Comments by J. Brian Byrd

Topic: Translational Versus Fundamental Research
by J. Brian Byrd
University of Michigan

Proposed Actions

1. Recognize that diminished public appreciation of fundamental science is a predictable outcome of a lack of translational research activity on the part of physician-scientists.

2. Encourage & incentivize physician-scientists to conduct research with patient contact, rather than “splitting themselves in two,” treating patients in the clinic and mice in the laboratory.

3. Increase the salary of physician-scientists engaged in this patient-oriented research.

4. Actively work to remove the stigma of the negative study, a stigma which disproportionately punishes scientists engaged in slow-cycle research, particularly studies in patients.

5. Build infrastructure to support recruitment of patients for investigator-initiated biomedical research studies.

6. Educate the public about the singular importance of participating directly in studies of health and disease.

7. Avoid shunting funding away from detailed, laborious disease phenotyping in patients to population-level observational clinical research with little granularity and greater confounding.

8. Invite the vanishing, but still extant clinical investigators to the table in study sections, discussions of research policy, and other key discussions of the future of research.

9. Educate the public and legislators about the value of fundamental research, as well as the void of patient-oriented research.

Optional Comments on the Problem

Biomedical research in the 1960’s was an enterprise that often involved studying patients with diseases. See any table of contents of the Journal of Clinical Investigation in the 1960’s. The predecessor of the American Society of Clinical Investigation (ASCI) was named the Association for the Advancement of Clinical Research (AACR). Its president said over a century ago that “clinical science will not thrive through chance investigations by friendly neighbors from the adjoining practical and scientific domains.” His correct idea was that clinicians per se are ill-prepared and have no time to adapt basic science findings to use in the clinical setting. As AACR renamed itself ASCI, there was reason to believe its focus still would be clinical research, and specifically the training of skilled clinical investigators. These highly trained research-oriented clinicians were the few people with the skills and societal sanction, funding, sense of direction, and protected time to translate new ideas to the benefit of patients.

The workforce of investigators with both clinical & scientific training is currently tiny. Let’s look at why this happened.

The rise of molecular biology in the 1980’s led physician-scientists to turn away from patient-oriented research. Producing and refining transgenic mouse models was easier, faster, less expensive, attractively reductionist, and more certain to secure continuous funding. Thus, fundamental investigation in the transgenic mouse became industrialized, and physician-scientists were extremely attracted to this new “normal science.” Collectively, these mouse models have produced a vast number of findings that might be of benefit to humanity, but only a tiny fraction of the most promising ideas have been evaluated. The physician-scientists who could pursue this work, who have the passion, interest, knowledge of the unmet medical needs, and clinical (i.e., human) investigational skill set to complete this work are almost universally working in mice or sometimes human tissues, to the exclusion of recruiting patients for studies. The result has been a great decrement in patient-oriented research activity as a percentage of all research endeavors. There is a vast deficit in translation relative to the pipeline of ideas ripe for translation. Physician-scientists are at the heart of this issue. Since the 1980’s, the physicians qualified to translate science to the bedside very frequently had satisfying careers in which they rarely or never recruited patients for studies. Incentives to participate in patient-oriented research were absent, or nearly so.

As a consequence, a tragic semantic substitution has occurred. In the place of research involving recruitment of patients, “clinical investigation” is now conducted in mice. See any table of contents of the Journal of Clinical Investigation from recent years. Similarly, research in mice is described as translational. Why is this sleight of hand required? The reason is that if we cannot have research on diseases in patients, we can pretend that research in mice is the same activity. This diminishes the value of two activities: biomedical research in patients, and biomedical research not conducted in patients. Each is spectacularly and self-evidently important. The current crisis-level deficit in biomedical research activity is in investigator-initiated research with patient contact. Reinvigorating this form of research should be the number one priority of the biomedical research system in the United State, lest it become a biology research system devoid of the medical.