(b. Strehlen, Germany [now Strzelin, Poland], 14 March 1854; d. Bad Homburg, Germany, 20 August 1915)
hematology, immunology, chemotherapy.
Among medical scientists of his generation Ehrlich was probably the most original, stimulating, and successful. The fruitfulness of his concepts initiated advances in all fields of biomedical research to which they were applied. Hematology became a recognized discipline through his pioneering studies of dye reactions on red and white blood cells. In exhaustive experiments on the production of high-potency diphtheria antitoxin and on methods of assaying and standardizing such products, he developed techniques and established fundamental principles of immunity. His crowning achievement was the synthesis of Salvarsan and the demonstration of its therapeutic efficacy in syphilis and allied diseases.
Paul Ehrlich was born into a comfortable, lively household in a country town in Prussian Silesia, about twenty miles south of Breslau (now Wrocław, Poland). He was the only son and fourth child of Ismar Ehrlich, a respected but somewhat eccentric Jewish distiller, innkeeper, and lottery collector, and his wife Rosa Weigert, an industrious woman of notable intelligence, charm, and organizational talent. Her cousin Carl Weigert, the distinguished pathologist, was only nine years older than Paul, and the two became close friends. Besides many of his mother’s characteristics the boy had his father’s excitability and interjection-ridden manner of speech, and perhaps inherited certain aptitudes from his paternal grandfather, Heimann Ehrlich, a prosperous liqueur merchant, who collected an extensive private library and late in life gave lectures on science to fellow citizens of Strehlen.
In 1860, when he was six years old, Ehrlich entered the local primary school. At age ten he went to the St. Maria Magdalena Humanistic Gymnasium in Breslau and boarded with a professor’s family. He accepted Spartan living and classroom conditions; was unobtrusive and conscientious; and though not outstanding, was often near the top of his class. He disliked all examinations, however. His favorite subjects were mathematics and Latin; his weakest was German composition.
After matriculating in 1872, Ehrlich took a disappointing introductory course in natural sciences at Breslau University and then spent three semesters at Strasbourg, which largely determined his life’s course. He was impressed by the anatomist Wilhelm von Waldeyer’s broad comprehension of medicine, and the professor in turn noted the many extra hours this unusual student devoted to making excellent histological preparations with his own modifications of new aniline dyes. Ehrlich visited the Waldeyer household, and a lasting friendship was established.
Although lacking formal courses in chemistry, Ehrlich became fascinated with the subject while studying for his Physikum at Strasbourg. Having passed this examination, he returned in 1874 to Breslau, where he completed studies for his medical degree, except for one semester in 1876 at the Physiology Institute of Freiburg im Breisgau and a final term at Leipzig in 1878. In Breslau he was influenced by the pathologists Julius Cohnheim and Carl Weigert, the physiologist Rudolf Heidenhain, and the botanist Ferdinand Cohn, sponsor of Robert Koch’s researches on anthrax bacilli. At the Pathology Institute, Ehrlich became friendly with such outstanding visitors as W. H. Welch, the American pathologist, and C. J. Salomonsen, the Danish bacteriologist. Weigert had introduced aniline dyes into microscopic technique, and in his cousin’s laboratory Ehrlich studied their selective action on cells and tissues. His first paper on the properties of these dyes appeared in 1877, in which year he passed the state medical examination. His doctoral dissertation, “Beiträge zur Theorize and Praxis der histologischen Färbung,” was approved at Leipzig University in 1878. These two works included descriptions of large, distinctively stained cells containing basophilic granules, for which Ehrlich coined the term “mast cells,” differentiating them from the rounded “plasma cells” observed in connective tissue by Waldeyer. In 1879 he defined and named the eosinophil cells of the blood.
Upon graduation Ehrlich was appointed head physician (Oberarzt) in Friedrich von Frerichs’ renowned medical clinic at the Charité Hospital in Berlin. Frerichs, an imaginative clinician with deep interests in experimental pathology, encouraged Ehrlich’s histological and biochemical researches, and the latter thereby gained lasting insights into diagnostic and therapeutic problems. His reports on the morphology, physiology, and pathology of the blood cells advanced hematology into a new era by establishing methods of detecting and differentiating the leukemias and anemias. Further, the observations that basic, acidic, and neutral dyes reacted specifically with such cellular components as leukocyte granules and nuclei implanted in Ehrlich’s mind the fundamental concept underlying his future work: that chemical affinities govern all biological processes. He extended comparable staining methods to bacteria and protozoa and rendered Koch’s discovery of the tubercle bacillus immediately more important by showing that its failure to stain in aqueous dye solutions could be circumvented by use of basic dyes in an aqueous-aniline oil solution, which penetrated the bacillary coating and then remained acid-fast.
Ehrlich was determined to explore the avidity of living tissues for certain dyes. In 1885 a remarkable monograph, Das Sauerstoffbedürfnis des Organismus, reporting his investigations into the distribution of oxygen in animal tissues and organs, gained widespread attention from medical scientists. Using two vital-staining dyes, alizarin blue (reducible to a leuko form with difficulty) and indophenol blue (readily reducible), he demonstrated that while living protoplasm in general has potent reducing properties, bodily organs are classifiable into three categories according to their oxygen avidity. Challenging Pflüger’s assertion that tissue oxidation and reduction entail direct entry and exit of oxygen, he contended that these processes involve withdrawal and insertion of hydrogen atoms. Two years later the monograph won the Tiedemann Prize and served as Ehrlich’s Habituation thesis before he became Privatdozent in internal medicine at Berlin University. In 1886 he described methylene blue as a selective vital stain for ganglionic cells, axis cylinders, and nerve endings. Later, with A. Leppmann, he used this dye therapeutically to kill pain in neuralgias; and in 1891, with P. Guttmann, he pursued to its logical conclusion the finding that malaria parasites stain well with methylene blue, administering the dye to two malarial patients with apparent success.
Further by-products of Ehrlich’s ingenuity with dyestuffs were the use of fluorescein to observe the streaming of the optic humors (1882) and his diazo reaction, a color test for the presence of bilirubin in the urine, regarded long afterward as a useful prognostic test in severe acute infections, such as typhoid fever (1883). His other Charité investigations that strengthened the developing conviction that chemical composition, distribution within the body, and pharmacological effect of biologically active substances were interrelated included the treatment of iodine poisoning by detoxification with sulfanilic acid (1885); the lipotropism of thalline and its homologues, and the dependence of thalline’s antipyretic action on the ortho-position of the methoxyl group in the molecule (1886); the correlation between lipotropism and neurotropism, as displayed in rabbits inoculated with certain dyes of the basic and the nitrated, but not the sulfonic acid, groups (1887); and the demonstration that liver degeneration in cocainepoisoned mice was not caused by the benzoyl radical responsible for the drug’s anesthetizing properties (1890).
In 1883 Ehrlich had married Hedwig Pinkus, daughter of a prosperous textile industrialist of Neustadt, Upper Silesia, whom he had met during a visit to Strehlen. Ten years his junior, she proved an understanding, faithful companion, and their marriage was happy. They had two daughters—Stephanie, born in 1884, and Marianne, born in 1886—to whom he was greatly attached. One year after his marriage Ehrlich was made a titular professor at Berlin, on Frerichs’ recommendation. When Frerichs died suddenly in 1885 and the more conservative Karl Gerhardt succeeded him, Ehrlich found his researches disturbingly impeded. In 1888, discovering tubercle bacilli (presumably of laboratory origin) in his sputum, he ended’ a decade of fruitful association with the clinic and journeyed with his young wife to Egypt, where he stayed over a year. In 1889 he returned to Berlin apparently cured of pulmonary tuberculosis, received Koch’s newly discovered tuberculin treatment, and never had a recurrence.
Now without appointment, Ehrlich set up a small private laboratory in a rented flat and launched a series of fundamental studies in immunity that captured attention for many years. Using as antigens the toxic plant proteins ricin and abrin, he demonstrated that young mice could be protected against these agents if fed or injected with them in initially minute but increasing dosages. Such “actively” immunized mice developed high levels of specific antibodies in their blood. After describing these observations in two papers entitled “Experimentelle Untersuchungen über Immunität” (1891), Ehrlich showed that the progeny of a ricin- or abrin-immunized mother inherited a specific transient immunity, sustainable at higher levels by sucklings through absorption of antitoxin in the maternal milk. A similar state of “passive” immunity was induced in the progeny of a nonimmune mother that were suckled by an actively immunized mouse. Further, a normal lactating mouse injected with antiserum from an animal highly immunized against abrin, ricin, or tetanus toxin conferred specific passive immunity upon her offspring. These “wet nurse” and related experiments were reported in 1892.
Some of this work was carried out during Ehrlich’s brief appointment (arranged by Koch in 1890) as clinical supervisor at the Moabit Municipal Hospital in Berlin. There he and P. Guttmann found that small doses of tuberculin were valuable in pulmonary and laryngeal tuberculosis. Ehrlich reported this finding at the Seventh International Congress for Hygiene and Demography at London in 1891. Thereafter he performed his immunological studies in a small laboratory at the newly founded Institute for Infectious Diseases in Berlin, of which Koch had become director. Ehrlich worked here for more than three years without salary, despite his appointment as extraordinary professor at Berlin University in 1891.
The institute’s dedication to problems of infection, his own experiences with tuberculin, and Emil von Behring’s discoveries of diphtheria and tetanus antitoxins led Ehrlich to investigate bacterial toxins and antitoxins by methods comparable with those employed in his plant protein studies. With L. Brieger he produced potent antitoxic serums in actively immunized large animals and demonstrated that these substances could be concentrated and partially purified. In 1894 he reported, with H. Kossel and A. von Wassermann, on 220 unselected diphtheritic children treated with antitoxin, stressing the importance of early, liberal dosages. Meanwhile, Behring had overcome serious difficulties in diphtheria antitoxin production by exploiting Ehrlich’s assistance, procuring for himself a remunerative contract for supervising commercial manufacture of antitoxin.
Early in 1895, on the initiative of the director of the Prussian Ministry of Educational and Medical Affairs, Friedrich Althoff, an enlightened public servant who admired Ehrlich’s ability, an antitoxin control station was established at Koch’s institute under the supervision of Ehrlich, assisted by Kossel and Wassermann. This function was transferred in 1896 to a center for serum research and testing at Steglitz, a Berlin suburb. Ehrlich was appointed director, with Wilhelm Dönitz, and later Julius Morgenroth and Max Neisser, as his associates. The Institut für Serumforschung und Serumprüfung consisted of a one-story ramshackle building, variously described as a former almshouse or disused bakery, with an adjacent stable for laboratory animals. Nevertheless, Ehrlich took pride in his unpretentious establishment, and excellent work was done in it.
After months of arduous work involving “hecatombs” of guinea pigs, he concluded that serum samples should be assayed in terms of a relatively stable international unit of antitoxin, distributable in dried form in vacuum tubes. Moreover, in titration the “test dose” of toxin should be the minimum amount that, added to one standard unit of antitoxin, kills within four days a 250-gram guinea pig injected therewith. These recommendations were widely adopted, and Ehrlich’s L†, or Limes-Tod, designation for the test dose survives among his striking legacy of biomedical terms. Besides such practical accomplishments he sought theoretical explanations for the instability of diphtheria toxins that involved their lethality for guinea pigs and their ratio of lethality to antitoxinbinding power. He considered the interaction between diphtheria toxin and antitoxin a chemical process in which the reagents combine in constant proportion, as did abrin and ricin with their respective antiserums.
