GENE  THERAPY  IN  THE  WOMB

Don't imagine that the abysmal failure of gene therapy to date means there is going to be any backing off on the agenda for genetic engineering humans, as recently outlined for example by Lord Winston in the final programme of his BBC1 series.

Winston is just one of many leading figures within the science establishment supporting the claims of inevitability and benefit put forward by the promoters of a designer-baby future.

Consider the following two items and how they link into the following article:

1.    New Scientist editorial, "The Last Taboo: If genetic engineering could be made safe, would
       you let your baby have it?", which concluded "It would be a mistake to expect the taboo on
       human genetic engineering to last forever."

2.    The comment by James Watson, founding director of the Human Genome Project: "...if we
        could make better human beings by knowing how to add genes, why shouldn’t we?  What’s
        wrong with it?... to say that we’ve got a perfect genome and there’s some sanctity to it..  I’d
        just like to know where that idea comes from.  It’s utter silliness."

That New Scientist editorial and Watson's challenge seem to find an echo in the sub-heading of the New Scientist article below: "If gene therapy in the womb could cure common diseases, what's the problem?"

The New Scientist article notes: "some feel that it is only a matter of time before in utero gene therapy is endorsed, and perhaps germline gene therapy too.  In fact, Newman suspects that some people may be deliberately downplaying concerns about in utero gene therapy in order to soften up public opinion and pave the way for germline therapy..."

Note also the way that side-effects from chemo-therapy and the effects of some IVF practices are being used as a way of muddying the waters as to the acceptability of medical interventions affecting the genetic outcome of human sexual reproduction.

This fast emerging agenda clearly needs to be challenged. As Dr Marcy Darnovsky writes, whatever the limitations of such an approach:   "...we cannot dismiss the possibility that scientists will achieve enough mastery over the human genome to wreak enormous damage - biologically and politically."
["The New Eugenics: The Case Against Genetically Modified Humans":
https://members.tripod.com/~ngin/technoeugenic.htm]

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1.    Generation game -  by Joanna Marchant,  New Scientist - 2 December 2000
If gene therapy in the womb could cure common diseases, what's the problem?

GENE therapy has proved one of medical research's greatest disappointments. Not only has it failed to make many people better, it's made a significant number worse. And following the exposure of activities at the University of Pennsylvania, we now know that unethical use of gene therapy has killed at least one patient.

But researchers haven't given up hope of finding ways to treat inherited diseases. "We were frustrated that not much was happening, that it was short-term, and that even if we succeeded we would not be able to reverse the disease," says Charles Coutelle, a leading researcher in gene therapy at London's Imperial College School of Medicine.

So Coutelle, and a handful of groups in the US, are pinning their hopes on using gene therapy to treat someone before they're born.

This was a hot topic among delegates to the Millennium Festival of Medicine in London last month. Treating the baby in the womb has several advantages. First, because it's small there's a better chance of getting the genes to all the cells that need to be corrected. Going in early, before the immune system is fully developed, also avoids an immune reaction to the products of the introduced genes, and the systems that deliver them. And finally, in utero therapy for disorders such as cystic fibrosis would prevent them causing lasting damage.

Animal tests are already showing success. In a recent trial, Coutelle and his colleagues used non-infective virus-like particles to carry the gene for the human blood clotting agent factor IX into sheep embryos. The added genes produce the protein for as long as they remain in the animals' cells, but they are not incorporated into the cells' DNA. When the lambs were born, their levels of human factor IX were 80 per cent of the normal human level - -which in people would be enough to keep haemophilia at bay.

The lambs only made factor IX for around 40 days after birth, highlighting a problem with any form of gene therapy that doesn't integrate the introduced genes into the patient's own DNA. Eventually, Coutelle and his team are hoping to find ways of doing this, allowing fetal gene therapy to introduce genes that will remain active for life.

