The Promise and Perils of New Genetic Screening : Science: More diseases will be diagnosed and better therapies developed. But how should the tests be used?

By the turn of the century, scientists should be able to quickly test a small sample of our cells for dozens of genetic conditions, ranging from rare ailments to inherited susceptibilities to heart disease, cancer and other common causes of death. Genetic tests may even suggest if we are likely to become mentally ill or an alcoholic.

Until recently, this scenario would have been dismissed as science fiction. But advances in molecular medicine now hold the promise of prevention and early treatment of a wide range of diseases.

The advances may also create what one medical ethicist terms the “unpatient.” Such people, while outwardly well, will know they are at increased risk of serious disorders, particularly those with no therapy or preventive approach.

“The ‘unpatient’ is a little like the ‘undead’ in horror movies,” said the medical ethicist, Albert R. Jonsen of the University of Washington School of Medicine in Seattle. “They are both dead and not dead.”

Unpatients may develop severe anxiety and believe that they are under a death sentence. They may visit doctors frequently, seeking monitoring and reassurance. In extreme cases, they may contemplate suicide. They may be ostracized by friends and family and be discriminated against in insurance and employment.

These phenomena are already seen in some people who know that they will develop Huntington’s disease, an untreatable ailment characterized by abnormal movements and mental deterioration that occurs in middle age.

The specter of the unpatient illustrates the promise as well as the perils of the new genetics. The advances that will allow scientists to identify an increasing number of genetic diseases and predispositions represent a technological tour de force that should advance human knowledge and lead to better therapies. But it will be a far more daunting challenge for society to determine how and when the tests should be used and how to protect people against potential, adverse consequences.

“The whole benefit of the revolution in human genetics . . . is put at risk the longer we delay resolving the public and political issue of how much discrimination we are going to allow to be based on genetics,” said Dr. Paul R. Billings of California Pacific Medical Center in San Francisco, who has studied the problem. “It is my belief that basic human rights and entitlements should never be put at risk because of one’s heredity.”

Genetic screening is the study of people in order to find an inherited disease. Depending on the illness, the screening can be conducted before birth, immediately after birth, or at any time during life. The information could be used to guide decisions about treatment or reproduction or to help predict and perhaps prevent health problems.

For years, physicians have tested for diseases such as sickle cell anemia, which is most often found among blacks, and Tay-Sachs disease, a fatal nerve disorder that primarily occurs in families of Eastern European Jewish origin.

In some instances, such as a positive test for Tay-Sachs in a fetus, the result is a guarantee that fatal illness will develop. In other instances, such as for some neuromuscular ailments, a positive screening test may simply identify an increased susceptibility. There may be no way to predict when and if the illness will occur or how severe it will be.

The explosion of genetic knowledge has created many volatile dilemmas for society:

* How good are the screening tests? Some are nearly 100% accurate, but others, such as tests for cystic fibrosis, typically miss 10% to 15% of gene carriers. A negative screening test for cystic fibrosis does not mean that there is no chance of passing the disease on to one’s children; it just means that the odds are greatly decreased. Studies have found that people have far more difficulty understanding medical advice based on such probabilities than simple “yes-no” information.

* Should advances in genetic testing chiefly be used to spur research on treatments for deadly or disabling diseases, or to avoid the birth of people who carry genes for the illnesses? Many physicians and ethicists see an inevitable competition for resources between those who champion new but potentially expensive treatments, such as gene therapy or new rehabilitation strategies, and those who seek to use genetic testing to reduce medical costs by preventing births.

“There is a belief among policy-makers and the public that disabled people bleed the society of scarce resources,” said Barbara Faye Waxman of Los Angeles, a disability policy consultant who is disabled. “As a result of this belief, there is pressure to use prenatal testing to prevent the birth of disabled people in the first place.”

* Will individuals, consistent with the principles of medical ethics, truly be free to decide for themselves whether or not to be screened for an inherited illness. If they are screened, will they be free to decide what to do with the information or subtly coerced to make the decision that is “best” for society?

In a recent case, described by Billings, a health maintenance organization pondered withdrawing coverage of a woman’s pregnancy and her future baby’s health care after a prenatal test indicated that the fetus had cystic fibrosis. A threat of legal action was required before the HMO backed down.

“It is not really an entirely free-choice situation,” said Barbara Katz Rothman, a professor of sociology at the City University of New York.

Rothman, a critic of many genetic screening proposals, charges that social problems, such as society’s commitment to the disabled, will increasingly be “solved in the bellies of pregnant woman.”

An expectant mother, according to Rothman, may be told: “You can inflict the child upon the world and the world upon the child, or you can terminate the pregnancy, grieve the loss of the baby, and the medical community and society at large will tell you how lucky you were.”

Proponents of genetic screening counter this view by arguing that physicians should not withhold potentially valuable information from their patients and should do their best to assure accuracy and balance in discussions.

* How good are laws to prevent genetic discrimination in insurance and employment? While many experts view the 1990 American with Disabilities Act as a step in the right direction, they believe it is not sufficient to guard against discrimination, particularly for individuals who harbor a potential genetic illness but have yet to develop symptoms. Only a handful of states have laws that specifically address genetic discrimination. In California, such a law was passed by the Legislature in 1991, but vetoed by Gov. Pete Wilson.

Some believe that the only way to avoid genetic discrimination in health insurance may be to establish universal access to health care “The real bottom line is that employers are under tremendous pressure to do anything they can to hold down health costs,” said Mark A. Rothstein of the University of Houston Law Center. Until the system is reformed, he added, “the incentives are just too great to discriminate.”

* How can the enthusiasm for genetic screening be reconciled with efforts to limit the availability of abortions? The results of prenatal genetic tests may increasingly be used to terminate pregnancies, said Vicki Michel, associate director of the Pacific Center for Health Policy and Ethics at USC.

“On the one hand, you are offering people the possibility of technologies that are going to allow them to avoid the birth of children with disabilities,” Michel said. “On the other hand, you have a climate (that is) . . . more restrictive about the availability of abortion.”

Michel’s colleague, Alexander M. Capron, a USC professor of law and medicine, notes that prenatal diagnosis can also be viewed as a technology that can help prevent abortions. This is because such tests often reveal that a feared genetic defect is not present in the fetus. In many instances, “you have couples who feel that they are at risk and would abort a pregnancy if they did not have the information,” he said.

* Will the general public want to be screened, particularly for diseases many have never heard of? Some physicians charge that the push for screening is being fueled by companies who stand to profit from increased sales of genetic tests, such as those for cystic fibrosis.

The 4 million women who give birth in the United States each year represent a vast potential market. “It says in the Bible, where your treasure is, there your heart will be,” said Dr. Norman Fost of the University of Wisconsin School of Medicine in Madison. “Many people’s hearts (at biotechnology companies) have suddenly turned to cystic fibrosis screening.”

Biotechnology companies dispute such charges. “There are enormous debates that go on within every company . . . (producing screening tests) as to what is appropriate,” said John Richard, a vice president of Collaborative Diagnostics in Waltham, Mass., which markets a cystic fibrosis test. At this point, cystic fibrosis testing is not a “big moneymaker” for anybody, he said.

In addition, the public has often been less enthusiastic about screening tests than have the experts, particularly when it seems unlikely that a condition will develop or people are asked to pay for expensive tests themselves.

When testing is offered, “a minority of the population eligible for the testing takes advantage of it,” said Dr. Wylie Burke of the University of Washington. “But for some individuals . . . the opportunity is very, very important.”

Many of these dilemmas are part of the debate over mass screening for cystic fibrosis, one of the most common of all potentially lethal inherited diseases.

There are about 30,000 people with cystic fibrosis in the United States, primarily whites. People with the disease have two copies of an abnormal gene. Those with only one copy of the gene are not at risk to become ill but may pass the gene on to their offspring.

Since the cystic fibrosis gene was discovered in 1989, most physicians have offered voluntary testing to family members of patients. But beyond that there is little agreement on the best course of action. In 1992, an estimated 63,000 people were likely to be screened, according to a report by Office of Technology Assessment.

Experts debate whether screening should be encouraged to prevent the birth of cystic fibrosis children when promising new treatments, such as gene therapy, are on the horizon. If mass screening were implemented, millions of people might be tested each year, creating a vast and potentially lucrative market for biotechnology companies.

The American Society of Human Genetics, whose members include most physicians with expertise in genetic diseases, says mass screening programs are premature.

Cystic fibrosis “is not Tay-Sachs disease, where the outlook for meaningful childhood development is nil,” a group of prominent geneticists wrote in the American Journal of Human Genetics last year.

The geneticists, who favor a cautionary approach to widespread screening, noted that “individuals with cystic fibrosis commonly live to adulthood; there is every indication that survival will continue to improve, and the possibility of breakthroughs in therapy is greater now than at any time in the past.”

According to Fost, of the University of Wisconsin, cystic fibrosis patients “could be stigmatized if the public comes to perceive that they would have been better off not having been born. . . . A highly public prevention program may undermine efforts at improving treatment, as the public comes to see cystic fibrosis as a disease that will or should disappear.”

But some prominent geneticists take a different view. They note that 80% of babies with cystic fibrosis are born to couples without a family history of the condition and argue that all individuals should be routinely informed about the availability of screening, so they can decide for themselves whether or not to be tested.

“It is not a question of if we will proceed with cystic fibrosis carrier testing, but how rapidly the utilization will increase,” said Dr. Arthur Beaudet of the Baylor College of Medicine in Houston.

Physicians and genetic counselors are still learning how best to educate people about their test results and the disease.

A typical counseling session for a couple with positive tests may take several hours. “We are dealing with rough concepts for people to comprehend,” said Joan H. Marks of Sarah Lawrence College in Bronxville, N.Y., who directs the nation’s leading training program for genetic counselors. “It is not something you can read on a mimeographed sheet and understand. You need someone who is really good at communicating scientific information at the layman’s level.”

