is the result of toxicity in both the early and late phases of development, including
clinical trials. These failures increase the costs of drug development dramatically, and raise
ethical concerns.
FunGenES
Basic research on murine ES cells is a highly competitive field which offers the prospect of
economic growth in Europe, as long as technological tools, diagnostic targets and long-
term drug development are successfully translated into advances in clinical science. Growth
is expected to occur in the following areas in the near future: ES cell developmental biology
and genomics tools, drug development and gene and cell therapy.
Keywords: functional genomics, murine embryonic stem cells, differentiation,

gene atlas, cellular, stem cells
Partners
Prof. Jürgen Hescheler
University of Cologne
Institute of Neurophysiology
Faculty of Medicine
Robert-Koch-Str. 39
50931 Cologne, Germany
j.hescheler@uni-koeln.de
Project Manager:
Annette Ringwald
ARTTI
58A, rue du Dessous des Berges
75013 Paris
France
Dr. Laurent Pradier

Aventis Pharma Recherche-Développement,
(now Sanofi-Aventis)
Neurodegenerative Disease Group
Genomics Department
Vitry sur Seine, France
Dr. Pierre Savatier

Unité 371 “Cerveau et vision”
Bron, France
Dr. Antonis Hatzopoulos

GSF-Research Center for Environment and Health
GSF-Institute of Clinical Molecular Biology and Tumor
Genetics - Laboratory of Vascular Genetics
Munich, Germany
Dr. Lesley Margaret Forrester

University of Edinburgh
John Hughes Bennet Laboratory / Division of Oncology
School of Molecular and Clinical Medicine
Western General Hospital
Edinburgh, UK
Functional Genomics in Engineered ES cells
Dr. Timothy E. Allsopp Dr. Melanie J. Welham

Stem Cell Sciences Ltd University of Bath
Roger Land Building Department of Pharmacy and Pharmacology
Edinburgh, UK Faculty of Science, Laboratory of Molecular Signalling
Bath, UK
Dr. Matthias Austen
DeveloGen Aktiengesellschaft Prof. Anna M. Wobus
Stem Cell Research Institute of Plant Genetics and Crop Plant Research
Goettingen, Germany Cytogenetic, In vitro Differentiation Group
Gatersleben, Germany
Dr. Norbert Hübner, Michael Bader
Max-Delbrück-Center for Molecular Medicine
Molecular Biology and Genetics
Berlin, Germany
Prof. Angelo Luigi Vescovi (until 31 October 2006)

Fondazione Centro San Raffaele del Monte Tabor
DIBIT-Stem Cell Research Institute
Milan, Italy
Dr. Frank Buchholz

Max-Planck Institute of Molecular Cell
Biology and Genetics
Dresden, Germany
Dr. Heinz Himmelbauer

Max-Planck-Institute for Molecular Genetics
Department of Vertebrate Genomics
AG Himmelbauer
Berlin, Germany
Dr. Christian Dani, Dr. Hélène Boeuf

Institute of Signalling, Developmental Biology
and Cancer Research-UMR6543 (Nice)/
Laboratoire Composantes innées de la réponse
immunitaire et différenciation
UMR 5164 (Bordeaux)
Paris, France
Prof. Domingos Henrique

Instituto e Medicina Molecular
Faculdade Medicina Lisboa
Instituto Histologia e Embriologia
Lisbon, Portugal

Technical University Dresden
Biotec, Genomics
Dresden, Germany
Dr. Androniki Kretsovali

FORTH, Foundation for Research & Technology Hellas
Heraklion, Greece
Plurigenes
www.plurigenes.org
State-of-the-Art:
Project Type: A first step towards regenerative medicine consists in finding a mean to cause controlled ded-
Specific Targeted ifferentiation of adult tissue. The project Plurigenes aims at achieving major breakthroughs
Research project in the discovery and understanding of the function of genes controlling pluripotency in the
Contract number: central nervous system. Plurigenes will start by identifying candidate genes in model organ-
isms, following original approaches involving screens performed by in situ hybridisations
LSHG-CT-2005-018673
on well-characterised neural structures or by gain-of-function analysis. Innovative technolo-
Starting date: gies of transgenesis and imaging in several model organisms will be settled to reach this
1st January 2006 goal. The project will first characterise the functions of candidate genes in vitro and in
Duration: vivo. Then, for selected genes, it will validate the possibility to restore the pluripotency of
36 months terminally differentiated cells through transgenesis of the candidate genes. Thus, Plurigenes
should identify molecular actors and related pathways associated with pluripotency.
EC Funding:
`2 499 713
The overall objective of Plurigenes is to allow the dedifferentiation of differentiated neural
cells into pluripotent cells and, consequently, to improve the ability to manipulate those
cells and combat diseases, such as brain injury and/or aging. By using different animal
models belonging to the Chordate phylum and a large panel of in vitro and in vivo meth-
ods, the project partners plan to take advantage of a multi-organism approach. In parallel,
Plurigenes will improve transgenesis methods and develop novel imaging techniques in
several model organisms.
PLURIGENES aims to identify novel (that is, so far uncharacterised) pluripotency associated
genes in model organisms. This will be achieved through in situ hybridisation screens on
fish and gain-of-function screens in ascidians on several thousands genes. It will result in
30-40 genes considered as candidate regulators. The sequence identity of basal chordates’
proteins with their human counterpart will allow a straightforward exploitation of the newly
isolated genes in the frame of human researches.
Medaka embryo hybridised with
a probe for a gene signalling for Secondly, the consortium aims to assess the role of the latter genes in the maintenance of
cell cycle arrest (‘stop signal’) pluripotency and the dedifferentiation process, using fish, mice, and human cultured cells.
From the pool of 30-40 candidate genes identified, it will lead to the selection of about
one dozen selected genes. A third objective consists of validating the physiological role of
the selected genes in vivo. To achieve this, the expression of these genes will be perturbed
(abolished, over-expressed, and mis-expressed) primarily in the nervous system of the ani-
mal models. The effects on the neural stem cells (NSC) and neural progenitors will also be
examined. Finally, the Plurigenes team aims to create improved methods for transgenesis
and imaging in model organisms via an improvement of transgenesis. This will be achieved
by using meganucleases, a very promising class of endonucleases for many applications,
via the development of a novel technology for microscopy (SPIM) and the development of
Histological section through the highly innovative analyses of 4D images of embryos.
optic tectum showing expression
of one gene in the arrrest zone
Expected Results:
PLURIGENES aims at finding and characterising new determinants that regulate the mainte-
nance of the neural stem cell undifferentiated state and the reversal of differentiated neural
cells (neurons and glia) towards a neural stem cell pluripotent state. The partners predict
that several important regulators remain to be discovered, notably in the still large fraction
of vertebrate predicted genes (the function of which is not presently documented), and that
these novel actors could have many therapeutic uses. Once assayed for their dedifferentia-
tion activities, these newly identified genes may allow improved protocols for dedifferentia-
Pluripotency Associated Genes
to Dedifferentiate Neural Cells
into Pluripotent Cells
tion of neural cells to be established, sole or in combination with already known factors.
Other important enhancements expected from this project concern the development of new
methodologies, in particular the manipulation of gene expression (transgenesis) in model
organisms, and innovative microscopy methods for in vivo imaging of the fate of dediffer-
entiated cells.
Potential Impact:
PLURIGENES constitutes a unique opportunity to bring together specialists in developmental
genetics of model organisms, cellular biology of human NSC, and oncology. Compared
to programmes underway in non-European countries, the project focuses on a competitive
area. The ability to isolate and transplant NSC in vivo from differentiated cells should sim-
plify the development of stem cell-based therapies for a range of neurological disorders.
Pathways that regulate self-renewal of normal stem cells are deregulated in cancer stem
cells, resulting in the continuous expansion of cancer cells. Therefore, finding of new gene
families involved in pluripotency should have a significant impact on pharmaceutical com-
panies by allowing novel strategies of anti-tumour drug design.
Keywords: de-differentiation, pluripotency, transgenesis, central nervous system,

regenerative medecine, model organisms, embryos
Partners
Dr. Jean-Stéphane Joly
Institut National de la
Recherche Agronomique (INRA)
Physiologie animale et
systèmes d’élevage (PHASE)
UNIT 1126. DEPSN-bt
32-33 Avenue de la Terrasse Prof. Manfred Schartl
91198 Gif-sur-Yvette, France University of Wurzburg
joly@iaf.cnrs-gif.fr Department of
Physiological Chemistry
Dr. Jochen Wittbrodt Wurzburg, Germany
European Molecular
Biology Laboratory (EMBL) Dr. Philippe Gennes
Developmental Biology Unit ONCODESIGN
Heidelberg, Germany Dijon, France
Dr. Patrick Lemaire Dr. François Guillemot

Centre National de la Medical Research Council
Recherche Scientifique (CNRS) Molecular Neurobiology
Genetics and Physiology London, UK
Development Laboratory
Marseille, France Prof. Angelo Vescovi
University of Milano Bicocca
Dr. Filomena Ristoratore Istituto di Ricerca per le
Stazione Zoologica Anton Dorhn Cellule Staminali
Naples, Italy Milan, Italy
ESTOOLS
www.estools.eu

Integrated Project
Contract number: ESTOOLS will significantly advance the fundamental understanding that will underpin bio-
medical application of human embryonic stem (hES) cells. Pluripotent hES cells present a
LSHG-CT-2006-018739
unique opportunity to study human cellular differentiation and pathogenesis. hES cells also
Starting date: offer a new resource for cellular transplantation in human degenerative disease and a
1st August 2006 powerful platform for pharmaceutical and toxicology screening. The promise of hES cells
Duration: rests largely on unlimited expansion in stem cell numbers without genetic or epigenetic com-
48 months promise, and on directing differentiation with absolute phenotypic fidelity. Success entails
EC Funding: understanding the mechanisms controlling the choice between (a) proliferation and self
renewal, and (b) apoptosis or commitment to differentiation.
`12 000 000
Genetic intervention is a key tool for delineating the molecular circuitry of hES cells. ES-
TOOLS will develop the tools needed to elucidate the genetic and molecular networks
that control the self renewal, commitment and terminal differentiation of hES cells. Neural
commitment provides a paradigm for understanding the mechanisms by which embryonic
stem cells choose between self renewal and lineage commitment. Neuronal and glial dif-
ferentiation of hES cells offer major new experimental avenues for cellular neurobiology
and pathogenesis, with potential eventual application in bio-industry and medicine via
pharmaceutical and toxicological screening and cell replacement therapies. By character-
ising progression from embryonic stem cell through naive neuroectodermal precursors to
functionally differentiated neuronal and glial sub-types and establishing conditions for the
quantitative production of neurons and glia, ESTOOLS will provide vital new experimental
avenues for study of cellular neurobiology and neuropathogenesis. In parallel, an ethics
team will research ethical issues pertinent to the derivation and use (including commercial)
of hES cells and will engage with scientists in ESTOOLS and with stakeholders.
The overall goal of ESTOOLS is to standardise and optimise protocols for the culture of hu-
man embryonic stem cells, to ensure their genotypic and phenotypic stability and to estab-
lish techniques and understanding to allow their robust differentiation into functional cells of
the neural lineage. Other objectives include:
1) developing optimised culture conditions to enable standardised propagation of hu-
man embryonic stem cells;
2) permitting the use of reliable, defined serum-free culture protocols and automated cell
culture systems;
3) providing a toolkit of protocols and reagents for routine genetic manipulation of hu-
man embryonic stem cells, to establish them as a genetically tractable system compa-
rable with mouse embryonic stem cells;
4) determining mechanisms that control self renewal and commitment to differentiation
of human embryonic stem cells, allowing: (a) improved techniques to monitor the ge-
netic and epigenetic integrity of human embryonic stem cell cultures (b) development
of culture methods that minimise the genetic instability of human embryonic stem cells
(c) definition of the key parameters of epigenetic stability and variability in human
embryonic stem cells (d) development of methods to maintain human embryonic stem
cells in an undifferentiated state and prevent unwanted spontaneous differentiation;
5) establishing models of fate, choice and pathogenesis for the human central nervous
system and elucidation of the molecular mechanisms, regulatory networks and key
Platforms for biomedical discovery
with human ES cells
Neuronal cells differentiated

from hES derived neural stem
cells stained with beta-III tubulin
positive (green) and Hoechst
33342 (blue) University of
Sheffield (UK) Centre for Stem
Cell Biology, 2006
signalling pathways that govern choice between self-renewal and lineage commit-
ment, allowing: (a) development of protocols to promote the differentiation of human
embryonic stem cells to the neuroectodermal lineage; (b) delineation of the epige-
netic contribution to lineage commitment; (c) development of new tools for genetically
monitoring specific states of the cells from ‘undifferentiated’ to ‘lineage committed
and ‘terminally differentiated’; (d) identification of conditions for the robust produc-
tion of functionally validated, mature neuronal phenotypes;
6) promoting bio-industry exploitation of human embryonic stem cell biology through
small to medium sized enterprise (SME) partners and the biopharmaceutical sector
by developing: (a) procedures to automate biomanufacturing of human embryonic
stem cells and their differentiated progeny; (b) novel monoclonal antibodies to cell
surface markers for the identification of undifferentiated human embryonic stem cells
and for monitoring their differentiation; (c) tools for neurodegeneration.
Expected Results:
By the end of its fourth year ESTOOLS will have established that human embryonic stem
cells provide a genetically tractable system, comparable with mouse embryonic stem cells,
facilitating realisation of the potential benefits that these cells offer to human health care. The
following expected achievements will provide evidence for these conclusions:
1) a refinement, standardisation and optimisation of the culture conditions needed to
propagate human embryonic stem cells with phenotypic and genotypic fidelity and to
create associated user-friendly and reliable protocols;
2) the ability to monitor multiparametrically the genotypic and epigenotypic integrity of
human embryonic stem cell cultures;
3) a toolkit of protocols and reagents for the routine genetic manipulation of human
embryonic stem cells;
4) an understanding of the molecular mechanisms and regulatory networks that govern
a stem cell’s choice of self-renewal or lineage commitment;
ESTOOLS
5) a definition of the key parameters of epigenetic stability and variability in the human
embryonic stem cells;
6) an understanding of the molecular process and mechanism of lineage commitment;
7) a delineation of the epigenetic contribution to lineage commitment;
8) an ability to direct neuroectodermal lineage choice to 90% efficiency;
9) a description of the necessary conditions for robust production of functionally vali-
dated mature neuronal phenotypes and the generation of specific classes of neuronal
and glial progenitors;
10) the initiation of neuro-degeneration modelling and of neuro-modulatory drug
screens;
11) the introduction of quality-controlled ‘good manufacturing processes’ for human em-
bryonic stem cells;
12) procedures to automate the bio-manufacturing of human embryonic stem cells and
their differentiated progeny.
Potential Impact:
Human embryonic stem cell
biology provides new tools for
applications in a wide range of
fields from understanding hu-
man development and disease
processes to drug discovery
and toxicology and, eventu-
ally, to regenerative medicine.
ESTOOLS will help realise this
potential by widening and
deepening the range of skills
and experience in human em-
bryonic stem cell research
across Europe. The project will
play a significant role in the
development of standardised
techniques, protocols and rea-
gents, permitting standardisa-
tion of research with human
embryonic stem cells in Eu-
rope, and throughout the world, through the close relationship between ESTOOLS and the
International Stem Cell Initiative. The SME partners in ESTOOLS will be the springboard
for bio-industrial exploitation of the project’s results. Future research into the mechanisms
of human embryonic stem cell lineage commitment and differentiation, and development
of biopharmaceutical industry applications - eventually for regenerative medicine - requires
these cells to be genetically manipulated robustly in well-defined ways. Thus ESTOOLS will
develop a genetic ‘toolkit’ to help realise the potential of human embryonic stem cell re-
search in Europe. ESTOOLS will contribute to the social sustainability of continuing research
and application of knowledge outputs by analysis of the ethical issues surrounding use of
human embryos and their stem cells in the different social contexts of European countries.
Keywords:
differentiation, self-renewal, neural, stem cells, human embryonic stem cells
Platforms for biomedical discovery with human ES cells
Partners
Project Coordinator: Dr. Jim Walsh Dr. Danny Kitsberg
Prof. Peter W Andrews Axordia Ltd SCT Stem Cell Technologies Ltd
University of Sheffield Sheffield, UK Jerusalem, Israel
Centre for Stem Cell Biology
Department of Biomedical Sciences Dr. Petr Dvorak Dr. Andrew Smith
Western Bank Institute of Experimental Medicine University of Edinburgh
Sheffield, S10 2TN, UK Academy of Sciences of the Czech Republic Institute for Stem Cell Research
p.w.andrews@sheffield.ac.uk Prague, Czech Republic Edinburgh, UK
Project Manager: Prof. Goran Hermeren Dr. Konstantinos Anastassiadis

Andrew Smith Lund University Technische Universität Dresden
ESTOOLS Project Office Faculty of Medicine BIOTEC
c/o University of Sheffield - BMS Lund, Sweden Dresden, Germany
Western Bank
Sheffield, S10 2TN, UK Prof. Outi Hovatta Prof. Austin Smith
asmith@estools.eu Karolinska Institutet University of Cambridge
Department of Clinical Science School of the Biological
Dr. Tim Allsopp Intervention and Technology Sciences
Stem Cell Sciences UK Ltd Stockholm, Sweden Wellcome Trust Centre
Cambridge, UK for Stem Cell Research
Dr. Maarten van Lohuizen Cambridge, UK
Prof. Yves-Alain Barde Netherlands Cancer Institute
University of Basel Division of Molecular Genetics Dr. Meng Li
Biozentrum Amsterdam, The Netherlands Imperial College of Science
Basel, Switzerland Technology and Medicine
Prof. Timo Otonkoski London
Prof. Nissim Benvenisty University of Helsinki MRC Clinical Sciences Centre
Hebrew University of Jerusalem Biomedicum Stem Cell Center London, UK
Department of Genetics Helsinki, Finland
Institute of Life Sciences
Jerusalem, Israel
Prof. Riitta Lahesmaa

University of Turku
Turku Centre for Biotechnology
Turku, Finland
Prof. Oliver Brustle

Rheinische Friedrich-Wilhelms-Universität Bonn
Institute of Reconstructive Neurobiology
Bonn, Germany
Prof. Elena Cattaneo

Universita Degli Studi di Milano
Department of Pharmacological Sciences
Milan, Italy
Prof. Tariq Enver

Weatherall Institute of Molecular Medicine
Oxford, UK
Dr. Manuel Esteller

Centro Nacional de Investigaciones Oncológicas
Grupo de Epigenética del Cáncer
Madrid, Spain
EuTRACC
www.eutracc.eu

Integrated Project
Contract number: The EuTRACC consortium proposes to determine the regulation of the genome by mapping
the regulatory pathways and networks of transcription factors (TFs) that control cellular
LSHG-CT-2007-037445
functions. EuTRACC will be part of and work in close collaboration with the International
Starting date: Regulome Consortium (IRC), a worldwide network that will address the regulation of ge-
1st April 2007 nome function at a higher level by mapping the genetic regulatory nodes and networks
Duration: that control the activity of embryonic stem cells and the process of differentiation to specific
48 months cell types. It will focus on mapping the genetic circuitry that controls the formation of neural
EC Funding: tissues and the blood system. The project will utilise genetics, proteomics and genomics
tools in the mouse, zebrafish and Xenopus model organisms. These approaches will allow
`12 000 000
the characterisation of transcription factor complexes and the genome-wide identification
of binding sites for these TFs in undifferentiated and differentiated ES cells or differentiated
tissues (blood and neuronal system). It will systematically identify TF complexes and TF
binding sites in vertebrate genomes required for the differentiation into haematopoietic and
neural cells. The bio-informaticians will develop novel algorithms to extract and interpret the
data and viewers to integrate the information in the ENSEMBL database. Data will be made
available publicly through web based platforms and tools. Databases will be constructed
that will include annotated TFs, TF-DNA interactions, protein- and RNA TF interactions and
cellular regulation (gene, effect, cell type, cell state). The project databases will be inter-
faced with existing micro-array databases as well as other public databases. The project
will provide new insights into the regulation of cell function that stimulate translational re-
search, which is critical for developing novel therapies, particularly in the areas of stem cell
transplantation and tissue engineering.
1) to ensure a substantial contribution of EU based science to the field of transcriptional
regulation of differentiation and development;
2) to provide strong input from the EU to the International Regulome Consortium (IRC),
a worldwide consortium that represents a third generation genomics project ad-
dressing the regulation of genome function at a higher level by mapping the genetic
regulatory nodes and networks;
3) to identify protein complexes of basic, general and tissue-specific TFs and interacting
partners expressed in neuronal and haematopoietic cell types;
4) to use bioinformatic methods to correctly annotate mouse genes that encode bona
fide TFs and interacting proteins. Microarray data will be analysed to identify TF
complexes expressed in the selected cell types;
5) to validate interactions by IPs and/or BiFC;
6) to determine intracellular localisation of TFs and/or associated proteins;
7) to identify target genes of the different TF complexes;
8) to functionally analyse TFs and selected interacting proteins by morpholino injections
in zebrafish and Xenopus embryos;
9) to create computational procedures and models that describe the mechanism of
regulation of gene transcription in order to differentiate embryonic stem cells from
neuronal or haematopoietic cells. Specific databases and tools will be developed to
facilitate the collection, curation and analysis of the data, as well as for the public
dissemination of findings.
European Transcriptome, Regulome &
Cellular Commitment Consortium
Technical objectives for this application are:

1) to generate 100 knock-ins of protein tags for affinity purification of TF complexes and
concurrently generate conditional TF KOs in ES cells;
2) to generate homozygous null mutations in key TFs in ES cells and mice;
3) to culture and differentiate TF tagged ES cells in vitro and isolate the relevant tissues
from ES generated mice for genomic and proteomic analyses;
4) to characterise the protein components of transcriptional complexes containing the
tagged TFs in selected cell and tissue types;
5) to purify and identify TF binding sites in selected cell types by two approaches -
chromatin affinity purification, followed by DNA amplification, and hybridisation to
genome wide microarrays (Affymetrix, Agilent or Nimblegen). Fine mapping, when
required, will be done by in vivo footprinting.
6) to repeat cycles of tagging knock-ins for affinity purification etc. by tagging selected
interaction partners from the previous screen.
Expected Results:
The development of methodology to set up a ‘pipeline’ that allows:
1) the tagging of the N- or C-terminus of protein via homologous recombination in ES
cells (and/or other cell lines) of the gene coding for the protein of interest;
2) rapid affinity-based purification of proteins of interest;
3) concomitant generation of conditional KO alleles of the gene coding for the protein of
interest by inclusion of loxP sites for Cre mediated recombination in vivo or in vitro;
4) two rounds of affinity purification and protease mediated release to rapidly obtain
highly purified protein complexes that can be used for a variety of functional and
structural studies;
EUTRACC
5) rapid identification of transcription factor binding sites in vivo, using the protein
tags;
6) rapid functional analysis using morpholinos to functionally identify the key proteins
in a TF complex;
7) the generation of databases of transcription factors and interacting partners for
stem cells, haematopoietic cells and neuronal cells. This will also help to improve
the predictive power of in silico prediction methods;
8) the generation of algorithms to model transcription factor networks in collaboration
with IRC.
Potential Impact:
EuTRACC will focus on mapping the transcriptional circuitry on the molecular level and how
it controls the formation of neural tissue and the blood system. Understanding the regulatory
network is one of the big challenges for biology in the next decade. It will provide much bet-
ter insight into the normal and abnormal formation of stem cells and tissues and into disease
processes and be an essential part of future developments in medicine and biotechnology,
in particular those areas that are concerned with stem cell biology. EuTRACC will provide
a substantial impetus to fundamental and translational research by making its data publicly
available and seeking new collaborations and alliances where appropriate. The expecta-
tion is therefore that it will substantially contribute to the development of novel therapies and
improved health benefits for society. EuTRACC provides an excellent opportunity for the EU
to strengthen its competitive position in this area by bringing together a group of excellent
researchers with a high level of expertise in the different areas required for a successful,
comprehensive and integrated approach. Genomic research is an essential component of
an innovation-based economy, generating Intellectual Property, leading to the development
of new technologies, providing the basis for new companies and stimulating employment
in new industries.
Keywords:
transcriptome, regulome, cellular commitment, transcription factors, neurobiology, hemat-
opoiesis, embryonal development
Partners
Project Coordinator: Prof A. Francis Stewart
Prof. Dr. Frank Grosveld Biotec, Genomics
Erasmus MC University Medical Center Dresden, Germany
P.O. Box 2040 Dr. Irwin Davidson, Dr. Laszlo Tora
3000 CA Rotterdam, The Netherlands CERBM-GIE (IGBMC)
f.grosveld@erasmusmc.nl Illkirch, France
Project Manager: Prof. Dr. Meinrad Busslinger

Dr. Rini de Crom Research Institute of Molecular Pathology GmbH
Erasmus MC University Medical Center Vienna, Austria
P.O. Box 2040 Prof. Dr. Yves-Alain Barde
3000 CA Rotterdam, The Netherlands University of Basel
eutracc@erasmusmc.nl Department of Neurobiology
Basel, Switzerland
European Transcriptome, Regulome & Cellular Commitment Consortium
Prof. Dr. Uwe Straehle Dr. Michael Rudnicki

Institute of Toxicology and Genetics Ottawa Health Research Institute
Forschungszentrum Karlsruhe Ottawa, Canada
Karlsruhe, Germany
Dr. Ferenc Müller
Prof. Dr. Magdalena Goetz, Prof. Dr. Wolfgang Wurst University of Birmingham
Helmhotz Zentrum München Institute of Biomedical Research, Medical School
Deutsches Forschungszentrum für Birmingham, UK
Gesundheit und Umwelt GmbH
Neuherberg, Germany Prof. Dr. Michael Meisterernst
University of Münster
Dr. W. Skarnes Department of Medicine, Tumor Biology
Genome Research Ltd Münster, Germany
Hinxton, UK
Prof. Dr. H. Th. M. Timmers

University Medical Centre Utrecht
Department of Physiological Chemistry
Prof. R. Patient
Weatherall Institute of Molecular Medicine
John Radcliffe Hospital
Oxford, UK
Prof. J. Smith
Wellcome Trust/Cancer Research UK Gurdon Institute
Cambridge, UK
Prof. C. Bonifer
University of Leeds
Division of Experimental Haematology
Leeds Institute for Molecular Medicine
Wellcome Trust Brenner Building
St. James’ University Hospital
Leeds, UK
Prof. Dr. M. Vingron

Department of Computational Molecular Biology
Berlin, Germany
Prof. Dr. R. Aasland, Dr. Boris Lenhard

University of Bergen
Bergen, Norway
Prof. A. Simeone
CEINGE Biotecnologie Avanzate s.c.a.r.l.
Naples, Italy
Prof. R. Di Lauro
Instituto Ricerche Genetiche Gaetano Salvatore
Ariano Irpino (Av), Italy
7.4 RNA
BIOLOGY
RIBOREG
FOSRAK
Callimir
EURASNET
BACRNAs
RNABIO
SIROCCO
RIBOREG
www.isv.cnrs-gif.fr/mc/riboreg
State-of-the-Art:
Project Type: The post-genomic era is yielding tremendous amounts of data about plant and animal
Specific Targeted genomes and their expression. In order to exploit and understand this data it will be neces-
sary to determine the mechanisms leading to patterns of gene expression in differentiation
Research Project processes. The ability to understand how gene expression varies and how cytoplasmic
Contract number: processes communicate with the nucleus to establish an overall RNA-mediated regulation is
LSHG-CT-2003-503022 of key importance in the post-genomics phase.
Starting date: Riboregulators can be separated into three major classes, namely, the small (21-25nt) si/
miRNAs, the long non-protein coding RNAs produced by RNA polymerase II (npc-mRNAs)
1st February 2004 and the ncRNAs produced by RNA polymerase III or pol III riboregulators (e.g. snoRNAs,
Duration: SINE elements). The RIBOREG project concentrates on the identification of novel riboregula-
36 months tors involving all three types of riboregulators, in plants and animals.
EC Funding:
RIBOREG aims to identify novel non-coding RNA (ncR-
NA) genes linked to cell differentiation and disease
and analyse their mechanisms of action by developing
a multidisciplinary approach integrating bioinformat-
ics, cell biology, genetics and genomic strategies.
RIBOREG’s key objectives were to develop bioinfor-
matics tools for gene mining; isolate novel regulatory
ncRNAs; utilise genomics approaches to characterise
expression patterns for these genes; identify cellular
targets of ncRNAs by screening and/or preparing
mutants affected in their function in model organisms;
dissect cellular mechanisms involving selected RNAs
In situ hybridization of miRNAs in differentiation and disease; establish cell biologi-
in flower tissues of cal approaches for monitoring in vivo RNA-protein
arabidopsis thaliana using interactions; and to validate innovative technology
different LNA probes. for functional and structural analysis of ncRNAs. RI-
BOREG also aimed to integrate the results obtained
in different systems on the function of riboregulators. The project was therefore of extreme
importance for SMEs concerned with developing and validating tools for the analysis of this
novel area of gene regulation. The project gave European biotechnology a lead in explor-
ing the potential of genome information in relation to human health.
Expected Results:
The main expected results were:
s ABOUTNEWNC2.!SINHUMANMOUSEC. elegans and A. Thaliana;
s TRANSGENICMOUSEANDPLANTSAFFECTEDINNC2.!EXPRESSION
s MICROARRAYSCORRESPONDINGTONC2.!GENES
s INDEPTHANALYSISOFTHEMECHANISMSINVOLVINGNC2.!SINTHESEORGANISMS
s EXPRESSIONPATTERNOFNC2.!SINDIFFERENTIATIONANDDISEASE
s IDENTIlCATIONOFNC2.!TARGETSANDINTERACTINGPROTEINS
Throughout the project RIBOREG published its results in scientific journals (approximately
30 scientific publications with several in high-impact journals such as Molecular Cell, Na-
ture Genetics and Science). Technological developments in the project also resulted in two
patents that were applied for in Spain by an SME partner (Biomedal); one was undertaken
in collaboration with a University partner (ABC, Hungary) and the other with the Spanish
National Research Council partner (CSIC).
Finally, collaboration within the RIBOREG project has led to the acceleration of the devel-
opment of Locked Nucleic Acid (LNA) probe technology, which has allowed RIBOREG’s
partner, Exiqon, to commercialise a number of products based on this technology.
Novel non-coding RNAs
in differentiation and disease
Potential Impact:
RIBOREG’s work proves tremendously beneficial to researchers interested in genome min-
ing and novel regulatory mechanisms, biotechnologists dealing with RNA-based product
development in plants and animals, and clinicians interested in new RNA-based therapies.
The project also aims to integrate the results obtained in different systems on the function of
riboregulators. In this sense, RIBOREG helps SMEs concerned with developing and validat-
ing tools for the analysis of this novel area of gene regulation.
In general, the dissemination of project achievements, combined with a possible pooling of

resources and an active networking approach contributes to the development of skills and
know-how throughout the European industrial and scientific community. The technological
progress stimulated by RIBOREG’s innovative solutions also provides the foundation for en-
hanced cooperation between SMEs and public institutions. In particular, SMEs are able to
compare their genomic approaches for the study of non-coding RNAs, and develop market-
able products specifically suited for this purpose (as was notably the case for Exiqon and
the LNA technology and for BIOMEDAL and the c-LYTAG system). The validation of these
technologies is an area of considerable interest for SMEs.
Keywords: non-coding RNAs, riboregulator, differentiation, disease

Partners
Project Coordinator: Prof. Jürgen Brosius Dr. Erik Antonie Cornelis Weimer
Dr. Martin Crespi Westfaelische Wilhelms – Universitaet Erasmus Medical Center Rotterdam
Centre National de la Recherche Institute of Experimental Department of Medical Oncology
Scientifique (CNRS) Pathology ZMBE Josephine Nefkens Institute
Institut des Sciences du Münster, Germany RMB420
Végétal (UPR no 2355) Rotterdam, The Netherlands
Avenue de la Terrasse 1
91198 Gif-sur-Yvette, France
crespi@isv.cnrs-gif.fr
Dr. Jean-Marc Deragon, Dr. Peter Mouritzen
Dr. Claude Thermes Exiqon A/S
Centre National de la Recherche Department of Functional Genomics
Scientifique (CNRS) Vedbaek, Denmark
Gif–sur-Yvette, France
Dr. Palmiro Poltronieri
Dr. Jozsef Burgyan BIOTECGEN Srl
Agricultural Biotechnology Novoli, Italy
Centre (ABC)
Plant Biology Institute Dr. Angel Cebolla Ramirez
Godollo, Hungary BIOMEDAL S.L.
Sevilla, Spain
Dr. Hervé Vaucheret
Unité de Biologie Cellulaire
Versailles, France
Prof. Javier Paz-Ares Rodriguez

Consejo Superior de
Investigaciones Cientificas (CSIC)
Centro Nacional de Biotecnologia
Madrid, Spain
FOSRAK
www.fosrak.org
State-of-the-Art:
Project Type: Traditionally, the focus of molecular biology and biochemistry has been on DNA and pro-
Specific Targeted teins. However, important findings over the last 15 years or so, suggest that the role of small
Research Project RNAs (sRNAs) in the life sciences has been significantly underestimated. In eukaryotes,
sRNAs of approximately 20-25 nucleotides in length — so-called small interfering RNAs
Contract number: (siRNAs), and micro RNAs (miRNAs) — either induce degradation of homologous target
LSHG-CT-2004-005120 messenger RNAs (mRNAs) by RNA interference, or inhibit their translation.
Starting date: A second, important class of non-coding RNAs, involved primarily in the modification of
1st January 2005 ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs), is the small nucleolar RNAs
Duration: (snoRNAs) of eukaryotes and archaea. There are indications that some snoRNAs act on
hitherto unidentified cellular mRNAs. Equally of interest, is the high prevalence of regula-
36 months tory RNAs in bacteria. Bacterial sRNAs regulate specific functions in plasmids, phages and
EC Funding: transposons. Bacterial chromosomes encode many non-coding RNAs, most of which ap-
`1 442 000 pear to regulate target genes by antisense mechanisms. In Escherichia coli, sRNAs control
stress responses, while in Staphylococcus aureus they control virulence.
RNAs act as regulators of gene expression and also perform other activities, often aided by
proteins. Creating a division between bacterial and eukaryotic systems can be detrimental for
the development of a profound understanding of RNA biology. By contrast, it proves extreme-
ly fruitful to bridge the gap between different experimental systems, organismic backgrounds
and scientific cultures. FOSRAK aims to develop an understanding of the peculiarities of each
system. Furthermore, the team plans to ascertain what the fundamental similarities are be-
tween the functions of regulatory RNAs across kingdoms. Europe is currently lagging behind
in the field of RNA biology, and FOSRAK intends to make headway in closing that gap.
FOSRAK addresses the recently recognised importance of sRNAs in organisms across
kingdoms, and the mechanisms of gene regulation by which they control physiological
responses, developmental checkpoints and virulence in several human pathogens. The gen-
eral objective is to advance knowledge of sRNAs beyond the state-of-the-art, but also, more
specifically, to explore their potential for application in the prevention or treatment of human
diseases.
The project has several specific aims, summarised below: (1) Identification of molecular
targets for various RNAs acting in gene regulation (regulatory RNAs); (2) Characterisa-
tion of protein components that are part of the cellular machinery, and are involved in the
functionality of small regulatory RNAs; (3) Understanding the mechanisms by which small
Spontaneous systemic regulatory RNAs recognise and interact with their cognate molecular targets; and (4) Deci-
spreading of silencing phering the biological role of different classes of small regulatory RNAs and their general
of a GFP (green functional significance in regulating gene expression.
fluorescent protein)
transgene in a
Nicotiana benthamiana Expected Results:
leaf. Red areas
indicate loss of GFP Elucidation of the major aspects of RNA biology across kingdoms, and understanding the
similarities and differences in RNA-mediated molecular mechanisms between organisms,
expression.
are among the expected results of FOSRAK. During the first stage of the project, tremendous
progress was made relating to the identification of experimentally validated or strongly pre-
dicted targets for miRNAs, imprinted miRNAs and regulatory RNAs in protists and bacteria
(non-pathogenic and pathogenic). The enzymology of proteins associated with, or required
for, the functioning of regulatory RNAs, has been another focus of the project so far. For
instance, the role of the Hfq protein in bacteria, the roles of Dcr, helicases, RDRs and Ago
proteins in RNAi/miRNA-dependent regulation, and the role of ribonucleases in RNA me-
tabolism and regulation, have proved fruitful areas of investigation.
Function of small RNAs across kingdoms
Potential Impact:
The identification of the targets of regulatory RNAs and mechanistic studies,
will have critical implications for our understanding of cellular gene expres-
sion. The project also deals with the potential role of small regulatory RNAs in
human diseases, research that may influence the development of RNA-based
therapeutics.
FOSRAK will contribute to conceptual and technological advances, such as the
development of a bioinformatics platform for the prediction of sRNA targets,
and the use of sophisticated instruments (e.g. scanning force microscopy and
biosensors), which are not yet being used as standard methods for the analysis
of RNA-RNA and RNA-protein interactions.
Keywords: regulatory RNA, non-transcriptional gene regulation,

