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Produced by the Science/AAAS Custom Publishing OfficeThe Art and Science ofTraditional MedicinePart 2: MultidisciplinaryApproaches for StudyingTraditional MedicineSponsored by
ed by the Science/AAAS Custom Publishing OfficeContentsEditorial TeamTai-Ping Fan, Ph.D. (Guest project editor)University of Cambridge, UKJosephine Briggs, M.D.National Center for Complementary & Alternative Medicine, NIH, USALiang Liu, M.D., Ph.D.Macau University of Science & Technology, Macau SAR, ChinaAiping Lu, M.D., Ph.D.Hong Kong Baptist University, Hong Kong SAR, ChinaJan van der Greef, Ph.D.University of Leiden and TNO, The NetherlandsAnlong Xu, Ph.D.ArticlesS27 Herbal genomics: Examining the biology of traditionalmedicinesS29 A holistic approach to the quality control of traditionalChinese medicinesS32 Evolution of traditional medicines to botanical drugsS35 Developing influenza treatments using traditionalChinese medicineS38 A novel drug discovery strategy inspired by traditionalmedicine philosophiesS40 Deciphering ancient combinatorial formulas: TheShexiang Baoxin pillS43 Lessons from the development of the traditional Chinesemedicine formula PHY906Beijing University of Chinese Medicine, ChinaS45 The potential role of Chinese herbal medicines in cancermanagementEditor: Sean Sanders, Ph.D.Assistant Editor: Tianna Hicklin, Ph.D.Proofreader/Copyeditor: Yuse LajiminmuhipDesigner: Amy HardcastleS47 Evaluating the safety of herbal medicines: Integratedtoxicological approachesBill Moran, Global DirectorCustom Publishingbmoran@aaas.org 1-202-326-6438Ruolei Wu, Associate Director, AsiaCustom Publishingrwu@aaas.org 86-186-0082-9345S50 Combining 'omics and comparative effectivenessresearch: Evidence-based clinical research decisionmaking for Chinese medicineThe content contained in this special, sponsored section was commissioned, edited, and published by the Science/AAAS CustomPublishing Office. It was not peer-reviewed or assessed by the Editorial staff of the journal Science; however, all manuscripts havebeen critically evaluated by an international editorial team consisting of experts in traditional medicine research selected by theproject editor. The intent of this section is to provide a means for authors from institutions around the world to showcase theirstate-of-the-art traditional medicine research through review/perspective-type articles that highlight recent progress in this burgeoning area. The editorial team and authors take full responsibility for the accuracy of the scientific content and the facts stated.Articles can be cited using the following format: [Author Name(s)], Science 347 (6219 Suppl), Sxx-Sxx (2015).S26ILLUSTRATION (FRONT) CHARLOTTE LOKINIn this second of three special supplements, herbal genomics asa novel approach for revolutionizing research on, and ultimatelyuse of, traditional herbal medicines and other materia medica,as well as advances in their quality control and standardization, ishighlighted. A prominent focus is the U.S. Food and Drug Administration’s practical framework for developing botanicals (including traditional medicines) into new drugs based on the samestandards as small molecule drugs. The application of mechanistic studies to drug discovery and development from traditionaltherapies is discussed, with an emphasis on preclinical toxicology assessments, pharmacovigilance, comparative effectivenessresearch, and the practice of “P4” medicine, particularly in thecontext of influenza, ischemic heart disease, stroke, and cancer.
