Frank Macfarlane Burnet

Sir Frank Macfarlane Burnet OM, AK, KBE (3 September 1899 – 31 August 1985), usually known as Macfarlane or Mac Burnet, was an Australian virologist best known for his contributions to immunology. Burnet received his M.D. from the University of Melbourne in 1924, and his PhD from the University of London in 1928. He went on to conduct pioneering research on bacteriophages and viruses at the Walter and Eliza Hall Institute, and served as director of the Institute from 1944 to 1965. His virology research resulted in significant discoveries concerning their nature and replication and their interaction with the immune system.

From the mid-1950s, he worked extensively in immunology and was a major contributor to the theory of clonal selection, which explains how lymphocytes target antigens for destruction. Burnet and Peter Medawar were co-recipients of the 1960 Nobel Prize in Physiology or Medicine for demonstrating acquired immune tolerance. This research provided the experimental basis for inducing immune tolerance, the platform for developing methods of transplanting solid organs.

Burnet left the Walter and Eliza Hall Institute in 1965, he continued to work at the University of Melbourne until his official retirement in 1978. During his working life he wrote 31 books and monographs and more than 500 scientific papers. Burnet played an active role in the development of public policy for the medical sciences in Australia and was a founding member, and later the president, of the Australian Academy of Science. He was the most highly decorated and honoured scientist to have worked in Australia.^[1] For his contributions to Australian science, he was made the first Australian of the Year in 1960, and in 1978 a Knight of the Order of Australia. He was recognised internationally for his achievements: in addition to the Nobel, he received the Lasker Award and the Royal and Copley Medals from the Royal Society, honorary doctorates, and distinguished service honours from the Commonwealth and Japan.

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Early life

Burnet was born in Traralgon, Victoria; his father, Frank Burnet, a Scottish emigrant to Australia, was the manager of the Traralgon branch of the Colonial Bank. He was the second of seven children and from childhood was known as "Mac". The Burnets moved to Terang in 1909. Burnet was interested in the wildlife around the nearby lake; he joined the Scouts in 1910 and enjoyed all outdoor activates. While living in Terang, he began to collect beetles and study biology. He read biology articles in the Chambers's Encyclopaedia, which introduced him to the work of Charles Darwin. He was educated at Victorian state schools and later won a full scholarship to board and study at Geelong College, one of Victoria's most exclusive private schools.^[2]

From 1917, Burnet attended the University of Melbourne, where he lived in Ormond College on a residential scholarship and studied medicine. There, he read more of Darwin’s work and was influenced by the ideas of science and society in the writings of H.G. Wells. While at university, he became an agnostic; he was sceptical of religious faith, which he regarded as "an effort to believe what common sense tells you isn't true."^[3] The length of time required to study medicine had been reduced to train doctors faster following the outbreak of World War I, and Burnet graduated with a Bachelor of Medicine and a Bachelor of Surgery in 1922, and as a Doctor of Medicine late in 1924. In 1924 he was appointed resident pathologist at the Melbourne Hospital; the laboratories were a part of the Walter and Eliza Hall Institute. He conducted research into the agglutinin reactions in typhoid fever, leading to his first scientific publications.^[4][5]

The director of the Institute, Charles Kellaway, thought that Burnet would need experience working in a laboratory in England before he could lead his own research group in Australia.^[6] Burnet left Australia for England in 1925 and served as ship's surgeon during his journey. On arrival, he took a paid position assisting the curator of the National Collection of Type Cultures at the Lister Institute in London. He was awarded the Beit memorial fellowship by the Lister Institute in 1926 and began full-time research on bacteriophage. For this work he received a PhD from the University of London in 1928 and was invited to write a chapter on phage for the Medical Research Council's System of Bacteriology. While in London, Burnet became engaged to fellow Australian Edith Linda Druce. They married in 1928 after returning to Australia, and had a son and two daughters.

