心2 NIH Public access △ g Author Manuscript Fitoterapia. Author manuscript available in PMC 2012 January I Published in final edited form as Fitoterapia. 201 1 January; 82(1): 17-33. doi: 10. 1016/j. fitote 2010 11.017 Developing a library of authenticated Traditional chinese Medicinal (TCM) plants for systematic biological evaluation Rationale, methods and preliminary results from a sino American collaboration David M. Eisenberga, c,, Eric S.J. Harris, b, Bruce A Littlefield a, b, Shugeng Caoa,b,Jane A Craycrofta, Robert Scholtena, Peter Baylissd,e, Yanling Fuf, Wenquan Wang g, Yanjiang Qiao, Zhongzhen Zhao, Hubiao Chen, Yong Liu9, Ted Kaptchuka, C, Wi!liam C.Hahn Xiaoxing Wang d, Thomas Roberts, caroline E Shamu!, and Jon Clardya, b a osher Research Center, Division for Research and Education in Complementary and ntegrative Medical Therapies, Harvard Medical School, 77 Louis Pasteur Avenue Suite 1030 Boston mA 02115. USA b Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave, Boston MA 02115, USA c Department of Medicine, Division of General Internal Medicine, Beth Israel Deaconess Medical Center Boston ma 02215. USA d department of Cancer Biology and Medical Oncology Dana Farber Cancer Institute, Boston MA 02115. USA e Department of Pathology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115 USA f International Cooperation Center, Beijing University of Chinese Medicine, 11 Bai San Huan Dong Lu, Chao Yang District, Beijing 100029, PR China 9 School of Chinese Pharmacy, Beijing University of Chinese Medicine, No 6 Wangjing Zhong Huan Nan Lu, Chaoyang District Beijing 100102, PR China h School of Chinese Medicine, Hong Kong Baptist University 7 Baptist University Road, Kowloon Tong, Hong Kong Special Administrative Region, PR Chi ICCB-Longwood Screening Facility and Department of Systems Biology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA Abstract While the popularity of and expenditures for herbal therapies(aka"ethnomedicines)have creased globally in recent years, their efficacy, safety, mechanisms of action, potential as novel herapeutic agents, cost-effectiveness, or lack thereof, remain poorly defined and controversial Moreover, published clinical trials evaluating the efficacy of herbal therapies have rightfully been criticized, post hoc, for their lack of quality assurance and reproducibility of study materials, as DEdicated to Dr Norman R. Famsworth of the University of Illinois at Chicago for his pioneering work on botanical natural ld authority in the field of pharmacognosy Corresponding author. Osher Research Center, Division for Research and Education in Complementary and Integrative Medical Therapies, Harvard Medical School, 77 Louis Pasteur Avenue Suite 1030, Boston, MA 02115, USA. Tel:+1 6174328550, fax: + 617432 1616 David Eisenberg ahms. harvard. edu(D M. Eisenberg)
Developing a library of authenticated Traditional Chinese Medicinal (TCM) plants for systematic biological evaluation — Rationale, methods and preliminary results from a SinoAmerican collaboration☆ David M. Eisenberga,c,* , Eric S.J. Harrisa,b, Bruce A. Littlefielda,b, Shugeng Caoa,b, Jane A. Craycrofta, Robert Scholtena, Peter Baylissd,e, Yanling Fuf , Wenquan Wangg, Yanjiang Qiaod, Zhongzhen Zhaoh, Hubiao Chenh, Yong Liug, Ted Kaptchuka,c, William C. Hahnd, Xiaoxing Wangd, Thomas Robertsd, Caroline E. Shamui , and Jon Clardya,b a Osher Research Center, Division for Research and Education in Complementary and Integrative Medical Therapies, Harvard Medical School, 77 Louis Pasteur Avenue Suite 1030, Boston, MA 02115, USA b Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston MA 02115, USA c Department of Medicine, Division of General Internal Medicine, Beth Israel Deaconess Medical Center, Boston MA 02215, USA d Department of Cancer Biology and Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA e Department of Pathology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA f International Cooperation Center, Beijing University of Chinese Medicine, 11 Bai San Huan Dong Lu, Chao Yang District, Beijing 100029, PR China g School of Chinese Pharmacy, Beijing University of Chinese Medicine, No. 6 Wangjing Zhong Huan Nan Lu, Chaoyang District Beijing 100102, PR China h School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong Special Administrative Region, PR China i ICCB-Longwood Screening Facility and Department of Systems Biology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA Abstract While the popularity of and expenditures for herbal therapies (aka “ethnomedicines”) have increased globally in recent years, their efficacy, safety, mechanisms of action, potential as novel therapeutic agents, cost-effectiveness, or lack thereof, remain poorly defined and controversial. Moreover, published clinical trials evaluating the efficacy of herbal therapies have rightfully been criticized, post hoc, for their lack of quality assurance and reproducibility of study materials, as ☆Dedicated to Dr. Norman R. Farnsworth of the University of Illinois at Chicago for his pioneering work on botanical natural products, his superb inspiration and leadership as world authority in the field of pharmacognosy. *Corresponding author. Osher Research Center, Division for Research and Education in Complementary and Integrative Medical Therapies, Harvard Medical School, 77 Louis Pasteur Avenue Suite 1030, Boston, MA 02115, USA. Tel.: +1 617 432 8550; fax: +1 617 432 1616. David_Eisenberg@hms.harvard.edu (D.M. Eisenberg). NIH Public Access Author Manuscript Fitoterapia. Author manuscript; available in PMC 2012 January 1. Published in final edited form as: Fitoterapia. 