The immune system of vertebrates help keep the animal healthy by making millions of different proteins (immunoglobulins ) called antibodies to disable antigens (harmful foreign substances such as toxins or bacteria ). Scientists have worked to develop a method to extract large amounts of specific antibodies from clones (exact copies) of a cell created by fusing two different natural cells. Those antibodies are called monoclonal antibodies.
Antibody research began in the 1930s when the American pathologist Karl Landsteiner found that animal antibodies counteract specific antigens and that all antibodies have similar structures. Research by the American biochemists Rodney R. Porter (1917–1985) and Gerald M. Edelman (1929– ) during the 1950s determined antibody structure, and particularly the active areas of individual antibodies. For their work they received the 1972 Nobel prize in physiology or medicine.
By the 1960s, scientists who studied cells needed large amounts of specific antibodies for their research, but several problems prevented them from obtaining these antibodies. Animals can be injected with antigens so they will produce the desired antibodies, but it is difficult to extract them from among the many types produced. Attempts to reproduce various antibodies in an artificial environment encountered some complications. Lymphocytes, the type of cell that produces specific antibodies, are very difficult to grow in the laboratory; conversely, tumor cells reproduce easily and endlessly, but make only their own types of antibodies. A bone marrow tumor called a myeloma interested scientists because it begins from a single cell that produces a single antibody, then divides many times. The cells that divided do not contain antibodies and could, therefore, be crossed with lymphocytes to produce specific antibodies. These hybrid cells are called hybridoma, and they produce monoclonal antibodies.
One molecular biologist who needed pure antibodies for a study of myeloma mutations was the Argentinean César Milstein (1927– ). After receiving a doctorate in biochemistry , specializing in enzymes , from the University of Buenos Aires in 1957, he continued this study at the University of Cambridge in England. There he worked under the biochemist Frederick Sanger and earned another doctorate in 1961. Milstein had returned to Argentina, but political disturbances forced him to flee the country. He came back to Cambridge, where Sanger suggested that he work with antibodies.
In 1974, Milstein was working with Georges Köhler (1946–1995), a German postdoctoral student who had just received his doctorate from the University of Freiburg for work performed at the Institute for Immunology in Basel, Switzerland. To produce the needed antibodies, Milstein and Köhler first injected a mouse with a known antigen . After extracting the resulting lymphocytes from the mouse's blood, they fused one of them with a myeloma cell. The resulting hybrid produced the lymphocyte's specific antibody and reproduced endlessly. As Milstein soon realized, their technique for producing monoclonal antibodies could be used in many capacities. Milstein and Köhler shared part of the 1984 Nobel prize in physiology or medicine for their invention.
Today pure antibodies are made using the Milstein-Köhler technique and also through genetic engineering, which adds the gene for the desired antibody to bacteria that can produce it in large amounts. Monoclonal antibodies are instrumental in the performance of sensitive medical diagnostic tests such as: determining pregnancy with chorionic gonadotropin; determining the amino acid content of substances; classifying antigens; purifying hormones; and modifying infectious or toxic substances in the body. They are also important in cancer treatment because they can be tagged with radioisotopes to make images of tumors.
See also Antibody-antigen, biochemical and molecular reactions; Antibody and antigen; Immunity, cell mediated; Immunogenetics; Immunologic therapies; Immunological analysis techniques; In vitro and in vivo research