A SURVEY OF BIOTECHNOLOGY AND GENETICS

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by Oliver Morton An hour's drive from Cambridge, Massachusetts, takes you to the farming hamlet of Charlton. There, in pleasant but undistinguished countryside, Harry Meade has a farm; a few animal sheds, copious mud, a herd of good-natured goats and a fine New England barn to which they have added their own particular perfume. The barn would have seemed familiar to the people of Charlton a century ago, the smell familiar to farmers for millennia. However, at the end of one of the sheds sits something altogether more novel: an operating theatre and a laboratory. This is where new genes are put into the goats' embryos. It has taken this technology less than a decade to get from the intellectual hubbub of Cambridge--where Genzyme, Dr. Meade's employer, is based--to the rural charm of Charlton. The goats have taken significantly longer. This particular generation was brought from New Zealand, where their ancestors were shipped by white settlers a couple of centuries ago; their forefathers were first domesticated perhaps 10,000 years ago. That journey has changed the goats far more than anything Dr. Meade is planning to do. If they are good-natured now, not to mention abundantly lactiferous, it is a nature shaped by humanity for its own ends. Protection and selection by humans have made the goats what they are today. From their point of view, the addition of a gene that puts a medicine into their milk makes little difference. Yet from mankind's point of view it makes a huge difference. Until very recently, the only access to the genes which shape the natural world was through environmental change. Now those genes can be manipulated directly. That makes change easy, immediate and comprehensible; the technology that enables direct genetic manipulation also opens the genes's activity up to inspection. But at the same time it makes change arbitrary, because genes that no animal would spontaneously evolve become possible. These new techniques give humanity unprecedented powers to change the world--and to change itself. The text As goatherds have long known, kids resemble their parents. This resemblance can be broken down into individual characteristics which are either present or not. The idea that inherited characteristics are passed on in discrete packages is the basis of the genetic theory of inheritance. When a geneticist talks of a gene, he means a unit of inheritance. When a molecular biologist talks of a gene, though, he means something else; a piece of DNA. A strand of DNA is made up of a long series of sub-units, called nucleotides, which each carry one of four different chemical "bases", A, T, C, and G. as well as being able to form a chain-like link with the next nucleotide in the line, each component nucleotide can also form, by way of its base, looser bonds to a nucleotide facing it; A seeks out T, G has an affinity for C. If two strands of DNA have complementary sequences--an A to the other's T, and so on-then these weak bonds will hold them together belly to belly, like amorous centipedes in their double helices. -------------------*REPRINTED FROM: The Economist, February 25, 1995

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The way to reconcile these two views is to see the gene as information. The link between the generations is information about what a creature can be; the sequence of bases stores it. The most important aspect of this information are the names of the creature's proteins, names that are written in AS, TS, CS and GS. These are names such as those searched for by the magicians of antiquity, the true names that deliver power over the named. These true names define the essence and structure of the proteins that do most of the work in any body. This understanding is the basis of the extraordinary explosion of molecular biology over the past three decades. The nucleus of the cell, in which two sets of chromosomes carry all the genes allotted to an individual, has taken on the role of a mathematics textbook. The answers are there, unexplained but open to use. This treasure trove of data has not made biology simple, but it has allowed solutions to be checked more easily. Biotechnology explores the use of genes for a range of purposes, some new, some not so new. Mankind has been messing around with the genes of animals such as the Charlton goats since history began. The new technologies will make that messing about more effective, but they will not dramatically change its character. Yet the technology also opens up powers of understanding and ways to help humans which are entirely new and immensely exciting. This survey, therefore, will concentrate on the uses of gene technology in human health. As yet, the biotechnology industry has not lived up to its scientific promise. In America, where it first started, and which remains the world leader, the sector is steadfastly losing money, $1 billion or so last year. Only 1% of the biotech companies make a profit. Of those that do, one company, Amgen of Thousand Oaks, California, makes more than all its leading competitors put together; it has both of the industry's biggest selling drugs, neupogen and epogen. There is no necessary connection between great science and great business opportunities; the general theory of relativity has yet to be turned into a money-spinner. But the basic power over life and the understanding it is bringing should be capable of making a lot of money for someone. The biotechnology sector now sees itself as not just using recombinant DNA as a manufacturing technology. It is applying the scientific tools to understanding human disease in ways previously not available. That understanding, more than the ability to make proteins to order, holds the promise of future success. All the while, though, the laboratory sorcery is continuing apace. The first gene was cloned--isolated and reproduced on its own in a laboratory--in 1972. At the time, scientists were so worried about the implications of what they were doing that they considered a voluntary moratorium on the recombination of cloned genes into the DNA of other organisms. Now, in laboratories all around the world, dozens of genes are cloned everyday, thousands a year. The creation of recombinant people, with foreign genes stitched into their cells, is widely accepted. It is entirely conceivable that, by the end of the century, scientists will know the true names of all the proteins the human body uses; it is inconceivable that the names should not be known by 2010. In this sense, molecular genetics will soon be finished; but the true excitement is only just beginning. Once all the genes have been cloned, the raw stuff of all human inheritance will be laid bare. The implications of that go far beyond the fortunes of a bunch of biotechnology companies.

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The context To a geneticist, a unit of inheritance; to a molecular biologist, a stretch of DNA; to most laymen, fate. The gene has become a byword for the immutable, a permanent fact about the person who carries it. A complete genetic description of a person is seen as destiny revealed to inspection. This idea provokes fear in some, enthusiasm in others. It also happens to be wrong. This survey will contest the view that genes contain the immutable force of destiny. They do play a major role in human life but they do not, in most cases, direct it. They permit and limit, but do not control. Biologists divide the organism into two parts: the genotype, meaning the genetic makeup, and the phenotype, meaning its apparent qualities. It is easy and common to think of the relationship between the two as one of cause and effect. The genotype comes before the phenotype, and aspects of the phenotype are strongly correlated with aspects of the genotype. But the phenotype is not the work of the genotype alone. It is the result of the gentoype interacting with a particular environment. The genotype of a sequoia can reside in a bonsai tree or in a redwood that scrapes the sky. It is impossible to say which of the two, genes or environment, is more important; you might as well ask which of this sheet of paper's two dimensions matters more. The information-based approach that led to the discovery of the genetic code might seem to make the gene pre-eminent. Information, enshrined in the code, flows from the gene to the world: this is what Francis Crick, one of the crackers of the code, dubbed the "central dogma" of molecular biology, usually summed up as "one gene: one protein". The direction of this flow seems to favour the gene. But although that makes admirable sense at the level of molecular biology, in the wider biological picture it is incomplete. The information does not simply flow: once it is loose in the physical world it is processed, articulated, changed. If one version of a gene provides a better protein than another in a given environment, then that version will prosper and the other perish; this form of information processing is called natural selection. Through this processing, information about the phenotype will flow back into the genotype. The environment writes genes by choosing between phenotypes. The genes in every living cell on earth--of amoeba, sequoia, mushroom, man--have been written in this way, nucleotide by nucleotide, over some 4 billion years of life. Or rather, over some 3,999,999,980 years. For the past 20 years, genotypes have been under a new control--first the genotypes of laboratory bugs, then of higher animals and plants, now of the few humans who, in attempts to cure them of disease, have new genes added to the complement with which they were born. Treating the genotype as part of the phenotype, capable of being controlled, will contribute to new medical technologies. Allowing the genotype to be read directly from the phenotype, without having it processed through the exigencies of life, will allow the harsh judgements of the environment to be foreseen and pre-empted. Just as organisms are interpretations of genetic information within a specific environment, so the use of this genetic knowledge will depend on the environments-economic and ethical, personal and political-in which that use is made. But those uses, good or ill, will surely be made. The genes that imperiously limited and permitted will be bent to human will; limits will become movable, permissions stretched. Genes have never been the complete masters of human destiny, but nor have they been humanity's servants. Until now.

