Читать книгу Genome: The Autobiography of a Species in 23 Chapters - Matt Ridley, Matt Ridley - Страница 10

We’ve discovered the secret of life.

Francis Crick, 28 February 1953

Though he was only forty-five in 1902, Archibald Garrod was already a pillar of the British medical establishment. He was the son of a knighted professor, the famous Sir Alfred Baring Garrod, whose treatise on that most quintessential of upper-class afflictions, gout, was reckoned a triumph of medical research. His own career was effortlessly distinguished and in due course the inevitable knighthood (for medical work in Malta during the First World War) would be followed by one of the most glittering prizes of all: the Regius professorship of medicine at Oxford in succession to the great Sir William Osler.

You can just picture him, can you not? The sort of crusty and ceremonious Edwardian who stood in the way of scientific progress, stiff in collar, stiff in lip and stiff in mind. You would be wrong. In that year, 1902, Archibald Garrod risked a conjecture that would reveal him to be a man far ahead of his time and somebody who had all but unknowingly put his finger on the answer to the greatest biological mystery of all time: what is a gene? Indeed, so brilliant was his understanding of the gene that he would be long dead before anybody got the point of what he was saying: that a gene was a recipe for a single chemical. What is more, he thought he had found one.

In his work at St Bartholomew’s Hospital and Great Ormond Street in London, Garrod had come across a number of patients with a rare and not very serious disease, known as alkaptonuria. Among other more uncomfortable symptoms such as arthritis, their urine and the ear wax turned reddish or inky black on exposure to the air, depending on what they had been eating. In 1901, the parents of one of these patients, a little boy, had a fifth child who also had the affliction. That set Garrod to thinking about whether the problem ran in families. He noticed that the two children’s parents were first cousins. So he went back and re-examined the other cases: three of the four families were first-cousin marriages, and of the seventeen alkaptonuria cases he saw, eight were second cousins of each other. But the affliction was not simply passed on from parent to child. Most sufferers had normal children, but the disease could reappear later in their descendants. Luckily, Garrod was abreast of the latest biological thinking. His friend William Bateson was one of those who was excited by the rediscovery just two years before of the experiments of Gregor Mendel, and was writing tomes to popularise and defend the new creed of Mendelism, so Garrod knew he was dealing with a Mendelian recessive – a character that could be carried by one generation but would only be expressed if inherited from both parents. He even used Mendel’s botanical terminology, calling such people ‘chemical sports’.

This gave Garrod an idea. Perhaps, he thought, the reason that the disease only appeared in those with a double inheritance was because something was missing. Being well versed not only in genetics but also in chemistry, he knew that the black urine and ear wax was caused by a build-up of a substance called homogentisate. Homogentisate might be a normal product of the body’s chemistry set, but one that was in most people then broken down and disposed of. The reason for the build-up, Garrod supposed, was because the catalyst that was meant to be breaking down the homogentisate was not working. That catalyst, he thought, must be an enzyme made of protein, and must be the sole product of an inherited factor (or gene, as we would now say). In the afflicted people, the gene produced a defective enzyme; in the carriers this did not matter because the gene inherited from the other parent could compensate.

Thus was born Garrod’s bold hypothesis of the ‘inborn errors of metabolism’, with its far-reaching assumption that genes were there to produce chemical catalysts, one gene to each highly specialised catalyst. Perhaps that was what genes were: devices for making proteins. ‘Inborn errors of metabolism’, Garrod wrote, ‘are due to the failure of a step in the metabolic sequence due to loss or malfunction of an enzyme.’ Since enzymes are made of protein, they must be the ‘seat of chemical individuality’. Garrod’s book, published in 1909, was widely and positively reviewed, but his reviewers comprehensively missed the point. They thought he was talking about rare diseases, not something fundamental to all life. The Garrod theory lay neglected for thirty-five years and had to be rediscovered afresh. By then, genetics was exploding with new ideas and Garrod had been dead for a decade.¹

