Steve Jones.Evolution is now a practical subject in its own right although many who use it do not realise what they are doing. Inventors once used an approach close to that of the natural world. For gadgets and life, tinkering works; and can be the means to an unexpected end. Just like the engineers who designed stone tools or steam engines with no understanding of physics, the first farmers developed new crops with no knowledge of heredity at all. Pragmatism led, as always, to progress.
Nowadays, technicians in concrete or metal have a different attitude. They design what is needed with as much scientific theory as is necessary. Applied biology, from agriculture to medicine, has adopted this approach only in the last few years and has begun to advance as much as has transport since Stephenson's Rocket. For biology, a new steam age (albeit not yet a space age) is upon us.
A fusion of Mendelism and Darwinism has made agriculture much more productive. The amount of food available per head, worldwide, has gone up in the face of the greatest population explosion in history. In the developing world there is still room for progress as half of all crops are lost to weeds (a figure last seen in Europe in the Middle Ages) and disease can lead to the loss of entire harvests. In Africa, indeed, such is the rate of population growth that – against the world trend – the amount of food produced per person is decreasing. Third-world farming has a long way to go before it catches up. General economicweakness is much to blame, but some of its failure is because it lacks the technology used elsewhere.
Darwin or Mendel would each feel quite at home with most modern agricultural research. In Illinois in 1904 an experiment started in which, each generation, the maize plants most rich in oil were bred from. The work still goes on and, a hundred generations later, the amount of oil has gone up by a hundred times with no sign of any slowing of progress.
Such straightforward applied evolution can do remarkable things, as any cattle-breeder can attest. The `Green Revolution' took a step further down the genetic road. Its success came from crosses between new and productive stocks of rice and wheat, bred in the Darwinian way, and other lines with stiffer and shorter stalks. Just a few genes were involved. Dwarf varieties were crossed with others with rigid stems. Their descendants were mated with stocks that contained genes for high yield and rapid growth. Plants which combined the best qualities of their parents were chosen and the process continued for several generations. Sex – genetic recombination – did the farmers' job by making new mixtures of genes. It solved a major problem of tropical agriculture, the tendency of rice and wheat to grow tall when fertiliser is used, but to fall over in high winds. One simple trick transformed the rural economies of India and China. In fifty years, planned gene exchange gave a six-fold boost in yield, a figure as great as that at the origin of farming ten thousand years before.
Another refinement of Darwinism involves an increase in the flow of raw material upon which it feeds. To damage DNA can produce new genes ready for use by an alert • technologist. Penicillin once depended on tiny amounts of antibiotic made in vast vats of fungus. Breeding from the most productive strains gave a hundredfold increase. The next step did much more: mutations caused by radiation and chemicals led to a new generation of antibiotics, never seen in nature.
An even better way to renew the fuel for selection is to import genes from other species. One of the successes was the new crop triticale, a hybrid between wheat and rye. It can grow in dry places and is of benefit to agriculture in places (such as the American Great Plains) low in rainfall. It demonstrates the gains to be made by even a modest investment in moving genes between species. Another approach is to turn to a domestic planes untamed relatives, as has been done with wheat itself by crossing with wild grasses that contain genes of value on the farm.
The standard agricultural approach of breeding from the best – evolution writ large – has limits, which arc soon reached. Many crops and farm animals can evolve no further because they have used up their genetic reserves and have nu source from which to replenish them. The constraint is set by sex: by the fact that to make creatures with new mixtures of genes their parents roost mate. In spite of occasional lapses in the plant world, there are strict biological controls as to who mates with whom. Thc partners must be of different sexes but the saine species. A few modest exceptions – triticale being one – are allowed: but to recombine genes, in nature or on the farm, sex is unavoidable. That law much decreased the ambitions of evolutionary engineers because genes that might he useful in improving one form arc locked away within another.
Agriculture itself began with some mild infringements of sexual convention. Farmers ameliorated nature by clearing trees to allow vegetation to flourish. Plants that never normally meet came together and, from time to time, hybrids appeared. They contained combinations of genes never seen before. The process goes on. Many mudflats around Britain are covered by a tough grass, a hybrid between a local species and one introduced from America. The newmixture of genes does better in a harsh environment than does either parent, and has become a pest.
