H. WADDINGTON 



they can arise anew within cells from which they were originally absent. Their initia- 

 tion seems in all cases to depend on the functioning of corresponding genes in the 

 nucleus and is impossible if the effective gene is absent. Other conditions of an 

 environmental kind are usually necessary to bring the gene into play and cause it to 

 produce the cytoplasmic factor. Some of the best examples are the cytoplasmic 

 determinants of antogenic specificity in Paramecium studied by Sonneborn and 

 Beale (Beale, 1952). In these organisms, the environmental conditions control the 

 state of the cytoplasm. When the cytoplasm is brought into a new state, this 

 may initiate a process by which one particular gene, out of a group of possible ones, 

 causes the appearance of a cytoplasmic factor, which in turn controls the formation of 

 a corresponding antigen. Once they are formed, the cytoplasmic factors have some 

 degree of autonomy, in that they can continue to function after the gene which 

 initiated them has been removed by crossing. But this autonomy is very limited; 

 they persist for only five generations after the gene is removed. If, on the other hand, 

 the environment is changed to one which will eventually bring another gene into 

 operation, the formation of the original antigen may continue for a considerably 

 longer time; but in this situation the gene corresponding to the cytoplasmic antigen- 

 producing factor is still present in the nucleus, and what persists is the complex of 

 gene and cytoplasmic factor rather than the latter alone. 



Another example is the factor studied by Billingham and Medawar (1948) which 

 produces melanin pigmentation in the skin of the guinea-pig. This factor is detected 

 by the ability of black pigment-producing cells to infect neighbouring unpigmented 

 cells with the ability to deposit melanin. The possibility of a serial evocation needs 

 to be considered here, but it appears that the factor which is transmitted during 

 infection carries with it an immunological specificity which is too precise to be 

 attributed to a simple evocator molecule. The infective agent is gene-dependent, in 

 the sense that it only appears in the skin of animals whose genotype contains the 

 factors for the appearance of melanin pigment. Again, in individuals of this genotype 

 it appears only in the cells of the pigment-forming system, that is to say the deriva- 

 tives of the neural crest. The activity of the genes responsible for its production must 

 therefore be dependent on the internal environmental factors which control the 

 differentiation of this tissue. 



Finally we may mention the examples of adaptive enzyme formation in yeasts 

 and bacteria, etc., in which the conjunction of a particular substrate in the medium 

 and an appropriate gene in the nucleus seems to be necessary for the production of 

 the enzyme, the immediately effective agent being, according to some authors (e.g. 

 Spiegelman, 1951) a plasmagene-like factor in the cytoplasm. The factors concerned 

 with the formation of respiratory enzymes in yeast studied by Ephrussi (1953) prob- 

 ably are somewhat similar in character. 



It is questionable whether it is really appropriate to employ the word 'plasma- 

 genes' for these gene-initiated factors. The character they share with the true plasma- 

 genes is that of a certain ability to multiply through a number of cell generations 

 after the gene which initially endowed them with their specific characteristics has 

 been removed. It is not clear, however, that any case is known in which a gene- 

 initiated cytoplasmic factor possesses complete autonomy in its powers of reproduc- 

 tion. Certainly the Paramecium antigen determinants can only persist for a very 



no 



