Chromosome

History

We've discovered the secret of life.

Francis Crick, 28February1953

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 Osier.

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 Hynoice) 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 Olmiitz. But it was a struggle and Johann needed a wealthier sponsor, so he became an Augus-tinian friar, taking the name Brother Gregor. He trundled through theological college in Brunn (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 Brunn 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 Brunn 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 Brunn, 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 Janacek, a talented nineteen-year-old boy in the choir school, the choirmaster of Brunn.

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 particu-late 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 Nageli, professor of botany in Munich. With increasing boldness he tried to point out the significance of what he had found. For four years Nageli 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 'haplo-diploid' genetics?

Nageli 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 Nageli's own work - and still missed the point. Nageli 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

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