Discussion 43 



has had a long experience of growth in given conditions, such as normal 

 laboratory media and transfer routine, which are fairlj^ constant, it must 

 have adapted genetically to it. Genetic adaptation by natural selection 

 takes place automatically, in fact, and most of the favourable mutations 

 nuist have been fixed by it, thus decreasing the proportion of favourable 

 mutations available to the organism and increasing that of unfavourable 

 mutations. Of course, the strain must have had time to adapt to the 

 "usual" conditions, or in other words these must really be "usual"; 

 therefore, the previous history of the strain may have some importance. 

 On the other hand, the tendency of any new mutation to have a negative 

 fitness value is not only a theoretical expectation ; it is a fact, as for in- 

 stance the data in the present paper have show^n. 



Davis: It seems to me that we are using the term "drug resistance" 

 for two different concepts. When we say that one strain is more resistant 

 than another we mean operationally the following : two families of cells 

 are both grown under identical conditions and then identically tested to 

 determine the concentration of drug that brings about a certain degree 

 either of interference w ith growi;h or of active bactericidal action ; and 

 one family is found to require for this effect a higher concentration of 

 drug than the other. But ^vhen we say one cell is more resistant than 

 another we mean quite a different thing. If a number of cells are plated 

 on a medium containing a borderline concentration of drug, some cells 

 will die and others will give rise to colonies. We have a right to conclude 

 that the ones that died were less resistant, bj^ definition (i.e. if they 

 w^ould not have died in the absence of the drug). But we do not know 

 that the more resistant survivors are more resistant in an inheritable 

 way. They may be. They may also be simply those cells, in the inevi- 

 table range of physiological variation in a genetically homogeneous popu- 

 lation, that happened to be able to withstand the borderline concentration 

 of drug sufficiently to initiate colony formation. And, once initiated, the 

 microcolony could so modify its environment as to ensure its continued 

 growth. 



No geneticist would deny that such physiological variations can affect 

 the chance a cell has of resisting a borderline concentration of drug. 

 Indeed, it w ould be safe to predict that one could shift the average level 

 of such phenotypic resistance by varying the richness of the medium, 

 the aeration, the stage in the history of the culture at which the 

 organisms were harvested, etc. Furthermore, it seems inevitable 

 that the surviving cell, in beginning to grow in the presence of the drug, 

 would undergo further physiological changes in adaptive response to the 

 presence of the drug; such adaptive changes not only might alter the 

 susceptibility of the cell to the drug ; they also should be passed on to 

 the progeny as long as these progeny are grown in the presence of the 

 drug. But such adaptive changes in resistance, in contrast to inheritable 

 ones, would disappear after a suitable number of generations of growth 

 in the absence of the drug. 



While genetically orientated microbiologists have recognized the pos- 

 sibility of such adaptive influences on the resistance of a cell, they have 

 not been much inclined to investigate the problem. I think Sir Cyril 