2011 January ; 82(1): 17–33. doi:10.1016/j.fitote.2010.11.017. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Eisenberg et al. well as a lack of demonstration of plausible mechanisms and dosing effects. In short, clinical botanical investigations have suffered from the lack of a cohesive research strategy which draws on the expertise of all relevant specialties With this as background, US and Chinese co-investigators with expertise in Traditional Chinese Medicine(TCM), botany, chemistry and drug discovery, have jointly established a prototype library consisting of 202 authenticated medicinal plant and fungal species that collectively represent the therapeutic content of the majority of all commonly prescribed TCM herbal prescriptions. Currently housed at Harvard University, the library consists of duplicate or triplicate kilogram quantities of each authenticated and processed species, as well as" detanninized"extracts and sub-fractions of each mother extract. Each species has been collected at 2-3 sites, each separated geographically by hundreds of miles, with precise GPS documentation, and authenticated visually and chemically prior to testing for heavy metals and/or pesticides contamination. An explicit decision process has been developed whereby samples with the least contamination were selected to undergo ethanol extraction and hplc sub-fractionation in preparation for high throughput screening across a broad array of biological targets including cancer biology targets. As envisioned, the subfractions in this artisan collection of authenticate medicinal plants will be tested for biological activity individually and in combinations (i.e complex mixtures")consistent with traditional ethnomedical practice This manuscript summarizes the rationale, methods and preliminary"proof of principle" for the establishment of this prototype, authenticated medicinal plant library. It is hoped that these methods will foster scientific discoveries with therapeutic potential and enhance efforts to systematically evaluate commonly used herbal therapies worldwide P9z Keywords Herbal medicine; Library; Traditional Chinese; Ethnomedicine 1 Introduction The topic of whether and how plant based medicines(aka herbal remedies) predictably alter the natural course of human disease has been an essential and complex aspect of medicine for thousands of years. By contrast, efforts to systematically apply modern scientific strategies to prove or disprove the therapeutic value of specific medicinal plant individually or in complex mixtures, and to optimize their rightful place in modern health care, represent a more recent trans-disciplinary challenge Focusing on Traditional Chinese Medicine (tCm), there was a singular moment in recent history when practitioners of TCM and advocates of modern western medicine were explicitly called upon to jointly learn from one another, teach one another and, in the process, attempt to generate new knowledge for the common good of the next generation The time was August 1950. The setting was the first National Health Congress of the newly 933 established People's Republic of China. Chairman Mao Ze Dong spoke on the occasion of the proposed establishment of the first five accredited schools of TCM and the need for collaboration disparate expert groups. " We should unite all the young and experienced medical professionals from both Traditional Chinese Medicine and Modern Western Medicine to form a firmly united front to jointly strive for a great enhancement of the peoples health [l]! "Mao s intention was clear and practical. He sought to proactively engage medical experts from both eastern and western traditions to jointly explore what he called "The Treasurehouse of fraditional chinese medicin ng its rich Autho
well as a lack of demonstration of plausible mechanisms and dosing effects. In short, clinical botanical investigations have suffered from the lack of a cohesive research strategy which draws on the expertise of all relevant specialties. With this as background, US and Chinese co-investigators with expertise in Traditional Chinese Medicine (TCM), botany, chemistry and drug discovery, have jointly established a prototype library consisting of 202 authenticated medicinal plant and fungal species that collectively represent the therapeutic content of the majority of all commonly prescribed TCM herbal prescriptions. Currently housed at Harvard University, the library consists of duplicate or triplicate kilogram quantities of each authenticated and processed species, as well as “detanninized” extracts and sub-fractions of each mother extract. Each species has been collected at 2–3 sites, each separated geographically by hundreds of miles, with precise GPS documentation, and authenticated visually and chemically prior to