PERSPECTIVE

PUBLISHED: 31 JULY 2017 | VOLUME: 3 | ARTICLE NUMBER: 17109

Demystifying traditional herbal medicine with

modern approaches
Fu-Shuang Li1 and Jing-Ke Weng1,2*
Plants have long been recognized for their therapeutic properties. For centuries, indigenous cultures around the world have
used traditional herbal medicine to treat a myriad of maladies. By contrast, the rise of the modern pharmaceutical industry
in the past century has been based on exploiting individual active compounds with precise modes of action. This surge has
yielded highly effective drugs that are widely used in the clinic, including many plant natural products and analogues derived
from these products, but has fallen short of delivering effective cures for complex human diseases with complicated causes,
such as cancer, diabetes, autoimmune disorders and degenerative diseases. While the plant kingdom continues to serve as an
important source for chemical entities supporting drug discovery, the rich traditions of herbal medicine developed by trial and
error on human subjects over thousands of years contain invaluable biomedical information just waiting to be uncovered using
modern scientific approaches. Here we provide an evolutionary and historical perspective on why plants are of particular sig-
nificance as medicines for humans. We highlight several plant natural products that are either in the clinic or currently under
active research and clinical development, with particular emphasis on their mechanisms of action. Recent efforts in developing
modern multi-herb prescriptions through rigorous molecular-level investigations and standardized clinical trials are also dis-
cussed. Emerging technologies, such as genomics and synthetic biology, are enabling new ways for discovering and utilizing the
medicinal properties of plants. We are entering an exciting era where the ancient wisdom distilled into the worlds traditional
herbal medicines can be reinterpreted and exploited through the lens of modern science.

P
lants first appeared on land around 500millionyearsago, and
subsequently radiated to occupy almost every habitable terrestrial
niche. Although the exact number of land plant species remains a
tantalizing question, nearly 400,000species have been identified and
classified to date1. As sessile organisms, land plants constantly face
a myriad of stresses, ranging from harsh terrestrial environments to
co-evolving bacteria, fungi, and animals that consume plants as food.
To cope with these stresses, plants have greatly expanded their meta-
bolic systems to produce a dazzling array of structurally and function-
ally diverse small molecules, often known as specialized metabolites2.
Through evolutionary trial and error, new chemical traits continue to
emerge throughout land plant evolution, contributing to the diverse
physicochemical properties of extant plants, such as colours, flavours,
flagrances, rigidity, viscosity andtoxicity.
Modern humans arose in Africa approximately 200,000
100,000yearsago, and subsequently migrated out of Africa to other
parts of the world. The palaeolithic diet of early modern humans was
mostly plant based3. Archaeological findings from Neanderthal tombs
in Iraq that date back some 60,000years further hinted at the early use
of medicinal plants by modern humans, including Ephedraaltissima
(high-climbing jointfir) and Centaurea solstitialis (yellow star-this-
tle)4. In traditional medicine practiced around the world, plants are
the primary therapeutic agents used for treating illness. For our ances-
tors, the process of finding edible plants inevitably led to accidental
encounters with plants possessing medicinal properties that helped to
ease disease symptoms. As written languages emerged, such incidents
were recorded and passed through generations. Analogous to the rise
of plant chemodiversity across hundreds of millionyears of Darwinian
evolution, traditional herbal medicine emerged as an inseparable
component of human history through thousands of years of trial and
error on human subjects. Although developed long before modern
science, some of the traditional herbal medicine texts were rigorously
compiled, containing classical prescriptions that have withstood the
test of time. For example, the Egyptian PapyrusEbers, dated back to
1,500 bc, is arguably the earliest systematic medical text recorded
and documents more than 800 plant medicines, along with their
known utility in treating common ailments at that time5. TheDivine
Farmers Materia Medica, the earliest medical text in traditional
Chinese medicine, written around ad 200, describes the medicinal
and toxicological properties of 365entries, most of which are plants.
Medicinal plants illustrated in this book, including Ephedra sinica
(ma huang), Glycyrrhiza uralensis (liquorice), Cinnamomum cassia
(Chinese cinnamon) and Zingiberofficinale (ginger), are still widely
used as fundamental ingredients of Chinese herbal medicine today6.
The Compendium of Materia Medica, authored by LiShizhen in the
sixteenthcentury, is another remarkable example of classical Chinese
herbal medicine text, in which 1,892distinct herbs and 11,096pre-
scriptions for a wide range of illnesses were documented7. Although
modern medicine and pharmaceutics have now largely replaced trad
itional medicine as the mainstream treatment for human disease,
herbalism is still widely practiced around theworld.
The selection of plants as the primary source of medicine by mul-
tiple cultures over the past millennia was no accident. The chemical
space contained within the plant kingdom is astronomical, provid-
ing the probabilistic basis for hitting the right mechanistic targets
underlying various maladies. Moreover, a myriad of plant special-
ized metabolites evolved to mediate interspecies chemical commu-
nications, and therefore were adapted to possess drug-like properties.
When consumed by humans, these compounds are well placed to
interact with human protein targets, or to alter the growth of com-
mensal, pathogenic or parasitic organisms living inside the human
body, which in turn impact human health and diseasestates.

Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA. 2Department of Biology, Massachusetts Institute
1

of Technology, Cambridge, Massachusetts 02139, USA. *e-mail: wengj@wi.mit.edu

NATURE PLANTS 3, 17109 (2017) | DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants 1

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PERSPECTIVE NATURE PLANTS

a b
Morphine Paclitaxel
O

HO
O O OH

O H O NH O

H N O O
H
OH O O
HO OH

O
O

Papaver somniferum Taxus brevifolia

c d
Vincristine Artemisinin

OH
N
H
O
O
H N
HN O
O H H
O
H H
O
O N O O
O O OH
H O O

Catharanthus roseus Artemisia annua

Figure 1 | Four successful cases of single plant natural products that have been isolated from their respective medicinal plant hosts and introduced into
the clinic for treatment of various human diseases. a, Morphine from Papaver somniferum (opium poppy). b, Paclitaxel from Taxus brevifolia (pacific yew).
c, Vincristine from Catharanthus roseus (Madagascar periwinkle). d, Artemisinin from Artemisia annua (sweet wormwood).

The modern pharmaceutical industry emerged in the early nine-
teenth century, and has been partly propelled by research looking
for new therapeutic agents from medicinal plants. Among all Food
and Drug Administration (FDA)-approved new molecular entities
(NMEs) from natural sources, 25% are derived from plant natural
products8. Morphine, a benzylisoquinoline alkaloid painkiller iso-
lated from Papaver somniferum (opium poppy) and approved for
use in 1827, was the first plant-derived NME (Fig.1a)8. Since then,
many drugs have been discovered from plants. For example, the
diterpene alkaloid paclitaxel, which was isolated from Taxusbrevi-
folia (pacific yew) (Fig.1b)9, and the indole alkaloids vinblastine and
vincristine, isolated from Catharanthusroseus (Madagascar periwin-
kle) (Fig. 1c)10, are essential broad-spectrum cancer chemotherapy
drugs used in theclinic.
In many traditional herbal medicine systems, a prescription often
comprises several ingredients mixed in a given ratio in a single for-
mula, wherein each ingredient in isolation sometimes lacks therapeu-
tic activities seen in the holistic formulation, a phenomenon known
as the combinatorial effect11. It is postulated that pharmacological
efficacy may rise from the simultaneous action of multiple chemi-
cals targeting many sites, and/or synergistic action on a single site.
Considering the limited success of single-compound-based modern
pharmaceutics in treating complex diseases, such as cancer, typeII
diabetes, autoimmune disorders and degenerative diseases, elucida-
tion of the mechanistic basis for the combinatorial effect of those well-
established holistic traditional herbal prescriptions will shed light on
complex disease biology and help to devise noveltherapeutics.
Here, we review a number of plant natural products that have
either made it to the clinic for treatment of various human diseases,
or exhibit particularly interesting bioactivities that warrant further
pharmaceutical development. We pay special attention to the molec-
ular basis of the mechanisms of action behind these medicinal plant
natural products. We then provide an update on the current status
of legitimizing holistic traditional herbal medicines through mod-
ern scientific research, as well as FDA-guided clinical trials. Several
emerging methodologies that have enabled new ways of harnessing
the pharmacological properties of medicinal plants are alsodiscussed.
Single plant molecules as magic bullets to treat disease
The nineteenth and twentieth centuries witnessed a significant
advance in the field of phytochemistry12. The routine use of a vari-
ety of chromatographic separation techniques and the development
of multiple spectroscopic methods, such as mass spectrometry and
nuclear magnetic resonance spectroscopy, allowed single plant natu-
ral products to be efficiently isolated from their native hosts, and their
chemical structures to be unequivocally determined. In the search
for new drug entities, tremendous efforts were also spent in bioassay-
guided fractionation of plant extracts and high-throughput activity
screens using plant natural product libraries. This traditional phyto-
chemistry and pharmaceutical chemistry approach has resulted in
the discovery of a variety of therapeutic plant natural products, many
of which are widely used in the clinictoday.
Opium is one of the worlds oldest drugs. Drawings of opium
poppies were found in both ancient Sumerian and Egyptian artifacts.
The opiate-type painkiller morphine was first isolated from opium
poppy by Friedrich Sertrner in the beginning of the nineteenth
century (Fig.1a), and is regarded as the first bioactive natural prod-
uct to be isolated from plants13. Today, morphine and its structural
analogues are among the most commonly prescribed medications
for relieving severe pain. Morphine exerts a range of pharmacologi-
cal actions in humans, which include analgesia, euphoria, nausea,
decreased respiration and cough suppression14. Morphine affects
both presynaptic and the postsynaptic neurons, predominantly by
agonizing the G-protein-coupled -opioid receptors localized on
neuronal cell membranes (Fig. 2a)15. Morphine-induced inhibi-
tion of neurotransmitter release from the presynaptic neurons is

