Blind World


Stem Cells.
New technique eyed in stem-cell debate.





November 21, 2004.

By Gareth Cook,
Globe Staff,
The Boston Globe.




With the nation deadlocked over the morality of using human embryos for research, a member of the President's Council on Bioethics is quietly promoting a proposal that might allow scientists to create the equivalent of embryonic stem cells without destroying embryos, offering a potential path out of the controversy.


Dr. William Hurlbut, a Stanford bioethicist and staunch opponent of research on human embryos, has traveled the country developing and winning support for the idea in consultation with a small circle of scientists and conservative ethicists. The procedure, called altered nuclear transfer, would engineer a human egg that could generate cells with the full potential of embryonic stem cells, but without ever forming an actual embryo.


The technique has not been attempted with human cells, but biologists consider it feasible with today's technology. The larger question is whether the technique could overcome the strong ethical and religious opposition that has led to sharp limits on federal funding for embryonic stem-cell experiments and turned embryonic stem-cell research into a flashpoint in American politics.


How the alternate technique would work.


So far, three critics of current methods for creating embryonic stem cells -- Archbishop William J. Levada of San Francisco, Robert George, a member of the president's bioethics council, and Nigel M. de S. Cameron, a leading intellectual in the evangelical movement -- have seen Hurlbut's proposal and said they believe it could offer a way around their moral objections. Hurlbut will present his idea to the bioethics council early next month.


A proposal acceptable to moral conservatives would mark the first major shift in the debate over human embryonic stem cells since President Bush issued his policy Aug. 9, 2001, barring federal funding for research on embryonic stem cells created after that date. Many scientists see the cells, which can become any tissue in the body, as a uniquely powerful tool for medical research and possibly curing diseases. But religious conservatives have staunchly opposed the work because it involves destroying 5-day-old embryos.


In a debate that has come to resemble the seemingly irreconcilable American divide over abortion, Hurlbut's proposal offers the tantalizing hope of a middle ground.


"In this country, it is almost as if we would rather argue than find a solution," Hurlbut said. "It would be so much better if we could find a way to produce these cells with a genuine social consensus behind them."


Hurlbut's proposal would use biological tools and current cloning technology to create powerful embryonic-type stem cells without creating an embryo. As with cloning -- which produces embryos genetically identical to a cell donor -- scientists would implant DNA from a donor's cell into a human egg cell that has had its nucleus removed, and then induce the egg to begin dividing. The egg would produce embryonic-type stem cells. But by altering the donor cell's DNA first, Hurlbut suggests, the researchers can prevent the cells of the egg from organizing into a human embryo.


If the procedure works, and if critics of today's embryo research accept Hurlbut's ethical arguments, it could provide an avenue for scientists to create new human embryonic stem cells with government funding. If Bush, in consultation with his advisers, were to conclude that altered nuclear transfer does not use human embryos, he could allow federal funding of the work, according to Dr. James F. Battey, chairman of the stem-cell task force at the National Institutes of Health.


Though other biologists and ethicists have suggested that human embryonic stem cells could be created without destroying an embryo, Hurlbut's proposal is the most comprehensive and politically potent. It weaves together a specific scientific approach and a sophisticated ethical argument developed with conservative ethicists and Christian leaders. In a highly politicized environment, many said Hurlbut's public record as an opponent of embryo research could be key to bridging the gap between the two sides.


"Just given who is saying this, one of the best informed and most respected thinkers on the conservative side, this is something I take seriously," said Cameron, who runs a bioethics think tank in Illinois and has discussed the proposal with Hurlbut. "I think it has enormous promise."


Even if Hurlbut's proposal failed, its warm reception from religious conservatives offers a glimpse of how increasingly powerful biological tools might allow scientists not just to raise ethical dilemmas, but to solve them.


Idea with a twist.


The germ of the proposal, Hurlbut said, grew out of discussions on the president's council in 2002 about the morality of using cloning techniques to create human embryonic stem cells. Many biologists see research cloning -- which creates an embryo but not a human child -- as key to realizing the full potential of human embryonic stem cells because it can create genetically customized cells with the power to develop into any cell of the body. The current technique takes DNA from the cell of an adult and implants it into an egg, which is then induced to develop into an embryo that has several hundred cells. The work is controversial because the procedure means creating an embryo -- which some consider a human life -- and then destroying it purely for the purpose of harvesting its stem cells.


