VoLuME 69, No. 1 THE QUARTERLY REVIEW OF BIOLOGY Vosed + Moon Marcu 1994 UA COMMENTARY BURNET AND NOSSAL: THE IMPACT ON IMMUNOLOGY OF THE WALTER AND ELIZA HALL INSTITUTE Joun J. MARCHALONIS Microbiology and Immunology, University of Arizona College of Medicine Tucson, Arizona 85724 USA INTRODUCTION HE WALTER AND ELIZA HALL Institute of Medical Research in Mel- bourne, Australia is probably the world’s best known research center devoted to the study of immunology. This recognition was gained under the leadership of its third director, Sir Frank Macfarlane Burnet, who headed the Institute from 1944 to 1965. Subsequently, the Institute has shown explosive growth un- der the leadership of its present director, Sir Gustav Nossal (1966 to present). The two in- dividuals differ markedly in personal charac- teristics, but both made major and unique contributions to the definition of immunology as a modern science. T'wo recent publications have brought the Hall Institute to general at- tention: the first is Life among the Scientists: An Anthropological Study of an Australian Scientific Community (Charlesworth et al., 1989). The second is The Seeds of Time (1991), a biography of Sir Macfarlane Burnet by Christopher Sex- ton. The overall perspectives of the two books are quite distinct. The first has the stated purpose of attempting “to understand how a small group of scientists at a particular research institute, and in a spe- cific scientific field, do science, as distinct from what the received scientific mythology says they do and what philosophers of science and other science watchers suppose they do” (p. 1). For this study a group of anthropologists used in- terviews and techniques of anthropological analysis to characterize a group of scientists as if they were a separate subculture working within the context of its own historical, socio- logical and mythological milieu. Charlesworth et al. write from an avowedly Marxist per- spective, and address too many issues facing contemporary science to do justice to any sin- gle one or to give a coherent picture of the subject. The volume is interesting because it states many of the issues that have currently been brought to the front in various popular criticisms of science and analyses them within the philosophical context of the authors’ be- liefs and within the framework of interviews with scientists working in a single research institute. It should prove useful to historians of the Hall Institute and Australian Science and to future sociological or anthropological studies of the scientific subculture. Sexton’s book is a well-constructed biogra- phy of the life of Sir Macfarlane Burnet start- ing with the immigration of his father, Frank Burnet, to Australia in 1880 and ending with Burnet’s death in 1986. The biography makes extensive use of interviews with Burnet, his writings, and interviews of individuals closely associated with him. I found it to be a fascinat- ing book that provided an overall perspective of Burnet’s life and times. The Quarterly Review of Biology, March 1994, Vol. 69, No. 1 Copyright © 1994 by The University of Chicago. All rights reserved. 0033-5770/94/690 1-0003$1.00 53 54 THE QUARTERLY REVIEW OF BIOLOGY My association with Burnet began in 1967, after he had stepped down as director of the Hall Institute and no longer had an active role in experimental research. Previously, as an undergraduate, I had been impressed with his book, The Clonal Selection Theory of Acquired Immunity (1959), and the desire to work with him gave impetus to the decision that brought me to the Walter and Eliza Hall Institute as a postdoctoral fellow. I had the opportunity to work with Gus Nossal as his first postdoctoral fellow, and then, with Sir Mac’s urging and help, joined the staff; my association with Nos- sal continued for eight years. My view of Bur- net was comparable to that of a grandson. Burnet showed great interest in my research on evolution and lymphocyte receptors. He was not directly involved, however, and we worked in a spirit of mutual friendship that was free of the tensions expressed by Nossal, who saw him as a stern, aloof, and somewhat unsupportive taskmaster. Thus I did not see him in the role of the distant and extremely dedicated scientist that he played during his active research and administrative years. Burnet showed a strain of toughness that persevered throughout his life. In May 1984, he and I were seated out in the intense South Carolina sunshine while he was waiting to be awarded an honorary degree from the Medi- cal University of South Carolina. Another hon- orary degree recipient, Clare Booth Luce, was overcome by the heat and humidity and moved back into the shade. I asked Mac whether he wanted to move back out of the sun. He shook his head emphatically “No,” refusing to show any weakness whatsoever. In retrospect, this becomes more impressive because he must have known he was suffering from the cancer that would soon take his life. Sexton develops and points out threads of Burnet’s personality that were recognized by many of his associates and which shaped his contributions to both science and society. Bur- net and Nossal have had wide-reaching inter- national impact, and I felt that a major weak point of Charlesworth et al.’s book was the attempt to analyse the Hall Institute as an Australian phenomenon, rather than placing it in its international context. I welcome this Opportunity to use these two volumes as a springboard to comment on the Walter and VoLuME 69 Eliza Hall Institute and its most dominant directors. By international standards, the Hall Insti- tute is a relatively small operation, but it has had an enormous impact on the development of immunology. Furthermore, under Nossal’s leadership, it has provided a shining example of growth and support for research, while main- taining stability for individual investigators — and accomplishing this without becoming ex- cessively entangled with industrial concerns. Past books on the Hall Institute have devoted a good deal of attention to research contribu- tions. I will not consider these in detail, but instead will focus upon Burnet’s contributions to the intellectual growth of the Hall Institute and on the development of Australian science, as distinct from that of England, and upon Nossal’s transformation of the Institute from a small group of medical scientists working with relatively meager resources to a leading research center well equipped to carry out state- of-the-art studies in molecular biology, modern cell biology, and immunology. The following references provide additional information re- garding the Walter and Eliza Hall Institute and many of the personnel described here: Burnet, 1971; Nossal, 1978; Wood, 1984; Fen- ner, 1990; Baskin, 1991. BURNET: HIS CHARACTER AND IMPACT Burnet seems to have been basically a shy individual whose diffidence was misinterpreted as arrogance during the heyday of his scien- tific career. He grew up in the Australian bush country, where he developed a strong interest in nature that continued throughout his life. Although he preferred to collect beetles, he took pride in winning a place on the crew at Melbourne University in order to win his father’s approval. Burnet’s background in ama- teur naturalism predisposed him toward the “Darwinian view of immunology,” for which he served as an apostle throughout his life. The ingrained commitment to integrity that characterized his scientific life was developed early when he expressed dissatisfaction with shady real estate development policies sup- ported by his