If you put your ear to the tracks, you can hear the train coming.
In conference halls around the world, geneticists and developmental biologists have been gathering to discuss what once was unthinkable-genetically engineering human embryos so that they, and their children, and their children's children, are irrevocably changed. These experts are talking with remarkable candour about using germ-line engineering to cure fatal diseases or even to create designer babies that will be stronger, smarter, or more resistant to infections.
Doctors are already experimenting with gene therapy, in which a relatively small number of cells-in the lungs, say-are altered to correct a disease. Germ-line engineering, however, would change every cell in the body. People would no longer have to make do with haphazard combinations of their parent's genes. Instead, genetic engineers could eliminate defective genes, change existing ones or even add a few extra. Humanity would, in effect, take control of its own evolution.
So awesome is this idea, that until a year or so ago, the taboo on human germ-line engineering was absolute. But opinions have started to shift. Once barely considered a topic for polite conversation among even the most gung-ho of geneticists, germ-line engineering of humans is becoming so much grist to the mill of scientists gossiping around the coffee pot.
Not that the pillars of the scientific establishment agree on this emerging technology, not by a long way. In a straw poll, researchers variously described the idea of human germ-line engineering as "irresistible", "morally questionable" or just plain "dangerous". What they did agree on is that germ-line engineered humans are likely to become a reality. Tampering with a human embryo to create changes that can be passed from one generation to the next is still more or less verboten-countries have signed a Council of Europe convention that bans it, and officials at the US Food and Drug Administration promise not to give the go-ahead without much public deliberation. Despite this, however, most experts say they'd be surprised if designer babies are not toddling around within the next 20 years or so.
Gregory Stock, a biophysicist-turned-expert on technology and society at the University of California, Los Angeles, helped to organise a symposium in March called "Engineering the Human Germline". The task? Not to look way into the future, but at what we'll be faced with in the next decade or two. "There is no way to avoid this technology," explains Stock, who thinks that calling the evolutionary shots will create a happier, healthier society. "The knowledge is coming too fast, and the possibilities are too exciting."
Public enthusiasm could soon match Stock's: poll after poll shows that a sizeable minority of parents-sometimes as many as 20 per cent-say that they see nothing wrong with genetically altering their children for health reasons, to give them an edge over the child at the next desk-or even to stop them being homosexual.
So what is shifting the mind-set about human germ-line engineering from "never" to "well, maybe"? The main driving force, most experts agree, is the new technologies rolling inexorably along the tracks. We are discovering not only what our genes do, but how to make precise changes in them. And although the human genome isn't yet completely sequenced, already the databases contain details of thousands of genes, and of thousands of variations within them, along with information about how these variations affect physical and emotional traits. Added incentive comes, paradoxically, from frustrations with gene therapy.
Gene therapy promised to cure genetic disorders such as cystic fibrosis and sickle-cell anaemia, and even common illnesses such as cancer. But although the glitches are slowly being fixed, few people have so far benefited from the procedure. The problem is getting new genes into enough cells, and keeping them there for long enough to do any good.
With germ-line engineering you have to tweak only one cell-a fertilised human egg-which is "infinitely easier", says Leroy Hood, a molecular biologist at the University of Washington in Seattle. "We have terrific ways to do that." Once a genetic engineer has changed the genome of an egg fertilised in a lab dish, the egg divides over and over again, forming all the tissues of the body. Every cell will have exactly the same genetic make-up as the altered egg.
Now and forever
Genetically engineered mice and farm animals have been around for years and are used for everything from basic research to attempts to create "humanised" animal organs for transplant. But what might be considered a bonus in agricultural biotechnology-the fact that any changes are present in the animal's sperm and eggs (the "germ cells") and so will be passed on to succeeding generations-is for many the most worrying thing about genetic engineering in humans. The critics point out that if medicine has played a bit part in our recent evolution-antibiotics, for example, allow people with less than robust immune systems to survive long enough to pass this trait into the next generation-genetic engineering has the potential to be a star performer.
One reason for cold feet is that large-scale genetic engineering could actually rob society of desirable traits. What if the "disease" genes in combination with other genes, or in people who are merely carriers, also help produce such intangibles as artistic creativity or a razor-sharp wit or the ability to wiggle ones ears? Wipe out the gene, and you risk losing those traits too. And while no one would wish manic depression on anyone, society might be the poorer without the inventiveness that many psychologists believe is part and parcel of the disorder. In his book Remaking Eden, Lee Silver, a biologist at Princeton University, goes as far as to suggest that a century or two of widespread engineering might even create a new species of human, no longer willing or able to mate with its "gene poor" relations ("Us and them", New Scientist, 9 May, p 36).
"The potential power of genetic engineering is far greater than that of splitting the atom, and it could be every bit as dangerous to society," says Liebe Cavalieri, a molecular biologist at the State University of New York in Purchase. Cavalieri, who has worked in the field for more than 30 years, thinks it unlikely that the ugly side of genetic engineering will stop development of the technology in its tracks. "It is virtually inevitable it will get used and for the most banal reasons possible-to make some money, or to satisfy the virtuoso scientists who created the technology."
