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Karl Landsteiner and the Discovery of the Major Blood Types

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Austrian physician and immunologist Karl Landsteiner (June 14, 1868 — June 26, 1943) is most noted for his discovery of the major blood types and developing a system for blood typing. This discovery made it possible to determine blood compatibility for safe blood transfusions.

Fast Facts: Karl Landsteiner

• Born: June 14, 1868, in Vienna, Austria
• Died: June 26, 1943, in New York, New York
• Parent's Names: Leopold and Fanny Hess Landsteiner
• Spouse: Helen Wlasto (m. 1916)
• Child: Ernst Karl Landsteiner
• Education: University of Vienna (M.D.)
• Key Accomplishments: Nobel Prize for Physiology or Medicine (1930)

Early Years

Karl Landsteiner was born in Vienna, Austria in 1868, to Fanny and Leopold Landsteiner. His father was a popular journalist and Viennese newspaper publisher and editor. The death of Karl's father, when he was only six years of age, resulted in the development of an even closer relationship between Karl and his mother.

Young Karl was always interested in science and mathematics and was an honor student during his primary and secondary school years. In 1885, he began studying medicine at the University of Vienna and earned an M.D. in 1891. While at the University of Vienna, Landsteiner became very interested in blood chemistry. Upon earning his M.D., he spent the next five years doing biochemical research in laboratories of well known European scientists, one of whom was Emil Fischer, an organic chemist who won a Nobel Prize in Chemistry (1902) for his research on carbohydrates , specifically sugars.

Career and Research

Dr. Landsteiner returned to Vienna in 1896 to continue to study medicine at Vienna General Hospital. He became an assistant to Max von Gruber at the Hygiene Institute, where he studied antibodies and immunity. Von Gruber had developed a blood test to identify the bacteria responsible for typhoid and contended that chemical signals on the bacteria were being recognized by antibodies in the blood. Landsteiner's interest in antibody studies and immunology continued to develop as a result of working with Von Gruber.

In 1898, Landsteiner became assistant to Anton Weichselbaum at the Institute of Pathological Anatomy. For the next ten years, he conducted research in the areas of serology, microbiology, and anatomy. During this time, Landsteiner made his famous discovery of blood groups and developed a system for classifying human blood.

Discovery of the Blood Groups

Dr. Landsteiner's investigations of interactions between red blood cells (RBCs) and serum of different people were initially noted in 1900. He observed the agglutination , or clumping together, of red blood cells when mixed with animal blood or other human blood. While Landsteiner was not the first to make these observations, he is credited with being the first to explain the biological processes behind the reaction.

Landsteiner performed experiments testing red blood cells against serum from the same patient as well as serum from different patients. He noted that a patient's RBCs did not agglutinate in the presence of their own serum. He also identified different patterns of reactivity and categorized them into three groups: A, B, and C. Landsteiner observed that when the RBCs from group A were mixed with serum from group B, the cells in group A clumped together. The same was true when RBCs from group B were mixed with serum from group A. The blood cells of group C did not react to serum from either groups A or B. However, the serum from group C caused agglutination in RBCs from both groups A and B.

Landsteiner determined that blood groups A and B have different types of agglutinogens, or antigens , on the surface of their red blood cells. They also have different antibodies ( anti-A, anti-B ) present in their blood serum. A student of Landsteiner's later identified an AB blood group that reacted with both A and B antibodies. Landsteiner's discovery became the basis for the ABO blood grouping system (as the name of group C was later changed to type O ).

Landsteiner's work laid the foundation for our understanding of blood groupings. Cells from blood type A have A antigens on the cell surfaces and B antibodies in the serum, while cells from type B have B antigens on the cell surfaces and A antibodies in the serum. When type A RBCs contact serum from type B, A antibodies present in B serum bind to A antigens on the blood cell surfaces. This binding causes the cells to clump together. Antibodies in the serum identify the blood cells as foreign and initiate an immune response to neutralize the threat.

A similar reaction occurs when type B RBCs contact serum from type A containing B antibodies. Blood type O has no antigens on the blood cell surfaces and do not react with serum from either types A or B. Blood type O does have both A and B antibodies in the serum and thus reacts with RBCs from both A and B groups.

Landsteiner's work made blood typing possible for safe blood transfusions. His findings were published in the Central European Journal of Medicine, Wiener klinische Wochenschrift , in 1901. He received the Nobel Prize for Physiology or Medicine (1930) for this life saving accomplishment.

In 1923, Landsteiner made additional blood grouping discoveries while working in New York at the Rockefeller Institute for Medical Research. He helped to identify blood groups M, N, and P, which were initially used in paternity testing. In 1940, Landsteiner and Alexander Wiener discovered the Rh factor blood group, named for research conducted with rhesus monkeys. The presence of the Rh factor on blood cells indicates an Rh positive (Rh+) type. The absence of the Rh factor indicates an Rh negative (Rh-) type. This discovery provided a means for Rh blood type matching to prevent incompatibility reactions during transfusions. 

Death and Legacy 

Karl Landsteiner's contribution to medicine extended beyond blood groupings. In 1906, he developed a technique for the identification of the bacterium ( T. pallidum ) that causes syphilis using dark-field microscopy. His work with poliomyelitis (polio virus) lead to the discovery of its mechanism of action and development of a diagnostic blood test for the virus . In addition, Landsteiner's research on small molecules called haptens helped to elucidate their involvement in the immune response and the production of antibodies. These molecules ramp up immune responses to antigens and induce hypersensitivity reactions .

Landsteiner continued researching blood groups after retiring from the Rockefeller Institute in 1939. He would later change his focus to the study of malignant tumors in an attempt to find a cure for his wife, Helen Wlasto (m. 1916), who was diagnosed with thyroid cancer. Karl Landsteiner suffered a heart attack while in his laboratory and died a couple of days later on June 26, 1943.

• Durand, Joel K., and Monte S. Willis. "Karl Landsteiner, MD: Transfusion Medicine." Laboratory Medicine , vol. 41, no. 1, 2010, pp. 53–55., doi:10.1309/lm0miclh4gg3qndc. 
• Erkes, Dan A., and Senthamil R. Selvan. "Hapten-Induced Contact Hypersensitivity, Autoimmune Reactions, and Tumor Regression: Plausibility of Mediating Antitumor Immunity." Journal of Immunology Research , vol. 2014, 2014, pp. 1–28., doi:10.1155/2014/175265. 
• "Karl Landsteiner – Biographical." Nobelprize.org , Nobel Media AB, www.nobelprize.org/prizes/medicine/1930/landsteiner/biographical/. 
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Blood Groups, Blood Typing and Blood Transfusions

The discovery of blood groups.

Experiments with blood transfusions, the transfer of blood or blood components into a person's blood stream, have been carried out for hundreds of years. Many patients have died and it was not until 1901, when the Austrian Karl Landsteiner discovered human blood groups, that blood transfusions became safer.

Mixing blood from two individuals can lead to blood clumping or agglutination. The clumped red cells can crack and cause toxic reactions. This can have fatal consequences. Karl Landsteiner discovered that blood clumping was an immunological reaction which occurs when the receiver of a blood transfusion has antibodies against the donor blood cells. Karl Landsteiner's work made it possible to determine blood groups and thus paved the way for blood transfusions to be carried out safely. For this discovery he was awarded the Nobel Prize in Physiology or Medicine in 1930.

What is blood made up of?

An adult human has about 4–6 liters of blood circulating in the body. Among other things, blood transports oxygen to various parts of the body.

What are the different blood groups?

There are more than 20 genetically determined blood group systems known today, but the AB0 and Rh systems are the most important ones used for blood transfusions. Not all blood groups are compatible with each other. Mixing incompatible blood groups leads to blood clumping or agglutination, which is dangerous for individuals.

Nobel Laureate Karl Landsteiner was involved in the discovery of both the AB0 blood group (in 1901) and Rh blood group (in 1937).

AB0 blood grouping system

According to the AB0 blood group system there are four different kinds of blood groups: A, B, AB or 0 (null).

