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A correction has been published: N Engl J Med 2005;353(25):2728.
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Then, in mid-May, a Korean research team announced that they had derived lines of human embryonic stem cells carrying the genetic signatures of persons with disorders such as type 1 diabetes mellitus and spinal cord injury. This advance promises new opportunities for investigating the causes of disease and developing specific therapies — but also demonstrates that U.S. stem-cell researchers are falling behind their competitors.1
A few days later, the House of Representatives passed legislation supporting the expansion of federally funded human embryonic stem-cell research, setting the stage for a veto by President George W. Bush, who has ruled out providing funding for any such studies except those using certain cell lines that were derived before August 2001. Meanwhile, California and New Jersey are moving ahead with programs to sponsor the research, and similar initiatives are being considered by other states (see map).
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Human embryonic stem cells are derived from the inner cell mass of a blastocyst-stage embryo that has undergone cell division and development for about six days following fertilization. The new guidelines (see box) apply to research using stem cells obtained from human blastocysts, whether they have been created specifically for research or were originally made for reproductive purposes. They also apply to stem cells obtained by transferring the nucleus from a fully differentiated cell into a human oocyte whose own nucleus has been removed and inducing the resultant cell to develop into a blastocyst. This procedure, called somatic-cell nuclear transfer (SCNT), is the technique used by the Korean team. Although it holds great potential for yielding patient-specific therapies and cellular models of disease, SCNT requires that women donate fresh oocytes for research — a requirement that some find more ethically problematic than the donation of "leftover" frozen embryos by couples who have undergone in vitro fertilization (IVF) procedures. Unlike embryos, oocytes cannot be frozen for later use. So far, only a few U.S. researchers have sought permission to perform SCNT.
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The ethics guidelines contain detailed recommendations with regard to donor recruitment and informed consent. They describe how stem cells should be characterized, handled, transferred, and stored. They recommend the establishment of an embryonic stem-cell research oversight committee at each institution, and they offer guidance on what kinds of experiments should be considered for approval and what kinds should be proscribed.
Adhering to a limit established by the British Warnock Commission in 1984, the guidelines stipulate that no blastocyst should be maintained in culture for longer than 14 days or past the time of appearance of the primitive streak, a band of cells that establishes the embryo's head–tail and right–left orientations. "It's also the point at which twinning is no longer possible — biological individuation," explained ethicist Jonathan D. Moreno of the University of Virginia, cochair of the guidelines committee. "Now, as a philosopher, I always want to say, anatomy is not ethics. But it's a signpost that says, ‘Before this, you don't have structure; you don't have a biological individual.’"
The guidelines would also limit the creation of some kinds of chimeras, organisms containing both human and animal cells. Although chimeras have been made for years, the use of human embryonic stem cells creates the potential for much greater contribution of human cells to a chimeric animal. The committee recommended that chimeras made with the use of human embryonic stem cells not be allowed to breed and that such cells not be introduced into primate blastocysts. "I think the experiment one doesn't want to see done is to make some kind of human–primate chimera," Melton said. "That really causes us all to shiver and think about the essence of being human, about human dignity, and the rights of animals."
The guidelines urge caution on introducing human embryonic stem cells into the brains of nonhuman primates, an experiment that might be desirable, for example, during the development of cell-based therapies for disorders such as Parkinson's disease or stroke. Mice, points out John Gearhart, a stem-cell biologist at Johns Hopkins School of Medicine, do not live long enough to permit researchers to study the long-term fate of neural progenitor cells derived from embryonic stem cells and introduced into the mouse nervous system. "If you're concerned about your cells wandering off and doing something inappropriate, or turning into a tumor, how long does it take to reveal that?" asked Gearhart. The chances of creating a human-like brain in a monkey would be much smaller if human stem cells were introduced into an adult animal than if they were introduced into a primate embryo, fetus, or neonate, he added.
An estimated 400,000 frozen embryos are stored in the United States, primarily for use in IVF.2 Some stem-cell researchers arrange with IVF clinics to obtain embryos donated by couples for research, from which they may derive stem-cell lines. The guidelines stipulate that donors and clinics may not be paid for embryos and that decisions to create embryos during infertility treatment should not be influenced by stem-cell scientists. At Boston IVF, where Melton has obtained embryos for research, physicians do not mention the possibility of donating embryos for this purpose until a couple indicates a wish to discard their remaining embryos, according to surgical director Alan Penzias. Penzias estimates that only about 10 percent of frozen embryos can be induced to develop into blastocysts.
