families seem to be more prone to the spontaneous appearance of the Huntington’s mutation than others. The reason seems to be not only that they have a repeat number just below the threshold (say between twenty-nine and thirty-five), but that it jumps above the threshold about twice as easily as it does in other people with similar repeat numbers. The reason for that is again a simple matter of letters. Compare two people: one has thirty-five CAGs followed by a bunch of CCAs and CCGs. If the reader slips and adds an extra CAG, the repeat number grows by one. The other person has thirty-five CAGs, followed by a CAA then two more CAGs. If the reader slips and misreads the CAA as a CAG, the effect is to add not one but three to the repeat number, because of the two CAGs already waiting.11
Though I seem to be getting carried away, and deluging you with details about CAGs in the huntingtin gene, consider: almost none of this was known five years ago. The gene had not been found, the CAG repeat had not been identified, the huntingtin protein was unknown, the link with other neurodegenerative diseases was not even guessed at, the mutation rates and causes were mysterious, the paternal age effect was unexplained. From 1872 to 1993 virtually nothing was known about Huntington’s disease except that it was genetic. This mushroom of knowledge has grown up almost overnight since then, a mushroom vast enough to require days in a library merely to catch up. The number of scientists who have published papers on the Huntington’s gene since 1993 is close to 100. All about one gene. One of 60,000–80,000 genes in the human genome. If you still need convincing of the immensity of the Pandora’s box that James Watson and Francis Crick opened that day in 1953, the Huntington’s story will surely persuade you. Compared with the knowledge to be gleaned from the genome, the whole of the rest of biology is but a thimbleful.
And yet not a single case of Huntington’s disease has been cured. The knowledge that I celebrate has not even suggested a remedy for the affliction. If anything, in the heartless simplicity of the CAG repeats, it has made the picture look even bleaker for those seeking a cure. There are 100 billion cells in the brain. How can we go in and shorten the CAG repeats in the huntingtin genes of each and every one?
Nancy Wexler relates a story about a woman in the Lake Maracaibo study. She came to Wexler’s hut to be tested for neurological signs of the disease. She seemed fine and well but Wexler knew that small hints of Huntington’s can be detected by certain tests long before the patient herself sees signs. Sure enough this woman showed such signs. But unlike most people, when the doctors had finished their examination, she asked them what their conclusion was. Did she have the disease? The doctor replied with a question: What do you think? She thought she was all right. The doctors avoided saying what they thought, mentioning the need to get to know people better before they gave diagnoses. As soon as the woman left the room, her friend came rushing in, almost hysterical. What did you tell her? The doctors recounted what they had said. ‘Thank God’, replied the friend and explained: the woman had said to the friend that she would ask for the diagnosis and if it turned out that she had Huntington’s disease, she would immediately go and commit suicide.
There are several things about that story that are disturbing. The first is the falsely happy ending. The woman does have the mutation. She faces a death sentence, whether by her hand or much more slowly. She cannot escape her fate, however nicely she is treated by the experts. And surely the knowledge about her condition is hers to do with as she wishes. If she wishes to act on it and kill herself, who are the doctors to withhold the information? Yet they did the ‘right thing’, too. Nothing is more sensitive than the results of a test for a fatal disease; telling people the result starkly and coldly may well not be the best thing to do – for them. Testing without counselling is a recipe for misery. But above all the tale drives home the uselessness of diagnosing without curing. The woman thought she was all right. Suppose she had five more years of happy ignorance ahead of her; there is no point in telling her that after that she faces lurching madness.
A person who has watched her mother die from Huntington’s disease knows she has a fifty per cent chance of contracting it. But that is not right, is it? No individual can have fifty per cent of this disease. She either has a one hundred per cent chance or zero chance, and the probability of each is equal. So all that a genetic test does is unpackage the risk and tell her whether her ostensible fifty per cent is actually one hundred per cent or is actually zero.
Nancy Wexler fears that science is now in the position of Tiresias, the blind seer of Thebes. By accident Tiresias saw Athena bathing and she struck him blind. Afterwards she repented and, unable to restore his sight, gave him the power of soothsaying. But seeing the future was a terrible fate, since he could see it but not change it. ‘It is but sorrow’, said Tiresias to Oedipus, ‘to be wise when wisdom profits not.’ Or as Wexler puts it, ‘Do you want to know when you are going to die, especially if you have no power to change the outcome?’ Many of those at risk from Huntington’s disease, who since 1986 can have themselves tested for the mutation, choose ignorance. Only about twenty per cent of them choose to take the test. Curiously, but perhaps understandably, men are three times as likely to choose ignorance as women. Men are more concerned with themselves rather than their progeny.12
Even if those at risk choose to know, the ethics are byzantine. If one member of a family takes the test, he or she is in effect testing the whole family. Many parents take the test reluctantly but for the sake of their children. And misconceptions abound, even in textbooks and medical leaflets. Half your children may suffer, says one, addressing parents with the mutation. Not so: each child has a fifty per cent chance, which is very different. How the result of the test is presented is also immensely sensitive. Psychologists have found that people feel better about being told they have a three-quarter chance of an unaffected baby than if they are told they have a one-quarter chance of an affected one. Yet they are the same thing.
Huntington’s disease is at the far end of a spectrum of genetics. It is pure fatalism, undiluted by environmental variability. Good living, good medicine, healthy food, loving families or great riches can do nothing about. Your fate is in your genes. Like a pure Augustinian, you go to heaven by God’s grace, not by good works. It reminds us that the genome, great book that it is, may give us the bleakest kind of self-knowledge: the knowledge of our destiny, not the kind of knowledge that you can do something about, but the curse of Tiresias.
Yet Nancy Wexler’s obsession with finding the gene was driven by her desire to mend it or cure it when she did find it. And she is undoubtedly closer to that goal now than ten years ago. ‘I am an optimist’, she writes,4 ‘Even though I feel this hiatus in which we will be able only to predict and not to prevent will be exceedingly difficult…I believe the knowledge will be worth the risks.’
What of Nancy Wexler herself? Several times in the late 1980s, she and her elder sister Alice sat down with their father Milton to discuss whether either of the women should take the test. The debates were tense, angry and inconclusive. Milton was against taking the test, stressing its uncertainties and the danger of a false diagnosis. Nancy had been determined that she wanted the test, but her determination gradually evaporated in the face of a real possibility. Alice chronicled the discussions in a diary that later became a soul-searching book called Mapping fate. The result was that neither woman took the test. Nancy is now the same age as her mother was when she was diagnosed.13
Errors, like straws, upon the surface flow; He who would search for pearls must dive below.
John Dryden, All for Love
It is time for a cold shower. Reader, the author of this book has been misleading you. He has repeatedly used the word ‘simple’
