Professional Documents
Culture Documents
Biological Computers
INTRODUCTION
Biological computers have emerged as an interdisciplinary field that draws together molecular biology, chemistry, computer science and mathematics. The highly predictable hybridization chemistry of DNA, the ability to completely control the length and content of oligonucleotides, and the wealth of enzymes available for modification of the DNA, make the use of nucleic acids an attractive candidate for all of these nanoscale applications A DNA computer has been used for the first time to find the only correct answer from over a million possible solutions to a computational problem. Leonard Adleman of the University of Southern California in the US and colleagues used different strands of DNA to represent the 20 variables in their problem, which could be the most complex task ever solved without a conventional computer. The researchers believe that the complexity of the structure of biological molecules could allow DNA computers to outperform their electronic counterparts in future. Scientists have previously used DNA computers to crack computational problems with up to nine variables, which involves selecting the correct answer from 512 possible solutions. But now Adlemans team has shown that a similar technique can solve a problem with 20 variables, which has 220 - or 1 048 576 possible solutions. Adleman and colleagues chose an exponential time problem, in which each extra variable doubles the amount of computation needed. This is known as an NP-complete problem, and is notoriously difficult to solve for a large number of variables. Other NP-complete problems include the travelling salesman problem in which a salesman has to find the shortest route between a number of cities and the calculation of interactions between many atoms or molecules.
1
Seminar Report04
Biological Computers
Adleman and co-workers expressed their problem as a string of 24 clauses, each of which specified a certain combination of true and false for three of the 20 variables. The team then assigned two short strands of specially encoded DNA to all 20 variables, representing true and false for each one. In the experiment, each of the 24 clauses is represented by a gel-filled glass cell. The strands of DNA corresponding to the variables and their true or false state in each clause were then placed in the cells. Each of the possible 1,048,576 solutions were then represented by much longer strands of specially encoded DNA, which Adlemans team added to the first cell. If a long strand had a subsequence that complemented all three short strands, it bound to them. But otherwise it passed through the cell. To move on to the second clause of the formula, a fresh set of long strands was sent into the second cell, which trapped any long strand with a subsequence complementary to all three of its short strands. This process was repeated until a complete set of long strands had been added to all 24 cells, corresponding to the 24 clauses. The long strands captured in the cells were collected at the end of the experiment, and these represented the solution to the problem.
Seminar Report04
Biological Computers
DOCTOR IN A CELL
In previous biological computers produced input, output and software are all composed of DNA, the material of genes, while DNA-manipulating enzymes are used as hardware. The newest versions input apparatus is designed to assess concentrations of specific RNA molecules, which may be overproduced or under produced, depending on the type of cancer. Using pre-programmed medical knowledge, the computer then makes its diagnosis based on the detected RNA levels. In response to a cancer diagnosis, the output unit of the computer can initiate the controlled release of a single-stranded DNA molecule that is known to interfere with the cancer cells activities, causing it to self-destruct. In one series of test-tube experiments, the team programmed the computer to identify RNA molecules that indicate the presence of prostate cancer and, following a correct diagnosis, to release the short DNA strands designed to kill cancer cells. Similarly, they were able to identify, in the test tube, the signs of one form of lung cancer. One day in the future, they hope to create a doctor in a cell, which will be able to operate inside a living body, spot disease and apply the necessary treatment before external symptoms even appear. The neuron is a functional unit of the body's nervous system that transmits electro-chemical impulses through the system. These electrochemical impulses are the way information is exchanged in our bodies. Think of the neurons as phone or network lines that make up the Internet and the electrochemical impulses as e-mail, and you get idea. Just as e-mail is used to send messages between people, electrochemical impulses are used to send message between different body parts
Seminar Report04
Biological Computers
Computers use 1 or 0 and DNA uses 1 ,2 ,3 and four. Or in the geneticists jargon A C T G. We are built of proteins , each protein is assembled from twenty different building blocks called amino acids. The order in which these amino acids are assembled is obtained from the sequence contained in DNA. I am told this leads to 64 different combinations. DNA computers take advantage of DNA's physical properties to store information and perform calculations. In a traditional computer, data are represented by and stored as strings of zeros and ones. With a DNA computer, a sequence of its four basic nucleotides adenine, cytosine, guanine, and thymine is used to represent and store data on a strand of DNA. Calculations in a traditional computer are performed by moving data into a processing unit where binary operations are performed. Essentially, the operations turn miniaturized circuits off or on corresponding to the zeros and ones that represent the string of data. In contrast, a DNA computer uses the recombinative properties of DNA to perform operations.
