The true fathers of gene therapy most likely will never win Nobel prizes. Their reputations have been badly damaged by what many view as premature, and thus unethical, attempts to cure fatal disease by giving patients new genes.
But the brouhaha stirred up by past attempts cannot compare with the maelstrom of controversy yet to come. Egos and expertise will clash like cymbals as the technology of gene splicing keeps racing along so fast that it laps ethical debates about what it all means.
The first pioneer to tangle with taboos over tinkering with genes was American virologist Stanfield Rogers, who in 1969 was studying a benign virus that produces warts in rabbits.
Rogers was fascinated by a phenomenon he discovered by accident: the virus, the Shope papilloma virus, somehow lowered the level of the amino acid arginine in the blood of laboratory workers who had been inadvertently infected.
Other than that, the workers suffered no ill effects. Hence, Rogers reasoned that anybody who happened to have too much arginine in his blood could theoretically be cured by the virus. However, he knew of no such people. ”We had uncovered a therapeutic agent in search of a disease,” Rogers was to say later.
One day, though, Rogers was reading an account in a British medical journal that told of two young German sisters, aged 18 months and 5 years, who were desperately ill with seizures, palsy, and severe retardation–all because of too much arginine in their blood.
What would happen, Rogers wondered, if the papilloma virus were injected into the sisters` bodies?
In 1971, after having received permission from the girls` family and their physician, Rogers flew to Germany with a vial of virus. He had no idea how much the girls should be given and he and colleagues proceeded with caution. Too much caution, perhaps: ”The dose of virus first used was about one-twentieth of that which we had previously found harmless to mice,” Rogers later said.
”As might be expected from this tiny dose, no effect whatever was found in the condition of the children.”
Subsequent attempts using slightly more virus were inconclusive. But before he could proceed any further, Rogers was capsized by a wave of professional criticism from colleagues who labeled his work rash and irresponsible. His funding dwindled, and chastened, he turned to studying viruses in plants.
No further experiments were tried for nine years. Then in 1980, Martin Cline, chairman of hematology at the University of California at Los Angeles, ignored the lesson that Rogers had so painfully learned.
Cline wanted to put healthy hemoglobin genes into patients suffering from beta thalassemia, a progressively fatal blood disorder. Without waiting for approval from his home university`s human testing review committee, he flew to Israel and Italy, where he had already obtained permission to treat two young women.
Cline`s results were similarly inconclusive, but while he was abroad, UCLA rejected his application, saying more animal work was needed before any human experiments were tried.
More trouble followed after the National Institutes of Health (NIH) found Cline in violation of federal guidelines as well, stripped him of $190,000 in grants (half his federal funding), and let him know he was on bad paper.
The furor was so great that Cline resigned as chairman of his department at UCLA.
The stories of Rogers and Cline underscore the ethical quandaries posed by the prospect of human gene therapy. Scientists no less than churchmen and politicians are troubled by our newfound ability to manipulate the genes of human beings and other organisms.
The controversies are many. A litany of agonizing issues must be resolved by society in coming years.
Among them are these:
— Safety. No one knows for sure what will happen when a new gene is put into a person. Premature experimentation runs the risk of unleashing something dangerous and irreversible into the human gene pool.
— Abortion. Medicine`s enhanced ability to detect genetic diseases before birth will almost certainly lead to more abortions and political wrangling. In Illinois, for example, a controversial new law might forbid the most sophisticated prenatal testing unless it can be shown to be beneficial to the fetus.
— Body cell versus sex cell therapy. Body cell (or somatic) therapy affects only the patient whose disease is being treated. Sex-cell (or germline) therapy involves changes in the patient`s sperm or egg cells that would be passed on to future generations and could cause cataclysmic changes in the species. The distinction has been called the Maginot Line of genetics. — Eugenics. The ability to manipulate genes for medical purposes might prompt broader applications such as the intentional ”improvement” of the human species. A variety of traits, ranging from intelligence and physical prowess to character and even ethnic type could conceivably be altered some day.
— Genetic screening. It will be possible to test children and adults for their inherited vulnerabilities to environmental hazards and diseases. This will have obvious benefits in terms of people being able to alter their lifestyle, but the benefits carry risks: If the information gets out to employers and insurance companies, serious civil rights issues could ensue.
Gene therapy is not just a medical question,” says Jeremy Rifkin, a Washington attorney who is the most vocal critic of genetic engineering.
