Tinker With Our Genetic Future? Not Yet, Say Experts

As gene therapy researchers continue reeling from recent setbacks (see News, Jan. 19, p. 98), a group of prominent scientists is preparing to release a report on germline gene therapy—changing genes that can be passed through generations by altering sperm, egg cells, or embryos—that is sure to further stir the pot of public debate. The group, called the Human Germline Interventions Project, presented a draft report at the American Association for the Advancement of Science annual meeting in Washington in February. Like many ethical debates, this one raised more questions than it answered. But the panel, led by Theodore Friedmann, Ph.D., pediatrics professor at the University of California at San Diego, and Michael Blaese, M.D., president of Kimeragen Inc., Newtown, Pa., made two things clear: Technologies for tampering with the germline are rapidly becoming reality, and the ethical web that follows suit is too tangled to support any experimentation on the human germline. The group’s final report will be out later this year, said project leader Mark Frankel, Ph.D., director of AAAS’ program on scientific freedom, responsibility, and law. Frankel wants the document to direct policy discussion. “Scientists have brushed off germline possibilities until later, but I don’t want to keep putting it off,” he said. “People need to start thinking about how, as a society, we should handle germline gene therapy before it becomes a headline like Dolly the sheep.” The debate’s fundamental questions—Is the germline sacred, a holy ground where none shall tinker with humanity’s fate? Or is the chance to improve our collective gene pool too tempting to resist?—have been answered by one important body, the National Institutes of Health’s Recombinant DNA Advisory Committee (RAC), which reviews federally funded gene therapy studies. The RAC does not entertain proposals for experiments that would affect germline cells. But Eric Juengst, Ph.D., associate professor of biomedical ethics at Case Western Reserve University, Cleveland, called this a “policy of procrastination,” adding that it is just a matter of time before the issue will be forced, perhaps by private industry, which does not have to submit experiment proposals for NIH review. The germline envelope is already being pushed. Last year, the University of Southern California’s W. French Anderson, M.D., who along with Blaese pioneered the first human gene therapy trial, approached the RAC with a proposal for in utero gene therapy for adenosine deaminase deficiency. With that proposal, Anderson raised the prospect that the new genes might find their way into the sperm or egg cells of the fetus. The RAC responded with a statement that its members “unanimously agree that it is premature to undertake any human in utero gene transfer experiment.” This bottom line will apparently be echoed in the AAAS report. Audrey Chapman, Ph.D., director of AAAS’ program of dialogue on science, ethics and religion, said, “We think you’ve got to wait. We don’t see [germline gene therapy] being possible for at least 40 or 50 years, if our safety considerations are followed.” Those safety considerations include raising the efficiency of gene transfer into germline cells to nearly 100%, a feat not yet possible. For instance, transgenic mice, a staple of modern medical research, are created by injecting DNA into fertilized eggs, implanting the transgenic embryos into “pseudopregnant” females, and then screening to see which progeny have incorporated the new genes. But because the new DNA randomly integrates into the genome—sometimes even in the middle of another gene—the method creates many more misses than hits. “The transgenic model tells us in proof of principle that we can do this in rodents,” said Friedmann. “The problem is that the mechanism is highly inefficient, and mistakes that are made in the developmental process are simply discarded. In its present form, this technology is simply not ready for application to humans.” While the transgenic method can correct a laundry list of genetic diseases in family lines of mice, other newer technologies appear to be more efficient. One of the pioneers of transgenic mouse research, Ralph Brinster, Ph.D., professor of reproductive physiology at the University of Pennsylvania, Philadelphia, transplanted sperm stem cells, called spermatogonia, from fertile mice into the testes of sterile mice. The pre-sperm proliferated in the recipients, replete with the genes of the first animal. “These cells undergo self-renewal throughout life and have the ability to transmit genes to successive generations,” Brinster said in a press release. While the experiment did not alter genes in the pre-sperm, it demonstrates an effective method for delivering germline modifications. In related research reported in Nature Biotechnology in 1996, University of Tokyo scientists did alter genes in sperm cells using an adenovirus to transfect mouse sperm in vitro. They then replaced the sperm and watched as the new genes were passed to the offspring. Of 27 mice that developed from adenovirus-infiltrated embryos, three carried the new