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A season of growth Flowers in the spring, swaying in the wind; from a distance, a wash of red; up close, stains of blue, flashes of yellow and purple and white; hundreds of species, millions of plants: nature's commonplace diversity. So commonplace, indeed, that it is matched many billions of times within your body. Each cell of the immune system has such a meadow on its surface, millions of proteins of hundreds of types. These proteins co-ordinate the immune response. Immune cells bump into each other to find out who's who and what's to be done. If this signalling could be mimicked, the immune system could be spurred to action it normally avoids, such as full-blown attacks on some cancers; or it could be held back from the damaging over-exuberance of auto-immune disease. With cost-effectiveness the new watchword in medical purchasing for private organizations and governments alike, this range of powers is more tempting than ever for biotechnology companies: "novel solutions to unmet medical needs" is repeated around the industry like a mantra. Only such breakthrough success could conceivably recoup the huge costs of R&D: a new drug typically costs around $300M. That is why problem areas such as the immune system, the brain and cancer are under the microscope, and why the blood-cell fields are alive with the buzzing of inquisitive bees. Pass the proteins When it began, biotechnology was about using genetic engineering to create useful proteins in bulk. For medical applications, useful meant therapeutic. The first medical biotech product was a version of insulin in which the magic name of human insulin was read from a human gene by the protein-making apparatus of a bacterium. The industry extrapolated Crick's "one gene: one protein" to "one gene: one protein: one treatment: one market". For some, it worked; Amgen has made a good business out of proteins, as has Genentech, of South San Francisco. However, treatments with proteins are difficult to come up with, and hard to administer. The biotechnology industry quickly set its sights on the cytokines, the messengers that regulate the immune system. They were cloned, produced and tested--but they did not, by and large, live up to their promise as treatments. It took Chiron, a biotechnology company in Emeryville, California, years and many, many trials before it found a use for its artificial version of the cytokine beta interferon in the treatment of multiple sclerosis. Others have not been as lucky or persistent. Many were unprepared for the difficulties of clinical trials. But others came to realize that they did not grasp the underlying biology of what was going on. It seems that this is why they were stumped by the secrets of sepsis. Sepsis is a deadly cascade of immune responses and infections which kills many hospital patients every year. Between 1992 and 1994 half a dozen trials of sepsis treatments failed, taking with them the independent futures of a number of companies and a lot of goodwill from investors towards the industry as a whole. The mechnisms of sepsis were simply insufficiently understood--and remain so. Ed Penhoet, chief executive of Chiron, sums up: "it used to be that everyone knew what to do and the question was how to do it. Now the question is what to do."

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Across San Francisco Bay, Genentech's production facility is perhaps the most impressive solution yet developed to the question "how to do it". It produces, with matchless efficiency, human growth hormone and an enzyme for cutting through the mucus that clogs the airways of people with cystic gibrosis. But, like Chiron, Genentech knows that a successful future requires more than a mastery of production. It means a new understanding of biological systems, and a wider range of tools for altering them, tools more versatile than big, hard-to-administer proteins. That is why, throughout the industry, there is research such as that on CD40 (see box): detailed attempts to understand underlying mechanism that will suggest different ways of tackling them. Perhaps the best understood way is the use as drugs of small molecules, produced by bulk chemistry. The CD40 team, for example, will take this route, using the fact that they work for an established pharmaceutical manufacturer, Bristo;-Myers Squibb. Drug companies have long been interested in biotechnology companies for their know-how-Roche owns 60% of Genentech, Ciba has a large stake in Chiron. But now some biotech companies are becoming keen to get into the traditional small-molecule markets of pharmaceutical companies. Vertex, in Cambridge, Massachusetts, is a small biotech company devoted to small molecules, hoping to beat the big pharmaceutical firms through better understanding of biology and more advanced molecular design. --While some companies are going backwards to the future, others are going every which way. The diversity in biotechnology is growing almost as fast as the knowledge base underlying the field. Flowers are blooming and schools of thought contending all over the place, as companies try out new ways of doing new things. The wide range of technologies developed for working with cells in laboratories is quickly making its way to the clinic. ================================================================== Getting to know you To see how some of the tougher problems of gene technology can be approached, consider the process that lies behind understanding a single flower from the immune system's fields of proteins. As the story begins, it is unnamed. All that is known about it is that it interacts with a molecule on the surface of the immune system's B-cells called CD40. The B-cells produce the immune system's antibodies-proteins that recognise the shapes of foreign molecules in the body and stick to them-but for the most part only if their CD40 is touched by a molecule on another type of immune cell, a T-cell. It was with the gene for CD40 that Alejandro Aruffo and his colleagues went off looking for their flower. Although they worked for a big drug firm, Bristol-Myers Squibb, they used the techniques of biotechnology because the team had originally been part of a biotechnology company that Bristol bought up when it fell on hard times. They started by rewriting that CD40 gene, splicing the description of the business end of the protein on to the genes that describe antibodies to create free-floating molecules that stuck to the same things as CD40. Armed with these artificial molecules, the team then had to create artificial targets. When a cell makes a protein, it first copies the protein's name on to a molecule related to DNA called RNA. ThiS RNA is a messenger, taking the information out of the nucleus to the parts of the cell where the proteins are made; in laboratories such as Dr. Aruffo's they take the information a lot further. All the messenger RNAs in a cell can be removed and copied back

