Looking back at the Astbury-Bell model of thymonucleic acid, it is easy to spot where it diverges from the Watson-Crick structure of DNA. Most obvious was its singularity. The cylindrical pile of pennies was just that, with no other half to turn it into a double act. It was dead straight, with no reason to think that it might have any hint of a twist. More subtly, the flat units which were separated by 3.34 A and which Astbury visualised as pennies were not like the steps in the spiral staircase of the BRCA-1 gene down which you walked in Chapter 1. Each of those steps consists of two unequal halves which slot together, and each half-step is one of the bases, adenine, guanine, cytosine and thymine. Astbury’s pennies were quite different, each constructed from one of the bases coupled to the sugar, deoxyribose.
There was clearly much work to be done in the fifteen years which separated Astbury and Bell (Nature, April 1938) from Watson and Crick (Nature, March 1953). Hindsight does not necessarily make us wiser; it can help us to understand how things came to be, but at the risk of making us patronising or dismissive of the efforts of our predecessors. Astbury and Bell’s vision of the molecule of what we now call DNA was not just imperfect; it was fatally flawed. However, it was the first proper attempt to portray the molecule in three dimensions.
And it was revolutionary. The brief article in Nature contained no illustrations, but it instantly caught the imagination of scientists, including many of those who had been conditioned by Levene and Kossel to think of nucleic acids as small and boring. The tottering pile of pennies was hundreds of times bigger than Levene’s tetranucleotide, and its molecular weight of between 500,000 and 1 million outstripped that of most proteins. Surely a molecule that massive had to do something important inside the nucleus – but what?
Structure and function
In 1937, the English physiologist J.P.S. Haldane came to wonder how genes replicated themselves when the chromosomes divided. He reduced the process to its bare, theoretical essentials: ‘It must be a process of copying . . . the gene, considered as a molecule, must be opened out in a layer one Baustein thick; otherwise it could not be copied.’
Haldane thought that copying might be like crystallisation, where an identical layer of Bausteine was laid down on top of the original, or perhaps like running off copies of a gramophone record from a master disc.
He did not speculate about the chemical identity of the Bausteine in this molecular template, but others were convinced that they knew. Notions about the chemical nature of the gene had become even more entrenched. If variety really was the spice of life, then the infinitely diverse proteins still had to be the only serious contenders for the essential job of carrying all the instructions of heredity. The protein supremacists still ruled the roost, and even those who had invested their energy in thymonucleic acid were swept along. Torbjörn Caspersson trotted out the time-honoured catechism in 1935: proteins were ‘the only known substances which are specific for the individual . . . protein structure in chromosomes therefore takes on a very great significance.’
What about the nucleic acids? Their ‘most likely role’ wrote Caspersson in 1936,’seems to be that of the structure-determining supporting substance’ – which was a verbose restatement of the ‘scaffolding’ idea that Miescher had put forward over half a century earlier.
This was the soil into which Bill Astbury dropped the seed of an idea which quickly sprouted into an attractive notion of what thymonucleic acid might really do. He and Bell were struck (Bell used the word ‘ecstatic’) by the fact that the 3.34 Å periodicity in thymonucleic nucleic acid was ‘nearly equal’ to the distance between adjacent amino acids in extended protein chains such as beta-keratin (3.32 A). They found it ‘difficult to believe that it is no more than a coincidence’ and could not dismiss ‘the stimulating thought’ that this could underpin the ‘interplay of proteins and nucleic acids in the chromosomes’. Specifically, they suggested that the massively long thymonucleic acid molecule acted as a linear template against which the amino acids lined up in the correct order to be joined together to make the proteins. Thymonucleic acid was more than a passive scaffold to support the proteins in the nucleus; it was crucial in the synthesis of those proteins.
