by Steve Jones
Old age is itself in part the result of genetic accidents. Human cells in culture age more quickly when they carry a defect which increases the mutation rate and some children who inherit a tendency towards cancer also show symptoms of senility much earlier than normal. The immune system, which has the highest mutation rate of any part of the body, often fails as the years pass by. It seems that the decay of our elderly selves is, to some degree, a consequence of mutation. The influence of old age in damaging sperm and egg adds a certain irony to the claims of one institution devoted to the reversal of the decay of the human race, the Centre for Germinal Choice in California, in which Nobel Prize-winners make genetic deposits for hopeful mothers. The depositors may once, as they claim, have approached a genetic ideal, bur that perfection has been marred by age.
Why, if our genes change and decay through our lives, does the human race not degenerate as one generation succeeds another? The answer lies in sex. To define sex is simple; it is a process that brings together genes from different ancestors. It provides a chance to purge ourselves of the harmful mutations which arise in each generation and represents, in more ways than one, the antithesis of age.
Almost every novel, ptay or work of art revolves around the eternal triangle of sex, age and death. All three — and our very existence — emerge from errors in the transmission of genes. Humanity is not a degenerate remnant of a noble ancestor. Rather we are the products of evolution, a set of successful mistakes. Genetics has solved one of our oldest questions; why people decay, but Homo sapiens does not.
Chapter Five CALIBAN'S REVENGE
The plot of George Eliot's novel Daniel DcrotitLi is.1 convoluted one. It revolves around the adventures of himself, the adopted son of a baronet. After souk- hundreds of pages he develops an unexpected interest in things Hebrew and — some time later — it transpires that Daniel Deronda was, quite unaware, the son of a Jewish woman. His biology had triumphed over his background.
Many people are obsessed by the role of inheritance compared to that of experience. The infatuation goes back long before genetics. Even Shakespeare had a say: in The Tempest Prospero describes Caliban as "A devil, a born devil, on whose nature Nurture can never stick." There are still endless (and rather empty) discussions about whether musicality, criminality or intelligence is inherited or acquired and more serious debates about the role of genes and environment in illnesses such as cancer or heart disease. Such questions are often unresolved, and may be unresolvable.
Galton, in Hereditary Genius, went to great lengths to show that talent runs in families and was coded into their biology. He failed to point out that more than half his 'geniuses' turned up in families with no history of distinction at all and concentrated only on those who supported his hereditarian views. Most claims that talent (or lack of it) is inherited are based, like Galton's, on little more than a series of selected anecdotes. Even the descendants of Johann Sebastian Bach disappeared from the musical firmament after a few generations. Family likeness says little about the importance of biology; after all, one attribute much shared by parents and children is bank-balance.
Nevertheless, the question of nature versus nurture is of endless fascination. Dozens of studies purport to show that behaviour is under genetic control. Whole sets or degenerate families were once held up for inspection: the Tribe of Ishmael, the Jukes Clan and the Kalikaks (whose pseudonym is Greek doggerel for good/had). One was traced to an eighteenth century sailor who married an upright woman but had an affair with a slattern. His wife's branch gave rise to a lineage of spotless virtue while the other was a burden on society, as firm proof that morality lies in the genes.
Geneticists find queries about the importance of nature and nurture dull, for two reasons. First, they scarcely understand the inheritance of complex characters (those, like height, weight or behaviour which are measured rather than counted) even in simpler beings like flies or mice and even with traits which are easy to define. Second, and more important, geneticists know that the perpetual interrogation — gene or environment? — is often meaningless. Its only answer is that there is no valid question.
Although genetics is all about inheritance, inheritance is certainly not all about genetics. Almost every attribute involves the joint action of the internal and the external world. A characteristic such as intelligence (or height) is often seen as a cake ready to be sliced into so much 'nature' and so much 'nurture'. In fact, the two are so closely blended that to separate them is like trying to unbake the cake. A failure to understand this simple fact leads to confusion and worse.
Not far from Herbert Spencer's (and his neighbour Marx's) tomb is a large red-brick house. It was occupied by Sigmund Freud after he fled Austria to avoid racial policies which descended from the Galtonian ideal. On his desk is a set of stone axes and ancient figurines. Freud's interest in these lay in his belief that behaviour is controlled by biological history. Everyone, he thought, recapitulates in their childhood the phases experienced during evolution. Freud saw unhappiness as a sort of living fossil, the reappearance of ancient behaviour which is inappropriate today. Like Galton he saw the human condition.is formed by inheritance. The libido and ego.in1, lu* wrote, lat bottom heritages, abbreviated recapitulations of the development which all mankind passed through from its primaeval days'. Freud hoped that once he had uncovered the inborn fault which caused despair, he might be able to cure it.
Today's Freudians have moved away from their guru's Gaitonising of behaviour. They feel that nurture is important. Analysis looks for childhood events rather than race memories. In so doing they are in as much danger as their master of trying to unbake the cake of human nature. Any attempt to do so is futile.