Inspired by the debate over whether such a laboratory creation is truly human, Hurlbut said he began to wonder whether it might be possible to change the cloning process so that all parties to the debate would agree that nothing like a human life was ever created. If that were possible, he reasoned, then scientists might have a morally acceptable way to create embryonic stem cells.


His idea was a twist on the current technique for research cloning. Before implanting the DNA from a skin cell into an egg, scientists would turn off a gene that helps direct the formation of the trophectoderm, an outer layer of cells that is crucial in the first stages of development and which eventually forms the placenta. With this gene silenced, the trophectoderm does not form properly. All the cells eventually die, but scientists can still harvest embryonic-type stem cells from the mass, according to Dr. Felix Beck, a professor at the University of Leicester and one of the authors of a scientific paper in May that described how the gene affects the trophectoderm in mice.


"The embryo is forming," Hurlbut said. "And unless it forms itself properly, it is not an embryo."


Hurlbut and others involved in the initial discussion concede the idea faces two sets of hurdles before it can offer a workable compromise in the human embryo research debate.


First, there are several technical issues that still need to be settled in the lab. Some of the necessary steps have been demonstrated in mice, but not with human cells. Unlike the mouse work, where the key gene was removed, researchers will have to show they can turn the gene entirely off, preventing the formation of an embryo, and then turn it back on in the resulting stem cells, so that the cells are not flawed. Cloning human cells is still so difficult that only one research team in the world has successfully attempted it, though others are planning to work on it.


The other hurdle is the challenge -- scientific, ethical, and political -- of establishing a broad consensus that the mass of cells is not a human embryo.


In the past, scientists have suggested ways to ensure a healthy embryo does not develop such as silencing a gene needed to form the nervous system. But if the egg develops into something that might be considered a life -- even if it is genetically flawed and doomed to die while still microscopic -- then many ethicists will say that destroying it for research still amounts to killing. From a moral standpoint, creating and then destroying a damaged embryo is no different from creating and destroying a healthy embryo.


"At one extreme you have the case of the headless frog," Cameron said. "It is still a frog."


This question -- how to distinguish between a damaged embryo and something that can not be considered an embryo at all -- has been at the center of Hurlbut's project and his quiet campaign.


Hurlbut, 59, is a firm opponent of destroying embryos for human embryonic stem-cell research, but calls himself a passionate advocate for science and its possibilities. He graduated with a degree in biology from Stanford University and from the medical school there. A Christian who said he does not identify with any particular denomination, Hurlbut did three years of post-doctoral study in theology and medical ethics at Stanford. He said he has long been interested in "life's deeper questions."


The deeper question behind abortion and embryonic cells is: When does life begin? For all practical purposes, it is proving unresolvable: When some people look at a 5-day-old embryo, a ball of several hundred cells, they see a life. Others do not.


Hurlbut's idea would shift the terms of the debate to a narrower question that scientists should be able to answer: What is an embryo? To answer this question properly, Hurlbut said, means forcing not only science but also ethics into untested waters.


Biologists know that the formation of an embryo requires that all the cells establish an intricate web of communication, in the form of chemical signals. If this web of communication fails, then the cells cannot organize themselves and start the long path of specialization that eventually creates a baby.


In normal development, the appearance of an outer sheath, the trophectoderm, is the first sign that a fertilized egg has developed into more than one type of cell. In Hurlbut's technique, however, the trophectoderm would not form properly, and the normal flow of signals would stop. Thus, Hurlbut argues, the vital web of communication within the ball of cells is never able to establish itself fully, and the entity cannot be called an embryo.


He points to a parallel in natural biology: Sometimes an egg cell will begin dividing wildly on its own and turn into a tumor that can grow into virtually any type of tissue -- even hair and teeth. Catholic theologians and others have studied these tumors, called teratomas and have agreed that they are not embryos because they lack a coherent structure, or "integrated organization."