testing for heavy metals and/or pesticides contamination. An explicit decision process has been developed whereby samples with the least contamination were selected to undergo ethanol extraction and HPLC sub-fractionation in preparation for high throughput screening across a broad array of biological targets including cancer biology targets. As envisioned, the subfractions in this artisan collection of authenticated medicinal plants will be tested for biological activity individually and in combinations (i.e., “complex mixtures”) consistent with traditional ethnomedical practice. This manuscript summarizes the rationale, methods and preliminary “proof of principle” for the establishment of this prototype, authenticated medicinal plant library. It is hoped that these methods will foster scientific discoveries with therapeutic potential and enhance efforts to systematically evaluate commonly used herbal therapies worldwide. Keywords Herbal medicine; Library; Traditional Chinese; Ethnomedicine 1. Introduction The topic of whether and how plant based medicines (aka herbal remedies) predictably alter the natural course of human disease has been an essential and complex aspect of medicine for thousands of years. By contrast, efforts to systematically apply modern scientific strategies to prove or disprove the therapeutic value of specific medicinal plants, individually or in complex mixtures, and to optimize their rightful place in modern health care, represent a more recent trans-disciplinary challenge. Focusing on Traditional Chinese Medicine (TCM), there was a singular moment in recent history when practitioners of TCM and advocates of modern western medicine were explicitly called upon to jointly learn from one another, teach one another and, in the process, attempt to generate new knowledge for the common good of the next generation. The time was August 1950. The setting was the first National Health Congress of the newly established People’s Republic of China. Chairman Mao Ze Dong spoke on the occasion of the proposed establishment of the first five accredited schools of TCM and the need for collaboration across disparate expert groups. “We should unite all the young and experienced medical professionals from both Traditional Chinese Medicine and Modern Western Medicine to form a firmly united front to jointly strive for a great enhancement of the people’s health [1]!” Mao’s intention was clear and practical. He sought to proactively engage medical experts from both eastern and western traditions to jointly explore what he called “The Treasurehouse of Traditional Chinese Medicine,” including its rich pharmacopeia. Eisenberg et al. Page 2 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Eisenberg et al. 2. Relevance of herbal and TCM products Roughly half of all approved prescription drugs are natural products, mostly from plants and microbial sources, their semi-synthetic derivatives or fully synthetic analogs [2]. Close to 70% of all cancer drugs originated from natural products 3, 4]. Therefore, the application of state-of-the-art technologies to the systematic evaluation of traditionally used plant based >E9 medicines(aka ethnobotanicals) remains a highly relevant yet scientifically challenging line of inquiry. 3. Epidemiology and market relevance of herbal and TCM products Herbal medicine use by the American public has increased dramatically over the past two decades. The percentage of US adults reporting the use of herbal(non-vitamin, non-mineral) products to treat or prevent disease increased from 2.5% in 1990 [5] to 12% in 1997[6]to 14% in 2000[7] to 19%o in 2002 [8] and 18% in 2007[9]. The estimated out-of-pocket expenditures for herbal therapies by the US adult population in 2007 was $14 8B. This is equivalent to approximately one-third of the total out-of-pocket spending on all prescription drugs(476B)that same year [10] A marketing analysis suggested that sales of TCM herbal products from China increased at an annual rate of 24% between 2004 and 2008[11]. In 2008, TCM herbal product sales accounted for an estimated 22% of Chinas overall healthcare product revenue and were estimated at a value of $26 billion US dollars [111 P9z 4. Rationale to build a prototy pe library based on challenges and lessons learned 4.1. Lessons learned from selected clinical trials In 2003, the NIH,'s National Center for Complementary and Alternative Medicine (NCCAM)warned that a lack of reproducibility, quality control and dosage schedules involving natural products might lead to methodologically questionable and/or negative clinical studies, thereby diminishing opportunities for further investigations of thnobotanicals [12] By way of example, in 2004 a randomized trial was conducted to test the clinical effectiveness of an eight herb Chinese formula, sold under the product name"PC-SPES, in subjects with advanced prostate cancer [13]. As documented in the medical literature, this complex herbal mixture was found to be clinically superior to the standard, high dose estrogen salvage protocol in terms of overall reductions in PSA levels and time to progression of disease for 90 randomized study subjects. However, random testing of the herbal mixture