Unravelling the Double Helix

by Gareth Williams

  The pillar draws your gaze upwards to the ceiling, and to the large bunch of bananas that hangs there in parody of a chandelier. This is not the source of the smell. That comes from the milk-bottles, which each contain a generous dollop of mashed banana. The fruit looks dark and has an unsettling shimmering appearance. A closer look shows that it is alive with tiny flies, which constantly boil off the surface and fill the air inside the bottle.

  Welcome to the Fly Room. You are on the ninth floor of the Schermerhorn Hall, on the east side of Columbia University’s Morningside Campus in New York City. This room, just 23 feet by 16, is a breeding ground for millions of fruit flies that have earned their place in the history of science, and for a healthy but unstudied population of cockroaches. It is also a production line for brilliant thinking that ultimately ran off a brace of Nobel Prizes, including the first ever awarded in the new science of genetics.

  The recipient of that award was Thomas Hunt Morgan, the man who conceived the Fly Room in 1908 (Figure 5.1). Morgan was born in Kentucky in 1866, but his scientific life began twenty-four years later with a PhD on the tiny crab-like creatures known as sea spiders. He did this work at the Woods Hole Marine Biological Laboratory on Cape Cod, a haven to which he returned every summer as unerringly as Friedrich Miescher’s salmon homed in on the Rhine.

  In 1900, Morgan embarked on a European voyage of discovery which took him first to the Stazione Zoologica at Naples, the Old World counterpart of Woods Hole which was later described as ‘the Mecca of marine biology’. There, he proved himself to be an inspired experimental zoologist by discovering that sea-urchin eggs do not need to be fertilised to start dividing; simply adding magnesium salts to their sea-water did the trick. From Naples, he went to visit a Dutch expert in biological variation, who ran a huge experimental garden in Hilversum. This man was Hugo de Vries, who had recently rediscovered (or not) the work of Gregor Mendel.

  Figure 5.1 Thomas Hunt Morgan in the Fly Room at Columbia University, New York.

  At the time, Morgan was unimpressed by anything Mendelian and by chromosomes, which he thought were a sideshow to the serious business of heredity. Morgan’s agnosticism was curious because of all the cytological evidence from Sutton and others, which supported Mendel’s idea that two copies of a trait were present in an organism’s cells but that only one somehow found its way into the germ cells. Nonetheless, Morgan left de Vries fired up with a new excitement about mutations and what made them happen. On returning to America, his credentials were exactly what Columbia University wanted in their new Professor of Experimental Biology. Hackneyed though it sounds, the rest really was history.

  Morgan decided to investigate mutations in the fruit fly Drosophila melanogaster.§ At 3 millimetres long and with roughly 2 million to the kilogram, the flies are easy and cheap to keep, especially when milk-bottles can be obtained by ‘more or less unorthodox means’ (pre-dawn raids on the doorsteps of Manhattan). Helpfully, Drosophila need no aphrodisiac beyond decomposing bananas, and they excel at copulation: a single male put into a milk-bottle of females typically sires 1,400 offspring. Promiscuity and under-age sex could clearly ruin an experiment on genetics, but virgin female fruit flies are readily identified with the help of a good lens.

  The flies have a short reproductive cycle of just ten days, which means that three generations can be squeezed into a month. The popular magazine Scientific Monthly reported that the pedigree of some of Morgan’s flies went back 130 generations, and somehow calculated that this would take Homo sapiens back to 15,000 years before Adam. Finally, Drosophila has only four pairs of chromosomes, which lightened the burden of working out exactly where a particular mutation had hit.

  Morgan had found his perfect experimental model.

  The Fly Room must have been an extraordinary place in which to work. At full strength, the group comprised seven or eight men crammed together in the malodorous twilight. With one exception, they worked as a cooperative. They even took a pseudo-holiday together for a month each summer, when the whole lab decamped to Woods Hole, lock, stock and barrel. In fact, they took along several barrels, each carefully packed with the precious milk-bottles so that their research would not lose momentum.