Rh factor blood grouping system

Blood group notation

According to above blood grouping systems, you can belong to either of following 8 blood groups:

Do you know which blood group you belong to?

Blood typing – how do you find out to which blood group someone belongs?

1. You mix the blood with three different reagents including either of the three different antibodies, A, B or Rh antibodies.

2. Then you take a look at what has happened. In which mixtures has agglutination occurred? The agglutination indicates that the blood has reacted with a certain antibody and therefore is not compatible with blood containing that kind of antibody. If the blood does not agglutinate, it indicates that the blood does not have the antigens binding the special antibody in the reagent. 3. If you know which antigens are in the person's blood, it's easy to figure out which blood group he or she belongs to!

What happens when blood clumps or agglutinates?

For a blood transfusion to be successful, AB0 and Rh blood groups must be compatible between the donor blood and the patient blood. If they are not, the red blood cells from the donated blood will clump or agglutinate. The agglutinated red cells can clog blood vessels and stop the circulation of the blood to various parts of the body. The agglutinated red blood cells also crack and its contents leak out in the body. The red blood cells contain hemoglobin which becomes toxic when outside the cell. This can have fatal consequences for the patient. The A antigen and the A antibodies can bind to each other in the same way that the B antigens can bind to the B antibodies. This is what would happen if, for instance, a B blood person receives blood from an A blood person. The red blood cells will be linked together, like bunches of grapes, by the antibodies. As mentioned earlier, this clumping could lead to death.

Blood transfusions – who can receive blood from whom?

Of course you can always give A blood to persons with blood group A, B blood to a person with blood group B and so on. But in some cases you can receive blood with another type of blood group, or donate blood to a person with another kind of blood group. The transfusion will work if a person who is going to receive blood has a blood group that doesn't have any antibodies against the donor blood's antigens. But if a person who is going to receive blood has antibodies matching the donor blood's antigens, the red blood cells in the donated blood will clump.

First published 3 December 2001

Karl Landsteiner (1868-1943)

Karl Landsteiner studied blood types in Europe and in the United States in the late nineteenth and early twentieth centuries. Landsteiner won the Nobel Prize in Physiology or Medicine in 1930 for detailing immunological reactions in the ABO blood group system. The ABO blood group system divides human blood into one of four types based on the antibodies that are present on each cell. Landsteiner's work with blood types led physicians to safely perform blood transfusions and organ transplants. Additionally, Landsteiner researched the Rh blood factor, a protein marker on the surface of blood cells and that can impact pregnancy.

Karl Landsteiner was born on 14 June 1868 in Baden bei Wien, an upper middle class suburb just outside the city of Vienna, at the time belonging to the Austro-Hungarian Empire, that later became part of Austria. He was the only child of Fanny Hess and Leopold Landsteiner, a legal scholar, journalist, and founder of The Daily Presse . In 1874, Landsteiner's father died from a heart attack. At the age of twelve, Landsteiner attended the Staatsgymnasium, a public high school in Linz, Austria, as an honors student.

In 1885, Landsteiner entered the Vienna Medical School in Vienna at the age of seventeen and studied anatomy, zoology, blood chemistry, and organic chemistry. In 1888, he took a break from his studies to complete a year of mandatory military service. In 1890, Landsteiner and his mother converted from Judaism to Catholicism, just before Landsteiner graduated with his medical degree in 1891 at the age of twenty-three.

After graduating, Landsteiner began his post-doctoral studies in the laboratory of Ernst Ludwig, where he studied cancer of plasma cells, responsible for making antibodies. An antibody is a protein used by the immune system to identify and neutralize bacteria, viruses, and other foreign objects. Antibodies work by recognizing and attaching to little protein markers of the surfaces of cells called antigens. Between 1891 and 1896, Landsteiner worked in different laboratories across Europe. Landsteiner worked with Eugen von Bamberger in Munich, Germany, on hypertrophic pulmonary osteoarthropathy, a condition associated with lung cancer and later worked with Arthur Hantzsch and Roland Scholl in Zurich, Switzerland.

In 1896, Landsteiner obtained a position as the second assistant of Max von Gruber at the Institute for Hygiene at the Vienna General Hospital in Vienna. Landsteiner became involved in a debate that would set the course for future research on immunological reactions between his mentor von Gruber and Paul Ehrlich, the director of the Frankfurt Royal Institute for Experimental Therapy in Frankfurt, Germany. Ehrlich argued that the antigen-antibody relationship was one-to-one, such that antigens antibodies fit each other like a lock and a key. Von Gruber, on the other hand, theorized that an antibody worked best with the antigen that was used to produce it, but that the same antibody would work, though less effectively, with other antigens. The opposing theories led to a debate between von Gruber and Ehrlich. Landsteiner conducted an experiment that supported von Gruber's theory. In 1897, while working with von Gruber, Landsteiner published his first paper about a clumping reaction in blood serum, a process called agglutination, and its relationship to immunity.

In 1897, Landsteiner accepted a position at the Institute of Pathological Anatomy in Vienna, where he worked on cadavers. Over the next ten years he performed nearly four thousand post-mortem examinations and published over seventy-five articles on his observations. Fifty-two of these articles discuss blood chemistry. Landsteiner described the agglutination reactions that occur when blood from one individual is brought into contract with the blood of another individual. Landsteiner relegated his observation of agglutination to a footnote in a paper he wrote in 1900, but he expanded upon this observation the following year in in his paper "Agglutination of Normal Human Blood."

Landsteiner observed a pattern of antigen reactions that occurred when he combined blood serum from different individuals. Landsteiner observed that antigens on the outside of blood cells differed between individuals. If blood from what he called the A or the B group was introduced into a host of the opposing group, the host body would trigger an immunological reaction. Landsteiner found that this reaction caused the invading antigen carrying blood cell to burst. Large accumulations of burst cells created clumps that could clog small blood vessels (capillaries) and perhaps cause shock or death. Initially, Landsteiner recognized three different blood types: A, B, and C. The C-blood type was later more commonly called type-O. In 1902, one of Landsteiner's students found a fourth blood type, AB, which triggered a reaction if introduced into either A or B blood. In 1930, The Health Committee of the League of Nations in Geneva, Switzerland, formally adopted the Landsteiner nomenclature (A, B, AB, and O) in his honor, the naming convention that was still used up through the first decades of the twenty-first century.

Landsteiner's blood typing system had an immediate impact on forensic and surgical sciences. In 1902, Landsteiner and Max Richter, who worked at Vienna University Institute of Forensic Medicine in Vienna, described a method of using blood evidence gathered from the scene of a crime to aid in the investigation. Using this system, scientists could determine whether a blood sample contained A-antigen, B-antigen, both A- and B-antigen, or neither antigen (type-O). If a suspect's blood had a different antigen than the sample left at the crime scene, investigators could conclude the sample could was not from that particular individual. However, roughly fifty percent of the population has O-type blood and less than five percent has AB-type blood. So, if a sample and a suspect had matching blood types, investigators could not make a positive identification. The ABO system also enabled doctors to perform safe blood transfusions. Reuben Ottenberg at the Mt. Sinai Hospital in New York, New York, completed the first successful blood transfusion based on Landsteiner's blood type theory in 1907. During World War I, blood transfusions saved tens of thousands of lives. Later, the ABO blood grouping made it possible to successfully complete the first organ transplants by reducing the chance that a body rejected incompatible transplants.

