Steve Jones, 1993 The Language
of the Genes,
Harper-Collins, London ISBN 0-00-155020-2
MOST biologists have not read The Origin of Species. The same is true, no doubt, for most Marxists when it comes to Das Kapital. After twenty years of studying evolution and constantly referring to Darwin's ideas, first perused The Origin on a Greek beach to ward off the unbearable tedium of being oii holiday. It was a remarkably easy read. However, the first couple of chapters were a surprise: far from being a deep account of the philosophy of existence, or even the theory of evolution, they are mainly about pigeons. Darwin went to great lengths to show how animal breeders had, by selecting the birds they liked best, produced varieties as different as the roller, the tumbler and the pouter from that rather ordinary bird the rock dove. Exactly the same process had created breeds of domestic cattle, of dogs and of horses. Darwin used the results of those who had applied evolutionary ideas without reallsing it to show that his theory actually worked. He went further than the pigeon fanciers only in suggesting that, if selection went on long enough, barriers to genetic exchange would arise. A new form of life, a new species, would be born. Evolution is now an applied subject in its own right although many of those who use it still do not reallse quite what they are doing. Until recently the methods of applied evolution, or biological engineering, have always been close to those of life itself. In life, tliikering works; and, given enough time, can be the means to an unexpected end. All technical advance once had this utilitarian approach. The engineers who designed stone tools or steam engines had no idea of the physics of how their machines worked and the first farmers developed new crops with no knowledge of heredity at all. Pragmatism led to progress, much as it had throughout history.
Nowadays, engineers have a very different world view. Their philosophy is to plan ahead and design what is needed, using as much scientific theory as is necessary. Applied biology, from agriculture to medicine, has adopted this approach only in the last few years. By so doing it is at the beginning of an advance as spectacular as that of transport since the steam engine. The fusion of Mendelism and Darwinism has already made farming much more productive. The amount of food available per head, worldwi 'de, has gone up in the face of the greatest population explosion in human history. This success has already brought problems and, if one thing is certain about the new attempts to engineer nature, it is that nature will respond in unexpected and unwelcome ways.
Mendel or Darwin would feel quite at home with some of the new technology. The 'Green Revolution' is based on traditional methods of plant breeding. One of its most effective tools is to use stocks of rice and wheat with stiffer and shorter stalks than normal. just a few genes are involved. Dwarf varieties were crossed with others with particularly rigid stems. Their descendants were mated with stocks containing genes for high yield and rapid growth. Plants which had the best qualities of the parental types were chosen and the process continued for several generations. To use Thomas Hunt Morgan's term (see P. 43), these plants were recombinants; they contained mixtures of characters (short stem and high productivity) never previously found in nature. At a stroke, one of the main problems of tropical agriculture, the tendency for rice and wheat to grow tall when fertiliser is used but to fall over in high winds, was solved. This simple trick transformed the rural economies of India and China. Directed evolution in less than fifty years gave a sixfold boost in crop yield. The increase in production was as great as that at the origin of farming ten thousand years ago. just the same approach works in animals. The Origin of Species itself describes the improvement of sheep using a 'short-stemmed' mutation. The Ancon gene shortened the legs of the sheep who bore it. This was convenient as it stopped them from jumping over stone walls, and the breed became popular. Now, alas, with the invention of barbed wire fences it has disappeared. Other useful genes for disease resistance in tropical cattle, increased growth in pigs, and so on have been bred into farm animals and spread by selection in the Darwinian way. Often improvements depend not on choosing single genes, but simply on breeding from the best (which usually involves changes at many genes at once). The results can be spectacular. After all, the poodle and the St Bernard had a common ancestor only a few thousand years ago. In 1904 an experiment was started in Illinois in which, each generation, maize plants particularly rich in oil were bred from. The experiment still goes on and, nearly a hundred generations later, the average amount of oil per plant has gone up by a dozen times; with no sign of any slowing of progress. Straightforward applied evolution (which involves nothing more radical than changing the direction of natural selection or bringing new mixtures of genes together) can do remarkable things. Another way of refining Darwinism is to increase the flow of genetic raw material upon which it feeds. More mutations may mean quicker progress. Penicillin production once depended on tiny amounts of antibiotic from large vats of fungus. By breeding from the most productive strains there was a hundredfold increase in yield. The next step was to mutate the genes involved, using radiation and chemicals. A whole new generation of antibiotic drugs soon emerged. The same approach has had great success in