Burnet was born in the small country town of Traralgon, Victoria. Having spent three months there as a resident medical officer, I can vouch for the fact that Traralgon is a dull place. However, Burnet had a happy and uneventful childhood, and in later life he retained his affection for the bush. He went on to study medicine at Melbourne University, where he graduated in 1922 with high honours. During his year as resident at the Royal Melbourne Hospital, he aspired to become a clinical neurologist, but his mentors felt that his talents lay elsewhere, and steered him towards laboratory research. (Rolf Zinkernagel also aspired to become a neurologist, and it is fortunate that fate also took him in a different direction). Burnet became registrar in pathology, and thus gained entry to the Walter and Eliza Hall Institute, with which he remained associated for the next forty years until he retired as Director in 1965.

His first bench work began with diagnostic bacteriology and serology. Even at this early stage he was an acute observer. Starting with practical problems, he used opportunities generated by any unexpected results to expand his intellectual horizons and to seek generalisations. This pattern, repeated over a lifetime, ultimately created the foundations for our current understanding of the immune system.

Burnet's first significant observation came during his time as pathology registrar in 1925, with the finding of patches of bacteriophage lysis on a bacteriological culture plate. The concept of bacteriophages was relatively new. D'Herelle's book, The Bacteriophage; Its Role in Immunity, had been published only three years earlier.

He continued his work on bacteriophages in the Lister Institute in London. By the age of 27 he had become an expert on the subject, and was invited to write a chapter for the Medical Research Council's eight-volume System of Bacteriology. His interest in bacteriophages already went far beyond their medical importance. By the time he had submitted his PhD thesis in 1927, he had formed the belief that the bacteriophage "is a living bug but lives at the expense of bacteria". He saw that phage represented the "raw material of evolution" and might uncover more fundamental truths, including that of life itself (1, 2).

In 1928 he returned to the Hall Institute in Melbourne and was appointed Assistant Director to Charles Kellaway. One of his first tasks was to investigate the "Bundaberg disaster", in which 12 children died as a result of staphylococcal contamination of diphtheria vaccines. This led to his discovery of the alpha toxin of Staphylococcus aureus, but Burnet felt that this toxin was unlikely to be the culprit. The toxin that actually caused the illness was probably staphylococcal enterotoxin that causes what is now known as toxic shock syndrome.

In 1929 Burnet and Margot McKie suggested that bacteriophage could exist as a stable non-infectious "anlage" which multiplies in step with the bacterial host, a concept that was many years ahead of its time. He was thus one of the pioneers in the study of lysogeny, the process by which certain bacteriophages integrate their DNA into the chromosome of the bacterial host and replicate in a hidden fashion, only to emerge at a later stage, either randomly and unpredictably or by certain stimuli such as ultraviolet light, as shown by Lwoff in 1949 (3). In order to appreciate Burnet's vision, we must remember that D'Herelle denied the phenomenon of lysogeny, and even Delbrück initially refused to believe in it, feeling that the experiments by Burnet and others were worthless (3). The importance of bacteriophage in genetics was recognised by the award of Nobel Prizes to Jacob, Lwoff and Monod in 1965 and to Delbrück, Hershey and Luria in 1969.

In 1932-3 Burnet took leave of absence from WEHI to hold a fellowship at the National Institute for Medical Research in Hampstead, London, where he witnessed what can now be seen as a "golden age" of virology, including the isolation of the influenza virus and its transmission to ferrets. A major contribution at this time was his demonstration that canary pox virus (and by implication, other viruses) could be quantitated by making serial dilutions and counting pocks on the chorioallantoic membrane of embryonated eggs. This work became particularly important in his later studies on influenza.

He returned to the Hall Institute in 1934. Upon the departure of Kellaway to become Director of the Wellcome Foundation in 1943, Burnet became Director, a post which he held until his retirement in 1965. These years saw a stream of discoveries concerning infectious diseases, notably psittacosis, scrub typhus, Murray Valley encephalitis, myxomatosis, poliomyelitis, and Q fever, the causative organism of which was named Coxiella burneti in his honour.

During this time Burnet had a particularly strong interest in influenza virus. The world-wide influenza pandemic of 1918-1919 killed more people than were killed in the whole of the first world war, and he was conscious of the possibility that a similar pandemic might occur again. He devised novel methods for the growth and study of influenza virus in embryonated eggs, although the development of an effective influenza vaccine proved elusive.

