Washington Post Staff Writer
Sunday, March 22, 1998; Page A01
In 1990, a 4-year-old Ohio girl with an inherited immune system disease sat quietly in a small room at the National Institutes of Health and became the first patient to receive a radical new treatment called human gene therapy.
The experimental procedure, in which millions of copies of a gene that the girl lacked were infused into her blood, stirred excitement but also controversy. It was, after all, the most blatant tampering of the human genetic code ever attempted, and scientists gained permission to conduct the test only after assuring regulators that the genetic change would not be passed on to any children the girl might have.
Now, researchers are considering a much more contentious kind of gene therapy that could, for the first time, cross that generation barrier. The goal is to genetically reprogram patients' "germline" cells -- their sperm or egg cells. The technique could allow patients to prune unwanted genes from their family trees forever, and alter the genetic makeup of their unborn descendants.
Germline gene therapy has always been an ethically worrisome idea. Genes interact in complicated ways, and the eradication of certain so-called disease genes could have unexpected side effects in future offspring. Moreover, no technique is perfect, and an inadvertently introduced error would become a permanent part of a person's genetic legacy, perhaps wreaking biological havoc for generations to come.
Some experts worry, too, that germline gene therapy would give rise to a market in expensive elective genetic enhancements. Once gene therapy becomes heritable, these critics say, what will stop wealthy would-be parents from spiking their sperm or eggs with genes for beneficial traits, such as strong bones or tall stature, thus exacerbating the gulf between the rich and the poor?
The United States, Canada, England and other countries have policies that specifically preclude germline gene therapy. But a recent flurry of technical breakthroughs in test animals, and a gradual shift in people's perception about their right to shape their children's genetic inheritance, has prompted federal officials and others to reconsider the taboo.
"It was a line that was drawn in the moral sand way back when, and it appears in virtually all international and national ethics statements and guidances about genetics, but in the last year or so I have felt it beginning to soften," said John Fletcher, a bioethicist at the University of Virginia.
No one complained when smallpox was eradicated from the planet, advocates say. If it is ethical to wipe out infectious diseases with vaccines and drugs, why not make an equal effort to eliminate inherited scourges as well, such as sickle cell disease and cystic fibrosis?
"We are gaining the power to intervene in a realm that we've never had access to . . . by introducing new genes into the flow from one generation to another," said Gregory Stock, director of the program on science, technology and society at the University of California at Los Angeles. "Some people say you can't do that, you shouldn't do that. But I think we just have to take responsibility and move forward."
That sentiment has been heard increasingly at scientific meetings -- including one convened last Friday by Stock and UCLA colleague John Campbell, addressing the biological and ethical implications of human germline gene therapy.
The topic has also emerged as a priority for the American Association for the Advancement of Science, this country's largest general science organization, which recently appointed a panel of 20 experts to consider whether the time has come to open the door to germline alterations.
The federal government, too, is poised to reexamine the issue. A National Institutes of Health review of gene therapy regulations, scheduled to begin this spring, will focus in part on whether the current policy of not accepting germline proposals should be changed. That decision, experts said, will be among the most difficult the agency has faced.
"Alteration of the germline may be the most effective cure for some diseases, but it also contains unknown hazards," said Claudia Mickelson, chairman of the NIH's Recombinant DNA Advisory Committee, which reviews all human gene therapy proposals in the United States.
Germline gene therapy could be ideal for diseases that take their toll before a child is born, Mickelson said, since it is preventive rather than corrective. On the other hand, she warned, "insertion of genes into germline cells is a classic method for generating mutants." Given those risks, Mickelson is uneasy with the prospect of scientists, in essence, tinkering with evolution.
"Powerful techniques have powerful downsides," said W. French Anderson, director of the University of Southern California's gene therapy laboratory. Nonetheless, he said, germline gene therapy is sure to come, because "no parent will willingly pass on lethal genes to their children if they can prevent it."
