Eur. .I. Immunol. 1982.12: 1-3 Niels Kai Jerne on the Occasion of his 70th Birthday 1

To Niels Kai Jerne on the Occasion of his 70th Birthday An Appreciation of his Contribution to Immunology

The first paper of the first number of the European Journal of Immunology (1971) is by N. K. Jerne entitled “The somatic generation of immune recognition”. Although the author’s address is given as the Basel Institute for Immunology he had proposed the hypothesis in 1969 while he was still Director of the Paul Ehrlich Institute, Frankfurt/M., and the Basel Insti- tute was still in the planning stage. The paper consists of 8 pages of closely reasoned argument, based on data derived from 84 publications (only 2 his own) chosen to illustrate the basic problem of how the immense diversity of possible anti- bodies/receptors can be generated and maintained in the total lymphocyte population - which itself is constantly being des- troyed and replaced - and yet 1% or more of the population can be shown to be reactive with allogeneic major histocom- patibility determinants. Niel’s Jerne’s logic led him to postu- late that lymphocytes forming antibodies against foreign anti- gens arise as mutants in clones descended from lymphocytic stem cells which expressed V genes coding for recognition of histocompatibility antigens of the individual (i. e. anti-self; important during early development but later needing to be eliminated if not mutated). Alloreactive lymphocytes are descended from clones which recognize histocompatibility antigens of thespecies which the individual does not happen to possess.

This hypothesis seemed far-fetched, but it has not been refuted and is attracting increasing interest. Its essential postu- late that mutation of the V genes must be a frequent event has been confirmed, at least by the recognition that genetic recombination between three separately coded portions of the

Photograph by Mirek Pazdera

V region can occur and give rise to an immense diversity of possible antibodies, and that one of the genes may be addition- ally liabIe to mutation. I have referred to this paper at some length not because it represents the most illuminating of all Niels Jerne’s theoretical insights, but because it illustrates his preoccupation with the philosophical problems of immunol- ogy, his grasp of what observations are the most pertinent to those problems, and his capacity to put forward bold but con- ceptually clear hypotheses - and his tendency to be proved right!

On the occasion of the 500th meeting of the British Biochemi- cal Society in 1969, at which Immunology was selected as one of the four areas in which major advances had taken place, I discussed [l] how it had come about that biochemists working in that area had for many years - and for perfectly good reasons in light of then current knowledge - adopted the hypothesis that antigens directed the specificity of antibodies, and how they had carefully and laboriously proved themselves wrong. They had looked at the problems as chemists rather than biologists, and had asked the wrong questions. Niels Jerne, however, had asked the right questions, and in his paper “The natural-selection theory of antibody formation” [2] in 1955 had foreshadowed the clonal selection hypothesis. He postulated that pre-existing ‘natural’ antibodies captured antigens, and somehow caused them to return to and stimulate those cells which had synthesized the antibodies in the first place to make more of the same kind. This hypothesis did not make biochemical sense at the time, even though it had some analogy with bacterial permeases, and it would need to be stretched hard to make sense today ( e g . the stimulation of B memory cells by immune complexes retained on follicular

2 Niels Kai Jerne on the Occasion of his 70th Birthday Eur. J . Immunol. 1982.12: 1-3

dendritic cells in germinal centers), but it clearly faced up to the biological facts.

In his early work in the Biological Standards Department at the State Serum Institute, Copenhagen, Jerne had studied the changes in avidity of antibodies during immunization with diptheria toxoid and had concluded that even specific antisera contained a wide variety of different antibodies all reactive with the antigen [3]. He had also observed that when very sensitive assays were used, such as neutralization of T4 bac- teriophage, even sera from unimmunized animals contained some pre-existing ‘natural’ antibody [4]. Coupled with a philosophical intuition that the potential to synthesize a par- ticular antibody could not be imposed on nucleic acid, but must pre-exist, logic demanded a selective hypothesis. This was the first of Niels Jerne’s theoretical contributions to im- munology.