Produced by the Science/AAAS Custom Publishing OfficeHerbal genomics: Examining the biologyof traditional medicinesAuthors:Shilin Chen1*,Jingyuan Song2Chao Sun2,Jiang Xu1,Yingjie Zhu1,Rob Verpoorte3,Tai-Ping Fan4*Traditional herbal medicines, such asplant- and fungi-based remedies, have beenused for more than 5,000 years. However, thegenetic background, the agricultural traits, andthe medicinal quality of most traditional herbsare poorly understood. With rapid advancesin high throughput sequencing technologiesand greatly reduced costs, a new discipline called “herbalgenomics” has emerged. Researchers are now systematicallycategorizing medicinal herbs by sequencing, assembling,and annotating their genomes, and by analyzing their genes’functions. The genomes of some commonly used herbshave already been sequenced, such as Lingzhi (Ganodermalucidum or “mushroom of immortality”). This species hasprovided an effective model system that has facilitated thestudy of the biosynthetic pathways of secondary metabolitesin medicinal fungal species (1). Genomic information,together with transcriptomic, proteomic, and metabolomicdata, can therefore be used to predict secondary metabolitebiosynthetic pathways and their regulation, triggering arevolution in discovery-based research aiming to understandthe genetics and biology of herbs.Herbal genomics provides an effective platform to support the chemical and biological analyses of complex herbalproducts that may contain more than one active component.Therefore, it is now being applied to many areas of herbrelated biological research to help understand the quality oftraditional medicines and for molecular herb identificationthrough the establishment of an herbal gene bank. Moreover,functional herbal genomics can contribute to model herbresearch platforms, geoherbal research, genomics-assistedherb breeding, and herbal synthetic biology, all of which areimportant for securing the sourcing of the medicinal plantsand their active compounds in the future.Creating model herbsWith the recent developments in biotechnology andgenomics, several species including Ganoderma lucidum,Salvia miltiorrhiza, and Catharanthus roseus have emergedas valuable models for studying the genetics and metabolicactivities of herbs. These species have been shown tosynthesize active pharmaceutical components, includingtriterpenes, diterpene quinone, and indole alkaloids.Although the core biosynthetic pathways of secondarymetabolites in herbs are conserved, downstream pathwayshave evolved and became highly diverse (2). Therefore genesfrom different cultivars of medicinal herbs or evolutionarilyMaterials that appear in this section were not reviewed orassessed by Science Editorial staff, but have been evaluated byan international editorial team consisting of experts in traditionalmedicine research.related species can be evaluated using these herbal modelsto understand the mechanisms underlying natural variation.These model systems can also be used to identify novelbiosynthetic pathways for convergent secondary metabolitesin closely related herb species. Recent advances in genomeediting have provided feasible approaches by introducingor altering specific alleles; hence, genetic control overmetabolites can be investigated (3). Although the elucidationof biosynthetic pathways is one of their most appealingfeatures, model herbs can also provide information onperennial habits, development patterns, cultivationrequirements, and resistance to environmental or biologicalinsult (Figure 1).Biological basis of geoherbalismThe Chinese concept of geoherbalism encompasses theuse of “authentic” or “superior” herbs, which are producedin a specific region or environment, to generate remedialproducts that have a high efficacy. Through the applicationof new 'omics technologies to geoherbalism, informationcan be obtained concerning the optimal growth conditionsof medicinal products and specific herb genotypes, allowingboth genetic and environmental factors to be taken into account when considering herbal growth. 'Omics provide newand powerful tools to elucidate the molecular basis underlying geoherbalism and to select elite varieties. Creating herbpangenomes—the entire genetic code for all of the strainswithin a given species—can provide insights into identifyingthe “core genomes” and “dispensable genomes” of the species as well as the individual genetic variations that exist indifferent regions or ecological circumstances. Environmentalstressors can lead to epigenetic modifications; techniquessuch as DNA methylome analysis, chromatin immunoprecipitation (ChIP)-sequencing, and small RNA sequencing areuseful for investigating the influence of epigenetic factors. Inaddition, soil microbes can affect an herb’s environment, andmetagenomic analysis of soil microbial populations can pointto important interactions between microbes and herbs thatmay alter growth conditions (4).Targeted herb breedingMolecular breeding requires the availability of polymorphic markers and/or information about trait-associatedgenes. Since they are considered minor crops, herbs havebeen limited in genomics-assisted improvements due tothe high cost; however, next generation sequencing and itsincreasing affordability have dramatically accelerated markerselection breeding programs through the sequencing of wildvarieties and different cultivars of herbs that represent a valuable reservoir of genetic diversity. Herbal 'omics research has1WHO Collaborating Centre for Traditional Medicine, Institute of Chinese MateriaMedica, China Academy of Chinese Medical Sciences, Beijing, ChinaInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, China3Natural Products Laboratory, IBL, Leiden University, Leiden, The Netherlands4Department of Pharmacology, University of Cambridge, Cambridge, UK*Corresponding Authors: slchen@implad.ac.cn (S.C.) and tpf1000@cam.ac.uk (T.F.)2S27
