NATURE AND FORMATION OF ANTIBODIES 19 



but that they were indeed globuUns; we attributed their affinity for the respec- 

 tive antigens to complementariness in shape. We imagined that this comple- 

 mentariness arose by the influence of antigen molecules which orient the amino 

 acids during the process of globulin formation; we assumed originally that anti- 

 bodies might differ from normal serum globulins by the number and sequence 

 of amino acids in their peptide chains. Similar views were proposed shortly 

 thereafter and independently by Jerome Alexander (1931) and by ]Mudd (1932). 



In 1940 Pauling took up the problem of antigen-antibody relation and mod- 

 ified our view by assuming that the complementariness in shape was due to 

 changes in the mode of folding of the peptide chains rather than to changes in 

 the amino acid composition or in the sequence of amino acids. This view is 

 strongly supported by analyses (Haurowitz, 1954; McFadden and Smith, 

 1955) which show that the amino acid composition of antibodies is almost the 

 same if not the same as that of normal serum gamma-globulins and also that 

 the sequence of the first five or six N-terminal amino acids is the same (Porter, 

 1950; :\IcFadden and Smith, 1955). Although it is dangerous to extrapolate 

 from a sequence of 5 or 6 amino acids to a chain of about 1500 amino acids, 

 it is quite possible that the secjuence of the amino acids in an antibody mole- 

 cule is the same as in a normal gamma-globulin molecule of the same species. 

 According to this view, the antibodies produced by an animal species differ 

 from each other merely in the mode of folding of the common peptide chains. 

 This folding, evidently, occurs in such a fashion that the combining group of 

 the antibody is a negative print of the determinant group of the antigen. At 

 this meeting Dr. Pressman has discussed the methods for measuring comple- 

 mentariness in quantitative terms. 



In my own talk I would like to discuss the mechanism by means of which 

 this complementariness is brought about. The first question which arises is 

 whether complementariness is achieved by the rearrangement of preformed 

 proteins or whether it arises in the moment in which amino acids combine to 

 form the protein molecule. The latter view was proposed by Breinl and myself 

 (1930) and was included by Pauling in his theory of antibody formation (1940). 

 Pauling and Campbell also presented evidence that artificial antibodies can 

 be produced /;/ vitro by mild denaturation and renaturation of normal serum 

 globulins in the presence of an antigen; efforts to repeat the conversion of 

 normal globulins into antibodies made by Morrison were in the main unsuc- 

 cessful (1953). When isotopically labelled amino acids are used it can be shown 

 that they are incorporated into antibody molecules at the same rate as into 

 other serum globulins (Heidelberger, Treffers et al, 1942). This supports 

 strongly the view that antibodies are formed like other globulins by direct 

 synthesis from amino acids and not by rearrangement of preformed globulins. 



What is the role of the antigen in this process? The simplest idea is that the 

 antigen molecule acts as a template, a kind of mold, and that antigen and newly 