His interest in receptors for flu virus led, via an extraordinary combination of brilliance and intuition, to his discovery of a "receptor-destroying enzyme" (neuraminidase) secreted by Vibrio cholerae. This work led on to Alfred Gottschalk's discovery of glycoproteins and the neuraminidase substrate, sialic acid.

The golden age of virology continued at the Hall Institute under Burnet's direction. It included the work of Alick Isaacs on what was later called "interferon", as well as important contributions by Gordon Ada, who discovered the segmented RNA nature of the influenza genome, and the work of John Cairns, Stephen Fazekas de St. Groth, Eric French, Gray Anderson and Frank Fenner.

By the mid 1950s, Burnet had begun to feel that the biological study of viruses was coming to an end. There was a movement towards a more biochemical approach, as epitomised by Gottschalk and Ada. Burnet lamented that virology was becoming excessively "academic" and removed from its practical roots. He had always been interested in immunology, and in 1957 he decided to make a profound change in direction for the Institute. From now on, it would be immunology. Within a few years, all the virologists had departed, and a new era of immunology had begun.

As can be imagined, the change to immunology caused major ripples, and was criticised as being dictatorial. Gus Nossal had approached Burnet about coming to work with him. He arrived in 1957, expecting to work on viruses, and was somewhat taken aback to be told of the change in direction.

In the early 1950s, immunologists were struggling to understand the mechanism of antibody formation. Jerne's "natural selection hypothesis" was based on the observation that there were virtually always small amounts of "natural antibody" in serum against any given antigen, regardless of immunisation. He postulated that upon entry of antigen into the body, these "natural antibodies" were taken up by cells which were then induced to produce more of the same. Burnet felt that Jerne's idea was intriguing but wrong because it did not fit what was already known about the mechanism of how genes work and how proteins are synthesised, and he was struggling in his own mind to formulate a better solution.

Burnet published the Clonal Selection Theory in 1957 (4). Similar ideas were published by David Talmage at about the same time (5). We can never know whether Burnet's formulation was totally independent of that of Talmage. But as pointed out by Nossal (6), "Talmage was certainly the first to claim that Jerne's hypothesis made more sense if the unit of selection was a cell bearing natural antibody on its surface. It has been insufficiently recognised that Burnet actually cites the slightly earlier paper of Talmage (5) in his first articulation of clonal selection ... It is possible that Talmage's paper was the triggering point that persuaded Burnet to put pen to paper."

Cynics have claimed that Burnet published in the Australian journal so that if he was right, he could claim priority, while if he was wrong, it could be quietly buried. Did he use the Australian journal to "fast track" the paper? I don't know. However, I can say that forty years later it still makes exciting reading. Burnet's 1957 paper is remarkable for its clarity, its extraordinary vision, and the boldness in making new postulates to replace old ones.

Moreover, he was right. Burnet's exposition included the unambiguous postulate of clones bearing unique receptors, clonal abortion as a mechanism of self tolerance, the possibility of autoimmune disease as a result of "forbidden clones", clonal expansion as a basis for immunological memory, and somatic mutation as a mechanism for affinity maturation. This was a truly remarkable vision of almost all the key features of the immune system as we understand it today (6). He went on to publish a more detailed exposition in a monograph published in 1959 (7). Talmage also presented a more detailed account in the same year (8, 9).

The clonal selection theory set out to explain the diversity of immunological responses in the framework of the emerging principles of how genes work. Burnet was acutely aware of the serious conceptual difficulties associated with the prevailing "template" theories of antibody production, in which antigen was seen to instruct the specificity of antibodies. Instructionist theories ran counter to all that was emerging about the action of genes, in particular the "one way" flow of sequence information from gene to protein. His bold postulate that individual clones were pre-committed to a particular specificity swept away the clumsiness of the instructionist theories and placed antibody synthesis firmly into the general concept of how proteins are made.

The clonal selection theory did, of course, have some rather ad hoc aspects, such as the need to postulate an unknown mechanism by which individual clones were different from each other. It is a measure of Burnet's intellect that he had the confidence to feel that this was a less important issue. The essential need was to bring antibody synthesis back into the general fold of what was known about gene action. The actual mechanism of clonal diversification was not discovered for nearly 20 years, until the work of Hozumi and Tonegawa in 1976 (10).