father, a banker. Burnet had a long and fruitful life that encompassed major political changes within the context of Austra- lia, the British Empire, and the world. His Marcu 1994 thinking and his contributions were shaped by these political changes. In the first place, Burnet saw himself as an Australian rather than as a displaced colonial Englishman. His father set the example here. The elder Burnet served successfully as a bank manager in Tra- ralgon, Victoria, and was offered the presti- gious opportunity to return to the U. K. to open the first London office of the bank. He declined, having made the decision to remain and raise his family in Australia. Burnet’s growth in science and his period of leadership of the Hall Institute coincided with the time during which Australia grew in stature and self-confidence to become a strong and independent nation, rather than a British colony. Consistent with his Australian pride, he commented rather sarcastically on the first official director of the Hall Institute, Sidney Patterson, M. D., who spent three years as director before taking a prestigious clinical practice at Duff House (Ruthin Castle), a private clinic for wealthy invalids in North Wales. Burnet noted that Patterson “came and he went,” having little impact on the subse- quent development of the Institute. The first named director, Gordon C. Matheson, M. D., unfortunately never served because he was mortally wounded at Gallipoli in World War I, shortly after the decision was made to offer him the position. Burnet speaks quite highly of the second Director, Charles Kellaway, who “set Australia on a new path to achievement in medicine.” Burnet feels that Kellaway gave it the best 20 years of his professional life and “got it going” (Burnet, 1971). Burnet’s Australian patriotism and respect for the elitism of achievement and ability caused him to turn from the tired class-directed ap- proaches of Britain to the positive egalitarian successes shown then in the United States. For example, Burnet spoke highly of Harvard Medical School “as probably the best in the world,” and sought to further academic ties with the United States, as opposed to the pre- occupation with England expressed by his pre- decessors. This spirit is illustrated in his pride that his hand-picked successor, Nossal, had spent two years at Stanford in Lederberg’s department and built a first-class reputation in America. In Burnet’s words, he had ad- sorbed the American approach that demands WALTER AND ELIZA HALL INSTITUTE 35 “the right tools for the job,” rather than carrying out postdoctoral studies in England prior to taking up the directorship. Burnet took particular pride and vigorously defended his uniqueness in his application of Darwinian principles to immunology. Immu- nology began in an applied and clinical set- ting. Even today, the vast majority of studies are carried out either on humans or on com- mon laboratory rodents, and studies with lower vertebrates are looked upon as unimportant. Burnet pioneered in the view that much could be learned from studying lower animals such as protochordate tunicates, or even from at- tempting to understand recognition and de- fense mechanisms of plants. Moreover, Bur- net put his ideas into practice. One example of his broad interests is re- corded in a photograph taken in 1975 in the garden of the School of Botany at Melbourne University (Fig. 1); it shows the core speakers at a widely significant conference on self/non- self discrimination that was put together largely because of Burnet’s inspiration. Burnet was instrumental in attracting R. Bruce Knox to the School of Botany because of his interest in the biochemistry and genetics of nonself recognition in plants and in establishing col- laborations between Knox and me because of my interest in the molecular evolution of immune recognition. Burnet’s ability to see common biological problems across disciplines is reflected in the individuals in this photo- graph who represent botany, immunology, and physical chemistry. The spirit of Burnet’s attempt to get people together who would give a final synthesis to common problems of de- fense and differentiation relating to self/non- self recognition continues today with interna- tional meetings held in Europe and the United States, the latest of which was “Primordial Immunity,” held at the Marine Biological Lab- oratory, Woods Hole, Massachusetts in May 1993. These conferences are dedicated to the general appreciation of the fact that basic de- fense and recognition mechanisms are broadly shared among living animals. Further illus- trating the generality of his perspective, Burnet took great pride in the fact that he had been instrumental in bringing the pioneer etholo- gist Konrad Lorenz to the attention of the Nobel Selection Committee. 56 THE QUARTERLY REVIEW OF BIOLOGY Fic, 1. VOLUME 69 SPEAKERS IN THE SYMPOSIUM ON BroLocicaL REcoGNITION HELD AT THE Scuoot or Botany, University oF MELBOURNE, JULY 31st, 1975 The participants are from left: Sir Macfarlane Burnet, John J. Marchalonis, John Heslop-Harrison (Director, Royal Botanical Gardens, Kew, England), R. Bruce Knox (School of Botany, University of Melbourne), and Sir Rutherford Robertson (Research School of Biological Sciences, Australian National University). The symposium reflected Burnet’s broad approach to the crucial biological prob- lem of recognition; viz, self and nonself in plants (Heslop-Harrison), the evolution of biological recogni- tion (Burnet), membrane biochemistry (Robertson), molecular aspects of lymphocyte membranes (Marchalonis) and the interaction of plant proteins with human cells (Knox). Despite his shyness, Burnet held many strong opinions and was not afraid to state them. The question of whether Burnet would have been capable of leading the Hall Insti- tute through its modern period of growth has been asked. He probably would not have been able to do so. Despite his enormous intellec- tual contributions, today’s society would see Burnet as someone who is not “politically cor- rect.” He had an absolute commitment to sci- entific truth, and would not alter his opinions to meet political circumstances. He was an una- shamed elitist, with the qualification that his respect was for individual ability and achieve- ment. During his years of leadership, he made his views quite clear; he maintained that seri- ous research*could not be carried out at a university or medical school, and he had as little to do with faculty committees as possible. David White of the Department of Microbiol- ogy commented that “presumably he [Burnet] assessed his priorities and quickly concluded that his principal responsibility was to admin- ister the Hall Institute and conduct his own research. Moreover, he had no liking for the cut and thrust of university politics, let alone the desire to waste precious hours battling com- mittees for a larger share of the cake. I think history has shown his decision to be correct” (p. 130). Burnet’s commitment was to the de- velopment of the Hall Institute and to his own research. He resisted opportunities to inte- Marcu 1994 grate the Institute fully into the academic in- stitutional structure of the University College of Medicine, and became unpopular in the process for his lack of collegiality. In fact, at the time of his retirement, Burnet took some pride in his unpopularity with the general Uni- versity faculty. Despite his diffidence, Burnet became a very effective scientific debater. A vignette re- counted by Edward A. Boyse, FRS, describes an encounter in 1958 between Burnet and