Reproduction Research Held Back By Diffuse Rules, Charged Politics

The current sociopolitical climate in the United States affects funding and the ability to draw new investigators into the field, scientists contend.

It seems as if one aspect of reproduction research or another is perpetually making headlines. In the most recent example, reports of cloned animals touched off a firestorm of debate on human cloning. Some researchers and ethicists contend that the field's notoriety comes from its connection with abortion-rights issues, an association that has stimulated confusion about policies governing federally funded research. In turn, the abortion stigmatization affects funding and the ability to attract young investigators to the field, scientists maintain.

SOCIOCULTURAL ASPECTS: Debate surrounding reproduction research is reflective of "our democratic form of government," remarks NIH’s Michael McClure.

"We live in a time of unresolved consensus regarding human reproduction research at the national level," says Michael McClure, chief of the reproductive science branch at the National Institute of Child Health and Human Development (NICHD), referring to the general climate in which reproduction research is conducted. "We also live in a time of very rapid scientific progress that has outpaced the public comfort in how the knowledge gained may be used."

After last month's momentous announcement of the first cloning of an adult animal-the infamous lamb named Dolly-and this month's cloning of a primate, even the president is drawing connections between the possibility of cloning humans and human reproduction research. On March 4, President Bill Clinton issued a prohibition on using federal funds to clone humans. In the ban, he reiterated that 1996 and 1997 appropriations bills barred federal support for "certain human embryo research."

Differing interpretations of the wording of the amendment that governs federal funding for human embryo research have cost one investigator his NIH funding. Late last year, the agency ruled that Mark Hughes-a former professor of obstetrics and gynecology, pediatrics, and pathology and director of the Institute for Molecular and Human Genetics at Georgetown University-violated the embryo policy because he used agency funds, in part, to conduct genetic tests on DNA derived from human embryos destined for in vitro fertilization.

"If you go across the country and ask the average scientist-or, for that matter, administrator-at a university, no one knows what the rules are because they're so poorly written and diffuse," says Hughes.

ACCEPTABILITY: "I think that research with human embryos ought to be allowed up to a certain point after fertilization," maintains Caltech’s Daniel Kevles.

The debate in the last few years over human embryo research has centered on work supported by the public sector (F. Hoke, The Scientist, Nov. 28, 1994, page 1; F. Hoke, The Scientist, Jan. 23, 1995, page 1; S. Benowitz, The Scientist, June 24, 1996, page 1). Some bioethicists agree with Hughes's assessment of the current state of policies governing reproduction research. "I think that there ought to be some more coherent guidelines," asserts Daniel J. Kevles, the Koepfli Professor of the Humanities at the California Institute of Technology. "I think that research with human embryos ought to be allowed up to a certain point after fertilization."

Arthur L. Caplan, director of the Center for Bioethics at the University of Pennsylvania Medical Center, sees the status of guidelines for reproduction research, especially research with human embryos, in more black-and-white terms: "What I will say is that there are no guidelines. There's either a ban or do what you want. I guess you could call that guidelines."

Privately funded research is a different story, notes Ronald M. Green, the John Phillips Professor of Religion and director of the Ethics Institute at Dartmouth College. "NIH cannot currently fund research that involves the human embryo, but that's not to say there's not research going on out there," he says. "There's research going on in several hundred infertility clinics across the country."

PRIVATE SECTOR: Private clinic director Joe Massey thinks clinic guidelines should remain loose in order to keep people’s reproductive options open.

This private research is largely unregulated, and scientists and clinicians in these settings hope to keep it that way. "In general, my personal position is that it's not helpful to have much in the way of regulations in terms of reproductive options for people," says Joe Massey, director of Reproductive Biology Associates, an Atlanta-based private fertility clinic. "I think the guidelines should be loose. To me, anything that's short of cloning that enables people to reproduce would be acceptable."

It's tough even to define all that reproduction research encompasses. "Reproduction research, in the broadest sense, includes research on the biomedical and behavioral mechanisms that permit us to reproduce our kind," according to McClure. "In the biomedical area, the major research areas [consist] of efforts to understand the mechanisms that provide our ability to create, transport, and promote the union of the gametes carrying our genetic essence as individuals, on the one hand, and the efforts to understand the maternal-fetal mechanisms that accept, nurture, protect, and deliver into the world the conception product we all recognize as a baby."

Contraceptive research and development, infertility studies, and genetic testing in embryos and fetuses, among other topics, have been in the limelight in the recent past. Studies at the National Institute of Child Health and Human Development cover many of these topics (see Research, page 11).

Mammalian models of reproduction and development are also being developed at a rapid pace. The ultimate goal of these models is to one day apply the knowledge gained from mouse studies to humans, researchers explain.

But Hughes and others question whether the application of those insights to humans will be forever forestalled under current policies. "The goal eventually is to take that information and apply it to humans," Hughes says. "I don't want to imply in any way that most developmental biology is not important. It's critically important, and some of the most beautiful biomedical science that is going on is in mouse developmental biology. What I mean is, somewhere along the line we have to realize that it isn't the National Institutes of Mouse Health, it's the National Institutes of Human Health. And we've treaded water because of a national inability to come to grips with this."

In the past five years, a steady stream of reports from blue-ribbon panels has attempted to give some guidance to reproduction research. In 1994, the Institute of Medicine (IOM) issued a report entitled "Fetal Research and Applications." Two years later, IOM weighed in on contraceptives with its 1996 report, "Contraceptive Research and Development: Looking to the Future" (M.E. Watanabe, The Scientist, Sept. 16, 1996, page 1).

Also in 1994, an advisory committee called the NIH Human Embryo Research Panel heartily recommended government funding for research using preimplantation embryos. But in early December 1994, President Clinton issued a statement that called for NIH to block funding for experiments using embryos made expressly for research. However, this statement didn't forbid using federal dollars for work with spare embryos, those left over from in vitro fertilization (IVF) treatments.

