This article was published in Australian Dictionary of Biography, Volume 17, (MUP), 2007
Sir Frank Macfarlane (Mac) Burnet (1899-1985), medical scientist, was born on 3 September 1899 at Traralgon, Victoria, second of seven children of Frank Burnet, bank manager, and his wife Hadassah, née McKay. Born in Scotland, Frank migrated to Australia as a young man; Hadassah was born in Victoria and also had Scottish forebears. Presumably to distinguish him from his father, the boy was known as Mac from an early age, and the sobriquet stuck. The family does not seem to have been close. Hadassah was busy looking after a handicapped daughter and Frank was a somewhat remote authority figure. A shy, serious child, Mac had a passion for reading. The family moved to Terang in 1909, and during rambles in the countryside the lad developed an avid interest in collecting and drawing beetles.
Following his primary education at Traralgon and Terang state schools, Mac went as a boarder to Geelong College on a scholarship. He later recounted that these years were not particularly happy, due in part to his retiring nature. Nevertheless he did well academically, winning a scholarship to Ormond College, University of Melbourne (MB, BS, 1922; MD, 1924), where he continued to excel, coming second in a class that included (Dame) Jean Macnamara, (Sir) Roy Cameron, (Professor) Rupert Willis and (Dame) Kate Campbell. During his residency at the (Royal) Melbourne Hospital, he became fascinated with the intellectual challenges of neurology, but his superiors deemed him more suitable for laboratory than clinical work. He was appointed a senior resident in pathology at the Walter and Eliza Hall Institute of Research in Pathology and Medicine.
The institute’s director, Charles Kellaway, soon spotted Burnet’s great promise and took him under his wing. Then, as now, it was thought that a young Australian medical researcher’s training was incomplete without a spell abroad, so Burnet spent 1925-27 at the Lister Institute of Preventive Medicine, University of London (Ph.D., 1928). Back in Melbourne in 1928, he was made assistant-director of the Hall institute. On 10 July that year at Kew he married, with Presbyterian forms, Edith Linda Marston Druce. Linda was to prove a pivotal influence in his life, shielding him from mundane practical concerns, supporting his diligent work habits, acting as a sounding board for ideas and, later, as finances permitted, accompanying him on his many overseas trips. Theirs was a truly close union which produced two daughters and a son.
A major turning point in Burnet’s career came when (Sir) Henry Dale, director of the National Institute for Medical Research, London, offered him a two-year fellowship (1932-33) to carry out research on viruses (Dale was later to nominate him for a Nobel prize). Viruses had been hard to work with and had not been clearly visualised, but, early in the 1930s, a series of advances, particularly the isolation of the influenza virus, made the field exciting. The next twenty-five years of Burnet’s life were to be devoted to the study of viruses, principally influenza, that threaten people and animals. Dale wanted him to stay in London but he elected to return to his post in Melbourne.
In 1944 Kellaway left to become director of the Wellcome Research Institution in London. Burnet, too, had temptation thrown in his way. On his first trip (1943-44) to the United States of America, he was offered a chair at Harvard University. He refused and instead applied for the directorship of the Hall institute, despite the fact that Kellaway had advised him against it, fearing that his protégé might not be suited to administration. Burnet’s application was successful and he assumed office in March 1944; he was also appointed professor of experimental medicine at the University of Melbourne. In the event, he proved to be an inspiring leader of a team small by international standards but at the forefront of world virology.
While Kellaway and Dale strongly supported Burnet, neither was really a scientific mentor. In both Melbourne and London he forged his own path, initially authoring most papers by himself or with a research assistant. His first solid body of work had dealt with bacteriophage viruses, tiny parasites that infect and grow within bacteria. Having read in 1924 Félix d’Hérelle’s The Bacteriophage (1922), Burnet soon established that many types existed, characterised by the different bacteria they could infect, their different patterns of growth, and the different kinds of antibodies they elicited when injected into laboratory animals.