Dicer, non-coding RNA, bioinformatics, fundamental genomics, functional
genomics, gene expression, structure analysis, miRNA, snoRNA
Partners Upper left: Electron microscopy

picture of Escherichia coli cells
Project Coordinator: Prof. Martin Tabler †, Dr. Kriton Kalantidis
Prof. E.Gerhart Wagner (artificially colored)
Foundation for Research
Uppsala University and Technology - Hellas Upper right: 3D model of the
Department of Cell and RNA laboratory catalytically active hammerhead
Molecular Biology Heraklion, Greece ribozymes in Arabidopsis thaliana
Biomedical Center (acc. to Przybilski et al., 2005,
Husargatan 5 Dr. Michael Wassenegger Plant Cell). The catalytic centre
75124 Uppsala, Sweden RLP AgroScience GmbH, is shown in green and orange,
Gerhart.Wagner@ICM.UU.SE AIPlanta-Institute for Plant Research and the tertiary interacting apical
Gene Silencing and Epigenetics loops are in magenta.
Prof. Wolfgang Nellen, Neustadt/Weinstrasse, Germany Lower left: Schematic model of
Christian Hammann antisense RNA inhibition of ri-
Universität Kassel Prof. Witold Filipowicz bosome “standby” in control of a
Faculty of Natural Sciences Friedrich Miescher Institute for bacterial toxin (acc. to Darfeuille
Institute of Biology Biomedical Research et al., 2007, Mol. Cell).
Laboratory of Genetics Basel, Switzerland Lower right: Example of a lead(II)
Kassel, Germany probing experiment; binding of a
Dr. Bastian Zimmermann complementary RNA to its target
Dr. Martina Paulsen Biaffin GmbH & Co KG site results in a “footprint” on
Universität des Saarlandes Faculty of Natural Sciences the 5’-end-labeled mRNA (two
FR 8.3 Biowissenschaften Institute of Biology right-hand lanes).
Genetik / Epigenetik Kassel, Germany
Saarbrücken, Germany
Dr. Pascale Romby

UPR 9002 CNRS-SMBMR “Structure des
Macromolecules et Mecanismes de
Reconnaissance Moleculaire”
Institut de Biologie Moleculaire et Cellulaire
Strasbourg, France
Dr. Fredrik Söderbom

Swedish University of Agricultural Sciences
Uppsala, Sweden
Callimir
www.fmv.ulg.ac.be/genmol/Callimir_Page/Callimir_home.htm
Project Type:
State-of-the-Art:
Specific Targeted In addition to the protein-encoding messenger RNA (mRNA), genome transcription gener-
Research Project ates a flurry of so-called non-coding RNA genes, including ribosomal RNAs, transfer RNAs,
small nuclear and small nucleolar RNAs (snRNAs and snoRNAs respectively). This family
Contract number:
has recently witnessed a spectacular expansion, with the discovery of a multitude of small
LSHG-CT-2004-005255 RNA species that are involved in RNA interference-related biology (including micro RNAs,
Starting date: or miRNAs), and long, non-coding RNA species of unknown function.
1st January 2005 The aim of Callimir is to decipher the biological role of non-coding RNA genes by studying
Duration: the imprinted Dlk1-Gtl2 domain, due to this domain possessing one of the highest densities
of miRNAs in the mammalian genome. The region contains several long, non-coding RNA
36 months genes exclusively expressed by the maternal allele, which are the hosts of a very large
EC Funding: number of snoRNAs and miRNAs. A series of unique genetic mutants will permit the study
`958 849 of these non-coding RNAs.
The Dlk1-Gtl2 domain is an evolutionarily con-
served, 1 megabase cluster of imprinted genes that
contains at least three protein-encoding genes ex-
pressed by the paternal allele (Dlk1, Rtl1, Dio3), a
series of non-coding RNA genes expressed by the
maternal allele (Gtl2, Meg8, Mirg), and multiple,
small, non-coding RNA genes. The latter include
a pair of miRNA genes (mir127 and mir136) that
are antisense to Rtl1, a cluster of snoRNA genes
processed from the introns of Meg8, and a cluster
of miRNA genes processed from a large precursor
transcript (Mirg). Callimir intends to analyse the
biological function of miRNA in Mirg, and the role
of Mirg miRNAs in mediating the CLPG trans effect.
Callimir aims to elucidate the function and mode
of action of these miRNA genes, by studying the
nature of their interaction and the consequences of
Schematic representation of the Dlk1-Gtl2 imprinted domain: their elimination. Due to an existing battery of unique reagents
Key elements are depicted: paternally expressed genes in already available or generated as part of the project, the con-
blue, maternally expressed non coding RNA, including clusters sortium is well-equipped to determine the role of mir127 and
of snoRNA and miRNA in red, localization of two regulatory mir136 in regulating the expression of Rtl1, and to analyse the
elements, the callipyge mutation (yellow dot) and the intergenic developmental roles of Rtl1 and mir127/136.
differentially methylated region (IG-DMR, black dot when
methylated, white dot when unmethylated).
Brackets and numbers represent animal models currently Expected Results:
analysed: [1] the callipyge sheep (left picture) and two
transgenic mice lines for this mutation; [2] a There have been several major achievements within the project’s
mouse model with a deletion of the IG-DMR; [3] first year:
several mouse models targeting each miRNA of 1) For the first time, there has been demonstration of the role
the antiPeg11 gene as well as introducing a stop of miRNA-mediated RNA interference in regulating imprinted
codon in the Rtl1/Peg11 gene; [4] a mouse model genes.
carrying a conditional deletion of the entire miRNA 2) Using multicolour RNA FISH at the single nucleus level, there
cluster in Mirg. has been demonstration that non-coding RNAs transcribed
from the Dlk1-Gtl2 domain form large elongated ‘nuclear
track’ structures, and accumulate as single-molecule nuclear
RNA foci within the interchromatin space.
Studying the biological role of microRNAs
in the Dlk1-Gtl2 imprinted domain
3) A comparative evolutionary analysis identified the origin and identity of members
of the Rtl1/Peg11 gene family in the mammalian genome. The hypothesis that this
retrotransposon-like gene plays a role in conferring imprinting was tested and dis-
proved.
4) By studying a muscular hypertrophy in sheep, the Callimir consortium has identified an
important novel class of mutations that affect the interaction between miRNAs and their
targets. Bioinformatics analyses of SNPs databases for human and mice has demonstrat-
ed that mutations creating or destroying putative miRNA target sites are abundant, and
might be important effectors of phenotypic variation. A publicly accessible database
with this information compiled on it, has been created - http://www.patrocles.org/
Potential Impact:
Callimir is studying fundamental biological mechanisms related to the role and mode of
action of miRNAs. It has been demonstrated recently that miRNAs regulate as much as a
third of our genes, if not more. Hence miRNAs play a key role in orchestrating and fine-
tuning mammalian gene expression, and perturbation of miRNA-mediated gene regulation
contributes to disease.
The Callimir consortium has unique genetic models, either created by genetic engineering
or discovered as naturally-occurring oddities, which express mutations that perturb miRNA-
mediated gene regulation, causing complex phenotypes. These models will allow the study
of the mechanisms of miRNA-mediated gene regulation in vivo. In addition, the Patrocles
database, which compiles mutations that have the potential to perturb miRNA-target interac-
tions and hence gene regulation, in a variety of species including man and mouse, will be
of benefit to the genetics community at large.
Keywords: micro RNA, sno RNA, imprinting, callipyge
Partners
Project Co-Coordinators:
Dr. Michel Georges, Prof. Anne Ferguson-Smith
Dr. Carole Charlier University of Cambridge
University of Liège Department of Physiology
Unit of Animal Genomics Development & Neuroscience
Faculty of Veterinary Medicine Cambridge, UK
1 Avenue de l’Hôpital
4000 Liège, Belgium
michel.georges@ulg.ac.be
carole.charlier@ulg.ac.be
Dr. Jérôme Cavaillé

Laboratoire de Biologie Moléculaire
des Eucaryotes
UMR 5099
Toulouse, France
EURASNET
www.eurasnet.eu

Contract number: The rationale behind the sequencing of the human genome and that of other model organ-
isms stemmed from the assumption that, by knowing the content of the genetic material, it
LSHG-CT-2005-518238
would be possible to understand the processes that control development and reproduction
Starting date: in living organisms. This would consequently lead to better insights into how these processes
1st January 2006 are altered in disease.
Duration:
60 months The concept of the gene is central for the understanding of these issues. The “dogma” of
EC Funding: molecular biology has classically treated a gene, as a genetic unit directing the synthesis of
a single protein product. From this perspective, the genetic program of an organism is dic-
`10 000 000
tated by the subset of genes transcribed into RNA and translated into protein in a particular
cell or at a particular time during development.
Schematic overview of the gene-

expression pathway in eukaryo-
tic organisms. The genome is
located in the cellular nucleus
where it is transcribed and the
pre-mRNA is formed. After
several RNA processing steps
(including splicing) the mature
mRNA is transported to the
cytoplasm where protein produc-
tion proceeds (translation).
One of the most surprising results of the human genome project and of similar projects on
other metazoan genomes was the surprisingly low number of protein-coding genes found.
A dramatic gap was noted between the possibly only 25 000 protein-coding genes and
the observed huge diversity of the human proteome, that is, the complete spectrum of all
expressed protein forms in the cell. This figure has to be placed at least in the order of
100 000 proteins. The “missing diversity” on the DNA level is compensated for by the
alternative mRNA-splicing mechanism. This posttranscriptional event affects most human
genes and is responsible for the creation of potentially thousands of distinct proteins from
a single gene.
A eukaryotic gene encoding the message used for the production of a protein during trans-
lation is composed of various DNA segments: protein coding exons alternate with DNA
sequences that do not carry a protein coding function (introns). During the first step of gene
expression, DNA is transcribed into messenger RNA (mRNA). While the primary RNA tran-
European Alternative Splicing
script still contains both the exonic and the intronic

sequences, only a mature mRNA without intronic
sequences can serve as a template for ribosomal
protein synthesis. The process which removes the
introns from the primary mRNA transcript is called
pre-mRNA splicing. Introns are excised and the
remaining exons are joined to form a continuous
stretch of protein-coding sequence.
Pre-mRNA splicing not merely removes introns, it

also serves as a unique mechanism to create pro-
tein diversity. During the splicing process not all of
the exons are retained in the mature mRNA, some
exons are either included or excluded, the inclu-
sion of exons can be mutually exclusive, and for Alternative splicing dramatically
other exons there exists a large set of variants of which only one is selected for inclusion. By increases the complexity
employing such a combinatorial approach, alternative splicing creates a variety of distinct of the proteome.
proteins from one single gene. Protein variants (isoforms) thus created often have distinct
and often antagonistic functions.
Consequently, alternative splicing can greatly expand the information content of genom-
es, and understanding the mechanisms that lead to alternatively spliced transcripts will
be essential for a functional interpretation of genomic sequences. We will not be able
to decipher the genetic program of a higher eukaryotic genome unless we understand
the rules leading to the generation of alternatively spliced transcripts and the functional
diversity they provide.
The splicing reaction is catalyzed in the cell nucleus by a highly complex molecular ma-
chine, the spliceosome. The spliceosome is an RNP (for ribonucleoprotein) machine com-
posed of several RNAs and numerous proteins organized in several distinct subcomplexes
which are themselves RNP particles. A plethora of highly dynamic RNA-RNA, RNA-protein
and protein-protein interactions holds together this intricate mechanism. The recognition
and selection of the intron-exon borders (that is the substrates of the splicing reaction), the
assembly of the spliceosome and the structural and functional remodelling the spliceosome
undergoes during the course of the splicing reaction, are all part of an extraordinarily com-
plicated process.
It is therefore not surprising that alternative splicing during recent years has been in-
creasingly recognized as the causative agent or as a severity modifier behind an ever
increasing number of human pathologies, including cancer, neurodegenerative diseases,
viral infection and inflammatory responses. Current conservative estimates assume that
more than 15% of genetic diseases are caused by aberrant splice events. Our current
understanding of alternative splice events still lacks sufficient insight into the molecular
mechanisms of the combinatorial action of multiple regulators that govern splice site selec-
tion. Also the interplay between alternative splicing and other cellular processes requires
enhanced research efforts.
Thirty leading laboratories in the field of pre-mRNA splicing and splicing regulation have
joined efforts to create a Network of Excellence. These groups cover a wide range of
complementary expertise including computational, biochemical, proteomic, genomic, cell-
biological and organism-biological approaches to the study of post-transcriptional gene
regulation and its alterations in disease.
EURASNET
The primary purpose of this network will be to develop an integrated approach to the study
of alternative splicing that will (1) provide durable structures that will change the way re-
search in this research topic is carried out in Europe, (2) establish an ambitious, innovative
and multidisciplinary program of joint research activities with high impact, and (3) spread
excellence within Europe, disseminate knowledge about alternative splicing in the molecu-
lar biology and medical communities, and foster public awareness of genomics and RNA
research and their applications.
EURASNET aims not only to improve our knowledge of alternative splicing but also to raise
awareness on alternative splicing related issues, particularly in the health science community.
Mis-splicing and disease:

The Joint Program of Research has a strong focus on alternative splicing events and regulatory
mechanisms related to genetic disease or influencing disease progression. Our understand-
ing of signals involved in the mis-regulation of splice events is incomplete. Moreover, their
often elusive nature as mutations not resulting in obvious amino acid changes complicates
diagnostics and therapeutic strategies of aberrant splicing. Regulatory splicing factors and
their disease-dependent changes in abundance and tissue-specific concentration will be scru-
tinized.
Data on particular diseases is still too sparse and, in order to establish the concept of “RNA
and Disease”, a wide range of diseases needs to be surveyed. Deciphering the regulatory
networks of cell-type specific alternative splicing, governed by expression and regulation of
splicing factors and their isoforms associated with a particular pathology, poses a problem
addressable through the concepts and tools of systems biology. In parallel therapeutic strate-
gies to correct splicing defects will be developed.
Development of High-Throughput-Enabling Technologies:

Another important Network activity comprises development and application of High-Through-
put-Enabling Technologies for the study of alternative splicing, in particular of microarrays
for the detection of alternative splice forms and the screening of small chemical compound
libraries. Most of the currently available microarray designs ignore the fact that the majority
of genes in higher eukaryotes generates multiple mRNAs that encode proteins with distinct,
sometimes opposite functions. Therefore results from such designs are at best incomplete, if
not misleading. Analyzing the full complement of cellular transcripts under different biological
or pathological conditions requires microarray platforms able to distinguish between alterna-
tively spliced mRNAs. EURASNET envisions the task of establishing these microarrays as one
of the key contributions of EURASNET to European scientists, regardless of whether they are
in the splicing field or not, and to the clinicians.
A second Network effort is directed towards high-throughput identification of compounds that

inhibit or modulate specifically the splicing reaction. An initial explorative phase will comprise
the development of an assay with suitable fluorescence readout for screening purposes and
the screening of small to medium-sized chemical libraries. Selecting appropriate target reac-
tions and the right class of chemical compound are then preconditions for large-scale screen-
ing. While exhaustive screens for compounds useful as therapeutic agent for specific splicing
defects associated with a human disease are clearly beyond the scope of this Network, the
validation of the general screening strategy will help to raise interest among potential com-
mercial partners to engage in further collaborative studies.
The alternative splicing database

EURASNET research requires close communication and joint activities between computer
biologists and experimentalists. The mere task of accurate intron identification in eukaryotic
European Alternative Splicing Network of Excellence
genomes still poses a considerable challenge. Even more so the prediction, which potentially
alternatively spliced mRNA will appear in which tissue and under what conditions. The ex-
ploding number of mRNA and EST sequences and high-throughput enabling technologies
producing large data sets of transcripts, their structure, abundance, tissue distribution and
developmental specificity, require a strong bioinformatics infrastructure to secure the acquisi-
tion of quality data in user-friendly databases and to ensure efficient data analysis which in
the long run wants to become a highly predictive analysis of splice signals and regulatory
elements.
The Young Investigator Program

As part of the Network’s integration activities, young investigators and their research will be
integrated.
Expected Results:
As the outcome of EURASNET research activities the team expects: i) a significant number
of important publications (estimated 150 publications in the five years period) ii) a several-
fold increase in high impact joint publications by members of the network iii) the develop-
ment and optimization of experimental designs and technological platforms applicable to
studies of alternative splicing in a variety experimental systems. In particular, standards for
High-Throughput technologies like microarrays and small-compound screening will be de-
veloped. iv) the development of user-friendly software of high predictive power to support
the experimental design of experimentalists.
Potential Impact:
The ambitious, innovative and multidisciplinary Joint Programme of activities of EURASNET
will give a massive impetus to progress in elucidating the mechanisms of alternative splic-
ing and will thus greatly enhance the scientific community’s understanding of one of the
most important steps in the expression of genetic information. Insights into this process are
a prerequisite for allowing us to decipher, and ultimately to predict, the genetic program
of eukaryotic genomes. EURASNET and its Young Investigator Program (YIP) will also play
an important role in making Europe attractive for young and talented scientists in the field.
Moreover, it will ensure their integration into the “alternative splicing” community and, on
account of the importance of this field today, it will in turn make a significant contribution to
the spread of sustained excellence within European life sciences.
The information generated from the activities of this NoE can

realistically be expected to have a significant impact, not only
on the academic research community, but also on the industri-
al research and medical communities. Further, developments
resulting from the information generated by EURASNET will
form an important knowledge base that ultimately will aid
public policy makers in making decisions that will shape the
socio-economic future of our society. Efforts by EURASNET
will also contribute to the enhancement of public awareness
of genomics and RNA research, with corresponding indirect
benefits to society as a whole. EURASNET represents a con-
sortium of many of the world’s best laboratories investigating
the process of alternative splicing and its implications for hu-
man health. Transcribed genes localize in close
proximity two nuclear speckles
Keywords: alternative RNA splicing, RNA splicing
EURASNET
Partners Dr. Gil Ast

Tel Aviv University
Project Coordinator: Department of Human Genetics
Prof. Reinhard Lührmann Tel Aviv, Israel
Max-Planck Institute for Biophysical Chemistry
Department of Cellular Biochemistry Prof. Francisco E. Baralle
Am Fassberg 11 International Centre for Genetic Engineering
37077 Göttingen, Germany and Biotechnology
Reinhard.Luehrmann@mpi-bpc.mpg.de Molecular Pathology Group
Trieste, Italy
Project Manager:
Dr. Reinhard Rauhut Prof. Andrea Barta
Max-Planck Institute for Biophysical Chemistry Medical University Vienna
Department of Cellular Biochemistry Department of Medical Biochemistry
Am Fassberg 11 Vienna, Austria
37077 Göttingen, Germany
Reinhard.Rauhut@mpi-bpc.mpg.de Prof. Jean Beggs
University of Edinburgh
Dr. Karla Neugebauer Institute of Cell Biology
Max-Planck Institute of Molecular Edinburgh, UK
Cell Biology and Genetics
Dresden, Germany Dr. Giuseppe Biamonti
Consiglio Nazionale delle Ricerche (CNR)
Dr. Henning Urlaub Istituto di Genetica Molecolare
Max-Planck Institute for Biophysical Chemistry Pavia, Italy
Göttingen, Germany
Dr. Juan Valcárcel Consiglio Nazionale delle Ricerche (CNR)
Centre de Regulació Genòmica Istituto di Biologia Cellulare
Regulation of Alternative Pre-mRNA Splicing Monterotondo Scalo, Italy
Barcelona, Spain
Prof. Albrecht Bindereif
Prof. Stefan Stamm Justus Liebig Universität Giessen
Friedrich-Alexander-Universität Erlangen-Nürnberg Institut für Biochemie
Institute for Biochemistry Giessen, Germany
Erlangen, Germany
Prof. Jamal Tazi, Dr. Edouard Bertrand
Prof. Göran Akusjärvi Centre National de la Recherche Scientifique (CNRS)
Uppsala University Institut de Genetique Moleculaire
Department of Medical Biochemistry (JRU 5535 CNRS-UMII)
and Microbiology (IMBIM) Montpellier, France
Faculties of Medicine and Pharmacology
Uppsala, Sweden Dr. Bertrand Séraphin
Dr. Peer Bork Centre de Genetique Moleculaire (CGM), UPR2167
European Molecular Biology Laboratory (EMBL) Gif-sur-Yvette, France
Structural and Computational Biology Programme
Heidelberg, Germany Dr. Christiane Branlant
Dr. Rolf Apweiler, UMR 7567 CNRS-UHP
European Molecular Biology Laboratory (EMBL) Maturation des ARN et Enzymologie Moléculaire MAEM
European Bioinformatics Institute (EBI) Vandoeuvre les Nancy, France
Sequence Database Group
Hinxton, UK Prof. Daniel Schümperli
Universität Bern
Institut für Zellbiologie
Bern, Switzerland
European Alternative Splicing Network of Excellence
Dr. John W.S. Brown Prof. Hermona Soreq

Scottish Crop Research Institute Hebrew University of Jerusalem
Gene Expression Programme - RNA Processing Lab Department of Biological Chemistry
Dundee, UK Institute of Life Sciences
Jerusalem, Israel
Dr. Javier Fernando Cáceres
Medical Research Council Dr. James Stévenin
MRC Human Genetics Unit Centre Européen de Recherche en
Edinburgh, UK Biologie et Médecine – GIE
Institut de Génétique et de Biologie
Prof. Maria Carmo-Fonseca Moléculaire et Cellulaire (IGBMC)
Instituto de Medicina Molecular Illkirch, France
Cell Biology Unit
Lisbon, Portugal Dr. Didier Auboeuf
Prof. Ian Eperon de la Recherche (INSERM)
University of Leicester AVENIR/Inserm U685
Department of Biochemistry Centre Hayem-Hôpital Saint Louis
Leicester, UK Paris, France
Prof. Artur Jarmolowski Dr. Davide Gabellini

Adam Mickiewicz University in Poznan Fondazione Centro San Raffaele del Monte Tabor
Department of Gene Expression / Institute of Milan, Italy
Molecular Biology and Biotechnology (IMBB)
Poznan, Poland Dr. Mihaela Zavolan
Biozentrum, University of Basel
Prof. Jørgen Kjems ISB-SIB RNA Regulatory Networks Group
University of Aarhus Basel, Switzerland
Aarhus, Denmark
Prof. Alberto R. Kornblihtt

Universidad de Buenos Aires
Departamento de Fisiolgía
Biología Molecular y Celular
Buenos Aires, Argentina
Prof. Angela Krämer

Université de Genève
Département de Biologie Cellulaire
Geneva 4, Switzerland
Prof. Angus Lamond

Division of Gene Regulation & Expression
School of Life Sciences
Dundee, UK
Dr. Christopher Smith

Cambridge, UK
BACRNAs

Specific Targeted
Research project From being regarded as a minor class of RNAs, non-coding RNAs (ncRNAs - mostly an-
tisense RNAs) have recently emerged as ubiquitous players in important life processes in
Contract number:
animals, plants, fungi and metazoans. Similarly, over 85 small ncRNAs, encoded by the
LSHG-CT-2005-018618 Escherichia coli genome, have recently been identified, while others are being discovered
Starting date: in many bacterial species. Many of these RNAs play key roles in global regulatory net-
1st February 2006 works. The BACRNAs consortium investigates novel ncRNAs and their targets (messenger
Duration: RNA (mRNA) and proteins) in several representative pathogens and analyses their roles in
36 months the establishment of bacterial pathogenicity. Infection studies using cell cultures will allow
the validation of ncRNAs and their targets in virulence. Exploration of structural and mecha-
EC Funding:
nistic aspects of ncRNAs will elucidate how they interact with those targets. This research
`2 599 988 will lead to an understanding of how regulatory ncRNAs are integrated into the general
network that controls stress responses, host adaptation and bacterial virulence.
1) Many non-coding RNAs act as antisense RNAs, via a base-pairing mechanism, where-
as sensor elements, mostly located in the 5’ untranslated region (UTR) of mRNA, can
act as ‘riboswitches’. The consortium focuses mainly on ncRNAs that belong to these
two classes, and that are implicated in the regulatory networks controlling bacterial
pathogenicity. It develops tools for the identification, characterisation and structural
analysis of ncRNAs in pathogenic bacteria, as well as for the identification and vali-
dation of targets (virulence factors) controlled by ncRNAs involved in virulence.
2) Current studies have reported a growing number of small RNAs, including ncRNAs
that play key roles in the regulation of fundamental adaptive processes such as
cell-to-cell communication (quorum sensing), transition to the stationary phase, iron
homeostasis and bacterial virulence. The BACRNAs project aims to elucidate how
regulatory RNAs are integrated into the general network of pathogenesis control
whilst also taking into account other mechanisms such as response and adaptation to
bacterial stress or changing environment.
3) The determination of the most relevant virulence factors amenable to drug develop-
ment is the concluding step within the present BACRNAs project. The relevance to
drug development is determined by the ability of small molecules to bind virulence
factors. These small molecules (compounds) on one hand are needed to verify the
functionality and on the other the modification ability of identified virulence factors.
The outcome describes the prove-of-concept and builds the basis for further drug
development by the pharmaceutical industry. Therefore the analysis of the virulence
mechanism that is triggered by ncRNAs, as well as the expression/regulation of
virulence factor and its influence to pathogenicity needs to be investigated by the
consortium. Further information on drug design will be guided by structural informa-
tion provided by nuclear magnetic resonance techniques.
Expected Results:
The consortium expects to see the following results: (1) Development of tools for the identifi-
cation/analysis of ncRNAs involved in bacterial pathogenicity; (2) Identification of ncRNAs
Non-coding RNAs
in Bacterial Pathogenicity
involved in bacterial pathogenicity; (3) Identification of targets (virulence factors) controlled

by ncRNAs involved in virulence; (4) Identification of the structure of the ncRNAs as well as
the regulatory mechanisms of ncRNAs involved in bacterial pathogenicity and (5) Valida-
tion of novel targets for therapy and initial identification of compounds that interfere with
the function of those targets.
Potential Impact:
The project has set its sights on facilitating the establishment of European leadership in the
innovative field of regulatory RNAs. It aims to generate fundamental knowledge that can be
translated directly into new therapeutic strategies. The identification of novel drug targets
builds the basis to develop new drugs and thus to combat widespread bacterial infections.
Keywords: antisense RNA, non-coding RNA, biochemistry, antimicrobial agents,

regulatory networks, bacterial virulence
Partners
Prof. Renée Schroeder
“Max F. Perutz Laboratories”
Dr Bohr Gasse 9/5
renee.schroeder@univie.ac.at
Dr. Pascale Romby

UPR 9002 CNRS-ARN
“Architecture et réactivité des ARN”
Strasbourg, France
Prof. Pascale Cossart

Institut Pasteur
Unité des Interactions Bactéries-Cellules
Paris, France
Prof. Gerhart Wagner

Uppsala University Dr. Shoshy Altuvia
Department of Cell and Molecular Hebrew University
Biology (ICM), Biomedical Center of Jerusalem
Uppsala, Sweden Institute for Microbiology
Jerusalem, Israel
Dr. Jörgen Johansson
Umeå University Ms Brigitte Rohner
Department of Molecular Biology Brigitte Rohner punkt
Umeå, Sweden Vienna, Austria
RNABIO
State-of-the-Art:
Project Type:
Specific Support Action RNA molecules such as microRNAs, riboswitches, or regulatory RNAs in bacteria (broadly
Contract number: called noncoding RNAs or ncRNAs) have become extremely active areas of research in
basic science such as cell development, cancer and therapeutic research. The prediction of
LSSG-CT-2006-037604
the secondary structure of an RNA molecule is the most extensively studied aspect in com-
Starting date: putational methods for ncRNAs. Despite this, the accuracy in predicting secondary structure
1st July 2006 is limited (56 to 76 percent). Alternatives to standard models are probabilistic models, the
Duration: systematic use of comparative analysis, and the incorporation of known 3D structures. RNA
4 months bioinformatics is now following two paths.
EC Funding:
The first is structure-based analyses in which three-dimensional structures are central. The
`22 500
second is sequence-based analyses in which sequence and sequence recognition dominate
the analysis. These two paths are running parallel courses at the moment, but they will
soon converge. This must occur if scientists are to fully understand RNA evolution and the
relationships between sequence, structural folding and reactivity. Science is now facing
new challenges in trying to identify the function of these ncRNAs. For this to happen, it is
necessary to refine the algorithms involved so that structures can be systematically searched
in genomes and reliably predicted. The result will be that homology searches for ncRNAs
can take into account the overall structure, alignment algorithms for RNA structure and will
be fast enough to search whole databases.
A workshop entitled ``Computational approaches to noncoding RNAs’’ and organized
by Elena Rivas (Washington University, USA) and Eric Westhof (University Louis Pasteur,
France) was held in Benasque (Spain) from the 16th of July to the 28th of July 2006. It gath-
ered a group of 55 researchers mostly theoreticians and computational scientists working
on problems related to the computational analysis of functional and regulatory RNAs.
The main objectives of the RNABIO workshop were:
1) To present and discuss the state of RNA computational biology, to identify the needs
and to propose new developments for the identification, annotation and the computa-
tional analysis of functional and regulatory RNAs present in genomes.
2) To try to identify the function of ncRNAs. In order to do this it is necessary to refine al-
gorithms in order to perform structure predictions reliably and do research on ncRNAs
that take into account the structure and alignment algorithms for RNA structures and
are fast enough to search whole databases. This permits, for instance, the alignment
of thousands of ribosomal RNA molecules.
3) To identify new ncRNAs, which may lead to novel regulator mechanisms.
4) For biologists working on RNA to make reliable annotations of eukaryotic genomes.
5) To make grammatical models to describe RNAs, to provide more information on the
parameters of the models, along with more complex objective functions to describe
the nature of a functional RNA.
6) The development of improved methods for the efficient classification of short RNAs
(using techniques such as support vector machines).
7) To create statistical modelling of new high throughput data in the RNA context.
8) To relate genome location of small RNAs to RNA type (eg through characterising
clustering behaviour).
Computational approaches
to non-coding RNAs
Expected Results:
One major problem with ncRNA prediction has been that they require substantially more com-
puter time than the methods employed for more traditional protein coding gene finding, which
can exploit much more regular search patterns. However, the recent progress in ncRNA gene
discovery promises to reduce search time significantly.
Secondary structures predicted by various methods are at variance with the fact that RNAs are
three-dimensional molecules. Thus, basepairing can be impossible due to steric clashes. An at-
tempt to approach this problem is currently being planned. The result will be the incorporation of
a model for the RNA backbone, using directional statistics, into the secondary structure predic-
tion. This should weed out impossible structures and could, in time, be extended to do ab initio
3D prediction of RNA structures.
The data produced on RNA is made freely available without restrictions through web pages and
database downloads. The computational RNA community already makes heavy use of Rfam
data as training and testing sets for developing algorithms. Both RNA databases, Rfam and
miRBase are heavily used by genome annotation projects, and miRBase is central to the rapid
growth and progress of microRNA research. One of the expected results of the project is to make
such resources far more community oriented by hosting diverse data types on the database. The
RNA bioinformatics community are immensely supportive and the RNABIO workshop proved to
be very efficient at generating and maintaining ideas and collaborations to this end.
Potential Impact:
Now, several groups, especially in Europe, have been involved in developing
computational methods which seek simultaneously to align and fold two or more
RNA sequences while screening - eg two genomes or matching up regions with
low sequence similarity.
The major outcome was to valuate the state of RNA computational biology,
to identify the needs, and to propose new developments for the identifi-
cation, annotation, and the computational analysis of functional and
regulatory RNAs present in genomes. The long- term goal of applying
such methods is to help identify ncRNA genes or structural elements,
which will have an important impact on phenotypes,
diseases and production traits in domestic animals.
Keywords: microRNAs, riboswitches,

noncoding RNAs
Partners
Prof Eric Westhof
Centre National De La Recherche Scientifique (CNRS)
Université Louis Pasteur
Institut de biologie moléculaire et cellulaire
ARN ‘Architecture et Réactivité de l’ARN’
15 Rue Rene Descartes
F-67084 Strasbourg, France
e.westhof@ibmc.u-strasbg.fr
Sirocco
www.sirocco-project.eu