Boyse’s mentor, Peter Gorer, one of the found- ers of immunogenetics. Gorer felt that Burnet was quite “off the mark” in his ideas regarding immunology and cancer, and resolved to at- tend his London appearance and take him to task. Gorer was a dreadful speaker, so when he very much wanted to make a point, he would prepare himself by coming in, repeat- edly, to rehearse and polish what he would say — in this case, at question time. Boyse knew Gorer’s points exactly, and wondered earnestly how Burnet would be able to respond to them. Tn the actual confrontation, Gorer stated that he had some difficulty with Burnet’s results and made his case with considerable force and clarity. Burnet, however, was able to sidestep the issues adroitly by responding “Yes, Dr. Gorer, I can see your difficulty,” and signaled for the next question. Burnet’s strongly stated general views often caused considerable ruckus. In 1966 Burnet wrote a position paper for Lancet entitled “Men or molecules? A tilt at molecular biol- ogy.” Here, following his retirement, he made statements of such extremity that rebuttals are still being written. In essence, Burnet wrote that molecular biology and cell biology had not contributed anything positive to the ad- vance of medicine, and that their further pur- suit might even be an evil thing. Although one can argue that molecular biology is not even a discipline, much less a religion, the extremity of Burnet’s parting shots is indefen- sible. In 1989 Sydney Brenner wrote a strong rebuttal to Burnet’s editorial, arguing that “to- day we are all molecular biologists,” and in- deed we are. In his last book, Endurance of Life, published in 1978, Burnet develops a theory of aging based upon the accumulation of damage to DNA and considers the social implications of WALTER AND ELIZA HALL INSTITUTE 57 various aspects of aging and natural selection. His characteristic genius and ability to inte- grate diverse material shines in his approach to, paradoxically, the molecular basis of aging (see Bernstein and Bernstein, 1991 for a re- cent discussion of DNA repair in aging). Fur- thermore, he makes extrapolations to social philosophy that he knows are politically con- tentious. Among these are advocacy of abor- tion when there is a known risk of serious abnormality in the infant either from genetic causes or resulting from toxicity or infectious diseases, the advocacy of voluntary euthana- sia for individuals suffering from incurable diseases, and the conviction that individuals of “low intelligence and slovenly habits,” should be restrained from having excessively large numbers of children. Burnet was aware of the unpopularity of these views among both the general public and many academics, yet felt that the issues had to be addressed. Burnet had a love of science that underlies all his achievements. This is best articulated by his statement that “science to me is the finest sport in the world.” In our unceasing contem- porary quest to obtain increasingly more tar- geted grant funds and to deal with a skeptical public, we tend to emphasize the importance of science to the cure and prevention of dis- ease and to the improvement of the general human condition. Furthermore, we tend to get lost in the minutiae of limited projects that provide short-term research support and offer realistic short-term payoffs. These drives and pressures are indeed real, but the outstanding scientist is motivated by the enjoyment of fac- ing new challenges and conquering them. Burnet stated that the Hall Institute was “his life for 42 years,” beginning with his hum- ble appointment as a pathology registrar and culminating with his 21 years of service as director. During his years as a research fel- low, Burnet developed a reputation for com- plete dedication to science, an unflinching com- mitment to scientific integrity and personal ethics, and a lack of toleration for academic manipulation and political cant. Although these are ideal qualities of an intellectual leader, or a “tribal god figure,” they are not the qualities required of an administrator who must deal with university and governmental politics in order to ensure the growth and recognition 58 THE QUARTERLY REVIEW OF BIOLOGY of his institute. This perception of Burnet was shared by Kellaway, who felt that even though Burnet was the obvious choice to become the third director, based upon his scientific achieve- ments and international recognition, it might be a personal disservice to burden him with the political responsibilities of serving in that role. In Burnet’s words “his [Kellaway’s] view was that I was probably near my peak as an investigator and that I should go on at the bench and remain shielded by someone else from the administrative responsibilities which I would obviously find difficult and frustrating” (p. 54). Burnet, however, was quite firm on impressing to Kellaway that he did want the directorship, and Kellaway finally gave his blessing. Burnet feels that the Board of Direc- tors most probably shared Kellaway’s doubts, but their confidence in him was increased when Burnet was invited to give the Dunham Lectures at Harvard. Burnet assumed the directorship and brought the Hall Institute to a position of international prominence in immunology. He changed the focus of the Institute from an interest in gen- eral infectious disease problems with particu- lar service in times of crises to an institution devoted to the study of immunology. He re- cruited many leading scientists who either re- mained at the Institute and achieved interna- tional renown, such as Ian Wood, the Chief of Clinical Research and a leading gastroen- terologist; Gordon Ada, head of the Biochem- istry Unit, who went on to become Professor of Microbiology at Australian National Uni- versity; John Cairns, a virologist who went on to become Director of The Cold Spring Harbor Laboratory of Quantitative Biology; Donald Metcalf, who remains at the Hall In- stitute as a leading scientist in cell biology and cancer; and G. J. V. Nossal, who joined the Institute in 1957. In addition, Burnet put to- gether an administrative staff, two members of which continued to provide valuable ser- vice long into the Nossal years. One is Mar- garet Holmes, who ran the extensive animal facility and supervised the training and job performance of the technical staff, where she served admirably as mentor and counselor. The other is Arthur Hughes (“Hughsie”), who served as General Manager for the Physical Operations of the Institute. These people con- VoLuME 69 tinued to provide valuable assistance to the new director and also helped faculty and vis- iting postdoctoral fellows. Burnet thus left for his successor an intellec- tual legacy and a cluster of dedicated scientists, as well as a helpful staff. He did not, however, leave a well-funded or well-equipped institu- tion. All of the sources describing the Hall Institute in those days complain of a lack of resources, particularly of equipment. Burnet’s research was strong in ideas. He focused upon experiments that could be done with simple tools such as a microscope, petri dishes, and the Pasteur pipette. My time at the Institute was spent during the transition years, and I personally can attest to the lack of biochemical equipment needed to bring the Institute into technological parity with the world’s leading research centers at the time. Another aspect of the contradictions shown by Burnet is in his attitude toward equipment and new tech- nology. Despite deemphasizing these aspects of science, he wrote wistfully in the Foreword to my