Keith A. Wailoo

Department of Social Medicine and Department of History, University of North Carolina at Chapel Hill

This chapter focuses not on genes per se, but on the history of genetics itself. Over the past quarter-century, many historians of science and medicine have engaged in the study of such scientific disciplines and of the diseases scrutinized by these discipline (Fox and Fee, 1990; Rosenberg and Golden, 1992; see also Bates, 1992; Bayer, 1987; Brandt, 1985; Brumberg, 1988; Jones, 1981; Leavitt, 1996; Rogers, 1992; Rosenberg, 1962; Rosner and Markowitz, 1991). For historians, the biomedical sciences are themselves important historical formations —always changing, especially as their tools and objects of study have changed. As biomedicine itself has become an important force in our society, historians of biomedicine have become increasingly interested in the intellectual and technical developments that shape what scientists themselves say about disease. This historical endeavor has taken us, of course, into the realm of particular disciplines, such as genetics, immunology, virology, and so on. But as the very character of biomedicine has changed, our historical studies have taken us also into the history of society, of social movements, and of politics.

Thus, the recent history of oncology and breast cancer could not be written without understanding the significance of the women’s movement in the late 1960s and early 1970s. The history of immunology, virology,

and AIDS could not be written without attention to the history of gays in American culture. And the history of cancers like leukemia could not be written without attention to the prominence of children and catastrophic children’s diseases after World War II; and the history of prostate cancer could not be written without attention to the demographic history of men and their aging in late twentieth century America. The history of disease in this century also takes us increasingly, therefore, into the political realm—into the realm of disease-specific legislation, policy making, and activism. And finally, the history of disease introduces us not only to science and the history of scientific theories of disease, but also to the history of technology. By the history of technology, I mean to focus on new drugs and new diagnostic technologies like the HIV test, on the ways they are used to shape public health agendas, and on the economics of how these technologies are used in the context of managed care. These are the kinds of concerns—the intellectual, the social, the political, and the cultural concerns-that shape the work I do as a historian of medicine, a historian of the biomedical sciences, and a historian of disease.

Using this kind of model—this very synthetic, complex model of disease—historians and other scholars have been writing fascinating new histories over the past 20–30 years. Our knowledge of disease is expanding dramatically through these histories. I can cite, for example, a number of examples of innovative histories. The history of anorexia nervosa, written by Brumberg (1988), reveals the entanglement of this eating disorder with the history of diet, nutrition, and also the history of body image among adolescent girls and young women in American culture. We see in recent histories of AIDS that the disease can be studied in particular cultural contexts. These studies —such as Farmer’s (1992) study of AIDS and Haiti—make us aware that the face of disease varies not only from one time to the next, but also from place to place (Farmer, 1999). And historians of medicine and the biomedical sciences have not been afraid to tackle controversial issues. Bayer (1987), for example, has explored the ways in which the very definitions of disease have changed with moral concerns in America. His study examines the ways in which homosexuality was viewed as a “disease”—and particularly how it first appeared as a “disease” in the Diagnostic and Statistical Manual of the American Psychiatric Association in the early 1950s, only to be removed in the 1970s in a very different cultural climate. The story of this disease’s evolution is linked, of course, to patterns of psychiatric categorization and to changing social mores.

It might be said that these types of disorders—anorexia nervosa, homosexuality, and AIDS—because they are so controversial, are particularly vulnerable to being shaped by cultural forces. My work, however, examines diseases and medical fields that we might regard as not so vul-

nerable to cultural influences—the cancers, immune system disorders and immunology, the definition and management of pain, etc.

Diabetes, however, provides an excellent case in point of the complexity of the historical evolution of disease (Bliss, 1982; see also Feudtner, 1995). After the discovery of insulin in the early 1920s, one of the ironies of this sort of medical progress has been the transformation of diabetes from an acute, fatal disease into a chronic, fatal disease —a disease that has now become a lived experience. After insulin in the 1920s came penicillin in the wake of World War II, and these two technological therapeutic developments transformed diabetes into what we now recognize as a chronic disease—a disease that affects a far larger group of people than at any other time in human history. Thus, one of the ironies of technological development—from the standpoint of the historian of science and medicine—is the role of therapeutic intervention in solving old problems and creating new problems. Technologies have literally altered the face of disease, bringing a kind of ironic progress in the fight against disease (Plough, 1986; see also Fox and Swazey, 1992). More people live now with diabetes and die with diabetes than ever before—because of insulin, penicillin, and the ability to treat infections and, more recently, the advent of kidney dialysis to treat late-stage renal failure in diabetes patients (Peitzmann, 1992).

The story of diabetes can be taken as an archetypal story of disease in the twentieth century. We have seen the dramatic decline of infectious diseases that predominantly affected children—including diphtheria, tuberculosis, pneumonia—and, in the wake of that decline, we have seen the rise of new diseases associated with (1) medical progress, (2) aging of the population, and (3) increasingly higher cultural standards regarding health and well-being. This sort of ironic progress was captured in a joke by a colleague of mine at the University of North Carolina at Chapel Hill. He told me the anecdote of two men arguing about which of their people came from more culturally superior stock. Amassing evidence for their superiority, they went back and forth. Finally, one man said to the other, “When your people were still living in caves and painting themselves blue, my people already had diabetes.” This is the sort of progress I believe we can witness in the history of disease in the twentieth century.¹

My concern as an historian of the biomedical sciences is not with the history of disease alone, but with a particular relationship that has shaped that history. Particularly, my research will focus on the triangular relationship among science, the human experience and understanding of disease, and clinical practices. By “the science of disease” I mean the emergence and transformation of models of disease as they have been developed in various scientific disciplines. One aspect of this research project involves investigating how science has, or has not, influenced how pa-

tients think about their diseases. This aspect of the research examines the relationship between scientific tools and theories and the individual, cultural, political, and social meanings of disease throughout the century. Another aspect of the research explores how these two ways of thinking about disease—the human experience and the scientific understanding—have, or have not, informed clinical practice from one time to the next.² This is primarily the model I have used both in my previous work and in the model that I plan to use in the pursuit of the James S. McDonnell Foundation Centennial Fellowship Program.

