- Addison-Biermer disease
- Ehrlich's finger test
- Ehrlich's mast cells
- Ehrlich's reaction
- Ehrlich's reagent
- Ehrlich's side chain theory
- Ehrlich's stain
- Ehrlich's tumour
- Ehrlich-Böhme reagent
- Ehrlich-Türk line (Siegmund Türk)
- Ehrlichia bovis
- Ehrlichia canis
- Ehrlichia ovina
- Ehrlichia phagocytophilia
- Heinz' bodies
- Levinthal-Lillie-Coles bodies
Biography of Paul Ehrlich
Paul Ehrlich was undoubtedly one of the geniuses of his time. He could well be regarded as the father of haemoatology, immunology, chemotherapy and pharmacology, and is particularly remembered for the first effective cure for syphilis. He was the first to relate chemical structure with function successfully. He shared the 1908 Nobel Prize for physiology or medicine with Elya Mechnikov. 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 of high-potency diphteria 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 effacy in syphilis and allied diseases.
Paul Ehrlich was born into a comfortable, lively household in a country town in Prussian Silesia, about twnty miles south of Breslau. He was the only son and fourth child of Ismar Ehrlich, a respected but somewhat eccentric Jewish distillier, 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 mothers 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 later 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 favourite subjects wer 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 Strassburg, which largely determined his life’s course. He was impressed by the anatomist Wilhelm von Waldeyer-Hartz (1836-1921) 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 the Physikum at Strasbourg. He was a seemingly easy-going student, but devoted much of his time to the development of staining techniques. In Strassburg he developed a fuchsin stain indentifying lead in tissues. This set him on the concept that certain types of tissue have a specific affinity to certain chemicals. Having passed the 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.
As a medical student in Leipzig Ehrlich undertook independent research work, he wrote on the distribution of foreign substances in the body, and, with the help of previous discoveries in colour analysis, proved that the chemical mechanism active in therapeutic and toxic processes, also determine the nourishment of the cells.
In Breslau Ehrlich was influenced by the pathologists Julius Cohnheim (1839-1884) and Carl Weigert (1845-1904), the physiologist Rudolf Heidenhain (1834-1897), and the botanist Ferdinand Cohn (1828-1898), sponsor of Robert Koch’s researches on anthrax bacilli. At the Pathology Institute, Ehrlich became friendly with such outstanding visitors as William Henry Welch (1850-1934), the American pathologist, and Carl Julius Salomonsen (1847-1924), 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 Theorie und 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 Ehrlic 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 in Friedrich von Frerichs’ (1819-1885) 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 leukaemias and anaemias.
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. Ehrlich himself considered this the most important of the 37 scientific contributions he published during the years 1879-1883. Using two vitamin-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. Two years later the monograph won the Tiedemann Prize and served as Ehrlich’s habilitation thesis before he became Privatdozent in internal medicine at Berlin University.
In 1886 Ehrlich described methylene blue as a selective vital stain for ganglione cells, axis cylinders, and nerve endings. Later, with Arthur Leppmann (1854-1921), he used this dye therapeutically to kill pain in neuralgias; and in 1891, with Paul Guttmann (1834-1893), 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.
It was in his book on the oxygen requirements of the organism Ehrlich presented his side-chain theory: A lock and key model for antibody formation now accepted as one of the ways antigens can select the appropriate lymphocyte to transform and produce clones of lymphocytes producing specific antibodies (see above).
Ehrlich was able to demonstrate experimentally that rabbits which were exposed to a slow and measured increase of toxic substance were able to survive 5.000 times leathal dose.
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 (1833-1902) succeeded him, Ehrlich found his researches disturbingly impeded. In 1888, discovering tubercle bacilli (propbably 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 tuberculine treatment, and never had a recurrence. Upon his return to Berlin he fitted out a modest workplace in Steglitzerstrasse.
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.
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 Paul Guttmann found that small doses of tuberculin were valuable in pulmonary and laryngeal tuberculsosi. 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 there for more than three years without salary, despite his appointment as extraordinary professor at Berlin University in 1891.
