JOSHUA LEDERBERG 



induced by radiations (45-Demerec). Later, Newcombe postulated a similar 

 lag for spontaneous mutations to account for discrepancies in the estimation of 

 mutation rates by different methods, according to whether they counted 

 mutant individuals or mutant clones (4). In both of these instances, however, 

 the interpretation is complicated by the cytological structure of the bacterial 

 cell (15) which speaks for the concurrence of several nuclei (and therefore of 

 several replicate gene sets) in each cell. Recessive mutations such as phage 

 or drug resistance would require for their phenotypic expression that mutant 

 and nonmutant nuclei be segregated, so that there would also be a segregation 

 lag in the genesis of the mutant phenotype (103, 14, 47). The description of 

 phenomic lag in the development of nutritionally sufficient "back-mutations" 

 induced by ultra-violet light (UV) (7) avoids this difficulty, for these mutations 

 are presumably dominant, and would not require segregation for their expres- 

 sion. A final caution which must be entered is that we cannot be entirely certain 

 that the mutation-producing event within the cell is coincidental with the 

 experimental irradiation (mutation delay hypothesis) (26, 49). 



Mutant characters. — Something is known of the phenogenetics of phage 

 resistance. The extraction of sensitive and resistant cultures results in prepara- 

 tions differing in the ability to neutralize the phage "in vitro." This argues 

 strongly for the concept that phage sensitivity is correlated with the presence 

 of a specific receptor substance (44, 61 ) . Another metabolic correlate of phage 

 resistance is less explicable. In certain specific combinations of bacterium and 

 phage, the resistance mutation simultaneously leads to new nutritional require- 

 ments, (often for tryptophane or proline). Unfortunately, this correlation has 

 not been found in strains which can be studied by recombination, so that it 

 is not certain whether a simple genetic change causes the two effects, (23, 139, 

 45-Luria) . 



Phage resistant mutations play such a large part in genetic study because 

 of the ease with which they can be selected out of large populations, simply by 

 adding suspensions of the virus under appropriate conditions. This facility is 

 shared by antibiotics and other antibacterials as selective agents. The advantage 

 that the "drug" is not another biological system whose variability must be 

 watched is counterbalanced by the fact that resistance to most chemicals is a 

 quantitative rather than an all-or-none phenomenon, and that a great many 

 genes may be involved. The probable reason for this is that antibiotics interfere 

 with key metabolic steps that are linked to a wide diversity of other reactions, 

 so that any one of a number of biochemical changes may influence the growth 

 response to an inhibitor. The initial reaction between phages and cells is, on the 

 other hand, directly associated with the presence of a receptor substance with a 

 high order of specificity. 



Current interest in drug-resistance mutations is largely motivated by their 

 importance in limiting the effectiveness of chemotherapy (95), but they have 

 provided interesting material for more theoretical genetic studies as well. In 



