The Nature of Chemotherapy

For Domagk and his chemist-collaborators Mietzsch and Klarer, the invention of Prontosil was a momentous event, marking a watershed in their careers as much as in the history of medicine. It is not surprising that all three subsequently wrote accounts of the investigations that resulted in Prontosil. Domagk and Miet-zsch, in particular, each wrote about their early collaboration, Domagk in several articles of the mid-1930s, and Mietzsch in a series of publications of the early 1950s. These articles are useful not only for reconstruction of the process that led to Prontosil, but still more for what they reveal about how each party, medical researcher and chemist, viewed the nature of chemotherapeutic research and for what these views, in some ways contrasting and contradictory, tell us about the nature of chemotherapy as an entity and its place in the system of industrial innovation that had emerged at I.G. Farben.

For Domagk, the essential aims of chemotherapeutic research were practical, not theoretical. Though informed by science, its primary goal was not creation of new knowledge of nature but identification of compounds effective in the treatment of bacterial infections. He acknowledged the largely empirical character of the research, in the face of inadequate knowledge of the biology of parasites and hosts. The practical character of the goals shaped the field, for example, leading Domagk to adopt divergent classifications of bacteria and to emphasize those aspects of the biological specificity of bacteria that might suggest targets for chemotherapeutic agents.34

Chemotherapeutic research was also, for Domagk, a distinctly medical and biological endeavor. This meant that the researcher needed to focus on the complexities and specificities of the interactions among hosts, the microbes causing disease, and the chemical agents used in treatment. The aim of the physician in chemotherapy was to come to the aid of the body's defenses against infection, not to replace them. Explorations of these interactions required, in Domagk's view, a three-tiered methodology comprising in vitro, animal, and clinical tests of prospective chemotherapeutic agents. One aspect of this methodology was Domagk's conviction that failure of a compound in vitro did not mean that it would necessarily fail in the animal or human host, a view that was crucial to the discovery of Prontosil. Domagk recognized the essential role of chemistry in chemotherapeutic research but tended to assign to chemists a subordinate role.

For Mietzsch, this order of things was reversed. While he conceded the necessary place of medical researchers in the development of chemotherapy, Miet-zsch's view of the field is better captured by Horlein's description of pharmaceuticals as "a branch of chemical technology." Put differently, Mietzsch thought that the primary engine of chemotherapeutic research was chemistry. He characterized all of the major turning points in the field's history in chemical terms. In particular, in Mietzsch's story the sulfonamides emerged from study of basic alkylated compounds and from use of azo dyes in chemotherapy. Azo dyes were appealing to Mietzsch and Klarer above all for a chemical reason, their ease of variability. The "decisive turning point" for Mietzsch came when a sulfon-amide group was introduced in a definite position in the azo dye molecule. Thus, Mietzsch characterized the decisive turning point in the invention of the sulfon-amides chemically and located it in the chemical side of chemotherapeutic research at Elberfeld.35

Mietzsch was at pains to display the mental effort behind the chemical side of chemotherapeutic research. The research process is not merely trial and error, the blind grinding out and testing of one compound after another. Patterns emerge. A new chemical procedure or phenomenon is found that leads to a useful result in the sense of an effective chemotherapeutic agent. The finding is then applied to other classes of compounds in the hope of getting such a useful result with them. In one series in which it is tried, a promising compound is identified. That leads to more systematic work on that series, which in turn may lead to finding a successful chemotherapeutic agent. Thus, the research process on the chemical side is not random, although it does have a trial-and-error quality. The trial and error takes place within certain boundaries that are determined by some combination of what it is possible to do chemically and previous experience with certain chemical processes or certain classes of compounds regarding identification of successful chemotherapeutic agents. The trial-and-error process appears to have two phases: an initial, relatively loose phase in which promising leads are sought within a fairly broad domain of possibilities, and a second, more intense and systematic phase in which a lead that has been identified is followed up, for example, within a well-defined class of compounds.

For Mietzsch, the search for a chemotherapeutically effective compound therefore involved a narrowing down to the right kind of chemical specificity: the right series, the right position on the compound, the right substituent. For the chemists, the problem was one of chemical variation and chemical specificity, with the goal of achieving a precise match with the target organism.

Central to Mietzsch's message was the conviction that he and other Bayer/I.G. Farben chemists were pursuing not merely a chemical, but a specifically chemotherapeutic research program. Their role was not simply instrumental but involved deliberate judgments and choices based on rational and goal-directed considerations, chemical reasoning in the service of chemotherapeutic goals. Mi-etzsch saw the chemotherapeutic research process from the standpoint of a chemist's—specifically, a dye chemist's—training, a chemist's way of thinking, and a chemist's vivid intuitive sense of the creative process in the chemical as distinct from the biomedical side of the research.36

Taken together, the images of chemotherapeutic research presented by Hörlein, Domagk, and Mietzsch yield a sharper picture of the development of Pron-tosil as a case of industrialized invention. Among the most important elements of this picture are a systemic approach to innovation, continuities between dyestuff chemistry and pharmaceutical chemistry and between the different chemical lines of pharmaceutical research, and the robust optimism of the Bayer/I.G. Farben industrial team in the midst of a general atmosphere of caution and resignation.

