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Jerne, Niels Kaj

JERNE, NIELS KAJ

(b. London, England, 23 December 1911; d. Castillon-du-Gard, France, 7 October 1994), immunology, molecular biology, serology, biosemiotics, theoretical biology.

Jerne was one of the leading immunologists of the post–World War II period. He received the Nobel Prize in 1984 for three theoretical contributions: the natural selection theory of antibody formation, the somatic generation theory of antibody diversity, and the idiotypic network theory of the immune system. In addition, he invented a method for the detection of single-antibody-producing cells that became one of the most cited techniques in cellular immunology.

Latecomer to Science . Niels Jerne was the fourth of five children of the inventor and industrialist Hans Jessen Jerne (1877–1950) and Else Marie (née Lindberg, 1874–1956). His parents were Danish but had emigrated to London in 1910 to start a celluloid factory. Right after the outbreak of World War I the family moved to the Netherlands, where his father acquired a refrigerated storehouse in Rotterdam and later became reasonably wealthy. Later in life Jerne never felt exclusive ties to any single nation and often described himself as a citizen of the North Sea: Denmark provided his family roots, Dutch was the language in which he was most fluent, and England represented his cultural preferences and political sympathies. In addition to carrying a Danish passport he remained a British subject throughout his life.

Jerne’s road to an academic career took a number of twists and turns. In his own words he was a Spätzünder (one who is late to ignite). After leaving high school in 1928 with fairly average grades he was employed as a junior clerk in the Elders and Fyffes banana company in Rotterdam. The diaries and correspondence of his late adolescent years bear witness to an arrogant and ironic young man who loved to play language games, immersed himself in romantic and modernist literature, and was drawn to Kierkegaard and Nietzsche. Accordingly he wanted to study philosophy but, at his father’s request, began with chemistry at the University of Leiden in 1931. He preferred a fairly hectic schedule of extracurricular student union activities, to serious academic work, however, and dropped out of university after two years.

In 1934 his father supported a renewed attempt at a higher education, this time in medicine at the University of Copenhagen. Soon after his arrival in Denmark, however, Jerne met a Czech painter, Ilse (“Tjek”) Wahl (1910–1945), whom he married and with whom he had a son in 1936. Thus he quit university again, began working for his father, who was experimenting with new bacteriological methods for bacon curing, and only resumed his medical studies in 1939. For most of the war years in German-occupied Copenhagen he divided in his time among medical textbooks, basic clinical training, and a bohemian night life with his wife’s artist friends.

In order to support his growing family (another son was born in 1941), Jerne took a part-time position as a secretary in the Department of Standardization at the Danish State Serum Institute in 1943. The department had been set up by the Health Committee of the League of Nations in the 1920s for the establishment of international serum standards. Here Jerne discovered his aptitude for mathematical analysis and statistical thinking (“chance governs all” became one of his favorite expressions), and he began to immerse himself in problems of biometrics and methods of biological standardization of antigens and antisera. Significantly, prime numbers and chess were among his favorite pastimes besides literature and language.

Antibody Avidity and the Selection Theory . His wife’s suicide in the autumn of 1945 was a turning point in Jerne’s life. He succeeded in finishing his medical degree in 1947 and decided, after internship and marriage with his former mistress, Adda Sundsig-Hansen (1914–1993), to go into research. The head of the standardization department, Ole Maaløe, who later became the pioneer of Danish molecular biology, encouraged him to follow up on his earlier observation that the measure of the strength of an antiserum depends on its concentration, indicating that the chemical reaction between antibody and antigen is reversible. Using a rabbit skin assay system to measure the amount of surplus toxin, Jerne set out to investigate the kinetics of the reaction between diphtheria toxin and diphtheria antitoxin to get a quantitative measure of the binding strength of the antibody (its “avidity”). His published dissertation, A Study in Avidity (1951), was received by the international serological community as an example of experimental rigor, statistical prowess, and conceptual clarity.

