Muller: Production of Mutations 



considered of especial interest, affected 

 the mutation frequency. The plan was 

 ultimately to use the method as a gen- 

 eral one for studying the effects of vari- 

 ous conditions. The condition chosen 

 for the first experiment was tempera- 

 ture, and the results, verified by later 

 work of the writer's, indicated that a 

 rise of temperature, within limits normal 

 to the organism, produced an increase 

 of mutation frequency of about the 

 amount to be expected if mutations 

 were, in essentials, orthodox chemical 

 reactions. 



Mutations as Chemical Reactions 



On this view, however, single muta- 

 tions correspond with individual molecu- 

 lar changes, and an extended series of 

 mutations, in a great number of identi- 

 cal genes in a population, spread out 

 over thousands of years, is what cor- 

 responds with the course of an ordinary 

 chemical reaction that takes place in a 

 whole collection of molecules in a test 

 tube in the course of a fraction of a 

 second or a few seconds. For the indi- 

 vidual gene, in its biological setting, is 

 far more stable than the ordinary chemi- 

 cal molecule is, when the latter is ex- 

 posed to a reagent in the laboratory. 

 Thus, mutations, when taken collective- 

 ly, should be subject to the statistical 

 laws applying to mass reactions, but the 

 individual mutation, corresponding to 

 a change in one molecule, should be sub- 

 ject to the vicissitudes of ultramicro- 

 scopic or atomic events, and the appari- 

 tion of a mutant individual represents an 

 enormous amplification of such a phe- 

 nomenon. This is a principle which gives 

 the clue to the fact, which otherwise 

 seems opposed to a rational, scientific 

 and molarly deterministic point of view, 

 that differences in external conditions or 

 conditions of living do not appear to af- 

 fect the occurrence of mutations, while 

 on the other hand, even in a normal and 

 sensibly constant environment, muta- 

 tions of varied kinds do occur. It is also 

 in harmony with our finding, of about 

 the same time, that when a mutation 

 takes place in a given gene, the other 

 gene of identical type present nearby in 



the same cell usually remains unaffected 

 though it must of course have been sub- 

 jected to the same macroscopic physico- 

 chemical conditions. On this conception, 

 then, the mutations ordinarily result 

 from submicroscopic accidents, that is, 

 from caprices of thermal agitation, that 

 occur on a molecular and submolecular 

 scale. More recently Delbruck and 

 Timofeeff, in more extended work on 

 temperature, have shown that the 

 amount of increase in mutation frequen- 

 cy with rising temperature is not merely 

 that of an ordinary test-tube chemical 

 reaction, but in fact corresponds closely 

 with that larger rise to be expected of a 

 reaction as slow in absolute time rate 

 (i.e. with as small a proportion of mo- 

 lecular changes per unit of time) as the 

 observed mutation frequency shows this 

 reaction to be, and this quantitative cor- 

 respondence helps to confirm the entire 

 conception. 



Now this inference concerning the 

 non-molar nature of the individual mu- 

 tation process, which sets it in so differ- 

 ent a class from most other grossly ob- 

 servable chemical changes in nature, led 

 naturally to the expectation that some 

 of the "point effects" brought about by 

 high-energy radiation like X-rays would 

 also work to produce alternations in the 

 hereditary material. For if even the rela- 

 tively mild events of thermal agitation 

 can, some of them, have such conse- 

 quences, surely the energetically far 

 more potent changes caused by power- 

 ful radiation should succeed. And, as a 

 matter of fact, our trials of X-rays, car- 

 ried out with the same kind of genetic 

 methods as previously used for tempera- 

 ture, proved that such radiation is ex- 

 tremely effective, and inordinately more 

 so than a mere temperature rise, since 

 by this method it was possible to obtain, 

 by a half hour's treatment, over a hun- 

 dred times as many mutations in a group 

 of treated cells as would have occurred 

 in them spontaneously in the course of 

 a whole generation. These mutations, 

 too, were found ordinarily to occur 

 pointwise and randomly, in one gene at 

 a time, without affecting an identical 



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