Scientists differ on how imminent germline gene therapy may be; some say the first proposal may emerge in the next several years, while others think it's still a decade or more away. Either way, several said, now is the time to start a national debate on the issue.
"As opposed to every other decision made in medicine, this involves more than the patient, the family and the doctor," Anderson said. "The gene pool is not owned by anyone. It is the joint property of society. And when you manipulate the gene pool, before one attempts to do that, one needs the agreement of society."
A Question of Trust
"More than 3,000 people have received new genes now and no one has grown mouse fur and people are relaxing a bit," Anderson said. Still, he conceded, not one patient has been cured by standard gene therapy yet, and with germline gene therapy the stakes are even higher.
At its core, the key question is whether people can be trusted to engineer their own genetic lineage.
"As with cloning, there are real concerns about whether we are wise enough to mold ourselves to the extent these technologies may allow us to mold ourselves," said Erik Parens, an ethicist at the Hastings Center in Garrison, N.Y. "It certainly makes me nervous."
There are many facets to that consideration. One perspective says that, since there is always the chance that something will go wrong, it is simply unethical to alter people's genome without their permission. And since future generations, by definition, cannot consent, the genetic stream into the future should be left unengineered.
Following that logic, some countries have gone so far as to view germline gene therapy in the context of human rights. LeRoy Walters, director of Georgetown University's Kennedy Institute for Ethics, said a growing number of countries have included in their human rights manifestos language that says, in essence, "Every human being has a right to a genetic heritage that has not been artificially tampered with." Still, Walters said, it is in many cases unclear whether these countries would consider a genetic cure of a deadly disease to be a case of "tampering."
The answer to that question depends in part on how people define "disease."
"There will be clear-cut cases where everyone in the world will agree, 'this is a disease,' but the concept of health and disease at the margin will always involve judgment calls," Walters said. A slippery slope to genetic enhancement could ensue.
The distinction between therapy and enhancement can be surprisingly confusing. Consider vaccination: In some respects it is an enhancement, since it gives a person immunological powers not previously enjoyed. So what about giving a person a gene that builds big muscles, since muscle mass can reduce the odds of falling and breaking a hip? Or genes for good looks, since handsome people have been shown to get higher salaries, and annual income is closely linked to general health?
Ironically, if germline gene therapy veers far from its initial goal of fighting genetic diseases and into the realm of genetic enhancement, it might eventually lead to an increase in genetic diseases, said Michael Rose, a University of California at Irvine biologist. That's because the most popular genetic traits in an open market may not necessarily be the healthiest.
"If everyone wants to be blonde with blue eyes and if that's associated with an increased susceptibility to skin cancer, then you've got a problem," said Rose.
Even if people limit germline gene therapy to bona fide inherited scourges, unexpected side effects may arise from the obliteration of these disease genes. Scientists know, for example, that the genetic glitch that causes sickle cell disease also protects many people against malaria. The mutations that cause cystic fibrosis may, in small doses, protect people against cholera. No one knows what would happen if all "disease genes" were annihilated.
"It definitely will affect the variability and diversity that has developed such wonderful capacities in the human population," said Sherif E. Gabriel, the University of North Carolina researcher who, while developing a gene therapy for cystic fibrosis, has studied the potential evolutionary benefits of that mutation.
Leaping Technical Hurdles
"In the beginning there was a lot of agreement for various ethical as well as technical reasons that we would never go ahead with this and everybody was happy with that," said Parens. "But inevitably, once you have the technical capacity, everything changes."
Proof that germline gene therapy could work, at least in animals, first appeared in the early 1980s. In a key experiment, Leroy Hood and colleagues at the California Institute of Technology added curative genes to mouse embryos that were doomed to develop an inherited nervous system disorder. The new genes got into all the embryo cells -- including those that later developed into sperm and eggs -- so not only were the mice born free of disease, but all their offspring were as well.