In 1908, as the head of the pathology department at the Imperial Wilhelminen Hospital in Vienna, Landsteiner showed that polio is a viral disease. Together with his assistant Erwin Popper, Landsteiner conducted an autopsy of a boy who had died of polio. To determine whether bacteria or a different agent had caused the polio, Landsteiner collected some of the boy's spinal fluid and strained it through a filter fine enough to trap bacteria. He then cultured this filtered particles and found that no bacteria grew there. To determine if the infected spinal fluid material was infectious, Landsteiner injected it into rabbits, mice, and guinea pigs, but none of the animals became sick. Landsteiner and Popper injected the filtered spinal fluid into two Old World rhesus monkeys ( http://eol.org/pages/327960/overview Macaca mulatta ), and they found that both died within two weeks. Landsteiner performed autopsies on the rhesus monkeys that revealed spinal cord lesions like those observed in human polio victims. Because Landsteiner and Popper had eliminated bacteria as a potential cause of the infection earlier in the experiment, they concluded that a virus must have caused the infection. Landsteiner proposed that it could be possible to create a polio vaccine. However, it took forty-seven years until Jonas Salk at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, developed and successfully administered the polio vaccine in 1952.

During World War I, Landsteiner performed blood transfusions on many injured soldiers. In 1916 and at the age of forty-eight, Landsteiner met and married Leopoldine Helene Wlatso. A year later, they had to their only child, Ernst. Because of economic difficulties in post-war Austria, Landsteiner and his family moved to Netherlands in 1919. Landsteiner soon obtained a job at the Catholic R.K. Hospital in The Hauge, Netherlands, performing routine tests on urine and blood. During his stay in the Netherlands, he published twelve papers about immune responses triggered by changes in small fat or sugar molecules.

In 1923, the Rockefeller Institute for Medical Research in New York City, New York, offered Landsteiner a position to research immunity and allergies. Landsteiner accepted and moved with his family to the US. Most biographers report that Landsteiner's move to the US was very difficult for him. He disliked the fame that came with his status as an authority on immunology and avoided invitations to speak publicly, preferring instead to stay in his laboratory. Landsteiner became a US citizen in 1929, and he won the Nobel Prize in Physiology or Medicine in 1930

Landsteiner continued researching until the end of his life and compiled a comprehensive summary of his contributions to medicine in his 1936 book Die Spezifitat Der Serologischen Reaktionen (The Specificity of Serological Reactions). Landsteiner retired in 1939 at the age of seventy-one, but he continued to work as an emeritus professor. Along with his assistants, Philip Levine and Alexander Wiener, Landsteiner further studied new blood factors.

In the late 1930s and early 1940s, Landsteiner studied rhesus monkeys and found that the presence or absence of a particular factor could affect the compatibility of mixed blood, even if the blood came from two organisms with the same blood type. Landsteiner called this the Rh-factor, named after the rhesus monkeys he had used for such research. The Rh-factor became a part of Landsteiner's blood typing system, indicated by a positive or negative qualifier after the blood group, for example O+ or AB-. With the Rh-factor identified, researcher could better study and explain newborn hemolytic disease, a condition that arises when an Rh negative woman gives birth to second-born Rh positive fetus. During her first Rh positive pregnancy, an Rh negative mother develops Rh positive antibodies that can cause her body to attack the second Rh positive fetus.

Landsteiner also analyzed blood chemistry and defined genetic differences between individuals in regard to blood type. This also proved to be important for forensic scientists who used blood groups to exclude suspects suspected of leaving blood at the scene of a crime.

Towards the end of his life, Landsteiner turned his attention to the study of malignant tumors to find a treatment after his wife developed thyroid cancer. Karl Landsteiner died from a heart attack on 26 June 1943.

• American National Red Cross. " Blood Types ." American Red Cross. http://www.redcrossblood.org/learn-about-blood/blood-types (Accessed October 28, 2015).
• Durand, Joel K. and Monte S. Willis. "Karl Landsteiner, MD." Lab Medicine 41 (2010): 53–5. https://academic.oup.com/labmed/article/41/1/53/2504910/Karl-Landsteiner-MDTransfusion-Medicine (Accessed February 17, 2017).
• Eibl, Martha M. Epitope Recognition Since Landsteiner's Discovery: 100 Years Since the Discovery of Human Blood Groups . Berlin: Springer, 2002.
• Heidelberger, Michael. Karl Landsteiner 1868–1943 . Washington D.C.: National Academy of Sciences, 1969. http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/landsteiner-karl.pdf (Accessed February 16, 2017).
• Landsteiner, Karl. "Ueber den Einfluss der Nahrung auf die Zusammensetzung der Blutasche." [The Influence of Diet on the Composition of Blood Ash]. Zeitschrift für Physiologische Chemie [Journal of Physiological Chemistry] 16 (1892): 13–9. http://vlp.mpiwg-berlin.mpg.de/library/data/lit16840? (Accessed October 28, 2015).
• Landsteiner, Karl. "Ueber die Folgen der Einverleibung Sterilisirter Bakterienculturen." [On the Consequences of the Incorporation of Sterilized Bacterial Cultures]. Wiener Klinische Wochenschrift [Vienna Clinical Weekly] 10 (1897): 439–44.
• Landsteiner, Karl. "Zur Kenntnis der Anti Fermentatives, Lytischen und Agglutinierenden Wirkungen des Blutserums und der Lymphe." [To the Knowledge of Non-Fermentative, Lytic and Agglutinating Effects of Blood Serum and Lymph]. Zentralblatt für Bakteriologie [Central Journal for Bacteriology] 27 (1900): 357–62.
• Landsteiner, Karl. "Ueber Agglutinationserscheinungen Normalen Menschlichen." [Agglutination of Normal Human Blood]. Wiener Klinische Wochenschrift [Vienna Clinical Weekly] 14 (1901): 1132–4.
• Landsteiner, Karl. "Über heterogenetisches Antigen und Hapten. XV. Mitteilungen über Antigene." [On Heterogeneous Antigens and Partial Antigens XV. Information on Antigens]. Biochemische Zeitschrift [Biochemical Journal] 119 (1921): 294–306.
• Landsteiner, Karl. Die Spezifität der Serologischen Reaktionen [The Specificity of Serological Reactions]. Berlin: Springer, 1933.
• Landsteiner, Karl, and John Jacobs. "Studies on the sensitization of animals with simple chemical compounds." Journal of Experimental Medicine 61 (1935): 643–57. https://https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2133244/pdf/643.pdf (Accessed February 17, 2017).
• Landsteiner, Karl, and Philip Levine. "On individual differences in human blood." Journal of Experimental Medicine 47 (1928): 757–775. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2131399/pdf/757.pdf (Accessed February 17, 2017).
• Landsteiner, Karl, and C. Philip Miller Jr. "Serological Studies in the Blood of Primates II." Journal of Experimental Medicine 42 (1925): 853–62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2131087/pdf/853.pdf (Accessed February 17, 2017).
• Landsteiner, Karl, and Erwin Popper. "Übertragung der Poliomyelitis acuta auf Affen." [Transfer of poliomyelitis acuta to monkey]. Zeitschrift für Immunitätsforsch und experimentelle Therapie [Journal for Immunology Research and Experimental Therapies] 2 (1909): 377–390. https://babel.hathitrust.org/cgi/pt?id=uc1.b3208372;view=1up;seq=389 (Accessed February 17, 2017).
• Landsteiner, Karl, and Alexander S. Wiener. "An Agglutinable Factor in Human Blood Recognized by Immune Sera for Rhesus Blood." Proceedings of the Society for Experimental Biology and Medicine 43 (1940): 223. http://journals.sagepub.com/doi/pdf/10.3181/00379727-43-11151 (Accessed February 17, 2017).
• Landsteiner, Karl, and Alexander S. Wiener. "Studies on an agglutinogen (Rh) in human blood reacting with anti-rhesus sera and with human isoantibodies." The Journal of Experimental Medicine 74 (1941): 309. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135190/pdf/309.pdf (Accessed February 16, 2017).
• Nobel Prizes and Laureates. "Karl Landsteiner – Biographical." Nobelprize.org. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1930/landsteiner-bio.html (Accessed October 28, 2015).
• Ottenberg, Reuben. "Studies in Isoagglutination I." The Journal of Experimental Medicine 13 (1911): 425–438. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2124873/pdf/425.pdf (Accessed February 16, 2017).
• Peters, Stephanie True. The Battle Against Polio . New York, NY: Benchmark Books, 2005.
• Salk, Jonas Edward. "Studies in human subjects on active immunization against poliomyelitis. I. A preliminary report of experiments in progress." Journal of the American Medical Association 151 (1953): 1081–98.
• Tilstone, William J., Kathleen A. Savage, and Leigh A. Clark. "Forensic Science." An Encyclopedia of History, Methods and Techniques . California: ABC-Clio, 2006.

