César Milstein | |
---|---|
Born | Bahía Blanca, Argentina | 8 October 1927
Died | 24 March 2002 74) Cambridge, England | (aged
Nationality | Argentine, naturalised as British |
Alma mater | |
Known for | Receiving Nobel Prize "for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies" |
Spouse | Celia Prilleltensky (m. 1953) |
Awards |
|
Scientific career | |
Fields | Biochemistry |
Doctoral advisor | Andrés O.M. Stoppani [3] |
(1928-2020)
César Milstein, CH, FRS [2] (8 October 1927 – 24 March 2002) was an Argentine biochemist in the field of antibody research. [4] [5] [6] [7] [8] Milstein shared the Nobel Prize in Physiology or Medicine in 1984 with Niels Kaj Jerne and Georges J. F. Köhler for developing the hybridoma technique for the production of monoclonal antibodies. [9] [10] [11] [12] [3] [13] [14]
Milstein was born in Bahía Blanca, Argentina. His parents were Máxima (Vanarks) and Lázaro Milstein, a Jewish Ukrainians Jewish Ukrainian immigrant. [15] He graduated from the University of Buenos Aires and obtained a PhD under Professor Stopani [16] (Professor of Biochemistry). Later he became a member of the Medical Research Council Laboratory of Molecular Biology, Cambridge, England; he acquired British citizenship and had dual British-Argentinian nationality. [17] In 1956, he received an award from the Sociedad Argentina de Investigation eon Bio Quimica (SAIB) for his work on enzyme kinetics kinetic studies with the enzyme aldehyde dehydrogenase. In 1958, funded by the British Council, he joined the Biochemistry Department at the University of Cambridge to work for a PhD under Malcolm Dixon on the mechanism of metal activation of the enzyme phosphoglucomutase. [18] During this work, he collaborated with Frederick Sanger, whose group he joined with a short-term Medical Research Council appointment.
Science will only fulfill its promises when the benefits are equally shared by the really poor of the world
— César Milstein
The major part of Milstein's research career was devoted to studying the structure of antibodies and the mechanism by which antibody diversity is generated. It was as part of this quest that, in 1975, he worked with Georges Köhler (a postdoctoral fellow in his laboratory) to develop the hybridoma technique for the production of monoclonal antibodies—a discovery recognized by the award of the 1984 Nobel Prize for Physiology or Medicine. This discovery led to an enormous expansion in the exploitation of antibodies in science and medicine. The term hybridoma was coined by Leonard Herzenberg during his sabbatical in Milstein's laboratory between 1976 and 1977. [19]
Milstein himself made many major contributions to improvements and developments in monoclonal antibody technology—especially in the use of monoclonal antibodies to provide markers that allow distinction between different cell types. In collaboration with Claudio Cuello, he helped lay the foundation for the use of monoclonal antibodies as probes for the investigation of the pathological pathways in neurological disorders as well as many other diseases. [20] Milstein and Cuello's work also enabled the use of monoclonal antibodies to enhance the power of immuno-based diagnostic tests. [21] In addition, Milstein foresaw the potential wealth of ligand-binding reagents that could result from applying recombinant DNA technology to monoclonal antibodies and inspired the development of the field of antibody engineering, which was to lead to safer and more powerful monoclonal antibodies for use as therapeutics.
Milstein's early work on antibodies focused on their diversity at the amino acid level, as well as on the disulfide bonds by which they were held together. Part of this work was done in collaboration with his wife, Celia. The emphasis of his research then shifted towards the mRNA encoding antibodies, where he was able to provide the first evidence for the existence of a precursor for these secreted polypeptides that contained a signal sequence. [22] The development of the hybridoma technology coupled to advances in nucleic acid sequencing allowed Milstein to chart the changes that occurred in antibodies following antigen encounter. He demonstrated the importance of somatic hypermutation of immunoglobulin V genes in antibody affinity maturation. In this process, localized mutation of the immunoglobulin genes allows the production of improved antibodies, which make a major contribution to protective immunity and immunological memory. Much of his work in later years was devoted to characterizing this mutational process with a view to understanding its mechanism. He contributed a manuscript [23] for publication on this topic less than a week before he died.
Quite apart from his own achievements, Milstein acted as a guide and inspiration to many in the antibody field, as well as devoting himself to assisting science and scientists in less developed countries. Milstein patented the production of monoclonal antibodies, [24] and held three other patents.
In addition to the Nobel Prize in 1984, Milstein was elected a Fellow of the Royal Society (FRS) in 1975, [2] was a fellow of Darwin College, Cambridge, from 1980 to 2002, awarded the Louisa Gross Horwitz Prize from Columbia University in 1980, won the Copley Medal in 1989, and became a Member of the Order of the Companions of Honour in 1995. In 1993, the Argentinian Konex Foundation granted him the Diamond Konex Award, one of the most prestigious cultural awards of Argentina, as the most important scientist in the last decade of his country.
Milstein married Celia Prilleltensky in 1953.
Milstein died early on 24 March 2002, in Cambridge, England, at age 74, as a result of a heart condition that he had suffered from for many years. [25] [26] [27] [28] [29] His wife died in 2020 aged 92.
The film "Un fueguito, la historia de César Milstein" was released in 2010. Directed by Ana Fraile, the film was awarded Best Documentary by the Academy of Film in Argentina.
A monoclonal antibody is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Niels Kaj Jerne, FRS was a Danish immunologist. He shared the Nobel Prize in Physiology or Medicine in 1984 with Georges J. F. Köhler and César Milstein "for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies".
