César Milstein, CH, FRS (8 October 1927 – 24 March 2002) was an

Argentine Argentines, Argentinians or Argentineans are people from Argentina. This connection may be residential, legal, historical, or cultural. For most Argentines, several (or all) of these connections exist and are collectively the source of their ...

biochemist Biochemists are scientists who are trained in biochemistry. They study chemical processes and chemical transformations in living organisms. Biochemists study DNA, proteins and Cell (biology), cell parts. The word "biochemist" is a portmanteau of ...

in the field of

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

research. Milstein shared the

Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, acco ...

in 1984 with Niels Kaj Jerne and Georges J. F. Köhler for developing the hybridoma technique for the production of

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...

Biography

Milstein was born in

Bahía Blanca Bahía Blanca (; English: ''White Bay''), colloquially referred to by its own local inhabitants as simply Bahía, is a city in the Buenos Aires Province, Buenos Aires province of Argentina, centered on the northwestern end of the eponymous Blanc ...

, Argentina. His parents were Máxima (Vanarks) and Lázaro Milstein, a Jewish Ukrainian immigrant. He graduated from the

University of Buenos Aires The University of Buenos Aires (, UBA) is a public university, public research university in Buenos Aires, Argentina. It is the second-oldest university in the country, and the largest university of the country by enrollment. Established in 1821 ...

and obtained a PhD under Professor Stopani (Professor of

Biochemistry Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, a ...

). 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. In 1956, he received an award from the Sociedad Argentina de Investigation eon Bio Quimica (SAIB) for his work on

enzyme kinetics Enzyme kinetics is the study of the rates of enzyme catalysis, enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme' ...

with the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...

. In 1958, funded by the

British Council The British Council is a British organisation specialising in international cultural and educational opportunities. It works in over 100 countries: promoting a wider knowledge of the United Kingdom and the English language (and the Welsh lang ...

, he joined the

Department at the

University of Cambridge The University of Cambridge is a Public university, public collegiate university, collegiate research university in Cambridge, England. Founded in 1209, the University of Cambridge is the List of oldest universities in continuous operation, wo ...

to work for a PhD under

Malcolm Dixon Malcolm Dixon may refer to * Malcolm Dixon (biochemist) (1899–1985), English biochemist * Malcolm Dixon (actor) Malcolm Watson Dixon (1934 – 9 April 2020) was an English actor. He is known for having played the role of Strutter in the 198 ...

on the mechanism of metal activation of the enzyme

phosphoglucomutase Phosphoglucomutase () is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction. More precisely, it facilitates the interconv ...

. During this work, he collaborated with

Frederick Sanger Frederick Sanger (; 13 August 1918 – 19 November 2013) was a British biochemist who received the Nobel Prize in Chemistry twice. He won the 1958 Chemistry Prize for determining the amino acid sequence of insulin and numerous other prote ...

, 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 worked with Georges Köhler (a postdoctoral fellow in his laboratory) to develop the hybridoma technique for the production of

—a discovery recognized by the award of the 1984

Nobel Prize for Physiology or Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute, Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single ...

. 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. Milstein himself made many major contributions to improvements and developments in monoclonal antibody technology—especially in the use of

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. These advances in biology and clinical medicine would take several years to realize their potential. 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 Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

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 Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ami ...

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 Somatic hypermutation (or SHM) is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it (e.g. microbes). A major component of the process of affinity maturation, SHM diversifies B cell receptors used t ...

of immunoglobulin V genes in antibody

affinity maturation In immunology, affinity maturation is the process by which TFH cell-activated B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce ...

. In this process, localized mutation of the immunoglobulin genes allows the production of improved

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

, 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 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, and held 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, was a fellow of

Darwin College, Cambridge Darwin College is a Colleges of the University of Cambridge, constituent college of the University of Cambridge. Founded on 28 July 1964, Darwin was Cambridge University's first graduate-only college, and also the first to admit both men and wo ...

, from 1980 to 2002, awarded the

Louisa Gross Horwitz Prize The Louisa Gross Horwitz Prize for Biology or Biochemistry is an annual prize awarded by Columbia University to a researcher or group of researchers who have made an outstanding contribution in basic research in the fields of biology or biochemist ...

from

Columbia University Columbia University in the City of New York, commonly referred to as Columbia University, is a Private university, private Ivy League research university in New York City. Established in 1754 as King's College on the grounds of Trinity Churc ...

in 1980, he was awarded the Wolf Prize in Medicine in 1980, he won the

Copley Medal The Copley Medal is the most prestigious award of the Royal Society of the United Kingdom, conferred "for sustained, outstanding achievements in any field of science". The award alternates between the physical sciences or mathematics and the bio ...

in 1989, and became a

Member of the Order of the Companions of Honour The Order of the Companions of Honour is an order of the Commonwealth realms. It was founded on 4 June 1917 by King George V as a reward for outstanding achievements. It was founded on the same date as the Order of the British Empire. The orde ...

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 Cambridge ( ) is a List of cities in the United Kingdom, city and non-metropolitan district in the county of Cambridgeshire, England. It is the county town of Cambridgeshire and is located on the River Cam, north of London. As of the 2021 Unit ...

, England, at age 74, as a result of a heart condition that he had suffered from for many years. 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.

References

External links

* *
The Papers of César Milstein
held at

Churchill Archives Centre The Churchill Archives Centre (CAC) at Churchill College at the University of Cambridge is one of the largest repositories in the United Kingdom for the preservation and study of modern personal papers. It is best known for housing the papers ...