improving tomatoes. The supply of genes can be boosted in another way. The wild plants from which today's crops were derived are full of potentially useful variation. In modern farming, as in modern life, efficiency is gained at a price. Most crops are highly inbred. Each plant has exactly the same set of genes. They have reached an evolutionary dead end as no variability is left. However, their enemies, climate and disease, are not so constrained. During the 196os there was a setics of expensive disasters in th6 grain combines of North America. Nearly all of them had turned to growing the same variety of corn. Suddenly, fungi evolved to overcome its resistance to disease and millions of acres were wiped out. In 1970 2 sixth of the whole crop, worth billions of dollars, was destroyed. This sparked off a frantic search for their semi-domesticated ancestors (which retained many of the genes for disease resistance which had been bred out from the modern crops). Expeditions were sent to the Middle East and to the other great centres of plant diversity such as the Andes to find native stocks before they were replaced by western varieties. Although many genes had been lost for ever, there are now seed banks (some in unexpected places such as in the cold dry air of Spitzbergen) for most crops. They contain a mass of inherited variation, the fuel upon which biological engineering depends. Who owns this precious resource is another issue: at present, as in the exploitation of Africa by the nineteenth century colonial powers, genes are exported without much benefit to local people. Plenty of grains are preserved in excavations of the farms and homes of peoples long dead: the DNA which codes for a protein improving bread quality has been extracted from some wheat seeds collected in a British Iron Age fort two thousand years old. It is still a long way before such genes could be re-inserted into modern crops, but perhaps some of the inherited diversity driven to extinction by the spread of modern varieties has been spared in an unexpected way. The standard agricultural approach of breeding from the best evolution writ large has limits, which are often reached. The North Amerlcan maize crop and some of the more disgusting breeds of domestic dog can evolve no further: they have used up their genetic reserves. The most important constraint is set by sex: the fact that to make creatures with new mixtures of genes their parents must mate. There are strict biological controls as to who can mate with whom. The partners must, of course, be of different sexes, but they must also come from the same species. This is the best way of defining what a species actually is: two individuals belong to the same one if they can combine genes in their offspring. To recombine genes in nature or on the farm sex is unavoidable. Although this restriction seems inevitable it decreases the raw material available to the evolutionary engineer. Genes which might be useful in improving one creature cannot be used because they are locked away within another. Usually there is no way of getting through the reproductive blockade. Species put limits on genetic free trade. They mark biological frontiers which mean that a profitable gene which emerges in one species cannot be exported to another. The biggest advances in applied genetics come from breaking the sex barrier. This is how agriculture itself began. Early farmers ameliorated nature by irrigation or by clearing trees to allow vegetation to flourish. This disturbed the local ecology. In such habitats plants which never normally meet came together. The barriers between plant species are more permeable than those which divide animals and, occasionally, hybrids appe ared. They contained combinations of genes which had not been seen before. The process can be seen at work today. Many mudflats around Britain are being covered by a tough grass. It is a hybrid between a local species and one accidentally introduced from America. The new species, a mixture of the genes of its predecessors, is better at coping with a harsh and salty environment than was either of its parents, and is rapidly becoming a pest. Crop plants, like those who cultivate them, retain their genetic history within themselves. Chromosomes show that modern wheat began when two species of grass hybridised. Each survives today in the Middle East and produces seeds which can be used for food. As in the estuarine grass, the hybrid was more productive than either parent. Perhaps the barrier to mating was broken by chance; or one species may have been planted among natural populations of the other. However the hybrid was formed, the farmers of ten thousand years ago quickly made use of it. Soon, another grass crossed with the new crop, improving it further. This was the predecessor of every one of the billions of wheat plants grown today. The new crop contained a wider range of genes than any of its ancestors. Inadvertently, the early farmers had moved chromosomes, genes and DNA from one species to another. They were the first genetic engineers. Now, trading genes between species in this way no longer depends on good luck. Planned parenthood is involved. The new crop triticale is a hybrid between wheat and rye. It can grow in hot dry places and will be of great benefit to tropical agriculture. Triticale and the other hybrids are just the first step towards a free market in genes. Genetic engineering is a way of circumventing sex altogether. Molecular biology makes it possible to shift genes among lineages which are normally insulated from each other; to make recombinant DNA without bothering with sex. Improvements