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Home , Frank Fenner, Gordon Ada, Macfarlane Burnet, WEHI

HISTORICAL COMMENTARY

Frank : two personal views

Frank Fenner &

In honor of the fiftieth anniversary of Frank MacFarlane Burnet’s presentation of the theory, two of his former staff reminisce about their interactions with this –winning scientist.

here is no shortage of publications about experiments that kindled his interest in anti- TFrank MacFarlane Burnet. His autobiogra- body production. http://www.nature.com/natureimmunology phy1, Sexton’s biography2 and the biographical In 1931, he received an offer that changed memoir for the Australian Academy of Science3 his life: two years at the National Institute of all provide detailed information about his Medical Research in , to study animal career as a scientist. Here, in honor of the fifti- . There, he witnessed the first isolation eth anniversary of Burnet’s presentation of the of human , an agent that was clonal selection theory, we attempt to convey, to dominate much of his subsequent scientific in a more personal manner, an account of our work, and he initiated investigations using interactions with and impressions of Burnet. developing chicken embryos to grow various (a technique still used in 2006). Back Burnet’s early work in , he continued this work and also

Nature Publishing Group Group Nature Publishing As a child, Burnet was an enthusiastic collec- published his first book, Biological Aspects of 7 tor of beetles. He graduated MB BS in 1922 Infectious Diseases5.

200 and MD (by examination) in 1924, and after

© serving as a house physician to the leading neu- ’s association with Burnet rologist of Melbourne, , Sir Richard In October 1944, while I was still serving in Stawell, he was convinced that his future lay the Australian Army, my boss, the Director of Frank MacFarlane Burnet at the time of his retirement. Courtesy of the Walter and in clinical neurology. However, the Melbourne Hygiene and , Colonel E.V. Keogh, Institute of Medical Research. Hospital superintendent judged (correctly) made arrangements for me to work at WEHI that his character and personality were more for six weeks. In July 1945, I received a letter compatible with laboratory . In from Burnet offering me a senior position influenza in the United States. In contrast, he 1924, he was appointed to the position of hos- there, to work on the experimental epidemi- allowed me complete freedom to do as I wished pital pathologist, then operated as part of the ology of ectromelia virus, which he had just in my project on ectromelia. He did not like Walter and Eliza Hall Institute (WEHI). The shown to be closely related to the vaccinia driving a car, so the laboratory manager used new director of the Institute, Charles Kellaway, virus. I took up the post in February 1946 and to pick him up and take him home. He worked decided that Burnet should train overseas and worked with Burnet’s group until August 1948, at the laboratory bench from 9:30 a.m. until sent him to the Lister Institute in the UK, where when I went to the Rockefeller Institute in New 4 p.m. each weekday. Although we met at the he gained a PhD working on York as a postdoctoral fellow. tea room, he was a reserved man and talked at the . Back in Australia Burnet was the most creative and imaginative little. He smoked cigarettes then, although in 1928, he was asked by Kellaway to carry out scientist that I have known; and I worked for a he later campaigned energetically against bacteriological investigations on children who year at the Rockefeller Institute in 1948–1949, smoking. died after immunization against diphtheria4. when it was the leading medical research insti- When I had completed an investigation and Burnet showed that these deaths were due tute in the world, and at Cambridge University written it up, I would give the draft to Burnet. to staphylococcal and carried out in 1961–1962. When I arrived at WEHI in 1946, He would read it that evening, and at 4 p.m. the Burnet and all other staff were working on next day we would meet in his office to discuss Frank Fenner and Gordon Ada are at the Australian influenza virus. Burnet kept tight control over its publication. He would ask about my cur- National University, , Australian Capital their investigations, for in those days of almost rent and ongoing work; and in contrast to the Territory 2601, Australia. nonexistent overseas travel, he thought that practice common in many laboratories then e-mail: [email protected] he had to compete with large teams studying and now, Burnet never put his name on a paper