One of the unexpected findings of the dissertation was that avidity increases in the course of immunization. Stimulated by James D. Watson and Gunther Stent’s visit to Maaløe’s department in 1951–1952, Jerne began to orient himself to the problems and methods of phage research and created a new, and more sensitive, bacteriophage-antiphage assay system for studying the details of early avidity increase. After a couple of years of inconclusive experimentation, interrupted by an inspection tour he undertook for the World Health Organization (WHO) to standardization centers in Asia in 1953, he was struck, in the summer of 1954, by an experiment that, in his eyes, demonstrated the existence of specific antibodies without the prior presence of a corresponding antigen. A few weeks later he formulated a theory of antibody formation that could explain, he thought, a whole array of serological and immunological phenomena, including the avidity increase. All possible kinds of specific antibody molecules already exist in normal serum, he stated, and one of these specific molecules fits, “by chance,” any given antigen, not necessarily exactly but approximately. The intruding antigen selects such specific fitting antibody molecules and transports them to antibody-producing cells, where they are further multiplied and released into the bloodstream.

The natural selection theory of antibody formation flew in the face of the ruling dogma of immunology. The existence of preformed antibodies had been highly disputed in immunology for more than half a century. In 1897 Paul Ehrlich had speculated that all cells in the body carry preformed molecular groups, so-called side chains (Seitenketten, what would be called receptors in the early twenty-first century), which were assumed to play a part in the absorption of specific nutritional substances. Intruding antigens—toxins, for example—would also be recognized by such side chains, which were supposed to be released into the bloodstream as specific antibodies.

After Karl Landsteiner’s experiments, beginning in the 1910s, with synthetic haptens (small molecules that are coupled to the antigen and change its antigenic properties) Ehrlich’s theory fell into disrepute. Whatever particular antigen was synthesized in the chemist’s laboratory, it gave rise to a specific antibody response. It was considered impossible for organisms to have all these specific molecules in stock waiting for whatever might intrude. Instead, from the middle of the 1930s varieties of template theories became dominant among serologists and immunologists who claimed that the specificity of antibodies was determined de novo by the antigen. The chemically most sophisticated of these template theories was put forward by Linus Pauling, who suggested that specific antibodies were formed when normal, nonspecific globulin molecules that had not yet received their final tertiary configuration wrapped around antigen molecules and so took on a specific, complementary structure.

Accordingly, preformed antibodies were considered an anomaly, and Jerne’s demonstration of specific antibody activity without prior antigen presence could easily be dismissed as an experimental error. Jerne was immediately convinced of the anti-template alternative interpretation, however. The writings of his intellectual hero, the British biometrician and evolutionist Ronald A. Fisher, were an important cognitive resource for thinking about the match between antigen and antibody in terms of random fitness and Darwinian selection. But there is also much to suggest that Jerne’s dogged anti-template position drew on his personal and emotional proclivities. He repeatedly referred to himself as a person with a repertory of preformed states of mind that could be elicited in interactions with other people. The creation of the natural

selection theory of antibody formation can thus be seen as an act of metaphorical projection: His experience of his own self became an emotional charged cognitive resource for the new immunological theory.

Jerne worked out the details of the natural selection theory during a fellowship at the California Institute of Technology in 1954–1955, and the paper was sent to the Proceedings of the National Academy of Sciences by his mentor, Max Delbrück. It received a positive response from molecular biologists inclined toward neo-Darwinism—for example, Salvador Luria—but most immunologists were lukewarm. The doyen of American immunology, Alwin Pappenheimer, thought the theory was “all baloney … all hocus pocus” (cited in Söderqvist, 2003, p. 200). Upon his return to Copenhagen, Jerne felt discouraged, and a year later, in 1956, he left his family and a permanent research job at the Serum Institute to take up an administrative position at the Section of Biological Standardization at the WHO in Geneva.

