Unbalanced Growth and Death 81 



thymine is first supplied, DNA synthesis begins and rapidly doubles. 

 DNA synthesis then stops and division begins. This process is also 

 completed rapidly, and DNA synthesis begins again, starting a new- 

 cycle. It appears that continuing growth in the absence of DNA syn- 

 thesis has brought all of the cells to the same point in the division 

 process, wherein the supply of the appropriate nuclear constituents 

 triggers the actual division. The relations of DNA and division in 

 this system are entirely analogous to the phenomena observed among 

 higher organisms. In cytochemical studies on many types of higher 

 cells it has been found that DNA synthesis and doubling occur during 

 the interphase and very early prophase. 



Since this phenomenon described above provides a considerable de- 

 gree of synchrony to large populations of cells, it should be possible 

 to investigate many phenomena from the point of view of their occur- 

 rence in particular phases of the life cycle of a cell. If the effects 

 of thymine depletion and the inhibition of DNA synthesis are observed 

 to be widespread phenomena, application of appropriate agents should 

 induce synchrony in many kinds of cell populations, tissue cultures, 

 and perhaps even intact tissues. 



Let us return to the phenomenon of death caused by thymine 

 deficiency and unbalanced growth. How widespread is it? It is pos- 

 sible to induce thymine deficiency in other bacteria by growth of the 

 organisms in the presence of sulfonamides. The division rate is con- 

 siderably slower than the rate in the absence of sulfanilamide but it 

 can be increased by the supply of compounds containing the one-carbon 

 fragments dependent on the coenzyme containing folic acid. These 

 compounds include a purine, e.g., xanthine, methionine, serine, histidine 

 pantothenate, and thymine. If thymine is omitted from this fortified 

 medium containing sulfanilamide, the cells die. 5 If any other metabo- 

 lite is omitted from the medium while thymine is present, death does 

 not occur. 



Sulfanilamide is generally considered to be bacteriostatic. It is so 

 because it prevents the synthesis of cytoplasm and nucleus alike. It 

 may be converted to a bactericidal substance by providing compounds 

 essential specifically for cytoplasmic synthesis and not for nuclear 

 division. It has been observed that the folic acid antagonist, Amethop- 

 terin, can specifically inhibit the synthesis of thymine and DNA. 

 Is it possible that this compound can be made more useful in killing 

 leukemic cells by the concurrent supply of metabolites important for 

 cytoplasmic synthesis? 



In point of fact, there is reason to beieve that many agents exert 



