Good Eggs, Bad Eggs

By Frederic Golden/Los Angeles

They were hardly the sort of couple you would expect to have trouble with prenatal testing. The father, Dallas geneticist Dr. Paul Billings, was the author of pioneering studies about genetic screening and its problems. The mother, Suzi, was also a physician. When she became pregnant at 37, she not only opted for amniocentesis--mainly to check for Down syndrome, an increased risk for children of mothers her age--but also for a newer genetic probe for an inheritable neuromuscular disease. She knew that a member of her family carried the gene for it and realized she might have it too. "It was a straightforward matter and deemed valid by our doctor," says Billings. "But Blue Cross adamantly refused to pay the bill--even though it was only $300."

The Billingses are now the parents of a healthy three-month-old girl. And as well-off professionals, they can afford to brush off the incident as a minor bureaucratic irritation. But for many other would-be parents, the rapidly expanding availability of genetic tests to identify inherited ailments before or after birth often raises issues that are not so easily resolved.

On the contrary, it often opens a Pandora's box of questions that tear not only into pocketbooks but at our psyches: What if the news from a test is bad? Or ambiguous? Should the fetus be aborted? Or should the child be brought into the world in hopes that a cruel disease can be managed or cured? And will insurance coverage be available if the condition was known at birth?

Beyond the poignantly personal dilemmas are broader family and societal issues. If a test is positive, should blood relatives be warned that their genes may contain the same inherited flaw? If so, should such findings become part of a permanent record, like a college transcript or an income tax return? And should doctors alert public health authorities, as they would for contagious conditions such as typhoid, hepatitis and AIDS? More disturbing, isn't there a hint of eugenics in all this picking and choosing, an attempt to shape people to our own genetic prejudices?

Indeed, the almost daily advances in our ability to forecast any of the 4,000 inherited diseases our genes might bequeath us have created such a thorny knot of private, ethical and social issues that the new genetic procedures are the subject of some 20 bills before Congress. In addition, 3% or 4% of the federal investment in the Human Genome Project--about $90 million--is now going to studies seeking to untangle them. One result is the imminent appointment of an 11-member blue-ribbon panel to advise Secretary of Health and Human Services Donna Shalala on how to guide us into this new era of genetic testing.

Testing is, of course, already commonplace. As many as 9 out of 10 pregnant women in the U.S. submit to some prenatal screening. Typically, this involves sampling the mother's blood--so-called serum-alpha-fetoprotein testing to seek out telltale proteins that may indicate spina bifida, neural-tube defects or Down syndrome--or looking directly at the fetus with ultrasound scans. For women over 35, doctors usually recommend more invasive procedures in which actual fetal cells are gathered from the womb's amniotic fluid (amniocentesis) or placenta (chorionic villus sampling).

Even so, these tests can spot only visible abnormalities in the 23 pairs of chromosomes we inherit from our parents, such as the extra chromosome associated with Down syndrome, a form of mental retardation, or biochemical errors, such as a reduced level of hex-A enzyme that brings on Tay-Sachs disease, a fatal metabolic disorder. Moreover, the results may be confused by so-called chromosome structural abnormalities--oddball configurations that may or may not have a genetically significant effect, thus exasperating couples who expect clear-cut answers from amniocentesis or CVS.

To look more closely at the baby's genetic prospects, doctors must probe the long stretches of DNA along the chromosomes constituting its genes. Thanks to the spectacular success of molecular biologists in identifying specific disease genes, burgeoning U.S. genetic centers now offer DNA tests for 30 or 40 of the more commonly inherited disorders, including cystic fibrosis, susceptibility to some types of breast cancer, fragile X syndrome (after Down, the most common cause of mental retardation), Huntington's disease, Duchenne muscular dystrophy, and various types of degeneration of the brainstem, spinal cord and peripheral nerves. If you include testable variants of some diseases, such as the many different genetic mutations that can cause cystic fibrosis, the number of available DNA probes rises to some 400, with the count growing almost daily. What's more, some tests provide accuracy as high as 99%.

Even more genetic gee-wizardry lies just down the road. Using biochips--thumbnail-size pieces of material imprinted with hundreds of different DNA probes--scientists should be able to identify genetic errors almost as quickly as a supermarket scanner prices a load of groceries. In some systems, the probes use different fluorescent dyes that glow under laser light when they hook up with target genes, allowing sensors to tabulate the results automatically. Genetic researchers are already talking about using "FISH [for fluorescent in-situ hybridization] and chips," as they whimsically call these new tools, to look for any number of genetic characteristics, including the more elusive web of genes that may lurk behind familial patterns of heart disease and stroke, cancer, diabetes, Alzheimer's, various kinds of mental disorders and even gingivitis. Says Dr. Wayne Grody, head of the DNA diagnostic lab at the UCLA Medical Center: "We'll soon be governed by a new paradigm--genomic medicine--with tests and ultimately treatment for every disease linked to the human genome."

Benefits from this new era are coming fast. Prenatal screening has helped to reduce more than 95% the number of Tay-Sachs births among American Jews of East European descent, a high-risk group. As a result of early identification, a few congenital conditions, such as spina bifida, a disabling hole in the spinal cord, are being treated in the womb by experimental surgery at about seven months. Sex-selection techniques based on in-vitro fertilization can reduce the risk of giving birth to a baby with sex-linked disorders, such as Duchenne muscular dystrophy and hemophilia, which affect only males.