We now know that the main purpose of genes is to store the recipe for making proteins. It is proteins that do almost every chemical, structural and regulatory thing that is done in the body: they generate energy, fight infection, digest food, form hair, carry oxygen and so on and on. Every single protein in the body is made from a gene by a translation of the genetic code. The same is not quite true in reverse: there are genes, which are never translated into protein, such as the ribosomal-RNA gene of chromosome 1, but even that is involved in making other proteins. Garrod’s conjecture is basically correct: what we inherit from our parents is a gigantic list of recipes for making proteins and for making protein-making machines – and little more.

Garrod’s contemporaries may have missed his point, but at least they honoured him. The same could not be said of the man on whose shoulders he stood, Gregor Mendel. You could hardly imagine a more different background from Garrod’s than Mendel’s. Christened Johann Mendel, he was born in the tiny village of Heinzendorf (now Hynöice) in Northern Moravia in 1822. His father, Anton, was a smallholder who paid his rent in work for his landlord; his health and livelihood were shattered by a falling tree when Johann was sixteen and doing well at the grammar school in Troppau. Anton sold the farm to his son-in-law so he could afford the fees for his son at school and then at university in Olmütz. But it was a struggle and Johann needed a wealthier sponsor, so he became an Augustinian friar, taking the name Brother Gregor. He trundled through theological college in Brünn (now Brno) and emerged a priest. He did a stint as a parish priest, but it was not a success. He tried to become a science teacher after studying at Vienna University, but failed the examination.

Back to Brünn he went, a thirty-one-year-old nonentity, fit only for monastic life. He was good at mathematics and chess playing, had a decent head for figures and possessed a cheerful disposition. He was also a passionate gardener, having learnt from his father how to graft and breed fruit trees. It is here, in the folk knowledge of the peasant culture, that the roots of his insight truly lay. The rudiments of particulate inheritance were dimly understood already by the breeders of cattle and apples, but nobody was being systematic. ‘Not one [experiment]’, wrote Mendel, ‘has been carried out to such an extent and in such a way as to make it possible to determine the number of different forms with certainty according to their separate generations, or definitely to ascertain their statistical relations.’ You can hear the audience dozing off already.

So Father Mendel, aged thirty-four, started a series of experiments on peas in the monastery gardens that were to last eight years, involve the planting of over 30,000 different plants – 6,000 in 1860 alone – and eventually change the world forever. Afterwards, he knew what he had done, and published it clearly in the proceedings of the Brünn society for the study of natural science, a journal that found its way to all the best libraries. But recognition never came and Mendel gradually lost interest in the gardens as he rose to become the abbot of Brünn, a kindly, busy and maybe not very pious friar (good food gets more mention in his writing than God). His last years were taken up with an increasingly bitter and lonely campaign against a new tax levied on monasteries by the government, Mendel being the last abbot to pay it. Perhaps his greatest claim to fame, he might have reflected in old age, was that he made Leos Janáček, a talented nineteen-year-old boy in the choir school, the choirmaster of Brünn.

In the garden, Mendel had been hybridising: crossing different varieties of pea plant. But this was no amateur gardener playing at science; this was a massive, systematic and carefully thought-out experiment. Mendel chose seven pairs of varieties of peas to cross. He crossed round-seeded peas with wrinkled ones; yellow cotyledons with green ones; inflated seed pods with wrinkled seed pods; grey seed coats with white seed coats; green unripe pods with yellow unripe pods; axial flowers with terminal flowers; tall stems with dwarf stems. How many more he tried we do not know; all of these not only breed true, but are due to single genes so he must have chosen them knowing already from preliminary work what result to expect. In every case, the resulting hybrids were always like just one parent. The other parent’s essence seemed to have vanished. But it had not: Mendel allowed the hybrids to self-fertilise and the essence of the missing grandparent reappeared intact in roughly one-quarter of the cases. He counted and counted – 19,959 plants in the second generation, with the dominant characters outnumbering the recessives by 14,949 to 5,010, or 2.98 to 1. It was, as Sir Ronald Fisher pointed out in the next century, too suspiciously close to a ratio of three. Mendel, remember, was good at mathematics and he knew well before the experiments were over what equation his peas were obeying.²