in technology mean that genes can be moved from more or less anywhere to anywhere else. Already, they are routinely transferred between creatures as distinct as humans and bacteria. DNA can be used throughout the living world, wherever it comes from. Genetic engineering began in bacteria, which have a commendably wide range of sexual interests. They exchange genes in many ways; by taking up naked DNA, by a process of mating rather like that of higher animals and by using a whole range of third parties, such as viruses, to transfer DNA. This 'Infectious heredity' (which suggests that venereal disease evolved before sex) has been subverted by science. The gene to be engineered (which may be from another bacterium, from a plant or from a human being) is inserted into a piece of viral DNA using various technical tricks. The manipulated virus plus its new gene is used to infect a new host. With luck, the recipient will treat the immigrant DNA as its own, making a copy every time its cells divide. In this way bacteria can be persuaded to make vast numbers of copies of the engineered gene and vast amounts of whatever it manufactures; pure human proteins, drugs, or an array of other things. The same methods can be used on plants, animals and even humans. A new field of applied Darwinism has been born. Crossing the sexual divide, deep though it is, between bacteria and other creatures proved surprisingly easy. One of the first human genes to be used was that for the hormone insulin. Insulin was once extracted from the pancreas of pigs. Now the human gene has been cloned and large quantities of the pure protein can be produced. Human growth hormone, too once extracted laboriously and with much controversy from the pituitary glands of the recently dead is now made in the same way. This gets round a macabre and unexpected problem. A few patients caught a nervous degenerative disease from corpses carrying a virus. The story of this medical disaster is close to that of those infected with AIDS when factor VIII from donated blood was used to treat haemophiliacs. Now, the factor VIII gene, too, has been inserted into bacteria and some patients are treated with the bacterial product. Genetic engineering can be used against infectious disease. Jenner could use the cowpox virus to vaccinate against smallpox (an experiment which would fall foul of even the most lenient Ethics Committee today) because the two viruses share antigens, cues of identity recognised by the immune system as the basis of its defensive response. Antibodies against cowpox protect against smallpox. However, there are dangers; cowpox itself can cause problems and even in modern vaccines there is a small risk of infection or of a reaction to the injection of foreign proteins. Man@, diseases (such as leprosy) cannot be helped by vaccination because it is hard to grow their causative agents in the laboratory. A cunning piece of engineering gets round the problem. The antigen genes from an agent of disease are inserted into a harmless bacterium. There is no risk of accidentally spreading the disease as the genes for virulence have been left out. Antigens from several different sources can be inserted into the same bacterium, to give a single vaccine against many infections at once. A modified strain of Salmonella (which in its native state can cause food poisoning) is used. The bacterium, with its added antigens, flourishes for a short time in the gut. By persuading the host that it has been infected it ensures that antibodies are made. A vaccine made in this way is being used to treat wild foxes in the hope of slowing the spread of rabies across Europe. Engineering a way through the sex barrier is also important in agriculture. Huge sums of money can be made by increasing crop yield and huge amounts of work are being done by those who hope to benefit. Some of the tricks are simple. Plants can make copies of themselves from only a few cells. This makes it possible to produce many plants from one without bothering with sex at all. It is hard to improve trees by breeding from the best, because it takes so long. By finding a superior specimen and breaking its tissue into single cells, copies of that super-tree can be grown to give, within a single generation, a super-forest. The process is used to grow improved oil palms and there is hope of replacing the elms which once filled the English countryside (and were devastated by Dutch Elm Disease) with clones resistant to infection. A related method may replace natural vanilla, now extracted at great experise from a tropical orchid, with the same chemical extracted from cultures of vanilla cells grown in the botanical equivalent of a factory farm. Genes can also be inserted into plants. As most lack certain amino acids it is hard to stay healthy on a strict vegetarian diet. Much could be done by moving the right genes in. Many plants produce powerful natural pesticides not surprisingly, as they are at constant risk of attack. Some of them, coffee, cocaine and pepper for example, are used as drugs for pleasure or profit. Now the pesticide genes from one species can be shifted into another; which may cut down the use of toxic sprays. Another trick is to introduce a gene which makes the plant resistant to weed-killers. The field can be sprayed, killing the weeds but leaving the crop untouched. Plants can even be 'vaccinated' by introducing a few of the genes from their natural virus enemies. When the virus strikes, it uses the plant's machinery to make copies of itself. If parts of its own structure are already being made, this interferes with the copying mechanism and the attack falls.
