Diversity and the genesis of high affinity antibodies.

My only claim to any connection with Sir Frederick Gowland Hopkins goes no further than being the last of the Argentinian biochemists who came to the Department of Biochemistry at Cambridge while several of its members were still those appointed by him. As from now, I will be able to claim a more direct connection, and I am grateful to the Biochemical Society for such an honour. I am not aware that Hopkins was particularly interested in antibodies. This is not surprising, since in his time vitamins, hormones and enzymes were more exciting biochemical subjects. Yet. it was the time when Landsteiner was publishing his seminal papers on the specificity of antibodies. I t was later that the early theories to explain the nature of antibody-antigen interactions began to be formulated and only after the development of protein chemistry methods and their application to the study of myeloma proteins that the real problems became tractable. I t thus became established that antibodies were proteins containing a basic scaffolding made of heavy and light chains (Fig. 1) . There were a small number of classes and subclasses of heavy chains, which were responsible for different effector properties of the antibodies (complement fixation. allergic reactions etc.) and two types of light chain (kappa and lambda). Each chain in turn contained a constant region which was essentially invariant within a type or class, and responsible for the effector function, and a variable region which differed from one immunoglobulin to another. and was responsible for antibody specificity. This apparent structural simplicity. coupled to the antibody specificity, which required a remarkable diversity, needed a genetic explanation, and led to an exciting controversy which lasted for at least two decades. There were two major currents of opinion. One consisted of germline theories whereby all the diversity was inherited as genes present in the germline. The other included somatic diversification theories, whereby somatic processes were responsible for the generation of diversity (GOD), starting from a small number of germline genes (Lennox & Cohn, 1967; Milstein & Pink, 1970). Once again, i t was necessary to wait for the development of new techniques and approaches. The combined developments in recombinant DNA methods, fast DNA-mRNA sequencing, and hybridoma technology made i t possible to unravel the unpredictable complexity of the system (Tonegawa. 1983). As i t turned out, although none of the several theories prevalant at the time was right, all of them contained a grain of truth. There was indeed considerable diversity in the germline, but antibody specificity was largely the result of not one, but several GODS operating at various levels.