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• Karl Landsteiner - Biographical

Karl Landsteiner

Biographical.

K arl Landsteiner was born in Vienna on June 14, 1868. His father, Leopold Landsteiner, a doctor of law, was a well-known journalist and newspaper publisher, who died when Karl was six years old. Karl was brought up by his mother, Fanny Hess, to whom he was so devoted that a death mask of her hung on his wall until he died. After leaving school, Landsteiner studied medicine at the University of Vienna, graduating in 1891. Even while he was a student he had begun to do biochemical research and in 1891 he published a paper on the influence of diet on the composition of blood ash. To gain further knowledge of chemistry he spent the next five years in the laboratories of Hantzsch at Zurich, Emil Fischer at Wurzburg, and E. Bamberger at Munich.

Returning to Vienna, Landsteiner resumed his medical studies at the Vienna General Hospital. In 1896 he became an assistant under Max von Gruber in the Hygiene Institute at Vienna. Even at this time he was interested in the mechanisms of immunity and in the nature of antibodies. From 1898 till 1908 he held the post of assistant in the University Department of Pathological Anatomy in Vienna, the Head of which was Professor A. Weichselbaum, who had discovered the bacterial cause of meningitis, and with Fraenckel had discovered the pneumococcus. Here Landsteiner worked on morbid physiology rather than on morbid anatomy. In this he was encouraged by Weichselbaum, in spite of the criticism of others in this Institute. In 1908 Weichselbaum secured his appointment as Prosector in the Wilhelminaspital in Vienna, where he remained until 1919. In 1911 he became Professor of Pathological Anatomy in the University of Vienna, but without the corresponding salary.

Up to the year 1919, after twenty years of work on pathological anatomy, Landsteiner with a number of collaborators had published many papers on his findings in morbid anatomy and on immunology. He discovered new facts about the immunology of syphilis, added to the knowledge of the Wassermann reaction, and discovered the immunological factors which he named haptens (it then became clear that the active substances in the extracts of normal organs used in this reaction were, in fact, haptens). He made fundamental contributions to our knowledge of paroxysmal haemoglobinuria.

He also showed that the cause of poliomyelitis could be transmitted to monkeys by injecting into them material prepared by grinding up the spinal cords of children who had died from this disease, and, lacking in Vienna monkeys for further experiments, he went to the Pasteur Institute in Paris, where monkeys were available. His work there, together with that independently done by Flexner and Lewis, laid the foundations of our knowledge of the cause and immunology of poliomyelitis.

Landsteiner made numerous contributions to both pathological anatomy, histology and immunology, all of which showed, not only his meticulous care in observation and description, but also his biological understanding. But his name will no doubt always be honoured for his discovery in 1901 of, and outstanding work on, the blood groups, for which he was given the Nobel Prize for Physiology or Medicine in 1930.

In 1875 Landois had reported that, when man is given transfusions of the blood of other animals, these foreign blood corpuscles are clumped and broken up in the blood vessels of man with the liberation of haemoglobin. In 1901-1903 Landsteiner pointed out that a similar reaction may occur when the blood of one human individual is transfused, not with the blood of another animal, but with that of another human being, and that this might be the cause of shock, jaundice, and haemoglobinuria that had followed some earlier attempts at blood transfusions.

His suggestions, however, received little attention until, in 1909, he classified the bloods of human beings into the now well-known A, B, AB, and O groups and showed that transfusions between individuals of groups A or B do not result in the destruction of new blood cells and that this catastrophe occurs only when a person is transfused with the blood of a person belonging to a different group. Earlier, in 1901-1903, Landsteiner had suggested that, because the characteristics which determine the blood groups are inherited, the blood groups may be used to decide instances of doubtful paternity. Much of the subsequent work that Landsteiner and his pupils did on blood groups and the immunological uses they made of them was done, not in Vienna, but in New York. For in 1919 conditions in Vienna were such that laboratory work was very difficult and, seeing no future for Austria, Landsteiner obtained the appointment of Prosector to a small Roman Catholic Hospital at The Hague. Here he published, from 1919-1922, twelve papers on new haptens that he had discovered, on conjugates with proteins which were capable of inducing anaphylaxis and on related problems, and also on the serological specificity of the haemoglobins of different species of animals. His work in Holland came to an end when he was offered a post in the Rockefeller Institute for Medical Research in New York and he moved there together with his family. It was here that he did, in collaboration with Levine and Wiener, the further work on the blood groups which greatly extended the number of these groups, and here in collaboration with Wiener studied bleeding in the new-born, leading to the discovery of the Rh-factor in blood, which relates the human blood to the blood of the rhesus monkey.

To the end of his life, Landsteiner continued to investigate blood groups and the chemistry of antigens, antibodies and other immunological factors that occur in the blood. It was one of his great merits that he introduced chemistry into the service of serology.

Rigorously exacting in the demands he made upon himself, Landsteiner possessed untiring energy. Throughout his life he was always making observations in many fields other than those in which his main work was done (he was, for instance, responsible for having introduced dark-field illumination in the study of spirochaetes). By nature somewhat pessimistic, he preferred to live away from people.

Landsteiner married Helen Wlasto in 1916. Dr. E. Landsteiner is a son by this marriage.

In 1939 he became Emeritus Professor at the Rockefeller Institute, but continued to work as energetically as before, keeping eagerly in touch with the progress of science. It is characteristic of him that he died pipette in hand. On June 24, 1943, he had a heart attack in his laboratory and died two days later in the hospital of the Institute in which he had done such distinguished work.

This autobiography/biography was written at the time of the award and first published in the book series Les Prix Nobel . It was later edited and republished in Nobel Lectures . To cite this document, always state the source as shown above.

Karl Landsteiner died on June 26, 1943.

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• v.42(1); 2013

A Brief History of Human Blood Groups

Dariush d farhud.

1 School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

2 Tehran Genetic Clinic, 22 Keshavarz Blv, Tehran, Iran

Marjan ZARIF YEGANEH

3 Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

The evolution of human blood groups, without doubt, has a history as old as man himself. There are at least three hypotheses about the emergence and mutation of human blood groups. Global distribution pattern of blood groups depends on various environmental factors, such as disease, climate, altitude, humidity etc. In this survey, the collection of main blood groups ABO and Rh, along with some minor groups, are presented. Several investigations of blood groups from Iran, particularly a large sampling on 291857 individuals from Iran, including the main blood groups ABO and Rh, as well as minor blood groups such as Duffy, Lutheran, Kell, KP, Kidd, and Xg, have been reviewed.

Introduction

It was not until the year 1900, when Karl Landsteiner at the University of Vienna, discovered why some blood transfusions were successful while others could be deadly. Landsteiner discovered the ABO blood group system by mixing the red cells and serum of each of his staff. He demonstrated that the serum of some people agglutinated the red cells of other. From these early experiments, he identified three types, called A, B and C (C was later to be re-named O for the German “Ohne”, meaning “without”, or “Zero”, “null” in English). The fourth less frequent blood group AB, was discovered a year later. In 1930, Landsteiner received the Nobel Prize in physiology and medicine for his work ( 1 ).

The gene that determines human ABO blood type is located on chromosome 9 (9q34.1) and is called ABO glycosyltransferase. The ABO locus has three main allelic forms: A, B, and O, as mentioned above and each of them is responsible for the production of its glycoprotein. It is therefore the combination of alleles that are inherited from parents that determines which glycoproteins (antigens) are found on persons’ blood cells and thereby their ABO blood type ( 1 ).

