The Prospects of Chemotherapy

Looking back in 1955 at what he called "the immense vogue" for mercurachrome in the 1920s, British physician Lawrence P. Garrod marveled that so many people seriously believed the compound to be an efficient intravenous antiseptic. His own explanation, that the episode was a case of therapeutic fraud, is surely mistaken. The vogue for mercurachrome emerged from, and placed in sharp relief, several features of the medical world of the 1920s. It expressed the intense desire of researchers, physicians, and patients alike for some defense against the relentless suffering and death associated with bacterial infections. It expressed even more clearly an optimism, motivated in part by Ehrlich's program, in part by other successes of chemotherapy, and in part perhaps by the spectacular impact of insulin against a very different kind of disease, that such a thing as bacterial chemotherapy was even possible. And it expressed, or was made possible by, a lack of settled consensus on principles, methods, and standards of evaluation in chemotherapy. Mercurachrome rose on a wave of need and expectation. When it declined, the need remained, but expectations inevitably cooled as well. For some, by the early 1930s, the failure of mercurachrome and countless other compounds warranted an increasing pessimism where bacterial chemotherapy was concerned. For most of those engaged in research, it meant not so much pessimism as a new sobriety, a concentration on methods and standards of investigation, and a sense that bacterial chemotherapy would emerge not from a quick victory but from long, steady, and determined effort.63

The pre-sulfa drugs decade of the late 1920s and early 1930s has sometimes been portrayed as a time of increasing gloom over the prospects for bacterial chemotherapy.64 A survey of leaders of the scientific and medical communities in Europe and America, however, found little evidence of genuine pessimism. More evident are varied assessments of the achievements of chemotherapy so far, a proliferation of diagnoses of its shortcomings, and prescriptions for its future success.

At the Toronto meeting of the British Association for the Advancement of Science in 1924, the president of the association's section of physiology, Henry H. Dale, spoke on the "progress and prospects in chemotherapy." Dale was both critical of the current state of chemotherapeutic theory and expansive on the practical achievements and future prospects of the field. On the theoretical side, he questioned Ehrlich's views on the mode of action of chemical agents on microbes as ad hoc and insufficiently precise in a biochemical sense and called for greater attention to the interactions of synthetic compounds with host organisms. He pointed to the need for such knowledge, and of knowledge of microbial physiology, if chemotherapy was to be put on a rational basis. At the same time, just because of the limits of theory to date, he expressed wonder and admiration that so much of practical value has already been achieved—the treatment of spirochetal infections, syphilis, yaws and relapsing fever, revolutionized; leishmania infections, kala-azar and Baghdad boil and bilharzia infections which crippled the health of whole populations in countries such as Egypt, now made definitely curable; trypanosome infections, such as the deadly African sleeping sickness, after years of alternating promise and disappointments, brought now at last within the range of effective treatment.

And the end was nowhere in sight, he continued, for "if such results have already been attained, in a period during which practice has inevitably and often outrun theory, we may well be hopeful for a future in which fuller understanding should make for more orderly progress."65

Although Dale nowhere mentioned bacterial chemotherapy, his optimism seemed to embrace prospects for treatment of all infectious disease. The author of the foremost American textbook of chemotherapy, John A. Kolmer, was much more explicit in his hopes for bacterial chemotherapy. Kolmer, a professor of pathology and bacteriology at the University of Pennsylvania medical school, devoted most of his Principles and Practice of Chemotherapy (1926) to syphilis. Not only had chemotherapy's greatest successes been scored against syphilis, he argued, but the treatment of syphilis provided a model for laboratory and clinical investigations of the chemical therapy of other infectious diseases. Among these, he gave bacterial infections a prominent place. Some 140 pages of the 1,000-page text were devoted to chemotherapy of bacterial diseases, a figure that reflected both the relative lack of progress of the subfield and Kolmer's close attention to what had been done.66

Kolmer was aware of the difficulties. He referred to "the skepticism so frequently expressed in regards to the future of the chemotherapy of bacterial diseases." He noted that while the bacteria, because of their relative simplicity and greater distance from mammalian organisms, might have been considered easier targets for chemotherapy than protozoa or metazoa, exactly the opposite had been the case. He even suggested that the discovery of spirochetes and trypanosomes and of the means of conducting large numbers of inexpensive experimental infections with them "was a wonderfully fortunate circumstance, for had the early experiments in chemotherapy been conducted with the bacteria, disappointments would probably have extinguished enthusiasm by a lack of sufficient success and encouragement as subsequent events have amply indicated."67

Whatever the problems, Kolmer thought that grounds for optimism could be found in recent work in bacterial chemotherapy that had produced drugs of practical value. Among the latter, he included the work of Young and his associates on mercurachrome and that of himself, J. F. Schamberg, and Raiziss on synthesis of other mercurial compounds, including mercuraphen. Kolmer brightened the picture of recent work and future prospects considerably by loosening his definition of bacterial chemotherapy to include local as well as systemic treatment.68