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into DNA, providing a DNA record of the true names of every protein the cell is making: in the jargon, a library. A library of the genes being used by activated T-cells contains the genetic seeds for all the flowers on the cell's surface. To find the flower they wanted, Dr. Aruffo's team "amplified" the genes, producing millions of copies where before there was only one. Others took the approach of spreading the seeds across a number of cells, and seeing which ones the hybrid CD40-antibodies stuck to. Both techniques provided the gene quite quickly. The gene gave them the power to make large amounts of the protein, which might have proved necessary. Proteins are long chains of sub-units called amino acids, bunched up and twisted back on themselves. The description in the DNA specifies only the order of amino acids; it does not tell you what shape such a chain will fold itself into. To find the shape,you have to analyse fairly large amounts of protein with x-rays and a lot of computer time. Unless, that is, the sequence is recognisably similar to one the shape of which has already been worked out. Then you can look at the other protein's shape and see where the differences will be. The target protein, now called gp-39, turned out to look very like a well known protein called tumour necrosis factor (TNF). The researchers had discovered the shape of their flower. They also had the gene. They found that, in the nucleus, the sequence of DNA they had sifted out of their library sat on the x chromosome. In fact, it was at the spot that, using other methods, geneticists had allocated to an inherited inability to make virtually any antibodies. So the families with this disability were carrying defective gp-39 genes. Exciting news, because it showed that there was no back-up for rgp-39, no alternative way to kick Bcells into life. The protein the scientists were busy characterising was fundamental to a whole branch of the immune system. From more or less nothing the team had got: the gene; an understanding of a previously unknown genetic disorder; a detailed view of a fundamental mechanism within the immune system; a protein structure; the knowledge of which bits of the structure mattered most in the interaction with CD40, and of how that interaction could be blocked. They had the makings of an exciting drug-development project to treat people with overactive antibodies. All this in a couple of years--which is the sort of time it now takes to redefine a research topic. Dr. Aruffo recall that at a 1992 conference on the 17 or so immune disorders linked to the x chromosome, there were cloned genes for only a few. Two years later, when the conference was repeated, almost all the genes had been cloned, and their functions were well on the way to being explained. Many of the techniques, maybe most, were less than ten years old, and ten years is the sort of time that it takes to move a drug from idea to market. That time lag helps to explain why the biotechnology industry's achievements to date do not match its extraordinary technological progress. Throughout the fields, the flowers are being picked, but the road that will take them to market is long and twisting. ================================================================== Riding the tiger When the laser beam was first developed in the 1960s, weapon designers saw the promise of precisely targeted death rays. In monoclonal antibodies--monoclonal meaning that, because they all come from identical B-cell, they all recognise exactly the same molecules-6

the drug developer of the 1970s saw magic bullets, able to aim themselves at any given kind of sick cell. But, as yet, monoclonal antibodies, while invaluable in the laboratory, have not delivered much therapeutic benefit. NeoRx, a Seattle company that specialises in antibodies, hopes to change that. Its anticancer therapy does not rely on an antibody acting as a drug. The patient is given antibodies that recognise cancer cell; these slowly coat his tumour. When they have finished, a small, highly radiocative molecule that recognises the antibody is sent in. Being small, it floods all the recesses of the body quickly, and is equally quickly flushed out--except where it has stuck to the antibody. There it stays, killing the surrounding tomour cells. The radiation received by the tumour is maximised, that deliverd elsewhere minimised. This is a neat idea because it breaks down the problem into sections--targeting and killing--and solves them with separate parts of a system. Like the laser that guides a smart bomb, the antibody is a high-tech way of delivering precisely aimed lethality in a small dose. This may be the way of the future--the combination of different technologies, old and new, into system that can deliver when single purported breakthroughs in therapy do not. New approaches are coming out of the laboratories at as fast a rate as ever. The challenge is to build them into systems that work. The best example may be gene therapy. Biotechnology is based on the ability to move genes around. Gene therapy moves them into people. Although most trials of the technique to date have been tiny, commercial interest in the idea is swelling. Viagene, of San Diego, is already mounting the second phase of efficacy trials of one such therapy, and many more small biotech companies are active in the field. Established biotech firms such as Genzyme, Chiron and Genentech are also looking hard at the possibilities, as are pharmaceutical companies. Over the next few years gene therapy runs a fair risk of becoming a spectacular casualty of its own hype. In the longer run, though, it will undoubtedly led to workable therapies. To understand the idea, start with something simple. Jean Michel Heard, who runs the gene therapy laboratory at the Institutes Pasteur in Paris, is working on a genetic defect called Hurler's disease, which from infancy leads the sufferer down a path of deformity to early death. The defect is a lack of the gene for a particular enzume--one that can be transported in the blood. Dr. Heard's plan is to take cells from the skin of a child diagnosed with the disease and infect them with a virus carrying the gene. These invigorated cells will be embedded in a ball of sticky collagen and GoreTex and, thus immobilised, reimplanted in the child's abdominal cavity, there to secrete the enzyme. The cells that need it will pick it up, and all will be well. It works satisfactorily on animals, and should do the same in people when it is eventually tried on them. This approach could have applications beyond Hurler's disease. In principle, it could work for any disease where a stable level of secreted protein in the blood is needed. The level of secretion might even be modulated. There DNA sequences that flank the coding section of a gene and turn it on and off, controlling when and where the gene is expressed. Such controls can be mimicked. Systems of this kind might replace the mass production of protein that is the mainstay of traditional biotechnology, especially in small markets like Hurler's.