Ehrlich also surmised arbitrarily that one standard unit of antitoxin should fully neutralize exactly 200 minimal doses of pure toxin. When unpredictable rates of toxin degradation and varying avidities among antitoxin samples challenged this oversimplified view, he postulated the formation of toxoids (with combining power intact but toxicity absent) and of epitoxoids or toxones (with lessened combining power and altered toxicity). According to Ehrlich, each preparation of crude toxin had its own “spectrum” (Giftspektrum), divided into 200 segments, in which toxin, toxoid, and other designated components showed simple quantitative interrelationships.
Although certain of these proposals, set forth in the papers “Die Wertbemessung des Diphtherieheilserums und deren theoretische Grundlagen” (1897), and “Ueber die Constitution des Diphtheriegiftes” (1898), mystified some readers and aroused opposition from others, in the main they won acceptance and brought their author international recognition. He was appointed Geheimer Medizinalrat in 1897. Althoff realized that Ehrlich’s genius deserved better facilities, and with the lord mayor of Frankfurt am Main, Franz Adickes, arranged for construction of a suitable building near the city hospital. Opened in 1899, the Royal Prussian Institute for Experimental Therapy was directed by Ehrlich until his death sixteen years later.
The new “Serum Institute” was not only responsible for routine state control of immunotherapeutic agents, such as tuberculin and diphtheria antitoxin, but also for research and training in experimental therapy. To this latter function Ehrlich devoted him-self and his disciples, including Dönitz, Neisser, and Morgenroth, who followed him from Steglitz, and such subsequent staff members as Hans Sachs, E. von Dungen, E. Marx, Hugo Apolant, and Alfred Bertheim. In 1906 the adjacent Research Institute for Chemotherapy (designated the Georg-Speyer-Haus) was erected and endowed by Franziska Speyer in memory of her late husband. She did so on the advice of her brother, L. Darmstädter, to whom the promising possibilities of the specific chemotherapy of infectious diseases had been expounded by Ehrlich early in 1905. His spreading fame brought numerous visitors from abroad to work in the combined institutes, including Reid Hunt, Christian Herter, and Preston Keyes from the United States, Carl Browning and H. H. (later Sir Henry) Dale from Britain, and Kiyoshi Shiga and Sahachiro Hata from Japan.
Ehrlich’s activities in Frankfurt fall into three periods. The first, 1899–1906, was marked by the emergence and elaboration of his side-chain theory, the conclusion of his work on diphtheria, extensive researches into the mechanisms of hemolytic reactions (with Morgenroth), and his cancer investigations (with Apolant). The second period dates from an address at the ceremonial opening of the Georg-Speyer-Haus in September 1906, in which Ehrlich prophesied the creation of substances “in the chemist’s retort” that would “be able to exert their full action exclusively on the parasite harbored within the organism and would represent, so to speak, magic bullets which seek their target of their own accord.” It culminated in his announcement before the Congress for Internal Medicine at Wiesbaden, in April 1910, that a synthetic arsenical compound, which he called dioxydiamidoarsenobenzol (Salvarsan), had shown curative properties in rabbit syphilis and fowl spirillosis, and also in clinical trials on syphilitic patients. The third period, 1910–1915, covered Ehrlich’s gallant struggle to handle the multiplex problems that followed the discovery of Salvarsan. The highlights of these periods will be reviewed consecutively.
In the final publications begun at Steglitz, Ehrlich summarized his doctrine of the interrelationship of “composition, distribution, and effect” and outlined his side-chain theory. This theory, presaged in his Sauerstoffbedürfnis (1885), was brought into focus mainly to account for diphtheria toxin’s two distinct attributes, toxicity and antitoxin-binding power. It postulated two different chemical groups in the toxin molecule, one designated haptophore and the other toxophore. The former “anchors” the toxin molecule to the side chains (later termed “receptors”) of a cell for which it has chemical affinity, by a process akin to the “lock and key” simile of the organic chemist Emil fischer, thus exposing the cell to damage or destruction by the toxophore group. If the cell survives the attack, the receptors rendered inert by combination with the haptophore group are replicated to excess, following Weigert’s theory that tissue injury incites proliferative regeneration. Some of these surplus receptors, adapted to absorbing and neutralizing the toxin molecules, are shed and appear as circulating antitoxin—in Ehrlich’s words, “handed over as superfluous ballast to the blood.”
The theory was expounded by Ehrlich in his Croonian lecture, “On Immunity With Special Reference to Cell Life,” delivered before the Royal Society in 1900. This fertile, heuristic hypothesis was a bold attempt to integrate the newer knowledge of nutrition, immunology, and pharmacology, but the ingenious arguments advanced by Ehrlich to bring fresh data within its purview were sometimes farfetched or obscure. He investigated the hemolytic reactions of animal serums reported by Jules Bordet in 1898 because they showed analogies to bacteriolytic phenomena and could be studied precisely in vitro. Bordet’s observation—that the heterolysin produced by injecting an animal with red blood cells from an alien species became manifest only in the presence of a heat-labile factor (designated “alexine” by Bordet and “complement” by Ehrlich), found in most fresh normal serums—was confirmed. Whereas Bordet contended that alexine destroyed the red cells after their sensitization by a single immune body (substance sensibilatrice), Ehrlich visualized a far more complex situation. In several papers written with Morgenroth (1899–1901) he postulated two haptophore components in the immune body of an active hemolysin, one having strong affinity for the corresponding red blood cell receptor, the other combining with complement. Later he compared the immune body (amboceptor) and complement to the haptophore and toxophore groups of a toxin and presupposed an “extraordinary multiplicity” of hemolysins and a plurality of complements.
From Steglitz, in the midst of illuminating and practically unchallenged toxin-antitoxin titrations, Ehrlich had confided his perplexity and disenchantment to Carl Weigert. The situation now was different. In 1901 Max von Gruber launched a twoyear polemic, which became inexcusably insulting, against the side-chain theory. Moreover, Svante Arrhenius and Thorvald Madsen, and Bordet as well, constructively criticized Ehrlich’s views on the strictly chemical nature of the union between diphtheria toxin and antitoxin. At Frankfurt pertinacious efforts to clarify the mechanisms of hemolytic and toxinantitoxin reactions continued. When J. Bang and J. Forssman criticized the side-chain theory anew in 1909, Ehrlich and Sachs defended it in two final papers. To confound contemporaries who proclaimed the theory without practical value and its creator a “theoretician,” Wassermann testified that the complement-fixation test for syphilis could not have been developed without Ehrlich’s teaching.
In 1901 Adickes and Althoff persuaded the Theodor Stern Foundation to finance a cancer research station at the Serum Institute. After two rather unproductive years, C. J. Jensen’s discovery that mouse mammary tumors are malignant and transplantable incited Ehrlich and Apolant to perform thousands of tumor-grafting experiments. Applying familiar techniques to this new field, they increased the tumor virulence for mice tenfold, until 100 percent of grafts took; and with single injections of slightly virulent cell suspensions they induced high degrees of immunity against virulent transplanted tumors. While closely following over many generations the structural changes that accompanied increased virulence, they observed a strain of mouse carcinoma apparently transforming into sarcoma. To explain the failure of a second graft to grow in an animal already carrying a tumor, whereas after resection of the first tumor a subsequent graft would take, Ehrlich coined the term “athreptic immunity.” “Athrepsia,” derived from the Greek тρєфω, “to nourish,” signified exhaustion of the host’s supply of nutrients essential for tumor growth. In his second Harben lecture (1907), Ehrlich suggested broader applications of the term—which, however, found little acceptance. This cancer work represented an unsought digression from his main course, and by 1909 chemotherapeutic researches had entirely superseded it.
In his long-standing aim to discover synthetic chemicals that act specifically upon pathogenic microorganisms, Ehrlich was aided by Arthur Weinberg and Ludwig Benda, director and chemist, respectively, of the Farbwerke Cassella & Co. near Frankfurt, who made compounds to his specifications even before the Georg-Speyer-Haus was established. In 1904 he reported with Shiga that one such substance, trypan red, cured mice experimentally infected with Trypanosoma equinum, causal parasite of mal de caderas. When he and Bechhold investigated the relationship between molecular constitution and disinfectant action of phenolic compounds upon bacterial suspensions, they found these effects inhibited by serum; moreover, the agents proved toxic and failed to produce “internal antisepsis” when injected into artificially infected animals. Hence Ehrlich pursued his earlier chemotherapeutic studies on trypanosomeinfected mice and rats.
Recurrent infections in treated animals were ascribed to specific resistance to trypan red and related dyes acquired by the surviving parasites. However, such resistant strains were susceptible to atoxyl, an arsenical compound reported by H. W. Thomas and A. Breinl in 1905 to cure trypanosome-infected rodents. Ehrlich therefore postulated sessile “chemoceptors” (including an “arsenoceptor”) in the parasite’s protoplasm that were not released into the blood like antitoxin but had anchoring facilities for certain specific radicals. In 1907, having discovered that atoxyl was the sodium salt of p-aminophenylarsonic acid, or arsanilic acid, he and Bertheim synthesized and tested several hundred derivative compounds. By tailoring molecular appendages to fit the receptors of broadly resistant trypanosomal strains, they hoped to create drugs of maximum “parasitotropism” and minimum “organotropism.”
Meanwhile, Paul Uhlenhuth and others, stimulated by E. Roux and Elie Metchnikoff’s successful transfer of syphilis to apes (1903), Fritz Schaudinn’s discovery of the spirochete of syphilis (1905), and certain parallels between spirochetal and trypanosomal infections in animals and man, reported beneficial effects from atoxyl treatment of dourine, fowl spirillosis, and syphilis in rabbits, apes, and man. Since blindness sometimes followed treatment of human sleeping sickness with this agent, Ehrlich sought safer and more effective remedies. For example, arsacetin, prepared by introducing the acetyl radical into the amino group of atoxyl, was less poisonous and cured mice a few hours away from death, but it was still too toxic for clinical use.
Late in 1908, lecturing before the German Chemical Society, Ehrlich described a trivalent arsenobenzene compound of low toxicity for mice that was derived from atoxyl by two-stage reduction. This was arsenophenylglycine, number 418 in the series under test. Its high trypanocidal effectiveness inspired Ehrlich to introduce one of his favorite and bestknown Latin tags, “therapia sterilisans magna,” denoting “complete sterilization of a highly infected host at one blow.” Six weeks later, in his Nobel lecture, “Ueber Partialfunctionen der Zelle,” he asserted that through this substance “one can actually, with all kinds of animals and with every kind of trypanosome infection, achieve a complete cure by a single injection.” In trials elsewhere, particularly by his friend from earliest school days, the Breslau dermatologist Albert Neisser, arsenophenylglycine gave excellent results in the treatment of dourine and other treponemal diseases of animals but was less satisfactory in fowl spirillosis and in simian and human syphilis. Moreover, it was unstable, forming toxic oxidation products.
The search for an agent whose therapeutic index (ratio of curative to tolerated dose) was very small halted in 1909. Hata arrived that spring from Tokyo to work with Ehrlich. He was familiar with rabbit syphilis, and the emphasis switched to this and fowl spirillosis for appraisal of the many new compounds now on hand. Hata found number 606, dihydroxydiamino-arsenobenzene-dihydrochloride (distantly related to arsanilic acid through a three-stage reduction process), had a “dosis curativa” to “dosis tolerata” ratio for fowl spirillosis of only 1:58. Intensive trials on rabbit syphilis confirmed the outstanding spirocheticidal properties of this compound. Ehrlich released limited supplies to selected specialists for clinical trials. Paralytic syphilis cases showed little improvement, but in relapsing fever and early syphilis the results were excellent. After additional favorable trials, Ehrlich, Hata, and several clinicians announced their findings in April 1910, before the Congress for Internal Medicine at Wiesbaden.
