From the structure of antibodies to the diversification of the immune response. Nobel lecture, 8 December 1984.

When an animal is infected, either naturally or by experimental injection, with a bacterium, virus, or other foreign body, the animal recognises this as an invader and acts in such a way as to remove or destroy it. There are millions of different chemical structures that the animal has never seen and yet which it is able to recognise in a specific manner. How is this achieved? Scientists have been fascinated by this question for most of this century, and we continue to be fascinated by the intricacies and complexities that still need to be clarified. Even so, looking back over the years since I myself became involved in this problem, progress in the understanding of the process has been phenomenal. Suffice it to remind our younger colleagues that 20 years ago we were still trying to demonstrate that each antibody differed in its primary amino acid sequence. What attracted me to immunology was that the whole thing seemed to revolve around a very simple experiment: take two different antibody molecules and compare their primary sequences. The secret of antibody diversity would emerge from that. Fortunately at the time I was sufficiently ignorant of the subject not to realise how naive I was being. Back in 1962, when I had by accident become the supervisor of Roberto Celis in Argentina, it occurred to me that antibody diversity might arise from the joining by disulphide bridges of a variety of small polypeptides in combinatorial patterns. I don’t know whether anybody else had the same idea at that time, but of-all the prevailing theories about antibody diversity that I am aware of, this is one that was widest of the mark. I hold it to my credit that I never put it into print. But it was of great value to me as it provided an intellectual justification to work on disulphide bonds of antibodies. By the time I joined the Laboratory of Molecular Biology in 1963, the model of two heavy and two light