My research at WEHI

I was discharged from the army in February 1946 and immediately joined the Hall Institute staff. Burnet suggested that I should study the experimental epidemiology of infectious ectromelia. The reason for selecting this topic was the publication by a British group on studies of experimental epidemiology using mice, special cages and two bacterial pathogens and ectromelia virus.³ In addition, he had just shown that ectromelia virus is an orthopox virus, that is, it belongs to the same group of viruses as smallpox and vaccinia viruses.⁴

For most of the mice, ectromelia was a severe disease characterized by acute hepatitis, considerable swelling of the spleen and about 50% death rate. In some strains of mice, notably C57 Black, it was usually sub clinical and never lethal. Altogether I wrote 11 papers in my two and half years at the Hall Institute, 10 describing experimental results and a final review paper.⁵ The most interesting were two papers describing a previously unrecognized feature of ectromelia, namely a rash on the body of susceptible mice which did not die of acute hepatitis, which led to use of the name 'mousepox' for the disease and its causative virus.^{6, 7}

My impressions of Burnet

Burnet was the most creative and imaginative scientist that I have known, and my relations with him were very cordial. At the time I arrived there in 1946, he and all other staff were working on influenza virus. Burnet kept tight control over their investigations, for in those days of non-existent air travel, little effective radio and no television he thought that he had to compete with large teams in the USA and England. In contrast, he allowed me complete freedom to do as I wished within my topic. He did not like driving a car, so the laboratory manager would pick him up and take him home. At that time he worked at the laboratory bench from 9.30 am to 4 pm each week day and although we met in the tearoom, he was a reserved man and talked little. He always smoked a cigarette even though he later became a passionate crusader against smoking. When I had completed an investigation and written it up, I would give him a copy of the manuscript. He would read it that evening and at 4 pm the next afternoon, we would meet in his office to discuss its publication and he would then ask about my current and ongoing work. In contrast to common practice in many laboratories, then and now, Burnet never put his name on a paper involving experimental work, unless he had done some of the bench work and so all 11 of my papers on mousepox were published in my own name or sometimes linked with that of my wife, who was my unpaid laboratory assistant. I have followed the same tradition throughout my life.

Burnet's early work on immunology

This conference celebrates the 50th anniversary of Burnet's first publication of the clonal selection theory of antibody production, and most papers will deal some aspect of this, now recognized as probably the most important development in immunology. From his earliest days in the laboratory, beginning in 1928 and extending until the mid-1950s, he studied viruses, initially bacterial viruses, and from 1928 animal viruses. He was twice nominated for the Nobel Prize for this work.

Looking back on his publications, it is clear that the critical event in kindling his interest in immunology was the 'Bundaberg Disaster'. This is described at length in the history of the Commonwealth Serum Laboratories.⁸ In the early 20th century, diphtheria was one of the most life-threatening diseases of children and, following overseas discoveries, in 1921 CSL introduced a diphtheria toxin–antitoxin mixture for the vaccination of children. After a severe outbreak of diphtheria in the Queensland town of Bundaberg in 1926, late in 1927, a diphtheria vaccination campaign was initiated using CSL's toxin–antitoxin mixture, which was supplied in rubber-capped bottles and was stored in an unrefrigerated cupboard. Some of the contents of one bottle was used on 17, 20, 21 and 24 January 1928, with no ill-effects. Later, on 27 January, 18 of the 21 children inoculated became ill and 12 died. A royal commission was appointed in February 1928, chaired by Dr Charles Kellaway, the director of the Walter and Eliza Hall Institute. Burnet, who was working there on bacterial viruses, was appointed to carry out the laboratory part of the investigations. He soon showed that Staphylococcus aureus could be recovered from both the fluid in the toxin–antitoxin bottle and pus from the abscesses in surviving children. Over the next 4 years, he published nine papers on staphylococcal toxin, which was regarded as the cause of the deaths: among them, one paper was on the antibody response in rabbits. He found that the secondary antibody response of rabbits to the injections with staphylococcal toxoid, and in subsequent experiments with bacteria, rickettsiae and viruses was more rapid in onset than the primary response, and that it then increased logarithmically to reach a higher and more sustained level than the primary response. He interpreted this to mean that antibody-producing cells were reproducing at a relatively constant speed somewhere within the body. To Burnet's surprise, his paper was not accepted by the British journal to which he had sent it, so he decided to publish in an unrefereed monograph published by the Hall Institute.⁹ Essentially, this rendered the Haurowitz–Mudd–Pauling 'chemical' theory of antibody production obsolete.¹⁰