One of Nossal's first projects was to test Burnet's hypothesis. In an elegant series of experiments, he showed that single cells from rats immunised with two different strains of Salmonella would make antibody to one or other strain, but rarely to both. This classical experiment was published in 1958 (11). Although we now consider the result almost self-evident, it was not universally accepted for many years (12). Other workers came to the opposite conclusion, and it was not until the Cold Spring Harbor Conference in 1967 that the Clonal Selection Theory was generally accepted and regarded as the foundation for all immunological thinking (12, 13).

Burnet's vision of the clonal selection theory was extraordinarily prescient, even in its details. In addition to precommitment of individual clones, he correctly anticipated the existence of somatic mutation as a mechanism for affinity maturation in secondary responses. However, he was uncomfortable with the idea that a clone could be forced in a "required direction". He felt that this idea would be a "rather unhappy hybrid", having just rejected instructionist theories. Recent work has indeed shown multiple mechanisms of somatic diversification, including the re-activation of recombinases in mature B cells and change of V gene usage and light chain type in mature B cells during secondary responses (14). However, his central idea of mutation and selection survives intact.

The other side of the coin to immunological diversity is immunological tolerance. The need to avoid immunological reactions against self had been termed "horror autotoxicus" by Paul Ehrlich in 1900. For years, Burnet had puzzled over this issue. As early as the 1940s he had predicted the existence of acquired immunological tolerance, the idea that self tolerance must be learned in each individual (15). However, he had not been able to prove this experimentally. In 1953, Billingham, Brent and Medawar demonstrated the experimental induction of tolerance by injecting fetal mice with living cells from other strains, and the subsequent acceptance of skin grafts from the donor strains (16). This work was immensely important, both for the understanding of the immune system and also for its practical implications. In principle at least, it suggested that it might be possible to induce tolerance in humans and thereby allow the transplantation of organs, and it resulted in the award of the 1960 Nobel Prize in Medicine or Physiology to Medawar and Burnet.

Many Nobel Prizes have been awarded for work that does not reflect the winner's greatest contribution. This is arguably true for Burnet. Although the prize was for tolerance, he considered the clonal selection theory to be his greatest achievement (1,13). He could also have won it for his work on bacteriophages.

Burnet went on to consider the question of "horror autotoxicus" in more detail. Was it really out of the question? Even in Ehrlich's day, there had been evidence that autoimmunity might sometimes occur (17). In 1963, Burnet and Mackay wrote their classic monograph on autoimmune disease (18), which remained a highly controversial topic for many years to come. Autoimmunity is now accepted as a major disease mechanism (30). Together with allergy, autoimmunity may be considered to be the price that populations have to pay for having a versatile immune system to defend them against infection.

The 1960s were marked by Burnet's preparation for retirement and handover to his logical successor, Gus Nossal. By then, he had received virtually every honour that was possible, including FRS 1942, Knighthood 1951, Order of Merit 1958, and the Nobel Prize in 1960.

What was Burnet like as Director? It is interesting to note that Kellaway had reservations about Burnet's appointment on the grounds that he was too shy and lacked the necessary leadership skills, and also that appointment might destroy his research. Burnet himself had some worries about whether he was suited (1,13). However, Kellaway was overruled by the Institute board, and Burnet got the job.

There can be no doubt that the Hall Institute thrived under Burnet's leadership, becoming a "Mecca" for infectious disease research, and later for immunology (28, 29). It spawned many brilliant scientists who went on to become famous in their own right, both at the Hall Institute and afterwards. Burnet's style was a mixture of benign dictatorship and freedom for individual scientists. Unlike many others, Burnet did not put his name on papers to which he had not contributed. The discussions over morning and afternoon tea were a lively feature of Institute life. He read every paper from all WEHI staff, and wrote in or over any points that he felt unclear or dubious and returned the manuscript the following day.

When he felt the need to steer the ship in another direction, he proceeded to do so, knowing the resentment and problems that it would cause. However, the change revitalised the Institute and was the start of a highly productive new era. Burnet's lack of interest in the day to day affairs of the University and the Faculty of Medicine caused a modicum of resentment, but in my opinion, this was a wise choice. Had he participated in interminable meetings, in University politics and marking exam papers, there is no doubt that his scientific productivity would have been greatly diminished.