Walter and Eliza Hall Institute

Virology

When Burnet returned to Australia, he went back to the Walter and Eliza Hall Institute, where he was appointed assistant director. His first assignment was to investigate the "Bundaberg disaster", in which 12 children had died after receiving a contaminated diphtheria vaccine. He identified Staphylococcus aureus in the toxin-antitoxin mixture that had been administered to the children, although turned out to be another toxin that had caused the children's deaths; this work on staphylococcal toxin piqued his interest in immunology.^[7] During this time, he continued to study bacteriophage, writing 32 papers on phages between 1924 and 1937. In 1929, Burnet and his graduate assistant Margot McKie wrote a paper suggesting that bacteriophage could exist as a stable non-infectious form that multiplies with the bacterial host.^[8] 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.^[9]

  Between 1932 and 1933, Burnet took leave of absence to undertake a fellowship at the National Institute for Medical Research in London. Significant breakthroughs in virology were made while he was there, including the isolation and first demonstration of the transmission of the influenza virus. His own research was on the canarypox virus, which he used in developing a chick embryo assay for the isolation and quantification of animal viruses. 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. During the time he worked on Q fever with Australian scientist E.H. Derrick, the causative organism of which was named Coxiella burnetii in Burnet's honour, he became the first person to acquire the disease in the lab.^[10] His epidemiological studies of herpes and Q fever displayed an appreciation of the ecology of infectious disease that became a characteristic of his scientific method.^[11]   During World War II, Burnet's research moved to influenza and scrub typhus. His first book, Biological Aspects of Infectious Disease, was published in 1940. In 1942 he was made a Fellow of the Royal Society, and in 1944 he travelled to Harvard University to deliver the Dunham Lectures. There he was offered a chair, but he refused and returned to Australia. In 1944, he was appointed director of the Institute when Kellaway was appointed director of the Wellcome Foundation. Under his direction, scientists at the Institute made significant contributions to infectious disease research during a period that has been called the "golden age of virology".^[12] 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, when the segmented genome of influenza was demonstrated.^[1][13]

Immunology

  In the mid-1950s, Burnet decided that research at the Institute should focus on immunology. Many virologists left the Institute and settled the Australian National University's John Curtin School of Medical Research.^[14] After 1957 all new staff and students at the Institute worked on immunological problems; Burnet was involved in work relating to autoimmune diseases and the graft-versus-host reaction, and increasingly in theoretical studies of immunology, immunological surveillance and cancer.^[1]

Burnet began to write about immunology in the 1940s. In 1941 he wrote a monograph called the "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. The distinction between self and non-self was an integral part of Burnet’s biological outlook, of his interest in the living organism in its totality, its activities, and interactions.^[15] Burnet regarded that the "self" of the host body was actively defined during its embryogenesis through complex interactions between immune cells and all the other cells and molecules within an embryo.^[16]

Using the concept of self, Burnet introduced a hypothesis about the situation where the body failed to make antibodies to its own components (autoimmunity) [autoimmunity results when the body makes antibodies to its own components, not when it fails to do so] 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.^[17]

Burnet was, however, unable to prove this experimentally.^[18] Peter Medawar, Rupert E. Billingham and Leslie Brent did 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.^[19] 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 noted that his contributions to immune tolerance were just 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.^[20]

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.^[21] 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.^[22] 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.^[23] Burnet proposed that each lymphocyte bears on its surface specific immunoglobulins reflecting the specificity of the antibody that will later be synthesised once the cell is activated by an antigen. The antigen serves as a selective stimulus, causing preferential proliferation and differentiation of the clones that have receptors for that antigen.^[24]

In 1958 Gustav Nossal and Joshua Lederberg showed that one B cell always produces only one antibody, which was the first evidence for clonal selection theory.^[25] 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.^[26] 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, and wrote that he and Jerne should have received the Nobel for this work.^[27] Jerne was recognised for his contributions to the conceptualisation of the immmune system when he was a co-recipient of the Nobel Prize in 1984.