  In 1910, Morgan recruited two undergraduates, Calvin Bridges and Alfred Sturtevant, and the three of them formed the nucleus of the nascent group. Bridges, who spent two-thirds of his scientific career in this room, explained that ‘the group worked as a unit . . . each carried on his own experiments but knew exactly what the others were doing’. Anything new was instantly shared and celebrated as a collective achievement, with ‘little priority’ given to the one who had made the breakthrough. Democracy flowed from the man at the top. ‘The Boss’ was respected for his ‘enthusiasm, combined with a strong critical sense, generosity, open-mindedness and a remarkable sense of humour’. And there was always a buzz in the air that had nothing to do with the inmates of the milk-bottles – the ‘atmosphere of excitement’ which Sturtevant saw as an essential ingredient for an outstanding ‘record of sustained achievement’.

  With Morgan’s reputation and charisma, the Fly Room quickly turned into a honeypot that, over the next fifteen years, pulled in a swarm of fiendishly bright young minds and some unusual personalities. Calvin Bridges was a quiet innovator who replaced Morgan’s trusty hand-lens with the binocular microscope and the flies’ beloved banana purée with the less offensive nutrient agar jelly. His creativity extended outside the Fly Room. At home, he was working on his design for ‘The Bug’, a sleek, revolutionary car which was aerodynamic outside and ergonomic inside. His restlessness of body as well as intellect was also ahead of its time. Forty years before the Sixties began to swing, Bridges was an adherent of the concept (and especially the practice) of free love.

  Another early recruit was Herman Muller, intellectually brilliant but with a prickly personality that sat awkwardly within the ‘one for all, all for one’ brotherhood of the Fly Room. Nursing a grudge against Morgan for not recognising his personal achievements, Muller stuck it out for a couple of years and then moved to Texas. This was the first step in a nomadic scientific journey which later criss-crossed the Atlantic and included well-timed escapes from both Berlin (Hitler) and Moscow (Stalin).

  Morgan somehow managed to combine work and family life, but others were less successful. Calvin Bridges’s daughter Betsey later described him as ‘a pretty strange fellow who found it difficult to detach himself from work’ and came home late for supper, with flies in his socks. She also provided an outsider’s view of the lab, recalled from a visit to this alien place at the age of ten: ‘dark, cluttered, claustrophobic, smelly’.

  Inside the cocoon of the Fly Room, such sentiments were irrelevant. ‘What mattered was to get ahead with work,’ wrote Bridges. Which they did, and with spectacular success.

  Changelings

  Mutations (literally, ‘changes’) had long been recognised in humans and in domesticated animals. Notable human examples included the ‘Habsburg lip’, a protruding lower jaw which had afflicted the eponymous aristocrats since the fifteenth century. Elsewhere, abnormalities of the fingers or toes – extra or missing digits or a ‘lobster claw’ – similarly appeared out of the blue and then became part of the family. Some mutations in animals were deliberately exploited by selective breeding, such as the short legs of both dachshund dogs and Ancom sheep, which allowed the former to get down burrows after badgers and prevented the latter from jumping to freedom over low walls.

  In Drosophila, mutations can affect all aspects of anatomy and physiology, but those studied by Morgan and his team concerned only the fly’s external appearance. Knocked out with a whiff of ether, flies could be scrutinised under the binocular microscope for tell-tale abnormalities which showed that a mutation had occurred. The normal (wild-type) Drosophila has a grey body with a smart black underside, bright red eyes and straight wings that fold neatly over its back. Some mutants have black or yellow bodies instead of grey; or eyes that are sepia
, pink, white or colourless; or wings that are smaller than normal (‘vestigial’ and ‘miniature’) or misshapen (‘crumpled’ and ‘forked’).

  Initially, Morgan simply kept a watching brief and waited for Mother Nature to produce mutations for him to study. This was a slow process. Two years into his research programme, a dejected Morgan was found standing in front of shelves stacked with humming milk-bottles, complaining that he had been wasting his time.