monograph, Immunity in Evolution, that “he [Marchalonis] has been able to make use of all the more refined biochemical and radio- chemical techniques which my own generation lacked” (my italics) (p. xx). NOSSAL’S DIRECTORSHIP AND THE GROWTH OF THE INSTITUTE Burnet realized that he had made his con- tributions and that someone with a new out- look and personality was required to provide the resources necessary to catalyze and sus- tain the material growth of the Institute. Just as Burnet was Kellaway’s handpicked succes- sor, Nossal was Burnet’s. Nossal took over the directorship at the age of 34. He was a friendly, outgoing and likeable individual who was not reluctant to enter the academic and governmental political fray. Rather, he actu- ally relished the interactions. The point comes across in the Charlesworth et al. book that the ghost of Burnet is still a powerful presence at the Institute, and that his example reminds today’s scientists that “small can be both beau- tiful and successful.” By contrast, Nossal is “not seen so much as a role model for the budding young scientist in the Institute, but as a skilled administrator and entrepreneur.” Many of the comments in the Charlesworth Marcu 1994 et al. book remind me of the gossip I heard on almost a daily basis when I was a member of the Institute. In addition, there was consid- erable jealousy expressed toward Nossal by faculty members at other research centers and universities, who felt that the Hall Institute was obtaining a disproportionate share of Aus- tralian research funds. Possibly this sort of criticism is inevitable to a “front-runner,” but due credit has not been given to Nossal’s scien- tific achievements. It should also be stressed that he was extremely generous in providing support to young investigators. His approach was, and still is, unusual because he ensured that even postdoctoral fellows had technical and resource support, and he did not feel that it was necessary to put his name on every paper. On the research front, Burnet provided the concept of clonal selection, and it was Nos- sal who has fought the battles that continue to this day in defending various aspects of it. I will return to this point later. One can find fault with details of Nossal’s leadership, but there is no question that he took an extremely small research operation and turned it into a large center that is intel- lectually and technologically competitive with major international centers in immunology, cancer research, immunopathology, molecu- lar immunology, and autoimmunity. It is in- structive to analyse the budgetary growth of the Hall Institute as a function of time and to correlate this with changes in staff and pub- lications. Despite the inherent limitations of this type of analysis, it is also worthwhile to compare the Hall Institute data with corre- sponding data from other institutions. The Institute started with a modest annual bequest from the Walter and Eliza Hall Foundation that amounted to £2500 a year (approximately $5000). The total income of the Hall Institute in 1926 as estimated by Burnet was $13,275, and in 1965 it was $358,600. During Nossal’s first five years, this amount doubled and sub- sequently (Fig. 2) grew with an average rate of 18% per year until 1991. The data shown here are taken from the Hall Institute Annual Reviews for the period 1987 through 1992, and are not corrected for inflation. The growth of the Institute largely reflects the results of a productive ongoing partnership with the Australian Government. WALTER AND ELIZA HALL INSTITUTE 59 Budget (x, millions) ° o 3 a 8 g I ! xq 37 ~4 wa aa ® oF 2 S a oJ wd 24 od o Staff (e) Publications (¢) Fic. 2. Grapu SHOWING THE ANNUAL BUDGET (in MILLtons oF AusTRALIAN DoL.ars), THE NuMBER OF STAFF, AND THE NUMBER OF PUBLICATIONS GENERATED BY THE WALTER AND Exiza HALL INSTITUTE FoR 1967 THROUGH 1991 Data were taken from the Annual Reports of the Hall Institute covering that time period. In order to ensure stability of the Institute research operation and to allow the possibility for necessary growth, Burnet recognized the need for obtaining a “special relationship” with the National Health and Medical Research Council (NHMRC). Burnet was unsuccess- ful in attaining this goal, but Nossal established a working relationship with the NHMRC in 1968 that ensured that staff salary and much of the research expenses were covered by that federal agency. He also negotiated an arrange- ment with tle State of Victoria that covered the operating expenses of the Institute, such as maintenance of the plant and facilities— those activities that scientists in the U. S. think of as covered under “indirect costs.” In 1991- 1992, the Australian Federal Government con- tributed 42.9% of the operating revenue and the State of Victoria contributed 8% . Austra- lian grants and fellowships contributed 10.2%, whereas “other Australian sources” generated 14.9%. Industrial grants and contracts gen- erated 12.1% and 11.9% was contributed by overseas grants and fellowships. This balance is of interest, because the Hall Institute has grown without developing a special relation- ship with any particular industry, unlike the 60 THE QUARTERLY REVIEW OF BIOLOGY VOLUME 69 TABLE 1 Growth of funding for WEHI and NIAID from 1988 through 1993 Data for the Walter and Eliza Hall Institute (WEHI) were taken from the Annual Reports for the corresponding years. The data for National Institute of Allergy and Infectious Diseases (NIAID) were kindly provided by Kristin Adamson, Budget Analyst at that Institute. WEHI?* NIAID Year $$ (millions) % increase $$ (millions) % increase 88 14.9 8.4 638,800 17.1 89 15.9 6.5 744,152 16.5 90 16.4 3.3 843,745 13.4 91 18.4 11.9 906,251 7.5 92 20.5 11.7 960,082 5.9 93 Not available 979,471 2.0 * The monetary values for WEHI are given in Australian dollars, $1 Australian = 0.7 $U.S. Basel Institute for Immunology, which is a sub- sidiary of Hoffman-LaRoche, or the Scripps Institute, which has received 300 million dol- lars in research support from Sandoz. The continuing growth of the Hall Institute, de- spite bad economic times in Australia as well as the United States, is reflected in Table 1. This table compares the growth of the Hall Institute with that of the National Institute of Allergy and Infectious Diseases (NIAID) in millions of dollars and in percentage in- crease in the years from 1988 through 1993. In the first place, it is clear that the Hall Insti- tute has an extremely small budget by com- parison with NIAID. It is a large budget by Australian standards, however, where the In- stitute now receives approximately 7% of the NHMRC budget. The striking feature of this table is that the operating budget of the Insti- tute continued to increase until 1992, whereas that of the NIAID has been declining since 1988. Nossal has informed me that the Insti- tute is not immune from budgetary stagna- tion, and he expects the 1993 research spend- ing figure to be approximately equal to that for 1992. An extremely serious issue with respect to U. S. funding is seen in 1992, when the per- centage increase fell below the rate of infla- tion. This trend continues with the U. S. sci- entific community facing catastrophe, even though as Nossal states “the absolute level of medical research funding in the United States is still the envy of the whole world” (pers. com- mun.). Science and medicine in the United States are under attack from all sides, and similar attacks are occurring in Australia, as reflected in Charlesworth et al.’s book. The trend shown for NIAID, coupled with