When Nossal took over in 1965, the Hall Institute had reached something of a plateau and had not capitalised on its earlier glories. The nature of the work had changed. Burnet had developed an "unjustified distrust" of technology (19), which he did not understand. He felt that events were overtaking him. The day when important papers were published by single authors was drawing to a close, and the era of "big science" had arrived. He did not feel comfortable with these developments. For Burnet, ideas were paramount, and technology was unimportant.

For Nossal, ideas were still central, but he saw the need for new technology, new equipment, and larger scale work. He had to buy the first Sorvall centrifuge and the first gamma counter for the Institute and move it into a more technologically sophisticated era. Nossal also made two extremely important staff changes. Burnet had little time or regard for cancer research, which he felt was a waste of time. Cancer was inevitable in a multi-cellular organism, and there was little that could be done for it. Nossal brought Don Metcalf from his "exile" above the old animal house into the main building, and appointed him Deputy Director. He also recruited Jacques Miller. Both moves were oustandingly successful.

"Predictions are hard to make, especially ones about the future". Peter Medawar has written at length on the subject, and strongly advised against the practice (20). Burnet made many predictions, many good, and some bad.

Burnet's clarity of vision and ability to synthesise and generalise helped him make stunningly accurate predictions concerning immunological tolerance and clonal selection, for which he received well-deserved recognition.

However, not all of Burnet's predictions were as good, and a balanced view requires some discussion of his less accurate prognostications. Most of these seem to have involved a feeling of negativity towards the practical usefulness of scientific research. In spite of the fact that his work on tolerance had the potential for facilitating transplantation, a contemporary newspaper headline quoted him: "No great value in transplants, says top scientist" (19).

He was similarly pessimistic about the prospects for a poliomyelitis vaccine. In 1949 he wrote: “I can see no hope at present of such a vaccine being produced ... I have adopted a frankly defeatist attitude towards the problem of poliomyelitis and I hope that future developments will prove me wrong ... No means of controlling poliomyelitis is at present visible.” (21). Events overtook this prediction very rapidly. In the same year, Enders, Weller and Robbins grew large quantities of polio virus in non-neural tissue, leading to an effective vaccine a few years later, winning them the Nobel Prize in 1954.

After his retirement in 1965, Burnet's predictions became even more pessimistic. In 1970, he wrote: “I can see no practical application of molecular biology to human affairs ... DNA is a tangled mass of linear molecules in which the informational content is quite inaccessible.” (22). This was more or less true in 1970, but within a few years cloning and sequencing of DNA were routine.

It is ironic that although Burnet was one of the pioneers of molecular biology, he developed a negative attitude towards it, feeling that it was of little practical significance (23). In 1971, he wrote: “Rightly or wrongly I think that, with those two discoveries, Nobel Prizes in molecular biology will stop.” (24). How wrong he was! In the years that followed, Nobel Prizes were awarded for discovery of retroviruses (1975), restriction enzymes (1978), DNA sequencing and recombinant DNA (1980), transposable elements (1983), oncogenes (1989) and split genes (1993).

Burnet was pessimistic about gene therapy. “The next step would be the crucial and probably impossible one: to incorporate the gene into the genetic mechanism of a suitable virus vehicle in such a fashion that the virus in its turn will transfer the gene it is carrying to cells throughout the body and in the process precisely replace the faulty gene with the right one. I should be willing to state in any company that the chance of doing this will remain infinitely small to the last syllable of recorded time.” (25). Well, we have not quite got there, but there has been substantial progress. It is ironic that even if we do overcome these technical difficulties, the barrier to successful gene therapy may be immunological. Will the new therapeutic gene product be seen as foreign and hence destroyed by the immune system?

Burnet particularly lamented what he perceived to be the movement of Nobel Prizes towards "academic" and away from practical (13). What would he make of prizes for radioimmunoassay (1977), CAT scanner (1979), histocompatibility antigens (1980), prostaglandins (1982), monoclonal antibodies (1984), anti-cancer drugs (1988), organ transplantation (1990) and PCR (1993)?

In addition to the fact that they were just plain wrong, these gloomy prognostications, coming from such an eminent scientist, were potentially damaging to research funding. On the occasions that I got to know Burnet socially, I challenged him concerning his predictions. When confronted with the spectacular progress since his predictions, he would say: "I stand corrected", but then immediately reiterate his belief that most of the really important work had been done, and our generation was just tidying up loose ends. What motivated this attitude in such an intelligent man? According to Nossal, it may have reflected "the real pain that he felt in having to leave the scene of discovery" (19, 26).