Seminar Report04
Biological Computers
disease in cells. They could even be used in late-stage cancer, to detect and prevent secondary growths That is the dream. However, the biology in the latest experiments was hugely simplified: the little machine identified cancer molecules in a sterile saline solution in a laboratory under ideal conditions. To actually track down and disable cancer cells in a human body, it would have to survive the hurly-burly of proteins, lipids, polysaccharides and nucleic acids, any of which could block or disable it. "There could be many reactions with many other molecules that may be detrimental to either the computer or the cell in which it operates,'' said Prof Shapiro.
Seminar Report04
Biological Computers
This computer is able to run approximately one billion operations per second with 99.8% accuracy. Astonishingly, one billion of these biological computers could fit inside a drop of water!
Seminar Report04
Biological Computers
The Leechulator
A group of scientists from Emory University and Georgia Tech made a calculator (called the "leech-ulator") with neurons taken from leeches. In normal silicon computers, connections are made between the computer's chips only when the programmer directs the connections to occur. However, in a biological
7
Seminar Report04
Biological Computers
computer the neurons are able to connect on their own and are often said to be "thinking" by making connections with their neighbors, possibly increasing computational power. Since the processing power of the silicon chip is close to being maximized, the next generation of computer technology may rely on the use of biological computing. A billion operations per second is impressive indeed, but when the prospect of massive neural connectivity is considered, the speed is almost unfathomable. The device the team has built can "think for itself" because the leech neurons are able to form their own connections from one to another. Normal silicon computers only make the connections they are told to by the programmer. This flexibility means the biological computer works out it own way of solving the problem. "With the neurons, we only have to direct them towards the answer and they get it themselves," This approach to computing is particularly suited to pattern recognition tasks like reading handwriting, which would take enormous amounts of power to do well on a conventional computer. The neurons are harnessed in a Petri dish by inserting micro-electrodes into them. Each neuron has its own electrical activity and responds in its own way to an electrical stimulus. These features can be used to make each neuron represent a number. Calculations are then performed by linking up the individual neurons. Leech neurons are used because they have been extensively studied and are well understood. Though much simpler, the neuron computer works in a similar way to the human brain. Professor Ditto says a robot brain is his long-term aim, noting that conventional supercomputers are far too big for a robot to carry around
Seminar Report04
Biological Computers
Each neuron's electrical activity corresponds to a number The "leech-ulator" demonstrates that the ability of neurons to make local connections might be an advantage on which artificial intelligence could capitalize. Living computer: interconnected leech neurons can add up
Seminar Report04
Biological Computers
10
Seminar Report04
Biological Computers
DNA COMPUTING
Hamilton path problem
In the DNA computing approach to this problem, each city was represented by a unique strand of DNA that stretched 20 nucleotides long. Each possible route between any two cities was represented by another 20-nucleotide-long strand. This strand connecting cities was also related to the nucleotide sequence of each city connected by that route. For example, the route between City 1 and City 2 consisted of two sets of 10 nucleotides; the first 10 nucleotides on the strand's route complemented the last 10 nucleotides of City 1, while the second 10 nucleotides on the strand's route complemented the first 10 nucleotides of City 2. In this way, if strands for cities 1 and 2 came in proximity to the route 1-to2 strand, the three strands would bind. To solve the traveling salesman problem, strands representing all seven cities and strands representing all possible routes between any two cities were placed in a test tube. The end result was a series of longer, recombined strands. The correct answer was contained in a strand that started with City 1, ended with City 7, contained the strands of all seven cities, and had no one city represented more than one time in this longer strand. When the experiment was first done in 1994, the complexity of finding the strand with the correct answer was considered a downside to DNA computing. DNA works in nature is a form of Turing Machine and such a machine can be used to solve computational problems. He therefore devised a way of applying DNA manipulation techniques to the "Hamilton Path Problem" - for several cities, some of which are connected by non-stop flights, does a path exist to travel from A to B which passes through every other city once and only once? When the number of cities gets to around one hundred it could take
11
Seminar Report04
Biological Computers
hundreds of years of conventional computer time to solve the problem, even with the most advanced parallel processing available. Adleman developed a method of manipulating DNA which, in effect, conducts trillions of computations in parallel. Essentially he coded each city and each possible flight as a sequence of 4 components. For example he coded one city as GCAG and another as TCGG.