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Dr. Heard deliberately chose this rare disease because it looked easy. Others have gone for the hard stuff. Cystic fibrosis (CF) is the most common genetic disorder among white people, and thus the largest market for replacement gene therapy, but it is tricky to deal with. The protein missing in CF is one that regulates the passage of chlorine in and out of the cell. Its absence affects every cell in the body. To remedy it perfectly would mean putting the new gene into every cell. In practice, though, since people with CF tend to die from the effects on the lungs, that is where gene therapists are aiming. The team at Genzyme is hoping to get the genes there in adenoviruses, which infect the respiratory tract and cause colds; others, such as the British Medical Research Council's CF team, want to put them in little balls of fat: liposmes. Neither approach is without its problems. The liposomes are quite safe but will not necessarily get the genes into many cells. The viruses provoke an immune reaction. And since the cells of the lung lining are short-lived, the treatment will need to be repeated--which an immune resistance could make difficult. Moreover, the therapy works only in the lungs. It will not reach other parts of the body that may be in trouble, such as the pancreas. Some of these problems can undoubtedly be overcome. As Axel Kahn , who runs another gene-therapy laboratory in Paris, points out, both the viruses and liposomes are infant technologies. These rudimentary "vector" -- agents of transmission -- will be improved. They may converge into somethings safe and efficient, "virosomes" that can carry large genes, avoid the immune system, and easily penetrate any given type of cell. That targeting could be crucial to treating genetic diseases where the gene has to be in particular type of cell. One such disease, ADA deficiency, is the only genetic disorder yet successfully treated with a gene; but the cells have to be taken out of the body first, and then put back. The man who pioneered that, French Anderson, now at the University of Southern Califonia, is one of those trying to make better vectors. When they become available, many genetic diseases might be treatable to some extent. But the ambitions of the gene therapists go further. After all, only about 30 people in the world suffer from ADA deficiency. Hurler's disease is more common, but not much; even cystic fibrosis affects only about one in 1,000 people in Britain, for example. Genetic diseases are rare almost by definition; genes that kill tend not to be passed on. That is why, to the dismay of advocates for people with genetic disease, a great deal of gene-therapy research is aimed at something common: cancer. Cancer is a disease of the genes. There are many genes responsible for regulating the growth and division of cells; if enough of them come to shirk their responsibilities, either through inherited deficiency or just through the wear and tear that knocks genes out over time, then the cell can run amok. Gene therapists think they may have a number of remedies for this. The most widely discussed and attempted is the use of "suicide genes" which, correctly triggered, will kill the cell they sit in. Vectors take these genes into the cells, the trigger is applied and the cells die in a fairly messy way that takes some of their neighbours with them. A related approach can be used to booby-trap the immune system against AIDS, using suicide genes that will kill any cell infected by the AIDS virus before the invade can reproduce. There is also the possibility of stopping genes doing their work, rather than starting them. Tumour-suppressor genes might be replaced in tumours that have lost them. Or wholly artificial genetic messages, "antisense" messages, might be sent in. Take a sequence of DNA that is the exact opposite to the gene you are interested in: the RNA made by the gene itself and that made by the anti-gene will be mirror images, too. They will stick to each other in the cell, and none of the protein will be made. You do not have to make your antisense message
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in the cell. Companies such as Gilead, in Redwood City, are making short, robust bits of antisense to be taken as a normal drug. Alternatively, you can use the inserted gene to make a short piece of RNA that will seek out the RNA for a particular protein and tip it to pieces: a hammerhead ribozyme. The field is not short of possibilities. It is, however, short of tangible products. This surplus and shortfall is felt throughout the biotech industry. Few companies think they can do all they need to do on their own, nor do many have the money to try. Investment has not been heavy in recent years, and young companies are reducing their development spending on all but the highest priorities. Corporate alliances are blossoming, as are all sorts of other mutual-aid arrangements. Companies gutted by failed drug development are bought by other that have had a success. Big companies are developing networks of partners, and encouraging their entourage of smaller fry to work together. Chiron is keen on this approach; Rhone-Poulenc, a pharmaceutical company, has set up a wide-ranging consortium of small companies to explore the possibilities of gene therapy. The biotechnology field is no longer united in anything. Companies are pursuing a huge range of strategies with a matching range of technologies. Big pharmaceutical companies are devoting resources to biotech, both in-house and through acquisition. Small companies no longer uniformly apply a particular technology. In search of definition Leroy Hood developed the automatic gene-sequencing machines found in laboratories around the world and is now a professor at the University of Washington in Seattle. He is also a founder of Darwin Molecular, a biotech company backed by Microsoft's Bill Gates, among others. Dr. Hoods definition of biotechnology is one of the few broad enough to encompass the ferment of the field: he simply calls it the industrial use of biological information. The true names of proteins found in DNA are a priviledge source of such information, a unique digital record of immense value and relative accessibility. At first, it was the only source of information that mattered. But now vast swathes of harder-to-find biological information beyond the names of the proteins found in DNA are becoming available--information about how genes are controlled, when and where they are turned on and off, how they interact. Then there is information represented by the shapes of proteins, and the signalling pathways that tie them into chains of interaction.

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-----------------------------------------------------------------------------------------------------------------------------Profitable proteins -----------------------------------------------------------------------------------------------------------------------------Top ten biotechnology drugs on the market Product Developer Marketer Net Sales 1993,$m

-----------------------------------------------------------------------------------------------------------------------------Neupogen Epogen Intron A Humulin Procrit Engerix-B Amgen Amgen Biogen Genentech Amgen Genentech Amgen Amgen Schering-Plough Eli Lilly Ortho Biotech SmithKline Beecham RecombinNAK HB Activase Protropin Roferon-A Chiron Genentech Genentech Genentech Merck Genentech Genentech Hoffman-La Roche ----------------------------------------------------------------------------------------------------------------------------Total sales of top ten 4,288 ----------------------------------------------------------------------------------------------------------------------------Total industry sales 7,700 ----------------------------------------------------------------------------------------------------------------------------Source: Med Ad News ----------------------------------------------------------------------------------------------------------------------------And there is information that can actually created, rather than discovered, in the same sort of way that evolution has generated the information now stored in the genes. This is the burgeoning field of combinatorial chemistry. To see the principle, think of an RNA molecule. Unlike DNA, relatively little bits of RNA take on all sorts of different shapes depending on their sequence--biologically active shapes, like that of a ribozyme. So how do you find the bestshaped RNA? One way is to make them all--which is to make a vast number. There are almost 1 trillion different 20-nucleotide RNAs. From this richness, choose the exemplars that do the job best. Then, if you like, create a similarly huge range of variations on those themes. Such techniques, pioneered by Gerald Joyce of the Scripps Institute in La Jolla, California, who is another founder of Darwin Molecular, produce new information at an
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719 587 572 560 500 480

245 236 217 172

extraordinary rate by applying the same process to a large number of items at the same time. It is similar to the parallel processing that goes on in fast computers now. This unusual form of information technology is now being applied to all sorts of drug design problems. So is traditional information technology; as Dr. Hood stresses, computers are ever more essential to biotech. Around the world companies are developing computational approaches to the problems of generating and sifting biological information--nowhere more than in the San Francisco Bay area, where the world's highest concentration of biotech firms mixes with Silicon Valley. One peculiarly powerful mixture of the technologies is the DNA chip. Affymetrix of San Jose uses the masking technologies developed for making printed circuits to produce arrays of short DNA molecules stuck to a little glass slide. Steve Fodor, one of the company's founders, describes what the technology might achieve - a form of parallel processing reminiscent of the flowering field in the previous section of this survey. Take a chip one centimetre on a side and subdivide it into 100m squares, each a thousandth of a millimetre wide--simple stuff, to chip makers. On each square, build up a chain of nucleotides, applying the masking technology of the chip maker to the ends of the combinatorial chemist. With just 120 steps (four, reflecting the four nucleotides, for each place along each strand) you could produce a different 30-nucleotide strand in each position. There would be 3 billion nucleotides on the chip. That number has a significance beyond its size. It is the number of nucleotides in a human egg or sperm, the number needed to describe a full set of human genes. It is the measure of the grandest of all exercises in the gathering and use of biological information: the human genome project. All the genes there are... The aim of the human genome project is simple: to analyse and sequence all the human chromosomes. In America the National Institutes of Health (NIH) and the Department of Energy--which has long had an interest in genes because of what radiation does to them-are spending $180m a year on it. Other countries, and the European Union jointly, now have their own programmes, all loosely held together by an international group of scientists called the Human Genome Organization; many are supplemented by money from charities, such as the Howard Hughes foundation in America, the Wellcome Trust in Britain and AFM in France. The eventual bill has been estimated at $3 billion. This is "big science" on the scale of particle physics and space travel.

