Professor Cesar Milstein

Born 8th October, 1927 (Bahia Blanca, Argentina) - Died 24th March, 2002 (Cambridge, United Kingdom)

Together with Georges Kohler, Milstein developed the first unlimited supply of monoclonal antibodies, which today underpin many diagnostics and therapeutics. Milstein is the subject of an exclusive exhibition kindly supported by the Medical Research Council. Please go to this page to view the exhibition.

(Photo credit: MRC Laboratory of Molecular Biology)

Family

Milstein was the middle son of three boys born to a Jewish immigrant father who came to Argentina from the Ukraine and an Argentinian mother who was the daughter of immigrants from the Ukraine. His father had started life as a farm labourer and then had become a travelling salesman, while his mother had begun her career teaching and rapidly rose to become a headmistress. During his childhood Milstein became fascinated in science when he read of the adventures in The Microbe Hunters by de Kruif and heard stories from his older cousin trying to develop a vaccine for snake venom. In 1953 Milstein married fellow chemistry graduate Celia Prilleltensky.

Education

In his early years Milstein attended schools in his hometown, Bahia Blanca, including Colegio Nacional. His last year of schooling was spent in Buenos Aires to prepare for university. Milstein completed a chemistry degree in 1952 and a biochemistry doctorate in 1958 at the University of Buenos Aires. Funding his studies by working part-time and undertaking research with only the most basic of equipment, Milstein came close to abandoning his doctorate when to his horror on making an enzyme preparation he broke three of the five expensive flasks in his department. He completed this doctorate in 1957. In 1958 Milstein was awarded a British Council fellowship to study at the University of Cambridge, which resulted in a second doctorate in biochemistry.

Career

In 1961 Milstein took up a prearranged appointment as head of a new Department of Molecular Biology at the National Institute of Microbiology in Argentina, a pioneering institue in Latin America with an infrastructure and scientific base that matched other research institutes in the United States and France. With his work in Argentina thrown into disarray by the political turmoil of a military coup in 1962 Milstein returned to Cambridge in 1963 to work in the newly established Laboratory of Molecular Biology. This move marked a shift in research from enzymes to what would become a lifelong study of the formation and diversity of antibodies. In 1983 Milstein was appointed Head of the Division of Proteins and Nucleic Acids at the Laboratory of Molecular Biology. From 1988 to 1995 Milstein was Deputy Director of the Laboratory of Molecular Biology. In 1987 Milstein was declared Honoary Citizen of the City of Bahia Blanca and received an honorary doctorate from the Universidad Nacional del Sur.

Achievements

Milstein was important in advancing the knowledge of antibodies, notably their structure, expression and diversity. In 1984 he was awarded a Nobel Prize for his development, with Georges Kohler, of monoclonal antibodies in 1975. Developed originally as a tool for basic research, monoclonal antibodies opened up new frontiers in diagnostics and therapeutics for over 50 major diseases. Milstein was at the forefront of showing the applications of monoclonal antibodies for automated cell fractionation, studying cell surfaces, tumours, neuropharmacology, typing blood and tissue for blood transfusion and organ transplants, and laying the groundwork for many current blockbuster drugs.

Milstein is the subject of an exclusive exhibition kindly supported by the Medical Research Council. Please go to this page to view the exhibition.

