Life's Greatest Secret (3 page)

Beadle returned to the US, determined to crack the problem of how genes could affect biochemistry, but equally certain that he had to use an organism that could be studied biochemically. He found the answer in the red bread mould
Neurospora.
This hardy fungus can survive in the near absence of an external supply of vitamins because it synthesises those it needs. To gain an insight into the genetic control of biochemical reactions, Beadle decided to create
Neurospora
mutants that could not synthesise these vitamins.

Together with microbiologist Edward Tatum, Beadle followed Muller’s approach and irradiated
Neurospora
spores with X-rays in the hope of producing mutant fungi that required added vitamins to survive, thereby opening up the possibility of studying the genetics of vitamin biosynthesis. Beadle and Tatum soon found mutants that were unable to synthesise particular vitamins, and published their findings in 1941.
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Each mutation affected a different enzymatic step in the vitamin’s biosynthetic pathway – this was experimental proof of the widely held view, going back to the beginning of the century, that genes either produced enzymes or indeed simply were enzymes.
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When Beadle presented their findings at a seminar at the California Institute of Technology (Caltech) in Pasadena, the audience was stunned. He spoke for only thirty minutes and then stopped. There was a nonplussed silence – one member of the audience recalled:

We had never heard such experimental results before. It was the fulfilment of a dream, the demonstration that genes had an ascertainable role in biochemistry. We were all waiting – or perhaps hoping – for him to continue. When it became clear that he actually was finished, the applause was deafening.

In the following year, Beadle and Tatum suggested that ‘As a working hypothesis, a single gene may be considered to be concerned with the primary control of a single specific chemical reaction.’
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A few years later, a colleague refined this to the snappier ‘one gene, one enzyme hypothesis’. There was support for this view from work on human genetic diseases such alkaptonuria – in 1908 Archibald Garrod had suggested that this disease might involve defective enzyme production. But Beadle and Tatum’s hypothesis met with opposition at the time, partly because it was known that genes have multiple effects, while their hypothesis – or rather, the ‘one gene, one enzyme’ catch-phrase by which it came to be known – seemed to suggest that each gene did only one thing: control an enzyme.
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*

Trinity College sits in the heart of Dublin, its grey three-storey neoclassical buildings positioned around lawns and playing fields. At the eastern end of the campus there is another grey building, built in 1905 in a rather different style. This is the Fitzgerald Building, or the Physical Laboratory as it is called in deeply engraved letters on the stone lintel. On the top floor there is a lecture theatre, and in the late afternoon of the first Friday of February 1943, around 400 people crowded onto the varnished wooden benches. According to
Time
magazine, among those lucky enough to get a seat were ‘Cabinet ministers, diplomats, scholars and socialites’, as well as the Irish Prime Minister, Éamon de Valera.
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They were there to hear the Nobel Prize-winning physicist Erwin Schrödinger give a lecture with the intriguing title ‘What is life?’ The interest was so great that scores of people were turned away, and the lecture had to be repeated the following Monday.
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Schrödinger had arrived in Dublin after fleeing the Nazis – he had been working at Graz University in Austria when the Germans took over in 1938. Although he had a reputation as an opponent of Hitler, Schrödinger published an accommodating letter about the Nazi takeover, in the hope of being left alone. This tactic failed, and he had to flee the country in a hurry, leaving his gold Nobel medal behind. De Valera, who was interested in physics, offered Schrödinger a post in Dublin’s new Institute for Advanced Studies, and the master of quantum mechanics found himself in Ireland.
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On three consecutive Fridays, 56-year-old Schrödinger walked into the Fitzgerald Building lecture theatre to give his talks, in which he explored the relation between quantum physics and recent discoveries in biology.
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His first topic was the way in which life seems to contradict the second law of thermodynamics. Since the nineteenth century it has been known that, in a closed system, energy will dissipate until it reaches a constant and even level: physicists explain this in terms of the increasing amount of disorder, or entropy, that inevitably appears in such systems. Organisms seem to contradict this fundamental law because we are highly ordered forms of matter that concentrate energy in a very restricted space. Schrödinger’s explanation was that life survives ‘by continually sucking orderliness from its environment’ – he described order as ‘negative entropy’. This apparent breach of one of the fundamental laws of the Universe does not cause any problems for physics, because on a cosmological scale our existence is so brief, our physical dimensions so minute, that the iron reality of the second law does not flutter for an instant. Whether life exists or not, entropy increases inexorably. According to our current models, this will continue until the ultimate heat death of the Universe, when all matter will be evenly spaced and nothing happens, and it carries on not happening forever.

Schrödinger encountered far greater difficulties when he came to discuss his second topic: the nature of heredity. Like Koltsov and Delbrück before him, Schrödinger was struck by the fact that the chromosomes are accurately duplicated during ordinary cell division (‘mitosis’ – this is the way in which an organism grows) and during the creation of the sex cells (‘meiosis’). For your body to have reached its current size there have been trillions of mitotic cell divisions and through all that copying and duplicating the code has apparently been reliably duplicated – in general, development proceeds without any sign of a mutation or a genetic aberration. Furthermore, genes are reliably passed from one generation to another: Schrödinger explained to his audience that a well-known characteristic such as the Hapsburg, or Habsburg, lip – the protruding lower jaw shown by members of the House of Hapsburg – can be tracked over hundreds of years, without apparently changing.

