22 A. C. R. Dean and Sir Cyril Hinshelwood 



to be destructive, and in the course of their normal hfe the 

 cells encounter destructive agencies such as radiations in an 

 unpredictable manner. 



Nevertheless, in the absence of more detailed knowledge of 

 the structural changes which determine difference in bio- 

 chemical properties, it would be unwise to neglect the possi- 

 bility that spontaneous mutations giving rise to positive new 

 capacities in the cell may sometimes occur, and if they do 

 they could be selected. The fact that sometimes such mutants 

 can be enriched by selective methods (though we are rather 

 doubtful about the evidence of successful application of these 

 methods except in the case where the passive type of resist- 

 ance is at least possible) does not in any way show that direct 

 adaptation is not also a common method by which drug 

 resistance appears. 



The positive evidence for this direct adaptation is strong, 

 and the arguments have already been summarized. One final 

 comment may be added: by methods of accelerated training 

 high degrees of unstable resistance can be produced under 

 conditions where selection could not possibly have operated. 

 We do not believe that the gradual and progressive stabiliza- 

 tion of this represents the complete substitution of one 

 phenomenon by another having no connexion with it. 



In conclusion, perhaps we should make clear once more 

 that we have never contested the part that selection of 

 mutants may play {cf. Hinshelwood, 1946). If that denial has 

 sometimes been gratuitously made for us by others, it is per- 

 haps because we have been more interested in investigating 

 and following up the nature of the adaptation process itself. 

 This, indeed, is a matter of very great biochemical and bio- 

 physical interest, and should need no apology, though it may 

 not seem the aspect of major interest to those whose approach 

 is through classical genetics. Similar efforts to form a picture 

 of how spontaneous mutations occur, and how they lead to 

 resistance, is another problem well worthy of attention. 



