Indirect Selection and Drug Resistance 33 



of bacterial genetics) to see if the model which was so fruitful 

 for the study of evolution in higher organisms, namely the 

 selection of spontaneous genotypic changes, could be applied 

 to explain changes in resistance, in particular to viruses and 

 drugs. The elegant methods of Luria and Delbriick, and of 

 Newcombe, were used successfully and gave practically unequi- 

 vocal answers in favour of the preadaptation theory. 



Both the strength of these methods and the validity of the 

 conclusions which rely on the statistical properties of clones 

 have been questioned. While the present author would agree 

 as to their insufficient strength, which leaves the door ajar to 

 equivocal results or interpretations, the evidence collected 

 later has fully confirmed the validity of the early conclusions. 

 In view of the existence of such stronger evidence, methods of 

 analysis such as the so-called "fluctuation test", the test of 

 " average clones " and the " correlation between relatives " will 

 not be considered here. They have been reviewed elsewhere 

 (Cavalli-Sforza, 1952; Cavalli-Sforza and Lederberg, 1953). 

 A method will be considered instead, the strength of which 

 nobody would question, namely that of indirect selection. 



Indirect selection 



Indirect selection was first introduced by Lederberg and 

 Lederberg (1952) in streptomycin- and Tl phage-resistance. 

 It uses sib-selection (or, in general, selection by tests on 

 relatives) to obtain strains which are resistant to some agent, 

 without using this agent for sorting out the resistant mutants. 

 By substituting genetic testing for direct isolation with the 

 drug, it can be proved, and has been proved unequivocally 

 that the resistant cells are present in the population spon- 

 taneously, as they can be isolated from it without exposure 

 of the population to the drug. To express the principle in 

 simple terms, suppose we can isolate the two descendants of 

 one cell for a great number of cells, and test for resistance to 

 a drug one of the daughter cells, keeping the other for repro- 

 duction in the absence of the drug: if the mother cell was 

 sensitive, apart from rare mutational events both cells should 



DRUG RES. — 2 