In the summer of 1938, Astbury was invited to present a paper at the prestigious Cold Spring Harbor Conference on ‘The Chemistry of Proteins’, held on Long Island, New York. His talk focused on the thymonucleic acid-protein story and he unveiled an artist’s impression of the cylindrical ‘pile of pennies’ of thymonucleic acid, showing how each flat ‘penny’ was made up of the sugar (deoxyribose) linked to a base (Figure 13.1). He also presented evidence to support his view that thymonucleic acid was the framework on which proteins took shape. Thymonucleic acid incubated with a nuclear protein, clupein, formed a ‘nucleoprotein’ complex which showed the same X-ray periodicity as the acid alone – proving, Astbury believed, that the protein had clicked into place along the nucleic acid template.
The lecture stimulated lively discussion, and drew out a wasted prophecy. Stuart Mudd, bacteriologist and immunologist from Philadelphia, noted that Astbury’s bold new structure marked the end of an era. Thymonucleic acid was vastly more interesting than Levene and the ‘analytical chemists’ had decreed. Specifically, Mudd found it ‘reassuring . . . that such a long molecule had more than enough variation possible’ to transmit hugely complicated information. He suggested that ‘slight changes in the order in which nucleotides occur . . . might give us an adequate basis for specificity.’ In other words, thymonucleic acid could itself be the vehicle that carried the instructions of heredity. It was as though he had looked twenty years into the future and had seen the workings of the genetic code.
Astbury agreed that ‘changes in the order of nucleotides’ could provide ‘another chance of great variation’ to be engraved in the chromosomes, but he was not swayed by Mudd’s argument. Thymonucleic acid was a passive partner that supported proteins and helped in their synthesis. Astbury was in complete agreement with the party line that genes could only be proteins: ‘Fibrous protein molecules . . . form the long scroll on which is written the pattern of life. No other molecules satisfy so many requirements.’
Closedown
In March 1939, Astbury chose Florence Bell to act as spokesman for his lab’s research at the Third Conference on Industrial Physics, held in Leeds. The world was suddenly looking a dangerous place once more, and the meeting only went ahead after ‘much consideration given to its postponement’. It was ‘a slightly muted affair’, but still attracted over 220 delegates and twenty industrial exhibitors. Bell did an excellent job, even if the media were unsure how to react to this atypical ambassador from the testosterone-rich world of science. Under the headline ‘WOMAN SCIENTIST EXPLAINS’, the Yorkshire Evening Post seemed surprised that this ‘slim 25-year-old’ was a Cambridge graduate who could talk with such authority about the mysteries of physics. Her topic was the one which now held her attention: the molecular structure of textile fibres. Thymonucleic acid was a year and a couple of papers ago; she had taken it as far as she could and had now moved on.
Even though he had no new data, Astbury was still dining out on thymonucleic acid and what he thought it did. That autumn, he was a keynote speaker at the Seventh International Genetical Conference in Edinburgh. This was thirty-five years since the Third (more accurately, the first) Genetical Conference at which William Bateson had floated the notion of ‘genetics’, and sixteen years after Edinburgh had hosted the International Physiological Congress at which Albrecht Kossel had been given the standing ovation for both his science and his principles.
The Seventh Genetical Conference should have attracted 600 geneticists from fifty-five countries, but it was an awkward affair from the start. The larger-than-life Russian botanist-geneticist Nikolai Vavilov had organised the meeting and was due to preside, but pulled out several weeks beforehand, improbably citing pressure of work. Then the rest of the Russian delegation announced that they too would be unable to attend.
After the first uneasy day, ‘the air became disturbed . . . with murmurings outside’, and the thirty-four German delegates excused themselves with regret as they had been summoned home. They were quickly followed by the seventeen geneticists from the Netherlands.
The attention of the depleted audience may well have been elsewhere when Astbury delivered his talk on ‘protein and virus studies in relation to the problem of the gene’. He had not defected from physics and become a virologist. Various viruses had recently been analysed and found to consist largely of nucleic acid; ‘virus’ had become accepted shorthand for ‘nucleic acid’. In his lecture, Astbury defended his view that the ‘close dimensional correspondence between protein chains and polynucleotide columns’ was not a coincidence of ‘mere numerology’, but provided a privileged insight into the operation of the genetic mechanisms inside the nucleus. The precise ‘fitting’ of protein and thymonucleic acid molecules one against the other was critical – but as before – it was the proteins that carried all the useful information and that played the leading role.
