Altered Nuclear Transfer in Stem-Cell Research — A Flawed Proposal
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《新英格兰医药杂志》
The study of human embryonic stem cells is a matter of intense public debate, primarily because derivation of such cells requires the destruction of human blastocysts, a procedure that some find morally objectionable. William Hurlbut, M.D., of Stanford University and a member of the President's Council on Bioethics has recently proposed to the council an alternative way to derive embryonic stem cells that, he argues, circumvents this objection.1 The chair of the council, Leon Kass, M.D., Ph.D., favors Hurlbut's proposal.2 We believe that it is flawed.
Hurlbut's proposal is based on the observation that mouse embryos carrying a mutation in the Cdx2 gene die at the blastocyst stage because they fail to form a trophectoderm (from which the placenta normally develops).3 These embryos can still give rise to mouse embryonic stem cells, and Hurlbut argues that a human embryo with a similar mutation would lack the capacity to become a human being and would thus represent an ethically uncontroversial source of human embryonic stem cells. He proposes that embryonic stem cells could be derived by a process he calls altered nuclear transfer, in which a CDX2 mutation would be introduced in vitro into a human cell that would then be used as a nuclear donor to obtain embryonic stem cells by nuclear transfer.
There are several problems with this approach. First, it is not known whether human CDX2-deficient embryos die at the same stage as mice and whether they could be used to derive embryonic stem cells. To answer these questions would require a substantial research effort that would consume time and precious resources that we believe could be put to better use. Moreover, this research would itself require the use of human embryos, and it is therefore unlikely to quell the ethical debate.
Second, in mice, Cdx2 is required not only for trophectoderm formation but also for the subsequent development of a normal embryo.3 It is likely that human embryonic stem cells carrying a mutation in CDX2 will be restricted in their developmental capacity in ways that are impossible to predict but that will probably limit their usefulness in research and clinical applications. Hurlbut suggests that this problem could be circumvented by inactivating CDX2 reversibly, perhaps by RNA interference. This adds another layer of complexity and would require further time-consuming experiments. Even if these extra manipulations proved technically feasible, it is not clear that reversible inactivation of CDX2 is ethically distinct from destroying the embryo by the immunosurgical method that is routinely used to derive human embryonic stem cells.
In addition to these major technical obstacles, we believe that Hurlbut's argument for the ethical superiority of altered nuclear transfer rests on a flawed scientific assumption. He argues, on the basis of supposed insights from systems biology, that it is acceptable to destroy a CDX2 mutant embryo but not a normal embryo, because the former has "no inherent principle of unity, no coherent drive in the direction of the mature human form." But these are ill-defined concepts with no clear biologic meaning, and an alternative interpretation would be that embryos lacking CDX2 develop normally until CDX2 function is required, at which point they die. Philosophers may debate these and other interpretations. We see no basis for concluding that the action of CDX2 (or indeed any other gene) represents a transition point at which a human embryo acquires moral status.
We fully support the search for alternative methods to derive pluripotent human cells, but no such method currently exists. In our opinion, Hurlbut's proposal is a distraction from the central issue, which is whether it is morally justifiable to use preimplantation-stage human embryos in the search to understand human biology and cure serious diseases. We believe it to be justified, and the diversion of resources to alternative approaches that offer no scientific benefit merely diminishes the likelihood of success.
Source Information
Dr. Melton is codirector, Dr. Daley a member of the executive committee, and Dr. Jennings executive director of the Harvard Stem Cell Institute. Dr. Melton is a professor of molecular and cellular biology and an investigator of the Howard Hughes Medical Institute at Harvard University, and Dr. Daley is an associate professor of biologic chemistry and molecular pharmacology at Harvard Medical School and of pediatrics at Children's Hospital, Boston.
References
Hurlbut WB. Altered nuclear transfer as a morally acceptable means for the procurement of human embryonic stem cells. Washington, D.C.: The President's Council on Bioethics, December 2004. (Accessed December 13, 2004, at http://www.bioethics.gov/background/hurlbut.html.)
Zucker HA, Landry DW, Hurlbut W. Session 6: seeking morally unproblematic sources of human embryonic stem cells. Washington, D.C.: The President's Council on Bioethics, December 3, 2004. (Accessed December 13, 2004, at http://www.bioethics.gov/transcripts/dec04/session6.html.)
Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F. Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci U S A 2004;101:7641-7645.(Douglas A. Melton, Ph.D.,)
Hurlbut's proposal is based on the observation that mouse embryos carrying a mutation in the Cdx2 gene die at the blastocyst stage because they fail to form a trophectoderm (from which the placenta normally develops).3 These embryos can still give rise to mouse embryonic stem cells, and Hurlbut argues that a human embryo with a similar mutation would lack the capacity to become a human being and would thus represent an ethically uncontroversial source of human embryonic stem cells. He proposes that embryonic stem cells could be derived by a process he calls altered nuclear transfer, in which a CDX2 mutation would be introduced in vitro into a human cell that would then be used as a nuclear donor to obtain embryonic stem cells by nuclear transfer.
There are several problems with this approach. First, it is not known whether human CDX2-deficient embryos die at the same stage as mice and whether they could be used to derive embryonic stem cells. To answer these questions would require a substantial research effort that would consume time and precious resources that we believe could be put to better use. Moreover, this research would itself require the use of human embryos, and it is therefore unlikely to quell the ethical debate.
Second, in mice, Cdx2 is required not only for trophectoderm formation but also for the subsequent development of a normal embryo.3 It is likely that human embryonic stem cells carrying a mutation in CDX2 will be restricted in their developmental capacity in ways that are impossible to predict but that will probably limit their usefulness in research and clinical applications. Hurlbut suggests that this problem could be circumvented by inactivating CDX2 reversibly, perhaps by RNA interference. This adds another layer of complexity and would require further time-consuming experiments. Even if these extra manipulations proved technically feasible, it is not clear that reversible inactivation of CDX2 is ethically distinct from destroying the embryo by the immunosurgical method that is routinely used to derive human embryonic stem cells.
In addition to these major technical obstacles, we believe that Hurlbut's argument for the ethical superiority of altered nuclear transfer rests on a flawed scientific assumption. He argues, on the basis of supposed insights from systems biology, that it is acceptable to destroy a CDX2 mutant embryo but not a normal embryo, because the former has "no inherent principle of unity, no coherent drive in the direction of the mature human form." But these are ill-defined concepts with no clear biologic meaning, and an alternative interpretation would be that embryos lacking CDX2 develop normally until CDX2 function is required, at which point they die. Philosophers may debate these and other interpretations. We see no basis for concluding that the action of CDX2 (or indeed any other gene) represents a transition point at which a human embryo acquires moral status.
We fully support the search for alternative methods to derive pluripotent human cells, but no such method currently exists. In our opinion, Hurlbut's proposal is a distraction from the central issue, which is whether it is morally justifiable to use preimplantation-stage human embryos in the search to understand human biology and cure serious diseases. We believe it to be justified, and the diversion of resources to alternative approaches that offer no scientific benefit merely diminishes the likelihood of success.
Source Information
Dr. Melton is codirector, Dr. Daley a member of the executive committee, and Dr. Jennings executive director of the Harvard Stem Cell Institute. Dr. Melton is a professor of molecular and cellular biology and an investigator of the Howard Hughes Medical Institute at Harvard University, and Dr. Daley is an associate professor of biologic chemistry and molecular pharmacology at Harvard Medical School and of pediatrics at Children's Hospital, Boston.
References
Hurlbut WB. Altered nuclear transfer as a morally acceptable means for the procurement of human embryonic stem cells. Washington, D.C.: The President's Council on Bioethics, December 2004. (Accessed December 13, 2004, at http://www.bioethics.gov/background/hurlbut.html.)
Zucker HA, Landry DW, Hurlbut W. Session 6: seeking morally unproblematic sources of human embryonic stem cells. Washington, D.C.: The President's Council on Bioethics, December 3, 2004. (Accessed December 13, 2004, at http://www.bioethics.gov/transcripts/dec04/session6.html.)
Chawengsaksophak K, de Graaff W, Rossant J, Deschamps J, Beck F. Cdx2 is essential for axial elongation in mouse development. Proc Natl Acad Sci U S A 2004;101:7641-7645.(Douglas A. Melton, Ph.D.,)