He used the same graphs of the primary and secondary responses in the second edition of this monograph, of which I was a co-author.¹¹ In addition, the second edition explored some very interesting work on the absence of an antibody response in animals exposed to a foreign antigen during fetal life. The most important paper was that by Owen,¹² who studied examples of twin births in cows in which there had been a single placenta but the embryos were of multi-ovular origin. After birth, each calf had antigenically different cells. Under normal circumstances, the blood cells of one calf should have produced a serological response if injected into the circulation of the other; in fact, the calves behave like identical twins. What Owen had discovered was that animals exposed to foreign antigens during fetal life failed to produce the relevant antibodies if exposed to them in adult life. In the second edition of the monograph, Burnet commented 'If in embryonic life expendable cells from a genetically distinct race are implanted and established, no antibody response should develop against the foreign cell antigen when the animal takes on independent existence.' This prediction was to form the basis of the award of the 1960 Nobel Prize to Burnet and Peter Medawar, a British scientist. There is little doubt that Burnet's inclusion in the 1960 award was influenced by the fact that he had been nominated twice before for his highly original work in virology. At the Prize presentation, Medawar spoke about immunological tolerance^{13, 14} and Burnet devoted the whole of his Nobel Prize Lecture to an account of clonal selection, which he had first described in 1957.^{15, 16}

I, and especially my wife Bobbie, had another unique association with Burnet and his family. In February 1950, we returned to Melbourne from our first trip to New York where I had spent a year at the Rockefeller Institute of Medical Research. While there, I had been appointed as foundation professor of microbiology at the John Curtin School of Medical Research, and since there were no laboratories in Canberra, the Australian National University with Burnet had arranged that I should have access to two laboratories in the Hall Institute. Burnet was anxious to spend a year abroad and knowing that we were coming back to Melbourne and also knowing my wife Bobbie, who had been my unpaid laboratory assistant during my years at the Hall Institute, they made arrangements for us to look after their house and three children while they spent a year abroad.

References

1. Andrew R, Bonnin JM, Williams S. Tick typhus in North Queensland. Med J Austr 1946; 2: 253–258.
2. Fenner F. The epidemiology of north Queensland tick typhus: natural mammalian hosts. Med J Aust 1946; 2: 666–668.
3. Greenwood M, Bradford Hill A, Topley WWC, Wilson J. Experimental Epidemiology., Medical Research Council, Special Report Series No. 209, His Majesty's Stationery Office, 1936.
4. Burnet FM. An unexpected relationship between the viruses of vaccinia and infectious ectromelia of mice. Nature 1945; 155: 543.
5. Fenner F. Mouse-pox (infectious ectromelia of mice): a review. J Immunol 1949; 63: 341–373. | PubMed | ISI | ChemPort |
6. Fenner F. The clinical features and pathogenesis of mousepox (infectious ectromelia of mice). J Pathol Bacteriol 1948; 60: 529–552. | Article | ISI |
7. Fenner F. The pathogenesis of the acute exanthems. An interpretation based on experimental investigations with mousepox (infectious ectromelia of mice). The Lancet 1948; 2: 915–920. | Article |
8. Brogan AH. Committed to Saving Lives. A History of the Commonwealth Serum Laboratories. Hyland House Publishing Pty Ltd: Melbourne, 1990.
9. Burnet FM, Freeman M, Jackson AV, Lush D. The Production of Antibodies: a Review and Theoretical Discussion., Monograph from the Walter and Eliza Institute of Research in Pathology and Medicine, No. 1 Macmillan: Melbourne, 1941.
10. Pauling L. A theory of the structure and process of formation of antibodies. J Am Chem Soc 1940; 62: 2643–2657. | Article | ISI | ChemPort |
11. Burnet FM, Fenner F. The Production of Antibodies. 2nd edn. Monograph from the Walter and Eliza Institute, Melbourne, Macmillan and Company Ltd: Melbourne, 1949.
12. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102: 400–401. | Article | PubMed | ISI |
13. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953; 172: 603–606. | Article | PubMed | ISI | ChemPort |
14. Billingham RE, Brent L, Medawar PB. Quantitative studies in tissue transplantation immunity. III. Actively acquired tolerance. Philos Trans Roy Soc London 1956; B239: 357–414.
15. Burnet FM. A modification of Jerne's theory of antibody production using the concept of clonal selection. Austr J Sci 1957; 20: 67–69.
16. Burnet FM. Clonal Selection Theory of Acquired Immunity. Cambridge University Press: Cambridge, UK, 1959.