Unravelling the Double Helix Read online

  Miescher, Friedrich (1844–1895)

  Swiss doctor forced into biochemistry because deafness prevented him from practising as a clinician. In 1868, discovered a novel substance in extracts of white blood cells harvested from pus-soaked bandages. Miescher showed that the substance was acidic, rich in phosphorus and came from the nucleus – hence his name ‘nuclein’ – but argued that it played no role in heredity. Nuclein was later renamed ‘thymonucleic acid’ and then deoxyribonucleic acid (DNA).

  Mirsky, Alfred (1900–74)

  American biochemist and world expert on nucleic acids. Isolated ‘chromosin’ from cell nuclei, as white fibres that could be wound around a rod like candy floss, and showed that it consisted of DNA associated with protein. Mirsky was convinced that genes could only be made of protein and dedicated himself to attacking the evidence from Avery and others that DNA was the genetic material.

  Morgan, Thomas Hunt (1866–1945)

  American zoologist and geneticist, initially sceptical about Mendel’s findings and the role of chromosomes, but was converted by his own experiments on the inheritance of mutations in the fruit fly, Drosophila. Led research in the Fly Room at Columbia University, New York; co-wrote The Mechanism of Mendelian Inheritance (1915) and won the first Nobel Prize for genetics (1933).

  Pauling, Linus (1901–94)

  American chemist, peace activist, polymath and showman of whom it was said: ‘His name will be remembered for as long as there is a science of chemistry.’ Wrote the bestselling The Nature of the Chemical Bond (1939) and described the alpha-helix, which determines the shape of proteins; also suggested a woefully erroneous structure for DNA (1952). Won Nobel Prizes for Chemistry (1954) and Peace (1962).

  Randall, John (1905–84)

  English physicist and lead inventor of the cavity magnetron, a revolutionary radar component which was decisive in winning air and sea campaigns during the Second World War. Founded (1946) and led the Biophysics Unit at King’s College, London, where Maurice Wilkins (his former PhD student) and Rosalind Franklin worked independently on the structure of DNA. Randall’s management style was described as ‘Napoleonic’ and ‘divide and conquer’, and was instrumental in preventing Wilkins and Franklin from collaborating.

  Sutton, Walter (1877–1916)

  American surgeon who did a PhD on cell division in the grasshopper, before giving up genetic research for clinical practice. Formulated the ‘Chromosome Theory of Heredity’, postulating that the hereditary ‘factors’ identified by Mendel are situated on the chromosomes.

  Vavilov, Nikolai (1887–1943)

  Russian botanist and geneticist, regarded internationally as one of Russia’s greatest scientists. Famous for his work on the genetics of wheat and his attempts to improve wheat yields using Mendelian principles. Fell foul of Trofim Lysenko, third-rate researcher and top-class political animal, who detested Mendelism and classic genetics. In 1940, Vavilov was arrested during a plant-collecting trip; his fate was not known until after the war.

  Watson, James D. (Jim) (born 1928)

  Child prodigy, with encyclopaedic knowledge of ornithology; went to university aged 15 and was awarded his PhD at 23. Inspired to understand the gene by reading What is Life? by Erwin Shrödinger, and to crack the structure of DNA by hearing Maurice Wilkins talk about the crystalline nature of DNA. On moving to the Cavendish Laboratory, Cambridge in 1951, persuaded Francis Crick to focus on solving the structure of DNA. Watson spotted the crucial linkages that hold together the bases in the two strands of DNA, which led directly to the structure of the double helix. Shared the Nobel Prize (1962) with Crick and Wilkins, and wrote his controversial personal account, The Double Helix (1968).

  Wilkins, Maurice (1916–2004)

  English physicist and contemporary of Francis Crick. After war work on radar screens (as John Randall’s PhD student) and the atom bomb, became Randall’s deputy in the Biophysics Unit at King’s. Studied DNA as fibres and in the heads of spermatozoa, using optical methods and X-ray diffraction. Wilkins’s description of crystalline DNA galvanised Jim Watson to crack the structure of the molecule. Wilkins shared the Nobel Prize (1962) with Watson and Crick – but were his publishers right to subtitle his autobiography ‘The Third Man of the Double Helix’?

