Fertile Ground

IVF researchers pioneer the bioethical frontier

When researchers at George Washington University cloned 17 dysfunctional human embryos last summer, they were testing a possible new tool for in vitro fertilization (IVF). Their experiment opened a Pandora's box of hypothetical moral concerns—an increasingly familiar experience in IVF research—among them the prospect that many identical copies of an individual might someday be created. But the public uproar that followed has obscured a much more immediate ethical issue: how and when to test embryos for genetic disorders.

"We have developed tests for cystic fibrosis, Duchenne's muscular dystrophy, myotonic dystrophy, Lesch-Nyhan syndrome, which is a vicious neurological disorder, Tay-Sachs disease, and hemophilia A, which is a clotting deficiency. And we are working on fragile X, an inherited mental retardation syndrome," reports Mark R. Hughes, director of the Baylor College of Medicine's prenatal genetics center.

From a technological perspective, this is a remarkable feat. The technique involves retrieving eggs from a woman's ovary, fertilizing them in vitro and letting them grow to the eight-cell stage. One or two of the cells are then removed from the embryo and analyzed by making millions of copies of one bit y y of the gene of interest or by injecting fluorescent DNA probes that can be made to home in on certain mutations. If the embryo is judged acceptable, it is transferred (often with several others) back into the woman. The analysis is typically performed in a single day to maximize the odds that at least one embryo will attach itself to the uterine wall and launch a pregnancy.

As of December, researchers could boast of at least 18 such pregnancies. Despite worries about accuracy—the tests have reportedly failed to diagnose afflicted embryos in three cases—the screening techniques are moving rapidly toward clinical use in IVF centers. There are more than 300 such centers in the U.S., most of them private and largely unregulated. Carlene W. Elsner, a clinician at Reproductive Biology Associates in Atlanta, plans to offer genetic embryo testing to patients later this year. "We could do it next treatment cycle if we wanted to," she says.

But some clinical researchers think the tests are not yet ready for commercial use. "The way they are done in the academic setting wouldn't work in the clinic," says Donald S. Wood, vice president of science and technology for IVF America, which operates six fertility clinics. Having to produce conclusive results in a single day places a lot of pressure on doctors—"This is not something you want to rush," he argues.

Wood says IVF America has worked out a way to freeze embryos after a cell has been removed so that researchers can do their analysis at a more leisure-

GENETIC MUTATIONS can be identified before pregnancy begins by sucking one cell out of an eight-cell embryo and amplifying bits of DNA. The remainder can grow into a healthy baby.

ly pace. Acceptable embryos can then be thawed and returned to their mother during a later menstrual cycle. The company is planning three clinical trials to test the idea.

Meanwhile Hughes is collaborating with Alan H. Handyside of Hammersmith Hospital in London to increase the number of disorders for which a single embryonic cell can be screened simultaneously. "We can currently examine 10 different genetic locations from one cell," Hughes says. "It looks as though you may be able to do as many as 28" using DNA amplification.

In the private sector, research is proceeding along slightly different lines toward a similar goal. Wood thinks the polymerase chain reaction currently used to search for mutations is too slow and destructive. "It would be far better to be able to drop the sampled cell in a cocktail of probes and have the results in 30 minutes," he says, adding that IVF America is developing probes for chromosomal defects that could do just that. Although they could not identify mutations in individual genes, Wood claims that the probes could be removed without damaging the cell, so that another battery of different tests could be run. "We're still three to five years away from clinical use," he says, "but we're far enough along that we know it's going to happen."

The emerging capability to test for many different genetic and chromosomal disorders has some ethicists worried that the technology might be used for screening embryos regardless of any known risk of inherited disease. This is particularly disturbing in the absence of a consensus about what is and is not a disorder. A 1990 survey conducted by Dorothy C. Wertz, a senior scientist with the Shriver Center for Mental Retardation, found that 12 percent of those polled would terminate a pregnancy if they discovered that the fetus possessed a gene for unbeatable obesity. (No such gene is known.) Most physicians would consider that unethi-„ cal. Yet, Wertz reports, in a 1 1985 poll the "vast majority" 3 of practitioners said they would perform amniocentesis and chromosome analysis of a fetus at a patient's request without any medical reason.

A few IVF clinics have reportedly begun offering to select embryos of a particular gender even for those who have no history of sex-linked disease. "This is inevitable," Wood warns. "You're going to see sex selection become more widespread." Wertz, who is tallying the results of a recent survey, claims it indicates that "perhaps half of the geneticists in the U.S. have had a request for sex selection." John C. Fletcher, a bioethicist at the University of Virginia, worries about "selecting embryos for traits that don't have anything to do with disease. Society has an interest in trying to help people sober up rather than entertaining fantasies about the ideal child," he says.

Hughes dismisses the notion that embryo testing might lead to an increase in unethical reproductive choices. "Right now you can terminate any pregnancy for almost any reason up until 20 weeks," he argues. "We think of testing as an alternative to abortion, because it allows you to make the decision before a pregnancy even begins."

If the debate were limited to test-tube babies, many ethical questions might be moot. After all, of the more than three million couples in the U.S. thought to be unable to reproduce without IVF, only about 20,000 go to clinics every year. Costs of $6,000 to $10,000 per treatment keep many away. Others recoil when they learn that 85 percent of IVF treatments fail to produce babies.

Rapid advances in the art of fertilization promise to improve these odds, primarily in the 50 percent of cases with male factor infertility. By cutting holes in the egg's tough coating or by injecting sperm directly into the ovum, researchers can now fertilize eggs with even the weakest sperm. If such tricks improve IVF's dismal success rate, demand for the procedure and for embryo testing could increase.

But John E. Buster of the University of Tennessee-Memphis College of Medicine, among others, is working on a technique that might have a far greater impact. Called uterine lavage, the idea is to wash a naturally conceived embryo from the uterus before it has a chance to become implanted, then test it for genetic defects and return it only if it is healthy. Unfortunately, the chances that just one returned embryo will develop into a pregnancy are slim. If this technical hurdle can be cleared, however, uterine lavage might allow parents to look for mutations in embryos produced the old-fashioned way—at a fraction of the cost of IVF.

As the pace of innovation continues to accelerate, concern is growing among researchers, clinicians and regulators alike that there needs to be more discussion of the issues raised by genetic screening and more oversight of its development. Wood reports that leading

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