The Language of the Genes

by Steve Jones

  Medicine has also succeeded in treating genetic diseases that once killed young. The main concern of the eugenics movement was the biological future. Sterilisation was an easy way to reverse what they saw to be undesirable trends. The new biology hopes to become a positive force rather than a mere filter for the imperfect. Cystic fibrosis is lethal because the lungs fill with mucus, and because certain digestive enzymes cannot be made. Conventional medicine — careful treatment of the lung problem, and the use of an enzyme that helps break down mucus — has increased both the quality and the length of life of those with the disease. For some patients a heart-lung transplant can help.

  Such successes mean that medicine has already altered the genes of years to come, for many of those who once would have died of cystic fibrosis and other diseases can now be saved to pass on their faulty DNA. Opticians, too, have played a part. A short-sighted hunter-gatherer may well have starved, but the invention of spectacles removed the penalty attached to any genes involved and they have gained as a result. Only if spectacles were banned would that en use problems. Any success in treating inborn disease causes the gene to become commoner in later generations; but as long as medical treatments remain available that will have little practical impact.

  Whatever these local triumphs, the biggest problem of modern genetics is one that the public has scarcely realised; the ubiquity of inborn disease. About one child in thirty in Britain is born with an overt genetic problem of some kind and inborn illness causes about a fifth of infant deaths. Over a third of blind people face their plight for genetic reasons and more and more illnesses have been revealed to have an inherited component. In some places the problem is even greater. Around the Mediterranean and in Africa errors in red blood cells, which evolved to protect against malaria, affect millions. Cyprus has many genes for various forms of thalassaemia, loss of a segment of the haemoglobin molecule. Any child born with two copies suffers from severe anaemia. The treatment is blood transfusion, which works but is so expensive that to treat all affected children might soon soak up half the health budget. One person in fifteen, worldwide, is a carrier of one of the malaria resistance genes. Without a medical breakthrough no society will be able to treat the millions of anaemic children who will be born unless something is done to reduce their number. High cost will mean hard choices.

  Most genetic technology is simple: to identify a damaged gene and offer the choice of therapeutic abortion. AH the common defects can be detected in this way and many more have the prospect of a test. But, as the screens become more sophisticated, where should the line be drawn? In Russia pregnancies have been terminated because the foetus is thought to carry genes that dispose to diabetes. But diabetes is a disease that can sometimes be treated with insulin. And what about diseases for which no treatment is yet available, but might be curable by the time the child is in danger of dying? In muscular dystrophy, for example, we now know what protein has gone wrong and a normal version can help mice with a gene for a similar condition. It is not impossible that some treatment may be available within the next couple of decades. As many boys born now with the disease are likely to live as long this poses a moral dilemma of its own. For pre-natal diagnosis, the equation is affected by the age of parents (and hence the mutation rate), how related they are, any family history of inherited disease, the severity of symptoms, the possibility of treatment, and attitudes to abortion. All this make the process more and more ambiguous.

  Decisions based on appraisals of inborn quality;uc not new but now, for the first time, may be accurate. Should damaged genes be allowed to pass to the next generation, or should the human race attempt to enhance its quality in some way? There are each year, worldwide, about ninety million births and sixty million induced abortions. Britain alone in 1998 had a hundred and eighty thousand abortions, only two thousand of which were on grounds of abnormality. Many more pregnancies end without the woman knowing of her condition, often because the foetus has a severe genetic defect. Even more eggs are lost. A baby girl has a million or so in her ovaries. Three quarters disappear before puberty, and at the age of twenty five she loses, on average, forty or so a day while producing only one a month. The waste of sperm is even more prodigious and, for either sex, many of the sex cells are doomed because of their biological weakness. Genetic selection is a natural part of reproduction. Even so, attempts to choose sperm or eggs or to change the balance between uncompleted and completed pregnancies lead to bitter controversy. Some demand that the state control reproductive choices but others feel that such decisions must be the parents' alone.

  Galton, no doubt, would approve the many conceptions that arc ended for genetical reasons. In the end, what genetic screening achieves will be limited by attitudes more than technology. They can be hard to predict. In the bad old days, Germany was much at fault; but liberal Sweden sterilised sixty thousand in a programme that lasted long after the end of the War. As late as 1995, South Australia's Reproductive Technology Act forbade treatment for infertility to those who had faced criminal charges. Britain, in contrast, the home of the whole idea, never put eugenics into practice. Ninety-five per cent of the twenty-first century's children will be born in the third world. Although in most places genetics has still to make an appearance, China already has a well-established service. In 1993 the country passed a law that was designed to 'put a stop to the prevalence of abnormal births and heighten the standards of the whole population'. Most of the country's geneticists are in favour of compulsory tests before marriage, and of pre-natal diagnosis of severe genetic diseases (with the implication that a termination is called for).

