DNA: One Teacher's Reflection

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Science  11 Apr 2003:
Vol. 300, Issue 5617, pp. 213
DOI: 10.1126/science.300.5617.213

This issue of Science appears amid a swirl of contemporary reminiscence about DNA, triggered by the 50th anniversary of James Watson and Francis Crick's paper in which its structure was proposed. What they gave us was a model that derives its beauty from the way in which it fit with what was already known about the biology of genetic control and the chemistry of DNA's nucleotide components. Of course, there was a splendid storehouse of information already available to provide that resonance. Sometimes we forget how much; I now encounter undergraduates who believe that Watson and Crick “discovered” DNA—a claim those authors would be quick to disavow. In fact, much was known about the biochemistry of DNA; in particular, Chargaff's demonstration that across species, A = T and G = C. The experiments of Avery, McCarty, and MacLeod in 1944 in bacteria, followed by those of Hershey and Chase in bacteriophage, had already demonstrated that it was DNA and not protein or something else that was the molecule of heredity. These experiments provided the background behind Watson and Crick's interpretation of the x-ray crystallographic data of Rosalind Franklin.

The Watson-Crick model appeared as I was becoming a novice teacher of introductory biology. Later, as a physiologist trying to learn and then teach the “new biology,” the unfolding story struck me as a kind of marvel. Meselson and Stahl fed bacteria with nucleotides labeled with heavy nitrogen and then used density-gradient centrifugation in cesium chloride to demonstrate the semiconservative nature of replication. Kornberg showed that DNA polymerase could support replication in a cell-free system if only it was given some “primer” DNA and a supply of the four nucleoside phosphates. From that point on, the transcription part of the problem shifted to the molecular mechanisms of unwinding and replication, to the knotty problem of how damage is repaired, and to the regulation of transcription.

Translation became the key issue as the “central dogma” established the sequence of complementary synthesis that ran from gene to messenger RNA to protein, and led to the deciphering of the code through working out the associations of transfer RNAs and specific amino acids. That, too, depended on some much earlier biology that I came to know through historical proximity. In a Stanford basement laboratory, Beadle and Tatum switched abruptly from Drosophila to Neurospora and soon developed screens for nutritional mutants to show that single mutations blocked specific enzymatic steps in a synthetic pathway. Later work continued to be informed by the “one gene, one enzyme” concept, in a worldwide explosion of results that exposed the roles of various RNA species in the task of protein synthesis.

Making maps (that is, establishing the relation between DNA sequences and the location of genes) began in microorganisms through work on bacteria by Lederberg and Tatum and on viruses by Benzer's group. To do the same in eukaryotic cells proved a more difficult challenge. Many years later, I could hang around and watch as Yanofsky's group used the same organism as Beadle and Tatum had used in the same basement to establish the co-linearity of the amino acid sequence of an enzyme with the nucleotide sequence of the gene encoding it.

A biochemistry teacher of mine was fond of pointing out that if we look deeply enough into the cell, chemistry becomes anatomy. The Watson-Crick structure achieved that fusion for the front end of the central dogma, by uncovering the spatial geometry that makes replication and the conservation of information work in the cell. At the other end, we have now learned from the Noller and Steitz groups that the spatial geometry of the ribosome makes possible the final assembly required by the instructions originally contained in the Watson-Crick structure. In an interesting surprise, the enzyme responsible for this last task in translation is not a protein but RNA itself—an odd exception to the central dogma. Surely that tells us that the book is not yet closed and that the line of work begun 50 years ago will continue to yield the unexpected. For example, who would have expected a decade ago that a brand-new family of small RNA molecules would be able to control gene expression? Will that be the anniversary we celebrate in 2053?

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