Meanwhile, Hana’s team in Israel was growing mouse embryo models in a similar way, as described in a paper in Cell that was published shortly before the paper by Zernicka-Goetz’s group. Hanna’s models were also made only from embryonic stem cells, some of which had been genetically induced to become TSCs and XEN cells. “The entire synthetic embryo filled with organs, including extra-embryonic membranes, can be generated starting with naïve pluripotent stem cells alone,” Hanna said.
Hannah’s embryo models, like those made by Zernicka-Goetz, went through all the early stages of expected development. After 8.5 days, they had a crude body shape, with a head, limb buds, a heart and other organs. Their bodies were attached to a pseudo-placenta made by TSC from a column of cells like an umbilical cord.
“These embryonic models recapitulate natural embryogenesis very well,” said Zernicka-Goetz. The main differences may be the consequences of the incorrect formation of the placenta, since it cannot contact a uterus. Imperfect signals from the defective placenta can impair the healthy growth of certain embryonic tissue structures.
Without a better substitute for a placenta, “it remains to be seen how much further these structures will evolve,” she said. That’s why she thinks the next big challenge will be getting embryo models to a stage of development that normally requires a placenta as an interface for the maternal and fetal circulatory blood systems. No one has yet found a way to do this in vitro, but she says her group is working on it.
Hanna admitted he was surprised by how well the embryo models continued to grow beyond gastrulation. But he added that after working on it for 12 years, “you’re excited and surprised at every milestone, but in a day or two you get used to it and take it for granted, and focus on the next goal.”
Jun Wu, a stem cell biologist at the University of Texas Southwestern Medical Center in Dallas, was also surprised that models of embryos made only from embryonic stem cells could get so far. “The fact that they can form embryo-like structures with clear early organogenesis suggests that we can obtain apparently functional tissues ex utero, based purely on stem cells,” he said.
In a further wrinkle, it turns out that the embryo models don’t have to be grown from actual 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 “renewal” of mature cell types was the revolutionary discovery of Japanese biologist Shinya Yamanaka, which won him a share of the Nobel Prize in Physiology or Medicine in 2012. Such reprogrammed cells are called induced pluripotent stem cells, and they are created by injecting mature cells (such as skin cells) with some of the key genes active in embryonic stem cells.
So far, induced pluripotent stem cells seem capable of doing almost everything that true embryonic stem cells can do, including growing into embryo-like structures in vitro. And this success seems to sever the last crucial connection between model embryos and real embryos: you don’t need an embryo to make them, which puts them largely outside existing regulations.
Growing organs in the laboratory
Even if the embryo models bear an uncanny resemblance to real embryos, they still have many shortcomings. Nicolas Rivron, a stem cell biologist and embryologist at the Institute of Molecular Biotechnology in Vienna, admits that “embryo models are rudimentary, imperfect, inefficient and do not have the ability to create a living organism.”
The failure rate for growing embryo models is very high: Less than 1 percent of the initial clusters of cells make it very far. Subtle abnormalities, mostly involving disproportionate organ sizes, often obliterate them, Hanna said. Wu believes more work is needed to understand the similarities to normal embryos and the differences that may explain why mouse embryo models have been unable to grow beyond 8.5 days.