Life's Greatest Secret (18 page)

In the middle of this discussion there was a half-sentence, almost a throwaway remark, that echoed the terms used in Crick’s letter to his son, but which expanded them to a far broader conception and propelled biology into the modern age:

The phosphate-sugar backbone of our model is completely regular, but any sequence of pairs of bases can fit into the structure. It follows that in a long molecule many different permutations are possible, and it therefore seems likely that the precise sequence of the bases is the code which carries the genetical information.

With the exception of Ephrussi and Watson’s unfunny satirical letter to
Nature
seven weeks earlier, this was the first time that the content of a gene had been described as information. It is not known where the phrase ‘genetical information’ came from – Watson recalls that Crick wrote most of the manuscript in less than a week at the end of April, and the form and the content are more typical of Crick’s style than of Watson’s.
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Given the growing presence of ‘information’ in scientific articles from a wide range of disciplines, and the popular interest in communication theory and cybernetics, it seems likely that the idea just came naturally to Crick, as part of the zeitgeist. There is no indication that either Crick or Watson had read Shannon or Wiener, or that they were using the term in explicit reference to their mathematical ideas. As with the word ‘code’, ‘information’ seems to have been used as an intensely powerful metaphor rather than a precise theoretical construct.

In the past, scientists had spoken of genetic specificity, but with the introduction of the idea that the DNA sequence contained ‘the code which carries the genetical information’ a whole new conceptual vocabulary became available. Genes were no longer mysterious embodiments of specificity, they were information – a code – that could be transmitted (another word from the electronic age), and the central hypothesis was that the code was composed of a series of letters – A, T, C and G. How exactly that code might function, what it might represent, was not stated. Nevertheless, the words used so lightly by Crick and Watson changed the way in which scientists could speak and think about genes. Eventually this new vocabulary contributed to the development of novel parallels between genes and electronic communication and processing.

None of this was obvious at the time. Watson was not particularly keen on the article being published at all, as he explained to Delbrück in May:

Crick was very much in favour of sending in the second

note. To preserve peace I have agreed to it and so it shall come out shortly.

Wilkins was not impressed, either. He recalled: ‘Some of Francis and Jim’s friends, however, thought the second paper was rather “going over the top”.’ Among those friends was Wilkins himself.
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Despite these doubts, the advantage of Crick’s approach was that it explicitly set out the two revolutionary implications of the double helix: complementary base pairing explained gene duplication, while the sequence of bases explained genetic specificity. Here were two hypotheses that would revolutionise biology, if they were true.

Crick recognised the links between the discovery of the double helix and Schrödinger’s ideas from a decade earlier. On 12 August 1953, he sent copies of the two
Nature
articles to Schrödinger, accompanied by a brief letter:

Watson and I were once discussing how we came to enter the field of molecular biology, and we discovered that we had both been influenced by your little book, ‘What is Life?’

We thought you might be interested in the enclosed reprints – you will see that it looks as though your term ‘aperiodic crystal’ is going to be a very apt one.

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In July 1953, Watson and Crick received a strange letter from the US. Handwritten in big letters on headed notepaper from the University of Michigan students’ union, the letter was full of crossings-out and spelling mistakes and looked as though it was from a crank. In fact it was from the Russian-born cosmologist George Gamow (pronounced ‘Gam-off’), who was a long-time friend of Max Delbrück and had chaired the 1946 meeting on ‘The Physics of Living Matter’.
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Although he was an expert in nuclear physics, Gamow had not passed security clearance for the Manhattan Project and had not been involved in the development of the atomic bomb at all. FBI surveillance of Gamow continued after the war, and he was interviewed by them as late as 1957, although they never found any evidence against him.
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Gamow was an eccentric 50-year-old who liked his whisky and had a sideline in popular science books based around an everyman character called Mr Tompkins. In his odd letter, Gamow seized upon Watson and Crick’s suggestion that the sequence of bases contained a ‘code’, and audaciously tried to come up with ways of cracking that code. Gamow’s starting point was that each organism could be characterised by ‘a long number’, which corresponded to the number of positions in the DNA sequence. He then dismissed decades of research in classical genetics showing that genes are located in definite positions on chromosomes, and argued that it seemed ‘more logical’ if genes were instead ‘determined by the different mathematical characteristics of the entire number’. In an attempt to make his idea clearer, Gamow wrote, with his typically erratic spelling:

the animal will be a cat if Adenine is always followed by cytosine in the DNA chain, and the characteristics of a hering is that Guanines allways appear in pairs along the chain … This would open a very exciting possibility of theoretical research based on mathematics of combinatorix and the theory of numbers!

Gamow said he would be in England in the autumn, and asked whether they could meet. Watson and Crick were both about to leave Cambridge and pursue their separate careers – Watson was going to Pasadena, while Crick was headed for Brooklyn Polytechnic, once he had finished his PhD on the structure of haemoglobin. So the pair simply ignored Gamow’s letter.
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Or, rather, they did not reply to it. Crick did not ignore it: Gamow had planted an idea that would not go away.

Gamow did not give up easily. Over the next couple of months he worked up his ideas about the genetic code and in October he sent a brief note to
Nature,
which was published in the following February. He tried to publish a longer article on the same subject in
Proceedings of the National Academy of Sciences,
co-authored by his fictitious character Mr Tompkins. The Editor of
PNAS
spotted the jape and was not amused, so Gamow sent the article to the Royal Danish Academy, with Tompkins’s name excised.
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Gamow addressed the link between the DNA code and proteins by pointing out that the central question was how four-digit ‘numbers’ in the gene (A, C, T and G) were translated into an amino acid ‘alphabet’ in a protein.

