DNA Today

DNA TODAY FRANCIS CRICK* In 1953 Jim Watson and I proposed a structure for DNA, based mainly on the experimental X-ray data of Wilkins, Franklin, and their colleagues and on the base ratios measured by Erwin Chargaff. The structure was a double helix, in which the bases of the two chains were paired together in a specific manner: Aenine pairing only with Thymine and Guanine only with Cytosine. At the time we were very excited because although the experimental evidence in favor of the structure was not decisive, the pairing of the bases suggested a neat way for the cell to duplicate the structure exactly and thus implied that the main genetic material was nucleic acid and not protein, the original favorite for that role before the discovery of the nature of the transforming factor by Avery and his colleagues. It also suggested that the genetic information was carried by the exact sequence of the four types of base. Few had imagined that underlying the complexities of genetics there was a simple scheme of this kind, and for this reason, if no other, many people at the time felt that our ideas were too simplistic to be true. Where do things stand after an interval of nearly 30 years? A brief answer would be that although the mechanisms of gene replication and gene expression were vastly more complicated than we then imagined, nevertheless they are indeed based on the simple ideas we put forward. Because of this basic theoretical framework, and helped by cheap, quick, and powerful experimental methods, molecular biology has made spectacular progress, far beyond anything imagined in 1953. This progress took place in two broad phases. The initial phase, from 1953 to 1966, started slowly but advanced very rapidly from 1959 onward , till by the end of that period the universal genetic code—the little dictionary which connects the four-letter language of the nucleic acids with the 20-letter language of the proteins—was deciphered using a variety of biochemical and genetic methods. The mechanism of protein *Salk Institute, Post Office Box 85800, San Diego, California 92138.© 1982 by The University of Chicago. All rights reserved. 003 1-5982/82/2504-0303$01 .00 512 I Francis Crick · DNA Today synthesis was understood in broad outline, and, thanks mainly to the work of Jacob and Monod, the general way genes were turned on and off was known for several genes in bacteria. After 1966 there was a period ofconsolidation. More and more details were discovered for each of these mechanisms, but two problems made very slow progress: what was the actual base-sequence for any gene of interest (in viruses, bacteria, or higher organisms), and how were genes controlled in eukaryotes and especially in the higher plants and animals? These problems appeared very difficult, but during the early seventies a number of breakthroughs took place, so that now, in 1982, we can achieve results which were almost unthinkable as little as 10 years ago. DNA can be delicately divided by restriction enzymes; lengths of DNA can be moved from one position to another, so that, grown in microorganisms , relatively large amounts of any desired stretch of DNA can be obtained with a high degree of purity. Given a suitable probe, which in some cases can be obtained without too much difficulty, it is possible to select the desired stretch of DNA out of an entire genome having some billions of base-pairs. Sanger, Gilbert, and their colleagues have developed very rapid sequencing methods so that stretches of DNA a few hundred base-pairs long can, in a properly equipped lab, be sequenced in a few days. The total rate, worldwide, ofbase-sequence determination is approaching a million base-pairs a year, an input of precise information so fast that special arrangements are having to be made to store the results on one or more central computers. In addition, chemical methods of synthesizing long stretches of DNA have become both accurate and rapid. Techniques in related fields, such as the amino acid sequencing of proteins on a micro scale and the development of monoclonal antibodies, have enabled most problems to be attacked from more than one...