This was not the final say by the federal government on human embryo research. An amendment to the 1996 NIH appropriation bill, entitled the Continued Ban on Funding Human Embryo Research reads, in part: "Grant, cooperative agreement, and contract funds may not be used for (1) the creation of a human embryo for research purposes; or (2) research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero."

Policies concerning research involving fetuses, pregnant women, and human IVF are stated in the Department of Health and Human Services Code of Federal Regulations for the protection of human subjects (Title 45, part 46).

Regulations in a related area-using fetal tissue for therapeutic research-have also shifted with the political winds. One day after his 1993 inauguration, President Clinton lifted a five-year ban on federally funded fetal-tissue research instituted in the Reagan-Bush years. Under current regulations, fetal tissue can be obtained only from women who have terminated their pregnancies and have given permission to donate the fetal tissue.

The situation between Hughes and NIH over the ban may be associated with vague wording regarding genetic material derived from embryos. NIH first enforced the Continued Ban on Funding Human Embryo Research in October 1996, when it ruled that Hughes had violated the ban and withdrew funding from his embryological studies. At the time, Hughes was in the midst of phasing out his intramural relationship with NIH.

According to NIH, Hughes had used a refrigerator and part of an NIH-supported postdoc's time to conduct genetic tests on DNA from human embryos destined for in vitro fertilization. Hughes did not think he was violating the ban because he viewed his work as examining genetic material rather than research on whole embryos. When NIH deemed his work a violation of the ban, he stopped using agency resources to perform the tests.

Last month he also resigned from Georgetown University, a Jesuit Catholic institution, "out of respect for their traditions," he states.

Hughes, who was also a member of the 1994 NIH embryo research panel, says what is needed is "a whole set of guidelines about reproductive medical research. Right now, we don't have any." He sees a lack of clarity in the current set of laws in that NIH okays studies using DNA derived from 24-week-old fetuses, for example, and not from an eight-cell embryo.

"There is no contradiction," states McClure. The fetal tissue guidelines that are in effect govern that area, he says. "[Embryo research] is a very different matter. These are quite separate issues that have quite different guidelines."

"Well there are rules, but what I would say is that the application of those rules is diffuse," remarks George J. Annas, a professor of health law at the Boston University School of Medicine. "It's arbitrary, and it's basically left up to individual Institutional Review Boards [IRBs]."

These boards approve research on human subjects at universities, hospitals, and medical centers, with embryos qualifying as human subjects. "IRBs have tremendous authority in this country to interpret the regulations," maintains Annas. "Essentially what the IRB says, goes, because a researcher can't appeal an IRB decision."

Caltech's Kevles points out a difference between embryo and fetal tissue research: "Fetal tissue is just tissue, but the embryo is a living entity. The point is that the fetal tissue is not viable; it's not going to develop into anything."

MONEY PROBLEMS: "The whole field of human development--not only preimplantation embryos--is very poorly funded," notes Vanderbilt’s Brigid Hogan.

The politicizing of some areas of reproduction research, according to some investigators, affects the future viability of the field. Brigid L.M. Hogan, a professor of cell biology at Vanderbilt University School of Medicine and science cochairwoman of the 1994 embryo research panel, says that the stigmatization of research in human reproduction has implications for funding and attracting new talent into the field.

"One of the driving forces behind trying to implement the NIH [embryo research] guidelines in place was to enable funding of scientists in academic institutions, so as to attract the very best talent to work on any question in reproductive biology," comments Hogan. "This means that research is only going to be done in the private sector, where it is driven largely by what the public will bear in terms of paying for these services. The whole field of human development-not only preimplantation embryos-is very poorly funded. Why isn't work being properly funded in institutions where there are lots of grad students, or by NIH?"

"It's definitely affecting research," agrees Caplan. "Most people believe that private research in this area is minimally funded. So the only real way to move research along is to put government resources behind it because it's closer to basic science."

SOURCE OF CONFUSION: "The problem is that there are no regulations at all," contends Dartmouth’s Ronald Green.

"The best way of fostering responsible research in human reproduction is to federally fund it by supporting the best and most responsible researchers and by making sure there's continual dialogue on the moral guidelines affecting it," maintains Green, who was also cochairman of the NIH embryo research panel.

Hughes contends that because most reproduction research is conducted in the private sector, important areas of study such as determining reasons for spontaneous, early miscarriages are being neglected. "The science becomes entrepreneurially driven and oriented for the purposes of improving IVF," he argues.

Although ethicists and researchers paint a bleak picture for the future funding of reproduction research, some fledgling efforts are helping. The Burroughs Wellcome Fund, a private foundation in Durham, N.C., supports annual Career Awards in Biomedical Sciences for up to six years of support for early-career scientists. The three-year-old awards include support for reproduction science, an area that the foundation has deemed particularly underfunded. For 1997, according to Martin Ionescu-Pioggia, program officer for career development and reproductive science, the foundation is funding more than $850,000 in reproductive scientific research, which includes the career awards. One of the critical areas, says Ionescu-Pioggia, is training ob-gyn clinicians in molecular or cellular methods.

While the private sector is starting to take action to train the next generation of reproduction scientists, Caplan thinks that the chances are nil that the federal government will devise a coherent set of guidelines for reproduction research. "Society is still so riven by disagreements on abortion that the chance of a Republican, conservative Congress and a centrist, Democratic president agreeing on this issue is zero."

McClure sees the situation in more philosophical terms: "[The discussion] surrounding most aspects of reproduction research actually reflects the positive sociocultural aspects of our democratic form of government. . . . History teaches us that, with time, such resolutions are attained. So it will be, with time, for reproduction research."