“It will be obvious that this attempt at a comprehensive discussion of antibody production is hampered in all directions by lack of knowledge.”
This is how Frank MacFarlane Burnet and co-author Frank Fenner start to summarise their seminal 142-page monograph, The Production of Antibodies, published in its second edition in 1949, eight years after the original 1941 edition with Burnet as sole author.
Despite the lack of knowledge, Burnet’s monograph, later updated with the aid of Fenner, is widely viewed as one of the most important documents in the history of immunology. Immunologists today judge it as the start of the move away from seeing immunology as a purely chemical endeavour to one where biology is placed centre stage.
The 1949 edition introduced the concept of “self” and “non-self”. Burnet, a taciturn Australian working at the Walter and Eliza Hall Institute of Medical Research in Melbourne, hypothesised that the concept of “self” was actively defined by the immune system during the development of the embryo, a concept that was later to be proven correct experimentally by Peter Medawar working in London.
In his seminal monograph, Burnet theorised on the concept of “immunological tolerance”. He suggested that if a foreign substance were to be introduced into the embryo before its immune system matured, the antigen would be accepted as self and no specific antibodies to that antigen would be produced when exposed to the same antigen later in life.
Medawar then successfully demonstrated Burnet’s hypothesis in his laboratory at University College London. Their combined work led the discovery of acquired immunological tolerance, for which both shared the 1960 Nobel Prize in Physiology or Medicine.
Burnet, who is widely regarded as the greatest scientist Australia has ever produced, later introduced the concept of clonal selection theory in immunology to explain the formation and diversity of antibodies during the initiation of the immune response. His idea, published in 1957, was that when a pre-existing, diverse group of lymphocytes, now known as B cells, are exposed to a specific antigen, only its counter-specific cell is activated. The activation causes this particular cell type to multiply within the population of B cells, resulting in an expanding clone that produced identical targeted antibodies against the antigen.
The first experimental support for Burnet’s radical idea came in 1958 when Gustav Nossal and Joshua Lederberg demonstrated that one B cell always produces one antibody. Burnet’s theory of clonal selection lies at the foundation of molecular immunology.