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Cesar MilsteinNobel Prize in Physiology or Medicine, 1984 jointly with Niels K. Jerne and Georg Köhler
Date of Birth: 08.10.1927
Country:  Argentina |
Content:
- Biography of César Milstein
- Research at Cambridge University
- Return to Argentina and Development of the Hybridoma Technology
- Impact of Monoclonal Antibody Technology
- Nobel Prize and Other Honors
Biography of César Milstein
Early Life and EducationCésar Milstein was born in Bahía Blanca, Argentina, in 1927. He was the second of three sons of Lázaro and Maxima Milstein. Milstein attended Colegio Nacional in Bahía Blanca from 1939 to 1944, and in 1945, he enrolled at the University of Buenos Aires to study exact sciences. During his university years, he actively participated in student political life and worked as a clinical assistant in the laboratory of Doctor Libescutz, a position he held until 1956.
In 1952, Milstein obtained a chemistry degree from the University of Buenos Aires. Despite average grades in most subjects, he decided to pursue a doctorate in biochemistry and joined the graduate studies program at the University of Buenos Aires' Institute of Biological Chemistry. Milstein's doctoral dissertation, completed in 1957, focused on the chemistry of the enzyme aldehyde dehydrogenase.
Research at Cambridge University
Milstein's doctoral research was influenced by Frederick Sanger's work at Cambridge University, which demonstrated that the function of an enzyme is determined by the arrangement of amino acids within it, particularly in an antigen-binding region of the enzyme molecule known as the active site. With a British Council grant, Milstein joined Sanger's laboratory from 1958 to 1961, where he conducted studies on the active sites of enzymes. In 1960, he was awarded a PhD degree and joined the Medical Research Council (MRC) Unit for Biochemistry (now the MRC Laboratory of Molecular Biology) at Cambridge University.
Return to Argentina and Development of the Hybridoma Technology
In 1961, Milstein returned to Argentina to lead the new Molecular Biology Unit at the National Institute of Microbiology in Buenos Aires, where he planned to continue his research on enzymes. However, a military coup shortly after his return led to the dismissal of several staff members, including the director, Ignacio Pirosky. In protest, Milstein and several other young scientists resigned.
In 1963, Milstein returned to Sanger's laboratory at Cambridge. At Sanger's suggestion, Milstein shifted his focus from enzymes to antibodies, proteins produced by the immune system to bind and neutralize foreign substances (antigens). As Karl Landsteiner had shown in the 1930s, animals can produce thousands of different types of antibodies, each specific for a particular antigen; all antibodies share a similar chemical structure. Sanger believed that Milstein could use his enzymological methods to study the amino acids in the active sites of different antibodies. "The idea was to see whether, and if so how, the sequences of amino acids in any two different antibodies were different," Milstein wrote.
However, this experiment proved unsuccessful. A major problem Milstein faced was the practical impossibility of isolating just two antibodies. Rodney R. Porter showed that even antibody-containing serum that reacts with only one antigen is a mixture of antibodies with differing active sites. Porter, Gerald M. Edelman, and others studying the chemical structure of antibodies overcame this difficulty by examining myeloma proteins. Myeloma is a tumor containing antibody-producing cells. Cells in a particular myeloma are clonal and genetically identical to successive generations of cells from the same progenitor tumor. As Macfarlane Burnet had predicted a few years before these studies, all cells in the clone produce the same antibody.
Milstein and his colleagues at the MRC Laboratory spent much of the 1960s conducting amino acid analyses of different myeloma proteins. In the early 1970s, they shifted their focus to the deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) of antibodies, with Milstein making important deductions about the structure of antibodies and their genes.
A central question in antibody research in the 1960s was how the immune system generates an apparently infinite array of antibodies from a finite amount of DNA. Many researchers believed that antibody genes underwent high levels of mutation. In the early 1970s, Milstein and his colleagues searched for evidence of mutations among myeloma cells growing in laboratory cultures. However, the results were inconclusive, mainly because identifying a mutated cell proved very difficult. "We came to the increasing realization that there was only one way out—to use a myeloma culture that was definitely expressing its antibody," Milstein later wrote. The myeloma cells they had been using did produce antibodies, but Milstein and his colleagues were unable to find antigens that these antibodies reacted with. They needed to start with an antigen and then find a myeloma that produced the corresponding antibody. This would make it easy to recognize mutants among the progeny of this myeloma because they would have lost the ability to bind to the antigen.
In 1974, Milstein began working on this problem with Georges Köhler, a postdoctoral fellow from Switzerland. The two scientists used a method developed by one of Milstein's collaborators, R.J.H. Cotton, who had found that it was possible to fuse cells from two different myelomas, resulting in a hybrid that produced both proteins from its parent tumors. Köhler immunized a mouse with a specific antigen, then removed the antibody-producing plasma cells and fused them with myeloma cells. This produced a hybrid myeloma, or hybridoma, that had the ability to produce antibodies, like its normal counterpart, but that grew indefinitely like its tumor counterpart. If properly manipulated, hybridomas can be isolated as clones derived from a single cell fusion. Their products are single, monoclonal antibodies. Milstein and Köhler published their method for producing monoclonal antibodies in 1975.
Impact of Monoclonal Antibody Technology
It soon became clear that the potential for the method extended far beyond the problem of antibody gene mutation. Monoclonal antibodies could be produced that gave remarkably clear, specific, and standardized reactions with any antigen. By the early 1980s, a substantial commercial market had developed for monoclonal antibodies for diagnostic purposes, and the development of hybridoma-based controlled vaccines and antitumor therapeutics was underway.
Throughout the late 1970s, Milstein refined his monoclonal antibody techniques and worked to accelerate their applications, while at the same time returning to his original scientific interests: studying the genetic basis of antibody diversity and the modification of immune responses over long-term exposure to antigens. In 1983, Milstein was appointed Head of the Protein and Nucleic Acid Chemistry Division of the MRC Laboratory.
Nobel Prize and Other Honors
Milstein shared the 1984 Nobel Prize in Physiology or Medicine with Köhler and Niels K. Jerne. "We are in the early stages of a new era of immunochemistry—the 'molecular engineering' of antibodies," he said in his Nobel lecture. Milstein added that the hybridoma technique he and his colleagues developed "was generated as a by-product of basic research. Its practical success was due largely to features of the method that were unexpected and unpredictable. The story provides another excellent illustration of the enormous practical value of funding research in areas of science that do not at first glance seem either commercially relevant or directly applicable to medicine."
In 1953, Milstein married Celia Prilletsky, a biochemist; the couple had no children.
Among Milstein's awards are the Israel Wolf Foundation's Wolf Prize in Medicine (1980), the Columbia University Louisa Gross Horwitz Prize (1980), the Gairdner Foundation International Award (1981), the Royal Medal of the Royal Society of London (1982), the Albert Lasker Award for Basic Medical Research (1984), and the Dale Medal of the Society for Endocrinology, London (1984). He is a Fellow of the European Molecular Biology Organization, the Royal Society of London, the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, and the Royal College of Physicians, London.
