Translation of basic research into useful treatments: how often does it occur?

Abstract

The article by Contopoulos-Ioannidis et al. (1) in this issue of the Journal addresses a much-discussed but rarely quantified issue: the frequency with which basic research findings translate into clinical utility. The authors performed an algorithmic computer search of all articles published in six leading basic science journals (Nature, Cell, Science, the Journal of Biological Chemistry, the Journal of Clinical Investigation, the Journal Experimental Medicine) from 1979 to 1983. Of the 25,000 articles searched, about 500 (2%) contained some potential claim to future applicability in humans, about 100 (0.4%) resulted in a clinical trial, and, according to the authors, only 1 (0.004%) led to the development of a clinically useful class of drugs (angiotensin-converting enzyme inhibitors) in the 30 years following their publication of the basic science finding. They also found that the presence of industrial support increased the likelihood of translating a basic finding into a clinical trial by eightfold. Retrospective studies are often plagued by methodological concerns, such as the thoroughness of the algorithm, the completeness of the follow-up search, and the extrapolation and representative nature of the findings from these journals. These concerns are particularly appropriate for this article, especially because the algorithm used failed to unearth several key articles related to the cloning of growth hormone and cytokines. Not only did their algorithm miss these articles in the very journals they searched, but the proteins described therein have led to successful clinical trials and the subsequent development of therapeutic agents (2– 4). Still, regardless of the study’s limitations, and even if the authors were to underestimate the frequency of successful translation into clinical use by 10-fold, their findings strongly suggest that, as most observers suspected, the transfer rate of basic research into clinical use is very low. It is important to recall that one of the attractive features of curiosity-driven research to many investigators is the unpredictability of its applications to any given field and hence its exciting potential to steer investigation in new directions. There are many examples of important solutions to clinical problems that have emerged from basic inquiries that could never have been predicted at their outset. Recent notable examples include the successful treatment of leukemia, which emerged from seemingly unrelated basic inquiries into the structure of a family of intracellular protein kinases (5,6); the use of bisphosphonates (originally used to dissolve boiler crud) and parathyroid hormone as powerful antiosteoporosis agents (7,8); and the Human Genome Project, whose applicability will be widespread, even beyond the initial expectations (9,10). Given this intrinsic unpredictability of how and when basic research becomes ready for clinical utility, a considerable breadth of basic research must be in place to sustain a robust program of bench-to-bedside transfer. Hence, use of the data by Contopoulos-Ioannidis et al. to limit basic research or prematurely mandate its clinical outcomes must be tempered by recognition of the often-meandering path and unpredictable outcomes of basic investigation. As noted by the authors, sustaining a vigorous rate of transfer of basic findings into clinical application requires a stable and well-trained cadre of ‘translational’ investigators to patrol the borders of the basic/clinical interface. These investigators need to be recruited, educated, and continuously brought up-to-date in scientific techniques. The traditional ‘translational block’ occurring at this bench-to-bedside interface exists in part because of the attrition of such clinical investigators from academic health centers, a phenomenon addressed in previous reports from the Institute of Medicine (11,12). There are several reasons for this current dearth of translational investigators. The bench-to-human interface involves a dynamic agenda of scientific techniques. During the past decade, these techniques have varied from cellular and molecular biology, to genetics and genomics, to bioinformatics and proteomics. These tools that permit new basic truths to surface and that signal their readiness for transfer to human use are ever changing. Therefore, an equally dynamic educational training program must be devised that operates with similar flexibility at this critical interface if investigators are to continue translating new truths into clinical utility, and this has generally not been put together as a coherent educational program. Finally, such investigators have a traditionally short academic “halflife.” Already late entrants into the research arena, clinical investigators are often early departures for other jobs such as departmental chairs, deans, or industrial positions. Their ability to talk many languages from basic research to clinical parlance to operational linguistics, all gleaned from their ability to survive and succeed in acaAm J Med. 2003;114:503–505. From the Reproductive Endocrine Unit & Clinical Research Program, Massachusetts General Hospital, Boston, Massachusetts. Requests for reprints should be addressed to William F. Crowley, Jr, MD, Reproductive Endocrine Unit/Clinical Research Program, Massachusetts General Hospital, 55 Fruit Street, Bartlett Hall Extension Room 511, Boston, Massachusetts 02114, or crowley.william@mgh.harvard. edu.