Cesar Milstein: timeline of key events

Milstein was an Argentinian biochemist. Together with Georges Kohler, Milstein developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 1927-10-08T00:00:00+0000Cesar Milstein studies at the University of Buenos Aires.1945-01-01T00:00:00+0000Milstein investigates the enzyme dehydrogenase for his doctorate under the supervision of Andres Stoppani in the Department of Medicine, University of Buenos Aires1954-01-01T00:00:00+00001957-01-01T00:00:00+0000Milstein's first publication is C. Milstein, and A.O.M. Stoppani, 'Sensibilidad de aldehido deshidrogenasas para reactivos de tioles', An. Asoc. Quimica Argentina, 45 (1957), 33-51.1957-01-01T00:00:00+0000Milstein studies the enzyme phosphoglucomutase under the supervision of Malcolm Dixon and Edwin Webb at the Sir William Dunn School of Biochemistry.1958-01-01T00:00:00+00001961-01-01T00:00:00+0000Milstein heads up the newly-created Department of Molecular Biology, part of the National Institute of Microbiology within the Instituto Malbran.1961-01-01T00:00:00+0000Milstein decides to leave Argentina when the director of the Instituto Malbran and his supporters are dismissed in the wake of the tumoil created by a military coup led by General Raul Poggi.1962-01-01T00:00:00+0000Milstein is awarded a three-year MRC contract, arranged by Fred Sanger, to work at the Laboratory of Molecular Biology.1963-01-01T00:00:00+0000C.M. Milstein, 'Disulphide bridges and dimers of Bence-Jones Protein,' Journal of Molecular Biology, 9 (1964), 836-8.1964-01-01T00:00:00+0000S. Brenner, C. Milstein, 'Origin of antibody variation', Nature, 211 (1966), 242-3.1966-07-16T00:00:00+0000Milstein working with his doctoral student, David Secher, and post-doctoral researcher Dick Cotton, start their hunt for somatic mutants among antibodies. Reported in R.G.H. Cotton, D.S. Secher, C. Milstein, 'Somatic mutation and the origin of antibody diversity, Clonal variability of the immunoglobulin produced by MOPC21 cells in culture', European Journal Immunology, 3 (1973), 135-40. 1970-07-01T00:00:00+0000Kohler hears Milstein present work on myeloma cellular fusions and asks to join Milstein's team in Cambridge1973-01-01T00:00:00+0000Milstein and Cotton's create hybrid cell to study allelenic exclusion in antibodies. Reported in R.G.H. Cotton, C. Milstein, 'Fusion of two immunoglobulin-producing myeloma cells', Nature 244 (1973), 42-3. This work lays the foundation for the later development of monoclonal antibodies.1973-07-06T00:00:00+0000The investigation into somatic mutation lays the basis for the hunt for an antibody which has known specificity for particular antigens.1974-06-01T00:00:00+0000Cesar Milstein, an Argentinian scientist, and Georges Kohler, a German scientist, develop the first long-lasting monoclonal antibodies as part of their basic research project to investigate the mechanism behind the diversity of antibodies. 1975-01-01T00:00:00+0000The Argentinian born scientists Claudio Cuello and Cesar Milstein generate a monoclonal antibody against substance P, a peptide involved in the neurotransmission of pain. This marks the first application of monoclonal antibodies to neuroscience paving the way to an explosion of research into the brain the central nervous system bringing with it better understandings of neurological disease and neuropharmacological intervention. The work is published in A.C. Cuello, G. Galfre, C. Milstein, 'Detection of substance P in the central nervous system by a monoclonal antibody', Proceedings of the National Academy Science, USA, 76 (1979), 3532-6. 1975-01-01T00:00:00+0000Cesar Milstein, with the help of Tony Vickers, submits the monoclonal antibody technique to the British National Development Corporation for patenting,1975-08-07T00:00:00+0000Providing a means to produce limitless quantities of antibodies for the first time, Milstein and Kohler's technique was a major breakthrough. It provided a major tool for unravelling disease pathways, and brought major changes to diagnosis and the treatment of over 50 major diseases. The technique was published in G. Kohler, C. Milstein, 'Continuous cultures of fused cells secreting antibody of predefined specificity', Nature 256 (1975), 495-7. Article highlighted that monoclonal antibodies could be invaluable for medical and industrial purposes. By 1993 the paper had been cited in more than 6,905 publications.1975-08-07T00:00:00+0000Koprowski uses myeloma cells from Milstein's laboratory to generate monoclonal antibodies against tumour antigens. This work forms the basis of the first patent later awarded for monoclonal antibodies.1976-09-01T00:00:00+0000The British National Research Development Corporation executives indicate that they will not pursue a patent the technique for producing monoclonal antibodies because they cannot see what diagnostic application it can be used for or any industrial end-products.1976-10-01T00:00:00+0000American geneticist and biochemist, Leonard Herzenberg and Argentinian biochemist, Cesar Milstein, devise monoclonal antibodies for use on an automatic fluorescence-activated cell sorter, FACS. This improves the reliability of the FACS allowing the instrument to go on to become a major tool not only for cell sorting and cellular biology but the diagnosis of disease. The work is done in collaboration with the American geneticist and immunologist Leonore Herzenberg and Vernon Oi, then a graduate student in genetics at Stanford University. 1977-01-01T00:00:00+0000Cesar Milstein and David Murray from Sera-Lab agree partner to commercially distribute cells for producing monoclonal antibodies to meet the worldwide requests flooding into Milstein's laboratory for access to such cells. 