“This is very complex information, even a lot of physicians would not be able to interpret what the test means,” said Dr. Wayne W. Grody of the UCLA Medical Center, who directs a federally funded study of screening for the disease. “If we find that even telling people about this test creates so much anxiety that we are doing more harm than good or the carriers feel stigmatized, we may decide it is not worth screening the population.”

In addition, there are only about 1,000 trained genetic counselors in the United States and “there is no way” we could meet the demands of potentially conducting millions of screening tests for the disease each year, said Barbara Bowles Biesecker, a genetic counselor at the University of Michigan.

Others say that concerns about adverse reactions to testing may be overrated. Cystic fibrosis screening “is not going to be a big deal” to many people, said Dr. Neil A. Holtzman of the Johns Hopkins University School of Medicine, who directs another federally funded study of the illness.

A British study of more than 3,000 women, published in the Lancet in July, concluded that “the great majority of both carriers and non-carriers are pleased that they have been tested and many commented that they would like to see the test made more widely available.”

One of the biggest challenges is what to tell people about cystic fibrosis. The severity of cases varies tremendously; some children may be profoundly affected and die before adulthood, others may lead essentially normal lives well into middle age.

“In genetics, we try to be completely non-directive and just offer patients information and they can do with it what they want,” Grody said. “On a videotape, do I show a horribly affected kid who is carrying an oxygen tank around or do I show a kid who is playing soccer? By what I tell patients, I can skew who is going to want the test and who might decide to terminate a pregnancy based on positive results. There is a big debate over how to give information and still be non-directive.”

On a recent morning at UCLA, pregnant women who were scheduled for other prenatal tests were volunteering for the ongoing study of cystic fibrosis screening. As an alternative to a blood specimen, they used a small brush to scrape a sample of their cells from the inside of their cheek. To most, the decision to participate in the testing seemed routine. “I know I am probably not a carrier, but it is best to know for sure,” one said.

Another participant said she was not bothered by the inaccuracies of the test. “I don’t think of medicine as being an exact science,” she said. “Any sort of information that can increase my knowledge is useful.”

One 35-year-old Los Angeles woman found to her surprise that she had tested positive. Her husband was then tested; he was found not to carry the gene. “We had maybe a few days when we were a little concerned,” said the woman, who requested anonymity. “I think it is great that (physicians) have these methods available now.”

The UCLA study and six others funded by the National Institutes of Health will take several years to complete. By 1995, the NIH hopes to make recommendations about whether testing of the general population is advisable.

The Genetic Probe

Genetic testing involves looking for the presence or absence of specific genes, both normal and abnormal. A genetic probe takes a known genetic pattern and tries to find the same pattern in the genetic material being studied, a person’s or that of a fetus in the womb. Here is how the probe works:

1. DNA is obtained from white blood cells or fetal tissue obtained in a prenatal test.

2. The DNA is treated with restriction enzymes that can recognize a specific pattern in the DNA and cut it where the pattern occurs. The result is pieces of DNA of varying lengths.

3. The pieces--numbering in the millions--are put on the surface of a special gel. The gel receives an electrical charge, which separates the pieces according to size.

4. The gel is treated with a solution that divides the double-stranded DNA into single strands. Those are transferred to a nylon membrane.

5. A genetic probe is added to the membrane. The probe, a radioactively labeled single strand of DNA, matches the DNA pattern of the gene under scrutiny.

6. If the suspect gene is present, the probe will bind to the piece of DNA that matches the pattern and give off radiation. A film called an autoradiograph will show the binding as a dark band. If a match for the pattern is not found, no radiation is present so no dark band shows on the film.

7. Band patterns in a series of autoradiographs might look something like this: The normal pattern is in column D; other columns show where bands are missing.

Passing the Test

After researchers identify the defective gene that causes an inherited disorder, they are able to test for it. Some tests can be done prenatally or almost immediately after a baby is born. Some genes discovered in the last two years cause:

Alzheimer’s disease. Inherited form, which accounts for 15% of all cases.

Amyotrophic lateral sclerosis (Lou Gehrig’s disease). Degenerative disease of the nervous system.

Charcot-Marie-Tooth disease. Causes foot and hand deformities.

Cystic fibrosis. The most common lethal genetic defect, causing pancreas malfunction.

Duchenne muscular dystrophy. Major form of muscular dystrophy in children.

Familial colon cancer, accounting for about 15% of all cases of colon cancer.

Fragile X syndrome. Leading cause of mental retardation.

Gaucher’s disease. A disorder that strikes Ashkenazic Jews.

Huntington’s disease. Another crippling neurodegenerative disorder.

Marfan syndrome. Disease of connective tissue that often strikes athletes.

Myotonic dystrophy. Most common form of muscular dystrophy in adults.

Retinoblastoma. Inherited eye tumors in children.

Retinitis pigmentosa. Researches has discovered genes that cause 43% of the cases of this blinding disorder.

Source: Genes and Inheritence