Lederberg: Genetics 



may be needed to spell one amino acid (19). 

 While a protein is also defined by the se- 

 quence of its monomeric units, the amino 

 acids, the protein molecule lacks the "aperiodic 

 crystallinity" (80) of DNA. The differentiae of 

 the amino acids vary widely in size, shape, and 

 ionic charge (e.g., H;NCH/CH>CH,CH, •; 

 COOHCH 2 CH 2 -; HOC 8 H 4 -CH,-; CH 3 -, 

 H*) and in the case of proline, bond angles. 



Fig. 2. — The scheme of Watson and Crick for 

 DNA replication. "Unwinding and replication 

 proceed pari passu. All three arms of the Y ro- 

 tate as indicated" ( 14). 



The biological action of a protein is, therefore, 

 attributable to the shape of the critical surface 

 into which the polypeptide chain folds (73). 

 The one-dimensional specificity of the DNA 

 must therefore be translated into the three-di- 

 mensional specificity of an enzvme or anti- 

 body surface. The simplest assumption would 

 be that the amino acid sequence of the ex- 

 tended polypeptide, as it is released from the 

 protein-building template in the cytoplasm, 

 fully determines the folding pattern of the 

 complete protein, which may, of course, be 

 stabilized by nonpeptide linkages. If not, we 

 should have to interpose some accessory mech- 

 anism to govern the folding of the protein. 



This issue has reached a climax in speculations 

 about the mechanism of antibody formation. 

 If antibody globulins have a common se- 

 quence on which specificity is superimposed 

 by directed folding, an antigen could directly 

 mold the corresponding antibody. However, 

 if sequence determines folding, it should in 

 turn obey nucleic information. As this should 

 be independent of antigenic instruction, we 

 may look instead to a purely selective role of 

 antigens to choose among nucleic alternatives 

 which arise by spontaneous mutation (8, 50). 

 The correspondence between amino acids 

 and clusters of nucleotides has no evident basis 

 in their inherent chemical make-up and it 

 now appears more probable that this code has 

 evolved secondarily and arbitrarily to be trans- 

 lated by some biological intermediary. The 

 coding relationship would then be analogous 

 to, say, Morse-English (binary linear) to Chi- 

 nese (pictographic). Encouragingly, several 

 workers have reported the enzymatic reaction 

 of amino acids with RNA fragments (22, 75). 

 Apparently each amino acid has a different 

 RNA receptor and an enzyme whose twofold 

 specificity thus obviates any direct recognition 

 of amino acid by polynucleotides. The align- 

 ment of amino-acyl residues for protein syn- 

 thesis could then follow controlled assembly of 

 their nucleotidates on an RNA template, by 

 analogy with the model for DNA replication. 

 We then visualize the following modes of in- 

 formation transfer: 



(1) DNA replication — assembly of comple- 

 mentary deoxyribonucleotides on a DNA 

 template. 



(2) Transfer to RNA by some comparable 

 mechanism of assembling ribonucleotides. 

 Our understanding of this is limited by 

 uncertainties of the structure of RNA 

 (16). 



(3) Protein synthesis: 



(a) Aminoacylation of polynucleotide 



fragments; 

 (/?) Assembly of the nucleotidates on an 



RNA template bv analogy with step 



(1);. 



(c) Peptide condensation of the amino 

 acid residues. 



Some workers have suggested that RNA is 



101 