Kolmer's broad-ranging optimism was echoed two years later by Voegtlin, a pharmacologist with the U.S. Public Health Service's Hygienic Laboratory, in his chapter for the Chemical Foundation's Chemistry and Medicine. Voegtlin's tone, as befitted the volume as a whole, was forward-looking, militant, and upbeat. He pointed to the real triumphs of chemotherapy against protozoal diseases and to promising beginnings in bacterial chemotherapy. Although Voegtlin regarded these successes as "a sufficient demonstration of the practical value of this new science," he, like Dale, lamented the contemporary lack of knowledge of mechanism of action of drugs and of microbial physiology. Such ignorance, he thought, blocked establishment of a scientific foundation for chemotherapy and slowed discovery of useful drugs.69

A cooler view of the state of the field, and especially of bacterial chemotherapy, was taken by Findlay in the first edition (1930) of his major British textbook. Findlay was acutely aware of the tendency for hope to triumph over experience in a field with potentially enormous impact on medical practice. "In perhaps no other department of science," he remarked, "is there psychologically so great a will to success as in chemotherapy."70 In Findlay's view, bacterial chemotherapy had so far proved a failure in both local and systemic infections. He regarded all chemical antiseptics then in use as general protoplasmic poisons. As such, they killed bacteria but at the same time weakened the body's defenses by inhibiting phagocytosis by leukocytes and weakening the leukocytes' bactericidal action. Only their rapid elimination from the body, he thought, prevented them from seriously compromising the body's defenses. He pointed out that, even when applied locally, as in infected wounds, known antiseptics quickly lost effective concentrations and, while present, interfered with the action of leukocytes. Findlay's strictures applied to mercurachrome as well as to many other compounds. From them, he also drew the conclusion that in vitro tests of an antiseptic's action could throw little or no light on its effectiveness in vivo.71

Failure so far did not preclude future success, however, and Findlay had no hesitation in listing the properties of an ideal compound for use in bacterial infections. It should have a well-marked bactericidal action when brought into contact with bacteria in the presence of tissue fluids; it should be non-toxic to tissue cells; it should stimulate the bactericidal powers of the leucocytes; it should retain its bactericidal powers for a prolonged period when present in blood or tissue fluids; and it should readily diffuse from the blood into serous cavities and tissue spaces.

Such a compound had not yet been found, but the very act of defining its ideal properties affirmed the possibility.72

Findlay's prescription for cure of chemotherapy's troubled state emphasized more rigorous research methods. At the base had to be experimental infections in appropriate laboratory animals. In vitro tests alone were unreliable, Findlay held, and the chemotherapeutic activity of powerful compounds such as the ar-sphenamines in syphilis, Bayer 205 (Germanin) in sleeping sickness, or Plasmo-quine (chloroquine) in malaria "could hardly have been determined" without trials on infected animals. Chemotherapeutic action in animals did not guarantee chemotherapeutic action in humans, he admitted, but "broadly speaking, it may be said that any drug which is devoid of action in experimental animals will also be devoid of action in man." Passing through the sieve of animal trials was therefore a necessary, but not sufficient, condition for the success of a compound as chemotherapeutic agent. Clinical trials were also required. To ensure the value of animal trials, Findlay specified six criteria to be satisfied regarding kinds and numbers of animals used and the experimental conditions. He offered the clinician a parallel list of eight measures to be taken to establish credible results in tests of chemotherapeutic agents on humans.73

The most novel aspect of Findlay's exhortation was his call for application of statistical methods to chemotherapy. Findlay urged laboratory researchers and clinicians to familiarize themselves with simple statistical concepts. Not only could use of such methods save considerable time and energy, he argued, but "little solid progress can be made in chemotherapeutic research until both the laboratory worker and the clinician realise the errors into which lack of elementary statistical knowledge may lead them." With statistical thinking would come "a healthy skepticism," to be applied to a researcher's own work as well as that of others.74

A cautious and critical reserve was also the keynote of the 1934 edition of Zinsser and Bayne-Jones' Textbook of Bacteriology. The authors devoted a chapter to "the effects of chemical agents on bacteria" but restricted its coverage almost entirely to antiseptics or disinfectants. They did not formulate a program for research, did not mention Ehrlich's program, did not issue a call for more effort in bacterial chemotherapy, and thought that any results claimed to be achieved so far against systemic bacterial infections were at best unproven, at worst unsuccessful. All of this added up to a relatively passive and expectant optimism. Not pessimism, surely, but equally not a posture that was likely to drive innovation.75