My previous work has focused on blood and ideas about blood disease. My first book, Drawing Blood: Technology and Disease Identity in Twentieth Century America, was not simply a study of blood diseases that have become more prevalent (Wailoo, 1997a). It also involved the study of diseases that have disappeared over time. (It is a curious fact about historians that we like to study things that no longer exist, for they reveal as much as does the study of ideas or things that live on.) One of the diseases in my study was a disorder called “splenic anemia,” a disease that came into existence in the 1890s but which was gone by the 1930s (Wailoo, 1997b). The question I asked was, “how could a disease come into existence and then disappear 40 years later?” To study that problem, I looked at the people who were writing about splenic anemia, and they were, by and large, abdominal surgeons. What I noted was that this was an era when abdominal surgery was coming into its own. In the wake of antiseptic surgery in the late nineteenth century, the human abdomen became something that surgeons could actually venture into with the possibility of solving problems—rather than creating infections that would kill their patients. In the wake of antiseptic surgery (and the lowered risk of mortality from abdominal operations), surgeons began to theorize about the way that certain organs worked. One of these organs was the spleen, which previously was a mysterious organ that seemed to have no particular function. Surgeons were called upon at this time to remove many injured spleens, and they observed that removal of the spleen resulted often in a rise in the red blood cell count. They theorized that injured or enlarged spleens might be responsible for low red blood cell counts, thus inventing a new disease concept—splenic anemia. They argued that removal of the spleen could be curative in these cases of “splenic anemia.”

This way of thinking about a new disease gained prevalence in the early twentieth century and then disappeared for a number of reasons in the 1920s and 1930s. One of the reasons it disappeared was because some of the colleagues of this generation of surgeons began to question this kind of dubious definition of disease, and (moreover) internists and pathologists questioned the surgeons’ diagnostic practices as well as their optimistic assessment of their rates of “cure.” This kind of scrutiny of

surgeons became especially rigorous in the changing hospital environment —a more corporate workplace where diagnosis was no longer a matter for individual authorities, but was now a corporate (group) activity involving a number of specialists. With these changes in the hospital work, the disease “splenic anemia” gradually disappeared. It did so, according to one renown surgeon, not because it did not exist, but because it was not allowed to exist—that is, all the patients who surgeons would diagnose with splenic anemia were now being diagnosed with other disorders by other specialists. And surgeons were simply not given the kind of freedom to operate that they had been given in the first two decades of the century.

Such stories of how a disease moves through time in a clinical context are complicated. They are entangled with clinical politics, with the changing science of disease as practiced by different specialists, with speculation and theorizing, and (as discussed below) with the history of patients and changing attitudes toward patients. It is this particular relationship—among science, medicine, and patients ’ perspectives on disease—that I seek to explore through this project.

The history of the patients’ perspectives on disease takes us into the realm of trying to understand individual experience of illness, culture attitudes, as well as patients ’ social and political concerns regarding health care. To explore the scientific perspective, of course, we must learn more about the history of particular disciplines, about disciplinary debates, and about the theoretical models and technologies used by particular disciplines to shape their understanding of disease. Finally, the project explores how all of this is applied (or not applied) in concrete clinical settings, shaped by the style or politics of specialties such as surgery, pediatrics, obstetrics, and so on. The goal of the study is to examine how this interaction has worked in the course of the twentieth century and how this interaction has shaped the history of disease in this century.

A current example of this dynamic reveals the continuing complexity of this relationship of science, medicine, and human experience of illness. Just a few years ago, the discovery of the BRCA1 gene for breast cancer began to transform the ways in which patients and clinicians as well as scientists thought about what breast cancer is and how we should respond to it. One of the results of the discovery of the BRCA1 gene has been an increased awareness of the hereditary nature of some breast cancers (indeed a tiny number of breast cancers). Inheritance of the BRCA1 gene explains why only a tiny percentage of women develop breast cancer. Yet the level of cultural sensitivity to new findings in genetics is so high that such findings have been widely disbursed. The spread of information about the “inheritance of breast cancer” has produced confusion rather than clarification of thinking about breast cancer. As one recent article in

the New York Times notes, it has produced a combination of new data, hope, fear, and confusion (Grade, 1999). The Times article was based on a clinical study that suggested that many, many women are convinced that breast cancer is hereditary—many more women than ought to believe it. And this perception has important clinical and human consequences. Many women and their physicians misread the message of science, believe that the presence of the BRCA1 gene determines that cancer will appear, and increasingly opt for “preventive mastectomies ” in order to safeguard against a cancer that has not yet (and may not) appear. The popularity of the belief in the inheritance of breast cancer and genetic testing has much to do with the importance of genetics as a biomedical specialty in our time (not unlike the importance of abdominal surgery in the early twentieth century). Indeed, if there is a general conclusion to be drawn here it is that even at the end of the century, the interaction among scientific findings, human perceptions, and clinical practices continues to be complicated and problematic.

