CHAPTER 7
DISEASE AND DISCOVERY

The five case studies presented in this volume, as we pointed out in chapter one, revolve around a common theme that has been largely neglected in analyses of past and present biomedical research: many paths of inquiry and discovery about life processes have begun through efforts to understand the nature of and to intervene in states of disease. Although they focus, in current parlance, on the flow from categorical or disease-oriented research to basic research and consequent advancement of fundamental knowledge, rather than the more frequently charted flow from basic research to clinical application, these case studies belong to a larger body of historical and sociological studies, and less directly, policy studies, that have sought to articulate the processes involved in various areas of research.

In the realm of policy-related studies, a number of reports over the past decade have analyzed selected examples of research-to-application developments in biomedicine and other fields. Either explicitly or implicitly, these reports have been concerned with bolstering a given position on the "proper" allocation of federal funds for "applied" or "basic" research, in response to the debates engendered by President Johnson's call in 1966 to "zero in on the targets by trying to get our knowledge fully applied" (see chapter one).

The first of these studies, commissioned by the Department of Defense, was Project Hindsight, in which a group of engineers and scientists retrospectively analyzed the development of 20 major military weapons (Sherwin and Isenson 1966).

Although it was issued only as a "first interim report," and despite methodological criticism of the short historical time-span of the analyses and the validity of transferring findings from the development of military weapons to biomedical research, Project Hindsight's arguments for "targeted" research buttressed the new policy climate in Washington vis a vis how federal support for research ought to be apportioned.

Given the strongly and widely held counter-ethos among those engaged in biomedical research, affirming the importance of "basic, undirected" research for medical progress, it is scarcely surprising that Project Hindsight triggered a series of rebuttals, in the form of case studies documenting the role of basic research in various medical innovations and other areas of technological advances. These included Shannon's account of the development of the polio vaccine and Visscher's study of the rubella vaccine, and the studies of various technological innovations commissioned by the National Science Foundation (Shannon 1967; Visscher 1967; Illinois institute of Technology 1968/69; Batelle/Columbus Laboratories 1973). More recently, critiquing studies such as the above for being either "anecdotal" single case reports or for being biased because the examples were selected by those who did the analyses, Comroe and Dripps used panels of consultants to help them select and analyze the development of ten major advances in cardiovascular and pulmonary medicine and surgery since the early 1940s (Comroe and Dripps 1974, 1976; see also Comroe 1977).

All of these post-Hindsight studies, particularly the work by Comroe and Dripps by virtue of its methodology, argue persuasively for the importance of basic research in the pursuit of greater knowledge about disease states and diagnostic, preventive, and treatment capabilities.

As historians of science and medicine, familiar with a range of developments in many fields over many centuries, we could not but argue that basic research plays an essential role in shaping medical progress. Nor, as we stated in chapter one, has this study sought to argue otherwise. But, accepting the fact that research proceeds in complex ways and by many routes, it would be equally absurd to argue, as did an eminent biomedical researcher in 1977, that "it has yet to be shown that basic science progress can be a byproduct of applied research" (Visscher 1977).

Such completely unidirectional statements, while rare, reflect in part both stereotypic views about the relationship between basic and applied research, and the dearth of well-documented studies of how "important elements of the fundamental biomedical sciences of the past have emerged from the study of human beings and their diseases" (Report of the President's Biomedical Research Panel, App. A 1976, p. 16).[END OF PAGE 115]

The present study has been directed primarily toward beginning to fill in this gap in the literature on biomedical research. As such, whatever policy implications may be read into it should be of a different order from the Project Hindsight genre. For, we make no arguments about, and draw no conclusions concerning, the relative importance of basic or categorical research and in turn the relative balance between the two broad categories that should obtain in federal research funding. Indeed, for reasons that we also explored in chapter one, we have by and large avoided labelling the lines of research that we examine in the case studies with terms such as applied, categorical, mission-oriented, fundamental, basic, etc.

From our perspective, if this study has any latent policy "message" it is to underscore the fact that scientific knowledge and discoveries come from many sources, by often unforeseen routes, and that we still know far too little about the course and determinants of those research processes that may variously result in therapeutic innovation or in fundamental knowledge. Here, we concur with the views of a Rand Corporation report for the President's Biomedical Research Panel concerning the need for "improved conceptual frameworks of scientific progress." The report, characteristically, focuses on the flow from basic to applied biomedicine and notes only parenthetically that "questions arising in an area of clinical medical science may become important research questions for several areas of basic medical science." But, more generally, the report observes that "as a practical matter, no analytical models adequately capture the processes by which biomedical R & D results flow into medical practice [or, we would add, the converse processes]. The search for a single comprehensive model that simultaneously has great generality and great capacity to reflect the detail of these processes is futile. Rather, the search should be for a number of models of intermediate levels of generality, able to handle a wide variety of cases with adequate respect for their detail and complexity" (Report of the President's Biomedical Research Panel, App. 8 1976, pp. 77, 78).