2 NATURE PLANTS 3, 17109 (2017) | DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants

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NATURE PLANTS
thought to be the major mechanism underlying its action in the
nervoussystem16.
Numerous plant natural products have successfully entered the
clinic as cancer chemotherapeutic agents. As mentioned previ-
ously, paclitaxel, a phenolic diterpene alkaloid, was initially isolated
from the tree bark of Taxusbrevifolia (pacific yew) during a screen-
ing programme led by the US National Cancer Institute in the 1960s
(Fig. 1b)9. Paclitaxel blocks the progression of mitosis by targeting
-tubulin (Fig. 2b). Binding of paclitaxel to -tubulin stabilizes the
microtubule polymer and prevents the dynamic microtubule disas-
sembly process required for proper mitotic spindle assembly and
chromosome segregation during cell division17. Currently, paclitaxel
is used to treat ovarian, breast, lung, pancreatic and other types of
cancer, as well as human herpesvirus-8-induced Kaposi sarcoma18.
Similar to paclitaxel, vinca alkaloids vinblastine and vincristine from
Madagascar periwinkle are also cytoskeletal anti-cancer drugs that
target -tubulin (Fig. 1c). However, vinca alkaloids bind to a dif-
ferent site of -tubulin to paclitaxel (Fig. 2c), inhibit microtubule
assembly, and, in turn, cause M-phase-specific cell cycle arrest19.
Homoharringtonine is an anti-tumour alkaloid isolated from the
bark extract of Cephalotaxusharringtonii (Japanese plum yew), and
has been approved by the FDA to treat adult patients with chronic
myeloid leukaemia(CML) who are resistant or intolerant of tyrosine
kinase inhibitors20. Homoharringtonine was identified as a potent
protein translation inhibitor. It binds to the A-site of the eukary-
otic 60S ribosomal subunit, blocking the access of amino acid side
chains of incoming aminoacyl-transfer RNAs21 (aminoacyl-tRNAs)
(Fig.2d). As CML is driven by overproduction of the BcrAbl onco-
genic fusion protein, which has an intrinsically short half-life, protein
translation inhibition by homoharringtonine effectively lowers the
BcrAbl protein level in CML cancer cells, and consequently induces
PERSPECTIVE
apoptosis22. In addition, a recent study shows that homoharringtonine
is also a selective binder of the phosphorylated form of the human
eukaryotic translation initiation factor 4E (p-eIF4E)23. Unlike total
eIF4E (t-eIF4E), which is essential for normal cell survival, p-eIF4E
is specifically required for cell growth of numerous types of cancer23.
Homoharringtonine binds to p-eIF4E through specific interaction
with the phosphorylated Ser209 residue, causing p-eIF4E to oligomer-
ize and become recognized for proteasome-dependent degradation
by a SUMOylation-mediated process23. This new study therefore pro-
vides an alternative mechanism of action underpinning the potent
anti-cancer activity of homoharringtonine. Camptothecin is a quino-
line alkaloid isolated from the bark and stem of Camptothecaacumi-
nata (happy tree) that engages in specific interactions with the typeI
topoisomeraseDNA complex and causes DNA damage by inhibiting
DNA re-ligation (Fig.2e)24. Based on the same principle, two more
soluble camptothecin analogues, topotecan and irinotecan, were
developed and approved by the FDA to treat ovarian, lung, colon and
other cancer types25. Similarly, etoposide and teniposide, semisyn-
thetic analogues derived from the cytotoxic lignan podophyllotoxin
found in the rhizome of Podophyllum peltatum (American mayap-
ple), are potent inhibitors of the typeII topoisomeraseDNA com-
plex26 (Fig.2f). Etoposide and teniposide cause cancer cell apoptosis
by inducing single- and double-stranded DNA breaks during DNA
replication, and are currently used as broad-spectrum cancer chemo-
therapy drugs27.
Besides the aforementioned plant-derived anti-cancer drugs that
have received FDA approval, other plant natural products continue
to emerge as promising lead anti-cancer compounds in biomedical
researchtwo of which are discussed here. Berbamine, a bisbenzyliso-
quinoline alkaloid isolated from Berberisamurensis (Amurbarberry)
used in traditional Chinese medicine for treating inflammation-related

