‘Embryo models’ challenge the legal, ethical and biological concepts of an ’embryo’ -TGN

Meanwhile, Hanna’s team in Israel cultured mouse embryo models in a similar way, as described in a paper in it Cell which was published shortly before the Zernicka-Goetz group’s paper. Hanna’s models, too, were made exclusively from embryonic stem cells, some of which were genetically coaxed to become TSCs and XEN cells. “The whole synthetic organ-filled embryo, including extraembryonic membranes, can all be generated just starting with naïve pluripotent stem cells,” Hanna said.

Hanna’s embryo models, such as those created by Zernicka-Goetz, have gone through all the expected early stages of development. After 8.5 days, they had a rough body shape, with head, limbs, a heart and other organs. Their bodies were attached to a pseudo-placenta made of TSCs by a column of cells like an umbilical cord.

“These embryo models recapitulate natural embryogenesis very well,” Zernicka-Goetz said. The main differences may be consequences of improper formation of the placenta, as it cannot contact the uterus. Imperfect signals from the defective placenta can impair the healthy growth of some embryonic tissue structures.

Without a better placental replacement, “it remains to be seen how much these structures will develop further,” she said. So she thinks the next big challenge will be to get embryo models through a stage of development that normally requires a placenta as an interface for the maternal and fetal circulating blood systems. No one has yet found a way to do that in vitro, but she says her group is working on it.

Hanna admitted he was surprised by how well the embryo models grew beyond gastrulation. But he added that after 12 years of working on this, “you’re excited and surprised at each milestone, but within a day or two you get used to it and take it for granted, and focus on the next goal.”

June Wu, a stem cell biologist at the University of Texas Southwestern Medical Center at Dallas, was also surprised that embryo models made from embryonic stem cells alone can get this far. “The fact that they can form embryo-like structures with marked early organogenesis suggests that we can obtain apparently functional tissues ex utero purely from stem cells,” he said.

In a further wrinkle, it turns out that embryo models don’t need to be grown from literal embryonic stem cells—that is, stem cells harvested from actual embryos. They can also be grown from mature cells taken from you or me and revert to a stem cell-like state. The possibility of such “rejuvenation” of mature cell types was the revolutionary discovery by the Japanese biologist Shinya Yamanaka, with whom he is part of the Nobel Prize 2012 in physiology or medicine. Such reprogrammed cells are called induced pluripotent stem cells and are made by injecting mature cells (such as skin cells) with some of the key genes that are active in embryonic stem cells.

So far, induced pluripotent stem cells seem to be able to do almost everything real embryonic stem cells can do, including growing into embryo-like structures in vitro. And that success seems to break the last essential link between embryo models and real embryos: you don’t need an embryo to make them, making them largely outside of existing regulations.

Growing organs in the laboratory

Even if embryo models bear unprecedented resemblance to real embryos, they still have many shortcomings. Nicholas Rivrona stem cell biologist and embryologist at the Institute of Molecular Biotechnology in Vienna, acknowledges that “embryo models are rudimentary, imperfect, inefficient and incapable of giving rise to a living organism.”

The failure rate for growing embryo models is very high: less than 1 percent of the initial cell clusters get very far. Subtle abnormalities, usually involving disproportionate organ sizes, often dull them, Hanna said. Wu believes more work is needed to understand both the similarities to normal embryos and the differences that may explain why mouse embryo models failed to grow beyond 8.5 days.