Like a man possessed, Mendel turned from peas to fuschias, maize and other plants. He found the same results. He knew that he had discovered something profound about heredity: characteristics do not mix. There is something hard, indivisible, quantum and particulate at the heart of inheritance. There is no mingling of fluids, no blending of blood; there is instead a temporary joining together of lots of little marbles. In retrospect, this was obvious all along. How else could people account for the fact that a family might contain a child with blue eyes and a child with brown? Darwin, who none the less based his theory on blending inheritance, hinted at the problem several times. ‘I have lately been inclined to speculate’, he wrote to Huxley in 1857, ‘very crudely and indistinctly, that propagation by true fertilisation will turn out to be a sort of mixture, and not true fusion, of two distinct individuals…I can understand on no other view the way in which crossed forms go back to so large an extent to ancestral forms.’³

Darwin was not a little nervous on the subject. He had recently come under attack from a fierce Scottish professor of engineering, strangely named Fleeming Jenkin, who had pointed out the simple and unassailable fact that natural selection and blending inheritance did not mix. If heredity consisted of blended fluids, then Darwin’s theory probably would not work, because each new and advantageous change would be lost in the general dilution of descent. Jenkin illustrated his point with the story of a white man attempting to convert an island of black people to whiteness merely by breeding with them. His white blood would soon be diluted to insignificance. In his heart Darwin knew Jenkin was right, and even the usually ferocious Thomas Henry Huxley was silenced by Jenkin’s argument, but Darwin also knew that his own theory was right. He could not square the two. If only he had read Mendel.

Many things are obvious in retrospect, but still take a flash of genius to become plain. Mendel’s achievement was to reveal that the only reason most inheritance seems to be a blend is because it involves more than one particle. In the early nineteenth century John Dalton had proved that water was actually made up of billions of hard, irreducible little things called atoms and had defeated the rival continuity theorists. So now Mendel had proved the atomic theory of biology. The atoms of biology might have been called all sorts of things: among the names used in the first years of this century were factor, gemmule, plastidule, pangene, biophor, id and idant. But it was ‘gene’ that stuck.

For four years, starting in 1866, Mendel sent his papers and his ideas to Karl-Wilhelm Nägeli, professor of botany in Munich. With increasing boldness he tried to point out the significance of what he had found. For four years Nägeli missed the point. He wrote back to the persistent monk polite but patronising letters, and told him to try breeding hawkweed. He could not have given more mischievous advice if he tried: hawkweed is apomictic, that is it needs pollen to breed but does not incorporate the genes of the pollinating partner, so cross-breeding experiments give strange results. After struggling with hawkweed Mendel gave up and turned to bees. The results of his extensive experiments on the breeding of bees have never been found. Did he discover their strange ‘haplodiploid’ genetics?

Nägeli meanwhile published an immense treatise on heredity that not only failed to mention Mendel’s discovery; it also gave a perfect example of it from Nägeli’s own work – and still missed the point. Nägeli knew that if you crossed an angora cat with another breed, the angora coat disappeared completely in the next generation, but re-emerged intact in the kittens of the third generation. A clearer example of a Mendelian recessive could hardly be found.

Yet even in his lifetime Mendel came tantalisingly close to full recognition. Charles Darwin, normally so diligent at gleaning ideas from the work of others, even recommended to a friend a book, by W. O. Focke, that contained fourteen different references to Mendel’s paper. Yet he seems not to have noticed them himself. Mendel’s fate was to be rediscovered, in 1900, long after his own and Darwin’s deaths. It happened almost simultaneously in three different places. Each of his rediscoverers – Hugo de Vries, Carl Correns and Erich von Tschermak, all botanists – had laboriously duplicated Mendel’s work on different species before he found Mendel’s paper.