My project involves an eight-year study of four different categories of disease, disorders, and illness experiences—cancers, genetic diseases, disorders associated with the immune system (from smallpox to polio to AIDS), and the problem of pain (Mann, 1988; Pernick, 1985; Rey, 1995). Within these vast areas, I have chosen to write the history of particular disorders—a task that I believe can capture some of the complexity of the history of the fields themselves. The goal at the end of the project is to produce a synthetic study of disease in the biomedical sciences in the twentieth century that can speak not only to patients’ experiences as they have evolved, but a history that can inform contemporary clinical debates and can inform science policy as well. In the remainder of this chapter, I discuss the history of one genetic disease—cystic fibrosis—and present a model for how this project will unravel the history and evolution of particular diseases.

Because cystic fibrosis (CF) is one among several genetic disorders and fields that will be a focus on this project, it may be useful to say a few words about some of the other areas under study. Before describing its historical evolution as a disease, it might be useful to say a word or two about why these four areas—genetic disease, immunology, cancer, and pain—have been selected for this project. These particular areas, I argue, illuminated the transformation of disease in the twentieth century. In their different ways, they highlight some of the major shifts of the past 100 years—such as the decline of acute infectious diseases associated with

childhood and the rise (almost in the wake of that decline) of new diseases that were previously invisible and unseen. Among these new diseases were genetic disorders such as CF and sickle cell disease. Their rising profile in clinics across America began to occur in the post-World War II era. Also revealed in the history of these disorders is the gradual aging of the population, a process that has brought about higher prevalence of many cancers (for example).

Each of the cancers at the center of this study, however, tells its own story. Childhood leukemia and breast cancer, of course, each tell stories about the illnesses and suffering of different segments of the population and how their particular suffering has become visible in scientific, clinical, and popular culture. The visibility of these diseases is shaped not only by the visibility of those groups affected —women and children—but also by new technologies. For example, radiation and chemotherapy after World War II were direct results of the wartime research on mustard gas and radiation. In the war’s wake, these tools transformed medical institutions, creating new institutions like St. Jude’s Children ’s Research Hospital in Memphis, Tennessee. The new research hospital symbolized the high hopes that Americans invested in these new tools. The hospital also symbolized the new visibility of previously obscure childhood diseases, in this case leukemia. This was all happening in the context of the post-World War II “baby boom,” at a time in which Jonas Salk was pursuing the vaccine for polio, in which parents were signing up their children in droves for field trials despite the fact that no real serious trials had ever been done on the polio vaccine (Smith, 1990; see also Maier, 1972; Meldrum, 1994). (Indeed, the day that Salk’s field trials began was called “V-Day,” and the children who participated were handed certificates of bravery to reward their participation. There was much talk of heroism, wrapping the children in the atmosphere of wartime triumph.) It was a time of enormous faith among middle-class Americans in the science and technology that were used to solve human problems (a kind of faith that we do not see today). It is this complex of forces —the new technologies of chemotherapy and radiation, public faith in science, and the symbolism of childhood suffering—that explains why childhood leukemia rose dramatically in social prominence and why many Americans focused on this particular disease and on the new science of oncology during this era.³

In the case of immunology (and particularly the history of vaccination and transplantation), we find a different kind of clinical science —with a different history and social significance.⁴ We find a clinical science that has been shaped overwhelmingly by technical innovations such as vaccination and transplantation and by controversies surrounding these innovations. Immunology was defined by vaccines and antitoxins in the late nineteenth and early twentieth centuries (some were successful and

others failed) for disorders like diphtheria, tuberculosis, as well as poliomyelitis. The popular support for Salk’s vaccine stands in sharp contrast to a much more checkered history of skepticism and public ambivalence about vaccination. One important reason for this difference is that vaccination depends on a particular kind of faith —a willingness to believe that intervention will protect a healthy individual from a future of disease. Thus, the study of vaccination —from the early twentieth century through the age of polio, and into the era of controversy surrounding a potential AIDS vaccine—allows us to explore not only the transformation of a science and the transformation of disease problems, this history also allows us to examine the ways in which immunology has intersected with matters of individual belief and public faith.

Each of these fields, then, reflects an important transformation in science, technology, culture, and medicine in the twentieth century. Pain—the fourth area under consideration—seems to sit apart from these other areas, but its study also reveals particular features of the biomedical sciences in the twentieth century. Pain is not disease itself, but a diffuse set of experiences —some of which can be associated with disease. Pain is a clinical problem and an ongoing scientific dilemma that changes with the disease in question. But the scientific understanding of pain and the clinical approach to pain has also changed over time, varied according to context, and has been shaped by cultural attitudes.⁵ Pain relief in the context of American society is also big business —and understanding much more about the economics of disease management (a major theme in twentieth century biomedicine) will be facilitated by the focus on pain. Indeed, all of the problems I have chosen to highlight in this study—cancer, genetic disease, pain, and immunology —are areas where one sees pharmaceutical production and popular consumption intertwined. The practice of speeding relief along to the patient has been a dominant theme in American medicine, and this practice has also been important in shaping scientific ideas about disease, in shaping clinical practices, and in shaping how patients think about their disorders.

