Ethics of genetically reconstituting oocytes

In the 16 December issue of Nature, researchers reported that the addition of eight transcription factors to pluripotent stem cells converted them into a primary oocyte-like cell. While these cells did not undergo normal meiosis, and therefore did not have the correct number of gamete chromosomes, they could be fertilised by sperm to initiate partial embryonic development, with some even progressing to an eight-cell morula stage.

This achievement enhances our understanding of oocyte maturation and may have useful clinical applications in reproductive technologies. In mitochondrial donation, for instance, an oocyte is obtained from a woman with genetically defective mitochondria. The nucleus from this oocyte is removed and put into an enucleated donor oocyte obtained from a woman with healthy mitochondria. This transcription-stem cell-based approach could one day be used to generate enucleated oocytes (cytoplasts) free of mitochondrial defects that could serve as the recipient cells for the oocyte nucleus of a woman undergoing mitochondrial donation, thereby avoiding the need to hormonally stimulate donors to obtain their oocytes.

Beyond mitochondrial donation, this approach may have applications in other fertility treatments, such as situations when a woman has no viable oocytes to be extracted for IVF or in cases of prepubescent girls who require chemotherapy and/or radiation treatments - procedures that destroy their developing oocytes and render them infertile. In the latter scenario, physicians can remove ovaries or ovarian tissue slices from these cancer patients prior to initiating cancer treatment and freeze the tissues until they can be thawed and transplanted back into the bursa of these women. But this cryopreservation approach is still insufficient to enable many patients to have children and the tissue may still contain malignant cells.

In these cases, oocyte-like cells generated from induced pluripotent stem cells (iPSCs) could present a solution to generate viable oocytes from non-ovary tissues such as skin, avoiding unnecessary transplantation surgery and hopefully improving pregnancy outcomes. The oocyte-like cell could be employed in IVF. This technology coupled with recent studies on the in vitro system for the production of germ cells, might also enhance the ability to create artificial ovaries.

Currently, artificial ovaries are generated by removing the cells of existing ovaries and subsequently incubating the scaffolds with induced pluripotent stem cells, to differentiate into a functional ovary that is hormonally competent to generate mature eggs. Preliminary studies indicate that artificial ovaries can lead to successful pregnancies. But perhaps researchers could use essential oocyte transcription factors to more precisely direct stem cell differentiation into ovarian follicles and thereby achieve better artificial ovaries.

More research is needed to engineer these oocyte-like cells into fully competent oocytes for normal fertilisation, and to apply this technology to human cells. Moreover, the risk of tumorigenicity is a major problem when using this technology to reconstitute differentiated cells and needs to be carefully studied. But assuming that science will meet these challenges, it's important to look forward to the potential ethical implications of using the stem cell-based approach for aiding human reproduction.

From an ethical perspective, new reproductive technologies have an interesting multi-faith history. From a Catholic perspective, for example, scholars view IVF as unethical because it involves both the destruction of nonimplanted embryos and conception without marital relations. Moreover, using donor oocytes in IVF, raises the ethical issue whether maternity is predicated upon the genetics of the offspring or the woman who carries and delivers the child. Catholics would likely view the new transcription factor–based reproductive approach as unethical as well, because conception occurs in the lab and outside the context of sex between husband and wife.

The Jewish, Islamic and secular perspectives would favourably view the use of iPSCs to generate oocytes for IVF because it eliminates the use of genetically different donor oocytes avoiding issues of maternity identification. There are other more controversial ethical issues that need to be addressed. For example, theoretically, it's possible to make oocytes from a male iPS cell. Thus, an embryo could be generated from two male donors challenging the holy grail that the generation of offspring requires a male and female partner. Another ethical dilemma is the use of induced oocytes from stocked embryonic stem cells/iPSCs without any consents of the donor. In the latter case, this would be viewed as unethical by both religious and secular ethicists.

In conclusion, transcription factor modification of stem cells to generate oocyte-like cells is clearly a breakthrough technology for potentially enhancing reproductive capacity in infertile women, and as such, the ethical discussions that surrounds its use is worth starting now.