Paul Ehrlich's Magic Bullets
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《新英格兰医药杂志》
March 14, 2004, marks the 150th anniversary of the birth of Paul Ehrlich, one of the generation of pioneers who, during the 50 years that led up to World War I, laid the foundation of modern medicine. Pasteur, R?ntgen, Curie, Koch, Freud, and Lister were his contemporaries in this company of trailblazers.
Ehrlich's prodigious talents in the laboratory — he was called a virtuoso of test tubes — were matched by a combination of intuition and deduction that marked him as a genius. He was the father of hematology, a revolutionary immunologist, and the creator of the field of chemotherapy. Ehrlich's dream of the "magic bullet" — his term — that would seek out and specifically destroy invading microbes or tumor cells is now not only a reality but a major aspect of clinical medicine.
Ehrlich's numerous accomplishments arose from a single overarching theme that was inspired by the work of his cousin Karl Weigert, a pathologist who was developing methods for staining bacteria and tissue sections. From his student days until his death in 1915, Ehrlich was transfixed by the idea that organic chemicals can have differential and specific reactions with microbes and tissues. His doctoral thesis, "Contributions to the Theory and Practice of Histological Staining," presented to the Faculty of Medicine of Leipzig in 1878 when he was 24 years old, compares the problem of histologic staining with the dyeing of textiles and argues that both the coloring of fabrics and the staining of cells result from a true chemical reaction — an unconventional idea at the time. The first description of the mast cell appears in this remarkable thesis, the original of which was destroyed in an air raid on Leipzig in 1943.
Ehrlich's dissertation launched his studies of the differential staining of blood cells, in which he defined neutrophils, eosinophils, basophils, lymphocytes, erythrocytes, and reticulocytes on the basis of their affinities for acidic or basic dyes (see Figure). In addition to conducting this research on normal blood, Ehrlich distinguished lymphocytic leukemia from myelogenous leukemia and recorded the first example of aplastic anemia. These historic investigations, always performed with an eye toward the clinic, inaugurated modern hematology.
Figure. Blood Corpuscles Stained with a Triacid Solution.
Reprinted from The Collected Papers of Paul Ehrlich, Volume I. London and New York: Pergamon Press, 1956. Originally published in 1900.
In 1878, Ehrlich moved to the Charité Hospital in Berlin, where he continued his work on dyes and wrote an influential thesis on the oxygen requirements of cells. More important was the acid-fast method of staining the tubercule bacillus, which he developed only six weeks after the sensational disclosure by Robert Koch of the cause of tuberculosis. Ironically, Ehrlich later discovered the acid-fast bacillus in his own sputum and, as a result, took the rest cure in Egypt for almost two years. When he had recovered completely, he returned to Berlin, where he set up a small private laboratory funded by his father-in-law and, soon thereafter, accepted an unpaid position in Koch's new Institute for Infectious Diseases.
There, Ehrlich played a major role in the development of a therapeutic antiserum against diphtheria, which was a leading cause of death in children at the time. In 1892, he began a collaboration with Emil von Behring and Shibasaburo Kitasato, who were attempting to produce such an antiserum in animals. Ehrlich's precise methods of quantifying and standardizing the antiserum made the project feasible, and ultimately he moved from the institute to an abandoned bakery to pursue studies of the antiserum and other immunologic problems. (Of these bare-bones quarters, Ehrlich remarked, "It's nothing, but it's mine.") After Behring reneged on a promise to include Ehrlich in a commercial contract for producing the antiserum, the two split acrimoniously and never saw each other again.