No one is ready to conduct gene therapy experiments on human embryos or fetuses (although a proposal to do so is under development by USC's Anderson and colleagues and may be ready for federal consideration by this fall). So for now, scientists who want to make changes in the human germline will have to do so in the eggs or sperm of adults.
That is a tricky problem, but not insurmountable, said Ralph Brinster of the University of Pennsylvania. In the past few years, Brinster has successfully inserted genes into the cells that give rise to sperm in adult rats and mice. He has shown that these genetically altered cells can be transplanted into other animals -- even other species -- where they will grow and produce sperm that contain the added gene.
That suggests a scenario: Human sperm-cell precursors could be removed from the testes of a man with a genetic disease, "fixed" by the addition of a curative gene, then reimplanted into the man, where they would generate repaired sperm. Children conceived with such sperm would not have their father's disease, nor would their offspring.
If things don't go well, however, the man might now produce sperm even more defective than before -- perhaps forever. So a better plan, Brinster speculated, may be to transplant the repaired human sperm precursor cells into mice or rat testes. The rodents would then produce an endless supply of genetically corrected human sperm, which could be harvested and tested before getting mixed with eggs from the man's wife using standard in vitro fertilization procedures.
One last technical hurdle remains before such a plan can be implemented: Scientists need to perfect a way of doing in people what Brinster has done in rodents -- reliably get the desired genes into germ cells. But that problem, too, appears to be on the brink of being solved.
Until last year, researchers assumed that new therapeutic genes would have to be inserted directly into the chromosomes of a patient's cells -- a process that is inefficient and potentially damaging to the cell.
Then, last year, scientists announced they had invented artificial human chromosomes -- miniature, synthetic chromosomes that can be manufactured complete with one or more genes. These chromosomes make themselves at home inside cells, and they divide each time the cell divides, just like real chromosomes do. No artificial chromosomes have been inserted into living people's cells yet, but several scientists said they think the constructs may be ideal vehicles for germline gene therapy.
Revisiting Old Objections
"All of the reasons people have given for saying [germline gene therapy] is wrong are either irrational or religious-based," said Lee Silver, a Princeton University molecular biologist. "Some people say we should not go against nature, but that's illogical because every time we cure a disease or prevent a disease we go against nature."
Silver and others dismiss the argument that germline engineering breaks new ground by allowing people to "design" their children. "People choose a mate, either consciously or subconsciously, based on their genes," through their preferences for partners who are fat or thin or blonde or brunette, Silver said. "So we choose the genes we're going to put into our children right from the start."
(Not everyone buys that analogy; germline gene therapy is a much more precise method of trait selection than is mate choice, and that difference in precision is relevant, some ethicists said.)
Advocates also dismiss the argument that people don't have the right to alter future generations without their permission. "Parents already have the right to go against their child's wishes," Silver said. "There's not a person in society who would say it's wrong to give your child a vaccination. So why is it wrong to give what amounts to a genetic vaccine?"
If there is one objection to germline gene therapy that even advocates say they are still deeply concerned about it is the prospect of its evolving into a cosmetic procedure for the privileged classes.
"I think it would be a big mistake to think we can say 'yes' to germline gene therapy and 'no' to enhancement," Parens said. "And if germline gene therapy could be used to improve the competitiveness of your offspring, and only a few had access to the technology, then it's easy to see how the technology could widen the gap between the haves and the have nots."
But, as with so many of the bioethical quandaries now facing society, misuse is not assured -- and the potential for helping is real. So ultimately, experts said, it will be up to everyday people, living in the present, to decide whether practices like germline gene therapy ought to be plainly precluded or whether humankind can be trusted to do the right thing as science moves forward.
"Think about confronting a person in the future with a genetic disease that you could have prevented," said Walters, the Georgetown ethicist, "and telling them that even though you knew how to fix it, you stopped because you thought society might abuse this thing."
Scientists may indeed misuse their increasingly firm handle on genetics, Walters said. But the prospect of facing that future patient, he said, is at least as haunting.
© Copyright 1998 The Washington Post Company