Finally, more than a decade after Dale's optimistic remarks, a note of frustration and resignation was struck by Max Gundel in his German textbook on infectious diseases. Gundel, a physician and medical researcher at the Robert Koch Institute in Berlin, aimed the multiauthored anthology at practitioners. Following brief introductory sections, the first, longest, and most elaborately subdivided portion of the text covered bacterial infections. Gundel himself contributed the first subsection, on streptococcal infections. He regarded most chemotherapeutic agents as having failed in streptococcal infections. He looked grimly ahead to a long struggle in which chemotherapy did not play an explicit, let alone a prominent, role. "If one looks over the whole field of the streptococcal infections of humans," he reflected, "then one comes in every respect to an ever more resigned attitude." Neither the biology of streptococci nor the specific therapy of strepto-coccal diseases had made any essential advance in recent decades, Gundel believed, and "only the most intensive common work of all disciplines will perhaps bring progress, which is all the more urgent and to be desired, as with the strepto-coccal infections it is a matter of diseases of the greatest significance for public health."76

Gundel's emphasis on sera and vaccines at the expense of chemotherapy, an emphasis evident elsewhere in his text, reminds us that more was involved in the status of chemotherapy than the record of its own past achievements or lack of them. Other approaches to infectious disease competed for the attention and energy of investigators and the institutions that funded them. By the mid-1930s, vast effort had been expended on the development of sera alone. Major successes had been scored in serum treatment of diphtheria and pneumococcal pneumonia, and pharmaceutical companies and clinicians continued to test sera against other bacterial infections. Serum therapy of streptococcal infections was frustrated in part by the large number of varieties of the target organism, Streptococcus pyogenes. It would be a presentist fallacy, however, to see something inevitable in the triumph of chemotherapy and to fault investigators of the early 1930s for failure to anticipate it. In the struggle with bacterial infections, it was by no means obvious in what direction success might be found.77

Whatever their views on the most promising path to be taken, several investigators of the pre-1935 decade called for major new efforts in the search for treatments of bacterial disease. A common theme in these appeals was a perception that previous efforts had been inadequate in both quantity and quality. Gundel thought that only research "of an entirely other extent" from that of the present, "put in motion from the most various directions and focuses," would improve the prognosis for streptococcal infections. Kolmer made his optimism on the prospects for bacterial chemotherapy conditional on a tremendous expenditure of brains and money not yet thrown into the struggle. To these would have to be joined "hard, conscientious, and unremitting, but systematized toil coupled with the ever alluring chance of making a 'lucky strike.' "78

The most emphatic, and the most carefully thought out, call to action came from Voegtlin. Commenting on the treatment of tuberculosis, he remarked ruefully that "it is very likely that if but half of the energy and money which has been spent in the search for a serum, had been devoted to chemotherapeutic investigation, greater progress might have been recorded." In this context, he ascribed the disproportionate emphasis on sera and vaccines to physicians' lack of chemical training: "There are few Paul Ehrlichs in medicine."79

In mentioning Ehrlich, Voegtlin had in mind not only the need for chemically trained doctors. More fundamental were the commitment of resources and the organization of research exemplified by Ehrlich's institute. Voegtlin conceded that valuable discoveries had been made in laboratories not organized specifically for chemotherapeutic research. He pointed out, however, that work in such locales was often hindered by inappropriate use of personnel and equipment, by lack of financial resources, or by unwillingness of laboratory directors to wait the years often necessary for practical results. Ehrlich's institute embodied a formula for success that should be adopted in the United States, Voegtlin argued. The essential ingredients included mobilization of substantial financial resources and their long-term commitment to chemotherapeutic research. With these resources laboratories should be organized that embodied cooperative associations of chemists, pharmacologists, bacteriologists, and other specialists, all working full time on problems of chemotherapy. Equally important, in Voegtlin's view, was the close association of such a laboratory with the fine chemicals industry. "The secret of the success of the immense organic chemical industry in Germany," he remarked, "is to a great extent due to their policy of establishing within the works true research laboratories which, as far as personnel and equipment is concerned, are not surpassed by the chemical departments of German universities." The same industrial laboratories also maintained consulting arrangements with leading academic chemists. Voegtlin lamented that, despite its growth since the war, the U.S. organic chemicals industry did not yet encourage fundamental research, still preferring to exploit existing knowledge.80

That Voegtlin's blueprint for chemotherapeutic research was not yet realized in the United States despite the availability of its separate ingredients points to the limitations of American optimism about the field. The venture into chemotherapy that resulted in mercurachrome embodied the optimism, but also the constraints of funding, focus, and organization that characterized many efforts in the field in the 1910s and 1920s. What Voegtlin did not take note of was that in Germany the fine chemicals industry not only cooperated with institutes like Ehrlich's but also had long ago incorporated Ehrlich's program into its own research organizations. By the time Voegtlin's comments were published in 1928, the pharmaceutical research division of one such company was already embarked on work that would produce a major breakthrough in the chemotherapy of bacterial infections.

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