If couples know they carry genes for life-threatening illnesses that they don't want to pass on to the next generation, they can opt for a remarkable procedure called pre-implantation genetic diagnosis (PGD). It starts with standard in-vitro fertilization, in which sperm from the father are mixed with eggs collected from the mother in a Petri dish. Then comes the genetic magic.

The fertilized eggs are subjected to intense DNA analysis. Only those that pass the test are implanted. Says Dr. Jeffrey Botkin, a University of Utah pediatrics professor: "Instead of aborting a fetus, you're flushing down a bunch of 16-cell embryos--which, to a lot of folks [who oppose abortion], is a lot less of a problem."

Only a few thousand PGDs have been performed worldwide since Dr. Alan Handyside developed the procedure at London's Hammersmith Hospital in 1989. The majority of candidates for PGD are infertile couples or older women who suffer repeated miscarriages, a condition often due to chromosomal errors easily identified in the embryo stage. But for most couples the cost is prohibitive; a screen for a single disease costs $20,000. Says Santiago Munne of St. Barnabas Medical Center in Livingston, N.J.: "The limit is not that the population doesn't want it; it's that they cannot pay for it. We could do many more diseases if PGD were covered by insurance." In fact, insurance has become a central issue of this brave new world (see following story).

Another major concern is privacy. If screening reveals all the faults our flesh may be heir to, can that information be kept secret, so that it won't be used by potential employers or insurers to deny us a job or health coverage? Or, if we let our imaginations fly, by still other types of snoops--for example, an overzealous father eager to check out the genes of a potential son-in-law, just as he once might have checked the suitor's credit rating?

Such scenarios are not science-fiction. With the prestidigitation of gene-amplification, only a single drop of blood or a snippet of hair or a scraping of skin can reveal the full length of the human genome, including its myriad flaws. And the potential for abusing that information is already here, as a surprised Paul Billings found in surveys of testing abuses that he conducted. "I advertised for people who had had negative experiences with social agencies, insurers or employers after genetic diagnosis, and I was shocked by the response." The most common complaint was against hard-nosed health insurers, but many talked of being denied a job or losing a promotion. Some even reported that they had been prevented from adopting children because of information found in genetic tests. Billings recalls, for example, a couple who had a child with phenylketonuria (PKU), an inherited condition that can lead to retardation but is easily--and inexpensively--treated by diet. "Insurance companies not only refused to write policies for the couple but effectively ostracized the entire family," he says.

Genetic screening is also becoming an issue in the courts, not just as a forensic tool to catch criminals but even to settle private squabbles, says Professor Lori Andrews of Chicago-Kent College of Law. In a custody case in South Carolina, a judge ordered a man's former wife to be tested for Huntington's because it might impair her ability to care for their children. In another case, a manufacturer demanded a genetic test of an ailing boy in order to show that his illness was caused not by the toxicity of substances made by the company but by his genetic predisposition.

Still more concerns, legal or otherwise, could arise with the increasing availability of tests for so-called low-penetrance genes, such as those associated with breast or colon cancer. These don't necessarily mean that the carrier will be stricken but suggest an increased risk, especially in the presence of certain "co-factors" like poor diet, alcohol or smoking. Such tests are already available for the BRCA1 and BRCA2 breast-cancer genes but at a cost of about $2,700 each, and with their limited predictive abilities, only a few are performed. Still, they raise critical questions for any woman who tests positive. Should she undertake a pre-emptive strike against possible cancer with radical measures like mastectomy and chemotherapy? And if so, will insurers pick up the tab? In the absence of any firm reimbursement policies, says Dr. Ellen Clayton, a pediatrician and lawyer at Vanderbilt University in Nashville, Tenn., "I think you'd have to be nuts to let anybody know [about these genes]."

So far, medicine seems ill equipped to handle the issues spawned by genetic testing. Primary-care physicians, who guard the portals of today's managed-health-care system, rarely have had any training in clinical genetics. "My job is centered almost as much on educating doctors as patients," says genetics counselor Michelle Fox of the UCLA Medical Center. If they uncover a genetic problem in patients, like a family history of muscular dystrophy in a couple who want a child, savvy physicians will enlist a trained specialist like Fox. These specialists can explore with the couple what it means to care for a child with muscular dystrophy (under improved treatment, such children can survive well into middle age).

Unfortunately, there are only about 2,000 counselors nationwide. The only thing most women know about genetic screening is what they learn from pamphlets handed out in the course of routine prenatal care, and too often the message there is sugarcoated. "They talk about 'making your baby better' or 'having a better birth outcome' instead of talking about the fact that this is really a test about selective termination," says medical anthropologist Nancy Press of Oregon Health Sciences University. The failure to make explicit that message--and the decision it forces--says Press, "is simply, clearly, morally wrong."

Sugarcoating the message, however, doesn't change the fact that the message is fundamentally problematic. Genetic testing tells us things about ourselves we may not want to know. Like the twists and turns of the gene-bearing DNA molecule, it brings with it great promise, occasional hidden perils and many, many unresolved questions.

--With reporting by David Bjerklie and Alice Park/New York

With reporting by DAVID BJERKLIE AND ALICE PARK/NEW YORK