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The Invention of the Genetic Code

Brian Hayes

What We Didn't Know Then

To enter the world of molecular biology circa 1953, you must first forget all you know. This isn't easy when you come from a world where the sequencing of entire genomes is almost routine, and you can buy custom-made DNA by mail order for 69 cents a base pair.

In 1953 no one had yet read the sequence of bases in any DNA molecule—not one scrap of one gene. For proteins the situation was only a little better. Frederick Sanger was finishing his work on the amino acid sequence of insulin, and a few other fragmentary protein sequences had been published. But the very idea that every protein has a precisely defined sequence, the same in all copies of the molecule, was not yet universally accepted. Even the set of amino acids from which proteins are assembled was still subject to dispute (although Watson and Crick would soon sit down at the Eagle to write out the canonical list of 20). And all the biochemical apparatus for translating DNA into protein awaited discovery. Messenger RNA and transfer RNA were unknown. Ribosomes had been glimpsed in electron micrographs, but their function was unclear.

One area that was not quite so murky was the replication of DNA. From the moment Watson and Crick saw that the four nucleotide bases fit together in specific pairs—adenine with thymine, guanine with cytosine—the mechanism of replication seemed obvious: Unzip the double helix and form two new strands complementary to the original ones. One reason this process was so much easier to fathom was that the replication machinery does not have to consider the meaning of a base sequence in order to duplicate it, any more than a Xerox machine has to understand the documents it copies.

Translation, in contrast, cannot avoid semantics—and yet no one had a clue about how to interpret a sequence of bases. Even the most fundamental questions remained open. For example, since DNA is a double helix, should you look for information on both strands? If only one strand carries the message, how do you know which one it is? And which direction do you read in? Trying to make sense of the genome was like being given a book in a language so unfamiliar you couldn't be sure you were holding it right side up.

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