Ehrlich's success with antitoxins was, however, rewarded by an offer to join the Royal Prussian Institute for Experimental Therapy in Frankfurt, this time with a real salary and adequate funds for research. The institute opened in 1899 with Ehrlich as its director. Of all the fruits of Ehrlich's research in immunology, his side-chain theory, first advanced in 1897, was the most daring, original, and controversial. In modern terms, Ehrlich's theory proposed that cells have specific receptors for antigens and that they shed these receptors into the blood when they come into contact with antigen. Ehrlich likened the process to a key fitting a lock — an idea that was openly mocked by his competitors and was probably responsible for Ehrlich's being denied the Nobel Prize for seven years, despite his receipt of numerous nominations. Ehrlich's theory, a precursor to the concept of clonal selection that underlies contemporary immunology, was buried for almost 60 years, because it was incredible even to a scientist of the stature of Linus Pauling, writing in the 1940s, that before immunization, immune cells would display receptors for almost any imaginable synthetic compound.
Ehrlich's third triumph was in chemotherapy, another term that he coined. Reapplying the notion of the magic bullet that he had conceived in characterizing antibodies, he developed the concept of a chemical that binds to and specifically kills microbes or tumor cells. The culmination of this work was arsphenamine (Salvarsan, or compound 606), the first effective treatment for syphilis. At a meeting in Wiesbaden in 1910, Ehrlich and his colleagues announced the experimental and clinical effects of their treatment of syphilis with this compound. The result was an avalanche of demands for the drug, which the H?chst Chemical Works began to manufacture on a large scale. More than 65,000 doses were distributed free of charge. Arsphenamine was the first in the line of antibiotics — sulfamidochrysoidine (prontosil), a sulfonamide discovered in 1932 by Gerhard Domagk, was the next one — that revolutionized medicine.
Smoking 25 cigars a day, pockets filled with precisely sharpened colored pencils, writing daily instructions to his research team on color-coded cards, controlling every detail of a large research establishment, knowing the literature better than anyone, and above all, defying convention, Ehrlich at 50 years of age was in his prime. In her biography of Ehrlich, Martha Marquardt, Ehrlich's private secretary for 13 years, wrote this tribute: "Ehrlich's whole life was one long fight for the promotion of medical science in the service of mankind. He had a deep-rooted, unwavering optimism, aiming always at perfection and ever more difficult targets, supported always by an unshakable faith in progress." On the 150th anniversary of his birth, we need Ehrlich's faith in progress more than ever.(Robert S. Schwartz, M.D.)
Ehrlich's prodigious talents in the laboratory — he was called a virtuoso of test tubes — were matched by a combination of intuition and deduction that marked him as a genius. He was the father of hematology, a revolutionary immunologist, and the creator of the field of chemotherapy. Ehrlich's dream of the "magic bullet" — his term — that would seek out and specifically destroy invading microbes or tumor cells is now not only a reality but a major aspect of clinical medicine.
Ehrlich's numerous accomplishments arose from a single overarching theme that was inspired by the work of his cousin Karl Weigert, a pathologist who was developing methods for staining bacteria and tissue sections. From his student days until his death in 1915, Ehrlich was transfixed by the idea that organic chemicals can have differential and specific reactions with microbes and tissues. His doctoral thesis, "Contributions to the Theory and Practice of Histological Staining," presented to the Faculty of Medicine of Leipzig in 1878 when he was 24 years old, compares the problem of histologic staining with the dyeing of textiles and argues that both the coloring of fabrics and the staining of cells result from a true chemical reaction — an unconventional idea at the time. The first description of the mast cell appears in this remarkable thesis, the original of which was destroyed in an air raid on Leipzig in 1943.
Ehrlich's dissertation launched his studies of the differential staining of blood cells, in which he defined neutrophils, eosinophils, basophils, lymphocytes, erythrocytes, and reticulocytes on the basis of their affinities for acidic or basic dyes (see Figure). In addition to conducting this research on normal blood, Ehrlich distinguished lymphocytic leukemia from myelogenous leukemia and recorded the first example of aplastic anemia. These historic investigations, always performed with an eye toward the clinic, inaugurated modern hematology.
Figure. Blood Corpuscles Stained with a Triacid Solution.
Reprinted from The Collected Papers of Paul Ehrlich, Volume I. London and New York: Pergamon Press, 1956. Originally published in 1900.
In 1878, Ehrlich moved to the Charité Hospital in Berlin, where he continued his work on dyes and wrote an influential thesis on the oxygen requirements of cells. More important was the acid-fast method of staining the tubercule bacillus, which he developed only six weeks after the sensational disclosure by Robert Koch of the cause of tuberculosis. Ironically, Ehrlich later discovered the acid-fast bacillus in his own sputum and, as a result, took the rest cure in Egypt for almost two years. When he had recovered completely, he returned to Berlin, where he set up a small private laboratory funded by his father-in-law and, soon thereafter, accepted an unpaid position in Koch's new Institute for Infectious Diseases.
There, Ehrlich played a major role in the development of a therapeutic antiserum against diphtheria, which was a leading cause of death in children at the time. In 1892, he began a collaboration with Emil von Behring and Shibasaburo Kitasato, who were attempting to produce such an antiserum in animals. Ehrlich's precise methods of quantifying and standardizing the antiserum made the project feasible, and ultimately he moved from the institute to an abandoned bakery to pursue studies of the antiserum and other immunologic problems. (Of these bare-bones quarters, Ehrlich remarked, "It's nothing, but it's mine.") After Behring reneged on a promise to include Ehrlich in a commercial contract for producing the antiserum, the two split acrimoniously and never saw each other again.
Ehrlich's success with antitoxins was, however, rewarded by an offer to join the Royal Prussian Institute for Experimental Therapy in Frankfurt, this time with a real salary and adequate funds for research. The institute opened in 1899 with Ehrlich as its director. Of all the fruits of Ehrlich's research in immunology, his side-chain theory, first advanced in 1897, was the most daring, original, and controversial. In modern terms, Ehrlich's theory proposed that cells have specific receptors for antigens and that they shed these receptors into the blood when they come into contact with antigen. Ehrlich likened the process to a key fitting a lock — an idea that was openly mocked by his competitors and was probably responsible for Ehrlich's being denied the Nobel Prize for seven years, despite his receipt of numerous nominations. Ehrlich's theory, a precursor to the concept of clonal selection that underlies contemporary immunology, was buried for almost 60 years, because it was incredible even to a scientist of the stature of Linus Pauling, writing in the 1940s, that before immunization, immune cells would display receptors for almost any imaginable synthetic compound.
Ehrlich's third triumph was in chemotherapy, another term that he coined. Reapplying the notion of the magic bullet that he had conceived in characterizing antibodies, he developed the concept of a chemical that binds to and specifically kills microbes or tumor cells. The culmination of this work was arsphenamine (Salvarsan, or compound 606), the first effective treatment for syphilis. At a meeting in Wiesbaden in 1910, Ehrlich and his colleagues announced the experimental and clinical effects of their treatment of syphilis with this compound. The result was an avalanche of demands for the drug, which the H?chst Chemical Works began to manufacture on a large scale. More than 65,000 doses were distributed free of charge. Arsphenamine was the first in the line of antibiotics — sulfamidochrysoidine (prontosil), a sulfonamide discovered in 1932 by Gerhard Domagk, was the next one — that revolutionized medicine.
Smoking 25 cigars a day, pockets filled with precisely sharpened colored pencils, writing daily instructions to his research team on color-coded cards, controlling every detail of a large research establishment, knowing the literature better than anyone, and above all, defying convention, Ehrlich at 50 years of age was in his prime. In her biography of Ehrlich, Martha Marquardt, Ehrlich's private secretary for 13 years, wrote this tribute: "Ehrlich's whole life was one long fight for the promotion of medical science in the service of mankind. He had a deep-rooted, unwavering optimism, aiming always at perfection and ever more difficult targets, supported always by an unshakable faith in progress." On the 150th anniversary of his birth, we need Ehrlich's faith in progress more than ever.(Robert S. Schwartz, M.D.)