Genesis and Evolution

As investigations have demonstrated on monkeys ( Table 1 ), human blood groups are very old genetic indicators which have evolved during several million years ( 2 ). Based on the primary races hypothesis, it was thought that in the three major races of man, blood groups A in Europe, B in Asian, and finally O in South America have been emerged and gradually due to the migration and mixing of the races, became the present situation. But we know that in each continent, the isolated populations are seen that have completely different blood groups. For example, there is relatively high prevalence of blood group O in Siberian inhabitants; also this blood group is very common in some areas of Switzerland ( 3 ).

Percentage of blood groups in monkeys (collected by Kramps 1960)

According to another hypothesis, the emergence of all blood groups A and B and their subgroups, are resulted from successive mutations, from a basic and common blood group, which is the O group, and have been branched over millions of years ( Fig. 1 ).

According to this hypothesis, the emergence of all blood groups is resulted from successive mutations, from the O group

Based on this theory, the old races have O blood group, such as Red Indians of South America, and Eskimos that among them the frequency of O blood group is between 75–100%. While in most of recent ethnic groups A and B blood groups are dominant.

In another hypothesis, the first blood group had been AB blood group, which gradually and over the time due to genetic mutations was resulted in A and B and finally O blood groups ( Fig. 2 ). Base on this theory, perhaps a few million years ago all people have had type O blood only, which is more resistant against many infectious diseases.

Based on the second hypothesis, the first blood group had been AB, which gradually has been resulted in A and B and O blood groups

The emergence and evolution of blood groups in humans is still not clear. Geographic distribution and racial blood groups A and B and O in the world (according to the Mourant design 1958) are shown in Figures 3 to ​ to5 5 ( 4 ). The geographical spread not only is a result of the above assumptions, but the current process of natural selection against environmental factors such as diseases, climate, humidity, altitude and etc. will continue.

Geographical distribution of blood group A, percentage (Mourant 1958)

Geographical distribution of blood group O, percentage (Mourant 1958)

After discovery of the first human blood groups (ABO) by Karl Landsteiner in 1901 ( 5 ), gradually from 1927, other blood groups were also discovered and reported which its collection is given in Table 2 . It is important to mention that Landsteiner together with his American colleague Alexander Wiener discovered the Rh blood group and reported it in 1940, 1941.

Major blood groups, year of report, discoverer/s

Karl Landsteiner was born on 14 th June 1868, in Vienna, Austria; he died on 26 th June 1943 AD, at 75 years old, in the United States.

Landsteiner in his 17 th scientific paper in 1901 reported blood group ABO which was displayed at the beginning with the letters ABC. In 1930, he received the Nobel Prize in Medicine for his discovery.

In addition to the known blood groups ( Table 2 ), nearly twenty public antigens and also sixty-specific antigen or family antigen (Private Antigens) have been reported ( 3 ).

Moreover, the main blood groups ABO, gradually discovered and reported ( 3 ) which the most notably of them are as follows:

• A subgroups, including A1, A2, A3, and also rare types A4, A5, A6, Z, X, End, boutu, g, i.
• B subgroups, including B1, B2, B3, and rare types w, x, v, m.
• Subgroups, including O1, O2, O3, and other types such as Yy, Hh, Xx, and Bombay.

Blood groups in Iran

In a compilation by Mourant in 1958 ( 4 ), referring to a limited and small sampling from Iran (Tehran) by A.Ajir was seen, but there was no systematic and comprehensive research about types and frequencies of blood groups, serum proteins, and red blood cell enzymes, found in Iran.

The first report about the frequency of Lutheran blood group in Iran was published in 1979 ( 23 ). After a long study and targeted collection, detailed reports of the frequency of ABO blood groups in different Iranian ethnic groups was released ( 24 ). In another study, the frequency of blood groups, serum proteins and red cells enzymes in various Iranian populations were reported ( 25 ). Furthermore, a collection of valuable and extensive cooperation with Iran Blood Transfusion Organization, different types of blood groups in various population of Iran, was reported. This report included the study of ABO and Rh blood groups phenotype and genotype frequencies among 291857 individuals and their geographical spread in different provinces of Iran ( 26 ). In this report, in addition to the ABO blood groups and Rh, genotype and phenotype frequencies of rare blood groups, including Kell (n=5522), Daffy (n=3764), Kidd (n=3650), Lutheran (n=3199), Kp (n=1489), Xg (n=3227), were also presented ( 26 ).

Since over 20–30 years have passed from that sampling in different provinces of Iran, population displacement, and various environmental factors, diseases, immigration, exogamous marriages within different ethnic groups, no doubt that provincial prevalence of blood groups distribution, at this time has changed, too. However, over time, case reports and local frequencies of blood groups in different regions of Iran, were prepared and published, including ABO and Rh blood groups report in population of Larestan and Lamerd, Fars ( 27 ).

Ethical considerations

Ethical issues (Including plagiarism, Informed Consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc) have been completely observed by the authors.

Geographical distribution of blood group B, percentage (Mourant 1958)

Acknowledgments

The authors declare that there is no conflict of interest.

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• Published: 25 July 2005

What would Karl Landsteiner do? The ABO blood group and stem cell transplantation

• J M Heal 1 ,
• J L Liesveld 1 ,
• G L Phillips 1 &
• N Blumberg 2  

Bone Marrow Transplantation volume  36 ,  pages 747–755 ( 2005 ) Cite this article

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ABO blood group antigens, of great importance in transplantation and transfusion, are present on virtually all cells, as well as in soluble form in plasma and body fluids. Naturally occurring plasma IgM and IgG antibodies against these antigens are ubiquitous. Nonetheless, the ABO blood group system is widely ignored by many transfusion services, except for purposes of red cell transfusion. We implemented a policy of transfusing only ABO identical platelets and red cells in patients undergoing stem cell transplantation or treatment for hematologic malignancies. Major bleeding episodes have occurred in about 5% of patients undergoing induction therapy for acute leukemia as compared with 15–20% in the literature. Overall survival times appear to be superior to that in historical cohorts. In 2002–2004, treatment-related mortality at 100 days in our Blood and Marrow Transplant Unit was 0.7% for autologous transplants ( n =148), 13% for sibling allogeneic transplants ( n =110), and 24% ( n =62) for matched unrelated allogeneic transplants, suggesting that our approach is safe. We speculate that more rigorous efforts on the part of transfusion services to provide ABO identical blood components, and to remove incompatible supernatant plasma, when necessary, might yield reduced morbidity and mortality in patients undergoing stem cell transplantation.

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Heal, J., Liesveld, J., Phillips, G. et al. What would Karl Landsteiner do? The ABO blood group and stem cell transplantation. Bone Marrow Transplant 36 , 747–755 (2005). https://doi.org/10.1038/sj.bmt.1705101

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Karl Landsteiner and the Blood Classification System

Karl Landsteiner (1868-1943)

On June 14, 1868, Austrian biologist, physician, and immunologist Karl Landsteiner was born. Landsteiner distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the blood, and identified, with Alexander S. Wiener , the Rhesus factor , in 1937, thus enabling physicians to transfuse blood without endangering the patient’s life.

“A single kind of red cell is supposed to have an enormous number of different substances on it, and in the same way there are substances in the serum to react with many different animal cells. In addition, the substances which match each kind of cell are different in each kind of serum. The number of hypothetical different substances postulated makes this conception so uneconomical that the question must be asked whether it is the only one possible. … We ourselves hold that another, simpler, explanation is possible.” — Karl Landsteiner, [8] (1902)

Karl Landsteiner – Youth and Education

Karl Landsteiner was born in Baden, near Vienna, Austria. His father Leopold, a well-known journalist and first editor-in-chief of the newspaper Die Presse, died at the age of 58 when Karl was six years old. This gave him a very close relationship with his mother Fanny, née Heß. Her death mask hung in his bedroom until his death. Landsteiner studied medicine at the University of Vienna from 1885, after passing his school-leaving examination at today’s Gymnasium Wasagasse in Vienna with distinction, and received his doctorate there in 1891. During his studies he already published a paper on the influence of diets on the composition of the blood.

