190 



which the transforming substance was 

 isolated. Once transformation has oc- 

 curred, the newly acquired character- 

 istics are thereafter transmitted in 

 series through innumerable transfers 

 in artificial media without any further 

 addition of the transforming agent. 

 Moreover, from the transformed cells 

 themselves, a substance of identical 

 activity can again be recovered in 

 amounts far in excess of that originally 

 added to induce the change. It is evi- 

 dent, therefore, that not only is the 

 capsular material reproduced in suc- 

 cessive generations but that the pri- 

 mary factor, which controls the oc- 

 currence and specificity of capsular 

 development, is also reduplicated in the 

 daughter cells. The induced changes 

 are not temporary modifications but 

 are permanent alterations which per- 

 sist provided the cultural conditions are 

 favorable for the maintenance of cap- 

 sule formation. The transformed cells 

 can be readily distinguished from the 

 parent R forms not alone by serolog- 

 ical reactions but by the presence of 

 a newly formed and visible capsule 

 which is the immunological unit of 

 type specificity and the accessory 

 structure essential in determining the 

 infective capacity of the microorgan- 

 ism in the animal body. 



It is particularly significant in the 

 case of pneumococci that the experi- 

 mentally induced alterations are defi- 

 nitely correlated with the development 

 of a new morphological structure and 

 the consequent acquisition of new anti- 

 genic and invasive properties. Equally 

 if not more significant is the fact that 

 these changes are predictable, type- 

 specific, and heritable. 



Various hypotheses have been ad- 

 vanced in explanation of the nature of 

 the changes induced. In his original 

 description of the phenomenon Grif- 

 fith ( 1 ) suggested that the dead bac- 

 teria in the inoculum might furnish 



AVERY, MACLEOD, MCCARTY 



some specific protein that serves as a 

 "pabulum" and enables the R form to 

 manufacture a capsular carbohydrate. 



More recently the phenomenon has 

 been interpreted from a genetic point 

 of view (26, 27). The inducing sub- 

 stance has been likened to a gene, and 

 the capsular antigen which is produced 

 in response to it has been regarded as 

 a gene product. In discussing the phe- 

 nomenon of transformation Dobzhan- 

 sky (27) has stated that "If this trans- 

 formation is described as a genetic 

 mutation— and it is difficult to avoid 

 so describing it— we are dealing with 

 authentic cases of induction of specific 

 mutations by specific treatments. . . ." 



Another interpretation of the phe- 

 nomenon has been suggested by Stan- 

 ley (28) who has drawn the analogy 

 between the activity of the transform- 

 ing agent and that of a virus. On the 

 other hand. Murphy (29) has com- 

 pared the causative agents of fowl 

 tumors with the transforming prin- 

 ciple of Pneumococcus. He has sug- 

 gested that both these groups of agents 

 be termed "transmissible mutagens" in 

 order to differentiate them from the 

 virus group. Whatever may prove to 

 be the correct interpretation, these 

 differences in viewpoint indicate the 

 implications of the phenomenon of 

 transformation in relation to similar 

 problems in the fields of genetics, 

 virology, and cancer research. 



It is, of course, possible that the 

 biological activity of the substance 

 described is not an inherent property 

 of the nucleic acid but is due to mi - 

 nute amounts of some other substance 

 adsorbed to it or so intimately associ- 

 ated with it as to escape detection. If, 

 however, the biologically active sub- 

 stance isolated in highly purified form 

 as the sodium salt of desoxyribonucleic 

 acid actually proves to be the trans- 

 forming principle, as the available evi- 

 dence strongly suggests, then nucleic 