The rush for the new remedy was uncontrollable. Ehrlich tried to restrict its distribution to qualified acquaintances in various countries but was importuned by mail and by physicians who flocked to Frankfurt. Five months later, at another congress in Königsberg, he announced that “606” would not be generally available until 10,000–20,000 cases had received treatment, but further enthusiastic reports increased the demand. By the year’s end, when the full resources of the Georg-Speyer-Haus had provided about 65,000 doses gratis, large-scale facilities at the nearby Höchst Chemical Works were enlisted and the product patented under the name Salvarsan. In the United States it later became known as arsphenamine.
The invention of Salvarsan brought Ehrlich four years of both tragedy and triumph. He battled problems that stemmed from the drug’s imperfections, from the complex pathology of syphilis, and from human carelessness, cupidity, and malice. The tricky manufacturing process and rigid biological tests on every batch came under his scrutiny. The best method of administration for counteracting the product’s oxidizability and acidity and for reducing reactions remained uncertain; and although Ehrlich emphasized the therapeutic principle “frapper fort et frapper vite,” routes of injection and dosages were still largely empirical. His ideal, “sterilisatio magna,” was apparently feasible for relapsing fever, yaws, and certain animal diseases, but it seemed elusive or unattainable in syphilis. Neurological recurrences in undertreated cases and Jarisch-Herxheimer reactions (from hypersensitivity to massively destroyed spirochetes) were alarming, despite Ehrlich’s explanations. Again, on every possible patient serological reports on Wassermann’s complement-fixation test were correlated with clinical progress. As each complaint or complication was pursued, Ehrlich’s correspondence reached staggering proportions and the institute overflowed with visiting physicians and would-be patients. Meanwhile, he published several reviews and edited collections of reports on Salvarsan and chemotherapy. Despite all the turmoil, he devised an arsenical derivative, number 914, which went into neutral solution without loss of effectiveness. It was introduced for clinical use in 1912 as Neosalvarsan. With Paul Karrer, his last collaborator, Ehrlich attempted further improvements by combining Salvarsan with such metals as copper, silver, bismuth, and mercury.
Such burdens would have daunted and overtaxed any man. Ehrlich’s frail health began to crumble, and his peace of mind was disturbed by calumnies. Fanatic sensationalists accused him of charlatanism, profiteering, and ruthless experimentalism. The slander continued, led by the Berlin police doctor, until in March 1914 the Reichstag, forced to debate the merits of Salvarsan, endorsed it as “a very valuable enrichment of the remedies against syphilis.” Three months later Ehrlich was defense witness for the Frankfurt Hospital when a local newspaper brought suit alleging that prostitutes were being forcibly subjected to dangerous treatment with Salvarsan. The complainant was sentenced to one year in jail. The outbreak of World War I drew public attention else-where, and Ehrlich suffered no further indignities.
Ardently although quietly patriotic and on friendly terms at court, Ehrlich was grievously distressed by the war; he brooded over his isolation from scientific friends abroad and was disconcerted by the enforced diversion of the institute’s activities. In December 1914 he suffered a slight stroke. The arteriosclerotic and diabetic manifestations were treated by banning the strong cigars that he habitually smoked to excess and by regimenting his diet, but he regained neither health nor sanguine temperament. Persuaded early in August 1915 to enter a sanatorium for treatment and rest, he shortly had a second, peacefully terminal stroke. He was buried in the Frankfurt Jewish Cemetery.
Many honors came his way. After sharing the 1908 Nobel Prize with Metchnikoff, awarded in recognition of their work on immunity, Ehrlich was renominated in 1912 and 1913 for his contributions to chemotherapy. The value of Salvarsan was considered still too disputed; and before the question was settled, Ehrlich had died. He received the Prussian Great Gold Medal for Science (1903), the Liebig Medal (1911), and the Cameron Prize (1914). Twelve orders (ten from foreign governments) and five honorary doctorates were conferred on him. He was granted the title of Geheimer Obermedizinalrat in 1907 and of Wirklicher Geheimer Rat, with predicate Excellenz, in 1911. From 1904 he was honorary ordinary professor at Göottingen, and in 1914 he became ordinary professor at the new Frankfurt University. He held honorary or foreign memberships in about eighty scientific and medical societies. In 1912 he received the freedom of the city of Frankfurt, and the street containing his institutes was renamed Paul-Ehrlich-Strasse. His friends and disciples celebrated his sixtieth birthday in 1914 by preparing a remarkable Festschrift, each of whose thirty-seven chapters commemorated one aspect of his manifold accomplishments. The Paul Ehrlich Prize for outstanding achievement in one of his fields of research is given biennially by the Paul Ehrlich Institut as a living memorial to him.
Despite the varied nature of his investigations, a unifying principle is discernible throughout. As a student Ehrlich was fascinated by E. H. Heubel’s observation (1871) that in chronic lead poisoning the organs showed wide differences in content of the toxic element, differences that were paralleled in organs from normal animals immersed in dilute lead solutions. Thus the fruitful doctrine was initiated that biological activities are determined by specific chemical affinities and are quantitatively measurable. Ehrlich’s early work on dyes, on the oxygen need of the tissues, and on methylene blue treatment of malaria strengthened this belief, which also animated his chemotherapeutic strivings. The adapted aphorism “Corpora non agunt nisi fixata,” introduced in his address on chemotherapy before the 1913 International Congress of Medicine in London, epitomized a concept that is still valid and fruitful, particularly in cytochemistry.
To the creative momentum of a sound original principle of broad applicability, Ehrlich harnessed brilliant talents: a darting intelligence linked to untrammeled imagination; compulsive industriousness; the faculty of stereognostically visualizing benzene rings and structural chemical formulas; technical ingenuity and punctiliousness, and unique virtuosity in “test-tube” chemistry; the capacity to direct several lines of research simultaneously, through a system of daily “blocks” carrying written instructions to every co-worker; and the foresight to abandon paths that were unpromising. An autodidact, he was nobody’s disciple. His gift for coining words, phrases, and metaphors enriched the common vocabulary of science. Ehrlich conversed and lectured in German only, but he could read English and French and perused relevant scientific publications avidly and rapidly (reading “diagonally”). His tastes in general literature aspired no higher than Conan Doyle and he lacked feeling for art, but he was refreshed by simple music.
By nature Ehrlich was enthusiastic, good-humored, at times even bantering; but meanness, unfair criticism, or false claims to priority aroused fierce indignation. Although genuinely modest, he knew the importance of his work. He never lobbied for his own ends, was devoid of mercenary instinct, and was completely honorable in all his dealings. Lovably loyal to his family and countless friends, he was the very embodiment of minor eccentricity and true genius. As Sir Robert Muir wrote, “Ehrlich must be with the greatest, however small that company may be.”
I. Original Works. The most complete edition is The Collected Papers of Paul Ehrlich, compiled and edited by F. Himmelweit, assisted by Martha Marquardt, under the general direction of Sir Henry Dale (London-New York, 1956–1960). The first 3 vols. contain all his important papers, including a few hitherto unpublished. These are grouped according to topics: vol. I,Histology, Biochemistry, and Pathology; vol. II, Immunology and Cancer Research; vol. III, Chemotherapy. Vol. IV (not yet published) will include his letters and a complete bibliography. Of 158 publications reproduced in this edition, all are in German except 11 articles which originally appeared in English or French. Fresh English translations are appended to 15 of the remaining 147 items.
Ehrich’s pupil and co-worker Hans Sachs compiled a bibliography in 1914 as an appendix to Ehrlich’s sixtieth birthday Festschrift (see below). This listed 212 separate publications in well-known journals, as well as several monographs, over the period 1877–1913. Ehrlich was sole author of roughly three-quarters of these items, many of which underwent multiple publication. Sachs also appended a bibliography of 400 reports by Ehrlich’s disciples.
Apart from the special translations in the Collected Papers, Ehrlich;s Croonian (1990), Herter (1904), and Harben (1907) lectures were first published in English-language journals (see below). The Harben lectures were republished as Experimental Researches on Specific Therapy (London, 1908). Collected Studies in Immunity (New York, 1906), C. Bolduan, trans., includes 41 reports by Ehrlich and his co-workers between 1899 and early 1906, of which 38 had appeared previously in Gesammelte Arbeiten zur Immunitätsforschung (Berlin, 1904). A later edition of Collected Studies (1910) contains Boldun’s translations of Ehrlich’s Nobel Prize address and of seven additional papers by his pupils.
Other collections of Ehrlich’s papers in book form are Farbenanalytische Untersuchungen zur Histologie und kilink des (Berlin, 1891); Constitution, Vertheilung und Wirkung Chemischer Körper; ältere und neuere Arbeiten (Leipzig, 1893); and Beiträge zur experimentellen Pathologie und Chemotherapie(Leipzig, 1909), He also published several monographs, including his Habilitation thesis, Das Sauerstoffbedürfnis des Organismus. Eine farbenanalytische Studie (Berlin, 1885); Die Anaemie (Vienna, 1898–1900), written with A. Lazarus; Leukaemie. Pseudoleukaemie. Haemoglobinaemie (Vieena, 1901), written with A. Lazarus and F. Pinkus; Die experimentelle Chemotherapie der Spirillosen (Berlin, 1910), written with S. Hata; Aus Theorie und Praxis der Chemotherapie (Leipzig, 1911); and Grundlagen und Erfolge der Chemotherapie (Stuttgart, 1911). Ehrlich was coeditor, with R. Krause, M. Mosse, H. Rosin, and C. Weigert, of Enzyklopaädie der mikroskopischen Technik, 3 vols. (Vienna, 1902–1903; 2nd ed., 1910; 3rd ed., 1926–1927); he was sole editor of Abhandlungen über Salvarasan, 4 vols. (Munich, 1911–1914); contributed chapters and forewords to several monography; and wrote obituaries of or tributes to E. Albrecht, H. Apolant, A. Bertheim, R. Koch, and C. Weigert.
Among his more important and characteristic reports in scientific and medical journals are “Beiträge zur Kenntnis der Anilinfärbungen und ihrer Verwendung in der mikroskopischen Technik,” in Archiv für mikroskopische Anatomie, 13 (1877),263–277, published while he was still a medical student; “Beiträge zyr Theorie und Praxis der histologischen Färbung,” his inaugural dissertation at Leipzig University (1878); “Beiträge zur Kenntnis der granulirten Bindegewbszellen und der ecosinophilen Leukocythen,” in Archiv für Anatomie und Physiologie, Physiologische Abteilung (1879), 166–169; “Ueber die spezifischen Granulationen des Blutes” ibid., 571–579; “Methodologische Beiträge zur Physiologie und Pathologie der verschiedenen Formen der Leukocyten,” in Zeitschrift für klinische Medizin, 1 (1880),553–560;“Ueber paroxysmale Hämoglobinurie,” in Deutsche medizininische Wochenschrift, 7 (1881), 224–225; “Ueber provocirte Fluorescenzerscheninungen am Auge,” ibid.,8 (1882), 21–22,35–37,54–55;“Ueber eine neue Methode zur Färbung von Tuberkelbacillen,” in Berliner klinische Wochenschrif, 20 (1883), 13; “Ueber eine neue Harnprobe,” in CharitéAnnalen,8 (1883),140–166; and “Zur biologischen Verwertung des Methylenblaus,” in Zentrablatt für die medizinische Wissenschaft, 23 (1885), 113–17.