  Elsewhere, though, attitudes can be unexpected. Sardinia is a rather traditional Catholic society in which many marriages risk having a child with thalassaemia. Nine tenths of the couples who face that predicament now know this; and when the woman has an affected foetus nine tenths of those choose termination. Tests offered to older mothers in Denmark led to a fivefold decrease in the number of Down's Syndrome children. Perhaps illnesses such as Huntington's will soon become rare as those at risk decide not to reproduce. Some of the most enthusiastic campaigners for tests for inborn disease are parents who have had an affected child. That in itself says something about where the ethical balance lies. In some places though, such is the passion for the 'right to life' that charities who appeal for funds for genetical research never mention the idea of abortion, but instead concentrate on the {often hopeless) search for a cure.

  Genetics as a negative force embodies another subtle tyranny; the dictatorship of the normal, the pressure to produce an average child. The United States has seen demands for growth hormone to be given to children who grow up a few inches shorter than average aiul would once have been accepted as ordinary. One in len Unions would consider termination of pregnancy for a foetus found to have two missing Hngers; and, in a mirror image ol genetic discrimination, a majority of deaf people claim th;t(ihcy should have the right to prefer the birth of a deaf child who might fir better into their family. Achondroplasia, the common form of dwarfism, arises from a dominant mutation. It has some effect on the health of those who bear the gene, but most of the time they are well, and many are positively proud of their condition. Almost all cases arise from new mutations and are born to parents who had no idea of the risk. The gene has been found. Any pregnancy in which the child appears to be growing slowly is monitored. At first, to find that the growth problem was due only to achondroplasia was seen by doctors as useful reassurance to the parents. Many physicians were alarmed to find that the response was often to demand a termination. Now, some centres do not reveal the results — but who has the right to conceal the truth?

  Achondroplasia is a reminder that genes involve people as much as DNA. That lesson has been learned again and again. The first attempts to use the new knowledge ran into difficulties because they ignored social realities. A search for carriers of the sickle-cell gene in the American black community thirty years ago led to great bitterness. Although
carriers are quite healthy except in conditions of extreme oxygen shortage (which few experience) some states made screening compulsory. Those carrying one copy of the mutation were discriminated against in jobs and for insurance. Even worse, people who did not carry sickle cell considered those who did to be less healthy and less happy than did the carriers themselves. The carriers were discriminated against when it came to marriage and the programme gave hints of eugenic attempts to improve the quality of the population rather than the health of individuals. The scheme — albeit conceived with the best of motives — was a model of the way in which genetic information should not be used.

  Even so, the genetic inquisition is here to stay. Why not, after all, extend testing to the adult population, for their own good or for that of society and leave society to work out how to deal with the difficulties as they arise? The history of discrimination against the genetically unfortunate is a miserable one: but, after all, that was long ago. Would not someone at great risk of heart disease like to know before real damage is done, in time to choose his vices to reduce the risks or to ask for early treatment? The idea is seductive and much-discussed. The truth, alas, is not always so simple, for several reasons.

  How far testing can go is set first by the pervasiveness of imperfection. Any recessive disorder always involves far more carriers of a single copy of the variant than of two. If an illness of this kind affects one birth in ten thousand, about one normal person in fifty carries the gene — which means hundred times as many copies in healthy people as in those who are ill. As a result, the notion that one can improve the long-term health of the population by preventing those with inherited disease from having a child is simply wrong. Almost everyone carries one or more different genes for recessive inherited disease. A universal screen would provide information which is unwelcome and is of almost no use.

  Take cystic rlbrosis. One British child in two thousand five hundred is born with the condition, so that about two million Britons carry a single copy and in a tenth of marriages one or other of the partners is a carrier. Any screening programme would turn up millions of such couples. If married couples were checked for all recessives, so many carriers would be detected that it is hard to know what to do with the information — or wherher ir was worth gathering in the first place.

  That problem is compounded by a dawning realisation that screening itself may be much more difficult than was once hoped. Mendel's laws are so straightforward ih.it the map of the genes should, it seems, make it easy to pick out those at risk. The public — and many doctors — believes as much and demand is strong. It seems that a new era of certainty is near, but at least where genetic screening is concerned the truth is more ambiguous.

  There are two main difficulties in this application of simple rules to complex problems. First, for most genetic conditions, the DNA involved can be damaged in a number of ways. Every population — sometimes, every family — may have its own mutation in different parts of a structure that may be tens of thousands of bases long. A test that detects an error in one group hence may not work for others. As a result, instead of a universal screen, many separate checks may be needed. To speak of 'the' test for — say — cystic fibrosis means less than it seems. More important, many inborn conditions, although they run in families, involve several or many genes that come together each generation in shifting constellations whose effects are hard to predict.