  Later, he nudged Mother Nature along by subjecting flies to adverse conditions – extreme temperatures, toxic chemicals, ultraviolet light and radiation emitted by radium – in the hope of inducing mutations. High-powered X-rays, pioneered by Herman Muller, proved the best of all and greatly increased both the rate (by over 150-fold) and variety of mutations. Scientific Monthly later provided a dramatic account of the ceiling-high X-ray tube that did the job in just three seconds: ‘A sharp hissing sound came faintly through the concrete and lead walls as a million-volt flame of electricity crashed across the spark gaps.’ Hundreds of new mutants were created by this Frankensteinesque procedure, including flies that had no eyes, or no wings, or two bodies, or a leg where an antenna should be. There was also a tragic counterpart to the dachshund dog; flies with the ‘dachs’ mutation had legs so short that they were unable to drink and died of dehydration.

  Morgan’s first success came in early 1910, when a male fly appeared from nowhere with white eyes that made it stand out clearly from its red-eyed fellows. The white-eyed fly had to compete with another new arrival – the Morgans’ first baby, recently delivered and still in hospital with his wife Lilian. Morgan gave it¶ his undivided attention; safe in its nursery jar, it went everywhere with him (even to bed) until it had passed through its week-long childhood and was ready to breed. Which it was happy to do, and with fascinating results. Strikingly, all its descendants that had white eyes were also male. Moreover, the proportion of white-eyed flies among the grandchildren of the white-eyed male crossed with a red-eyed female was 25 per cent – exactly the same as a recessive ‘element’ in Mendel’s pea experiments.

  This was both exciting and profoundly embarrassing for Morgan, the rabid anti-Mendelian. Here was sound evidence that Mendel’s ‘explanations’ also applied to animals. Even worse for a non-believer in chromosomes, the findings pointed firmly to a physical home for Mendel’s airy-fairy ‘elements’. As only males ever developed white eyes, the factor responsible must reside on the distinctive ‘X’ chromosome which determines maleness in Drosophila.

  The team quickly discovered further mutations – the underdeveloped ‘miniature’ wings and yellow body colour – that only affected males and were therefore also associated with the sex-determining chromosome. By contrast, other mutations (e.g. black body colour and ‘vestigial’ wings) were not ‘sex-linked’, indicating that they lay on different chromosomes. The compendium of mutations grew rapidly, from 12 in 1913, to 200 in 1915, and 500 just four years after that.

  Morgan’s team did much more than catalogue the oddities in their fly freak-show. They moved on from proving that a particular mutation involved just one chromosome, to pinning the mutation down to a specific physical location on that chromosome. They began by studying the co-inheritance of various mutations that only affected male flies, by carefully cross-breeding vast numbers of mutants and examining their children and grandchildren. Some combinations of mutations (e.g. white eyes and yellow body) were often inherited together, whereas others (e.g. ‘miniature’ wings) did not show any tendency to appear with these. Morgan and Sturtevant postulated that the mutations which were frequently co-inherited must be located close together on the same chromosome, whereas those that travelled separately must lie further away.

  Their stroke of genius was to turn the frequency with which particular genes were co-inherited into a measure of the distance which separated them. From these measurements, they began plotting the relative positions of mutations, like stations on a straight length of railway track, on each of the four chromosomes. The glory for this discovery belongs to Sturtevant, who came up with the idea and worked out a draft map during a heroic all-night brainstorming session. This was all the more amazing because he was a nineteen-year-old undergraduate who should have been finishing off an overdue student essay.

  Their first chromosomal ‘maps’ were rudimentary. In 1913, Sturtevant reported ‘the linear arrangement of six factors’ on the sex-determining chromosome. From there, they steadily accumulated a wealth of detail. This was where the tall, square-section wooden post (a Bridges invention) came in. Each side of the ‘Totem Pole’ represented one of the four chromosomes of Drosophila, and was marked with a vertical scale that corresponded to the length of the chromosome. When a new mutation was identified and its location found, a drawing-pin labelled with the mutation’s code was pushed into its place on the scale.

  By now, Morgan had executed a perfect, evidence-driven U-turn and had become an evangelist for Mendel and chromosomes. In January 1912, he admitted that chromosomes appeared to be ‘the bearers of the hereditary material’; in 1915, he publicly purged himself of his earlier sins in The Mechanism of Mendelian Heredity, written by himself, Sturtevant, Bridges and Muller. This landmark book rapidly assumed scriptural significance in the field.