The incredible thing is that once the DNA sequences had been created he simply "just added water" to initiate the "computation": The DNA strands then began their highly efficient process of creating new sequences based on the input sequences. If an "answer" to the problem for a given set of inputs existed then it should amongst these trillions of sequences. The next (difficult) step was to isolate the
12
Seminar Report04
Biological Computers
"answer" sequences. To do this Adleman used a range of DNA tools. For example, one technique can test for the correct start and end sequences, indicating that the strand has a solution for the start and end cities. Another step involved selecting only those strands which have the correct length, based on the total number of cities in the problem (remembering that each city is visited once). Finally another technique was used to determine if the sequence for each city was included in the strand. If any strands were left after these processes then: a solution to the problem existed, and the answer(s) would be in the sequence(s) on the remaining strands.
His attempt at solving a seven-city, 14 flight map took seven days of lab work. This particular problem can be manually solved in a few minutes but the key point about Adleman's work is that it will work on a much larger scale, when manual or conventional computing techniques become overwhelmed. "The DNA computer provides enormous parallelism... in one fiftieth of a teaspoon of solution approximately 10 to the power 14 DNA 'flight numbers' were simultaneously concatenated in about one second".
This approach to computing is particularly suited to pattern recognition tasks like reading handwriting, which would take enormous amounts of power to do well on a conventional computer.
Working principle
'The living cell contains incredible molecular machines that manipulate information-encoding molecules such as DNA and RNA in ways that are fundamentally very similar to computation,' says Prof. Shapiro of the Institute's Computer Science and Applied Mathematics Department and the Biological Chemistry Department. 'Since we don't know how to effectively modify these machines or create new ones just yet, the trick is to find naturally existing machines that, when combined, can be steered to actually compute.'
13
Seminar Report04
Biological Computers
Turing machine
A finite automaton that detects whether a list of 0's and 1's has an even number of 1's. Benenson came up with a solution using DNA molecules and two naturally occurring DNA-manipulating enzymes: Fok-I and Ligase. Operating much like a biological editing kit, Fok-I functions as a chemical scissors, cleaving DNA in a specific pattern, whereas the Ligase enzyme seals DNA molecules together. As the lab work progressed, Shapiro and his team realized that the automaton they built could be programmed to perform different tasks by selecting different subsets of the molecules realizing the eight possible rules of operation controlling the performance of a two-state, two-symbol finite automaton. The software molecules, together with two 'output display' molecules used to visualize the final result of the computation, can be used to create a total of 765 software programs. Several of these programs were tested in the lab, including the 'even 1's checker' and the '0's before 1's' test mentioned above, as well as programs that check whether a list of 0's and 1's has at least (or at most) one 0, and whether it both starts with a 0 and ends with a 1. The nanocomputer created by Shapiro's team uses the four DNA bases known as A, G, C and T, to encode the input data as well as the program rules underlying the computer 'software.' Both input and software molecules are designed to have one DNA strand longer than the other, resulting in a single-strand overhang called a 'sticky end.' Two molecules with complementary sticky ends can temporarily stick to each other (a process known as hybridization), allowing DNA Ligase to permanently seal them into one molecule. The sticky end of the input molecule encodes the current symbol and the current state of the computation, whereas the sticky end of each 'software' molecule is designed to detect a particular state-symbol combination. A two-state, two-symbol automaton has four such combinations. For each combination the nanocomputer has two possible next
14
Seminar Report04
Biological Computers
