by Steve Jones
The brash biologist can — and does — argue that we know enough not to repeat such mistakes. Biologists also point out that much of what engineering does is quite natural. Recombinant DNA is made every time sperm meets egg; species are not fixed entities as they evolve from one into another, and — often in bacteria and sometimes in plants — they even exchange genes by natural means. Huge numbers of bacteria are produced, mankind alone excreting ten with twenty-two zeroes after it of the minute creatures each day. Because of mutation many are genetically new and a few, because of the vagaries of reproduction, must include genes incorporated from other Species. None has spread and gut bacteria are, in the main, benign.
Viruses give fewer grounds for comfort. Most of the flu epidemics that cross the world each winter begin in China, when the human flu virus picks up genes from those of wild birds. Only when they pass from ducks to pigs to ourselves do the new mixtures cause trouble, but they are salutary reminder of our vulnerability to rare events in distant places.
The release of manipulated organisms was long delayed by such concerns. In California, crops are damaged by frost. As the air cools, patches of ice appear on the leaves around natural colonies of Pseudomonas bacteria. One bacterial gene causes this tiresome behaviour. Sometimes it changes by mutation to produce an 'ice-minus' strain that does less harm. Now an artificial ice-minus bacterium is sprayed onto plants and cuts down frost injury by displacing the natives. The gene was moved from a normal bacterium, sections cut out and the altered DNA reintro-duced. Although the bacteria are in some senses not engineered at all as the genes come from their own species, the plan caused an uproar. This irritated agricultural researchers. As they pointed out, legal controls would not allow DNA to be moved from a weed to a crop, which is what happened when the first wheat was made. After many battles the release was approved.
During the court cases it emerged that the military had already played with Californian bacteria. They wanted to know how best to infect people. In the 1950s huge numbers of Serratia marcescens bacteria, then assumed to be harmless, were sprayed over San Francisco to see how they spread. Now it is known that Serratia can infect those already debilitated by disease and that a number of mysterious infections at the time were due to the bug. Even a natural bacterium which appears to have no ill effects is, it seems, dangerous when placed in unnatural circumstances.
And what if a new gene gets out of its own species and into another? Herbicide resistance genes might get from crop plants to their weedy relatives. For plants like potatoes, with no wild species in the Old World or in North America, that is unlikely, but oil-seed rape and sugar-beet in Britain, and sunflowers in the United States have plenty of local relatives with which they could hybridise. In places where wild turnip and oil-seed rape grow close together as many as one seed in a hundred is a hybrid and many of the plants that emerge are perfectly healthy. The Round-Up resistance gene has been crossed into the hybrids and works perfectly well with no apparent effects on survival. A spray-resistant wild turnip — perhaps the first of many resistant weeds — may be around the corner. Animal genes, too, may stray into unwelcome places. So many fish escape from farms that the genetic structure of North Atlantic salmon has already been damaged by crosses between farmed and local populations. Some plan to move anti-freeze genes from Antarctic fish to their warm-water relatives to farm them in colder and more productive waters. What might happen if escaped tropical fish hybridise with the natives?
To release manipulated beings is to play with the unknown and hence, inevitably, to take a risk. Some scientists suggest that it is so tiny as to be not worth considering. They are still in a phase of technological absolutism. Trust us, they say; bur like the engineers who developed nuclear power or drained the Florida Kverglades, or the Bourbons, they have forgotten nothing of the successes and learned nothing from the failures of history.
Such enthusiasts disregard the nature of their subject. They claim that the chances of an inadvertent monster are no greater than those of a television made from a random mix of electronic components. In this they echo n familiar creationist argument; that the chances of an organ as complex as an eye arising without divine intervention are the same as those of a whirlwind building an aeroplane as it blows through a factory.
For aeroplanes that is true enough. Those who set safety standards for the first experiments on genetic engineering demanded that the risk be worked out in the same way as in the Boeing factory; if the chance of valve number one failing is one in a thousand, and of valve number two is the same, then the joint chance of both failing at once is one in a million. Such calculations made for the risk of a manipulated virus used to attack caterpillars changing to resemble a relative that attacks humans suggest that the danger to be one in innumerable billions.
Such figures, precise though they can be made to seem, are meaningless, for natural selection is all about assembling almost impossible things; not by instant and improbable leaps but by tiny and feasible steps. Not until the unlikely has been reached, do we notice what evolution can do. Engineered organisms will, like any other being, evolve to deal with their new condition and, in spite of the confidence of their designers, some will cause problems. Low risk is not no risk. It is an economic issue — will the benefits outweigh the costs? For genetically manipulated organisms nobody knows as the experiment has not yet been done. There is, though, a precedent in another much-vaunted piece of biological engineering.
DDT was introduced at the end of the Second World War to control lice. It was a spectacular success. The optimists took charge and used the engineer's approach: with money and technology one can do anything. However, biological bumbling soon triumphed over engineering elegance.