Coutelle says that his therapy could eventually be simple and safe enough to treat genetic risk factors for even common conditions such as raised cholesterol. "You could treat it with a single shot during pregnancy." Already, Janet Larson from the Ochsner Medical Foundation in New Orleans and her colleagues have used gene therapy on unborn mice carrying the genes for cystic fibrosis. The treatment completely and permanently prevented the disease appearing in the animals.

It's a rosy vision, but there's a problem. The earlier you put genes into a fetus or an embryo, the better the chances that they get where they are supposed to go. But this also makes it more likely that the DNA will reach developing eggs or sperm, introducing "germline" changes - genes that will be passed on to future generations.

Because of this risk, gene therapy on fetuses is effectively banned in Britain. "With in utero gene therapy, you are dealing with a much smaller target," says Norman Nevin, chair of the Government's Gene Therapy Advisory Committee, which decided in 1998 that it would not approve any proposals for this type of treatment.

"At this point in time, if a proposal is submitted for in utero gene therapy, it is unlikely to be approved, because of the risk of accidentally introducing germline changes.  We don't know what the consequences of that would be," Nevin said.

According to Coutelle, this is unfair, as it applies more stringent standards to gene therapy than to other treatments. "It is a well known fact that medically we are creating mutations by chemotherapy," he says. "No one seems to worry about that." Because the mutations are random, it is impossible to trace any damage to the germline, he says. "We should try to avoid germline gene transfer, but if it happens, it has to be balanced against the benefits. And that holds for all gene therapy trials."

According to Coutelle, his team could be ready for human clinical trials of fetal gene therapy in four or five years' time. But will they be allowed permission? "When we are in a position to apply for it, then we'll return to the issue," he says. There is similar pressure to push forward fetal gene therapy in the US too. In 1998, French Anderson, director of the gene therapy laboratories at the University of Southern California, submitted two proposals to the National Institutes of Health for carrying out gene transfer into human fetuses which would have a "distinct possibility" of leading to germline changes. He submitted the proposals with the aim of stimulating debate in the area. But soon the question could be of more than academic interest. Anderson says that after more than a decade of research on fetal gene therapy in animals, he could be ready for human trials in as little as three years. Other researchers think the regulators are right to be cautious.

Cell biologist Stuart Newman from New York Medical College agrees. "Somatic modification in embryos is a grey area because there is a greater likelihood of germline modification. If it is ever going to be done, it has to be done right. We would have to be assured that there was a vanishingly small chance of affecting the germline."

"My concern is that we don't know what we're doing," says John Bell, head of clinical medicine at Oxford University.  "Maybe it will be acceptable in a thousand years' time, but not today."

A report by the American Association for the Advancement of Science entitled "Human Inheritable Genetic Modifications", published in September, concludes that it is "very likely" that some of the adult gene therapy trials authorised in the US have had unintentional impacts on the germline. It adds that the possibility of genetic problems occurring because of these germline side effects seem "at least as great or greater" than problems that might arise from altering the germline intentionally.

With such unintentional changes already taking place, some feel that it is only a matter of time before in utero gene therapy is endorsed, and perhaps germline gene therapy too. In fact, Newman suspects that some people may be deliberately downplaying concerns about in utero gene therapy in order to soften up public opinion and pave the way for germline therapy. Most researchers, however, think deliberate germline modification is some way off, not least because its medical uses are limited. For carriers of recessive disorders such as cystic fibrosis, for example, IVF procedures would be needed to correct an embryo's DNA. And if you're going to perform IVF, then other techniques such as prenatal genetic diagnosis (PGD) could be used to select embryos for implantation that did not have CF.

While the AAAS concludes that germ-line therapy cannot yet be carried out safely in people, it looks ahead to the day when it might be used. The report suggests, though, that the first use of the technique will not be aimed at introducing genes that will be passed down the generations, but will simply be to correct motility defects in sperm.

And while the debate over in vitro gene therapy rages, other developments are causing consternation. Babies are already being made in the US with mitochondria from a donor, meaning that they have DNA from three different individuals. "It is starting to blur the question, 'who are the parents of the child ?'" says Newman. "Society has not worked out what the implications of children having three, four or ten parents might be. It's a whole mess."