Produced by the Science/AAAS Custom Publishing Officeaccelerated the identification of manyfunctional genes in model species andhas also allowed the development offunctional markers specific to the production of desired compounds, information that can be used for targetedmolecular breeding (5).Researching herbal syntheticbiologyAlthough herbs are sourcesof novel and known therapeuticcompounds, problems in sourcingare common. Biotechnology andgenetic engineering offer approachesto alternative production methods.Metabolic engineering of medicinalplants has been studied extensively,resulting in, for example, Atropabelladonna plants producingscopolamine instead of atropine.However, it is clear that in order toimprove the overall production of aplant compound, the overexpressionof the primary coding genes oreven regulatory genes in thepathway are not sufficient, sincecompartmentalization, transport,storage, and co-factor availability mayFIGURE 1. Model herb systems and their applications.be important rate limiting factors. Abetter understanding of pathwaysinvolved would build a foundation fora more comprehensive approach tometabolic engineering. This is the goal of herbal syntheticmedicines through the accurate identification of herbalbiology, which involves the alteration or de novo synthesismaterials.of genomes, with the potential to address resource andpurity issues. Furthermore, natural products for drugConstructing an herbal gene bankdiscovery can be structurally diversified by combining andHerbal genetic information is being accumulated withintroducing plant metabolic pathways into other organisms,increasing speed, making the need for a common platformsuch as bacteria or yeast (6). The conventional practice infor integrated and consolidated access to all 'omicsherbal synthetic biology is to introduce the heterologousdata paramount. Several herb-related databases havebiosynthetic pathway into an expression system able toalready been developed to categorize current resources,produce the products. However, a different approach forincluding genomic information (http://herbalgenomics.org),the large-scale production of a pure compound could betranscriptomic information (http://medicinalplantgenomics.the engineering of an entirely novel synthetic genome, asmsu.edu), a DNA barcode database (http://tcmbarcode.described for Mycoplasma (7).cn/en), and a metabolic pathway database (http://cathacyc.org). However, these distributed resources are not subjectedto long-term maintenance and require bioinformatics skillsDefining a molecular identityto use. A comprehensive and easily accessible database isDNA barcoding is revolutionizing the practice of herbalrequired that stores molecular and biological data for herbalidentification, utilizing the concept of “one sequence,medicines. The DNA/protein sequences and metabolomesone species.” Standardized DNA barcoding identificationof herbs can be integrated into such a database (10, 11).systems are available, but the process can be tedious.With improved bioinformatics approaches, genomic andAnalysis of a plastid genome as a superbarcode is achemical information can be used to identify the biosyntheticpromising alternative for closely related species or cultivarspathways of secondary metabolites leading to the design ofthat cannot be unambiguously distinguished by traditionalmore efficient and targeted searches for plant- and fungiDNA barcoding (8, 9). With the increasing availability ofbased remedies (12).DNA barcodes, current market issues with herbal medicinesDespite its success thus far, herbal genomics still facesthat result from the use of inferior substitutes, adulterants,significant technological and ethical challenges. For instance,and counterfeits could be resolved. Overall, a standardizedthere have been only a few well-assembled herbal genomesidentification system based on DNA barcoding can playreleased to date, partly because of their complexity. Highan important role in controlling the quality of traditionalS28
Produced by the Science/AAAS Custom Publishing Officeheterozygosity, repetition-rich DNA sequences, andpolyploidy are factors that impede data assembly from shortread, whole-genome shotgun sequencing. Furthermore,the lack of high throughput methods reduces the efficiencyof identifying enzymes and pathways involved in thebiosynthesis of secondary metabolites. There have alsobeen ethical and biosecurity concerns regarding syntheticbiology expressed by the scientific community and thepublic. Nevertheless, herbal genomics provides anunprecedented opportunity to revolutionize the useand acceptance of traditional herbal medicines, whilecontributing to the knowledge base essential for furtherproteomic and metabolomic studies.References1. S. Chen et al., Nat. Commun. 3, 913 (2012).2. S. J. Gagne et al., Proc. Natl. Acad. Sci. U.S.A. 109, 12811(2012).3. Q. Shan, Y. Wang, J. Li, C. Gao, Nat. Protoc. 9, 2395 (2014).4. P. R. Hirsch, T. H. Mauchline, Nat. Biotechnol. 30, 961 (2012).5. R. K. Varshney, A. Graner, M. E. Sorrells, Trends Plant Sci. 10, 621(2005).6. F. Geu-Flores, N. H. Sherden, V. Courdavault, Nature 492, 138(2012).7. D. G. Gibson et al., Science 329, 52 (2010).8. X. Li et al., Biol. Rev. Camb. Philos. Soc. doi:10.1111/brv.12104(2014).9. S. Chen et al., Biotechnol. Adv. 32, 1237 (2014).10. B. Berger, J. Peng, M. Singh, Nat. Rev. Genet. 