Immunology as a Theoretical Discipline . At the WHO, Jerne’s main responsibility was to create new guidelines, so-called minimum requirements, for the standardization of vaccines and sera, including vaccines against smallpox, poliomyelitis, yellow fever, and cholera. Diplomatic skills and extensive committee work were needed to coax the expert recommendations through the internal bureaucracy, and Jerne’s achievements soon earned praise in the organization. In 1960 he was assigned the task of organizing a new program to foster international cooperation and training in immunology, especially in the developing countries. Another advantage of working in Geneva was, of course, the tax-free salary at the WHO, the international atmosphere, and the city’s culinary offerings. Jerne worked hard, but he also appreciated the material pleasures of life.

Meanwhile the natural selection theory began to win the attention of a growing number of immunologists, especially after Sir Frank Macfarlane Burnet (Nobel Prize winner in 1959 for his work on acquired immunity) revised it by suggesting that selection works at the level of cells rather than on circulating antibody molecules. Within a few years the clonal selection theory acquired the status of a central dogma in immunology, and as a consequence Jerne’s star rose. He began considering a scientific comeback. The opportunity came in 1962 when the medical faculty at the University of Pittsburgh asked him to become professor and chairman of its Department of Microbiology.

The vigorous intellectual activity in Pittsburgh put Jerne under pressure to achieve. The opportunity came only a few months after his arrival when, together with his first and only postdoc, Albert Nordin, he constructed a powerful method for the quantification of antibody-producing cells in vitro. The idea was to combine the plaque assay technique he had used in Copenhagen a decade earlier with the well-known principle of complement-mediated immune hemolysis, discovered by Jules Bordet in 1901 and further developed by August von Wassermann for the diagnosis of syphilis. Each antibody-producing cell produced a zone of hemolyzed red blood cells around it, like small, bright stars in a dark sky. These aesthetic qualities, together with the ingeniousness and simplicity of the assay, rapidly made it one of the most frequently used quantitative methods in cellular immunology; the short paper in Science in March 1963 was one of the most cited papers in the biomedical literature in the 1960s through 1980s.

Together with a small group of coworkers Jerne spent the next couple of years refining the plaque assay method to get a quantitative picture of the kinetics of the early immune response, but without any conclusive results. He also cultivated other interests. In Geneva he had been interested in the analogies between language and the immune system; now he mused about the analogies between cognitive and immune learning—ideas that would later be taken up by Gerald Edelman in his Darwinian notion of the nervous system.

But these were sidetracks; it was Jerne’s immunological star that rose. These were the years when the number of immunological journals, textbooks, and societies proliferated and when immunology became established as an independent scientific discipline with its own departments and chairs. Jerne received offers from the University of Copenhagen and Harvard Medical School, but chose instead, partly for financial, partly for nostalgic reasons (he loved to fashion himself as a European intellectual, while disdaining American culture) to take up a position as director of the venerable Paul-Ehrlich-Institut in Frankfurt, West Germany. A year later, in 1967, his reputation as the leading theoretician in the discipline was cemented at the Cold Spring Harbor symposium on immunology, where his final report of the meeting, “Waiting for the End,” was considered a brilliant summary of the state of the field, especially in his problematization of the entrenched division between chemically and biologically oriented immunologists.

Antibody Diversity and Idiotypic Networks . Jerne’s explicitly stated goal for going to Frankfurt was that he wanted to build up a European counterpart to the strong U.S. domination in the field. He traveled widely giving lectures and organized the first course in immunology for the newly founded European Molecular Biology Organization in 1967. However, he soon became frustrated by the German research bureaucracy and the relaxed work habits at the Paul-Ehrlich-Institut, so when the multinational pharmaceutical company Hoffmann-La Roche invited him, in 1968, to become the first director of a new research institute for immunology in Basel, Switzerland, Jerne quickly accepted.

Roche’s funds were seemingly unlimited. Jerne traveled worldwide to recruit the best available scientists. His ideal was to establish a new kind of research institute based on the idea of a nonhierarchical, communicative network where both the architecture and the organization were designed to encourage maximum interaction between its members. When it opened in June 1971 the Basel Institut für Immunologie was the largest of its kind in the world, with a staff of around 150. It remained the world’s leading center for immunological research throughout the 1970s and 1980s, housing, among others, three future Nobel laureates (Jerne, Susumu Tonegawa, and Georges Köhler). According to the immunological grapevine, Jerne spent most of his time in perpetual discussions and never visited the laboratories, because, as he allegedly once said, “the reality would confuse me” (Söderqvist, p. 269.)

