Discussion 181 



in binding affinity, which may increase, decrease or remain unchanged. 

 The mechanism of resistance in these variant cultures is totally obscure. 

 Pollock: Prof. Davis, would you care to expand on this case of Cohn 

 and Novick in which, apparently, there is an almost perpetual inheritance 

 of an acquired character? 



Davis: The essential facts are these. As I noted earlier, when p-thio- 

 methylgalactoside (TMG) is added to a growing culture of Esch. coli the 

 cell is induced to form two new entities: one is the well known intra- 

 cellular p-galactosidase, and the other is the inore recently discovered 

 system which transports various (3-galactosides into the cell, and even 

 concentrates some of them (e.g. TMG). When the concentration of TMG 

 is sufficient — say 10"^m — induction is maximal, and within a minute or 

 two exponentially growing cells start forming the new components at a 

 constant rate per unit of new cellular material synthesized. AVhen the 

 concentration of TMG is too low — between 10"^ and 10-^m — there is no 

 induction. However, Melvin Cohn found that such a low concentration 

 of TMG will maintain induction in cells that had been previously grown 

 in a sufficient concentration to bring about induction. Furthermore, it 

 is known that at intermediate concentrations of TMG the culture is 

 induced gradually, the rate of enzyme synthesis per cell rising for many 

 generations. Aaron Novick and Milton Weiner have recently found that 

 under these circumstances the rate of synthesis is not increasing gradually 

 in each cell. Instead, the population is heterogeneous, cells being either 

 fully induced or uninduced. This is shown by transferring single cells 

 from such a population to tubes of medium containing a maintenance 

 concentration of inducer. The induced cells formed fully induced clones ; 

 the others yielded uninduced clones. Evidently at intermediate concen- 

 trations of inducer a cell has a small chance of being induced to form its 

 first permeation unit. This w ill concentrate the TMG, which will increase 

 the effectiveness of induction, and in this autocatalytic way the cell will 

 soon be fully induced. Then even low external concentrations of TMG 

 will provide sufficient internal TMG to maintain full induction. 



This system has a close formal resemblance to an environmentally 

 directed mutation. On growth in an intermediate concentration of TMG 

 a fraction of the cells are altered (induced). The difference between these 

 and the uninduced cells can then be transmitted indefinitely through 

 future generations, provided the medium contains a maintenance con- 

 centration of inducer. A difference between these cells and mutants, 

 however, is that the pseudomutations can be uniformly reversed by a 

 few generations of growth in medium with no inducer at all. 



Whether this phenomenon will be relevant to problems of drug 

 resistance remains to be seen. 



Knox: Suppose you were to produce resistance with a drug acting as 

 an inducer of an adaptive enzyme which enabled the organism to grow 

 in the presence of the drug either by destroying it as with penicillinase 

 or in some other more indirect way. It is conceivable that some normal 

 metabolite present in very low concentrations inight, by being concen- 

 trated in some such way as you suggest, also act as a permanent inducer 

 of the same enzyme, so that the organism would remain permanently 