We grow plants because they make useful products food, for example. They could be used as much more versatile biological factories. There is already the prospect of using potatoes to make proteins from human blood and tobacco to make antibodies. The glittering prize for the agricultural engineers is to introduce genes which allow crops to make their own fertilisers. Clover has already evolved an arrangement with certain bacteria. The bacteria take nitrogen from the air and turn it into a form which can be used by the plant. In return they gain food and protection. Farmers plant mixtures of grass and clover which are more productive than either grown alone. Putting nitrogenfixing genes directly into crops would dramatically reduce the need for fertilisers. No-one has yet succeeded in making the right bacterial genes work in a plant cell. The rewards for doing so are huge; and no doubt there will be success one day. All this may mean that plants will soon do almost everything and that animals will fade in importance as perhaps the salmon-flavoured banana takes over. No doubt a few unregenerate carnivores will remain. Applied evolution can help them, too. Cow embryos are made in the laboratory by fertilising desirable eggs with superior sperm, allowing them to divide and splitting them into smaller portions which are introduced into new mothers (who need not themselves have any particular merit). This multiplies the number of high-quality calves. It is easy to freeze the embryos until they are needed and surrogate motherhood is already used on thousands of cows each year. Perhaps it will become possible to use adult cells in the same way. The rural landscape may become one in which asexual cows feed on engineered grass under the shade of clonal trees. Foreign DNA can be introduced into animal cells, too (although the process is not as easy as in bacteria or plants). Body cells or eggs can be used: in the latter case the gene may be passed on to later generations. Already, genes for human proteins such as one of the haemophilia clotting factors has been introduced into sheep so that the pure protein is produced in their milk (giving a new rural pastime called 'pharmaceutical farming', which will, no doubt, one day attract a subsidy from the Common Market). Mice with human growth hormone genes inserted grow up larger than normal. The same DNA has been put into pigs, but although the animals grow quickly they are unhealthy. Fish are easier to handle. Their large eggs take up foreign DNA and the growth hormone gene can make hatchery fish grow more quickly. Another ingenious idea is to introduce the DNA which codes for a natural 'antifreeze' found in arctic fish into tropical species, enabling them to grow in northern waters. Even insects can be engineered. It will soon be possible to insert genes for insecticide resistance into useful creatures (such as a mite which attacks crop pests) allowing crops to be sprayed without destroying the pests' natural enemies. All this is all very well. However, to interfere with the boundaries between species can stir a deep unease. It has met with resistance, up to and including some fairly decorous German riots. Part of the problem is the word 'engineering', which contains more of a threat than does the cosy term 'domestication' used of the first genetic engineers. Part comes from the caution of biologists themselves who, at the beginning of the new age twenty years ago, froze new experiments until safety rules were worked out. There is also a fear of germs, based on the idea that all bacteria are harmful. They are in fact essential, each one of us containing ten times as many bacteria as we have cells of our own. Most important, people are suspicious of technical fixes; the idea that technology can overcome all problems. From nuclear power to irrigating the desert the optimism of engineers has often turned out to be a shortlived thing. There are concerns about economic side-effects, too. The Green Revolution, although it improved food production, drove farmers from the land as large companies gained control of seed production and the sale of fertillsers. Much the same happened in the early days of American farming. In the 1930S there appeared new strains of hybrid corn which as at the beginning of agriculture were made by crossing two lineages together. Their sale was controlled by a few combines who by manipulating the price drove niany small farmers out of business. Genetically engineered stocks (which are protected by patent law) pose the same danger of a new harvest of the grapes of economic wrath. Few farmers could bargain with an organisation which had a monopoly on the sale of a herbicide-tolerant plant and sold it in consort with the herbicide involved. It also makes little sense to spend money increasing the numbers of dairy cattle by embryo transfer when there is already a surplus of butter, or genetically manipulating wheat to add to the grain mountain.
