New Technologies Could Turn Ancient Herbal Remedies Into Effective Drugs

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NATURE PLANTS 3, 17109 (2017)

DOI: 10.1038/nplants.2017.109

www.nature.com/natureplants 1

PERSPECTIVE

PUBLISHED: 31 JULY 2017

VOLUME: 3

ARTICLE NUMBER: 17109

lants first appeared on land around 500millionyearsago, and

subsequently radiated to occupy almost every habitable terrestrial

niche. Although the exact number of land plant species remains a

tantalizing question, nearly 400,000species have been identified and

classified to date

. 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 metabolites

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 andtoxicity.

Modern humans arose in Africa approximately 200,000–

100,000yearsago, and subsequently migrated out of Africa to other

parts of the world. The palaeolithic diet of early modern humans was

mostly plant based

. Archaeological findings from Neanderthal tombs

in Iraq that date back some 60,000years further hinted at the early use

of medicinal plants by modern humans, including Ephedraaltissima

(high-climbing jointfir) and Centaurea solstitialis (yellow star-this–

tle)

. 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 gen erations. Analogous to the rise

of plant chemodiversity across hundreds of millionyears 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

Demystifying traditional herbal medicine with

modern approaches

Fu-Shuang Li

and Jing-Ke Weng

1,2

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 cent ury 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 world’s traditional

herbal medicines can be reinterpreted and exploited through the lens of modern science.

science, some of the trad itional herbal medicine texts were rigorously

compiled, containing classical prescriptions that have withstood the

test of time. For example, the Egyptian PapyrusEbers, dated back to

1,500 , 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 time

. TheDivine

Farmer’s Materia Medica, the earliest medical text in traditional

Chinese medicine, written around  200, describes the medicinal

and toxicological properties of 365entries, most of which are plants.

Medicinal plants illustrated in this book, including Ephedra sinica

(mahuang), Glycyrrhizauralensis (liquorice), Cinnamomumcassia

(Chinese cinnamon) and Zingiberofficinale (ginger), are still widely

used as fundamental ingredients of Chinese herbal medicine today

The Compendium of Materia Medica, authored by LiShizhen in the

sixteenthcentury, is another remarkable example of classical Chinese

herbal medicine text, in which 1,892distinct herbs and 11,096pre–

scriptions for a wide range of illnesses were documented

. 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 theworld.

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 metab olites 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 diseasestates.

Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.

Department of Biology, Massachusetts Institute

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

2 NATURE PLANTS 3, 17109 (2017)

DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants

PERSPECTIVE

NATURE PLANTS

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

products

. 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)

. Since then,

many drugs have been discovered from plants. For example, the

diterpene alkaloid paclitaxel, which was isolated from Taxusbrevi–

folia (pacific yew) (Fig.1b)

, and the indole alkaloids vinblastine and

vincristine, isolated from Catharanthusroseus (Madagascar periwin–

kle) (Fig. 1c)

, are essential broad-spectrum cancer chemotherapy

drugs used in theclinic.

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 effect

. 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, typeII

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 noveltherapeutics.

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 alsodiscussed.

Single plant molecules as magic bullets to treat disease

The nineteenth and twentieth centuries witnessed a significant

advance in the field of phytochemistry

. 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 clinictoday.

Opium is one of the world’s 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 Sertürner in the beginning of the nineteenth

century (Fig.1a), and is regarded as the first bioactive natural prod–

uct to be isolated from plants

. 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 suppression

. Morphine affects

both presynaptic and the postsynaptic neurons, predominantly by

agonizing the G-protein-coupled -opioid receptors localized on

neuronal cell membranes (Fig. 2a)

. Morphine-induced inhibi–

tion of neurotransmitter release from the presynaptic neurons is

Morphine

Artemisinin

Taxus brevifolia

Catharanthus roseus

Papaver somniferum

Artemisia annua

Vincristine

NHO

Paclitaxel

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).

NATURE PLANTS 3, 17109 (2017)

DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants 3

PERSPECTIVE

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thought to be the major mechanism underlying its action in the

nervoussystem

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 Taxusbrevifolia (pacific yew) during a screen–

ing programme led by the US National Cancer Institute in the 1960s

(Fig. 1b)

. Paclitaxel blocks the progression of mitosis by targeting

β-tubulin (Fig. 2b). Binding of paclitaxel to β-tubulin stabilizes the

microtubule polymer and prevents the dynamic microtubule disas–

sembly process required for proper mitotic spindle assembly and

chromosome segregation during cell division

. Currently, paclitaxel

is used to treat ovarian, breast, lung, pancreatic and other types of

cancer, as well as human herpesvirus-8-induced Kaposi sarcoma

Similar to paclitaxel, vinca alkaloids vinblastine and vincristine from

Madagascar periwinkle are also cytoskeletal anti-cancer drugs that

target β-tubulin (Fig. 1c). However, vinca alkaloids bind to a dif–

ferent site of β-tubulin to paclitaxel (Fig. 2c), inhibit microtubule

assembly, and, in turn, cause M-phase-specific cell cycle arrest

Homoharringtonine is an anti-tumour alkaloid isolated from the

bark extract of Cephalotaxusharringtonii (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 inhibitors

