NATURE AND FORMATION OF ANTIBODIES 23 



sideration the molecular weights of diphtheria toxin and antitoxin, this gives 

 approximately 1 million antitoxin molecules per molecule of toxoid in three 

 weeks, or approximately two antibody molecules per second. This is a minimum 

 value based on the assumption that all of the injected toxoid molecules act as 

 templates. Many of the toxoid molecules are excreted, others are destroyed by 

 the action of enzymes or deposited in tissues where antibodies are not formed; 

 the number of serologically active toxoid molecules is, therefore, smaller and 

 the number of antibody molecules formed per toxoid molecules much higher 

 than two, probably about 10-20 per second. Accordingly, the time during 

 which complementariness is accomplished is less than about 0.05 to 0.1 second. 



How should we imagine formation of a complementary antibody molecule 

 in such a short time? We cannot do more than speculate when we try to answer 

 this question. We can assume that formation of globular proteins quite gen- 

 erally takes place in two phases, the first of these consisting in the formation 

 of an extended, threadlike peptide chain, the second in its folding. One of the 

 reasons for this assumption is that the amino acid composition of the peptide 

 chains of all antibodies formed by an animal seems to be the same, independent 

 of the nature of the antigens involved in their formation; evidently, the amino 

 acid composition and their sequence are determined by the genes and are in- 

 herited from mother cell to daughter cell. In contrast to the constant amino 

 acid composition, the complementariness of antibodies is not transmitted to 

 the next generation. Acquired immunity is not inherited. Evidently, the fold- 

 ing pattern, which is the basis of complementariness, is not under the con- 

 trol of the genes. We have all reason to assume, therefore, that formation of 

 the peptide chain and its folding takes place in two phases, the first of them 

 controlled by the genes, the second independent of the genes. 



We can imagine that the extended peptide chain is unstable, that it collides, 

 after its formation, with the template and, on collision, folds up to form a com- 

 plementarily shaped globular molecule. This globular form is stabilized by 

 numerous cross-links such as H-bonds and salt-bridges, possibly also by dithio- 

 bridges (Karush); the folded globular antibody molecule is then detached from 

 the template. We know from in vitro experiments that dissociation of the anti- 

 body from the antigen can be accomplished by acidification, by increasing the 

 salt concentration and by other changes in the physical-chemical conditions. 

 Similar changes may suffice to cause removal of the globular antibody particle 

 from the template immediately after its formation and may lead to its passage 

 into the blood stream, thus making the template available for collision with 

 other extended peptide chains. Accepting this two-phase process of protein 

 formation, we have to remember that the period of less than 0.1 second at 

 which we arrive is the time of the second phase only. The first phase, the forma- 

 tion of the peptide chain from amino acids, may last much less than 0.05 sec- 

 onds. It can last longer, but not very long since radioactive amino acids in- 



