By the early 1980s, the question of how the immune system generates diverse Ag receptors of (what we now call) the primary repertoire had been solved: Recombination between different gene segments, V and J or V and J for the Ig L chain and VH, DH, and JH for the H chain, achieves an astounding diversity (1). In contrast, the mechanism of somatic, or intraclonal, diversification of Ag receptors remained mired in controversy. We know now that the diversification of receptors during the growth of a B cell clone is essential for affinity maturation, a defining feature of secondary immune responses. In secondary Ag responses, affinity increases over time as B cells with mutations that improve binding to Ag gain a selective advantage over cells with receptors that contain deleterious mutations or no mutations.

In 1970, Martin Weigert and colleagues came close to proving that somatic mutations diversify Ab receptors (2). At that time, Weigert was a postdoc with Mel Cohn at the Salk Institute. Weigert had learned bacterial genetics from Alan Garen and had picked up crucial knowledge about mutations and protein chemistry. Together, Weigert and Garen had unambiguously determined the base composition of the nonsense codons UAG and UAA (3). When Weigert joined Cohn, they agreed that Darwinian evolutionary principles must also apply to B cell Ag receptors and they passionately confronted the germline hypothesis of Ab diversity. Proponents of the germline hypothesis maintained that B cell immunity might be able to get by with 10,000 different Abs, a repertoire that could be achieved by combining 100 different L chains with 100 different H chains. To counter this deterministic view, Weigert et al.(2) decided to test the idea that Ab mutations are integral to B cell Ag responses.