New Funds Possible For Embryo Research

The moratorium on human embryo research coincided with the Republican presidencies of Ronald Reagan and George Bush. Both administrations opposed abortion, with support from some conservative political and religious groups, based on the view that human life begins when the ovum is fertilized and that the resulting embryo has legal rights to protection similar to those of an infant, child, or adult. In recent years, the Bush administration also effectively opposed fetal tissue research on related grounds, a position reversed early in Bill Clinton's presidency. Opposition to the NIH panel's recommendations is being voiced by some of the same forces. For example, in a September 19 letter to NIH director Harold Varmus, Rep. Robert Dornan (R-Calif.) and about 30 other members of Congress argued that such research should not be funded by the agency. The U.S. election results earlier this month, in which Republicans gained control of both houses of Congress, appear likely to slow NIH progress toward formulating policy in this area, although panel members and agency officials decline to speculate on this possibility. In addressing the ethics of performing research involving embryos, the panel concluded that "the preimplantation human embryo warrants serious moral consideration as a developing form of human life, but it does not have the same moral status as infants and children." The panel counseled that most investigations be discontinued about 14 days after fertilization when the so-called primitive streak appears, a groove that develops along the midline of the embryonic disk of cells. The primitive streak is the first morphological evidence of what will later develop into the nervous system and is, thus, the earliest suggestion of sentience, according to panel member Ronald M. Green, a professor of religion at Dartmouth College, Han-over, N.H. It also establishes the embryo's head-tail and left-right orientations. In addition, it is the first developmental point at which the embryo can be called an individual, he noted at the news conference. Prior to this time, the embryo, if divided, can give rise to twins. Critics, however, say the primitive streak may have no special ethical significance as a stopping point on the developmental continuum from conception to birth (see accompanying story). "For the life of me, I really cannot understand why this specific morphological development, which speaks to where the nervous system is going to be formed, becomes a landmark," says Robert J. White, a professor of neurosurgery and a neuroscience researcher at Case Western Reserve University Medical Center, Cleveland. White believes fertilization delineates the start of human life. "There is no neurochemical or electrical event that speaks to when something becomes human, to when something equivalent to the soul or spirit_and not so much the mind_is infused into an embryo." Patricia A. King: The human embryo "does not have the same moral status as infants and children." In forming its recommendations, the panel attempted not to construct an unassailable moral stance on a controversial subject but to create defensible public policy, according to panel chairman Steven Muller, president emeritus of Johns Hopkins University, Baltimore. That process included public testimony at panel sessions before the report's release, as well as a solicitation of public comment leading up to a meeting of the NIH director's standing advisory committee to be held early next month. At that meeting, the committee, of which the panel was a temporary subgroup, will discuss the report's recommendations and advise director Varmus, who will then make a final decision on what research in this area the agency will fund. These steps are, by and large, the usual ones in the development of new policy at NIH and here in the government, but may be crucial in advancing policy in such a controversial area as human embryo research, Muller observed at the news conference. "In a democracy, public policy is not simply imposed on citizens by a higher authority," he said. "Proper public policy develops through a public process rooted in public participation. Public participation involves a multitude of interests, many in conflict with one another. The public process which produces public policy, therefore, must strive for a balance among divergent interests, a balance sufficient to obtain and justify public support." Muller added, however, that the content of some letters received by the panel during this process prompted them to request that NIH undertake a concerted public education effort to explain the complex scientific and ethical issues involved in human embryo research. To this end, NIH held an extended special briefing for science writers a week prior to the report's release and prepared comprehensive educational materials for distribution with the report. Scientists note that the types of research that NIH may begin funding if Varmus accepts the panel's proposals are well supported in a number of other countries and that U.S. investigators who now must rely on private funding find themselves at a comparative disadvantage as a result. "It's very clear that this is all competitive and that countries like England and Australia are way ahead of us," says Uta Francke, a professor of genetics and pediatrics at Stanford University Medical Center in California, and chairwoman of the Institute of Medicine committee that produced the July 1994 conference report Fetal Research and Applications (Washington, D.C., National Academy Press, 1994). "Our colleagues [in other countries] have sort of looked at [us as] the poor American brothers who couldn't really do anything because there wasn't any funding for it." One promising area likely to receive an immediate boost from new government grant support, according to Francke and other researchers, is genetic diagnosis of blastomeres_embryos at the eight-cell stage, in this case_produced through in vitro fertilization techniques. Currently, prospective parents who know that one or both of them carry a disease gene are faced with few options if