Integrated Project
Contract number: RNA silencing is the natural ability of a cell to turn off genes. Only a few years ago it was
unknown, but now RNA silencing is one of the most powerful tools available to researchers.
LSHG-CT-2006-037900
Recent discoveries have revealed a previously unknown role for RNA (ribonucleic acid). They
Starting date: have shown how, in addition to the previously understood role as a cellular messenger that
1st January 2007 directs protein synthesis, RNA can also silence expression of genes. By introducing specific
Duration: silencing RNAs into an organism, the expression of genes can be turned down in a controlled
48 months way. The phenomenon of RNA silencing is thought to have evolved as a defence mechanism
EC Funding: against viruses. In primitive cells it was a type of immune system that could recognize and then
silence viral genes. Later in evolution the silencing mechanism was recruited for switching off
`11 781 445
genes involved in normal growth of cells and responses to stress. Small regulatory RNAs (sR-
NAs) are the mediators of
RNA silencing and are
important integrators of
genetic, epigenetic and
other regulatory systems.
They are the focus of the
SIROCCO programme.
sRNAs have been referred
to as the dark matter of ge-
netics: a recently discov-
ered mass of molecules
that crucially affect the
behaviour of the genetic
universe through interac-
tions at the RNA level.
The exploitation of sRNAs
Secondary siRNA production in offers many opportunities
plants and animals. Baulcombe for improving the diagno-
DC Amplified silencing Science sis and therapy of human
2007 Jan 12;315(5809): disease and for advances
199-200. in biotechnology.
sRNAs fall into two major classes: i) short interfering RNAs (siRNAs) which are 21-24 nucle-
otide RNAs derived from long double-stranded RNA and ii)microRNAs (miRNAs) which are
derived from transcripts containing partially double-stranded stem-loop “hairpin” structures
about 70 nucleotides long. Both are cleaved from their precursor RNA by double stranded
RNA-specific endonucleases. One strand of the resulting small RNA is loaded into RNA-
induced silencing complex (RISC) that also contains Argonaute (AGO) proteins. Binding to
the correct Argonaute protein is necessary for cleavage of the target messenger RNA. siRNAs
and miRNAs have been found in a variety of organisms including plants, fruit flies, zebrafish,
mice, and humans. sRNAs are also a useful tool in the laboratory, where they can be used to
silence gene expression (RNA interference).
The overall objectives of the SIROCCO project are:
1) Create catalogues of sRNAs from healthy and diseased cells. Novel sRNAs will
Silencing RNAs:
organisers and coordinators
of complexity in eukaryotic organisms
be identified through using a combination

of bioinformatics and high throughput se-
quencing. FIGURE 1: Somite-specific
2) Determine the tissue- and cell-type pattern of expression of miR-206. Mouse
miRNA expression using microarray, RNA embryo (E10.5) was hybridised
blot and in situ hybridisation methods to an LNA oligonucleotides
3) Fully refine methods for sRNA detection. complementary to miR-206.
These detection methods will be enhanced The blue staining indicates the
using locked nucleic acid-containing and very specific accumulation of
other oligonucleotide probes, and by modi- miR-206 in the somites.
fied PCR methods. Wheeler G, Valoczi A, Havelda
4) Characterise proteins and subcellular com- Z, Dalmay T. In situ detection of
partments required for sRNA processing and animal and plant microRNAs.DNA
activity. At present, there is a foundation of Fig.1 Cell Biol. 2007 Apr;26(4):251-5.
knowledge about miRNAs, but very little is
known about siRNAs. Genetic, biochemi-
cal and imaging approaches will be used
to fully characterise the molecular machines
responsible for both miRNA and siRNA bio-
genesis
5) Dissect sRNA regulatory networks. It is
known that miRNAs may affect particular
target mRNAs but how their activity fits into FIGURE 2: RNA silencing of a
more complex regulatory networks is poorly green fluorescent protein.
understood. Developing this understanding The red areas illustrate how a
is one of the major objectives of the SIROC- signal of silencing is spreading
CO programme. out of the veins in a leaf
6) Identify rules for sRNA efficiency and spe- of Nicotiana benthamiana.
cificity. The RNA-silencing efficiency of sR- Eventually the signal spreads
Fig.2
NAs will be determined by assay of sRNAs, throughout the plant.
their precursors or their DNA in transgenic
organisms, in cell cultures or in vitro
7) Explore delivery methods for sRNAs or sRNA precursors.
Efficient use of sRNAs as pharmaceuticals will depend on the development of methods for
their efficient delivery into cells and animals. Current technology uses modified viruses to
introduce siRNAs into cells to reduce expression of a target gene. In the later stages of the
project, the SIROCCO consortium will initiate research into the suppression of genes impli-
cated in various diseases.
The mechanism of RNA silencing must be thoroughly understood in order to use RNA as a
drug without side effects. It is also necessary to understand more about the role of silencing
RNAs in normal growth and development. That information will then allow us to use the
presence of silencing RNAs to diagnose disease states in a cell.
Expected Results:
The SIROCCO consortium will investigate the stages in growth, development and disease
that are influenced by sRNAs. The project can be considered to have three overlapping
phases. The first is descriptive and will continue throughout the programme. This phase
aims to describe the full complement of sRNAs in a range of organisms and cell types and
SIROCCO
correspondingly to develop a complete understanding of the proteins that act as enzymes,

co-factors and structural components of the sRNA machinery.
The second phase involves testing the function of sRNAs and sRNA-related proteins in
the basic sRNA mechanisms, and eventually establishing their role in regulatory networks
through experimental intervention. Genetic and molecular methods will be used to manipu-
late the expression of these components, while biological assays and molecular profiling of
RNA will be used to assess the role of the targeting components.
In the third, predictive phase of the programme, the aim will be to develop rules to describe
the behaviour of sRNA systems as isolated regulatory modules and as part of complex
regulatory networks. Component activities in this phase will involve the computation of rules
and their validation by experimentation. It will be possible from this phase to design sRNA
mimics of natural sRNAs, and to predict their effects in cells and organisms. It will also be
possible to predict the behaviour of cells or organisms in which the sRNA machinery is
regulated by developmental or external stimuli.
Potential Impact:
RNA silencing technology has enormous potential for use as a therapeutic agent in the
treatment of infectious diseases and for any condition involving the mis-regulation of gene
expression. It is known that different microRNAs can function as tumour suppressors or on-
cogenes and that their expression levels have diagnostic and prognostic significance. The
role of small RNAs in complex neuropathological disorders such as schizophrenia and in
neurodegenerative conditions such as Alzheimer’s Disease is being investigated by mem-
bers of the SIROCCO consortium. Diagnostic or therapeutic advances in these areas would
have powerful public health implications.
The SIROCCO consortium aims to understand and exploit the diversity of sRNA mecha-
nisms. The elucidation of the genomics of sRNA and of sRNA-based regulation will lead
to novel and fundamental insights into the composite genetic networks that underlie nor-
mal and diseased growth and development. Achieving these aims will reinforce European
competitiveness in fundamental research and innovation and will solve important societal
problems relating to public health by improving diagnosis and treatment of diseases.
Keywords:
RNA silencing, microRNA, RNA interference, short interfering RNA, developmental biol-
ogy, molecular biology, gene expression
Partners
Project Coordinator: Project Manager:
Prof. David Baulcombe Dr. Aileen Hogan
The Sainsbury Laboratory The Sainsbury Laboratory
John Innes Centre John Innes Centre
Norwich, NR4 7UH, UK Norwich, NR4 7UH, UK
david.baulcombe@sainsbury-laboratory.ac.uk aileen.hogan@sainsbury-laboratory.ac.uk
Dr. József Burgyán

Agricultural Biotechnology Centre
Institute of Plant Biology, Molecular Virology Group
Godollo, Hungary
Silencing RNAs: organisers and coordinators of
complexity in eukaryotic organisms
Dr. Annick Harel-Bellan Prof. Jørgen Kjems

Centre National de la Recherche Scientifique (CNRS) University of Aarhus
FRE 2944 - Epigenetique et cancer Department of Molecular Biology
Institut André Lwoff Aarhus, Denmark
Villejuif, France
Prof. Xavier Estivill
Dr. Olivier Voinnet Center for Genomic Regulation (CRG)
Centre National de la Recherche Scientifique (CNRS) Genes and Disease Program
UPR 2357 Barcelona, Spain
Institut de Biologie Moléculaire des Plantes
Strasbourg, France Prof. Caroline Dean
John Innes Centre, Norwich Research Park
Prof. Witold Filipowicz Department of Cell & Developmental Biology
Friedrich Miescher Institute for Biomedical Research Norwich, UK
Basel, Switzerland
Dr. Michael Wassenegger
Dr. René Ketting AlPlanta-Institute for Plant Research
Netherlands Institute for Developmental Biology Neustadt, Germany
Hubrecht Laboratory
Utrecht, The Netherlands Dr. Peter Mouritzen
Exiqon A/S
Dr. Detlef Weigel, Dr. Elisa Izaurralde Research and Development
Max-Planck Institute for Developmental Biology Vedbaek, Denmark
Tübingen, Germany
Dr. Stephen Cohen
Dr. Gunter Meister Temasek Life Sciences Laboratory Ltd
Max-Planck Institute for Biochemistry National University of Singapore
Laboratory for RNA Biology Singapore, Republic of Singapore
Prof. Thomas Meyer

Max-Planck Institute for Infection Biology
Berlin, Germany
Dr. Gyorgy Hutvagner, Dr. Simon Arthur

Dundee, UK
Dr. Tamas Dalmay

University of East Anglia
Norwich, UK
Prof. Irene Bozzoni. Prof Giuseppe Macino

University of Rome ‘La Sapienza’
Rome, Italy
Dr. Eric Miska

Wellcome Trust/Cancer Research UK Gurdon Institute
Cambridge, UK
Prof. Roberto Di Lauro

BIOGEM Biotecnologie Avanzate s.c.a r.l.
Laboratory of Animal Genetics
Naples, Italy
7.5
CHRONOBIOLOGY
EUCLOCK
TEMPO
EUCLOCK
www.euclock.eu
State-of-the-Art:
Project Type: Behaviour, physiology and biochemistry are temporally structured, and therefore gener-
Integrated Project ate daily oscillations. These cycles are not driven simply by external changes (such as the
Contract number: changes of light/dark or warm/cold), but are controlled by an endogenous clock that exists
LSHG-CT-2006-018741 in the most diverse organisms, from cyanobacteria to humans. In real life, this circadian
clock is synchronised with the outside world by rhythmic environmental signals, called ‘zeit-
Starting date: gebers’, through a process called entrainment. Circadian rhythms exist at all levels of biol-
1st January 2006 ogy. They are present, for example, in rest, arousal or vigilance activities; in temperature,
Duration: urinary output, blood pressure or heart rate; in enzyme activity, hormone concentrations or
60 months gene expression. Previous experiments have shown that circadian rhythms continue even in
the absence of environmental time cues. This internal ‘day’ is self-sufficient but not entirely
EC Funding:
independent from the external day. A critical feature of the clock is its synchronisation with
`12 299 389 the external day. This so-called entrainment is the key to understanding the circadian clock
and its control mechanisms. Human beings rarely experience constant conditions and, as a
consequence, any research on humans entails concentrating on the entrained state.
EUCLOCK, a large research network, was launched in January 2006. Its main aim is to
investigate the circadian clock in different organisms, from cells to humans. More specifi-
cally, the project seeks to understand how circadian clocks synchronise with their cyclic
environment.
Within this field of research, EUCLOCK investigates the circadian clock in the context of
entrainment. The project aims to understand, for example, the misalignment between inter-
nal and external time, as a consequence of shift-work, as well as insufficient entrainment
owing to age-related changes, both elements which can have a strong impact on health and
well-being. A major objective of EUCLOCK is to enable large-scale, non-invasive studies
(the CLOCK-watcher device) that can prove or disprove the efficacy of medical treatment
of pathologies, ranging from heart diseases to cancer, using 24-hour monitoring of impact
of these treatments.
Expected Results:
In EUCLOCK, European researchers join forces to investigate the circadian clock under en-
trainment. Utilising the most advanced methods of functional genomics and phenomics, the
team will compare genetic model organisms and humans. Important findings, such as the
prerequisites for large-scale, non-invasive research on human entrainment as well as the first
animal models for shift-work, will be developed. As with 20% of the human working popula-
tion, flies and mice will likewise be exposed to ‘shift work’ schedules, i.e. will be active and
feed out of phase, with respect to their natural rhythms. The ensuing ‘dys-entrainment’ will
be investigated at different levels, from genes to behaviour, so as to provide insights into
the prevention of negative consequences of human shift-work.
New genetic components that control the circadian clock and its entrainment will be identi-
fied (both in animals and humans). Moreover, new tools will be developed and new circadi-
an model organisms will be explored. These findings will enable the field of chronobiology
to exploit the advantages of systems’ biology research on circadian timing, and to perform
and integrate the findings at the level of the genome, the proteome, and the metabolome.
The innovations of EUCLOCK are predestined to shape the future of circadian research.
Entrainment of the Circadian Clock
Potential Impact:
Contributions to standards
This IP uses an entirely novel approach to
understanding entrainment of the circadi-
an clock. It will, therefore, establish stand-
ards on several levels.
A tissue bank from EUCLOCK lab subjects
will be established. The EUCLOCK web-
site will compile the accumulating data on
tissue-specific clock gene expression under
different entrainment of dys-entrainment
protocols. The integrated use of many dif-
ferent entrainment protocols will produce
standard operating procedures, for means of investigating the effects of clock gene
polymorphisms on the endogenous daily programme, from behaviour, to physiology,
and to molecules. The first-time use of dawn and dusk simulation in entrainment will have
wide-ranging consequences on how entrainment will be investigated in all circadian
model systems.
The first-time use of forced dys-entrainment protocols will set new standards for animal
models for shift work research. The development of a “Real Life Routine” (CLOCK-watch-
er), will provide researchers of the human clock with a standard set of parameters that
are useful and meaningful, when the daily programme of humans is investigated in field
experiments (e.g. in shift workers).
Our results concerning circadianly effective light environments will be shared (via an
advisory committee) with the European lighting industry.
Impact on European science
The circadian clock was discovered in Europe. With the advent of molecular genetics,
the centre of gravity in circadian biology shifted from Europe to the USA. This IP now
supports a developing area of European scientific expertise (the accumulative impact
factor of EUCLOCK’s scientists is well over 11,000, with an average of 420), and
importantly lends financial support in an area where dedicated financial funding in all
European countries cannot match corresponding funding in the USA.
Impact on European healthcare
EUCLOCK will contribute significantly to the understanding of how the different parts
of the circadian clock come together to form an entrained system, from molecules to
behaviour. These insights will form an essential basis for understanding all temporal
aspects of normal physiology and of pathology. They will also contribute to developing
chrono-pharmacological interventions.
Impact on Europe’s societal problems and economy
Modern society creates conditions which frequently challenge the optimal function of the
circadian clock. For example, approximately 20% of employees have shift- or night-work
schedules; this creates enormous societal problems. Any measure intended to counteract
the detrimental effects of shift-work, must encompass both health and sociological issues
(e.g. who undertakes the responsibility of childcare while one of the parents is working
night shifts?). In order to solve these problems (e.g. through the development of better
shift schedules) the bio-medical sciences need to strongly communicate with the social
sciences. The management of EUCLOCK will facilitate bridges between its own basic
science approaches, and the approaches of other networks which deal with the cogni-
tive and social aspects of daily work (e.g. the Daimler-Benz-network, “Optimising the
daily structure of work”).
Due to their ‘mal-entrained’ circadian clocks, shift-workers show reduced vigilance (both
in night and other shifts), and suffer from health problems. The consequences are far-
reaching, in terms of both societal and economic costs, due to reduced productivity, faulty
EUCLOCK
workmanship, absenteeism and increased

health problems upon retirement, not to Partners
mention mistakes and accident rates. The Project Coordinator:
results of EUCLOCK could therefore vitally Prof. Till Roenneberg
impact on work productivity. Ludwig Maximilians University
EUCLOCK will also increase the poten- Institute for Medical Psychology
tial for development and optimisation of Goethstr. 31
industrial products. For example, lighting Munich, Germany
conditions have profound effects on cir- roenneberg@lmu.de
cadian entrainment in particular, and on
human health in general. By developing Prof. Urs Albrecht
the potential for measuring the human University of Fribourg
clock in real life, we enable scientific ap- Department of Medicine
proaches to test new products, which aim Fribourg, Switzerland
to improve entrainment.
Dr. Howard Cooper
Added value in carrying out the work at a Institut National de la Santé et de la
European level Recherche Médicale (INSERM)
At the end of the last century, attention Unite 371, Cerveau et Vision
in the field was focused on the search Bron, France
for the molecules and intracellular regu-
latory mechanisms of the circadian clock Prof. Rodolfo Costa
— with great success. As a consequence, University of Padua
a consortium of US universities (the NSF Dipartimento di Biologia
Center for Biological Timing) was estab- Padova, Italy
lished, which has now completed opera-
tions, concluding 10 years of success. Prof. Dominicus G.M. Beersma
The next critical step will be EU-based. University of Groningen
EUCLOCK is poised to become the pre- Department of Chronobiology
eminent chronobiological ‘power’ of the Groningen, The Netherlands
new century.
Prof. Charlotte Förster
The objectives and aims of EUCLOCK can University of Regensburg
only be implemented if many laboratories, Institut für Zoologie/Entwicklungsbiologie
specialising in different circadian aspects und Chronobiologie
and methods, cooperate with clearly defined Regensburg, Germany
SOPs. This can work only if resources are
drawn Europe-wide. Prof. Russel Foster
Keywords: Nuffield Laboratory of Ophthalmology
Circadian and Visual Neuroscience Group
Oxford, UK
circadian clock, shift work models, light, en-
trainment, chronobiology, animal models Prof. Achim Kramer
Charité Universitatsmedizin Berlin
Institute of Medical Immunology
Triangle plot of the NPAS2 gene variants. Berlin, Germany
Prof. Charalambos Kyriacou

University of Leicester,
Leicester, UK
Dr. Johanna Meijer

Department of Neurophysiology
Entrainment of the Circadian Clock
Prof. Thomas Meitinger Dr. Konstantin Danilenko

GSF Institute of Human Genetics Chronobiology Centre
GSF Nat. Res. Centre Institute of Internal Medicine SB RAMS
Neuherberg, Germany Novosibirsk, Russia
Prof. Andres Metspalu Dr. Emma Perfect

Estonian Biocentre LUX Biotech
Gene Technology Laboratory Research and Development Department
Tartu, Estonia Edinburgh, UK
Prof. Dr. Andrew Millar Uwe Strobel

University of Edinburgh Technical Light Control Development
Institute of Molecular Plant Science Lichtblick
Edinburgh, UK Bonstetten, Germany
Prof. Ferenc Nagy Prof. Hans-Peter Lipp

Plant Biology Institute NewBehavior AG
Biological Research Center Zurich, Switzerland
Szeged, Hungary
Anand Kumar
Dr. Pat Nolan Personal Health Inst
Medical Research Council Int. VOF
Mammalian Genetics Unit Amsterdam, The Netherlands,
Neurobehavioural Genetics
Oxfordshire, UK Dr. Juha Hintsa
Sowoon Technologies
Dr. François Rouyer Lausanne, Switzerland
Institute de Neurobiologie Alfred Fessard Dr, Jakob Weber
Gif-sur-Yvette Cedex, France Buehlmann Laboratories AG
Schonenbuch, Switzerland
Prof. Ueli Schibler
University of Geneva Prof. Ralf Stanewsky
Department of Molecular Biology Queen Mary, University of London
Geneva, Switzerland School of Biological and
Chemical Sciences
Prof. Debra Skene London, UK
University of Surrey
Neuroendocrinology Group
Guildford, UK
Dr. Alena Sumova

The Academy of Sciences of the Czech Republic
Institute of Physiology
Department of Neurohumoral Regulations
Dr. G.T.J. van der Horst

Erasmus MC-Rotterdam
Prof. Dr. Anna Wirz-Justice

University of Basel
University Psychiatric Clinics / Centre for Chronobiology
Basel, Switzerland
TEMPO
www.chrono-tempo.org

Research Project Non-communicable, chronic diseases represent the bulk of morbidity, disability and prema-
ture deaths in Europe, and account for 75 per cent of disability-adjusted life years. Among
Contract number:
those diseases, cancer is the second most important cause of morbidity and mortality. Dif-
LSHG-CT-2006-037543 ferences in the molecular characteristics of tumour cells, as well as differences in patients’
Starting date: genetic make-up, gender, age, lifestyle and circadian rhythms, account for large variability
1st October 2006 in the time-course of cancer and in patients’ responses to treatment.
Duration:
36 months
EC Funding:
`2 086 720 The general objective of TEMPO is to design mouse
and in silico models that reflect this variability and
allow the prediction of optimal chronotherapeutic
delivery patterns for anti-cancer drugs.
Expected Results:
TEMPO combines functional genomics, proteom-
Schematic representation of
ics, cell signalling, systems biology and pharma-
cellular circadian rhythms.
cokinetics to optimise the therapeutic index in pa-
tients. This index in turn determines the chronotherapeutics schedules, according to which
temporal delivery patterns of the same anticancer drug vary. Each schedule is adjusted
to a different dynamic class of temporal genomics and phenomics parameters, relating to
interwoven circadian and cell division cycles as well as drug metabolism. The multidiscipli-
nary nature of the consortium means that in vivo, in vitro and in silico approaches will be
integrated to achieve this end.
Potential Impact:
TEMPO epitomises the transla-
tion of basic research findings
into useful clinical applications.
Through the identification of
nodes in the interplay between
the circadian timing system,
the cell division cycle and drug
pharmacology parameters, it
will provide critically important
information for the targeted de-
velopment of new anti-cancer
drugs.
Keywords:
Programmable in time drug cell cycle, circadian clock
delivery pump.
Temporal Genomics
for Tailored Chronotherapeutics
Circadian rhythms in cellular

proliferation in humans.
Partners
Project Coordinator: Prof. Stefano Iacobelli
Dr. Francis Lévi Consorzio Interuniversitario Nazionale
Institut National de la Santé et de la per la Bio-oncologia
Recherche Médicale (INSERM) Laboratory of molecular oncology center of
U776 - Rythmes biologiques et cancers excellence on aging Ce. S.I.
Hôpital Paul Brousse Chieti, Italy
Avenue Paul-Vaillant Couturier 14
94807 Villejuif, France Dr. Marco Pirovano
levi-m@vjf.inserm.fr H.S. Hospital Services S.p.A.
Therapeutic delivery
Project Manager: Aprilia (Latina), Italy
Dr. Isabelle Geahel
INSERM - Transfert SA Dr. Todor Vujasinovic
European Project Management Department Helios Biosciences Sarl
Rue de Tolbiac 101 Créteil, France
75654 Paris, France
Dr. Christophe Chassagnole
Prof. Franck Delaunay Physiomics Plc
Centre National de la Recherche Scientifique (CNRS) The Magdalen Centre
Université de Nice - CNRS UMR 6348 Oxford, UK
Bâtiment de Sciences Naturelles
Physiologie cellulaire et moléculaire des
systèmes intègres
Nice, France
Prof. Laurent Meijer

Laboratoire Mer et Sante UMR7150
Station Biologique - Amyloïds and Cell Division Cycle
Roscoff, France
Dr. Jean Clairambault

Institut National de Recherché en Informatique
et Automatique (INRIA)
Rocquencourt Research Unit -
Teams Bang and Contraintes
Le Chesnay, France
7.6
BIOLOGY OF PROKARYOTES
AND OTHER ORGANISMS
BACELL HEALTH
DIATOMICS
BACELL HEALTH
State-of-the-art:
Project Type: Pre-genomic research in cell biology has yielded a wealth of knowledge about individual
Specific Targeted regulatory pathways and metabolic processes that are obligatory for the survival of patho-
Research Project gens in their host, and for the productivity of microbes in industrial bioprocesses. The major
Contract number: challenge for the BACELL HEALTH consortium, using state-of-the-art post-genomic technolo-
gies, is to understand how individual regulatory pathways are networked to maintain cel-
LSHG-CT-2004-503468
lular homeostasis. The networking of individual regulatory pathways ensures that the cell
Starting date: provides a balanced response to stress, sensing both the magnitude of the stress, and the
1st March 2004 effectiveness of the response. In the case of pathogens, the identification of key nodes in
Duration: these regulatory networks will provide new targets for the development of antimicrobial
48 months compounds that perturb or disrupt the cell stress management system. For industrial produc-
tion strains, the inactivation of stress-induced processes that limit the production of heterolo-
EC Funding: gous proteins will lead to the development of a new generation of host/vector systems for
`2 000 000 the production of pharmaceutically-active proteins.
The BACELL HEALTH consortium aims to unravel the integrative cell stress-management sys-
tems and stress-resistance processes required to sustain a bacterial cell when exposed to
the types of environmental insults that are encountered in two very specific environments —
macrophages and industrial fermentors. Although both of these environments induce generic
stress responses, they also induce non-overlapping specific stress responses (eg. pH, iron and
oxidative stress in the case of macrophages, protein synthesis, secretion and nutrient stress
in the case of industrial fermentations). A specific scientific objective is to determine how
the induced responses function to relieve the applied stress. In the case of pathogens, the
consortium has identified key elements in stress-resistance mechanisms, and their signalling
pathways, for development as potential drug targets. With respect
to bio-production strains, the consortium has identified stress path-
ways that specifically limit product formation and have constructed
prototype production strains. Previous EU-funded studies (BACELL
NETWORK) have demonstrated regulatory crosstalk between gen-
eral and specific stress responses. A further specific scientific objec-
tive is to develop a model for the regulatory interactions that occur
within the cell’s stress management system. The scientific objectives
were therefore aimed at improving European competitiveness and
helping to meet the health needs of society.
Expected results:
BACELL HEALTH has built on the technological knowledge and in-
Detail of a non ribosomal dustrial base developed in Europe by focusing on aspects that directly influence human
peptide synthetase as health, namely the establishment of novel targets for anti-infective agents and the improved
a novel drug target production of pharmaceutically-active proteins. The added-value nature of this project was
confirmed by the participation of three European companies and the support of the Bacillus
Industrial Platform (BACIP). The realised deliverables included knowledge of fundamental
biological systems, the identification of novel targets for the development of broad-spectrum
and/or Gram-selective drugs, an improved understanding of microbial virulence and the
regulatory response of bacteria to host-mediated stress responses, prototypes of production
strains and new protein functions. In addition, the consortium trained a group of young Eu-
ropean scientists, and disseminated its knowledge via European and international meetings
and publications.
Bacterial stress management relevant to
infectious disease and biopharmaceuticals
Potential impact:
European research groups and industries are global leaders in the development of Bacillus
technology and the commercial exploitation of bacilli. A direct industrial benefit of BACELL
HEALTH will therefore be to help maintain Europe’s competitive market position in the face
of competition from the US and the Far East. The project will impact on human health by
providing knowledge of the mechanisms bacteria use to avoid the immune response.
Keywords:
bacterial pathogens, drug targets, comparative genomics, proteome, transcriptome, iron
homeostasis, infectious diseases, biopharmaceuticals
Partners
Project Coordinator: Prof. Michael Hecker Prof. Oscar Kuipers
Prof. Colin R Harwood Greifswald University Groningen University
Newcastle University Institut for Mikrobiologie Department of Genetics
Molecular Microbiology Group Greifswald, Germany Groningen, The Netherlands
Institute for Cell and
Molecular Biosciences Dr. Rocky Cranenburgh Dr. Marc Kolkman
6 Kensington Terrace Cobra Biomanufacturing R&D Genencor International BV
Newcastle upon Tyne, NE1 7RU, UK Stephenson Building Leiden, The Netherlands
colin.harwood@ncl.ac.uk The Science Park
Keele, UK Dr. Michael Dolberg Rasmussen
Project Manager: Bacterial Gene Technology
Dr. Sierd Bron Bagsvaerd, Denmark
University of Groningen
Haren, The Netherlands
s.bron@rug.nl Prof. Jan Maarten van Dijl
Groningen University
Prof. Kevin Devine Department of
Trinity College Dublin Medical Microbiology
Department of Genetics Laboratory of
Dublin, Ireland Molecular Bacteriology
Prof. Mohamed Marahiel
Marburg University
Fach Bereich Chemie
Marburg, Germany
Prof. Wolfgang Schumann

Bayreuth University
Bayreuth, Germany
Dr. Tarek. Msadek

Institute Pasteur
Unit de Biochimie Microbienne
Paris, France
DIATOMICS
www.biologie.ens.fr/diatomics
State-of-the-Art:
Project Type: The world’s oceans cover 70 percent of the Earth’s surface and are the largest ecosystem
Specific Targeted on our planet. This ecosystem is formed by more than 5,000 species of marine phyto-
Research project plankton, but only a few taxonomic groups of phytoplankton are responsible for most of
the system’s primary production and subsequent energy transfer to higher trophic levels as
Contract number:
well as vertical export to the deep ocean. The most significant phytoplankton are diatoms,
LSHG-CT-2004-512035 which contribute around 40 percent of marine primary production, thereby providing
Starting date: close to one fifth of the oxygen we breathe. Diatoms are therefore central to all life on
1st January 2005 Earth, although to date, remarkably little is known about their basic biology and how it is
Duration: affected by environmental change.
36 months The challenge for marine biologists in the genomics era is to exploit genomics technologies
EC Funding: for all the potential they have, whilst maintaining the holistic view necessary for understanding
`1 800 000 marine ecosystem function. For diatom researchers, this is especially difficult because there
are more than 100,000 extant species occupying widely varying habitats, from temperate to
polar waters, and so it has been extremely difficult to derive a consensus ‘model’ species.
DIATOMICS will make use of whole genome sequences from diatoms to provide information
about gene function and its relationship to ecology and evolution. Four scientific work
packages will deal with aspects of diatom biology that are ecologically relevant and critical
for diatom success and survival. Important topics that will be addressed include carbon-
concentrating mechanisms, nutrient acquisition, the rise and fall of blooms and adhesion.
Investigations into these areas will be carried out through the following steps: (1) The study
of gene expression profiles in response to a range of ecologically relevant
stimuli, such as nutrients and stress; (2) The manipulation of the expression of
key candidate genes in Phaeodactylum tricornutum, by reverse genetics; (3) The
study of the phylogenetic histories and ecological significance of these genes in
a range of diatoms. A fifth work package is designed to utilise the knowledge
generated from the other four work packages for the development of non-neutral
probes for assessing diatom physiology in the natural environment.
Expected Results:
The DIATOMICS project is divided into five scientific work packages, plus one
work package dealing with project management. Four of the scientific work
packages will deal with an aspect of diatom biology that is ecologically relevant
and critical for diatom success and survival. Important topics that will be ad-
Pictures of fusiform, oval, dressed include carbon-concentrating mechanisms, nutrient acquisition, the rise and fall of
triradiate cells respectively. blooms, and biofouling. A fifth work package is designed to utilise the knowledge generated
There is a big difference in shape from these other four work packages for the development of non-neutral probes for assessing
between the morphotypes. diatom physiology in the natural environment.
Potential Impact:
Climate change is occurring on a global scale and it is of major concern. It is therefore es-
sential that the secrets of diatom biology be discovered so as to increase our knowledge of the
role they play in global biogeochemical cycles, and to understand how they are influenced by
environmental change. These issues are being addressed in DIATOMICS using post-genomics
tools. Furthermore, the SME partner in DIATOMICS is interested in transferring diatom genes
into rice, in order to reduce fertiliser inputs, to increase stress tolerance and to improve their
carbon sequestering capabilities.
Understanding Diatom Biology by
Functional Genomics Approaches
An improved understanding of diatom biology can lead to advances in human health care
and well being, due to the phylogenetic relatedness of diatoms to important human patho-
gens, eg ciliates and apicomplexans, and to the potential biomedical applications of diatom
silica nanofabrication. In summary, DIATOMICS is stimulating multidisciplinary basic research
in Europe to exploit the full potential of diatom genome sequences to underpin applications of
relevance for human health, and for predicting and monitoring global climate change.
Keywords: cell biology, diatoms, genomics, reverse genetics
Partners
Project Coordinator: Dr. Chris Bowler Prof. Wim Vyverman
Dr. Chris Bowler Centre National de University of Ghent
Stazione Zoologica Anton Dohrn la Recherche Scientifique Laboratory of Protistology and
Cell Signalling Laboratory (CNRS) UMR 8186 Aquatic Ecology
Villa Comunale Biologie Moléculaire Ghent, Belgium
80121 Naples, Italy des Organismes
chris@szn.it Photosynthétiques Dr. Richard Wetherbee
Ecole Normale Supérieure University of Melbourne
Prof. Colin Brownlee Paris, France School of Botany
Marine Biological Association Parkville, Australia
of the UK
The Laboratory, Citadel Hill
Plymouth, UK
Prof. Veronique Martin-Jezequel

University of Nantes
Faculty of Sciences ISOMer Prof. Linda Karen Medlin
EA 2663 Stiftung Alfred
Nantes, France Wegener Institut fur Polar
und Meereschforschung
Prof. James A Callow Department of Biological
University of Birmingham Oceanography
School of Biosciences Bremerhaven, Germany
Birmingham, UK
Dr. Leszek Rychlewski
Prof. Julie La Roche BioInfoBank Institute
Leibniz Institut fuer Bioinformatics Laboratory
Meereswissenschaffen Poznan, Poland
Department of Marine
Biogeochemistry Prof. Valerie Frankard
Kiel, Germany Cropdesign NV
Technology Management
Prof. Aaron Kaplan Group
Hebrew University of Jerusalem Zwijnaarde, Belgium
Department of Plant Sciences
Institute of Life Sciences
Jerusalem, Israel
8. SYSTEMS BIOLOGY
8.
SYSTEMS
BIOLOGY
EUSYSBIO RIBOSYS
SYMBIONIC EUROBIOFUND
EMI-CD VALAPODYN
QUASI AGRON-OMICS
COMBIO BaSysBio
COSBICS BioBridge
DIAMONDS SYSBIOMED
EU-US Workshop SysProt
ELIfe Streptomics
ESBIC-D SYSCO
YSBN Proust
AMPKIN
EUSYSBIO
www.eusysbio.org/index.htm

Contract number: Systems biology (SB) covers research into in silico simulation of complex life processes,
combining concepts from molecular biology, engineering sciences, mathematics and IT in a
LSSG-CT-2003-503218
holistic approach to complex biological systems such as living cells. SB is currently receiv-
Starting date: ing widespread attention in Japan and the USA and is being intensively researched and
1st November 2003 promoted. Europe is lagging behind in systems biology research and EUSYSBIO was set up
Duration: with the aim of bringing together research groups to create a future research network.
24 months
EC Funding:
`500 000 Scientific/Technical Objectives:
A survey carried out by the EUSYSBIO team indicated that the training of young scientists
is essential to the creation of a European systems biology network and also university
training programmes in interdisciplinary subjects. The consortium therefore set up training
activities, including a series of lectures in Austria. They also began a search for research
networks outside Europe to make links with groups for future cooperative research projects.
The team carried out the task of identifying the strengths and weaknesses in the European
systems biology field and consequently began the task of forming a research network that
can compete worldwide.
Expected Results:
The project laid the foundations of the successful start of European systems biology research
and will form the foundation of further SB research activities. Researchers met in Germany
in 2004 to discuss how to establish standards for cooperation and data exchange across
Europe and beyond. EUSYSBIO also set up a website and database to contact potential
research collaborators and advertise vacancies in the field of SB.
Potential Impact:
European SMEs have the necessary knowledge to use opportunities given by the commer-
cialisation of SB results. If Europe exploits this competitive advantage it can move into a
leading position in the field of international SB research.
Keywords:
systems biology, research policies
The Take-off of European Systems Biology
Partners
Dr. Petra Wolff
Forschungszentrum Juelich GmbH
Project Management Juelich (Ptj)
Leo-Brandt-Strasse
52425 Juelich, Germany
p.wolff@fz-juelich.de
Dr. Thomas Reiss

Fraunhofer Institute for Systems and
Innovation Research (Isi)
Munich, Germany
Prof. Hans Victor Westerhoff

Vrije Universiteit Amsterdam
Faculty of Earth and Life Sciences
Department of Molecular Cell Physiology
Prof. Karl Kuchler