a b c d
Morphine analogue BU72 Homoharringtonine
Vinblastine

Paclitaxel
-Tubulin

-Tubulin

-Opioid receptor 60S ribosomal subunit

e f g h
Topotecan Etoposide

Icarisid II

Huperzine A

Type I topoisomerase Type II topoisomerase Cholinesterase Phosphodiesterase type 5

Figure 2 | Structural basis for the therapeutic effects of several plant natural products in the context of interaction with their primary mammalian protein
targets. a, Opioid painkiller morphine and many of its structural analogues, such as BU72, exert their action by antagonizing the mammalian -opioid receptor
(PDB 5C1M). b,c, Chemotherapy drugs paclitaxel (b, PDB 2HXF) and vinblastine (c, PDB 2Z2B) both inhibit the normal function of microtubules, causing
mitotic arrest by exploiting distinct sites of -tubulin. d, Chemotherapy drug homoharringtonine binds to the A-site of the eukaryotic 60S ribosomal subunit,
therefore preventing the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs (PDB 4U4Q). e,f, Anti-cancer drugs topotecan (e, PDB
1K4T) and etoposide (f, PDB 3QX3) bind to the DNA complex of human type I and type II topoisomerase, respectively, which disrupt DNA re-ligation and cause
single- and double-stranded DNA breaks during DNA replication. g, Huperzine A is a reversible inhibitor of mammalian acetylcholinesterase, a mechanism
thought to help improve cognitive function in Alzheimers patients (PDB 4EY5). h, Similar to several synthetic drugs for treating erectile dysfunction and
pulmonary arterial hypertension, icariin and its related natural products are inhibitors of the mammalian cGMP-specific phosphodiesterase type 5 (PDB 2H44).

NATURE PLANTS 3, 17109 (2017) | DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants 3