It is similar to space travel also in the sense of perspective it allows. Satellites allowed scientists their first opportunities to appreciate planets as whole systems. Genome research, which looks at the totality of genetic material in an organism, is similar in its widening of its horizons. The genes themselves make up only 3% of human DNA; the rest of the genome keeps them in order, controls their expression and so on. Where once there were just studies of single genes, now whole genetic systems--including their control sequences, their historical oddities, everything about them--will be open to inspection. Alien planets-the genomes of the fruit fly and the mouse, for example--will be explored for clues as to how genomes achieve all this. But just as most spacecraft look down at the earth, not out, so

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most genome research will focus on the human genome. As with spacecraft, the main activity is mapping; the search for distinctive markers that allows genes to be found. The genome project is not really science in itself, anymore than a rocket or a particle accelarator is. It is a way of getting science done--a scientific instrument big enough to qualify as a major piece of infrastructure. It is often hard to tell infrastructure from political pork-spending for its own sake to keep favoured laboratories and institutions in business. The genome is no exception. Many scientists have been critical of it, claiming that genes will be found as and when they are needed, and that the big science approach is simply not necessary. It is now facing the opposite criticism as well. Some genome mappers feel that the project could be done much more quickly and cheaply if it were more like traditional big science. And outside the project a number of companies, loosely identified as being in the genomics sector, are hunting for genes in a more focused way that may prove far more influential over the next few years. Invasion of the genome snatchers The defining characteristics of the genome project are its scale and its tedium. To sequence a chromosome, you first have to cut it up into sequenceable chunks; you also have to know what order those chunks come in. The greatest progress made so far in the genome programme is the development of procedures for this sort of dissection that allow it to be made ever more routine, and thus capable of being automated. With production-line techniques and robot help in the laboratories, the sequencing machines can be kept gainfully employed. Although there has been much talk of, and expenditure on, radically new technologies for sequencing much faster than is now possible, few if any people in the project believe that they will come on stream before the sequencing work is more or less done. The problems lie in the scale and organisation of the jobs, not the tools. To some, these problems in essence now seem to be solved. At Britain's Sanger Centre for genome research, they have been honing their skills on the genomes of lower organismsthe genomic equivalent of a small hop to the moon. They and their colleages at the genome centre at Washington University in St. Louis hope to have an almost complete sequence of the nematode worm's 100m nucleotides of DNA by 1998. An international network of laboratories should have finished work on the yeast genome, 20 little chromosomes adding up to 15m nucleotides, by the end of this year. John Sulston, the Sanger's director, is now bullish. He thinks that the technique of ignoring small intrasigent bits of DNA which that centre has applied to the nematode could dramatically speed up work on humans. If 95% of the sequence, with the gaps clearly marked, were seen as sufficient, he thinks that a small group of centres such as the Sanger and Washington University could do it in five years. Daniel Cohen, one of the first to understand that the secret of genome research was the use of automation in a properly designed organisation, has a similar view. He and his colleages at Genethon, a charity-backed laboratory in Paris, finished the first complete physical map of the human genome last year. That map is a set of DNA chunks the same size as yeast chromosomes; he is now working on a second-generation map on a much finer scale. With that second map, he thinks that $500m spent on a centre with a staff of 200 could get a sequence like Dr. Sulston's in just two or three years. The difficult bit is getting such a focused, selfless team together--especially if it means taking funding away from a large number of other genome centres, all happily plugging away at their favourite chromosomes.

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Other approaches can deliver results even more quickly. One that has already achieved a great deal is to go not for the DNA itself but for the RNA copies of genes being used. You can get a little bit of the sequence for each RNA quite easily--a "tag" long enough to identify the whole. Then you can come back later and, using the tag, get the sequence in its entirety. This is the approach pioneered by Craig Venter, originally at the NIH. He now runs a nonprofit organisation, the institute for Genome Research (TIGR), which is allied with an extremely profit-driven organisation, Human genome Sciences (HGS) in Rockville, Maryland. According to William Haseltine, HGS's boss, the many different RNA libraries that the company has developed and tagged now include between 80% and 90% of the genes in the genome. When a new gene sequence is announced by another team, HGS expects to find that it already has it tagged--and that it has related tags that probably come from similar, as yet undiscovered, genes. This cream-skimming approach has earned HGS a lot of critics and a lot of money. The criticism comes from the company's attempts to patent the sequence it discovers. In general, legal opinion holds that for a patent to be awarded on a sequence, a function is needed. The HGS Tags do not have an obvious use, and as yet have not been granted patents, though HGS continues to apply for them. However, the company also hopes to secure intellectual property rights in another way. Its database is proprietary. It also has the potential to be wonderfully useful, and many scientists would love to lay their hands on it. They can, as long as they make a deal allowing HGS first refusal on any commercial development of what they find. This looks like an attempt to corner the gene market. Dr Haseltine grins and says that every capitalist should be trying for an unfair advantage. The approach certainly has fans. SmithKline Beecham, a pharmaceutical company, has made a $125m deal with HGS to gain access to its information, and that which other researchers provide it with. Its rival Merck has been sufficiently worried by this to finance the launch of a similar project which will make similar tags for all the genes it finds freely available, at a substantial cost to the company. Other firms are offering similar tag and whole-gene databases. TIGR is planning an openaccess map that gives the position of 40,000 of its tags. To Dr. Cohen the complaints are foolish. The point of the genome programme is, eventually, to provide medical services; these will be developed by companies. That these companies are competing now to prvide information is all to the good. The number of genes, after all, is vast. If patents are granted only when applicants provide statements of utility, There will be more than enough for everyone.

The road to complexity The HGS approach is to work from the genotype out. It starts with the database, which may on its own permit discoveries. By finding sets of similar sequences, researchers there could discover whole new sets of proteins, families of unknown function. At the moment, scientists recognise a family resemblance with already known genes in about a half or a third of new discoveries. It may be that the other genes are not members of families; but if they are, then the the families might be found in Rockville before anyone else has wind of them.

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Now that its database is looking fairly full, though, the company is putting a lot of effort into more traditional genetics and biology; working from tags to whole sequences to functions. Other companies in the field take the opposite approach, working from the phenotype in. Myriad of Utah worked on hunting a gene for inherited breast cancer; Millenium of Cambridge, Massachusetts, is looking for genes associated with heart disease, obesity and diabetes. By looking at genetic components to common diseases, they hope to tap markets far larger than those for specific gene disorders such as cystic fibrosis. Such searchers are hard, because there is more than one gene involved. To find the genes, you must study large numbers of people and look at lots of genetic markers. Another approach that Millennium and other are using is to breed mice with diseases analogous to the human ones and find the genes in them through huge breeding programmes. Once a gene is found in the mouse, it is fairly easy to find in humans. Once the various genes involved are found, a picture can be built up of the complex sets of protein interactions that take place in the disease, so that the therapies can be designed. This takes considerable resources-and at the moment pharmaceutical companies seem happy to provide them. Roche, a swiss drugs giant, has made a $70m deal with Millennium. These companies-others include Sequana in California and Darwin Molecular in Seattle--are aiming to use both molecular and traditional genetics to crack the biggest healthcare problems. If even a few of the programmes are successful, the revenues generated will dwarf the "big science" of the genome project. But treatments, as the traditional biotechnology companies have found, take time to develop. Test, on the other hand, become available more or less as soon as a gene is found--yet raise complex problems. A little knowledge Huntington's disease inflicts premature and catastrophic senility on its sufferers-the result of a single gene, which can be inherited from either parent. Until recently, the child of a sufferer lived with a 50-50 chance of following in the parents sorry path. Now that Child has the option of certainly; a test can discover whether the defective gene is present. However , it is thought that fewer than one in five of those potentially affected have taken the test.

