134 S. S. COHEN 



linkage was required between genes involved in consecutive steps in a 

 series of milliniicro molar reaction systems (Pontecorvo, 1952). Although 

 Mcllwaine's hypothesis has not yet been proved or disproved, a remarkable 

 result has recently been obtained by Demerec et al. (1955) and Hartman 

 (1957), who have shown that in Salmonella typMmurium the Unear order of 

 many genes controlling the enzymes involved m tryptophan and histidine 

 biosynthesis corresponds to the sequence of reactions of intermediary 

 metabohsm. The significance of these apparent evidences of a genetic order 

 correspondmg to metabohc order is obscure at present. 



How may a gene control the enzyme itself? No instance is known wherein 

 specificity of an enzyme has been altered by a mutant gene. However, 

 several instances are known in which an altered protein may be produced. In 

 the case of the hereditary disease resulting in the production of sickle cell 

 hemoglobm, it has been reported (Ingram, 1957) that the mutant hemoglobin 

 differs from normal hemoglobin by the replacement of one amino acid 

 (glutamic acid) by another (valine) in a single peptide sequence per half- 

 molecule of hemoglobin. 



Maas and Davis (1952) have studied a temperature-sensitive mutant of 

 E. coli that required pantothenate above 30°C. It was foimd that the panto- 

 thenate-spithesizing enzyme produced by the mutant was extraordinarily 

 heat-labile, as compared to the enzyme produced by the wild type organism. 

 Thus, an altered protein had been produced. In Neurospora crassa, a pair of 

 allelic genes has been found governing the thermostability of tyrosinase; the 

 enzymes produced in the mutant organisms also appear to be structurally 

 different (Horowitz and Fhng, 1953). In neither instance has evidence been 

 obtained of the formation of inhibitors. 



In neither of these two cases has it been possible to distinguish between 

 the possibilities that there has been an alteration in the template leading to 

 differences in primary structure, as appears to be the case for the production 

 of sickle cell hemoglobin, or that the genes affect the organization of secon- 

 dary or tertiary structure and that the primary polypeptide chains are 

 invariant. In a series of allehc tryptophan-requiring mutants lacking trypto- 

 phan synthetase, in aU but one a protein was detected which cross-reacted 

 with antibody to tryptophan synthetase and possessed other structural 

 features in common with the enzyme (Suskind et al., 1955). This suggests 

 that in these instances the gene does not affect primary protein structure 

 related to serological specificity, but perhaps controls that aspect of organized 

 tertiary structure related to specific catalytic activity (also see Lerner and 

 Yanofsky, 1957). 



It is evident from the above that genetic investigation has so far provided 

 little direct information of the contribution of the gene to the synthesis of 

 polymers. In an unusual approach to this type of problem, Horowitz and 