The Siamese cat shows how pointless the task may be. Siamese have black fur on the tips of the ears, the tail and the feet, but are white or light brown elsewhere. They carry the 'Himalayan' mutation, which is also found in rabbits and guinea pigs (but not, alas, in humans). Crosses show that a single gene that follows Mendel's laws is involved. At first sight, then, the Siamese cat's fur is set in its nature: if coat colour is controlled by just one gene then surely there is no room for nurture to play a part.
However, the Himalayan mutation is odd. The damaged gene cannot produce pigment at normal body temperature but works perfectly if it is kept cool. As a result, the colder parts of the cat's body, its ears, nose and tail (and, for a male, its testicles) are darker than the rest. An unusuallydark cat can be produced by keeping a typical Siamese in the cold and a light one by raising it in a warm room. Inside every Siamese is a black cat struggling to get out. To ask whether its pattern is due to gene or to environment means nothing. It results from both. What the Siamese cat — and every other creature- inherits is an ability to respond to the circumstances in which it is placed.
Many inborn diseases show this effect. The recessive abnormality phenylketonuria (or PKU) affects about forty British children a year. V.Ach has an inherited defect in a particular enzyme which means that they cannot process an amino acid, phenylalanine, found in most foods. As a result they build up large amounts of a harmful by-product. Untreated, such children have low intelligence and die young. The fate of those with PKU is, it seems, sealed by their genes.
Rut most PKU children born today lead more or less ordinary lives. A change in the environment saves them. If they are diagnosed early (and all babies are tested at birth), they can be given food which lacks all but a tiny amount of phenylalanine. They then develop as healthy infants. Their nature has been determined by careful nurturing and the question of whether DNA or diet is more important to their health has no answer.
Hundreds of genes show the same interaction. A whole new science turns on individual differences in the response to drugs. The genes involved were unknown until humans began to manipulate their chemical milieu. A few people carry an inherited variant which makes them fatally sensitive to a muscle-relaxant used before surgery and everyone is now tested to see whether they are at risk befor
e the drug is given. One of the stranger injunctions of Pythagoras was a caution to his followers not to eat broad beans. He died because, pursued by a mob enraged by his philosophical views, he refused to escape across a beanfield. Pythagoras lived in the Italian city of Croton. Many of its modem inhabitants feel unwell if they eat partly cooked beans. One of the side-effects of the thalassaemia gene (which is common there) is to remove the ability to break down a chemical found in broad beans {and another one used as an anti-malarial drug). When gene and bean (or drug) are brought together, the results can be unpleasant or, in the case of the drug, worse.
All this means that the boundaries between inherited disease and what is governed by the extern.il world have become blurred. That alters the way we think abiuii medicine. Individual treatments may soon be tailored to a patient's biological heritage. Two disorders, anencephaly and spina bifida, cause a failure of development of the spinal cord; and each runs in families. Part of the problem, though, has to do with poor diet. Their incidence shot up in Holland after the famine of 1945 and both are frequent in Ireland and in Scotland (places known for an unhealthy diet). Mothers who have had an affected child now take vitamin supplements in later pregnancies. This reduces the chance of their genes damaging their children.
A change in the environment can also cause genetic disease. Hay fever was not recognised as a distinct illness until 1819, when it (and its relatives asthma and eczema) were seen as afflictions of the rich. Now, about half the people of the western world are, or claim to be, allergic to one substance or another. In Britain one child in four has asthma. The lung becomes inflamed and its muscles sensitive to the slightest irritation. The unfortunate patient wheezes and coughs, and may suffer permanent damage — and, sometimes, even sudden death. The illness involves an over-reaction by the immune system to an external stimulus. House-dust mites are one culprit, cats another, pollen a third. They were around before 1819, but, for some reason, caused few problems.
Part of the reason lies in the modern world, with its obsession with cleanliness. This may have abolished many infectious diseases, but allows others, once rare, to reveal our inborn weaknesses. Asthma is a disease of the middle class; more common in those well fed as children, in infants dosed with antibiotics, and in Western rather than Eastern Europe. The children of farmers and of those with dogs have less chance of the illness than do vegetarians in a pet-free home. It is an affliction of Thrushcross Grange rather than of Wuthering Heights.
Emily Bronte knew the answer. Cathy, when she returns clean and demure after her convalescence at Thrushcross Grange is faced by Heathcliff's: 'I shall be as dirty as I please; and I like to be dirty, and I will be dirty!' Filth is the key. Infants born into clean households are deprived of an essential learning experience. Not their brain but their immune system lacks stimulation. Middle-class homes lack the grime with which humankind evolved. The immune system, like the brain itself, must be trained to deal with the challenges that it will face later in life. Each needs stimulation; but the immune system demands tapeworms rather than Mozart.
Whatever the importance of dirt, asthma and its relatives have an inherited component. Identical twins are more likely each to suffer than are non-identicals, and those who bear certain variants in genes that code for elements of the immune system are also liable to become ill. Tristan da Cunha, that distant and inbred island in which many people share the same genes, has an epidemic of asthma, with almost half the population affected.
Allergy is a classic of the interaction of gene and environment. Long ago, the genes that today cause problems may have been useful as those with an active immune system were good at resisting infection. After soap, in an unnaturally clean household, an over-active immune system became a nuisance as it disposes to allergy. The environment has changed, but the genes remain the same. Today's DNA has quite different effects on health than it once did, and a change in the interaction of nature with nurture leads to an outbreak of illness.
