Virology and medicine When Burnet returned to Australia, he went back to the Walter and Eliza Hall Institute, where he was appointed assistant director by Kellaway. His first assignment was to investigate the
Bundaberg tragedy, in which 12 children had died after receiving a contaminated
diphtheria vaccine. During this time, he continued to study bacteriophages, writing 32 papers on phages between 1924 and 1937. In 1929, Burnet and his graduate assistant Margot McKie wrote a paper suggesting that bacteriophages could exist as a stable non-infectious form that multiplies with the bacterial host. Their pioneering description of
lysogeny was not accepted until much later, and was crucial to the work of
Max Delbrück,
Alfred Hershey and
Salvador Luria on the replication mechanism and genetics of viruses, for which they were awarded the 1969
Nobel Prize in Physiology or Medicine. '', the causative agent of
Q fever, was named after Burnet. Between 1932 and 1933, Burnet took leave of absence to undertake a fellowship at the
National Institute for Medical Research in London. which he used in developing a chick embryo assay for the isolation and quantification of animal viruses. Dale offered Burnet a permanent position but he declined and returned to the Hall Institute. Following his productive work in London, the Rockefeller Institute agreed to fund a new virus research laboratory in Melbourne for Burnet. He brought back a set of viruses from the National Institute to begin the basis of research in Melbourne. When Burnet returned to Australia, he continued his work on virology, including the
epidemiology of
herpes simplex. He was also involved in two projects that were not viral, the characterisation of the causative agents of
psittacosis and
Q fever. This was attributed to his nationalistic tendencies, as well as his sense of loyalty to the Hall Institute. During his trip he also visited the US military facility at
Fort Bragg, where he discussed his work on influenza with the scientists working there. In 1944, he was appointed director of the Hall Institute when Kellaway was appointed director of the
Wellcome Foundation. Virologists including
Alick Isaacs,
Gordon Ada,
John Cairns,
Stephen Fazekas de St. Groth, and
Frank Fenner made significant contributions on
Murray Valley encephalitis,
myxomatosis,
poliomyelitis,
poxviruses, herpes and influenza. Burnet made significant contributions to influenza research; he developed techniques to grow and study the virus, including
hemagglutination assays. He worked on a live vaccine against influenza, but the vaccine was unsuccessful when tested during World War II. His interest in the influenza receptor led him to discover the
neuraminidase that is secreted by
Vibrio cholerae, which later provided the foundation for
Alfred Gottschalk's significant work on
glycoproteins and the neuraminidase substrate,
sialic acid. Between 1951 and 1956, Burnet worked on the genetics of influenza. He examined the genetic control of virulence and demonstrated that the virus recombined at high frequency; this observation was not fully appreciated until several years later,
Immunology undergoes differentiation and genetic rearrangement to produce (2) immature lymphocytes with many different antigen receptors. Those that bind to (3) antigens from the body's own tissues are destroyed, while the rest mature into (4) inactive lymphocytes. Most of these will never encounter a matching (5) foreign antigen, but those that do are activated and produce (6) many clones of themselves. In 1957, Burnet decided that research at the Hall Institute should focus on immunology. Burnet reached the decision unilaterally, leaving many of the research staff disillusioned and feeling the action was arrogant; for Burnet's part he was comfortable with the decision as he thought it to be effective. Many virologists left the Institute and settled the
Australian National University's
John Curtin School of Medical Research. After 1957 all new staff and students at the Institute worked on immunological problems; At the time, immunology was becoming more sophisticated, with the increasing role of
molecular biology and
biochemistry. Burnet was suspicious of the direction in which immunology was headed, and the increasing emphasis on technology and more intricate experiments, and colleagues felt that Burnet's conservative attitude was a factor in his decision to turn the Institute's focus to immunology. Burnet began to switch his focus to immunology in the 1940s. In 1941 he wrote a
monograph called "The Production of Antibodies", which was revised and reissued in 1949 with Frank Fenner as a co-author. This book is seen as a key publication in immunology—it marks the move from the study of immunology as a chemical endeavour to a biological one. Importantly in this work, he introduced the concept of "self" and "non-self" to immunology. He claimed that the interactions between an organism's immune cells and its other cells and molecules defined the organism's "self". Using the concept of self, Burnet introduced a hypothesis about the situation where the body failed to make antibodies to its own components (
autoimmunity) and by extension the idea of
immune tolerance. He proposed that 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. Burnet was, however, unable to prove this experimentally.
