Ontogeny of the clonal selection theory of antibody formation. Reflections on Darwin and Ehrlich.

This is an idiosyncratically personal account of the origins, about 30 years ago, of the clonal selection theory, a no longer controversial integrating theme of immunological research. As an interested participant, the perspectives I can offer are those within my own ken, inevitably an egocentric one. This will unfortunately understate the independent roles played by a host of others, including several in these proceedings. Other historical accounts’*2 may give a more objective view. However, some parts of my story have not been told before. It will be of particular interest to students of the philosophy and socioiogy of science to analyze the processes of resistance and acceptance of clonal selection theory after 1957, until its general acceptance around 1967.3m5 My personal mise-en-scene begins in 1955. I had been at the University of Wisconsin since 1947, having gone there directly from my work in Ed Tatum’s lab at Yale and Francis Ryan’s at Columbia. If I needed any reinforcement about the interest antigens and antibodies would have for general biological theory, I would have received this amply from M. R. Irwin. Ray Owen had left Wisconsin for Caltech just before I arrived, but his intellectual trace was everywhere. However, my own work was strictly confined to the genetics of Escherichia coli and of salmonella. The diversity of serotypes in salmonella had been one of the conceptual clues to genetic recombination in bacteria, and I had at least one experimental contact with immunology, namely, serology of tlagellar and somatic antigens.6 The principal antecedental threads of clonal selection, at least for this microbiologist, were: (1) physicochemical concepts of serological specificity, spanning from Paul Ehrlich to Karl Landsteiner and Linus Pauling; (2) the revalidation of Darwinian models (namely, prior spontaneous mutation and natural selection) in their application to adaptation in microorganisms, such as the development of specific resistance to antibiotics; (3) an emerging understanding of gene expression in protein synthesis, particularly in substrate-induced enzyme synthesis in bacteria; and (4) a developing conception of a genetics of somatic cells by analogy with the genetics of bacteria (Mendelian models). Karl Landsteiner’s “The Specificity of Serological Reactions” focused attention on antigen-antibody reaction as a prototype of biological specificity. Pauling’s chapter in the 1945 edition’ showed how “specificity can arise in the interaction of large molecules as a result of the spatial configuration of the molecules.” The seminal value of this stereochemical axiom was unfortunately not matched by well-founded speculations on the mechanism of antibody synthesis. In the early 1950s there was notably little serious discussion of the mechanism of antibody formation. The most prevalent