The term 'cancer' covers a multitude of conditions. All are due to a failure to control cell division. Hundreds of genes control the growth of cells anil, when they mutate, the process may go out of control. As in ****** all kinds of mistakes can happen. A single DNA I use may change or whole sections of the message be lost. Sointlitnes the error involves genes moving from one chromosome to another, or from the effects of viruses. Often, several different genetic accidents are needed to promote the development of a tumour. The general picture is not much different from that of mutation in sperm or egg.
Cancer is a Siamese cat of an illness, and the chances of contracting it depend both on the genes and the circumstances with which they are faced. Cell division needs brakes and accelerators. The first, tumour suppressor genes as they are called, control a set of proto-oncogenes that encourage cells to grow. If either party goes wrong, then division speeds up. The cell, though, has a set of speed cameras that control rogue genes. It must pass through a number of checkpoints on the road to division, and if anything is suspicious the cell dies (which is, after all, the natural fate of most cells}. Many of the causes of cancer increase the amount of a specific protein — P53, as it is called — that is sensitive to any sign of DNA damage in the cells under attack. Most then commit suicide rather than causing trouble. Indeed, many cancer treatments (themselves often agents of the illness, like radiation and certain chemicals) themselves wake up the P53 genes and persuade the cells to do the decent thing. Damage to the checkpoint itself (either inherited, or caused by the external agent) means real trouble: by that time the rogue line of cells is through the last safety barrier and may be impossible to contain.
Some cancers are more common among those exposed to a particular hazard. Many chimney-sweeps died of a skin cancer, which appeared first on the scrotum. The English physician Percival Pott suggested that soot was to blame. He was right. Soot, oil and tar contain many carcinogenic chemicals. Radiation, too, can be dangerous. As many as two thousand cases of lung cancer per year in Britain — a twentieth of the total — arise from exposure to radon. There were once thought to be clusters of childhood leukaemia cases around nuclear power-stations but these have now been dismissed on statistical grounds. For most Britons, exposure to radiation is so low that it cannot be an important general cause of cancer.
Some may be less fortunate. The Techa River tuns through Chelyabinsk, once the nuclear capital of Russia. During the height of the Cold War, so much waste was dumped that a fisherman on its banks could get a lethal dose in a week. Many riverside villages have been moved, but the inhabitants of those that remain have increased levels of leukaemia and of cancers of the thyroid and other organs. Even so, the effects are less than those suffered by the survivors of the Hiroshima bomb, so that a sudden burst of radiation may be more dangerous than the same dose given over a longer period. As western safety standards are based on the Japanese cancer figures, there have been calls to relax the minimum dose, but those are resisted by many who believe that no safe lower limit exists.
Whatever the effects of radiation on cancer, chemicals are more important. Those in tobacco smoke are potent agents and some industrial chemicals are just as bad. Alcohol, too, is far from blameless. Certain chemicals bind to DNA to cause their damage. The amount of bound material gives an estimate of exposure to mutagens. The Polish city of Gliwice, which burns much soft coal, is one of the most polluted places in the world. Gliwice has a high rate of cancer. Many inhabitants have large amounts of poisonous chemicals stuck to their DNA. The amount goes up in the winter, when the smoke is at its worst. Many of those exposed will develop the disease.
Other cancers (such as retinoMastoma, a degenerative disease of the retina) run in families, with no obvious environmental link. The causes of the disease run all the way from gene (predominant in retiiioblasioiu.i) to environment (equally so in scrotal cancer), but usually includes both. Workers in the primitive oil industry believed that people with fair hair and freckles should not be employed they were at risk of
'sootwort', as scrotal cancer was known. As such people are in more danger of skin cancer when exposed to sunlight, there may be some truth in the idea.
Seven million die of cancer each year. Many expose themselves to environments so dangerous that even the finest genes cannot save them. Caliban himself could not have devised a contrivance as fiendish as the cigarette: a cheap drug delivery system that provides a narcotic as addictive as heroin and some of the most carcinogenic of all chemicals. Hundreds of millions of people have volunteered themselves as subjects in a gigantic experiment and millions have obligingly died. Their generosity proves the joint actions of nature and nurture. If everybody smoked, lung cancer would be a genetic disease. Many of the cellular checks and balances have a lot of natural variation. For one crucial member, about one person in ten has a highly active form which, when faced with tobacco smoke, does its job very well — and, as it does so, produces a dangerous carcinogen. As a result, light smokers with this form of the gene face a seven times greater risk of lung than do those with other variants (although in heavy smokers, who batter all their defences into submission with massive doses of poison, the risk merely doubles).
Even when DNA is damaged, it can be repaired. A few families lack one or other of the enzyme systems involved,uid as a result are at high risk. Their activity in the population as a whole varies a hundredfold; and, once again, those with the feebler forms are at increased risk if they smoke. Indeed, such forms are five times commoner among smokers with lung cancer than in those who escape the disease. Blacks who smoke have higher rates than do whites, and this too is associated with some unidentified genetic difference among the groups.
