Unravelling the Double Helix

by Gareth Williams

  Levene had brought up a loop of its intestine to the skin, and opened a tiny window in the wall.* Conditions in canem were gentler than those in the test tube, and the delicate sugar duly appeared in the intestinal juice.

  The mystery ingredient was a previously unknown pentose sugar, and a variation on an existing theme. It was like D-ribose, the pentose in yeast nucleic acid, but with an H (hydrogen atom) instead of an OH (hydroxyl group). As it was effectively ribose minus an oxygen atom, Levene called it ‘desoxyribose’, later shortened to ‘deoxyribose’ (Figure 9.2).

  Levene had taken a big step forward by finding the last component of desoxyribonucleic acid, but he had also taken at least two steps back – and had dragged everyone who mattered with him. His ‘tetranucleotide hypothesis’, which postulated that the nucleic acid molecule only contained one of each of the four nucleotides, had somehow become fact. Various structures had been proposed, from Levene’s linear chain (Figure 7.2) to a closed ‘cyclic’ shape in which the nucleotides were linked like four people holding hands. These were no more than doodles on thin air, but they looked believable and carried the stamp of the world’s greatest authority on nucleic acids.

  Figure 9.2 Ribose and deoxyribose, the pentose sugars in RNA and DNA. Spot the difference.

  Any evidence that challenged Levene’s tetranucleotide was swiftly trampled underfoot. When someone proved that the molecular weight of the nucleic acids was far too high, Levene first tried to discredit the research and then conceded that a nucleic acid molecule could contain more than four nucleotides – as long as it was made up of identical tetranucleotide units, joined together to form a chain. The tetranucleotide hypothesis drove the entire field of nucleic acid chemistry into a cul-de-sac. It spawned the belief that the nucleic acids were much smaller than typical proteins, and had a boring and inflexible structure which ruled out any important biological function.

  In 1929, Levene rounded off twenty-five years of research by writing a book. Nucleic Acids was comprehensive and bang up to date, but the preface might have left the reader wondering why he had bothered:

  The chemistry of nucleic acids can be summed up very briefly. Indeed, a few graphic formulas which need not even fill a single printed page might suffice to express the entire store of our present-day knowledge on the subject.

  In Heidelberg, Albrecht Kossel had already written the definitive book about his own greatest obsession. This had kept him busy during the three years after he retired in the summer of 1924. He finished the manuscript just in time to be knocked flat by a nasty attack of angina, but not quickly enough to hold his labour of love in his hands. The book was published in early autumn 1927, a few weeks after Gertrude and Walter Kossel had placed a brief notice in the newspapers. Headed ‘Zum Gedächtnis’ (In Memoriam), it announced the death of their beloved father on 5 July.

  The late editor of Hoppe-Seylers Zeitschrift für Physiologische Chemie was remembered with respect and affection in the obituary which the journal carried in March 1928. The fruits of an outstandingly rich life in science were laid out: Kossel’s discoveries, papers, Nobel and other prizes – and the book by which he wished to be remembered. This was devoted to the molecules which had excited him the most during his forty years in biochemistry and was entitled The Protamines and Histones. Nucleic acids were mentioned only in passing as minor players that happened to share the stage with those fascinating proteins, which were ‘biologically the most important of all the substances in the nucleus’.

  ‘Zum Gedächtnis’ would also have made a good title for the single page on which Phoebus Levene could have summarised ‘the entire store of our present-day knowledge’ about the nucleic acids. They had been written off as unworthy of further interest by the two greatest experts in the field – just in time to celebrate the sixtieth birthday of nuclein. And inevitably, this negative verdict played directly into the emerging debate about the chemical identity of the ‘hereditable substance’ which transmitted the characteristics of a living organism to its descendants.

  Sole contender

  Genes had come far since their christening in 1909, but two great mysteries remained completely unsolved as the Roaring Twenties got under way. How did genes work? And as a first step towards answering that question, what were genes made of?