Peter Medawar,
Rupert E. Billingham and
Leslie Brent did find support for Burnet's hypothesis in 1953 when they showed that
splenocytes could be engrafted by intravenous infusion into mice in utero or just after birth and that when these mice matured, they could accept skin and other tissues from the donor but not from any other mouse strain. Burnet and Medawar were co-recipients of the 1960 Nobel Prize in Physiology or Medicine for this work, as it provided the experimental basis for inducing immune tolerance, thereby allowing the transplantation of solid organs. Burnet and Medawar were able to coordinate their work effectively despite their rather different personalities and physical separation; Burnet was taciturn whereas Medawar was urbane, but they greatly respected one another. However, later studies showed that cells or tissues transplanted before the immune system development of the recipient, such as in embryonic recipients, could be treated as foreign and trigger rejection, countering Burnet's explanation for self tolerance. In contrast to the Burnet hypothesis of a special tolerance-inducing period defined by the age of the animal,
Joshua Lederberg proposed in 1959, that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance-sensitive. Lederberg's concept is now known as central tolerance, and is widely accepted. It may also explain the success of some transplants given early in life and the failure to induce tolerance in other studies. Burnet noted that his contributions to immune tolerance were strictly theoretical: My part in the discovery of acquired immunological tolerance was a very minor one—it was the formulation of an hypothesis that called for experiment. Burnet was interested in how the body produces antibodies in response to antigens. The dominant idea in the literature through the 1940s was that the antigen acted as a template for antibody production, which was known as the "instructive" hypothesis. Burnet was not satisfied with this explanation, and in the second edition of "The Production of Antibodies", he and Fenner advanced an indirect template theory which proposed that each antigen could influence the genome, thus effecting the production of antibodies. In 1956 he became interested in
Niels Kaj Jerne's natural selection hypothesis, which described a mechanism for immune response based on an earlier theory of Nobel-winning immunologist
Paul Ehrlich. Jerne proposed that the antigen bound to an antibody by chance and, that upon binding, more antibodies to that antigen would be produced. Burnet developed a model which he named
clonal selection that expanded on and improved Jerne's hypothesis. In 1958
Gustav Nossal and Lederberg showed that one
B cell always produces only one antibody, which was the first evidence for clonal selection theory. Burnet wrote further about the theory in his 1959 book
The Clonal Selection Theory of Acquired Immunity. His theory predicted almost all of the key features of the immune system as we understand it today, including autoimmune disease, immune tolerance and
somatic hypermutation as a mechanism in antibody production. The clonal selection theory became one of the central concepts of immunology, and Burnet regarded his contributions to the theoretical understanding of the immune system as his greatest contribution to science, In his paper Burnet cited Talmage's review, and in a later interview, Talmage said he believed that Burnet "truthfully had developed the idea before he received my paper". The theory is now sometimes known as Burnet's clonal selection theory, which overlooks the contributions of Ehrlich, Jerne, Talmage, and the contributions of Lederberg, who conceptualised the genetics of clonal selection. Burnet's work on graft-versus-host was in collaboration with Lone Simonsen between 1960 and 1962. Simonsen had shown in 1957 that a graft-versus-host reaction occurred when the blood of an adult fowl was injected into a blood vessel of a chick embryo; this was known as the Simonsen phenomenon. Their work in this system would later help to explain
passenger leukocytes in transplantation. They looked at the inheritance of autoimmune disease, and their use of immunosuppressive drug
cyclophosphamide to treat the disease influenced the use of immunosuppressive drugs in human autoimmune disease. In 1960, Burnet scaled back his laboratory work, taking one day off per week to concentrate on writing. In 1963,
Autoimmune Diseases: Pathogenesis, Chemistry and Therapy, which he authored with
Ian Mackay, was published. He also oversaw an expansion of the Hall Institute and secured funding from the
Nuffield Foundation and the state government to build two further floors in the building and take over some of the space taken up by the pathology department at the Royal Melbourne Hospital. Despite this, Burnet believed that a world class research body needed to be small enough that one person could effectively run it, and maintained tight control over its activities throughout his leadership. He determined the policies himself, and personally selected all of the research staff and students, relying on a small staff to enforce his plans. He continued to be active in the laboratory until his retirement in 1965, although his experimental time began to decrease as the operations became increasingly focused on immunology; Burnet's work in this area had been mostly theoretical. Gustav Nossal became the next director of the Hall Institute. However, with the increasing sophistication in medical science and its reliance on more complicated technology, Burnet's lone-wolf approach became less compatible with the research environment, which required more collaboration. In his final years at the helm, Burnet allowed more technical modernisation during the transition period to Nossal's leadership. ==Public health and policy==