Division of Molecular Genetics
Vienna, Austria
Dr. Roland Eils

Theoretical Bioinformatics
Heidelberg, Germany
Dr. Barbara Streicher

Dialog Gentechnik
Vienna, Austria
Dr. Rudiger Marquardt

Dechema Gesellschaft Fuer Chemische
Technik Und Biotechnologie E.V.
Vbu Vereinigung Deutscher Biotechnologie
-Unternehmen (Vbu)
Frankfurt, Germany
Dr. Sirpa Nuotio

Academy of Finland
Health Research Unit
Helsinki, Finland
SYMBIONIC
www.symbionicproject.org

Contract number: In the next few years, systematic data from proteomics and genomics will allow the design
of an in silico virtual cell, a model that will have an enormous impact on biomedical and
LSHG-CT-2003-503477
pharmaceutical areas, as it will contribute to a rational design of treatments for human neu-
Starting date: rodegenerative diseases. Hence, there is a pressing need to start a European-wide initiative
1st November 2003 on the systems biology (SB) of neuronal cells and synapses. The SYMBIONIC project aims
Duration: at putting the issue of a systems biology approach in the field of neuronal cell study at the
24 months centre of interest for a wide scientific community, from cell and molecular neurobiology
EC Funding: and neurophysiology to functional genomics, proteomics, bioinformatics, biophysics and
computational biology.
`200 000
The SYMBIONIC project was designed to capitalise on the enormous scientific potential in
Europe and fill a significant void in the international scientific arena. Its long-term aim is to
be the driving force for a future set-up of a European-based exhaustive and reliable compu-
tational model of the neuron. The activity of the SYMBIONIC project was mainly focused
on training and dissemination and on the coordination of the project with other European
initiatives in the SB field. Further objectives were:
s TOCOLLABORATEANDCOORDINATEWITHOTHER%UROPEAN3"INITIATIVES
s TOTRAINANEWGENERATIONOFYOUNGSCIENTISTSINNEURONAL3"BOTHINTHECOMPUTA-
tional and experimental fields
s TOSPREADKNOWLEDGEABOUTTHE3"OFNEURONALCELLEVENTONON SPECIALIZEDAUDI-
ences
s TO RAISE THE AWARENESS OF BIOTECHNOLOGY PHARMACEUTICAL AND COMPUTER INDUSTRIES
about the great potential of neuronal cells
s TOCONTRIBUTETOHIGHSTANDARDSVI TOGIVEBIRTHTOMOREAMBITIOUS%UROPEANRESEARCH
and technological projects
Expected Results:
The SYMBIONIC project helped to integrate knowledge and expertise, provided a general
assessment of the existing data and know-how in several different scientific domains (from
neurophysiology to computer science), triggered the growth of a consensus on the initiative
from pharmaceutical, biotechnological and computing industries and found new strategies
for fundraising. Furthermore, it helped to integrate and coordinate the ongoing European-
wide initiatives on different aspects of systems biology. The project organized workshops,
conferences and training courses on the scientific and technological themes involved for the
growth of a future generation of scientists.
Potential Impact:
SYMBIONIC is creating a broad European network of research institutions and industries
with interdisciplinary expertise in the SB field, which will be a driving force for future am-
bitious initiatives in neuronal cell modelling. Through its workshops and conferences the
project is contributing to the training of young scientists and to making the pharmaceutical
Towards European Neuronal Cell Simulation:
a European consortium to integrate
the scientific activities for the creation
of a European Alliance devoted to
the complete in-silico model of Neuronal Cell
and biotechnology industries more aware of the opportunities offered by SB and its huge
potential impact on the economy, The European network of scientists and research groups
created through SYMBIONIC activities are now likely to generate new and more ambitious
research projects in the area of SB.
Keywords:
protein-protein interaction, simulation, neuron, protein network, signaling pathway, syn-
apse, computational systems biology, in silico models, research policies
Partners
Dr. Ivan Arisi
Lay Line Genomics SpA.
c/o San Raffaele Scientific Park
Building B, Floor 4
Via di Castel Romano 100
00128 Rome, Italy
i.arisi@laylinegenomics.com
Prof. Antonio Cattaneo

Scuola Internazionale Superiore Di Studi Avanzati
Department of Biophysics
Trieste, Italy
Dr. Christopher Sanderson

MRC Human Genome Mapping Project
London, UK
Prof. Marta Cascante

Universitat de Barcelona
Departament de Bioquimica i Biologia Molecular
Barcelona, Spain
EMI-CD
http://pybios.molgen.mpg.de/EMICD
Project Type:
State-of-the-Art:
Specific Targeted The main sociological and economical impact of genome research lies in the molecular un-
Research Project derstanding of major human diseases, and the development of new therapies. However, de-
Contract number: spite significant increases in pharmaceutical R&D spending, the number of new approved
medicines has remained fairly constant. One possible reason for this development might be
LSHG-CT-2003-503269 the fact that analytical methods and tools are not yet significantly installed in the drug develop-
Starting date: ment process. While bioinformatics are used in drug target discovery, this is not the case for
1st January 2004 the later stages. In particular, the simulation and modelling of biological processes, such as
Duration: disease-relevant signalling pathways and metabolic processes, are underdeveloped in drug
42 months target validation. )NĺSILICO experiments could be the basis for successful screening, and the en-
tire drug development process should be accompanied by bioinformatics and systems biology
EC Funding:
approaches, especially through the introduction of simulation techniques and experimental
`1 905 772 design at all phases of the process. Furthermore, the need for integration of rules and methods
is fundamental in current functional genomics research. Multiple databases exist already, a va-
riety of experimental techniques have produced gene and proteome expression data from vari-
ous tissues and samples, and important disease-relevant pathways have been investigated.
The analysis of the processes involved in the course of multigenic diseases, necessitates coping
with data from diverse experimental platforms. Consequently, important elements of the EMI-
CD software platform target data integration, as well as data standardisation. In particular,
the EMI-CD platform is designed in a modular way. The main modules are set out below:
Database integration: The role of several partners (BioWisdomSRS, EBI and MicroDiscovery)
in the EMI-CD project is to provide an information layer on the biological objects needed by
the modelling software (Max Planck Institute for Molecular Genetics), and is therefore of key
importance to the project, due to it providing a central repository for the data sources used
by the project.
Experimental data integration: Due to limitations of the current state-of-the-art in data integra-
tion, there is an essential need for a computer application. Even more crucial for the EMI-CD
project is access to data of high quality, indispensable for modelling and simulation tasks.
Modelling of high-throughput data: Computational methodologies are expected to direct
biological discovery, by enabling formalisation of the current biological knowledge into a
formal model, and improving our knowledge, by refining the model systematically, according
to the high-throughput data. Tel-Aviv University has introduced an extended computational
framework for studying biological systems. The approach combines formalisation of existing
qualitative models that are in wide but informal use today, with probabilistic modelling and
integration of high throughput screening.
Expected Results:
The main purpose of EMI-CD is to provide a software platform complex enough to cope with
various experimental techniques, aimed at discovering the gene function, and at understand-
ing disease processes. Another important issue is the tight cooperation with experimental
projects, on the design of experiments for combined strategies to combat human diseases
(such as cancer and diabetes). Compatibility with other systems is also an issue, but by using
SBML, models can be interchanged between different systems. A further issue stems from scal-
ing of the platform to large systems (i.e. whole cell models). At the current stage, systems with
a few thousand reactions are computationally feasible. EMI-CD will be an open system for the
integration of advanced analysis tools and other database systems.
European Modelling Initiative
combating complex diseases
Potential Impact:
In silico modelling ap-
proaches will have an in-
creasing impact on Life Sci-
ence and Health programs.
More specifically, they will
create immense potential
for improving the quality
of life, through their crea- PyBioS database interface.
tion of highly skilled jobs in The PyBioS system is linked
the health sector, improved to the other platforms of the
competitiveness and eco- EMI-CD project that are providing
nomic growth in Europe, topological data on cellular
and better healthcare and reaction systems
new tools to address the and experimental data via
diverse and important chal- specific interfaces.
lenges of the European Community. In terms of health care, the post-genomics era will
enable the invention and production of new diagnostic and analysis tools. A revolution in
health care is anticipated with the move towards personalised medical treatments, by
means of genetic medicine and the modelling of patient-specific therapy. This is
bound to have an important impact on the future health status and quality of life
of European citizens, and also to affect the cost implications for the population.
Keywords: bioinformatics, modelling complex diseases,

network analysis, complex diseases
Partners
Dr. Ralf Herwig
Max Planck Institute for Molecular Genetics
Vertebrate Genomics
Ihnestr. 73
herwig@molgen.mpg.de
Prof. Dr. Ron Shamir

Tel Aviv University
School of Computer Science
Tel Aviv, Israel
Dr. Ewan Birney

European Moleculer Biology Laboratory (EMBL)
Hinxton, UK
Dr. Chris Hodkinson Dr. Arif Malik

BioWisdom Ltd MicroDiscovery GmbH
Cambridge, UK Berlin, Germany
QUASI
www.idp.mdh.se/quasi
State-of-the-art:
Project Type: Present understanding of cellular signal transduction is restricted, at best, to the wiring
Specific Targeted schemes of signalling pathways. Little is known about the details of their dynamic operation
Research Project and the importance of quantitative, spatial and time-dependent parameters for signalling
Contract number: output. These are, however, crucially important for drug discovery and application.
QUASI is a multidisciplinary project which aims at obtaining a coherent and detailed pic-
LSHG-CT-2003-503 230 ture of the dynamic operation of a model signalling transduction network. The signalling
Starting date: pathways contain the evolutionarily conserved MAP kinase cascade module, which is of
1st January 2004 central importance for signalling in human cells and is implicated in human diseases such
Duration: as cancer and inflammatory disorders. MAP kinase pathways are currently being explored
42 months as drug targets. A better understanding of the dynamic operation of these pathways offers
new opportunities for drug discovery and for efficient individualised treatment based on the
EC Funding: genetic makeup of the patient (pharmacogenomics).
`1 920 410
The overall objective of QUASI is to assess the dynamic and quantitative operation of sig-
nal transduction pathways and to elucidate relevant paradigms. The individual scientific,
technical and innovation objectives of the project are:
1. To monitor activated protein kinases in the cell. A range of immunoreagents is being
used to quantify key phosphorylation events.
2. To determine dynamic signalling events in single living cells using advanced micro-
scopic and optic tools. These methods aim at the determination of protein movements
within the living cell.
3. To specifically, rapidly and temporarily inhibit signalling components in the living
cell. For this purpose, the team will design functional protein kinase variants that are
sensitive to highly specific inhibitory compounds. In addition, QUASI is initiating
development of inhibitors based on protein kinase target structure.
4. To identify direct protein kinase targets and quantify kinase-substrate reactions. In or-
der for QUASI to reach its objective the team will develop and verify ATP analogues
recognised by specific, modified protein kinases.
5. To follow protein complex formation dynamics in the living cell. More specifically, the
team is employing protein tags that allow the use of specific cross-linking reagents for
protein complexes in solutions as well as on DNA templates in the cell. In addition,
activatable Green Fluorescent Protein (GFP) variants and advanced microscopy/op-
tics are also being used to determine cellular movement and assembly of individual
subunits and protein complexes.
Yeast cells stained for cell wall

usinf calcofluor white (top) and
Expected results:
plasma membrane Using an 1. A better understanding of the importance and role of quantitative aspects of signal
Aqy2-GFP fusion (bottom). The transduction. Particular attention will be given to the signal amplitude and period for
diameter of the cell is about 5 the quality and intensity of different responses. This is vital for improved concepts in
micrometer. Yeast cells actively drug development and in drug applications such as personalised medication.
control their volume via con- 2. A better understanding of the signalling of protein complex formation and protein
served signalling systems that movement as possible targets for pharmacological intervention.
are Studied in QUASI using a 3. Identification of overriding rules of signalling pathway control including feed-forward
systems biology approach. and feed-back control principles and robustness.
4. A better understanding of how pathway specificity is achieved and maintained dur-
ing signal transduction and how cross-talk between pathways is regulated.
5. A set of optimised tools and approaches of general applicability.
6. Mathematical models, which could be applied with adjusted parameters to MAP
Quantifying signal transduction
kinase pathways from any system.
7. Information design and visualisation tools of wide applicability for the communica-
tion of signalling and other dynamic events.
Potential impact:
QUASI is a project at the frontline of fundamental biomedical research. The results obtained
will have a direct impact on drug development and drug application in diseases associ-
ated with altered MAP kinase signalling, and therefore can potentially contribute to giving
Europe a competitive advantage in signal transduction research.
Diseases such as cancer, and chronic inflammatory diseases such as rheumatoid arthritis,
asthma and autoimmunity affect many millions of Europeans; they are either life-threatening
or affect a person’s quality of life for many years. Because of this they require treatment
over long periods of time and are a huge financial burden on society. Hence, QUASI has
the potential to open new avenues leading to better treatment of these diseases, thereby
contributing to disease prevention in Europe and cost reductions for health services.
Keywords: signal transduction, MAP kinases, cellular dynamics, mathematical

models
Partners
Prof. Stefan Hohmann
Department of Cell
and Molecular Biology
Box 462 (Medicinaregatan 9E)
405 30 Gothenburg, Sweden
stefan.hohmann@hu.se
Dr. Per Sunnerhagen,

Dr. Markus Tamas
Dr. Morten Grötli
Gothenburg University Prof. Matthias Peter
Department of Cell and Swiss Federal Institute of
Molecular Biology Technology Zurich (ETH Zurich)
and Department of Chemistry Institute of Biochemistry
Gothenburg, Sweden Zurich, Switzerland
Prof. Francesc Posas Dr. Edda Klipp

Universitat Pompeu Fabra (UPF) Max-Planck Institute for
Cell Signalling Unit Molecular Genetics
Department de Ciències Department of Vertebrate Genomics
Experimentals i de la Salut Berlin Centre for Genome
Barcelona, Spain Based Bioinformatics (BCB)
Berlin, Germany
Dr. Gustav Ammerer
University of Vienna Dr. Rune Pettersson
Institute of Biochemistry Mälardalens Högskola
and Molecular Cell Biology Institutionen för Innovation
Vienna Biocenter Design och Produktutveckling
Vienna, Austria Eskilstuna, Sweden
COMBIO
State-of-the-Art:
Project Type: It is increasingly becoming recognised that progress in biology depends on an understand-
Specific Targeted ing of the interactions between genes and proteins, and the functional systems they gener-
Research Project ate. Given the complexity of even the most primitive living organism, and the fact that our
knowledge of these interacting networks is still very limited, it is unreasonable to expect that
Contract number: we might achieve such understanding at the level of the cell in the near future. However, sig-
LSHG-CT-2004-503568 nificant progress towards a system-level understanding should be achievable by applying
Starting date: an integrated approach to the analysis of a set of well-defined and biologically important
1st March 2004 cellular processes.
By combining experimental, simulation and bioinformatics approaches, COMBIO aims to
Duration: increase understanding of two biologically important systems: the first is the p53-Mdm2
36 months regulatory network, in which the oncoprotein Mdm2 controls the activity of the tumour sup-
EC Funding: pressor ‘gatekeeper’ protein p53, via a negative feedback loop, and the second is the self-
`1 998 000 organisation process whereby chromatin controls microtubule nucleation and organisation
during spindle formation. These two systems have been selected because they represent
two important and different kinds of biological system — one which can be described
approximately as a network of free components, and the other in which localisation, self-
organisation and gradients play an important role.
The general objective of COMBIO is to benchmark the ability of current modelling and
simulation methods to generate useful hypotheses for experimentalists, and to provide new
insights into complex biological processes.
In both systems COMBIO has selected to study — the p53-Mdm2 regulatory network, and the
dynamics of spindle assembly — the consortium will use different approaches to obtain quan-
titative data, as well as data regarding localisation and the dynamics of the system. Three of
the consortium’s partners are leaders in the field of database construction and display. Work-
ing in close collaboration with experimentalists, they will develop databases that are adapted
to experimental work and computer modelling. Data will be stored in such a way that they
will be accessible to various simulation packages, and will be displayed in such a way that
non-experts will be able to make sense of them. This aspect of the project will require signifi-
cant technological innovation. Two of the groups in COMBIO develop modelling approxima-
tions while simultaneously conducting experiments to validate the models’ predictions. These
groups will act as a kind of bridge between the dry and wet labs in the consortium. The dif-
ferent modelling tools will be assessed and a handbook drawn up, which will allow the rapid
dissemination of these tools to the broader experimental community.
Expected Results:
It is the ambition of the COMBIO consortium to create a truly interdisciplinary environment,
in which a range of theoretical and experimental approaches that were hitherto considered
separate areas of research, will be integrated and applied to the understanding of complex
biological systems. In so doing, it hopes to make an important contribution to functional
genomics, and to provide means for elucidating the mechanisms of action of pharmacologi-
Prolonged oscillations in the cal compounds.
nuclear levels of fluorescently-
tagged p53 and Mdm2 in
individual MCF7 cells following
Potential Impact:
gamma irradiation. Systems biology recognises the importance of wholeness, acknowledging that systems can-
not be understood by investigation of their parts in isolation. Today, systems biology brings
mathematics, engineering, physics and computer science expertise to the exploration of
complex biological systems and their regulation.
The current emphasis on systems in biology is the result of recent developments in molecular
An integrative approach
to cellular signalling and control processes:
Bringing computational biology to the bench
biology and biochemistry, which have enabled researchers to collect comprehensive data
sets on the performance of systems, and to acquire information about their molecular sub-
strates. These developments have implications for medicine and drug development.Human
disease phenotypes are controlled not only by individual genes and their products, but also
by networks of interactions that exist between those genes and their products, and the system-
wide dynamic behaviour that they display. The networks range from metabolic pathways to
signalling pathways that regulate hormone action. Study of the dynamics of these networks,
using approaches such as metabolic control analysis (for metabolic networks), or stochastic or
logical approaches (for gene regulation networks), may provide new insights into the patho-
genesis and treatment of complex diseases such as cancer.
Keywords: systems biology, computer modelling, gene & protein networks, gra-
dients, software evaluation, network design, computational biology,
signalling
Partners
Prof.. Luis Serrano Prof. Béla Novák Dr. Cayetano Gonzales
CRG - Centre de Regulació Genòmica Technical University of Budapest Institute of Biomedical
Systems Biology Research Unit Molecular Network Dynamics Research
Dr. Aiguader 88 Research Group Cell Division Laboratory
08003 Barcelona, Spain Budapest, Hungary Barcelona, Spain
luis.serrano@crg.es
Prof. Alfonso Valencia Dr. Isabelle Vernos
Dr. Francois Nedelec National Centre for Biotechnology Centre for Genomic
European Molecular Biology Protein Design Group Regulation (CRG)
Laboratory (EMBL) Madrid, Spain Barcelona, Spain
Cell Biology and Biophysics Unit
Heidelberg, Germany
Dr. Olga Kel-Margoulis

Prof. Edgar Wingender
BIOBASE Pathway Databases
Wolfenbüttel, Germany
Dr. Uri Alon

Department of Molecular Cell Biology
Rehovot, Israel
Dr. Marcelle Kaufman

Université Libre de Bruxelles
Centre for Nonlinear Phenomena
and Complex Systems
Brussels, Belgium
Dr. Amancio Carnero

Centro Nacional de
Investigaciones Oncológicas
Madrid, Spain
Prof. Edgar Wingender

University of Göttingen
Department of Bioinformatics
Göttingen, Germany
COSBICS

Specific Targeted
Research Project Cancer can be considered a disease of communication at molecular level. The area of cell
signalling investigates the transmission of information from receptors to gene activation by
Contract number:
means of biochemical reaction pathways, which form complex signalling networks and
LSHG-CT-2004-512060 impinge on the development and health of organisms. COSBICS will establish and apply
Starting date: a novel computational framework in which it will investigate dynamic interactions of mole-
1st January 2005 cules within cells. Instead of simply mapping proteins in a pathway, COSBICS is concerned
Duration: with ‘dynamic pathway modelling’. Dynamic pathway modelling establishes mathematical
39 months models to predict quantitatively the spatial-temporal response of signalling pathways and
subsequent target gene expression. This project considers two important systems: the Ras/
EC Funding:
Raf/MEK/ERK and the JAK-STAT pathways. With these pathways, COSBICS will investigate
`1 684 159 the heart of the intracellular communication network that governs cell growth, differentiation
and survival.
COSBICS’ main goals are to identify and quantify dynamic interactions of signalling path-
ways using system- and signal-orientated approaches, and to develop methodologies that
are applicable to the dynamic and predictive analysis of signalling networks in general. As
paradigms, we consider two important systems at the heart of the intracellular communica-
tion network that govern cell growth and survival: the Ras/Raf/MEK/ERK pathway and the
JAK-STAT pathway. COSBICS combines mathematical modelling with biological knowledge
to improve our understanding of how these two central communication networks are sub-
verted in tumour cells.
JAK2-STAT5
pathway map
Expected Results:
The COSBICS project will develop two complete mathematical models of the JAK2-STAT5
and Ras/Raf1/MEK/ERK pathways. The structure and parameter values of these models
are based on quantitative time series data generated by the consortium. The consortium
Computational Systems Biology
of Cell Signalling
will develop mathematical and computational methods that are generic and should be
applicable to a wide range of cell signalling systems. The ultimate biological goal is an
understanding of the two signalling pathways that play an important role in cell differentia-
tion and proliferation. We are hoping that our models and experiments will reveal general
principles by which cells decide upon cell growth and development.
Potential Impact:
The tools we are developing for the mathematical analysis of nonlinear signal transduction
pathway models are generic and can be applied to other systems biology projects as well.
We aim to develop models that can predict the biochemical behaviour of pathways in re-
sponse to perturbations, which will be experimentally tested. We also will use this informa-
tion to help in the design of biological experiments, for example, by determining how many
measurements need to be taken at what time intervals for a robust result to be obtained.
Both applications will be useful for academic as well as industrial research mainly through
minimising the ‘wet’ experimental load, which is very expensive and time-consuming.
Keywords: dynamic modelling of signal transduction pathways
Partners
Prof. Olaf Wolkenhauer Dr. Jens Timmer
Universität Rostock Albert-Ludwigs-Universität Freiburg
Department of Computer Science Freiburger Zentrum für
Universitätsplatz 1 Datenanalyse und Modellbildung
18051 Rostock, Germany Freiburg, Germany
wolkenhauer@informatik.uni-rostock.de
Dr. Ursula Klingmuller

Theodor Boveri Nachwuchsgruppe:
Systembiologie der Signaltransduktion
Heidelberg, Germany
Prof. Walter Kolch

Beatson Institute for Cancer Research
Glasgow, UK
Dr. Julio Rodriguez Banga

Instituto de Investigaciones Marinas del
Consejo Superior de Investigaciones Cientificas
Process Engineering Group
Madrid, Spain
Prof. Valko Petrov

Bulgarian Academy of Sciences
Institute of Mechanics and Biomechanics
Laboratory of Biodynamics and Biorheology
Sofia, Bulgaria
DIAMONDS
www.SBcellcycle.org
State-of-the-Art:
Project Type: The field of systems biology aims to build on the success of novel functional genomics tech-
Specific Targeted nologies, by improving data extraction and data modelling in order to get an understand-
Research Project ing of biological processes as ‘control systems’. Essential to systems biology is the math-
Contract number: ematical modelling of biological processes, and its use to build hypotheses and to carry
out subsequent experimental validation. The complexity of biological processes is such that
LSHG-CT-2004-512143 without modelling and simulation its dynamics cannot be fully understood. Systems biology
Starting date: requires strong skills in biology and in computational analysis. Within DIAMONDS we wish
1st January 2005 to set in motion a multinational systems biology effort to study and model cell cycle control
Duration: in baker’s and fission yeast, and in !RABIDOPSISĺTHALIANA and human cells.
42 months
EC Funding:
`2 500 000
The overarching objective is to demonstrate the power of a systems biology approach
to study fundamental biological processes. We focus on eukaryotic cell cycle regulation,
and will develop and implement a computational model that will function as a hypothesis-
generating engine in a systems biology ‘wet lab’ environment. To reach this we set out to
develop two parts: a cell cycle knowledge base and an integrated platform of data mining,
modelling and simulation tools. This will allow the integrated analysis of that data in a sys-
tems biology approach: the development of a basic model, the use of this model to design
new experiments, the production and analysis of novel data and the integration of these
into a refined model.
The major means of reaching this target is to harvest and/or produce a large body of cell
cycle-related biological knowledge. This will function as the central resource for the model-
ling and simulation environment that will be developed. The project will showcase the fact
that a systems biology approach toward analysis of a fundamental biological process can
in fact become mature today, and hinges on an integrated data analysis pipeline, extended
with modelling and simulation tools.
Expected Results:
At the end of the project we will have an integrated toolbox for
the analysis of functional genomics data, and the modelling of
cell cycle information for simulation purposes. We will also de-
liver a knowledge base (GIN-db) containing detailed information
about core cell cycle genes. The project is in its final year. We
have begun concrete experiments to synchronise cells in culture in
order to study the dynamics of expression with microarrays and
proteomics approaches. We have also finished the design of the
data analysis platform and will deliver the first working version
by early 2008.
Potential Impact:
The project will allow extensive data integration and modelling,
and will deliver new insights in cell cycle regulation and the
mechanisms that prevent the uncontrolled proliferation of cells,
opening the way to novel anti-tumour drugs and strategies. The potential for applications of
life sciences and biotechnology promises to be a growing source of wealth creation in the
future, leading to the creation of jobs, particularly in the areas of highly skilled labour, and
new opportunities for investment in further research.
Dedicated Integration and Modelling
of Novel Data and Prior Knowledge
to Enable Systems Biology
Keywords:
functional genomics, systems biology, cancer, regulatory networks, dynamical modelling
Partners
Project Coordinator: Marta Acilu
Prof. Martin Kuiper Noray Bioinformatics, S.L.
Flanders Interuniversity Institute Derio, Spain
for Biotechnology
Department of Plant Systems Biology Dr. Jürg Bähler
Computational Biology Group Genome Research Ltd
Technologiepark 927 Wellcome Trust Sanger Institute
9052 Ghent, Belgium Cambridge, UK
makui@psb.ugent.be
Prof. Alfonso Valencia
Dr. Kristian Helin Fundación Centro Nacional De
University of Copenhagen Investigaciones Oncológicas Carlos Iii
Biotech Research and Innovation Centre Structural Biology And Biocomputing Programme
Copenhagen K, Denmark Madrid, Spain
Prof. Denis Thieffry

Technologies Avancées pour le
Génome et la Clinique (TAGC)
Faculté des Sciences de Luminy
Marseille, France
Prof. Søren Brunak

Analysis (CBS), BioCentrum, DTU
Kgs. Lyngby, Denmark
Dr. Alvis Brazma

Laboratory (EMBL)
Hinxton, UK
Prof. Michal Linial

Hebrew University of Jerusalem
Department of Biological Chemistry
Institute of Life Sciences, Faculty of Science
Jerusalem, Israel
Dr. Tor-Kristian Jenssen

PubGene AS
Oslo, Norway
EU-US Workshop

Contract number: DNA is under constant attack from physical and chemical agents that weaken and com-
promise it. This means there is a potential risk for cancer and other health problems. Large
LSSG-CT-2004-013079
numbers of chemicals in our food and in the environment have a potentially harmful affect
Starting date: on our DNA under conditions in which its repair capacity is lowered. More research is
1st September 2004 needed to increase our knowledge of DNA repair pathways and interacting processes and
Duration: to obtain a better understanding of DNA responses at cellular level. As a response to this
18 months the Systems Biology of DNA-Damage-Induced Stress Responses workshop was organised
EC Funding: as a follow up to the Molecular Signature of DNA Damage Induced Stress Responses work-
shop that was held in 2003.
`60 000
The main objective was to provide unique opportunities for interactions between American
and European researchers in DNA repair and systems biology and to discuss a future vision
for this series of workshops.
Expected Results:
s 4HE FACILITATION OF NEW SCIENTIlC COLLABORATIONS BETWEEN %UROPEAN AND !MERICAN
researchers that will be of great benefit to both.
s !FORMAL%5 53COLLABORATIVERESEARCHPROGRAMMEINTHEAREAOFSYSTEMSBIOLOGY
DNA repair (possibly NIH-EU co-funded).
s !TRAINING ORIENTEDSYSTEMSBIOLOGY$.!REPAIRPROGRAMME
s !-ARIE#URIEFELLOWSHIPPROGRAMMEFORAMAJORCONFERENCEORASERIESOFWORK-
shops.
s !RESEARCHPROGRAMMETODEVELOPANOVELINTEGRATEDDATABASEKNOWLEDGEBASETHAT
combines approaches represented by CEBS, the Reactome Database and Fabio Pi-
ano’s C. elegans developmental phenotype database.
The Workshop was held in

Vermont and had about 70
participants both from the EU
and the USA. The relatively
small size of the group and
open mindedness allowed for
very fruitful discussions on the
state of the art in the field of
“Systems level understanding of
DNA damage responses” and an Potential Impact:
assessment of future possibilties
and collaborations. It is hoped that the workshop will lead to an invigorating effect on the international scientific
community, particularly scientists researching DNA repair pathways, and it was agreed that
participants of the workshop would make a point of researching into specific collaborations
that have been organised as a direct result of the previous workshop.
Workshop on “Systems biology of
DNA-damage-induced stress responses”
Y2H and literature–curated

interactions. This figure shows
the human protein interactome
deduced from yeast-two-hybrid
(Y2H) data (red edges) or from
literature–curated (LC) data (blue
edges). The overlap is relatively
low (2.3% of all LC interactions
and 8.4% of the most highly
conserved LC hypercore
interactions), suggesting
relatively strong sociological
or technical bias for literature-
based or Y2H-based interactome
mapping, respectively.
Keywords:
systems biology, DNA damage, stress response, EU-US collaboration, genome wide tran-
scriptional profiling
Partners
Dr. Harry Vrieling
Albinusdreef 2
2300 Leiden, The Netherlands
h.vrieling@lumc.nl
ELIfe
www.lipidomics.net
State-of-the-Art:
Project Type:
Specific Support Action Research dealing with the molecular constituents of cells is referred to as genomics for
Contract number: genes and nucleic acids, proteomics for proteins and glycomics for carbohydrates. What
has been missing in the ‘-omics’ realm to date has been lipidomics. Since both carbohy-
LSSG-CT-2004-013032
drates and lipids are cellular metabolites, glycomics and lipidomics represent sub-divisions
Starting date: of metabolomics.
1st January 2005 Lipids are essential constituents of cell membranes, where multiple cellular machines and
Duration: signalling systems carry out their functions. An imbalance in lipid metabolism results in vari-
30 months ous diseases, such as obesity, cardiovascular disease, stroke and Type 2 diabetes, which
EC Funding: pose a serious human and economic burden on the developed world. Lack of technology
has hampered the analysis of lipids. However, new, fast and sensitive mass spectrometry
`487 200
methods are now revolutionising the field, and are on the verge of being applied to dis-
eases related to the lipidome.
The aim of ELIfe was to mobilise and organise key stakeholders in the field of metabolomics,
especially in lipidomics research. Its objectives were as follows:
1) Encourage the formation of alliances between stakeholders in the metabolomics field,
including academic research groups and representatives of the healthcare profession
and industry;
2) Link metabolomics initiatives with genomics and proteomics initiatives, and to adapt
bioinformatics tools used in the latter for metabolomics;
3) Define a strategy for metabolomics research, using lipidomics as an example;
4) Establish a Lipidomics Expertise Platform as a first step towards mobilising the field.
This virtual platform should be linked to the European Federation for the Science and
Technology of Lipids (Euro Fed Lipids) and was to act as a test centre for benchmark-
ing new lipidomics technology;
5) Hold both science-related and policy meetings.
Expected Results:
The ELIfe consortium was to make significant contributions towards the development of a
comprehensive classification system for lipids. In addition to this, it expected to produce
the following two results: 1) The Lipidomics Expertise Platform (http://www.lipidomics-ex-
pertise.de), based on a survey of lipidomics expertise and infrastructure in Europe and 2)
The organisation of, and contribution to, multiple workshops and conferences (http://www.
lipidomics.net).
Potential Impact:
Cholesterol monohydrate crystals ELIfe brought together and co-ordinated European expertise in metabolomics and lipid-
in murine gallbladder bile at the omics, drawing attention to these fields and establishing strategic alliances that should result
polarizing light microscopy. in the translation of basic research findings into medical and commercial applications.
The project will help shape European and national policies and activities in relation to ap-
plied and fundamental research. The improvements in analysis of lipid patterns in diseased
and healthy people that it aims to generate, will yield insights into the potential effects of
different types of (lipid) nutrition on human health.
The European Lipidomics Initiative:
Shaping the life sciences
Keywords: lipidomics, metabolomics, clinical application of lipids
Partners
Prof. Gerrit van Meer Prof. Elina Ikonen Prof. Friedrich Spener
Utrecht University University of Helsinki Universität Graz
Bijvoet Center and Institute of Biomedicine Department of
Institute of Biomembranes Helsinki, Finland Molecular Biosciences
Utrecht, The Netherlands Graz, Austria De P4-ATPase structure is from:
g.vanmeer@uu.nl Prof. Michel Lagarde Lenoir, G. & Holthuis, J. C. The
Institut National des Sciences Prof. Sandro Sonnino elusive flippases Curr Biol 14,
Prof. Gerd Schmitz Appliquées de Lyon University of Milan R912-913 (2004).
University Hospital Regensburg Pathophysiology of Lipids Department Medical Chemistry
Institute for Clinical Chemistry and Membranes (PLM) Biochemistry and Biotechnology
and Laboratory Medicine Villeurbanne, France Segrate, Italy
Regensburg, Germany
Prof. Konrad Sandhoff Prof. Gerd Utermann
Prof. Kai Simons Rheinische Friedrich-Wilhelms Medical University Innsbruck
Max-Planck Institute of Molecular Universität Bonn Institute for Medical Biology
Cell Biology and Genetics: Kekulé-Institut für Organische and Human Genetics
MPI-CBG Chemie und Biochemie Innsbruck, Austria
Dresden, Germany Bonn, Germany
Prof. Jürgen Borlak

Fraunhofer-Gesellschaft zur
Förderung der angewandten
Forschung e.V.
Fraunhofer Institut für
Toxikologie und
Experimentelle Medizin
Hannover, Germany Prof. Balázs Sarkadi
National Medical Center
Prof. Raymond Dwek Institute of Haematology
University of Oxford and Immunology
Glycobiology Institute Department of Molecular
Oxford, UK Cell Biology
Budapest, Hungary
Prof. Pam Fredman
Institute of Neuroscience
and Physiology
Mölndal, Sweden
Prof. Félix M. Goñi

