The Language of the Genes

by Steve Jones

  Given that any medical advance is likely to alter the genes of future generations that seems a little too inclusive; and the failure of gene therapy puts the notion for the time being in the field of speculation. However, another set of technologies which once seemed impossible has — in contrast to gene manipulation itself- turned out to be remarkably simple. Their potential use on humans has caused a storm; but that is nothing new.

  Genetics outside the uterus allows reproduction to be controlled. It ranges from artificial insemination to surrogate motherhood to germ-line therapy to cloning. Each one was, on its introduction, greeted with horror (and British children born by donor insemination were once defined to be illegitimate because of the objections by the bishops) but most in the end were accepted. However, as Raskolnikov puts it in Crime and Punishment: 'Man gets used to everything — the beast!' Philosophers talk of the 'yuk factor', the automatic revulsion about interfering with our reproduction. Forty years ago it was, on just those grounds, illegal in Britain to save eyesight by grafting on a cornea from a dead person. Philosophy, it seems, is not much help to the blind.

  The first recorded artificial insemination was by the eighteenth century Scottish anatomist John Hunrer who used a syringe to impregnate a woman whose husband had a deformed penis. Since then, to assist the work of nature has become commonplace. Artificial insemination outside the body had to wait until 1978, when sperm met egg in a test-tube to produce Louise Brown. The technology is less simple than it sounds, as eggs in the right stage of development must be retrieved from a potential mother; but, even so, about one in four attempts succeed. After hormone treatment, eggs are sucked from the ovary with a fine needle and fertilised with the relevant sperm. This need not happen at once as eggs can be frozen for later use. After a few divisions, the fertilised egg is returned to the uterus; either of the natural mother or, if she has reproductive problems, into a volunteer. Often, more than one is used (which sometimes leads to several children being born); and, somerimes, the ball of developing cells is screened to check whether it carries a genetic abnormality before deciding to continue. About one British birth in a hundred is a test-tube baby and there are about half a million such children in the world today.

  Often, the problem lies with the male. Perhaps his sperm is of such low quality that it cannot penetrate the egg. Sometimes, indeed, it is quite unable to move and cannot escape from the testes. In such cases, sperm can be extracted with a needle and sperm heads injected into the egg. Fertilisation over, the egg is implanted or frozen for later use. Some suggest, indeed, that given the increase in genetic damage in the children of older parents it might be wise for a woman to freeze a sample of her eggs during her teens to ensure the health of future children. For a man the task would be even easier.

  All this has led to controversy (including questions as to who might own a dead man's sperm) but is becoming part of medical practice, with hundreds of clinics available across the world. Genetics is often involved, with a check for defects in the fertilised egg. Surrogate motherhood, too, has become common since the first fertilised egg was implanted into an unrelated female in Iceland in 1989. It contains some unpleasant reminders of social reality. In almost every case the surrogate is poorer and less educated than the egg-donor (which, at up to $50 000 a pregnancy in the United States, is not surprising). For all these procedures the yuk factor has been forgotten, but for cloning it remains.

  I write as a clone and the son of a clone; and one of the few British citizens entitled to commit incest. A clone, of course: we are all one of those, for the billions of cells that we contain are — each of them — copies of the fertilised egg that made us, reproduced without benefit of sex. My mother, as it happens, is an identical twin (one of two hundred thousand or so in Britain), so that another individual shares all her genes. Her twin — her clone — in turn, has a daughter who is legally my cousin, but in genetic terms a half-sister. The question has never arisen, bur there is no legal impediment to marriage, close relative though she is.

  My mother and aunt are different individuals, so why the fear of clones? Cloning is, after all, common. It is sex that is rare — to persuade two cells to fuse to make one is, in some ways, the antithesis of reproduction (which, in its clonal version, involves one cell splitting into two). Plenty of creatures, from fungi to lizards, manage without it (and even turkeys can be persuaded to lay eggs without benefit of males). Potatoes are clones and animals can, in principle, be multiplied in the same way. Take an early embryo, split it into pieces and, sometimes, each will grow into an identical twin. This has been successful in rhesus monkeys and, no doubt, could also be done on ourselves. Sheep and cattle have been split at the eight-cell stage, to give (so far) a maximum of five identical offspring. Cows from the same herd may differ greatly in the amount of milk they yield, and as it takes several years per generation it is much more efficient to clone the champion rather than mating her with some favoured bull. In the 1990s, the method was used by breeders in the United States. It failed because the calves tend, for some reason, to develop much larger than usual and either die or demand an expensive caesarian birth.

  Cloning of the Dolly kind is more sophisticated, with the movement of nuclei between cells, but is, after all, just another form of reproductive technology. It follows in the tradition of the great Italian biologist Spallanzani who artificially inseminated a bitch in 1782. Cloning itself — the growth of an organism from an egg containing a foreign complement of genes-began in the 1950s with frogs. They have lazy embryos, because frog eggs are so stuffed with food that they divide to make several thousand cells before they use any of their own genes. Their eggs hence scarcely notice the insertion of another piece of DNA as they are well on in development before genetic information is needed. Sheep wait for just four cell divisions — the 16-cell stage of the embryo — before switching on their genes, while humans DNA becomes active after three division, pigs after two, and mice even before cell divisions begins. This slight delay might explain why sheep proved easier to clone than work on mice (which were recalcitrant about accepting alien genes) had suggested.