Mendelism took biology by surprise. Nothing about evolutionary theory demanded that heredity should come in lumps. Indeed, the notion seemed to undermine everything that Darwin had strived to establish. Darwin said that evolution was the accumulation of slight and random changes through selection. If genes were hard things that could emerge intact from a generation in hiding, then how could they change gradually or subtly? In many ways, the early twentieth century saw the triumph of Mendelism over Darwinism. William Bateson expressed the views of many when he hinted that particulate inheritance at least put limits on the power of natural selection. Bateson was a man with a muddled mind and a leaden prose style. He believed that evolution occurred in large leaps from one form to another leaving no intermediates. In pursuit of this eccentric notion, he had published a book in 1894 arguing that inheritance was particulate and had been furiously attacked by ‘true’ Darwinists ever since. Little wonder he welcomed Mendel with open arms and was the first to translate his papers into English. ‘There is nothing in Mendelian discovery which runs counter to the cardinal doctrine that species have arisen [by natural selection]’, wrote Bateson, sounding like a theologian claiming to be the true interpreter of St Paul. ‘Nevertheless, the result of modern inquiry has unquestionably been to deprive that principle of those supernatural attributes with which it has sometimes been invested…It cannot in candour be denied that there are passages in the works of Darwin which in some measure give countenance to these abuses of the principle of Natural Selection, but I rest easy in the certainty that had Mendel’s paper come into his hands, those passages would have been immediately revised.’⁴

But the very fact that the dreaded Bateson was Mendelism’s champion led European evolutionists to be suspicious of it. In Britain, the bitter feud between Mendelians and ‘biometricians’ persisted for twenty years. As much as anything this passed the torch to the United States where the argument was less polarised. In 1903 an American geneticist called Walter Sutton noticed that chromosomes behave just like Mendelian factors: they come in pairs, one from each parent. Thomas Hunt Morgan, the father of American genetics, promptly became a late convert to Mendelism, so Bateson, who disliked Morgan, gave up being right and fought against the chromosomal theory. By such petty feuds is the history of science often decided. Bateson sank into obscurity while Morgan went on to great things as the founder of a productive school of genetics and the man who lent his name to the unit of genetic distance: the centimorgan. In Britain, it was not until the sharp, mathematical mind of Ronald Fisher was brought to bear upon the matter in 1918 that Darwinism and Mendelism were at last reconciled: far from contradicting Darwin, Mendel had brilliantly vindicated him. ‘Mendelism’, said Fisher, ‘supplied the missing parts of the structure erected by Darwin.’

Yet the problem of mutation remained. Darwinism demanded variety upon which to feed. Mendelism supplied stability instead. If genes were the atoms of biology, then changing them was as heretical as alchemy. The breakthrough came with the first artificial induction of mutation by somebody as different from Garrod and Mendel as could be imagined. Alongside an Edwardian doctor and an Augustinian friar we must place the pugnacious Hermann Joe Muller. Muller was typical of the many brilliant, Jewish scientific refugees crossing the Atlantic in the 1930s in every way except one: he was heading east. A native New Yorker, son of the owner of a small metal-casting business, he had been drawn to genetics at Columbia University, but fell out with his mentor, Morgan, and moved to the University of Texas in 1920. There is a whiff of anti-semitism about Morgan’s attitude to the brilliant Muller, but the pattern was all too typical. Muller fought with everybody all his life. In 1932, his marriage on the rocks and his colleagues stealing his ideas (so he said), he attempted suicide, then left Texas for Europe.

Muller’s great discovery, for which he was to win the Nobel prize, was that genes are artificially mutable. It was like Ernest Rutherford’s discovery a few years before that atomic elements were transmutable and that the word ‘atom’, meaning in Greek uncuttable, was inappropriate. In 1926, he asked himself, ‘[Is] mutation unique among biological processes in being itself outside the reach of modification or control, – that it occupies a position similar to that till recently characteristic of atomic transmutation in physical science?’

