Perspectives in Biology and Medicine

TURNING POINTS IN CELLULAR IMMUNOLOGY: THE SKEIN UNTANGLED THROUGH A GLOBAL INVISIBLE COLLEGE G. J. V. NOSSAL* Since its first golden age, in the days of Pasteur, Metchnikoff, Ehrlich, and their contemporaries, the science of immunology has been characterized by international collaboration at its best, embodying spirited controversy and competition at the basic science end, vigorous information flows, and rapid globalization of practical fruits. Cellular immunology became a recognizable discipline only after World War II. Indeed, its explosive growth dates back little more than 20 years. Over that period, a global "invisible college" of perhaps 200 individuals has been its custodian , and the present insights that we have into nature's defence system owe much to the network of meetings, student exchanges, informal collaborations, sharing of reagents, and, above all, fearless and friendly debate across the oceans. From the rich array of research results that has been the harvest of these years, I have picked four endeavors that marked turning points in thinking about the immune system. Each of these depended enormously on international collaboration. As is the norm for science, each represents an unfinished symphony, with beautiful movements yet to come. Clonal Selection: The Immune System as a Repertoire of Cells, Each Preadapted to Make One Antibody The modern era of immunology really began in 1955, with Jerne's natural selection theory of antibody formation. Niels Jerne, Danish by The author is supported by the National Health and Medical Research Council, Canberra , Australia, and by grant AI-03958 from the National Institute of Allergy and Infectious Diseases, U.S. Public Health Service. ?Director, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria 3050, Australia.© 1986 by The University of Chicago. All rights reserved. 003 1-5982/86/2932/$0 1 .00 S166 I G. /. V. Nossal ¦ Cellular Immunology birth, British citizen, distinguished worker in four countries, founder of the most international immunology institute in the world, pondered the puzzle of the immune system, with its bewildering capacity to produce proteins of such diverse types, at the time that the deep significance of Watson and Crick's double helix was beginning to be realized. He speculated that "a great variety of configurations, due, perhaps, to various amino acid sequences at the sites of the globulin molecules, may develop at random" [I]. If the serum of an unimmunized animal contains 1019 molecules of immunoglobulin/ml and ifonly 1 percent of this is natural antibody, this could mean 1011 different types of natural antibody with 1 million molecules/ml of each. Then, all antigen had to do was to amplify the numbers of the right sort, that is, act as a selective stimulus of a synthetic capacity that the body already possessed. Burnet, working in Australia, had also come to have doubts about the direct-template theory of antibody formation. He had introduced a somewhat clumsy theory, likening antibody production to the synthesis of adaptive enzymes [2], that had received a poor press from the international scientific community. The yeast of Jerne's inspiration fermented only slowly for Burnet. One day in 1957, when I was a fresh postdoctoral fellow in his laboratory, he gave me the 1955 Jerne paper to read and asked me what I thought of it. "Pretty crazy!" was my view—and, I guess, that of most immunologists. Still, Burnet remained intrigued and, one weekend, wrote a short speculative article that retained the essence of Jerne's idea of selection, that is, the idea of a large repertoire of naturally formed antibodies, but placed these antibodies as receptors on the surface of lymphocyte cells. Each lymphocyte was supposed to have only one receptor, and all that the antigen had to do was selectively to stimulate the lymphocyte with the "right" receptor. The consequent wave of division and differentiation was seen as producing a clone of antibody-forming plasma cells. Burnet thought the idea "felt right" but was worried about creating another poor impression. Accordingly, he placed the short piece in a rather obscure journal, the AustralianJournal ofScience [3], reasoning that if the idea did turn out to be crazy it would not attract much attention there but if it stood the test of time...