In this eight-year project, the first two years will be dedicated to studying the cancers, the second two-year period will be devoted to studying pain, the third two-year period will focus on immunology, and the final segment moves to the history of genetic disease. The research process will bring together scientists, clinical practitioners, clinical researchers, policy makers, and historians to talk about not only this history, but also the ways in which these histories are relevant to their practices today. This research project is an effort to generate a richer discussion about what we mean when we say we are pursuing “cures” for disease. What has that meant in the past? How have science, medicine, and human experi-

ence combined to shape the pursuit of cures in the past, and how should they interact in the future?

After these quite general statements, it might be useful to underscore these points through a specific case study in the history of genetic disease.⁶ I focus here on the history of CF, a disorder that was identified as a discrete entity certainly before World War II, but which earned a particular level of visibility and prominence in the decades after the war. The history of this particular malady underscores many of the interactions I described above—the changing role of science in the clinic, the role of aging in reshaping patients’ expectations, the business of therapeutics and how it shapes medical practice (sometimes in negative ways), and the ways in which cultural understanding of disease can shape the course of science and medicine. The presentation here stems from research conducted with a graduate student, Stephen Pemberton, at the University of North Carolina at Chapel Hill as part of a project funded by the National Institutes of Health (NIH) over the past three years (Wailoo and Pemberton, forthcoming).

Throughout most of its history, CF has been framed as a rare disease, as a complex therapeutic challenge for patients, for physicians, and for clinical scientists. In the late 1930s, Dorothy Anderson, one of the pioneers in CF research, saw the disease as “cystic fibrosis of the pancreas”—a disease, as she saw it, characterized by severe nutritional malabsorption in small children and as potentially treatable by dietary supplements and nutritional management (Anderson, 1938; see also Farber, 1944, 1945). The diagnosis relied on the identification of pancreatic insufficiency until the 1950s, when researcher di Sant ’ Agnese and colleagues (1953) first noted that the electrolytes in the sweat of CF patients were elevated by comparison with people without CF. During the first two decades of CF’s cultural history, then, researchers typically believed that malabsorption problems were the primary clinical features of the disease, and that this problem was accompanied by secondary but severe problems of mucus overproduction in the pancreas, lungs, and other organs.

One of the important transformations in how clinicians saw CF was the advent of antibiotics, first for wartime use and then subsequently for use in civilian populations. The production of synthetic antibacterial agents in the 1940s and 1950s allowed physicians to tackle a wide range of infections that manifested themselves as pulmonary congestion, pneumonia, tuberculosis, and so on in CF patients. The decline of these disorders

which affected CF children meant a kind of unmasking of CF as a “new” disease—more clinically visible in this era than ever before. As antibacterial agents were more widely produced by a burgeoning pharmaceutical industry and deployed in a wide range of clinical contexts, CF became characterized as a “great impersonator.” The challenge to clinical medicine was to recognize and to unmask this multidimensional disorder that affected so many parts of the body, and which so easily mimicked asthma, bronchitis, as well as infectious disease. This theme—the proper diagnosis and recognition of CF—dominated the clinical and scientific literature of the 1950s and 1960s.

At the same time, however, writing on antibacterial therapy as early as 1951, three CF researchers (Garrard et al., 1951, p. 485) noted that the enlarged antibiotic armamentarium of the physician today was “a mixed blessing” and “a double-edged sword.” (This is a limitation of antibiotics that we are still familiar with today.) As these researchers noted, “any long continued therapy with a single antibacterial agent invites the development of highly resistant organisms which may flourish in an environment rendered more favorable by the absence of susceptible bacteria.” So from the outset, clinical scientists and physicians were well aware of the problem of antibacterial therapy—that it was a balancing act for every clinician between combating the infectious organism that colonized the thick mucus of the lungs and preventing the proliferation of more-resistant bacterial strains that resulted from antibiotic overuse. Indeed by 1967, some researchers could point out that overuse of antibiotic therapy had actually produced a new biological problem in CF. “There is little doubt,” wrote one researcher, “that the establishment of new species of Pseudomonas aeruginosa in the respiratory tract is encouraged by the suppression of other bacteria by antibiotics” (Boxerbaum et al., 1972; Burns and May, 1968; Kulczycki et al., 1978). Nevertheless, as Isles et al. (1984) pointed out, through the 1960s and 1970s the trend was toward the use of more and more antibiotics (in increasing varieties because of the wealth of pharmaceutical agents on the market). This style of practice continued into the late 1970s.

Physicians involved in the care of CF patients developed a kind of individualism in clinical practice. Individual practitioners developed their own therapeutic styles. These styles often involved alternating among different kinds of antibiotic agents, carefully tilting and tailoring their interventions to keep these bacteria off balance, carefully weighing each new agent on the market, and trying to manage the increasing variety of antibacterial therapies that became available —wide spectrum, narrow spectrum, oral, intravenous, and so on. By the 1970s and early 1980s, however, some researchers began to rigorously scrutinize these practices.

In the view of some, the treatment of CF patients had become little more than a set of individual rituals—as opposed to a standardized science.