Other papers include “Ueber Wesen und Behandlung des Jodismus,” in Charité-Annalen, 10 (1885), 129–135; “Zur Physiologie und Pathologie der Blutscheiben,” ibid., 136–146; “Ueber die Methylenblaureaction der lebenden Nervensubstanz,” in Deutsche medizinische Wochenschrift, 12 (1886), 49–52; “Beiträge zur Theorie der Bacillenfärbung,” in Charité-Annalen, 11 (1886), 849–851, 889–891; “Zur therapeutischen Bedeutung der substitutierenden Schwefelsäuregruppe,” in Therapeutische Monatsheft, 1 (1887), 88–90; “über die Bedeutung der neutrophilen Körnung,” in Charité-Annalen, 12 (1887), 288–295; “Ueber schmerzstillende Wirkung des Methylenblau,” in Deutsche medizinische Wohenschrift, 16 (1890), 493–494, written with A. Leppmann; “Studien in der Cocainreihe,” ibid., 717–719; “Die Wirksamkeit kleiner Tuberkulindosen gegen Lungenschwindsucht,” ibid., 793–795, written with P. Guttmann; “Recent Experiences in the Treatment of Tuberculosis (With Special Reference to Pulmonary Consumption) by Koch’s Method,” in Lancet (1891), 2 , 917–920, trans. by T. W. Hime from a paper presented by Ehrlich at the Seventh International Congress of Hygiene and Demography, London; “über die Wirkung des Methylenblau bei Malaria,” in Berliner klinische Wochenschrift, 28 (1891), 953–956, written with P. Guttmann; “Experimentelle Untersuchungen über Immunität. I. über Ricin. II. über Abrin,” in Deutsche medizinische Wochenschrift, 17 (1891), 976–979, 1218–1219; and “über Immunitat durch Vererbung und Säugung,” in Zeitschrift für Hygiene, 12 (1892), 183–203.
See also “Uber die Uebertragung von Immunität durch Milch,” in Deutsche medizinische Wochenschrift, 18 (1892), 393–394, written with L. Brieger; “Ueber Gewinnung und Verwendung des Diphtherieheilserums,” ibid, 20 (1984), 353–355, written with H. Kossel and A. Wassermann; “Die staatliche Kontrolle des Diphtherieserums,” in Berliner klinische Wochenschrift, 33 (1896), 441–443; “Die Wertbemessung des Diphterieilserums und deren theoretische Grundlagen,” in Klinische Jahrbuch, 6 (1897), 299–326; “Zur Kenntnis der Antitoxinwirkung,” in Fortschritte der Medizin, 15 (1897), 41–43; “über die Constitution des Diphtheriegiftes,” in Deutsche medizinische Wochenschrift, 24 (1898), 597–600; “Observations Upon the Constitution of the Diphtheria Toxin,” in Transactions of the Jenner Institute of Preventive Medicine, 2 (1899), 1–16; “Zur Theorie der Lysinwirkung,” in Berliner klinische Wochenschrift, 36 (1899), 6–9, written with J. Morgenroth, as was “ber Haemolysine,” ibid., 36 (1899), 481–486; 37 (1900), 453–458; 38 (1901), 251–257, 569–574, 598–604.
Other papers published after 1900 include “On Immunity, With Special Reference to Cell Life,” in Proceedings of the Royal Society, 66 (1900), 424–448, the Croonian lecture; “Die Schutzstoffe des Blutes,” in Deutsche medizinische Wochenschrift, 27 (1901), 865–867, 888–891, 913–916; “über die Beziehungen von chemischer Constitution, Vertheilung, und pharmakologischen Wirkung,” in Ernst von Leyden-Festschrift, I (Berlin, 1902), 645–679, address delivered to Verein für innere Medicin, Berlin, 12 December 1898, trans. by C. Bolduan as “The Relations Existing Between Chemical Constitution, Distribution, and Pharmacological Action,” in Studies on Immunity (1906), pp. 404–442; “Ueber die Vielheit der Complemente des Serums,” in Berliner klinische Wochenschrift, 39 (1902), 297–299, 335–338, written with H. Sachs, as was “über den Mechanismus der Amboceptorenwirkung,” ibdi, 492–496; “über die complementophilen Gruppen der Amboceptoren,” idid., 585–587, written with H. T. Marshall; “über die Giftcomponenten des Diphtherie Toxins,” ibid., 40 (1903), 793–797, 825–829, 848–851; “Toxin und Antitoxin. Entgegnung auf den neuesten Angriff Grubers,” in Münchener medizinische Wochenschrift, 50 (1903), 1428–1432, 1465–1469; “Toxin und Antitoxin. Entgegnung auf Grubers Replik,” ibid., 2295–2297; “Vorläufige Bemerkungen zur Mittheilungen von Arrhenius zur Theorie der Absättigung von Toxin uns Antitoxin,” in Berliner klinische Wochenschrift, 41 (1904), 221–223 ; “The Mutual Relations Between Toxin and Antitoxin,” in Boston Medical and Surgical Journal, 150 (1904), 443–445; “Physical Chemistry v. Biology in the Doctrine of Immunity,” ibid., 448–450; the Herter lectures; “Farbentherapeutische Versuche bei Trypanosomenerkrankungen,” in Berliner klinische Wochenschrift, 41 (1904), 329–332, 362–365, written with K. Shiga; and “Uber den Mechanimus der Antimboceptorenwirkung,” ibid., 42 (1905), 557–558, 609–612, written with H. Sachs.
Also of interest are “Beobachtungen über maligne Mäusetumoren,” ibid., 871–874, written with H. Apolant; “Beziehungen zwischen chemischer Konstitution und Desinfektionswirkung. Ein Beitrag zum Studium der ‘innern Antisepsis,” in Hoppe-Seyler’s Zeitschrift für physiologische, 47 (1906), 173–199, written with H. Bechhold; “On Immunity With Special Reference to the Relationship Between Distribution and Action of Antigens,” in Journal of the Royal Institute of Public Health, 15 (1907), 321–340; “On Athreptic Functions,” ibid., 385–403; “Chemotherapeutic Studies on Trypanosomes,” ibid., 449–456, the Harben lectures; “Ueber p-Aminophenylarsinsäure. Erste Mittelung,” in Berichte der Detschen chemisaure Gesellscheaft, 40 (1907), 3292–3297, written with A. Bertheim; “über spontane Mischtumoren der Maus,” in Berliner klinische Wochenschrift, 44 (1907), 1399–1401, written with H. Apolant; “über den jetzigen Stand der Chemotherapie,” in Berichte der Deutschen chemischen Gesellschaft, 42 (1909), 17–47; “über Partialfunktionen der Zelle,” in Münchener medizinische Wochenschrift56 (1909), 217–222, Nobel Prize address, 11 December 1908; “über serumfeste Trypanosomenstamme,” in Zeitschrift für Immunitätsforschung, 3 (1909), 296–299, written with W. Roehl and R. Gulbransen; “Kritiker der Seitenketten-theorie im Lichte ihrer experimentellen, und literarischen Forschung. Ein Kommentar zu den Arbeiten von Bang und Forssman,” in Münchener medizinische Wochenschrift, 56 (1909), 2529–2532, written with H. Sachs, as was “Ist die Ehrlichsche Seitenkettentheorie mit den tatsächlichen Verhältnissen vereinber? Bemerkungen zu der II Mittheilung von Bang und Forssman,” ibid., 57 (1910), 1287–1289; “Reduktionsprodukte der Arsanilsäure und ihre Derivate. Zweite Mittheilung: Ueber p, p′-Diamino-arsenobenzol,” in Berichte der Deutschen chemischen Gesellschaft, 43 (1910), 917–927, written with A. Bertheim; “Allgemeines über Chemotherapie,” in Verhandlungen des 27, Kongresses für innere Medizin, Wiesbaden, 27 (1910), 226–234; “Die Behandlung der Syphilis mit dem Ehrlichschen Präparat 606,” in Deutsche Münchener medizinische Wochenschrift, 58 (1911), 1–10; “Ueber Salvarsan,” ibid., 2481–2486; “Chemotherapeutics: Scientific Principles, Methods, and Results,” in Lancet (1913), 2, 445–451, address in pathology to 17th International Medical Congress, London, 1913; and “Deaths After Salvarsan,” in British Medical Journal (1914), 1, 1044–1045.
Ehrlich’s former institute at Frankfurt contains a small collection of memorabilia (group photographs and laboratory notebooks. Other relics were donated by his family to the New York Academy of Medicine. His surviving papers, retrieved from the bomb-damaged institute after World War II and from a village hiding place in the Taunus Mountains, were placed by Ehrlich’s executor, his grandson, on indefinite loan in the custody of the Wellcome Institute of the History of Medicine, London. These include most of his copybooks of handwritten letters, from late 1898 to early 1903, and of typed ones thereafter to 1915, as well as copies of his “blocks” to collaborators, 1906–1915.
II. Secondary Literature. Obituaries in German include G. Joannovics, “Paul Ehrlich 1854–1915,” in Wiener klinische Wochenschrift, 28 (1915), 937–942; M. Kirchner, “Paul Ehrlich†,” in Zeitschrift für ärtzliche Fortbildung, 12 (1915), 513–515; A. Neisser, “Paul Ehrlich, Gestorben den 20 August 1915,” in Archiv für Dermatologie und Syphilis, 121 (1919), 557–578; F. Pinkus, “Paul Ehrlich geboren 14 März 1854, gestorben 20 August 1915,” in Medizinische Klinik, 11 (1915), 985, 1116–1117, 1143–1145; H. Sachs, “Paul Ehrlich†,” in Münchener medizinische Wochenschrift, 62 (1915), 1357–1361; and “Paul Ehrlich, geb. 14. III. 1854, †20. VIII. 1915,” in Natur und Volk, 46 (1916), 139–152; A. von Wassermann, “Paul Ehrlich†,” in Deutsche medizinische Wochenschrift, 41 (1915), 1103–1106, 1135–1136; and A. von Weinberg, “Paul Ehrlich,” in Berichte der deutschen chemischen Gesellschaft, 49 (1916), 1223–1248.
Obituaries in English include C. H. Browning, “Professor Paul Ehrlich,” in British Medical Journal (1915), 2 349–350; R. Muir, “Paul Ehrlich. 1854–1915,” in Journal of Pathology and Bacteriology, 20 (1915), 349–360; and the following unsigned tributes: “Wirkl-Geheimrat Paul Ehrlich,” in Lancet (1915), 2, 525–526; “Professor Paul Ehrlich,” in British Medical Journal(1915), 2, 349; “Professor Paul Ehrlich,” in Boston Medical and Surgical Journal, 173 (1915), 637–640; and “Death of Paul Ehrlich,” in Journal of the American Medical Association, 65 (1915), 814, 1123.
Other references in German to Ehrlich’s life and work are H. Apolant, L. Benda, A. Bertheim, et al., Paul Ehrlich. Eine Darstellung seines wissenschaftlichen Wirkens, (Jena, 1914), the Festschrift for his sixtieth birthday; S. Arrhenius and T. Madsen, “Anwendung der physikalischen Chemie auf des Studium der Toxine und Antitoxine,” in Zeitschrift für physikalische Chemie, 44 (1903), 7–62; L. Aschoff, Ehrlich’s Seitenkettentheorie und ihre Anwendung auf die künstlichen Immunisierungsprozesse (Jena, 1902) ; A. Beyer, Paul Ehrlich and Emil v. Behring (Berlin, 1954); W. Dönitz, “Bericht über die Thätigkeit des königlichen Instituts für Serumforschung und Serumprufung zu Steglitz. Juni 1896-September 1899,” in Klinische Jahrbuch, 7 (1899), 1–26; A. von Engelhardt, “Hundertjahrfeier der Geburtstage von Paul Ehrlich und Emil von Behring in Frankfurt-Main, Marburg-Lahn und Hoechst,” (Marburg, 1954); I. Fischer, “Paul Ehrlich,” in Biographisches Lexikon der hervorragender Aerzte, I (1932), 352–353.
