Macfarlane Burnet

Australian biologist

• Born: September 3, 1899
• Birthplace: Traralgon, Victoria, Australia
• Died: August 31, 1985
• Place of death: Melbourne, Victoria, Australia

Burnet was awarded the 1960 Nobel Prize in Physiology or Medicine for the discovery of acquired immunological tolerance to tissue transplants, but he also discovered a method for identifying bacteria by the viruses that attack them, as well as a technique for cultivating viruses in chicken embryos.

Early Life

Macfarlane Burnet (BUHR-neht) was born in a small Australian country town, the son of the local bank manager, Frank Burnet, and the former Hadassah McKay. He was brought up on the Shorter Catechism of the Presbyterian Church, and the Calvinist influence of his religious training led him, as he has admitted, to concentrate on the genetic influences on human behavior. As a young boy, he had an enthusiastic interest in living things, especially insects, and beetles in particular, just as Charles Darwin had a century earlier.

Burnet was educated at the Victoria State Schools. Then he studied biology and medicine at Geelong College, before moving on to the University of Melbourne, where he received his M.D. degree in 1923. On graduation Burnet went to the Walter and Eliza Hall Institute at the University of Melbourne to do research on the agglutinin reaction in typhoid fever. From 1923 to 1924 he was resident pathologist at the Melbourne Hospital, his first professional appointment. In 1926 he was awarded a Beit Fellowship for Medical Research and worked for a year at the Lister Institute of Preventive Medicine in London. For his accomplishments he received a Ph.D. degree in bacteriology from the University of London in 1927.

On his return to Australia in 1928, he became assistant director of the Walter and Eliza Hall Institute of Medical Research at the Royal Melbourne Hospital. At this time he married Linda Druce, a schoolteacher. The marriage produced two daughters, Elizabeth and Deborah, and a son, Ian. Burnet assumed the directorship of the Hall Institute in 1944, a position he held until his retirement in 1965. He was also professor of experimental medicine at the University of Melbourne. In 1932 he spent a year at the National Institute for Medical Research in Hampstead, London. Otherwise, apart from many visits to various countries to give lectures, he worked steadily at the Hall Institute in Melbourne.

Life’s Work

After 1923, Burnet became wholly concerned with biology. His first scientific activities were in the field of infectious diseases. He studied the multiplication of bacteriophages, the viruses that grow inside bacteria. He also showed how both bacteria and bacteriophages could be classified. During the 1930’s, he studied Australian strains of the swine influenza virus, and he calculated the mutation rates of this virus. In his first book, Biological Aspects of Infectious Diseases (1940), he tried to bring a more ecological viewpoint to the problems of infection and immunity.

In 1932, Burnet developed a method of multiplying viruses by injecting them into living chick embryos. His technique was the standard way of studying viruses for more than two decades, until tissue-culture methods were perfected. During the course of this work he realized that embryos injected with a virus do not produce the appropriate antibodies to combat infection by that virus. He speculated that an organism’s ability to distinguish its own tissue from foreign tissue had not yet developed at the embryonic stage. It seemed to him, therefore, that the ability of a chick embryo to form antibodies against foreign proteins might not be inborn. In humans, antibodies against disease develop only after exposure to the microorganism causing the disease. When in the course of life, Burnet wondered, did the ability to resist foreign proteins develop? Could it be in the embryonic stage? If so, then immunological tolerance to certain substances might be induced artificially at the embryonic stage. If an antigen were injected into an animal embryo, the animal would not form antibodies against the antigen, but would instead become tolerant of the antigen and accept it as if it were a normal part of its body.

This prediction that tolerance could be established experimentally was tested in Burnet’s laboratory, but all of his attempts failed. The British immunologist Peter Medawar was the first to demonstrate conclusively that this tolerance to potential antigens could indeed be acquired by the embryo. He and his colleagues showed that the inoculation of fetal mice with living cells from a future donor made them tolerant of grafts from those donors in later life. The fact of acquired immunological tolerance had important implications in immunity, especially in the ability of an organism to tolerate foreign transplants. It is obvious that an animal must not destroy its own cells, but how an animal’s body can recognize the difference between what is its own and what is foreign (and therefore to be destroyed) is not obvious. Most of Burnet’s work was dominated by this problem of the recognition of “self” and “not self.”

Besides these studies on immunological tolerance, for which he was knighted in 1951 and for which he and Medawar shared the 1960 Nobel Prize in Physiology or Medicine, Burnet performed other important investigations in virology and immunology. For example, he found that the filamentous forms of some viruses, such as those that cause influenza and mumps, could be ruptured by suspending them in water. He suggested that the infectivity of these viruses was limited to their tips, so that these filamentous forms could, as later work showed, be regarded as having an infective “warhead” composed of nucleic acid. He explored these filamentous forms further by studying their surface properties. He found that virus surfaces were similar to cell surfaces. He has also made contributions of fundamental importance to knowledge of the genetic complexity of virus particles, the genetic interactions between related viruses that simultaneously infect the same cell, and the inhibition of viruses by various substances.

