César Milstein, 1927-2002

A Fellow of Darwin College and Honorary Fellow of Fitzwilliam College, Cambridge, Milstein was one of the leading figures at the Medical Research Council's Laboratory of Molecular Biology, where he was Deputy Director from 1988 until 1995.

Dr David Secher, Director of the Research Services Division at the University of Cambridge and a former colleague of César Milstein, here pays tribute to this influential Cambridge scientist.

César Milstein was one of the best-loved and most important scientists of the 20th century. He was part of the tradition of assimilating foreign genius into the British academic community and his achievements vindicate the policy of identifying and supporting research talent with long-term funding. His most famous contribution to science was the invention of monoclonal antibodies, for which he and Georges Köhler shared the 1984 Nobel Prize in Physiology or Medicine, together with Niels Jerne, who had laid the theoretical foundation for part of their work.

Milstein was born in 1927 in Bahia Blanca, Argentina, the middle of three sons. His father was a salesman, his mother a schoolteacher. His family were active in the local Jewish community but non-religious. Though he rarely entered a synagogue, César Milstein was proud of his Argentinian Jewish origins. As a child he was bright, but neither precocious nor particularly interested in school. His parents had to coax and bribe him through his studies, because he would rather have been exploring the countryside or travelling abroad.

An older cousin, from Buenos Aires, visited the Milsteins when César was nine or 10 years old. She worked on the production of anti-sera to snake venom and her descriptions fascinated the young boy. He recently recalled this first interest in immunology - an interest that lay dormant while he pursued studies in chemistry.

He moved to Buenos Aires to complete his secondary education and then studied at Buenos Aires University, where he was awarded his BSc in chemistry and PhD. The latter - a study of the roles of metals and sulphur in an enzyme (aldehyde dehydrogenase) - was conducted in the laboratory of Andres Stoppani, an enzymologist to whom he had been referred by the Argentinian Nobel prizewinner Luis Leloir.

In 1958 Milstein, by now a staff member of the National Microbiological Institute, won a British Council travelling scholarship. He chose to work with Malcolm Dixon in Cambridge's Department of Biochemistry. Here Milstein was strongly influenced by Fred Sanger, who had just won his first Nobel Prize, for determining the structure of insulin.

In 1961, with a second PhD on another enzyme, phosphoglucomutase, Milstein returned to Buenos Aires as head of a division of molecular biology in his old institute. Within a short time, political interference in the running of the institute forced him to resign and he returned to Cambridge at the invitation of Sanger, who had by then moved to the MRC Laboratory of Molecular Biology. Milstein joined the magical team of scientists that brought together the cream of British molecular biologists (Crick, Sanger, Kendrew, Huxley) with foreign scientists who had come from politically extreme regimes (Perutz, Brenner, Klug, Milstein).

Sanger steered Milstein towards antibodies, the blood proteins involved in immunity. The structure of antibodies was a "hot" topic of the time and Milstein soon became a leading figure in the field. He 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.

Milstein sought out innovative experimental techniques to shed new light on the problem. He collaborated with George Brownlee on RNA, with Richard Cotton on cell fusion and with David Secher on mutation in antibody genes. These threads all came together shortly after Georges Köhler, a German postdoctoral fellow, joined the group. 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 produce monoclonal antibodies. These pure antibodies could, for the first time, be manufactured in large quantities and to a defined and consistent specification. Although the purpose of the experiment was basic research, the commercial potential was recognised in the final sentence of their publication in Nature in 1975.

Much has been written about the failure to patent monoclonal antibodies. Margaret Thatcher, as Prime Minister, criticised Milstein and the MRC's failure to apply for a patent. Whilst it was the scientific potential of the discovery that interested him most, Milstein also wanted to see the commercial and clinical potential realised. He was extremely loyal to the MRC and had submitted the manuscript for commercial consideration. He felt that the criticism 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 the many subsequent honours and public recognition of his service, he hoped that one day a correct account of this history would be written.

Monoclonal antibodies have revolutionised the way in which biologists view living systems. Used as research tools, they allow biological systems to be analysed and dissected with exquisite specificity. But they have become much more than research reagents. In hospital laboratories and in home pregnancy kits, for example, monoclonals are used as diagnostics to measure blood levels of hormones and proteins. Labelled with radio-isotopes, monoclonals can image and localise cancers and, coupled to drugs or isotopes, they can be used as "magic bullets" to deliver a lethal dose specifically to cancer cells. Herceptin, recently recommended for the treatment of breast cancer in the NHS, is a monoclonal antibody; other monoclonals are used to treat rheumatoid arthritis and to prevent viral infections.

That invention became one cornerstone 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 this that had led him to discover monoclonal antibodies and it was to this that he successfully returned in the 1990s when the distractions of the post-Nobel euphoria had subsided.

In addition to the Nobel Prize, he was awarded a host of international prizes and honours; he was elected a Fellow of the Royal Society in 1975 and appointed 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 "retirement" in 1995, Milstein continued to pursue his research with vigour, publishing more than 25 scientific articles and working in the laboratory until the last. In July 2000 the MRC organised a conference in London to celebrate the 25th anniversary of the discovery of monoclonals. It gave Milstein great pleasure to see this political recognition of his work, but the event also showed that the authoritative history of this important lesson in technology transfer still needs to be written. Fortunately there is a video recording of this event and also a long autobiographical interview commissioned by the Laboratory of Molecular Biology last year.

Milstein's daily routine was unchanging and included, until his retirement, Saturday mornings in the laboratory. Even on his 50th birthday (a Saturday), his young co-workers were able to count on being able to surprise him with champagne on ice, waiting on hi
s laboratory bench.

Outside the laboratory Milstein was equally stimulating to be with. 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, travelling, walking and skiing. When cardiovascular problems were diagnosed in middle age, he adapted to the new challenges in life style with none of the misery that might have sent others to the anti-depressant bottle. Whole-animal gaucho-style barbecues were replaced by cholesterol-free paellas, and 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, 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 Dictaphone or hold discussions with a student or colleague, or both simultaneously.

Milstein was lucky to live so close to Papworth Hospital, a leading centre of cardiac surgery, and his surgeon fondly boasted that his contribution to science was in keeping Milstein alive. He refused to allow his health problems to deter him. Even 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.

For nearly 50 years he was married to Celia, whom he had met at a student political meeting in Buenos Aires and with whom he shared his love of science and life. To generations of students, visitors and friends, their home in Cambridge was always open and theirs was the perfect marriage. He was much in demand and in recent years he generously gave of his time, encouraging and supporting the development of young scientists in less developed countries.

Although they had no children, César Milstein was a scientific father to a dynasty of molecular biologists, now scattered throughout the world.

David Secher

César Milstein, molecular biologist: born Bahia Blanca, Argentina 8 October 1927; staff, Instituto Nacional de Microbiologia, Buenos Aires 1957-63, Head of Division of Molecular Biology 1961-63; staff, MRC Laboratory of Molecular Biology 1963-95, Head of Sub-division of Protein Chemistry 1969-80, Head of Sub-division of Molecular Immunobiology 1980, Joint Head, Division of Protein and Nucleic Acid Chemistry 1981-93, Deputy Director 1988-95; FRS 1975; Fellow, Darwin College, Cambridge 1981-95 (Emeritus); Nobel Prize for Physiology or Medicine 1984; CH 1995; married 1953 Celia Prilleltensky; died Cambridge 24 March 2002.

Reproduced by permission from The Independent, Obituaries, 27 March 2002.