See also W. Greuling, Paul Ehrlich. Leben und Werk (Düsseldorf, 1954); M. Gruber, “Zur Theorie der Antikörper. I. Ueber die Antitoxin-Immunitat,” in Münchener medizinische Wochenschrift, 48 (1901), 1827–1830, 1880–1884; “II. Ueber Bakteriolyse und Haemolyse,” ibid., 1924–1927, 1965–1968; “Neue Früchte der Ehrlichschen Toxinlehre,” in Wiener klinische Wochenschrift, 16 (1903), 791–793; “Toxin und Antitoxin. Eine Replik auf Herrn Ehrlichs Entgegnung,” in Münchener medizinische Wochenschrift, 50 (1903), 1825–1828; and “Bemerkungen zu Ehrlich’s Entgegnung auf Grubers Replik,’” ibid., 2297; M. Gruber and C. Von Pirquet, “Toxin und Antioxin,” ibid., 1193–1196, 1259–1263; B. Heymann, “Zur Geschichte der Seitenkettentheorie Paul Ehrlichs,” in Klinische Wochen schrift, 7 (1928), 1257–1260, 1305–1309; Janina Hunwitz, “Paul Ehrlich als Krebsforsher,” in Zürcher medizingeschichtliche Abhandlungen, n.s. no. 7 (1962); G. Joannovics, “Referat: Paul Ehrlich. Eine Darstellung seines wissen schaftlichen Wirkens. Festschrift zum 60. Geburtstage des Forschers,” in Wiener klinische Wochenschrift, 28 (1915), 93–95; A. Lazarus, “Paul Ehrlich,” in M. Neuberger, ed., Meister der Heilkunde, I (Vienna, 1921), 9–88; W. Leibbrand, “Paul Ehrlich, Schöpfer der Chemotherapie,” in Grosse Naturforscher, VIII (Stuttgart, 1950); Leonor Michaelis, “Zur Erinnerung am Paul Ehrlich: Seine wiedergefundene Doktor-Dissertation,” in Die Nturwissenschaften, 7 (1919), 165–168; A. Neisser, “Ueber das Arsenophenylglyzin und seine Verwendung bei der Syphilisbehandlung,” in Archiv für Dermatologie und Syphilis, 121 (1916), 579–612; A. Neisser et al., “Die Behandlung der Syphilis mit den Ehrlichschen Präparat 606,” in Deutsche medizinische Wochenschrift, 36 (1910), 1889–1924; and Beiträge Zur Pathologie und Therapie der Syphilis (Berlin, 1911); H. Satter, Paul Ehrlich, Begründer der Chemotherapie (Munich, 1962); P. Uhlenhuth, Experimentelle Grundlagen der Chemotherapie der Spirochaetenkrankheiten mitbesondere Berücksichtigung der Syphilis (Berlin-Vienna, 1911); O. H. Warburg, “Paul Ehrlich, 1854–1915,” in Die grossen Deutschen, IV (1957), 186–192; and A. Wassermann, “Paul Ehrlich”, in Münchener medizinische Wochenschrift, 56 (1909), 245–247.
English and French references to Ehrlich’s life and work include J. Almkvist, “Reminiscences of Paul Ehrlich”, in Urologic and Cutaneous Review, 42 (1938), 214–220; H. Bauer, “Paul Ehrlich’s Influence on Chemistry and Biochemistry”, in Annals of the New York Academy of Sciences, 59 (1954), 150–167; J. Bordet, “Sur le mode d’action des antitoxines sur les toxines”, in Annales de i’Institut Pasteur, 17 (1903), 161–186; C. H. Browning, “Paul Ehrlich—Memories of 1905–1907”, in British Medical Journal1, 664–665; and “Emil Behring and Paul Ehrlich. Their Contributions to Science”, in Nature, 175 (1955), 570–575, 616–619; Henry Dale, “Paul Ehrlich, Born March 14, 1854”, in British Medical Journal (1954), 1 659–663; C.E. Dolman, “A Fiftieth Anniversary Commemorative Tribute to Paul Ehrlich, With Two Letters to American Friends”, in Clio Medica, 1 (1966), 223–234; and “Paul Ehrlich and William Bulloch: A Correspondence and Friendship (1896–1914),” ibid,. 3 (1968), 65–84; H. Goodman, “Paul Ehrlich. ‘A Man of Genius and an Inspiration to Humanitarians’”, in American Medicine, 42 (1936), 73–78; L. W. Harrison, “Paul Ehrlich and the Development of 606,” in st. Thomas’s Hospital Gazette, 52 (1954), 37–42; E. Jokl, “Paul Ehrlich— Man and Scientist”, in Bulletin of the New York Academy of Medicine, 30 (1954), 968–975; Martha Marquardt, Paul Ehrlich (London, 1949); and “Paul Ehrlich, Some Reminiscences”, in British Medical Journal (1954), 1, 665–667; G. H. F. Nuttall, “Biographical Notes Bearing on Koch, Ehrlich, Behring and Loeffler, With Their Portraits and Letters From Three of Them”, in Parasitology, 16 (1924), 214–238 (“Paul Ehrlich, 1854–1915”, pp. 224–229); H. G. Plimmer, “A Critical Summary of Ehrlich’s Recent Work on Toxins and Antitoxins”, in Journal of Pathology and Bacteriology, 5 (1897), 489–498; C. P. Rhoads, “Paul Ehrlich and the Cancer Problem,” in Annals of the New York Academy of Sciences, 59 (1954), 190–197; and “Paul Ehrlich in Contemporary Science,”, in Bulletin of the New York Academy of Medicine, 30 (1954), 976–987; L. Vogel, “Paul Ehrlich (1854–1915),” in Revue d’histoire de la médecine hebraïque, 22 (1969), 75–85, 107–117; W. Wechselmann, “Beobachtungen an 503 mit Dioxydiamido-Arsenobensol behandelten Krankheitsfallen”, in Deutsche, medizinische Wochenschrift, 36 (1910), 1478–1481; and The Treatment of Syphillis With Salvarsan (New York London, 1911), A. L. wolbarst trans.; and E. Witebsky, “Ehrlich’s Side-Chain Theory in the Light of Presents Immunology”, in Annals of the New York Acadadmy of Sciences, 59 (1954), 168–181.
Claude E. Dolman
Ehrlich, Paul (1854-1915)
Ehrlich, Paul (1854-1915)
Paul Ehrlich's pioneering experiments with cells and body tissue revealed the fundamental principles of the immune system and established the legitimacy of chemotherapy—the use of chemical drugs to treat disease. His discovery of a drug that cured syphilis saved many lives and demonstrated the potential of systematic drug research. Ehrlich's studies of dye reactions in blood cells helped establish hematology, the scientific field concerned with blood and blood-forming organs, as a recognized discipline. Many of the new terms he coined as a way to describe his innovative research, including "chemotherapy," are still in use. From 1877 to 1914, Ehrlich published 232 papers and books, won numerous awards, and received five honorary degrees. In 1908, Ehrlich received the Nobel Prize in medicine or physiology.
Ehrlich was born on March 14, 1854, in Strehlen, Silesia, once a part of Germany, but now a part of Poland known as Strzelin. He was the fourth child after three sisters in a Jewish family. His father, Ismar Ehrlich, and mother, Rosa Weigert, were both innkeepers. As a boy, Ehrlich was influenced by several relatives who studied science. His paternal grandfather, Heimann Ehrlich, made a living as a liquor merchant but kept a private laboratory and gave lectures on science to the citizens of Strehlen. Karl Weigert, cousin of Ehrlich's mother, became a well-known pathologist. Ehrlich, who was close friends with Weigert, often joined his cousin in his lab, where he learned how to stain cells with dye in order to see them better under the microscope . Ehrlich's research into the dye reactions of cells continued during his time as a university student. He studied science and medicine at the universities of Breslau, Strasbourg, Freiburg, and Leipzig. Although Ehrlich conducted most of his course work at Breslau, he submitted his final dissertation to the University of Leipzig, which awarded him a medical degree in 1878.
Ehrlich's 1878 doctoral thesis, "Contributions to the Theory and Practice of Histological Staining," suggests that even at this early stage in his career he recognized the depth of possibility and discovery in his chosen research field. In his experiments with many dyes, Ehrlich had learned how to manipulate chemicals in order to obtain specific effects: Methylene blue dye, for example, stained nerve cells without discoloring the tissue around them. These experiments with dye reactions formed the backbone of Ehrlich's career and led to two important contributions to science. First, improvements in staining permitted scientists to examine cells, healthy or unhealthy, and microorganisms , including those that caused disease. Ehrlich's work ushered in a new era of medical diagnosis and histology (the study of cells), which alone would have guaranteed Ehrlich a place in scientific history. Secondly, and more significantly from a scientific standpoint, Ehrlich's early experiments revealed that certain cells have an affinity to certain dyes. To Ehrlich, it was clear that chemical and physical reactions were taking place in the stained tissue. He theorized that chemical reactions governed all biological life processes. If this were true, Ehrlich reasoned, then chemicals could perhaps be used to heal diseased cells and to attack harmful microorganisms. Ehrlich began studying the chemical structure of the dyes he used and postulated theories for what chemical reactions might be taking place in the body in the presence of dyes and other chemical agents. These efforts would eventually lead Ehrlich to study the immune system.
Upon Ehrlich's graduation, medical clinic director Friedrich von Frerichs immediately offered the young scientist a position as head physician at the Charite Hospital in Berlin. Von Frerichs recognized that Ehrlich, with his penchant for strong cigars and mineral water, was a unique talent, one that should be excused from clinical work and be allowed to pursue his research uninterrupted. The late nineteenth century was a time when infectious diseases like cholera and typhoid fever were incurable and fatal. Syphilis, a sexually transmitted disease caused by a then unidentified microorganism, was an epidemic, as was tuberculosis , another disease whose cause had yet to be named. To treat human disease, medical scientists knew they needed a better understanding of harmful microorganisms.
At the Charite Hospital, Ehrlich studied blood cells under the microscope. Although blood cells can be found in a perplexing multiplicity of forms, Ehrlich was with his dyes able to begin identifying them. His systematic cataloging of the cells laid the groundwork for what would become the field of hematology. Ehrlich also furthered his understanding of chemistry by meeting with professionals from the chemical industry. These contacts gave him information about the structure and preparation of new chemicals and kept him supplied with new dyes and chemicals.
Ehrlich's slow and steady work with stains resulted in a sudden and spectacular achievement. On March 24, 1882, Ehrlich had heard Robert Koch announce to the Berlin Physiological Society that he had identified the bacillus causing tuberculosis under the microscope. Koch's method of staining the bacillus for study, however, was less than ideal. Ehrlich immediately began experimenting and was soon able to show Koch an improved method of staining the tubercle bacillus. The technique has since remained in use.