Within the scope of this study, however, we have not attempted to construct an analytical model for the flow from categorical to basic research, nor to test existing models of the flow from basic research to medical practice to see how well they can incorporate the "reverse lines" that we have traced in our case studies. Neither, and this would be perhaps the more intellectually satisfying and ultimately useful task, have we examined fully the types of research and discovery processes that we have analyzed in relation to various philosophical and sociological theories about the nature of science, as one of us has attempted to for neuroscience research (Swazey and Worden 1975).

All three types of model building and testing are needed to help us better understand how categorical research can contribute to basic science research, and to better understand the nature of scientific research and discovery more generally. Such efforts, however, will be sounder when there is a larger body of detailed case studies, whether of the sort in this volume or the types sponsored by the NSF or conducted by Comroe and Dripps.

The type of historical analyses we have done, as we have noted, is only one of several possible approaches, one we used because of our particular shared training in the history of science, and because one of us has found the detailed case study format a particularly congenial and fruitful mode of historical and sociological analysis (Swazey 1969, 1974; Fox and Swazey 1974; Worden, Swazey, and Adelman 1975).

A particular merit that we find in the case study format is that it can reveal and illustrate many processes and phenomena involved in research. Thus, each of our cases does more than document the fact that categorical research can contribute in significant ways to the advancement of basic knowledge.

The other phenomena and patterns that the cases illustrate include, first, the nature of serendipity, a phenomenon we discussed at some length in chapter one in relation to its frequent misinterpretation as a discovery resulting from a totally fortuitous event, and its invocation as the distinguishing characteristic of basic research. As we noted, more careful historical and sociological analyses show that serendipity involves far more than chance - that, in Pasteur's famous dictum, chance favors the prepared mind - and that there is no inherent reason why serendipity should occur only in basic rather than applied or categorical research. Both of these points are borne out, once again, in the instances of serendipity recorded in our case studies: for example, Pasteur's observation of fermentation in the solution of racemic ammonium tartrate lying in his laboratory; Eijkman's pursuit of the sudden outbreak and equally sudden disappearance of polyneuritis in his chickens; Minkowski's discovery that the removal of a dog's pancreas caused diabetes mellitus; and Ingram's decision [END OF PAGE 116] to study the protein chemistry of sickled cells.

A second point about research that we addressed in chapter one was the problems that commonly ensue when, for heuristic, policy, or other purposes, one tries to neatly label a given research activity as basic, applied, mission-oriented, fundamental, etc. These problems are seen in this volume as one thinks about the work on thiamine's structure and functions by researchers such as Williams and Peters, the study of minimal diets by Hopkins, McCollum, and others, the many reasons that the strange proteins of multiple myeloma were studied in the 1950s, and, perhaps preeminently, in the work of Louis Pasteur on the diseases of wine and vinegar.

Another frequently discussed factor in scientific and technological advances is the role of technique, embracing both methods and instrumentation. Technique, not surprisingly, played an important role at many junctures in our cases. To recall but a few examples: technique helped to resolve competing theories, as was the case in surgical and aseptic techniques in endocrinology and with Pasteur's experimental denunciation of the spontaneous generation theory; permitted the identification of a new substance, the beriberi "vitamine," by means of improved assay, extraction, and purification; and detected the molecular basis for sickle cell anemia by "fingerprinting" the hemoglobin molecule.

The case studies also illustrate the important role that interdisciplinary fusions played in many of the advances we charted. As exemplified by the development of endocrinology as a field of research and the subsequent emergence of neuroendocrinology, and by the enormous yield of the mergers of genetics, microbiology, and biochemistry that engendered molecular biology, the coming together of different disciplines, with a new sharing of perspectives, interests, and methods, is an important pattern in the course of research and discovery.

Another common and important pattern in research seen in our cases, a pattern that has been analyzed in detail by Comroe, is the occurrence of lags, which may be of various types and occur for various reasons (Comroe 1976). In the delays that ensued in the acceptance of the concepts of gene action put forward by Mendel, Garrod, and Beadle and Tatum, for example, we see instances of lags that occurred in part because of the persistent feeling, in Beadle's words, "that any simple concept in biology must be wrong." The conflict of a new finding or theory with prevailing views also can cause lags in acceptance and utilization, as was partly the case in biochemical genetics and as occurred in the resistance that the Scharrer's concept of neurosecretion encountered. Here, we see elements of the pattern of resistance by scientists to scientific discovery, a pattern that has been examined in detail by sociologists, historians, and philosophers of science (see Barber 1961; Frank 1961; Kuhn 1970). Depending on their nature and consequence, as Comroe points out, lag times in research between discovery and rediscovery, discovery and acceptance, discovery and application, etc., may be too long, too brief, or of an appropriate duration. Thus, for example, what may seem at first to be an unduly long period of time between a discovery and the understanding of what that discovery means, as in the over 100 years between the discovery of Bence Jones proteins and their identification, may turn out to be an appropriate "latency" period when one examines the knowledge and technique prerequisite to the proteins' characterization.

The case studies further bear upon several questions about the development of theories that have long drawn the attention of those interested in the nature of science, and engaged them in often intense debates. In traditional formulations, briefly, science is viewed as an "objective" endeavor that uses the cutting "edge of objectivity" to separate truth from error. Traditional accounts of the nature of science, such as those perpetuated in textbooks, also place strong emphasis upon the value of hypothetico-deductive thought, the use of experimentation, and the scientist as one who "does not blindly accept established dogma" (Brush 1974; Gillispie 1960).

