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Paul Ehrlich (1854-1915): Founder of Chemotherapy and Pioneer of Haematology, Immunology and Oncology

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Paul Ehrlich (1854-1915): Founder of Chemotherapy and Pioneer of Haematology, Immunology and Oncology Journal of BUON 9: 485-491, 2004 © 2004 Zerbinis Medical Publications. Printed in Greece HISTORY OF ONCOLOGY Paul Ehrlich (1854-1915): founder of chemotherapy and pioneer of haematology, immunology and oncology G. Androutsos Institute of History of Medicine, University Claude Bernard, Lyons, France Summary tion in immunology he was awarded the Nobel Prize of Medicine and Physiology in 1908. The Jewish-German histologist, microbiologist, bio- chemist, immunologist and pharmacologist Paul Ehrlich, by his research founded chemotherapy and pioneered im- Key words: chemotherapy, Ehrlich, haematology, immunolo- munology, haematology and oncology. For his contribu- gy, “magic bullet”, oncology Ehrlich’ first years German chemical industry. These synthetic dyes would prove useful for staining cells and tissues, and this is Paul Ehrlich was born on 14 March 1854 in the where Ehrlich made his first important scientific con- little town of Strehlen, not far from Breslau. His Jew- tribution. Ever since his schooldays, he had been fas- ish family had lived there since the 18th century. Paul cinated by dyes and the possibility of using them in grew up in economically favourable conditions with a medical research, and he was encouraged by his moth- kind-hearted father, Ismar and an energetic, business- er Rosa’s cousin Carl Weigert (1845-1904) an outstand- minded mother, Rosa, who dominated the family. Paul ing pathologist. During the holidays, Paul conducted was a bookish child who preferred to spend his time experiments in Strehlen with anilin dyes that he mixed reading rather than participating in the wild games of into the food of his mother’s domestic white pigeons. his schoolmates. He was a diligent schoolboy who was The idea was that they should assume a nice blue co- particularly good in mathematics and the natural sci- lour, but the most obvious result of the experiment was ences. His grandfather’s distillery with all its chemical that the pigeons died. The intended result, in this case apparatus had obviously made an indelible impression the change of colour, had an undesired side effect. on the boy and this experience probably laid the foun- This early experience made a deep impression on the dation of his lifelong interest in chemistry. On the other young Ehrlich and illustrated a central problem in che- hand, both at school and later on as an adult, he had motherapy, the medical field that he would devote a difficulties expressing himself in German both orally great part of his life to develop. and in writing. The same was true of English and French. After graduating from the Gymnasium (second- This would cause some complications in the years to ary school), he studied natural sciences somehow un- come, when as a world-famous scientist he had to systematically for a term at the University of Breslau. present his results before an international audience [1]. Ehrlich had a strong inclination towards medical re- search, but the actual practice of medicine had no ap- peal to him. With his sensitive, not to say timid disposi- First experiments with colours and their che- tion, he was reluctant to witness the suffering of his motherapeutic action patients, and perhaps also not willing to inflict pain on them during their treatment. In the end, coupled with Ehrlich’s student years coincided with the almost the strong support of Weigert, his family managed to explosive development of organic chemistry during the persuade him. During his medical studies, first in Stras- latter half of the 19th century and the synthesis of a bourg where he passed a preparatory examination great number of dyes that laid the foundation of the (“Physikum”) and after that in Breslau, he became 486 more and more fascinated with dyes and their medical en method - after Franz Ziehl (1857-1926) and Friedrich uses. Weigert had already established himself in this Neelsen (1854-1894). In 1882 Ehrlich introduced his field, where he became a pioneer in the staining of diazo-reaction for the diagnosis of typhoid fever, and tissue sections for microscopic examination in pathol- in 1885 his work on the oxygen affinities of the tissues ogy. Through him, Ehrlich came in contact with the led to vital staining [4]. botanist Ferdinand Cohn and the pioneer of experimen- Ehrlich’s discovery of the mast cells and his new tal pathology Julius-Friedrich Cohnheim (1839-1884). methods for the staining of cells and tissues had gained In Cohn’s laboratory, Ehrlich met Robert Koch (1843- him international recognition. The head of the Medi- 1910) for the first time [2]. cal Clinic II at the well-known Charité Hospital in He reasoned that the biological effect of a sub- Berlin, professor Friedrich-Theodor von Frerichs stance, for instance a dye, is