"Few men escape the weakness, as age overtakes them, of looking back on the days of youth as a more propitious and grateful time, and the remembered enthusiasm of earlier days carries the mind back to youthful triumphs ... He seems to have suffered his full share of this malady, so common among those from whom youth has already fled, and in spite of his own prodigious innovations he appears to have nourished a bitter resentment against all forms of change, seeing in them a challenge to his well-established reputation..."

Were these words written about Burnet? No, they were written about John Dowland (1563 - 1626), the greatest lute player and composer who ever lived (27).

It must be said that Burnet's tendency to introspection showed a good deal of self-understanding. Socially, he was shy and awkward, and he knew it. He did not enjoy the cut and thrust of debating "on his feet". He preferred to go away and think about problems in the quiet of his study, and then return the next day with some suggestions. It is therefore somewhat surprising that in 1927 he was invited to give a talk at the Royal Society for Medicine, but lamented the lack of robust discussion: "Nobody arises and attempts to slay you when the paper is finished which is disappointing to a dramatically minded author..." (1).

Burnet anticipated many wider current concerns. He was deeply interested in ecology and the need for sustainable development, and was very concerned by the population explosion. He was a champion of solar energy. He took a strong stand on smoking long before this became fashionable. And yet, his boldness in science was counterbalanced by a certain social conservatism. He was something of a genetic determinist. Many of his social views have dated badly (28). But we must remember that he was a man of his time. It would be unfair to judge him by contemporary values, which might themselves be seen in a different light in the years to come.

Burnet's life was exceptionally creative and productive. In the Pasteurian tradition, he was committed to tackling practical problems, and in so doing he illuminated vast areas of basic understanding. Burnet was Australia's greatest immunologist, and one of the founding fathers of immunology.

While this article was in preparation, I attended the Mannix Memorial Lecture given by Sir Gustav Nossal on September 9, 1998. This lecture enabled me to check the accuracy of a number of facts concerning Burnet, and inspired some changes to the manuscript. I would also like to thank Dr. Ian Mackay for critical reading of the manuscript. However, any errors of fact or interpretation are mine alone. References 1 and 31 are recommended for more detailed information.

References

1. Sexton, C. (1991) The Seeds of Time. The Life of Sir Macfarlane Burnet. Oxford University Press, Australia.
2. Nossal, G.J.V. (1985) Sir Frank Macfarlane Burnet. (1899-1985) Nature 317: 108.
3. Judson, H.F. (1979) The Eighth Day of Creation. Simon and Schuster. pp 373-375.
4. Burnet, F.M. (1957). A modification of Jerne's theory of antibody production using the concept of clonal selection. Austral. J. Sci. 20, 67-69.
5. Talmage, D. W. (1957). Allergy and immunology. Annu. Rev. Med. 8, 239-256.
6. Nossal, G.J.V. (1995) One Cell - One Antibody. In: Immunology: The making of a modern science. Eds Gallagher, R.B., Gilder, J., Nossal, G.J.V., and Salvatore, G. Academic Press. pp 39-47.
7. Burnet, F.M. (1959) The Clonal Selection Theory of Acquired Immunity. Cambridge University Press.
8. Talmage, D.W. (1959) Immunological specificity. Science 129: 1643-1648.
9. Talmage, D.W. (1995) Origins of the Cell Selection Theories of Antibody Formation. In: Immunology: The making of a modern science. Eds Gallagher, R.B., Gilder, J., Nossal, G.J.V., and Salvatore, G. Academic Press. pp 23-38.
10. Hozumi and Tonegawa, S. (1976) Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. Proc. Nat. Acad. Sci. USA 73: 3632-3637.
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13. Burnet, F.M. (1968). Changing Patterns: An Atypical Autobiography. William Heinemann, London.
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15. Burnet, F.M., and Fenner, F. The Production of Antibodies. 2nd edition. (Monograph of the Walter and Eliza Hall Institute, Melbourne). Macmillan, 1949.
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18. Burnet, F.M., and Mackay, I.R. (1963) Autoimmune Diseases: Pathogenesis, Chemistry and Therapy. Charles C. Thomas, Springfield, Illinois.
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20. Medawar, P. 1984. Expectation and Prediction. In: Pluto's Republic. Oxford University Press. pp 298-310.
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