When Emil Adolf von Behring (1854-1917) came to Koch’s institute to develop diphteria toxin in quantities sufficient for use in the treatment of diphteria, he needed a quantitative technique for measuring its efficacy. There seems to be little doubt that he used Ehrlich’s method for doing this, and the whole thing caused a lot of bitterness and discussion. In 1901 Behring became the first recipient of the Nobel Prize for physiology or medicine.
Early in 1895, on the initiative of the director of the Prussian Ministry of Educational and Medical Affairs, Friedrich Althoss, 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 Hermann Kossel (1864-1925) and August Paul von Wassermann (1866-1925). 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 (1838-1912) and later Julius Morgenroth (1871-1924) and Max Neisser (1869-1938), as his associates. The Institut für Serumforschung und Serumprüfung consisted of a one-story ramshackle building, variously described as a former almshouse or disused baker, with an adjacent stable for laboratory animals. Nevertheless, Ehrlich took pride in his unpretentious establishment, and excellent work was done in it.
Ehrlich 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 conruction 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 diphteria antitoxin, but also for research and training in experimental therapy. To this latter function Ehrlich devoted himself and his disciples, including Dönitz, Neisser, and Morgenroth, who followed him from Steglitz, and such subsequent staff members as Hans Sachs (1877-1945), Emil von Dungern (1867-), E. Marx, Hugo Apolant, and Alfred Bertheim. In 1906 the adjacent Research Institute for Chemotherapy (designated the George-Speyer-Haus) was erected and endowed by Franziska Speyer in memory of her late husband.
Ehrlich’s spreading fame brought numerous visitors from abroad to work in the combined institutes, including Reid Hunt (1870-1948), Christian Archibald Herter (1865-1910), and Preston Keyes from the United States, Carl Hamilton Browning (1881-1972) and Henry Hallett Dale (1875-1968) from Britain, and Kiyoshi Shiga (1871-1957) and Sahachiro Hata (1873-1938) from Japan.
Ehrlich’s activities in Frankfurt fell 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 diphteria, extensive reseraches 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 chemists 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.» He conceived this idea of creating a "magic bullet" drug to kill living organisms when he observed in his early work with dyes that bacteria would take up dye while the tissue remained unaffected. It was a first step toward the present-day extensive use of chemotherapy.
The third period, 1910-1915, covered Ehrlich’s gallant struggle to handle the multiplex problems that followed the discovery of Salvarsan.
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 (1853-1927) launched a two-year polemic, which became inexcusably insulting, against the side-chain theory. Moreover, Svante August Arrhenius (1859-1927) and Thorvald Madsen (born 12870) and Jules Jean Baptiste Vincent Bordet (1870-1961) as well, constructively criticized Ehrlich’s views on the strictly chemical nature of the union between diphteria toxin and and antotoxin. At Frankfurt pertinacious efforts to clarify the mechanisms of haemolytic and toxin-antotoxin reactions continued. When J. Bang and John Forssmann (1868-1947) 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, Carl Oluf Jensen’s (1864-1934) discovery that mouse mammary tumours 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.
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, at the Farbwerke Cassella & Co. near Frankfurt, who made compounds to his specifications even before the Georg-Speyer-haus was established.
Late in 1908, lecturing before the German Chemical Society, Ehrlich described a trivalent arseno-benzene 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 favourite and best-known Latin tags, «therapia sterilisans magna», denoting «complete sterilization of a highly infected host at one blow.» Six weeks later, in his Nobel lecture, «Über 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 hies friend from earliest school days, the Breslau dermatologist Albert Neisser (1855-1916) 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 oxodations products.
A cure for galant disease – at last
The search for an agent whose therapeutic index (ratio of curative to tolerated dose) 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 that number 606, dihydroxydiamino-arsenobenzene-dihydrochlroide, 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.
This culminated in April 1910, when Ehrlich, Hata, and several clinicians announced their findings, that a synthetic arsenical compound, which he called dioxydiamidoarsenobenzol, had shown curative properties in rabbit syphilis and fowl spirillosis, and also in clinical trials on syphilitic patients.