On April 14, 1883, Ehrlich married 19-year-old Hedwig Pinkus in the Neustadt Synagogue. Ehrlich had met Pinkus, the daughter of an affluent textile manufacturer of Neustadt, while visiting relatives in Berlin. The marriage brought two daughters. In March, 1885, von Frerichs committed suicide and Ehrlich suddenly found himself without a mentor. Von Frerichs's successor as director of Charite Hospital, Karl Gerhardt, was far less impressed with Ehrlich and forced him to focus on clinical work rather than research. Though complying, Ehrlich was highly dissatisfied with the change. Two years later, Ehrlich resigned from the Charite Hospital, ostensibly because he wished to relocate to a dry climate to cure himself of tuberculosis. The mild case of the disease, which Ehrlich had diagnosed using his staining techniques, was almost certainly contracted from cultures in his lab. In September of 1888, Ehrlich and his wife embarked on an extended journey to southern Europe and Egypt and returned to Berlin in the spring of 1889 with Ehrlich's health improved.
In Berlin, Ehrlich set up a small private laboratory with financial help from his father-in-law, and in 1890, he was honored with an appointment as Extraordinary Professor at the University of Berlin. In 1891, Ehrlich accepted Robert Koch's invitation to join him at the Institute for Infectious Diseases, newly created for Koch by the Prussian government. At the institute, Koch began his immunological research by demonstrating that mice fed or injected with the toxins ricin and abrin developed antitoxins. He also proved that antibodies were passed from mother to offspring through breast milk. Ehrlich joined forces with Koch and Emil Adolf von Behring to find a cure for diphtheria , a deadly childhood disease. Although von Behring had identified the antibodies to diphtheria, he still faced great difficulties transforming the discovery into a potent yet safe cure for humans. Using blood drawn from horses and goats infected with the disease, the scientists worked together to concentrate and purify an effective antitoxin. Ehrlich's particular contribution to the cure was his method of measuring an effective dose.
The commercialization of a diphtheria antitoxin began in 1892 and was manufactured by Höchst Chemical Works. Royalties from the drug profits promised to make Ehrlich and von Behring wealthy men. But Ehrlich, possibly at von Behring's urging, accepted a government position in 1885 to monitor the production of the diphtheria serum. Conflict-of-interest clauses obligated Ehrlich to withdraw from his profit-sharing agreement. Forced to stand by as the diphtheria antitoxin made von Behring a wealthy man, he and von Behring quarreled and eventually parted. Although it is unclear whether bitterness over the royalty agreement sparked the quarrel, it certainly couldn't have helped a relationship that was often tumultuous. Although the two scientists continued to exchange news in letters, both scientific and personal, the two scientists never met again.
In June of 1896, the Prussian government invited Ehrlich to direct its newly created Royal Institute for Serum Research and Testing in Steglitz, a suburb of Berlin. For the first time, Ehrlich had his own institute. In 1896, Ehrlich was invited by Franz Adickes, the mayor of Frankfurt, and by Friedrich Althoff, the Prussian Minister of Educational and Medical Affairs, to move his research to Frankfurt. Ehrlich accepted and the Royal Institute for Experimental Therapy opened on November 8, 1899. Ehrlich was to remain as its director until his death sixteen years later. The years in Frankfurt would prove to be among Ehrlich's most productive.
In his speech at the opening of the Institute for Experimental Therapy, Ehrlich seized the opportunity to describe in detail his "side-chain theory" of how antibodies worked. "Side-chain" is the name given to the appendages on benzene molecules that allow it to react with other chemicals. Ehrlich believed all molecules had similar side-chains that allowed them to link with molecules, nutrients, infectious toxins and other substances. Although Ehrlich's theory is false, his efforts to prove it led to a host of new discoveries and guided much of his future research.
The move to Frankfurt marked the dawn of chemotherapy as Ehrlich erected various chemical agents against a host of dangerous microorganisms. In 1903, scientists had discovered that the cause of sleeping sickness , a deadly disease prevalent in Africa, was a species of trypanosomes (parasitic protozoans). With help from Japanese scientist Kiyoshi Shiga, Ehrlich worked to find a dye that destroyed trypanosomes in infected mice. In 1904, he discovered such a dye, which was dubbed "trypan red."
Success with trypan red spurred Ehrlich to begin testing other chemicals against disease. To conduct his methodical and painstaking experiments with an enormous range of chemicals, Ehrlich relied heavily on his assistants. To direct their work, he made up a series of instructions on colored cards in the evening and handed them out each morning. Although such a management strategy did not endear him to his lab associates, and did not allow them opportunity for their own research, Ehrlich's approach was often successful. In one famous instance, Ehrlich ordered his staff to disregard the accepted notion of the chemical structure of atoxyl and to instead proceed in their work based on his specifications of the chemical. Two of the three medical scientists working with Ehrlich were appalled at his scientific heresy and ended their employment at the laboratory. Ehrlich's hypothesis concerning atoxyl turned out to have been correct and would eventually lead to the discovery of a chemical cure for syphilis.
In September of 1906, Ehrlich's laboratory became a division of the new Georg Speyer Haus for Chemotherapeutical Research. The research institute, endowed by the wealthy widow of Georg Speyer for the exclusive purpose of continuing Ehrlich's work in chemotherapy, was built next to Ehrlich's existing laboratory. In a speech at the opening of the new institute, Ehrlich used the phrase "magic bullets" to illustrate his hope of finding chemical compounds that would enter the body, attack only the offending microorganisms or malignant cells, and leave healthy tissue untouched. In 1908, Ehrlich's work on immunity , particularly his contribution to the diphtheria antitoxin, was honored with the Nobel Prize in medicine or physiology. He shared the prize with Russian bacteriologist Élie Metchnikoff .
By the time Ehrlich's lab formally joined the Speyer Haus, he had already tested over 300 chemical compounds against trypanosomes and the syphilis spirochete (distinguished as slender and spirally undulating bacteria ). With each test given a laboratory number, Ehrlich was testing compounds numbering in the nine hundreds before realizing that "compound 606" was a highly potent drug effective against relapsing fever and syphilis. Due to an assistant's error, the potential of compound 606 had been overlooked for nearly two years until Ehrlich's associate, Sahashiro Hata, experimented with it again. On June 10, 1909, Ehrlich and Hata filed a patent for 606 for its use against relapsing fever.
The first favorable results of 606 against syphilis were announced at the Congress for Internal Medicine held at Wiesbaden in April 1910. Although Ehrlich emphasized he was reporting only preliminary results, news of a cure for the devastating and widespread disease swept through the European and American medical communities and Ehrlich was besieged with requests for the drug. Physicians and victims of the disease clamored at his doors. Ehrlich, painfully aware that mishandled dosages could blind or even kill patients, begged physicians to wait until he could test 606 on ten or twenty thousand more patients. There was no halting the demand, however, and the Georg Speyer Haus ultimately manufactured and distributed 65,000 units of 606 to physicians all over the globe free of charge. Eventually, the large-scale production of 606, under the commercial name "Salvarsan," was taken over by Höchst Chemical Works. The next four years, although largely triumphant, were also filled with reports of patients' deaths and maiming at the hands of doctors who failed to administer Salvarsan properly.
In 1913, in an address to the International Medical Congress in London, Ehrlich cited trypan red and Salvarsan as examples of the power of chemotherapy and described his vision of chemotherapy's future. The City of Frankfurt honored Ehrlich by renaming the street in front of the Georg Speyer Haus "Paul Ehrlichstrasse." Yet in 1914, Ehrlich was forced to defend himself against claims made by a Frankfurt newspaper, Die Wahrheit (The Truth), that Ehrlich was testing Salvarsan on prostitutes against their will, that the drug was a fraud, and that Ehrlich's motivation for promoting it was personal monetary gain. In June 1914, Frankfurt city authorities took action against the newspaper and Ehrlich testified in court as an expert witness. Ehrlich's name was finally cleared and the newspaper's publisher sentenced to a year in jail, but the trial left Ehrlich deeply depressed. In December, 1914, he suffered a mild stroke.
Ehrlich's health failed to improve and the start of World War I had further discouraged him. Afflicted with arteriosclerosis, his health deteriorated rapidly. He died in Bad Homburg, Prussia (now Germany), on August 20, 1915, after a second stroke. Ehrlich was buried in Frankfurt. Following the German Nazi era, during which time Ehrlich's widow and daughters were persecuted as Jews before fleeing the country and the sign marking Paul Ehrlichstrasse was torn down, Frankfurt once again honored its famous resident. The Institute for Experimental Therapy changed its name to the Paul Ehrlich Institute and began offering the biennial Paul Ehrlich Prize in one of Ehrlich's fields of research as a memorial to its founder.
See also History of immunology; History of microbiology; History of public health; History of the development of antibiotics; Infection and resistance
EHRLICH, PAUL (1854–1915), German bacteriologist.
Paul Ehrlich was born on 14 March 1854 in Strehlen in Upper Silesia, the son of well-to-do Jewish citizens, and died on 20 August 1915 in Bad Homburg. He attended grammar school in Breslau, completing his entrance requirement for university education in 1872. He then studied in Breslau as well as Strasbourg, whence he had followed the anatomist Wilhelm Waldeyer, who familiarized him with microscope technology. Already in Strasbourg a catchy phrase came into existence, which punned on a German proverb and his last name. The proverb, "Ehrlich währt am längsten" (literally, "honest lasts longest," that is, honesty is the best policy), was rendered "Ehrlich färbt am längsten" ("Ehrlich stains the longest"); this phrase accompanied him all his life. His dissertation at Leipzig University was entitled "Contributions to Theory and Practice of Histological Staining."
In 1878 the internist Friedrich Theodor von Frerichs asked Ehrlich to come to Berlin's CharitéHospital. There Ehrlich succeeded in introducing dyes into living cells. By means of this technique he managed to differentiate between leukocytes (white blood cells) and lymphocytes (typical cellular elements of lymph) and shortly afterward to classify them even further according to their stainability.
Ehrlich married Hedwig Pinkus, the daughter of a Jewish textile manufacturer from Silesia (1883). He received the title of professor (1884) two years before actually qualifying as a university teacher. His 1885 monograph entitled The Requirement of Oxygen for the Organism was accepted as a qualification to become university lecturer. After recovering completely from an encounter with tuberculosis, which had forced him to spend two years in Egypt, he returned to Berlin in 1889 and equipped a laboratory of his own.
In 1891 the Prussian government set up the Institute for Infectious Diseases with Robert Koch as director, and Paul Ehrlich moved his laboratory to the institute in that same year. At this time Emil Adolf von Behring and Shibasaburo Kitasato were reporting about their research on diphtheria and tetanus immunity. However, production of an immune serum turned out to be extremely difficult, and serum quality was inadequate. Robert Koch intervened and brought Behring together with Ehrlich.
Ehrlich had demonstrated that feeding small, steadily increasing amounts of poison to laboratory animals rendered them immune against an otherwise lethal dose. Owing to these studies he had developed the basic notions of active and passive immunity. The collaboration between Ehrlich and Behring resulted in the production of substantial amounts of a standardized serum used in German children's hospitals. The 1895 German Internists' Congress recommended the new medication unanimously, praising it as the best method of treatment hitherto offered. At last, a therapeutic concept had been discovered that would be used for years to come.
In order to ensure the standardization of the serums more effectively, a separate testing department was initially founded at the Institute for Infectious Diseases; not long after, it was reorganized as the Institute for Serum Research and Testing (1896). The institute was set up in an old bakery, and Ehrlich quipped that in order to conduct his research he needed only the most rudimentary equipment, like test tubes, a flame, and blotting paper. Yet in later years he struck a different note: "The guarantee of good results consists of the four Ps: proficiency, patience, providence, and pennies."