The emergence of this kind of skepticism about the previous generation ’s therapeutic practice, and the embrace of a more “scientific” approach, should be put in historical perspective. Why did this shift occur? It happened in part because of the growing frustration of clinicians with the ways in which antibacterial agents were being used, but there is more to the story than that. The disease itself had been transformed by the advent of antibacterial therapy, and the “new” CF posed new problems to clinicians—problems that they hoped would be solved by a turn to science. Not only had Pseudomonas infection emerged as a by-product of individualized treatment styles, but a demographic transformation among CF patients had occurred. The number of adolescents with CF had grown in number through the 1950s, 1960s, and 1970s. Children with CF were growing up; they were becoming adults with an intimate familiarity with the medical system. As a result, their concerns could be voiced more effectively, and they could become more contentious in the clinical arena. As one CF physician recently noted, adolescents are a little harder to manage clinically—as well as socially. The changing demographics of the disease offered a new social profile as well.

As I noted above, when CF first emerged it was understood as a multidimensional disorder affecting many different organs. Certainly the pulmonary problems were significant, but it was understood in the early years as a nutritional disorder. Very early in the 1950s, one well-known NIH CF researcher Paul di Sant’ Agnese insisted that another way (indeed the best way) of understanding the disorder was to think of it as a metabolic disease. That is, it should be understood as a disorder stemming from a faulty metabolic system—in which an underlying inability to regulate the production of mucus throughout the body caused problems in the lungs, pancreas, gastrointestinal tract, and elsewhere. This shift in scientific thinking and terminology occurred at the same time that antibacterial management grew. Indeed, as shown below, there emerged an important tension between the scientist’ s understanding of the disease and the clinician’s understanding of the primacy of lung deterioration in the lives of people with CF. This tension would be resolved not in scientific conferences or in clinical discussion, but, perhaps surprisingly, in the political arena—reflecting the rising social stakes surrounding such diseases.

In 1972, the U.S. Congress considered legislation to increase research funds in several areas: heart disease, blood disorders, and lung disease. Looking to the established scientific conception of CF as a complex, metabolic disease, representatives of the NIH and the Department of Health, Education and Welfare insisted that CF was a “metabolic disease,” and as

such did not fit any of the funding categories (DuValm, 1972, p. 86). The proper characterization of CF was particularly important because funding for regional pulmonary pediatric centers (where CF patients had found care in recent years) had been greatly reduced. But legislators echoed the pronouncements of NIH scientists, asserting that CF was in fact a general metabolic disorder and that the biochemical disturbance responsible for the disease was not confined to the lungs. According to normative scientific thinking, the way to study CF was to tackle the underlying metabolic disturbances.

This view conflicted, however, with the view of the Cystic Fibrosis Foundation (CFF) that had come into existence in the 1950s and had grown in significance in political power and in lobbying force by the 1970s (Barbero, 1972, p. 216). Sitting before Congress in 1972, its director argued that CF was unquestionably a lung disease. Well aware of the need for more research dollars to study CF and of the declining funding for pulmonary pediatric centers, the CFF director argued that CF was a lung disease because pulmonary failure was the principal cause of death for children with CF. His point was an important one, for it reflected the very different sensibilities of clinicians as opposed to clinical scientists. The most important feature of the disease, in his thinking, was the way in which it killed patients (the cause of mortality), and not the underlying biological mechanisms of disease. “Children’s lung diseases, in which many contributing causes exist —genetic and non-genetic—are known, and are a major source of concern in this day.” He appealed to Congress to include CF in the 1972 legislation especially because of the decline of the regional medical programs. He concluded his remarks by noting, “it would be unsound to separate cystic fibrosis out from any of these acts of legislation. It is a lung disease” (Barbero, 1972, p. 217).

His words and his disagreement with NIH scientists over the categorization of CF offer a fine example of a broader process at work. This tension provides insight into the ways in which politics and the search for funding reframed these scientific debates and how the politicization of such diseases (increasingly an issue within biomedical research in the 1960s and 1970s) shaped the ways in which experts thought about people with disease. For both NIH scientists and CFF representatives, CF was one single disease. But which aspect of the disease warranted the most attention? The answer depended on the broader social, economic, and political context. For the CFF, it was imperative that Congress recognize the pulmonary mortality of the disorder and acknowledge that, in the patient’s and clinician’s perspective, lung deterioration had become the principal cause of mortality and the primary concern—replacing mortality from infectious disease. The director’s argument, however, failed to sway legislators, who turned for expert advice to NIH scientists who

would be carrying out the research in question. CF was not included in the final legislation.

But in many ways, the CFF’s representation of disease resonated much more than the scientific perspective with the public, with patients (who were now adolescents and young adults), and their families. Not only had life expectancy increased, but also the number of people receiving care had more than doubled in the period from 1965 to 1975. Indeed, the higher profile of CF resulted in President Richard Nixon holding a Rose Garden ceremony with a CF poster child and the CFF in order to raise awareness of the disorder (New York Times, 1972).

At this juncture, then, the clinical realities of CF were complex, and clinicians were somewhat uncertain about what the science of CF meant for their clinical concerns. CF patients presented with biological problems such as Psuedomonas infection that resulted from the individualized antibacterial therapies. That is, CF physicians had literally created new biological problems for their patients because of their complex antibacterial management, and they were not compelled to manage the consequences. A wealth of such drugs made this style of practice the norm. CF patients were living longer, treated by a wider range of antibiotics, physiotherapy techniques, and other therapeutic modalities, but still dying from their lung deterioration. The standard laboratory-based, scientific understanding of the disease, however, did not stress this aspect of the problem. Rather, scientists stressed the need for studies of the basic underlying metabolic disturbances that cause mucus overproduction as well as the deterioration of lungs and other organs. Faced with a growing population of CF patients, clinicians also became aware of large variations among these patients—in the ways their disease actually appeared from one case to the next. One crucial problem seized upon by clinicians in the 1970s—and a route toward improving treatment—was to study whether any standard routines, based in science, could be applied to the care of CF patients? What was the actual efficacy of antibacterial therapies, especially in the context of these increasing variations in the disease biology and in clinical care. As one author noted in 1978, “while it is accepted by many that the increased longevity of the CF patient is strongly related to antibiotic use, this has never been adequately documented” (Kulczycki et al., 1978).

