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date: 07 March 2021

Milstein, Césarfree

(1927–2002)
  • David Secher

César Milstein (1927–2002)

by Nick Sinclair, 1993

Milstein, César (1927–2002), molecular biologist and immunologist, was born on 8 October 1927 in Bahía Blanca, a provincial town in Argentina, the second of three sons of Lázaro Milstein, a salesman who had travelled to Argentina at the age of fourteen as a Jewish immigrant from the Ukraine before the First World War, and his wife, Máxima, also from a poor immigrant family, who was a schoolteacher and headmistress. The family lived in the teacher's house in Bahía Blanca and were active in the local Jewish community, but not religious. Though Milstein rarely entered a synagogue, he was proud of his Argentinian Jewish origins.

Education and early research

As a child Milstein was bright, but neither precocious nor particularly interested in school. His parents had to coax and bribe him through his studies, since he would rather have been exploring the countryside. His mother encouraged his interest in reading, by providing adventure stories, novels, and, significantly, Microbe Hunters (1926) by Paul de Kruif. An older cousin from the vaccine institute in Buenos Aires visited the Milsteins when César was nine or ten years old. She worked on the production of anti-sera to snake venom and her descriptions fascinated the young boy. Nevertheless this interest in immunology lay dormant for many years, while he pursued his studies in chemistry.

After the Colegio Nacional, Bahía Blanca (1939–44), Milstein moved to Buenos Aires to complete his secondary education and then (from 1945) studied at the university there. It was while he was an undergraduate that he met his future wife, Celia Prilleltensky, at a student political meeting. With her he shared a developing interest in social and political issues. Having been a strongly anti-Peronist president of the student union, Milstein risked attracting the unwelcome attention of the military government. To support himself during his studies, he worked part time at the Laboratorios Liebeschutz, a clinical biochemistry laboratory. This is where, he later said, he learnt to organize his time, work carefully, and understand the accuracy and limitations of the scientific methods used. During his final year at university he had an accident that delayed his graduation. At a faculty picnic, he dived into a shallow river and hit a log. Serious damage to his pancreas entailed rest for several months. However, on return to university he found himself working on a laboratory bench next to Celia's. They both graduated in chemical sciences in 1952 and married the following year before setting off to tour Europe for what they intended to be a two- to three-month honeymoon. In fact, they managed to extend the trip to a year. According to Celia, when people enquired why they had not travelled to England on that trip, Milstein answered with confidence that England would be the place where he would go to work after his PhD.

Milstein applied to study for a PhD under the Argentinian Nobel prize-winner Luis Leloir. However, Leloir was unable to find space for Milstein and referred him to Andres Stoppani, an enzymologist in the University of Buenos Aires. By 1954, following his European trip, the political environment had improved and Milstein managed to start serious work on his thesis. The work he did for his PhD—a study of the roles of metals and sulphur in an enzyme (aldehyde dehydrogenase)—won him a prize from the Argentinian Chemical Society in 1958 for the best thesis of the previous year.

Later in 1958, by now a staff member of the Instituto Nacional de Microbiología in Buenos Aires, Milstein won a British Council travelling scholarship. On the recommendation of Stoppani, he chose to work with Malcolm Dixon in the University of Cambridge department of biochemistry. The department provided an outstanding environment for biochemical research in the late 1950s. Fred Sanger, Dorothy Needham, Peter Mitchell, and Robin Hill were producing exciting—and often controversial—discoveries. Milstein was strongly influenced by Sanger, who had just won his first Nobel prize, for determining the structure of insulin. Using Sanger's methods and radio-isotope labelling, Milstein identified the active site of the enzyme phosphoglucomutase, and showed that the description of the active site previously published by Daniel Koshland's group in the USA was wrong.

