286 



Embryogenesis: Progressive Differentiation 



val of the fittest," namely the accumulative 

 and self-reinforcing propagation of tissue- 

 specific compounds extending over successive 

 cell generations. Yet some cells, especially 

 those capable of sexual or asexual reproduc- 

 tion, remain omnipotent throughout the life 

 cycle. How did they avoid specialization? 

 Other cells, having become incapable of 

 shifting into a new trend of normal differ- 

 entiation, may still react to proper stimuli 

 by "mutating" cytoplasmically into cancer- 

 ous tissues (Graffi, '40; Haddow, '44; Potter, 

 '45; Holtfreter, '48a). 



This comparison of enzymatic adaptation 

 of yeasts with tissue determination has some 

 weaknesses: whereas the former requires con- 

 tinued external application of a specific 

 substrate (as in the case of hormones), em- 

 bryonic tissues proceed to differentiate inde- 

 pendently of the initial inductive stimulus. 

 Moreover, it remains to be explained how 

 ectoderm explants can be switched into 

 neural differentiation simply by an unspe- 

 cific injury. Finally, some primordia, espe- 

 cially those of the entoderm, do not seem to 

 require exogenous inductive stimuli for their 

 normal differentiation. 



To fit these data into the above concept 

 it seems necessary to assume that the sub- 

 strates required for the autocatalytic syn- 

 thesis of specific tissue proteins pre-exist in 

 the reacting cells, and that the inducing 

 stimulus acts neither like a virus nor as 

 an enzymatic substrate but as an agent 

 which activates or liberates certain intra- 

 cellular substrates. The "unmasking" of the 

 neuralizing agent in killed or slightly in- 

 jured ectoderm may be due to autolytic dis- 

 sociations comparable to those which occur 

 in dying amphibian cells (Holtfreter, '48a; 

 Brachet, '49, '50) and in the isolated nucleo- 

 protein granules (Claude, '46). It has also 

 been suggested that some enzymes are in- 

 active in the living cell because they are 

 separated from their proper substrates. This 

 may give a clue to the observations of Pas- 

 teels ('47a,b; '49a) that centrifuged blastu- 

 lae give rise to accessory neural and meso- 

 dermal structures in the affected ectoderm. 

 The cell content of the latter becomes clearly 

 stratified, suggesting that these "auto-induc- 

 tions" (Holtfreter, '47b, '48a) may origi- 

 nate from a mechanically produced union 

 and reaction of morphogenetic precursors 

 with certain substrates present in the same 

 cell. 



In a thoughtful article, Waddington ('48) 

 has discussed these problems from a some- 

 what different angle, emphasizing likewise 



that one must assume the existence of dif- 

 ferent intracellular substrates and gene prod- 

 ucts, subject to competitive interactions, in 

 order to account for the autocatalytic syn- 

 thesis of tissue-specifying protein compounds. 

 At present, such attempts to arrive at gen- 

 eral concepts by coordinating genetic, physi- 

 ological and embryological data are liable 

 to be of a highly speculative natvire. How- 

 ever, they suggest outlines for future 

 research. 



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