  Thinking had moved on from idioplasm, gemmules and other will-o’-the-wisp notions of twenty years earlier. Niels Bohr, the great Danish quantum physicist, had strayed into the alien territory of biology after winning his Nobel Prize in 1922. Bohr argued that life was not infused into an organism by some mysterious ‘vital’ force but, like everything else in the universe, must be grounded in atoms and molecules that behaved according to the laws of physics and chemistry. The same diktat must apply to genetics, even though it was difficult to see how the hard facts of quantum physics could be translated into the inheritance of features as unfathomable as eye colour, height or intelligence.

  This meant that genes had to consist of a chemical substance or substances of some sort – hence Herman Muller’s prediction in 1922 that ‘we may be able to grind up genes in a mortar and cook them in a beaker’. There were just two candidates for the ‘genetic material’, namely the only substances so far found in the nucleus: proteins (Kossel’s beloved protamines and histones) and nucleic acids. And there was only one serious contender, because proteins looked the part and nucleic acids did not.

  Only proteins appeared to have enough structural diversity to carry the information of heredity. Their Bausteine – by now, nearly twenty different amino acids – could be joined end to end ‘like carriages on a train’ in any order and to any length, thus creating billions of possible structures. Just as the twenty-six letters of the alphabet could be assembled to describe ‘an infinitely large number of thoughts’, so different sequences of amino acids in specific proteins could spell out all the instructions for life. Proteins came in ‘an inexhaustible variety’ of shapes and sizes, and a quick glance around the human body strengthened the impression that proteins could do anything. Collagen held skin and bones together; myosin made muscles contract; haemoglobin carried oxygen to every cell; digestive enzymes such as pepsin and amylase made light work of breakfast; and insulin could quell the metabolic anarchy of diabetes and rescue diabetic children from death row. If proteins did all those things, then surely genes must be made of long-lived ‘hereditary proteins’ which were handed from one generation to the next.

  By contrast, nucleic acids lacked that crucial versatility. Levene’s tetranucleotide hypothesis had struck the fatal blow to their candidacy. Even if tetranucleotides were strung into a long chain, the units were all identical and therefore could not carry much useful information. Moreover, nucleic acids appeared ‘remarkably uniform’ in composition, even between vastly different species of animals and plants. This seemed to rule out any controlling role for the nucleic acids. How could the same molecule tell a plant to make chlorophyll, and a mammal to fill its red blood cells with haemoglobin?

  The verdict was obvious. Proteins were ‘of the first importance’ in transmitting what Kossel eloquently called ‘the peculiarity of species’ to the next generation, while nucleic acids simply ‘cannot be the hereditable substance’. To shut off any further pointless discussion, Phoebus Levene was characteristically blunt: ‘Nucleic acids carry no individuality, no specificity . . . It may be just to accept the conclusion of the biologist that they do not determine species specificity, nor are they carriers of the Mendelian characters.’

  Disconnect

  The year of Albrecht Kossel’s death, 1928, also signalled the demise of the Fly Room. Thomas Hunt Morgan had been approached with an unrefusable offer, to set up a new Institute of Biology at the California Institute of Technology (Caltech) in Pasadena. He was sixty-two years old and just two years off retirement at Columbia. Caltech promised generous funding, an environment that had already nurtured two Nobel prizewinners, and a new lease of life. After seventeen years hemmed in by all those
milk-bottles, Morgan decided that it was time to go. He took with him his two longest-serving Drosophila veterans, Alfred Sturtevant and Calvin Bridges. Sturtevant, who dreamed up the original chromosomal map, had continued mining that highly profitable seam. Bridges had shown that the mutations in Drosophila were clustered in four groups of different sizes, which corresponded to the fly’s four chromosomes. This was powerful supporting evidence that the chromosomes carried all the information of heredity, and that the genes were arranged along each chromosome in a fixed order.

  Morgan and his group prospered at Caltech. He recruited geneticists at the peak of their powers and welcomed in a stream of distinguished visitors, including the novelist H.G. Wells, a visionary in a different dimension, who had written about the dangers of science running free. Unsurprisingly, it was only a matter of time before Morgan’s work came to the attention of the Nobel Prize Committee in Stockholm. By then (1933), he and his team had pinpointed, down to the level of a tiny band on a particular chromosome, the physical locations of almost 3,000 genes.

