Worldly wise: 20. French Anderson's controversial plans to inject engineered genes into foetuses in the womb have met with condemnation - and a death threat. Tim Cornwell reports

The Federal Bureau of Investigation is investigating a death threat delivered to French Anderson soon after news broke of his "pre-proposal" to conduct experimental gene therapy on foetuses in the womb. The anonymous letter ends with the message: "It is the duty of God's disciples to strike you dead."

Anderson, director of gene therapy at the University of Southern California, handed the letter to university officials; it found its way to the postal inspectors and thence to the FBI. Anderson's office has been cautious of strange packages since the late 1980s, when he carried out the first gene-therapy treatments on human patients. The hate mail dropped off after a while, but the new proposal inspired hundreds of emails, faxes and phone calls.

The death-threat letter began with a paraphrase of an "action alert" put out by the Council for Responsible Genetics. The council's board includes scientists such as the eminent biologist Stephen Jay Gould, "whom I know well and have known for years", says Anderson. Nevertheless, he is clearly unhappy that the letter draws on CRG material.

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For the council did not mince its words about his proposal to inject engineered genes into foetuses in a bid to correct hereditary ailments. Under the headline "Say No To Designer Children!!!" it announced: "This is it. This is how it begins." It warned that Anderson was one of a group of scientists who "favour a future in which the human race would be 'improved' through genetic engineering".

"If this first proposal is accepted, how much longer will it be before difference becomes defect, and any child who does not measure up to some arbitrary standard of health, behaviour or physique is seen as flawed?" the council asks. "Do we want a future in which babies are produced according to genetic recipes?" This kind of rhetoric is misleading, says Anderson. It ignores the terrible suffering families are having to live through. Last month Anderson made a submission to the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health, the body that establishes guidelines for sensitive scientific research. He outlined gene therapy to treat two conditions in the womb - ADA deficiency disease and alpha-thalassaemia.

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Children born with ADA deficiency have no immune system. They are fated to live as "bubble children" in an infection-free plastic chamber. Foetuses with the blood disorder alpha-thalassaemia, meanwhile, do not produce haemoglobin. Mothers are forced to abort before 24 weeks as the dying foetus becomes toxic.

Anderson has led experimental gene-therapy for ADA-deficient children. Over 3,000 patients have received gene-engineered cells in the hope of replacing defective or missing genes. But the results have been inconclusive. There is no evidence yet of a miracle cure, and the research has left many questions unanswered. Anderson keeps in close touch with the families of two young women, Ashanti DeSilva and Cindy Cutshall, whose treatment began in the early 1990s. "Individual patients have been helped but there is not a high enough percentage of cells that get corrected to really be effective," he admits.

Sadly, most of the patients have developed terminal cancer. One possibility is that the genetic experimentation itself precipitates cancer - though this has not yet been proved in humans or monkeys, "so the risk is clearly not high", says Anderson. Although several hundred patients are still alive, there is not a large enough pool to screen for possible long-term side-effects of the gene therapy.

Some American scientists regard gene therapy on the foetus - when cells are dividing at a rapid rate - as a Holy Grail. If the therapy works in the womb, in theory, children could be born healthy and never need another treatment in their lives.

But Anderson's proposal to treat foetuses with alpha-thalassaemia - foetuses never expected to survive long enough even to be born - is a painful lesson in medical ethics, not to mention the politics of abortion. Critics have agonised about the risk that partially successful treatment might produce a severely damaged child, who would live only a few weeks, possibly in great pain.

There is a second ugly issue too: the image of a medical team poring over an aborted foetus to check whether the therapy has worked. Anderson says it was an RAC member who suggested the "stage-zero" study; to take a mother who had already decided to terminate her pregnancy, carry out gene therapy in the womb at 18-20 weeks and then evaluate the aborted foetus at 24 weeks. "My response was that logically it would make sense, but I would have great difficulty doing it," he says.

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"Since then, as this discussion has evolved, I have suggested going ahead with treatment, then testing the foetus at 24 weeks. If we cure the foetus, it shouldn't be aborted, but allowed to grow to term. But if we are only partially successful, then go ahead with the abortion."

It sounds like an almost unbearable scenario for parents, see-sawing between hope and despair. But parents, says Anderson, "are extraordinarily supportive of doing things that will help not just their own future children but will also help future mothers. We would want to insist on having outside advocates for the family to turn to so they could really communicate about these issues...What one has to avoid is false hope, and it is very easy for desperate couples to develop a false hope."

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Anderson says his team submitted 180 pages to the RAC outlining potential problems with the research back in July; this report was sent to reviewers, who weighed in with an inch-thick list of observations. He was not asking so much for approval, he told committee members, as opening a public debate.

And it is to this debate he feels groups such as the CRG should contribute. So far he feels the council's rhetoric has sometimes obfuscated rather than clarified his research. For instance, it led to some assuming Anderson's work was opening the door to germ-line transfer, where an altered gene can be passed down to future generations in sperm or egg. But this is not necessarily true, says Anderson. Rather, he wants to pursue research into one-off gene therapy for individual children, although he accepts there is a risk the therapy could have unforeseen consequences.

The plan to treat ADA deficiency, for instance, involves injecting a stretch of DNA containing the gene for the ADA enzyme into a foetus during the second trimester. Experts agree there is a risk of the new gene being absorbed not just by somatic cells in the baby's body but by germ cells in the eggs and sperm. Parents who decide on the procedure might in effect be making genetic choices not just for one child but for descendants ad infinitum.

Whether or not Anderson's research eventually gets the go-ahead will hinge in part on animal studies to gauge the level of risk. Beyond that, he says, there is the question of what risk is acceptable, and that is why he is seeking to force a discussion now. "Most people would feel the risk:benefit ratio acceptable if the choice were between a dead foetus and a healthy individual who could have his own family, with a one in ten million chance of carrying an engineered gene and a 50-50 chance such a gene will be beneficial," he says. "On the other hand, if the chances of an engineered gene getting into the germ-line were 50 per cent, then I would not go forward."

But for all his caveats and cautions there is a very real distinction between Anderson and many others in his field. He says any deliberate germ-line transfer is a decade or more away from satisfying medical and ethical criteria that it is safe, reliable and reproducible. But, in time, it should take its place as a medical option for physician and patient.

His critics, and much of medical and public opinion, maintain a blanket "no" to meddling with the human gene pool. They argue there are other options enabling people to have children free from inherited conditions, such as adoption. "I feel it would be unethical to do an intentional germ-line gene transfer at this time because we don't know enough scientifically to do it safely, we don't know enough medically to do it effectively and we don't know enough ethically to do it wisely," says Anderson.

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"We are years away from satisfying any of those three criteria. But if you ask me 'do I believe in germ line gene therapy?', the answer is yes. When the time comes, then we must do it, because it is just plain human nature. What parent would willingly pass on lethal genes to their children if there's a safe, effective way of eliminating them?"