The year 1899 saw the opening in Frankfurt am Main of the Royal Institute for Experimental Therapy; Ehrlich was appointed director of the facility. Using funds from an endowment by the Frankfurt banker's widow Franziska Speyer, the Georg-Speyer House began operations in 1906 right next door to the institute, managed by Ehrlich at the same time.
During the period from 1890 to 1900 Ehrlich worked on his immunity and side-chain theories. In Ehrlich's view, apart from a performing nucleus there had to be side chains situated in the protoplasm; these side chains must have specific characteristics allowing them to bind certain toxins into the shape of receptors. Secreted into the circulation, these receptors acted as antitoxins or antibodies. Hypothetically, these second-order receptors would include, in addition to the haptophoric group (capable of combining), a zymphoric group (carrying enzymes) conducting the agglutinating, or binding activity of the antibodies. In postulating this idea of the lock-and-key reaction, Ehrlich had supplied the crucial theory for understanding immune response, even though in detail his concepts did not prove correct.
The side-chain theory also led Ehrlich in the direction of the therapia magna sterilisans, the search for the magic bullet. He was envisaging control of pathogens and toxins in the human body by means of a chemical substance that, just like the side chains, would have a special affinity to the disease-causing agent, yet would be effective in concentrations not harming the body.
Taking as a starting point atoxyl, which he had studied together with Kiyoshi Shiga, Ehrlich developed the notion of the development of pathogenic "drug resistance," conducted trials with arsenic compounds, and from May 1909 intensified the search in collaboration with his Japanese assistant Sukehachiro Hata. Preparation number 606 spelled success. In the summer of 1909 the Hoechst Company applied for a patent on arsphenamine, later known as salvarsan, used in the treatment of syphilis. In 1908 Paul Ehrlich received jointly with lie Metchnikoff the Nobel prize for his work in immunology. This award—given to the main proponents of the humoral and, respectively, the cellular principles of antibody development—inadvertently showed the direction in which immunology was to evolve over the next one hundred years.
Ehrlich, Paul. Collected Papers. Edited by Fred Himmelweit with Martha Marquardt, under the direction of Henry Dale. London and New York, 1956–1960.
Silverstein, Arthur M. Paul Ehrlich's Receptor Immunology: The Magnificent Obsession. San Diego, Calif., 2002.
Winau, Florian, Otto Westphal, and Rolf Winau. "Paul Ehrlich: In Search of the Magic Bullet." Microbes and Infection 6 (2004): 786–789.
The German bacteriologist Paul Ehrlich (1854-1915) advanced the science and practice of medicine by applying the fast-growing achievements of organic chemistry to the problems of disease. He is known for his discovery of Salvarsan.
Paul Ehrlich was born on March 14, 1854, at Strehlen, Upper Silesia. While still at school he took a great interest in chemical experiments and even got the local druggist to compound throat lozenges according to his original prescription.
At first Ehrlich attended Breslau University but found it dull and uninteresting because it lacked biology and organic chemistry, his favorite subjects. Accordingly, he passed on to the new University of Strasbourg, where he experimented with histological staining, but he returned to Breslau in his third term. In 1878 he graduated in medicine at Leipzig. His thesis was a contribution on the theory and practice of histological staining—the conception of the processes in their chemical, technological, and histological aspects—in which his idea of a chemical binding of heterogeneous substances to protoplasm was first expressed. Already in 1876, he had discovered the "mast" cell by its basophilic granules.
Early in his student career Ehrlich started investigations which in spite of their apparent diversity converged on a common principle: the action of drugs as a manifestation of their specific affinity for particular constituents of cells. According to Ehrlich, substances which affect bodily functions do so by virtue of combining with particular components of the animal. In chemical idiom, certain atom groups (side chains) of the drug combine with receptor atom groups of the cellular protoplasm and lead to the action. This was his famous "side-chain theory."
Ehrlich spent several years in Egypt recovering from a severe case of phthisis. On his return to Germany, Robert Koch, from whom Ehrlich had received an understanding of the modern discipline of cellular pathology and also the relation of bacteriology to disease processes, offered him a place in his new Institute for Infectious Diseases. Here Ehrlich perfected methods of preparing and standardizing diphtheria antitoxin from horses. Meanwhile he was appointed director of the State Institute for Serum Research and Serum Control at Steglitz near Berlin. Work on tumors and immunological studies occupied the forefront of his research until about 1909. In 1908 Ehrlich received the Nobel Prize in medicine for his studies on immunity.
Science of Chemotherapy
The Speyer-Ellissen family of Frankfurt offered to endow a research institute for Ehrlich's work on chemo-therapy. The institute, named George Speyer-Haus, was built, and in 1906 Ehrlich became director. The methods of chemotherapy, that is, treating infections with synthetic compounds antagonistic to pathogenic agents without seriously damaging the host, had arisen in 1891, when it was observed that methylene blue exercises a curative action on human malaria. Before the founding of the institute, Ehrlich had conducted work on an experimental scale with a small staff, and this resulted in a veritable miracle: the cure of a trypanosome infection that was invariably fatal in mice in 3—4 days. Cure followed one subcutaneous injection of a synthetic dye, trypan red, administered within 24 hours of the anticipated time of death. Other drugs were found to possess a degree of therapeutic effect, and certain organic arsenical compounds, "atoxyl" derivatives, also proved to be trypanocidal. From these the drug Salvarsan was derived, which Ehrlich found to be the most efficient curative agent for human syphilis then known, although it was sometimes liable to produce toxic effects. The science of chemotherapy was thus born.
Ehrlich's tremendous achievements were the outcome of a life of unremitting scientific preoccupation to which almost everything was sacrificed. The furor of Salvarsan made him one of the celebrities of his time, both in science and commerce. He died in Bad Homburg, Hesse, on Aug. 20, 1915.
For Ehrlich's own writings see F. Himmelweit, ed., The Collected Papers of Paul Ehrlich (1956). Accounts of Ehrlich's life and work are Herman Goodman, Paul Ehrlich: A Man of Genius and an Inspiration to Humanitarians (1924), and Martha Marquardt, Paul Ehrlich (1951). A sketch of his life is in Theodore L. Sourkes, Nobel Prize Winners in Medicine and Physiology, 1901-1965 (1953; rev. ed. 1966). □
Paul Ehrlich is recognized as the founder of hematology (the study of the blood) and chemotherapy (the treatment of disease with chemicals.) His many accomplishments include the development of the side-chain theory of immunity, the use of dyes to treat tropical diseases, and the discovery of a treatment for the dreaded disease syphilis. Ehrlich was awarded the 1908 Nobel Prize in medicine for advancing the field of immunology and contributing to the production of a serum for diphtheria.
Ehrlich was born on March 14, 1854, into a respected middle-class Jewish family in Strehlen, Silesia, Germany (now part of Poland.) Although he was an excellent pupil, Ehrlich found school a dutiful bore until his cousin, a bacteriologist, introduced him to dyes and the world of the microscope. He developed such an all-consuming interest in staining that fellow students teased him about it. He continued his dye investigations through his university work at Breslau, Straubourg, and Freiberg. When he graduated with a degree in medicine from Leipzig in 1878, he was already a respected authority on dyes and received an appointment to the prestigious Berlin Charite' Hospital.
At Charite' he became so deeply engrossed with the investigation of blood through the medium of staining that he seldom ventured out of the hospital. He developed dyes like methylene blue to stain bacteria and used aniline dyes to stain blood cells. His staining techniques advanced the diagnosis of the tuberculosis bacillus discovered by Robert Koch. By 1883 Ehrlich had published 37 scientific studies.
In 1884, at 30 years of age, he became a professor at Berlin University where he joined a group of distinguished scientists who were making Berlin the world center of research in bacteriology. In 1897 Ehrlich was appointed to a separate institute for serum research, which he described as "small but my own." Here, he perfected the famous side-chain theory of immunity, which states that each cell has a series of side chains or receptors which not only absorb nutrients but react to toxins. During exposure to the toxin, the cell is "trained" to produce excess side chains that are released into the bloodstream as antibodies. If the cell survives, at the next exposure, antibodies link up with the toxin very much like a lock and key fit together.
Ehrlich was barely settled into his small institute when he was invited to join Frankfurt's Royal Institute for Experimental Therapy in 1899. He initiated a study of cancer, or malignant tumors, and the possible use of chemicals to treat cancer and pathogenic organisms. He tested hundreds of chemicals looking for the "magic bullet" that would target a specific organism.
When he became interested in one-celled parasites, such as the cause of African sleeping sickness, he returned to his old love—dyes. While testing mice infected with the tropical disease he found that cured mice responded to compounds containing nitrogen and the element arsenic.
The spirochete Treponema pallidum had just been identified as the cause of the sexually transmitted disease syphilis. For three years he synthesized compounds. After 605 failed attempts, Preparation 606—later called Salvarsan—proved to be the "magic bullet" for syphilis. Following extensive experiments with mice and rats, he cautiously began testing human subjects. Salvarsan was finally released for use in 1910. Because the compound contained arsenic, questions about side effects emerged, and Ehrlich was attacked—even accused of fraud. However, Salvarsan was finally accepted in 1914 as a great medical breakthrough.
The strain took its toll on Ehrlich, and he suffered a series of strokes. He was buried in the Jewish cemetery in Frankfurt on August 23, 1915. Ehrlich was known for his remarkable energy, his work ethic, as well as his kindness and modesty. His wife, Helwig, whom he married at age 28, was concerned about his health habits of eating little and smoking twenty-five strong cigars a day. The Frankfurt street on which the institute was located was renamed Paul Ehrlich Strasse for the famous scientist. When the National Socialists (Nazis) came to power in 1938, they changed the name to eliminate anything Jewish. However, after World War II, Poland renamed Strehlen, his hometown, to Ehrlichstadt in honor of its famous son.
EVELYN B. KELLY
GERMAN CHEMIST AND BACTERIOLOGIST
Paul Ehrlich made notable contributions in several areas of medicine including selective dye staining of cells, immunology, cancer research, and chemical therapy of infectious diseases.
Ehrlich was born in Strehlen, Germany, and attended school in Breslau where an older cousin, Carl Weigert, was a physician at a local hospital. Weigert was researching cell staining with synthetic dyes, a procedure that makes cells more visible under a microscope. Weigert demonstrated the technique for his teenage cousin who was immediately fascinated by the process.
As a medical student Ehrlich undertook his own investigations into cell staining techniques, observing that dyes could selectively stain different types of cells. Most of his dyes came from the flourishing German dye industry, and Ehrlich noted that different chemical structures of the dyes gave them different cell staining properties, leading him to the hypothesis that there was a very specific chemical attraction between the dye and certain cells or parts of cells. This concept of specific chemical attractions was to guide much of his life's work.
Following graduation from medical school in 1878, Ehrlich accepted a position at a Berlin hospital where he employed his knowledge and skill with synthetic dyes to make numerous important contributions to medicine. He was able to use dyes to differentiate several types of red and white blood cells, including leukemia cells, and to assist German bacteriologist Robert Koch in staining and identifying the tuberculosis bacterium. Cell staining remains in use to identify both healthy and cancerous cells.
In 1883 Ehrlich married a young woman named Hedwig Pinkus, to whom he was quite devoted. They had two daughters, Stephanie and Marianne. In 1888 Ehrlich himself developed tuberculosis, left employment at the hospital, and took a yearlong trip to Egypt where he recovered from the infection.