The second came during the 6 years which he spent as Chief of the Division of Biological Standardizations at WHO, in the form of a contribution in 1960 to Annual Reviews of Micro- biology entitled “Immunological Speculations” [5]. In this he attempted to clarify terminology, and through it thinking about antigens and antibodies by introducing the terms “epitope”, “paratope”, “idiotype”, etc. Most of these have caught on and been adopted by immunologists. While still at WHO in 1962 he also persuaded 46 immunologists of interna- tional repute to meet in five scientific groups, each of which spent several days formulating what they regarded as the main problems for general and applied immunological research. Their report “Research on Immunology” [6] persuaded WHO to establish an Immunology Section, which was later responsi- ble (under Howard Goodman) for setting up a network of Research and Training Centres around the world, for the WHOiIUIS Standardization Committee and for much practi- cal help to immunologists, especially in developing countries. To Niels Jerne should be given the credit for, in this case, a highly practical initiative.

Institute for Immunology to be set up and funded by F. Hoff- mann-La Roche and Co. Ltd. It is not the place of this article to describe the structure and organization of this unique Insti- tute, except to state that its uniqueness and success owe a very great deal to Niels’ concept of how the ideal institute should work and his wise choice of persons to work in it. The mem- bers of the Basel Institute and those who have passed through it will surely agree that his leadership, his questioning and his breadth of vision constitute yet another - possibly his most important - contribution to immunology.

However, he still had time to think, and in 1973 at a collo- quium in Paris on the genetics of immunoglobulins and of the immune response in honor of the 150th anniversary of the birth of Pasteur he enunciated what has proved to be the most sig- nificant and fruitful of all his theoretical contributions “Towards a network theory of the immune system” [lo]. In this he took into account the newer work on idiotypes and on specific immune suppression, and with inexorable logic deduced that the specific combining site on any antibody must itself represent a unique antigenic determinant in any animal, and that if the concentration of antibodies with a unique idiotype rises above a negligible level the immune system will recognize it and make an anti-idiotype response. The anti- idiotype will in turn elicit formation of anti-anti-idiotype, and an infinite network will be potentially set up. This proposal is based on the clonal selection theory, but incorporates it into the wider frame of a network without sacrificing it. Greeted at first with a mixture of excited admiration and dismay at the complexity which it introduced and at the difficulty of testing it, the concept has since been amply shown to be valid. By 1976 at a discussion on “Idiotypes”, chaired by Niels Jerne [ l l ] T cells had been. subsumed into the network, and many of his collegues were able to give examples of the truth of predictions based upon it. Since anti-anti-idiotype inevitably resembles the antigenic determinant which stimulated the elaboration of a given idiotype, it is even possible to propose that in an immune response all that the antigen has to do is to disturb the

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network and the rest of the response is solely due to idiotype- anti-idiotype interactions - and this could be true! Practical applied immunology however has never really suited

his bent. He left Geneva to become Chairman of the Depart- ment of Microbiology at Pittsburgh, with the intention of developing a simple, accurate and quantitative method for detecting specific antibody-secreting cells, even when they might be few and far between, in order to test his hypotheses. With the help of Albert Nordin and Claudia Henry he developed the haemolytic plaque technique which often bears his name [7] and which opened up completely new possibilities for cellular immunology. In fact developments in relation to the structure of antibodies on the one hand and of cellular immunology on the other proceeded so fast that Niels Jerne’s summarizing lecture at the 32”d Cold Spring Harbor Sym- posium on Quantitative Biology in 1967 was entitled “The beginning of the end” [8] and at a Symposium in honor of Sir Macfarlane Burnet’s 70th birthday in 1969 he proposed that the complete solution of immunology (from the theoretical point of view at least) would be achieved by the answers to 20 ques- tions, of which 10 had already been answered [9]. They are good questions, but avoid the complication introduced by the recognition that T and B lymphocyte cooperation is an essen- tial part of the immune response.

Niels Jerne has never been concerned with the minutiae of the immune response which make all the difference to the practi- cal outcome - such as complement, activation of macrophages, the circulation of lymphocytes and their micro-environments - though he is prepared to concede their importance to others. But his ideas have enormously influenced even practical immunologists by indicating the sorts of consideration which they must keep in mind. The recently published Festschrift in his honor [12], containing 125 articles by colleagues and friends, in an indication of how wide his influence has been, Along with the editors and readers of this Journal I wish him continuing happiness. John Humphrey

References

1 Humphrey, J. H., “The nature of the immune response” in Crood- win, T. W. (Ed.), British Biochemistry Past and Present, Academic Press 1970.