they wish to have a healthy child with genetic contributions from both parents. They can test for the gene by chorionic villus sampling at 10 weeks' gestation or by amniocentesis at 16 weeks. If the disease gene is present in the fetus, the couple face the difficult decision of whether to end the pregnancy. "People who are at risk and who have done that a few times often are not willing to do it again," Francke says. "It's a tremendous emotional burden." A new experimental procedure, however, allows researchers to separate a single cell from the eight-cell embryo, amplify the genetic material from the cell using polymerase chain reaction technology, and then analyze the material for the disease gene's presence. If the gene is not found, the now-seven-cell embryo can be transferred to the womb where, if it implants, it will develop normally. In practice, a number of eggs are released from the ovaries through a hormone-stimulation protocol, fertilized in vitro, and tested. Multiple embryos that have been screened for their genetic health are then introduced into the uterus in the hopes that one will implant. Worldwide, fewer than 50 pregnancies have resulted from this diagnostic technique, according to the panel's report, and more research is needed to extend and refine the procedure. Genetic disorders successfully tested for, however, already include cystic fibrosis, Lesch-Nyhan syndrome, Duchenne muscular dystrophy, and Tay-Sachs disease, as well as a number of X-chromosome-linked recessive disorders such as hemophilia A, adrenoleukodystrophy, myotubular myopathy, spastic paraplegia, and certain forms of mental retardation. Certain areas of cancer research, too, may benefit from federal funding for preimplantation human embryo research. A number of genes that play critical roles in the normal development of the embryo are also suspected to play a part in some cancers. "The oncogenes that are a part of the cancer situation and the growth factors that are part of cancer scenarios are also part and parcel to those that are involved in development," says Neal L. First, a professor of reproductive biology and biotechnology at the University of Wisconsin, Madison. First is also a member of the National Advisory Board on Ethics in Reproduction (NABER), an interdisciplinary group established in 1992 by the American College of Obstetricians and Gynecologists and the American Fertility Society, but now a separate entity funded by private foundations. "Most often, oncogenes are genes that are useful in developmental processes when normally regulated, but when the oncogenes become improperly regulated, the tissues become tumorous." First adds: "We would probably enhance our understanding of cancer if we really understood the gene, growth factor, and cytokine situations for embryos as they pass through from one [developmental] stage to the next to the next." Research on human embryos will be crucial for these studies, First asserts, because animal studies have demonstrated that important developmental differences exist between species. "There's a lot of suspicion that the textbooks are not very accurate relative to human embryo development," he says. "What are the things that cause an early human cell to make its [developmental] changes, to differentiate? We can speculate from [what we know about] other species, but we wouldn't actually know until we were able to study humans." Studies involving parthenotes_unfertilized eggs that proceed to either spontaneous or induced early development as embryos_may lead to important new information about development, according to Brigid Hogan. Animal studies have shown that there are profound intrinsic barriers to normal development of parthenotes, which contain genetic material from only one parent. The reason involves a little-understood process called imprinting, in which chromosomes from both parents must be present in the embryo for normal development. Several tumor forms, relatively benign and easily treated, now appear to be linked to embryos in which only maternal or paternal genes are present. One example is a kind of trophoblast tumor called hydatidiform moles, which can progress to malignant choriocarcinoma. "We're not going to be curing anybody of these tumors by doing research," Hogan says. "On the other hand, the basic biology is extremely interesting. Studies in mice and in humans show that choriocarcinoma arises with a particularly high frequency when there are only paternal genes present. And, so, the question is why. Presumably, this is because of imprinting problems, in the sense that certain genes are going to be either active or inactive, oncogenes are going to be active, or tumor suppressors are going to be inactive in those cells." Another potentially significant area of research that may expand with federal support is in the development of techniques for culturing pluripotential human embryonic stem cells, according to Hogan. The creation of so-called immortal lines of undifferentiated cells might lead to crucial advances in cell-transplantation therapies. "A really important [advance] over the last 10 years in mouse embryo research is the development of these immortal, continuously proliferating embryonic stem cells from blastocyst-stage em-bryos," Hogan says. "You can culture them, and, as long as you continue growing them under ideal conditions and subculture them routinely, they will remain undifferentiated. But then you can stimulate them with various treatments to differentiate into various cells types. You can get muscle and nerve and bone and cartilage and so forth. So, the idea would be that maybe, down the line, you could use these for making blood cells for transplantation, and maybe some kinds of neuronal stem cells or muscle stem cells." More than 70 proposals for grants in human embryo research have already been received at NIH, in anticipation of Varmus's approval of the panel's recommendations. Most of the new proposals have been submitted to the National Institute of Child Health and Human Development at NIH.

New Funds Possible For Embryo Research

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