14, 333 (2013).11. M. Yandell, D. Ence, Nat. Rev. Genet. 13, 329 (2012).12. L. Chae, T. Kim, R. Nilo-Poyanco, S. Y. Rhee, Science 344, 510(2014).A holistic approachto the quality controlof traditional ChinesemedicinesAuthors:De-an Guo1*,Wan-Ying Wu1,Min Ye2,Xuan Liu1,Geoffrey A.Cordell3Plants and traditional medicines (TMs) areused around the world for the prevention andtreatment of diseases as well as the sourcesof numerous prescription and over-the-counter therapeutics (1). In many cases, these TMshave been used for thousands of years andare still largely harvested from the wild. However, the qualitycontrol for the growth and isolation of most TMs is poor ornonexistent. Patients and practitioners alike need to be confident of the quality, safety, efficacy, and consistency (QSEC) ofTMs, which requires standardization of all aspects of the plantpreparation. This begins with the identification of the correctplant, and includes isolation and characterization of all bioactive constituents. The evidence-based criteria to determine theQSEC of TMs differs considerably across the globe. As a result,the evidentiary standards required for the marketing of TMproducts can vary greatly from country to country.As acknowledged by the famous Chicago architect, LouisSullivan, “form forever follows function.” For patients andpractitioners, the expectation for the TMs is that they must beeffective (function). Strategies (form) to assure this outcomerequire a strong evidence base and necessitate overcomingcertain barriers to success. In many societies, the acceptanceof TMs precedes integration into the health care system, causing them to face philosophical and regulatory barriers due, atleast in part, to the absence of an evidence base.The World Health Organization has recognized some ofthese issues (1, 2) and, through the Beijing Declaration, has encouraged the integration of evidence-based TMs into nationalhealth care systems and promoted regulations and standardsthat “ensure appropriate, safe, and effective use of traditionalmedicine” (3).In order to fully integrate TMs into national health caresystems, and provide an evidence-based justification for theiruse, certain entrenched customs and beliefs need to be addressed. These include the ideas that a traditional medicineused for thousands of years must be safe and effective; thatsimply using the “correct” plant is adequate; that the biological1National Engineering Laboratory for TCM Standardization Technology, ShanghaiInstitute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaSchool of Pharmaceutical Sciences, Peking University, Beijing, China3Natural Products Inc., Evanston, IL 60203, U.S.A. and Department of PharmaceuticalSciences, College of Pharmacy, University of Florida, Gainesville, FL*Corresponding Author: daguo@simm.ac.cn2Materials that appear in this section were not reviewed orassessed by Science Editorial staff, but have been evaluated byan international editorial team consisting of experts in traditionalmedicine research.S29
Produced by the Science/AAAS Custom Publishing Officeeffects will be consistent, irrespective of the geographicorigin of the plant, the plant part used, or the method ofplant preparation; that older or cultivated plant materialis less effective than fresh, wild plants; that complex plantmixtures are necessary for effectiveness, but cannot bestandardized; and that the traditional knowledge and theparticular medicinal plant will always be available. Theapplication of contemporary information, together withbotanical, chemical, biological, and clinical research, provides an evidence-based research agenda for traditionalmedicine that serves both the practitioner and the patient(4). The next step, standardization (5), includes properplant authentication through DNA barcoding (6, 7), andthe chemical profiling and quantification of all bioactiveconstituents in the material (8, 9).Traditional Chinese medicine (TCM) is an ancient,holistic treatment system established through empiricalevaluation, and exists in many related forms in GreaterChina, Japan, Korea, Vietnam, Malaysia, and Singapore.It seeks to restore energy (qi) and balance (yin and yang)through the use of medicinal plants, fungi, animal products, and minerals, and, superficially, appears quite different from the reductionist approach of Western medicine.However, modern biomedical science is now embracing the concept of systems biology, which views humandiseases as the result of a multifactorial instability inhomeostasis (10). Treatment of cancer or HIV-AIDS nowinvolves a cocktail of drugs targeting different mechanisms of action. At the same time, TCM is embracingnetwork pharmacology, which investigates how the majorconstituents in a plant (or plants) act on various biologicalpathways to produce multiple, synergetic actions (11, 12).The quality control (QC) of TCMs should begin in thefield and continue throughout the production process.Developing a QC system for a TCM preparat
Produc Science/AAAS t e S27 T raditional herbal medicines, such as plant- and fungi-based remedies, have been used for more than 5,000 years. However, the
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Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. Crawford M., Marsh D. The driving force : food in human evolution and the future.
Le genou de Lucy. Odile Jacob. 1999. Coppens Y. Pré-textes. L’homme préhistorique en morceaux. Eds Odile Jacob. 2011. Costentin J., Delaveau P. Café, thé, chocolat, les bons effets sur le cerveau et pour le corps. Editions Odile Jacob. 2010. 3 Crawford M., Marsh D. The driving force : food in human evolution and the future.