revealed it had been adulterated with small quantities of synthetic estrogen and Coumadin [ 13]. The authors concluded that the true efficacy of this, and other, herbal mixtures will remain uncertain until the quality, consistency and purity of the natural 9 products under evaluation can be ensured [13].A of the medical literature in 2005 documented that most publications involving the assessment of herbal therapies in clinical trials involved no independent verification of the herbal contents under evaluation [14] The authors of the PC-SPES study also commented on the fact that the levels of estrogen identified in the commercial PC-SPES products were far too low to have explained the apparent clinical superiority of the PC-SPES therapy as compared with the estrogen salvage protocol. As such, their comments could be interpreted to raise the possibility, albeit remote that specific components(i.e. chemical compounds) within the PC-SPES mixture, when Autho
2. Relevance of herbal and TCM products Roughly half of all approved prescription drugs are natural products, mostly from plants and microbial sources, their semi-synthetic derivatives or fully synthetic analogs [2]. Close to 70% of all cancer drugs originated from natural products [3,4]. Therefore, the application of state-of-the-art technologies to the systematic evaluation of traditionally used plant based medicines (aka ethnobotanicals) remains a highly relevant yet scientifically challenging line of inquiry. 3. Epidemiology and market relevance of herbal and TCM products Herbal medicine use by the American public has increased dramatically over the past two decades. The percentage of US adults reporting the use of herbal (non-vitamin, non-mineral) products to treat or prevent disease increased from 2.5% in 1990 [5] to 12% in 1997 [6] to 14% in 2000 [7] to 19% in 2002 [8] and 18% in 2007 [9]. The estimated out-of-pocket expenditures for herbal therapies by the US adult population in 2007 was $14.8B. This is equivalent to approximately one-third of the total out-of-pocket spending on all prescription drugs ($47.6B) that same year [10]. A marketing analysis suggested that sales of TCM herbal products from China increased at an annual rate of 24% between 2004 and 2008 [11]. In 2008, TCM herbal product sales accounted for an estimated 22% of China’s overall healthcare product revenue and were estimated at a value of $26 billion US dollars [11]. 4. Rationale to build a prototype library based on challenges and lessons learned 4.1. Lessons learned from selected clinical trials In 2003, the NIH’s National Center for Complementary and Alternative Medicine (NCCAM) warned that a lack of reproducibility, quality control and dosage schedules involving natural products might lead to methodologically questionable and/or negative clinical studies, thereby diminishing opportunities for further investigations of ethnobotanicals [12]. By way of example, in 2004 a randomized trial was conducted to test the clinical effectiveness of an eight herb Chinese formula, sold under the product name “PC-SPES,” in subjects with advanced prostate cancer [13]. As documented in the medical literature, this complex herbal mixture was found to be clinically superior to the standard, high dose, estrogen salvage protocol in terms of overall reductions in PSA levels and time to progression of disease for 90 randomized study subjects. However, random testing of the herbal mixture revealed it had been adulterated with small quantities of synthetic estrogen and Coumadin [13]. The authors concluded that the true efficacy of this, and other, herbal mixtures will remain uncertain until the quality, consistency and purity of the natural products under evaluation can be ensured [13]. A review of the medical literature in 2005 documented that most publications involving the assessment of herbal therapies in clinical trials involved no independent verification of the herbal contents under evaluation [14]. The authors of the PC-SPES study also commented on the fact that the levels of estrogen identified in the commercial PC-SPES products were far too low to have explained the apparent clinical superiority of the PC-SPES therapy as compared with the estrogen salvage protocol. As such, their comments could be interpreted to raise the possibility, albeit remote, that specific components (i.e. chemical compounds) within the PC-SPES mixture, when Eisenberg et al. Page 3 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Eisenberg et al. added to low dose estrogen, might have resulted in an additive or synergistic effect powerful enough to alter the course of disease in men with advanced prostate cancer A second case of note involved the evaluation of the herb Echinacea echinacea angustifolia DC. )in the prevention of rhinovirus infection(i.e. the common cold). In this study, 437 volunteers were proactively infected with rhinovirus [15. Subjects were then randomized to four groups. Three of the groups received various preparations and doses of a commonly sold Echinacea extract and one group received a placebo. There were no significant differences across groups with regard to rates of infection, severity of symptoms or viral titers. as such. the