After rhe conquest of the louse, DDT was sprayed onto malarial mosquitoes. Victory soon seemed imminent. The number of infections fell, in Ceylon from millions to scores. The rot set in as genes for resistance spread. The counterattack has been so effective that malaria is raging at levels greater than before and the World Health Organisation admits that 'the history of anti-malaria campaigns is a record of exaggerated expectations followed sooner or later by disappointment1. The parasites, too, have subverted attempts to engineer them out of existence and in many places malaria treatments are now useless as the disease organism has evolved means of coping with them. Mutation and natural selection helped both parties survive.
The parasites have a variety of tactics. Chloroquine was developed in the 1940s. Forty years ago it worked almost everywhere. In the 1960s resistance appeared in south-east Asia and South America and has now spread over the tropical world. One defence resembles the mechanism used by cancer to combat drugs. Massive amounts of a transporter protein are made and pump the drugs out of the cell at fifty times the normal rate. Genes that give resistance to other drugs — sometimes several at a time — have also turned up. The Walter Reed Army Institute in the USA screened more than a quarter of a million compounds in the search for a new anti-malarial drug. Only two proved suitable. One was mefloquine, and in Thailand almost all the parasites are now resistant. Medicine is now down to the last remedy, with nothing new in sight. As a result doctors are returning to quinine and to an extract of wormwood (first used in China a thousand years ago), treatments that are toxic and not very effective.
The history of genetic engineering may, when it is written, turn out not to be too different from that of the war against the insects, in which evolution prevailed after initial setbacks. All is not gloom. For some targets, insecticides have worked well and continue to do so. Without them, there would have been no Green Revolution, lice might still be carrying typhus through the poorer parts of Hurope and malaria killing even more than it does today. In rime, no doubt, economics will prevail over hysteria when it comes to genetically manipulated plants as well. The triumph of ingenuity will not be unalloyed. Only one thing is certain about the new attempts to engineer nature; that nature will respond in unexpected ways. Because living organisms deal with new c
hallenges by evolving to cope, genetic engineers, unlike those who build bridges, must face the prospect that their new toys will fight back.
Chapter Sixteen THE MODERN PROMETHEUS
Geneticists never use the F-word but often have it turned against them. This chapter takes the subtitle of Mary Shelley's great work. Her monster has been used again and again to berate the efforts of scientists. Frankenstein's creation almost gained a Scottish mate, for his maker journeyed to the Orkneys to manufacture a female for his fierce original. He destroyed it at the last moment: 'Even if they were to leave Europe, and inhabit the deserts of the New World, yet one of the first results of those sympathies for which the daemon thirsted would be children, and a race of devils would be propagated upon the earth who might make the very existence of the species of man a condition precarious and full of terror. Had I the right, for my own benefit, to inflict this curse upon everlasting generations?'
Two centuries later, and two hundred miles south, in the Scottish Borders, was born a lamb which, according to the report in one New World newspaper, at once turned carnivore and devoured her flock-mates. She became the most famous sheep in history. Dolly is not a curse, but has a sweet nature (although, like some biologists — her makers not included — she rushes bleating to the front whenever she sees a camera). Reproduction without sex had hit the headlines. It had in fact been around for some time, but the public was not much interested; even when, in 1985, the genes from a sheep embryo cell were put into a different egg and made a cloned lamb.
Dolly was different. Her birth in 1997 amazed researchers because her genes came from an adult cell that had been persuaded to take a leap back into infancy and to start again. Since then, there have been many more cloned mammals — sheep, mice, cattle and goats — with yet more on the way. The egg that made the sheep Tracy was engineered to make valuable drugs in her milk and there may soon be cows that make human breast milk. Dolly herself has a daughter, Bonnie, made in the traditional sexual way, and the descendants of Tracy and her fellows may grow into factory flocks, worth millions.
And what about the ultimate clone? People have long chosen partners, but now, for the first time, comes the chance of the most perfect choice of all, that of a child in one's image. Quite what that implies is not clear — would a cloned Mozart have written Don Giovanni? — and quite why anyone would want to do so is uncertain; but the chorus is against it. The World Health Organisation calls the procedure 'contrary to human integrity and morality', the European Parliament is convinced that cloning '. cannot under any circumstances be justified or tolerated by any society, because it is a serious violation of fundamental human rights and is contrary to the principle of equality of human beings as it permits a eugenic and racist selection of the human race, it offends against human dignity and it requires experimentation on humans' and the Vatican is certain that it is 'contrary to moral law' as it is 'in opposition to the dignity both of human procreation and the conjugal union1. Political knees jerk as one when they see the chance for a headline, but Dolly's own progenitor — whose views deserve respect — calls human cloning 'an ugly diversion; superfluous and in general repugnant' (which does not inhibit the seven per cent of Americans who, according to one poll, would be happy to clone themselves).
Cloning, though, is but the latest stage in the manipulation of our reproductive machinery. Most people are ready to accept pregnancy termination on genetic grounds; and, in spite of the concerns about modified plants and animals, have no complaints about gene therapy, should that ever come to fruition. However, to interfere with the next generation, by engineering eggs or sperm or by cloning is, it seems, a step too far.
