Stem cells: Egg engineers

ILLUSTRATION BY VIKTOR KOEN

Since last October, molecular biologist Katsuhiko Hayashi has received around a dozen e-mails from couples, most of them middle-aged, who are desperate for one thing: a baby. One menopausal woman from England offered to come to his laboratory at Kyoto University in Japan in the hope that he could help her to conceive a child. That is my only wish, she wrote.

The requests started trickling in after Hayashi published the results of an experiment that he had assumed would be of interest mostly to developmental biologists1. Starting with the skin cells of mice in vitro, he created primordial germ cells (PGCs), which can develop into both sperm and eggs. To prove that these laboratory-grown versions were truly similar to naturally occurring PGCs, he used them to create eggs, then used those eggs to create live mice. He calls the live births a mere 'side effect' of the research, but that bench experiment became much more, because it raised the prospect of creating fertilizable eggs from the skin cells of infertile women. And it also suggested that men's skin cells could be used to create eggs, and that sperm could be generated from women's cells. (Indeed, after the research was published, the editor of a gay and lesbian magazine e-mailed Hayashi for more information.)

Ewen Callaway reports on the ethical challenges of using lab-made sperm and egg cells in fertility treatments.

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Despite the innovative nature of the research, the public attention surprised Hayashi and his senior professor, Mitinori Saitou. They have spent more than a decade piecing together the subtle details of mammalian gamete production and then recreating that process in vitro all for the sake of science, not medicine. Their method now allows researchers to create unlimited PGCs, which were previously difficult to obtain, and this regular supply of treasured cells has helped to drive the study of mammalian reproduction. But as they push forward with the scientifically challenging transition from mice to monkeys and humans, they are setting the course for the future of infertility treatments and perhaps even bolder experiments in reproduction. Scientists and the public are just starting to grapple with the associated ethical issues.

It goes without saying that [they] really transformed the field in the mouse, says Amander Clark, a fertility expert at the University of California, Los Angeles. Now, to avoid derailing the technology before it's had a chance to demonstrate its usefulness, we have to have conversations about the ethics of making gametes this way.

In the mouse, germ cells emerge just after the first week of embryonic development, as a group of around 40 PGCs2. This little cluster goes on to form the tens of thousands of eggs that female mice have at birth, and the millions of sperm cells that males produce every day, and it will pass on the mouse's entire genetic heritage. Saitou wanted to understand what signals direct these cells throughout their development.

Over the past decade, he has laboriously identified several genes including Stella, Blimp1 and Prdm14 that, when expressed in certain combinations and at certain times, play a crucial part in PGC development3, 4, 5. Using these genes as markers, he was able to select PGCs from among other cells and study what happens to them. In 2009, from experiments at the RIKEN Center for Developmental Biology in Kobe, Japan, he found that when culture conditions are right, adding a single ingredient bone morphogenetic protein 4 (Bmp4) with precise timing is enough to convert embryonic cells to PGCs2. To test this principle, he added high concentrations of Bmp4 to embryonic cells. Almost all of them turned into PGCs2. He and other scientists had expected the process to be more complicated.

Saitou's approach meticulously following the natural process was in stark contrast to work that others were doing, says Jacob Hanna, a stem-cell expert at the Weizmann Institute of Science in Rehovot, Israel. Many scientists try to create specific cell types in vitro by bombarding stem cells with signalling molecules and then picking through the resulting mixture of mature cells for the ones they want. But it is never clear by what process these cells are formed or how similar they are to the natural versions. Saitou's efforts to find out precisely what is needed to make germ cells, to get rid of superfluous signals and to note the exact timing of various molecules at work, impressed his colleagues. There's a really beautiful hidden message in this work that differentiation of cells [in vitro] is really not easy, says Hanna. Harry Moore, a stem-cell biologist at the University of Sheffield, UK, regards the careful recapitulation of germ-cell development as a triumph.

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Stem cells: Egg engineers