César Milstein

César Milstein (October 8 1927 – March 24 2002) was an Argentine biochemist in the field of antibody research. Milstein shared the Nobel Prize in Physiology or Medicine in 1984 with Niels K. Jerne and Georges Köhler.

Biography
Milstein was born in Bahia Blanca, Argentina. He graduated from the University of Buenos Aires and obtained a PhD under Professor Stoppani (Professor of Biochemistry) in the Medical School 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 to work for a PhD under Malcolm Dixon on the mechanism of metal activation of the enzyme phosphoglucomutase. During this work he collaborated with Frederick Sanger whose group he joined with a short-term Medical Research Council appointment.

Career
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, together with Georges Köhler (a postdoctoral fellow in his laboratory), developed the hybridoma technique for the production of monoclonal antibodies - a discovery recognised 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.

Milstein himself made many major contributions to improvements and developments in monoclonal antibody technology - especially focusing on the use of monoclonal antibodies to provide markers that allow distinction between different cell types. He also 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.

Milstein's early work on antibodies focused on the nature of their diversity at the amino acid level as well as on the disulphide 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. The development of the hybridoma technology coupled to advances in nucleic acid sequencing then 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, localised 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 recent years was devoted to characterising this mutational process with a view to understanding its mechanism and, indeed, he contributed a manuscript 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 well developed countries.

He was elected a Fellow of the Royal Society in 1975, 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.

Milstein died early on 24 March, 2002 in Cambridge, England at age 74 as a result of a heart condition from which he had suffered for many years. ...