  However, another great mystery in genetics was no closer to being solved. Back at the turn of the century, the gene had been an impenetrable black box; now, almost three decades later, it still was. The nature of the gene was still completely unknown. Towards the end of 1928, the eminent biologist Edmund Wilson described the gene as ‘a complex of specific, autocatalytic, colloidal particles in the germ-cell’ that, ‘in accordance with the recognised principles of physics, can engineer the construction of a vertebrate organism’ – which was a verbose way of saying that he had no idea what it really was.

  One thing, however, was blindingly obvious. Faced with the damning verdicts of Phoebus Levene and Albrecht Kossel, the two greatest names from the heroic age of nucleic acid chemistry, only a brave man or a fool would have dared to suggest that the nucleic acids had anything to do with genes or the transmission of inherited characteristics.

  * Levene need not have gone to all this trouble. Pavlov had recently begun marketing canine digestive juice as a tonic.

  10

  INVENTIONS AND IMPROVEMENTS

  It is very rare for the river of scientific discovery to run a straight and uncomplicated course. Short of flowing uphill, this river can do almost anything, mainly because it is fed by tributaries whose behaviour can be unruly and unpredictable. Some of those tributaries bring clarity, fresh ideas and new perspectives, like a mountain stream brimming with oxygen and vitality. Others are virtually lifeless, thick with the sediment of spent thought and ready to dump their burden at the first opportunity.

  At risk of overstretching the metaphor, the history of DNA is a fine illustration of these principles. Phoebus Levene and Albrecht Kossel effectively killed off all life in their tributary, which then threatened to pollute the much broader waters downstream. Meanwhile, another tributary was gaining strength and transforming the landscape around it – but without showing any sign that it was destined to merge with a different stream which was meandering towards an understanding of the gene and its mysteries.

  That second tributary was the discipline of X-ray crystallography. Everyone familiar with the climax of the saga of the double helix knows that this was the decisive technology which made it all happen. However, there is much more to the role of X-ray crystallography and its practitioners than that dramatic but brief episode. To skate over the twenty years of research that led there – as many authors have done – would be another kick in the teeth for several largely unsung heroes, without whom that final chapter would never have been written in a form that we would recognise. And as well as denying them their moments of glory, this would rob us of the chance to meet some of the most colourful characters in the cast.

  With that preamble, we return to London on the threshold of the Roaring Twenties, and a once noble institution that was in urgent need of resuscitation.

  Diffusion of knowledge

  A cursory glance around the auditorium would have confirmed that this was something that William Bragg did supremely well. He had been invited to give the 1919 Christmas Lectures at the Royal Institution in London and had chosen the theme of ‘Sound’. Over six successive evenings, his topics ranged from ‘Sound and Music’ to ‘Sounds of Nature’, finishing with a subject that was still fresh in everyone’s memory. ‘Sounds of War’ featured the Bragg family’s interests in U-boat detection and artillery sound-ranging – while remaining within the limits of what the Official Secrets Act allowed him to talk about. Throughout, Bragg held his audience absolutely captivated. They sat silently around the steeply tiered lecture theatre, all ears and eyes focused on the man at its centre, then filed down to crowd excitedly around his demonstration table when invited to come and take a closer look at the experiments.

  At the time, there were deepening concerns that German technology, now recovering from its post-war privations with the help of a massive injection of American cash, would regain its former might and surge ahead of Britain. However, anyone observing the Christmas Lectures would have felt huge optimism for the future of British science. In accordance with the directive of Michael Faraday, who had established the tradition in 1825, the lectures were tailored for a ‘Juvenile Auditory’, because the target audience was children. Bragg knew intuitively how to tune into those fresh young minds, and as far as the juveniles were concerned, his pitch was perfect.