Chromosomes show that modern wheat began when two species of grass (each of which is still used for food in the Middle East) hybridised. As on the mudflats, the new cross was more productive than either parent. Soon, another grass crossed with the new recombinant, improving it further. This was the predecessor of every one of the billions of wheat plants grown today. Thc early farmers had moved chromosomes, genes and DNA front one species to another. They werc the first genetic engineers. Now, science has made sex universal. Molecular biology allows genes to be shifted among lineages which were once quite alien to one another; to make recombinant DNA not by the joint efforts of male and female, but by bypassing the inconvenience of reproduction altogether. Genes can he moved from more or less anywhere to anywhere else. At last, DNA can be used where it is needed, wherever it cones from. The biological rules have been broken and a new era of agriculture is at hand.
Genetic engineering began in bacteria, which have a commendable range of sexual interests. They exchange information in many ways; by taking up naked DNA, by a process of mating rather like that of higher animals and by the use of a range of third panics or viruses. This 'infectious heredity (which suggests that venereal disease evolved before sex) has been subverted by science. The gene to be engineered (which may he from a bacterium, a plant or a human) is put into a piece of viral DNA with the help of various technical tricks. The manipulated virus plus its fellow-traveller is then used to infect a new host. With luck, the recipient will treat the immigrant DNA as its own and make a copy every time its divides. It can be persuaded to generate vast numbers of duplicates of the engineered gene – and large amounts of whatever it manufactures; pure human proteins, drugs, or other materials.
To cross the sexual divide, deep as it is, between bacteria and the rest of life proved unexpectedly easy. Insulin was once extracted from the pancreas of pigs. The human gene was moved to bacteria and large quantities of the pure protein can now be made. Human growth hormone, too – once extracted with much controversy from the pituitary glands of the dead – is now made in the same way. This avoids a macabre and unexpected problem. A few patients caught a nervous degenerative disease from corpses that carried a virus. Now, the factor VIII gene, too, has been inserted into bacteria and patients are treated with its product.
Genetic engineering can also be used against infectious disease. Jenner could use the cowpox virus to vaccinate against smallpox (an experiment which would fall foul of the most lenient Ethics Committee today) because the viruses share antigens, cues of identity recognised by the immune system as the basis of its response. As a result, antibodies against cowpox protect against smallpox. Cowpox itself can cause problems and even modern vaccines have a small risk of a reaction to the foreign protein. In any case, many diseases (such as leprosy) cannot be helped by vaccination because it is hard to grow their agents in the laboratory.
Some clever engineering gets round the problem. Antigen genes from an agent of disease are inserted into a harmless bacterium, avoiding the risk of infection as the genes for virulence have been left out. Antigens from several sources can be put into the same host to give a single vaccine against many infections. 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 and, by persuading the recipient that he has been infected, ensures that antibodies are made.
Some of the tricks are simple. Plants can make copies of themselves from a few cells so that many can be produced from one without sex. It is hard to improve trees by breeding from the best, because it takes so long. Instead, a superior specimen has its tissues broken into single cells. Copies of that super-tree can then be grown to give, within a single generation, a super-forest. In the same way, natural vanilla, once extracted at great expense from a tropical orchid, has been replaced with the same chemical made by cultures of cells grown in the botanical equivalent of a factory farm.
The real promise for farming comes from inserting genes from one species into another. A certain virus causes what is almost a plant cancer: tissues lose their identity and the plant grows up distorted. This crown gall virus is good at picking up foreign genes and has been used to move them into new hosts. The first transformed plant, a strain of tobacco, was made in 1984, to great lack of public interest. A dozen years later, tomato puree made from engineered plants was on sale without much controversy. Then, though, public alarm began; and the 'Frankenstein Food' label was invented, gathering around itself a variety of cranks who claimed, with no evidence, that such foods were harmful to health.
Part of the problem is the word 'engineering', which sounds more of a threat than does the 'domestication' used of the first genetic manipulators. Part comes from the caution of biologists themselves. Thirty years ago they declared a moratorium (soon abandoned) on new experiments until safety rules were worked out. Most important, people are always suspicious of technical fixes; the idea thai science can overcome all problems. From nuclear power to Concorde the optimism of engineers has often turned out to he short-lived. For the companies involved, public concern (helped by their own bland assurances about safety and by simple arrogance in refusing to label engineered food) has proved a real problem. Monsanto makes many things (although it has now changed its name to disguise that fact); but became synonymous with a supposed attempt to poison the public. So alarmed is industry that it has set absurd standards of safety. One project used genes from Brazil nuts put into soybeans to provide a certain amino acid. As this is in short supply in the third world it might have saved thousands of children. Instead the project was abandoned as a very few people are allergic to the nut itself. The new plant might have killed one or two Americans a year. The end of the research was greeted as a triumph by the Greens. Other false accusations turn on the supposed dangers of resistance to an antibiotic, kannamycin, used to help pick out which engineered plants have incorporated foreign DNA. Kannamycin is not used in medicine, is widespread in nature, and its use in genetic manipulation is in any case becoming obsolete. Even so, kannamycin has been used as a stick with which to beat those keen to improve food production.