moves, to remain in the same state or to change to the other state, allowing eight software molecules to cover all possibilities. So how does such a computer work? Let's say the computer wants to know whether the number of times a "B" DNA type appears in a DNA section is odd or even. The DNA section - the "input" - is inserted into a chemical solution along with enzymes to be used as the computer's "hardware". Other DNA sections are added, which act as "software". A software section sticks to the input with the help of an enzyme. If the tip of the input is "B", the input will be labeled as having an odd number of "B" sequences. Another enzyme then cuts the section and reveals the next sequence. Each time "B" appears, the label on the input changes from "even" to "odd" and back again. Once the computer has dissected the entire input, it can determine whether the sequence appeared an even or odd number of times according to the last label - the "output". The computer can also do other calculations, such as checking whether the "B" sequence appears at least once, or at most once, by inserting different types of software DNAs.
Output Display
In each processing step the input molecule hybridizes with a software molecule that has a complementary sticky end, allowing Ligase to seal them together using two ATP molecules as energy. Then comes Fok-I, detecting a special site in the software molecule known as the recognition site. It cleaves the input molecule in a location determined by the software molecule, thus exposing a sticky end that encodes the next input symbol and the next state of the computation. Once the last input symbol is processed, a sticky end encoding the final state of the computation is exposed and detected, again by hybridization and
15
Seminar Report04
Biological Computers
ligation, by one of two 'output display' molecules. The resulting molecule, which reports the output of the computation, is made visible to the human eye in a process known as gel electrophoresis.
Molecular-Level Treatment
The bio-computer uses two naturally occurring enzymes that can manipulate DNA as its "hardware." The "software" and "hardware" molecules, when mixed in a solution, operate in harmony on what is known as the "input" molecule. What results is a simple mathematical computing machine known as a "finite automaton." It then can be programmed to perform simple tasks by choosing different "software" molecules to be mixed in solution. "Such machines might analyze natural DNA, human or otherwise, in the lab within a few years," Shapiro said. "The time when such machines can actually operate within the
16
Seminar Report04
Biological Computers
human body, programmed with medical knowledge so that they can effect some medical treatment at the molecular level, is at least a few decades away
ADVANTAGES
17
Seminar Report04
Biological Computers
As long as there are cellular organisms, there will always be a supply of DNA. The large supply of DNA makes it a cheap resource. Unlike the toxic materials used to make traditional microprocessors, DNA biochips can be made cleanly. DNA computers are many times smaller than today's computers. DNA will make computers smaller than any computer that has come before them, while at the same time holding more data Unlike conventional computers, DNA computers perform calculations parallel to other calculations. Conventional computers operate linearly, taking on tasks one at a time. It is parallel computing that allows DNA to solve complex mathematical problems in hours, whereas it might take electrical computers hundreds of
Diagnosis of cancer Application in biological & pharmaceutical applns Recoverability There are a lot of things that are always going to happen,accidents, different
conditions, something that's going to fool your computer program, but a biological computer can actually heal itself, adapt and get better at what it does
18
Seminar Report04
Biological Computers
DISADVANTAGES
Biological computers (literally) have a few bugs that need to be worked out before they start appearing regularly in mail order catalogues. For one thing, while they can do rudimentary sort of calculation, input/output is exceedingly slow. That slimy blob would take a long time to do something as simple as balance your checkbook, and it would need regular feedings as well. Silicon computers can switch between calculations. But you would have to construct a biological computer anew for each problem. The electronics behind your computer chips run at almost the speed of light. Transistors are limited by "gating time," which is how long it takes the gate to open and close when you apply voltage. The gates of transistors composing chips now on the market are 130 nanometers (really small), which make them fast and power efficient. But a biological computer is limited by diffusion, a relatively slow process. Plus, cells need a medium in which to grow. That biological computer could be a gooey mess.