In 1961, with a second (Cambridge) PhD, Milstein declined Sanger's invitation to remain in Cambridge, and returned to Buenos Aires as the first head of a division of molecular biology in the Instituto Nacional de Microbiología. Within a short time of arriving back in Buenos Aires, he produced exciting biochemical results on yet another enzyme. However, a military coup soon threw the country into turmoil again, and political interference in the running of the institute led to the dismissal of the director and other scientists. Despite support from Leloir, Milstein felt that his position was untenable and resigned in solidarity with his colleagues. He wrote to Sanger in Cambridge, who by then had moved to the Medical Research Council (MRC) Laboratory of Molecular Biology. Sanger immediately offered Milstein a three-year contract. In 1963 he returned to Cambridge and joined a team that brought together the cream of British molecular biologists (Sanger, Francis Crick, John Kendrew, and Hugh Huxley) with foreign scientists who had gone there as refugees from politically extreme regimes (Max Perutz, Sydney Brenner, Aaron Klug, and Milstein himself).

Research on antibodies

Sanger steered Milstein towards antibodies, the blood proteins involved in immunity. Rodney Porter (a former student of Sanger) and Gerald Edelman had recently established the basic four-chain structure of antibody molecules (two ‘heavy’ protein chains and two ‘light’ chains, linked together by sulphur bonds). The more detailed structure of antibodies was a key topic of the time and Milstein soon became a leading figure in the field. His first publication was on the structure of the di-sulphide bonds of an antibody ‘light’ chain. This work was done with the technical assistance of John Jarvis, who remained Milstein's research assistant for the next forty years. A series of important papers followed, the result of collaborations with his wife, Celia, his first Cambridge PhD student, Richard Pink, and an Argentinian postdoctoral visitor from New York, Blas Frangione. These papers described the key features of the detailed structure of antibody proteins. Milstein grew particularly interested in the mechanism by which the genes of a single person produce millions of different antibodies, each specific to a particular infectious agent or foreign substance. In an article published in Nature in 1966, co-written with Sydney Brenner, Milstein postulated a molecular mechanism for generating antibody diversity. During the 1960s he enjoyed being at the centre of an international debate with more established scientists. The key issue was whether the enormous diversity of antibody molecules in the blood was reflected in the human genome, or whether, as Milstein correctly predicted, an (unknown) special mechanism was able to generate the millions of antibodies from a small number of genes. Brenner and Milstein enjoyed referring to this postulated mechanism as the 'generator of diversity' (GOD).

Milstein explored his hypothesis by shifting attention from the structure of antibody proteins to the genes (DNA) that code for them. With Terry Rabbitts, whom he recruited from the University of Edinburgh, he used and developed emerging technology to count the number of genes involved. While others went on to use the new DNA technology of the 1970s to investigate the molecular arrangement and rearrangement of antibody genes, Milstein focused on the mutational mechanisms that underlie both the diversity of antibody molecules and the way in which the antibody response of a person to infection ‘matures’ and strengthens. The mechanism of this phenomenon, which underpins the success of vaccination, had been studied since the pioneering days of Edward Jenner. However it was still unexplained, at the molecular level, in the 1970s.

In the course of studying the antibody proteins and the genes that code for them, Milstein, working with other colleagues in the MRC laboratory, noticed that the antibody proteins were sometimes made in a longer form, which was then converted into the normal size, by removal of a short section at one end of the protein. They coined the term ‘signal peptide’ for the piece that was removed and wrote a paper that was published in Nature in 1972. Independently—and unknown to Milstein—a group in New York were working in a parallel direction. The New York work—but not the Cambridge discovery—was recognized in the award of a Nobel prize to Günter Blobel some twenty-seven years later.

Milstein continued to seek out innovative experimental techniques to shed new light on the antibody diversity problem. In 1970 he was joined by a new research student, David Secher, whose PhD work involved screening 7000 different ‘clones’ of antibody-producing cells for spontaneously arising mutants. Milstein had suggested that a study of such mutants could shed light on the normal mechanisms of antibody production in human blood cells. The mutants that were identified were the first of their kind to be characterized, but turned out not to be relevant to the diversity problem. An Australian postdoctoral visitor, Richard Cotton, who later joined the group, was also involved in this work, and, with the help of Abraham Karpas, developed cell fusion techniques in Cambridge.