Other complaints, with more weight than all this pseudo-science, are based on fears about the future of the landscape or of farming itself. Many people do not like modern industrial agriculture (in spite of its productivity) and genetically manipulated foods will, without doubt, help it to prevail. It also, say the opponents, makes little sense to manipulate wheat to add to the grain mountain; or to drive peasants from the land to the cities. The Green Revolution itself forced Indian farmers from the land as large companies gained control of seed production.
Much the same happened half a century ago in the American mid-West. In the 193os new strains of_ hybrid corn were made by crossing two lineages together. Their sale was controlled by combines who manipulated the price and put small farmers out of business. Another commercial trick played a part. No longer could a producer use his own seed for the following year because a hybrid plant produces new and unfavourable mixtures among its offspring. Engineered seeds pose the same danger of a harvest of the grapes of economic wrath. Few farmers can bargain with an organisation with a monopoly on the sale of a herbicide-tolerant plant – and the herbicide involved. The companies have threatened to sue those who plant the new seeds in a subsequent year without a new purchase (and have been sued in their turn by clients disappointed by its yield and by others whose own crops are polluted by manipulated pollen). New 'terminator technology' prevents engineered plants from setting seed and – as in the mid-West – forces those who use them to buy new stocks for every harvest.
As is often the case in genetics, much more has been promised by biotechnology than has been achieved (particularly in the third world, where few profits are to be made). Some GM crops have lower yields than others, which has led some farmers to give them up. Such is the storm generated by their use that their potential may be long delayed. Thirty million hectares of land were planted with GM crops in 1998; and a million Chinese farmers used engineered cotton. So alarmed is the public (and so over-priced the seeds) that in the west at least the acreage has been reduced since then.
Most of the brouhaha turns on economics and emotion rather than science. Science, indeed, has got rather lost in the fuss. What might genetic manipulation of plants do, given the chance?
Some of the technology aims to increase the range of places in which particular crops can live, with genes that make them tolerant to salty soil, or high temperature, or shortage of water, or allow growth for a larger portion of the year. The Green Revolution turned on a natural mutation that caused plants to grow less tall than normal. Now the gene involved (which prevents the plant from responding to growth hormones) has been cloned and could be introduced into other crops, to give an instant revolution in unexpected places.
Other genes might fight biological enemies. Many creatures produce natural pesticides as they are at constant risk of attack. Such genes from one species can be shifted into another, to cut down the use of chemical sprays. A pesticide much used by organic farmers is taken from a bacterium, Bacillus thuringiensis, which is lethal to many insects. The toxin genes have now been introduced into cotton, reducing the chemicals used on the fields. A related trick inserts a gene that makes the plant resistant to artificial weedkillers. `Round-Up' is much used by soya-bean farmers. 'Round-Up Ready' plants (which represent about three quarters of all genetically modified crops) have a gene that breaks down the chemical, so that the field can be sprayed to kill the weeds but leave the harvest untouched. Plants can even be 'vaccinated' by introducing a few genes from their viral enemies. When the virus strikes it uses the plant's machinery to make copies of itself. If parts of its own structure are already there, the mechanism is disrupted and the attack fails. Virus resistance has been introduced into rice and peppers, and genes that resist parasitic worms into potatoes and bananas, although none has yet been used on farms.
We grow plants because they make useful things; food, for example. As most plants 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 and many hopes are pinned on 'golden rice', which has within it a new gene for vitamin A (whose deficiency causes half a million third-world children to go blind each year). Some foodstuffs, such as broccoli, contain anti-cancer substances and the DNA responsible might be introduced to other species. Plants could even be used as biological factories, with the prospect of using potatoes to make antibodies or other blood proteins. Already, rice can make a human protein used to treat cystic fibrosis and other lung diseases.
Other species might be persuaded to make natural oils for use in plastics or fuel. Another option is to interfere with the DNA of trees to reduce the toughness of the wood and to cut down the amount of energy needed when it is converted into paper. Blue cotton and black carnations are on the horizon. The great hope for agricultural engineers is to introduce genes that allow crops to make their own fertiliser. Clover has evolved an arrangement with certain bacteria. The bugs 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 have long used mixtures of grass and clover that are more productive than either grown alone. To put nitrogen-fixing genes into crops would much reduce the need for fertilizers. The potential rewards are huge. All this may mean that plants may rule and that animals will fade in importance as – perhaps – the salmon-flavoured banana takes over.