  PREFACE

  Not another one

  It is never good practice to begin with a confession, but I have to admit that I’m not the first to have come up with this idea. You could easily fill a six-foot shelf with books about DNA, including a bestseller or two. So why should you bother to accompany me down such a heavily trodden road?

  I could try to tempt you with the ‘unique selling points’ to which publishers attach much importance. It is true that there isn’t anything quite like this book out there already. This is not so much a history of research into a molecule as the stories of the people who became entangled with it and who were variously enthralled, seduced or infuriated. The book’s focus – the first eighty-five years of DNA – is also unusual, because it ends with the discovery of the double helix. The famous paper by Watson and Crick stormed into the scientific firmament a decade before the year in which (if we can believe Philip Larkin) sexual intercourse began. This means that DNA was born in 1868, much earlier than I (and possibly you) had suspected. The elucidation of the double helix was one of the most brilliant gems of twentieth-century science, but this was just one episode in a long, grumbling crescendo of discovery; to ignore everything that went before is as irrational as prising the flashiest diamond out of the Crown Jewels and turning your back on the rest.

  In case you are wondering how and why this book came to be written, I can reveal that it was the result of ignorance, curiosity and a couple of chance encounters. Like everyone else, I assumed that I knew the history of DNA. I was given a copy of James Watson’s The Double Helix at an impressionable age, and it pitched me straight into a grandstand seat at one of the greatest scientific shows of the century. It was a page-turner with a gripping storyline, written by a real Nobel laureate, and I absorbed every atom of it: the two young heroes locked into a winner-takes-all race for the glittering prize; a villain of sorts (the ferociously bright but prickly ‘Rosy’ Franklin); and some treachery with a hint of espionage. There were glimpses of what makes a great scientist tick: long summer days in Cambridge were filled with tennis, parties and pretty girls, but at night Watson dreamed of molecular structures. He told his story with a mixture of nonchalance and breathless excitement and ended by announcing that, having reached his twenty-fifth birthday, he was now ‘too old to be unusual’.

  I was only a few years younger than Watson had been when I went up to Clare College, Cambridge in the autumn of 1971 to begin studying medicine. My copy of The Double Helix came with me, perhaps in the hope that it would connect me with the brilliance and excitement which permeated Watson’s Cambridge. The double helix still cast its shadow, eighteen years after the event. Watson had been a research fellow at Clare; the Cavendish Laboratory, where it all happened, was on the way to the dissection room in Anatomy; and close by was the Eagle, the pub where Crick burst in one lunchtime and told everyone that he and Watson had discovered the secret of life.

  But a surprise was waiting for me later in my first term, over tea with Dorothy Strangeways, an old family friend. Dorothy was Cambridge and academia personified: ex-Newnham College, onetime tissue-culture researcher, and a no-nonsense spinster who would not have minded in the least being called a bluestocking. She had mellowed in retirement and was entirely benign until I mentioned the source of my inspiration. ‘That dreadful book!’ she snapped. ‘That man should never have written it, and they should never have published it.’

  I was both taken back and intrigued, but she firmly diverted the conversation on to something else. The topic never came up again, and I had long since forgotten the episode when, fourteen years later, I heard that Dorothy had died. Then, thirty years after that, I ran into Watson, Crick and Franklin again while researching a book about
the history of polio. I was surprised to learn that they had all worked on the structure of viruses; Franklin’s last papers, published posthumously, were on the crystallography of the poliovirus.

  Meeting these familiar characters out of context made me look at them with fresh eyes. I reread The Double Helix for the first time since 1971 – and wished that I had pressed Dorothy Strangeways to tell me more. The autobiographies of Francis Crick and Maurice Wilkins (‘The third man of the double helix’) were less outrageous, but still appeared one-sided. A tragically early death robbed Rosalind Franklin of the chance to finish the papers sitting on her desk, let alone begin her autobiography, but others tried to write her story for her – and to erase the memory of the frumpy, toxic ‘Rosy’ portrayed by Watson in The Double Helix. It was obvious that deep passions had been stirred up, leaving these fascinating waters well and truly muddied.