Universidad del País Vasco/
Euskal Herriko Unibertsitatea
Molecular Biology
Leioa (Bizkaia), Spain
ESBIC-D
State-of-the-Art:
Project Type: Activities to combat multigenic complex diseases such as cancer, diabetes, obesity, heart
Co-ordination Action diseases and diseases of the nervous system are primary targets of the Sixth Framework
Contract number: Programme. After decades of research, cancer remains a devastating disease, responsible
LSHG-CT-2005-518192 for roughly one quarter of the deaths in Europe.
Starting date: Essentially, there are three main causes of cancer: infection, environmental influence and
1st November 2005 genetic predisposition. However, on a more analytical and molecular level, the ontogeny
Duration: of cancer is less evident and both clinical as well as basic research suggests that cancer is
24 months the result of an accumulation of many factors that promote growth and metastasis (Hanahan
EC Funding: and Weinberg, 2000). Consequently, it is not clear whether much of the current cancer
research, especially the research focussed on analysing subprocesses which involve at
`350 000 most a few genes or gene products at a time, will ever be able to “understand” such a
complex phenomenon and form the basis for dramatic improvements in cancer treatment.
It is also clear that, in spite of all the successes in some specific areas, the current research
approaches have not resulted in any dramatic increase of the rates of cure for the most
common cancers. Within this context, it is the goal of the project’s Coordination Action (CA)
to establish a European framework for a systems’ biology approach to combat complex
diseases using cancer as a prototypical problem. The project’s Coordination Action will be
fundamentally based on existing resources of leading research groups in Europe. It unites
groups with a strong clinical focus, with experience in high throughput functional genomics,
as well as with computational and systems biology resources. Moreover, it brings together
groups from some of the largest European cancer research organisations and centres.
ESBIC-D will set up a cancer-relevant model repository consisting of known pathways and
gene regulatory networks associated with cancer, the role of specific mutations or other
changes in key genes/gene products in these pathways, and, as far as available, detailed
clinical data with special emphasis on the influence of different anti-cancer drugs on these
pathways. In this CA, important test cases that combine experimental and clinical data with
theoretical models and which will guide further analyses and approaches of the participat-
ing groups, will be identified. Attention will be given to in silico models of cancer-related
(e.g. signalling) pathways, which analyse the feedback of theoretical models and experi-
mental data as well as the construction of a complete human metabolic network in order to
test responses to drugs and chemical treatments.
Moreover, the ESBIC-D project aims to create a network of leading groups in the fields of
cancer research, genomics, proteomics and computational biology and to strengthen the
expertise and research infrastructure in Europe.
Expected Results:
1) Change and dissemination of information by combining leading EU wide resources;
2) Performance of joint studies and analyses by bridging experiment and model;
3) Performance of benchmarking exercises by defining test cases for systems biology ap-
proaches in Cancer;
DNA microarrays. Andre Nantel 4) Organisation and management by setting up an expert group for a European wide
©Shutterstock,2007 systems approach towards the combat of complex diseases (cancer).
The major added-value of ESBIC-D to the European scientific community is the provision of
the necessary groundwork for the integration and dissemination of essential parts of systems
biology initiatives to tackle cancer.
European Systems Biology Initiative for
Combating Complex Diseases
Potential Impact:
Systems biology approaches will have an increasing impact on Life Science and Health
programmes in general and on anticancer drug development in particular. They provide a
huge potential for improving the quality of life through the creation of highly skilled jobs,
improved competitiveness and economic growth in Europe, better healthcare and new tools
to address different important challenges of the European Community.
In health care, the post genomics era will enable the invention and production of new diag-
nostic tools and analysis tools. A revolution in health care is anticipated through a move to-
wards personalised medical treatments by means of genetic medicine and the modelling of
patient-specific therapy. This will represent an impact on the future health status and quality
of life of European citizens as well as on the cost implications. The technical progress within
the health care sector will make many new or improved, but costly, medical treatments pos-
sible. However, in the long run this is expected to change as there will be a direct positive
effect on the exploding health budgets throughout Europe.
Keywords: systems biology, complex diseases, mathematical modelling,

bioinformatics
Partners
Prof. Dr. Hans Lehrach
Vertebrate Genomics
Ihnestr. 73
E-mail: lehrach@molgen.mpg.de
Prof. Dr. Annemarie Poustka

German Cancer Research Center (DKFZ)
Molecular Genome Analysis
Heidelberg, Germany
Dr. Jean-Philippe Vert

Ecole des Mines de Paris
Computational Biology Group
Paris, France
Prof. Dr. Ron Shamir

Tel Aviv University
School of Computer Science
Tel Aviv, Israel
Dr. Crispin Miller

Paterson Institute for Cancer Research
Manchester, UK
Dr. Emmanuel Barillot Prof. Dr. Kurt Zatloukal

Institut Curie Medical University Graz
Bioinformatics Group Institute for Pathology
Paris, France Graz, Austria
YSBN
www.ysbn.eu
State-of-the-Art:
Project Type: The field of systems biology is expected to significantly affect biological and medical re-
Co-ordination Action search. It aims to develop a systems-level understanding of biological processes, by em-
Contract number: ploying mathematical analyses and computational tools, so as to integrate the information
content obtained in experimental biology. Gaining insight into the complete behaviour of
LSHG-CT-2005-018942
the cell will assist in the understanding of specific cellular processes and human diseases.
Starting date: Systems biology will also be used for biotechnological production of pharmaceuticals, food
1st November 2005 ingredients, fuels and chemicals.
Duration: The Yeast Systems Biology Network (YSBN) project uses the yeast Saccharomyces cerevi-
36 months siae as a model system, in order to advance the understanding of cellular systems. The
central focus of YSBN is on facilitating cooperation between experimental and theoretical
EC Funding: yeast researchers, thus exploiting the interdisciplinary characteristics of a systems biology
`1 300 000 approach.
The YSBN project aims to provide a platform that will integrate data acquisition, data
generation, modelling and recursive model optimisation. The achievement of the overall
objectives of YSBN involves meeting the following targets:
s/FFERINGADElNITIONOFSTANDARDSFORTHEDOCUMENTATIONOFPROTEOMETRANSCRIPTOME
metabolome, interactome, locasome and fluxome data;
s$EVELOPINGTHESTRUCTUREOFADATABASEFOCUSEDONSaccharomyces cerevisiae, allow-
ing for queries about experimental conditions and data from miscellaneous sources;
s$ElNINGTHESTANDARDSTHATWILLESTABLISHQUALITYCRITERIAFORMODELSTOENSURESUSTAIN-
able model development;
s#REATINGANDMAINTAININGSOFTWARETOOLSFORMATHEMATICALCELLMODELLING
s/RGANISINGANINTERNATIONALCONFERENCEANDCREATINGA93".WEBSITETHATCANFUNC-
tion as a port, allowing the entire international community to access the tools pro-
duced by YSBN;
s%STABLISHING A PLATFORM FOR HIGH QUALITY INTERDISCIPLINARY STUDENT TRAINING IN SYSTEMS
biology in Europe;
s)LLUSTRATINGHOWSYSTEMSBIOLOGYCANBEUTILISEDINTHEDESIGNOFEFlCIENTCELLFACTORIES
for the production of fuels and chemicals.
Expected Results:
The YSBN collaboration action is expected to:
s)NCREASEINTEGRATIONANDNETWORKINGAMONGTHEKEY%UROPEANRESEARCHGROUPSTHUS
generating new ideas for future projects and collaborations;
s&ACILITATETHECOMPARISONOFEXPERIMENTALDATATHROUGHSTANDARDISATIONOFDATADOCU-
mentation and mathematical model development;
s/RGANISEADVANCEDLECTURESAPRACTICALCOURSEANDREGULARWORKSHOPSONSYSTEMS
biology;
s/RGANISEANINTERNATIONALCONFERENCEONTHESYSTEMSBIOLOGYOFYEASTEXPECTEDTO
take place in Helsinki, in June 2006 (http://issy25.vtt.fi);
s$EVELOPADATABASEINWHICHINFORMATIONABOUTTHEEXPERIMENTALDATAGENERATEDCAN
be collected, maintained and queried, also allowing for links to information contained
in other databases;
s#REATEANDCONTINUOUSLYIMPLEMENTTHE93".WEBSITEWWWYSBNEU CONSIDEREDAS
a dissemination site for the tools generated by the project, and as an interface for the
communication between experimental and theoretical scientists
s4RAINNOVICESCIENTISTS
Yeast Systems Biology Network
Potential Impact:
YSBN is expected to have a powerful impact upon the scientific community; by setting
standards and providing a template for a focussed systems biology initiative, the project
will decrease fragmentation in European research, consequently benefiting systems biology
of other organisms. More specifically, the positive effects of YSBN will be noted in drug dis-
covery (directly connected to human health), in the development of new biotech processes
(which influence society), and also in education and training.
Within YSBN, there are two SMEs that will further improve the competitiveness of the Euro-
pean Biotechnology industry, by providing a new software platform for model simulations,
and by developing biotechnological processes based on cell factories.
Keywords: systems biology, Saccharomyces cerevisiae, bioinformatics,

mathematical modelling
Partners
Project Coordinator: Prof. Matthias Reuss Dr. Jochen Förster
Prof. Jens Nielsen University of Stuttgart Fluxome Sciences A/S
Technical University of Denmark Institute of Biochemical Engineering Copenhagen, Denmark
Centre for Microbial Biotechnology Stuttgart, Germany
Biocentrum Dr Johan Gunnarsson
Lyngby, Denmark Prof. Jack Pronk InNetics AB
jn@biocentrum.dtu.dk Technical University of Delft Linköping, Sweden
Delft, The Netherlands
Prof. Stefan Hohmann Dr. Macha Nikolski
University of Gothenburg Prof. Merja Penttilä University Bordeaux
Department of Cell and VTT Biotechnology Bordeaux, France
Molecular Biology/Microbiology Espoo, Finland
Gothenburg, Sweden Prof. Betul Kirdar
Dr. Edda Klipp Bogazici University
Prof. Stephen Oliver Max-Plank Institute for Istanbul, Turkey
University of Manchester Molecular Genetics
School of Biological Sciences Department of Vertebrate Genomics
Manchester, UK Berlin, Germany
Prof. Hans Westerhoff Prof. Bela Novak

Free University of Amsterdam Budapest University of
Biocentrum Technology and Economics
Amsterdam, The Netherlands Budapest, Hungary
Prof. Karl Kuchler Prof. Lilia Alberghina

Medical University of Vienna University of Milan
Division of Molecular Genetics Bicocca, Italy
Medical Biochemistry
Vienna, Austria Dr. Uwe Sauer
Swiss Federal Institute of Technology
Prof. Peter Philippsen Institute of Molecular
University of Basel Systems Biology
0Biocentrum Zurich, Switzerland
Basel Switzerland
Dr. Bärbel Hahn-Hägerdal
University of Lund
Lund, Sweden
AMPKIN
www.sbi.uni-rostock.de/projects_ampkin.html
State-of-the-Art:
Project Type: Systems Biology aims at understanding design principles and dynamic operation of cellular
Specific Targeted modules, entire cells, and organisms. The quantitative approach to biological systems is
Research Project driven by technological advances and close collaboration between different disciplines. A
Contract number: better understanding of the properties of biological systems is vital for drug development,
LSHG-CT-2005-518181 treatment of diseases and for the improvement of bioprocesses.
Starting date: In the AMPKIN project, experimental and theoretical studies will be integrated to achieve
1st January 2006 an advanced understanding of the dynamic operation of the AMP-activated protein kinase
Duration: (AMPK) signalling pathway. This pathway plays a central role in monitoring the cellular en-
42 months ergy status and controlling energy production and consumption. The main objective of the
project is to generate predictive kinetic mathematical descriptions of pathway activation/
EC Funding:
deactivation in yeast and mammalian cells and thereby to identify potential drug targets to
`2 106 593 treat human metabolic diseases.
The main technological and scientific objectives of the AMPKIN project are the following:
1. Establish and critically compare the network structures of the AMPK pathway from acti-
vation to response in yeast and mammalian cells by using existing data and knowledge
from literature, databases and own research;
2. Generate, optimise and verify assay systems for as many different steps as possible in
the AMPK pathway of yeast and mammalian cells in order to generate quantitative data
and maximise the use of real data in modelling;
3. Generate reference quantitative dynamic datasets following activation and deactivation
of the AMPK pathway in yeast and mammalian cells. This reference data set will be
used for generating dynamic models of the pathways and to optimise parameters that
can not be determined experimentally;
4. Generate and critically compare dynamic models for the yeast and mammalian AMPK
pathway. In addition, the project aims to use information from the yeast model to com-
plement gaps in the mathematical description of the mammalian model;
5. Produce tools for system perturbation, which will be used to generate data for model
testing, iterative model improvement, and for the potential development of drug screen-
ing approaches;
6. Provide ‘dynamic’ datasets from experiments, employing a range of defined system
perturbations in both yeast and mammalian cells with the aim of testing and iteratively
improving the models and of optimising the underlying parameters;
7. Generate iteratively improved mathematical models in order to determine system prop-
erties and to provide an assessment of similarities and dissimilarities of the models in
yeast and mammalian cells. As a consequence, to establish the significance and the
limitations of the approach of comparative modelling from experimental and theoretical
perspectives;
8. Predict the result of pharmacological system perturbations and, where possible, to assess
these experimentally, thereby implementing the models in drug screening programmes.
Expected Results:
The AMPK pathway plays a central role in yeasts, fungi, plants, animals and humans in the
control of the energy balance, and therefore it is crucial for life. The overall objective of this
project is to generate mathematical models, that is, computational replicas of the AMPK
pathway that will be used in drug target identification and drug screening. The results have
major potential for tackling some of the most rapidly advancing diseases in the modern
Systems biology of the AMP-activated
protein kinase pathway
world, such as obesity and type-2 diabetes. The project will result in a case study for em-
ploying systems biology in drug target identification and in drug development. Moreover, it
will produce results exploitable for engineering of microbial metabolism and systems biol-
ogy software development.
Potential Impact:
Innovation: the project is at the frontline of post-genomic research.
Competitiveness: the project strengthens the European research base in an emerging field
and it helps European companies to develop and optimise products for worldwide markets.
Exploitation: the results will be exploited by SMEs’ in different sectors of the European bio-
industries.
Dissemination: the results will be made widely visible to different audiences.
Solving societal problems: AMPKIN supports the development of treatments for emerging
diseases, such as obesity and type-2 diabetes.
Integration of research activities: the project uses EC funding to mobilise national resources. It
makes use of the results obtained in other EC-funded projects and is linked to other European
initiatives.
Training of the work force: the project will contribute to training and life-long learning of the
people employed by the project.
European added value: in order to tackle the project, AMPKIN brings together strong and
unique European expertise that cannot be found in a single country.
Keywords:
signal transduction, matabolism, mathematical models, drug development, diabetes,
protein kinase, systems biology
Partners
Prof. Stefan Hohmann
Department of Cell and
Molecular Biology
Box 462 (Medicinaregatan 9E)
40530 Gothenburg, Sweden
stefan.hohmann@gu.se
Prof. Olaf Wolkenhauer Prof. Jens Nielsen

University of Rostock Technical University
Systems Biology & of Denmark
Bioinformatics Center for Microbial
Rostock, Germany Biotechnology
BioCentrum-DTU
Prof. David Carling Kgs. Lyngby, Denmark
Imperial College London
MRC Clinical Sciences Centre Dr. Thomas Svensson
Cellular Stress Group Arexis AB (Biovitrum AB)
Hammersmith Hospital Campus Bioinformatics
London, UK Stockholm, Sweden
RIBOSYS
State-of-the-Art:
Project Type: The RIBOSYS project will use systems biology approaches to model RNA metabolism in
Specific Targeted yeast. In order to develop kinetic models, we will quantify RNA precursors and determine
Research Project their rates of production, their processing and degradation through the various post-tran-
scriptional pathways. Starting with ab-initio models describing the processing and deg-
Contract number:
radation of yeast pre-messenger RNAs and pre-ribosomal RNAs, we will produce two
LSHG-CT-2005-518280 comparable mathematical representations and populate the parameters using quantitative
Starting date: experimental data. Manipulation of the parameters will permit predictions to be made about
1st January 2006 the behaviour of the systems. These will be tested experimentally, using yeast mutants that
Duration: block specific steps. Imaging techniques will be refined to visualise individual transcripts to
determine whether the population data reflect the situation in individual cells. Comparison
48 months of the performance of the two models should provide further insights and enrich our under-
EC Funding: standing of both pathways.
`2 400 000
s 0RODUCTIONOFMULTI FEATUREDREPORTERCONSTRUCTSANDYEASTSTRAINSANDGENERATIONOF
optimised experimental protocols (standard operating procedures) for quantitative
analyses of in vivo RNA processing
s !DAPTATIONOFTHESYSTEMSBIOLOGYMARK UPLANGUAGETOPERMITACOMPARISONOFOUR
models with each other and with data existing in the literature
s $EVELOPMENTOFANAB INITIOMODELOFPRE M2.!PROCESSINGTRANSFORMTHEMODELINTO
a mathematical representation and populate it with parameters from the experimen-
tal data; perturb model parameters and make qualitative predictions about system
behaviour and verify against other experimental data
s $EVELOPMENTOFAQUANTITATIVEMODELFORPRE R2.!METABOLISMASABOVE
s $ELIVERYOFDATASETSFORTHELEVELSOFNASCENTREPORTERPRE M2.!ANDPRE R2.!TRAN-
scripts as normalisation standards for evaluation of processing defects observed in
mutants affecting downstream processing/degradation events
s 1UANTITATIVEANALYSESOFPOLYADENYLATIONOFREPORTERM2.!SANALYSESOFGENOME
wide mRNA polyadenylation status using microarrays
s )NVESTIGATION OF THE INmUENCE OF INTRONS AND THE EFFECTS OF MUTATIONS IN SPLICING AND
degradation factors on rates of pre-mRNA transcription, processing and degradation
s 1UANTIlCATIONOFLEVELSOFPRE R2.!PROCESSINGINTERMEDIATESANDR2.!SANDESTI-
mates for levels of their degradation. Development of a quantitative model for the flux
through the pathway. Testing and refinement of the model by analyses of the effects
This figure shows the use of of different growth conditions and mutations in the ribosome synthesis machinery
fluorescence to detect the and in the rRNA precursors
s )DENTIlCATION AND CHARACTERISATION OF ANTISENSE 2.!S AND THEIR ROLES IN REGULATION
localisation of molecules in yeast
of gene expression, using yeast tiling arrays and wild-type or mutant strains grown
cells. Red represents protein; blue
under different conditions
represents nuclear DNA. Shown
s -ICROSCOPIC ANALYSES TO QUANTIFY 2.! PROCESSING AT THE LEVEL OF SINGLE CELLS AND
are RNA-associated proteins thereby test and refine the RNA processing models
that are present A) exclusively
in the nucleus, B) throughout
the whole cells, C) exclusively
in the cytoplasm. The cellular
Expected Results:
localisations of these proteins A notation for RNA
reflect where they function in A notation system is needed that permits RNA molecules to be described in a universal
RNA metabolism. format, comparable between species/organisms, which are also compatible with a math-
ematical description.
Enhanced mechanistic understanding
Quantitative analyses will allow us to understand better the relationships between different
Systems Biology of
RNA Metabolism in Yeast
steps, activities and factors in the pathway than has been achieved by qualitative analyses
and intuitive interpretations. This will lead to fresh insights into, for example, the key steps
at which regulation would most likely be exerted, and should lead to testable hypotheses,
which would be addressed experimentally.
Enhanced insight across systems
Comparison of the pre-mRNA and pre-rRNA models will enrich our understanding of each
pathway, providing further insights. This should illuminate equivalent pathways in human
cells which are less amenable to direct experimentation, enhancing understanding of hu-
man genetic disorders.
Potential Impact:
This project will provide valuable new biochemical and genetic tools for the community and
will set experimental standards for a variety of other RNA studies.
Modelling precursor RNA processing in yeast will be of great benefit for understanding
these pathways in human cells, which are less amenable to direct experimentation, and
their significance for human genetic disorders.
This collaboration will bring together experimental biologists, mathematicians and compu-
ter scientists and promote better understanding across these disciplines.
Keywords: modelling, yeast, RNA metabolism
Partners
Prof. Jean Beggs
University of Edinburgh,
The Wellcome Trust Centre for Cell Biology
The Kings Buildings, Mayfield Road EH9 3JR
Edinburgh, UK
J.Beggs@ed.ac.uk
Dr. Edouard Bertrand

Centre National de la
Recherche Scientifique (CNRS)
Universite Montpellier II
Institut de Génétique
Moléculaire de Montpellier
Montpellier, France Dr. Joanna Kufel
Warsaw University
Zipi Fligelman-Shaqed Department of Genetics
Compugen Ltd Botany Faculty
Computational Life-Sciences Warsaw, Poland
Tel Aviv, Israel
Dr. Oleg Demin
Prof. Bernhard Dichtl Institute for Systems Biology
Universität Zürich-Irchel SPb Company Ltd
Institut fur Molekularbiologie Department of Bioenergetics
Zurich, Switzerland Saint Petersburg, Russia
EuroBioFund

Contract number: Life sciences and biotechnology have become extremely important in our knowledge-based
economy. However, they have also undergone a revolution in terms of research approaches,
LSSG-CT-2005-019009
infrastructure, technology developments, and costs. The EuroBioFund project will address
Starting date: these challenges by combining expertise and resources in an organized and coordinated
1st January 2006 manner. Currently, the lack of coordination at the European level is a major obstacle to
Duration: achieving EuroBioFund’s objectives and is jeopardizing Europe’s position on the global
36 months scene. Against this background new strategies are needed to help match research dynam-
EC Funding: ics and funding opportunities.
`907 790
The EuroBioFund project has been created to foster dialogue and coordination between
funding organizations and to promote and coordinate interaction among European life sci-
ences researchers and funders. Other important objectives are: i) to provide a platform for
funding organisations and life science researchers to foster joint research initiatives through
networking; ii) to help organise research communities and facilitate Europe-wide research
programmes; iii) to develop a new funding process in Europe by helping to develop joint
investments and funding of life sciences research. The project also aims to identify future
challenges in the life sciences which require a coordinated European approach for their
financing and implementation. Identification of these topics will be based on ideas put
forward by the scientific community in line with the strategic goals of public and private
funding organisations across Europe.
Expected Results:
EuroBioFund will formulate answers to some of the numerous challenges faced by the life
sciences in Europe. It will provide a platform for funding organizations and life sciences
researchers to create joint research initiatives through networking. It will also organise re-
search communities and facilitate research programmes of European scale and scope and
promote information exchanges and discussions of research policies. All of the above will
be crystallized through an annual conference, consisting of national agencies, intergov-
ernmental organisations, private foundations, charities and industry. The conference will
provide a framework for dialogue between the various bodies funding the life sciences and
help achieve better programme and policy coordination.
Potential Impact:
EuroBioFund will help to establish an invigorating new approach to life sciences in Europe
through new methods of funding and research, joint investments and information exchang-
es, creating a single European market for research. The project will have an impact on
European science by bringing together leading scientists and research funding agencies to
debate, plan and implement initiatives, resulting in European life sciences becoming much
more dynamic and competitive.
A Strategic Forum for the Dialogue and
Coordination of European Life Sciences,
Funders and Performers
Keywords:
life sciences, networking,
research initiatives
Partners
Prof. Marja Makarow
European Science Foundation (ESF)
1 quai Lezay-Marnésia
67080 Strasbourg, France
ceo@esf.org
Project Manager:
Dr. Wouter Spek
1 quai Lezay-Marnésia
67080 Strasbourg, France
wspek@esf.org
VALAPODYN
www.valapodyn.eu
State-of-the-Art:
Project Type: Mathematical modelling is generally based on (1) the understanding or theory of the way
SME-Specific Targeted the modelled system behaves, and (2) experimental data (e.g. measures) of elements of
Research Project the system, and how it reacts under certain conditions. Genetic regulatory networks (or
Contract number: MINs) are very robust; it is therefore possible to model them, although this means that
a vast amount of data (thousands of genes and proteins) needs to be considered, with
LSHG-CT-2006-037277 highly redundant interactions. Moreover, the different networks behave with non-linear and
Starting date: non-additive responses. All these characteristics therefore necessitate the development of a
1st October 2006 large-scale MIN modelling method, allowing one to rationally address the physiopathology
Duration: of many diseases.
36 months
EC Funding:
`1 488 560
The overall aim is to develop an innovative systems biology approach, in order to model the
dynamics of Molecular Interaction Networks (MINs) related to cell death and survival in the
organism. The aim of the VALAPODYN project is to set up the scientific and technological
basis, for tasks within the following areas:
s 0ATHWAY ANALYSIS functional annotation of genes and proteins, investigation of

structure and dynamics of signal transduction and transcription regulatory networks.
s 0REDICTIVE BIOINFORMATICS PLATFORM FOR DYNAMIC MODELLING use of innovative
biomathematics / bioinformatics to integrate experimental MIN data with biological
tissue and pathological states data obtained through the use of transcriptomic and
proteomic approaches.
s "IOINFORMATICSestablishment of a highly specialised database on the genomics and
proteomics of MIN modelling.
s 0ATHOLOGICALTISSUEANIMALMODELSanalysis of validated animal models of brain
pathologies to evaluate gene/protein expression during initial cell death.
s -ICROARRAYS extensive multi-level global gene expression profiling using the Affimetrix
platform.
s 0ROTEOMICS application of advanced quantitative proteomics technologies (MALDI,
ICAT, 2-DPAGE, Heavy Peptides isotopic dilution) for large-scale proteome
screening.
s .EUROPROTECTIVE MOLECULES characterization of molecules in the MIN of cell
death, the modulation of which should improve or cure
A B neurodegenerative brain disease.
Expected Results:
The VALAPODYN network is composed of leading authori-
ties in the fields of genomics, proteomics, bioinformatics and
neuroscience in Europe. They have decided to join their ef-
forts to develop a new innovative System Biology approach
Cell loss and plasticity observed in to model the dynamics of Molecular Interaction Networks (MIN) related to cell death and
the hippocampus in a mouse model survival in the brain.
of mesiotemporal lobe epilepsy
(A) compared to controls (B) This model will be dedicated to the selection of drug targets for human brain. The project
will first validate dynamic models for cell death through the characterisation of new poten-
tial drug targets in an animal model for epilepsy where neurodegeneration is the initial step
of the development of epileptic seizures.
Validated Predictive Dynamic Model
of Complex Intracellular Pathways related
to cell death and survival
Potential Impact:
The development of new and unique dynamic model-
ling tools will allow the Consortium to participate in the
process of applying integrative biology to pathology
research. This should significantly improve the quality
of life for EU citizens, by advancing the identifica-
tion of new generations of more efficient drug targets;
these drugs will be used to treat numerous diseases
accounting for mortality and several serious illnesses
in the EU, such as cancer, cardiovascular diseases,
neurological diseases, etc. Dynamic models will form
the basis for the next generation of biological vali-
dations for novel therapeutic targets, instead of the
methods currently in use. VALAPODYN will also have
a significant impact on the ERA, by creating a new
foundation for the exchange of fundamental research and knowledge. The development of
the international R&D network of SMEs in the biotechnology sector (HELIOS, BIOBASE and
SynapCell through INSERM during the project) will accelerate the emergence of the EU as
a powerful contender in the global technological market. The VALAPODYN consortium will
also allow for optimal use of the available EU resources and human potential.
Keywords: predictive dynamic models, systems biology, molecular

interaction networks, cell death and survival,
neurodegeneration
Partners
Dr. Antoine Depaulis
Grenoble – Institut des
Neurosciences
Centre de Recherche INSERM U 836
Université Joseph Fourier
BP 170
38042 Grenoble, France Prof. Edwin de Pauw
University of Liege
Dr. Olga Kel-Margoulis, Department of Chemistry
Prof. Edgar Wingender Mass Spectrometry Laboratory
BIOBASE, GmbH Liege, Belgium
Wolfenbuettel, Germany
Prof. Hermona Soreq
Dr. Todor Vujasinovic Hebrew University of
HELIOS Biosciences Jerusalem
Creteil, France Department of
Biological Chemistry
Dr. Despina Sanoudou Institute of Life Sciences
Foundation of Biomedical Research Jerusalem, Israel
of the Academy of Athens (FBRAA)
Molecular Biology Division Dr. Raffaella Catena
Center for Basic Research Alma Consulting Group ALMA
Athens, Greece Levallois Perret Cédex, France
AGRON-OMICS
www.agron-omics.eu
State-of-the-Art:
Project Type: Agriculture is crucial to humankind. Crops supply food, animal feed, chemicals, pharma-
Integrated Project ceuticals and renewable sources of materials and energy. Plant growth results in biomass
Contract number: accumulation, which, in turn, is the major determinant of crop yield. Despite its importance
LSHG-CT-2006-037704 and complexity, plant growth is, however, a poorly understood trait. Plants evolved multicel-
lular bodies independently from animals and fungi. This evolutionary step, coupled with
Starting date:
the unique photosynthetic lifestyle, explains why plants rely on mechanisms for growth and
1st November 2006 development that are unique. It is therefore crucial to investigate how these mechanisms
Duration: function in plants in order to forge novel technological tools for tomorrow’s agriculture.
60 months
EC Funding: At the present time, Arabidopsis thaliana is the only plant species for which the necessary
resources are accessible for studying complex traits. The typical growth and development
`12 000 000 of Arabidopsis has been accurately described, providing a solid platform on which to
base experimental studies of growth processes. Arabidopsis also has unparalleled genom-
ics resources, including high quality genome sequence and annotation comprising over
30,000 genes of which 26,000
code for proteins; tagged mutant
alleles for 73 percent of these
genes; a choice of DNA arrays
to investigate genome transcrip-
tion; modification and polymor-
phisms; comprehensive transcrip-
tome, proteome and metabolome
atlases; cloned repertoires for
functional proteomics; and RNA
interference. Furthermore, haplo-
type maps of unprecedented den-
sity for any eukaryote, including
humans, will soon be released for
20 Arabidopsis ecotypes, helping
association mapping. Finally, the
genome sequencing of close rela-
tives (Arabidopsis lyrata, Capsel-
la rubella) has been launched and
will help to improve the accuracy
of comparative genome analyses.
Growth results from a complex

network of processes occurring
at different organisational levels
(whole plant, organ, cell, molecu-
lar module, molecule). Some of
the key factors involved in these
processes have been identified in
the past decades via (eco)physiol-
ogy, cell biology and molecular
genetics but many more still have
to be found. The major challenges
are the elucidation of the interac-
tion networks (eg macromolecular
complexes, cell-to-cell signalling
etc) that constitute each of the dif-
ferent levels of organisation, and
the understanding of how these
Arabidopsis growth network
integrating OMICS technologies
different levels are linked. For example, plant growth regulators such as auxin and cytoki-
nin, which coordinates the integration of growth at the cell-organ and organ-whole plant
interfaces, have been extensively studied in plants for many years. However, although a
few components of their biosynthetic and signalling networks have been uncovered, very
little is known about how they impinge on the machinery underlying cell expansion and
cell division.
The main research goals of the project are: (i) to investigate systematically the components
controlling growth processes in plant cells (genome sequences, proteins, metabolites); (ii) to
understand how they coordinate their action; (iii) to explain quantitative growth phenotypes
at the molecular level. The growth process will be studied within a common research frame-
work of five work packages (WP). In particular, the project will generate high-throughput
(HTP) quantitative data defining growth variables, genetic components of growth, the mo-
lecular composition of leaves at successive stages of development, molecular interaction
networks and small molecules affecting growth (WP1-5). Finally, mathematical and statisti-
cal methods to model and predict leaf processes will be developed and tested in close
collaboration with computer scientists, statisticians and experimentalists (WP7). The suite of
analytical tools will be exhaustively tested and modified before being made available as a
package of integrated systems biology applications and as web services.
The technology platforms at the core of the research programme have been selected to
provide quantitative information at all relevant levels of organisation: growth variables re-
corded at the level of whole plant, organ and cell; profiling of the genome, transcriptome,
proteome and metabolome; protein-protein and protein-DNA interaction networks. They
can be ranked in four classes:
1) Well-established methods, but only exceptionally applied at this scale to study a single
biological system in an integrative framework, requiring standardisation of existing
protocols and datasets; they include microarray transcript profiling, HTP real time RT-
PCR, flow cytometry, large-scale recombinational cloning methods, GFP-fusion subcel-
lular localisation, yeast two-hybrid, tandem affinity purification, mass spectrometry,
chromatin immunoprecipitation.
2) More advanced profiling techniques; they include large-scale SNP genotyping, sys-
tematic enzyme profiling (>40 activities) of identical samples, ITRAQ for relative pro-
tein quantification, cell flow sorting, FT-IR microspectroscopy, bimolecular fluorescence
complementation.
3) Novel HTP techniques requiring extensive development and aimed at taking full ad-
vantage of Arabidopsis as a model species; they include automated leaf structure
analysis at cell-level resolution, in planta two-hybrid based on antibiotic selection,
Arabidopsis cell-based assays and high content screening to study systematically the
results of genetic (genome scale) or chemical (library scale) perturbations.
4) Software tools enabling data integration and biological system modelling.
Expected Results:
AGRON-OMICS will yield four types of results:
1) Novel analytical pipelines will be developed to measure cellular processes across
multiple levels, including mass spectrometry, remote macroscopic and microscopic
imaging and environmental control. These research efforts require the generation
AGRON-OMICS
of specific informatics infrastructure, common data standards and analytical tools

required to capture, store, distribute and analyse high-throughput data. The resulting
knowledge and equipments will be accessible to the participant’s laboratories and
the know-how will be propagated further through training programmes and scientific
exchanges.
2) Novel well-documented integrated software applications will form the basis for a
“plant systems biology toolbox”. These applications will be constructed to allow
adaptability and integration with pre-existing software, and will be made freely
available to other scientists working in systems biology.
3) Transgenic lines, genetic stocks and constructs created or characterised in the

project’s framework will be disseminated via stock centres.
4) AGRON-OMICS will generate primary data and biological knowledge including

the identification of genes/loci and molecules that control growth, and the construc-
tion of models that explain how these components interact and function across path-
ways and processes. The information relative to leaf growth control networks will be
exploited to postulate how best to combine inputs to increase plant biomass produc-
tion via improved germplasm and the use of growth regulators. AGRON-OMICS
results will be published as soon as practicable both in peer-reviewed articles and
via online databases. Unlike most data produced in biological investigations, data
obtained in this project will be represented according to standard formats, in the
context of networks, and supported by ontology.
Potential Impact:
AGRON-OMICS will have a significant impact in several research ar-
eas. Firstly, the consortium is pioneering systems biology approaches
in order to understand biological complexity in the context of a mul-
ticellular organism, and across multiple levels of organisation (cells,
tissue, and whole organism). The tools, techniques and expertise built
up in the course of the project may be used to inform research on
the complex mechanisms involved in human disease, which result
in alteration of cell growth and development. In particular, current
knowledge shows that core molecular processes regulating cell pro-
liferation and cytoplasmic growth are conserved between plants and
animal cells. Secondly, progress in the mechanistic analysis of these
molecular pathways in plants may contribute fundamental insight into
the biology of human cancers. In addition, in-depth knowledge and
modelling of specific molecular pathways may result in the potential
to develop translational research projects for biomedical purposes
(eg production of natural compounds for therapeutic use, and produc-
tion of vaccines against human diseases in plants). Thirdly, growth
processes are difficult to characterise in mammalian species at a
scale comparable to the one which is the target of AGRON-OMICS,
or without breaching ethical barriers. In this respect, the ability to
systematically genotype, phenotype and profile at the molecular level
thousands of individual plants in a unique asset of this project and will
be of great value in developing similar system level research in mam-
mals. Fourthly, AGRON-OMICS may help to reduce the environmen-
tal impact of agriculture. Agricultural practices withdraw about 70 percent of groundwater
resources worldwide. In the long-term, irrigation increases soil salinity and leads to the
permanent destruction of otherwise fertile soils. Using plants that have improved water use
efficiency will help contain the amount of water consumed by agriculture and mitigate the
impacts of irrigation. Finally, a major goal in plant science is the development of crops as a
source of renewable resources and industrial feedstock. In the coming years, 20 percent of
transport energy will hopefully come from renewable resources. As leaves are the primary
harvesters of energy, the integrated knowledge of mechanisms controlling metabolism,
Arabidopsis growth network integrating OMICS technologies
growth and environmental responses developed in this project will provide a strong founda-
tion for future work in this area.
Keywords: Arabidopsis, plant, leaf, functional genomics, growth, integrative

biology, systems biology
Partners
Project Coordinator: Prof. George Coupland Prof. Sean May
Dr. Pierre Hilson Max-Planck Institute for European Arabidopsis
Ghent University Plant Breeding Research Stock Centre (NASC)
Flanders Institute for Biotechnolgy (VIB) Cologne, Germany University of Nottingham
VIB Department of Plant Systems Biology Loughborough, UK
Technologiepark 927 Prof. Wilhelm Gruissem
9052 Ghent, Belgium ETH Zurich Prof. Gerco Angenent
pierre.hilson@psb.ugent.be Swiss Federal Institute of Technology Plant Research
Institute of Plant Sciences International (PRI)
Project Manager: Zurich, Switzerland Bioscience
Dr. Fabio Fiorani Wageningen, The Netherlands
Ghent University Prof. John Doonan
VIB Department of John Innes Center Prof. José Luis Micol
Plant Systems Biology Norwich Research Park Universidad Miguel Hernández
Technologiepark 927 Department of Cell and Insituto de Bioingeniería
9052 Ghent, Belgium Developmental Biology División de Genética
Fabio.fiorani@psb.ugent.be Norwich, UK Elche, Alicante, Spain
Prof. Herman Höfte Dr. Vicky Buchanan Wollaston Dr. Johan Geysen
Institut National de la University of Warwick Maia Scientific
Recherche Agronomique (INRA) Warwick Systems Biology Center Geel, Belgium
Institut Jean-Pierre Bourgin (IJPB) Warwick, UK
Versailles, France
Dr. Christine Granier