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PERSPECTIVE NATURE PLANTS

symptoms for centuries, was reported to demonstrate potent invitro
and invivo anti-cancer activity when used to treat liver cancer, CML,
breast cancer, prostate cancer and melanoma28. Recent studies suggest
that berbamine exerts its anti-cancer activity by selective inhibition of
the andisoforms of human Ca2+/calmodulin-dependent protein Modernizing holistic traditional herbal prescriptions
kinaseII, which are important regulators of carcinogenesis in numer-
ous cancer types28,29. In the case of the second product, several groups
using different screening methods independently identified bouvar-
din, a bicyclic hexapeptide found in Bouvardiaternifolia (firecracker
bush) and Ayurvedic herbal medicine derived form Rubiacordifolia
(Indian madder), both of which belong to the Rubiaceae family, as
an efficacious anti-tumour agent3032. Bouvardin is a unique protein
synthesis inhibitor that blocks translation elongation by hamper-
ing the dissociation of elongation factor 2 from the ribosome31, a
mechanism that differs from that of homoharringtonine21. Both
berbamine and bouvardin are currently under active preclinical and
clinicalinvestigations.
Natural products isolated from medicinal plants have also played
important roles in fighting against human parasites33. This can-
not be better illustrated than by artemisinin, a highly effective anti-
malaria natural product identified by the Chinese phytochemist
Youyou Tu from Artemisia annua (sweet wormwood) during the
1970s (Fig.1d)34. Tus initial motive to examine Artemisia was spurred
by the documented anti-malarial activities of the plant in an ancient
Chinese medical book, Prescriptions for Emergencies, authored by
GeHong (ad 284346). Interestingly, the ancient text also suggests
that fresh Artemisia should be prepared by simply squeezing it in cold
water, which differs from the typical way of preparing Chinese herbal
decoction by boiling the plant product. This notion hinted to Tu to
adopt a low-temperature extraction protocol using ether as a solvent,
which helped to preserve the bioactivity of heat-sensitive artemisinin
during extraction. Tu was awarded the 2015Nobel prize in medicine
for her role in the discovery of artemisinin, which helped to save mil-
lions of livesparticularly in developing countries. Despite the world-
wide use of artemisinin in treating malaria since the 1970s, its action
mechanism in clearing the malaria parasite Plasmodiumfalciparum
was elucidated only recently35. It was shown that the signature endop-
eroxide bridge of artemisinin can be activated by a cleavage reaction
upon reacting with haem iron35. The resultant reactive carbon-centred
radicals can then covalently bind to more than 120protein targets in
P.falciparum, many of which serve essential biological functions in
the parasite35. As haem is highly enriched in the blood-eating para-
sites compared to most human cell types, artemisinin selectively kills
parasites with little side effects in humans. Besides treating malaria,
artemisinin and some of its structural derivatives also exhibit promis-
ing indications in treating other diseases, such as lupus erythemato-
sus36, typeI diabetes37 andcancer38.
Although not as prominent as some of the blockbuster drugs dis-
cussed above, many plant natural products have found diverse thera-
peutic niches, either as FDA-approved drugs or supplements. A few
interesting examples are discussed here. Galantamine, an alkaloid iso-
lated from Galanthuscaucasicus (Caucasian snowdrop), is used to treat
Alzheimers disease and other dementias39. Galantamine is a strong
allosteric potentiating ligand of the human nicotinic acetylcholine
receptors, as well as a weak reversible inhibitor of the human cholinest-
erase39. Galantamine improves brain cognitive function by increasing
acetylcholine release in cholinergic neurons39. HuperzineA, a sesquit-
erpene alkaloid identified from Huperziaserrate (firmoss), is another
reversible inhibitor of the human cholinesterase40 (Fig.2g), and is also
capable of antagonizing the human N-methyl-d-aspartate receptor41.
Although not approved by the FDA, huperzine A is widely used as a
supplement for treating Alzheimers disease and other cognition dis-
orders. Epimedium, also known as horny goat weed, is a Chinese tra-
ditional herbal medicine that has been used for centuries to enhance
sexual function in males. The active principles of Epimedium were
found to be icariin and its related prenylated flavonoid glycosides,
which inhibit the human phosphodiesterase type5 in a similar fash-
ion to several widely prescribed synthetic drugs used to treat erectile
dysfunction, including sildenafil, vardenafil and tadalafil(Fig.2h)42.
As each plant species contains a multitude of metabolites in their
metabolome, consumption of a whole plant as medication is a form
of combinatorial medicine. Moreover, in many traditional herbal
medicine systems, especially those of Asian countries, well-established
prescriptions often contain multiple ingredients mixed in a defined
ratio, suggesting that a synergistic effect from multiple active compo-
nents contained in different plant parts underlies the efficacy of these
treatments. Although the initial development of these holistic tradi-
tional herbal prescriptions predated modern science, the process was
based on thousands of years of phenotype-based and personalized
human clinical trials. Meanwhile, meticulous descriptions of disease
symptoms and systematic medical theories have also been recorded
by generations of herbal doctors, relating therapeutic properties of
diverse medicinal plants to their utility in treating specific symptoms.
Yet most of the foundational concepts in the traditional medical sys-
temsfor example, the concepts of yin versusyang and cold versus
hot in traditional Chinese medicineare disconnected from the
modern descriptions of normal and disease states in the language of
physiology and molecular biology. The lack of modern scientific and
clinical evidence for safety, efficacy and action mechanisms further
prevented those holistic herbal medicine prescriptions from being
accepted beyond their culture of origin. Thus, detailed phytochemical,
pharmacological and clinical studies of traditional holistic herbal pre-
scriptions are of urgent need to establish modern guidelines for drug
administration. Moreover, understanding the molecular basis for the
synergistic effects within these holistic herbal remedies will probably
yield new insights into complex disease mechanisms and new clues for
future pharmaceutical development. Three promising cases of such
investigations are discussed in depthbelow.
Food allergies are abnormal immune responses triggered by anti-
gens present in certain foods, such as peanuts, eggs and shellfish, and
affect millions of people in the United Statesalone43. No standard treat-
ment is currently available to prevent or cure food allergies43. Inspired
by similarities in the symptoms of food allergies and intestinal parasitic
infections that have been treated extensively using traditional Chinese
medicine, Xiu-MinLi and co-workers developed Food Allergy Herbal
Formula2 (FAHF2) (Table 1)44. FAHF-2 is a nine-herb formula
refined from an ancient traditional Chinese medicine prescrip-
tion known as Wu Mei Wan (Mume Fruit Pill), which was origi-
nally documented in Treatise on Cold Pathogenic and Miscellaneous
Diseases by Zhang Zhongjing (ad 150219). Mechanistically, food
allergies and intestinal parasite infection both result in ectopic pro-
duction of the ImmunoglobulinE (IgE) antibody by Bcells, via the
Thelper2(Th2)-cell-mediated pathway43. IgE binds to Fc receptors
on the surface of mast cells and basophils, and induces degranulation
and the release of several chemical mediators (for example, histamine
and cytokines) to the intercellular environment, which causes aller-
gic reactions. In a series of preclinical studies, FAHF-2was found to
effectively reverse anaphylaxis in a mouse model of peanut allergy44.
Levels of the Th2-specific cytokines, interleukin-4 (IL-4), IL-5 and
IL-13, and IgE were significantly reduced upon FAHF-2 treatment,
whereas the level of CD8+ T-cell-related interferon- was enhanced,
contributing to prolonged protection against anaphylaxis post-treat-
ment45. The pharmacological effect of each herbal ingredient was also
tested individually46. Although some show anti-anaphylactic activity,
neither single ingredients nor simpler combinations offer the full effi-
cacy seen in the complete formula, suggesting that synergistic effects
arose from the multiple compounds present in different ingredients46.
While FAHF-2is currently under FDA-guided phaseII clinical trials
in the US, it has already been used in the clinic as a supplement and
has cured many patients who suffer from severe foodallergies47.