When we look at the clinical literature of the 1970s, we are stuck by a new development—the turn toward clinical research studies, placebo-controlled clinical trials, and other such studies in order to determine which of these antibacterial agents more effectively and efficiently controlled infections in CF (Beaudry et al., 1980; Hyatt et al., 1981; Kearns et al., 1982; Loening-Baucke et al., 1979; Nolan et al., 1982; Parry et al., 1977; Warwick, 1977). In these highly structured clinical trials, researchers ex-

plicitly questioned the impressionistic, ritualistic basis on which doctors in the past reported failures or successes in antibacterial treatment. What was the impulse behind this new science of CF? This research was guided, in some part, by the urge and need to manage the very excesses of pharmaceutical production. That is, there was a kind of embarrassment of riches in the realm of antibacterial therapy; the clinical scientists of the 1970s hoped to figure out how to rationalize the care of CF patients.

A “clinical science” emerged to address the complexities of medical care in the early 1970s. This science of CF stood in contrast to NIH science, for NIH researchers and others had seen CF as a test case for the study of metabolic disease. For them, an understanding of the relationship between pancreatic deficiency and mucoviscidosis would shed light on the physiology of metabolic diseases at large. But in this emerging clinical science, research on antibacterial agents could focus on the acute stage of CF lung failure, on the standardization of individualistic medical care, and on the problem of pharmaceutical abundance—significant problems for patients and practitioners. This was a very different kind of science than the science advocated by di Sant’ Agnese because “clinical science” attempted to answer very specific, therapy-related, questions. How do we use drugs responsibly? Are there standard rules for managing the wealth of therapeutic options? In many ways, the story of CF at this juncture touched on fundamental questions regarding the responsible practice of science and the responsible use of science. Both of the sciences and the views of disease debated in this era were products of the time and context.

The science of clinical trials to study antibacterial agents emerged from the clinical frustrations and social changes of the 1960s, but it also immediately predated another turn in the scientific understanding of CF—the rise of genetic identification and prospects for CF gene therapy. It is particularly important to place in proper historical and social perspective the new scientific models of CF that emerged from clinical medicine and genetics, beginning in the late 1970s and early 1980s. As a science that offers yet another definition of CF as a disease, gene therapy must be placed in its proper historical continuum if we are to fully understand and evaluate its claims. In many respects, “gene therapy” emerged itself from the frustration with clinical trials in the 1970s. Indeed, the clinical studies envisioned in the 1970s had failed to create standard models of CF care for one important reason—the disease itself resisted standardization in clinical care.

One reason that CF resisted standardization was the extreme varia-

tion and the complexity of the disease from one sufferer to the next. As one pediatrician noted in 1985, the issue of antibacterial management was still clouded and possibly unresolvable. He pointed to a number of reasons. Perhaps the variation in how CF actually manifested itself from one patient to the next made it impossible to hold to standard rules of antibacterial management. Faced with precisely these frustrations and at this point in the disease’s history, genetics (and the gene therapy approach to CF) offered a new set of therapeutic possibilities. Pointing back to the deficiencies of basic science knowledge, one pediatrician noted, for example, “perhaps when the basic defect in cystic fibrosis is understood, the relationship between the host to the microorganism will be better understood” (Nelson, 1985). In the past 10–15 years, the possibilities of gene therapy have been enthusiastically embraced by many parts of the CF community—by pulmonologists, by clinical researchers, by patients and families, by the CFF, by biotechnology companies, and by many others. Indeed, one of the implicit promises of genetics and gene therapy was to enter this very frustrating atmosphere of clinical science and to provide a way out of lingering dilemmas in patient care and scientific understanding. Gene therapy, as the very name suggested, promised to make clinical science directly relevant to patient care. Since the early 1980s, gene therapy has attracted significant public and professional attention as a potential therapeutic modality in CF care and in other diseases. Much of the attention on gene therapy has been overly optimistic from this historian ’s point of view—especially for an experimental procedure in its early stages of testing that has produced no proven benefits for any single human patient with any disorder.

Speculation about altering genetic material to cure disease grew throughout the 1980s. But the advent of high optimism for gene therapy followed directly on the heels of the discovery in 1989 of one of the defective genes implicated as the cause of some cases of CF (Riordan et al., 1989; Seligmann and Glick, 1989). It was this missing gene that resulted in the failure of chloride to pass through the membranes of the cells of CF patients. Gene therapy was envisioned as a method of repairing the chloride transport process by inserting the repaired gene into the lungs. To understand and evaluate the science of “ gene therapy,” however, it is crucial to situate that science in its proper context —just as we situated the antibiotic clinical trials in their context. The science of gene therapy is a speculative, entrepreneurial science —a science shaped by a culture of economic risk taking, venture capital, and financial speculation. This is a very different science than the science of Dorothy Anderson, the science of NIH researcher Paul di Sant’ Agnese, or the science of clinical trials in the 1970s and 1980s.