The pharmaceutical industry could not wait for further trials. Farbwerke-Hoechst, with whom Ehrlich had collaborated closely, conducted an unheard of transaction when the factory gave away 65.000 units for free to physicians all over the world. Although only few side effects were later to show up, jealous adversatries did not hesitate to attack Ehrlich. The worst mud-slinger of them all was taken to court by Ehrlich, and was sentenced to prison.
The rush for the new remedy was uncontrollable. Ehrlich tried to restrict distribution to qualified acquaintances in various countries, but was importuned by mail and 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 gravest opposition, however, did not come from the world of medicine, but from those who have taken upon themselves to be the guardians of both the truth and the moral of their fellow men. The Russian orthodox church, for instance, held the opinion tha venereal diseases were God’s punishment for immorality. The German police worked against Salvarsan because any prostitute sooner or later had to become infected with syphilis, and if Ehrlich’s compound was as efficient as was maintained, she could be healed and infected repeatedly, and so remain a ant health hazard. However, this did not prevent him from receiving the 1908 Nobel Prize for physiology or medicine. But then, maybe the members of the Nobel Committe were really so grateful!
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.
Despite all the turmoil, Ehrlich devised an arsenical derivative, number 1914, which went into neutral solutions without loss of effectiveness. It was introduced for clinical use in 1912 as Neosalvarsan. With Paul Karrer 1889-1971, his last collaborator, Ehrlich attempted further improvements to 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 elsewhere, and Ehrlich suffered no further indignities.
Ehrlich was a patient and kindly man and had a habit of jotting down ideas and instruction to his assistant in a notebook interleaved with carbon paper. The recipient would have to sign and take away the written instruction while the copy remained in Ehrlich’s book, a practice some of his colleagues found disagreable.
He was always an extremely modest person who enjoyed the simple pleasures of life and apparently was a good raconteur and listener to broad stories, as well as an avid reader of thrillers. One of his proudest moments was the receipt of a postcard from a patient thanking him for being cured with Salvarsan. He carried that in his wallet all the time.
When asked what he considered was the guiding idea of his scientific life he mentioned that when he was 20 years old he was waiting in his uncles laboratory (Weigert) and he looked down the microscope at a prepared slide which was coloured blue and red although at the time he had no histological knowledge, it struck him that some parts of the cells were coloured red and others blue. He realised at once that certain parts of the cell had an affinity for the acid red dye stuff while the other parts had the same affinity for the basic blue and therefore was able to take up the colour. That meant different parts of the cell could be differentiated by different dye stuffs. This led on to all of his studies of drug affinity.
One of Ehrlich’s maxims was that good research required «Geduld, Geschick, Glück und Geld» - patience, ability, luck and money.
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 from 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 at the Frankfurt Jewish cemetary.
Many honours 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 of Science in 1903, the Liebig Medal in 1911, and the Cameron Prize in 1914. Twelve orders - ten of them 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 the predicate Excellenz, in 1911, from 1904 he was honorary ordinary professor at Göttingen, and in 1914 became ordinary professor at the new Frankfurt University. He held honorary or foreign memberships in about eighty scientific and medical societies.
In 1912 Ehrlich 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 biennaly by the Paul Ehrlich Institute as a living memorial to him.
Ehrlich harnessed brilliant talents: a darting intelligence linked to untrammeled imagination; compulsive industriousness; the faculty of stereognostically visualizing benzene rings and structural chemical fomulas; 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, Ehrlich 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-humoured, 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.»
Ehrlich’s name was a household word in Germany until the Nazis came to power when they persecuted his widow and confiscated his property. Professor Sir Almoth Wright, a pupil of Ehrlich’s, arranged for Burroughs Wellcome to provide an income for her to live comfortably until her death.
- «Much testing; accuracy and precision is experiment; no guesswork or self-deception.»
Quoted by Martha Marquardt in Paul Ehrlich, Chapter XIII.
He was sole editor of Abhandlungen über Salvarsan. 4 volumes. Munich, 1911-1814.
He contributed chapters and forewords to several monographs; and wrote obituaries of or tributes to Eugen Albrecht (1872-1908), H. Apolant, A. Bertheim, Robert Koch, and Carl Weigert.