In Breslau he worked in the laboratory of his cousin Carl Weigert, a pathologist who pioneered the use of aniline dyes as biological stains. After he showed that dyes react specifically with various components of blood cells and the cells of other tissues, he began to test the dyes for therapeutic properties to determine whether they could kill off disease-causing microbes.
He met with promising results using methylene blue to kill the malaria parasite. After a bout with tuberculosis and his subsequent cure with tuberculin therapy, developed by fellow German Robert Koch, Ehrlich focused his attention on bacterial toxins and antitoxins.
In carrying out this work, he determined how to boost immunity systematically and how to produce high-grade sera. In the institute moved to Frankfurt to more suitable quarters and was renamed the Royal Prussian Institute for Experimental Therapy.
By that time most scientists agreed that both explanations of the immune system were necessary. Early in his career Ehrlich began to develop a chemical structure theory to explain the immune response. He saw toxins and antitoxins as chemical substances at a time when little was known about their exact nature. Up to that time, those scientists who were synthesizing therapeutic agents came at their tasks with few hypotheses about where and how these agents interacted with living systems.
During this period Ehrlich studied bacteriology and tried to learn more about the special affinities of certain chemical compounds to parts of bacterial and cellular protoplasm. He met Emil von Behring who had discovered specific immune substances in the blood serum of animals infected with diphtheria or tetanus bacilli. When Behring had difficulties in producing clinically reliable antisera, Ehrlich developed methods to produce higher effective titers and a reliable means of measurement in units which are still valid.
Ehrlich also formulated his "side chain theory" to explain the phenomenon of specific affinities between toxins and antitoxins. In he took charge of the new Institute and made most of his greatest discoveries and contributions in the last 16 years of his life.
In he produced trypan red which was effective against trypanosomes, especially those causing sleeping sickness. When Thomas and Breinl discovered atoxyl and found it to be effective against trypanosomes, but highly toxic to the optic nerve, Ehrlich directed his efforts toward finding a more effective but less toxic derivative.
In Ehrlich and his staff produced their th preparation, arsenophenylglycin, a most potent substance against tropical diseases caused by trypanosomes.
Ehrlich tested his arsenical preparations on animals infected with the spirochete that causes syphilis. Hata came to work in Ehrlich's laboratory, infecting rabbits with syphilis, testing compounds for its effects on infected rabbits. He now devoted himself to chemotherapy, basing his work on the idea, which had been implicit in his doctorate thesis written when he was a young man, that the chemical constitution of drugs used must be studied in relation to their mode of action and their affinity for the cells of the organisms against which they were directed.
His aim was, as he put it, to find chemical substances which have special affinities for pathogenic organisms, to which they would go, as antitoxins go to the toxins to which they are specifically related, and would be, as Ehrlich expressed it, «magic bullets» which would go straight to the organisms at which they were aimed. To achieve this, Ehrlich tested, with the help of his assistants, hundreds of chemical substances selected from the even larger number of these that he had collected.
He studied, among other subjects, the treatment of trypanosomiasis and other protozoal diseases and produced trypan red, which was, as his Japanese assistant Shiga showed, effective against trypanosomes. He also established, with A. Bertheim, the correct structural formula of atoxyl, the efficiency of which against certain experimental trypanosomiases was known. This work opened a way of obtaining numerous new organic compounds with trivalent arsenic which Ehrlich tested.
At this time, the spirochaete that causes syphilis was discovered by Schaudinn and Hoffmann in Berlin, and Ehrlich decided to seek a drug that would be effective especially against this spirochaete. Among the arsenical drugs already tested for other purposes was one, the th of the series tested, which had been set aside in as being ineffective. Hata did so and found that it was very effective.
When hundreds of experiments had repeatedly proved its efficacy against syphilis, Ehrlich announced it under the name «Salvarsan».
Subsequently, further work on this subject was done and eventually it turned out that the th arsenical substance to which the name «Neosalvarsan» was given, was, although its curative effect was less, more easily manufactured and, being more soluble, became more easily administered. Ehrlich had, like so many other discoverers before him, to battle with much opposition before Salvarsan or Neosalvarsan were accepted for the treatment of human syphilis; but ultimately the practical experience prevailed and Ehrlich became famous as one of the main founders of chemotherapy.
During the later years of his life, Ehrlich was concerned with experimental work on tumours and on his view that sarcoma may develop from carcinoma, also on his theory of athreptic immunity to cancer. The indefatigable industry shown by Ehrlich throughout his life, his kindness and modesty, his lifelong habit of eating little and smoking incessantly 25 strong cigars a day, a box of which he frequently carried under one arm, his invariable insistence on the repeated proof by many experiments of the results he published, and the veneration and devotion shown to him by all his assistants have been vividly described by his former secretary, Martha Marquardt, whose biography of him has given us a detailed picture of his life in Frankfurt.
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