1977-02-01T00:00:00+0000Together with Australian immunologist, the Argentinian biochemist Cesar Milstein and Italian biochemist Giovanni Galfre develop monoclonal antibodies against rat histocompatibility antigens. This research demonstrates the practical applications of monoclonal antibodies for the first time, opening the way to their use for tissue typing for organ transplants. he work is published as A. F. Williams, G. Galfre, C. Milstein, 'Analysis of Cell Surfaces by Xenogeneic Myeloma-Hybrid Antibodies Differentiation Antigens of Rat Lymphocytes', Cell 12 (Nov 1977), 663-73. This paper would go on to cited in more than 1,490 publications by 1993. 1977-04-01T00:00:00+0000Hilary Koprowski, Polish born virologist and Carlo Croce, Italian born geneticist, both based at the Wistar Institute, file for the first US patent for monoclonal antibodies. The antibodies are made against viral antigens using cells supplied from Milstein's laboratory in September 1976. 1977-06-01T00:00:00+0000Argentinian biochemist Cesar Milstein, Italian biochemist Giovanni Galfre, and Australian scientist Alan Williams publish technique for the development of monoclonal antibodies against unknown rat cell surface antigens, predicting it will be possible to make monoclonals against any sort of cell surface molecule. The publication marks the beginning of the major use of monoclonals for understanding cellular function and disease. The article is published as A.F. Williams, G. Galfre and C. Milstein, 'Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: Differentiation antigens of rat lymphocytes', Cell, 12/3 (1 Nov 1977), 663-73.1977-11-01T00:00:00+0000Argentinian biochemist Cesar Milstein and British immunologist Andrew McMichael produce the first monoclonal antibodies that target human T-cells. This lays the foundation for new understandings of the immune responses and disease. While initially rejected for publication, this work is published in A.J. McMichael, J.R. Pitch, J.W. Fabre, David Y. Mason, G. Galfre, 'A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody', European Journal of Immunology, 9/3 (March 1979), 205-210. 1978-01-01T00:00:00+0000Cesar Milstein and Alan Williams generate a monoclonal antibody that targets blood group A cells. 1978-01-01T00:00:00+0000Sera-Lab, a British company specialising in antiserum, issues its first catalogue advertising monoclonal antibody cells from Milstein's laboratory. It represents the first commercialisation of monoclonal antibodies. 1978-02-01T00:00:00+0000Hilary Koprowski, Polish-born virologist, and colleagues granted US patent for monoclonal antibodies against tumour antigens (US Patent 4,172,124). The patent helps in the building of Centocor, the second American biotechnology set up to commercialise monoclonal antibodies. It also causes a major political controversy in Britain as the patent makes broad claims, essentially patenting the technique first developed by Cesar Milstein and George Kohler in 1975.1979-10-01T00:00:00+0000The British scientist, David Secher, based at the Laboratory of Molecular Biology in Cambridge, together with Derek Burke, a British scientist at Warwick University, create the first monoclonal antibody suitable for purifying interferon. This lays the foundation for the use of monoclonal antibodies as tools for the purification of human therapeutic proteins and other natural compounds.1980-01-01T00:00:00+0000Milstein suggests at a Wellcome Foundation lecture that by using genetic engineering scientists might be able to design tailor-made monoclonal antibodies that mimic antibodies made by the human body. This would free them up from a dependence on rodents for producing monoclonal antibodies. He publishes the idea in C. Milstein, 'Monoclonal antibodies from hybrid myelomas: Wellcome Foundation Lecture 1980', Proceedings Royal Society of London, 211 (1981), 393-412.1980-01-01T00:00:00+0000Chaired by Alfred Spinks, the report which examined Britain's state of biotechnology, unfairly singled out Cesar Milstein and his colleagues for the failure. Milstein, however, had approached the National Research Development Corporation to patent the monoclonal antibody technology, but the Corporation failed to take the appropriate action. 1980-02-07T00:00:00+0000Argentinian scientists Cesar Milstein and Claudio Cuello demonstrate the feasibility of monoclonal antibodies for use in radioimmunoassay.1981-01-01T00:00:00+0000Encouraged by Cesar Milstein, collaborative research undertaken by Steven Sacks, Edwin Lennox and Douglas Voak produces monoclonal antibodies suitable for patenting and commercialisation for routine blood typing. 1982-01-01T00:00:00+0000Argentinian scientists Cesar Milstein and Claudio Cuello demonstrate the feasibility of creating bispecific monoclonal antibodies for use in immunohistochemistry, but application for patent, filed in 1983, is abandoned as result of prior patent promoting theory of such a technique. 1983-01-01T00:00:00+0000Developed to treat Gram-negative sepsis, Centoxin originated from research conducted by Henry Kaplan and Nelson Teng based at Stanford University. It was licensed to Centocor, a small biotechnology company in Philadelphia. Following the FDA's request for more information, Centocor watched US$1.5 billion of its market capitalisation disappear. The news also had a devastating impact on other companies developing monoclonal antibody drugs. 1992-02-20T00:00:00+0000Milstein was an Argentinian biochemist. Together with Georges Kohler, Milstein developed the first unlimited supply of long-lasting monoclonal antibodies. Their technique now underpins the development and application of many diagnostics and therapeutics. Kohler and Milstein devised the method as part of their search for a tool to investigate how the immune system can make so many different kinds antibodies, each able to bind to a highly specific receptor on foreign substances that invade the body. 2002-03-24T00:00:00+0000