4 NATURE PLANTS 3, 17109 (2017) | DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants

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NATURE PLANTS PERSPECTIVE
Table 1 | Ingredients and therapeutic indications of three high-profile multi-ingredient holistic herbal medicines currently under
FDA-guided clinical trials in the United States.
Name Species and plant part used Therapeutic indications
FAHF-2 Sophora flavescens fruit Treatment of food allergy.
Zanthoxylum bungeanum seed Preclinical studies show that FAHF-2 is safe and prevents anaphylaxis in a mouse
Coptis deltoidea root model of peanut allergy.
Phellodendron amurense root FAHF-2 functions to restore the Th1/Th2 cytokine balance in the immune system.
Zingiberis officinalis root
Cinnamomum cassia twig
Panax ginseng root
Angelica sinensis root
Ganoderma lucidum fruiting body
ASHMI Sophora flavescens root Treatment of asthma.
Glycyrrhiza uralensis root Clinical studies show that ASHMI is as effective as the standard corticosteroid
Ganoderma lucidum fruiting body treatment but bears no adverse effects on adrenal function known for the
corticosteroid treatment.
ASHMI inhibits smooth muscle contraction in the lung through the EP2/EP4
prostanoid receptor signalling pathway.
ASHMI functions to restore the Th1/Th2 cytokine balance in the immune system.
PHY906 Scutellaria baicalensis root Reduction of gastrointestinal toxicity caused by chemotherapy in cancer patients.
Paeonia lactiflora root PHY906 promotes intestinal epithelial regeneration by activation of Wnt signalling.
Ziziphus jujuba fruit PHY906 reduces CPT-11-induced intestinal inflammation, but activates autophagy
Glycyrrhiza uralensis root and apoptosis pathways in tumour cells.