As early as November 1985, well before the discovery of the gene for

CF, Business Week magazine ran a cover story on the emergence of “gene doctors” who were portrayed as “erasing nature’s mistakes” and “curing life’s cruelest diseases” (Shulman, 1985; see also Ohlendorf, 1985). Other media pointed out that these new doctors were “closing in on CF” and “laying siege to the deadly gene” itself. Into the early 1990s, public, professional, and business enthusiasm for “gene therapy” as a potential cure for CF reached a peak as the successful testing of a new therapy seemed imminent (Brady, 1990; Nichols, 1993; Seligmann, 1990)⁷ In early 1993, pulmonologist Ronald Crystal began a first experiment at the National Heart, Lung, and Blood Institute, “fulfilling hopes that had gathered steam like a locomotive force in the past several months,” according to the New York Times (Angier, 1993b; see also Angier, 1992; Cowley, 1993). The study, one of three approved studies, involved a 23-year-old man with CF who, in the words of the newspaper, “inhaled the cold virus, the adenovirus, that had been altered to enclose a healthy copy of the CF gene the patient lacked.” It would have been more precise for Crystal and the newspaper to label this a “gene transfer experiment ” rather than “gene therapy” because the study was simply a test of the uptake of the viral vector and a study of its ability to alter chloride transport. The test was never envisioned as a test of the efficacy or a treatment. This was made clear elsewhere in the article, although the language of the article suggested that this was a therapeutic milestone.

At the same time, other pharmaceutical enterprises had turned to CF, sensing a lucrative marketplace of patients. Genetech, Inc. had requested Food and Drug Administration permission to market its CF drug, Dnase. Shortly after its approval, Genetech stock rose sharply by fifty cents a share. A third article from the same period pointed out, however, that Dnase was only one part of a “six hundred million dollar horse race,” a race in which gene therapy was the much-celebrated, highly praised, but unproven front-runner (Hamilton, 1993; New York Times, 1993; see also Carey, 1993; New York Times, 1991). The key question was this: Who would capture this potentially huge market? Crystal himself was in the race. Indeed, as many articles noted, Crystal was cofounder of a gene therapy startup company named Genvec that had received $17 million in capital support from Genetech. Here was the scientist as entrepreneur in the business world of the 1990s. Indeed, many of Crystal’s (and other “gene therapists’”) vaunted predictions about the rapid development of gene therapy must be evaluated against this backdrop.

In late 1993, Crystal’s experiments hit a technical and public relations snag. One research subject enrolled in his studies showed signs of lung inflammation, as well as drops in oxygen levels in the blood and evidence of pulmonary damage (Anglier, 1993a). These events provoked Crystal to speculate that this particular patient might have been idiosyncratic, or

that perhaps the upper limits of adenovirus therapy had been found. For reporters, however, the problem underscored the severe difficulty of translating a highly speculative, experimental procedure into work-a-day clinical practice. Over the next few years, the early wild enthusiasm for “gene therapy” would begin to ebb. Predictions would be scaled back gradually, as geneticists, pulmonologists, and patients began to look somewhat more skeptically upon the enterprise. The unmitigated enthusiasm of the mid-1980s had given way to a willingness to characterize “gene therapy” for what it is—an experimental long-shot. In one survey in Science magazine in 1995 on “gene therapy’s growing pains,” the author noted that right from the start, gene therapists recognized that their central challenge would be technical ones: finding safe vectors capable of transporting genes efficiently into target cells and getting the cells to express the genes once they were inserted (Kolata, 1995; Marshall, 1995; Palca, 1994). These modest goals would define gene therapy in the late 1990s.

In this new environment in which commercial pressures no longer drove the high enthusiasm of scientists as much as it had earlier, researcher and director James Wilson of the Institute for Gene Therapy at the University of Pennsylvania could look back and comment that “this commercial pressure may also account for some of the hype surrounding developments in gene therapy” (quoted in Marshall, 1995). After all, he pointed out, if you are the leader of a gene therapy company “you try to put as positive spin on it as you can, on every step of the research process because you have to create promise out of what you have. That is your value.” This was a very different type of science shaping the history of CF at the close of the twentieth century. Clinical science in this instance had become part of entrepreneurial development, and the very pronouncements about the promise and possibility of “gene therapy” for CF could be understood as part of the positioning of entrepreneurs for capital and market share (Baggot, 1998; Brown, 1995; Martin and Thomas, 1998).⁸ The scientist-physician-businessman spoke highly of the promise of gene therapy, in large part, in order to generate enthusiasm and interest (Friedmann, 1994).

What conclusions can we make about the history of this disease, particularly when we ponder the relationship between the science of disease, the clinical management of disease, and the patients’ perspectives on disease? Through tracing the history of this one disease, CF, I have made some inroads into this question. Indeed, the disease’s history reveals a great deal about (1) the transformation of science; (2) the historical evolution and impact of clinical practice; and (3) important changes in the politics, the social reality, and the lived experience of disease in American society. Demographic trends in the aging of the CF population—a trend

driven in large part by therapeutics—has brought a patient’s perspective into public view. Science itself has produced many changing models of CF—as a nutritional disease, as a metabolic disease, as a lung disease, and as a genetic disease—and (as demonstrated above) each of these models has been shaped by technical developments and by the politics of the time. Each of these scientific models of disease has spoken to patients’ and cultural perspectives in quite different ways. Finally, I have attempted to sketch how these sciences as well as the cultural history of CF have been shaped by (and shape) the clinical management of the disease and how clinical practices themselves—such as the use of antibacterial agents—have altered the biology of the disease and the patient ’s experience.