The following year he answered the question. By bombarding fruit flies with X-rays, Muller caused their genes to mutate so that their offspring sported new deformities. Mutation, he wrote, ‘does not stand as an unreachable god playing its pranks upon us from some impregnable citadel in the germplasm.’ Like atoms, Mendel’s particles must have some internal structure, too. They could be changed by X-rays. They were still genes after mutation, but not the same genes.

Artificial mutation kick-started modern genetics. Using Muller’s X-rays, in 1940 two scientists named George Beadle and Edward Tatum created mutant versions of a bread mould called Neurospora. They then worked out that the mutants failed to make a certain chemical because they lacked the working version of a certain enzyme. They proposed a law of biology, which caught on and has proved to be more or less correct: one gene specifies one enzyme. Geneticists began to chant it under their breath: one gene, one enzyme. It was Garrod’s old conjecture in modern, biochemical detail. Three years later came Linus Pauling’s remarkable deduction that a nasty form of anaemia afflicting mostly black people, in which the red cells turned into sickle shapes, was caused by a fault in the gene for the protein haemoglobin. That fault behaved like a true Mendelian mutation. Things were gradually falling into place: genes were recipes for proteins; mutations were altered proteins made by altered genes.

Muller, meanwhile, was out of the picture. In 1932 his fervent socialism and his equally fervent belief in the selective breeding of human beings, eugenics (he wanted to see children carefully bred with the character of Marx or Lenin, though in later editions of his book he judiciously altered this to Lincoln and Descartes), led him across the Atlantic to Europe. He arrived in Berlin just a few months before Hitler came to power. He watched, horrified, as the Nazis smashed the laboratories of his boss, Oscar Vogt, for not expelling the Jews under his charge.

Muller went east once more, to Leningrad, arriving in the laboratory of Nikolay Vavilov just before the anti-Mendelist Trofim Lysenko caught the ear of Stalin and began his persecution of Mendelian geneticists in support of his own crackpot theories that wheat plants, like Russian souls, could be trained rather than bred to new regimes; and that those who believed otherwise should not be persuaded, but shot. Vavilov died in prison. Ever hopeful, Muller sent Stalin a copy of his latest eugenic book, but hearing it had not gone down well, found an excuse to get out of the country just in time. He went to the Spanish Civil War, where he worked in the blood bank of the International Brigade, and thence to Edinburgh, arriving with his usual ill luck just in time for the outbreak of the Second World War. He found it hard to do science in a blacked-out Scottish winter wearing gloves in the laboratory and he tried desperately to return to America. But nobody wanted a belligerent, prickly socialist who lectured ineptly and had been living in Soviet Russia. Eventually Indiana University gave him a job. The following year he won the Nobel prize for his discovery of artificial mutation.

But still the gene itself remained an inaccessible and mysterious thing, its ability to specify precise recipes for proteins made all the more baffling by the fact that it must itself be made of protein; nothing else in the cell seemed complicated enough to qualify. True, there was something else in chromosomes: that dull little nucleic acid called DNA. It had first been isolated, from the pus-soaked bandages of wounded soldiers, in the German town of Tübingen in 1869 by a Swiss doctor named Friedrich Miescher. Miescher himself guessed that DNA might be the key to heredity, writing to his uncle in 1892 with amazing prescience that DNA might convey the hereditary message ‘just as the words and concepts of all languages can find expression in 24–30 letters of the alphabet’. But DNA had few fans; it was known to be a comparatively monotonous substance: how could it convey a message in just four varieties?⁵

Drawn by the presence of Muller, there arrived in Bloomington, Indiana, a precocious and confident nineteen-year-old, already equipped with a bachelor’s degree, named James Watson. He must have seemed an unlikely solution to the gene problem, but the solution he was. Trained at Indiana University by the Italian émigré Salvador Luria (predictably, Watson did not hit it off with Muller), Watson developed an obsessive conviction that genes were made of DNA, not protein. In search of vindication, he went to Denmark, then, dissatisfied with the colleagues he found there, to Cambridge in October 1951. Chance threw him together in the Cavendish laboratory with a mind of equal brilliance captivated by the same conviction about the importance of DNA, Francis Crick.