Phenylketonuria was originally diagnosed as a form of idiocy: it leaves sufferers retarded. Again it is the result of a faulty gene. Again there is a test. This one is given many millions of times every year; almost every newborn in the developed world can expect it. The difference between the tests is simple. Phenylketonuria can be stopped by removing an amino acid, phenylalanine, from the diet. Huntington's disease is unstoppable. The researchers who first developed the scientific concept of information had simple definition of their topic, a way of telling signal from noise: information is the difference that makes a difference. At the moment, knowing that you have the gene for Huntington's disease makes, in medical terms, little difference. Knowing that a newborn has phenylketonuria makes a big difference, which explains why one test is used so much more widely than the other. For now, genetic testing is still something of a rarity, and --with some expectations--its use is not particularly controversial. But the number of tests available, and the range of diseases and disorders thay will apply to, is set to increase quickly. Unlike medicines, genetic tests are fairly lightly regulated. They do not need to go through years of clinical trials, nor do they have to be shown to be efficacious in the same way. So it is a fair bet that
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one result of the human genome project will be tests for a wide range of genetic dysfunctions. These will not just be for diseases, but also for predispositions to diseases. Such tests are potentially a great boon. Although Huntington's disease fits the widespread "fatalist" image of genetic destiny, many genes are probably more like that involved in phenylketonuria; in the right environment, they simply have no effect. Increasing medical knowledge should allow such environments to be devised for some inherited disorders. They may be micro-environments within the body, kept up by medication; or more thoroughgoing chances in way of life, diet, exercise, stress level, exposure to toxins and so on. It may be possible to create an environment in which the metabolic problem which causes Huntington's disease never develops into a problem. But the knowledge needed to devise such environments will be hard-won, and much less quickly available than the tests. Meanwhile, the technology of tests, at present straightforward but cumbersome, could be improved greatly. In the laboratory, samples of DNA chip technology could analyse such amplified samples for any number of ills. So there is a risk, as more and more tests are devised and easily available, that more and more people will end up in a bind akin to that of the Huntington's victims: they will have the option of knowing, but no way of putting that knowledge to good use. Worse, there will be the fear that the knowledge will give power to others, such as insurers and employers. Tell me more At the moment, most genetic testing has to do with reproduction--which is, after all, the point in life when genes come most to the fore. Embryos are tested for various disorders, such as the chromosomal defect that results in Down's syndrome. Such test are likely to become easier, and to be available earlier in pregnancy, as the technology for isolating fetal cells from maternal blood improves. Tests are not just for the unborn, but also for parents-to-be, especially from families with histories of genetic disease. For example, they can be tested to see whether they are carrying the cystic fibrosis gene. If each parent is a symptomless carrier of cystic fibrosis--that is, has one copy of the good version--then a child has a one-in-four chance of inheriting a bad version from each, and thus getting the disease. Discovering that you are a carrier normally has no medical significance in itself. Some carrier screening programmes, such as that for Tay Sachs disease among American Jews of East European descent, have proved a great help, in part because the community screened has been a partner in the process, consulted at every step to dispel any prejudice. But finding yourself to be a carrier can also cause enormous stress. In some circumstances this may be an entirely rational response. In the 1970s large screening programmes for sickle cell anaemia were put into place in America, in an attempt to help black Americans. The gene is common in people of African descent. One copy has almost no effect, except to confer some resistance to malaria--a useful trait in central Africa. Two copies cause disease. But the healthy carriers uncovered by screening found themselves discriminated against in all sorts of ways. If such problems are encountered where the test is for carrier status, which has no real repercussions except in choices about reproduction, much worse may be to come when tests for predispositions to diseases become widely available. In these cases, there is no affected community, as there is for Tay Sachs, or network of support, as there is for disorders like
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Huntington's. Such tests have been made possible by recent advances in cancer genetics. The gene for an inherited form of bowel cancer has been found, with the help of HGS'S gene database; Myriad Genetics of Salt Lake City (where good Mormon genealogies provide genehunters with well-prepared ground) is developing tests for one of the genes involved in inherited breast cancer. Cancer is a disease of the genes; such tests seem inevitable. Neil Hotzman of Johns Hopkins University points out some of the difficulties in testing for the inherited form of breast cancer. No one knows what the right response to having a breast cancer gene is. Repeated mammograms might help--or, through irradiating the tissue, might cause harm. Double mastectomy to eliminate the source of trouble might suit some people (indeed, some have chosen it on the basis of family history alone) but will not be acceptable to others. Frequent examination is a good idea, but that applies to everybody. The risks may be highest, in fact, for those women who do not have the gene. They are just as likely as the carriers to get non-inherited breast cancer, which accounts for more than 90% of all cases. Yet the absence of the gene will suggest a clean bill of health, and might discourage self-examination. So for this group the test may be a bad thing.

Redefining disease One of the effects of testing for predispositions will be blur the boundaries between health and disease, creating new half-way houses of sick genotypes in healthy phenotypes. Other tests will introduce new subtleties into the diagnosis of those who are definitely ill. Cancers, for example, may be subdivided according to which particular genes for cellular selfrestraint have gone wrong. Such differences may matter. People with some tumour suppressor genes left in their cancers, for example, may respond much better to drugs than those without. The drugs themselves may be metabolised differently and thus have different effects. At the moment, the fact that some people respond to particular drugs while others do not is an accepted fact of medical life. But if ever a difference was making a difference, here is an example--and that means there is useful information to be found. There are clearly similar disease phenotypes associated with different genomes; and the treatments may be gene specific. By dissecting diseases genetically, it may be possible to match diagnosis to treatment much more effectively. This is the promising infant field of pharmacogenetics. It could help a lot. Many in the biotechnology world feel that the string of failed sepsis trials over the past few years has a simple explanation: people with a wide range of different problems were being treated identically because the symptoms looked similar. If the patients had been subdivided correctly, the outcome might have been different. One of the differences would probably have been that the potential market for the drugs would have been smaller, but at least the companies might have got some drugs that worked. Paul Abrams, of NeoRx in Seattle, points out that if doctors 50 years ago had been given erythropoietin, one of biotech's biggest drugs and an excellent treatment for many anaemias, they would have discarded it since they did not have the right classification of anaemias to be able to pick out the patients who would respond. Genetics testing will provide drug developers with more knowledge about the diseases they are tackling, and the patients they are treating. Some, perhaps many, of the drugs now available will be re-evaluated, and may prove to be better than now, though for a smaller number of patients. The design of clinical trials is likely to benefit; so is the quality of life. In
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appropriate medication is one of the banes of modern illness. Reducing it will help both consumers and providers of health care. At Chiron, which has taken over the diagnostic tests division of Ciba as part of a larger deal between the companies, this sort of knowledgebased medicine is seen as a big part of the future.

