S CIENCE’ S C OMPASS 65 RETROSPECTIVE IMMUNOLOGY hybridomas. A huge number of cell surface 64 were soon identified. Milstein, Gal- 63 fré, and Alan Williams produced the first 62 César Milstein (1927–2002) monoclonal against a T lympho- 61 cyte subset antigen, CD4. Len Herzenberg, 60 Timothy A. Springer who had just introduced fluorescence-acti- 59 vated cell sorting to biology, was on sabbati- 58 ésar Milstein, the coinventor with investigate a different immunological prob- cal in Milstein’s lab; the synergy between 57 Georges Köhler of monoclonal anti- lem. They selected myelomas producing dis- sorting and monoclonal immedi- 56 Cbodies, died on 24 March 2002 at the tinctive IgG proteins for their susceptibility ately became apparent. Milstein and 55 age of 74. Monoclonal antibodies form one to various drugs, and fused them together in Jonathan Howard generated the first all 54 of the pillars of modern biotechnology and different combinations. Somatic cell hybrids, specific monoclonal antibodies against the 53 are indispensable tools for biomedical re- selected on the basis of their drug resistance, rat major histocompatibility complex. With 52 search. They are also used extensively in di- secreted Ig types from both Andrew McMichael, he 51 agnostics, including everyday applications myeloma parents. The fact obtained the first mono- 50 such as home pregnancy test kits. Some that the variable and constant clonal antibody to a human 49 have been approved for use as drugs, bene- regions of the two different leukocyte differentiation 48 fiting more than a million patients with can- antibodies were not inter- antigen, CD1. Milstein and I 47 cer, rheumatoid arthritis, and heart disease. mixed suggested that they had made the first monoclonal 46 Milstein received his first Ph.D. in bio- been joined at the DNA rather Image not antibodies to cell adhesion 45 chemistry from the Universidad de Buenos than the RNA level. molecules. In collaboration 44 Aires, Argentina, in 1957, and his second Köhler arrived in Mil- available for with Claudio Cuello, he 43 from the in 1960. stein’s lab with the idea of online use. worked on the immunocyto- 42 Working with Fred Sanger in Cambridge, he screening for in chemistry of the nervous 41 identified amino acid sequences in enzyme the antigen-combining sites system, and with Herman 40 active sites. After a 2-year stint back in Ar- of myeloma IgGs using anti- Waldmann on making anti- 39 gentina, he joined Sanger and others under gens. However, there were bodies to human hematopoi- 38 the chairmanship of Max Perutz at the re- only a few myeloma cell etic cell antigens. One of 37 cently created Medical Research Council lines secreting antibodies that these was “humanized” by 36 (MRC) Laboratory of Molecular Biology. bound to antigen, and these cell lines failed Greg Winter and was subsequently approved 35 Milstein decided to work on a hot new top- to grow. Frustrated, Köhler and Milstein hit as a therapeutic for treating chronic lym- 34 ic—the molecular basis of antibody diversity upon an ingenious idea. They made their phoblastic leukemia. 33 and specificity. His early interest in somatic own antibody-secreting cells by fusing Despite Milstein’s efforts, monoclonal 32 hypermutation as a mechanism for generating myeloma cells with lymphocytes from ani- antibodies were never patented. Prime 31 antibody diversity was the impetus that led mals immunized with a specific antigen. In Minister Thatcher, a chemist herself, was 30 him to invent monoclonal antibodies. He ob- the resulting hybrid cells, the immune lym- reported to have criticized this bureaucrat- 29 tained early evidence for the variable and con- phocyte parent contributed the specific anti- ic failure under her predecessor’s watch. 28 stant