Date Event People Places
8 Oct 1927Cesar Milstein was born in Bahia Blanca, ArgentinaMilsteinLaboratory of Molecular Biology
1945 - 1945Cesar Milstein studies for a chemistry degreeMilsteinUniversity of Buenos Aires
1954 - 1954Cesar Milstein pursues his first doctorate in biochemistryMilstein, StoppaniUniversity of Buenos Aires
1957The Associacion Quimica Argentina awards Milstein a prize for the best doctoral thesis in chemistry that yearMilsteinUniversity of Buenos Aires
1957 - 1957Cesar Milstein publishes papers from his doctorate with his supervisor Andres StoppaniMilsteinUniversity of Buenos Aires
1958 - 1958Cesar Milstein takes up a British Council Scholarship at Cambridge UniversityMilstein, Dixon, WebbSir William Dunn School of Pathology
1961Cesar Milstein is awarded a second doctorate in biochemistry at Cambridge UniversityMilsteinSir William Dunn School of Pathology
1961Cesar Milstein takes up a position at the Instituto Malbran, Buenos AiresMilsteinInstituto Malbran
1962An Argentinian military coup throws Cesar Milstein's academic work into disarrayMilsteinInstituto Malbran
1963Cesar Milstein returns to Cambridge and begins researching the structure and diversity of antibodiesMilsteinLaboratory of Molecular Biology
1964Cesar Milstein publishes his first paper on antibodiesMilsteinLaboratory of Molecular Biology
July 1966Cesar Milstein and Sydney Brenner publish theory attributing antibody diversity to somatic mutationBrenner, MilsteinLaboratory of Molecular Biology
July 1970Cesar Milstein launches experiments to determine whether somatic mutation underlies antibody diversityCotton, Milstein, SecherLaboratory of Molecular Biology
1973Cesar Milstein meets Georges Kohler at the Basel Institute of ImmunologyKohler, MilsteinBasel Institute of Immunology
July 1973Cesar Milstein and Dick Cotton report the successful fusion of two different myeloma cell lines, one from a mouse and the other from a ratCotton, MilsteinLaboratory of Molecular Biology
June 1974Georges Kohler joins Cesar Milstein's research team to investigate somatic mutation and antibody diversityKohler, MilsteinLaboratory of Molecular Biology
January 1975Unlimited long-surviving monoclonal antibodies createdMilstein, KohlerLaboratory of Molecular Biology
1975 - 1975First monoclonal antibody created to target a neurotransmitter peptideMilstein, CuelloLaboratory of Molecular Biology, MRC Neurochemical Pharmacology Unit, Oxford University
August 1975First step taken to patent Kohler and Milstein's monoclonal antibodiesMilsteinLaboratory of Molecular Biology
7 Aug 1975Cesar Milstein and Georges Kohler published their technique for monoclonal antibodiesKohler, MilsteinLaboratory of Molecular Biology
September 1976Cesar Milstein supplies myeloma cells to Hilary Koprowski at the Wistar Institute for producing monoclonal antibodiesKoprowski, MilsteinLaboratory of Molecular Biology, Wistar Institute
October 1976British government declines to patent monoclonal antibodiesMilsteinLaboratory of Molecular Biology
1977Monoclonal antibodies developed for automatic fluorescence-activated cell sorter Milstein, Herzenberg, OiLaboratory of Molecular Biology, Stanford University Medical School, University of Toronto
February 1977Partnership begun for first commercial distribution of cells for producing monoclonal antibodiesMilstein, Murray 
1977Monoclonals produced against histocompatibility antigensMilstein, Galfre, HowardLaboratory of Molecular Biology, Brabraham Institute
June 1977First US patent application filed for monoclonal antibodiesCroce, Koprowski, MilsteinWistar Institute
1977Monoclonal antibodies made to unknown cell surface antigensMilstein, Galfre, WilliamsLaboratory of Molecular Biology, Sir William Dunn School of Pathology
1978First monoclonal antibodies generated to human T-cellsMilstein, McMichaelLaboratory of Molecular Biology, Oxford University
1978First monoclonal antibody generated for blood typingMilsteinLaboratory of Molecular Biology, Oxford University
February 1978First commercialisation of monoclonal antibodies as laboratory reagentsMilstein, MurrayLaboratory of Molecular Biology, Sera-Lab
October 1979First US patent for monoclonal antibodies grantedKoprowski, MilsteinWistar Institute
January 1980First monoclonal antibody created to purify a human therapeutic protein.Burke, Milstein, SecherLaboratory of Molecular Biology, Warwick University
1980Cesar Milstein proposed the use of recombinant DNA to improve monoclonal antibodiesMilsteinLaboratory of Molecular Biology
1980British government report criticised non-patenting of monoclonal antibody technologyMilstein 
1981First monoclonal antibodies generated for use in radioimmunoassaysCuello, MilsteinLaboratory of Molecular Biology, Oxford University
1982Monoclonal antibodies generated for routine use in ABO blood typingLennox, Milstein, Sacks, VoakLaboratory of Molecular Biology, Addenbrookes Hospital
1983First bispecific monoclonal antibody producedCuello, MilsteinLaboratory of Molecular Biology, Oxford University
February 1992Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, CentoxinSchoemaker, Koprowski, MilsteinCentocor, Wistar
March 2002Cesar Milstein diedMilsteinLaboratory of Molecular Biology

