César
Milstein, CH, FRS (8 October 1927 – 24 March 2002) was an Argentine biochemist in the field of antibody research. 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. Milstein
was born in Bahía Blanca, Argentina.
His parents were Máxima (Vapniarsky) and Lázaro Milstein, a Jewish Ukrainian immigrant. He graduated from
the University of Buenos Aires and
obtained a PhD under Professor Stoppani (Professor of Biochemistry). Thereafter, he was a member of the Medical
Research Council Laboratory of Molecular Biology, Cambridge, England, and held
dual Argentine and British citizenship. In 1956, he received an award from
the Sociedad Bioquímica Argentina 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. During
this work, he collaborated with Frederick Sanger whose group he joined with a
short-term Medical Research Council appointment.
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.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, Milstein 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.
Milstein and Cuello's work also enabled the use of monoclonal antibodies to
enhance the power of immuno-based diagnostic tests. 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. 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 recent years was devoted to characterizing this mutational process, with a
view to understanding its mechanism. 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
developed countries. It is also worth mentioning, that even though the Nobel
Prize would have made him a wealthy man, Milstein did not patent his enormous
discovery since he believed that it was mankind's intellectual property.
According to his beliefs, his work did not have any economic interest, only
scientific.