Nucleic Acid Synthesis

INTRODUCTION Synthesis in the field of nucleic acids has been a major and continuing interest in my laboratory ever since we knew the structures of the nucleic acids. Clearly the foundations of synthetic work in the nucleotide field were laid by the prolonged and intensive efforts of Professor Todd's laboratory (Cambridge, England) and it was my good fortune to be associated with this laboratory before our own work in the field got going. With the elucidation of the internucleotidic linkage in the nucleic acids, polyiiucleotide chemistry entered a new area of complexity in. which the major problems to be posed were those of sequence and synthesis of poiynucleotides. In principle, organic chemists could attempt to put together nucleosides and nucleotides to form short chains of polynucleotides which would be identical in every way with the naturally-occurring nucleic acids. It was very reminiscent of the developments of protein chemistry at the turn of the century and into the twenties and thirties which followed the proposal of the peptide theory of protein structure. There was a strong and clear case for sustained effort in developing synthesis in the nucleic acid field, especially when one looked around at that time at the level of sophistication that many other areas of natural product chemistry had attained. However, in addition to the intrinsic interest in developing the organic chemistry of nucleic acids, there was the hope that the availability of synthetic polynucleotides of known size and structure would provide many opportunities for chemical, physico-chemical, and enzymatic studies of nucleic acids. So we began to undertake work on the organ.o-chemical synthesis of polynucleotides in the middle fifties. While our, early work proceeded hand-in-hand with a broader study of the problems of phosphate chemistry, e.g., methods of phosphorylation of nucleosides and of carbohydrates, properties of phosphate esters, specific activation of mononucleotides to form nucleotide coenzymes, polynucleotide synthesis became the most serious commitment in due course of time. Looking back over the years, three phases of our work in this field can be discerned. Up till the early sixties, the main preoccupation was with the organo-chemical synthesis and chemical and enzymatic characterization of polynucleotides. While even at present, organo-chemical methods demand further investigation and refinement, nevertheless, synthesis of short chains of deoxypolynucleotides with known and controlled sequences became possible in the early sixties. A second phase of our work then started and a central question which was posed at this time was "Can chemical synthesis make a contribution to the study of the fundamental process of biological information flow, DNA-÷ RNA—protein ?".