Without an egg cell, sperm or uterus, researchers have produced synthetic mouse embryos from stem cells in a test tube. The artificial embryos developed very similarly to real embryos over a period of 8.5 days - almost half the gestation period of a mouse - and during this time formed all regions of the brain, a beating heart and the cellular basis of all other organs. The study shows the potential of artificial embryos for research and medicine, but also raises new ethical questions.
An embryo is formed naturally when an egg is fertilized by a sperm, then begins to divide and implant in the lining of the womb. For a long time it was considered inconceivable that all these factors could be dispensed with. But in early August, an Israeli research team reported that they had made synthetic mouse embryos from stem cells and grown them for several days in an incubator also developed by the team.
Artificial organisms with heartbeat and brain
A team led by Gianluca Amadei from the University of Cambridge has now published similar results. They grew synthetic mouse embryos, so-called embryoids, from three different types of stem cells and allowed them to mature in the incubator developed by the Israeli team. The development only stopped after 8.5 days for reasons that are not yet known. Since natural gestation in mice only lasts about 19 days, the embryoids had already gone through significant developmental steps by then: "Our mouse embryo model develops not only a brain, but also a beating heart and all the components that the body will later consist of," reports Amadeis Colleague Magdalena Zernicka-Goetz.
With the help of single-cell analyses, Amadei's team examined the embryoids in detail. It turned out that the synthetic embryoids were astonishingly similar to natural mouse embryos. All 26 cell types that occur in natural embryos and from which the individual organs later develop were also present in the embryoids. Moreover, in the embryoids, all brain regions had emerged. "This opens up new possibilities for investigating the mechanisms of neurodevelopment in an experimental model," says Zernicka-Goetz
Insights into the earliest pregnancy
From the authors' point of view, the new development could offer numerous new research opportunities. For one, it offers a previously impossible glimpse into the earliest stages of pregnancy. "This early phase is the basis for everything that follows in pregnancy," says Zernicka-Goetz. “The stem cell embryo model gives us access to the developing structure at a stage normally hidden from view by the implantation of the tiny embryo in the mother's uterus. This period of human life is so mysterious that it is very special to see it unfold in a dish, to have access to these individual stem cells, to understand why so many pregnancies fail and how we might be able to prevent it. "
Among other things, the researchers observed how the three types of stem cells used communicate with each other. In order to simulate natural conditions, they used not only embryonic stem cells but also two types of so-called extra-embryonic stem cells, from which the placenta and the yolk sac are formed. Amadei and his team discovered that these extra-embryonic cells not only interact with the embryonic cells via chemical signals, but also stimulate them mechanically and thus control the development of the embryo. "We have seen how the dialogue between the different types of stem cells takes place and what can go wrong," says Zernicka-Goetz.
Genetic manipulation of embryoids
In addition to insights into the earliest embryonic development, the model also offers the opportunity to better understand genetic diseases and the role of certain genes. To demonstrate this potential, Amadei's team knocked out a gene in some of the artificial embryoids known to be essential for neural tube formation and brain and eye development. "If this gene is missing, the synthetic embryos show exactly the same defects in brain development as in an animal that carries this mutation," explains Zernicka-Goetz. "This means that we can apply this type of approach to the many genes with unknown function in brain development." In this way, the embryo model could help replace animal experiments.
ethical challenges
While the current research took place on mouse embryoids, the researchers are already working on applying the methods to synthetic human embryos. How realistic this goal is is currently unclear. Even with the mouse embryoids, the success rate was only about one percent and development stopped at the beginning of organ formation. From the point of view of Michele Boiani, head of the "Mouse Embryology" working group at the Max Planck Institute for Molecular Biomedicine in Münster, who was not involved in the study, the transfer to humans from a technical point of view is definitely within the realm of the imaginable. "However, the bioreactors would not have to last for days or weeks, but for months - a challenge that is currently almost insurmountable," he says.
From his point of view, however, the ethical framework is problematic: “The guidelines of the International Society for Stem Cell Research (ISSCR) allow the production of synthetic human embryos, but prohibit their transfer to the uterus, which is always considered the most important barrier to preventing highly unethical embryos experimentation,” explains Boiani. "Now, as we see in these two mouse studies, transfer to the uterus is unnecessary, and so the ISSCR guidelines become a toothless tiger." So far, human embryos can be cultivated in the laboratory for a maximum of 14 days - but there are already discussions about relaxing this rule in selected cases. How synthetic embryoids are to be classified is currently still unclear worldwide.
Source: Gianluca Amadei (University of Cambridge, UK) et al., Nature, doi: 10.1038/s41586-022-05246-3