increas- ing political pressure on federal grant agen- cies either to fund the “political priority of the month” or to prepare for cuts, signals a crisis for research in immunology (and science in general), unless immediate steps are taken to remedy the situation. Charlesworth et al. are correct in pointing out that science is a social phenomenon and one that reflects perceived economic realities. I would disagree with the Marxist analysis, however, and emphasize that science is an ex- tremely challenging and essential aspect of hu- man endeavor that does not have a stable fund- ing base. In the United States, it is possible to obtain relatively large short-term funding to carry on research, but these funds confer no stability to the effort. Projects that have be- gun to make great progress are terminated after three years because there is insufficient fund- ing to continue them. This is irrespective of the progress they have made and the quality of the people involved. It reflects predominantly short-term perceptions of financial needs, sci- entific trends, or political directions. Nossal is to be commended for developing a unique nongovernmental institution (the Institute is incorporated in Victoria as a Company) that allows individuals the stability to pursue re- search that does not produce immediately mar- ketable or clinically relevant ends. One of the major aspects of Nossal’s philosophy that im- Marcu 1994 pressed me as a postdoctoral fellow and sub- sequently a faculty member, was that these individuals were allowed both technical and research support, irrespective of their genera- tion of particular grants. It was expected, of course, that the individuals would apply for extramural funding, if their Institute-funded initiatives were successful. In the 1970s, the junior faculty at the Insti- tute were extremely successful in competing for funds from U. S. agencies, including the National Institutes of Health and the National Cancer Institute. Their competitiveness was predicated on, first, their ability to generate critical primary data because of in-house sup- port and, second, on the fact that the Hall Institute did not ask for indirect costs on the U. S. federal grants. This was a very attrac- tive selling feature, since U. S. universities can ask for add-ons of more than 100% of the direct or research part of the grant. The stability provided by this kind of in-house sup- port is characteristic of the Hall Institute and also of the Basel Institute for Immunology. It has enabled the initiation and development of projects that could not be funded in a short- term peer-reviewed mechanism. The need for this stability was recognized by Burnet and incorporated into a central feature of the Hall Institute under Nossal’s leadership. Figure 2 also includes annual data on the number of staff and on publications gener- ated. The current staff numbers 270, plus 44 postgraduate students. Analysis of the graph indicates that the number of staff remained relatively constant from 1966 to 1986, when the new enlarged Institute building came on- line, after which the staff size approximately doubled. The number of permanent faculty at the Institute is relatively small (35), and there is a large number of postdoctoral fellows and support staff representing technicians, people involved in the animal facility, secre- taries, and other service capacities. Technical support and individuals involved in running the animal facility are essential to the success- ful operation of the Institute, with its particu- lar focus on research in mice. The relative constancy of staff size in the years 1966 through 1985, coupled with a generally small budget from 1966 through 1980, raises some amusing issues when annual publications are consid- WALTER AND ELIZA HALL INSTITUTE 61 ered. Each year at the public board meeting the chairman of the board, Sir Colin Syme, the CEO of Broken Hill Propriety Ltd., would begin his remarks by saying that when he dealt with his stockholders in the mining industry, he knew how to analyse productivity, but when it came to reporting on what the annual pro- ductivity of the Hall Institute was, he was at a loss. Thus, he would refer to the number of publications as an indication of productivity. The data show that there were essentially three “bubbles” of generation of papers. The first was from 1969 through 1972, which was es- sentially independent of staff size and budget. The second was from 1980 through 1984; it correlated with a large increase in budget. The most recent one in the late 1980s corres- ponded with both budgetary and staff increases. The move to the new building in 1986 af- forded the possibility of expanding the gradu- ate student and postdoctoral population con- siderably, as is evident in the bubble. The first publication bubble of the Nossal years reflects a time of great excitement at both the Institute and with immunology throughout the world. Miller and Mitchell had recently initiated their forays into the function of the thymus, and a nucleus of advanced technol- ogy in cell culture and molecular immunology was growing at the Institute, allowing it to make new explorations into the nature of re- ceptors for antigens on B and T cells and on mechanisms of T and B cooperation. Every- thing we did was new and exciting and gener- ated general interest, as evidenced by publica- tion in quality journals and by invitations to present the data at international meetings. It was the initiation phase of a new field, which was subsequently followed by a consolidation phase in which investigators from other insti- tutions became involved and paradigms were continually being reexamined. Nonetheless, the impact of publications by Hall Institute workers during that time period was large on an international scale as reflected by citations of publications, and the fact that many of the concepts and presentations of the time either are generally accepted or are still being actively debated. In Contemporary Classics in the Life Sciences (Vol. 1), which covers cell biology including immunology, publications by the following Hall Institute investigators 62 THE QUARTERLY REVIEW OF BIOLOGY were given status as “citation classics”: Gor- don Ada, Anthony Basten, Alistair Cunning- ham, John Marbrook, John Marchalonis, Don Metcalf, J. A. F. P. Miller, Graham Mitchell, Gus Nossal, Ken Shortman, and Alex Szen- berg. This short list of Institute personnel during the early Nossal years illustrates con- tributions by individuals who remained at the Institute through the whole of their research careers (Miller, Shortman, and Szenberg), and the contributions of individuals who trained at the Institute and went on to other positions and careers (Basten, Cunningham, Marbrook, Marchalonis, and Mitchell). We would agree with a disclaimer by Nossal that it is easier to publish papers in cellular immunology than it is in other areas, such as biochemistry or molecular biology, so that the number of pa- pers alone should not be taken to reflect the entire productivity or quality of the Institute. The papers by the investigators cited here, however, range from cellular immunology to techniques for the analysis of antibody-secret- ing cells, the separation of lymphocytes, and to biochemistry. Thus a small group of inves- tigators generated a relatively large burst of papers that stimulated general interest. Many of the points of view and findings were contro- versial and generated intensive debate, which continues today. This is another feature of science as a social entity that was alluded by Charlesworth