dependent on a chemi- (1819-1885), offered the young physician a position cal affinity between the substance and different struc- at the clinic with excellent opportunities for research. tures which occur in cells and tissues. This chemical Frerichs gave to his new chief assistant (“Oberarzt”) affinity is specific and it must consequently be possi- complete freedom to choose his own line of research, ble, by systematic testing, to select substances suit- in accordance with one of the professor’s leading able as drugs, i.e. with well-defined biological effects principles: “Science is a bird that only sings in free- and no undesired side effects. For instance, among dom.” Here, Ehrlich spent seven happy years while the seemingly endless number of new compounds he worked on improving his staining methods and produced in organic chemical laboratories, there must made fundamental contributions to haematology. be some that kill or inhibit certain bacteria, but are During this time, he married Hedwig Pinkus, the harmless to the human organism. daughter of a wealthy textile mill owner [5]. In 1885, Ehrlich published the results of an in- vestigation of the uptake of oxygen in the animal or- A pioneer of histological staining and haematology ganism. By staining living organs and tissues, he could show that they had a markedly variable ability to take Ehrlich passed the examinations for his MD in up oxygen. These results were received with great 1877 and the next year he completed a thesis in Bre- interest, and two years later he got a prestigious prize slau entitled “Some Contributions to the Theory and for his discoveries. Nevertheless, the year 1885 was Praxis of Histological Staining” [3]. In his thesis, he an unlucky one for Ehrlich. His professor and enthusi- reported the discovery of an, until then, unknown kind astic patron, von Frerichs, died suddenly and the new of cell, which he called “mast cell”, that surrounded head of department, Karl Gerhardt, was a clinician of the blood vessels and contained granules that could a more conventional type. He was not at all prepared be stained with basic dyes. The discovery of the mast to give Ehrlich the rather privileged position that he cells is of course of considerable interest as such, but had enjoyed under Frerichs which had been a prereq- it also illustrates a line of thought which would be- uisite for his successful research. Ehrlich found his come central in Ehrlich’s research. His demonstra- position at the clinic as well as his research opportuni- tion of the staining characteristics of the white blood ties unsatisfactory, and this contributed to the deterio- cells with aniline dyes allowed others to understand ration of his health. He had a persistent cough. In 1888 better the abnormalities of blood cells, thus contribut- he detected tubercle bacilli in his expectorations. Ehr- ing to the foundation of haematology. lich suddenly left his position at the Charité and he set While still a student, Ehrlich began investigations out for the dry desert climate of Egypt in an attempt to on the aniline dyes. With their aid he discovered (1877- cure his supposed tuberculosis. A year later he returned 1881) all the different types of white blood corpuscles; to Berlin, apparently cured of tuberculosis but without he distinguished leukaemia according to the prevalent a position that would allow him to continue his research. type of cell; and he introduced his tri-acid stain for blood. The staining of bacteria was very difficult, and in 1881 Ehrlich introduced the highly satisfactory me- A pioneer of immunology thylene blue stain. Much of Koch’s work was done with stain, and by laborious staining over a prolonged The only remaining solution was to establish him- period, he discovered the tubercle bacillus. On the day self as a private researcher. Fortunately, Ehrlich’s fa- following Koch’s announcement of his discovery, Ehr- ther-in-law generously provided the means for this. lich evolved a rapid method for staining the microor- Not far from his private residence, he established his ganism. This method is now known as the Ziehl-Neels- laboratory. This was a new beginning for him as he 487 also embarked on a completely new line of research. It was now that he started his investigations of the plant poisons, ricin and abrin, and their ability to cause the formation of antibodies in mice. This research naturally led to a collaboration with Emil von Behring (1854-1917). A close friendship, that would last their whole lives. In 1891 Ehrlich discovered that the injection of poisons, such as ricin, induced the production of anti- bodies in the blood, and in the same year he discov- ered the latent period in the development of active immunity [6]. In 1892 he illuminated the distinction between active and passive immunity. About this time many unsuccessful attempts had been made to pro- vide standards for the dosage of the diphtheria anti- toxin. In 1897 Ehrlich published his classic paper on this subject.
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