Few scientific discoveries have made an impact on so many branches of medicine and biomedical research as that for which César Milstein, who died on March 24th aged 74, won a Nobel Prize for medicine in 1984.
He shared the prize with Georges Kohler for groundbreaking research into the control of the body's immune system. They applied that knowledge to develop a test-tube method for producing a supply of antibodies, the proteins that are produced by the lymphocyte cells of the immune system in response to attacks by foreign bodies, called antigens, that range from infectious bacteria and viruses to the substances to which individuals might be allergic.
There are millions of chemical structures the body has never seen; yet its immune system is able to respond by making the appropriate defensive molecule to detect and destroy the threatening substance. César Milstein and Kohler's invention in 1975 provided a way of manufacturing to order supplies of pure antibodies called monoclonal antibodies. The method was known as the hybridoma technique, and sparked an enormous expansion in the exploitation of antibodies in science and medicine.
Monoclonal antibody production was one of the principal driving forces in the creation of the biotechnology industry. It opened the way for the commercial development of new types of drugs and diagnostic tests in fields as diverse as cancer, the prevention of transplant rejection, pregnancy testing and treatment of arthritis.
César Milstein spent most of his career in Cambridge. He was born on October 8th, 1927, in Bahía Blanca, Argentina, the middle of three sons of a Jewish immigrant father and a teacher, who was herself the daughter of a poor immigrant family. After graduating from Buenos Aires University in chemistry in 1945, he started his research career there in enzymology. In 1958, he went to Cambridge and did a Ph.D, working on the mechanism of an enzyme called phosphoglucomutase.
He returned to Argentina in 1961 but, after two years, when dozens of faculty members were dismissed following the military coup, he resigned his job and went back to Cambridge to work in the division of protein chemistry in the Medical Research Council's laboratory of molecular biology.
On the advice of the head of the laboratory, the Nobel laureate Fred Sanger, César Milstein changed his field of study to begin his groundbreaking work on the synthesis of antibodies.
In order to study the behaviour of the immune system, he and his colleagues wanted to produce long-lived laboratory cell lines that would make antibodies of a known and easily identifiable kind. They knew that antibody-producing cells could be harvested easily from the spleens of mice that had been exposed to a known protein, but these cells would grow only briefly in laboratory cultures.
They also had available cells of a cancer called myeloma that would grow indefinitely in the laboratory and would produce immunoglobulin, the substance of antibody, but would not produce specific antibodies of any kind that could be identified easily.
César Milstein and Kohler decided to fuse cells from tumours of the immune system (myelomas) with antibody-producing B lymphocyte of cells. They found that the combination they created, called a hybridoma, possessed the property of infinite life and could continuously synthesise antibodies. The antibodies produced by this type of hybridoma cell were identical, the same as those produced by the B cell before it was fused.
One of the key characteristics of antibodies is that they are extremely specific; that is, each antibody binds to and attacks one particular antigen. It is that trait that makes monoclonal antibody technology so valuable. This meant that monoclonal antibodies offered a new way of designing drugs to attack disease. Researchers have used them as a form of guided missile against cancer. The antibodies acted as carriers that targeted, for example, specific cancerous cells and then killed them because they were carrying a chemical poison or radioactive agent.
Similarly, they could be equipped with markers and used to help in the diagnosis of a wide variety of illnesses, and to detect the presence of drugs, viral and bacterial products, and other unusual or abnormal substances in the blood, and neutralise them.
César Milstein and Kohler shared the Nobel Prize with Niels Kaj Jerne, a Danish scientist: it was his theories of the immune system that the two researchers developed in their research.
In his acceptance speech to the Nobel Foundation, César Milstein stressed that the hybridoma technology was an unexpected by-product of basic research to understand the immune system. It was, he said, a clear example of the value of investment in research that might not have an obvious immediate commercial relevance.
There was some regret in the 1980s when it was found that the British government's National Research Development Corporation had decided not to attempt to patent the hybridoma technology. It is now the basis of a multi-billion pound industry.
In an interview 25 years ago, César Milstein said that, as a schoolboy in Argentina, he was attracted to science after reading about early microbe hunters like Antoni van Leeuwenhoek and Louis Pasteur. He was elected Fellow of the Royal Society in 1975, and appointed CH in 1995.
In addition to the Nobel Prize, he received the Wolf Prize in Medicine, the Louisa Gross Horwitz Prize from Columbia University, the Royal Society Wellcome Foundation Prize, the Albert Lasker Medical Research Award and the General Motors Cancer Research Foundation Sloan Prize. He was also a foreign associate of the National Academy of Sciences.
César Milstein's wife, Celia, whom he married in 1953 and who survives him, was also an immunologist, and for many years was a collaborator in research.
Pearce Wright César Milstein: born 1927; died, March 2002