et al. but, unfortunately, was not developed. It would be an extremely in- teresting and insightful exercise to analyse in sociological and individual terms some of the major immunological debates in which the Hall Institute plays major roles. Two areas that merit in-depth analysis are the determi- nation of the nature of the antigen-specific re- ceptor on T lymphocytes and the role of the major histocompatibility complex in the regu- lation of the immune system. Study of these key immunological issues would demonstrate how different positions are taken by smaller groups, as well as by larger groups represent- ing national viewpoints, and how a definitive position is chosen. Nossal took a relatively small institution that was poor in equipment and resources but rich in the quality of its few scientists and gave it both growth and stability to pursue novel or unpopular research that allowed it to be VOLUME 69 competitive in resources with leading institu- tions in immunology and molecular biology worldwide. As an example that illustrates the success in building the financial base of the Institute, Burnet reports that the endowment and working capital of the Institute in 1965 was £690,100. In 1992, Nossal reported that the total invested principal has a book value of $25,719,684.00 and a market value of greater than $40 million (Australian). The Institute is now housed in a modern building of seven floors (15,000 sq. meters) and includes a ma- jor animal facility. The area of the Institute and the support generated do not reflect accurately the impact that the Hall Institute under Nossal’s leader- ship has had on the development of immunol- ogy as a widely recognized independent disci- pline. From that standpoint, the real product is the people who were trained at the Institute and who went on to make contributions in the field and carry with them principles they learned during their period of training there. In the first place, the Institute was a magnet for some of the best people within the British Empire, and trained some outstanding indi- viduals from the United Kingdom. A large number of individuals from the United States received training, beginning in Burnet’s days and continuing to the present. There have also been times when numbers of Europeans (particularly French and Germans) and Japa- nese have trained either directly with Nossal or with other permanent faculty. The list is too long to even attempt to include everyone, but it is worthwhile mentioning a few individuals who have cometo prominence outside of Aus- tralia. These include Erwin Diener (Canada), Noel Warner (USA), Harold Von Boehmer (Switzerland), Marc Feldmann (UK), Masaru Tanaguchi (Japan), Martin Rollinghoff (Ger- many), Gregory Warr (USA), John T. Boyer (USA), Robert E. Cone (USA), John Mar- brook (New Zealand), and John Schrader (Canada). The impact of the Institute was large in the number of individuals trained. This is reflected in the content of immunology courses taught to graduate students, under- graduates, and medical students. Even here, at the University of Arizona, we have six indi- viduals who received training at the Hall In- stitute (J. M. Decker, D. DeLuca, J. T. Boyer, Marcu 1994 G. 8. Boyer, M. Schumacher, and myself). This aspect of the Hall Institute as a training ground for future contributors to immunol- ogy deserves special attention because a small institution has imprinted its philosophies and modes of operation upon a large group of peo- ple, many of whom have achieved positions of leadership in areas of immunology and medical research. CLONAL SELECTION: THE CONTINUING SAGA By the late 1940s and the early 1950s, it was clear that mammals had the capacity to respond immunologically to a potentially lim- itless array of foreign antigens, including mi- crobes, proteins, carbohydrates, and even small organic molecules termed haptens, in an ex- tremely specific fashion. The structure of anti- bodies and even the nature of the cells produc- ing them was not established, but a number of theories were proposed to explain how one individual could respond specifically to an ex- tremely large set of foreign antigens, The prob- lem was an intellectually challenging one and leading figures, including Linus Pauling and Felix Haurowitz, entered the fray that came up with instructive theories, but they missed the mark on anumber of grounds. Niels Jerne (past director of the Basel Institute for Immu- nology; Nobel Laureate, 1984) recognized the importance of preexisting natural antibodies in the recognition of foreign antigens and pro- posed a selective theory based upon this inter- action. Burnet built upon Jerne’s theory but added a dimension, following from his experi- ence as a microbiologist and naturalist, that allowed him to formulate what has proven to be the correct theory. Burnet had worked on bacterial phages, on viruses such as influenza, and on bacteria. His contributions in the area of infectious disease were widely recognized; for example, he was honored by having the causative agent of Q fever, Coxtella burnetti, named after him. In solving the problem of the generation of specific antibodies, Burnet assumed that Dar- winian principles of genetics must apply. He made the insightful prediction that the lym- phocytes in the body were analogous to a popu- lation of microbes in a test tube, where individ- ual variants were generated by spontaneous mutation and selective conditions could be WALTER AND ELIZA HALL INSTITUTE 63 SIE “TAM \ \ \ QQ @) of QSL ABC %h 99° ore Fic. 3. Burnet’s ORIGINAL ILLUSTRATION OF THE CLONAL SELECTION THEORY OF IMMUNITY He states that “contact of the corresponding anti- genic determinant Ag.C with cells of clone c stimu- lates proliferation to antibody-producing plasma cells cp and non-producing type c” (Fig. 7 from Burnet, 1959, with permission of the Vanderbilt University Press and the Cambridge University Press). set up for the particular mutants. A selective theory is in principle Darwinian, whereas in- structive theories are Lamarckian. The micro- bial analogy for the lymphocyte population is depicted with Burnet’s original diagram in Figure 3. The lymphocyte pool consists of a large population of individual cells marked a, b, c, . . ., on the basis of expression of a cell surface form ef receptor immunoglobulin that can bind in a complementary manner to an antigen designated here by the capital letter C. Specificity is imparted because that anti- gen will interact only with one or a small num- ber of the large set with sufficient affinity to initiate activation and clonal proliferation. The end stage is the production of plasma cells that secrete antibodies specifically reac- tive with antigen C. The system is Darwinian in that the antigen does not provide new infor- mation, but merely selects among the cells on the basis of interaction with a receptor en- coded by an existing gene. Burnet assumed that by analogy with mi- crobes the variation would occur by a sponta- 64 THE QUARTERLY REVIEW OF BIOLOGY neous mutation process that was essentially random in nature. Since this process is ran- dom, the likelihood of the surface antibody receptors reacting with self antigens would probably be just as great as their probability of reacting with foreign or nonself markers. In order to get out of this trap of autoimmu- nity or “horror autotoxicus,” Burnet invoked the concept of “tolerance,” in which an animal deletes cells capable of reacting with self when they arise early in the development of the ani- mal and come in contact with self antigens. To account for