Medical Research and Further Studies

After his studies Landsteiner spent five years abroad in laboratories in Zurich with Arthur Hantzsch , in Würzburg with the famous German chemist Emil Fischer and in Munich with Eugen Bamberger . In 1896 he returned to Vienna and initially became a surgical trainee at the 1st Surgical Clinic under Theodor Billroth . After completing this practical training, he devoted himself again to theory and became an assistant at the Institute of Hygiene headed by Max von Gruber . There he conducted studies on the mechanism of immunity and the nature of antibodies. Between 1898 and 1908 Landsteiner was an assistant at the Pathological Anatomy of the University of Vienna, then until 1919 he was prosector at the Wilhelminenspital in Vienna.

University Career and Polio

In 1903 he habilitated in pathology under Anton Weichselbaum and in 1911 Landsteiner was appointed associate professor of pathology. During this time he published many medical papers, among others on the transmission of polio. Landsteiner’s achievement – together with Erwin Popper – was the definitive proof that polio is an infectious disease, proven by injecting spinal fluid from a child who died of the disease into monkeys and subsequently transmitting it from one animal to another.

The Human Blood Group System

Landsteiner noticed in 1900 that blood of two people often clumped together when mixed. The significance of this observation was not yet clear to him when writing the manuscript, as he only describes the process of haemagglutination  in a footnote. He reported that this effect also occurred through contact of blood with blood serum. In his work “ On Agglutination Phenomena of Normal Human Blood “, he demanded for the first time, again in a footnote, that there must be three blood groups. He succeeded in identifying the blood group characteristics A, B and 0 (the latter referred to as C). The blood group trait AB (which Emil von Dungern and Ludwik Hirszfeld only designated as such in 1910) was discovered in 1902 by two of Landsteiner’s colleagues, the Viennese internist Alfred von Decastello-Rechtwehr and his colleague Adriano Sturli. The AB0 nomenclature proposed by Dungern and Hirszfeld in 1910 was not adopted internationally until 1928.

Blood Transfusions

It was also Landsteiner who recognized that blood transfusion between persons of the same group did not lead to the destruction of blood cells, but rather between persons of different blood groups, so that in 1907 the first successful blood transfusion based on his work was performed at Mount Sinai Hospital in New York by Reuben Ottenberg . Today we know that people with blood group AB accept erythrocytes of all other blood groups (universal recipient), erythrocytes of blood group 0 can be received by all groups (universal donor). This is because people with blood group AB do not produce antibodies against blood group A or B. Blood group 0, on the other hand, has neither characteristic A nor characteristic B, so no antibodies against it can be formed in the recipient after the transfer. Nowadays, blood transfusions only transfer erythrocyte concentrates without blood serum containing antibodies. This knowledge is particularly important for blood transfusions and operations. Landsteiner was awarded the Nobel Prize for Medicine in 1930 for his discovery of blood groups.

The Rh Blood Group System

In 1937 Landsteiner discovered the rhesus factor (later Rh Blood Group System) together with Alexander Solomon Wiener , who named it after a similar factor found in rhesus monkey blood. The significance of the discovery was not immediately apparent and was only realized in 1940, after subsequent findings by Philip Levine and Rufus Stetson. The serum that led to the discovery was produced by immunizing rabbits with red blood cells from a rhesus macaque. The antigen that induced this immunization was designated by them as Rh factor to indicate that rhesus blood had been used for the production of the serum.

Further Research

After the end of the First World War, economic hardship in Austria was great and the prospects for an orderly academic career in Vienna seemed extremely uncertain. Landsteiner therefore accepted job offers from abroad. In 1919 he went to The Hague, where he managed the prosection of a small Catholic hospital. He remained scientifically active and treated various serological problems in a total of twelve publications. In 1921, for example, he reported on low-molecular “specific substances” which require binding to a protein in order to become a so-called full antigen, and for which he proposed the name haptene. In 1922 Landsteiner accepted a position at the Rockefeller Institute in New York, where in 1940, together with his students Philip Levine and Alexander Solomon Wiener, he described the rhesus factor that he had discovered in the blood of rhesus monkeys. Besides working on the blood groups, he dealt with questions concerning the development of paroxysmal cold hemoglobinuria, which led to the development of the Donath-Landsteiner reaction as a test for the confirmation of a diagnosis

Later Years

In 1932 Landsteiner was elected to the National Academy of Sciences . For his groundbreaking findings, which are considered the foundation of polio control, he was posthumously inducted into the Polio Hall of Fame in Warm Springs, Georgia, inaugurated in January 1958. In his last years he worked on oncological issues, as his wife had a malignant tumour of the thyroid gland. Karl Lanfsteiner died on 26 June 1943 in New York City at age 75.  For his pioneering work, he is recognized as the father of transfusion medicine.

References and Further Reading:

• [1]  Karl Landsteiner  on Nobelprize.org including the Nobel Lecture, December 11, 1930  On Individual Differences in Human Blood
• [2]  Karl Landsteiner 1868—1943  A Biographical Memoir by Michael Heidelberger
• [3]  Landsteiner, K.;  Popper, E.  (1909). “Übertragung der Poliomyelitis acuta auf Affen”.  Zeitschrift für Immunitätsforschung und experimentelle Therapie  (in German).  2 : 377–390.
• [4]  National Academy of Sciences Biographical Memoir
• [5]  “Homage to scientist on Blood Donor’s Day” .  The Tribune . 15 June 2006 .  
• [6] Karl Landsteiner and Adriano Sturli, ‘ Hamagglutinine normaler Sera ‘, Wiener klinische Wochenschrift (1902), 15, 38-40.
• [7] Karl Landsteiner at Wikidata
• [8]  Dr. Preeti Tyagi,  Blood Groups, Physiology ,  Dr. Preeti Tyagi Lectures  @ youtube
• [9]  Dorner, Friedrich; Schwarz, Hans Peter (2003). “Karl Landsteiner and his major contributions to haematology”.  British Journal of Haematology .  121  (4): 556–565.

Harald Sack

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Karl Landsteiner and the First Human Marker Locus

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Ray Owen, Karl Landsteiner and the First Human Marker Locus, Genetics , Volume 155, Issue 3, 1 July 2000, Pages 995–998, https://doi.org/10.1093/genetics/155.3.995

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JUST a century ago, the year of the rediscovery of Mendelism, Karl Landsteiner published a short note on what we would now call antibody action in human blood serum, with a comment on the agglutination of the red cells of some people by the serum of others ( Landsteiner 1900 ). The following year he elaborated the observation ( Landsteiner 1901 ), and it is to that second short paper that reference is most appropriately made when dating the discovery of the normal human blood groups. As strict constructionists of the millennium would argue, the century began in 1901, not 1900.

Karl Landsteiner, 1931 . Photo courtesy of the National Academy of Sciences.

Landsteiner outlined the background of this discovery in his 1930 Nobel Lecture ( Landsteiner 1931 ), and it has been dealt with in detail in the Obituary Notices of Fellows of the Royal Society ( Rous 1947 ) and the Biographical Memoirs of the National Academy of Sciences ( Heidelberger 1969 ). Using serological methods, he had been impressed that “the proteins in various animals and plants are different and are specific for each species.” He wondered “whether … individuals within a species show similar … differences. As no observations whatever were available pointing to such behavior, I chose the simplest among the possible plans of investigation … allowing blood serum and red blood corpuscles of different human individuals to interact” ( Landsteiner 1931 , p. 403).

It had, in fact, been noted earlier by others that such interactions often resulted in agglutination or lysis of the red cells and severe incompatibility in attempted blood transfusion. The predominant opinion of the day was that immune reactions regularly reflected a history of disease. It was against this background that Landsteiner chose to emphasize his studies of “apparently healthy men.”

