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Biomedical inquiry as it is practiced in America today is an amalgam of three different kinds of research: basic research, population research, and clinical research. While all three are of critical importance, it is clinical research that underpins our national medical efforts. Only clinical researchers are able to apply the knowledge of the cell and organ systems developed by basic researchers, and the population data gathered by epidemiologists and biostatisticians, to patients, making this knowledge and data relevant to medical practice by “translating” it into novel diagnostics and therapeutics.

Unlike basic researchers, who work with model systems in laboratories, clinical researchers work with patients in hospitals. It is clinical researchers, many of whom are also laboratory workers, who conduct research on human subjects, applying new technologies to the analysis of the mechanisms of human disease and evaluating the effectiveness of new therapies. It is clinical researchers, working with population scientists, who conduct trials of new drugs and epidemiological studies. They also evaluate the quality of health services and the outcomes of medical procedures.

Without basic research, of course, there would be no new medical advances to test in practice. But without clinical research, all the knowledge acquired through basic research would remain sequestered in books and journals.

A case in point is Gleevec, the new trade name for STI571, a drug produced by Novartis. It is an inhibitor of certain signal transduction molecules called tyrosine kinases. In creating Gleevec, the chemists at Novartis depended not only on the basic research produced in universities, but also on the clinical research done in a hospital. Basic scientists isolated the new chemical STI571. But it was a clinical investigator who first applied the new chemical in laboratory studies of the white cells in chronic myelogenous leukemia. He found that the leukemic cells stopped proliferating in vitro when the drug was present. He then launched a clinical trial that was remarkably successful. In twenty-five patients, the disease disappeared with almost no toxicity. Gleevec is the first “smart” chemotherapeutic agent: it works like an antibiotic and blocks a specific pathway that is not required by normal cells. But without the efforts of a clinical researcher, the therapeutic use of the new chemical might have gone undetected.

Gleevec is not an isolated success story, and I am convinced that we can do even better in the future. But in order to quicken the pace of progress, we need to address some of the persistent problems faced by clinical researchers.

One problem is disciplinary: there has been a towering increase in the budget of the National Institutes of Health (NIH) in recent years. The number of Ph.D.’s applying for NIH research grants has risen pari passu, but the number of M.D. applicants has increased very slowly. These changes jeopardize the traditional composition of clinical research teams. At the moment the principal investigators holding clinical research grants from the NIH are evenly divided between those holding M.D. and Ph.D. degrees. Though new advances will require effective clinical research in all areas, particularly great strides must be made in the translational component of clinical research. By translational, I mean research that uses the findings of basic science and applies that new knowledge in the clinic–in patients with the very diseases that are being studied in the laboratory. Most translational investigators should hold the M.D. degree, because safe application of new therapeutic interventions requires the oversight of a trained physician.

The prospect of a shortage of clinical researchers with M.D.’s could be explained by several factors, including the effects of the managed care revolution in medicine. Managed care has minimized reimbursement of academic hospitals and clinical departments. The dwindling resources of academic health centers have deprived physician-investigators of the cushion formerly offered by their institutions to protect them from the vicissitudes of NIH funding, relieve them of administrative burdens, and provide them with data managers, research nurses, information scientists, and core laboratories. Furthermore, aspiring physician-investigators must invest in at least twelve years of training at low salaries and with staggering tuition debts.

The era of molecular medicine has brought vast new scientific power to the medical researcher. However, the accrual of that power requires far more scientific experience and methodological skills than was the case two or more decades ago. Acquiring the necessary laboratory skills demands nearly the full time of the young physician-faculty member; at the same time, the complexities of modern clinical medicine have grown apace. A translational investigator must be highly skilled in both fields, an increasingly difficult task. Forced to choose, and often feeling undervalued, underpaid, debt-ridden, and priced out of the housing market, a growing number of promising young translational clinical researchers are dropping out in order to pursue more secure and, they hope, more lucrative medical practices that fully exploit the clinical skills they have developed over a very long period of training.

Given the stress on young clinical investigators and facing an era in which academic health centers struggle to find the financial wherewithal to help them, we need to rethink our research support policies. We simply cannot fund every worthy individual. Instead we should rethink our academic planning and evaluation process. We need to establish teams of basic, population, and clinical researchers, urge collaborations among the disciplines, define the contributions of a team, and then dissect the individual contributions of the team members. This would encourage cost savings and productive collaborations directed toward the solution of important medical problems. Every team needs a leader, and perhaps the leaders should receive most of the recognition, but each of the contributing skills must be rewarded, because the project cannot succeed unless all of the participants, each of whom brings a unique skill to the project, are firmly motivated.

No matter what system of funding and academic evaluation we may adopt, we clinical researchers and academic health centers must constantly remind ourselves that the final arbiter of our value is the public. Throughout the postwar period, we have been blessed with remarkably strong public and political support in the United States. But there are signs that this support may be weakening–and that clinical researchers are partially responsible for the change.

Clinical research can inspire popular fear, especially if media reports suggest a callous disregard for individual patients. We encourage criticism if we fail to conduct clinical trials within strict ethical guidelines and with clear and unambiguous informed consent. Consider, for example, the recent gene therapy trials at the University of Pennsylvania. Because these trials resulted in a patient’s death, they provoked a public outcry and reinforced the calls from critics for far more stringent external control if the public is to be properly protected.

Our relationships with the pharmaceutical industry can also leave us open to criticism. We depend on drug companies not only for the development of new drugs, but also for certain kinds of financial support. The terms of that support must be very carefully defined. Grants from pharmaceutical companies cannot be seen as endorsements by academic investigators for the products of the grant-making companies. Academic investigators must be free to publish results, whether they are supportive or critical of a specific drug. Universities and their affiliated academic health centers must be scrupulously careful to protect the intellectual independence of their investigators. This can be difficult, particularly when companies not only support the specific research but also make large unrestricted gifts to the university or hospital.

Recent events at the University of Toronto drive this point home. At one of the university’s affiliated institutions, The Hospital for Sick Children, a faculty member came under attack for expressing doubts about a drug produced by a relatively small company that had also given a major gift to the hospital. Angry colleagues harassed the investigator on the job. The hospital and university did little to support her, and the case continues to fester. The reputations of both the university and the hospital have been damaged. In another case involving the University of Toronto, it has been alleged that the university withdrew an offer to hire a well-known British psychopharmacologist immediately after he had publicly criticized the safety of a drug produced by a major pharmaceutical company that was also a major benefactor of the university.

These cases find their way regularly into the media and understandably provoke dismay. The financial stake of researchers in their own research can shake public confidence in the integrity of that research. It is important for publicly supported academic health centers to do excellent basic and clinical research and to patent useful inventions that arise from the research effort. Standard patent and licensing arrangements enable pharmaceutical and biotechnical companies to produce the drugs and screening techniques necessary for developing new medical therapeutics and diagnostics. It is perfectly reasonable for the research institutions and their inventive investigators to profit from important basic discoveries. But institutions and funding agencies must develop thoughtful and rational guidelines in this contentious arena. I firmly believe that a central guideline should be a complete prohibition of any researcher receiving consulting fees or stock options from a company that produces a product if that investigator’s research involves studying the product in his or her patients. It is not right for a physician to turn a research patient into a source of personal profit.

Despite all the problems I have described, clinical researchers still hold the future of medicine in their hands. If they work hard and honorably enough they will, in the next two or three decades, successfully lower the defenses of persistent diseases. That is a remarkable prospect–one that should inspire young physicians to join the clinical research teams that are committed to winning these victories.