Let me conclude with a few observations from this history, conclusions that establish some of the parameters of my project as I turn to examining the histories of cancer, pain, immunology, and genetic disease. Diseases are evolving entities, changing with the interaction of science, technology, clinical practices, politics, and culture. When we speak of the responsible use of science, it is important that we understand the character of the science in question and understand its historical trajectory and its broader social entanglements. This kind of knowledge, I believe, contributes to an enriched and informed discussion about the future direction of science and society.

The history of CF is only one aspect of this James S. McDonnell Centennial Fellowship research project. This fellowship will allow me to purchase books, it will allow me to hire research assistants, and it will allow me to organize workshops and symposia to discuss and disseminate the findings of my research. The goal is to programmatically influence the kinds of discussions that happen in the clinical arena, in the scientific arena, and in the history of medicine and science regarding the problem of disease in our time. Envisioned in this project are a series of annual scholarly workshops, the first of which will be held in 2000 on cancer, possibly breast cancer. Such workshops will bring together breast cancer researchers, clinical scientists, policy makers, and historians to discuss the interaction of science, medicine, and the patient’s disease experience. It is possible that the workshops will produce edited volumes on the history of cancer. Every other year the project will result in a public symposium to disseminate this research to a wider audience. It is possible that the workshops and symposia will lead to the production of papers and books that inform the public and mass media about how to evaluate the science of disease, or about understanding this dynamic, changing relationship among science, medicine, and society.

I thank the James S. McDonnell Foundation and the selection committee for the Centennial Fellowship in history and philosophy of science for their extraordinarily generous support for this research project.

1. On the rise of chronic disease and the decline of acute infectious disease, see Boas (1940).

2. A wide range of scholarship has explored the complex relations among clinical practice, science, and disease experience. See Harvey (1981, p. xvii), Lederer (1995), Marks (1997), and Matthews (1995). For more on the development of the clinical sciences in their social and political contexts, see Beecher (1966), Booth (1993), Etheridge (1992), Harden (1986), and Rothman (1991). See also Beecher (1959), Bynum (1988), Katz (1972), and Pappworth (1967).

3. On the history of cancer, see Cantor (1993), Patterson (1987), Peller (1979), Rather (1978), and Strickland (1972). See also Bud (1978), Markle and Petersen (1980a, 1980b), Panem (1984), Peters (1993), Proctor (1995), Rettig (1977), Richards (1991), Sigerist (1932), Studer and Chubin (1980), and Young (1980). On the U.S. Public Health Service trials, see Endicott (1957), Fujimura (1996), Jacyna (1988), and Lowy (1996).

4. The literature on the history of immunology is vast. See, for example, Brent (1997), Hall (1997), Lowy (1989), Martin (1994), Moulin (1989a, 1989b), and Tauber (1994).

5. The literature on pain is also vast. See Mann (1988) and Pernick (1985). And for a statement from a twentieth century scientist, see Rey (1995), Unruh (1996), and Wall (1975). See also Friedlander (1992), Leavitt (1986), Mann and Plummer (1991), McTavish (1987), Meltzer (1990), Morris (1991), Nelson (1993), Papper (1992), Pitcock and Clark (1992), Rushman et al. (1996), Scarry (1985a, 1985b), Szasz (1957), Tweedie and Snowdon (1990), and Wear (1995). On the current science and politics of cancer, see Balshem (1993), Frank (1991), Sontag (1978), and Stacey (1997). Consider also these recent writings: Clorfene-Casten (1996) and Stabiner (1997). On prostate cancer, see Korda (1996).

6. On the history of hereditarian thinking about disease, see Haller (1971), Hutchinson (1884), Kevles (1985), Ludmerer (1972), and Rosenberg (1976). One exception to this trend in seeing Medelian genetics as peripheral to medical practice is Pernick (1996). See also Wailoo (1991). The literature on the history and social implications of modern genetics is vast. See, for example, Judson (1979), Kay (1993), Keller (1992), Kevles and Hood (1992), Kitcher (1996), and Olby (1974). Among the therapeutic by-products envisioned is gene therapy. See Alien (1975), Culver (1996), Hubbard and Wald (1993), Lyon and Gorner (1995), Nelkin and Lindee (1995), Nichols (1988), and Wexler (1995).

7. Noted one Wall Street Journal reporter in 1992, “the vast majority of Americans support the use of gene-based therapy to treat disease, even though they don’t know much about the emerging science, according to a new survey” (Tanouye, 1992; see also Purvis, 1992).

8. The subtitle to Brown’s 1995 article on the infusion of capital into gene therapy research noted, however, that “Cautious observers note, however, that the fate of the new industry may hinge on a flurry of recently approved trials” (Brown, 1995) Moreover, the death of Jesse Gelsinger in a gene therapy trial for a disease other than CF has placed increasing scrutiny on this new industry—leading to the scaling back of hopes, new regulatory oversight, and the closing of some trials (Nelson and Weiss, 2000; Weiss, 2000; Weiss and Nelson, 1999, 2000).

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