Portal de Periódicos da CAPES

Paul Ehrlich

2001; American Medical Association; Volume: 125; Issue: 6 Linguagem: Inglês

10.5858/2001-125-0725-pe

1543-2165

Venita Jay,

Historical Medical Research and Treatments

The father of immunology and pioneer of chemotherapy, Paul Ehrlich (1854–1915), was an indifferent student who disliked examinations. Ehrlich left an everlasting legacy in medicine with his eclectic career as an organic chemist, histologist, immunologist, hematologist, and pharmacologist. His fascination with the affinity of dyes for tissues and the underlying chemistry of the reaction would prove to be pivotal in leading him to formulate the fundamental principles of immunology.Ehrlich was born in Strehlin, Silesia. As a youth, he was drawn to Latin, mathematics, and chemistry, but he dreaded German composition. Ehrlich dedicated only minimum attention to subjects that he did not find challenging and instead engrossed himself passionately in science, especially the field of chemistry. His older cousin, Carl Weigert, would have a lasting impression on Ehrlich and steer him toward the world of medicine and dyes. Ehrlich and Weigert would remain lifelong friends.Ehrlich enrolled at Breslau University and soon came under the influence of the great anatomist Wilhelm Waldeyer. In addition to studying at Breslau University, Ehrlich had the freedom to study in other locations including Freiburg and Leipzig. He also followed Waldeyer to study in Strasbourg. While a student, Ehrlich described a new type of cell, which he named the "mast cell." During the same time, a large number of aniline dyes appeared on the market, giving zest to Ehrlich's research on tissue stains. Waldeyer recognized Ehrlich's immense talent and lent his support to Ehrlich's experiments.Returning to Breslau, Ehrlich was impressed by several outstanding histologists, physiologists, pathologists, and bacteriologists, including Weigert, Julius Cohnheim, Rudolf Heidenhain, and Ferdinand Cohn. Ehrlich was also introduced to the German bacteriologist Robert Koch. Weigert facilitated Ehrlich's research on aniline dyes and stimulated his interest in pathologic anatomy.Staining became a veritable obsession with Ehrlich, as it combined his affinity for chemistry and his love for histology. His stained hands, clothes, tabletops, lodgings, and laboratory reflected the many hours devoted to this passion. Ehrlich's doctoral thesis was entitled "Contributions to the Theory and Practice of Histological Staining" and was accepted at Leipzig University in 1878.After graduation, Ehrlich took an appointment as assistant to Friedrich von Frerichs in the famous Charité Hospital in Berlin. Professor Frerichs recognized the precocious talent of this newcomer and encouraged Ehrlich's pursuit of histology and chemistry. When Frerichs' life ended tragically, the new chief, Carl Gerhardt, who was strictly a clinician, was not favorably disposed to Ehrlich's research pursuits.Ehrlich worked in this unpleasant environment for 2 years. By 1887, he had contracted tuberculosis, a diagnosis he confirmed by using his own stain to see tubercle bacilli in his sputum. He left his post at the Charité and went to Egypt to recover from his tuberculosis. Ehrlich's wife, Hedwig Pinkus, accompanied him and remained supportive of his endeavors. Having conquered his tuberculosis, Ehrlich returned to Berlin within 2 years to work with Robert Koch, who gave him research facilities.When Koch had announced the discovery of the tubercle bacillus in 1882, Ehrlich lost no time in developing an effective stain to demonstrate the tubercle bacillus and established its acid fastness. Also in 1882, the German bacteriologist Franz Ziehl added a further modification to Ehrlich's method. Believing that not all samples of aniline oil worked consistently, Ziehl substituted phenol (carbolic acid) in its place. In 1883, German pathologist Friedrich Neelsen added his modification, using carbol fuchsin instead of carbol methyl violet and decolorizing with 15% sulfuric acid.Ehrlich's staining of blood films launched a new era in the history of hematology. Until his work, only 2 kinds of white blood corpuscles were known. When Ehrlich applied his aniline dyes to dried blood films, he established that there were blood cells with affinities to alkaline, acidic, and neutral dyes. Ehrlich's techniques of fixation and staining of blood films with aniline dyes greatly facilitated the study of blood and bone marrow. Ehrlich distinguished 3 types of granulated white blood cells, as well as normoblasts, megaloblasts, and leukemic cells. He classified aniline dyes as acidic and basic and showed that one group preferentially stained the red blood corpuscles and eosinophil leukocyte granules, whereas the other dye stained nuclei and lymphocyte cytoplasm. Ehrlich had made a clear distinction between acidophil and basophil leukocytes. In 1879, he developed a neutral stain that could simultaneously stain both groups, and with this stain, he documented the violet granules of the "neutrophil" leukocytes. He prepared his neutral stain by gradually pouring a saturated aqueous methylene blue solution into a saturated aqueous acid fuchsin solution until granules precipitated and later redissolved with additional acid fuchsin. By adding orange G and replacing methylene blue with methylene green, he created his "triacid" stain.In 1891, Ehrlich summarized his staining techniques in a small monograph. Working with Adolf Lazarus and using his triacid stain, Ehrlich identified different hematologic disorders including anemias and leukemias. With Lazarus, he published a book that dealt with normal blood and the appearance of blood cells in various pathologic states, including leukocytosis, leukopenia, leukemia, and anemia. Ehrlich also described platelets and the concept of aplastic anemia.Dimitri Romanowsky, Louis Jenner, Gustav Giemsa, and James Wright subsequently developed modifications of the Ehrlich methods for staining blood films. During the same time, the malarial parasite had been discovered. Modifications of Ehrlich's neutral stain were employed to highlight the malarial parasite in blood films by C. Chenzinsky and others.In Berlin, Koch's assistants Emil Behring and Shibasaburo Kitasato had discovered the principle of passive immunity and antitoxins. Working under the influence of Koch, Ehrlich's attention turned to immunology. He collaborated with Behring to produce a therapeutic diphtheria antiserum. Years of research were spent in establishing an effective diphtheria antitoxin and quantitating its strength, thus leading to the development and standardization of a practical serum.Ehrlich also founded the technique of methylene blue vital staining and established a test for urobilinogen. In 1885, he published a work entitled "The Organism's Need for Oxygen."With his research on toxins and antitoxins, Ehrlich established the basic laws of immunity and the "side chain theory," which has stood the test of time. Ehrlich also introduced the concept of "horror autotoxicus"—the production of autoantibodies against oneself—which would be incompatible with life.Ehrlich's success with serum therapy was viewed favorably by a Prussian minister of state, F. Althoff, who founded an institute for serologic research with Ehrlich as the chief. Ehrlich also later assumed leadership of the Royal Institute for Experimental Therapy and the Georg Speyer Haus for chemotherapy. He was also involved in research on hemolysins, complement, and cancer.Applying the concept of chemical affinity for specific tissues, Ehrlich was hopeful of finding a chemical capable of killing a microbe but not the body's cells. One of his favorite dyes, methylene blue, stained malarial parasites. Ehrlich tried methylene blue as an antidote for malaria and trypan red against trypanosomes, marking his initial attempts at chemotherapy. His studies on syphilis began with an arsenic compound, atoxyl. Ehrlich's experiments went on for years. His 606th preparation, salversan (or 606), was produced in 1910 and tested as a remedy for syphilis with the utmost caution. An improved version, Neosalversan, showed remarkable efficacy against syphilis. Salversan also proved effective against other maladies such as yaws.For his breakthrough work in immunology, Ehrlich, along with Elie Metchnikoff, received the Nobel Prize in Medicine in 1908. Seven years later, Ehrlich died of a stroke.