Using similar scientific principles, Xiu-Min Li and co-workers
also developed anti-asthma herbal medicine intervention (ASHMI),
which contains extracts from three traditional Chinese herbal medi-
cines, namely Ganoderma lucidum (reishi mushroom), Sophora
flavescens (shrubby sophora) and G.uralensis (Table1)48. Extensive
preclinical studies have shown that ASHMI mitigates bronchocon-
striction in a mouse asthma model by inhibiting smooth muscle con-
traction via prostaglandin E2 activation of EP2/EP4 receptors49 while
restoring Th1/Th2 cytokine balance, which contributes to prolonged
anti-asthma benefit post-treatment50. The superior efficacy of ASHMI
is achieved by the synergistic effect of chemical constituents pre-
sent in all three herbal ingredients acting via multiple pathways5153.
ASHMI is the only anti-asthma herbal remedy currently under
phase II clinical trial in the US48. A positive outcome of this ongo-
ing trial may result in the FDA approval of an alternative anti-asthma
therapy, especially for patients who develop resistance to the standard
corticosteroidtreatment49.
Huang Qin Tang (which translates to Scutellaria Decoction),
another classical herbal prescription from Zhang Zhongjings
Treatise on Cold Pathogenic and Miscellaneous Diseases, is currently
poised for phaseIII clinical trials under the name PHY906 in the US
as an adjuvant of standard chemotherapy in treating various types
of cancer (Table 1)54. PHY906 consists of four herbal ingredients,
Scutellaria baicalensis (Baikal skullcap), Paeonia lactiflora (Chinese
peony), Ziziphusjujuba (jujube) and G.uralensis, and has been used
for nearly 2,000 years in China to treat symptoms related to the
gastrointestinal tract, including diarrhoea, nausea and vomiting55.
Preclinical mouse model studies and phaseIandII clinical trial results
have shown that PHY906 reduces gastrointestinal toxicity caused by
several chemotherapy drugs and further enhances their anti-tumour
activities54,55. Such efficacy apparently results from several mecha-
nisms that act simultaneously. PHY906 promotes intestinal epithelial
regeneration by activation of Wnt signalling, restores the pathological
changes associated with the infiltration of inflammatory neutrophils
and macrophages caused by certain chemotherapy drugs, and acti-
vates autophagy and apoptosis pathways in tumourcells46,47.
Several other multi-ingredient traditional herbal prescriptions
have also entered FDA-guided clinical trials in the US in recent
years, thanks to decades of clinical usage in their countries of origin
as well as standardized formulation according to good manufactur-
ing practice56. Cases currently under phase II and phase III clinical
development include the compound Danshen dripping pill, which
consists of Salviae miltiorrhizae (danshen), Panax pseudo-ginseng
var. notoginseng (sanqi) and borneol, and is used for treating dia-
betic retinopathy57 and angina pectoris58; the coix seed extract-based
Kanglaite Injection, a broad-spectrum intravenous anti-cancer ther-
apy59; and the Fuzheng Huayu tablet, a six-ingredient formula con-
taining S.miltiorrhizae, Ophiocordyceps sinensis (caterpillar fungus),
peach kernel, pine pollen, Gynostemma pentaphyllum (jiaogulan) and
Schisandrae chinensis (five-flavour berry) that is used to treat liver
fibrosis in patients with chronic hepatitisC (ref.60).
Future perspectives
The HungarianAmerican psychiatrist Thomas Szasz once said,
formerly, when religion was strong and science weak, men mistook
magic for medicine; now, when science is strong and religion weak,
men mistake medicine for magic61. We are currently at an early but
exciting phase where modern scientific methods established in the
past 300years are being applied to re-examine the traditional herbal
medicine systems developed and used around the world for thou-
sands of years. This process faces both challenges and opportunities.
Future research should pay special attention to addressing at least
four main bottlenecks that currently limit the field. First, there is great
need for new analytical and computational methodologies to facili-
tate rapid identification of the exact chemical constituents responsible
for defined bioactivities from crude plant extracts. Second, significant
efforts should be dedicated to understanding how single natural prod-
ucts or a combination of natural productsas appearing in multi-
herb prescriptionsinteract with their mammalian protein targets to
achieve therapeutic effects. Third, following identification of bioactive
natural products from their respective native plant hosts, metabolic
engineering strategies should be developed to enable sustainable pro-
duction of these high-value compounds. Fourth, researchers should
strive to identify the minimum set of single plant natural products
that can largely replicate the efficacy of traditionally prepared multi-
ingredient herbalremedies.
Recent developments in the fields of genomics, informatics, analyt-
ical chemistry and synthetic biology have enabled new ways through
which the medicinal properties of plants can be discovered, utilized
and further expanded (Fig.3). For example, bioinformatic algorithms
have been employed to probe the whole-genome gene-expression
profiles of human cell lines treated with a small molecule library. This