His greatest contribution to immunological theory came in the late 1950’s, when he advanced the clonal selection theory of acquired immunity. This controversial theory was inspired not by any single discovery but by fitting many well-established facts into a conceptual framework that was partly old and partly new. This blend of ideas revolutionized the course of immunology. The most significant new idea in Burnet’s theory was the proposal that the cell (or, more explicitly, a clone of identical cells) was the structure selected to form the antibody for a particular antigen. (A clone is a group of genetically identical descendants of a single cell.) Very small amounts of many different antibodies are produced at a steady rate before the body experiences any antigen. The invasion of an antigen stimulates a lymphocyte (a type of red blood cell) to begin reproducing, and this results in the creation of a clone of lymphocytes, all capable of producing the antibody that neutralizes the invading antigen. So, in Burnet’s scheme, the only function of the antigen was to select the appropriate antibody and carry it to a specialized system of antibody-producing cells. Entrance of the antibody into this particular kind of cell led to the production of more of that antibody. For Burnet, then, the cellular response to selection by antigen involved cell multiplication. In this way the number of cells specific for that antigen increased within the entire population of antigen-reactive cells.

In his theory Burnet made a courageous assumption: that each cell was able to respond to only one antigen, so that its descendants would produce only one antibody. He also supposed that there were billions of potential antibody-producing cells, and he accounted for this diversity of cells by postulating various mutations of the genes responsible for antibody production. When his theory was initially proposed, he was hesitant to specify the cell type selected by the antigen, but he eventually stated that the lymphocyte was the most likely candidate. Not until the early 1960’s were lymphocytes shown to be antigen-reactive cells, and not until years later was it proved that each antigen does indeed select a particular clone of lymphocytes.

Throughout his career Burnet continued to make important contributions to the understanding of the epidemiology of several diseases, including influenza, polio, and herpes. For example, he isolated the organism that caused Q fever, and it is named in his honor (Rickettsia burneti).

Toward the end of his life Burnet moved away from immunology and found his main intellectual interest in the nature of aging. After 1973, he tried to develop a theory of the nature of human aging in genetic terms. He also wrote several books in which he applied his scientific ideas to the problems of politics and society. His work in medical research convinced him that the solutions to most political and social problems must in the last analysis be based on our inheritance from the last few million years of evolution.

Significance

Burnet’s professional interests moved away from virology through cellular immunology to genetics. When, in the 1930’s, he was shown the first evidence that a particular bacteriophage contained nucleic acid, he became fascinated by the universal relevance of the genetic material, and he watched every major step in the evolution of molecular biology with great interest, eventually witnessing this genetic influence enter into immunology.

His great successes in virology and immunology came from his biological approach. For example, his approach to the problem of antibody production, namely, that antibody formation should be interpreted on biological rather than chemical lines, seems to have become increasingly valid. Much relevant work has become centered on the genetic control of antigens and the processes of protein synthesis in the cell, and this is very much along the lines of Burnet’s ideas.

In the 1950’s, Burnet became impressed with how immunity could be regarded as a process of Darwinian selection among certain cells of the body. The clonal selection theory that grew out of this work has been generally accepted in principle by immunologists, but Burnet campaigned to get its full implications accepted by pathologists. In his book Immunological Surveillance (1970), he tried to apply his approach to cancer immunity. He attempted to look at cancer from the same Darwinian point of view that characterized most of his very productive career.

Bibliography

Brooks, Stewart M. The World of the Viruses. New York: A. S. Barnes, 1970. This book gives a good general account of modern virology for general readers. The author shows both how viruses cause diseases and how they have revolutionized the understanding of life.

Burnet, Frank Macfarlane. Credo and Comment: A Scientist Reflects. Carlton, Vic.: Melbourne University Press, 1979. In this book, intended for a general readership, Burnet tries to apply his knowledge acquired in the biological sciences to the understanding of a variety of human problems, such as social justice, war, ethics, and religion.

‗‗‗‗‗‗‗. Genes, Dreams, and Reality. New York: Basic Books, 1971. An attempt by Burnet to present to a wide readership a balanced account of where modern biological science has led and how its knowledge can be applied to matters bearing directly on the quality of human life.

‗‗‗‗‗‗‗. Self and Not Self: Book One and Book Two. New York: Cambridge University Press, 1969. Book I is an attempt to present immunology in terms of a Darwinian process of inheritable change and selection among the mobile cells of the mammalian body. It is written for readers with a scientific background. Book II offers a more technical and documented picture of the field.

Sexton, Christopher. Burnet: A Life. 2d rev. ed. Melbourne, Vic.: Oxford University Press, 1999. Biography, including descriptions of Burnet’s medical discoveries that led to his receipt of the Nobel Prize.

Stent, Gunther S. Molecular Genetics: An Introductory Narrative. 2d ed. San Francisco, Calif.: W. H. Freeman, 1978. This book provides an excellent historical background to modern molecular genetics, and the work of Burnet and many others is discussed in a disciplinary context. It is intended for readers with at minimum two years of undergraduate science training.

Wilson, David. The Science of Self: A Report of the New Immunology. London: Longmans, Green, 1972. This book by a science reporter was written for general readers. It surveys the history of the subject as well as giving an account of modern immunology. It looks at the failures as well as the future of immunology.

Wintrobe, Maxwell M. Blood, Pure and Eloquent: A Story of Discovery, of People, and of Ideas. New York: McGraw-Hill, 1980. This book, which has twenty-one sections written by twenty authors, is designed to tell the story of how the study of blood began, how understandings of it developed, and how well it was understood in the late twentieth century. Intended for general readers as well as scientists.