In the 1901 paper he tabulated the results of complete cross-testing of the sera and cells of six people working in his lab, including himself ( Table 1 ). He noted first, as you can see from the diagonal, that the serum of none of the six individuals reacted with the person's own cells—a clear observation of self-tolerance. [Only 3 years later, he made a key contribution to the subject of autoimmune disease in studies of paroxysmal hemoglobinuria ( Donath and Landsteiner 1904 )]. Second, the serum of Dr. Pletschnig reacted with Dr. Sturli's cells, and Sturli's serum reacted with Pletschnig's cells. Viewing the results as antigen-antibody reactions, he could suggest that at least two classes of antibodies were involved, what we would now call anti-A and anti-B, reacting with corresponding cellular antigens A and B. Dr. Sturli, whose cells can be said to have A antigen, has anti-B in his serum, and Dr. Pletschnig has B on his cells, anti-A in his serum. “Dr. St.,” like Landsteiner

Concerning the blood of six apparently healthy men

himself, has neither antigen and both antibodies; we call them Group O today. For both cell and serum reactions, “Dr. Erdh.” is like Sturli, and “Zar.” is like Pletschnig. The table therefore neatly distinguished three normal human blood groups, A, B, and O, and displayed each group in duplicate.

Application of blood grouping to transfusion came rather slowly. The main hazard, perceived from early attempts, was ordinary blood clotting, not incompatibility; when blood was taken from a prospective donor, it clotted during the transfusion process, to conspicuously ill effect on the recipient. Shortly after 1900 surgeons developed extraordinary methods of joining an artery of the donor with a vein of the recipient so that the blood was not exposed to clotting during transfer. The method was difficult, and although in 1907 the typing of bloods to match for transfusions was reported by Ottenberg, it was not until 1915 that the use of an anticoagulant (citrate) solved the clotting problem, just in time for the extensive use of transfusions in the First World War, and with it the clear value of cross-matching.

As we note shortly, Landsteiner was active in many areas relating mainly to immunology. His interests in individuality and red cell antigens continued through his life, and it is in that context that we celebrate his contributions to genetics. Erlich and Morgenroth had early shown that when blood of one goat was injected into another goat, immune antibodies that reacted with the donor's, not the recipient's, cells appeared and that these antisera recognized a complexity of individual differences among goats. By 1910, Todd and White ( 1910 ) had published similar studies of cattle and chickens, work indicating that any individual within a species had an almost unique individuality. Landsteiner wondered why, given a match for ABO, human transfusions did not readily reveal such individuality. It was not until well after he was established at the Rockefeller Institute that, with Levine, he tried injecting rabbits with human blood and using the immune sera to detect differences among people. This led to the next marker for human genetics, the M-N alternative, later to prove so complicated ( Landsteiner and Levine 1927 ; Race and Sanger 1975 ). The same experiments revealed the P groups.

Another approach to detecting human differences was conceived by Landsteiner in the late 1930s: inject cells from related animals (they used Rhesus monkeys) into guinea pigs and rabbits, and see if the resulting antisera distinguished human characteristics. This led to the recognition of the Rh system, named for the Rhesus donors.

The antisera reacted with all human cells, but appropriately diluted they recognized the red cells of many but not all New Yorkers ( Landsteiner and Wiener 1940 ). A year earlier Levine (Landsteiner's colleague in the M-N-P discoveries) had published a case study of a woman who had been admitted to Bellevue Hospital in July 1937. She gave birth to a macerated fetus in early September, and, needing a transfusion, she was given 500 cc of whole blood from her husband, also of group O. Within 10 min she began to have severe symptoms, followed by more bleeding. A cross-match later revealed that her serum agglutinated her husband's cells. A total of 104 group O bloods were tested against her serum; only 21 were compatible. The reactions were found to be independent of M, N, and P. The antiserum lost activity on storage, however; the system was not given a name or subjected to family studies, so briefly it remained only an interesting clinical observation ( Levine and Stetson 1939 ).

With the discovery of the Rhesus factor in 1940, Landsteiner and Wiener were able to relate it to the antigen recognized in the Levine and Stetson context. For some time the two were thought to be the same, and “Rh” became firmly established in the general literature as a basis for maternal-fetal incompatibility, dependent on the inheritance of an allele from the father, absent in the mother, and controlling an antigen that immunized her during pregnancy and childbirth. The system proved overwhelmingly complex and became the subject of heated controversy. Wiener and his supporters chose to regard it as dependent on a long series of multiple alleles, reflected in a symbolism that took Rh as its base, with alleles distinguished by upper- and lower-case, superscripts, numbers, and primes. R. A. Fisher, with R. Race, developed a hypothesis of three adjacent loci, designated D, C, and E, each polymorphic. Landsteiner died just as the controversy was initiated, so he did not become involved in it. It is unlikely that he would have taken part; his consistent philosophy from early in his scientific life was to focus on facts that forced one to an interpretation, and the facts to resolve the argument, from his viewpoint primarily of chemistry, were not at hand. Indeed, as later developments in molecular genetics have demonstrated, and as often is true in heated polemics, both sides were partly right. More recent knowledge of the biochemical genetics of the cellular antigens and the molecular biology of their controlling loci is beyond the scope of this Perspectives. A comprehensive and reasonably up-to-date reference is Cartron and Rouger ( 1995 ). We can expect that future developments in human genomics will greatly enlighten this area.

A further complication soon became evident: the antigens recognized in the Levine-Stetson system and in the Landsteiner-Weiner system and their corresponding antibodies were not the same. All newborn babies, whether Rh-positive or -negative with human anti-Rh sera, were positive with the guinea pig antibody. Extracts of human Rh-negative blood gave rise to Rh antibodies in guinea pigs. No matter how potent, human Rh antibodies do not clump Rhesus cells at all. Unusual human sera that appeared to test as anti-Rh, but from which the antibody could be absorbed by Rh-negative cells, began to be noticed. These sera, along with guinea pig antisera, defined a new locus, assigned the symbol LW (for Landsteiner-Wiener), that proved to be genetically independent of Rh. Thus LW came to designate a system dependent on the original Rhesus studies of Landsteiner and Wiener, while the symbol Rh came to designate a system that, in the original hands of Levine and Stetson, had nothing to do with Rhesus. Race and Sanger, in the final edition of their classic Blood Groups in Man , summarize their LW section: “If we were to do justice to the papers in this section, we should never finish the chapter” ( Race and Sanger 1975 , p. 232). I take the same way out for this Perspectives on Landsteiner.

Although his interests were extraordinarily broad and his contributions very extensive (his obituary lists 346 publications), Landsteiner's main base was in chemistry. He started medical school in 1885 at the age of 17 and soon engaged in experimental investigation, under Ernst Ludwig. Becoming “Doktor der gesamten Heilkunde” in 1891, he joined a clinic at University Hospital in Vienna and took up advanced study and research under several outstanding organic chemists of the day. He became interested in immunology and active in surgery, in pathological anatomy, and in a variety of medical and technological areas. He was among the first to prepare partially purified antibodies by dissociating antigen-antibody complexes and the first to use dark-field microscopy to visualize the spirochetes of syphilis and to transmit syphilis to monkeys. He and E. Popper transmitted poliomyelitis to monkeys, and he was importantly involved in the demonstration that polio is caused by a virus. His work was interrupted by World War I, during which he served as a medical officer, and conditions after the war made continued research there nearly impossible. So in 1919 he moved to The Hague, where conditions were more favorable, and in 1923 accepted a membership at the Rockefeller Institute in New York. He promptly became a U.S. citizen. There followed 20 very productive years, until his death in 1943. Aside from the red cell studies we have outlined, his other major interest over those later years was in the chemical and immunological basis of skin sensitization and allergy, seminal work conducted mainly with John Jacobs and Merrill Chase. But looking back on his life as a scientist, Landsteiner was proudest not of the work for which he received the prize, or of others of his many contributions, but of the insight he had provided into the primary specificity of serological reactions.