In the late 1960s and early 1970s Jerne’s immunological thinking developed along two lines. One basic question concerned the genetic basis for the origin of the antibody repertoire. Did the information for the coding of all specific antibodies exist in the germ line? Or did the final repertoire arise through somatic mutations during the differentiation of the antibody-producing cells? Jerne’s contribution to the problem was to invoke the well-known phenomenon of self-tolerance. In 1969 he proposed that self-tolerance and antibody diversity were generated in the same process during embryonic development, and a year later he assigned a central role to the thymus, both as a breeder of mutant, specific lymphocytes and as a generator of the organism’s tolerance against its own antigens. The theory was contested by many of his colleagues but was partly confirmed by Tonegawa in the mid-1970s, who received the Nobel Prize in 1987 for the discovery of the mechanism of somatic recombination which allows for a comparatively small number of genes to code for millions of specific kinds of antibodies.

The other question that incessantly occupied Jerne’s mind was how the immune system is regulated. Even though he had rapidly accepted Burnet’s clonal selection theory—“I hit the nail but Burnet hit it on its head” (Söderqvist, p. 222), he never gave up the idea that circulating antibodies might after all play a significant role in immune regulation. Throughout the 1960s he obtained experimental results pointing in this direction and consequently began to think of circulating antibodies as “receptors” for antigens. The findings of Henry Kunkel and Jacques Oudin that specific antibodies have unique antigenic determinants (idiotypes) furthered this line of thinking.

Further inspired by his reading of information theory and systems theory, Jerne began to think of the immune system as a self-regulating cybernetic system of idiotypic relations. In an article in Scientific American in 1973, Jerne proposed the idiotypic network theory of the immune system, according to which all antibodies and lymphocyte receptors are seen as mutually independent parts of a steady state system. In the following years Jerne published a series of theoretical articles to support the idea that every variable region of an antibody molecule (paratope) functions as a specific antigenic determinant (epitope) which is recognized by still another number of paratopes, which in turn function as specific epitopes, and so on ad infinitum. In Jerne’s vision, the immune system was a kind of “hall of mirrors,” a dynamic equilibrium system of mutual molecular recognition which in principle did not need any responses from the outside to work. The external world with its bacteria, viruses, and other antigenic determinants were of subordinate importance to the regulation; the system had an eigen behavior, that is, it was self-referential. Several experimental studies seemed to confirm the regulatory effect of anti-idiotypic antibodies, and around 1980 Jerne’s network theory was immensely popular among immunologists. Not everyone was convinced, however. The most vociferous of Jerne’s critics, Melvin Cohn, asserted that the theory was unscientific, even absurd, because it was incapable of being tested empirically. Jerne was not indifferent to such criticisms but nevertheless felt that they missed the point. He held that science is not just an accumulating series of falsifiable propositions that experimentalists in true Popperian fashion try to falsify, but also (and mainly) an arena for the imaginative mind. Indeed, the notion of imagination was a recurrent one in Jerne’s thinking; in one of the first international meetings on the formation of antibodies, in Prague 1958, he had asked the participants to “fly into the realm of imagination” and repeatedly stressed the importance of giving free rein to scientific fantasy.

Last Years . After his retirement from the Basel Institute in 1980, Jerne withdrew to his country home near Castillondu-Gard, Languedoc, France, together with his third wife, Ursula (Alexandra) Kohl (b. 1936), whom he had married in 1964. There he continued to develop his ideas, first expressed in the early 1960s, about the analogies between linguistics and immunology. For example, drawing on American linguist Noam Chomsky’s theory of generative grammar, Jerne suggested that the immune system was governed by a set of grammatical rules that allowed an open-ended number of sentences (antibody specificities). He increasingly viewed immunology as a philosophical subject and questioned the reductionism of experimental immunology. In his view the immune network was not built up by interacting material factors—it was an abstract principle, a pure recognition system. These ideas attracted only few adherents among the new generations of immunologists trained in more pedestrian sciences, such as biochemistry and molecular biology.

