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 focussing 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 was born in Argentina where he started his research career at the University of Buenos Aires in enzymology, working with Prof A Stoppani on aldehyde dehydrogenase. In 1958, he came to Cambridge, funded by the British Council, to work with Malcolm Dixon in the Biochemistry Department. Here he did a PhD, working on the mechanism of metal activation of phosphoglucomutase. He then returned to Argentina but, after two years, resigned his job there as a result of the political situation and came back to Cambridge in 1963 to work in the Division of Protein Chemistry in the MRC Laboratory of Molecular Biology. It was at this stage that, following the advice of Fred Sanger, Milstein changed his field of study from enzymes to antibodies.
Milstein's early work on antibodies focussed 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 the 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.
Information on César's Nobel Prize in 1984
Obituaries