If esoteric worries about what may or may not happen in a genetically engineered society are unlikely to change people's views, safety issues could-at least until they are solved. "There is a real risk of unforeseen, unpredictable problems," says Nelson Wivel, deputy director of the Institute for Human Gene Therapy at the University of Pennsylvania, and former executive director of the National Institutes of Health Recombinant DNA Advisory Committee. In gene therapy, genes are ferried into cells by modified viruses or other means. It's a risky business, because genes can get inserted in the wrong spot in the genome, killing the cell outright or, far worse, triggering cancer. But at least with gene therapy there is natural damage control-few cells pick up the genes even when the procedure goes well, cancer only affects one individual, and, as the procedure has always been carried out long after birth, there's no chance of upsetting key developmental genes.
With germ-line engineering, on the other hand, there's more scope for unpredictable, even monstrous, alterations. Take the so-called "Beltsville pig". This pig, a thorn in the side of high-tech agriculturists and an icon for animal rights activists everywhere, was engineered by scientists at the US Department of Agriculture to produce human growth hormone that would make it grow faster and leaner. The engineers added a genetic switch that should have turned on the growth hormone gene only when the pig ate food laced with zinc. But the switch failed. The extra growth hormone made the pig grow faster, but it also suffered severe bone and joint problems and was bug-eyed to boot. Of course, unlike human experiments, slaughtering "failures" is always an option for animal genetic engineers.
Before genetic engineering of humans can become a reality, each candidate gene and its switches would need to be extensively studied in animals first, and any changes would have to be made with a surgical precision that reduced the chances of a "Beltsville human" to just about zero. As it happens, over the past few years, molecular geneticists have been busily developing the tools to do just this sort of "genetic surgery".
For years, genetic engineers have altered farm animals by injecting genes into fertilised eggs and then placing them in an animal's womb. But the technique is far too unreliable to use in humans. Out of every 10 000 eggs injected, roughly three make it to adulthood with the gene functioning as planned. What's more, it is possible only to add whole genes, not to fine-tune existing ones.
With mice, the process is more refined. Mice embryos contain embryonic stem (ES) cells that will grow and divide in a flask. That allows the engineers to make use of "homologous recombination", the process by which DNA strands bind to, and sometimes replace, DNA strands of similar sequence. With homologous recombination it is possible to make tiny, surgically precise changes within genes, with the technique depending in part on being able to sort through a large number of ES cells, only picking out the ones that have taken the genetic change in the correct place. Those cells are then added back to an embryo, where they can form any part of the animal. The result is a "chimera", an animal whose body contains both normal and altered cells. To create an animal with the altered gene in every cell, a chimera with the change in its eggs is bred with one that has the change in its sperm—one reason the technique can't be used in humans.
But the efficiency of gene surgery is improving so that fewer cells are needed to start with. That has made it possible for several labs to try gene surgery directly on fertilised mouse eggs, says Dieter Gruenert, a molecular geneticist at the University of California, San Francisco, who is developing just such a technique. The process is still in its infancy, but it could one day make it possible to genetically engineer human eggs, eliminating the need for crossbreeding.
A more immediate solution will probably come from an alternative way of generating lots of identical embryonic cells: the technology that produced Dolly & Co.
Cloning relies on a combination of two new techniques. First, grow cells taken from an adult or an embryo in a flask under conditions that encourage them to divide and increase their numbers, and then trick them into reverting to a nonspecialised state with the potential to form an entirely new individual. Second, fuse one of these cells with an egg from which the nucleus has been removed, and implant this cut- and-paste embryo into a womb. The wrinkles still need ironing out, but these techniques promise engineers the luxury of an inexhaustible supply of cells to attempt genetic surgery upon, only transferring to an egg those nuclei they know have been properly changed. And unlike the mouse ES cells, these cells will generate an animal with the genetic change in every cell. Born last year, Polly, a sheep with a gene for a human clotting factor, was created in just this manner.
Batteries of genes
With the exception, perhaps, of Richard Seed-the Chicago physicist who in January said he would open a human cloning clinic-no one is openly attempting to develop cloning for humans. But hundreds of genetic engineers are working to perfect its use in other mammals, including primates. "None of the technologies [that will allow human engineering] is being developed only for that purpose, but when you put them all together, that is what you will have," says Wivel.
Even so, whether or not it is combined with cloning technology, "gene surgery" lets would-be human engineers go only so far. They could tweak a gene here or add one there, but they couldn't do much about characteristics such as intelligence, say, or disease resistance, or athleticism, which are under the control of numerous genes working in concert. For this, you'll need a budding technology that could soon make it possible to add whole batteries of genes to human cells.
When it comes to cell division, most of the DNA in each chromosome is irrelevant. But to be copied properly and sorted into the two daughter cells, a chromosome must have two types of highly specialised DNA sequences-one somewhere in the middle called a centromere, and bits on either tip called telomeres. Last year, Huntington Willard, a molecular biologist at the Case Western Reserve Medical School in Cleveland, Ohio, and his colleagues reported that they had created artificial chromosomes in cultured human cells that replicated every time the cells divided. "We cultured them for six months, and they looked like perfectly normal chromosomes," say Willard.
