Eisenberg et al. Lastly, there is the inherent conundrum which speaks to the heart of the conceptual difference between traditional (ie. ethnobotanical) herbal practice and modern(western) drug discovery and therapy. This conundrum can be conveyed through the articulation of two testable hypotheses, specifically; do herbal medicines work, when they work, predominantly because of single chemical compounds, albeit in small quantities? B extension, are herbal medicines and herbal medicine libraries merely repositories for sophisticated"bio-prospecting " in search of novel, and patentable, composition of matter discoveries(aka"new chemical entities")or derivatives of already known chemical compounds which can be shown to be of new therapeutic application and benefit? One must also consider the fact that herbal therapy as practiced in traditional settings rarely involves the prescription of a single herb at a time. Instead, traditional conceptual frameworks, which preceded contemporary understanding of chemical compounds and their specific effects on precise, biological targets, almost al ways involve multiple herbs and a presumed additivity and/or synergy of effects on the host subject. The shared view among herbalists, in Asia and elsewhere, has been that a mono-therapy approach will be inferior to a multi-therapy complex herbal mixture approach [26]. By way of example, a typical TCM prescription routinely includes 8-12 herbs, in varying ratios, with one of the herbs serving as the"king a second serving in the capacity of"minister", a third as"adjutant"and a fourth as the messenger”[27 Given this disparity of conceptual models, the fundamental( second)testable hypothesis is that herbal therapies work, when they work, due to complex yet predictable effects of multiple compounds within complex mixtures of plant compounds. As evidenced by the near miraculous success of the three drug"AIDS Cocktail, we now have unequivocal evidence that multi-drug therapy can sometimes be the best -or only -successful therapeutic option[28]. The work of Borisy et al. demonstrated the existence of synergistic effects involving multiple(FDa approved)compounds [29] and the work of Wagner has variety of natural products[30]. Might clinical successes attributed to herbal therapies ummarized the existence of synergistic effects involving multiple compounds found in evolve additive and/or synergistic biological effects which can now be more meticulously described and, ideally, optimized for maximal therapeutic benefit? Lastly, there is the non-technical challenge that Mao attempted to address a half century ago [1]; specifically, can the two schools of medical thought, Eastern and Western(modern biomedicine) develop shared research strategies which address the above mentioned known challenges without compromising the respective beliefs, practices and fundamental tenants of each tradition? Can ethnobotanists and modern drug discovery experts established an effective"united front, and will this exercise result in novel therapeutic discoveries or not? To reframe this question, can an artisan collection of authenticated TCM plants be established for the purpose of successful systematic biological evaluation and will such a 9 with regard to the second hypothesis mentioned earlier, might there also be a new opportunity to employ contemporary high-throughput screening facilities to search for anticipated as well as unanticipated combinations of single compounds which can be shown to be therapeutically effective due to biological additivity and/or synergy of multiple plant derived compounds? Will combinations with evidence of additivity and/or synergy confirm ethnobotanical knowledge about specific plant combinations (i.e. formulas)or might entirely unanticipated active combinations also be identified? AuthoLastly, there is the inherent conundrum which speaks to the heart of the conceptual difference between traditional (i.e. ethnobotanical) herbal practice and modern (western) drug discovery and therapy. This conundrum can be conveyed through the articulation of two testable hypotheses, specifically; do herbal medicines work, when they work, predominantly because of single chemical compounds, albeit in small quantities? By extension, are herbal medicines and herbal medicine libraries merely repositories for sophisticated “bio-prospecting” in search of novel, and patentable, composition of matter discoveries (aka “new chemical entities”) or derivatives of already known chemical compounds which can be shown to be of new therapeutic application and benefit? One must also consider the fact that herbal therapy as practiced in traditional settings rarely involves the prescription of a single herb at a time. Instead, traditional conceptual frameworks, which preceded contemporary understanding of chemical compounds and their specific effects on precise, biological targets, almost always involve multiple herbs and a presumed additivity and/or synergy of effects on the host subject. The shared view among herbalists, in Asia and elsewhere, has been that a mono-therapy approach will be inferior to a multi-therapy, complex herbal mixture approach [26]. By way of example, a typical TCM prescription routinely includes 8–12 herbs, in varying ratios, with one of the herbs serving as the “king”, a second serving in the capacity of “minister”, a third as “adjutant” and a fourth as the “messenger” [27]. Given this disparity of conceptual models, the fundamental (second) testable hypothesis is that herbal therapies work, when they work, due to complex yet predictable effects of multiple compounds within complex mixtures of plant compounds. As evidenced by the near miraculous success of the three drug “AIDS Cocktail,” we now have unequivocal evidence that multi-drug therapy can sometimes be the best – or only –successful therapeutic option [28]. The work of Borisy et al. demonstrated the existence of synergistic effects involving multiple (FDA approved) compounds [29] and the work of Wagner has summarized the existence of synergistic effects involving multiple compounds found in a variety of natural products [30]. Might clinical successes attributed to herbal therapies involve additive and/or synergistic biological effects which can now be more meticulously described and, ideally, optimized for maximal therapeutic benefit? Lastly, there is the non-technical challenge that Mao attempted to address a half century ago [1]; specifically, can the two schools of medical thought, Eastern and Western (modern biomedicine) develop shared research strategies which address the above mentioned known challenges without compromising the respective beliefs, practices and fundamental tenants of each tradition? Can ethnobotanists and modern drug discovery experts established an effective “united front,” and will this exercise result in novel therapeutic discoveries or not? To reframe this question, can an artisan collection of authenticated TCM plants be established for the purpose of successful systematic biological evaluation and will such a library, when screened strategically, lead to the identification of novel compounds, new uses for known single compounds and/or their derivatives; and/or novel biological mechanisms? With regard to the second hypothesis mentioned earlier, might there also be a new opportunity to employ contemporary high-throughput screening facilities to search for anticipated as well as unanticipated combinations of single compounds which can be shown to be therapeutically effective due to biological additivity and/or synergy of multiple plant derived compounds? Will combinations with evidence of additivity and/or synergy confirm ethnobotanical knowledge about specific plant combinations (i.e. formulas) or might entirely unanticipated active combinations also be identified? Eisenberg et al. Page 6 Fitoterapia. Author manuscript; available in PMC 2012 January 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript