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Gene therapy: the splice of life.

IN CONCORD, CALIF., a healthy 11-year-old boy rolls up his sleeve for his after-dinner injection of genetically engineered human growth hormone. His parents hope to "cure" their child of something most people don't think of as a disease--below-average height.

The therapy is unproven, costs $150,000 per year, and will take 10 years to complete. Nevertheless, the boy wants it--at 4'11" tall, he's four inches below average, and he's tired of being called "shrimp" at school--and his parents want it for him. His father, a bank vice president, justified the injections in the New York Times Magazine (June 16, 1991), saying, "You want to give your child that edge no matter what. I think you'd do just about anything."

Compare that boy to a four-year-old girl in Bethesda, Md., who received a transfusion of her own white blood cells in September, 1990. She had been born with a defective gene, leaving her without a critical enzyme and with a severely crippled immune system. To counter the hereditary defect, the child's doctors stitched copies of a normal gene into a group of her white cells in the laboratory. The modified blood cells were cultured until they numbered in the millions before being returned to her body. There, the physicians hoped, the normal gene would produce enough of the missing enzyme to relieve the symptoms of her disease, Adenosine Deaminase (ADA) Deficiency. That young girl had become a medical pioneer, the first human being in history to be treated by gene therapy.

These children are examples of a biological revolution made possible by recombinant DNA technology, which is the ability to locate, cut, alter, add, and even manufacture individual genes--flecks of DNA smaller than most viruses. "Gene manipulation gives us the ability to identify genetic problems and find simple, cheap, available-to-everyone remedies for them," explains Dana Wrensch, a geneticist and associate professor of entomology, Ohio State University. Because of it, "the day will likely come when no one has to be sick from a genetic disease or susceptible to cancer." Researchers also are investigating its use to treat heart disease, diabetes, AIDS, and cancers of the breast, bladder, and colon.

While gene manipulation holds promise, it also presents a wide spectrum of ethical issues and possible social perils. These range from invasion of privacy and misuse of information to further devaluing of the elderly and handicapped and designing babies to suit society's needs.

"This technology could be used very, very beneficially and improve the quality of life--if we spot these ethical problems now," notes Wrensch, who is a member of a bioethics discussion group at Ohio State. "We've been manipulating life for our benefit since prehistoric times by taking plants and making pastes that we apply to injuries. Antibiotics made it possible to get a wound and not die of gas gangrene. But now we've got something different. We're not just taking what nature has given us, massaging it a little, and using it. Now we have the ability to engineer life forms."

That ability to engineer life forms made it possible to isolate the gene for human growth hormone and transplant it into bacteria that churn out the stuff by the batch. Previously, the drug had to be extracted painstakingly from the pituitary glands of cadavers.

Simply put, healthy children now can use human growth hormone to "combat" normal shortness for the same reason that mountain climbers scale Mount Everest--because it's there. Such potions are tempting for parents, who of course want as many advantages and as few disadvantages as possible for their offspring.

Today, eliminating disadvantages begins in the womb or even earlier in the egg or sperm. These problems take the form of genetic birth defects--such as ADA deficiency--that arise due to damage to one or more genes. While most hereditary diseases are rare in terms of their incidence in the population (which also means they receive less attention by researchers), they bring incalculable suffering to the afflicted and untold sorrow and guilt to the unsuspecting parents who transmit them. They cost society billions of dollars annually and are responsible for nearly half of all pediatric hospital admissions, 20% of all infant deaths, half of all miscarriages, and 80% of mental retardation. Most are incurable and many are untreatable.

There are some 5,000 genetic diseases on the books. Many of these can be detected in the laboratory, 100 of them by direct study of DNA. "But that number could go up with the next issue of Science, Nature, or Cell," indicates Judith Westman, a clinical assistant professor of pediatrics at Ohio State University and a clinical geneticist with Children's Hospital, referring to three prominent scientific journals. The work is moving so fast that researchers talk in terms of the "gene of the week." When someone asks her if a test is available for a particular gene, Westman relies on a computer in her office to search the scientific literature in the National Library of Medicine in Washington, D.C., and on word of mouth for the latest in genetic disease research results from colleagues.

Prenatal gene testing is done using amniocentesis, in which amniotic fluid is drawn from the uterus through a needle and syringe. The fluid contains cells sloughed off by the fetus that can be analyzed for genetic defects. Cells collected from the young placenta by chorionic villus sampling, a newer technique, also can be used. Prenatal testing is recommended for parents from families with a history of hereditary disease, for women taking certain medications, and for females over age 35. It's also requested by mothers who want to ensure that, to the extent possible, they will have a healthy baby.