There is some contention over Burnet's publication of his version of the theory in the Australian Journal of Science in 1957. Some commentators argue he published in an Australian journal to fast-track his hypothesis and obtain priority for his theory over ideas that were published later that year in a paper written by David Talmage, which Burnet had read prior to its publication.^[1][28] 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".^[29] 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 when a chick embryo was inoculated intravenously with adult-fowl blood, a graft-versus-host reaction occurred; this was known as the Simonsen phenomenon. Their work in this system would later help to explain passenger leukocytes in transplantation.^[1] The last project he worked on at the Institute was a study with assistant Margaret Holmes of autoimmune disease in the New Zealand black mouse model; this mouse has a high incidence of spontaneous antuimmune [autoimmune] hemolytic anemia. 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 antoimmune [autoimmune] disease.^[30] He continued to be active in the lab until his retirement in 1965; Gustav Nossal became the next director of The Walter and Eliza Hall Institute. Under Burnet's leadership the Institute had become "probably the world's best known research centre devoted to the study of immunology."^[31]

Public health and policy

From 1937 Burnet was involved in a variety of scientific and public policy bodies. After he became the director of the Walter and Eliza Hall Institute in 1944, he was considered a public figure and overcame shyness to become a good public speaker. He recognised the importance of co-operation with the media if the general public was to understand science and scientists, and his writings and lectures played an important part in the formulation of public attitudes and policy in Australia on a variety of biological topics.^[1]

Burnet served as a member or chairman of scientific committees, both in Australia and overseas. Between 1947 and 1953, he was a member of the National Health and Medical Research Council – Medical Research Advisory Committee. The committee advised on funding for medical research in Australia. During this same period (1947–52), he was also a member of the Commonwealth government's Defence Research and Development Policy Committee. Declassified files from this committee show that Burnet made the recommendation that Australia pursue development of chemical and biological weapons to target neighbouring countries' food stocks and spread infectious diseases.^[32] Between 1955 and 1959, he was chairman of the Australian Radiation Advisory Committee; he was concerned that Australians were being exposed to unnecessary medical and industrial radiation.^[1]

Internationally, Burnet was a chairman of the Papua New Guinea Medical Research Advisory Committee between 1962 and 1969. His role on the committee enabled his interest in human biology. He was particularly interested in kuru (laughing sickness), and lobbied the Australian government to establish the Papua New Guinea Institute of Human Biology. Burnet served as first chair the Commonwealth Foundation (1966–69), a Commonwealth initiative to foster intraction [interaction] between the member countries [countries']elite, and he was also active in the World Health Organization, serving on the Expert Advisory Panels on Virus Diseases and on Immunology between 1952 and 1969 and the World Health Organization Medical Research Advisory Committee between 1969 and 1973.

Burnet was opposed to the use of nuclear power in Australia due [owing] to the issues of nuclear proliferation. He later retracted his objections to uranium mining in Australia, feeling that nuclear power was necessary while other renewable energy sources were developed.^[33] In the late 1960s and 1970s, he was also vocal in the anti-smoking movement; he was one of the first high-profile figures in Australia to educate the public on the dangers of tobacco, and appeared in an advertisement criticising the ethics of tobacco advertising.^[34]

Later life

Following his resignation from the Walter and Eliza Hall Institute, Burnet was offered an office at the University of Melbourne in the School of Microbiology. While at the university, he wrote 13 books on a variety of topics including immunology, ageing and cancer and human biology. He also wrote an autobiography entitled Changing Patterns: An Atypical Autobiography, which was released in 1968. He became president of the Australian Academy of Science in 1965. As president he was recognised by both governments and the public as the leading scientist in Australia.^[1] He helped establish the Academy's Science and Industry Forum and the foundations of the Australian Biological Resources Study. When his presidency ended in 1969, the Academy founded the Burnet Lecture and Medal, which is the Academy's highest award for biological sciences.