Laboratoire d’Ecophysiologie des
Plantes sous Stress Environnementaux (LEPSE)
Montpellier, France
Dr. Claire Lurin

Unité de Recherche en
Génomique Végétale (URGV)
Evry, France
Prof. Lothar Willmitzer

Max-Planck Institute of
Molecular Plant Physiology
Potsdam
Golm, Germany
Prof. Detlef Weigel

Developmental Biology
Tübingen, Germany
BaSysBio

Integrated Project
Contract number: BaSysBio aims to achieve major breakthroughs in the understanding of the regulation of
gene transcription in bacteria, on a global scale. The highly dynamic gene regulation is me-
LSHG-CT-2006-037469
diated by transcription factors (TFs), which trigger or repress the expression of their target
Starting date: genes. Transcription control is embedded into a hierarchical flow of information from genes
1st November 2006 to phenotype, in which many regulatory steps can occur.
Duration:
48 months BaSysBio adopts a systems biology approach, in which quantitative experimental data
EC Funding: will be generated for each step of the information flow, and will fuel computational mod-
elling. High-throughput technologies (such as living cell arrays, tiling DNA microarrays,
`12 029 619
multidimensional liquid chromatography proteomics and quantitative metabolomics) will be
developed, in conjunction with new computational modelling concepts, so as to facilitate
the understanding of biological complexity. In addition, models will simulate the cellular
transcriptional responses to environmental changes, and their impact on metabolism and
proteome dynamics. The iterative process of simulations and model-driven targeted experi-
ments will generate novel hypotheses about the mechanistic nature of dynamic cellular re-
sponses, unravel emerging systems properties and ultimately provide an efficient roadmap
to assist in tackling novel, pathogenic organisms.
This system-based strategy will enable BaSysBio not only to understand how transcriptional
regulation and metabolism are quantitatively integrated at a global level, but also to under-
stand cellular transcriptional responses in conditions mimicking pathogenesis. Finally, the
project will validate the general applicability of the findings, and integrate the modelling-
experimental strategy developed in the highly tractable B. subtilis model, towards an un-
derstanding of regulatory networks controlling pathogenesis in disease-causing bacteria.
BaSysBio will make a significant contribution towards overcoming the structural obstacles
that hinder the development of systems biology in Europe.
The overall objective of BaSysBio is to generate quantitative data about the network compo-
nents at all the levels of the information flow, in order to understand, at the system’s level,
the global regulation of gene transcription in bacteria. To achieve this objective, BaSysBio
will focus on developing and adapting high-throughput technologies to facilitate quantita-
tive measurements, in conjunction with developing and validating computational systems
biology methodologies; this will enable quantitative interpretation of the data and unravel
the underlying principles of regulatory network interactions.
At a technological level, BaSysBio aims to develop and adapt high throughput technologies
for the quantitative determination of the cellular transcriptional responses to standardised
genetic and environmental perturbations, as a function of time. In addition, the project will
develop new concepts in computational modelling and simulation of regulatory networks.
More specifically, the project involves the following activities:
1) Using a novel multi-purpose DNA tiling microarray to identify, in a systematic and
unbiased way, all the RNA transcripts (mRNAs and small RNAs) produced in the B.
subtilis cells, and to facilitate a comprehensive inventory of the cis-acting regulatory
sequences bound by transcription factors;
2) Bridging technological gaps by developing living cell arrays which allow the ge-
Towards an understanding
of dynamic transcriptional regulation
at global scale in bacteria:
a systems biology approach
nome-wide determination of promoter activities as a function of time during the cell

responses;
3) Exploiting the latest developments in mass spectrometry and non-gel-based protein
separation techniques, to quantify proteins and determine their modifications in re-
sponse to perturbations;
4) Developing methods for quantitative high-throughput metabolomics, using comple-
mentary mass spectrometry-based approaches (e.g. GC-TOF, LC (CE)-ESI-TOF and
LC-MS/MS), to analyse the vast chemical diversity of intracellular metabolites in
response to perturbations;
5) Extending the use of parallel 13C-flux analyses to novel substrates;
6) Developing chromosome engineering tools, based on the recombination systems of
prophages of Gram-positive bacteria, to facilitate high throughput tagging of genes
in Bacillus subtilis and related pathogens;
7) Developing new concepts and methodologies to improve modelling and simulation
of regulatory networks. This includes standardised and unequivocal representation
of networks basic components and interactions to be modelled; hybrid mathematical
models combining constraint-based approaches and detailed dynamic modelling.
Expected Results:
In contrast to the present large-scale and mostly descriptive studies on genome-wide data
sets, BaSysBio’s systems biology approach relies on iterative cycles of model prediction,
system perturbations and system response monitoring, which will incrementally refine the
models, thereby generating quantitative understanding of the in vivo operation of complex
regulatory networks. This system-based approach will combine an unprecedented number
of different experimental approaches, to generate data in a limited number of standard-
ised conditions for two biological processes, thus considerably reducing the need to make
hypotheses.
BaSysBio has made several technological contributions: 1) B. subtilis living cell arrays to
study the temporal regulation and the design principles of the transcription networks that
control the timing of gene expression; 2) efficient chromosomal engineering techniques for
Gram-positive bacteria, including the pathogens B. anthracis and S. aureus; 3) parallel
flux analysis based on 13C-labelling experiments in microtiter plates; and 4) adaptation
and improvement of existing high throughput technologies for the specific project needs.
Significantly, the developed methodologies will have additional benefits beyond the scope
of this project. The novel conceptual aspect of BaSysBio is the development of a theo-
retical framework for comprehensive, system-wide
data interpretation. This differs from the current fo- Proteomic analysis of mutants of Bacillus anthracis to oxidative stress.
cus of much of systems biology, which concentrates The ability of Bacillus anthracis to resist oxidative stress is a key component
of this bacterium’s ability to resist the innate immune response and to cause
infection. To determine the relative contributions of two genes, hemH2 encoding
a ferrochelatase and katB encoding a catalase to combating oxidative stress,
mutant cells were grown in the presence or absence of the oxidising agent
hydrogen peroxide and the resulting protein profiles determined by two-
dimensional gel electrophoresis. The resulting images were false-coloured
(untreated = green; treated = red), superimposed on each other and warped
so that corresponding proteins were coincident on the resulting image.
Proteins whose expression was up- regulated in the mutant in response
to oxidative stress appear as red spots. (Dr. Susanne Pohl, University of
Newcastle upon Tyne, UK)
BaSysBio
on signalling networks and

metabolic networks recon-
structed through compara-
tive genomics. It extends
conceptually beyond data
acquisition and interpreta-
tion approaches, through
quantitative interpretation
with the mathematical rigor
of computational models.
By integrating the multiple
Subtilis scanning – Electron regulatory levels in a bio-
Microscope logical system, models will
have high potential to simu-
late them accurately, to predict novel systems properties and properties of uncharacterised
systems components, and to drive mechanistic understanding of the global regulation of B.
subtilis metabolism, and of the adaptive transcriptional responses to stresses encountered
by cells during pathogenesis.
Potential Impact:
BaSysBio embraces the broad issues of the integration of transcriptional regulation and me-
tabolism at a global level in cells. It thereby has the ambition to understand the general prin-
ciples, as well as the mechanistic details of regulatory networks, and to drive key discoveries
and applications in systems biology. An important element that is critical for the success
of BaSysBio, is the integration effect generated by concentrating resources in European re-
search.
The common development and use of standardised methodologies, procedures and tools will
generate a large and unique body of data that will potentially allow a genuinely global under-
standing of genetic control in bacteria. The BaSysBio iterative theoretical-experimental strat-
egy, which provides quantitative data about the regulatory steps in the information flow from
DNA to phenotype, will become applicable to multiple cellular processes. This will open the
way to the construction of mechanistic models integrating basic regulatory components and
their combined interactions at a global scale, potentially leading to in silico models simulating
the dynamic behaviour of the whole cell. By elaborating on new concepts in computational
modelling, BaSysBio will provide new ways to grasp biological complexity, and will reveal
as yet unknown properties of dynamic biological systems. This will open entirely new fields of
investigation to experimental biology.
The new knowledge and the integrated modelling/experiments strategy developed by BaSys-
Bio will be applicable to other micro-organisms, and will promote understanding of the global
control of pathogenesis, thus leading to potential new strategies to combat disease-causing
bacteria. The research in BaSysBio will yield a wealth of detailed knowledge about the key
processes that lead to a bacterial cell ‘fit for pathogenesis’, and will also help translate gained
knowledge into practical applications for the control of infectious diseases. Along the same
lines, BaSysBio will facilitate the exploitation of the beneficial capabilities of microbes.
Keywords:
transcriptomics, metabolomics, fluxomics, proteomics, quantitative biology, modelling, bio-
informatics, living cell array, DNA tiling microarrays, chromosome engineering, Bacillus,
Staphylococcus
Towards an understanding of dynamic transcriptional regulation at global
scale in bacteria: a systems biology approach
Partners
Dr. Philippe Noirot Prof. Kevin Devine
Institut National de la Recherche Agronomique (INRA) Trinity College Dublin
147 rue de l Université Smurfit Institute of Genetics
75338 Paris, France Dublin 2, Ireland
philippe.noirot@jouy.inra.fr
Dr. Hanne Ø. Jarmer
Project Manager: Technical University of Denmark
Caroline Sautot Center for Biological Sequence analysis
INRA Transfert Lyngby, Denmark
10 rue Vivienne
75002 Paris, France Prof. Colin Harwood
caroline.sautot@paris.inra.fr University of Newcastle upon Tyne
Department of Cell and Molecular Biosciences
Dr. Alexander Jung Newcastle upon Tyne, UK
Applera Deutschland GmbH
Darmstadt, Germany Prof. Anthony Wilkinson
University of York
Dr. Franck Molina Department of Chemistry
Centre National de la Recherche Scientifique (CNRS) York, UK
Faculté de Pharmacie CPBS-CNRS UMR5160
Montpellier, France Dr. Peter J. Lewis
University of Newcastle of Australia
Dr. Julio R. Banga School of Environmental and Life Sciences
Consejo Superior de Inestigaciones Cientificas Callaghan, Autsralia
Madrid, Spain
Prof. Michael Hecker

Ernst-Moritz-Arndt Universität Greifswald
Institut fur Mikrobiologie
Greifswald, Germany
Prof. Uwe Sauer

Swiss Federal Institute of Technology (ETH Zurich)
Department of Biology
Institute of Molecular Systems Biology
Zurich, Switzerland
Dr. Othmar Pfannes

Genedata AG
Basel, Switzerland
Dr. Benno Schwikowski

Institut Pasteur
Department of Microbiology
Paris, France
Dr. Edda Klipp

Berlin, Germany
Prof. Jan Maarten Van Dijl

University Hospital Groningen
Department of Medical Microbiology
BioBridge
State-of-the-Art:
Project Type: Chronic diseases are usually the result of interactions between individual susceptibility and
SME- Specific Targeted different environmental and/or lifestyle factors, and are often modulated by multiple genes.
Research Project The interplay between these factors determines disease phenotype and hence, the prognos-
tic and therapeutic implications of the disease. This interplay between genetically predeter-
Contract number:
mined susceptibility and disease phenotype, can in turn be revealed by computer analysis
LSHG-CT-2006-037939 integrating clinical and biomedical data. Some examples of the application of computer
Starting date: analysis to clinical practice are the classification and prognosis of ovarian cancer (Wu et al,
1st December 2006 2003), the analysis of myocardial perfusion images and cardiograms (Fletcher et al, 1978)
Duration: and the development of a screening device for the diagnosis of heart murmurs (Bhatikar et
al, 2005). In addition, several projects in the European Union are implementing information
30 months technology-based services for diabetes management (Bellazzi et al, 2004). However, all the
EC Funding: approaches currently implemented in clinical practice use very limited datasets, despite the
`1 800 000 availability of vast amounts of data from various life science disciplines since the “-omics”
revolution. Only by integrating genomic, proteomic and metabolomic data can knowledge
that is useful for the understanding and treatment of complex human pathologies, begin to
be obtained. This is the goal of the BioBridge project.
BioBridge will focus on the application of simulation techniques on top of multilevel data,
in order to create models for understanding, how molecular mechanisms are dynamically
related to complex diseases at the systemic level.
The BioBridge objectives are twofold. Firstly, a bioinformatic aspect will involve the de-
velopment of software for integrated genomic, proteomic, metabolomic and kinetic data
analysis, in order to build a bridge between basic science and clinical practice. Secondly,
a biomedical aspect will focus on understanding the distortion of cellular metabolism that
is associated with certain target diseases. The diseases in question are congestive heart
failure (CHF), chronic obstructive pulmonary disease (COPD) and type II diabetes. The
available facts strongly indicate that these diseases comprise a cluster of chronic conditions,
all of which are associated with nitroso-redox imbalance. The integration of data into a
dynamic framework will enable the development of the first kinetic model of the metabolism
shared by COPD, CHF and type II diabetes, thereby revealing the common and individual
traits of these three complex diseases.
Expected Results:
After 30 months, BioBridge will have achieved the following goals:
1) Creation of a structured database for the collection of clinical information relating to
COPD, CHF and type II diabetes;
2) Identification of the metabolic pathways implicated in the target diseases;
3) Recording of genomic, proteomic, metabolomic and kinetic information into the rel-
evant structured databases;
4) Development of a software product designed for specific disease-related data search-
ing;
5) Development of standards for the different levels of data, which will be useful for their
integration from genomic and metabolomic databases, and from specific proteomics
and metabolomics profiling experiments, including microarray analysis and stable
isotope tracer data.;
6) Development of protocols for transferring data from the structured databases into
dynamic models;
7) Using a differential equation approach, the design and development of an innova-
Integrative Genomics and
Chronic Disease Phenotypes:
modelling and simulation tools for
clinicians
tive simulation environment that will accommodate the dynamic behaviour of com-
plex networks, and in particular the metabolic pathways that are altered by the target
diseases;
8) Development of generic tools that will be clinically useful beyond the target diseases
addressed during the lifetime of the project.
Potential Impact:
The main outcome of the project will be a protocol for organising multilevel data related
to the target diseases into a convenient form for use in the construction and refinement of
kinetic models of intracellular metabolic pathways. The software developed will be applica-
ble to more general cases of multilevel data integration. In helping to provide insights into
the key molecular mechanisms that determine poor prognosis in the CHF/COPD/type II dia-
betes disease cluster, BioBridge will generate novel strategies for personalised prevention
and enhanced delivery of patient care. Existing computational models have already proved
powerful in this context. For example, one of the BioBridge partners has recently developed
a statistical framework for analysis of multivariate models from large-scale datasets. This
software environment (GALGO) uses a genetic algorithm search procedure, coupled with
statistical modelling methods, for supervised classification and regression. BioBridge will
build on and improve this and other computational models.
Keywords: diabetes, chronic obstructive pulmonary diseases, COPD, chronic

heart failure, systemic effects, genomics, proteomics, metabolomics,
modelling
Partners
Josep Roca
Institut d’Investigacions
Biomèdiques August Pi i
Sunyer (IDIBAPS) Dieter Maier
Villarroel 170 Biomax Informatics AG
08036 Barcelona, Spain Martinsried, Germany
jroca@clinic.ub.es
Dr. Jordi Villa i Freixa
Dr. Marta Cascante Universitat Pompeu Fabra
University of Barcelona Computational Biochemistry
Institut d’Investigacions and Biophysics Laboratory
Biomèdiques August Pi i Barcelona, Spain
Sunyer (IDIBAPS)
Barcelona, Spain Dr. Pranav Sinha
Institut für Medizinische und
Peter Aronsson Chemische Labordiagnostik
MathCore Engineering AB Landeskrankenhaus Klagenfurt
Linköping, Sweden Klagenfurt, Austria
John Brozek Dr. Francesco Falciani

Genfit Laboratories University of Birmingham
Genfit SA School of Biosciences
Loos, France Birmingham, UK
SYSBIOMED
State-of-the-Art:
Project Type: The goal of systems biology (SB), or ‘integrative biology’, is to progress from a qualitative,
Specific Support Action static description of the constituents of living cells, to a quantitative, dynamic understanding of
Contract number: their systemic and functional properties. It is an interdisciplinary endeavour that has emerged
LSHG-CT-2006-037673 from the fields of genomics and bioinformatics. The obvious value of predictive SB models for
the elucidation of pathological processes beyond the cellular level, calls for closer investiga-
Starting date: tion of the potential applications of such models to medical research. Medical SB (MSB) must
1st December 2006 demonstrate the ability to cross levels: from cells to organs and organisms, from cell function
Duration: to physiological phenomena, and from model organisms to human diseases.
25 months Pioneering studies in the modelling of whole organ function have already demonstrated that
EC Funding: models can correctly predict certain physiological and pathological functions of the heart,
for example. However, SB as a field is in its infancy and this, combined with its emphasis
`362 500 on basic research, its focus on model organisms and individual intracellular pathway, are all
obstacles to the application of SB to medical research. Although many SB groups are working
on disease-related models and pathways, there is little crossover between this basic research
and clinical research. Europe urgently needs to build capacity, both in terms of knowledge
and in terms of personnel trained to bridge the gap between the two disciplines, so that the
field of MSB can be launched in a correct and timely fashion.
SYSBIOMED seeks to explore the potential application of SB to medical research, including
the development of drugs and other therapies. It will do this through a series of workshops
focusing on topics at the cutting edge of SB and physiology, which will be organised by a
core group of young scientists working in relevant areas.
The workshops will explore how SB can be applied to research in major disease areas
identified by the World Health Organization (infectious, neurodegenerative, metabolic and
cardiovascular diseases and cancer). They will promote the formation of collaborations,
teams and research programmes, and they should also contribute to the breaking down
of barriers — between theoreticians and clinicians, between basic researchers and those
interested in medical applications/drug development, and between newcomers and estab-
lished groups. These workshops will provide valuable opportunities for young academics
to enter the SB field, for theoreticians to meet experimentalists, and for representatives of
industry to meet academic researchers. Scientists from industrial enterprises are especially
encouraged to participate, so that they may assess the potential outcomes of applying SB
to medicine as early as possible.
Expected Results:
SYSBIOMED intends to provide an appropriate and timely response to the imminent chal-
lenge of applying SB to medical research. The field of MSB has potential for getting off
to a promising start, provided that Europe’s strengths are exploited wisely. Translational
by nature, it is expected to accelerate progress in medicine, in particular by opening up
new avenues to personalised medicine and to the development of multi-drug therapies.
The potential translation of MSB results into new markets will have a positive impact on
both large and small enterprises.
SYSBIOMED will supply decision-makers with useful information on the potential chal-
lenges and opportunities for action in the MSB field. The multidisciplinary nature of the
consortium means that it is well-placed to achieve its primary goal, which is to build a
network of talented young researchers who will drive SB towards medical applications.
SYSBIOMED will also benefit from an earlier, successful SSA, EUSYSBIO, when building
its network of experts.
Systems Biology for Medical Applications
The involvement of scientific journals in the SYSBIOMED consortium will be valuable for
informing non-specialists about MSB, for attracting young scientists (including theoreticians
and medical researchers) to the field, and for alerting ‘scouts’ from the biotechnology and
pharmaceutical industries to new advances. To this end, SYSBIOMED is pleased to have the
support of the journals The Scientist, Nature Biotechnology and IEE Proceedings Systems
Biology. The participating media will also prove extremely useful for disseminating SYSBI-
OMED’s results.
Potential Impact:
SYSBIOMED complements both ongoing and planned European SB initiatives. A first step
towards the establishment of MSB as a new discipline, has recently been taken by the Eu-
ropean Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), which
organised a workshop on the therapeutic applications of computational biology (TACB).
Although this workshop emerged from a bioinformatics background, SYSBIOMED will con-
sider its main findings and extend them, placing a stronger emphasis on the practical trans-
lation of SB-related research into clinical applications, and identifying the disease areas
which stand to benefit most from a coordinated SB approach. A representative of EMBL-EBI
is a member of the SYSBIOMED core group, and TACB workshop organisers will be invited
to join the consortium’s advisory board.
Regarded as a branch of translational research, MSB is likely to benefit from the spirit of
the younger generation of European SB experts. The success of SYSBIOMED will depend
on the efficient cooperation of this still-small community, but the consortium is also commit-
ted to joining forces with all relevant partners, including industry (both big pharma and
SMEs). The project could lead to strategy adjustments in the healthcare sector, with respect
to identifying the most promising therapies and technologies emerging from this branch
of biomedical research. It is intended that the young scientists’ network should provide a
consulting service beyond SYSBIOMED’s lifetime.
Keywords: systems biology, medicine, postgenomics
Partners
Dr. Karsten Schürrle
DECHEMA e.V.
Theodor-Heuss-Allee
60486 Frankfurt am Main, Germany
schuerrle@dechema.de
Prof. Olaf Wolkenhauer

Rostock University
Systems Biology and Bioinformatics
Rostock, Germany
Carole Moquin-Pattey
European Medical Research Councils
Strasbourg, France
SysProt
www.sysprot.eu
State-of-the-Art:
Project Type: Bioinformatics methods for diagnostic screening are a bottleneck in current biomedical
SME- Specific Targeted research. While exploratory methods – such as statistical hypotheses testing, clustering of
Research Project gene expression profiles and classification methods – have been successful in the detection
Contract number: of molecular markers for interesting diseases, these techniques fail to validate these markers
in their gene regulatory context and to integrate other data sources relevant for diagnostic
LSHG-CT-2006-037457 purposes. For these tasks, novel modelling techniques, network analyses, and data integra-
Starting date: tion methods are indispensable. The analysis of processes involved in the course of complex
1st January 2007 polygenic diseases, such as obesity and type-2 diabetes, is in fact a multi-step procedure
Duration: that has to cope with data from diverse experimental functional genomics platforms (gene
36 months and protein expression), physiological data, environmental factors, and others.
EC Funding:
The project SysProt aims to develop a new paradigm for the integration of proteomics data
into systems biology. The goal is to gain relevant knowledge on the biological processes
that are important for human health and to use this knowledge for the purpose of disease
modelling.
In order to achieve this objective, an innovative, explorative biological systems approach
(on both the molecular and the physiological level) will be adopted, with a strong focus on
protein function and modification. SysProt will produce proteomics data, indispensable for
the identification of novel circulating protein factors, and post-translational protein modifica-
tions that are important for the onset, dynamics, and progression of complex diseases.
Data generation will be complemented by the development of computational analysis meth-
ods for these novel data types and the creation of adequate modelling technology. The
project will benefit from the utilisation of established mouse
disease models, existing benchmarking modules for compu-
tational analysis, and the functional genomics platforms de-
veloped by and accessible to the partners. In particular, the
consortium aims to demonstrate newly developed technologies
in a proof-of-principle study within an obesity-induced type-2
Mouse model (left NZO mouse diabetes mouse model.
in comparison to a C57BL/6 The project consortium is headed by an SME and includes
mouse) used in SysProt for the four academic partners from three European countries. This
analysis of obesity induced type- composition of commercial and academic interests guarantees
2 diabetes. C57BL/6J mice serve high-level scientific research, as well as a strong focus on the
commercial relevance and exploitation of the project’s results.
as control strain.
Expected Results:
An important feature of the project’s approach will be the integration of phenotypic and
physiological parameters with proteomics data and expression profiles from time course
series representing the onset and progression of insulin resistance of type-2 diabetes. The
expected results of this project are:
1) Model the knowledge about biological objects (genes, proteins and protein complex-
es) in the context of nutrition and type-2 diabetes in equivalent computer objects;
2) Integrate heterogeneous data types from proteomics and functional genomics ap
proaches;
3) Develop and use a prototype framework for the automatic detection and localisation
of protein modifications on high-accuracy mass spectrometry data;
4) Generate specific proteomics and functional genomics data providing the necessary
information for disease model generation with an appropriate animal model;
System-wide analysis and modelling
of protein modification
5) Gain new knowledge on the pathways and marker genes relevant for obesity-in-
duced type-2 diabetes disease progression that will lead to the discovery of novel
diagnostic biomarkers for disease susceptibility;
6) Simulate perturbations of the disease-relevant pathways;
7) Develop tools and methods for the correlation of phenotype and genotype;
8) Accelerate the identification and positional cloning of disease candidate genes by
combining gene expression, proteomics, genotype, and clinical data;
9) Set up a knowledge base that integrates all available data and methodology as an
exploitable product for disease modelling.
The main result of the project will be an exploitable prototype that allows medical research-
ers to draw predictions on disease-relevant pathways.
Potential Impact:
Systems biology approaches will increasingly have an impact on Life Science and Health pro-
grammes in general and on drug development in particular. They provide a huge potential for
improving the European competitiveness. Through the application and broadening of systems
biology approaches, the SysProt project is likely to impact on the scientific understanding of
biological processes, with particular relevance to improving human health and wellbeing.
Keywords: systems biology, fundamental biological processes, proteomics,

bioinformatics
Partners
Dr. Arif Malik
MicroDiscovery GmbH
NutriSystemics
Marienburger Str.1
arif.malik@microdiscovery.de
Dr. Hadi Al-Hasani

Deutsches Institut fuer Ernaehrungsforschung
Department of Pharmacology
Nuthetal (OT Bergholz-Rehbruecke), Germany
Dr. Ralph Schlapbach

Eidgenössische Technische Hochschule, Zürich
Functional Genomics Center Zurich
Zurich, Switzerland
Prof. Rainer Cramer

The University of Reading
The Biocentre
Reading, UK
Dr. Ralf Herwig

Department Vertebrate Genomics
Berlin, Germany
Streptomics
www.streptomics.org

Research Project The biotechnology industry is constantly searching for better hosts for the production of bi-
opharmaceuticals and enzymes of diverse origin. The Gram-positive soil bacterium STREP-
Contract number:
tomyces has already proved an invaluable host for this purpose, since it can secrete several
LSHG-CT-2006-037586 heterologous proteins in satisfactory amounts. However, in order to optimise strain selec-
Starting date: tion, knowledge is required, concerning the following points: (1) How protein secretion
1st January 2007 processes are integrated within the metabolome, and how they interact; (2) How heterolo-
Duration: gous protein secretion stresses the metabolome and induces negative cellular cascades.
36 months
EC Funding:
`2 850 851
*Automated protein
engineering:* A precision
robot arm retrieves a custom
manufactured 1536-well plate
in one corner of a room full of
robotics-compatible equipment
including nano-litervolume liquid
handlers,single cell sorters,
humidified incubators, heating
and cooling blocks, centrifuges,
confocal laser-based plate
readers and other equipment
integrated for fully automated
high throughput protein
engineering at Direvo Biotech
AG in Cologne, Germany.
Systems biology, the science of analysing and modelling genetic, macromolecular and
metabolic networks, provides the means to address these questions. By combining bio-
chemical information with genetic and molecular data, the Streptomics consortium hopes to
gain novel insights into the functions of genes related to protein secretion, as well as how
that protein secretion mechanism responds to external and internal stimuli. With a better
understanding of this mechanism at the cellular level, it should be possible to optimise pro-
tein secretion.
Systems biology strategies
and metabolome engineering for
the enhanced production of
recombinant proteins in Streptomyces
Streptomics aims to enhance the production of heterologous proteins, using Streptomyces
as a host. More specifically, it has the following goals:
1) To evaluate Streptomyces lividans as a cell factory for the production of heterologous
proteins of interest;
2) To investigate the transcriptome and proteome of the host strain under different growth
conditions, with different expression/secretion vectors, and using different fermenta-
tion strategies, in order to identify the genes important for optimal cell performance,
with respect to heterologous protein secretion;
3) To analyse metabolic flux control and flux balance with a view to engineering meta-
bolic pathways found in a Streptomyces background, and hence to exploit cellular
pathways which provide improved energy transduction, balanced growth and su-
pramolecular assembly;
4) To engineer better production/secretion strains of Streptomyces based on the above,
and based on information about secretion bottlenecks that will be identified through
the production of muteins, either via direct mutation of specific amino acids, or by
directed evolution;
5) To optimise the protein production process.
Fig. 1 4. The secretome Platform Fig. 2
SecA optimization
• Rational mutagenesis
1. Heterologous genes cloned • Directed evolution
SPase binding
PMF and PspA
5. Strain engineering Platform
3. Metabolomics 2. Analytical Platform

Platform
4. Bioinformatics Platform 2.1 Transcriptomics
Flux analysis
In silico 2.2. Proteomics
In vitro
In vivo
6. Production process optimization
Fig. 1: The secretome Platform:

Production process optimization
Improved production process for
protein of interest
Fig. 2: Long oligo based/
S. coelicolor /microarray
(courtesy of Eurogentec)
Streptomics
Fig. 3 Fig. 4
Fig. 3: *Modern fermentation

capabilities:* Up to 100 liter
fermentors and downstream
protein purification and
characterization allow
preparation of engineered
“optimized” protein variants
for injectable or ingestible
animal trials, biorefining and
other industrial or pharmacetical
biotechnology applications at
Direvo Biotech AG in
Cologne, Germany.
Fig. 4: EM photograph of
branching and sporulating /
Streptomyces coelicolor
(courtesy of John Innes Institute,
Norwich, UK)
Expected Results:
Based on a better understanding of metabolome-secretome interplay, strategies for im-
proved protein secretion will be designed. These will combine better energy generation
and directed energy consumption for either cell mass production or heterologous protein
secretion. Ultimately, a “toolbox” of Streptomyces strains will be engineered and refined,
which optimally over-secrete proteins of interest during fermentation.
Consequently, Streptomics will generate knowledge which will assist SMEs in the biotech-
nology and other industries to develop new and more efficient systems for the industrial
production of heterologous proteins, using S. lividans as a cell factory. These systems will
be useful in both red (medical) and white (industrial) areas of biotechnology.
Potential Impact:
This project aims to increase the number of efficient cell factory platforms for the production
of heterologous proteins important in health, biocatalysis and the environment, using Strep-
tomyces as a host. It will therefore contribute to a competitive, knowledge-based economy
and sustainable development in Europe, by serving the needs of a research-intensive indus-
trial sector in which many SMEs have traditionally been involved.
Keywords: systems biology, Streptomyces, protein secretion, enzymes, biop-

harmaceuticals, directed evolution, metabolomics, transcriptomics,
proteomics
Systems biology strategies and metabolome engineering for the enhanced
production of recombinant proteins in Streptomyces
Partners
Prof. Jozef Anné
Catholic University of Leuven
Laboratory of Bacteriology
Rega Institute
Minderbroedersstraat 10
B-3000 Leuven, Belgium
jozef.anne@rega.kuleuven.be
Prof. Michael Hecker

Ernst-Moritz-Arndt-University
Institute for Microbiology
Greifswald, Germany
Dr. Wayne M. Coco

Direvo Biotech AG
Cologne, Germany
Prof. Anastassios Economou

Foundation of Research and Technology
Heraklion, Greece
Dr. Marc Daukandt

Eurogentec
DNA MicroArray Department
Seraing, Belgium
Prof. Jakob Kristjánsson

Prokaria Ltd
Reykjavik, Iceland
Dr. Benjamin Damien

BioXpr
Namur, Belgium
Prof. Roy Goodacre

School of Chemistry
Manchester, UK
Prof. Anna Eliasson Lantz

Centre for Microbial Biotechnology
Lyngby, Denmark
SYSCO

Research Project A study conducted by an international expert panel for the University of Toronto, ranked the
computational examination of host-pathogen interactions among the top 10 biotechnolo-
Contract number:
gies most likely to improve global health in the next 10 years (Daar et al, 2002). However,
LSHG-CT-2006-037231 information about fundamental aspects of the cellular machinery involved in the interactions
Starting date: between macrophages and intracellular pathogens has not yet been sufficiently catego-
1st September 2007 rised, particularly with regard to macrophage function, and there is a need for a systematic
Duration: and integrative approach to the identification of interconnected functional modules and
36 months salient modifications triggered by intracellular parasitism.
EC Funding:
The overall objective of the SYSCO project is to decipher the intracellular biological path-
ways and basic cellular processes that act in physiological conditions as well as in the
context of intracellular parasitism, in order to highlight the alteration in gene expression
that stems from the conflict between the host and pathogen genomes. More specifically,
the project will use human and mouse macrophages as cellular targets, and the Leishmania
parasite as a prototype for intracellular pathogens. Leishmania is one of the most intensively
studied biological models in terms of parasite, host immune response and genetics.
SYSCO will decipher and modularise the cascade of intracellular events generated by
parasite-cell interactions, and also how they result in either parasite elimination or infection
in humans. A comparative analysis with mouse strains expressing differing susceptibilities
will help identify key determinants of natural resistance or susceptibility to parasites acting
at the macrophage level.
In a combined strategy of experimental and theoretical work, the SYSCO consortium will
systematically capture data at different levels of cellular information, using state-of-the-art,
multi-parametric molecular technologies (both in human and in mouse). These data will be
used to identify regulatory motifs through systematic promoter analysis, and to populate
computer models with the relevant motifs and associated signalling pathways. The com-
puter models will be designed as independent modules covering gene regulation, gene
expression, protein interactions and signalling. This modular approach will be used to
mimic different types of innate macrophage responses, and to map theoretical predictions
to experimental data.
Expected Results:
After 36 months, SYSCO will have achieved the following aims:
1) Development of a hybrid, in silico model for the innate response of macrophages to
an intracellular pathogen, based on the composition of interconnected modules that
mimic different cellular events;
2) Development of a comprehensive systems ontology;
3) Experimental investigation and categorisation of four different modules, namely gene
regulation, gene and protein expression and signal transduction;
4) Complementary high throughput analysis of the macrophage transcriptome by Af-
fymetrix oligonucleotide arrays and serial analysis of gene expression, both in para-
site-infected and in non-infected cells;
5) Prediction and validation of the regulatory networks in macrophages;
Systematic Functional analysis
of Intracellular Parasitism
as a model of genomes conflict
6) Experimental determination of cell regulation by quantitative transcription factor as-

says and by RNA interference.
Potential Impact:
Leishmaniasis is one of the world’s major parasitic diseases, but there is no vaccine for it as
yet, and the drugs currently prescribed to treat it are fairly toxic. Millions of people living in
developing countries, mainly in southern and eastern Mediterranean regions and in central
and South America, are exposed to leishmaniasis. The Leishmania parasite is also a major
co-pathogen in the context of HIV infection in southern Europe. The results of this project will
be significant, not only in the context of leishmaniasis, but also for the understanding and
treatment of infection by other intracellular pathogens, such as Mycobacterium tuberculosis,
the bacterium which causes tuberculosis.
Partners
Project Coordinator: Prof. Winston Hide
Dr. Alexander Kel University of the Western Cape
BIOBASE GmbH South African National Bioinformatics Institute
Department of Research and Development Bellville, South Africa
Halchtersche strasse 33
34090 Wolfenbüttel, Germany Dr. Pierre-Andre Cazenave
Alexander.kel@biobase-international.com Université Pierre et Marie Curie-Paris VI,
Laboratoire d’Immunophysiopathologie
Dr. David Piquemal Infectieuse – URA 1961
SARL Skuld-Tech Paris, France
Montpellier, France
Dr. Ralf Herwig