Any impression that the Conference been running on borrowed time was entirely accurate. When the closing ceremony took place on 30 August 1939, the sense of foreboding that had permeated the meeting was within hours of crystallising into hard, brutal reality. The next day, Hitler’s army invaded Poland; two days later, Britain was at war with Germany.
* Marmite was born in 1902 in Burton-on-Trent.
14
UNHOLY GRAILS
Other hostilities had been in full swing for years before the Second World War began. The theatre of conflict, embracing Western Europe, the Soviet Union and North America, was the setting for two different campaigns. These were dirty wars, with mass murder, incarceration, torture and the slaughter of innocents. They were fought over something which seems abstract beside the usual motives for crimes against humanity: genetics.
One victim was Nikolai Vavilov, the Russian botanist who failed to travel to Edinburgh in August 1939 to preside over the Seventh International Genetical Conference. His absence was not due to the impending war in Europe, but to a difference of scientific opinion which should have been resolved without the intervention of the Soviet secret police. Vavilov was a world expert in the genetics of wheat, the author of over three hundred scientific papers and books, and respected internationally as ‘one of the greatest men’ produced by the Soviet Union. His trajectory had been spectacular, from a youthful Professor of Agriculture and Genetics at Saratov University, to chief of Genetics at the Academy of Sciences and finally the top job, President of the Soviet Academy of Agricultural Sciences. His grand vision was to give the Soviet Union the best wheat in the world, using the classic Mendelian strategy of selecting and cross-breeding improved strains. His famous book Five Continents reflected the sources of the massive seed collection – 30,000 strains of wheat and over 200,000 other plants – in his Genetics Institute in Leningrad. To make it all happen, he built up a network of 400 research institutions which employed over 200,000 workers.
Vavilov was a dark, stocky man with a huge ‘Falstaffian’ personality and a deep resonant voice like Paul Robeson’s (Figure 14.1). His gifts included ‘contagious enthusiasm, prodigious energy and encyclopaedic knowledge’, together with charm and a quick wit in all the major European languages and a few Asian ones as well. He enjoyed travel, whether lecturing at conferences or hunting for new varieties of wheat in the wilderness of Persia. From 1914-17, he worked with William Bateson in England; the voyage home could have been worse, as the mine which sank his ship and destroyed all his specimens left him undamaged. Having failed to entice the Canadian geneticist, Margaret Newton, to Leningrad (despite offering a camel train for her plant-collecting expeditions), Vavilov struck up a lasting collaboration with Herman Muller, who was then based at Rice University in Texas. Muller arranged Rockefeller scholarships for Israel Agol and Solomon Levit, two of Vavilov’s brightest young researchers, to work with him on X-ray induced mutations.
Figure 14.1 Nikolai Vavilov.
During the 1920s, Vavilov led a charmed life because he found favour at the very top; his promise to fill the bellies of the Russian people persuaded Lenin to overlook Vavilov’s non-proletarian roots and upbringing. In 1926, he won the ultimate seal of approval, the Lenin Prize. All the above powered Vavilov’s extraordinary ascent; and all the above contributed to his downfall. Everything went well until 1928, when a thirty-year-old agricultural graduate called Trofim Lysenko popped up in Odessa with the bizarre claim that he had produced prodigious wheat harvests out of season – not by tedious Mendelian crossbreeding, but simply by exposing the seeds to cold and moisture at a critical time. Even more sensational was Lysenko’s insistence that the change was transmitted to all future generations of the super-wheat. This was much better than anything that Nikolai Vavilov, the forty-five-year-old grandee of Soviet agricultural genetics, could dream up.
Vavilov’s first mistake was to accept Lysenko’s results at face value; he even praised Lysenko’s ‘remarkable discoveries’ at meetings in and outside Russia. His second mistake was to underestimate Lysenko’s capacity for evil. Lysenko had taught himself all he wanted to know about research. He was clearly ambitious; less obvious initially were his deluded thinking, his hypersensitivity to criticism and his lust for revenge against those who challenged him. He believed that songbird nestlings grew into cuckoos if they were fed with hairy caterpillars, and that living cells could be created from egg-yolk; he also falsified results to support his claims. Mainstream science quickly fell foul of Lysenko’s paranoia. A statistician who questioned his findings was told that ‘mathematics has no place’ in botanical research. Vavilov dropped into the trap by asking whether Lysenko really believed that he had refashioned heredity by tinkering with temperature and humidity. Of course, retorted Lysenko, because the ‘fake products of the Catholic church and capitalism’ – the theories of Mendel and Morgan – were rubbish.