For biologists, this apparently unchanging character of genes was simply a fact. However, as Schrödinger explained to his Dublin audience, it posed a problem for physicists. Schrödinger calculated that each gene might be composed of only a thousand atoms, in which case genes should be continuously shimmering and altering because the fundamental laws of physics and chemistry are statistical; although overall atoms tend to behave consistently, an individual atom can behave in a way that contradicts these laws.
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For most objects that we encounter, this does not matter: things such as tables or rocks or cows are made of so many gazillions of atoms that they do not behave in unpredictable ways. A table remains a table; it does not start spontaneously turning into a rock or a cow. But if genes are made of only a few hundred atoms, they should display exactly that kind of uncertain behaviour and they should not remain constant over the generations, argued Schrödinger. And yet experiments showed that mutations occurred quite rarely, and that when they did happen they were accurately inherited. Schrödinger outlined the problem in the following terms:

incredibly small groups of atoms much too small to display exact statistical laws … play a dominating role in the very orderly and lawful events within a living organism. They have control of the observable large-scale features which the organism acquires in the course of its development, they determine important characteristics of its functioning; and in all this very sharp and very strict biological laws are displayed.

The challenge was to explain how genes act lawfully, and cause organisms to behave lawfully, while being composed of a very small number of atoms, a significant proportion of which may be behaving unlawfully. To resolve this apparent contradiction between the principles of physics and the reality of biology, Schrödinger turned to the most sophisticated theory of the nature of the gene that existed at the time, the Three-Man Paper by Timoféef-Ressovsky, Zimmer and Delbrück.

As Schrödinger explored the nature of heredity for his audience, he was forced to come up with an explanation of what exactly a gene contained. With nothing more than logic to support his hypothesis, Schrödinger argued that chromosomes ‘contain in some kind of code-script the entire pattern of the individual’s future development and of its functioning in the mature state.’ This was the first time that anyone had clearly suggested that genes might contain, or even could simply be, a code.

Taking his idea to its logical conclusion, Schrödinger argued that it should be possible to read the ‘code-script’ of an egg and know ‘whether the egg would develop, under suitable conditions, into a black cock or into a speckled hen, into a fly or a maize plant, a rhododendron, a beetle, a mouse or a woman.’
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Although this was partly an echo of the earliest ideas about how organisms develop and the old suggestion that the future organism was preformed in the egg, Schrödinger’s idea was very different. He was addressing the question of
how
the future organism was represented in the egg and the means by which that representation became biological reality, and suggesting these were one and the same:

The chromosome structures are at the same time instrumental in bringing about the development they foreshadow. They are law-code and executive power – or, to use another simile, they are architect’s plan and builder’s craft – in one.

To explain how his hypothetical code-script might work – it had to be extremely complicated because it involved ‘all the future development of the organism’ – Schrödinger resorted to some simple mathematics to show how the variety of different molecules found in an organism could be encoded. If each biological molecule were determined by a single 25-letter word composed of five different letters, there would be 372,529,029,846,191,405 different possible combinations – far greater than the number of known types of molecule found in any organism. Having shown the potential power of even a simple code, Schrödinger concluded that ‘it is no longer inconceivable that the miniature code should precisely correspond with a highly complicated and specified plan of development and should somehow contain the means to put it into operation.’
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Although this was the first public suggestion that a gene contained something like a code, in 1892 the scientist Fritz Miescher had come up with something vaguely similar. In a private letter, Miescher had argued that the various forms of organic molecules were sufficient for ‘all the wealth and variety of hereditary transmission [to] find expression just as all the words and concepts of all languages can find expression in twenty-four to thirty alphabetic letters.’
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Miescher’s view can appear far-seeing, especially given that he was also the discoverer of DNA, or, as he called it, nuclein. But Miescher never argued that nuclein was the material making up these letters and his suggestion was not made public for nearly eighty years. Above all, the vague letter and word metaphor was nowhere near as precise as Schrödinger’s code-script concept.

Schrödinger then explored what the gene-molecule might be made of and suggested that it was what he called a one-dimensional aperiodic crystal – a non-repetitive solid, with the lack of repetition being related to the existence of the code-script. The non-repetition provided the variety necessary to specify so many different molecules in an organism. Although Troland, Muller and Koltsov had all suggested two decades earlier that genes might grow like crystals, Schrödinger’s idea was far more precise. His vision of gene structure was focused on the non-repetitive nature of the code-script, rather than on the relatively simple parallel between the copying of chromosomes and the ability of crystals to replicate their structure.
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*

Schrödinger’s words would have had little influence had they simply hovered in the Dublin air and briefly resonated in the minds of the more attentive listeners. The sole international report to describe the lectures, which appeared in
Time
magazine in April, did not refer in detail to anything that Schrödinger said, and there are no indications that any of his ideas escaped to the outside world. The only detailed account appeared in
The Irish Press,
which managed to condense his main arguments, and included both the code-script and aperiodic crystal ideas.
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Other newspapers found it difficult to give the story the attention it deserved; when Schrödinger gave a version of his lectures in Cork in January 1944, the local newspaper,
The Kerryman,
gave his talk equal coverage to the Listowel Pig Fair (there was good demand for the 126 pigs on sale, they reported).
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Schrödinger felt that the public would be interested in his views, and as soon as he had finished the lectures he began to turn them into a book, with the addition of a brief and deliberately controversial conclusion. Schrödinger had closed his lectures with a pious nod in the direction of his overwhelmingly Catholic audience, proclaiming that the ‘aperiodic crystal forming the chromosome fibre’ was ‘the finest masterpiece ever achieved along the lines of the Lord’s quantum mechanics’. But in a new Epilogue, written specially for publication and entitled ‘Determinism and free will’, Schrödinger explored his lifelong belief in the mystical Hindu philosophy of Vedanta. He argued that individual human identity was an illusion, and he criticised official Western creeds for their superstitious belief in the existence of individual souls. His point was not that there was no evidence that souls exist but rather that individual consciousness is the illusory expression of a single universal soul. He expressed this in what he admitted were ‘blasphemous and lunatic’ terms for the Christian tradition, but which he apparently considered to be true: ‘I am God Almighty’.