Ehrlich returned to Berlin in 1889 and established a small research laboratory where he began work on the chemical nature of immunity, antitoxin sera, and the nature of the binding of antibodies to antigens. Over a period of ten years this work led to his concept of complementary chemical binding of antigen to antibody and his famous side chain theory to explain why only part of an antigen was necessary to raise immunity. This work in immunology led to a 1908 Nobel Prize in physiology or medicine.
Ehrlich made significant contributions to understanding cancers, including developing a strain of mouse cancer cells known as Ehrlich ascites cells that are still used in cancer research. Ehrlich's work with the selectivity of staining dyes for specific cells, and the specific binding of one antigen to only one antibody, led to the hypothesis that it should be possible to develop drugs that were so specific to disease cells that they could be considered "magic bullets."
Ehrlich embarked on his search for magic bullets to treat parasitic disease with a vast supply of new chemicals from the German dye industry. In 1909 Ehrlich discovered the first effective cure for syphilis, "compound 606" (also called Salvarsan). For his insight and this achievement Ehrlich is known as the father of chemotherapy.
see also Dyes.
Robert K. Griffith
"Paul Ehrlich: Biography." The Nobel Foundation. Available from <http://www.nobel.se/medicine/laureates/1908/ehrlich-bio.html>.
"Paul Ehrlich: Summary of Important Dates." Paul Ehrlich Institute. Available from <http://www.pei.de/english/infos/epaul.htm>.
Through his comprehensive study of the effects of chemicals in the human body, Paul Ehrlich (1854-1915) fathered the fields of chemotherapy (the treatment of disease with chemical agents) and hematology (the study of blood). He also made important contributions to the understanding of immunity and discovered Salvarsan, the first effective treatment for syphilis.
Ehrlich was born in 1854 in Strehlen, Germany, to a prosperous Jewish family. His interest in biology and chemistry led him to study medicine. He attended universities in Breslau, Strasbourg, Frieberg-im-Briesgau, and Leipzig, earning his medical degree in 1878. Ehrlich was fascinated by the reactions of cells and tissues to dyes. He developed new ways of staining cells to identify different types during his research.
In 1890, Ehrlich became a professor at the University of Berlin, where he worked with Emil von Behring (1854-1917) and Shibasaburo Kitasato (1852-1931) on the study of the immune system (the body's method of fighting disease). The group searched for a substance that would give immunity against diphtheria (an infectious disease that effects the air passages) using antitoxins (natural antibodies). Ehrlich worked on the chemical aspects of the study and, in 1892, announced the development of a diphtheria antitoxin for medical use. He shared the 1908 Nobel Prize in medicine with Soviet biologist Elie Metchnikoff (1845-1916) for their work on immunity and serum therapy.
In 1894 Ehrlich was made director of a new institute for serum research in Frankfurt, Germany, where he studied the concepts of active and passive immunity. Ehrlich also continued his study of blood using staining techniques. Realizing that stains colored bacteria but not surrounding cells, he looked for a way to combine the stain with a substance that could kill the bacteria. He did identify dyes, such as trypan red, that had the ability to destroy microorganisms on their own.
Ehrlich began working with organic compounds containing arsenic because he thought its properties were similar to those of the nitrogen atoms that gave trypan red its effectiveness. He studied literally hundreds of arsenic compounds. By 1907, he had reached number 606, which he put aside because it was not effective against trypanosomes. However, two years later, Ehrlich's assistant, Sahachiro Hata (1872-1938), discovered that compound number 606 was effective against the fatal, sexually transmitted disease of syphilis. Triggered by a microorganism called a spirochete, syphilis causes the nervous system to break down, eventually leading infected people to experience intense pain and insanity prior to death. In 1910 Ehrlich announced that chemical 606, which he called Salvarsan, could cure syphilis.
For several years Ehrlich suffered personal and professional attacks because of his work with syphilis. Some people felt that the disease was a punishment for sinful sexual behavior and attacked Ehrlich for searching for a cure. The administration of the drug was also complicated, even risky at first, and when a few patients died because doctors administering the drug failed to follow Ehrlich's instructions, he was accused of fraud. The attacks finally ceased in 1914 when the German parliament finally endorsed his cure as authentic. Unfortunately, the strain surrounding his controversial efforts to cure syphilis took its toll on his health and he suffered a series of strokes during his last year which led to his death in Bad Homburg, Germany, in 1915.
[See also Antibiotic ]
Paul Ehrlich was a German bacteriologist who made tremendous contributions to medical science in the areas of immunology, hematology, and pathology. Although he was awarded the Nobel Prize for Physiology or Medicine in 1908 in conjunction with Elie Metchnikoff (1845-1916) in recognition of their work in immunology, he is best known as the pioneer of chemotherapy. He created the first successful treatment for syphilis. In another noteworthy accomplishment, Ehrlich put forth the side-chain theory, becoming the first person to attempt to correlate the chemical structure of a synthetic drug with its biological effects.
Paul Ehrlich was born in Germany on March 14, 1854, into a family of Jewish faith. His father was prominent in business and industry, while his mother was the aunt of exceptional bacteriologist and scientist Karl Weigert. His early education was at the Gymnasium at Breslau. Following that, he attended various institutions, which culminated in his completion of the doctorate of medicine degree at the University of Leipzig in 1878. The subject of his dissertation concentrated on the theory and methods of staining animal tissues, a practice he revolutionized during his lifetime.
After graduation, he was given an appointment at the Berlin Medical Clinic, where he continued researching tissue staining. During this time, Ehrlich demonstrated that all the stains could be classified as being acidic, basic, or neutral, depending on its properties. He also studied the effect dyes had on cells in the blood, which laid the foundation for hematology. Ehrlich studied the tuberculosis bacterium and published a staining method in 1882 that is still used today with only minor modifications. This paper was also significant in that it paved the way for the Gram method of staining bacteria that is widely used in modern medicine to help differentiate between certain types of microorganisms. In 1883 Ehrlich married Hedwig Pinkus, and they subsequently had two daughters.
Ehrlich's reputation as a skilled researcher allowed him to move up quickly through the hierarchy of German science, despite a bout with tuberculosis that forced Ehrlich to interrupt his work and travel to Egypt for treatment. He returned to Berlin in 1889 when the disease had arrested permanently. Ehrlich was appointed as assistant to Robert Koch (1843-1910), who was the director of the newly established Institute for Infectious Diseases in 1890. It was there that Ehrlich began a series of immunilogical studies for which he will always be remembered. The working hypothesis that Ehrlich developed was called the side-chain theory. He believed each cell consisted of a protein center surrounded by a series of side chains that are responsible for absorbing nutrients as well as toxins. If a toxin were to attach to a cell, the cell would produce large amounts of immune side chain bodies gauged to prevent a new infection.
Ehrlich recognized the limitations of the treatment therapies at that time and started experimenting with substances not normally found in nature that could kill or retard growth in parasites. For this, Ehrlich is often considered to be the father of chemotherapy. He worked primarily with arsenic compounds that could be effective against disease, yet have little side effects. After testing nearly 1,000 compounds, Ehrlich directed his colleague, Sahachiro Hata, to go back and retest the effectiveness of compound #606 against syphilis. It was found effective and was eventually marketed as a cure for syphilis as Salvarsan. This drug had a profound effect on Alexander Fleming (1881-1955), who, after administering it to patients, set out to find similar cures for bacterial diseases and subsequently discovered penicillin.
Ehrlich suffered a stroke in December of 1914. The following year, Ehrlich died of a second stroke, leaving a legacy of tremendous scientific achievement.
JAMES J. HOFFMANN
EHRLICH, PAUL (1854–1915), German chemist, pioneer of modern histology, immunology, and chemotherapy; Nobel Prize winner. Ehrlich was born in Strehlen near Breslau. He studied at German universities and began his scientific work in 1878 in Berlin University as an assistant, becoming an associate professor in 1890. In 1896 he became director of the Royal Institute for Serum Research in Steglitz (Berlin) and three years later director of the Institute of Experimental Therapy in Frankfurt on the Main, which was subsequently amalgamated with the Georg Speier Institute for Chemotherapeutic Research. In 1904 Ehrlich was appointed honorary professor at the University of Goettingen and in 1914 became a professor at Frankfurt University. He was awarded the Nobel Prize for Medicine in 1908. Ehrlich began his scientific work in the fields of hematology and histology. From methods of staining dead blood cells he progressed to staining living cells, and discovered methods of staining living nerve fibers. His research work on the staining of microorganisms led to the method of staining tb bacilli and he discovered the diazo reaction in urine for the recognition of aromatic compounds, which serves to diagnose typhoid fever.
From 1890 onward Ehrlich concentrated mainly on problems of immunization. He proved the specificity of immunity to toxins, and established the basic concepts of applied immunology: active and passive immunization. He laid the foundation for standardization of therapeutic sera by employing as standard serum a stable antitoxic serum capable of long-term preservation. On the basis of this method he developed, in 1897, the evaluation of the antitoxic sera and its theoretical basis, one of the vital practical achievements in the history of immunology.
Recognizing the particular specific affinity of dyes, active organic compounds, and toxins to certain cells, Ehrlich started to search for chemical compounds which would specifically attack the microorganisms causing disease without damaging the body cells. He first treated syphilis with the poisonous organic arsenic compound atoxyl and in 1909, after years of investigation, he discovered, together with his Japanese assistant Hatta, the compound "606," Salvarsan, which can inactivate the treponema causing syphilis, as well as other treponemas causing various tropical diseases. This was the greatest achievement in the fight against syphilis since its appearance in Europe four centuries earlier and marked the beginning of modern systematic chemotherapy.
Developments in theoretical and applied medical biology since Ehrlich's day have thrown new light on certain of his concepts and some of his theoretical assumptions have been modified. But his basic concepts and methods remain firm and still serve as fundamentals for research in the fields of hematology, immunology, and chemotherapy.
Ehrlich was interested in Jewish affairs all his life. He was an active member of Le-Ma'an Zion, and was also associated with and supported the Nordau Institute, one of the nuclei of the Hebrew University of Jerusalem.
A. Lazarus, Meister der Heilkunde, Paul Ehrlich (1922); M. Marquard, Paul Ehrlich als Mensch und Arbeiter (1924); W. Bulloch, The History of Bacteriology (1938); F. Himmelweit (ed.), The Collected Papers of Paul Ehrlich (1956–57); S. Munther, Paul Ehrlich, Founder of Chemotherapy (1966); C.E. Dolman (ed.),Paul Ehrlich and William Bulloch: A Correspondence and Friendship (1896–1914); Clio Medica, 3 (1968), 65–84.
[Aryeh Leo Olitzki]
Paul Ehrlich (1854–1915), a German chemist, was a pioneer in the field of applied organic chemistry. He worked initially on dyestuffs and staining methods for microscopic study of bacteria; and then, beginning in 1891, at the Koch Institute in Berlin, on the search for drugs that would be effective against some of the bacteria that had by then been identified as the specific causes of many diseases. Ehrlich's early work on antitoxins evolved into a systematic examination of many candidate chemicals that might be effective against Treponema pallidum, the spirochaete responsible for syphilis. At that time, syphilis was a common disease and a serious public health problem. This work was based on the observation that many chemicals exhibited selective affinity for specific organisms and tissues. In 1909, in collaboration with Sakahiro Hata, a Japanese colleague at the Koch Institute, he developed Salvarsan, an arsenical that killed the spirochaete without killing the patient—although it did have some toxic side effects. Ehrlich was awarded the Nobel Prize for medicine in 1908.
John M. Last
(see also: Syphilis )