  For single gene conditions such as cystic fibrosis some mutations happened long ago and have spread to millions of people. Others took place recently, and are found in just a few. In general, the older a mutation the wider it spreads and the easier it is to generate a useful test. For the hundred or so Mendelian diseases so far studied in detail, the news is not particularly good: most have high diversity, most individual mutations are rare, and — at a guess — the majority of errors have appeared within the past two thousand years and are still restricted in their spread.

  All this means that to establish whether someone is a carrier of a simple error, without prior knowledge of the mutation involved, may not be easy. Ironically enough, in alkaptonuria — the first inborn error to be discovered, with its simple pattern of inheritance — almost everyone who bears this rare condition has the same unique mutation. For the more frequent illness cystic fibrosis, however, well over a thousand different mutations are known. Some are quite common. One among them is responsible for seventy per cent of cases in Western Europe. Two thousand miles to the East, that change is found in just a small proportion of patients. Even in Jewish populations in the United States it is involved in only a third oi the damage and in some populations (such of those of North Africa) quite a different mistake causes the majority of harm. One illness, an alteration in a single gene, has, it transpires, a multiplicity of causes.

  Life is even harder for the many conditions that do not follow Mendelian rules. A few are affected by genes of moderate effect. One form of heart disease is much influenced by variation in a gene involved in the transmission of messages from nerves to muscles, although several other segments of DNA with a weak effect are also involved. Thousands of women die of breast cancer, and for a few, one of two genes known to predispose to the disease are responsible. These are carried by one in eight hundred or so women and represent hundreds of different DNA changes. Removal of the breasts is of some help to those who carry the gene, but this is a drastic move that is not acceptable to many (although small doses of anti-cancer drugs may also help). All this, combined with the rarity of the gene, the fact that nineteen out of every twenty breast-cancer patients do not carry a mutated version but develop the disease for unknown reasons, and the lack of any general test, means that a population screen would not be worthwhile.

  In Ashkenaze Jews some damaged versions of this gene are more common because, by chance, most ot tin* population descend from a rather small group of founders. One in fifty or so Ashkenazim carry one of three Jisiinct mutations that predispose to breast cancer. A screen ot the whole population might, it seems, pay off, but even here reality is complicated. Because many women with the disease get it for reasons unconnected with these two genes, and because the disease often does not show itself until middle age, the extra burden of risk faced by bearers of the gene is only about one in twenty. All this means that many geneticists feel that screening for an inherited predisposition to breast cancer is nor useful even here.

  To make life even more difficult for the hapless screener, what seems to be the same disease may arise from errors in quite different genes and, quite often, a condition that has a simple genetic cause in some patients may have almost no inherited component in others. Many illnesses that once appeared to be one have been subdivided. 'Fever' was seen as a unitary disorder with a single treatment and 'cancer' was much the same. That simplistic view changed long before genetics; but genes have speeded up the process.

  In spite of the complexity of mutation, nobody doubts that — say — cystic fibrosis is one disease. However, most inherited diseases are not due to simple errors in one or even a few genes: instead, they are (like fever itself) symptoms of a great constellation of failures in the body's machinery. A single gene may be involved in certain cases but not others, or genes of small effect may band together in unpredictable ways. The DNA at fault may differ from population to population, or from family to family; and an inborn problem may not show itself until it is exposed to a particular challenge. As a result, some conditions appear to have an environmental cause in some patients, and a genetic one in others. Such complexity means that to unravel the big killers like heart disease or obesity will not be easy. Even when the job is done, it is not clear how the information will be of much help in screening.

  Take, for example, diabetes. Diabetes mellitus affects one in ten people. The cause, a loss of control of blood sugar, seems simple. The illness causes kidney damage, blindness, heart disease, nerve destruction and death and, in the USA, costs $100 billion a year to treat.

  It comes in two
flavours. One results from a failure of the pancreas, the gland that makes insulin. That problem is quite rare (affecting about one child in a thousand), starts young and can be treated with the missing hormone. The other, non-insulin-dependent diabetes mellitus, is commoner, appears later, and is resistant to insulin treatment. Six million Americans have this illness without knowing it and it is becoming more common. The two forms, similar as they seem, involve separate sets of genes and present medicine with quite different problems. What is more, each condition itself conceals several ailments, some influenced by inheritance, some not.

  The insulin-dependent form was once thought to be caused by viruses, by diet, or even by urban living. None of the ideas was sustained. In fact, genes are involved, with the risk to brothers or sisters of patients twenty times higher than that to the general population. Early-onset diabetes is associated with the systems of recognition on the surface of cells. Those with certain combinations of cell-surface cues face a tenfold increase in risk. The illness, it seems, results from an attack by the immune system on its own body.

  A single gene explains a third of the variation in the chance of getting the disease. At least twenty others may predispose to it, some involved in the insulin machinery and others at work in unrelated pans <>