F. M. Burnet

A modification of jerne's theory of antibody production using the concept of clonal selection

There are three current theoretical inter pretations of antibody production which, following Talmage (1957), may be referredto as the directtemplate theoryinwhich theantigenservesasa template against which the specific pat tern of the antibody is synthesized, the indirect template theory which postu lates a secondary template incorporated intothegenetic-synthetic processesof the antibody producing cells (Burnet, 1956), and the natural selection theory in which the antigen acts essentially by selection for excess production of natu ral antibody molecules of corresponding type (Jerne, 1955). The two latter theories were devised primarily to account for two sets of phe nomena for which the direct template theory seems quite irrelevant. The first is the absence of immunological re sponse to “¿ self― constituents and the related phenomena of immunological tolerance; thesecondistheevidencethat antibody production can continue in the absence of antigen. Some means for the recognition anddifferentiation ofpoten tially antigenic components of the body from foreign organic material must be provided in any acceptable formulation. In Burnet and Fenners (1949) account, a positive recognition of “¿ self― material was ascribed to the presence of “¿ self markers― in all potentially antigenic macromolecules, and corresponding recognition units in the scavenger cells of the body. At the time it was regarded as inconceivable that a mechanism could exist which would recognise in positive fashion all foreign material and no at tempt was made to devise one, despite the fact that we have always recognised the clumsy character of the self-marker, self-recognition scheme. It is the great virtue of Jernes hypoth esis that it provides an approach to this alternative method of recognising self from not self. There is no doubt about the presence in all mammalian or avian sera of a wide range of reactive globulins whichcan legitimately be called“¿ natu ral antibodies.― Jerne assumed that amongst these globulin molecules were all the possible patterns needed for spe cific immunological type reaction with any antigen, except for those patterns corresponding to body antigens which would be eliminated by in vivo absorp tion. When a foreign antigen enters the blood it unites, according to Jernes scheme, with one of the corresponding natural antibody molecules. The com plex is taken up by a phagocytic cell in which the antigen plays no further part, but the antibody globulin provokes the Reprinted from The Australian Journal of Science 20 (3): 67-69, 1957.

Immunological Surveillance in Neoplasia

The objective of this introductory article is not to review current experimental work in the fields covered by the concept of immunological surveillance. Rather it is to provide a background of historical and theoretical aspects which may be found a useful introduction to the detailed analyses of experimental and clinical data in the articles which follow it. After a brief account to the origin of the concept, I shall try to relate it to current immunological theory and to the far less clearly formulated opinions on the nature of carcinogenesis. Specific tumour immunity must of necessity be highly relevant to the nature of the process by which a cell becomes malignant and I shall include some current speculation on the topic. This is influenced greatly by recent discussions on the evolution of immunoglobulins and the nature of the processes in the genome by which diversity of immune pattern is generated in the individual.

MEASLES AS AN INDEX OF IMMUNOLOGICAL FUNCTION

Abstract There are two distinct systems of adaptive immunity in the body: one, mediated by cells differentiated in the thymus (T.-D. immunocytes), is concerned with delayed hypersensitivity and homograft immunity; the other with immunoglobulin and antibody production, the cell lines concerned being differentiated in gut-associated lymphoid tissue (G.-D. immunocytes). The whole process of the eruptive stage of measles and subsequent immunity is mediated by the thymus-dependent system.

Intrinsic Mutagenesis: A Genetic Basis of Ageing

I should like to begin this talk at a rather philosophical level, based on a book by Jacques Monod, ‘Chance and Necessity’.(l) It is a book which impresses me as almost mandatory reading for any biologist, and, as you probably know, it was a best-seller in Europe. The central theme of the book could be regarded as a restatement of Darwin’s thesis, and its subsequent elaboration by modern evolutionists like Julian Huxley, R. A. Fisher and Ernst Mayr. Evolution is based on chance : random mutation, random recombination and redistribution of qualities; and on necessity: the invariance of DNA replication and the rigid selection for survival under the impact of the environment. Monod scoffs at the very suggestion of a teleological approach. In his words, ‘Destiny is written as and while, not before, it happens.’ But he does use the concept of teleonomy to cover the adaptedness for survival of every organism and the way in which genetic information is transmitted, each element invariant, from one generation to the next, to maintain that effectiveness. In a sense that, I think, Monod would tolerate but not applaud, we can say that, when an evolutionary need arises, nature can meet it only if some process of random change can be found or devised to provide the raw material, the possibilities from which what is wanted can be chosen and shaped. Monod’s examples of his thesis are of course drawn from his own field of the biochemical genetics of E. coli. But it is already an accepted dogma that all the really basic qualities and mechanisms of life are uniform. Perhaps some of you have come across Monod’s alleged epigram: ‘If it holds for E. coli, it holds for an elephant.’ I am as convinced as Monod about the validity of his general approach and its applicability to the whole of biology. I am inclined to think in fact that the development of the clonal selection theory of antibody production(*) means that I have held the view for many years. In 1957 it was postulated that the only way in which antibody could be produced was by a genetic process of random diversification and phenotypic restriction in the cell lines leading to what we then called immunologically competent cells. Such cells were subject to selective elimination of those whose immune pattern made them potential initiators of autoimmune disease; those which survived this censorship process were available for subsequent selective proliferation if they made effective contact with a sterically appropriate antigenic determinant. The concept of clonal selection is really pure Monod, though, if I remember correctly, he was rather sceptical when he first encountered it at a Ciba conference in 1959, and, on my side, I doubt if I fully realized its implications until I had read ‘Chance and Necessity’. Since

The Natural History of Autoimmune Disease in NZB Mice: A Comparison with the Pattern of Human Autoimmune Manifestations

Excerpt All mice of the NZB/Bl strain spontaneously develop serological and pathological evidence of autoimmune disease during adult life. The NZB/Bl strain was developed by Dr. Marianne Bielschows...

A possible role of zinc in the pathology of dementia.

Abstract All or most of the enzymes primarily concerned with DNA replication, repair, and transcription—all of which require accurate transfer of information—are zinc metalloenzymes. This holds for the DNA-polymerases of organisms ranging from viruses and bacteria to echinoderms and mammals. The zinc atoms are intrinsic to the enzyme, which loses its activity when the zinc is removed with a chelating agent and may change its degree of errorproneness if the zinc is replaced with manganese. It is suggested that dementia may represent the cascading effects, equivalent to an Orgel error catastrophe, of error-prone or ineffective DNA-handling enzymes in neurons which have an age-associated loss of ability to make zinc available for insertion into newly synthesised enzyme. Evidence for this is wholly indirect; but it is suggested that administration of additional zinc could prevent or delay the onset of dementia in subjects genetically at risk.

Evolution of the Immune Process in Vertebrates

This article is a slightly up-dated version of the presidential address to the Australian Society of Immunologists given by Sir Macfarlane Burnet in December 1967. He suggests that the mammalian immune system could have evolved from the haemocyte or primitive mobile cell of the invertebrate.

AN IMMUNOLOGICAL APPROACH TO AGEING

Abstract In a discussion of the theory that the process of ageing is largely mediated by autoimmune processes, as elaborated by Walford in a recent book, three additional suggestions are made. These are that progressive weakening of the function of immunological surveillance is important and that this may be related to weakness of the thymus-dependent immune system. In turn, this may be dependent on exhaustion of the Hayflick limit in the cells concerned in the thymus and dependent tissues.

A short description of the poxvirus group (vaccinia and related viruses).

Abstract At the International Microbiological Conference held in Rome in September, 1953 the Virus Subcommittee of the International Nomenclature Committee instructed the study groups concerned with the better known groups of animal viruses to prepare for publication descriptions of certain virus groups and group members. Descriptions of the Myxovirus and the Poliovirus groups have already been published ( Andrewes et al. , 1955 ; von Magnus et al. , 1955 ).

A Genetic Approach to Variation in Influenza Viruses: 4. Recombination of Characters Between the Influenza Virus A Strain NWS and Strains of Different Serological Subtypes

SUMMARY: Mice were inoculated intracerebrally with mixtures of the influenza virus strain NWS and the serologically distinct non-neurotropie strains MEL, OcI and SW. From mouse brains removed about the 5th or 6th day virus strains were obtained which, after at least two passages at limiting infective dilution, showed active encephalitogenic power with the serological character of the second strain of the original mixture. These are regarded as recombinants. The strains in general show in vitro characters close to those of the serologically similar ‘parent’. They have, however, diminished enzymie action on ovomucin and do not readily clute from red cells; in this they resemble the strain NWS. They are more readily converted to the indicator state than either of the original strains. The process by which these unusual types arise is discussed in the light of recent views that intracellular multiplication of bacterial viruses and of some animaal viruses takes place not by binary fission but by the breaking down of the infective unit into smaller particles which are the replicating units. It is concluded that the recombinants arise by recenstitution of infective particles from the pool of repticating units produced by double infection of a single cell by virus particles of both parent types.