The most widespread fear is of the escape of genetically manipulated creatures who may unleash a new plague upon the world. Biologists have some standard defences to this concern. Genetically manipulated creatures are likely to be less fit than those which have not been interfered with. After all, if the gene gives its carriers an advantage it might be expected to have evolved by natural means. The unfitness of artificial creatures is already obvious. Most farm animals and plants cannot survive outside farms, which is why the streets are not full of marauding cows, sheep or potatoes. The same is likely to be true of bacteria and viruses. In Britain and the United States, children are injected with live polio virus which has been 'attenuated' to make it less dangerous. Surveys of sewage show that this live virus is constantly escaping. This is the key to the scheme's success: even children whose parents do not allow them to be vaccinated are exposed to the virus emerging from their friends who have )'ust been treated. However, the attenuated virus has never survived in the wild; it depends on a constant supply of newly vaccinated children. If all genetically engineered organisms are as feeble as the polio virus, there is not much to worry about. Nevertheless, it is worth remembering that almost every domestic animal is a pest somewhere. Cats wiped out most of New Zealand's birds. Goats have done the same or worse in many places, feral pigs are everywhere in the subtropics and even horses can be a nuisance as they roam the California deserts. Plants are even more destructive. Everyone knows about the prickly pear in Australia, but a pretty yellow South African garden plant, the sour-sop, is doing enormous damage to grazing lands. Wherever domesticated creatures have escaped, native plants and animals have suffered. The brash biologist can and does argue that we know enough not to repeat these early mistakes. Biologists also point out, quite correctly, that much of what genetic engineering does is perfectly natural. Recombinant DNA is made every time sperm meets egg; species are not fixed enti i 't'es as they evolve from one into another and regularly in bacteria and sometimes in plants they even exchange genes by natural means. Huge numbers of bacteria are constantly produced, the human race alone excreting a total of ten with twenty-two zeros after it bacteria each day. Because of mutation, many must consist of genetically new forms and a few, through the vagaries of their reproduction, must include genes incorporated from other species. None has spread and gut bacteria remain benign. These arguments have persuaded those in charge to permit the release of a few genetically manipulated organisms. In California, crops are damaged by frost. As the air cools, small patches of ice appear on the leaves around natural colonies of Pseudomonas bacteria. One bacterial gene is response 'ble for this irritating behaviour. Occasionally it changes by mutation to produce an 'ice-minus' strain which does less harm. Now an artificial ice-minus bacterium has been made, which, when sprayed onto plants, cuts down frost injury by displacing the icy natives. The gene was removed from a normal bacterium, sections cut out and the altered DNA re-introduced into a Pseudomonas stock. Although the bacteria are in some senses not engineered at all as the genes involved come from their own species, the plan caused an uproar and was delayed for several years. This irritated agricultural researchers. As they pointed out, legal controls would prevent moving DNA from a weed to a crop to improve it which is what happened at the beginning of farming when the first wheat was made. After many courtroom battles the release was allowed (largely because ice-minus bacteria have turned up thousands of times by natural mutation with no apparent harm). During the court cases about ice-minus it emerged that the military had already done dreadful things without the public being allowed to know. Biological warfare was once a popular excuse for spending more on defence. What the army really wanted to study was how best to infect people. In the early 195os huge numbers of Serratia marcescens bacteria, then thought to be harmless, were sprayed over San Francisco and other American cities to investigate how they spread. Since the experiment it has been learned that Serratia can infect those already debilitated by disease and a number of then mysterious infections at the time were due to the bacterium (although they have never been tracked down to the strains sprayed by the army). The experiment shows that even a perfectly natural bacterium which appears to have no ill effects may be dangerous when placed in unnatural circumstances. There are other dangers in genetic engineering. What if the new gene gets out of its own species and into another? Herbicide resistance genes might get from Crop plants into their weedy relatives (which, for crops like oil-seed rape, occasionally hybridise with them), giving a new super-weed resistant to spraying. Fish-farming involves so many escapes that the genetic structure of North Atlantic salmon has already been damaged by breeding between farmed and local populations. What might happen if the anti-freeze gene allowed escaping tropical fish