The trouble is, the definition of "healthy" varies with time, and with culture and social class, points out David Horn, an anthropologist and assistant professor in comparative studies at Ohio State. "Few people would disagree with eliminating devastating dieases such as Tay-Sachs--if it could be done without violating people's rights to privacy."

At the beginning of the 20th century, the concept of health included much more than just freedom from physical suffering. It also meant possessing certain intellectual, moral, and even cultural traits that had been deemed conducive to the progress of the nation. "We didn't just want people who were free from certain inherited diseases, which in any case were poorly understood at the time. People also thought things like intelligence and fitness could be the results of rationally managed reproduction."


That philosophy led to the acceptance of eugenics, the hereditary improvement of human beings through genetic control. Even Supreme Court Justice Oliver Wendell Holmes succumbed to the concept when he wrote in a judgment, "It is better for all the world if society can prevent those who are manifestly unfit from continuing their kind."

Eugenics arose from an idea called Social Darwinism, premised on Darwin's theory of evolution. This included the concept that only those animals most fit to survive will survive, while those least fit will be killed or die off, thereby improving the quality of the species. Those believing in Social Darwinism extended the same principles to improve the quality of society--those most fit will excel at the top, and those least fit should be eliminated at the bottom.

The theory was spurious, however, because it ignored environmental influence, such as economic, social, or political advantage. Nonetheless, Nazi Germany used this so-called science to justify its policies against Jews, Gypsies, and other minorities. In the U.S. in 1922, it resulted in laws making it legal for society to sterilize "socially inadequate classes." These included criminals; the "feeble-minded"; the insane; alcoholics and drug addicts; those with tuberculosis, syphillis, leprosy, "and others with chronic, infectious, and legally segregate diseases"; the blind or deaf; the deformed and crippled; and the "dependent, including orphans, ne'er-do-wells, the homeless, tramps, and paupers." Between 1900 and 1930, such legislation resulted in the eugenic sterilization of 20,000-30,000 people. In many states, such laws remain on the books, although they are not enforced.

Since the end of the 19th century, Horn explains, many biologists have been interested in ways to manage human reproduction to produce better offspring. "Not just better results for individual couples, but better results for the nation." Today, our knowledge of the biological basis of life seems to reduce human beings to walking, talking collections of chemical reactions. If you believe that, "it becomes possible to do things to human beings that are unthinkable if you adopt another definition of what a human being is."

Could a eugenics program happen again in the U.S.? "Absolutely," maintains Father Richard A. McCormick, John A. O'Brian Professor of Ethics, Notre Dame University. We have things in both our practice and methods of thinking that, he says, "I would call fertile soil." He includes artificial insemination for people at risk for passing genetic disease and laws in some states for wrongful life and wrongful birth. The former allows a child born with birth defects to sue parents for not being aborted; the latter permits parents to sue a physician whose negligence led to a child with birth defects.

"We have people speaking about the right of a healthy couple to a healthy child, which is very loose language. The problem is that, if you've got a right to a healthy child, you've got a right to discard the unhealthy. What we ought to be saying is that people have a right to all those means reasonably available to see that their children are healthy."

McCormick cites literature given to prospective customers of sperm banks that lists the nationality, size, hobbies, and interests of the donors. "All of these things are in place, taken for granted, and I think that they provide powerful support for a move toward eugenics. " He also refers to popular cosmetic surgeries. "The notion of removing wrinkles, increasing the size of breasts, and diminishing the size of buttocks and so forth really sends out a powerful message that aging and elderly people are really toss-aways.

Improved gene testing could increase the number of toss-aways at the other end of the age spectrum as well. Some feel that the Human Genome Project (HUGO) runs the risk of being a giant step in that direction if we're not careful. A 15-year, $3,000,000,000 effort to map the location of each of the roughly 100,000 genes possessed by human beings, HUGO will identify the location of chromosomes of genes for all 5,000 hereditary diseases and those that predispose people for such things as Alzheimer's, certain cancers, and early coronary artery disease.

"The Human Genome Project won't immediately affect patients," indicates Leroy Walters, director of the Center for Bioethics, Kennedy Institute for Ethics, Georgetown University. "But month by month and year by year, it will help us to know what genes cause what conditions, where these genes are located, and what has gone wrong in the gene to make it defective."

Improvement in the diagnosis of genetic diseases will be among its early payoff, but treatment of those conditions by gene therapy or some other means will lag behind. "In fact, I think that's going to be an awkward interval. We're going to be able to tell people that they carry the cystic fibrosis gene, for example, and that there is a one-in-four probability that one of their children will have it." However, they then will have to be told that "we don't have a cure for cystic fibrosis, and we really can't do anything about the fact that you carry one of the mutations that causes it."

Nonetheless, great good is to be gained from the genome project, McCormick states. "But I think it's a question of how we use what comes out of it. The knowledge will be used to identify disease in advance of birth. What do you do as a result of that information--do you abort or not abort? You can't avoid that question." Prenatal diagnosis could be used in ways that simply will eliminate people with certain defects. "I think it's getting to be common to see someone born with those defects and say, |Why wasn't that person aborted?'"

Horn adds other possible consequences of improved genetic testing for those living with Down syndrome and other hereditary diseases: There's a danger that the issues raised in the 1960s and 1970s about incorporating the disabled into American society will be overshadowed by development of new technologies designed to screen out these people. "The focus could shift from the acceptance of 'imperfect' bodies to their medical prevention." Horn does not suggest that medical science forego gene manipulation for the sake of those already living, but he is convinced that these questions must be explored.

How will information be used?

Perhaps of greatest concern is how the information gained about individuals through HUGO and genetic testing will be used, who it will belong to, who will have access to it, and how it will be protected. HUGO will transform each white cell in a drop of blood into a microdot that contains all the information about what makes us physically who we are. Should that information fall into the wrong hands--insurance companies or prospective employers, for example--they could use it to gauge whether we are a "good risk," or carriers of genes for a genetic disease, cancer, Alzheimer's, coronary problems, and the many other diseases, weaknesses, and frailties that future research surely will associate in some way with genes.

In July, 1991, the Federal government announced plans to launch a national screening program to identify carriers of cystic fibrosis, the most common hereditary disease in Caucasians, one in 20 of whom carries a gene for the disorder. If two carriers marry, each of their children would have a one-in-four chance of having the disease. The program seems sensible, but Wrensch sees a red flag. "The objective is to identify carriers specifically, not statistically. What are they going to do with that information? The potential for abuse is mind boggling."

She poses a hypothetical situation to illustrate one possibility: "Suzy and Joey want to get married and have a baby. But before their employer's insurance will cover the cost of the birth, the parents must undergo genetic testing. They both turn out to be carriers of the gene for cystic fibrosis. So there's one chance in four that they will have a child with the disease. What happens? Perhaps they'll be required to get a prenatal diagnosis and abort an affected baby. All this screening and diagnostic ability has the implication of electing to abort affected children. The hidden message here is that you're going to cost society. If it isn't through the insurance company, it's going to be through welfare."

That attitude is already prevalent in society, she notes. "What do the anti-smoking groups say? You can't smoke because you're going to get a degenerative illness, wind up in the hospital, and it's going to cost society." The Cystic Fibrosis Foundation estimates the cost of raising a child with moderate cystic fibrosis to be $26,500 a year.

At the same time, Wrensch points out that gene therapy and manipulation hold the potential to reduce suffering equivalent to the discovery of antibiotics. They, in fact, are key to one day curing diseases through discoveries being made at a monthly--sometimes weekly--pace.

In March, 1991, for example, researchers announced discovery of a gene that plays an important role in the development of colon cancer. In May, others reported being close to locating a gene associated with amyotrophic lateral sclerosis (Lou Gehrig's disease). The following day, another group announced discovery of a gene that, when missing, produces lung cancer. Also that month, researchers discovered the mutation responsible for Fragile X syndrome, the most common inherited form of mental retardation.

In July, James Watson, director of the genome project at the National Institutes of Health, in an appearance before the Senate, estimated that discovery of the Fragile X mutation occurred five years sooner than it otherwise would have because of the genome project. He also noted that those mapping chromosome 19 had identified three genes involved in DNA repair, two of which seem linked to disease, and six genes that appear necessary for successful pregnancy.

Watson mentioned that 2,000 boys with Fragile X syndrome are born every year. Each will require $100,000 in care over their lifetime, for a total annual cost of $200,000,000--the same amount requested for the genome project. "The project," he pointed out in the July 26, 1991, issue of Science, "will pay for itself if we can go beyond the discovery of this one gene to doing something about it."

For many genetic diseases, "doing something about it" will involve gene therapy. In theory, gene therapy can be used in two ways: to install a new gene into a somatic, or body, cell; or to install a gene into a germ cell--an egg or sperm. Few people object to somatic gene therapy, indicates Arthur H.M. Burghes, assistant professor in neurology, molecular chemistry, and medical biochemistry at Ohio State. "Currently, genes can be transferred only to cells that can be removed from the body, cultured in the laboratory, and then returned to the body."

This was one reason a child with Adenosine Deaminase Deficiency--and not cystic fibrosis--was selected for the first gene therapy trial. The deficiency involved a single gene that could be placed in blood cells which were removed from the body and later returned.