In immunology, antiserum is a blood serum containing antibodies that is used to spread passive immunity to many diseases via blood donation (plasmapheresis). For example, convalescent serum, passive antibody transfusion from a previous human survivor, used to be the only known effective treatment for ebola infection with a high success rate of 7 out of 8 patients surviving.
Hybridoma technology is a method for producing large numbers of identical antibodies. This process starts by injecting a mouse with an antigen that provokes an immune response. A type of white blood cell, the B cell, produces antibodies that bind to the injected antigen. These antibody producing B-cells are then harvested from the mouse and, in turn, fused with immortal myeloma cancer cells, to produce a hybrid cell line called a hybridoma, which has both the antibody-producing ability of the B-cell and the longevity and reproductivity of the myeloma. The hybridomas can be grown in culture, each culture starting with one viable hybridoma cell, producing cultures each of which consists of genetically identical hybridomas which produce one antibody per culture (monoclonal) rather than mixtures of different antibodies (polyclonal). The myeloma cell line that is used in this process is selected for its ability to grow in tissue culture and for an absence of antibody synthesis. In contrast to polyclonal antibodies, which are mixtures of many different antibody molecules, the monoclonal antibodies produced by each hybridoma line are all chemically identical.
Georges Jean Franz Köhler was a German biologist.
Sir Gregory Paul Winter is a Nobel Prize-winning English molecular biologist best known for his work on the therapeutic use of monoclonal antibodies. His research career has been based almost entirely at the MRC Laboratory of Molecular Biology and the MRC Centre for Protein Engineering, in Cambridge, England.
In immunology, clonal selection theory explains the functions of cells of the immune system (lymphocytes) in response to specific antigens invading the body. The concept was introduced by Australian doctor Frank Macfarlane Burnet in 1957, in an attempt to explain the great diversity of antibodies formed during initiation of the immune response. The theory has become the widely accepted model for how the human immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens.
HAT Medium is a selection medium for mammalian cell culture, which relies on the combination of aminopterin, a drug that acts as a powerful folate metabolism inhibitor by inhibiting dihydrofolate reductase, with hypoxanthine and thymidine which are intermediates in DNA synthesis. The trick is that aminopterin blocks DNA de novo synthesis, which is absolutely required for cell division to proceed, but hypoxanthine and thymidine provide cells with the raw material to evade the blockage, provided that they have the right enzymes, which means having functioning copies of the genes that encode them.
The Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) is a research institute in Cambridge, England, involved in the revolution in molecular biology which occurred in the 1950–60s. Since then it has remained a major medical research laboratory at the forefront of scientific discovery, dedicated to improving the understanding of key biological processes at atomic, molecular and cellular levels using multidisciplinary methods, with a focus on using this knowledge to address key issues in human health.
The following are notable events in the Timeline of immunology:
The nomenclature of monoclonal antibodies is a naming scheme for assigning generic, or nonproprietary, names to monoclonal antibodies. An antibody is a protein that is produced in B cells and used by the immune system of humans and other vertebrate animals to identify a specific foreign object like a bacterium or a virus. Monoclonal antibodies are those that were produced in identical cells, often artificially, and so share the same target object. They have a wide range of applications including medical uses.
Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.
In immunology, an idiotype is a shared characteristic between a group of immunoglobulin or T-cell receptor (TCR) molecules based upon the antigen binding specificity and therefore structure of their variable region. The variable region of antigen receptors of T cells (TCRs) and B cells (immunoglobulins) contain complementarity-determining regions (CDRs) with unique amino acid sequences. They define the surface and properties of the variable region, determining the antigen specificity and therefore the idiotope of the molecule. Immunoglobulins or TCRs with a shared idiotope are the same idiotype. Antibody idiotype is determined by:
Brigitte Alice Askonas was a British immunologist and a visiting professor at Imperial College London from 1995.
A rabbit hybridoma is a hybrid cell line formed by the fusion of an antibody producing rabbit B cell with a cancerous B-cell (myeloma).
Jerrold Schwaber was an American biologist and geneticist. In 1973 he described, with Edward Cohen, a method of producing antibodies involving human–mouse hybrid cells, or hybridomas. They fused "mouse myeloma cells secreting immunoglobulin of known specificity and human peripheral blood lymphocytes not secreting detectable immunoglobulin. The hybrid cells continued secretion of mouse immunoglobulin and initiate synthesis and secretion of human immunoglobulin." The antibody producing cells did not survive long and the antigens that the antibodies targeted remained unknown. In 1975, Georges Köhler, César Milstein, and Niels Kaj Jerne, succeeded in making hybridomas that made antibodies to known antigens and that were immortalized. They shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. His work in laying the foundation for modern monoclonal antibody technology is recognized.
Elizabeth Marian Press was a British immunologist, best known for her work with Rodney Porter on the structure of antibodies. She worked side by side with Porter for 25 years, at the National Institute for Medical Research, St Mary's Hospital and in the Medical Research Council Immunochemistry Unit, and played a major role in him being awarded the Nobel Prize in 1972.
Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.
Terry William Pearson is a Canadian biochemist, immunologist, educator and biotechnology entrepreneur.
The term hybridoma was proposed by Len Herzenberg during a sabbatical in my laboratory in 1976/1977. At a high-table conversation at a Cambridge College, Len was told by one of the dons that hybridoma was garbled Greek. By then, however, the term was becoming popular among us, and we decided to stick to it.