. 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 RNAs

(aminoacyl-tRNAs)

(Fig.2d). As CML is driven by overproduction of the Bcr–Abl onco–

genic fusion protein, which has an intrinsically short half-life, protein

translation inhibition by homoharringtonine effectively lowers the

Bcr–Abl protein level in CML cancer cells, and consequently induces

apoptosis

. 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)

. Unlike total

eIF4E (t-eIF4E), which is essential for normal cell survival, p-eIF4E

is specifically required for cell growth of numerous types of cancer

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 process

. 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 Camptothecaacumi–

nata (happy tree) that engages in specific interactions with the typeI

topoisomerase–DNA complex and causes DNA damage by inhibiting

DNA re-ligation (Fig.2e)

. 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 types

. 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 typeII topoisomerase–DNA com–

plex

(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 drugs

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

research—two of which are discussed here. Berbamine, a bisbenzyliso–

quinoline alkaloid isolated from Berberisamurensis (Amurbarberry)

used in traditional Chinese medicine for treating inflammation-related

a b c d

g h

β-Tubulin

α-Tubulin

Vinblastine

Paclitaxel

Cholinesterase

Huperzine A

Phosphodiesterase type 5

Icarisid II

µ-Opioid receptor

Morphine analogue BU72 Homoharringtonine

60S ribosomal subunit

Type II topoisomeraseType I topoisomerase

e f

Topotecan Etoposide

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 β-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 Alzheimer’s 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).

4 NATURE PLANTS 3, 17109 (2017)

DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants

PERSPECTIVE

NATURE PLANTS

symptoms for centuries, was reported to demonstrate potent invitro

and invivo anti-cancer activity when used to treat liver cancer, CML,

breast cancer, prostate cancer and melanoma

. Recent studies suggest

that berbamine exerts its anti-cancer activity by selective inhibition of

the γandδisoforms of human Ca

/calmodulin-dependent protein

kinaseII, which are important regulators of carcinogenesis in numer–

ous cancer types

28,29

. In the case of the second product, several groups

using different screening methods independently identified bouvar–

din, a bicyclic hexapeptide found in Bouvardiaternifolia (firecracker

bush) and Ayurvedic herbal medicine derived form Rubiacordifolia

(Indian madder), both of which belong to the Rubiaceae family, as

an efficacious anti-tumour agent

30–32

. Bouvardin is a unique protein

synthesis inhibitor that blocks translation elongation by hamper–

ing the dissociation of elongation factor 2 from the ribosome

, a

mechanism that differs from that of homoharringtonine

. Both

berbamine and bouvardin are currently under active preclinical and

clinicalinvestigations.

Natural products isolated from medicinal plants have also played

important roles in fighting against human parasites

. 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)

. Tu’s 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

GeHong ( 284–346). 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 2015Nobel prize in medicine

for her role in the discovery of artemisinin, which helped to save mil–

lions of lives—particularly in developing countries. Despite the world–

wide use of artemisinin in treating malaria since the 1970s, its action

mechanism in clearing the malaria parasite Plasmodiumfalciparum

was elucidated only recently

. It was shown that the signature endop–

eroxide bridge of artemisinin can be activated by a cleavage reaction

upon reacting with haem iron

. The resultant reactive carbon-centred

radicals can then covalently bind to more than 120protein targets in

P.falciparum, many of which serve essential biological functions in

the parasite

. 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–

sus

, typeI diabetes

andcancer

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 Galanthuscaucasicus (Caucasian snowdrop), is used to treat

Alzheimer’s disease and other dementias

. Galantamine is a strong

allosteric potentiating ligand of the human nicotinic acetylcholine

receptors, as well as a weak reversible inhibitor of the human cholinest–

erase

. Galantamine improves brain cognitive function by increasing

acetylcholine release in cholinergic neurons

. HuperzineA, a sesquit–

erpene alkaloid identified from Huperziaserrate (firmoss), is another

reversible inhibitor of the human cholinesterase

(Fig.2g), and is also

capable of antagonizing the human N-methyl--aspartate receptor

Although not approved by the FDA, huperzine A is widely used as a

supplement for treating Alzheimer’s 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 type5 in a similar fash–

ion to several widely prescribed synthetic drugs used to treat erectile

dysfunction, including sildenafil, vardenafil and tadalafil(Fig.2h)

Modernizing holistic traditional herbal prescriptions

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–

tems—for example, the concepts of yin versusyang and cold versus

hot in traditional Chinese medicine—are 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 depthbelow.