trial was considered to have refuted claims of clinical effectiveness of Echinacea. Subsequently, the New England Journal of Medicine published criticisms of the study's design [16]. These included the suggestion that a different Echinacea species might have been preferable; that the dose used in the study was far too low(by a factor of 6 )and that a higher dose might have made this trial more clinically and cientifically relevant [16] a third study involved the evaluation of a popular over-the-counter preparation of the herb saw palmetto(Serenoa repens(w. BartramSmall) in the treatment of benign prostatic hypertrophy [17]. In this study, 225 subjects were randomized to two groups, one receiving a Saw Palmetto extract in the form of a popular over-the-counter supplement and the other group receiving a placebo. There were no significant differences observed between these two groups in terms of symptomatic improvement. An accompanying editorial [18] commented that the study authors had tested a single, commercially available preparation of saw palmetto, thereby leaving open the possibility that a different preparation might still be ffective. Furthermore, these authors contended that in the absence of a plausible mechanism of action, a fair comparison of this herb(or its constituents)to a more conventional FDA approved therapeutic drug, would be problematic if not impossible Lessons learned from these and other ambitious(and expensive)clinical trials suggest that uture human clinical trials involving herbal products must ensure the reproducibility and quality of the intervention materials; and, will require an understanding of mechanisms of action and dosing prior to the implementation of new, large scale(and expensive)Phase or Ill clinical trials. The current NIH guidelines involving candidate herbal therapies reflect many of these hard learned lessons [19] as do the Consort Guidelines for publications involving randomized controlled trials involving herbal interventions [201 In hindsight, these were methodological inadequacies uncovered by individuals skilled the design and conduct of clinical trials. They provided part of the rationale for the study described in this manuscript. What about methodological challenges from the vantage point of other relevant experts including researchers skilled in botany, chemistry, ethnobotany and drug discovery 4.2. Lessons learned from the vantage point of drug discovery and ethnobotany 933 The current place of natural products in modern drug discovery is inconsistent with their past performance and future potential. Natural products have made, and continue to make substantial contributions both to understanding basic biological processes and treating human disease. If we focus on cancer, natural products from plants have led to frontline therapies such as paclitaxel, vinblastine, camptothecin and etoposide [4]. If we look at the immediate future, geldanamycin analogs- to pick just one example-are being pursued in clinical trials [21, 22]. Thus there is a strong scientific argument for continuing to explore natural products in drug discovery -an argument that is largely unheeded as pharmaceutical companies cut back on, or eliminate, their natural product programs Autho
added to low dose estrogen, might have resulted in an additive or synergistic effect powerful enough to alter the course of disease in men with advanced prostate cancer. A second case of note involved the evaluation of the herb Echinacea (Echinacea angustifolia DC.) in the prevention of rhinovirus infection (i.e. the common cold). In this study, 437 volunteers were proactively infected with rhinovirus [15]. Subjects were then randomized to four groups. Three of the groups received various preparations and doses of a commonly sold Echinacea extract and one group received a placebo. There were no significant differences across groups with regard to rates of infection, severity of symptoms or viral titers. As such, the trial was considered to have refuted claims of clinical effectiveness of Echinacea. Subsequently, the New England Journal of Medicine published criticisms of the study’s design [16]. These included the suggestion that a different Echinacea species might have been preferable; that the dose used in the study was far too low (by a factor of 6) and that a higher dose might have made this trial more clinically and scientifically relevant [16]. A third study involved the evaluation of a popular over-the-counter preparation of the herb saw palmetto (Serenoa repens (W. Bartram) Small) in the treatment of benign prostatic hypertrophy [17]. In this study, 225 subjects were randomized to two groups, one receiving a Saw Palmetto extract in the form of a popular over-the-counter supplement and the other group receiving a placebo. There were no significant differences observed between these two groups in terms of symptomatic improvement. An accompanying editorial [18] commented that the study authors had tested a single, commercially available preparation of saw palmetto, thereby leaving open the possibility that a different preparation might still be effective. Furthermore, these authors contended that in the absence of a plausible mechanism