Burnet studied how invisible virus particles attached themselves to the bacterial host cell and how they grew inside it, finally bursting the cell and releasing a brood of progeny into the growth medium. He noted how the genetic material of the virus appeared to integrate with the genetic material of the bacterium, and how certain metabolic shocks could extract it again, activating viral growth. In addition, he investigated genetic mutations in both bacteriophages and their bacterial hosts. This preoccupation produced thirty-two papers by 1937. As he would prove to be on other occasions, he was ahead of the times. His work preceded by about a decade the studies of the so-called `phage club’, the members of which, led by Salvador Luria and Max Delbrück, used generally similar experiments to lay the foundations of microbial genetics, and thus indirectly of molecular biology.
Burnet’s interest in animal viruses had been stimulated at the National Institute for Medical Research. His first major contribution to the field was to improve and elaborate on Ernest Goodpasture’s technique of growing these organisms in fertile hens’ eggs. Burnet worked out how simple mouth or nasal washings could be injected into eggs as a convenient way of isolating a fresh virus. He learnt how to grow large quantities of a virus in eggs. The present method of producing enough influenza virus to mass-produce vaccines is based on this work. Burnet also carried out important studies into poliomyelitis (being the first to show that there was more than one strain, a crucial finding for the later development of a vaccine); many types of pox, including cowpox and mousepox; herpes; mumps; psittacosis; and numerous other viruses.
Microbe-hunting was not Burnet’s main interest, however. He wanted to get close to the nature of viral reproduction, and thus to the secret of life. Making ingenious use of the membranes surrounding the chick embryo, he developed a novel method of quantifying virus numbers, giving his work a degree of precision akin to what had been achieved in the simpler bacteriophage systems. He and his colleagues, particularly Alfred Gottschalk, studied how the influenza virus attached to its target cell before entry and also how it detached from the cell surface prior to the invasion of a new batch of cells. In 1951 Burnet and Patricia Lind made the then heterodox finding that when a cell was infected with two different influenza virus strains, some of the progeny viruses that came out were recombinants with traits of each of the parent strains. It is now known that such reassortant viruses are potential precursors of major epidemics. A member of Burnet’s team, Gordon Ada, was the first to show that the genes of the influenza virus consisted of ribonucleic and not deoxyribonucleic acid.
Though seemingly fundamental and reductionist, Burnet’s work had important practical applications. Chief among these were his unsuccessful attempts to produce a live, attenuated, anti-influenza vaccine that could be administered intranasally. A significant contribution was his identification of a rickettsial organism as the cause of the serious typhoid-like disease of abattoir workers, `Q’ fever. This microbe is now known as Coxiella burnetii. A discovery of great importance, that he had made in 1928, was the cause of the deaths of twelve children at Bundaberg, Queensland, following their immunisation against diphtheria. He found that the bottle containing the vaccine had been contaminated with Staphylococcus aureus (`golden staph’).
Thinking of himself as a naturalist and admiring Charles Darwin more than Louis Pasteur, Burnet sought to draw general biological and ecological truths from particular research findings. He examined specific problems from a broad biological and evolutionary viewpoint. Starting at his base in the ecology of human infectious diseases, he branched out into fields such as population genetics, human biology, cancer and ageing. His early, `semi-popular’ books were immensely influential. Two such works were Biological Aspects (title changed in later editions to Natural History) of Infectious Diseases (1940), which ran into four editions and was translated into Italian, Japanese, Spanish and German; and Virus as Organism (1945), which was translated into Russian and Japanese. All of his books reflected his belief in the unity of biology and his conviction that natural processes needed to be understood in a holistic sense if useful human action were to follow.
The decision by Burnet in 1957 to switch his work, and that of his institute, to immunology has come to be seen as a master-stroke, though some senior virologists were dismayed at first. His fascination with the immune response to infection had begun in 1928, following the Bundaberg disaster. He rendered staphylococcal toxin non-poisonous by formalin treatment and studied the immune response of rabbits to the injection of this `antigen’. A first injection evoked a very feeble antibody response, but a second dose a few weeks later gave a much faster and stronger boost to antibody levels, which rose in an exponential fashion for about five days. This outcome convinced him that `something’ must have been dividing as a result of antigen administration.