19
Seminar Report04
Biological Computers
APPLICATIONS
There are currently several research disciplines driving towards the creation and use of DNA nanostructures for both biological and non-biological applications. These converging areas are:
The miniaturization of biosensors and biochips into the nanometer scale regime, The fabrication of nanoscale objects that can be placed in intracellular locations for monitoring and modifying cell function, The replacement of silicon devices with nanoscale molecular-based computational systems, and The application of biopolymers in the formation of novel nanostructured materials with unique optical and selective transport properties.
20
Seminar Report04
Biological Computers
CONCLUSION
Biological software for computers of the future
Researchers from the Weizmann Institute in Rehovot and the Technion in Haifa have developed a computer so tiny that a trillion of them could fit into a laboratory test tube. The "computers" are biological molecules, using DNA for software and enzymes for hardware, and can solve a billion mathematical problems a second. Such tiny devices could one day fit into cells and supervise biological processes, or even synthesize drugs. DNA strands exist in almost every body cell - they are biological software that tell each cell and molecule what to do. "If you look at the mechanism of a cell, a lot of what goes on inside is computation. We don't need to teach the cell new tricks, we just need to put the existing tricks in the right order," says Prof. Ehud Shapiro of the Weizmann Institute, who headed the research.
21
Seminar Report04
Biological Computers
REFERENCES
www.news.bbc.co.uk/hi/english/ sci/tech/newsid_358000/358822.stm www.ece.uiuc.edu/pubs/centhist/six/bcl.htm www.sciencedaily.com/releases/1999/07/990702080524.htm www.sciencedaily.com/releases/2004/04/040430052921.htm www.cbhd.org/resources/biotech/tongen_2003-11-07.htm www.hindu.com/seta/2004/ 05/20/stories/2004052000611600.htm www.eurekalert.org/pub_releases/ 2004-04/wi-bcd042604.php www.findarticles.com/cf_dls/ m0COW/1999_June_10/55056092/p1/article.jhtml www.expeditionzone.com/story_detail.cfm
22
Seminar Report04
Biological Computers
ACKNOWLEDGEMENT
23
Seminar Report04
Biological Computers
ABSTRACT
New generation of fast and flexible computers that can work out for themselves how to solve a problem, rather than having to be told exactly what to do. Ordinary computers need absolutely correct information every time to come to the right answer A biological computer will come to the correct answer based on partial information, by filling in the gaps itself. The device the team has built can "think for itself" because the leech neurons are able to form their own connections from one to another. Normal silicon computers only make the connections they are told to by the programmer. This flexibility means the biological computer works out it own way of solving the problem. "With the neurons, we only have to direct them towards the answer and they get it themselves,"This approach to computing is particularly suited to pattern recognition tasks like reading handwriting, which would take enormous amounts of power to do well on a conventional computer. The method by which DNA works in nature is a form of Turing Machine and such a machine can be used to solve computational problems. A way of applying DNA manipulation techniques to the "Hamilton Path Problem" - for several cities, some of which are connected by non-stop flights, does a path exist to travel from A to B which passes through every other city once and only once? When the number of cities gets to around one hundred it could take hundreds of years of conventional computer time to solve the problem, even with the most advanced parallel processing available.
24
Seminar Report04
Biological Computers
TABLE OF CONTENTS
INTRODUCTION THE WORLDS SMALLEST COMPUTER DOCTOR IN A CELL THE BIOLOGICAL BITS AND BYTES OF DNA COMPUTING o Guinness Book of World Records COMPUTERS & BIOLOGICAL COMPLEXITY
o Computing Comes to Life o Biological 'computer' fits inside a drop of water ADVANTAGES DISADVANTAGES APPLICATIONS CONCLUSION o Biological software for computers of the future REFERENCES
25