of action, a fair comparison of this herb (or its constituents) to a more conventional FDA approved therapeutic drug, would be problematic if not impossible. Lessons learned from these and other ambitious (and expensive) clinical trials suggest that future human clinical trials involving herbal products must ensure the reproducibility and quality of the intervention materials; and, will require an understanding of mechanisms of action and dosing prior to the implementation of new, large scale (and expensive) Phase II or III clinical trials. The current NIH guidelines involving candidate herbal therapies reflect many of these hard learned lessons [19] as do the Consort Guidelines for publications involving randomized controlled trials involving herbal interventions [20]. In hindsight, these were methodological inadequacies uncovered by individuals skilled in the design and conduct of clinical trials. They provided part of the rationale for the study described in this manuscript. What about methodological challenges from the vantage point of other relevant experts including researchers skilled in botany, chemistry, ethnobotany and drug discovery? 4.2. Lessons learned from the vantage point of drug discovery and ethnobotany The current place of natural products in modern drug discovery is inconsistent with their past performance and future potential. Natural products have made, and continue to make, substantial contributions both to understanding basic biological processes and treating human disease. If we focus on cancer, natural products from plants have led to frontline therapies such as paclitaxel, vinblastine, camptothecin and etoposide [4]. If we look at the immediate future, geldanamycin analogs – to pick just one example – are being pursued in clinical trials [21,22]. Thus there is a strong scientific argument for continuing to explore natural products in drug discovery —an argument that is largely unheeded as pharmaceutical companies cut back on, or eliminate, their natural product programs. Eisenberg et al. Page 4 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Eisenberg et al. Identification of natural product-based leads for Western drug discovery has usually resulted from screening of extracts or compounds from diverse biological sources, generally without regard to preexisting knowledge of the therapeutic utility of the producing plant. A good example is the remarkable portfolio of hundreds of thousands of natural products and extracts amassed by the United States National Cancer Institute(NCD) since the inception of its natural product-based efforts in 1955[23]. Between 1960 and 1982, the NCI screened extracts of 35,000 plant species in collaboration with the U.S. Department of Agriculture (USDA). The strategy adopted was largely one of random selection of a broad range of natural product sources as opposed to selection based on medicinal use, i.e. ethnomedicine 4]. To a large extent, the driving force for NCI's efforts was biological and geographic diversity rather than pre-existing knowledge of therapeutic utility. Focusing on biological and geographic diversity is a typical paradigm of most natural product drug discovery successes, meaning that the use of natural products for Western drug discovery has largely been one of trial and error. This approach has been referred to as "bio-prospecting Paclitaxel, vinblastine and camptothecin were discovered using this approach. Interestingly, Verpoorte has pointed out that there are an estimated 250,000 flowering plant species on earth while as of 2000, fewer than 15,000(6%)had been screened for biological activity [24] n contrast, many cultures around the world have developed ethnomedical traditions based on therapeutic utility of selected local plants and animals. Such empirical traditions are often hundreds if not thousands of years old, as in the case of TCM for which written records exist going back over 2000 years. Unfortunately, the potential value of ethnomedicines has often been discounted by Western medicine and science, with several identifiable factors accounting for this. First, medical diagnoses in TCM and other ethnomedical systems are often portrayed in ways that are not readily understood by Western clinicians. Second, TCM and other ethnomedicines are often viewed as fundamentally lacking in the mechanistic scientific bases that usually underpin claims of Western medical efficacy. Third, there has been a lack of rigorous, well-controlled clinical trials demonstrating clinical efficacy(and mechanisms)of TCM and other ethnomedicines. Fourth, existing scientific and clinical studies of TCM have often utilized plants that have been quality compromised, may be contaminated with pesticides or heavy metals, may have been botanically misidentified, or are lacking a consistent and reproducible resupply chain. As such, and as noted earlier, prior udies have frequently been compromised by quality control and botanical authentication ues, as well as lot-to-lot variability and lack of knowledge of precise growing locations nd conditions, factors that have too often limited reproducibility. Finally, resupply of herbs for confirmation and follow-up studies is frequently