- Category : Science-Biology
- Type : MGE
- Profile : 1/3 - Investigating / Martyr
- Definition : Split - Small (56,62)
- Incarnation Cross : RAX Eden 1
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 hisSauerstoffbedürfnis (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 ofmal 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.”