At current rates of success of generation of NT blastocysts and ES cells, one major limitation of expansion of this approach will be the availability of oocytes for NT. Current and possible future sources of such oocytes include excess oocytes and unfertilized oocytes from IVF procedures, oocytes matured from ovariectomies or fetal ovaries from pregnancy terminations, oocyte donation, derivation of oocytes from nonreproductive material, and use of nonhuman oocytes.
• Excess oocytes and unfertilized eggs from IVF procedures. During IVF, hormonal induction is used to generate oocytes for fertilization in vitro. Often, more oocytes are generated than are needed for reproductive purposes, and some oocytes may be available for research donation. In addition, after IVF, not all oocytes are successfully fertilized, and unfertilized oocytes would otherwise be discarded if not donated for research. Experiments to explore use of such oocytes for NT derivation of hES cells have been approved and initiated in the United Kingdom. However, this source of oocytes is limited, and the unfertilized oocytes may be of lower quality for cell line production. It is ethically problematic to consider alteration of the IVF clinical procedure to deliberately induce more oocytes than needed for reproduction, even with the consent of the participants. Thus, this source of oocytes is likely to be limited and unreliable for any major NT ES cell program.
• Oocytes matured from ovariectomies or fetal ovaries from pregnancy terminations. Adult as well as fetal ovaries contain a large supply of immature oocytes, which in principle could be harvested from adult ovaries donated after removal for clinical reasons or from fetal ovaries that are obtained from legal pregnancy terminations. In the case of other mammals, it is possible to mature such oocytes in culture and achieve fertilization and normal development, although the process is not efficient (O'Brien et al., 2003). In humans, success has been limited and requires an intermediate xenograft (transplantation into an animal) of the ovarian tissue for oocyte maturation. Research on how to expand the supply and how to mature human oocytes in vitro could make this a reasonable source of donated material.
• Oocyte donation. The most reliable source of oocytes for NT ES cells today seems to be direct donation of oocytes by female donors after hormonal induction and oocyte recovery. Such third-party donation has much in common with organ donation and already occurs in some IVF programs for
reproductive purposes. However, this option raises significant issues about the risks to the donors, about a possible profit motive if excessive payment is made for donated oocytes, and about the nature of informed consent in such circumstances. Altruistic donation of oocytes by family members for generation of disease-related NT ES cells might be a good alternative source of material.
• Derivation of oocytes from nonreproductive material. The problems of the limited pool of oocytes for NT would be alleviated if a renewable source of oocytes can be found. The recent report that cells resembling oocytes could be formed from mouse ES cells in culture (Hubner et al., 2003) is intriguing in this regard. If confirmed and extended to human ES cells, this approach could eventually provide an extensive source of oocytes or something resembling oocytes for NT.
• Use of nonhuman oocytes. Obtaining large numbers of oocytes from nonhuman mammals is relatively easy, and the use of such oocytes to derive NT blastocysts and stem cells has been considered. If this were successful, the nuclear genome would be entirely human, but there could be some persistence of nonhuman mitochondria in the cells. The relevance of such interspecies mixing for the growth, potential, and safety of such cells would need to be evaluated. There has been one report of putative ES cell lines produced after transfer of human nuclei to rabbit oocytes (Chen et al., 2003), but the finding needs to be confirmed and extended before this approach can be considered feasible.
Given the strong scientific rationale for generating human NT ES cells, there is an urgent need to develop new ethically acceptable sources of cytoplasmic material for reprogramming adult nuclei. Further research into the molecular mechanisms by which the oocyte cytoplasm reprograms the adult nucleus for pluripotency should lead to methods to bypass altogether the need for oocytes to achieve NT reprogramming. In the long run, it may be possible to reprogram adult cells or nuclei di-rectly—not by transfer into oocytes but by other means, such as fusion with pluri-potent ES cells or exposure to factors from such pluripotent cells.
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