  Apart from simple vanity or dislike of the opposite sex, cloning might be useful as an aid to the infertile. Perhaps a male is unable to make sperm: and one of his cell nuclei might be inserted into his wife's egg to make a clone. Perhaps one partner has a genetic illness and prefers to use the other's genes to avoid the risk to a child. There are also various eccentric ideas about armies made of cloned copies of some dictator. Whether they would obey orders is another question, and any cloned child, identical as it is to its parent, is likely to prove a particular disappointment should it fail to live up to expectations

  None of these possibilities is legal — or feasible — at present. All the fuss about what might be done should be tempered with realism. Cloning, even of sheep, is a complicated business. First an egg must be harvested and the cells that are to provide the nucleus made ready. This is fused to an egg that has lost its own nucleus — with a Frankenstein touch — a burst of electricity, and stored in the reproductive tract of a second sheep. Those that pass the test are then moved to the surrogate mother herself. Dolly was the only one of three hundred experiments that worked and most cloned cattle, sheep and mice have been born dead or deformed. For humans, for the time being, moving cell nuclei around is just too risky. Even so it seems almost certain that cloning will, at least in one form, become part of medical practice.

  In the early 1980s it was found that cells from embryonic mice could be kept alive in the laboratory and that some, instead of moving down the path to adulthood, stayed forever young: ready to develop into any tissue when prompted to do so. They have been kept as perpetual adolescents for up to ten years. The technique involves a certain trickery, with various growth factors added to the culture. These embryonic stem cells, as they are called, when injected into another developing embryo, are happy to develop into blood cells, nerves and so on; or, if they find themselves in the rig
ht place, into the precursors of sperm or egg. The recipient grows up as a chimaera; a mixture of cells with different genes — in effect, a mouse with four parents.

  Human embryos, too, contain stem cells, but as these are obtained from the extras made after test-tube fertilisation, their use has caused controversy. They could be useful in making skin for burn victims, replacing the damaged nerve cells of those with Parkinson's disease, or even to generate whole organs, either for transplants, or to replace old tissue with new. Most illnesses nowadays are those of old age; and with the promise of such cells in fighting heart disease, cancer and so on as much as half the population might benefit from their use.

  Nerve cells from foetuses inserted into the brains of patients with Parkinson's disease can relieve their symptoms of slow movement and rigidity: such juvenile cells can, it seems, change their personalities to adapt to the adult brain in which they find themselves. Even adults have stem cells in parts of the body that, like blood, muscle or liver, often regenerate. Such cells can be retrained to take up new and quite different jobs. Stem cells from the brain or from muscles will, with some urging, make blood cells, while the bone marrow is even more flexible as its stem cells can change into brain, liver and muscle. To inject adult stem cells from the marrow of a healthy patient can strengthen the bones of children with inherited damage to the skeleton and the same approach may reduce the severity of symptoms in people who suffer from Huntington's disease. Perhaps other damaged tissues such as those involved in Alzheimer's disease or diabetes might be helped. In mice, those from a normal embryo injected into a mutant animal lacking part of the sheath of insulation around certain nerves (a structure damaged in multiple sclerosis) make the missing material. Such cells injected into paralyzed rats restore movement. Stem cells are rare - about one in ten billion in the marrow — and not all the news is good; in mice, such cells injected into adults can grow into tumours and it may be necessary to add a suicide gene to kill them off if they turn nasty. Their very malleability may cause problems — who, after all, wants teeth to grow in their brain?

  If stem cells pay off, a new era of medicine will begin. Perhaps everyone will keep a store of frozen cells taken at birth in the expectation that they will be needed later to repair an organ that fails with age or disease. On a more modest scale, it should be possible for every hospital to fill a freezer with such things taken from thousands of different people in the hope of having one ready for a match with some future patient who has not stored his own. Even if the hope of new organs is not fulfilled, they might be engineered to make them resistant to anti-cancer drugs so that anyone unfortunate enough to get the disease later in life can be treated with larger doses and his blood-making capacity maintained with material kept in frozen adolescence.

  Chimaeras made with the help of stem cells sometimes use them to make not liver or brain but sperm or eggs. Then, all its offspring resemble the stem-cell parent, and, if that individual has been engineered, will carry the inserted gene. That played a crucial part in the tale of Dolly. Remarkable animal as she is, Dolly is, in the end, just a sheep. By adding DNA a small proportion of the millions of cells in a culture dish can be persuaded to rake up the alien gene and, with luck, force it to do its job. To insert such transformed stem cells into another animal does to mammals what was once possible only with bacteria. Dolly's successor, Polly, was cloned from cells that contained a human gene for the blood protein missing in one form of haemophilia attached to an on-off switch for sheep milk proteins. Sheep cells can be transformed in this way and, from one engineered beast, a whole herd can grow. Not many may be needed: a thousand animals could satisfy the world demand for the enzyme used to help patients with emphysema, but each may be valued at many thousands of dollars.