gene in their own reproductive cells, the very definition of germline genetic engineering. So far this sperm-transfection method has not been used to correct disease-causing genes, but that possibility has arrived. Another possibility—using artificial chromosomes to add genes to germline cells—is rapidly becoming reality. Chromos Molecular Systems, Vancouver, has performed a series of experiments that show that lab-built chromosomes replicate reliably and can be passed from parent to offspring. In one test, Chromos assembled an artificial chromosome that was blank except for a marker gene, then injected the chromosome into mouse embryos. The chromosome was found not only in the first generation of mice that developed, but in two subsequent generations. Word of this work leaked into the media at a London biotechnology conference last year, leading to fears that Chromos was developing the technology for adding genes to the human germline. Elizabeth Whiting, Chromos’ manager of communications, dismissed these worries, saying that the company is not pursuing artificial chromosomes for germline transmission in people. Rather, she said, they are testing the technology for two other applications. One application involves adding genes to cows and other animals may make them produce much sought-after proteins, such as insulin, in their milk. Artificial chromosomes are also an enticing new vector for somatic—nongermline—gene therapy (see News July 2, 1997). Artificial chromosomes can carry several times more DNA than traditional virus vectors, do not elicit an immune response, and do not disrupt cells’ original DNA. Full results of Chromos’ germline mouse experiments are in the April issue of Chromosome Research. Given these advances, it is easy to envision a time when a woman with a BRCA mutation will walk into a clinic and have one of her eggs removed and repaired so she doesn’t pass the deleterious gene and its specter of breast cancer on to her planned, but not yet conceived, daughter. But what if she wants a daughter who’s not just healthier, but smarter, stronger, prettier? “There are cognitive, physiological, and behavioral targets for enhancement that are largely genetically determined,” said Friedmann. “We will soon have an enormous amount of information on hand to think about modifying traits that are not disease traits.” This kind of tinkering—not to prevent or cure genetic diseases, but to improve in some subjective way how we think, act, or look—presents the thorniest ethical issues in the germline debate. But given that every parent wants the best for his or her children, once the technology for germline therapies are available, demand for enhancement is sure to follow. This possibility makes observers so nervous they invoke the “e” word—eugenics. “Once you accept the inevitability of medical changes, you’ll have enhancement come along with it, and that amounts to a new form of eugenics. We’re willing to say no to enhancement, but the dilemma is that it’s difficult if not impossible to have one without the other,” said AAAS’ Chapman. Stuart Newman, Ph.D., a professor of cell biology at New York Medical College, Valhalla, views this dilemma from a different angle. In a May 1999 editorial in The Lancet, Newman and co-authors argued that “germline intervention would intentionally subject later generations to modifications undertaken on the basis of existing values and conditions. The chance that ‘desirable’ manipulations might later be viewed as disastrous makes germline enhancement unacceptable.” Indeed, the Hollywood scenario of profiteers madly selling genetic upgrades has a lot of scientists on edge. At the AAAS session, Friedmann mentioned the possibility of germline genetic enhancement, then moved on quickly. Blaese too skipped over the subject, pausing only to say he was troubled by the notion of access, the “who decides who gets to have enhanced children” question. Even after genetic enhancement is discounted, Newman, Blaese, and others see little medical need for germline gene therapy, at least in the sperm and egg cells of parents. Advances in prenatal genetic diagnosis and in vitro fertilization may weed out most genetic diseases long before technologies for altering sperm and egg cells are proven safe, they say. “No unmet need balances the risks of germline interventions to mothers, fetuses, and future generations,” wrote Newman. “Moreover, the costs associated with the general implementation of germline manipulation would be formidable.” Case Western’s Juengst, too, sees a higher priority, saying that we need to work the kinks out of somatic gene therapy before pursuing germline therapies. Friedmann ended his talk with a similar caution, saying, “I would suggest that germline modification is not feasible, and should not be entertained until we can get perfect, or almost perfect, with our technology.” Dr. Theodore Friedmann An artificial chromosome (arrow) is ready for microinjection into a mouse embryo. Experiments at a Canadian company show that artificial chromosomes reliably replicate and can be passed to future generations. Dr. Audrey Chapman

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