to displace or hybridise wi 'th the natives? Although some fears are exaggerated, to release genetically manipulated creatures is to play with the unknown and hence, inevitably, to take a risk. Some scientists' defences suggest that the risk is so tiny as to be not worth considering. They are still in a phase of technological absolutism. Trust us, they say, and nothing will go wrong. They sound incannily similar to the engineers who developed nuclear power, or drained the Florida Everglades. Like the Bourbons, certain biologists seem to have forgotten nothing of the successes and learned nothing from the disasters of previous occasions when a science evolves into a technology. A few enthusiasts even disregard the nature of their own subject. They claim that inadvertently creating a monster by genetic engineering is no more likely than making a television set by randomly mixing electronic components. In this they echo a standard creationist argument which is (to quote Duane Gish, one of the founders of the Institute for Creation Science) 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. Evolution is all about assembling the improbable by tiny steps; and not until the unlikely has been reached do we notice just what it can do. Genetically engineered organisms will, like any other creature, evolve to deal with their new condition. It is fairly certain that some of them will cause problems. Low risk is not no risk. The question is olle which is universal in economics will the benefits outweigh the costs? For genetically manipulated organisms nobody knows as the experiment has not yet been done. There may be a precedent in another much-vaunted piece of biological engineering, the chemical control of pests. The first modern insecticide, DDT, was introduced at the end of the Second World War to control lice. It was a spectacular success. The optimists were soon in charge. Their approach was that of an engineer: with money and technology one can do anything. Predictably enough, the animals responded by evolving to subvert the technical fix. Nowhere is the danger of certainty seen more clearly than in the fight against malaria, where biological bumbling triumphed over engineering elegance. After the conquest of lice, DDT was sprayed onto malarial mosquitoes. Victory soon seemed imminent. The number of infections fell dramatically, in Ceylon from millions to scores. The rot soori set in as genes for resistance to insecticides spread through the mosquito population. The counter-attack has been so effective that malaria is raging at unprecedented levels. The World Health organisation admits that 'the history of antimalaria campaigns is a record of exaggerated expectations followed sooner or later by disappointment'. The parasites, too, have subverted human attempts to engineer them out of existence. Although resistance took longer to develop than in the mosquitoes, in many places the old malaria treatments are now useless as the parasites have evolved means of coping with them. The standard Darwinian mechanisms of mutation and natural selection have helped insect and parasite to survive. Among the insects, there is a bewildering range of new mutations. Some break down insecticides or stop them from getting in. Some allow the insect to store the poison, some change the shape of the target molecule and others enable the insect to avoid places which have been sprayed. The parasites, too, have evolved a variety of tactics against their chemical enemies. The anti-malarial drug chloroquine was developed in the 1940s. Thirty years ago it worked almost everywhere. In the 196os resistance appeared in south-cast Asia and South America. It is now all over the tropical world. One of the most effective defences resembles the mechanism used by cancer cells to combat anti-cancer drugs. A massive amount of a protein involved in transporting material across membranes is produced and this pumps the drugs out of the cell fifty times more quickly than normal. More recently, genes which give resistance to other drugs sometimes several at the same time have turned up. The Walter Reed Army Institute in the USA screened more than a quarter of a million compounds in the hope of finding a new anti-malarial drug. Only two proved suitable. One was mefloquine, and in Thailand eighty per cent of the malaria parasites are now resistant to it. In iggi there were claims that malariologists are now down to the last drug, 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) although these treatments are toxic and not particularly effective. The history of genetic engineering may, when it is finally written, turn out not to be too different from that of the war against the insects, in which evolution prevailed after some initial setbacks. Insecticides have worked well and continue to do so. Without them, there would have been no Green Revolution and most tropical crops would be uneconomic. Lice might still be carrying typhus through the poorer parts of Europe and malaria killing even more people than it does today. However, the triumph of human ingenuity has not been unalloyed: because living organisms can deal with new challenges by evolving to cope, genetic engineers, unlike those who build bridges, must face the prospect that their new toys will fight back.