Burnet's essays and books published in his later life caused contention within the scientific community and to the chagrin of his peers, Burnet often made pessimistic proclamations about the future of science.^[35][12] In 1966 Burnet wrote an opinion article for the The Lancet entitled "Men or Molecules?" in which he questioned the usefulness of molecular biology, arguing that it had not and would not contribute anything of use to medicine and that manipulation of the genome as had been demonstrated in bacteria would do more harm to humans than good.^[36] Gustav Nossal subsequently described Burnet as "a biologist with a love-hate affair with biochemistry, which led to a brief but damaging rejection of the worth of molecular biology."^[24]

Burnet spoke and wrote widely on the topic of human biology after his retirement. In 1966 Burnet presented the Boyer Lectures, focussing on human biology. He provided a conceptual framework for sustainable development; 21 years later the definition provided by the Brundtland Commission was almost identical.^[37] In 1970 he revised an earlier book which was published as Dominant Mammal: the Biology of Human Destiny; it was followed by Endurance of Life, which was published in 1978. The books discuss aspects of human biology, a topic which Burnet wrote on extensively in his later years. In Dominant Mammal he argued that the roots of all human behaviour can be found in the behaviour of animals; in Endurance he addressed issues of ageing, life, death and the future of mankind. One reviewer described his ideas of sociobiology as "extreme" and giving "a dismal, unappealing view of humanity".^[38]

His first wife, Edith Linda Druce, died from lymphoid leukaemia in 1973, and in 1976 he married Hazel G. Jenkins. In 1978 Burnet decided to officially retire; in retirement he wrote two books. In November 1984 he underwent surgery for colorectal cancer; secondary lesions were found in August 1985, and he died on August 31 at his son's home at Port Fairy. He was given a state funeral by the government of Australia, and was buried after a private family service at Tower Hill cemetery, near Port Fairy. Following his death he was honoured by the House of Representatives which took the highly unusual step of moving a condolence motion in Parliament, an honour typically reserved for parliamentarians.^[39]

Honours and legacy

Burnet received extensive honours for his contributions to science and public life during his lifetime. He was the first recipient of the honorary Australian of the Year award, which was created to reward those Australians who have a consistent record of excellence, who have made outstanding achievements in their fields, and who have contributed in a significant way to the nation. In 1978 he was made a Knight of the Order of Australia. The British Empire created him Knight Bachelor in 1951, and he received the Elizabeth II Coronation Medal in 1953 and the Order of Merit in 1958. He was created Knight Commander of the Order of the British Empire in 1969 and received the Elizabeth II Jubilee Medal in 1977. He received a Gold and Silver Star from the Japanese Order of the Rising Sun in 1961.

He was a fellow or honorary member of 30 international Academies of Sciences. He received 10 honorary D.Sc. degrees from universities including Cambridge, Harvard and Oxford, an honorary M.D. from Hahnemann Medical College (now part of Drexel University), an honorary Doctor of Medical Science from the Medical University of South Carolina and a Doctor of Laws from the University of Melbourne. Including his Nobel, he received 19 medals or awards including the Royal Medal and the Copley Medal from the Royal Society and the Albert Lasker Award for Basic Medical Research; he also received 33 international lectureships and 17 lectureships within Australia.

Australia's largest communicable diseases research institute—the Burnet Institute (founded in 1986) —was named in his honour. The Burnet Clinical Research Unit of the Walter and Eliza Hall Institute was also named in his honour in 1986. In 1975 his work on immunology was recognised by a 33-cent stamp released by Australia Post. Seven Australian medical scientists were commemorated in the issue of a set of four Australian stamps released in 1995; he appears on the 45-cent stamp with fellow University of Melbourne graduate Jean Macnamara. He also appears on a Dominican stamp that was issued in 1997. The centenary of his birth was celebrated in Australia in 1999, a statue of him was erected in Franklin Street, Traralgon,^[40] and several events were held in his honour including the release of a new edition of his biography by Oxford University Press.^[41]

Burnet biographer Christopher Sexton suggests that Burnet's legacy is fourfold: (1) the scope and quality of his research; (2) his nationalistic attitude which led him to stay in Australia, leading to the development of science in Australia and inspiring future generations of Australian scientists; (3) his success establishing the reputation of Australian medical research worldwide; and (4) his books, essays and other writings.^[42] In spite if his sometimes controversial ideas on science and humanity, Peter Doherty has noted that "Burnet's reputation is secure in his achievements as an experimentalist, a theoretician and a leader of the Australian scientific community."^[14]

See also

• List of books by Frank Macfarlane Burnet
• History of immunology

References

General biographical references