The rest is history. Crick was the opposite of precocious. Already thirty-five, he still had no PhD (a German bomb had destroyed the apparatus at University College, London, with which he was supposed to have measured the viscosity of hot water under pressure – to his great relief), and his sideways lurch into biology from a stalled career in physics was not, so far, a conspicuous success. He had already fled from the tedium of one Cambridge laboratory where he was employed to measure the viscosity of cells forced to ingest particles, and was busy learning crystallography at the Cavendish. But he did not have the patience to stick to his own problems, or the humility to stick to small questions. His laugh, his confident intelligence and his knack of telling people the answers to their own scientific questions were getting on nerves at the Cavendish. Crick was also vaguely dissatisfied with the prevailing obsession with proteins. The structure of the gene was the big question and DNA, he suspected, was a part of the answer. Lured by Watson, he played truant from his own research to indulge in DNA games. So was born one of the great, amicably competitive and therefore productive collaborations in the history of science: the young, ambitious, suppleminded American who knew some biology and the effortlessly brilliant but unfocused older Briton who knew some physics. It was an exothermic reaction.

Within a few short months, using other people’s laboriously gathered but under-analysed facts, they had made possibly the greatest scientific discovery of all time, the structure of DNA. Not even Archimedes leaping from his bath had been granted greater reason to boast, as Francis Crick did in the Eagle pub on 28 February 1953, ‘We’ve discovered the secret of life.’ Watson was mortified; he still feared that they might have made a mistake.

But they had not. All was suddenly clear: DNA contained a code written along the length of an elegant, intertwined staircase of a double helix, of potentially infinite length. That code copied itself by means of chemical affinities between its letters and spelt out the recipes for proteins by means of an as yet unknown phrasebook linking DNA to protein. The stunning significance of the structure of DNA was how simple it made everything seem and yet how beautiful. As Richard Dawkins has put it,⁶ ‘What is truly revolutionary about molecular biology in the post-Watson–Crick era is that it has become digital…the machine code of the genes is uncannily computer-like.’

A month after the Watson–Crick structure was published, Britain crowned a new queen and a British expedition conquered Mount Everest on the same day. Apart from a small piece in the News Chronicle, the double helix did not make the newspapers. Today most scientists consider it the most momentous discovery of the century, if not the millennium.

Many frustrating years of confusion were to follow the discovery of DNA’s structure. The code itself, the language by which the gene expressed itself, stubbornly retained its mystery. Finding the code had been, for Watson and Crick, almost easy – a mixture of guesswork, good physics and inspiration. Cracking the code required true brilliance. It was a four-letter code, obviously: A, C, G and T. And it was translated into the twenty-letter code of amino acids that make up proteins, almost certainly. But how? Where? And by what means?

Most of the best ideas that led to the answer came from Crick, including what he called the adaptor molecule – what we now call transfer RNA. Independently of all evidence, Crick arrived at the conclusion that such a molecule must exist. It duly turned up. But Crick also had an idea that was so good it has been called the greatest wrong theory in history. Crick’s ‘comma-free’ code is more elegant than the one Mother Nature uses. It works like this. Suppose that the code uses three letters in each word (if it uses two, that only gives sixteen combinations, which is too few). Suppose that it has no commas, and nogapsbetweenthewords. Now suppose that it excludes all words that can be misread if you start in the wrong place. So, to take an analogy used by Brian Hayes, imagine all three-letter English words that can be written with the four letters A, S, E and T: ass, ate, eat, sat, sea, see, set, tat, tea and tee. Now eliminate those that can be misread as another word if you start in the wrong place. For example, the phrase ateateat can be misread as ‘a tea tea t’ or as ‘at eat eat’ or as ‘ate ate at’. Only one of these three words can survive in the code.