Even before Dolly, sexual technology had begun to explode. The demand is high. One married couple in six suffers from some failure of fertility, and miscarriages take place in about the same proportion of all pregnancies. At least a million people have been born by artificial insemination, and by 2005 there may be almost as many who trace their origins to a test-tube. Indeed, the chances of reproductive success in such a vessel are higher than those when trying to have a baby by more traditional means. Now, such methods are beginning to change the practice of genetics.
Many inborn illnesses, from PKU to cystic fibrosis, can be treated with some success. Such treatments deal with symptoms, rather than putting right the fundamental flaw — which is no more that what medicine does for most illnesses. Gene therapy gives hope of a cure. In its purest form, it offers the hope of replacing a faulty section of DNA with a normal equivalent, and putting right the problem at source. The idea is a powerful one: and nobody who accepts the necessity of inserting a new heart and lung can quarrel with the idea of replacing a piece of nucleic acid. Whatever its promise, gene therapy has, unfortunately, failed to live up to its headlines.
In principle, the job ought to be if not easy, at least feasible. DNA can be inserted into cells in culture in many ways. Copies made in a laboratory are infiltrated with the help of a virus or wrapped in envelopes of fat that are accepted by the cell as its own. Working genes can even be shot into cells by firing gold spheres coated with DNA from a tiny gun. Twenty years ago there were great hopes that such technology would revolutionise medicine. There have been many claims of success, but only one has much weight. Severe combined immunodeficiency is an inherited failure of the immune system that arises from the absence of a certain enzyme. Children with the condition are kept in a plastic bubble to reduce the chances of infection, and are given bone marrow transplants and injections of the enzyme to help their defences. Cells which lack the crucial protein have been 'cured1 with the appropriate DNA. Several children have been treated with such engineered cells- They are still alive and even go to school. As most of them were also given extracts of the enzyme it is not yet certain that their improved health is due to the gene manipulation.
Whatever this success, all other claims have been premature. Two hundred or so patients with cystic fibrosis have been treated and the best result has been a small and transient improvement in symptoms. The technology has risks of its own. One American patient with liver disease was injected with an engineered virus based on that for the common cold and died as a result. Many others in the trials have not survived (although most were already desperately ill). Some of the most frequent diseases are going to be difficult to treat. To cure sickle-cell would involve targeting tiny numbers of cells deep within the bone marrow, as it is these and not the red blood cells which produce the faulty haemoglobin. For diseases such as muscular dystrophy it might be necessary to deliver a gene direct to millions of separate muscle cells, and to ensure that it is switched on at just the right level of activity.
Molecular biology could be used in medicine in many other ways, some of which have attracted the 'gene therapy' label. Cells can be engineered to carry genes that destroy cancer cells or cause them to stop dividing. It might be possible to introduce DNA that stimulate the immune system's own defences inro cancer cells themselves, providing them with the seeds of their own destruction. Another ingenious idea is to insert drug-metabolising genes into such cells, and then to treat them with a chemical that is broken down into a poison — but only in cancer cells. To establish the DNA sequence of a faulty gene also gives the prospect of making 'anti-sense' nucleic acid which binds to the genetic message and blocks it to turn off genes that have gone wrong. All this lies in the future.
The new biology offers more hope for improvements in diagnosis. Molecular probes can detect mutations long before symptoms first appear. Cancer cells often develop unusual antigens on their surface as new genes are switched on. It may become possible to work out the shape of the protein involved and to make a match that sticks to the relevant place. Not only will this show where the damage lies, but if a drug is attached, it may be possible to point a treatment straight at its target.
Engineering might do even more: in theory it could be used to treat generations yet unborn. In mice this has already succeeded. Genes inserted into sperm
or egg cells may be passed on. The germ line, as it is known, has been changed. Such 'transgenic mice' are valuable research tools. If genes for a human disease are introduced they can used to study its symptoms (although these may differ those found in humans themselves) and the mice may be used to test drugs. Transgenic mice have been made for sickle-cell anaemia and other inherited illnesses, as have transgenic pigs with some of the genes for human cell surface variation. Their organs — heart and kidney — are about the right size for a transplant and are more acceptable to a human recipient than they otherwise would be. Such pigs look just like pigs; but, to our immune system, resemble a human being. A counterfeit heart has not yet been used for transplantation, but soon may be. As more than a hundred and fifty thousand people die in Britain each year because it is impossible to find a matching organ this may become important in medicine.
Every therapy must work to rules. Everyone has rights to their own body and can decide whether or not to accept treatment. The same logic can be applied to genes. To replace damaged DNA, should that become possible, is not much different from transplanting a kidney and the same choices must be made by the person who receives it. To change genes in sperm or egg is different because it alters the inheritance of someone who has no choice. Many feel that on this and other grounds germ line therapy is unacceptable and have tried to add to the Universal Declaration of Human Rights a statement that everyone has the right to a genetic constitution that has not been changed.