  When I tried to find out where the double helix itself had come from, I quickly realised how ignorant I was. The first eighty-five years of DNA witnessed the births of the Nobel Prizes, antibiotics, X-ray crystallography, radar and the atom bomb, not forgetting two devastating world wars. These events, strung along the narrative thread of DNA like beads on a necklace, are not chosen at random. Each of them moulded the story of DNA to some degree.

  To my embarrassment, I also discovered that I knew little or nothing about many of the scientists whose work had filled those eighty-five years and who paved the way for the elucidation of the double helix. In my defence, they barely figured, if at all, in most of the classic books on DNA. What had happened to them? Some were airbrushed out of the historical record because, as one eminent historian explained, everything that happened before 1900 was irrelevant to the ‘clear knowledge’ of the twentieth century. Others were plunged into darkness when the spotlight swung on to Watson, Crick, Wilkins and Franklin. And sadly, ancestor worship has fallen out of fashion. Newton acknowledged that he had seen further only by standing on the shoulders of giants, but few modern researchers are gracious enough to pay their respects to those who have gone before.

  Some of those neglected giants were the true pioneers of DNA. They cut into the forest of the unknown at times when the little clearings of knowledge were few and far between, carving a trail which those who came later simply took for granted. Watson, Crick and their peers solved a magnificent mystery, but they were in the uniquely privileged position of being able to click into place the last few pieces of a gigantic puzzle that their predecessors had taken several decades to assemble.

  As you already know the end of this saga, is it worth reading on? If you do, you will find a story that is well stocked with heroes and villains, beautiful science and ghastly mistakes. Just as spectacular as the giant leaps of inspiration are the bellyflops, some of them beautifully executed by world leaders in their field. And this is science in the raw, featuring researchers in their natural habitat and displaying their characteristic behaviours. Some conduct themselves with absolute integrity, while others may remind you more of Machiavelli than St Francis. You may find it hard to label particular cases as ‘hero’ or ‘villain’, and your verdict may change as the plot evolves. On occasions, you will see the process of scientific endeavour at its most noble; at other times, it degenerates into a rat-race with some notable rats. Some of the latter may be on a par with the polio vaccine pioneers who were described as (I quote) ‘real bastards’, and you may find yourself speculating that there are genes, tentatively called BRILLIANT and BASTARD, which lie so close together in the human genome that they tend to be inherited as a job lot.

  You will also be taken to places you might not have expected. Soho, London, where a microscopist has broken off from studying the sex life of orchids to prise out of a living plant cell a tiny, lens-shaped structure that he calls the ‘nucleus’. A sanatorium high in the Swiss Alps, where the man who started it all has gone to die – oblivious of sensational reports in America’s top medical journal that the substance he discovered can cure the disease which is killing him. A torchlit procession of students and academics, winding through the streets of Heidelberg to welcome home their professor, returning from Stockholm with his Nobel Prize. A laboratory in New York, where a brilliant new treatment for the dreaded infection known as ‘The Captain of the Men of Death’ has come just too late. ‘Site X’ and a team of American and British physicists working flat out on ‘49’, where ‘X’ = Berkeley, California, and ‘49’ = plutonium for the atom bomb. And a surprising treasure from the archives, but not in London or Cambridge: an X-ray photograph showing the bold black cross which proved that DNA was a helix – taken a year before Rosalind Franklin’s famous ‘Photograph 51’ and by someone I had never heard of.

  So here it is: the story of DNA and its lost heroes, as I never would have envisaged it. It’s a powerful story, and putting it together has been fun, exciting, thought-provoking and moving. I hope that I’ve managed to translate all that into the good read which it deserves to be.

  1

  REWIND

  Case No. 1. There was no mystery about the cause of death – a bullet-hole in the back of the skull – or when this nineteen-year-old male had died. Together with his brother and father, he was among the 8,100 Muslim men and boys murdered by Serbian soldiers when they swept into the Eastern Bosnian town of Srebrenica on 11 July 1995.

