关于Politically Correct Human Embryonic Stem Cells?的原因,关于Politically Correct Human Embryonic Stem Cells?的相关知识。 Human embryonic stem cells are currently viewed as a very promising basis for regenerative medicine of the future. However, to be eligible for federal funding in the United States, researchers must work with federally approved human embryonic stem-cell lines — that is, the few lines derived before August 2001. There is a concerted effort and hope among scientists and legislators that federal funding could be extended to cover as yet nonexistent embryonic stem-cell lines if such lines could be derived without destroying a viable human embryo. The authors of two recent studies1,2 have suggested that such lines can be derived either from one cell of a cleaving embryo, leaving the remaining embryo to develop normally, or from an "embryo" that is rendered genetically incapable of normal development.
Chung et al.1 derived mouse embryonic stem-cell lines from single blastomeres of embryos at the eight-cell stage and transferred the remaining seven-cell embryos into surrogate mothers, in which they developed into normal mice. They argue that the same procedure (single-blastomere biopsy) could be applied to human embryos obtained by in vitro fertilization (IVF), thus allowing the derivation of an embryonic stem-cell line concomitant with the normal development of the embryo from which the cell line originated (see Figure 1).
Figure 1. Derivation of Mouse Embryonic Stem Cells from an Eight-Cell Embryo.
Lanza and colleagues1 recently described the derivation of embryonic stem-cell lines from single cells (blastomeres) removed from eight-cell mouse embryos. The resultant seven-cell embryos, when implanted into pseudopregnant females, developed into apparently normal, live-born mice at a rate of efficiency similar to that achieved with eight-cell embryos.
Though theoretically possible, the procedure poses considerable problems that make its use unlikely in humans. Infertile couples resorting to IVF are unlikely to accept the additional risk imposed by both embryo biopsy (reduced probability of success) and the probable need to freeze the embryo while the embryonic stem cells are being obtained. It has been argued that the additional risk to the embryo will be balanced by the benefit of having genetically compatible embryonic stem cells in case of therapeutic need. This benefit can be realized only if the derivation of embryonic stem cells is successful; thus, all embryos that have undergone biopsy would have to be frozen until the results of embryonic stem-cell derivation are known. Institutional review boards would also be unlikely to approve this addition to standard IVF protocols, given the risk involved. For the procedure to be morally and politically justified, every embryo from which embryonic stem cells are derived must be given the chance to develop. How is this to be guaranteed, and who will act as the embryo recipient if, for example, 10 embryos undergo biopsy and cell lines are derived from all of them?
All this aside, the one insurmountable problem with the approach described by Chung et al. is the unknown capacity of a single blastomere from a human embryo at the eight-cell stage to develop into a normal human. Lanza, one of the study's authors, stated in the New York Times that viable embryos had never resulted from individual human blastomeres.3 This has never been tested in humans, nor will it ever be, since it would require the transfer in the uterus of a single blastomere from an eight-cell embryo to determine its developmental potential. Lanza presumably bases this assertion on the results obtained with mouse embryos, in which a blastomere from an eight-cell (as well as a four-cell) embryo was unable to form a viable embryo. However, a single blastomere isolated from a rabbit4 or sheep5 embryo at the eight-cell stage is perfectly capable of developing into a normal rabbit or sheep. The same may be true for human embryos, and thus, destroying a single blastomere with the potential to develop into a human being is tantamount to destroying the entire embryo. The derivation of human embryonic stem cells from embryo biopsy will remain the moral equivalent of murder in the eyes of anyone who views any entity with the potential to develop into a human as a being with unalienable human status and rights.
Meissner and Jaenisch2 describe the derivation of mouse embryonic stem cells by the so-called altered nuclear-transfer method suggested by William Hurlbut, a member of the President's Council on Bioethics. This method entails the creation of an embryo in which the gene essential for normal development is temporarily inactivated. Such an embryo would be deemed an entity "that lacks the attributes and capacity of a human embryo" and would be an acceptable source of embryonic stem cells, since no structure with the potential for becoming a human being would be destroyed.