Although his influence on immunological practice waned rapidly in the 1980s, Jerne was nevertheless duly remembered and honored for his lifelong contributions to immunology. He received honorary doctorates from the Erasmus University in Rotterdam and from the Weiz-mann Institute of Science in Rehovot, Israel, and was awarded several prestigious scientific prizes, including the Paul Ehrlich Prize in 1982 and the Nobel Prize for Physiology or Medicine in 1984. Jerne shared the Nobel with Georges Köhler and César Milstein, who had invented the hybridoma technique for producing monoclonal antibodies a decade earlier. Jerne was cited for his “visionary theories,” which had enabled modern immunology to make “major leaps of progress”; in fact he was the first medical Nobel Prize winner to be cited primarily for his theoretical contributions, and he did not shy away from emphasizing that he was not particularly fascinated by monoclonal antibodies which, in his mind, were mainly of practical interest. Neither did he see anything of immunological interest in the AIDS epidemic.

The expression of such politically incorrect views added to the web of myths and legends that were spun around Jerne in the immunological culture. Anecdotes circulated about his power of imagination, his working capacity, and his analytical keenness, but also about the aura of aloofness, elitism, and Bildung that surrounded him. Jerne was keen to present himself as an urbane European intellectual who would rather read Shakespeare and Proust than the Journal of Immunology and who preferred to sit in a wine bar and talk about art, politics, and life in general than work in the laboratory; conversation was his life’s breath. There is also a Faustian theme in Jerne’s life story: He wanted terribly to be unusual; he strove for perfection in science and eventually won the recognition of being “one of the most intelligent biologists of this century” (Burnet, 1968, p. 249). At the same time, he paid for his efforts by becoming a wanderer who continually tried to evade responsibility for his own life and the care of others, and he characterized himself as “a kind of misfit” (Söderqvist, p. 14). His life story epitomizes Alastair MacIntyre’s claim that biography is “neither hagiography nor saga, but tragedy” (p. 213).

BIBLIOGRAPHY

WORKS BY JERNE

A Study of Avidity Based on Rabbit Skin Responses to Diphtheria Toxin-Antitoxin Mixtures. Copenhagen: Munksgaard, 1951.

“The Natural-Selection Theory of Antibody Formation.” Proceedings of the National Academy of Sciences 41 (1955): 849–857.

With Albert A. Nordin. “Plaque Formation in Agar by Single Antibody-Producing Cells.” Science 140 (1963): 405.

“Summary: Waiting for the End.” Cold Spring Harbor Symposia on Quantitative Biology 32 (1967): 591–603.

“Generation of Antibody Diversity and Self-Tolerance: A New Theory.” In Immune Surveillance, edited by Richard T. Smith and Maurice Landy. New York: Academic Press, 1970.

“The Immune System.” Scientific American 229 (July 1973): 52–60.

“The Generative Grammar of the Immune System.” In Les Prix Nobel 1984: Nobel Prizes, Presentations, Biographies and Lectures. Stockholm: Almqvist and Wicksell International, 1985.

OTHER SOURCES

Burnet, F. Macfarlane. “A Modification of Jerne’s Theory of Antibody Production Using the Concept of Clonal Selection.” Australian Journal of Science 20 (1957): 67–68.

———. Changing Patterns: An Atypical Autobiography. Melbourne: Heinemann, 1968.

MacIntyre, Alasdair. After Virtue: A Study in Moral Theory. 2nd ed. Notre Dame, IN: University of Notre Dame Press, 1984.

Söderqvist, Thomas. Science as Autobiography: The Troubled Life of Niels Jerne. New Haven, CT: Yale University Press, 2003.

Thomas Söderqvist

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