2 Jerne, N. K., Proc. Natl. Acad. Sci. USA 1955. 41: 849. 3 Jerne, N. K., Acta Pathol. Microciol. Scand. 1951. Suppl. 86. 4 Jerne. N. K. and Skousted. L.. Ann. Inst. Pasteur 1953. 84: 73.

For the Previous three years Nick Jerne had been Director of the Paul Ehrlich Institute, FrankfurtIM. However, he had meanwhile been invited to become director of a new Basel 5 Jerne: N. K., Ann. Rev. Microbial. 1960. 14: 341.

Eur. J . Immunol. 1982.12: 1-3 A Festschrift in Honor of Niels Kai Jerne 3

6 WHO Tech. Rep. Ser. 1964. 286. 7 Jerne, N. K. and Nordin, A. A., Science 1963. 140: 405. 8 Jerne, N. K., Cold Spring Harbor Symp. Quant. Biol. 1967. 32:

9 Jerne, N. K . , Australas. Ann. Med. 1969. 18: 345.

10 Jerne, N. K., Ann. Immunol. (Inst. Pasteur) 1Y74. 125C: 373. 11 Idiotypes. Baumanikre Symposium 1976. Published by Basel Insti-

12 Steinberg, C. M. and Lefkowits, I. (Eds.), The Zmmune System, tute for Immunology 1980.

Karger, Basel 1981. 255.

The Immune System: A Festschrift in Honor of Niels Kai Jerne on the Occasion of his 70th Birthday, Volume 1, “Past and Future”, Volume 2, “The Present”, edited by Charles M. Steinberg and Ivan Lefkovits, S. Karger, Basel, 1981.

A Festschrift in honor of Niels Jerne must be an event in the world of immunology. The reader expects to find in it the fruits of the prodigious scientific achievements of Jerne as reflected in modern immunology, and his expectations are more than fu!filled. The two volumes, published by S. Karger and edited with loving care and ingenuity by Charles M. Stein- berg and Ivan Lefkovits, gather contributions from scientists who, at various points in time, happened to collaborate with Jerne, to witness the moments in which his thoughts erupted with clarity in the form of daring theories, or simply to obliquely cross the path of Jerne’s scientific career.

The first volume, appropriately entitled “Past and Future”, displays the vigor of good science and history blended in a series of magnificent articles. For whoever wants to under- stand how immunology emerged as a subtile and sophisticated science out of the boredom of blind serology, the perusal of these pages written by immunologists and non-immunologists will be both enlightening and delightful. The contributions of Stent, Maaloe, Mitchison, and Sat0 are probably the high- lights of this volume, excelling in the clarity of ideas and the beauty of style. But there is a unity of the volume. We find it in a central question, present here in most contributions, a ques- tion so carefully avoided in conventional papers submitted to established scientific journals: “How does the scientific

approach serve our understanding ?” This question, which authors ask themselves here freely, with dedication and with- out fear, sounds like an echo to Jerne’s famous “So what?” Titles like “Was an Idiotype Network Working in the Evolutionary Past” (Matsunaga and Ohno), “Specificity - or Why Immunology is Unlikely to Become Boring Soon” (Pohlit), or “The Joint Evolution of Antigens and Antibodies” (Fazekas de St. Groth) evoke only a few among a large set of contributions which together communicate to the reader the conviction that immunology today is healthy, with deep roots in experimental reality, and that it carries the weight of a good part of modern biological thinking. The general scholarly tone is refreshed by some good “boutades”: “The Ideal Rabbit” (Kelus), “Le TCtard et 1’Anticorps” (Du Pasquier), “Immuno- ornithological Conversations” (Pink and Ziegler).

The over 450 pages of the second volume cover so much sci- ence that we cannot review particular issues or cite outstand- ing articles. In order to connect the past with the future, the editors display here, in the most appropriate presentation, the elusive and evanescent “Present”. In doing so they let a large group of leading scientists tell their story. They do it at the historical moment when primitive immunology switched to sci- ence. But primitive societies, as noted by Graham Greene, generate legends. The living legend in immunology is Niels Jerne, and confronted with it in these volumes our leading scientists, one by one, spontaneously, as if driven by some mysterious force, show us more about themselves than they probably ever did before.

B. Pernis and A. A. Augustin