To develop such new crops is expensive and the research is, of course, done with profit in mind. It must, like the transistor or the vacuum cleaner, be protected. The first known patent was granted in t4at in Florence to the architect Filippo Brunelleschi for his invention of a barge with hoisting gear used to transport marble. The idea that inventions need protection spread, and – in spite of attempts to do without in places such as China – is now universal. The law works; and without it capitalism would not have' developed.
But what about the idea of patenting life (or, at least, genes)? It seems somehow wrong, but the pass was sold long before the days of DNA technology. In the 199os it became possible to protect agricultural varieties and in 198o, the US Supreme Court gave the green light to a patent for a bug whose genes had been altered to chew up oil spills. Such creatures were the products of years of work by those who sold them, with a real claim to be inventions, in the legal sense, rather than mere discoveries that cannot be patented.
With life, the boundary between the natural and the invented is soon blurred. Can genes themselves be patented? After all, they evolved and are not products of human ingenuity. In spite of much argument thousands of genes are now under legal protection. The law is still dubious about just how far this should be allowed, and an aggressive attempt to patent segments of DNA without even knowing what they do has failed. Patenting, though, is here to stay. It can, like capitalism itself, be unfair; but, like that economic system, seems unavoidable.
The interesting question is not about ethics, but about who owns the patents. 'Biopiracy' is the theft of genes from the third world. The sums involved are large. Seven of the globe's twenty-five top drugs are derived from natural products; aspirin from willow-bark, a cholesterol-lowering medicine from a Japanese fungus, and cyclosporin, a powerful anti-cancer agent, from a Norwegian equivalent. Those nations have gained from such drugs; but vincristine and vinblastine, developed in the 196os as a treatment for leukaemia, came from the Madagascan rosy periwinkle. That impoverished land has gained nothing from a trade worth millions (although had it obtained patent cover it might have done so). And what about the anti-cancer chemicals found in Asian corals or the material two thousand times sweeter than sugar made by a West African tree? Those genes will he worth millions when cloned – but who owns them? Some companies are quite blatant in their attempts to cull profit from ancient expertise. Basmatirice is an aromatic (and expensive) variety that has long been used in India and Pakistan. Both governments were outraged to find that, in 1998, the Ricetec Corporation of Texas had filed a patent application for its seeds – and, to add insult to injury, that they had been collected by American scientists invited in to search for new genes that might help feed the third world.
The West itself is dubious about the actions of its citizens. In 1997 the United States Patent Office overturned an attempt to patent the active ingredient of turmeric as an aid to wound-healing as this had long been used as a folk remedy in India. Indeed, the nation's own fingers have been burned. The enzyme used in the polymerase chain reaction comes from a bacterium collected in a hot spring in Yellowstone National Park. The Swiss company that owns the patent makes a hundred million dollars a year in royalties, while the Federal Government (the owner of the spring and presumably of the bacteria) gets not a cent. Now, the Parks Service charges a hundred thousand dollars a go (plus a guaranteed share in profits) for any company that wants to prospect for DNA on its land. Although the claims of wealth from tropical nature may be exaggerated – after all, only one of fifty thousand plants tested by the US National Cancer Institute gave a usable drug – the third world is understandably enraged. Now it is fighting back. Amazonian tribes use the skin of certain frogs as a source of poison for their darts. That substance is a pain-killer if used in minute amounts, and an American company is keen to patent it. But, counter the governments of Ecuador and Venezuela, was not the discovery made by their own people and should not at least some the profits come back' to them? The Americans disagree (and are annoyed by the Venezuelans, who have put a stop to the collection of frogs by outsiders).
All this is the stuff of commerce and is as familiar to already played with Californian bacteria. They wanted to know how best to infect people. In the 19 5o huge numbers of Serratia nzarcescens 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. Trustus, they say; but like the engineers who developed nuclear power or drained the Florida Everglades, 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 a 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 bath 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 he 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 the 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 disappointment'. 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 194os. Forty years ago it worked almost everywhere. In the 196os 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, Ike might still be carrying typhus through the poorer parts of Europe and malaria killing even more than it does today. In time, 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 challenges by evolving to cope, genetic engineers, unlike those who build bridges, must face the prospect that their new toys will fight back.
put on line on 01/05/2007 by Pierre Ratcliffe Contact: (pratclif@free.fr)