Deriving new cell lines by means of SCNT will require recruiting women to donate oocytes, which have rarely been solicited for research purposes in this country. Currently, healthy, fertile women are sought as egg donors primarily for reproductive purposes — by IVF programs, infertile couples, or egg-donor agencies. According to the Centers for Disease Control and Prevention, egg donors are the patients in about 10 percent of the approximately 100,000 cycles of oocyte collection performed annually at U.S. IVF clinics. During a cycle, a woman injects a daily dose of recombinant human follicle-stimulating hormone subcutaneously for 10 to 14 days to trigger the development of multiple ovarian follicles. Oocytes are then collected transvaginally in a brief surgical procedure. There is some medical risk, primarily of ovarian hyperstimulation syndrome, which affects 2 to 5 percent of women undergoing hormonal stimulation. This syndrome can be painful, may necessitate hospitalization, and can cause hypotension, respiratory distress, renal failure, hemorrhage due to ovarian rupture, and very rarely even death.3 The syndrome is related to the production of vascular endothelial growth factor, and severe cases can generally be prevented by administering the lowest doses of hormone necessary and carefully monitoring the ovarian response.
Women who donate oocytes for IVF are routinely paid, and some receive large sums. Penzias said the going rate in Boston is about $5,000 per cycle, and the American Society for Reproductive Medicine considers a fee of up to $10,000 acceptable under some circumstances. A recent advertisement in a college newspaper offered $25,000 for an egg donor who was an Ivy League student or alumna of northern or eastern European descent, 21 to 32 years of age, "healthy, athletic, very pretty, 5'7"–5'10.5", outgoing, sense of humor preferred."4 Expressing concern that financial incentives might unduly influence donors to accept unnecessary risk, the guidelines committee recommended that women who donate oocytes for research be reimbursed only for direct expenses and not receive payment for their time, for lost wages, or as compensation.
That recommendation surprised some observers. Bernard Lo, director of the program in medical ethics at the University of California at San Francisco (UCSF), said that it ignores the reality that a competitive market already exists for egg donors, especially for those who are young, white, and well educated. "This apparently neutral rule that we're not going to pay anybody for research in fact means you are closing off financial opportunities for women of certain socioeconomic and ethnic backgrounds," he said. "We pay people to undergo risks in other types of research. It doesn't seem fair to have [oocyte donors] undergo clear medical risks and not offer them something for that." But Lo, who chairs UCSF's Campus Advisory Committee on the Ethics of Oocyte, Embryo, and Stem Cell Research, acknowledged that the issue is so troublesome that UCSF has not yet approved any protocols allowing retrieval of oocytes for research. "We thought about this a lot and really could not come up with a good answer," he said.
Lo and others predict that if egg donors are not paid, most will probably be people with relatives affected by one of the diseases often mentioned as targets of stem-cell research. "It's hard to imagine someone who isn't motivated for that kind of reason, but it's also important that people realize that this is a long-term scientific project," Lo said. "It's very unlikely that someone who donates now is going to have their materials used therapeutically for someone in their family."
The guidelines will probably be used in state and institutional policymaking, but they may have little impact in Washington. The Castle–DeGette bill, passed by the House of Representatives in May, would expand federal funding for the use of donated embryos in stem-cell research, but it would not allow such funding for SCNT, which many consider the approach most likely to yield new therapies. Nonetheless, President Bush has promised to veto the measure if it passes the Senate, declaring, "There is no such thing as a spare embryo."5 Opponents of this research have lobbied for increased funding to study alternative sources of stem cells, but it is not yet clear whether a scientifically practical alternative that does not require the destruction of embryos can be identified.
Meanwhile, the funding of the $3 billion California stem-cell research initiative, passed by voters last year, has been delayed by lawsuits brought by its opponents. California universities and research institutions have been aggressively recruiting stem-cell scientists, and the new California Institute for Regenerative Medicine has assembled an impressive roster of outside advisers to set ethics standards and award grants. But some state legislators are seeking to amend the initiative, citing a lack of transparency, potential conflicts of interest among grant reviewers, and a desire to ensure that any therapies developed will be affordable. Zach Hall, the interim president of the institute, said that the proposed changes "would seriously impede our ability to do our science. . . . We haven't even gotten going, and already it's like they're crying, ‘Foul!’"
According to Harvard's Melton, the only way to ensure steady progress in this emerging field is to have a consistent national policy. "In general, I'm not a big fan of state-led initiatives, because I think this is a federal issue," he said. "Either this research should go forward or it shouldn't. But if it should, our present policies make no sense at all, because their only consequence is to make the research go more slowly."
Source Information
Dr. Okie is a contributing editor of the Journal.
An interview with stem-cell researcher John Gearhart can be heard at www.nejm.org.
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