The recipe for mammalian life is simple: take an egg cell, add sperm, and wait. But two new articles show there is another way. Under the right conditions, stem cells can divide and self-organize into an embryo on their own. In studies published in Cell other Nature this month, two groups report that they have grown synthetic mouse embryos longer than ever. The embryos grew for 8.5 days, long enough for them to develop various organs: a beating heart, an intestinal tube, and even neural folds.
The process is far from perfect. Only a small fraction of the cells develop these characteristics and those that do not fully mimic a natural embryo. But the work still represents a breakthrough that will help scientists see organ development in unprecedented detail. “This is very, very exciting,” says Jianping Fu, a bioengineer at the University of Michigan in Ann Arbor. “It is very likely that the next milestone in this field will be a human embryo based on synthetic stem cells,” he says.
The two research teams accomplished the feat using similar techniques. Magdalena Zernicka-Goetz, a stem cell and developmental biologist with laboratories at the University of Cambridge, UK, and the California Institute of Technology in Pasadena, has been working on this problem for a decade. “We started with just embryonic stem cells,” she says. “They can mimic the early stages of development, but we can’t go any further.” Then, a few years ago, her team discovered that when they added stem cells that give rise to the placenta and yolk sac, their embryos developed further. Last year they showed that they could use this technique to grow embryos up to day 7. In their latest article, published in Nature Today, the Zernicka-Goetz team describes how they developed embryos for another day and a half.
embryos in glass
Zernicka-Goetz’s team did it with the help of a technique developed by Jacob Hanna, a stem cell biologist at the Weizmann Institute of Science in Israel, who has also been working on this problem for years. Last year, Hanna’s team reported that they had developed a device that allowed them to grow natural mouse embryos for an unprecedented length of time outside the womb. This incubator, which kept embryos running from day 5 to day 11, takes aspects of an earlier technology, in which embryos reside in glass vials that rotate in a system similar to a Ferris wheel, and adds ventilation. The ventilation system controls the mixture of oxygen and carbon dioxide that enters the vials and the pressure.
After Hanna’s paper was published last year, her team shared part of their incubator with other stem cell and developmental biologists. “The brain of this machine we shared with everyone who asked for it,” she says, including Zernicka-Goetz and his colleagues, who modified it slightly for their experiments. In an article published in Cell on August 1, Hanna’s team describes how they used the system to also grow embryos for 8.5 days. Complete gestation in mice is about 20 days.
That period is long enough for brain regions to develop, the heart to start beating, and the neural and intestinal tubes to form. These synthetic embryos closely resemble the natural embryos that form when mouse sperm meets the egg, but “they weren’t 100% identical,” says Hanna. “You can see some defects and some changes in the size of the organ.”
Each team grew their embryos by combining three different cell types, and Hanna’s team also managed to create all three types from naive embryonic stem cells. “It offers a way to simplify the process,” says Hanna. “You can start everything from a population.” Zernicka-Goetz’s team reported a similar achievement in a preprint published on bioRxiv (In their Nature article, the researchers relied on placental precursor cells from a cell line to create the embryos).
Zernicka-Goetz’s team also performed an experiment in which they deleted a gene called Pax6, which has a key role in brain development. When they removed this gene, the mice’s heads did not develop properly, mimicking what happens in natural embryos that lack this gene. The result shows “that the system is really functional,” says Zernicka-Goetz.
“These two articles are mutually empowering,” says Martin Pera, a stem cell biologist at the Jackson Laboratory Center for Precision Genetics in Bar Harbor, Maine. “Two very skilled groups can actually produce quite similar results independently.”
For researchers, these synthetic models have many advantages over natural embryos created from eggs and sperm. Because they grow outside the uterus, they are much easier to see. They are also easier to manipulate using genome editing tools. “We can perturb, we can manipulate, we can delete every possible mouse or human gene,” says Fu. That could make them useful in discovering the role of different genes in birth defects or developmental disorders. Zernicka-Goetz plans to use this model to understand why pregnancies fail.
Hanna hopes to use the technique to develop synthetic human embryos that can be a source of new organs and tissues for people who need them.
What about humans?
But translating this work to humans will not be easy. Researchers have coaxed human stem cells to develop into blastocysts and even mimic some aspects of gastrulation, when the early embryo organizes itself into distinct layers made up of different cell types. But getting to the stage of organ formation in human cells, which occurs about a month after fertilization, presents a significant technical challenge. Still, Ali Brivanlou, a developmental biologist at the Rockefeller University in New York, is optimistic. “The field is not too far away.”
And the more advanced these embryos become, the greater the ethical concerns. A key question is whether these synthetic structures should be considered embryos, a point of debate in the field. The International Society for Stem Cell Research has long discouraged culturing human embryos after day 14 (equivalent to day 6 in a mouse), around the time the “primitive steak” appears, the structure that marks the beginning of gastrulation. In 2021, the society removed the cap and issued news guidelines saying such research should have a compelling scientific basis and should use the minimum number of embryos necessary to achieve the scientific goal.
Still, Pera sees the need for an ongoing conversation about the ethics of such models. Researchers have been working on human embryo models for years without much opposition. But she worries about a backlash as researchers begin to develop models of human embryos beginning to develop organs. “The backlash to that could jeopardize this entire field of research,” she says. “It is important that people know what they are proposing and that it be done with some kind of ethical consensus,” adds Pera. “We have to be cautious.”
This article is reproduced with permission and what first published on August 25, 2022.