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 Statesalone

. No standard treat–

ment is currently available to prevent or cure food allergies

. Inspired

by similarities in the symptoms of food allergies and intestinal parasitic

infections that have been treated extensively using traditional Chinese

medicine, Xiu-MinLi and co-workers developed Food Allergy Herbal

Formula-2 (FAHF-2) (Table 1)

. 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 ( 150–219). Mechanistically, food

allergies and intestinal parasite infection both result in ectopic pro–

duction of the ImmunoglobulinE (IgE) antibody by Bcells, via the

Thelper2(Th2)-cell-mediated pathway

. 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-2was found to

effectively reverse anaphylaxis in a mouse model of peanut allergy

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-γ was enhanced,

contributing to prolonged protection against anaphylaxis post-treat–

ment

. The pharmacological effect of each herbal ingredient was also

tested individually

. 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 ingredients

While FAHF-2is currently under FDA-guided phaseII 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 foodallergies

NATURE PLANTS 3, 17109 (2017)

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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 (Table1)

. Extensive

preclinical studies have shown that ASHMI mitigates bronchocon–

striction in a mouse asthma model by inhibiting smooth muscle con–

traction via prostaglandin E

activation of EP2/EP4 receptors

while

restoring Th1/Th2 cytokine balance, which contributes to prolonged

anti-asthma benefit post-treatment

. The superior efficacy of ASHMI

is achieved by the synergistic effect of chemical constituents pre–

sent in all three herbal ingredients acting via multiple pathways

51–53

ASHMI is the only anti-asthma herbal remedy currently under

phase II clinical trial in the US

. 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

corticosteroidtreatment

Huang Qin Tang (which translates to Scutellaria Decoction),

another classical herbal prescription from ZhangZhongjing’s

Treatise on Cold Pathogenic and Miscellaneous Diseases, is currently

poised for phaseIII clinical trials under the name PHY906 in the US

as an adjuvant of standard chemotherapy in treating various types

of cancer (Table 1)

. PHY906 consists of four herbal ingredients,

Scutellaria baicalensis (Baikal skullcap), Paeonia lactiflora (Chinese

peony), Ziziphusjujuba (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 vomiting

Preclinical mouse model studies and phaseIandII clinical trial results

have shown that PHY906 reduces gastrointestinal toxicity caused by

several chemotherapy drugs and further enhances their anti-tumour

activities

54,55

. 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 tumourcells

46,47

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 practice

. 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 retinopathy

and angina pectoris

; the coix seed extract-based

Kanglaite Injection, a broad-spectrum intravenous anti-cancer ther–

apy

; 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 hepatitisC (ref.60).

Future perspectives

The Hungarian–American 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 magic”

. We are currently at an early but

exciting phase where modern scientific methods established in the

past 300years 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 products—as appearing in multi-

herb prescriptions—interact 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 herbalremedies.

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

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

Zanthoxylum bungeanum seed

Coptis deltoidea root

Phellodendron amurense root

Zingiberis officinalis root

Cinnamomum cassia twig

Panax ginseng root

Angelica sinensis root

Ganoderma lucidum fruiting body

Treatment of food allergy.

Preclinical studies show that FAHF-2 is safe and prevents anaphylaxis in a mouse

model of peanut allergy.

FAHF-2 functions to restore the Th1/Th2 cytokine balance in the immune system.

ASHMI Sophora flavescens root

Glycyrrhiza uralensis root

Ganoderma lucidum fruiting body

Treatment of asthma.

Clinical studies show that ASHMI is as effective as the standard corticosteroid

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

Paeonia lactiflora root

Ziziphus jujuba fruit

Glycyrrhiza uralensis root

Reduction of gastrointestinal toxicity caused by chemotherapy in cancer patients.

PHY906 promotes intestinal epithelial regeneration by activation of Wnt signalling.

PHY906 reduces CPT-11-induced intestinal inflammation, but activates autophagy

and apoptosis pathways in tumour cells.

6 NATURE PLANTS 3, 17109 (2017)

DOI: 10.1038/nplants.2017.109 | www.nature.com/natureplants

PERSPECTIVE

NATURE PLANTS

led to the discovery of two plant triterpenoids as leptin sensitizers:

celastrol from the traditional Chinese herbal plant Tripterygiumwil–

fordii (thunder god vine) and withaferinA from the Ayurvedic herbal

plant Withania somnifera (ashwagandha), with strong anti-diabetic

and anti-obesity properties, respectively

62,63

. 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 quantities

, 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 resources

. 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 pharmacologicalproperties

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 sharply

. 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 humanhealth.