One day, somatic cell gene therapy also may help those with cancers that don't respond to traditional methods. One experimental treatment uses gene therapy to enhance the natural cancer-killing capability of certain white blood cells. The procedure involves isolating cancer-killing white-blood cells from the patient's tumor, arming them with a gene that produces a natural anti-tumor toxin, then returning the cells to the patient. The white cells, known as tumor-infiltrating lymphocytes, carry the toxin-producing gene directly to the tumor site, thereby maximizing the toxin's benefit while minimizing damage to healthy tissues. "This has tremendous potential, and we are all anxious to see how the initial trials testing this approach turn out," says Stanley Balcerzak, director of clinical research at Ohio State's Arthur G. James Cancer Hospital and Research Institute.

Gene therapy for tissues that can't be removed, modified, and then returned to the body will be more difficult. Treatment of cystic fibrosis, for example, would require placing a gene in cells lining the lung. Even in this case, new research offers hope. In April, 1991, scientists succeeded in using a virus to introduce a foreign gene into the lung cells of a mouse. It was the first time that anyone had introduced a foreign gene into cells within the body. The experiment might lead to gene therapy for both cystic fibrosis and a hereditary form of emphysema.

Burghes came to Ohio State from the Hospital for Sick Children in Toronto, Canada, where he contributed to the discovery of the gene and defect responsible for Duchenne's muscular dystrophy. At Ohio State, he collaborates with Jerry Mendell, professor of neurology and pathology. "Our aim is to clone genes and to develop a system for transferring genes to muscle tissue," he reports. Their major concern is Duchenne's muscular dystrophy, which occurs in one out of 3,000 male births, and spinal muscular atrophy, with an incidence of one in 20,000 births. "Our work is in very early stages and it's not clear what's going to work and what problems are going to arise. "

An ethical dilemma

Burghes has no qualms about injecting genes into individual muscle cells--somatic gene therapy--to help those cells to function. However, tinkering with the genes in eggs and sperm--germline therapy--presents a major ethical dilemma. "It's a completely different ballgame. The germline carries DNA code for every piece of information dealing with building a human being, not just the information needed for one cell type to function. It involves transferring copies of the gene into subsequent generations."

What's more, this technique will not be feasible for the foreseeable future. While gene therapy represents the frontier of medical science, it currently lacks technical finesse and more resembles a shotgun approach. A gene delivered to a cell, for instance, can be integrated randomly on any chromosome. "It can end up anywhere, including within another gene. If it's a critical gene, then you've got a problem."

Should that happen in a germ cell, it could spell disaster. "You don't want to create other genetic disorders." Secondly, "we're talking about putting in a piece of DNA that is going to stay there a long time--a lifetime. It's difficult to assure its safety when it can be tested for only a short time."

Because of these and other dangers, some critics demand that all gene therapy and recombinant DNA research be stopped. "But that attitude is mistaken," maintains Bernard Rosen, associate professor of philosophy at Ohio State. "One of the best aspects of human nature is the drive to explore new areas, to find new truths, and to solve problems by constructing new technologies. That's what's happening here. I agree we ought to go cautiously, but I don't agree with those people who say we ought not to go at all because something bad is going to happen."

The ideal thing to do, of course, is determine now whether gene therapy and recombinant DNA technology will benefit society in the future. However, Rosen explains, "there is no crystal ball. We are at a point where there is no more help from science or philosophy. We have to look very carefully at the history of human development and technology, look at the bad things people have done to each other, and recognize that people will do things such as develop a class of genetically engineered slaves, for example, if they are permitted to do it."

Without question, gene therapy and recombinant DNA technology hold untold promise. Nevertheless, says Westman, "they definitely need to be regulated. But by whom? The American Medical Association? The Federal government? Who's going to be in charge? Who's going to be the moral standard? "

Society should set the standard, Rosen suggests. "These are issues that have to be settled by all of us. In a democracy, we assume that if we have a rational public debate and we have educated people evaluating evidence, we will have the best chance of arriving at a social policy that will cause the least mischief and solve the problems best."

"This, as many other terrains, is fraught with ambiguity," notes Horn, "and that's not necessarily a bad thing. That these technologies are at once powerful and disturbing is a condition of life in the 20th century, and we need always to be alert to both possibilities and dangers. That doesn't mean rejecting new ideas or being anti-science or anti-technology. It means always asking questions about how we got where we are. "

Advances in DNA technology, which in the end is motivated and driven by our own DNA, hurls us ever faster into the future. "One part of me is hesitant to rush forward," Westman indicates. "But the other part of me is saying the good Lord gave us the ability to investigate this information. Would He have given it to us without wanting us to pursue it?"
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Title Annotation:ethical implications
Author:Ward, Darrell E.
Publication:USA Today (Magazine)
Date:Jan 1, 1993
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