Meissner and Jaenisch performed a series of elegant genetic manipulations to transiently inactivate the Cdx2 gene (essential for trophectoderm function) in the nuclear-transfer embryo by means of RNA interference (see Figure 2). They derived embryonic stem cells from these embryos and then removed the transgene producing the interfering RNA from these cells, thus reverting them to normal. There is no reason why this technique should not work in humans, so what is the problem? For the technique to be morally and politically acceptable, we must be certain that it will always produce an entity incapable of normal development, and this cannot be guaranteed for the following reasons.
Figure 2. Derivation of Mouse Embryonic Stem Cells from Blastocysts That Repress the Expression of Cdx2.
A recent report by Meissner and Jaenisch2 describes the derivation of embryonic stem cells from blastocysts that are engineered to render the blastocysts unlikely to implant into the uterus and, hence, unable to develop into a fetus. This is achieved by inserting a specific DNA cassette into a chromosome of the donor cell — that is, the cell from which the donor nucleus is derived. This DNA cassette contains a sequence that once transcribed into RNA, silences the Cdx2 gene, which is normally activated during implantation and is essential to implantation. (This RNA has a hairpin-like structure and is called "silencing" RNA.) It also contains a gene encoding green fluorescent protein. On its successful integration into a donor-cell chromosome, the Cdx2-silencing RNA is synthesized, as is the green fluorescent protein — the latter facilitates the selection of cells that have stably incorporated the DNA cassette. The donor-cell nucleus is then removed from the donor cell and injected into an enucleated ovum, which in turn develops into a blastocyst, the cells of which synthesize Cdx2-silencing RNA and green fluorescent protein. Meissner and Jaenisch showed that 40 such blastocysts failed to become implanted in pseudopregnant females — presumably owing to the repression of Cdx2 — in contrast with the successful implantation of 6 of 15 control blastocysts. Embryonic stem cells were derived from the inner cell mass of the Cdx2-repressing blastocysts and then liberated of both Cdx2-silencing RNA and green fluorescent protein through exposure to an enzyme that effectively clips the cassette from the chromosomal DNA.
First, we can only assume that Cdx2 (or any other gene that is essential for mouse development) has the same indispensable function in human development. Although likely, this assumption would have to be verified by experiments using human embryos, which would never be allowed, for ethical reasons.
Second, even assuming that we can somehow identify a gene essential for early development in humans, the method described would never allow us to be absolutely sure that each and every entity produced is incapable of normal development. Complete functional inactivation of the endogenous gene depends on the level of transcription in the embryo of the transgene encoding the interfering RNA. Since the degree of transcription of the transgene depends critically on the integration site, it would be necessary to test every single nuclear donor-cell line after nuclear transfer into the oocyte. The embryos would have to be tested for the absence of targeted RNA and for their developmental capacity. Obviously, such tests would necessitate the destruction of a certain number of nuclear-transfer embryos, some of which may have been capable of development if the expression of the transgene had not been sufficient to eliminate functional endogenous RNA. Even if only 1 in 1000 or 1 in 1 million alternative-nuclear-transfer embryos possesses the capacity for normal development, the raison d'être of the approach collapses.
Thus, neither of the two described methods can produce human embryonic stem-cell lines that would be ideologically acceptable to the forces that assume the prerogative to decide such issues in the United States. Playing politics for the sake of science is probably necessary and sometimes noble; manipulating science for the sake of politics is usually a waste of time.
Source Information
Dr. Solter is the director of the Department of Developmental Biology, Max-Planck Institute of Immunobiology, Freiburg, Germany.
References
Chung Y, Klimanskaya I, Becker S, et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature (in press).
Meissner A, Jaenisch R. Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature (in press).
Wade N. Stem cell test tried on mice saves embryos. New York Times. October 17, 2005.
