492 S. E. LURIA AND M. DELBRtlCK 



virus merely brings the variants into prominence by eliminating all sensitive 

 bacteria. 



Neither of these views seems to have been rigorously proved in any single 

 instance. Burnet's (1929) work on isolations of colonies, morphologically 

 distinguishable prior to the addition of virus, which proved resistant to the 

 virus comes nearest to this goal. His results appear to support the mutation 

 hypothesis for colony variants. It may seem peculiar that this simple and im- 

 portant question should not have been settled long ago, but a close analysis of 

 the problem in hand will show that a decision can only be reached by a more 

 subtle quantitative study than has hitherto been applied in this field of re- 

 search. 



Let us begin by restating the basic experimental finding. 



A bacterial culture is grown from a single cell. At a certain moment the 

 culture is plated with virus in excess. Upon incubation, one finds that a very 

 small fraction of the bacteria survived the attack of the virus, as indicated by 

 the development of a small number of resistant colonies, consisting of bacteria 

 which do not even adsorb the virus. 



Let us focus our attention on the first generation of the resistant variant — 

 that is, on those bacteria which survive immediately after the virus has been 

 added. These survivors we may call the "original variants." We know that 

 these bacteria and their offspring are resistant to the virus. We may formulate 

 three alternative hypotheses regarding them. 



a. Hypothesis of mutation to immunity. The original variants were resistant 

 before the virus was added, and, like their offspring, did not even adsorb it. On 

 this hypothesis the virus did not interact at all with the original variants, 

 the origin of which must be ascribed to "mutations" that occur quite inde- 

 pendently of the virus. Naming such hereditary changes "mutations" of course 

 does not imply a detailed similarity with any of the classes of mutations that 

 have been analyzed in terms of genes for higher organisms. The similarity 

 may be merely a formal one. 



b. Hypothesis of acquired immunity. The original variants interacted with 

 the virus, but survived the attack. We may then inquire into the predisposing 

 cause which effected the survival of these bacteria in contradistinction to the 

 succumbing ones. The predisposing cause may be hereditary or random. Ac- 

 cordingly we arrive at two alternative hypotheses — namely, 



bi. Hypothesis of acquired immunity of hereditarily predisposed individuals. 

 The original variants originated by mutations occurring independently of the 

 presence of virus. When the virus is added, the variants will interact with it, 

 but they will survive the interaction, just as there may be families which are 

 hereditarily predisposed to survive an otherwise fatal virus infection. Since we 

 know that the offspring of the original variants do not adsorb the virus, we 

 must further assume that the infection caused this additional hereditary 

 change. 



b2. Hypothesis of acquired immunity — hereditary after infection. The original 

 variants are predisposed to survival by random physiological variations in 

 size, age, etc. of the bacteria, or maybe even by random variations in the 