the occasional occurrence of autoimmunity, he proposed that this was the result of the activation of “forbidden” clones directed against self antigens. In a sense, auto- immunity would reflect a failure of tolerance. This concept is elegantly simple and explained much of the phenomenology of immunology and also provided an intellectual holy grail as people applied increasingly sophisticated biochemical and recombinant DNA technol- ogies to prove it and to explain it in molecular terms. For this concept and its implications, Burnet shared the Nobel Prize with Peter Medawar in 1960. Nossal and many others devoted consider- able effort to establishing clonal selection by showing that individual antibody-forming cells were indeed restricted in their capacity to re- spond to antigens, were monoclonal in the light and heavy chains of the antibodies they expressed, and finally, contained individual functional genes specifying immunoglobulin chains. In elegant molecular biological stud- ies, Susumu Tonegawa and his associates showed that clonal commitment results from the selection of one variable region gene seg- ment in the germ line and its recombination with a joining segment gene in B cell differen- tiation to form a rearranged gene capable of being translated into messenger RNA and eventually leading to synthesis and secretion of only that particular gene product by a par- ticular cell. The diversity in the first instance is caused by the existence of large numbers of variable region gene segments and the clonal restriction follows from the selective usage of particular ones in individual cells. An exam- ple of the type of diversity that could be gener- ated by this kind of mechanism would be 300 Vv, genes x 5 J, segments generates 1500 V, VOLUME 69 possibilities; 300 Vy segments x 10 diversity segments x 5 Jy segments generates 15,000 Vu possibilities. Since a combining site is formed by a VyV_ interaction, this allows the formation of a possible 22.5 million combin- ing sites that could be interpreted as the ability to recognize that many distinct antigens. Ad- ditional diversity comes from somatic muta- tion and variability caused by stabilized mis- reading of the D and J segment insertions. The clonal selection theory provided a major impetus to develop and apply new technolo- gies to lymphocytes and antibodies and ap- pears to have a solid place in history. The primal formulation of clonal selection, however, is currently under strenuous attack. Challenges to the clonal selective theory come from two areas. The first attack stems from the observation that “forbidden clones” are not rare and found only in autoimmune diseases, but are extremely common and expressed by virtually all normal individuals. This ques- tions the efficacy or existence of a clonal dele- tion or abortion mechanism and has raised possibilities that network type interactions in which antibodies recognize other antibodies by other combining sites and other control regions actually serve to regulate the system. Cohen (1992), for example, states that a “cog- nitive” rather than a “selective paradigm” is a more accurate theoretical description of the immune response. In a sense, the regulation of the immune system is depicted as being closer to Jerne’s early model of interactions among natural antibodies, as opposed to Bur- net’s emphasis on a specific clonal mechanism dependent upon the binding of the immuno- globulinlike cell surface receptors to the target. antigen, where specific regulation follows most readily from amplification or removal of ap- propriate clones. A second area stems from the application of the techniques of molecular biology to im- munoglobulin genes of primitive vertebrates. In particular, sharks are elasmobranchs that arose over 400 million years ago and have potent immune responses based upon IgM (immune macroglobulin) antibodies. Genes specifying light and heavy chains of immuno- globulins in at least two species of sharks are not arranged as described above for mam- mals, where there are large arrays of variable Marcu 1994 region gene segments and smaller arrays of joining (and diversity segments in some cases), with a few constant regions, the entire com- plex spreading over hundreds of kilobases. These complexes have been called translocons because of the need for rearrangement of at least the variable and joining elements. By contrast, the immunoglobulin genes in the elasmobranchs are arranged in little clusters, which in the case of light chains, are of only 3 kb in size and contain V, J, and C segments. Each cluster is different in the exact sequence of the V, J, and C elements, and there are many (hundreds or thousands) of these sepa- rated by large distances on the chromosome. Moreover, the V and J segments can be fused in register in the germ line (Hohman et al., 1992). Thus, diversity is generated in a differ- ent way than in mammals, but the capacity is there for expression of large numbers of immunoglobulin combining sites. If, for ex- ample, there are a minimum of 100 Vy and 100 V, genes each, at least 10,000 distinct combining sites can be generated. The diffi- culty with respect to clonal restriction is that if these individual clusters act independently, a new mechanism must be developed to ac- count for clonal restriction. To put the prob- lem in perspective, if the individual clusters are separated by roughly 100 kb, the first and last cluster would be separated by an enor- mous germ line distance and would be un- linked to one another. If the first one is acti- vated, how is the last one, or in fact any of the intermediate ones, to know this and not themselves be activated so that the cell would produce multiple immunoglobulin light or heavy chains? I believe that Sir Mac would be delighted to know that his theory is still generating this interest and even furor that may go on into the next century. My guess is that clonal selection will remain intact when the dust settles, but the use of recombination alone as a means of clonal restriction will fall by the wayside. THE INSTITUTE AND THE FUTURE Burnet turned the Walter and Eliza Hall Institute from its rather broad interests in ex- perimental medicine and infectious diseases to a focus on immunology, and brought inter- national recognition to this Australian institu- WALTER AND ELIZA HALL INSTITUTE 65 tion while laying the intellectual foundations for the emerging discipline. Nossal has been extremely successful in building a physical plant and obtaining resources allowing the Institute to be competitive with leading world centers. I have heard Nossal described as the “world’s most visible immunologist.” He holds fellow- ships in the Royal Society of the United King- dom and the National Academy of Sciences of the USA, and has recently completed a term as president of the International Union of Im- munological Societies. His scientific work, be- ginning with his training as a student in Bur- net’s laboratory, dealt originally with obtaining proof of the clonal selection theory and contin- ues to this day with a strong program applying the principles of clonal selection to B cell mem- ory and tolerance. Two conclusions gleaned from the experi- ences of Burnet and Nossal are extremely per- tinent to present day immunology and bio- logical science, in general. The first is that in order for a research institute to be competi- tive, there must be a financial base and a phil- osophical commitment that allows for long- term support of promising investigators and projects. This conclusion is particularly rele- vant to the