These various technological advances all came together shortly after Georges Köhler, a German postdoctoral fellow, joined the group in 1974. Köhler and Milstein discovered how to fuse mouse spleen cells to a cell line derived from a mouse tumour, creating new cells (later named 'hybridomas') that produced monoclonal antibodies. These pure antibodies could, for the first time, be manufactured in large quantities and to a defined and consistent specification. The purpose of the experiment was pure, basic research, driven by intellectual curiosity. However, the commercial potential, which was recognized in the final sentence of their paper published in Nature in 1975, turned out to be enormous. The scientific importance of this discovery was recognized by the award of the 1984 Nobel prize for physiology or medicine to Milstein and Köhler, together with Niels Jerne, who had laid the theoretical foundation for part of their work. Less widely known at the time was that shortly after the manuscript was submitted for publication, the experiments stopped working. Milstein even considered retracting the paper. By then Köhler had returned to Switzerland and a new Italian postdoctoral fellow, Giovanni Galfré, was given the task of getting the experiments working again. Working with Milstein, Galfré not only did this quickly, but also improved the method and made it more reliable. Many of the early successes in making important monoclonals were obtained under Galfré's supervision.

Monoclonal antibodies and the biotechnology industry

Much has been written about the failure to patent monoclonal antibodies. While it was the scientific potential of the discovery that interested him most, Milstein also wanted to see the commercial and clinical potential realized. He was extremely loyal to the MRC and had submitted his manuscript for commercial consideration, despite his personal left-wing political and social views, which naturally led him to question the growing tendency for research results of commercial potential not to be shared, freely and without restriction, throughout the scientific community. Margaret Thatcher, as prime minister, later criticized Milstein and the MRC for not applying for a patent. He felt that the criticism directed at him was groundless and that he had been let down by 'the bureaucracy'. (At that time the National Research Development Corporation had a monopoly over MRC inventions.)

Notwithstanding his many subsequent honours and the public recognition of his service, Milstein was often described, in the media and elsewhere, as 'the man who failed to patent monoclonals'. This hurt him, as he felt that he had done everything he could to bring his employer's attention to the possibility of patenting his invention. It was a great disappointment to him that he was not more actively defended and he hoped that one day a correct account of this episode would exonerate him. Towards the end of his life commentators began to question whether the patenting of monoclonals would indeed have resulted in billion-dollar profits, benefiting the UK economy. The business of technology transfer from academic laboratories existed only in embryonic form in 1975. Patenting offices had been set up in only four UK universities (as compared to more than 100 by the time of his death). Applying for a patent would have been the first step, but the business development and licensing expertise, and the will and the funds to pursue and protect the patent rights aggressively, would have taxed a major pharmaceutical company, let alone an inexperienced research council. Furthermore, the profits from monoclonals followed only some twenty-five to thirty years after the invention, by which time any original patents would have expired. When, in 1980, David Secher, collaborating with Derek Burke, produced a monoclonal antibody of clinical and commercial importance for the production of interferon, Milstein encouraged Secher's attempts to patent and commercialize this invention, despite continued lack of support by the MRC. As a result, the MRC received multi-million-pound royalties on sales of Anti-interferon from the biotechnology company Celltech. Milstein himself collaborated with colleagues in Cambridge, Oxford, and overseas on a wide variety of projects to develop new monoclonal antibodies of practical research or clinical use. These included antibodies for blood typing (with Edwin Lennox), to rat transplantation antigens (Jonathan Howard), to cell surface markers of rodents (Alan Williams, Timothy Springer, Herman Waldmann), and to brain peptides (Claudio Cuello).

