Genome: The Autobiography of a Species in 23 Chapters. Matt Ridley

thirty, sometimes more than a hundred times. Your destiny, your sanity and your life hang by the thread of this repetition. If the ‘word’ is repeated thirty-five times or fewer, you will be fine. Most of us have about ten to fifteen repeats. If the ‘word’ is repeated thirty-nine times or more, you will in mid-life slowly start to lose your balance, grow steadily more incapable of looking after yourself and die prematurely. The decline begins with a slight deterioration of the intellectual faculties, is followed by jerking limbs and descends into deep depression, occasional hallucination and delusions. There is no appeal: the disease is incurable. But it takes between fifteen and twenty-five horrifying years to run its course. There are few worse fates. Indeed, many of the early psychological symptoms of the disease are just as bad in those who live in an affected family but do not get the disease: the strain and stress of waiting for it to strike are devastating.

      The cause is in the genes and nowhere else. Either you have the Huntington’s mutation and will get the disease or not. This is determinism, predestination and fate on a scale of which Calvin never dreamed. It seems at first sight to be the ultimate proof that the genes are in charge and that there is nothing we can do about it. It does not matter if you smoke, or take vitamin pills, if you work out or become a couch potato. The age at which the madness will appear depends strictly and implacably on the number of repetitions of the ‘word’ CAG in one place in one gene. If you have thirty-nine, you have a ninety per cent probability of dementia by the age of seventy-five and will on average get the first symptoms at sixty-six; if forty, on average you will succumb at fifty-nine; if forty-one, at fifty-four; if forty-two, at thirty-seven; and so on until those who have fifty repetitions of the ‘word’ will lose their minds at roughly twenty-seven years of age. The scale is this: if your chromosomes were long enough to stretch around the equator, the difference between health and insanity would be less than one extra inch.²

      No horoscope matches this accuracy. No theory of human causality, Freudian, Marxist, Christian or animist, has ever been so precise. No prophet in the Old Testament, no entrail-gazing oracle in ancient Greece, no crystal-ball gipsy clairvoyant on the pier at Bognor Regis ever pretended to tell people exactly when their lives would fall apart, let alone got it right. We are dealing here with a prophecy of terrifying, cruel and inflexible truth. There are a billion three-letter ‘words’ in your genome. Yet the length of just this one little motif is all that stands between each of us and mental illness.

      Huntington’s disease, which became notorious when it killed the folk singer Woody Guthrie in 1967, was first diagnosed by a doctor, George Huntington, in 1872 on the eastern tip of Long Island. He noticed that it seemed to run in families. Later work revealed that the Long Island cases were part of a much larger family tree originating in New England. In twelve generations of this pedigree more than a thousand cases of the disease could be found. All were descended from two brothers who emigrated from Suffolk in 1630. Several of their descendants were burnt as witches in Salem in 1693, possibly because of the alarming nature of the disease. But because the mutation only makes itself manifest in middle age, when people have already had children, there is little selective pressure on it to die out naturally. Indeed, in several studies, those with the mutations appear to breed more prolifically than their unaffected siblings.³

      Huntington’s was the first completely dominant human genetic disease to come to light. That means it is not like alkaptonuria in which you must have two copies of the mutant gene, one from each parent, to suffer the symptoms. Just one copy of the mutation will do. The disease seems to be worse if inherited from the father and the mutation tends to grow more severe, by the lengthening of the repeat, in the children of progressively older fathers.

      In the late 1970s, a determined woman set out to find the Huntington gene. Following Woody Guthrie’s terrible death from the disease, his widow started the Committee to Combat Huntington’s Chorea; she was joined by a doctor named Milton Wexler whose wife and three brothers-in-law were suffering from the disease. Wexler’s daughter, Nancy, knew she stood a fifty per cent chance of having the mutation herself and she became obsessed with finding the gene. She was told not to bother. The gene would prove impossible to find. It would be like looking for a needle in a haystack the size of America. She should wait a few years until the techniques were better and there was a realistic chance. ‘But’, she wrote, ‘if you have Huntington’s disease, you do not have time to wait.’ Acting on the report of a Venezuelan doctor, Americo Negrette, in 1979 she flew to Venezuela to visit three rural villages called San Luis, Barranquitas and Laguneta on the shores of Lake Maracaibo. Actually a huge, almost landlocked gulf of the sea, Lake Maracaibo lies in the far west of Venezuela, beyond the Cordillera de Merida.

      The area contained a vast, extended family with a high incidence of Huntington’s disease. The story they told each other was that the affliction came from an eighteenth-century sailor, and Wexler was able to trace the family tree of the disease back to the early nineteenth century and a woman called, appropriately, Maria Concepcion. She lived in the Pueblos de Agua, villages of houses built on stilts over the water. A fecund ancestor, she had 11,000 descendants in eight generations, 9,000 of whom were still alive in 1981. No less than 371 of them had Huntington’s disease when Wexler first visited and 3,600 carried a risk of at least a quarter that they would develop the disease, because at least one grandparent had the symptoms.

      Wexler’s courage was extraordinary, given that she too might have the mutation. ‘It is crushing to look at these exuberant children’, she wrote,⁴ ‘full of hope and expectation, despite poverty, despite illiteracy, despite dangerous and exhausting work for the boys fishing in small boats in the turbulent lake, or for even the tiny girls tending house and caring for ill parents, despite a brutalising disease robbing them of parents, grandparents, aunts, uncles, and cousins – they are joyous and wild with life, until the disease attacks.’

      Wexler started searching the haystack. First she collected blood from over 500 people: ‘hot, noisy days of drawing blood’. Then she sent it to Jim Gusella’s laboratory in Boston. He began to test genetic markers in search of the gene: randomly chosen chunks of DNA, that might or might not turn out to be reliably different in the affected and unaffected people. Fortune smiled on him and by mid-1983 he had not only isolated a marker close to the gene affected, but pinned it down to the tip of the short arm of chromosome 4. He knew which three-millionth of the genome it was in. Home and dry? Not so fast. The gene lay in a region of the text one million ‘letters’ long. The haystack was smaller, but still vast. Eight years later the gene was still mysterious: ‘The task has been arduous in the extreme’, wrote Wexler,⁴ sounding like a Victorian explorer, ‘in this inhospitable terrain at the top of chromosome 4. It has been like crawling up Everest over the past eight years.’

      The persistence paid off. In 1993, the gene was found at last, its text was read and the mutation that led to the disease identified. The gene is the recipe for a protein called huntingtin: the protein was discovered after the gene – hence its name. The repetition of the ‘word’ CAG in the middle of the gene results in a long stretch of glutamines in the middle of the protein (CAG means glutamine in ‘genetish’). And, in the case of Huntington’s disease, the more glutamines there are at this point, the earlier in life the disease begins.⁵

      It seems a desperately inadequate explanation of the disease. If the huntingtin gene is damaged, then why does it work all right for the first thirty years of life? Apparently, the mutant form of huntingtin very gradually accumulates in aggregate chunks. Like Alzheimer’s disease and BSE, it is this accumulation of a sticky lump of protein within the cell that causes the death of the cell, perhaps because it induces the cell to commit suicide. In Huntington’s disease this happens mostly within the brain’s dedicated movement-control room, with the result that movement becomes progressively less easy or controlled.⁶

      The most unexpected feature of the stuttering repetition of the word CAG is that it is not confined to Huntington’s disease. There are five other neurological diseases caused by so-called ‘unstable CAG repeats’ in entirely different genes.