Moore NW, Adams CE, Rowson LEA. Developmental potential of single blastomeres of the rabbit egg. J Reprod Fertil 1968;17:527-531.
Willadsen SM. The developmental capacity of blastomeres from 4- and 8-cell sheep embryos. J Embryol Exp Morphol 1981;65:165-172. (文章出处：《新英格兰医药杂志》)
Chung et al.1 derived mouse embryonic stem-cell lines from single blastomeres of embryos at the eight-cell stage and transferred the remaining seven-cell embryos into surrogate mothers, in which they developed into normal mice. They argue that the same procedure (single-blastomere biopsy) could be applied to human embryos obtained by in vitro fertilization (IVF), thus allowing the derivation of an embryonic stem-cell line concomitant with the normal development of the embryo from which the cell line originated (see Figure 1).
Figure 1. Derivation of Mouse Embryonic Stem Cells from an Eight-Cell Embryo.
Lanza and colleagues1 recently described the derivation of embryonic stem-cell lines from single cells (blastomeres) removed from eight-cell mouse embryos. The resultant seven-cell embryos, when implanted into pseudopregnant females, developed into apparently normal, live-born mice at a rate of efficiency similar to that achieved with eight-cell embryos.
Though theoretically possible, the procedure poses considerable problems that make its use unlikely in humans. Infertile couples resorting to IVF are unlikely to accept the additional risk imposed by both embryo biopsy (reduced probability of success) and the probable need to freeze the embryo while the embryonic stem cells are being obtained. It has been argued that the additional risk to the embryo will be balanced by the benefit of having genetically compatible embryonic stem cells in case of therapeutic need. This benefit can be realized only if the derivation of embryonic stem cells is successful; thus, all embryos that have undergone biopsy would have to be frozen until the results of embryonic stem-cell derivation are known. Institutional review boards would also be unlikely to approve this addition to standard IVF protocols, given the risk involved. For the procedure to be morally and politically justified, every embryo from which embryonic stem cells are derived must be given the chance to develop. How is this to be guaranteed, and who will act as the embryo recipient if, for example, 10 embryos undergo biopsy and cell lines are derived from all of them?
All this aside, the one insurmountable problem with the approach described by Chung et al. is the unknown capacity of a single blastomere from a human embryo at the eight-cell stage to develop into a normal human. Lanza, one of the study's authors, stated in the New York Times that viable embryos had never resulted from individual human blastomeres.3 This has never been tested in humans, nor will it ever be, since it would require the transfer in the uterus of a single blastomere from an eight-cell embryo to determine its developmental potential. Lanza presumably bases this assertion on the results obtained with mouse embryos, in which a blastomere from an eight-cell (as well as a four-cell) embryo was unable to form a viable embryo. However, a single blastomere isolated from a rabbit4 or sheep5 embryo at the eight-cell stage is perfectly capable of developing into a normal rabbit or sheep. The same may be true for human embryos, and thus, destroying a single blastomere with the potential to develop into a human being is tantamount to destroying the entire embryo. The derivation of human embryonic stem cells from embryo biopsy will remain the moral equivalent of murder in the eyes of anyone who views any entity with the potential to develop into a human as a being with unalienable human status and rights.
Meissner and Jaenisch2 describe the derivation of mouse embryonic stem cells by the so-called altered nuclear-transfer method suggested by William Hurlbut, a member of the President's Council on Bioethics. This method entails the creation of an embryo in which the gene essential for normal development is temporarily inactivated. Such an embryo would be deemed an entity "that lacks the attributes and capacity of a human embryo" and would be an acceptable source of embryonic stem cells, since no structure with the potential for becoming a human being would be destroyed.