Molecular Genetics
Berlin, Germany
Dr. Béatrice Regnault

Institut Pasteur
Plate-forme Puce à ADN – Genopole Pasteur
Paris, France
Prof. Patricia Renard

Facultés Universitaires Notre-Dame de la Paix
Unite de Recherche en Biologie Cellulaire
Namur, Belgium
Prof. Koussay Dellagi

Institut Pasteur de Tunis
Laboratoire d’Immunopathologie
Vaccinologie et Genetique Moleculaire (LIVGM)
Tunis, Tunisia
Proust
State-of-the-Art:
Project Type: Knowledge about how regulatory genes and their mechanisms of expression change over
Specific Support Action time is expanding rapidly, and it is now clear that this temporal dimension is a common
Contract number: denominator of experimental systems studied in different life science disciplines. In the
LSHG-CT-2006-037654 post-genomic era, the focus of research has shifted from the identification of genes to un-
derstanding their function.
Starting date: Some fundamental aspects of gene function cannot be captured without taking into account
1st January 2007 the complex dynamics of interactions between genes, both in space and in time. A com-
Duration: plete understanding of gene function therefore requires the development of novel tools for
24 months the analysis of those dynamics, particularly in the temporal domain. Given the complexity
of known genetic networks, it seems inevitable that a purely deterministic approach will not
EC Funding:
generate realistic descriptions of cell function.
`250 000
The overall objectives of PROUST
are as follows: to bring together
scientists from different disciplines
or fields of research, to establish
genuinely leading-edge projects
on gene and protein networks
which focus on the temporal di-
mension, and to standardise tools
for the investigation of timescales
in functional genomics.
Picture taken at the Proust Furthermore, PROUST plans to
project first course, entitled coordinate knowledge on the
“The dimension of time and gene temporal dimension of intracel-
functioning: focus on the nervous lular and intercellular signalling
system” which was held at the pathways, in order to define their
Kristineberg Marine Station in role at the molecular, cellular, tis-
Sweden from June 7 to June 12. sue and organism levels.
The above will be crucial for the identification of therapeutic targets with time-dependent sus-
ceptibilities. The last general objective for PROUST is to foster and disseminate knowledge on
the temporal dimension of biological processes not only among students and scientists work-
ing in different disciplines, but also among other stakeholders in society. More specifically, the
highly interdisciplinary PROUST consortium will address the following topics:
1) Oscillation in gene expression, and the development of tools for investigating dynamic
parameters, including rhythmic expression of genes, rhythmic post-transcriptional regu-
lation, regulation of the cell cycle, timing in microRNAs, timing by natural antisense
transcripts, modelling of the timing factors in biological systems, and modelling of
intracellular signalling pathways for therapeutic targeting;
2) The implications of the above on human disease, including cardiovascular, neurologi-

cal and psychiatric diseases, abnormal cell proliferation and cancer, nutrition and me-
tabolism, infections and immunity;
3) The implications of the above across the human lifespan, from childhood to old
age, in males and females, as well as a focus on issues relating to reproduction and
pregnancy;
The temporal dimension
in functional genomics
4) The implications of the above across populations and species. This aspect of the con-
sortium’s research will draw on the disciplines of population genetics and comparative
genomics, focusing on genes that are conserved throughout evolution, as well as on
the issue of time and population history.
Expected Results:
PROUST plans to organise workshops and two training courses, ultimately delivering a
position paper on the temporal dimension in functional genomics. The expected output of
PROUST will contribute firstly to the standardisation of approaches to gene expression anal-
yses which take into account the temporal dimension as a stochastic variable. Secondly, it
will assist in narrowing the gap between clinically correlative data and causative data for
complex diseases such as cardiovascular and neurological diseases and cancer, as well as
for the regulation of normal lifetime events (e.g. pregnancy).
The mathematical and modelling approaches, whose development PROUST will further,
such as false discovery rate (FDR)-based methods for analysing time-course microarray
data, are of particular interest: they can be applied to typical comparisons and sampling
schemes or chaotic dynamics in neural networks.
Potential Impact:
PROUST offers European scientists a unique opportunity to interact in an innovative and
multidisciplinary field of research, providing them with a forum in which they can exchange
scientific information relevant to developments in biomedical technology. In particular,
PROUST will focus on common denominators (e.g. common genes, gene products and sig-
nal transduction pathways) in functional genomics, in relation to time. Such a coordinated
research effort will provide the European Research Area with an obvious strategic advan-
tage in relation to drug discovery, drug delivery, disease prevention, disease therapy and
the general wellbeing of the ageing European population.
Keywords: functional genomics, temporal dimension

Partners
Prof Marina Bentivoglio
University of Verona
Department of Morphological Biomedical Sciences
Strada Le Grazie 8
37134 Verona, Italy
marina.bentivoglio@univr.it
Dr. Maris Laan

Estonian Biocentre
Functional Genomics Workgroup
Tartu, Estonia Prof. Francis Lévi
Institut National de
Prof. Krister Kristensson la Recherche Medicale (INSERM)
Karolinska Instituet U776 Chronotherapie des cancers
Department of Neuroscience Hôpital Paul Brousse
Stockholm, Sweden Villejuif, France
INDEXES
PROJECTS INDEX
0
3D-EM New Electron Microscopy Approaches for Studying Protein Complexes
and Cellular Supramolecular Architecture //////////////////////////// 170
3DGENOME 3D Genome Structure and Function //////////////////////////////// 164
3D-Repertoire A Multidisciplinary Approach to Determine the Structures of Protein
Complexes in a Model Organism ////////////////////////////////// 190
A
AGRON-OMICS Arabidopsis growth network integrating OMICS technologies ///////////// 464
AMPKIN Systems biology of the AMP-activated protein kinase pathway //////////// 456
AnEUploidy AnEUploidy: understanding gene dosage imbalance in human health
using genetics, functional genomics and systems biology //////////////// 350
ATD The Alternate Transcript Diversity Project ///////////////////////////// 300
Autoscreen AUTOSCREEN for Cell Based High-throughput and High-content Gene
Function Analysis and Drug Discovery Screens ///////////////////////// 98
B
BACELL HEALTH Bacterial stress management relevant to infectious disease
and biopharmaceuticals ///////////////////////////////////////// 426
BACRNAs Non-coding RNAs in Bacterial Pathogenicity////////////////////////// 408
BaSysBio Towards an understanding of dynamic transcriptional regulation
at global scale in bacteria: a systems biology approach ///////////////// 468
BioBridge Integrative Genomics and Chronic Disease Phenotypes: modelling
and simulation tools for clinicians ////////////////////////////////// 472
BIOSAPIENS A European Network for Integrated Genome Annotation //////////////// 296
BIOXHIT Bio-Crystallography on a Highly Integrated Technology Platform
for European Structural Genomics////////////////////////////////// 166
C
Callimir Studying the biological role of microRNAs in the Dlk1-Gtl2 imprinted
domain ///////////////////////////////////////////////////// 400
CAMP Chemical Genomics by Activity Monitoring of Proteases ///////////////// 114
CASIMIR Co-ordination And Sustainability of International Mouse Informatics
Resources //////////////////////////////////////////////////// 238
ChILL Chromatin Immuno-linked ligation: A novel generation of biotechnological
tools for research and diagnosis /////////////////////////////////// 156
COMBIO An integrative approach to cellular signalling and control processes:
Bringing computational biology to the bench ///////////////////////// 442
COMPUTIS Molecular Imaging in Tissue and Cells by Computer-Assisted Innovative
Multimode Mass Spectrometry //////////////////////////////////// 126
COSBICS Computational Systems Biology of Cell Signalling ////////////////////// 444
D
DanuBiobank The Danubian Biobank Initiative - Towards Information-based Medicine ///// 286
DIAMONDS Dedicated Integration and Modelling of Novel Data and Prior Knowledge
to Enable Systems Biology /////////////////////////////////////// 446
DIATOMICS Understanding Diatom Biology by Functional Genomics Approaches /////// 428
DNA REPAIR DNA Damage Response and Repair Mechanisms ////////////////////// 334
E
ELIfe The European Lipidomics Initiative: Shaping the life sciences////////////// 450
EMBRACE A European Model for Bioinformatics Research and Community Education /// 302
E-MeP The European Membrane Protein Consortium ///////////////////////// 176
E-MeP-Lab E-MeP-Lab Training events in membrane protein structural biology ////////// 196
EMERALD Empowering the Microarray-Based European Research Area to Take
a Lead in Development and Exploitation ////////////////////////////// 96
EMI-CD European Modelling Initiative combating complex diseases ////////////// 438
EndoTrack Tracking the Endocytic Routes of Growth Factor Receptor Complexes
and their Modulatory Role on Signalling ///////////////////////////// 346
ENFIN An Experimental Network for Functional Integration //////////////////// 306
EpiGenChlamydia Contribution of molecular epidemiology and host-pathogen genomics
to understand Chlamydia trachomatis disease //////////////////////// 290
ESBIC-D European Systems Biology Initiative for Combating Complex Diseases ////// 452
ESTOOLS Platforms for biomedical discovery with human ES cells ///////////////// 386
EUCLOCK Entrainment of the Circadian Clock///////////////////////////////// 418
EUCOMM The European Conditional Mouse Mutagenesis Programme ////////////// 230
EUHEALTHGEN Harnessing the Potential of Human Population Genetics Research
to Improve the Quality of the EU Citizen ///////////////////////////// 280
EUMODIC The European Mouse Disease Clinic:
A distributed phenotyping resource for studying human disease /////////// 234
Eurasnet European Alternative Splicing Network of Excellence /////////////////// 402
EURATools European Rat Tools for Functional Genomics ////////////////////////// 244
EuReGene European Renal Genome Project ////////////////////////////////// 370
EURExpress A European Consortium to Generate a Web-Based Gene Expression Atlas
by RNA in situ Hybridisation ///////////////////////////////////// 218
EUROBIOFUND A Strategic Forum for the Dialogue and Coordination
of European Life Sciences, Funders and Performers ///////////////////// 460
EUROFUNGBASE Strategy to build up and maintain an integrated sustainable European fungal
genomic database required for innovative genomics research on filamentous
fungi, important for biotechnology and human health /////////////////// 310
EuroHear Advances in hearing science: from functional genomics to therapies //////// 362
EUROSPAN EUROpean Special Populations Research Network: Quantifying
and Harnessing Genetic Variation for Gene Discovery ////////////////// 284
EUSYSBIO The Take-off of European Systems Biology //////////////////////////// 434
EuTRAC European Transcriptome, Regulome & Cellular Commitment Consortium ///// 390
EU-US Workshop Workshop on “Systems biology of DNA damage-induced stress responses /// 448
EVI-GENORET Functional genomics of the retina in health and disease ///////////////// 374
Extend-NMR Extending NMR for Functional and Structural Genomics ///////////////// 202
F
FESP Forum for European Structural Proteomics //////////////////////////// 194
FGENTCARD Functional GENomic diagnostic Tools for Coronary Artery Disease ///////// 102
FLPFLEX A Flexible Toolkit for Controlling Gene Expression in the Mouse /////////// 228
FOSRAK Function of small RNAs across kingdoms //////////////////////////// 398
FSG-V-RNA Functional and Structural Genomics of Viral RNA ////////////////////// 180
FunGenEs Functional Genomics in Engineered ES cells ////////////////////////// 380
PROJECTS INDEX
G
GeneFun In-Silico Prediction of gene function///////////////////////////////// 174
GENINTEG Controlled gene integration:
a requisite for genome analysis and gene therapy ///////////////////// 130
GENOSEPT Genetics of Sepsis in Europe ///////////////////////////////////// 276
H
HEROIC High-Throughput Epigenetic Regulatory Organisation in Chromatin ///////// 152
HT3DEM High throughput Three-dimensional Electron Microscopy ///////////////// 198
HUMGERI Human Genomic Research Integration ////////////////////////////// 270
I
Impacts Archive Tissues: Improving Molecular Medicine Research
and Clinical Practice /////////////////////////////////////////// 288
IMPS Innovative tools for membrane structural Proteomics //////////////////// 204
INTERACTION PROTEOME Functional Proteomics: Towards defining the interaction proteome ////////// 108
L
LYMPHANGIOGENOMICS Genome-Wide Discovery and Functional Analysis
of Novel Genes in Lymphangiogenesis ////////////////////////////// 358
M
MAIN Targeting Cell Migration in Chronic Inflammation ////////////////////// 316
Med-Rat New Tools to Generate Transgenic and Knock-out Mouse and Rat Models /// 248
MEGATOOLS New tools for Functional Genomics based on homologous recombination
induced by double-strand break and specific meganucleases ///////////// 136
MICROSAT workshop Microsatellites and VNTRs: workshop on bioinformatics,
genomics and functionality /////////////////////////////////////// 278
MITOCHECK Regulation of Mitosis by Phosphorylation - A Combined Functional
Genomics, Proteomics and Chemical Biology Approach ///////////////// 322
MODEST Modular Devices for Ultrahigh-throughput and Small-volume Transfection //// 104
MOLECULAR IMAGING Integrated Technologies for In Vivo Molecular Imaging ////////////////// 120
MolPAGE Molecular Phenotyping to Accelerate Genomic Epidemiology ///////////// 272
MolTools Advanced Molecular Tools for Array-Based Analyses of Genomes,
Transcriptomes, Proteomes and Cells //////////////////////////////// 86
MUGEN Integrated Functional Genomics in Mutant Mouse Models as Tools
to Investigate the Complexity of Human Immunological Disease /////////// 222
MYORES Multiorganismic Approach to Study Normal and Aberrant Muscle
Development, Function and Repair ///////////////////////////////// 366
N
NDDP NMR Tools for Drug Design Validated on Phosphatases ///////////////// 188
NemaGENETAG Nematode Gene-Tagging Tools and Resources //////////////////////// 260
NEUPROCF Development of New Methodologies for Low Abundance Proteomics:
Application to Cystic Fibrosis ///////////////////////////////////// 112
NFG Functional Genomics of the Adult and Developing Brain ///////////////// 356
NMR-Life Focusing NMR on the Machinery of Life ///////////////////////////// 200
PROJECTS INDEX
O
OptiCryst Optimisation of Protein Crystallisation for European Structural Genomics //// 210
P
PEROXISOMES Integrated Project to decipher the biological function of peroxisomes
in health and disease /////////////////////////////////////////// 330
PHOEBE Promoting harmonisation of epidemiological biobanks in Europe ////////// 282
PLASTOMICS Mechanisms of transgene integration and expression in crop plant plastids,
underpinning a technology for improving human health ///////////////// 132
PLURIGENES Pluripotency Associated Genes to Dedifferentiate Neural Cells
into Pluripotent Cells //////////////////////////////////////////// 384
PRIME Priorities for mouse functional genomics research across Europe:
integrating and strengthening research in Europe ////////////////////// 226
ProDac Proteomics Data Collection /////////////////////////////////////// 116
Proust The temporal dimension in functional genomics /////////////////////// 484
Q
QUASI Quantifying signal transduction /////////////////////////////////// 440
R
REGULATORY GENOMICS Advanced Genomics Instruments, Technology and Methods for
Determination of Transcription Factor Binding Specificities:
Applications for Identification of Genes Predisposing to Colorectal Cancer //// 90
RIBOREG Novel non-coding RNAs in differentiation and disease ////////////////// 396
RIBOSYS Systems Biology of RNA Metabolism in Yeast ///////////////////////// 458
RNABIO Computational approaches to non-coding RNAs /////////////////////// 410
RUBICON Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation //////// 342
S
SIGNALLING & TRAFFIC Signalling and Membrane Trafficking in Transformation and Differentiation/// 326
Sirocco Silencing RNAs: organisers and coordinators
of complexity in eukaryotic organisms ////////////////////////////// 412
SMARTER Development of small modulators of gene activation
and repression by targeting epigenetic regulators ////////////////////// 158
SPINE2-COMPLEXES From Receptor to Gene: Structures of Complexes
from Signalling Pathways linking Immunology, Neurobiology and Cancer//// 206
STAR A SNP and Haplotype Map for the Rat ////////////////////////////// 242
STEROLTALK Functional Genomics of Complex Regulatory Networks from Yeast
to Human: Cross-Talk of Sterol Homeostasis and Drug Metabolism ///////// 338
Streptomics Systems biology strategies and metabolome engineering for the enhanced
production of recombinant proteins in Streptomyces //////////////////// 478
SYSBIOMED Systems Biology for Medical Applications //////////////////////////// 474
SYMBIONIC Towards European Neuromal Cell Simulation: a European consortium
to integrate the scientific activities for the creation of a European Alliance
devoted to the complete in-silico model of Neuronal Cell //////////////// 436
SYSCO Systematic Functional analysis of Intracellular Parasitism as
a model of genomes conflict ////////////////////////////////////// 482
SysProt System-wide analysis and modelling of protein modification ////////////// 476
PROJECTS INDEX
T
TAGIP Targeted Gene Integration in Plants: Vectors, Mechanisms
and Applications for Protein Production ///////////////////////////// 134
TargetHerpes Molecular intervention strategies targeting latent
and lytic herpesvirus infections //////////////////////////////////// 100
Tat machine Functional genomic characterisation of the bacterial Tat complex
as a nanomachine for biopharmaceutical production and
a target for novel anti-infectives //////////////////////////////////// 92
TEACH-SG Training and Education in High Volume and High Value Structural Genomics / 212
TEMPO Temporal Genomics for Tailored Chronotherapeutics //////////////////// 422
THE EPIGENOME Epigenetic plasticity of the genome ///////////////////////////////// 148
Tips4Cells Scanning Probe Microscopy techniques for real time, high resolution
imaging and molecular recognition in functional and structural genomics //// 124
TP Plants and Health The European Technology Platform on Plant Genomics and Biotechnology:
Plants for healthy lifestyles and for sustainable development ////////////// 262
TransCode Novel Tool for High-Throughput Characterisation
of Genomic Elements Regulating Gene Expression in Chordates //////////// 94
TransDeath Programmed cell death across the eukaryotic kingdom ////////////////// 328
TRANS-REG Transcription Complex Dynamics Controlling Specific
Gene Expression Programmes //////////////////////////////////// 142
U
UPMAN Understanding Protein Misfolding and Aggregation by NMR ///////////// 186
V
VALAPODYN Validated Predictive Dynamic Model of Complex Intracellular Pathways
related to cell death and survival ////////////////////////////////// 462
VIZIER Comparative structural genomics on viral enzymes involved in replication //// 182
W
WOUND A multi-organism functional genomics approach
to study signalling pathways in epithelial fusion/wound healing /////////// 320
X
X-OMICS Xenopus Comparative Genomics: Coordinating Integrated and Comparative
Functional Genomics for Understanding Normal and Pathologic Development 264
X-TRA-NET ChIP-Chip to Decipher Transcription Networks of RXR and Partners ///////// 144
Y
YSBN Yeast Systems Biology Network /////////////////////////////////// 454
Z
ZF-MODELS Zebrafish Models for Human Development and Disease ///////////////// 252
ZF-TOOLS High-throughput Tools for Biomedical Screens in Zebrafish /////////////// 256
INSTITUTION AND
COORDINATOR INDEX
A
■ Amaxa AG, Dr. Birgit Nelsen-Salz, MODEST //////////////////////////////////////////// 105
■ Agricultural Biotechnology Center, Genetic Reprogramming Group, Dr. Andras Dinnyes, Med-Rat ///// 249
■ Aston University, Department of Life and Health Sciences, Dr. Roslyn Bill, E-MeP ////////////////// 178
■ Aston University, Department of Life and Health Sciences, Dr. Roslyn Bill, E-MeP-Lab /////////////// 197
■ Aston University, Department of Life and Health Sciences, Dr. Roslyn Bill, OptiCryst //////////////// 211
B
■ BIOBASE GmbH, Department of Research and Development, Dr. Alexander Kel, SYSCO /////////// 483
■ Biomedical Sciences Research Center, Dr. George Kollias, MUGEN /////////////////////////// 224
C
■ Catholic University of Leuven, Laboratory of Bacteriology, Rega Institute,
Prof. Jozef Anné, Streptomics ///////////////////////////////////////////////////////// 481
■ CELLECTIS SA, Dr. Frédéric Pâques, MEGATOOLS //////////////////////////////////////// 137
■ Centre de Regulació Genòmica (CRG), Systems Biology Laboratory,
Prof. Luis Serrano, 3D repertoire ////////////////////////////////////////////////////// 192
■ Centre for Brain Research, Medical University of Vienna, Prof. Johannes Berger, Peroxisomes //////// 333
■ Centre National de la Recherche Scientifique (CNRS), Institut des Sciences du Végétal
(UPR no 2355), RIBOREG /////////////////////////////////////////////////////////// 397
■ Centre National de la Recherche Scientifique (CNRS), UMR 8080 Développement et Evolution,
Dr. Andre Mazabraud, X-OMICS ///////////////////////////////////////////////////// 265
■ Centre National De La Recherche Scientifique (CNRS), Université Louis Pasteur, Institut de biologie
moléculaire et cellulaire, ARN ‘Architecture et Réactivité de l’ARN’, Prof. Eric Westhof, RNABIO ////// 411
■ Centre National de la Recherche Scientifique (CNRS)/Université Paris-7 UMR 7099,
Institut de Biologie Physico-Chimique, IMPS ////////////////////////////////////////////// 205
■ Commissariat à l’Energie Atomique CEA), LIST/DETECS, Dr Haan Serge,
Dr Robbe Marie-France, COMPUTIS /////////////////////////////////////////////////// 127
■ Consejo Superior de Investigaciones Cientificas (CSIC), Instituto de Biologia Molecular
de Barcelona, Dr. Enrique Martin-Blanco, WOUND /////////////////////////////////////// 321
■ Consorzio Interuniversitario di Risonanze Magnetiche di Metalloproteine Paramagnetiche,
Magnetic Resonance Center (CERM), Prof. Ivano Bertini, NMR-Life //////////////////////////// 201
■ CRG - Centre de Regulació Genòmica, Systems Biology Research Unit, Prof. Luis Serrano, COMBIO // 443
D
■ DECHEMA e.V., Dr. Karsten Schürrle, SYSBIOMED //////////////////////////////////////// 475
■ Diagenode SA, Didier Allaer, ChILL//////////////////////////////////////////////////// 157
E
■ Erasmus MC University Medical Center, Department of Cell Biology and Genetics,
Prof. Dr. Frank Grosveld, EuTRACC //////////////////////////////////////////////////// 392
■ Erasmus Universitair Medisch, Centrum Rotterdam, Dept. of Cell Biology and Genetics,
Prof. Jan Hoeijmakers, DNA Repair /////////////////////////////////////////////////// 336
INSTITUTION AND COORDINATOR INDEX
■ ERM-0206 TAGC, Institut National de la Santé et de la Recherche Médicale (INSERM),

Prof. Daniel Gautheret, ATD ///////////////////////////////////////////////////////// 301
■ European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI),
Wellcome Trust Genome Campus, Dr. Graham Cameron, EMBRACE ////////////////////////// 304
Wellcome Trust Genome Campus, Prof. Ewan Birney, ENFIN //////////////////////////////// 308
Wellcome Trust Genome Campus, Prof. Janet Thornton, BioSapiens //////////////////////////// 298
■ European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Outstation,
Prof. Nadia Rosenthal, FLPFLEX /////////////////////////////////////////////////////// 229
■ European Molecular Biology Laboratory (EMBL), Outstation Hamburg,
Macromolecular Crystallography, Dr. Victor Lamzin, BIOXHIT //////////////////////////////// 168
■ European Plant Science Organisation, Dr. Karin Metzlaff, TP Plants and Health /////////////////// 263
■ European Science Foundation (ESF), Prof. Marja Makarow, EuroBioFund /////////////////////// 461
■ European Society of Intensive Care Medicine, Research Activities, Prof. Julian Bion,
Dr. Nathalie Mathy, GenOSept /////////////////////////////////////////////////////// 277
F
■ Flanders Interuniversity Institute for Biotechnology, Department of Plant Systems Biology,
Computational Biology Group, Prof. Martin Kuiper, DIAMONDS ///////////////////////////// 447
■ Fondazione Centro San Raffaele Del Monte Tabor, Department of Molecular Biology
and Functional Genomics, Prof. Ruggero Pardi, MAIN ///////////////////////////////////// 319
■ Fondazione Telethon, Telethon Institute of Genetics and Medicine, Molecular Biology Unit,
Dr. Sandro Banfi, TransCode////////////////////////////////////////////////////////// 95
■ Fondazione Telethon, TIGEM-Telethon Institute of Genetics and Medicine,
Prof. Andrea Ballabio, EURExpress //////////////////////////////////////////////////// 221
■ Forschungsinstitut für Molekulare Pathologie GmbH, Dr. Jan-Michael Peters, MitoCheck ///////////// 325
■ Forschungszentrum Juelich GmbH, Project Management Juelich (Ptj), Dr. Petra Wolff, EUSYSBIO ////// 435
■ Foundation for Research and Technology – Hellas, Institute of Electronic Structure
and Laser (IESL), Institute of molecular biology and biotechnology (IMBB),
Prof. Eleftherios Economou, MOLECULAR IMAGING /////////////////////////////////////// 122
■ Foundation for Research and Technology – Hellas, Institute of Molecular Biology and Biotechnology,
Dr. Nektarios Tavernarakis, NemaGENETAG //////////////////////////////////////////// 261
■ Foundation for Research and Technology – Hellas, Institute of Molecular Biology and Biotechnology,
Prof. Iannis Talianidis, TRANS-REG //////////////////////////////////////////////////// 143
G
■ Ghent University/Flanders Interuniversity Institute for Biotechnology, Department of Plant Systems
Biology, Computational Biology group, Prof. Martin Kuiper, EMERALD ////////////////////////// 97
■ Ghent University, Flanders Institute for Biotechnolgy (VIB), Department of Plant Systems Biology,
Dr. Pierre Hilson, AGRON-OMICS //////////////////////////////////////////////////// 467
■ Gothenburg University, Department of Cell and Molecular Biology, Prof. Stefan Hohmann, AMPKIN /// 457
■ Gothenburg University, Department of Cell and Molecular Biology, Prof. Stefan Hohmann, QUASI //// 441
■ Grenoble – Institut des Neurosciences Centre de Recherche INSERM U 836,
Université Joseph Fourier, Dr. Antoine Depaulis, VALAPODYN //////////////////////////////// 463
■ GSF-Forschungszentrum fur Umwelt und Gesundheit GmbH, Institute of Molecular Radiation Biology,
Prof. Dr. Jean-Marie Buerstedde, GENINTEG //////////////////////////////////////////// 131
H
■ Helmholtz Zentrum München, German Research Center for Environmental Health GmbH,
Institute of Developmental Genetics, Prof. Wolfgang Wurst, EUCOMM ///////////////////////// 233
I
■ Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Josep Roca, BioBridge /////////// 473
■ Institut Jacques Monod, Team ‘Avenir’ INSERM, Prof. Thierry Galli, SIGNALLING & TRAFFIC///////// 327
■ Institut National de la Recherche Agronomique (INRA), Dr. Philippe Noirot, BaSysBio ////////////// 471
■ Institut National de la Recherche Agronomique (INRA), Physiologie animale
et systèmes d’élevage (PHASE), Dr. Jean-Stéphane Joly, Plurigenes //////////////////////////// 385
■ Institut National de la Santé et de la Recherche Médicale, Faculte de Medecine Necker Inserm
U467, Dr. Aleksander Edelman, NEUPROCF //////////////////////////////////////////// 113
■ Institut National de la Santé et de la Recherche Médicale (INSERM), U384,
Dr. Krzysztof Jagla, MYORES //////////////////////////////////////////////////////// 368
■ Institut National de la Santé et de la Recherche Médicale (INSERM) U592,
Laboratoire de Physiopathologie Cellulaire et Moleculaire de la Retine, Institut de la Vision,
Prof. Jose-Alain Sahel, EVI-GENORET ////////////////////////////////////////////////// 376
■ Institut National de la Santé et de la Recherche Médicale (INSERM), U776
Rythmes biologiques et cancers ,Hôpital Paul Brousse, Dr. Francis Lévi, TEMPO /////////////////// 423
■ Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS 587- Institut Pasteur,
Unité de Génétique et Physiologie de l’Audition, Prof. Christine Petit, EuroHear /////////////////// 364
J
■ Johann Wolfgang Goethe-Universität, Center for Biomolecular Magnetic Resonance,
Institute for Organic Chemistry and Chemical Biology, Prof. Harald Schwalbe, UPMAN //////////// 187
K
■ Karolinska Institutet, Department of Cell and Molecular Biology, Prof. Maria Masucci, RUBICON ///// 345
■ King’s College, University of London, Department of Social Genetic and Developmental Psychiatry,
Institute of Psychiatry, Prof. David Collier, MICROSAT workshop ////////////////////////////// 279
L
■ Lay Line Genomics SpA, c/o San Raffaele Scientific Park, Dr. Ivan Arisi, SYMBIONIC////////////// 437
■ Leiden Institute of Physics, Leiden University, Dr. Tjerk Oosterkamp, Tips4Cells //////////////////// 125
■ Leiden University, Clusius Laboratory, Prof. Cees van den Hondel, EUROFUNGBASE ////////////// 311
■ Leiden University, Institute of Biology, Molecular Cell Biology, Dr. Annemarie H. Meijer, ZF-TOOLS //// 257
■ Leiden University Medical Center, Dr. Harry Vrieling, EU-US Workshop ///////////////////////// 448
■ Ludwig Maximilians University of Munich, Adolf-Butenandt Institute, Histone Modifications Group,
Protein Analysis Core Facility, Prof. Axel Imhof, SMARTER /////////////////////////////////// 159
■ Ludwig Maximilians University, Institute for Medical Psychology, Prof. Till Roenneberg, EUCLOCK ///// 420
M
■ Max-Delbrück-Center for Molecular Medicine, Cardiovascular Research Centre, Department
of Cardiovascular Research, Lipids and Experimental Gene Therapy, Thomas Willnow, EuReGene //// 373
■ Max-Delbrück-Center for Molecular Medicine, Experimental Genetics
of Cardiovascular Diseases, Dr. Norbert Hübner,STAR ///////////////////////////////////// 243
■ Max-Planck-Institute of Biochemistry, Department of Cellular Biochemistry,
Prof. F. Ulrich Hartl, INTERACTION PROTEOME ////////////////////////////////////////// 111
■ Max-Planck Institute for Biophysical Chemistry, Department of Cellular Biochemistry,
Prof. Reinhard Lührmann, Eurasnet //////////////////////////////////////////////////// 406
■ Max Planck Institute for Developmental Biology, Department of Genetics,
Dr. Robert Geisler, ZF-MODELS /////////////////////////////////////////////////////// 254
■ Max-Planck Institute of Molecular Cell Biology and Genetics, Prof. Marino Zerial, EndoTrack///////// 349
■ Max Planck Institute for Molecular Genetics, Vertebrate Genomics, Dr. Ralf Herwig, EMI-CD ///////// 439
■ Max-Planck Institute for Molecular Genetics, Vertebrate Genomics, Prof. Dr. Hans Lehrach, ESBIC-D /// 453
■ Medical Research Council, Mammalian Genetics Unit, MRC Harwell, Prof. Steve Brown, PRIME ////// 227
■ Medical Research Council, Mammalian Genetics Unit, MRC Harwell, Prof. Steve Brown, EUMODIC /// 236
■ Medical Research Council, Physiological Genomics and Medicine, MRC Clinical Sciences Centre,
Prof. Timothy J. Aitman, EURATools //////////////////////////////////////////////////// 246
■ MicroDiscovery GmbH, NutriSystemics, Dr. Arif Malik, SysProt /////////////////////////////// 477
N
■ Newcastle University, Molecular Microbiology Group, Institute for Cell and Molecular Biosciences,
Prof. Colin R Harwood, BACELL HEALTH //////////////////////////////////////////////// 427
■ Norwegian Institute of Public Health, Division of Epidemiology, Dr. Jennifer Harris, PHOEBE ///////// 283
R
■ Radboud University Nijmegen, IMM/Faculty of Science, Mathematics and Informatics,
Prof. Sybren Wijmenga,FSG-V-RNA /////////////////////////////////////////////////// 181
■ Research Institute for Molecular Pathology (IMP), Prof. Thomas Jenuwein, THE EPIGENOME ///////// 150
■ Ruhr-Universitaet Bochum, Medizinisches Proteom-Center, Prof. Helmut E. Meyer, ProDac /////////// 117
S
■ Saarland University, Department of Biochemistry, Prof. Rita Bernhardt, STEROLTALK//////////////// 341
■ SISSA (Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced
Studies), Neurobiology Sector, Prof. Anna Menini, NFG //////////////////////////////////// 357
■ Stazione Zoologica Anton Dohrn, Cell Signalling Laboratory, Dr. Chris Bowler, DIATOMICS ///////// 429
■ Stichting Katholieke Universiteit, Department of Molecular Biology, Prof. Henk Stunnenberg, HEROIC // 155
T
■ Technical University of Denmark, Centre for Microbial Biotechnology Biocentrum,
Prof. Jens Nielsen, YSBN /////////////////////////////////////////////////////////// 454
■ The Sainsbury Laboratory, John Innes Centre, Prof. David Baulcombe, Sirocco /////////////////// 414
■ The Wellcome Trust, Department of Biomedical Resources and Functional Genomics,
Dr. Alan Doyle, EUHEALTHGEN ////////////////////////////////////////////////////// 281
U
■ Universitat Autonoma de Barcelona, Institut de Biotecnologia i de Biomedicina,
Protein Engineering and Enzymology Unit, Prof. Francesc Xavier Aviles, CAMP /////////////////// 115
■ Universität Rostock, Department of Computer Science, Prof. Olaf Wolkenhauer, COSBICS ////////// 445
■ Universiteit van Amsterdam, Science Faculty, Swammerdam Institute for Life Sciences,
Prof. Roeland Van Driel, 3DGENOME ///////////////////////////////////////////////// 165
■ Université de la Méditerranée, Centre National de la Recherche Scientifique (CNRS), Laboratoire
Architecture et Fonction des Macromolecules Biologiques UMR 6098, Dr. Bruno Canard, VIZIER////// 184
■ Université Libre de Bruxelles, Service de Conformation de Macromolecules Biolgiques
et Bioinformatique, Biologie Moleculaire, Prof. Shoshana Wodak, GeneFun ///////////////////// 175
■ University Hospital Regensburg, Institute of Clinical Chemistry and Laboratory Medicine,
Prof. Gerd Schmitz, DanuBiobank ///////////////////////////////////////////////////// 287
■ University Medical Center Groningen, Department of Medical Microbiology,
Prof. Jan Maarten van Dijl, Tat machine ///////////////////////////////////////////////// 93
■ University of Basel, M.E. Miller Institute for Structural Biology, Biozentrum,
Prof. Andreas Engel, 3D-EM ///////////////////////////////////////////////////////// 173
■ University of Basel, M E Mueller Institute for Structural Biology, Biozentrum,
Prof. Andreas Engel, HT3DEM /////////////////////////////////////////////////////// 199
■ University of Bologna, Centro Interdipartimentale Galvani (CIG),
Prof. Gabriella Campadelli-Fiume,TargetHerpes ////////////////////////////////////////// 101
■ University of Cambridge, Professor Ernest D. Laue, Extend-NMR ////////////////////////////// 203
■ University of Cambridge, Department of Plant Sciences, Prof. John Gray, PLASTOMICS///////////// 133
■ University of Cambridge, Department of Physiology, Development and Neuroscience,
Dr. Paul Schofield, CASIMIR ///////////////////////////////////////////////////////// 239
■ University of Cologne, Institute of Neurophysiology, Faculty of Medicine,
Prof. Jürgen Hescheler, FunGenES ///////////////////////////////////////////////////// 382
■ University of Copenhagen, Institute of Molecular Biology, Prof. John Mundy, TransDeath //////////// 329
■ University of Debrecen, Medical and Health Science Center, Department of Biochemistry
and Molecular Biology, Dr. László Fésüs, HUMGERI /////////////////////////////////////// 271
■ University of Edinburgh, Public Health Sciences, Prof. Harry Campbell, EUROSPAN /////////////// 285
■ University of Edinburgh, The Wellcome Trust Centre for Cell Biology, Prof. Jean Beggs, RIBOSYS ////// 459
■ University of Freiburg, Institute for Biology II, Faculty of Biology, Center for Applied Biosciences,
Prof. Dr. Klaus Palme, Autoscreen ////////////////////////////////////////////////////// 99
■ University of Geneva, Faculty of Medicine, Department of Genetic Medicine and Development,
Prof. Stylianos Antonarakis, AnEUploidy //////////////////////////////////////////////// 353
■ University of Helsinki, Faculty of Medicine, Biomedicum Helsinki, Molecular Cancer Biology
Program, Prof. Kari Alitalo, LYMPHANGIOGENOMICS //////////////////////////////////// 361
■ University of Helsinki, Faculty of Medicine, Genome-Scale Biology Research Programme,
Prof. Jussi Taipale, REGULATORY GENOMICS //////////////////////////////////////////// 91
■ University of Liège, Unit of Animal Genomics, Faculty of Veterinary Medicine,
Dr. Michel Georges, Dr. Carole Charlier, Callimir ///////////////////////////////////////// 401
■ University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM),
Prof. Mark McCarthy, MolPAGE ////////////////////////////////////////////////////// 275
■ University of Oxford, Prof. John Bell, MolPAGE /////////////////////////////////////////// 275
■ University of Oxford, Wellcome Trust Centre for Human Genetics,
Dr. Dominique Gauguier, FGENTCARD ///////////////////////////////////////////////// 103
■ University of Oxford, Wellcome Trust Centre for Human Genetics, Division of Structural Biology,
Prof. David Stuart, TEACH-SG //////////////////////////////////////////////////////// 213
■ University of Sheffield, Centre for Stem Cell Biology, Department of Biomedical Sciences,
Prof. Peter W Andrews, ESTOOLS///////////////////////////////////////////////////// 389
■ University of Southern Denmark, Department of Biochemistry and Molecular Biology,
Prof. Susanne Mandrup, X-TRA-NET /////////////////////////////////////////////////// 145
■ University of Trieste, Department of Clinical Morphological and Technological Sciences,
International Centre for Genetic Engineering and Biotechnology, Molecular Histopathology
Laboratory, Prof. Giorgio Stanta, Impacts /////////////////////////////////////////////// 289
■ University of Verona, Department of Morphological Biomedical Sciences,
Prof. Marina Bentivoglio, Proust ////////////////////////////////////////////////////// 485
■ University of Vienna, Department of Biochemistry, “Max F. Perutz Laboratories”,
Prof. Renée Schroeder, BACRNAs ///////////////////////////////////////////////////// 409
■ Uppsala University, Department of Cell and Molecular Biology, Biomedical Center,
Prof. E. Gerhart Wagner, FOSRAK //////////////////////////////////////////////////// 399
■ Uppsala University, Department of Genetics and Pathology, Prof. Ulf Landegren, MolTools /////////// 89
■ Utrecht University, Bijvoet Center for Biomolecular Research, Faculty of Sciences,
Prof. Rolf Boelens, NDDP /////////////////////////////////////////////////////////// 189
■ Utrecht University, Bijvoet Center and Institute of Biomembranes, Prof. Gerrit van Meer, ELIfe ///////// 451
V
■ VU University Medical Center, Immunogenetics of Infectious Diseases, Department of Pathology,
Laboratory of Immunogenetics, Dr. Servaas A. Morré, EpiGenChlamydia /////////////////////// 291
W
■ Weizmann Institute of Science, Department of Structural Biology, Prof. Joel L. Sussman, FESP ///////// 195
■ Weizmann Institute of Science, Faculty of Biochemistry, Department of Plant Sciences,
Prof. Avi Levy, TAGIP /////////////////////////////////////////////////////////////// 135
■ Wellcome Trust Centre for Human Genetics, Division of Structural Biology,
Prof. David Stuart, SPINE2-COMPLEXES //////////////////////////////////////////////// 208
KEYWORDS INDEX
2D crystallisation: ................................................................................................199
3D electron microscopy: .......................................................................................172
3D structure: ..................................................................................................165, 178
3D-electron microscopy: ........................................................................................192
adult stem cells: ...................................................................................................105

