It was Paul Ehrlich who, in this context, most clearly grasped the historical opportunity and who most clearly defined a program for chemotherapy. Born in comfortable circumstances in Upper Silesia in 1854, Ehrlich followed his Gymnasium education with study of medicine at several universities, finally taking his medical degree at Leipzig in 1878. After nearly a decade of service as physician at the Charité Hospital in Berlin, and two years in Egypt recovering from a bout of tuberculosis, Ehrlich returned to Berlin and accepted a position at Koch's Institute. There he helped Emil von Behring develop effective therapeutic serums, especially the new diphtheria antitoxin.9 Serums, or antitoxins, were prepared by extracting the liquid part of the blood, or serum, from animals inoculated with a specific bacterium. This serum contained antibodies produced by the animal in response to the infection and could be used to treat humans infected with the same type of bacterium, a kind of therapy called passive immunization.
In 1896, recognizing Ehrlich's skill in devising methods to test serums, the Prussian government made him director of its new Institute for the Investigation
and Control of Sera. In 1899 this institute, with Ehrlich still in charge, was transferred to Frankfurt-am-Main. Finally, in 1906, Ehrlich became director of a second institute, set up beside the Serum Institute with private funds and devoted to research in chemotherapy.10
From the time that he completed his M.D. thesis on the theory and practice of histological staining in 1878 to the end of his career, Ehrlich's research was closely bound up with the new synthetic dyes and their selective affinities for living tissues. Taken in one direction, this interest led him to develop new staining techniques such as those he applied to a definitive classification of white blood cells. Taken in another direction, the same interest led him to reflect on the therapeutic potential of dyes. He had shown, for example, that methylene blue selectively stained cells of the peripheral nervous system. Would it also alleviate pain associated with those nerves? Therapeutic experience confirmed that it did have such an effect, although a temporary one.11
Ehrlich further reasoned that, just as with dye compounds, where part of the molecule attaches to the substance to be dyed while another part is responsible for the color, so too with therapeutic compounds: one part will attach to a specific tissue while another part is responsible for the therapeutic effect. Applying this concept to the problem of parasitic infection, Ehrlich reasoned that the goal should be to identify a compound with a selective affinity for the parasite but not for the cells of the host. To this compound should then be attached a toxic component that would kill or disable the parasite. Such a compound, prepared in the laboratory and administered in the right way, should disinfect the host organism by eliminating the parasites. In Ehrlich's memorable phrase, it would be a "magic bullet" in the same sense as those substances (antibodies) produced by the natural process of immunization, that is, compounds that selectively seek out and destroy the parasites.12
Ehrlich's first major effort along these lines focused on diseases caused by trypanosomes. Among these was sleeping sickness, which devastated large areas of central Africa. Alphonse Laveran in France had opened the way to chemother-apeutic research by showing how to create and maintain experimental trypanosome infections in mice. Now, Ehrlich and his collaborator, Japanese physician Kiyoshi Shiga, vied with Pasteur Institute researchers in Paris to find effective compounds to treat such infections. Both research teams tested hundreds of synthetic dyes, with Ehrlich relying heavily on help from dye chemist Arthur Weinberg, and the Pasteur Institute investigators drawing on the resources of the Bayer chemical company. Beginning in 1904, both teams reported promising results, with trypan red the best compound from Ehrlich's laboratory. Although neither group produced a cure for sleeping sickness, Ehrlich judged that even the limited successes achieved by 1906 "should encourage us to continue, without deviation, along this path."13
As it happened, Ehrlich was prompted to deviate from his path by a report from the Liverpool School of Tropical Medicine that atoxyl, an organic arsenic compound, was more effective than inorganic arsenic in the treatment of try-panosomal infections. Ehrlich set his chemists to synthesis of organic arsenicals, and they soon produced hundreds. Two of these, numbered 418 and 606, seemed especially promising.14
Meanwhile, Ehrlich's attention had been drawn to syphilis, for which the causative organism, a spirochete, had been discovered in 1905 by German zoologist Fritz Schaudinn. Schaudinn's opinion that the spirochete was related not to bacteria but to trypanosomes led Ehrlich to test his organic arsenical compounds against syphilis. Fortunately for this endeavor, an animal experimental model for syphilis had already been developed by Sahachiro Hata, a Japanese bacteriologist who joined Ehrlich's laboratory in 1909. Subjecting Ehrlich's compounds to tests on experimental infections in rabbits, Hata found that compound 606 was highly active.15
Ehrlich devoted the next few years, until his death in 1915, to the development of compound 606 into an effective chemotherapy for syphilis. Marketed in 1910 by the German chemical company Höchst under the trade name Salvarsan, compound 606 (also known as arsphenamine), transformed the treatment of syphilis. Although plagued by problems of toxicity and difficult to administer, Salvarsan and the related compound Neosalvarsan represented the first clear practical triumph of chemotherapy.16
Behind the fervent optimism of Ehrlich's 1913 speech, therefore, lay a theoretical formulation of the rational basis of chemotherapy and a practical research program that had already achieved notable successes. To these Ehrlich added a broad historical appreciation of changes in medicine since the 1860s that highlighted the potential role and opportunities of chemotherapy.
Looking at the sweep of medical history since the 1860s, Ehrlich easily discerned a broad pattern of advance. Isolation of pathogenic bacteria; study of protozoa; discovery of filterable viruses; recognition of insects as intermediate hosts and transmitters of disease; study of immunity, antitoxins, immunology, and sera; and the development of new diagnostic tests all contributed to an increasingly effective prevention, control, and therapy of infectious diseases. The place of chemotherapy was, wherever possible, to "fill gaps in the lines of attack, particularly, by curing diseases in which the natural powers of the body are inadequate." Since, to Ehrlich's mind, the scientific foundations of chemotherapy were in place, he felt confident in asserting that "the way lies in full view before us, a way which will not at all times be easy to follow, but which, nevertheless, it will be possible to follow."17
The chemotherapy of bacterial infections proved even more difficult and elusive than Ehrlich had predicted. By the end of the war, the five-year mark set in Ehrlich's optimistic 1913 prediction had come and gone without a major breakthrough in bacterial chemotherapy. If Ehrlich's hopes had not yet been realized, the urgency of the problem and belief in the possibility of a solution persisted, and the 1920s opened with ample evidence of international response to his program and example. In the minds of many leaders in relevant fields of biomedical science, the question was not whether there would be a chemotherapy of bacterial disease, but when and through what mix of research organization, theory, models, and methods it would be accomplished.
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