Meissner and Jaenisch performed a series of elegant genetic manipulations to transiently inactivate the Cdx2 gene (essential for trophectoderm function) in the nuclear-transfer embryo by means of RNA interference (see Figure 2). They derived embryonic stem cells from these embryos and then removed the transgene producing the interfering RNA from these cells, thus reverting them to normal. There is no reason why this technique should not work in humans, so what is the problem? For the technique to be morally and politically acceptable, we must be certain that it will always produce an entity incapable of normal development, and this cannot be guaranteed for the following reasons.
Figure 2. Derivation of Mouse Embryonic Stem Cells from Blastocysts That Repress the Expression of Cdx2.
A recent report by Meissner and Jaenisch2 describes the derivation of embryonic stem cells from blastocysts that are engineered to render the blastocysts unlikely to implant into the uterus and, hence, unable to develop into a fetus. This is achieved by inserting a specific DNA cassette into a chromosome of the donor cell — that is, the cell from which the donor nucleus is derived. This DNA cassette contains a sequence that once transcribed into RNA, silences the Cdx2 gene, which is normally activated during implantation and is essential to implantation. (This RNA has a hairpin-like structure and is called "silencing" RNA.) It also contains a gene encoding green fluorescent protein. On its successful integration into a donor-cell chromosome, the Cdx2-silencing RNA is synthesized, as is the green fluorescent protein — the latter facilitates the selection of cells that have stably incorporated the DNA cassette. The donor-cell nucleus is then removed from the donor cell and injected into an enucleated ovum, which in turn develops into a blastocyst, the cells of which synthesize Cdx2-silencing RNA and green fluorescent protein. Meissner and Jaenisch showed that 40 such blastocysts failed to become implanted in pseudopregnant females — presumably owing to the repression of Cdx2 — in contrast with the successful implantation of 6 of 15 control blastocysts. Embryonic stem cells were derived from the inner cell mass of the Cdx2-repressing blastocysts and then liberated of both Cdx2-silencing RNA and green fluorescent protein through exposure to an enzyme that effectively clips the cassette from the chromosomal DNA.
First, we can only assume that Cdx2 (or any other gene that is essential for mouse development) has the same indispensable function in human development. Although likely, this assumption would have to be verified by experiments using human embryos, which would never be allowed, for ethical reasons.
Second, even assuming that we can somehow identify a gene essential for early development in humans, the method described would never allow us to be absolutely sure that each and every entity produced is incapable of normal development. Complete functional inactivation of the endogenous gene depends on the level of transcription in the embryo of the transgene encoding the interfering RNA. Since the degree of transcription of the transgene depends critically on the integration site, it would be necessary to test every single nuclear donor-cell line after nuclear transfer into the oocyte. The embryos would have to be tested for the absence of targeted RNA and for their developmental capacity. Obviously, such tests would necessitate the destruction of a certain number of nuclear-transfer embryos, some of which may have been capable of development if the expression of the transgene had not been sufficient to eliminate functional endogenous RNA. Even if only 1 in 1000 or 1 in 1 million alternative-nuclear-transfer embryos possesses the capacity for normal development, the raison d'être of the approach collapses.
Thus, neither of the two described methods can produce human embryonic stem-cell lines that would be ideologically acceptable to the forces that assume the prerogative to decide such issues in the United States. Playing politics for the sake of science is probably necessary and sometimes noble; manipulating science for the sake of politics is usually a waste of time.
Source Information
Dr. Solter is the director of the Department of Developmental Biology, Max-Planck Institute of Immunobiology, Freiburg, Germany.
References
Chung Y, Klimanskaya I, Becker S, et al. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature (in press).
Meissner A, Jaenisch R. Generation of nuclear transfer-derived pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature (in press).
Wade N. Stem cell test tried on mice saves embryos. New York Times. October 17, 2005.
Moore NW, Adams CE, Rowson LEA. Developmental potential of single blastomeres of the rabbit egg. J Reprod Fertil 1968;17:527-531.
Willadsen SM. The developmental capacity of blastomeres from 4- and 8-cell sheep embryos. J Embryol Exp Morphol 1981;65:165-172. (文章出处：《新英格兰医药杂志》)