NATURE VOLUME 8 NUMBER 2 FEBRUARY 2007 111 HISTORICAL COMMENTARY

involving bench work unless he had done some Burnet, internationally recognized for his complementary patterns (receptors having the of that work himself. As a result, all 11 of the work on viruses, especially influenza virus, but same specificity as the secreted ). papers on mousepox (as we later called ectro- with a strong interest in immunology, went to This would result in the preferential prolifera- melia) were published under my name, some- in 1943–1944 to deliver tion of these cells, so that the response to a sec- times linked with that of my wife Bobbie, who the Dunham Lectures. He was due to return to ond dose of the same antigen would be much was my unpaid technician. Melbourne as the new director of WEHI, but greater and more rapid, a phenomenon that Although Burnet’s work focused largely on upon seeing how well-equipped the Harvard he had described in the first and second WEHI influenza, he retained a deep interest in anti- laboratories were, he was tempted to accept a monographs10,11. In contrast, Jerne discussed body production stemming from his early work professorship offered by Harvard. Nonetheless, the interaction of antigen with the secreted on children immunized against . In Burnet finally decided to return to Australia, , and its fate. Because one of his earlier the 1930s, the chemists Breinl and Haurowitz6 where he later received a grant of £20,000 from ‘bright ideas’ books13 had been severely criti- and Mudd7 had suggested that antibody pro- the to purchase equip- cized, Burnet published a brief account of his teins were folded in specific ways after contact ment. The senior biochemist at WEHI, Henry concept, which he called the clonal selection with antigenically important parts of antigens, Holden, told him about my experiences; hence theory, in a local Australian journal. Essentially, which acted as templates; this theory formed the letter in early 1948 inviting me to come to the article proposed that individual B lympho- the basis for an essentially ‘instructive’ hypo- the Institute and assist Holden in establishing cytes produce antibodies of a single specific- thesis about antibody production8. Some a biophysical unit. I accepted. ity14. There was much discussion of the theory years earlier, Glenny and others studying anti- At the time, WEHI housed about 30 insti- at WEHI seminars, and although he admitted body responses to diphtheria toxin had shown tute staff, most of whom were young virolo- he could not guarantee that there was not more that there were profound differences between gists. I spent all my time doing collaborative than one antibody specificity per B lympho- primary and secondary antibody responses9. research, which was easy to arrange. Burnet cyte, he very much preferred one. His book on In the early 1930s, Burnet repeated these spent most of the day in the laboratory that this topic was published two years later15. experiments with staphylococcal toxoid and he shared with others. He sat at a set spot at Then came the surprise. At a special staff http://www.nature.com/natureimmunology concluded that the exponential increase in lunch, and this was the place to catch him for meeting late in 1957, he announced that antibody titer that occurred during the sec- a quick discussion on a serious topic. Having henceforth all laboratory research in WEHI ondary response indicated that the multipli- earlier seen the effects of the 1918–1919 pan- would focus on immunological topics; virology cation of some entity concerned with antibody demic influenza in Melbourne, he decided that would be phased out. At about this time, the production was involved and therefore that the most laboratory staff should work on influenza eminent bacterial geneticist instructive hypothesis must be wrong. virus, in the hope that such studies might lead arrived on a quick visit to discuss viral gene- He did not publish these results until 1941, to a vaccine. Seminars were held on Saturday tics with Burnet. A recent medical gradu- when he produced the first WEHI monograph, mornings, and though we all appreciated his ate, G.J.V. Nossal, also arrived, intending to The Production of Antibodies10, in which he set attendance, Burnet was basically a shy person work on a virology topic for his PhD. Instead, out his reasons for discarding the instruc- and could be uncomfortable when answering using Lederberg’s expertise, together the two

Nature Publishing Group Group Nature Publishing tive hypothesis. Early in 1948, he asked me to some questions. He would usually return later devised a unique microscopic to deter- 7 collaborate with him in producing a second with a precise reply. mine whether rats, each immunized with two 11 200 edition of The Production of Antibodies . In the early 1950s, I was collaborating with serologically distinct salmonella flagella, pro-