ageing disorder: ..................................................................................................286
ageing: ...............................................................................................................336
age-related macular degeneration (AMD):...............................................................376
alternative RNA splicing: ......................................................................................405
amphipols: ..........................................................................................................205
Aneuploidy: ........................................................................................................352
animal dystrophies: ..............................................................................................376
animal immunology: .............................................................................................224
animal models: ................................................ 224, 227, 228, 236, 239, 249, 254, 257, 372, 420
animal mutants: ...................................................................................................376
anti-infectives: .......................................................................................................93
antimicrobial agents: ............................................................................................409
antisense RNA: ....................................................................................................409
anti-tumor drug discovery: .....................................................................................257
antiviral drugs: ....................................................................................................184
apoptosis: .....................................................................................................105, 329
applied optics:.....................................................................................................122
Arabidopsis:..................................................................................................135, 467
association: .........................................................................................................279
automated RNA ISH system: ..................................................................................220
automation techniques: .........................................................................................168
Bacillus, E. coli:.....................................................................................................93
Bacillus: ..............................................................................................................470
bacterial factors: ..................................................................................................290
bacterial pathogens:.............................................................................................427
bacterial virulence: ...............................................................................................409
basic biological processes:....................................................................................301
bioanalytical chemistry: ........................................................................................127
biobank: .............................................................................................................286
biobanks: ................................................................................................ 281, 283, 289
biochemistry: .......................................................................................................409
bioethics: ............................................................................................................283
bioinformatics algorithms: ......................................................................................95
bioinformatics: .............................. 93, 184, 192, 239, 254, 265, 303, 329, 399, 439, 453, 455, 470, 477
biomolecular complexes:.......................................................................................203
biopharmaceuticals: ...................................................................................93, 427, 480
biotechnology: .....................................................................................................131
brain: .................................................................................................................357
Caenorhabditis elegans: .......................................................................................261

callipyge: ............................................................................................................401
cancer metastasis: ................................................................................................348
cancer: ................................................................................... 91, 325, 329, 336, 360, 447
cardiovascular disease: ........................................................................................103
cardiovascular diseases: .......................................................................................372
cell adhesion: ......................................................................................................327
cell biology: ........................................................................................................429
cell cycle: ......................................................................................................325, 422
cell death and survival: .........................................................................................463
cell division: ........................................................................................................327
cell fate determination: .........................................................................................150
cell migration: ...............................................................................................318, 327
cell physiology:....................................................................................................364
cellular commitment: .............................................................................................392
cellular dynamics: ................................................................................................441
cellular: ..............................................................................................................382
central nervous system: .........................................................................................385
chemical biology: ................................................................................................325
chemical inhibitors: ..............................................................................................325
chemiotherapeutics:..............................................................................................101
chemogenomics: ..................................................................................................115
chemoproteomics: ................................................................................................115
ChIP assay: .........................................................................................................157
ChIP-chip: ...........................................................................................................145
Chlamydia: .........................................................................................................290
chromatin modification: ........................................................................................150
chromatin remodelling: .........................................................................................157
chromatin: ...........................................................................................................154
chromatin-IP:........................................................................................................145
chromosome engineering: .....................................................................................470
chronic heart failure: ............................................................................................473
chronic obstructive pulmonary diseases: .................................................................473
chronobiology: ....................................................................................................420
circadian clock: .............................................................................................420, 422
clinical application of lipids: ..................................................................................451
co-factors: ...........................................................................................................145
COGENE:...........................................................................................................283
comparative genomics: .................................................................................... 95, 427
comparative: .................................................................................................249, 279
complex disease: .................................................................................................283
complex diseases: ..........................................................................................439, 453
complex genetics: ................................................................................................372
complex traits: .....................................................................................................246
complex-complex interactions: ...............................................................................143
computational biology: .........................................................................................443
computational predictions: ....................................................................................308
computational systems biology:..............................................................................437
computer modelling: .............................................................................................443
conditionally mutated mouse ES cell library: ............................................................232
KEYWORDS INDEX
conserved genes: ...........................................................................................265, 321

conserved non-genic sequences: .............................................................................95
COPD:................................................................................................................473
copy number polymorphisms: ................................................................................352
coronary artery:...................................................................................................103
cryoelectron microscopy: ......................................................................................172
crystal structure: ...................................................................................................184
crystallization: .....................................................................................................205
crystallography: .............................................................................................208, 213
cystic fibrosis: ......................................................................................................113
data integration: ..................................................................................................298

data management: ...............................................................................................283
data modelling: ....................................................................................................97
databases: .............................................................................................. 117, 239, 298
datawarehouse development: ................................................................................290
de-differentiation: .................................................................................................385
degenerative diseases: .........................................................................................368
development: .......................................................................................................357
developmental biology: ..................................................................................368, 414
developmental genetics:........................................................................................265
diabetes:.......................................................................................................457, 473
diagnosis: .....................................................................................................301, 332
diagnostics: .................................................................................................... 88, 103
diatoms:..............................................................................................................429
Dicer: .................................................................................................................399
differentiation: ......................................................................................... 382, 388, 397
directed evolution:................................................................................................480
disease markers: ..................................................................................................301
disease mechanisms: ......................................................................................246, 254
disease: ..............................................................................................................397
disorders: ............................................................................................................187
diversification of muscle fibres: ..............................................................................368
DNA chips: .........................................................................................................357
DNA damage: ...............................................................................................336, 449
DNA methylation: ................................................................................................157
DNA repair mechanisms: ......................................................................................336
DNA tiling microarrays: ........................................................................................470
Drosophila: .........................................................................................................205
drug design: ........................................................................................................189
drug development: .........................................................................................246, 457
drug screening:.....................................................................................................99
drug targets: ..............................................................................................93, 254, 427
dynamic modelling of signal transduction pathways: ................................................445
dynamical modelling: ...........................................................................................447
electron microscopy techniques: .............................................................................172

electron tomography:......................................................................................172, 192
embryonal development: .......................................................................................392
embryos:.............................................................................................................385
endocytosis: ........................................................................................................348
endophenotypes: .................................................................................................285
entrainment: ........................................................................................................420
KEYWORDS INDEX
environmental factors:...........................................................................................290
enzymes: ............................................................................................................480
epidemiology: ......................................................................................... 274, 277, 283
epigenetic code: ..................................................................................................150
epigenetics: ............................................................................................. 154, 157, 159
ethics in health sciences: .......................................................................................289
European technology platform: ..............................................................................263
EU-US collaboration: ............................................................................................449
exploratory drug discovery: ..................................................................................224
expression profiling: .............................................................................................257
fluorescence: .......................................................................................................122
fluorescent in situ hybridization: .............................................................................165
fluxomics:............................................................................................................470
Function prediction: ..............................................................................................175
function:..............................................................................................................181
functional analysis of the mouse genome:................................................................232
functional biology: ...............................................................................................224
functional genomics: ......................................... 122, 135, 137, 203, 220, 224, 249, 254, 261, 289
308, 325, 340, 357, 364, 382, 399, 447, 467, 485
functional in vivo studies: ......................................................................................265
functional probing: ...............................................................................................115
functions of muscle-specific proteins: .......................................................................368
fundamental biological processes: ..........................................................................477
fundamental genomics: .........................................................................................399
fungal health applications: ....................................................................................311
fungal pathogenicity: ............................................................................................311
fusion; glycoproteins:............................................................................................101
gene & protein networks: ......................................................................................443

gene atlas: ..........................................................................................................382
gene discovery: ...................................................................................................285
gene dosage imbalance: ......................................................................................352
gene expression analysis: .....................................................................................220
gene expression regulation:.............................................................................. 95, 301
gene expression: ............................................................... 133, 143, 165, 352, 376, 399, 414
gene integration:..................................................................................................133
gene knock-out: ...................................................................................................261
gene regulation: ............................................................................................154, 159
gene silencing/knockdown: ..................................................................................105
gene targeting: .................................................................................. 135, 137, 246, 249
gene:..................................................................................................................131
general pathology: ...............................................................................................318
genetic engineering: .......................................................................................122, 228
genetic epidemiology and standardisation: .............................................................290
genetic epidemiology: ..........................................................................................283
genetic isolate: ....................................................................................................285
genetic predisposition: ..........................................................................................277
genetic testing: ....................................................................................................277
genetic variation: ...........................................................................................243, 285
genetics: .......................................................................................................279, 357
genome (in)stability: .............................................................................................336
genome annotation: .............................................................................................298
KEYWORDS INDEX
genome engineering: ...........................................................................................137

genome structure and maintenance: .......................................................................135
genome wide transcriptional profiling: ....................................................................449
GenomEUtwin: ....................................................................................................283
genomic databases: .............................................................................................311
genomic function:.................................................................................................131
genomics: .....................................88, 91, 99, 181, 184, 263, 265, 274, 285, 332, 336, 360, 429, 473
genotype-phenotype-correlation: ............................................................................376
genotyping: .........................................................................................................283
global target site array: ........................................................................................145
gradients: ...........................................................................................................443
growth: ...............................................................................................................467
hair bundle: ........................................................................................................364

haplotype map: ...................................................................................................243
hard-to-transfect cell lines: .....................................................................................105
hardware and software pipeline: ...........................................................................168
HBV: ..................................................................................................................181
HCV: ..................................................................................................................181
health sciences: ...................................................................................................281
hearing impairment: .............................................................................................364
hematopoiesis: ....................................................................................................392
herpes simplex virus: ............................................................................................101
herpesvirus: .........................................................................................................101
heterologous transposition: ....................................................................................261
high resolution: ....................................................................................................125
high throughput: ............................................................................................199, 211
high-throughput imaging analysis: ..........................................................................165
high-throughput screen: .........................................................................................348
high-throughput screening: ....................................................................................184
high-throughput techniques: ..................................................99, 145, 154, 203, 208, 257, 348
Histones: ............................................................................................................157:
HIV:....................................................................................................................181
homologous recombination: ...................................................................... 131, 135, 137
host factors:.........................................................................................................290
host response: .....................................................................................................101
human cytomegalovirus: .......................................................................................101
human development: ............................................................................................254
human disease models:.........................................................................................236
human disease:....................................................................................................336
human diseases: ..................................................................................................332
human embryonic stem cells: .................................................................................388
human genetics: ...................................................................................................281
human genomics: .................................................................................................271
human health:.......................................................................................................93
human herpesvirus 8: ...........................................................................................101
IFN: ...................................................................................................................101
imaging techniques: .............................................................................................125
imaging: ........................................................................................................ 99, 172
immobilised proteins:............................................................................................201
immune response markers: ....................................................................................257
immunology: .......................................................................................................318
KEYWORDS INDEX
imprinting: ..........................................................................................................401
improved human health: .......................................................................................340
in silico models: ...................................................................................................437
infectious diseases:...............................................................................................427
inflammation: ......................................................................................................318
inflammatory diseases: .........................................................................................360
informatics: .........................................................................................................246
infrastructures: .....................................................................................................227
innate immunity: ..................................................................................................101
inner ear: ............................................................................................................364
integrating research: ............................................................................................227
integration: .........................................................................................................303
integrative biology: ..............................................................................................467
intensive care medicine:........................................................................................277
interaction networks: ............................................................................................175
interactive databases: ...........................................................................................265
inverse problem: ..................................................................................................122
iron homeostasis: .................................................................................................427
isolated populations: ............................................................................................283
K+ homeostasis:...................................................................................................364
kidney diseases: ..................................................................................................372
labelling, synthesis:...............................................................................................181
lead: ..................................................................................................................105
leaf: ...................................................................................................................467
life sciences: ........................................................................................................461
ligand interfaces: .................................................................................................208
ligand specific effects: ..........................................................................................145
light:...................................................................................................................420
linkage: ..............................................................................................................279
lipid cubic phases: ...............................................................................................205
lipidomics: ..........................................................................................................451
living cell array: ...................................................................................................470
low abundance proteins:.......................................................................................113
lymphangiogenesis:..............................................................................................360
lymphoedema: .....................................................................................................360
MAP kinases: ......................................................................................................441

mapping: ............................................................................................................279
mass spectrometry: .........................................................................................127, 325
massive data processing and information treatment: .................................................127
mathematical modelling: .................................................................................453, 455
mathematical models: .....................................................................................441, 457
medical genetics: .................................................................................................228
medical pathway modelling: .................................................................................340
medicine: ......................................................................................................318, 475
meganucleases: ...................................................................................................137
membrane proteins:............................................................................ 178, 199, 201, 205
membrane trafficking: ...........................................................................................327
metabolic disorder: ..............................................................................................286
KEYWORDS INDEX
metabolism:.........................................................................................................457
metabolomics: ..............................................................................103, 451, 470, 473, 480
micro RNA: .........................................................................................................401
microarray technology: ..........................................................................................97
microarrays: ........................................................................................................301
microcrystallography: ...........................................................................................205
microRNA: ..........................................................................................................414
microRNAs: .........................................................................................................411
microsatellite: ......................................................................................................279
microscopy:.........................................................................................................122
miRNA: ..............................................................................................................399
mitosis: ...............................................................................................................325
model organisms:..................................................................................... 135, 254, 385
modelling complex diseases: .................................................................................439
modelling: ............................................................................................... 459, 470, 473
molecular biology: ........................................................................289, 336, 360, 368, 414
molecular chemistry: .............................................................................................122
molecular evolution: .............................................................................................187
molecular genetics: ....................................................................................91, 224, 228
molecular interaction networks: ..............................................................................463
molecular medicine: .............................................................................................289
molecular pathways: ............................................................................................224
molecular phenotyping: ........................................................................................274
molecular recognition: ..........................................................................................125
monosomy: .........................................................................................................352
morphogenesis: ...................................................................................................321
mortality: ............................................................................................................277
mouse disease models: ...................................................................................232, 236
mouse functional genomics: ...................................................................................227
mouse models: .....................................................................................................332
mouse transgenesis: .............................................................................................352
mouse:.........................................................................................220, 239, 249, 265, 372
murine embryonic stem cells: .................................................................................382
muscle differentiation: ...........................................................................................368
muscle patterning: ................................................................................................368
muscle regeneration: ............................................................................................368
muscle stem cells: .................................................................................................368
mutation genetics: ................................................................................................187
Mycobacterium: ....................................................................................................93
myoblasts fusion:..................................................................................................368
myogenic specification: ........................................................................................368
nanodrop technology: ..........................................................................................208

nanomachines: .....................................................................................................93
nematode:...........................................................................................................261
network analysis: .................................................................................................439
network design: ...................................................................................................443
networking: ...................................................................................................213, 461
neural: ................................................................................................................388
neurobiology: ......................................................................................................392
neurodegeneration: ..............................................................................................463
neuro-degenerative disorder: .................................................................................286
neuron: ...............................................................................................................437
neuronal cells: .....................................................................................................105
NMR spectroscopy: ..............................................................................................189
KEYWORDS INDEX
NMR: ..................................................................................................... 181, 201, 203

non-coding RNA: ...........................................................................................399, 409
non-coding RNAs: ..........................................................................................397, 411
non-transcriptional gene regulation: ........................................................................399
novel surfactants: .................................................................................................205
nuclear magnetic resonance: .................................................................................203
nuclear receptors: ................................................................................................145
nuclear replacement: ............................................................................................249
nucleation: ..........................................................................................................211
nucleofection: ......................................................................................................105
oncogenic cell implants:........................................................................................257

Organogenesis: ...................................................................................................372
overexpression:....................................................................................................205
P3G: ..................................................................................................................283
pathological anatomy: ..........................................................................................289
pathways: ...........................................................................................................308
peroxisome: ........................................................................................................332
personalised medicine: .........................................................................................289
pharmacogenomics: .............................................................................................145
phase diagrams: ..................................................................................................211
phenotyping: ................................................................................122, 236, 243, 274, 283
Phosphatises: .......................................................................................................189
phosphorylation: ..................................................................................................325
photoreceptors: ....................................................................................................376
plant models: .................................................................................................133, 263
plant technologies: ...............................................................................................135
plant:..................................................................................................................467
plastid transformation: ..........................................................................................133
pluripotency: .......................................................................................................385
policy recommendations: ......................................................................................263
population genetics: .............................................................................................281
population:..........................................................................................................279
population-based cohorts: .....................................................................................283
positional cloning: ................................................................................................243
postgenomics: .....................................................................................................475
predictive dynamic models: ...................................................................................463
primary cells:.......................................................................................................105
protein complexes: ................................................................................... 172, 192, 208
protein crystallisation: .....................................................................................168, 211
protein degradation: ............................................................................................133
protein deposition: ...............................................................................................187
protein engineering: .............................................................................................137
protein expression: ...............................................................................................208
protein interactions: ..............................................................................................201
protein kinase: .....................................................................................................457
protein ligand interactions: ....................................................................................201
protein network: ...................................................................................................437
protein production: ................................................................................... 135, 178, 184
protein secretion: .................................................................................................480
protein structure: ............................................................................................175, 208
protein-protein interaction:...............................................................................110, 437
KEYWORDS INDEX
protein-protein interactions: ...................................................................................175

proteolytic enzymes: .............................................................................................115
proteome: .....................................................................................................110, 427
proteomics: .............................................88, 99, 113, 117, 133, 325, 332, 336, 470, 473, 477, 480
QTL mapping: .....................................................................................................372

quality assurance: .................................................................................................97
quality control:......................................................................................................97
quantitative biology: .............................................................................................470
quantitative genetics: ............................................................................................103
quantitative traits: .................................................................................................285
rat model: ...........................................................................................................243

rat: .....................................................................................................................249
receptor trafficking: ..............................................................................................348
regenerative medicine: .........................................................................................385
regulation: ..........................................................................................................325
regulatory networks: .......................................................................................409, 447
regulatory RNA: ..................................................................................................399
regulome: ...........................................................................................................392
renal pathogenesis: ..............................................................................................372
reporter cell lines: ................................................................................................257
reprogramming: ...................................................................................................150
research initiatives:...............................................................................................461
research policies: .................................................................... 195, 197, 227, 271, 434, 437
Research Projecttomyces: .......................................................................................93
resources: ...........................................................................................................227
retinal development: .............................................................................................376
retinal dystrophies: ...............................................................................................376
reverse genetics: ..................................................................................................429
riboregulator: ......................................................................................................397
riboswitches: .......................................................................................................411
RNA in situ hybridisation: .....................................................................................220
RNA interference: ................................................................................................414
RNA metabolism: .................................................................................................459
RNA polymerase-II: ..............................................................................................143
RNA silencing:...............................................................................................150, 414
RNA splicing: ......................................................................................................405
RNA structure: .....................................................................................................181
RNA viruses: .................................................................................................181, 184
RNA: ..................................................................................................................181
RNAi: ..................................................................................................... 105, 181, 325
robotics: .......................................................................................................168, 211
Saccharomyces cerevisiae:....................................................................................455
sample collections: ...............................................................................................290
scanning force microscopy: ...................................................................................125
screening: .................................................................................................99, 105, 181
screening-cohorts: ................................................................................................290
screens: ..............................................................................................................257
self-renewal: ........................................................................................................388
KEYWORDS INDEX
sepsis: ................................................................................................................277
shift work models: ................................................................................................420
short interfering RNA: ...........................................................................................414
signal transduction: ............................................................................ 143, 318, 441, 457
signalling network: ...............................................................................................110
signalling pathway: ..............................................................................................437
signalling pathways:.......................................................................................208, 321
signalling: ............................................................................................... 327, 348, 443
simulation: ..........................................................................................................437
single particle: .....................................................................................................172
siRNA: ...........................................................................................................101,105
site-specific, integration: ........................................................................................131
skin: ...................................................................................................................321
small molecules: ...................................................................................................159
snoRNA: .......................................................................................................399, 401
SNP: ..................................................................................................................243
SNP-Chip: ...........................................................................................................290
software evaluation: .............................................................................................443
solute carrier: ......................................................................................................372
somatic cell: ........................................................................................................249
Specific Targeted: .................................................................................................93
spectrum assignment:............................................................................................203
splicing: ..............................................................................................................301
stabilization:........................................................................................................205
stakeholder forum: ...............................................................................................263
standardisation: .............................................................................................117, 168
standards: ...........................................................................................................303
Staphylococcus: .............................................................................................. 93, 470
stem cells: ............................................................................................... 360, 382, 388
Streptomyces: ......................................................................................................480
stress response: ....................................................................................................449
structural biology: ................................................................................................172
structural genomics: ................................. 93, 168, 175, 178, 184, 189, 192,195, 197, 203, 208, 211
structural proteomics: ................................................................................ 195, 197, 213
structure analysis: .................................................................................................399
structure calculation: .............................................................................................203
structure determination: ...................................................................................178, 213
synapse: .......................................................................................................364, 437
synchrotrons: .......................................................................................................168
systematic high-throughput gene expression studies: .................................................265
systemic effects: ...................................................................................................473
systems biology: ......................... 97, 308, 434, 443, 447, 449, 453, 455, 457, 463, 467, 475, 477, 480
tandem repeat: ....................................................................................................279

targeted mutagenesis: ...........................................................................................224
technology development: .......................................................................................97
technology platform:.............................................................................................168
temporal dimension: .............................................................................................485
therapy: ........................................................................................................332, 364
three-dimensional electron microscopy: ...................................................................199
tomography:........................................................................................................122
tools and technologies: .........................................................................................137
Trachomatis: ........................................................................................................290
training: ..............................................................................................................213
transcript: ............................................................................................................301
KEYWORDS INDEX
transcription factors: .............................................................................91, 143, 145, 392

transcription regulation: ..................................................................................143, 157
transcription: .......................................................................................................143
transcriptome analysis: .........................................................................................372
transcriptome atlas: ..............................................................................................220
transcriptome: .................................................................................... 301, 352, 392, 427
transcriptomics: ..............................................................................................470, 480
transformation: ....................................................................................................131
transgenes:..........................................................................................................131
transgenesis: .......................................................................................................385
transgenic animals: ..............................................................................................372
transposable elements:..........................................................................................261
transposon-mediated mutagenesis: .........................................................................261
transposontagged mutants: ....................................................................................261
trisomy:...............................................................................................................352
tumor markers: .....................................................................................................257
twin-arginine translocation: ....................................................................................93
ultra high throughput transfection: ..........................................................................105
vascular biology: .................................................................................................360

vascular disease: ...........................................................................................286, 360
vertebrate models:................................................................................................265
vision: ................................................................................................................376
VNTR:.................................................................................................................279
web services: ......................................................................................................303

web-based virtual microscope: ...............................................................................220
web-linked gene expression database: ...................................................................220
website: ..............................................................................................................213
workshops:..........................................................................................................213
wound healing:....................................................................................................321
Xenopus: .......................................................................................................265, 372

X-ray crystallography: ............................................................................... 168, 178, 192
yeast engineering:................................................................................................340
yeast: ..................................................................................................... 192, 205, 459
zebrafish embryo model: ......................................................................................257

zebrafish: .......................................................................................... 254, 257, 265, 372
European Commission
EUR 23132 — From Fundamental Genomics to Systems Biology: UNDERSTANDING THE BOOK OF LIFE
Luxembourg: Office for Official Publications of the European Communities
2008 —512 pp. — 21.0 x 29.7 cm
ISBN 978-92-79-08004-3
ISSN 1018-5593
DOI 10.2777/49314
Price (excluding VAT) in Luxembourg: EUR 40

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KI-NA-23132-EN-C
EUR 23132
The sequencing of the human genome and many other genomes heralded a new age in human biology, offering
unprecedented opportunities to improve human health and to stimulate industrial and economic activity. The global
understanding of the complete function of approximately 22 000 human genes constitutes a major challenge
for understanding normal and pathological situations. To tackle this challenge, the European Commission made
fundamental genomics research a priority in the Sixth Framework Programme for RTD (FP6) (2002-2006).
The European Commission has allocated approximately `594 million in FP6 to fundamental genomics research
activities with the overall aim of fostering the basic understanding of genomic information by developing the
knowledge base, tools and resources needed to decipher the function of genes and gene products relevant to
human health, and to explore their interactions with each other and with their environment.
impact of all the projects supported during FP6 in the fundamental genomics priority area in the following scientific
sub-areas: the development of tools and technologies for functional genomics; regulation of gene expression;
structural genomics and proteomics; comparative genomics and model organisms; population genetics and
biobanks; bioinformatics; multidisciplinary fundamental genomics research for understanding basic biological
processes in health and disease; and the emerging area of systems biology.
During FP6, the European Commission has supported several systems biology initiatives which paved the way for
further developing the genomics and systems biology programme in the Seventh Framework Programme for RTD
(FP7) (2007-2013). The introduction provides an overview of the FP6 research policies and the steps taken to
strengthen the European Research Area in each of the scientific sub-areas, as well as the FP7 vision in genomics
and systems biology collaborative research.
PROJECT SYNOPSES EUR 23132

FUNDAMENTAL GENOMICS RESEARCH EU-funded collaborative research projects

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PROJECT SYNOPSES EUR 23132

Contact: Christina Kyriakopoulou

From Fundamental Genomics

Synopses of EU collaborative research projects funded in Fundamental

edited by Christina Kyriakopoulou

Directorate-General for Research

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Cataloguing data can be found at the end of this publication.

Luxembourg: Ofﬁce for Ofﬁcial Publications of the European Communities, 2008

© European Communities, 2008

PRINTED ON WHITE CHLORINE-FREE PAPER

Dr Patrik Kolar, Head of Unit (patrik.kolar@ec.europa.eu)

7.1 27 Tools and technologies for functional genomics

From Fundamental Genomics to Systems Biology: Understanding the Book of Life 7

1. Tools and technologies for functional genomics

MolTools 86 Advanced Molecular Tools for Array-Based Analyses of Genomes,

1.2 Tools and technologies for proteomics

INTERACTION PROTEOME 108 Functional Proteomics: Towards deﬁning the

1.3 Tools and technologies for molecular imaging

MOLECULAR IMAGING 120 Integrated Technologies for In vivo Molecular Imaging

1.4 Tools and technologies for gene integration and recombination

GENINTEG 130 Controlled gene integration: a requisite for genome

8 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

TRANS-REG 142 Transcription Complex Dynamics Controlling Speciﬁc

2.2 Epigenetic regulation

THE EPIGENOME 148 Epigenetic plasticity of the genome

3. Structural Genomics and Proteomics

3DGENOME 164 3D Genome Structure and Function

From Fundamental Genomics to Systems Biology: Understanding the Book of Life 9

EURExpress 218 A European Consortium to Generate a Web-Based

STAR 242 A SNP and Haplotype Map for the Rat

ZF-MODELS 252 Zebraﬁsh Models for Human Development and Disease

4.4 Other models

NemaGENETAG 260 Nematode Gene-Tagging Tools and Resources

5.Population Genetics and Biobanks

HUMGERI 270 Human Genomic Research Integration

10 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

BioSapiens 296 A European Network for Integrated Genome Annotation

7.Functional Genomics approaches for Basic biological processes

MAIN 316 Targeting Cell Migration in Chronic Inﬂammation

From Fundamental Genomics to Systems Biology: Understanding the Book of Life 11

NFG 356 Functional Genomics of the Adult and Developing Brain

7.3 Stem cells

FunGenES 380 Functional Genomics in Engineered ES cells

7.4 RNA biology

RIBOREG 396 Novel non-coding RNAs in differentiation and disease

EUCLOCK 418 Entrainment of the Circadian Clock

7.6 Biology of prokaryotes and other organisms

BACELL HEALTH 426 Bacterial stress management relevant to infectious

12 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

EUSYSBIO 434 The Take-off of European Systems Biology

PROJECTS ACRONYM INDEX 488

KEYWORDS INDEX 498

From Fundamental Genomics to Systems Biology: Understanding the Book of Life 13

14 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

From Fundamental Genomics to Systems Biology: Understanding the Book of Life 15

1984-1987 1987-1991 1990-1994 1994-1998 1998-2002 2002-2006 2007-2013

16 From Fundamental Genomics to Systems Biology: Understanding the Book of Life

■ initiatives implemented and funded at European level.

A New European Research Strategy

A joint effort by the EU and MS to address structural deficits in European research

Unfavourable environment for research and innovation

4OTAL