Forget fairness? However, in other applications of genetic testing, the economic interest of the provider and the welfare of the consumer may not dovetail so nicely. In America, where the subject is particularly sensitive, discussion of testing inexorably moves to questions of insurance. Fears are widespread that insurance companies will try to use test data to exclude people from coverage. This is a reasonable supposition: at the moment insurers use family history, in large part a surrogate for genetics. They also use HIV status when allowed to-and being HIV positive is very similar to finding out about a genetic predisposition to cancer. The insurance companies do this to achieve actuarial fairness. If people can be sorted into different classes of risk, those in the lower risk categories should pay lower premiums for the same cover. At the moment, medical insurance is clearly unfair in those terms, since people with unknown predispositions to disease are treated the same as everyone else. Testing could make the system actuarially fairer. Yet actuarial fairness is only one aim of health care policy, along with considerations such as public health and social justice. If actuarial fairness means that people with real needs will not be able to get coverage, there will be strong political arguments against its enforcement. In California, the legislature has voted to ban all discrimination, by anyone, on the basis of genetic status; the governor has vetoed the legislation. Throughout the medical establishment there is strong opposition to the use by insurers of genetic information. Stopping insurance companies from using such information, however, puts them at a severe disadvantage vis-a-vis their customers. If the customers have even a tentative statistical indication of their future health prospects, that puts them in a privileged position when buying insurance. That privilege hurts insurers and put up premiums. Many observers-- including a good few within the biotechnology industry, which lobbied furiously against the price-control aspects of proposed health-care reforms in Washington--think the likely outcome will be a universal health-care system in America. It would be a way of getting the benefits of genetic testing without stigmatising the tested. It might be actuarially unfair on the utterly healthy; but one of the implications of genetic testing is that no one is utterly healthy. At some level, there is something in everyone's genome that could get them into trouble eventually.

Students of political philosophy will recognise the situation. In his "Theory of Justice", John Rawls uses a thought experiment as a device to allow the construction of fairness. He imagines discussions going on in front of a veil of ignorance, hidden behind which is the information that would allow people to know whether or not they would benefit from the system to be adopted. At the moment, that veil of ignorance hangs over the genome; people do not, by and large, know whether they are privileged or at risk. This, then, is the time to have a Rawlsian discussion about how care should be distributed. The veil is being lifted, bit by bit, everyday. And it is not just disease that seekers after justice will find behind it.

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The Veil Torn When he is interviewing people, Dean Hamer asks them whether they can curl their tongue so that the tip makes a little u, or even an o. He thinks there may be a genetic basis for the ability. This is a good idea. If you want to show a genetic basis for behaviour, it makes sense to choose something in which no one has any great emotional investment. But it is not the main thrust of Dr. Hamer's field of inquiry--just a sort-of-frivolous side show. Dr. Hamer is looking at a question which has a lot of emotion invested in it; the genetic basis for homosexuality. Two years ago, in a flourish of controversy, he published his initial findings. Every man receives one of his mother's two x chromosomes; any two brothers should have a 50-50 chance of having the same x chromosome. However, he found that gay brothers seemed often to share the same x chromosome. Particularly implicated was a reqion called xq-28; it might harbour a gene that had helped make the brothers gay. The media announced the discovery of a gay gene. But there is no such thing--at least, not in the sense that such an announcement would suggest. If Dr. Hamer's studies bear fruit, he will not have found a gene that all gays have, nor one that no hetorosexuals have. He will not have found a gene devoted to disposing male desires towards male bodies. Among other things, a gene that did nothing but promote such behaviour would have trouble moving from generation to generation. It may well fertility, giving its female carriers enough advantages to outweigh any reproductive drawbacks it may produce in a boy. Dr. Hamer's gene, if it is found, will mark a predisposition, not a destiny. That is still controversial, though, and some of the dimensions of the debate are surprising. Dr. Hamer always knew that some people would want to develop a test allowing fetuses feared to be "gay" to be aborted--wrongly, in his opinion. He did not expect that reprints of his paper would be sent by gay men to their mothers as Christmas presents, evidence that their sexuality was inherited, not acquired. In this, the fuss cut across traditional lines of argument. The right has, in the past, typically favoured the idea of innate characteristics while the left has stressed the influence of the social environment on the tabula rasa of the human soul. Yet here were liberal gays happy to be able to say that they did not choose their life, that it was their biological nature. Alongside that, though, and especially in Europe, people feared that appeals to biology might bring with them risks of medicalisation. It is not long since the World Health Organisation listed homosexuality in its registry of diseases. The nature that has been selected Homosexuality; romantic love; violence; intelligence; tongue-curling: all are aspects of human nature. Anyone who thinks that humans and their nature have evolved through natural selection will expect to find genes linked to these traits, or for almost anything that seems like a human universal. Scientists working with the tools of the genome project are bound to unearth some of them soon; in time, they may find many.

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This marks a significant change in human genetics. As Dr. Hamer points out, until recently human geneticists were not interested in particular genes; they were interested in statistics that showed a trait was inheritable. Now that they can study the specific genes involved, they may develop a biological understanding of how the trait works. From that should flow an understanding of the possibilities of environmental enhancement or mitigation. Even before getting down to the level of individual genes, the new biology is discovering things old human genetics could not. The variation between two people's genotypes can be measured (this is, among other things, the basis of genetic fingerprinting). These measures show that the amount of variation within groups is far greater than the variation between groups. Races do not differ very much in genetic terms; nothing like as much as individuals within a racial group may. The new genetics is a study of individuals. Yet at the same time it is a study of groups of genes. Like the genetic basis of common diseases, which the genome companies are teasing out, the genetic basis of behaviour will depend on the complex interaction between many different genes and the environment. Among these genes, scientists expect of find many that play a part in the development of the body's behaviour organ--the brain. These developmental genes are likely to highly interrelated, and each of them will have multiple effects. Proteins that regulate complicated developmental system are likely to have slightly different effects at different times and in different parts of the body. To call any such gene a gene for one thing is to miss the point. As an illustration, consider recent changes in neurology. At one point, it was thought that visual images from the eye were processed in a hierarchy of nerve cells. At the bottom there would be cells that responded to general information--lines, circles and so on. At the top there would be cells that responded to very specific images, such as grandmothers. Though there is some truth in this, the idea of a grandmother cell is out of date. Memories are seen as patterns of activity, rather than things stored in cells. There is no single cell without which you would not recognise your grandmother. Similarly, complex behaviours may be due to patterns of genes. Very similar patterns will have different effects; some quite different patterns may add up to much the same thing.

