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PERSPECTIVES IN BIOLOGY AND MEDICINE Volume III · Number 4 · Summer i960 THEORIES OF IMMUNITY F. M. BURNET* I. The Chemical Approach By common consent, the central problem ofbiology today is the nexus between the information carried by the genetic mechanism ofthe cell or organism and its expression as synthesis of specific protein, classically an enzyme. Currently the solution ofthat problem is being sought in terms of structural organic chemistry with the Watson-Crick model ofdeoxyribonucleic acid, DNA, as the starting point. Since the Meselson-Stahl experiment (i), there has been little doubt that the Watson-Crick model, with its double helix and "automatic" capacity to replicate, is essentially a true picture ofDNA as it exists in the cell. Nevertheless, it is still a very incomplete picture of the genetic mechanism. Much thought has been given to how a code expressed in sequences offour "letters," the purine and pyrimidine bases, can be translated into one using twenty "letters (amino acid residues) to characterize protein molecules. Most current interpretations assume that ribonucleic acid, RNA, is an essential intermediary and that the polypeptide chain is actually synthesized in accordance with information carried in anRNAtemplate. Thework of Zamecnikand Hoagland's group at Harvard offers a fairly detailed model ofan enzymological mechanism by which a polypeptide chain with a determinate sequence ofamino acid residues could be constructed (2). Along with the detailed chemical and enzymologicai study of some particularly suitable examples of protein synthesis, a powerful new approach has developed from the application ofbiochemical methods to the genetics ofmicroorganisms. The method might be summarized as making * The Walter and Eliza Hall Institute ofMedical Research, Melbourne, Australia. 447 use ofthe abnormalto uncover normalbiosynthetic processes. A normally functioning organism in one sense presents no problems.Just as one has no consciousness ofone's viscera until they become diseased, so the nutrition ofa bacterium becomes much more amenable to study when a series of its biochemical mutants are also available for comparison. In their work on Neurospora, Beadle and Tatum introduced a new dimension into biochemistry by obtaining and studying mutant forms ofmicroorganisms in which single deviations from the normal pattern ofmetabolism are present (3). The recognizable change in most such instances was that a certain process failed to occur as a result (sometimes directly demonstrable) ofthe corresponding enzyme being absent or being produced in inactive form. So far the chemical nature ofthe anomaly ofthe inactive enzyme has not been established in any instance. In the case of some of the inheritable anomalies of hemoglobin in man, however, Ingram and others have shown that the change may concern only a single amino acid residue in the half-molecule (4). This example has greatly strengthened the growing concept that the whole character ofa protein is determined by the sequence ofamino acids in the peptide chain. There is no doubt about the reality of the folding of the chain and of its internal stabilization by disulphide or hydrogen bonds, but the present tendency is to interpret the secondary and tertiary folding ofthe molecule as resulting inevitably from the nature ofthe primary sequence ofamino acid residues. A majority of immunochemists, however, still follow Pauling in holding that the facts ofimmunology point strongly in the other direction (5). They have held that a long polypeptide chain with a defined sequence ofamino acid residues can take up any one ofa large number ofalternative configurations and that at least two processes are necessary for the synthesis ofa specific protein molecule. In addition to the synthesis ofthe polypeptide chain, a specifically determined secondary foldingtakesplace, which maybe guided either by some genetically determined template or, in the case ofantibody production, by some intruding chemical pattern. Even before the formulation ofPauling's theory, Landsteiner's work on the chemical basis ofimmunological specificity had prepared the way for a concept claiming a specifically "directive" or "instructive" role for the antigenic determinant (6). Since 1937 or thereabouts, the ruling conception ofantibody has been that it represents one protein, gamma globulin, with a common amino acid residue sequence but modified by secondary folding to give an anti448 F. M. Burnet · Theories ofImmunity Perspectives in Biology and Medicine · Summer i960 body ofdifferent specificity. The agent that determines the form of the...


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