  That was William Bragg’s formal introduction to the Royal Institution. After the New Year break, he returned to University College London, where he had been appointed Professor of Physics in 1915. He found it just the same as it had been before Christmas: dull, unrewarding and strangling itself in the pompous politics in which universities revel.

  In 1923, the top job came up at the Royal Institution. A furnished flat (in Mayfair, no less) was included and the salary was acceptable if unspectacular. Once upon a time, running the Royal Institution had been as prestigious as any scientific professorship in the land, but the place had fallen on hard times and was now a research backwater. Going there was an odd move for a Nobel laureate, but Bragg (by now Sir William) took the risk and accepted the post of director. This time, it was for keeps: the Institution was where he took up residence and spent the rest of his career, and where he died.

  The Royal Institution had been conceived in London on 8 March 1799, by a group of the nation’s most eminent scientists. To demonstrate how small the world can be, they met in Sir Joseph Banks’s former house in Soho, where Robert Brown later popped nuclei out of plant cells; and their leader was Sir Henry Cavendish, whose name eventually graced the laboratory in Cambridge where Lawrence Bragg, Jim Watson, Francis Crick and the graceful twin spiral of DNA were destined to come together a century and a half later.

  The new Institution took shape behind the elegant colonnades of No. 20 Albemarle Street in Mayfair and opened its doors for business in 1800. From the start, its mission was to break new ground and to educate, by ‘diffusing the knowledge and facilitating the general introduction of useful mechanical inventions and improvements; and teaching, by courses of philosophical lectures and experiments, the application of science to the common purposes of life.’

  With Humphrey Davy as its first Professor of Chemistry, the Institution was launched straight into its golden age. In three heady months in 1808, Davy discovered one element after another by running an electric current through molten salts – sodium, potassium, boron, calcium and strontium, ending with barium to celebrate the New Year of 1809. Davy’s glory shone a flattering light on the Institution and on science in general. He became a celebrity who scaled the heights of society with the likes of William Wordsworth and Sir Walter Scott (and climbed Helvellyn with both of them in 1806).

  Davy’s legacy included the young man whom he appointed as assistant and note-taker after his own eyes were damaged in a laboratory explosion in 1812. Michael Faraday was already known for his experiments with ‘laughing gas’ (nitrous oxide), introduced as an analgesic at a time when surgery was no jo
ke. Faraday quickly revealed his true colours as a theoretician and inventor, and the proud possessor of a mind at least as brilliant and ingenious as Davy’s. They collaborated on designing a safety lamp for miners, then fell out and remained distant up to Davy’s death in Geneva in 1829.

  It was Faraday who turned the Institution’s aim of ‘diffusing knowledge’ into an art and a public spectacle. In addition to the ‘Juvenile Lectures’ at Christmas, he set up weekly Friday Evening Discourses, in which a leading scientist would hold forth on their subject, without hesitation, repetition or deviation, for just an hour and not a minute longer. He set a fine example, eventually giving nineteen Christmas Lectures and numerous Discourses. These included the first public appearance of his electric generator in 1831, and a show-stopping display of the disinhibiting effects of nitrous oxide, gamely demonstrated by Sir John Hippisley. The highlights of Friday Evening at the Institution included the Discourse in August 1897 when J.J. Thomson introduced the electron to the world. Many of these events played to an overfull house of at least 1,000 (over twice the number of seats in the auditorium), and regularly caused such congestion that Albemarle Street was designated the capital’s first one-way thoroughfare.

  Thereafter, the Institution became calmer and duller. In 1877, the ‘ruthless’ Scottish chemist James Dewar took over as Professor of Chemistry, and was appointed the first director of the new Davy Faraday Research Laboratory twenty years later. Dewar was interested in extremely low temperatures and had invented a vacuum flask for keeping liquids very hot or very cold. He succeeded in first liquefying, and then solidifying, hydrogen. That was in 1899. After that, his research tailed off, just as molecular activity ceases when the temperature of a gas winds down towards absolute zero. At the time of his death in 1923, he was eighty-one years old, had done nothing new for over fifteen years, and had no intention of retiring from the Institution.