message 'just as the words and concepts of all languages can find expression in 24—30 letters of the alphabet'. But D N A had few fans; it was known to be a comparatively monotonous substance: how could it convey a message in just four varieties?5
Drawn by the presence of Muller, there arrived in Bloomington, Indiana, a precocious and confident nineteen- year-old, already equipped with a bachelor's degree, named James Watson. He must have seemed an unlikely solution to the gene problem, but the solution he was. Trained at Indiana University by the Italian
Watson developed an obsessive conviction that genes were made of D N A , not protein. In search of vindication, he went to Denmark, then, dissatisfied with the colleagues he found there, to Cambridge in October 1951. Chance threw him together in the Cavendish laboratory with a mind of equal brilliance captivated by the same conviction about the importance of D N A , Francis Crick.
The rest is history. Crick was the opposite of precocious. Already thirty-five, he still had no PhD (a German bomb had destroyed the apparatus at University College, London, with which he was supposed to have measured the viscosity of hot water under pressure
- to his great relief), and his sideways lurch into biology from a stalled career in physics was not, so far, a conspicuous success. He had already fled from the tedium of one Cambridge laboratory where he was employed to measure the viscosity of cells forced to ingest particles, and was busy learning crystallography at the Cavendish.
But he did not have the patience to stick to his own problems, or the humility to stick to small questions. His laugh, his confident intelligence and his knack of telling people the answers to their own scientific questions were getting on nerves at the Cavendish. Crick was also vaguely dissatisfied with the prevailing obsession with proteins. The structure of the gene was the big question and D N A , he suspected, was a part of the answer. Lured by Watson, he played truant from his own research to indulge in D N A games. So was born one of the great, amicably competitive and therefore productive collaborations in the history of science: the young, ambitious, supple-minded American who knew some biology and the effortlessly brilliant but unfocused older Briton who knew some physics. It was an exothermic reaction.
Within a few short months, using other people's laboriously gathered but under-analysed facts, they had made possibly the greatest scientific discovery of all time, the structure of D N A . Not even Archimedes leaping from his bath had been granted greater reason to boast, as Francis Crick did in the Eagle pub on 28 February 1953,
'We've discovered the secret of life.' Watson was mortified; he still feared that they might have made a mistake.
5 0 G E N O M E
But they had not. All was suddenly clear: D N A contained a code written along the length of an elegant, intertwined staircase of a double helix, of potentially infinite length. That code copied itself by means of chemical affinities between its letters and spelt out the recipes for proteins by means of an as yet unknown phrasebook linking D N A to protein. The stunning significance of the structure of D N A was how simple it made everything seem and yet how beautiful. As Richard Dawkins has put it,6 'What is truly revolutionary about molecular biology in the post-Watson—Crick era is that it has become digital . . . the machine code of the genes is uncannily computer- like.'
A month after the Watson-Crick structure was published, Britain crowned a new queen and a British expedition conquered Mount Everest on the same day. Apart from a small piece in the
Many frustrating years of confusion were to follow the discovery of D N A ' s structure. The code itself, the language by which the gene expressed itself, stubbornly retained its mystery. Finding the code had been, for Watson and Crick, almost easy — a mixture of guesswork, good physics and inspiration. Cracking the code required true brilliance. It was a four-letter code, obviously: A, C, G and T.
And it was translated into the twenty-letter code of amino acids that make up proteins, almost certainly. But how? Where? And by what means?
Most of the best ideas that led to the answer came from Crick, including what he called the adaptor molecule - what we now call transfer R N A . Independendy of all evidence, Crick arrived at the conclusion that such a molecule must exist. It duly turned up. But Crick also had an idea that was so good it has been called the greatest wrong theory in history. Crick's 'comma-free' code is more elegant than the one Mother Nature uses. It works like this. Suppose that the code uses three letters in each word (if it uses two, that only gives sixteen combinations, which is too few). Suppose that it H I S T O R Y 5 1
has no commas, and nogapsbetweenthewords. Now suppose that it excludes all words that can be misread if you start in the wrong place. So, to take an analogy used by Brian Hayes, imagine all three-letter English words that can be written with the four letters A, S, E and T: ass, ate, eat, sat, sea, see, set, tat, tea and tee. Now eliminate those that can be misread as another word if you start in the wrong place. For example, the phrase ateateat can be misread as 'a tea tea t' or as 'at eat eat' or as 'ate ate at'. Only one of these three words can survive in the code.
Crick did the same with A, C, G and T. He eliminated A A A , C C C , G G G and T T T for a start. He then grouped the remaining sixty words into threes, each group containing the same three letters in the same rotating order. For example, A C T , C T A and T A C
are in one group, because C follows A, T follows C, and A follows T in each; while A T C , T C A and C A T are in another group. Only one word in each group survived. Exactly twenty are left - and there are twenty amino acid letters in the protein alphabet! A four-letter code gives a twenty-letter alphabet.
Crick cautioned in vain against taking his idea too seriously. 'The arguments and assumptions which we have had to employ to deduce this code are too precarious for us to feel much confidence in it on purely theoretical grounds. We put it forward because it gives the magic number - twenty — in a neat manner and from reasonable physical postulates.' But the double helix did not have much evidence going for it at first, either. Excitement mounted. For five years everybody assumed it was right.
But the time for theorising was past. In 1961, while everybody else was thinking, Marshall Nirenberg and Johann Matthaei decoded a 'word' of the code by the simple means of making a piece of R N A out of pure U (uracil - the equivalent of D N A ' s T) and putting it in a solution of amino acids. The ribosomes made a protein by stitching together lots of phenylalanines. The first word of the code had been cracked: U U U means phenylalanine. The comma-free code was wrong, after all. Its great beauty had been that it cannot have what are called reading- shift mutations, in which the 52. G E N O M E
loss of one letter makes nonsense of all that follows. Yet the version that Nature has instead chosen, though less elegant, is more tolerant of other kinds of errors. It contains much redundancy with many different three-letter words meaning the same thing.7