© Although I helped chase up some of the work Joyce Stone. One day, as we were comparing duced an individual plasma cell that secreted done since 1940, notably Medawar’s studies of results, Burnet approached and simply asked antibodies with two distinct specificities, transplantation immunity, Burnet was respon- us, “Do you think what you are working on is each capable of recognizing one flagellum16. sible for all the interpretation and speculation. worthwhile?” When we had overcome our sur- Altogether, 1,500 cells were examined, but not The second edition is notable because it con- prise, we simply replied, “Yes.” He then walked a single ‘double producer’ was found17. This tains the first mention of the concept of immu- away, lost in thought. Was this an indication of result was the first direct evidence consistent nological tolerance, which was the topic cited some looming change? Burnet was working on with Burnet’s hypothesis. Analyses of a similar in the award of the Nobel Prize to Burnet and influenza virus . The structure of DNA type were performed by others, but the results Medawar in 1960. had just been published, and he was concerned were not always so clear-cut. about the surge of interest in the new area of Burnet then began to study , Gordon Ada’s association with Burnet . but he traveled abroad most years until 1964, to Shortly after receiving a BSc Honors degree By that time, it had become clear that anti- give special lectures on clonal selection. Initially, in from Sydney University in bodies could be produced that recognized he had to argue strongly, as the theory was not 1943, I was invited to continue my work at almost any protein, even synthetic molecules popular. However, work aimed at elucidating the Commonwealth Serum Laboratories in made of different oligopeptides. Thus, it was the structure of antibody molecules and related Melbourne, where I achieved some success— realized that the range of different antibody topics forged ahead. At a meeting in southern and met Henry Holden at WEHI. I had begun specificities must be very great. It was a paper California in early 1965, different amino acid to realize the need for techniques such as ultra- by Niels Jerne12 in 1955, claiming that the sequences for different antibody molecules centrifugation and moving-boundary electro- blood contained tiny amounts of free anti- were reported. The slides were shown for only phoresis for studying and separating proteins. body to antigens that the body had never seen, a short time, to avoid details being copied. In These were unavailable in Australia, so in mid- that sparked a new idea for Burnet. As he later 1972, Gerard Edelman and Rodney Porter 1946 I went to the National Institute for Medical remarked about his reading of this paper, shared the Nobel Prize for their discovery of Research in Hampstead, UK, to work with them. “Suddenly, the penny dropped.” He now argued the chemical structure of antibodies. It was there, in early 1948, that I received a letter that when a foreign antigen entered the body, it When Burnet retired as director of WEHI from Burnet offering me a position at WEHI. would bind to those clones of cells that express in 1965, attitudes toward the clonal selection

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theory were changing. Burnet gave the intro- 1. Burnet, M. Changing Patterns: An Atypical Discussion (Monograph of the Walter and Eliza Hall 18 Autobiography (Heineman, Melbourne, Australia, Institute of Research in Pathology and Medicine, No. 1) ductory presentation at the first large 1968). (Macmillan, Melbourne, Australia, 1941). International Immunology Conference, which 2. Sexton, C. Burnet, A Life (Oxford University Press, 11. Burnet, F.M. & Fenner, F. The Production of Antibodies was held in Cold Spring Harbor in 1967. In Oxford, 1999). 2nd edn. (Monograph of the Walter and Eliza Hall 3. Fenner, F. Hist. Rec. Aust. Sci. 7, 39–77 (1987). Institute of Research in Pathology and Medicine, No. 2) summing up the meeting, Niels Jerne said, “Sir 4. Kellaway, C.H., MacCallum, P. & Tebbutt, A.H. Report of (Macmillan, Melbourne, Australia, 1949). MacFarlane Burnet must have been pleased not the Royal Commission into the Fatalities at Bundaberg 12. Jerne, N.K. Proc. Natl. Acad. Sci. USA 41, 849–857 only to witness at this symposium the vindica- (Government printer, Canberra, Australia, 1928). (1955). 5. Burnet, F.M. Biological Aspects of Infectious Disease 13. Burnet, F.M. Enzyme, Antigen and Virus: a Study tion of his Clonal Selection Theory of Acquired (Cambridge University Press, Cambridge, 1940). of Macromolecular Pattern in Action (Cambridge Immunity, but also to see how his stimulating 6. Breinl, F. & Haurowitz, F. Z. Physiol. Chem. 192, 45–57 University Press, Cambridge, 1956). (1930). 14. Burnet, F.M. Aust. J. Sci. 20, 67–69 (1957). ideas have led to a great proliferation of immu- 7. Mudd, S. J. Immunol. 23, 423–427 (1932). 15. Burnet, F.M. The Clonal Selection Theory of Acquired nologists and to know that the fate of immuno- 8. Pauling, L. J. Am. Chem. Soc. 62, 2643–2657 Immunity (Cambridge University Press, London, logy is deposited in so many capable hands.” (1940). 1959). 9. Glenny, A.T. in A System of in Relation to 16. Nossal, G.J.V. & Lederberg, J. Nature 181, 1419–1420 Medicine Vol. VI, 106–193 (His Majesty’s Stationary (1958). COMPETING INTERESTS STATEMENT Office, London, 1931). 17. Nossal, G.J.V. J. Exp. Path. 41, 89–96 (1960). The authors declare that they have no competing 10. Burnet, F.M., Freeman, M., Jackson, A.V. & Lush, D. 18. Burnet, M. Cold Spring Harb. Symp. Quant. Biol. 9, financial interests. The Production of Antibodies: a Review and Theoretical 1–9 (1967). http://www.nature.com/natureimmunology Nature Publishing Group Group Nature Publishing 7 200 ©

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