Used as tools in research, monoclonals now allow biological systems to be analysed and dissected with exquisite specificity. In hospital laboratories and in home pregnancy kits, for example, monoclonals are used to measure blood levels of hormones and proteins. Labelled with radio-isotopes, monoclonals can image and locate tumours. Coupled to drugs or radio-isotopes, they can be used as ‘magic bullets’ to deliver a lethal dose to cancer cells. Herceptin, used in the treatment of breast cancer, is a monoclonal antibody. Other monoclonals are used to treat rheumatoid arthritis (Humira), leukaemia (Campath), and to prevent viral infections (Synagis). Towards the end of his life Milstein derived great satisfaction from the fact that, despite the lack of an early patent, an annual multi-million-pound royalty revenue began to flow into the MRC and the Cambridge laboratory. This resulted largely from the later developments of monoclonal technology from Greg Winter's work, much of it in collaboration with Milstein.

The invention of monoclonals became one of the two pillars of the biotechnology industry. (The other was recombinant DNA technology.) Milstein took a close interest in the development of his invention from laboratory to billion-dollar industry and he helped many biotechnology companies. He also collaborated freely with other scientists on the application of the invention to scientific research and to medicine. But his real interest lay in understanding how the immune system works and in particular how each individual is able to make millions of different antibodies. It was his passion to elucidate the role of mutation in creating antibody diversity that had led him to discover monoclonal antibodies in 1975, and it was to this that he successfully returned in the 1990s when the distractions of post-Nobel euphoria had subsided.

In this next phase of his research Milstein worked with his research group in Cambridge and in collaboration with scientists in Finland and Munich. He continued to seek out and develop new techniques, with his characteristic knack of knowing just when to persevere and when to change tack. In the last ten to fifteen years of his life, he enjoyed a collaboration with Michael Neuberger and several of their respective students and postdoctoral fellows. They discovered that mutation mechanisms similar to those that Milstein and Brenner had postulated in 1966 do indeed play a role in generating antibody diversity, and in his last published paper, submitted shortly before his sudden and untimely death, Milstein postulated (correctly) that a protein recently identified by Japanese and French scientists acted in the cell nucleus to cause diversity-generating mutation.

Honours, retirement, and private life

In addition to the Nobel prize, Milstein was awarded a host of international prizes and honours, including the Royal and Copley medals of the Royal Society. He had been elected a fellow of the Royal Society in 1975 and became a Companion of Honour in 1995. He was a fellow of Darwin College, Cambridge, and an honorary fellow of Fitzwilliam College, where he had studied as a research student. After official retirement in 1995 he stood down as head of division and deputy director of the Laboratory of Molecular Biology. Nevertheless he continued to pursue his research with vigour, publishing more than twenty-five further scientific articles and working in the laboratory until the last. In July 2000 the MRC organized a conference in London to celebrate the twenty-fifth anniversary of the discovery of monoclonals. It gave Milstein great pleasure to see this recognition of his work by the MRC. His daily routine was unchanging and had included, until his retirement, Saturday mornings in the laboratory. Even on his fiftieth birthday (a Saturday) his young co-workers were able to count on being able to surprise him with champagne on ice, waiting on his laboratory bench.

Outside the laboratory Milstein was equally good company. Short and wiry, he never lost his strong Argentinian accent and his hesitant style of spoken English. (This belied an ability to write English with a fluency and clarity that served as a model for generations of his students and colleagues.) He had views on everything: politics, theatre, literature (both Spanish and English), music, and food—and he would talk at length and with authority about all of these. He loved cooking and eating, opera and theatre, travelling, walking, and skiing. When cardiovascular problems were diagnosed in middle age, he adapted to the challenges of a new lifestyle with none of the misery that would have sent others into depression. Whole-animal, gaucho-style barbecues were replaced by cholesterol-free paellas. The best London restaurants and Cambridge high tables were challenged to be creative without straying from his strict diet sheet. He became a familiar figure in Hills Road, Cambridge, walking round the neighbourhood with his dog and his headphones, listening to the latest Radio 4 news. As his stamina improved, the walks lengthened and he would dictate research papers into his recorder or hold discussions with a student or colleague—or both simultaneously. He was fortunate to live so close to Papworth Hospital, a leading centre of cardiac surgery, and his cardiologist, Andrew Grace, fondly boasted that his greatest contribution to science was in keeping Milstein alive. Milstein refused to allow his health problems to deter him. In retirement he pursued ever more adventurous trips: navigating the waterways of East Anglia in his motor cruiser, sailing in the Aegean, and white-water rafting in Chile.

