The year 2007 marks the 50th anniversary of the publication of Burnet's clonal selection theory. This theory provided an intellectual framework that revolutionized the field of immunology.
On 21 October 2007, it will be 50 years since the publication of Burnet's clonal selection theory in the Australian Journal of Science. To commemorate this landmark in the field of immunology, in this issue we have republished the original paper, “A Modification of Jerne's Theory of Antibody Production using the Concept of Clonal Selection,” at the end of the commentary by Phil Hodgkin, William Heath and Alan Baxter. In an accompanying essay, Gustav Nossal recounts his pioneering work that provided the first experimental support for Burnet's theory.
Theories about antibody production have had a long and rich history. In 1900, Paul Ehrlich offered his 'side-chain theory' to explain the large increases he noted in antibody production in mice after exposure to antigen. Ehrlich proposed that the cell is covered with many chemical side chains that form links with antigens they encounter. For every antigen in nature, at least one side chain would bind, inducing cells to produce more of the same type of chain, which would then be shed into the blood as antibodies.
Ehrlich's selective theory for antibody production fell out of favor when Karl Landsteiner showed that antibodies could be raised against haptens produced by chemical synthesis. It was deemed improbable that animals would express preformed antibodies specific for antigens not normally present in nature.
In the first half of the twentieth century, the 'template instructive hypothesis' proposed by Fritz Breinl and Felix Haurowitz and developed by Linus Pauling predominated in the literature. This hypothesis suggested that antigens serve as a template for antibody production, thus explaining how antibodies could be made to artificially generated substances.
But by the early 1950s the antibody template theory was rendered obsolete by many findings. Niels Jerne noted that the template theory could not explain the increasing rate of antibody production during the primary immune response. It also failed to explain the anamnestic (memory) response. These and other deficiencies in the instructive hypothesis led Jerne to propose the natural selection theory of antibody formation in 1955. Jerne's theory, which resembled the Ehrlich's side-chain hypothesis, stated that antigen binds to antibody by chance, and that after binding, the antigen triggers replication of more of the same antibody. Jerne's ideas inspired David Talmage and Frank Macfarlane Burnet to propose the correct paradigm: the clonal selection theory.
As described by Hogkin, Heath and Baxter in their commentary, there is some controversy as to who first put forth the clonal selection theory. Certainly Talmage was the first to suggest the cell as the basic unit of selection, as fully acknowledged by Burnet. Nevertheless, as noted by Nossal, Burnet's paper was the first to theorize that continued somatic mutations after antigenic selection would result in affinity maturation. In addition, he proposed that 'repertoire purging' could explain the phenomenon of tolerance. Finally, he proposed that aberrant cell division of clones bearing self-specific antibodies could lead to autoimmunity. Significantly, Burnet's theory set the scene for modern cellular immunology research, and his paper should be considered a seminal landmark in the history of immunology.
Burnet's clonal selection theory not only had great implications for modern immunology but was also monumental in spearheading immunology research in Australia. In 1957, he announced a switch from virology to immunology research at the Walter and Eliza Hall Institute and was instrumental in attracting some of the great names in immunology to the institute. What followed was a series of key discoveries that have given Australian immunology research a world-class reputation. Although it would be impossible to highlight all the important discoveries emanating from Australia in a single editorial, some notable studies include Nossal's experiments supporting the clonal selection theory, Jacques Miller's demonstration of the importance of the thymus for lymphocyte development, Donald Metcalf's documentation of the requirement of colony-stimulating factor in the culture of hemolymphocytic cells, Ken Shortman's elucidation of the specialized functions of distinct dendritic cell subsets, Robert Blanden's linkage of cytotoxic T cells to the control of virus infection, and last but certainly not least, the Nobel Prize–winning research by Peter Doherty and Rolf Zinkernagel that documented major histocompatibility complex restriction of T cell recognition.
In celebrating Burnet's clonal selection theory, the other seminal contributions that Burnet made to immunology must not be forgotten. He developed techniques for growing influenza virus in the chorioallantoic membrane of the chick embryo that are still in use today. He also identified the unknown agent of Q fever as Coxiella burnetii. More notable was his work with Frank Fenner, published in a monograph called “The Production of Antibodies,” that introduced the idea of self and non-self discrimination. This was later formally demonstrated by Peter Medawar and is the work for which Burnet and Medawar were co-recipients of the Nobel Prize in Physiology or Medicine.
Perhaps less well known are Burnet's 'near misses'. He abandoned his research on poliomyelitis that closely resembled John Enders' Nobel Prize–wining experiments. In addition, although Burnet demonstrated interferon activity in 1951, he did not realize its significance until his former colleague Alick Isaacs published in 1957. Nevertheless, his genius is clear, and for this he received many honors, including Knight of the Order of Australia and Australian of the Year. Testament to his important influence on immunology is the conference, “The Power of One Idea: The Golden Anniversary of Burnet's Clonal Selection Theory,” being held in October at the Walter and Eliza Hall Institute to celebrate the 50th year since the publication of the clonal selection theory. In this anniversary year, Nature Immunology would also like to salute the contributions of Frank Macfarland Burnet to immunology research.
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Immunologic Research (2014)
Clinical and Experimental Medicine (2009)