None of this made Lysenko a pariah; instead, he was fast on his way to becoming top dog. Vavilov’s patron, Lenin, had been succeeded by Josef Stalin, who publicly admired Comrade Lysenko – peasant stock, self-made, no allegiance to ‘fascistic’ pseudoscience, and the Communist genius whose plan to feed Russia was simple and cheap. As Lysenko’s star rose, that of the bourgeois, pro-Mendelian Vavilov began to fade.
In 1933, Herman Muller came to work with Vavilov in Leningrad. Muller had left racist, intolerant Texas for the Kaiser Wilhelm Institute for Brain Research in Berlin, moving on when it was attacked by a Nazi mob for employing foreigners. Muller’s two Rockefeller scholars, Agol and Levit, also returned to Vavilov’s lab. Unfortunately, Muller accused Lysenko of sorcery at a conference in Moscow. Lysenko, who now sat on the Supreme Soviet, sacked Vavilov and took over as President of the Academy of Agricultural Science and the Institute of Genetics. He then set about purging Soviet science of the ‘fascist’ lies promulgated by Mendel and Morgan. During Lysenko’s sixteen-year reign of terror, all the fruit flies in the Institute of Genetics were killed in boiling water, genetics books were burned, laboratories closed and research groups disbanded. When Levit and Agol were arrested in late 1936,* Vavilov told Muller to leave the country. They said their farewells in whispers outside Vavilov’s apartment, for fear of being overheard. Muller fled first to Spain and then to Edinburgh, leaving Vavilov to face his fate.
Nikolai Vavilov’s gravest error was to be a man of principle. In spring 1939, he told a group of the few remaining geneticists that ‘we may burn but we shall not retreat from our scientific convictions’, and signed a public statement condemning Lysenko’s pseudo-science. In revenge, Lysenko demonised Vavilov in Pravda and banned him and all Russians from attending the Genetics Conference in Edinburgh.
In early August 1940, Vavilov left on a plant-collecting expedition to the Ukraine. He got as far as the town of Chernovtsy, where he was arrested by the secret police. It later transpired that the charges against him included ‘sabotage of Soviet agri
culture’ and spying for England. It was known that Vavilov was taken back to Moscow. His likely destination was the Lubyanka prison, where most new arrivals were kept just long enough to be tortured into producing a false confession and executed. At that point, the trail went cold.
Bad blood
The other genetics war was not fought over science, but against individuals who harboured particular genes – or who should have done, even if there was no evidence that they did. It all began innocently before the turn of the twentieth century with the birth of what was billed as a new science. ‘Eugenics’ (the Greek ‘eu’ means ‘good’) embraced the improvement of hereditary stock, much as Vavilov did with wheat, but applied to Homo sapiens. The notion quickly took off, thanks to clever publicity and the support of prominent philosophers, social reformers, and politicians. Its followers depicted eugenics as a well-proportioned tree supported by sturdy roots labelled ‘genetics’, ‘medicine’, ‘religion’, ‘mental testing’ and so on. Academic credibility soon followed, with the establishment of the first Eugenics Institute in 1904, and the first chair in Eugenics, in a world-class university, in 1911.
Two practical strategies emerged for the ‘self-direction of human evolution’. ‘Positive eugenics’ meant encouraging people with desirable qualities – high intelligence, a Protestant work ethic and good health – to breed with others similarly endowed. ‘Negative eugenics’ was the removal from the gene pool of undesirable, weakening traits such as feeblemindedness, laziness and untreatable inherited diseases; the message was rammed home by powerful propaganda highlighting the huge costs of looking after the physically and mentally handicapped.
Unravelling the Double Helix Page 19