Another major component of traditional views of the nature of science is that science progresses incrementally, adding each discovery, like a new brick, to previously laid bricks in the slowly rising edifice of "truth." This image of science, as Ragnar Granit has noted, is reflected in one of the most prestigious symbols of scientific achievement, the Nobel Prize. "The young scientist often seems to share with the layman the view that scientific progress can be looked upon as one long string of pearls made up of bright discoveries. This standpoint is reflected in the will of Alfred Nobel, whose mind was that of an inventor, always loaded with good ideas for application. His great Awards in science presuppose definable discoveries" (Granit 1972, p. 3).

Without asserting that science never operates in the ways outlined above, views contradicting traditionally accepted accounts have long been offered by scientists themselves, as well as by philosophers, historians, and [END OF PAGE 117] sociologists; perhaps the most influential and controversial "unorthodox" account in recent years has been Thomas Kuhn's analysis of the structure of scientific revolutions (Kuhn 1970; Lakatos and Musgrave 1970; Scheff ler 1967; Swazey and Worden 1975).

One recurring pattern seen in our case studies that is particularly relevant to these varying interpretations of the nature of science, and on balance favors views such as Kuhn's, concerns the ways that scientific theories develop. Scientific theories, according to the canons of experimental science, arise out of data, and stand or fall solely on the basis of objective scientific evidence. To this thesis our case studies, as have many others, say "not so." We have, for example, already noted the types of resistance by scientists to new discoveries or theories, a recurring pattern that argues against the "edge of objectivity." Prevailing theories, secondly, may determine, at least for a time, the type of evidence that researchers seek, or the explanation they offer for a particular phenomenon. Thus, in two of our cases, we saw how the infectious disease model was applied to both the explanation of beriberi and the search for its cure, and to the view that the ductless glands function to neutralize or remove toxins in the blood.

Correlatively, we have encountered a number of the classic theoretical controversies that run throughout the history of science and medicine. These include Pasteur's engagement in the long debate over spontaneous generation; the competing theories of endocrine function in the late nineteenth and early twentieth century; debates over the nature of what came to be known as vitamins; the long and often heated battle between proponents of humoral and cellular theories of immunity; and the play between selective and instructive theories of antibody formation. The resolution of such controversies involves more than just the accumulation of new scientific evidence or what Kuhn calls "the methodological stereotype of falsification by direct comparison with nature" (Kuhn 1970, p. 77). Rather, as Kuhn argues, historical studies of scientific development indicate that "the act of judgment that leads a scientist to reject a previously accepted theory is always based upon more than a comparison of that theory with the world. The decision to reject one paradigm is always simultaneously the decision to accept another, and the judgment leading to that decision involves the comparison of both paradigms with nature and with each other" (Kuhn 1970, p, 77).

Finally, in this brief consideration of the relationship between scientific theories and data, scientists themselves have often made an "unorthodox" admission: their decisions as to what and how they will observe, as well as how they may subsequently interpret those observations, are predicated by their theoretical constructs, rather than vice versa. One of the best expressions of this way of "doing science" was made by Albert Einstein in 1926, when he responded to Heisenberg's statement that only observable magnitudes must be used in formulating a theory like that of relativity.

Possibly I did use this kind of reasoning, but it is nonsense all the same. Perhaps I could put it more diplomatically by saying that it may be heuristically useful to keep in mind what one has observed. But on principle, it is quite wrong to try founding a theory on observable magnitudes alone. In reality the very opposite happens. It is the theory which decides what we can observe. (quoted in Brush 1974, p. 1167)

Three comparable counter-instances to traditional views of doing science come at once to mind from our cases. Pasteur's preconceived and strongly held ideas about the role of molecular dissymmetry in the "organization of living organisms" both helped lead him to search under his microscope for living organisms in ferments, and structured many of his interpretations of his observations. Linus Pauling and his colleagues came to their analysis of sickled cells with Pauling's concept of "molecular disease" already in his mind, a concept triggered when he first discussed sickle cell anemia with William Castle in 1945 and related what he learned to his prior work on the nature of antibodies. Thirdly, reflecting in his Nobel Prize address on his and Tatum's experiments with Neurospora, George Beadle said, much as had Einstein: "It is sometimes thought that the Neurospora work was responsible for the 'one gene-one enzyme hypothesis . . . The fact is that it was the other way around - the hypothesis was clearly responsible for the new approach."

For us, in sum, Today's Medicine, Tomorrow's Science does more than chart the ways that the study of disease problems can lead to new vistas in our knowledge of basic biological phenomena. We do not claim to have made "discoveries" in this study, as that term is commonly understood to mean new and unexpected findings. But if, as Ragnar Granit suggests, the real goal of a [END OF PAGE 118] researcher's labors is understanding or insight, rather than the "eureka" of discovery, it is hoped that these essays have contributed to our understanding of the complex enterprise that is biomedical research. [END OF PAGE 119]

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