Gamow’s answer was ingenious and was not dissimilar to the template idea that Caldwell and Hinshelwood had published three years earlier. Gamow assumed that proteins were synthesised directly on the DNA molecule, so that the shape formed by the bases as the DNA molecule twisted round acted as a kind of template upon which the amino acids were arranged. Because of the spiral shape of DNA, there would be a diamond-shaped ‘hole’ between different rows of bases; the four bases on each side of this diamond therefore constituted the code.

4. Gamow’s ‘diamond’ model of the genetic code, from Gamow (1954). The round structures numbered 1–4 are the bases, the diamond shapes labelled a–t are the 20 naturally occurring amino acids.

Gamow noted that there were twenty different possible kinds of ‘hole’ and continued, ‘it is inviting to associate these “holes” with twenty different amino acids essential for living organisms.’ Gamow even came up with a prediction that would test his model: because each base contributed to the shape of the ‘hole’ of more than one amino acid, ‘there must exist a partial correlation between the neighbouring amino acids in protein molecules, since the neighbouring holes have two common nucleotides.’
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By treating the code as a mathematical problem rather than a biological one, Gamow was opening the door to years of speculation about the nature of the genetic code. He was also committing the classic physicist’s error of assuming that living systems are designed according to elegant, logical principles that can be revealed by mathematics. In fact they are historical, carrying the baggage of their evolutionary past, and have not been designed at all. They are often far from logical, nor are they generally elegant. They work, and that is enough.

Gamow sent Crick a copy of his paper and eventually the two men met in Brooklyn in December 1953. Crick’s office-mate Vittorio Luzzati recalled:

It was amazing. These two spirited men debated, argued and fought their way through the subject of the code disposing of issues, one after another, in their exuberance their voices rising to shouts.

Crick was not convinced by Gamow’s ideas – for a start, he did not think that protein synthesis took place on the DNA molecule, as Gamow assumed. It was by now well known that DNA was found in the nucleus, as part of the chromosomes, whereas RNA was found freely in the cell, where protein synthesis took place. Crick and Watson, following Caspersson, Brachet, Boivin, Vendrely and Dounce, considered that RNA acted as an intermediary between gene and protein. This was the meaning of the equation DNA → RNA → protein. The very starting point of the diamond code was wrong.

But Gamow had put his finger on a fundamental and seductive issue: the potential relation between the number of naturally occurring amino acids (twenty) and the number of possible combinations in the code formed by the bases A, C, T and G. As Gamow immediately realised, if the code were composed of two-letter ‘words’ (AA, AT, AC, AG, etc.), there would be sixteen possible combinations – not enough for each ‘word’ to correspond to a different amino acid. But if the code were composed of three letters (AAA, AAT, AAC, etc.), there would be sixty-four possible combinations – more than enough.

What Crick called ‘the magic twenty’ came to be the criterion against which all potential codes were measured.
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What was called ‘the coding problem’ began to have a whiff of numerology – coding schemes were developed, with the objective always being to come up with twenty possible combinations that might correspond to the twenty widely occurring amino acids. Neither Crick nor Watson had previously thought much about the relationship between a base sequence in DNA and the amino acid sequence – they were more focused on the problem of how the double helix might unwind during gene replication. They suggested that the sequence was ‘the code that carries the genetical information’, but they had not thought beyond that fundamental insight. As Watson told the Cold Spring Harbor meeting in the summer of 1953, he and Crick could not explain how the gene controlled the activity of the cell.
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Gamow’s intervention brought the question of coding to the forefront of everyone’s mind. For Crick, it occupied an important portion of his life for the next fifteen years.
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In the months following his letter to Watson and Crick, Gamow organised informal discussions involving biologists and a small gang of physicists and mathematicians – including Edward Teller (‘the father of the H-Bomb’) and the future Nobel Prize winner Dick Feynman – who were seduced by Gamow’s infectious enthusiasm and by his zany and intellectually provocative correspondence, which came complete with jokes, comments and cartoons. Gamow spent his time flitting from laboratory to laboratory, writing his slightly mad letters on headed notepaper from hotels or railway companies, scattering forwarding addresses like confetti.
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Gamow was larger than life – he was more than six feet tall, with a taste for hard liquor, practical jokes, magic tricks and women, and he spoke in a thick Russian accent that was often hard to understand.
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Having him around could be hard work – in February 1955, Watson wrote to Crick: ‘Gamow was here for 4 days – rather exhausting as I do not live on whisky.’
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Crick recalled:

And he was what is called good company, was Gamow. I wouldn’t quite say a buffoon, but – yes, a bit of that, in the nicest possible way. You always knew, if you were going to spend the evening with Gamow that you would have a ‘jolly time’. You know. And yet there was something behind it all.

When it came to discussing coding, Gamow was irrepressible; as soon as one of his schemes crashed into the hard wall of biochemical fact, he simply came up with another. So when it became evident that his DNA-based diamond model had little traction, Gamow, undaunted, switched to thinking about coding in RNA. This molecule was not so amenable to the diamond model – its precise structure was unclear, but it was probably some kind of single helix, meaning that Gamow’s original scheme would not work.