Free-Range Eggs?

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Science  20 Apr 2007:
Vol. 316, Issue 5823, pp. 339
DOI: 10.1126/science.1142267

Human eggs are in short supply, but much in demand. Many infertile women need donated eggs if they are to bear children. Researchers need eggs for somatic-cell nuclear transfer (SCNT) to try to develop stem cell lines. If SCNT-derived stem cells could be made from patients suffering from devastating conditions such as motor neuron disease, they could provide unlimited material for molecular and biochemical analyses and clues for future therapy. But where can all these eggs come from to make these stem cells? And what about the reverse situation: making human eggs from stem cells?

The United Kingdom allows women undergoing in vitro fertilization to donate eggs for either clinical or research use, in exchange for further treatment. “Altruistic” donation is also permitted, in spite of possible health risks, with monetary compensation. The United States allows women to sell eggs for clinical use as well. Still, there is much debate about the ethics. For research use, cow or rabbit eggs have been used as carriers of human nuclei, because any stem cell lines derived from these would be essentially human. But in most countries, these cytoplasmic hybrids (“cybrids”) are controversial. Earlier this month, a UK parliamentary committee said that restrictions on cybrids proposed by the Human Fertilization and Embryology Authority (HFEA) would delay important research on diseases. The HFEA plans to consult the public about such research this month and decide on its policy in September.


As far as making eggs from embryonic stem (ES) cells, we've known for more than 20 years that mouse stem cells mixed with embryo cells (chimeras) produce mice with functional gametes. Why then was it such a surprise when in 2003 and 2004, three groups reported deriving eggs and sperm from mouse ES cells in vitro rather than from chimeric embryos? After all, many other tissues could be derived from ES cells. Once the successful isolation of human ES cells had been reported in 1998, attention focused on their potential therapeutic value, and mouse modelers began seeking ways of inducing ES cells in vitro to make neural tissue, heart muscle, cartilage, and so forth.

But it is still not clear whether the reported stem cell-derived gametes are functional. Until this is firmly demonstrated, they should at best be referred to as “egglike” and “spermlike,” but never as “artificial” or “synthetic” gametes. What would be needed for “egglike” to become “egg” or at least “ES cell-derived egg”? The cell must undergo normal cell division to produce haploid eggs. It must form a normal blastocyst, either parthenogenetically or after fertilization. It should reprogram a somatic cell nucleus to the same extent as an ovarian egg. And genes that are normally imprinted during oogenesis should show an appropriate pattern of chemical modification. Probably, ES cell-derived eggs could be generated from both female and male ES cell lines, but could ES cell-derived sperm be made from female ES cell lines? Ultimately, animal studies will need to show that ES cell-derived eggs can give rise to normal fertile progeny.

All this implies much further research, requiring human and mouse ES cells. Already, primordial germ cells have been detected in a human ES cell line. There will be ethical implications, including the wording of the consent document given to embryo donors. But even without full validation, human ES cell-derived eggs could have many research uses, such as making SCNT-derived stem cells, thus reducing the ethically problematic demand for donated human eggs for research.

Looking into the future, if ES cell-derived gametes are conclusively shown to be safe and effective in animal reproduction, the first pressure for the clinical use of human ES cell-derived gametes will be from those wanting donated eggs for in vitro fertilization. If human ES cell lines from SCNT-derived embryos could by then be made, irretrievably infertile people might be able to have children that are genetically their own without recourse to reproductive cloning, and safety will be the major ethical consideration. In the meantime, the long waiting list of women needing donated eggs to have babies demands that scientists wanting such eggs for stem cell research act with great restraint.

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