8 Oct 1927

Cesar Milstein was born in Bahia Blanca, Argentina

1945 - 1952

Cesar Milstein studies for a chemistry degree

1954 - 1958

Cesar Milstein pursues his first doctorate in biochemistry

1957

The Associacion Quimica Argentina awards Milstein a prize for the best doctoral thesis in chemistry that year

1957 - 1959

Cesar Milstein publishes papers from his doctorate with his supervisor Andres Stoppani

1958 - 1961

Cesar Milstein takes up a British Council Scholarship at Cambridge University

1961

Cesar Milstein is awarded a second doctorate in biochemistry at Cambridge University

1961

Cesar Milstein takes up a position at the Instituto Malbran, Buenos Aires

1962

An Argentinian military coup throws Cesar Milstein's academic work into disarray

1963

Cesar Milstein returns to Cambridge and begins researching the structure and diversity of antibodies

1964

Cesar Milstein publishes his first paper on antibodies

Jul 1966

Cesar Milstein and Sydney Brenner publish theory attributing antibody diversity to somatic mutation

Jul 1970

Cesar Milstein launches experiments to determine whether somatic mutation underlies antibody diversity

1973

Cesar Milstein meets Georges Kohler at the Basel Institute of Immunology

Jul 1973

Cesar Milstein and Dick Cotton report the successful fusion of two different myeloma cell lines, one from a mouse and the other from a rat

Jun 1974

Georges Kohler joins Cesar Milstein's research team to investigate somatic mutation and antibody diversity

Jan 1975

Unlimited long-surviving monoclonal antibodies created

1975 - 1979

First monoclonal antibody created to target a neurotransmitter peptide

Aug 1975

First step taken to patent Kohler and Milstein's monoclonal antibodies

7 Aug 1975

Cesar Milstein and Georges Kohler published their technique for monoclonal antibodies

Sep 1976

Cesar Milstein supplies myeloma cells to Hilary Koprowski at the Wistar Institute for producing monoclonal antibodies

Oct 1976

British government declines to patent monoclonal antibodies

1977

Monoclonal antibodies developed for automatic fluorescence-activated cell sorter

Feb 1977

Partnership begun for first commercial distribution of cells for producing monoclonal antibodies

1977

Monoclonals produced against histocompatibility antigens

Jun 1977

First US patent application filed for monoclonal antibodies

1977

Monoclonal antibodies made to unknown cell surface antigens

1978

First monoclonal antibodies generated to human T-cells

1978

First monoclonal antibody generated for blood typing

Feb 1978

First commercialisation of monoclonal antibodies as laboratory reagents

Oct 1979

First US patent for monoclonal antibodies granted

Jan 1980

First monoclonal antibody created to purify a human therapeutic protein.

1980

Cesar Milstein proposed the use of recombinant DNA to improve monoclonal antibodies

1980

British government report criticised non-patenting of monoclonal antibody technology

1981

First monoclonal antibodies generated for use in radioimmunoassays

1982

Monoclonal antibodies generated for routine use in ABO blood typing

1983

First bispecific monoclonal antibody produced

Feb 1992

Monoclonal antibodies market crashed following FDA's call for more information for Centocor's drug, Centoxin

Mar 2002

Cesar Milstein died

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