César Milstein

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]

César Milstein
Born(1927-10-08)8 October 1927
Bahía Blanca, Argentina
Died24 March 2002(2002-03-24) (aged 74)
Cambridge, England
NationalityArgentine, naturalised as British
Alma mater
Known forReceiving 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)​
[1]
Awards
Scientific career
FieldsBiochemistry
Doctoral advisorAndrés O.M. Stoppani[3]

Biography

Milstein was born in Bahía Blanca, Argentina. His parents were Máxima (Vapniarsky) and Lázaro Milstein, a Jewish Ukrainian immigrant.[15] He graduated from the University of Buenos Aires and obtained a PhD under Professor Stoppani[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 Investigación en Bioquímica (SAIB) for his work on kinetic studies with the enzyme aldehyde dehydrogenase. In 1958, funded by the British Council, he joined the Biochemistry Department at the University of Cambridge at Darwin College 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.

Career

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 hold three other patents.

Awards and honours

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 Companion 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.

Personal life

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]

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.

See also

References
  1. "Michael Clark, Obituary César Milstein (1927–2002), biochemist.org" (PDF). Archived from the original (PDF) on 23 September 2015. Retrieved 11 February 2013.
  2. Neuberger, M. S.; Askonas, B. A. (2005). "Cesar Milstein CH. 8 October 1927 – 24 March 2002: Elected F.R.S. 1974". Biographical Memoirs of Fellows of the Royal Society. 51: 267–289. doi:10.1098/rsbm.2005.0017.
  3. César Milstein on Nobelprize.org
  4. Horenstein, A. L.; Ferrero, E.; Funaro, A.; Crivellin, F.; Said, M. (2002). "César Milstein, scientist (1927–2002)". Journal of Biological Regulators and Homeostatic Agents. 16 (1): 91–92. PMID 12425336.
  5. Springer, Timothy A (June 2002). "César Milstein, the father of modern immunology". Nature Immunology. 3 (6): 501–3. doi:10.1038/ni0602-501. PMID 12032559. S2CID 29375124.
  6. Springer, Timothy A (May 2002). "Immunology. Retrospective: César Milstein (1927–2002)". Science. 296 (5571): 1253. doi:10.1126/science.1073325. PMID 12016298. S2CID 161691240.
  7. Neuberger, Michael (April 2002). "César Milstein (1927-2002)". Current Biology. 12 (9): R308–10. doi:10.1016/S0960-9822(02)00823-0. PMID 12007427. S2CID 5279668.
  8. Rajewsky, Klaus (April 2002). "Obituary: César Milstein (1927-2002)". Nature. 416 (6883): 806. Bibcode:2002Natur.416..806R. doi:10.1038/416806a. PMID 11976669.
  9. Raju, T N (January 2000). "The Nobel chronicles. 1984: Niels Kai Jerne, (1911–94); César Milstein (b 1926); and Georges Jean Franz Köhler (1946–95)". The Lancet. 355 (9197): 75. doi:10.1016/S0140-6736(05)72025-0. PMID 10615922. S2CID 54392404.
  10. Bolhuis, R L; Haaijman J J (December 1984). "[Nobel Prizes for immunology 1984 (Niels K. Jerne, Cesar Milstein, George Köhler)]". Nederlands Tijdschrift voor Geneeskunde. 128 (52): 2433–5. PMID 6395024.
  11. Kaartinen, M. (1984). "The 1984 Nobel Prize in medicine (Cesar Milstein, George Köhler, Niels Jerne)". Duodecim; Laaketieteellinen Aikakauskirja. 100 (23–24): 1573–1578. PMID 6394268.
  12. Onneby, M. (1984). "Immunology in theory and practice. Nils K Jerne shares the Nobel prize in medicine with Georges JF Köhler and Cesar Milstein". Nordisk Medicin. 99 (11): 300, 304. PMID 6393048.
  13. The Story of César Milstein and Monoclonal Antibodies on WhatisBiotechnology.org
  14. The Papers of César Milstein – Churchill Archives Centre
  15. "conociendo a nuestros científicos" [Meeting our Scientists] (in Spanish). Archived from the original on 27 February 2014. Retrieved 9 December 2015.
  16. Stoppani, A. O. M.; Milstein, C. (1957). "Essential role of thiol groups in aldehyde dehydrogenases". The Biochemical Journal. 67 (3): 406–416. doi:10.1042/bj0670406. PMC 1200171. PMID 13479397.
  17. "César Milstein | Argentine immunologist". Encyclopedia Britannica. Retrieved 17 October 2018.
  18. Milstein, C. (1961). "Inhibition of phosphoglucomutase by trace metals". Biochem. J. 79 (3): 591–596. doi:10.1042/bj0790591. PMC 1205690. PMID 13771002.
  19. Milstein, César (11 October 1999). "The hybridoma revolution: an offshoot of basic research". BioEssays. 21 (11): 966–973. doi:10.1002/(SICI)1521-1878(199911)21:11<966::AID-BIES9>3.0.CO;2-Z. PMID 10517870. 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.
  20. Cuello, A. C.; Galfre, G.; Milstein, C. (1979). "Detection of substance-P in the central nervous system by a monoclonal antibody". Proc. Natl. Acad. Sci. USA. 76 (7): 3532–3536<<<. Bibcode:1979PNAS...76.3532C. doi:10.1073/pnas.76.7.3532. PMC 383862. PMID 386341.
  21. The Story of César Milstein and Monoclonal Antibodies.
  22. Milstein, C.; Clegg, J. B.; Jarvis, J. M. (1967). "C-Terminal half of immunoglobulin λ chains". Nature. 214 (5085): 270–272. Bibcode:1967Natur.214..270M. doi:10.1038/214270a0. PMID 4166495. S2CID 4144338.
  23. Rada, C.; Jarvis, J. M.; Milstein, C. (2002). "AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization". Proc. Natl. Acad. Sci. USA. 99 (10): 7003–7008. Bibcode:2002PNAS...99.7003R. doi:10.1073/pnas.092160999. PMC 124518. PMID 12011459.
  24. espacenet, patents (n.d.). "production of monoclonal antibodies". Retrieved 1 October 2023.
  25. "The Nobel Prize in Physiology or Medicine 1984". NobelPrize.org. Retrieved 10 December 2021.
  26. "César Milstein | Argentine immunologist | Britannica". www.britannica.com. Retrieved 10 December 2021.
  27. "Obituary: César Milstein". the Guardian. 27 March 2002. Retrieved 10 December 2021.
  28. "Cesar Milstein". www.jewishvirtuallibrary.org. Retrieved 10 December 2021.
  29. "Nobel-Winning Biologist Cesar Milstein Dies at 74". The Washington Post.
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