Perspectives in Biology and Medicine

MAKING PROGRESS: DOES CLINICAL RESEARCH LEAD TO BREAKTHROUGHS IN BASIC BIOMEDICAL SCIENCES? ELLIOT S. GERSHON * The need for basic science research to generate advances in clinical understanding of disease biology is an axiom of biomedical research and has no credible opposition (see [I]). However, a corollary is often drawn, that this is a one-way process; in other words, basic biology advances do not follow from applied or targeted (clinical) research. This is entirely wrong. Ever since the beginnings of scientific medicine, clinical observations have repeatedly generated breakthroughs in biology that could not, at the time, have been otherwise achieved. This assertion has been made before [2, 3] , but it bears repeating now, particularly in relation to clinical observations on disease or its treatment, followed by research aimed at identifying a biological aspect or mechanism of these observations (called disease-oriented research [DOR] by Goldstein and Brown [4] ) . There are many historical examples that exemplify this point, and I have chosen two instances to present here: the discovery in the 1940s that DNA is the substance that carries genetic information, and the discovery in the 1990s of unstable DNA sequences as a new mechanism of mutation. These are basic science breakthroughs, discoveries of new biological mechanisms of fundamental importance beyond the diseases on which the researchers were working. For a reader not immersed in today's biomedical research community, it might seem obvious that these are indeed basic science breakthroughs, but itwould also appear that they resulted from basic research. The popular understanding is that basic science is what occurs in the laboratory and clinical research is research on patients in the clinic or hospital. Within The author wishes to thank Dr. Alan Schechter for providing stimulating discussions and excellent advice during the preparation of this paper. *Clinical Neurogenetics Branch, National Institute ofMental Health, Bethesda, MD 20892. [Current address-Dept. ofPsychiatry, Biological Sciences Division, University ofChicago, Chicago , IL 60637.]© 1998 by The University of Chicago. All rights reserved. 0031-5982/98/4104-1073$01.00 Perspectives in Biology and Medicine, 42, 1 ¦ Autumn 1998 95 the research community, however, the prevailing outlook conceives of two types of research, basic research and applied (including clinical) research. Basic research, in this view, is research based on a hypothesis about how biology works (e.g., that a certain enzyme exists), whereas clinical research is applied research, which determines if known biological mechanisms apply to a disease or treatment (e.g., testing whether this now-discovered enzyme is altered in a particular disease). It is also generally understood that the borderline between the two kinds of work is not always distinct, and in recent years the concept of "translational research" has come into use. Now, translation from one spoken language to another can flow in either direction, but as currently used in biomedical research, translational research refers to a one-way process in which the findings of basic research are applied to clinical problems. This derives from the sense in which translation is used in molecular biology to refer to the decoding ofinformation contained in a nucleic acid sequence to determine the amino acid sequence of a protein. Although the term is useful to describe research thatjoins basic and clinical work, its use reveals the prevailing directional bias that the most basic (and most important) discoveries are made in the basic laboratory and applied to the clinic. This bias is a costly one. It enshrines an antagonistic "two cultures" mentality in the vast segment of society related to biomedicine, and it inhibits intellectual voyages of discovery that do not go in the prescribed direction, thus inhibiting rather than stimulating scientific progress. To show that these consequences are plausible, I will offer a brief description of two historical breakthroughs that occurred, about 50 years apart, in the course of applied laboratory research on disease characteristics. In each case, the discovery would not have followed from the basic science of its day, but did follow from the intellectual temerity of the researcher wrestling with a clinical question. The Discovery that DNA Is the Substance that Contains Genetic Information Oswald Avery, a physician researcher, at the Rockefeller Institute, labored with his colleagues for manyyears to discover the...