  The achievements of the Fly Room were extraordinary. Morgan’s tools were the same as Mendel’s: a lens, to see more clearly; pen and paper; and an imagination that transported him to places where nobody had been before. His team’s chromosome blueprints were purely mathematical mind-maps, constructed by counting unusual external features in millions of flies. This work provided the first evidence that genes – their positions flagged up by mutations that caused a visible, phenotypic change – lay in a fixed linear sequence along the chromosomes, like beads on a string.

  And although Morgan never made any attempt to study these himself, his work helped to focus attention on the next big questions:

  What actually was a gene? And what was it made of?

  * These can be enjoyed (as ‘uni’) in good sushi restaurants.

  † The word ‘chromosome’ was not invented until 1887; Van Beneden used the term ‘anse chromatique’ (‘chromatin loop’).

  ‡ The urine was turned black by the precursor, which the metabolic blockage caused to accumulate.

  § In Greek, the name means ‘the dew-lover with the black belly’.

  ¶ The fly.

  6

  BAUSTEINE

  In 1900, everything had looked good for Protonuclein, the new wonder drug which – according to medical testimony – should have been able to save the life of Friedrich Miescher. It was selling briskly as tablets (100 for $1) or a powder (8 ounces for $7.50) which could be dusted on to wounds, rubbed into cancers, or puffed into diseased lungs with a special vaporiser ($1.50). The label on the distinctive amber bottle explained that Protonuclein was extracted from ‘mixed glands, particularly rich in nuclear material, including: thymus – thyroid – lymphatic – spleen – pineal – pituitary’. Purists might have been surprised to see the spleen described as a gland, but no matter.

  There seemed to be no end to its uses. It had worked ‘wonders’ for an unfortunate patient with liver cancer (‘thirteen cysts filled with material not unlike underdone tapioca and weighing 36 pounds’). Dr D.W. Boone of Bellaire, Ohio, reported ‘perfect results’ in a subject with impotence, but declined to identify the beneficiary. Another miraculous action was discovered by accident when Protonuclein was given to pep up patients judged unlikely to survive surgery. ‘In this way,’ an anonymous doctor wrote cryptically, ‘I learned the power of Protonuclein as an aphrodisiac.’

  In Europe, substances from the cell’s nucleus had a less excitable following. There was complete silence from Basel. The sealed glass tubes labelled ‘Nuclein’ in Miescher’s handwriting lay forgotten in a neglected corner of his former laboratory. He believed to the end that nuclein was a substance of no importance, and his research died with him. Nuclein was the most
tragic casualty of the ‘obstructing and weakening factors’ which wrecked Miescher’s career. Even as his interest and energy shrivelled away, his first and greatest discovery slipped through his fingers and into the hands of others. And before long, nuclein had won a Nobel Prize for someone else.

  Down to basics

  Albrecht Kossel was born in 1853, nine years after Miescher, in the Hanseatic port of Rostock. Throughout his life, he remained proud of his birthplace, and the Baltic coast of northern Germany never lost its magnetism for him. Kossel’s early career could almost have been a replay of Miescher’s. He graduated in medicine from Rostock in 1877 but never practised as a doctor; having fallen under the spell of a charismatic teacher during his initial medical training in Strasbourg, he went straight into the laboratory to dedicate himself to physiological chemistry. The man who knocked Kossel off course was the ever-energetic Felix Hoppe-Seyler, who had stormed into the Chair of Chemistry in Strasbourg a few years earlier.

  Hoppe-Seyler set the new graduate to work on the peculiar substance which had been discovered nearly a decade earlier by that promising young student in Tübingen. Kossel’s first year as apprentice to the biochemical sorcerer produced an eye-catching paper and hinted at a glittering future. This was where the careers of Hoppe-Seyler’s two bright prospects began to diverge. Miescher had burned himself out, but Kossel went from strength to strength.

  Kossel’s first big paper (1878) reported a finding which was striking enough at the time, but whose full significance would not be appreciated for half a century. He managed to extract nuclein, not from pus cells or salmon testes but from yeast, an organism only slightly more sophisticated than bacteria. At first, it was assumed that ‘yeast nuclein’ was identical to that in animal tissues, but Kossel would later show that it was subtly and crucially different.