Challenges of translating basic research into therapeutics: resveratrol as an example.

Basic science literature abounds with molecules that promise to ameliorate almost any disease, from curing cancer to slowing the aging process itself. However, most of these compounds will never even be evaluated in humans, let alone proven effective. Here, we use resveratrol as an example to highlight the enormous difficulties in understanding pharmacokinetics, determining side effects, and, ultimately, establishing mechanisms of action for a natural compound. Despite extensive interest and effort, and continuing promising results from basic science groups, very little is known even today about the effects of resveratrol in humans. Part of the problem is the unattractiveness of natural compounds to large, well-funded companies that could run clinical trials because developing their own molecules affords much greater protection for their intellectual property. In fact, selling unpatentable material motivates smaller nutraceutical companies to complicate the scientific problem even more--each creates its own proprietary blend, making it extremely difficult to compare their data with those of other companies, or of academic labs using pure compounds. But even beyond these problems lies a deeper one; resveratrol, and almost every natural compound, is likely to have many clinically relevant targets with different dose-response profiles, tissue distributions, and modifiers. Tackling this type of problem efficiently, and even beginning to address the spectrum of other molecules with claimed benefits, is likely to require the development of new paradigms and approaches. Examples include better molecular modeling to predict interactions, large-scale screens for toxic or other common effects, affinity-based methods to identify drug-interacting proteins, and better synthesis of existing data, including legislation to promote the release of trial results, and tracking of voluntary supplement usage. The evidence for benefits of resveratrol in humans remains too sparse to be conclusive; yet, the limited data that are available, combined with a growing list of animal studies, provide a strong justification for further study.