Rifkin is scared silly by the ramifications of technologies that are about to leave the laboratory and enter the everyday world.
”Where do we draw the line?” asks Rifkin. ”We`ll want to eliminate Tay-Sachs disease, an early childhood killer. Heart disease can kill you at 20, emphysema at 60 and Alzheimer`s at 80. All may be genetically induced. Would you say no to curing any of them? Probably not. But what about myopia
(near-sightedness), a genetic trait? How about acne? At what point do we move from trying to cure horrible genetic diseases to trying to enhance genetic traits?”
In Rifkin`s mind, we are in quixotic quest of perfection.
”Immortality, that`s what it is. We`re trying to perfect our gene structure over the long run so that we never die. Do we really want to perfect ourselves in that way? That gets us into the area of eugenics and civilization, a very troubling possibility. That`s the most impressive social question the human family has ever had to deal with, excepting the dropping of a nuclear bomb.”
The mechanisms have been put in place for discussing these issues, believes Leroy Walters, a prominent Georgetown University ethicist who has been an active consultant to the federal government in creating the guidelines for the first gene therapy experiments.
”Gene therapy is a very promising approach, and initial applications to try it in humans will go through a public national review process,” Walters says. ”I think the most reasonable application will be to cure intractable diseases. What`s important is that we protect individual freedoms and engage in public debate.”
Basic safety concerns are paramount to Inder Verma, a renowned virologist at the Salk Institute for Biological Studies in La Jolla, Calif. Verma worries that the use of engineered viruses to ferry new genes into sick bodies raises the specter of runaway viruses. As the scientist who has helped design most of these delivery systems, Verma`s fear is that a doctor may prematurely use the viruses to try to save a dying child.
”The viruses we make are innocuous, but not totally inert,” Verma says. The engineered virus itself probably would cause no trouble: ”By itself, it can`t do it,” Verma says. ”But let`s imagine that there`s another virus in the body. Could the two of them combine and spread to other tissues? I don`t know. We need more animal testing to find out.”
The revolutionary and perhaps perilous nature of the new therapy is being soft-pedaled to the public, some ethicists believe.
Says NIH bioethicist John Fletcher, who stresses that he is speaking for himself: ”The feeling is that we should try gene therapy and see if it will work. Because in essence it`s not different from other kinds of new drug trials, or the use of human products (such as blood transfusions) for the first time. DNA (basic genetic material) is just another human product–so the thinking goes.”
Such thinking is flawed, Fletcher says.
In fact, says bioethicist Mark Lappe, it`s ”short-sighted, unimaginative, and straight-out wrong.”
Medicine, Fletcher and Lappe emphasize, has never treated genes before.
”There really is no assurance,” says Lappe, ”that the gene being replaced can be sufficiently targeted to go into the cell nucleus at just the right site so as to correct the defect in an ideal way. We don`t know what will be the effect of putting novel genes in our chromosomes. They may inadvertently activate neighboring genes. They may set off oncogenes and cause cancer.
”So I see a dearth of imagination on the part of the bioethics community and researchers to fully anticipate all the ramifications for making this technique available for the first time. ”Instead the discussions have focused on minutia and consent procedures for kids suffering from ADA (adenosine diaminase deficiency) or Lesch-Nyhan syndrome. Everyone is totally missing the really revolutionary nature of this therapy. They`re trivializing it. Minimizing its impact.”
But, predicts Lappe, ”we`ll probably just go ahead and try it anyway. We`ll just make our mistakes as we attempt to find out if some of these tragic diseases can be miraculously cured.”
Fletcher points out that ”genetic burdens are among the most significant burdens that human beings have. The promise of treatment is absolutely thrilling to everyone in the field. ”There is a very strong consensus in virtually every quarter of ethics and religion that somatic cell gene therapy is ethically acceptable. At the same time, the power and control over a hitherto undisclosed area of life is foreboding–at least to people like me. It makes me very cautious.”
What happened to Martin Cline and Stanfield Rogers, though, apparently could never happen again. No medical event will have been so carefully scrutinized as the first attempts at gene therapy.
Anyone who applies to try the procedure as well as the rules of the institution at which the experiment will be performed.
The thinking embodied in the guidelines and likely to be applied by those reviewing applications for experiments is straightforward:
Only a life-threatening or horrible debilitating illness should be a candidate for body-cell (somatic) gene therapy. The patient must have no other option.