initiation of novel projects, to the pursuit of difficult areas that do not lend them- selves to quick solutions, and to unpopular avenues that may prove to be correct. Science would not have progressed without these op- portunities. One of the best examples is, of course, Burnet’s clonal selection theory. The other is a fundamental scientific discovery that set the stage for the modern burst of mo- lecular biglogy. Oswald T. Avery, Colin M. MacLeod, and Maclyn McCarty would not | have been able to dedicate ten years to the arduous biochemical proof that DNA was the pneumococcal transformation (i.e., genetic) factor if it were not for the stability offered by The Rockefeller Institute for Medical Re- search. There is, thus, a need for stability allow- ing for the pursuit of unpopular and even con- troversial research. Burnet’s strong advocacy of this position was clear in his advice given to me in 1976 in an attempt to dissuade me from leaving the Institute and returning to the U. S. He remarked that he had turned down chairs at Oxford and Harvard because he could be as controversial as he wanted to 66 THE QUARTERLY REVIEW OF BIOLOGY be, and could safely ride out the storms of response, at his Australian institute. The second issue of contemporary concern is related to the first, and is shown in Burnet’s repeated convictions that serious science can- not be done in a university or medical school setting. His argument is that an outstanding scientist must be totally committed to the pur- suit of his research, whereas this is only a part- time occupation in the traditional academic environment. Furthermore, universities have other agendas and constituencies to satisfy. With one recent exception, all of the Austra- lian universities are “state universities” and the downturn of the economy with its loss of tax revenues has most probably hit Australia. This downturn has already had a devastating effect on U. S. state universities. Major Ameri- can universities have not only had their fund- ing fall behind inflation but also have suffered numerical cuts. In this environment of decere- brate cost cutting, universities do not support research, Rather, they use research-generated funds to support underfunded instructional and accessory programs. Burnet chose not to become involved in formal instruction and in the university politics that would have ensued had the director of the Institute also become chairperson of the Department of Medicine. The Institute achieved the necessary stability by forming a special partnership with the Aus- tralian Federal Government and with the State of Victoria. The Hall Institute and the much larger Rockefeller Institute (University) have been landmarks in both the development of new ave- nues of research and in maintaining continu- ity. Burnet clearly recognized the problem in the 1930s and 1940s and worked to strengthen his Institute. The fundamental problem was masked by the economic growth of the 1960s, 1970s, and 1980s, but as illustrated in Table 1 above, it is back with a vengeance. Was Bur- net right in concluding that serious research could be carried out only at a research insti- tute? The general attitudes of public skepti- cism or hostility as outlined by Charlesworth et al. indicate that today’s scientist has a con- siderable barrier to surmount in convincing politicians that the biological sciences should be adequately supported. Australia has a rigid policy that retirement is mandatory at age 65. Nossal is approaching VOLUME 69 retirement and rumors are already spreading among the international immunological com- munity concerning the future of the Hall In- stitute. In particular, when a new director is chosen, will that person retain the emphasis in immunology or expand into new areas? Under Nossal’s leadership, strong programs have been developed in parasitology, an area of major concern to the Third World, and in hemato- oncology, where Metcalf has spearheaded an internationally acclaimed program on colony stimulating factors and their identification as cytokines. Despite wrestling with various po- litical crises tending toward cutting support for research, particularly in the early 1970s, Nossal has always maintained a strongly posi- tive attitude in stressing the importance of immunology and medical sciences in general. Following his retirement as director, he will probably play an even greater role on an inter- national scale in convincing governments and industry of the importance of supporting ba- sic science. His legacy will not be the creation of a major scientific paradigm as was Burnet’s, but it will be the major center he has built and, possibly more importantly, the large cadre of young scientists he imbued with enthusiasm and a commitment to immunology. The two men differed markedly in their attitudes to- ward their imminent retirements. Burnet made statements to the effect that everything of im- portance had been done and, in some ways, it might even be dangerous to apply new ap- proaches, such as molecular biology, to hu- man problems. The ramifications of this are still felt. His attitude has been characterized as a “Gotterdammerung” or an “aprés moi le déluge” attitude. ‘Nossal, on the other hand, has stated that he “truly takes great joy in the observation that there are so many colleagues in their thirties who are so much brighter and more knowledgeable than I am and in whose very good hands one can leave the future of science and immunology!” (pers. commun.). Burnet was a complex and often contradictory figure. I would like to close with a perception that I believe captures the essential spirit of the man and underlies both his drive for suc- cess in science and his capacity for outra- geous, but often correct, statements: “Science to me is the finest sport in the world. . . . The higher the animal the longer is the period of play and the more keenly it is enjoyed. There Marcu 1994 is something of Peter Pan in all of us and in good scientists more than most.” ACKNOWLEDGMENTS I am grateful to Sir Gus Nossal for his cri- tique and provision of factual information, to Kristen Adamson and James Hill of the WALTER AND ELIZA HALL INSTITUTE 67 National Institute of Allergy and Infectious Diseases for budgetary information, and to for- mer WEHI alumni, John T. Boyer, Robert E. Cone, and Laurens Ruben (sabbatical visitor) for comments and criticisms on the manu- script. I thank Diana Humphreys for her as- sistance in the preparation of this manuscript. REFERENCES Barrett, J. T. (ed.). 1986. Contemporary Classtcs in the Life Sciences, Vol. I: Cell Biology. ISI Press, Philadelphia. Baskin, Y. 1991. Manifest destiny at the Scripps Research Institute. Science, 253:140-142. Bernstein, C., and H. Bernstein. 1991. Aging, Sex and DNA Repair. Academic Press, New York. Brenner, S. 1989. The useless and the dangerous. In J. Drews and F. 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Australian Society for Microbiology, Marybor- ough. Hohman, V.5S., 8. F. Schluter, and J. J. Marcha- lonis. 1992. Complete sequence of a cDNA clone specifying sandbar shark immunoglobu- lin light chain: Gene organization and implica- tions for the evolution of light chains. Proc. Nail. Acad. Sci. USA, 89:276-280. Nossal, G. J. V. 1978. Antibodies and Immuntty. Ba- sic Books, New York. Sexton, C. 1991. The Seeds of Time: The Life of Sir Macfarlane Burnet. Oxford University Press, Ox- ford. Walter and Eliza Hall Institute of Medical Re- search, Annual Reports, 1967-68 to 1991-92. Wood, I. J. 1984. Discovery and Healing in Peace and War. Acton Graphic Arts, Hawthorne.