The finding that zygotes, and not just unfertilized eggs, can be used to create clones from adult cells will help unravel how development gets started.

Few women are willing to give their unfertilized eggs to scientists. But many researchers believe these are the only suitable source material for making genetically tailored human embryonic stem cells (ES cells) — cells that could help us understand the biology of disease or, perhaps some day, be used in cell-transplant therapy. The shortage of eggs has spawned bitter debate over whether women should be allowed to donate, barter, or even sell their eggs to research laboratories.

But if recent work in mice translates to humans, unfertilized eggs might no longer be needed. In the 7 June issue of Nature, Kevin Eggan and his colleagues at Harvard University report that fertilized mouse eggs, or zygotes, can be used both to clone mice and to create cloned mouse ES cells1. The trick seems to be hitting the right point in the cell cycle and swapping chromosomes, rather than, as is done conventionally, entire nuclei. The researchers arrest a zygote in the middle of its first division, replace its chromosomes with those from an adult cell of another mouse, and then let the zygote go on to form a blastocyst, which can either be implanted into a surrogate mother to produce a live cloned mouse or cultured in the laboratory to generate cloned ES cells.

Though this work can help unravel how early animal development begins, other implications are more practical. “That could be a huge resource,” says Linda Giudice, chair of obstretics, gynecology, and reproductive science at the University of California San Francisco Medical School. The failure to clone human ES cells is largely blamed on too few attempts, and the limited number of attempts is blamed on the scarcity of high-quality unfertilized human eggs for research.

One source of human zygotes could be those that are discarded from assisted reproduction programmes because they did not get fertilized correctly. If an egg is fertilized by two sperm, which happens fairly regularly, it then has the wrong number of chromosomes and cannot develop normally. Intriguingly, Eggan's team was able to create cloned mouse ES cells from mouse zygotes that carried an extra set of chromosomes, removing all of the zygote's chromosomes before introducing the correct number from another cell.

Giudice cautions that it's hard to know how many human zygotes, normal or abnormal, would be available for research. Frozen embryos that are eventually donated for research have usually been grown to the blastocyst stage — too late for use as recipients for chromosomal transfer. Zygotes that fail to develop normally are routinely discarded in fertility clinics across the world, but obtaining the most suitable zygotes for research is not trivial. It's not always obvious whether a zygote has an abnormal number of chromosomes, and chromosomal abnormalities occur most often in older women, whose eggs seem to be less able to make stem cells.

Over the past decade or so, researchers have attempted to make cloned human ES cells using donated misfertilized eggs, but without success. Renee Reijo Pera, head of Stanford's Center for Human Embryonic Stem Cell Research, says a single clinic could have hundreds of such zygotes, though not all of them would be suitable or have donor consent forms. She's excited about trying Eggan's “new trick”, but she's not counting on an immediate breakthrough. ES cells can now be cloned routinely from mice, but the process has many steps, each of which needs to be adjusted for a different species. “We have so much animal work, but we haven't optimized any of this for the human system,” she says.

Still, some aspects of human embryonic development might work in favour of Eggan's technique. Rodent development happens in a hurry. In most mammals, the embryonic genome becomes active only at the four- to eight-cell stage, but embryonic mouse genes are expressed even at the two-cell stage. And mouse eggs divide more rapidly than human eggs do. That could mean that the donor chromosomes transferred into human zygotes would have more time for the zygote cytoplasm to reprogramme them to behave like the chromosomes in an embryo.

That sounds overly optimistic to Robert Lanza of Advanced Cell Technology in Worcester, MA. “Mouse and cow eggs seem more effective than human eggs at reprogramming cells,” he says. His team has made live animals and early human embryos through cloning and found that techniques don't translate well between species. “You do manipulations where you get lots of blastocysts with mice, but with humans you rarely even see the cells divide,” he says. Ultimately, he thinks there's no way to predict what will be the best way to clone human ES cells. “What concerns me in the field of stem cells is people are saying, 'oh, we've already done this in the mouse so we don't need to pursue other strategies'; I think that's folly.”

And even if human triploid zygotes could be used to make ES cells, ethical objections would remain. Triploid zygotes form severely deformed fetuses (called partial hydatiform moles) that usually abort spontaneously in the first trimester and never survive long after birth. Robert George, a law professor at Princeton University and a member of the President's Council of Bioethics, says that a fertilized egg does not necessarily count as an embryo, but that a partial hydatiform mole has “a sufficient degree of organization” so that a zygote capable of forming one must count as a human embryo, and thus as a human being. Even if zygotes with even more severe abnormalities could be used, Eggan's procedure requires making a second, cloned embryo, which to George and many other ethicists has the same moral status as one produced by any other means.

But Eggan's work could still have important ethical implications, says Tom Murray, head of the Hastings Center, a bioethics think tank in Garrison, New York. Critics of unfertilized egg collection worry that women could be harmed, coerced, or commoditized. “If you can reduce the number of women involved, it's going to decrease the number of concerns.”

And the potential to use abnormal fertilized eggs instead of unfertilized ones poses a huge practical advantage in terms of the material available, says Barry Behr, who collaborates with Reijo Pera at Stanford University. For over a year, Behr has been designing a protocol to collect unfertilized eggs for research, he says, and not only does he need to be confident that the procedure won't harm donors, he needs to file applications and attend meetings to show Stanford's review committees that his protocol meets ethical guidelines. “It's a lot of work,” he says, “and I'm not confident that I'll get anyone.”