Because these human artificial chromosomes (HACs) promise the ultimate in genetic engineering, they have done more to fire up discussion about human germ-line engineering than just about any other technology. Once perfected, HACs will make it possible for genetic engineers to ship complex custom-made genetic programmes into human embryo cells. Each gene could come with control switches geared to trip only in particular tissues, or when the patient takes a particular drug.
Suppose, for instance, that men in your family tend to get prostate cancer at a young age. Insert into your fertilised egg an HAC containing a gene for a toxin that kills any cell that makes it, and two switches for that gene-one that is turned on only by prostate cells and another by ecdysone, an insect hormone that humans cannot make. Nine months later, you're delivered of a bouncing baby boy. Fifty years later, he gets prostate cancer. He takes ecdysone, which activates the prostate poison, killing every prostate cell in his body. Even cancer cells that have spread to other parts of the body should be wiped out.
It's scenarios like this-dreamt up by John Campbell, a molecular biologist at the University of California, Los Angeles, who helped to organise the March symposium-that make the promise of human germ-line engineering so tantalising. Hood is convinced that the benefits of germ-line engineering are going to be substantial: "We could probably engineer people to be totally resistant to AIDS, or to certain kinds of cancers. We might engineer people to live much longer. I would say all these are good qualities."
Willard agrees that the prostate cell scheme, or others like it, might someday be made to work. At the moment, his team is trying to create HACs that contain specific human genes so that they can check that the genes function normally in cell cultures. "Everybody wants to [use artificial chromosomes] in mice," he says, "But we're years away from even contemplating putting HACs into humans."
Still, when that day comes, as most experts predict it will, who and what will be the first candidates for human genetic engineering? Geneticists are more willing to kick around the possibilities than ever before. Gruenert speaks for many when he says that the crucial issue is whether germline engineering would save lives and prevent suffering. "For medical reasons, I have no problems," says Gruenert. "But for making superwomen or supermen? I have some problems with that."
The first candidates for human genetic engineering are likely to be children who could inherit a disorder that kills young, is incurable both now and for the foreseeable future, and is caused by a relatively simple defect. Tay-Sachs disease, which causes the brain to degenerate in the first few years of life, is just such a disease. Fix the gene, goes the argument, and you stop the disease both in that child and all his or her offspring.
If the safety issues are resolved, the idea of wiping out such diseases could sway the opinions of the public and regulatory agencies, paving the way for the first attempt at human germ-line engineering, says Jeremy Rifkin of the Foundation on Economic Trends in Washington DC, a longstanding opponent of biotechnology. "I've seen this pattern before in biotech. First there is some discussion in journals, then a conference, then they go ahead and do it. I think there are protocols being readied now, and we'll see them within a year or two."
Rifkin may have some unusual allies in his fight against human engineering. Many researchers who are otherwise decidedly pro-biotechnology are vocal in their concerns about engineering humans. Allen Roses, who heads Glaxo Wellcome's worldwide genetics research effort, is emphatic that any attempts at germ-line engineering would be "morally questionable". The milder-mannered Francis Collins, director of the National Human Genome Research Institute near Washington DC, says simply: "It is very hard to come up with compelling scenarios of why you'd want to."
Collins, Roses and others take issue even with the idea of using genetic engineering to prevent genetic disorders. They point out that parents known to be at risk of certain serious genetic abnormalities are already offered genetic testing and the option of an abortion if their fetuses have the disorders. Using this approach, the number of Tay-Sachs births has been reduced by more than 95 per cent among American Jews. For women willing to have IVF, an embryo can even be tested before pregnancy starts.
Of course, repairing rare genetic defects is not the only factor likely to endear genetic engineering to the public. Who could resist the chance to bequeath their children freedom from Alzheimer's, cancer, heart disease and diabetes?
Then there's the possibility of cosmetic changes and enhancements that have nothing to do with saving lives and preventing disease. Many behavioural traits, from cheerfulness to sexual orientation, have already been linked, if tenuously, to variations in single genes. Many more such links will be reported in the near future. "There will come a time when we will understand enough to manipulate even complex genetic systems," says Hood. "For example, we will be able to dramatically affect intelligence. That, I think, will be pretty irresistible."
"Evolution is being superseded by technology, and the time scale will be far more rapid," says Stock. "Humans are becoming the objects of conscious design."
And no matter how wild the idea of designer children sounds now, technology has a way of making believers out of sceptics. Silver argues that parents will provide the market forces that will eventually make germ-line engineering of humans routine. When IVF was first being developed in the 1970s, he points out, doctors and lay people alike thought the idea absurd and repellent. Even though success rates are still low, IVF created such demand among couples with fertility problems that it has become widely accepted and commonplace.
For now, however, the regulative barriers are firmly down, even as the research hurtles forward with breathtaking speed. Which is perhaps why talk about engineering humans is now coming into the open. It no longer makes sense to shy away from discussing what we're going to do when all the technical obstacles are overcome, and genetic engineering offers us the profound power to sculpt our children-and the future of our species.
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