problematic. The limiting factors mentioned earlier fall into two main categories: variables related to starting materials, and ariables related to execution or interpretation of scientific and clinical studies. While the two are interdependent, without addressing the former, there is little value in pursuing the From the vantage point of ethnobotany, researchers have highlighted the difficulties 9 replicating the biological activity of a given plant when attempts are made to repeat an experiment after subsequent recollection[25]. As such, the challenge of reproducibility remains a formidable one here are also challenges in terms of sourcing plant species to be studied. These include collecting them according to traditional techniques, documenting the precise collection sites using GPS technology, authenticating them visually, chemically and, through DNA sequencing, processing and extracting them according to established, traditional and reproducible techniques, storing them properly and so on Autho
Identification of natural product-based leads for Western drug discovery has usually resulted from screening of extracts or compounds from diverse biological sources, generally without regard to preexisting knowledge of the therapeutic utility of the producing plant. A good example is the remarkable portfolio of hundreds of thousands of natural products and extracts amassed by the United States National Cancer Institute (NCI) since the inception of its natural product-based efforts in 1955 [23]. Between 1960 and 1982, the NCI screened extracts of 35,000 plant species in collaboration with the U.S. Department of Agriculture (USDA). The strategy adopted was largely one of random selection of a broad range of natural product sources as opposed to selection based on medicinal use, i.e. ethnomedicine [4]. To a large extent, the driving force for NCI’s efforts was biological and geographic diversity rather than pre-existing knowledge of therapeutic utility. Focusing on biological and geographic diversity is a typical paradigm of most natural product drug discovery successes, meaning that the use of natural products for Western drug discovery has largely been one of trial and error. This approach has been referred to as “bio-prospecting.” Paclitaxel, vinblastine and camptothecin were discovered using this approach. Interestingly, Verpoorte has pointed out that there are an estimated 250,000 flowering plant species on earth while as of 2000, fewer than 15,000 (6%) had been screened for biological activity [24]. In contrast, many cultures around the world have developed ethnomedical traditions based on therapeutic utility of selected local plants and animals. Such empirical traditions are often hundreds if not thousands of years old, as in the case of TCM for which written records exist going back over 2000 years. Unfortunately, the potential value of ethnomedicines has often been discounted by Western medicine and science, with several identifiable factors accounting for this. First, medical diagnoses in TCM and other ethnomedical systems are often portrayed in ways that are not readily understood by Western clinicians. Second, TCM and other ethnomedicines are often viewed as fundamentally lacking in the mechanistic, scientific bases that usually underpin claims of Western medical efficacy. Third, there has been a lack of rigorous, well-controlled clinical trials demonstrating clinical efficacy (and mechanisms) of TCM and other ethnomedicines. Fourth, existing scientific and clinical studies of TCM have often utilized plants that have been quality compromised, may be contaminated with pesticides or heavy metals, may have been botanically misidentified, or are lacking a consistent and reproducible resupply chain. As such, and as noted earlier, prior studies have frequently been compromised by quality control and botanical authentication issues, as well as lot-to-lot variability and lack of knowledge of precise growing locations and conditions, factors that have too often limited reproducibility. Finally, resupply of herbs for confirmation and follow-up studies is frequently problematic. The limiting factors mentioned earlier fall into two main categories: variables related to starting materials, and variables related to execution or interpretation of scientific and clinical studies. While the two are interdependent, without addressing the former, there is little value in pursuing the latter. From the vantage point of ethnobotany, researchers have highlighted the difficulties in replicating the biological activity of a given plant when attempts are made to repeat an experiment after subsequent recollection [25]. As such, the challenge of reproducibility remains a formidable one. There are also challenges in terms of sourcing plant species to be studied. These include: collecting them according to traditional techniques, documenting the precise collection sites using GPS technology, authenticating them visually, chemically and, through DNA sequencing, processing and extracting them according to established, traditional and reproducible techniques, storing them properly and so on. Eisenberg et al. Page 5 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript