Karl Landsteiner investigated the chemistry of the immune response and discovered the A-B-O blood groups, the most significant advance toward safe blood transfusions.

In the late 1800’s, immunology Immunology was developing rapidly as scientists examined the various physiological changes associated with bacterial infection. Some pathologists studied the way cells helped the body fight disease; others favored a central role for noncellular, or humoral, factors. In 1886, George Nuttall showed how serum (the fluid remaining after a clot is removed from blood) can be toxic to microorganisms. Others obtained similar results, and although debate continued regarding cellular versus humoral immunity, most researchers focused on the humoral response to disease. It was during this period that the term “antigen” was used to refer to any substance inducing a reaction against itself by the host organism. “Antibody” referred to the factor in the serum that could react with the foreign substance. Blood groups
Biology;blood groups
Medicine;blood transfusion
[kw]Discovery of Human Blood Groups (1901)
[kw]Human Blood Groups, Discovery of (1901)
[kw]Blood Groups, Discovery of Human (1901)
Blood groups
Biology;blood groups
Medicine;blood transfusion
[g]Austria;1901: Discovery of Human Blood Groups[00040]
[c]Health and medicine;1901: Discovery of Human Blood Groups[00040]
[c]Biology;1901: Discovery of Human Blood Groups[00040]
Landsteiner, Karl
Levine, Philip A.
Weiner, Alexander S.

In 1894, Richard Friedrich Johannes Pfeiffer Pfeiffer, Richard Friedrich Johannes of the Institute for Infectious Diseases in Berlin injected cholera into guinea pigs and observed a series of changes in the cholera organisms: loss of mobility, clumping, loss of stainability, and eventual disappearance. His work inspired others. Max von Gruber, Gruber, Max von a bacteriologist at the Hygiene Institute in Vienna, was particularly interested in the clumping, or agglutination, of foreign cells. He and his student Herbert Edward Durham Durham, Herbert Edward discovered that antibodies cause the agglutination of disease organisms and that particular antibodies react only with like or closely related microorganisms. Also influenced by Pfeiffer, Jules Bordet Bordet, Jules of the Pasteur Institute demonstrated in the late 1890’s that agglutination and hemolysis occurred after red blood cells from one species were injected into another. He pointed out that this response was similar to the body’s reaction to foreign microorganisms.

Paul Ehrlich, Ehrlich, Paul a German physician and brilliant biologist, along with his coworker, Julius Morgenroth, Morgenroth, Julius injected blood from goats into other goats and discovered that the goats produced “isoantibodies,” a term that Bordet coined to describe antibodies to cells of the same species. Ehrlich could discern no pattern and barely missed discovering goat blood groups, but he interpreted his results to signify biochemical differences between individuals. He inferred from the artificial nature of the experiment that the reaction may not have any obvious function for the animal. Rather, it might be an unrelated effect of another physiological process and not part of the body’s response to disease.

Karl Landsteiner.

(The Nobel Foundation)

Samuel Shattock, Shattock, Samuel an English pathologist, almost discovered the human blood groups. In 1899 and 1900, he described the clumping of red cells by serum from patients with acute pneumonia and certain other diseases. He could not find the clumping in the serums of normal persons because of his small sample size, and he concluded that his results reflected a disease process.

Karl Landsteiner synthesized the results of all the experiments noted above and provided a simple but correct explanation. He joined the University Hospital in Vienna and began advanced study in organic chemistry. At the age of twenty-eight, he joined Gruber at the Hygiene Institute in Vienna and soon began a lifelong interest in immunology. Almost two years later, he transferred to the Institute of Pathological Anatomy of Anton Weichselbaum.

Landsteiner recognized early the chemical nature of the serological reactions that make immune processes visible. He used Bordet’s work as his model. He made antibodies by injecting harmless forms of bacteria into a variety of animals, and, like Bordet, he independently produced antibodies to the blood cells of another species by injecting guinea pig blood into rabbits. Landsteiner withdrew his manuscript that he had already submitted for publication when Bordet’s article was published in 1898. In 1900, before Ehrlich and Morgenroth had published their work on goats, Landsteiner commented in a footnote that serums from healthy humans agglutinated animal red cells and cells from other humans (the first mention of human isoantibodies). He did not believe there was sufficient evidence to tell whether agglutination was solely a function of disease or a result of individual differences; however, by late 1901, he had elaborated on his footnote and provided the supporting experimental evidence.

Pauline M. H. Mazumdar considers Landsteiner’s 1901 paper a logical extension of Ehrlich’s goat studies. Landsteiner took blood samples from his colleagues, separated the cells from the serum, and suspended the red blood cells in a saline solution. He then mixed each person’s serum individually with a sample from every cell suspension. Agglutination occurred in some cases; there was no reaction in others. From the pattern he observed, he hypothesized that there were two types of red blood cells, A and B, whose serum agglutinated the other type of red cell. There was another group, C (in later papers, group O), whose serum agglutinated red blood cells of both types A and B, but whose red cells were not agglutinated by serum from individuals with either blood type A or type B. He concluded that there were two types of antibodies, now called anti-A and anti-B, found in persons of blood types B and A, respectively, and together in persons with blood type C. The absence of antibodies to one’s own antigens was referred to later as Landsteiner’s rule.

In 1902, two students of Landsteiner, Alfred von Decastello Decastello, Alfred von and Adriano Sturli, Sturli, Adriano working at Medical Clinic II in Vienna with more subjects, tested blood samples with the three kinds of cells. Out of 155 individuals, 4 had no antibodies in their serums (2.5 percent), but their cells were clumped by the other types of serums. This fourth rare kind of blood was called type AB, because both A and B substances are present on red cells. Decastello and Sturli proved also that the red cell substances were not part of a disease process when they found the markers equally distributed in 121 patients and 34 healthy subjects.

In Landsteiner’s 1901 paper, he anticipated forensic uses of the blood when he observed that serum extracted from fourteen-day-old blood that had dried on cloth would still cause agglutination. He suggested that the reaction could be used to identify blood. He noted also that his results could explain the devastating reactions that occurred after some blood transfusions. Human-to-human transfusions had replaced animal-to-human transfusions, but cell agglutination and hemolysis still resulted after some transfusions using human donors. In a brief paper, Landsteiner interpreted agglutination as a physiological and not a pathological process. He laid the basis for safe transfusions and forensic serology, and he became the “father of blood groups.”

Louis Klein Diamond points out that Landsteiner’s experiments were performed at room temperature in dilute saline suspensions, which made possible the agglutination reaction of anti-A and anti-B antibodies to antigens on red cells but hid the reaction of warm “incomplete antibodies” (small antibodies that coat the antigen but require a third substance before agglutination occurs) to other, yet undetected, antigens such as the rhesus antigens, which are so important for understanding hemolytic disease of the newborn. Further developments in blood grouping did not take place for another thirty years.

Landsteiner made his discovery of the A-B-O blood groups early in his career. His later contributions to immunology and medicine are numerous. He was particularly interested in how an antibody reacts with a particular antigen—and only that antigen—and demonstrated that the specificity is dependent on the chemical structure of blood factors (usually more than one) present on an antigen. His extensive investigations in this area are presented in his monograph Die Spezifität der serologischen Reaktionen (1933; The Specificity of Serological Reactions, 1936). Specificity of Serological Reactions, The (Landsteiner)

Landsteiner’s blood group work was initially ignored. Others eventually rediscovered the A-B-O blood groups and provided new classifications, which led to confusion over nomenclature and credit for the discovery. In 1908, Albert A. Epstein and Reuben Ottenberg suggested that blood groups are inherited, but the exact mode of inheritance remained controversial until the work of Felix Bernstein in 1924. Results of tests for the A-B-O groups were soon admitted as evidence in paternity cases, and state legislation followed that permitted courts to order such tests.

Ludwik Hirszfeld and Hanna Hirszfeld, army doctors in the Balkans during World War I, tested many soldiers from different countries and showed that racial and ethnic groups differed in their A-B-O blood type frequencies. Much later, William C. Boyd, an immunochemist, convinced anthropologists to use blood marker distributions in inferring population histories (a practice that is now routine).

The most important practical outcome of the discovery of blood groups was the increased safety of blood transfusions, something that, initially, few were able to appreciate. In 1907, Ottenberg was the first to apply Landsteiner’s discovery by matching blood types for a transfusion. Citrate had been discovered to be an anticoagulant in 1890, but it was not until 1914 that it was used in a blood transfusion. Richard Weil, Weil, Richard a New York pathologist, discussed this breakthrough in an influential article published in the Journal of the American Medical Association in 1915. He was also familiar with Landsteiner’s work and argued for testing blood to ensure compatibility. Anticoagulants and “cross-matching” were soon part of standard practice.

Subgroups of blood type A were discovered in 1911, but it was not until 1927 that Landsteiner, now working at the Rockefeller Institute in New York, and his student Philip A. Levine discovered additional blood group systems. They injected different human red cells into rabbits and eventually obtained an antibody that could distinguish human blood independently from A-B-O differences. The new M, N, and P factors were not important for blood transfusion but were used for resolving cases of disputed parentage. More scientists became aware of the multiple applications of Landsteiner’s blood group research, and in 1930 he was awarded the Nobel Prize in Physiology or Medicine. Nobel Prize recipients;Karl Landsteiner[Landsteiner]

Transfusion reactions between A-B-O-compatible people still occurred, and finally, in 1940, Landsteiner and Alexander S. Weiner reported an antibody to another antigen, the rhesus factor, responsible for most of the adverse transfusion reactions and hemolytic disease of the newborn. This and Levine’s work reawakened interest in blood groups, and new methods developed in the 1940’s that led to discoveries of many more antigens.

The addition of new antigens has facilitated population analysis and individual identification in paternity and criminal cases, and two world wars and additional methodological advances have hastened the acceptance of the use of blood transfusions for the treatment of injuries and sickness. In 1980, Diamond estimated that more than ten million blood transfusions were being given yearly in the United States. Blood groups
Biology;blood groups
Medicine;blood transfusion

• Diamond, Louis Klein. “The Story of Our Blood Groups.” In Blood, Pure and Eloquent, edited by Maxwell M. Wintrobe. New York: McGraw-Hill, 1980. An excellent, very readable discussion (by a knowledgeable insider) of the people involved in the study of blood groups, their ideas, and methodological advances in this area. See also the preceding chapter, also by Diamond, titled “A History of Blood Transfusion.”
• Erskine, Addine G., and Wladyslaw Socha. The Principles and Practice of Blood Grouping. 2d ed. St. Louis: C. V. Mosby, 1978. The first chapter, titled “History of Blood Transfusion and Blood Grouping,” is recommended; it discusses Weiner’s work more than Levine’s. The text also includes a selective bibliography after each chapter and a helpful glossary.
• Giangrande, Paul L. F. “The History of Blood Transfusion.” British Journal of Haematology 110 (2000): 758-767. Focuses on the key developments in the early history of transfusion medicine, including Landsteiner’s work on blood types. Includes illustrations and references.
• Lechevalier, Hubert A., and Morris Solotorovsky. Three Centuries of Microbiology. New York: McGraw-Hill, 1965. Details the various related discoveries that preceded and followed Landsteiner’s work. The connectedness of the scientific ideas is broken up by minibiographies of all the major personalities. Includes a limited bibliography.
• Mazumdar, Pauline M. H. “The Purpose of Immunity: Landsteiner’s Interpretation of the Human Isoantibodies.” Journal of the History of Biology 8 (Spring, 1975): 115-133. A detailed discussion of the relevant ideas and experiments that set the stage for Landsteiner’s work. Emphasizes the elegant simplicity of Landsteiner’s explanation.
• Race, R. R., and R. Sanger. Blood Groups in Man. 6th ed. Oxford, England: Blackwell Scientific Publications, 1975. Known as the “blood groupers bible,” this text (the first edition of which was published in 1950) describes all the blood group antigens.
• Speiser, Paul, and Ferdinand Smekal. Karl Landsteiner. Translated by Richard Rickett. Vienna, Austria: Hollinek Brothers, 1975. A revision and translation of the 1961 German edition written solely by Speiser. A comprehensive and fascinating description of Landsteiner’s personal life and each of his many scientific achievements. Includes a complete bibliography.
• Starr, Douglas P. Blood: An Epic History of Medicine and Commerce. New York: Alfred A. Knopf, 1998. A study of the role blood has played throughout human history. The chapter titled “A Strange Agglutination” includes discussion of the discovery of blood types and the effect of that discovery on blood transfusions.

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