Crick did the same with A, C, G and T. He eliminated AAA, CCC, GGG and TTT for a start. He then grouped the remaining sixty words into threes, each group containing the same three letters in the same rotating order. For example, ACT, CTA and TAC are in one group, because C follows A, T follows C, and A follows T in each; while ATC, TCA and CAT are in another group. Only one word in each group survived. Exactly twenty are left – and there are twenty amino acid letters in the protein alphabet! A four-letter code gives a twenty-letter alphabet.

Crick cautioned in vain against taking his idea too seriously. ‘The arguments and assumptions which we have had to employ to deduce this code are too precarious for us to feel much confidence in it on purely theoretical grounds. We put it forward because it gives the magic number – twenty – in a neat manner and from reasonable physical postulates.’ But the double helix did not have much evidence going for it at first, either. Excitement mounted. For five years everybody assumed it was right.

But the time for theorising was past. In 1961, while everybody else was thinking, Marshall Nirenberg and Johann Matthaei decoded a ‘word’ of the code by the simple means of making a piece of RNA out of pure U (uracil – the equivalent of DNA’s T) and putting it in a solution of amino acids. The ribosomes made a protein by stitching together lots of phenylalanines. The first word of the code had been cracked: UUU means phenylalanine. The comma-free code was wrong, after all. Its great beauty had been that it cannot have what are called reading-shift mutations, in which the loss of one letter makes nonsense of all that follows. Yet the version that Nature has instead chosen, though less elegant, is more tolerant of other kinds of errors. It contains much redundancy with many different three-letter words meaning the same thing.⁷

By 1965 the whole code was known and the age of modern genetics had begun. The pioneering breakthroughs of the 1960s became the routine procedures of the 1990s. And so, in 1995, science could return to Archibald Garrod’s long-dead patients with their black urine and say with confidence exactly what spelling mistakes occurred in which gene to cause their alkaptonuria. The story is twentieth-century genetics in miniature. Alkaptonuria, remember, is a very rare and not very dangerous disease, fairly easily treated by dietary advice, so it had lain untouched by science for many years. In 1995, lured by its historical significance, two Spaniards took up the challenge. Using a fungus called Aspergillus, they eventually created a mutant that accumulated a purple pigment in the presence of phenylalanine: homogentisate. As Garrod suspected, this mutant had a defective version of the protein called homogentisate dioxygenase. By breaking up the fungal genome with special enzymes, identifying the bits that were different from normal and reading the code therein, they eventually pinned down the gene in question. They then searched through a library of human genes hoping to find one similar enough to stick to the fungal DNA. They found it, on the long arm of chromosome 3, a ‘paragraph’ of DNA ‘letters’ that shares fifty-two per cent of its letters with the fungal gene. Fishing out the gene in people with alkaptonuria and comparing it with those who do not have it, reveals that they have just one different letter that counts, either the 690th or the 901st. In each case just a single letter change messes up the protein so it can no longer do its job.⁸

This gene is the epitome of a boring gene, doing a boring chemical job in boring parts of the body, causing a boring disease when broken. Nothing about it is surprising or unique. It cannot be linked with IQ or homosexuality, it tells us nothing about the origin of life, it is not a selfish gene, it does not disobey Mendel’s laws, it cannot kill or maim. It is to all intents and purposes exactly the same gene in every creature on the planet – even bread mould has it and uses it for precisely the same job that we do. Yet the gene for homogentisate dioxygenase deserves its little place in history for its story is in microcosm the story of genetics itself. And even this dull little gene now reveals a beauty that would have dazzled Gregor Mendel, because it is a concrete expression of his abstract laws: a story of microscopic, coiled, matching helices that work in pairs, of four-letter codes, and the chemical unity of life.