"If you don't have that, you may have organic material, but you don't have an organism," said Stephen Pope, an associate professor of social ethics at Boston College.


George, a professor of jurisprudence at Princeton University, said that the proposal meets what he considers to be three key ethical benchmarks: The entity should not have integrated organization, it must not have "the self-directed active disposition to become the next mature stage," and crucially, he said, the genetic alteration must be made "ab initio" -- or from the beginning -- so it cannot be argued that the procedure merely creates a disabled embryo.


George said that he was initially skeptical when Hurlbut started discussing the idea of altered nuclear transfer with him. But after long discussions, he said that he became convinced that, if scientific experiments in animals show that the procedure works and does not create an embryo, the proposal could meet the three central ethical considerations.


The analogy with a teratoma is powerful, George said, and he is eager to see the proposal proceed.


"It looks to be very persuasive," he said. "I think animal experiments would make it pretty clear."


Quiet campaign.


Because of the uncertainty in both science and ethics, Hurlbut has mostly worked on altered nuclear transfer behind the scenes. Hurlbut described the rough outlines of the idea in a statement attached to the council's report on cloning in 2002, but said he had shied away from actively promoting the idea until he saw that the science was feasible and worked through the ethical issues.


Since then, he has held long conversations with some of the country's top biologists, including Dr. Rudolf Jaenisch of the Massachusetts Institute of Technology, Dr. Irving Weissman of Stanford, and Douglas Melton of Harvard University. He also discussed his idea with Archbishop Levada of San Francisco. Levada cautioned Hurlbut that he could not speak for the Catholic Church, but was sufficiently impressed that in August he wrote a letter to Bush declaring his belief that the idea could end the controversy.


"As Chairman of the United States Conference of Catholic Bishops' Committee on Doctrine, I want to assure you of our interest in and encouragement of Dr. Hurlbut's proposal," Levada wrote. "We support his efforts and encourage you and your advisors advisers to share with us in this support."


Now, watching the deepening political divide on the issue, Hurlbut said he feels the project is not just important, but urgent. "It seems to me that the impasse is just getting intolerable," Hurlbut said.


Hurlbut has prepared a six-page paper that outlines the proposal, and next month he will present it to the President's Council on Bioethics. The council, which advises the president, has not taken any position on the idea, Hurlbut emphasized. But the council's high-profile deliberations can help shape public opinion.


Already, one leading stem-cell biologist has said he is interested in pursuing some of the scientific work suggested by the Hurlbut proposal, and is considering applying for money from California's new Institute for Regenerative Medicine, which is being formed after a ballot initiative there. The scientist, Dr. Evan Snyder, said that there are many genes that might accomplish what Hurlbut has in mind, and that he would envision beginning by searching the scientific literature for possibilities and testing the effects of silencing each gene in mice.


As much as Hurlbut hopes he will start a new conversation between science and ethics, he cautioned that it would begin with suspicion on all sides. A number of ethicists interviewed said that they worry that many stem-cell scientists are not interested in a serious moral discussion. And a number of the stem-cell scientists said that they doubt anything they do would satisfy opponents of the work, and that a scientifically complex proposal could only divert attention and money from current research.


Some foresee that even if Hurlbut's idea can shift the debate, it will not go away. Beneath the fine points of theology and ethics, many people say they feel a deep unease about what biologists are doing as well as a sense that mankind is "playing God," said John Evans, an associate professor of sociology at the University of California at San Diego. If the question of embryo destruction were resolved, Evans said, some opponents could simply articulate new objections.


"In a sense, this could be calling their bluff," said Evans, who is working on a book about the attitudes of religious people towards reproductive technologies.


But Hurlbut said that the potential of stem-cell research is too great, and the social divisions too poisonous, to not search for a solution, even if it has to be done one person at a time.


Snyder, a professor and director of the stem-cell and regeneration program at the Burnham Institute in La Jolla, Calif., said that after long discussions with Hurlbut, he considers the conservative ethicist a good friend. "I think many people think of science as the problem," Snyder said. "But I think we both believe that science might also give us the solutions."


Gareth Cook can be reached at cook@globe.com.


Copyright 2004 Globe Newspaper Company.




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