Despite many invitations to return permanently to Argentina, Milstein was proud of his adopted British nationality and determined to remain in the UK. He was much in demand and generously shared his time. He particularly enjoyed encouraging and supporting the development of young scientists and travelled widely to Argentina, Spain, Thailand, and elsewhere, until a few months before his death. For nearly fifty years he and Celia shared a love of science and life—and a perfect marriage. To generations of students, visitors, and friends, their home in Cambridge was always open and a stimulating and fun place to visit. Though they had no children, Milstein was a scientific father to a dynasty of molecular biologists, scattered throughout the world.

Milstein died on 24 March 2002 at Addenbrooke's Hospital, Cambridge, of heart failure, and his remains were cremated in Cambridge; he was survived by his wife, Celia. He was one of the best loved and most important scientists of the twentieth century. He was part of the tradition of assimilating foreign genius into the British academic community and his achievements vindicated the (later less fashionable) policy of identifying and supporting research talent with long-term funding, without a requirement to demonstrate short-term accountability and achievement. While he will always be remembered as the inventor of monoclonal antibodies, his scientific legacy spanned more than four decades of continuous insight into the molecular mechanisms that defend all vertebrates (including humans) against infection and disease.

Sources

  • C. Milstein, ‘From the structure of antibodies to the diversification of the immune response’, Nobel lectures, physiology or medicine 1981–1990, ed. T. Frängsmyr and J. Lindsten (1993) [Nobel lecture, www.nobelprize.org/medicine/laureates/1984/milstein-lecture.html, accessed 1 Aug 2005]
  • ‘César Milstein: autobiography’, www.nobelprize.org/medicine/laureates/1984/milstein-autobio.html, 1 Aug 2005
  • ‘César Milstein, 1927–2002’, www2.mrc-lmb.cam.ac.uk/Cesar_Milstein.html, accessed 1 Aug 2005
  • The Times (26 March 2002)
  • Daily Telegraph (26 March 2002)
  • The Guardian (27 March 2002)
  • The Independent (27 March 2002)
  • T. Springer, ‘César Milstein, the future of modern immunology’, Nature Immunology, 3 (2002), 501–3
  • M. Neuberger and B. Askonas, ‘César Milstein’, Memoirs FRS, 51 (2005), 267–89
  • personal knowledge (2006)
  • private information (2006)
  • d. cert.

Archives

Film

  • MRC Laboratory of Molecular Biology, Cambridge, interview with D. Secher, 2001

Sound

  • BL NSA, ‘In exile: César Milstein’, interview with J. Steinberg, B5555/12

Likenesses

  • G. Argent Studio, photograph, 1977, RS
  • double portrait, photograph, 1980 (with A. R. Todd), RS
  • B. Thuresson, double portrait, photograph, 1984 (with G. Köhler), Getty Images, London
  • N. Sinclair, bromide print, 1993, NPG [see illus.]
  • obituary photographs
  • photograph, repro. in nobelprize.org/medicine/laureates/1984/milstein-autobiog.html
  • photographs, repro. in www2.mrc-lmb.cam.ac.uk/cesar-milstein.html

Wealth at Death

£753,719: probate, 20 Feb 2003, CGPLA Eng. & Wales

British Library, National Sound Archive
National Portrait Gallery, London
(1849–)
Royal Society, London
Churchill College, Churchill Archives Centre, Cambridge