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REWIND
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 molecule.
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.
Case 2, the young woman with a high-risk mutation in BRCA1, the commonest gene determining inherited breast cancer, shows us how the DNA revolution has transformed medical genetics – and how far we still have to go. Harmful mutations can now be detected and pinpointed with exquisite precision: for example, the young woman’s mutation is a single-letter switch affecting the 5,325th ‘base’ (a letter in the genetic code) of the BRCA1 gene, which is 125,951 bases in length and begins at base 43,044,295 of chromosome 17. As well as giving prognostic information, molecular genetics can bring hope. In some conditions, it is possible to work out how the abnormal protein generated by the mutated gene does harm, and to design new drugs to correct the defect. So far, though, that dream has been translated into therapeutic reality for only a few diseases, which do not include hereditary breast cancer.
The young woman’s predicament also draws our attention to an achievement for which conventional superlatives are inadequate: the letter-by-letter deciphering of the entire DNA sequence (genome) of Homo sapiens, which runs to 3.24 billion bases. Our DNA is chopped into different lengths and crammed into our forty-six chromosomes. This is an extraordinary feat of packing. A total length of around three metres of DNA is somehow coiled up and squashed small enough to squeeze into the nucleus of a single cell – and in a way that still allows the ever-busy units of cellular machinery to dive inside the tangle and lock on to the genes of the moment.
If the DNA is unpacked from the nucleus and all those coils are ironed out, the molecule is still left with a purposeful twist. It is a thing of beauty: two graceful spirals that track each other perfectly, always precisely the same distance apart, as they wind around an invisible long axis. This is the fabled double helix, to which the names of Watson and Crick are attached as intuitively as E = mc2 goes with Einstein, and tonic with gin.
And it can only sound like a cliché, but this structure holds the key to the whole of life and heredity.
The double helix: a brief interactive tour
The DNA molecule looks like an architecturally implausible stairway to heaven. It certainly goes up a long way. Scaled up to the width of a spiral staircase in a medieval turret – such as in the castle where it was discovered – the DNA from the nucleus of a single cell would stretch for over 3 million kilometres, or eight times the distance to the dark side of the moon.
This is too early in the book to start delving into the bowels of molecular genetics, but a gentle stroll down a short stretch of the human genome will help to set the scene. First find chromosome 17 and walk along it until you reach base number 43,044,295, then chop out the section that begins here and ends 125,951 bases further on. You may recall that this is the inherited breast cancer gene, BRCA1. Enlarge the sequence until it is as wide as a medieval spiral staircase, stand it on its end and look at how the whole thing is put together (Figure 1.1).
You will notice immediately that the two spirals running parallel to each other are graceful but unexciting. They are both made of the same two components, joined together and repeated ad infinitum: a chemical group called ‘phosphate’ because it is dominated by a phosphorus atom, and a small sugar molecule (deoxyribose) which gives DNA (deoxyribonucleic acid) its name. The monotonous structure of the spirals could not possibly be eloquent enough to make the genetic code, which somehow has to contain enough letters to write the instructions for making millions of different molecules. In fact, the spirals are purely structural, each acting as a backbone that keeps its helix in shape.
The magic of the double helix lies in the constant interval that separates the two spiral backbones. With the molecule standing vertically, you will see that the gap is bridged by horizontal steps set at regular intervals, with ten steps to each complete turn of the staircase. A careful look will show that all the steps share a common design, but that you cannot predict exactly how a particular step will be constructed. Every step is made up of two different halves, each rooted firmly on its spiral backbone, joined together in the middle. You will soon realise that there are only four different half-steps, and that two are long and two are short. To maintain a constant distance between the spiral backbones, all the steps must be the same length. This can only be achieved by making each step from one short and one long half-step; a step made of two shorts or two longs would make the elegant spirals buckle or bulge, and would wreck the beauty and functionality of the double helix.
Figure 1.1 The DNA molecule, pictured as a spiral staircase, with and without the ‘backbone’. Right: the four possible steps; A and T always go together, as do C and G.
Working your way through a larger sample of steps – as many as you care to examine – will show that the construction of each step is unpredictable but not entirely random. This is because the molecule always obeys a simple rule: each of the two short half-steps can only be joined to a specific long one. If we designate (not quite arbitrarily) the short half-steps C and T and the long ones A and G, then an A is always connected to a T, and a G to a C.
This rule means that if you can only see the half-steps attached to one of the spiral backbones, you can predict with absolute certainty the ones which are joined to the opposite backbone and form the other half of each step. For example, if the sequence of half-steps on one side was C, then A, T and finally G, then the corresponding half-steps on the other side can only have been G, T, A and C, in that order. The half-steps are the flat, geometric molecules called ‘bases’; the inviolable rule that C goes with G and A with T is therefore called ‘base-pairing’. The discovery of this phenomenon was judged significant enough to win a Nobel Prize; this seems reasonable, because it underpins the genetic mechanisms that make each of us what we are.
While digesting that, you can make a closer inspection of the BRCA1 gene. Go to the very top and stand on the highest step. If you’re bad with heights, don’t look down: the bottom is over 67 kilometres below you. Now set off down the staircase, at a steady pace of one step each second. It’s not a comfortable walk, with a drop of over 30 cm from one step to the next, and it will take about 35 hours to reach the bottom. If you start at 9 a.m., then at 45 seconds after 10.28 that morning, you will land on the 5,325th step from the top. The half-step attached to the spiral backbone on your left will be an A, because this is the version of BRCA1 that belongs to lucky people. In the case of the young woman waiting nervously to hear the verdict handed down to her in the Genetic Counselling clinic, that A was a G. That is the only difference between lucky and unlucky; every one of the other 125,950 steps is identical.
Blockbuster
That moment is captured, carefully posed in 1950s monochrome, in the familiar photograph of the two pioneers and their discovery (see Figure 24.3). Francis Crick, still youthful but already balding, stands on the right, pointing at their model of the double helix with a slide-rule, extended as if in mid-calculation. Seated opposite is Jim Watson, gawky and shockingly young, gazing up at their handiwork with his mouth open as though the photographer had told him to look awestruck at what they’d created. And the spidery metal contraption standing on the laboratory bench between them is what lined them up for their Nobel Prize and their places at the top table reserved for the greatest scientists of all time.
The events leading to that photograph and the Nature paper were triggered by Watson making a connection that everyone else had missed. He spotted how the two kinds of base – one short, one long – could reach across the gap between the two spiral backbones and click together to make one of those horizontal steps. Many people would regard this stroke of genius as the greatest discovery in the history of DNA. But it is also a wonderful example of chance favouring the prepared mind and, in this case, virtually all the preparation of Watson’s precociously brilliant brain had been done by other people. Not just the person who showed him ‘Photograph 51’ with its tell-tale helical pattern, or who corrected his calculations for fitting the bases together, but all those who had worked out the basic chemistry of DNA or pursued the outrageous notion that it might play a role in heredity.
Compare that with the revelation that fell like a bolt from the blue into a mind that was totally unprepared, because this was the very beginning and, as with the Big Bang, nothing existed before this moment.
The story of DNA opens with a bright young man of around Jim Watson’s age who also happened to work in a university city with medieval buildings overlooking a picturesque river. At that point, any resemblance ends. This young man’s experimental facilities are grim, mainly because he likes it that way; in our fussier age, his laboratory would have been shut down by the European Agency for Safety and Health at Work because of multiple infringements of Directive 89/684/EEC.
And his starting material, which spawned the whole saga of DNA, is even less wholesome: heavily soiled, stinking clinical waste that nowadays would go straight into the incinerator.