GENERAL DISCUSSION 



Lederberg: At the risk of some diversion, another murky problem 

 should be illuminated, that of genetic variation of the human 

 population in the metabolic disposition of drugs. It has been found, 

 for example, that different individuals respond differently to 

 isoniazid in the chemotherapy of tuberculosis. This finding also 

 rationalizes the effectiveness of combined PAS + INH, since PAS 

 competes with INH as an acetyl-acceptor. These differences are 

 correlated with the extent to which the drug is metabolized by the 

 patient to microbiologically inactive derivatives. The metabolic 

 individuality is uncorrelated with disease status, nutrition, sex or 

 age, and remains fixed for the whole interval of the studies that 

 were reported. To a geneticist, it is hardly escapable that we are 

 dealing here with hereditary differences in the disposition of the 

 drug, but family studies have not been made. This possibility is 

 one that may have great generality, but has scarcely been gone into 

 at all, though it may have much to do with isolated cases of treat- 

 ment-failure, or of idiosyncratic responses, such as the renal toxicity 

 of the sulphonamides, or aplastic anaemia from chloramphenicol. 

 Even with experimental animals, there has been very little sys- 

 tematic study of genetic differentials in response to drugs, though 

 we know the famous example of atropine-esterase in rabbits, and 

 there are more recent reports of variation in sleeping- time following 

 doses of hypnotics in inbred lines of mice. We have also to consider 

 the possibility of adaptive changes in metabolic pattern which, 

 though it must underlie such an important effect as tolerance to 

 the opiates, is equally understood. 



We just do not know the extent to which the genetic variability 

 of the human population must be superimposed upon that of its 

 parasites in the analysis of chemotherapeutic failure, and this is a 

 field that calls for more incisive attention than formerly. However, 

 since micro-organisms that have demonstrably higher resistance to 

 antibiotics are generally isolated from such cases, microbial rather 

 than host variation must be the typical answer. 



Hayes: Prof. Hinshelwood mentioned the Akiba type of experi- 

 ment where well washed cells which were streptomycin-sensitive 

 were exposed to streptomycin for long periods of time in a non- 

 nutrient medium, in which total counts suggested that no multipli- 

 cation had taken place. The total number of cells of the population 

 exposed in this way was relatively small, and far below the number 



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