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PERSPECTIVE NATURE PLANTS

Plant crude extract Transcriptomics

Fractions Metabolomics
Single compounds Phylogenomics

E1 E2 E3
A B C D

Natural product biosynthesis

Medicinal plants

E1 E2 E3

HO

Metabolic engineering

Bioinformatics

Molecular phenotyping

Herb-inspired new medicine

Figure 3 | A new workflow for exploring and exploiting medicinal properties of plants in the post-omics era. Technological advances in the fields of
systems biology, bioinformatics, plant specialized metabolism and synthetic biology in recent years present tremendous opportunities for developing
herb-inspired new medicine. On the one hand, systems-level gene-expression profiles obtained from mammalian cell lines, animal models and patients
upon plant natural product chemical perturbations will help to connect unknown mechanisms of action to established molecular pathways. On the other,
microbial production and further derivatization of high-value plant natural products through metabolic engineering will yield new chemical diversity to aid
future drug development.

led to the discovery of two plant triterpenoids as leptin sensitizers:
celastrol from the traditional Chinese herbal plant Tripterygiumwil-
fordii (thunder god vine) and withaferinA from the Ayurvedic herbal
plant Withania somnifera (ashwagandha), with strong anti-diabetic
and anti-obesity properties, respectively62,63. In the field of analytic
chemistry, the crystalline sponge method recently developed by the
Makoto Fujita lab presents a transformative technology that allows
the absolute chemical structures of natural products to be resolved at
microgram to nanogram quantities64, greatly reducing the amount of
starting plant material needed for compound isolation. Moreover, the
increasing capability to genetically engineer metabolic pathways in
microorganisms and crop plants by means of synthetic biology is cre-
ating new routes for harnessing plant chemistry without the danger of
over-exploiting vulnerable natural resources65. Combinatory biosyn-
thesis using natural and evolved catalysts isolated from different plant
hosts will further generate new diversity of natural-like unnatural
products that contain further expanded pharmacologicalproperties65.
Target-based pharmaceutical development is facing tremendous
difficulties in delivering effective cures for several major complex
diseases that afflict the human race. The overall cost and failure rate
of new drug development continues to rise sharply66. One of the root
causes for such a dilemma lies in the tremendous complexity of many
human diseases. Multiple pathogenic pathways at different tissue and
organ levels intertwine to arrive at particular disease states that cannot
be rectified by manipulating a single target. The impasse can also be
partly attributed to the limited chemical space contained in the cur-
rent chemical libraries used for pharmaceutical development, most
of which are generated through high-throughput organic synthesis.
Interrogation of how traditional herbal medicines antagonize com-
plex diseases at the molecular level and exploration of new ways to
efficiently harness plant chemodiversity for medicinal uses therefore
offer an attractive gateway into a new era of systems-level and person-
alized medicine with tremendous potential to advance humanhealth.
Received 11 January 2017; accepted 8 June 2017;
published 31 July 2017
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Additional information
Reprints and permissions information is available at www.nature.com/reprints.
Correspondence should be addressed to J.-K.W.
How to cite this article: Li, F.-S. & Weng, J.-K. Demystifying traditional herbal medicine
with modern approaches. Nat. Plants 3, 17109(2017).
Publishers note: Springer Nature remains neutral with regard to jurisdictional claims in
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Competing interests
The authors declare no competing financial interests.

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