His interest thus piqued, Burnet investigated theories of antibody formation as part of his virus work. The central puzzle was the fact that animals and people can make so many antibodies, all different, in reaction to whatever antigen is presented. The prevailing explanation for this diversity was the direct template hypothesis, which held that, as the antibody molecule was synthesised, it fitted itself against a template of the antigen, much as metal is moulded against a die. With each passing year, Burnet became more convinced that this theory was wrong. In particular, it could not explain the booster response, the exponential increase in antibody levels, the observation that the quality of antibody improved with successive immunisations, and the fact that people and animals do not form antibody against their own tissues. Finding a better theory became a magnificent obsession.
Burnet published several monographs on the subject, at first reporting little progress. In his and Frank Fenner’s The Production of Antibodies (1949), however, he made the prediction that was to win him the 1960 Nobel prize in physiology or medicine. Burnet argued that if a foreign substance were introduced into an embryonic animal, before its immune system had matured properly, the antigen would `trick’ the body into accepting the relevant molecule or molecules as `self’ rather than `not-self’. As a result, no antibody would be formed, even when the antigen was introduced later in life. This phenomenon, which came to be termed immunological tolerance, was not supported by Burnet’s own experiments, but was validated in 1953 by (Sir) Peter Medawar (who shared the Nobel prize with Burnet), Rupert Billingham and Leslie Brent.
In 1955 Niels Jerne published a paper arguing that antibodies pre-existed in the body before the antigen was introduced, and for Burnet `the penny dropped’. The antigen merely had greatly to accelerate the production of this naturally occurring substance. Jerne said nothing about how such a vast range of natural antibody types could be fabricated, and the mechanism he proposed for the accelerated synthesis was clumsy. Burnet’s clonal selection theory, published in the Australian Journal of Science in 1957 after he became aware of a similar insight by David Talmage, postulated the idea of a large repertoire of spontaneously synthesised antibodies but located these as receptors on lymphocytes (white blood cells), each lymphocyte making only one antibody specificity. All an antigen had to do was to find the lymphocyte with a corresponding receptor, and to stimulate its repeated division, at the same time promoting accelerated antibody synthesis.
Burnet reasoned that the improvement in the quality of antibodies as immunisation progressed reflected the mutation and selection of cells with improved antibody on their surface. Immunological tolerance, he thought, was due to the deletion of antigen-binding cells if antigen (self-antigen) was encountered too early in life. Autoimmune diseases, where the body permits an immune attack against one of its own tissues, was seen as being due to `forbidden clones’, reflecting some failure of the tolerance mechanism. Both the booster response and the exponential rise in antibody levels were ascribed to sequential divisions of antibody-forming, clonally selected cells. Curiously, Burnet was not tempted to test his theory experimentally but it turned out to be essentially correct, and it set the agenda for much of immunology research over the next fifteen years. He considered clonal selection to be his most important scientific contribution.
There were other, less admirable reasons for Burnet’s move away from virology. The subject was becoming more and more closely tied to molecular biology, which he detested. Virology also depended increasingly on the growth of viruses in test tubes and not in his beloved fertile eggs. Moreover, it was making greater use of high technology, for example in research involving radioisotopes, of which he had an exaggerated fear. Fortunately, the Hall institute’s numerous contributions to cellular immunology vindicated his change in direction. In his last years as director he had much joy in examining disease progression in certain strains of mice genetically prone to autoimmunity.
Burnet’s was a contemplative, almost solitary kind of genius. To forge his imaginative, synthetic constructs, he needed quiet and isolation. The thrust and parry of a vigorous discussion with a gifted colleague were not for him. He preferred the peace of his own small study at home—usually on the very evening of the day’s experiment—when striving to accommodate a new finding into the constantly changing pattern of his speculative framework. For him, there was never a failed experiment. When the results did not pan out as expected, he believed that nature was trying to tell him something. He would simply force the uninterpretable data into some kind of order, designing the next experiment to test the appropriately modified hypothesis. He published quickly, his critics accusing him of sloppy work. Although a talented and ingenious experimentalist, he left it for others to refine the results, preferring to move on to the next big problem.