The choices yet to be made For all this difficulty, some behavior patterns will be linked to some genes. Dr. Hamer may find his gene. Another group of scientists has found a gene associated with some forms of dyslexia. The field of behavioural genetics is strewn with retracted findings, and others that turned out to be only narrowly applicable: mutation that seemed to cause unwarranted aggression among some men in a Dutch family is turning out to show little variation in the population at large. In general, the variation in an evolved trait may not be closely linked to the genes, even though the biological underpinning is.

Where there is behaviour-linked variation, though, there will be tests. They could be helpful on the phenylketonuria principle, where knowing the gene lets you adapt the environment to compensate. A child with a genetic predisposition to dyslexia may be far better served by his educators if that predisposition is known. An informed, supportive environment makes a huge difference: just compare the abilities of people with Down's syndrome brought up in worlds adapted to their needs and those written off as idiots.

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Yet for all that, many people with Down's syndrome are not born at all. Fetal tests are, and will continue to be, used to inform choices about abortion Attempts to allow such choices only on purely medical grounds are hampered by the nature of the dividing line: a broad swathe of grey. In general, people should be able to choose what they want for their child-individuals' religious convictions permitting--and that includes a degree of genetic choice. Any rules limiting this choice would, in effect, force women to bear children that they do not want. If, as may happen, some deaf families want deaf children, it may be right to allow them that choice. Some observers worry that certain choices could not be economically accommodated within a society's health-care system, giving rise to a new eugenics based on the rationing of health care. But the overall effect of choice will undoubtedly be a decline in gene-linked disorders. Choice will be influenced by social pressures, and perhaps even by public policy. If people were choosing boys in excessive numbers, social disapproval or even tax regimes favouring girls might stop them. In principle choice is desirable. If the range of choice is to be wide, then abortion, even abortion made much easier and less stressful than it is today, is an unsatisfactory way of choosing. Instead, in-vitro fertilisation may become quite common; among the affluent, it could be the norm. In effect, it allows the choice to be made in parallel from among an array of embryos open to inspection, rather than forcing selections to be made one at time in the womb. Birth has, in many places, moved from the bedroom to the hospital. Conception--already divorced from sex by contraception--could easily follow it. People could thus be allowed to choose among a range of different combinations of their genes, representing a range of children they might have. But what of children who would never be born without the test tube--children with genes present in neither parent? The gene therapies that put new genes into cell can be applied to egg cells and sperm cells or to embryos; in laboratories they are routinely used on animals such as the goats mentioned at the beginning of this survey. So such children are possible, but for various reasons they are unlikely. Very few medical applications of genetics would call for the genetic manipulation of an embryo; choice provides sufficient remedy. Why engineer a replacement cystic fibrosis gene into an embryo when you can simply choose an embryo that does not need such treatment? Few couples will be so unlucky in the genetic draw that some combination of their genes will not look pretty healthy. An altogether more perplexing reason for genetic manipulation of the embryo might be the desire to give the child certain traits absent from the parents. Such manipulation might become technologically possible, but it would raise profound moral issues. Axel Kahn, a French gene therapist, speaks for many when he rejects it on the basis that it requires human beings to be treated as means, rather than as ends in themselves. This would be particularly true of experimental people on whom such a technology would need to be developed-- embryos who had genes added to them in order to see what the effect might be. There is no other way of finding out. Any such experiment is far beyond the ethical pale, and there it should remain.

The technologies offered by genetics are best used as a source of information allowing people to achieve a better fit between environment and genome. A person's genome should, perhaps, be seen as something akin to the Freudian notion of the subconscious: a strong influence on a person's life, but normally hidden. With help it is at least partially inspectable and explainable, and such explanations can provide helpful insights into how that life might be led. To use genetic technology as a way of trying to control what other people will become is not only immoral; it is also to miss the point. The true significance of genetic technology, and
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the power that it is delivering over life, is not that people can be designed from scratch, but that they can break free from some of the limitations imposed by their inbuilt genes. Childhood's end Four billion years ago, a set of molecules found that it contained the wherewithal to make another such set. The information which described it was contained within it. What sort of molecules they were, no one knows; what matters is that, because of the information they embodied, they could reproduce themselves. That was the moment when life began--and with it began natural selection, the process that shapes life. From that beginning, it blindly and relentlessly built up the entire natural world seen today, endlessly recording information, processing it and re-recording it. Today's humans have brought about something almost as dramatic as that first spark of life. The information encoded in life has become readable through another means. Selection, whether natural or not, is no longer the only way to change and deal with this information. It can be done directly. This discovery is the grandest step in the remorseless march of biology. It does not explain everything, but it helps bring forward the day when everything might be explained. There are still hard biological questions to be tackled, especially those of the brain; some may prove intractable for a long while, in human terms. On the 4billion-year scale of the history of life, though, they seem likely to be cracked in an instant. The possibilities of this biology are almost endless. The natural world, including the human body and mind, will become malleable. Implanted organs may refashion the brain, designer viruses rebuild old tissue. Human organs grown in animals for transplant are already being designed. New types of creature may appear; creatures to marvel at. If humanity can find no peers among the stars, it could create new intelligences on earth. The genetic difference between man and chimp is small; new sentient species are not inconceivable. All this will be made possible by genetics. But, at the same time, the pre-eminence of the gene will fade away. Genes have lost their privileged position as the carriers of information. Biological information will be stored in minds and computers as well as in genes, and the genes will become just one of the many means of manipulating the world, appropriate for some things and not for others, just like therapeutic proteins. Their romance will wear off, and it will become obvious that genes are simply not necessary for most of the purposes to which fevered imaginations would have them put. If you want an army of blue-eyed blondes, try peroxide and contact lenses; if you want a different sort of mind, try new types of education. Or design new drugs. What was once unique to genes is now in humanity's grip. That grip could soon have all the power that has at times been attributed to genes, and more. The same intelligence will be able to shape the gene and the environment, which between them make all organisms what they are. The control of biological information on this scale--of the raw data and the way that it is processed--means the control of biology, of life itself. The power of the gene has been revealed as partial and counteractable; the awesome biological power of humanity is still only embryonic. This interregnum is a good time to start making decisions about how best to effect the handover of power from nature to man. Those decisions will be difficult. But the general principles to help and guide them can be identified now: respect for autonomy, respect for variety, respect for equality.

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Of these, equality might seem most open to challenge. People are different, and the genes show the depths of those differences. But equality has never been something for nature to provide. It is something that societies create in certain areas, particularly areas of opportunity. It is social, not biological; for society to protect and cherish, come what may. To think of genes is to think, at some level, of generations: of the birth of a child in whom the old has been made young again, and which will, in time, grow to adulthood itself. Who can say when that transition is made, and the child becomes an adult? Perhaps it is when it can, itself, give birth; perhaps when it can see its parents for what they truly are. On either count, humanity is coming to the end of its childhood. We are seeing the natural world that created us for what it is. We are within reach of the power to create it anew. It is a moment for joy; and for fear; and, most of all, for responsibility.

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