Doctors should fully understand the disease under consideration. They should be able to identify the specific genetic defect, as well as the course of biochemical events that make people sick.
Adequat animal work must indicate the therapy is safe. The new gene must be deposited in the right target cells, and stay there. The gene should also make proper amounts of its product and do no harm to any cells.
The experiment must be planned in such a way that even if results are not successful, scientists should have a good idea of why the failure occurred. Shots in the dark should not be tried.
Few, if any, controls exist, however, for a spin-off technology–prenatal diagnosis by means of fetal DNA testing. Pro-life activists fear that large-scale screening of the unborn for inherited illnesses will necessarily result in a greater number of abortions, which already total 1.5 million per year, the overwhelming majority of them for reasons other than genetic defects.
Scientists and doctors agree about the potential for broader prenatal diagnosis, but most don`t fear the possibility. Nobel Prize-winning biologist David Baltimore, director of the Whitehead Institute, affililated with the Massachusetts Institute of Technology, warns that society will soon have big choices to make.
”The real question is to what extent are we going to want to have children born with genetic diseases,” Baltimore says.
”Within the next few years we will be able to identify nearly all children who are the potential recipients of deleterious genes in utero early enough to abort them.
Except for the perspective of those who are opposed to abortion, ”it would be cheaper, and cause less pain and suffering to abort most cases of genetic lesions, rather than to allow them to come to term, and then try to deal with their disease.”
In the near future, Baltimore says, only families that are alert for individual genetic problems probably will avail themselves to the new tests.
”But eventually, we`ll be able to survey the whole population. Because, increasingly, people are going to know whatever they can know about their inheritance when they have a child.
”When we find the genes responsible for cystic fibrosis, for example, I can imagine a desire to screen the entire adult population to see if they`re carriers. Then, individuals would know wgeter it`s worthwhile having amniocentesis done to check their children. It`s solely a matter of how much money we`re willing to spend once we got those genes. And getting the genes is a technical problem, not a theoretical one.”
In Illinois, pro-life legislators may have cast a shadow on the ability of geneticists to perform state-of-the-art prenatal diagnosis. Both Illinois houses recently overrode Gov. Thompson`s veto of a bill that says: ”No person shall sell or experiment upon a fetus . . . unless such experimentation is therapeutic to the fetus.”
The law specifically says that it is ”not intended to inhibit the performance of in-vitro fertilization,” the laboratory mating of sperm and egg.
But Charles Strom, a University of Chicago physician and molecular researcher, says the bill`s real effect may be to ”severely cripple our ability to do genetics in this state.” Strom serves as president of the Genetics Task Force of Illinois, mandated by the state ”to foster the development and delivery of genetic services and research in Illinois.”
Strom, women`s groups and the American Civil Liberties Union believe that the new law may forbid prenatal diagnosis by a new–and experimental
–technique called chorionic villus sampling (CVS).
With CVS, a bit of fetal genetic material is suctioned out of the mother within the first 10 weeks of pregnancy. The material can then be exposed to a variety of DNA probes to detect inherited diseases in time for a first trimester abortion.
”It`s an incredibly vague law,” Strom says. ”What`s experimental? CVS is an experimental procedure, of no benefit to the fetus.”
If the fetus is defective, Strom asks, isn`t the likely outcome an abortion?
”They`ve made it a right-to-life issue. I see it as an issue over whether the state is going to interfere with the right of geneticists to practice modern genetics.”
One of the bill`s sponsors, Rep. John O`Connell (D., Western Springs)
denies this was his intention. O`Connell, in fact, says he never heard of CVS. He sponsored legislation, he said, after anti-abortion groups told him of reports that doctors in other states were doing laboratory experiments on human embryos ostensibly resulting from in-vitro fertilization.
O`Connell says he knows of no such experimentation going on in Illinois. Moreover, he says, his bill was not designed to interfere with prenatal testing.
”Prenatal diagnosis is not experimenting by my definition,” O`Connell says. ”That`s a device used to ascertain the status of the child. As the law exists now, the mother has the option to either proceed or abort. It was not my intent that prenatal testing would be included under the term,
experimentation.”
Lawyers for the ACLU are expected to challenge the constitutionality of the new law. Its effect on CVS remains to be determined.