Hörlein viewed bacterial chemotherapy as a reverse salient in a broadly advancing front along which chemistry and medicine joined battle with disease. Working within and expanding a well-developed industrial research organization, he embraced a systemic approach to innovation. He expected technically and scientifically novel results to emerge not from individuals working alone but from groups of specialists working cooperatively under a team leader and supported by a strong research infrastructure. He saw and expected patterns in the work, with innovation occurring in typical steps or phases depending on the fields or kinds of problems involved. He acted the role of research manager to the fullest: setting aims, concentrating resources and personnel, assessing results, and representing his organization's efforts to the medical and scientific communities. It was Hörlein who brought Domagk, Mietzsch, and Klarer into the pharmaceutical research division, and it was in close association with him that their research program in bacterial chemotherapy was formulated and conducted.

For Hörlein's program to succeed, however, critical problems had to be defined and solved by the medical researcher and the chemist, each working in his own domain and with his own concepts, methods, and habits of thought. Both medical researchers and chemists confronted the problem of specificity. The difference was that in one case the specificity was biological, while in the other case it was chemical. Biological specificity meant identification of the difference between host and pathogen, such that a means was available to attack the pathogen without harming the host. It meant, in addition, definition of differences between the kinds of bacteria, differences that could manifest in subtle metabolic, nutritional, or other aspects of the organism. Chemical specificity meant conceiving and synthesizing all possible variants on a given kind of compound, that is, by starting with a nucleus of some sort and building around it; or, in a more general sense, the division and subdivision of chemical compounds—in this case, mainly or exclusively organic ones—into classes and subclasses.

Both the medical researcher and the chemist ostensibly had the same goal: to identify a specific compound that would attack a specific pathogen that was harming a specific host. But to reach the goal, two complementary but distinct efforts had to be mounted in which each investigator wrestled with his own problems of specificity. The medical researcher had to find an experimental model that was adequate to the pathogen in the sense that experimental infections could be consistently produced with that type of pathogen, and that was adequate to the host in the sense that it was the same pathogen that attacked the human host and against which a chemotherapy was sought. He also had to take into account the reaction of the host organism, both to the pathogen and the changes it induced and to any chemical agent introduced as a therapeutic measure. The medical researcher also had to consider specificity in the sense of the particular locale (tissue, organ, cells) attacked by the pathogen and the pattern of distribution of the chemical agent in the host organism.

The chemist had to decide—with or without the aid of the medical researcher—which class or classes of compounds to try against the kinds of infections in question. His criteria for doing so might be chemical, for example, ease of variability by changes in coupling components or substituents, or prompted in some way by prior experience with living organisms, such as in vitro activity against bacteria. Once a promising compound was identified by the medical researcher, the chemist's task was to produce variations around this starting point with the aim of increasing the specificity of the match between the chemical agent, the pathogen, and the host. Here, indeed, was a signal difference between the two components of chemotherapeutic research. Whereas the medical researcher took the variability given in nature, tried to analyze it in detail, and identified points where chemical therapy might find a purchase, the chemists produced variability by synthetic manipulation.

Chemotherapy so conceived and practiced cannot be regarded as a unitary scientific discipline in the academic sense. The nature of its problems necessitates cooperation between chemists and medical researchers, the latter variously identifying themselves as pathologists, bacteriologists, physiologists, or in other ways. Neither the chemist nor the medical researcher by himself has the necessary experience to conduct research in the field. Chemotherapy in Hörlein's conception therefore is defined not as much by a move for autonomy vis-à-vis other disciplines—for example, physiological chemistry or biochemistry vis-à-vis physiology—as by the necessary cooperative linkage of two or more disciplines that continue to retain distinct identities while interacting at specific sites on their boundaries. That is, chemotherapeutic research can be characterized as a permanent cooperative association of two or more disciplines around certain problems.

The problems were first defined by Ehrlich. To some degree, as Hörlein pointed out, Ehrlich embodied in himself the two necessary components of the field, the medical and the chemical, although even in his case he relied on chemists for part of the work. But the fine chemicals industry, because of its prior commitment to pharmaceuticals, already had in place one of the institutional arrangements required by Ehrlich's program, that is, an organization in which chemists and medical researchers were in cooperative association. What was needed was the addition of a new component that would emphasize the particular aspect of the medical-chemical interaction defined by Ehrlich. At Bayer, for example, this took the form of the new chemotherapy laboratory added in 1910, or of Domagk's laboratory established in 1927 and expanded in 1930. In the setting of the fine chemicals industry, the components of Ehrlich's program were more clearly differentiated in both methodology and organization. Thus, the primary aim of chemotherapeutic research—essentially an engineering goal—could be most effectively realized in a setting that was interdisciplinary, in the sense of juxtaposing more than one field in a single institutional setting, and industrial, because of the massive resources that could be brought to bear to set up and maintain a differentiated research infrastructure and—in the case of the fine chemicals industry—to make available thousands of synthetically produced chemicals and the expertise to vary these compounds in determinate ways to achieve the ends in view.

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