Passionately committed to the world of ideas, Burnet had the extraordinary gift of being able to take apparently unconnected observations, forge a link between them, pose the next question and, during his heyday as a bench-scientist, design the next deceptively simple experiment to create a new paradigm. His originality was fed by wide and disciplined reading; in a sense the whole world was a laboratory waiting to confirm or refute the latest flight of his imagination.
Burnet served on numerous national and international committees, chairing the (Australian) Radiation Advisory Committee (1955-59) and the (British) Commonwealth Foundation (1966-69). Never afraid to speak out on public issues—such as the use of nuclear energy, which he first opposed then later supported—he assumed greater prominence after winning the Nobel prize. He worked extensively with publishers and the media to promote his blend of popular science, history, social and political theory and philosophy. To this endeavour, as previously to science, he brought originality, imagination, intuition, naïve honesty, conceptual breadth and daring, and an idealistic, impractical wisdom.
Showered with honours, Burnet won more than twenty major scientific awards, including the Copley medal (1959) of the Royal Society, London (to which he had been elected a fellow in 1942), the (American) Lasker award (1952) and the (German) Emil von Behring prize (1952). Thirteen Australian and overseas universities conferred honorary degrees on him. He was president of the International Association of Microbiological Societies (1953-57), the Australian and New Zealand Association for the Advancement of Science (1957), the Australian Academy of Science (1965-69) and other learned bodies, and was a fellow or member of many more. He was knighted (1951), appointed to the Order of Merit (1958), and appointed KBE (1969) and AK (1978). Between 1941 and 1978 he delivered some fifty named lectures, most overseas. In 1961 he was named Australian of the Year.
`Sir Mac’ officially retired at 66, but, as guest professor in the University of Melbourne’s department of microbiology, kept up a routine of daily work for the next twelve years. In this period he produced a remarkable thirteen books on a wide range of topics including virology, immunology, human biology, ethics and philosophy. His publications included an autobiography, Changing Patterns (1968), and a history, Walter and Eliza Hall Institute, 1915-1965 (1971). Some of his later books, among them Genes, Dreams and Realities (1971) and Endurance of Life (1978), received a critical reception; for example, his eugenicist and sociobiological views provoked controversy.
In 1973 Burnet suffered a severe loss: Linda died of a leukaemia affecting the very cells (lymphocytes) which he had been studying so assiduously. For a brief period he tried to cope alone in the small retirement house they had built at Kew, but he was not very good at looking after himself. Moving to Ormond College, he found himself out of tune with the younger generation there. On 16 January 1976 at Canterbury he married, with Presbyterian forms, Hazel Gertrude Jenkin, née Foletta, a widow who had been a singer and was a volunteer librarian in the microbiology department. They shared nine companionable years at her home in Canterbury.
Although he left his office and ceased his daily routines in 1978, Burnet continued to write, his last paper being published in 1983. He died on 31 August 1985 at Port Fairy and, following a state funeral, was buried in Tower Hill cemetery. His wife and the children of his first marriage survived him. Many consider him to be the greatest scientist Australia has produced, and it is noteworthy that his sixty years of sustained creativity were lived, almost continuously, in his homeland. No one who loves Australian science will ever forget his example.
G. J. V. Nossal, 'Burnet, Sir Frank Macfarlane (Mac) (1899–1985)', Australian Dictionary of Biography, National Centre of Biography, Australian National University, http://adb.anu.edu.au/biography/burnet-sir-frank-macfarlane-mac-12267/text22019, published in hardcopy 2007, accessed online 21 August 2014.
This article was first published in hardcopy in Australian Dictionary of Biography, Volume 17, (MUP), 2007