  The public has an impressive capacity for boredom; and many of the methods used to manipulate genes and produce animals without sex are becoming commonplace. In 1998, Switzerland, where the gothic tale of Frankenstein begins, held a referendum on whether to ban gene technology, electrical fusion included, altogether. The motion was defeated and the research has gone on. Perhaps cloning itself will, in a few years, be a standard medical technology.

  A passage written in 1818 on the first Swiss genetic engineering experiment: 'With an anxiety that almost amounted to agony, I collected the instruments of life around me, that I might infuse a spark of being into the lifeless thing that lay at my feet. It was already one in the morning, the rain pattered dismally against the panes, and my candle was nearly burnt out, when, by the glimmer of the half-extinguished light, I saw the dull yellow eye of the creature open; it breathed hard, and a convulsive motion agitated its limbs.' That reads better than its modern equivalent: The birth of lambs from differentiated fetal and adult cells reinforces previous speculation that by inducing donor cells to become quiescent it will be possible to obtain normal development from a wide variety of differentiated cells'. The report of Dolly's genesis does not have quite the ring of Mary Shelley; but marks the beginning of an era that will tax the most Gothic of imaginations. And what would Dolly's spiritual ancestor, that failed Scottish clone, the Bride of Frankenstein, have thought?

  Chapter Seventeen. THE EVOLUTION OF UTOPIA

  One reason why science fiction is so boring is that it is nearly all the same. The monsters may differ, but the plots do not. The same is true for most imaginary Utopias. From The War of the Worlds to Planet of the Apes an alien life form appears, masters the human race, and meets its doom because of its own weakness. Most novels of the future ignore one of the few predictable things about evolution, which is its unpredictability. No dinosaur could have guessed that descendants of the shrew-like beasts that played at its feet would soon replace it, and rhe chimpanzees who outnumbered humans a hundred thousand years ago would be depressed to see that their relatives arc now abundant while their descendants are an endangered species.

  Evolution always builds on its weaknesses, rather than making a fresh start. The lack of a grand plan is what makes life so adaptable and humans — the greatest opportunists of all — such a success. That utilitarian approach means that speculations about the future of evolution are risky. As Hegel put it, the greatest lesson of history is that no one ever learns the lesson of history.

  In the earliest Utopian novels, from Thomas More onwards, societies of the future were quite different from those of the writer's day. They might have golden chamberpots; but there imagination ended. The people who urinated into them were much like those who preferred to hoard the metal. After Darwin, Utopia evolved: society stayed the same bur people changed instead. Many of the best-known Utopian novels trace their visions of the future to Darwin. Samuel Butler, author of Erewhon (called in its first version Darwin Among the Machines), shared an education — Shrewsbury School and Cambridge — with the great man and was himself a keen evolutionist (albeit an anti-Darwinian). Aldous Huxley's Brave New World owes much of its plot to his biological brother Julian and to their grandfather Thomas Henry Huxley, Darwin's bulldog. H. G. Wells — whose Utopia, in The Time Machine, was based on the evolutionary theme of the human race splitting into two species — himself wrote a biological textbook with Julian Huxley; and, as we have seen, George Bernard Shaw, author of Back to Methuselah, was a follower of Galton and appeared on public platforms with him.

  Sometimes the link between the Utopian novel and eugenics is painfully clear. Shaw felt that 'if we desire a certain type of civilization we must exterminate people who do not fit into it'. H. G. Wells, in his scientific vision of the world to come, the (now obscure) Anticipations of the Reaction of Progress upon Human Life and Thought, published in 1901, wrote in favour of euthanasia for 'the weak and sensual' and of genocide for 'the dingy white and yellow people who do not come into the needs of efficiency'. Many Utopias would not have been comfortable places for those forced to live in them.

  This book has been a tale of how humankind has evolved by the same rules as those that propel less pretentious beings. Humans are, of
course, more than apes writ large. We have two unique attributes: to know the past and to plan the future. Both talents guarantee that our prospects depend on much more than genes. Nevertheless, it should be possible to make some guesses from biological history about what the evolutionary forecast might be.

  One pessimistic but accurate prediction is that it means extinction. About one person in twenty who has ever lived is alive today, but only about one in a thousand of the different kinds of animal and plant has survived. Our species is in its adolescence, at about a hundred and fifty thousand years old, compared to several times this for our relatives. Its demise is, one hopes (and in spite of the advances of nuclear physics) a long way away and we can at least reflect about what might happen before then.

  The rules of evolution are simple and will not change. They involve the appearance of new genes by mutation, their test by natural selection, and random changes as some, by chance, fail to be passed on. To speculate about the future of each process is to predict human evolution. Will the biological Utopia be like its fictional equivalents; will we continue to evolve as rapidly as we have since our beginnings, or is our evolution at an end?