  The young man had spent most of the intervening years packed into a mass grave with several hundred other corpses. When his remains were unearthed, his skeleton was reassembled and a small block of bone, sawn out of his right femur, was sent away for genetic testing. The analysis threw up a close match with another skeleton from the same burial pit, and with one of the 100,000 blood samples provided by surviving relatives of the massacre victims.

  A few months later, on the nineteenth anniversary of the atrocity, their mother laid her two sons to rest. She buried them alongside her husband, whose bones had been identified from a different grave a decade earlier.

  Case No. 2. This twenty-five-year-old woman with a strong family history of breast cancer attended the Genetic Counselling clinic with her husband. They had come to find out the results of her recent screening test. The doctor explained that she had a point mutation in a gene called BRCA1. She wanted to know what that meant, so he spelled it out for her. It was a change so small that it could be easily overlooked: just a single typographical error in the genetic code near the start of the gene. However, it had implications. After further discussion, she went home to think it all through.

  When she returned a few days later, she told the doctor that she had decided to undergo surgery to remove both breasts.

  Case No. 3. Another mass burial site filled in haste, but this time in England. Most of the 188 individuals in the three plague pits near Hereford Cathedral were children between five and fifteen years of age. They had died in late spring 1349, when the Black Death had already killed half of the population of mainland Europe and was approaching its peak in Britain.

  Analysis of material sampled from the teeth of several skeletons in Plague Pit 2 showed DNA fragments which matched the sequence of Yersinia pestis, the bacterium which causes bubonic plague.

  Case No. 4. The egg was one of a clutch collected from a nest beside a dry stream bed in the Xixia Basin of Henan Province, central China. Even though the egg was somewhat past its best-by date, samples of its contents revealed DNA fragments in good enough condition to be analysed.

  The DNA sequences were published, to great excitement, as the first glimpses into the genetic makeup of the egg-laying dinosaurs which had slipped into extinction over 65 million years ago.

  These four cases illustrate, in various ways, the immense power wielded by a mere molecule: deoxyribonucleic acid, or DNA. ‘It’s in my DNA’ has entered the vernacular. We take for granted the scientific credo of the ‘genetic code’, namely that the millions of instructions which create life and enable it to be passed on to successive generations are engraved into the structure of this molecu
le.

  DNA technology is something else that we believe in. Devilishly clever techniques, now so commonplace that they have been robbed of their magic, can amplify an unimaginably tiny amount of DNA, deduce its sequence and match this against a vast library of reference samples. As a result, a nearly invisible skein of cells swabbed off the inside of your cheek can determine whether or not you fathered your child, or committed a crime half a century ago, or are descended from Genghis Khan. The DNA fingerprinting techniques used in Case 1 have also helped to give names and identities to unknown soldiers from First World War battlefields; to work out the ancestry of Ötzi, the Bronze Age hunter-gatherer who died high in the Italian Alps over 5,000 years ago; and to track the extent of interbreeding between Neanderthals and Homo sapiens some 60,000 years before that.

  Cases 3 and 4 remind us that DNA underpins the existence of all living organisms, except for those viruses (which anyway are not strictly ‘alive’) that are based on DNA’s close relative, ribonucleic acid (RNA). As well as clinching a bacteriological diagnosis over 650 years post-mortem, Case 3 highlights the extraordinary longevity of DNA. Like the Dead Sea Scrolls, fragments of the molecule can persist in a readable form for millennia, and possibly for tens of millennia.

  However, all good things come to an end. DNA cannot survive for millions of years, which unfortunately means that cloned dinosaurs are forever doomed to roam the landscapes of the imagination. It also means that the ‘ancient DNA’ extracted from the fossilised dinosaur egg must have come from somewhere else. On more careful analysis, it turned out to belong to less exotic species, including fungi, flies and man. When DNA is amplified millions of times in the laboratory, artefacts are embarrassingly easy to create; submicroscopic traces of contaminants – a single fungal spore, a defecating fly, a flake or two of dandruff – will quickly push molecular palaeobiology into the realm of wishful thinking. Case 4 nicely illustrates the dangers of allowing DNA to abuse its power.