That was the chemist's approach, which laid the groundwork for immunochemistry. Recognizing that simple substances (haptens) could be coupled to proteins and that immune antisera to these modified proteins included antibodies directed against the introduced haptens, Landsteiner worked out the technology of studying just those antibodies. Their specificity could be related to particular defined groups on the antigen and evaluated quantitatively with precipitin reactions and hapten inhibition of precipitation. These earlier studies were summarized in German (in 1933) and published in a second, English edition that became a bible for many of us in immunology and immunogenetics ( Landsteiner 1936 ). A revised edition was published 2 years after Landsteiner's death, edited by his son Ernest K. Landsteiner and acknowledging help from Merrill Chase and Alexander Wiener. The books dealt in depth with the serological specificity of proteins, cell antigens, antibodies, simple chemical compounds, specific nonprotein cell substances, and antigen-antibody reactions. The 1945 edition includes an appendix by Linus Pauling, on molecular structure and intermolecular forces, and thereby hangs a tale I've found interesting.

The tale is told by Thomas Hager in his biography of Pauling ( Hager 1995 ) and is based on the author's extensive studies of the Pauling papers and conversations with Linus himself and others. In 1936, Pauling lectured at the Rockefeller Institute on hemoglobin. Responding to a note from Landsteiner (about whom he knew mainly because Landsteiner had received a Nobel Prize 5 years earlier), Pauling listened while Landsteiner raised puzzling questions about antibodies: How did their great diversity arise, and what was the molecular basis for their specificity? What were the physical-chemical forces that led to their specific reaction with antigens? How could the immune system tailor these antibody proteins to recognize a myriad of molecules the body had never before encountered?

Pauling could not enlighten any of these questions, but they piqued his interest. He bought a copy of Landsteiner's book, the brand new 1936 edition, read it on the train, and arrived in Pasadena an enthusiast. He soon had a rough draft of a manuscript about how an antibody might be formed and the physical-chemical basis of its specific reaction with antigen. But he was distracted by other events and set the draft aside. When he gave a lecture at Cornell University in November 1937, Landsteiner journeyed to Ithaca, and a brief visit turned into what Pauling recalled as “the best course of instruction in a complicated field that anyone ever received,” an intensive 4-day tutorial. The two remained in mutually stimulating contact until Landsteiner's death.

They were, however, quite different. Landsteiner, from his start, shunned the airing of hypotheses. New ideas came to him very frequently, and he was constantly suggesting to his juniors and colleagues trial experiments which “would take no time.” But he was “incorrigibly doubtful and when a discovery declared itself he would instantly conclude that it could not be real.” “Experiments which revealed anything were done many times over, and not until the data on a point under determination were, in his term, ‘thick’ would he publish” ( Rous 1947 , pp. 306–307).

Pauling, in contrast, readily pressed generalizations. As he put it, “I found that Landsteiner and I had a much different approach to science. Landsteiner would ask, ‘what do these experimental observations force us to believe about the nature of the world?’ and I would ask, ‘what is the most simple, general and intellectually satisfying picture of the world that encompasses these observations and is not incompatible with them?’” ( Hager 1995 , pp. 239–240). I would guess that it takes both kinds to press on with science. Do we tend to teach the Landsteiner approach, but to remember better the Pauling place in history?

So, if we had word from Landsteiner today, it might be as Tennyson's Ulysses: I am become a name; For always roaming with a hungry heart Much have I seen and known, cities of men And manners, climates, councils, governments, Myself not least, but honor'd of them all. He deserves to be remembered as more than a name and more than the discoverer of the first human marker locus.

Cartron J P , Rouger P , Editors, 1995   Blood Cell Biochemistry, Vol. 6: Molecular Basis of Human Blood Group Antigens . Plenum Press , New York .

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Hektoen International

A Journal of Medical Humanities

Karl Landsteiner and the discovery of blood groups

Safia Benaissa Mostganem, Algeria

Karl Landsteiner was the Austrian scientist who recognized that humans had different blood groups and made it possible for physicians to transfuse blood safely. He entered medical school at the University of Vienna, where he developed an interest in chemistry. After taking off a year to complete his military service he returned to finish his studies and received his M.D. in 1891 at age twenty-three.

He subsequently worked in the laboratories of the greatest chemistry specialists of his time, publishing many papers with them and developing an interest in immunology. Working in Vienna between 1897 and 1920, first as assistant and later as associate professor, he carried out studies on poliomyelitis, showing it was infectious and isolating its virus. 1 In 1900 he began to test the sera and red cells from the scientists working in his laboratory, including his own, showing that blood from certain scientists caused the blood of others to clump, and postulating the existence of at least two blood groups. He published a paper that first mentioned agglutination of human blood and proposed that this was linked to the uniqueness of an individual’s blood rather than having a pathological cause. This valuable conclusion led to the identification of the four blood groups.

He then discovered that the cause of agglutination was an immunological reaction in which the host produced antibodies against donated blood cells. This immune response is elicited because blood from different individuals may vary in certain antigens located on the surface of red blood cells. Landsteiner identified three such antigens, which he labeled A, B, and C (later changed to O). A fourth blood type, later named AB, was identified the following year. He found that if a person with one blood type—A, for example—received blood from an individual of a different blood type, such as B, the host’s immune system will not recognize the B antigens on the donor blood cells and thus will consider them to be foreign and dangerous.

To defend the body from this perceived threat, the host’s immune system will produce antibodies against the B antigens, and agglutination will occur as the antibodies bind to the B antigens. This discovery laid the groundwork for the first successful blood transfusions and also suggested other uses for his findings, such as in paternity cases or solving crimes if blood stains were left on the scene. 2

He also pioneered the use of dark-field microscopy to detect the spirochetes of syphilis and studied human-to-animal transmission, hoping to find antibodies to the disease. His examination of these antigen-antibody reactions ultimately led him to explore the chemical and immunological basis of skin sensitization and allergy. 3 Moving after World War I first to the Netherlands and then to the United States, he worked with Philip Levine to discover in 1927 the M, N, and P factors blood factors. 4 But he considered his greatest work to be his investigation into antigen-antibody interactions, which he carried out primarily at Rockefeller Institute in New York City (1922–43). In this research he used small organic molecules called haptens—which stimulate antibody production only when combined with a larger molecule such as a protein—to demonstrate that small variations in a molecule’s structure can cause great changes in antibody production.

Landsteiner retired officially in 1939, but worked with Alexander Wiener to discover the Rhesus (Rh) factor in 1940, supplying the “pathophysiological basis for erythroblastosis” and illustrating the relationship between a mother and a fetus’s blood types and antibodies. He also worked with the Romanian bacteriologist Constantin Levaditi on poliomyelitis and laid the groundwork for the development of a polio vaccine. After years of work, at the age of seventy-five Karl Landsteiner had a heart attack in his laboratory on June 24, 1943 and died two days later 6 in the same hospital where he had done such distinguished work. 5 His discovery, which won him the Nobel Prize in Physiology or Medicine in 1930, made blood transfusion a life-saving medical practice and saved many lives. In the 1800s doctors knew that transfusing blood between individuals could cause red blood cells to clump, a phenomenon called agglutination. But they did not know why, and it was Landsteiner who showed that agglutination is a response of the immune system.

References:

• https://www.healio.com/hematology-oncology/news/print/hemonc-today/%7Bf3e8beac-8565-4919-bd91-34b9b3b78c64%7D/karl-landsteiner-discovered-the-four-blood-groups
• https://www.britannica.com/biography/Karl-Landsteiner.
• https://www.healio.com/hematology-oncology/news/print/hemonc-today/%7Bf3e8beac-8565-4919-bd91-34b9b3b78c64%7D/karl-landsteiner-discovered-the-four-blood-groups.
• https://www.britannica.com/biography/Karl-Landsteiner
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077641/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077641/.

SAFIA BENAISSA  graduated from the French media and the communication license in 2015 and completed her master’s education in 2017. While she has teaching experience, Safia is an aspiring journalist from Algeria.

Submitted for the 2019–2020 Blood Writing Contest

Winter 2020

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Karl Landsteiner, the discoverer of blood groups

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• 1 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, and Department of Anaesthesiology and lntensive Care Medicine, Lorenz Boehler Trauma Centre, Vienna, Austria. [email protected]
• PMID: 15582758
• DOI: 10.1016/j.resuscitation.2004.09.001

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