Side-by-side comparison of natural and synthetic embryos showing brain and heart formation

Mouse embryos without eggs or sperm: why and what’s next?

Natural and synthetic mouse embryos grown by the research group of developmental biologist Magdalena Zernicka-Goetz.Credits: Gianluca Amadei, Charlotte Handford

The secret to mammalian life is simple: take an egg, add sperm, and wait. But two new papers suggest there is another way. Under the right conditions, stem cells can divide and self-organize into embryos on their published research cell1 and nature2 This month, two groups reported that they were growing synthetic mouse embryos longer than ever before. Embryos grow for 8.5 days, long enough for them to develop different organs—a beating heart, bowel, and even nerve folds.

The process is far from perfect. Only a small percentage of cells develop these features, and those that don’t exactly mimic the natural embryo. But the work still represents a major advance that will help scientists understand organ development in unprecedented detail. “It’s very, very exciting,” said Jianping, a bioengineering master at the University of Michigan in Ann Arbor. “The next milestone in the field is likely to be human embryos based on synthetic stem cells,” he said.

Two research teams achieved this feat using similar techniques. Magdalena Zernicka-Goetz is a developmental and stem cell biologist who spent ten years in his lab at the University of Cambridge, UK, and the California Institute of Technology in Pasadena. “We only started with embryonic stem cells,” she said. “They can mimic the early stages of development, but we can’t go any further.” Then, a few years ago, her team discovered3 When they added stem cells that give rise to the placenta and yolk sac, their embryos developed further.Last year, they showed4 They can use this technique to culture embryos until day 7.In their latest paper, published in nature Today, Zernicka-Goetz’s team describes how they grew the embryos for another 1.5 days.

embryo in glass

Zernicka-Goetz’s team did this with the help of a technique developed by stem cell biologist Jacob Hanna of the Weizmann Institute of Science in Israel, who has also been studying the problem for years.Last year, Hannah’s team reported5 They developed a device that allowed them to grow native mouse embryos outside the womb for an unprecedented time. This incubator, which keeps embryos from day 5 to day 11, uses aspects of the previous technique—the embryos sit in glass vials, spinning on a Ferris wheel-like system—with added ventilation. The ventilation system controls the mixture and pressure of oxygen and carbon dioxide entering the vial.

After Hannah’s paper was published last year, his team shared part of their incubator with other developmental and stem cell biologists. “We share the brain of this machine with everyone who needs it,” he said, including Zernicka-Goetz and her colleagues, who tweaked it slightly in their experiments.published in cell On August 1, Hanna’s team described how they used the system to grow embryos for 8.5 days. The full gestation period for mice is approximately 20 days.

This time is long enough for areas of the brain to develop, the heart to beat, and nerves and gut tubes to form. These synthetic embryos look a lot like the natural embryos formed when mouse sperm meet an egg, but they “are not 100 percent identical,” Hanna said. “You can see some defects and some changes in organ size.”

Synthesis of four synthetic mouse embryo model images taken inside the beaker on days 5 to 8

Synthetic mouse embryos grown in vials by stem cell biologist Jacob Hanna’s team.Credit: S. Tarazi et al/cell (cc 4.0)

Each team grew their embryos by combining three different cell types, and Hanna’s team also managed to create all three types of cells from naive embryonic stem cells. “It provides a way to simplify the process,” Hannah said. “You can start everything with a group.” Zernicka-Goetz’s team reports a similar achievement in a published preprint6 on bioRxiv (in their nature For the paper, the researchers relied on placental precursor cells from a cell line to make embryos. )

brain development

Zernicka-Goetz’s team also conducted an experiment in which they knocked out a gene called Pax6, which plays a key role in brain development. When they eliminated the gene, the mice’s heads did not develop correctly, mimicking what happens in natural embryos that lack the gene. The results show that “the system actually works,” Zernicka-Goetz said.

“The two papers reinforce each other,” says Martin Pera, a stem cell biologist at the Jackson Center for Precision Genetics Laboratory in Bar Harbor, Maine. “Two very skilled teams can indeed independently produce fairly similar results.”

For researchers, these synthetic models have many advantages over natural embryos produced from eggs and sperm. Because they grow outside the womb, they are easier to observe. They are also easier to manipulate with genome editing tools. “We can interfere, we can manipulate, we can knock out every possible mouse or human gene,” Fu said. This could make them useful for uncovering the role of different genes in birth defects or developmental disorders. Zernicka-Goetz plans to use the model to understand why pregnancy fails.

Hannah hopes to use the technology to develop human synthetic embryos, a source of new organs and tissues for those who need them.

What about humans?

But translating this work to humans isn’t easy. Researchers have coaxed human stem cells to become blastocysts and even mimic some aspects of gastrulation — the organization of early embryos into distinct layers made up of different cell types. However, reaching the stage of organ formation in human cells about a month after fertilization presents a major technical challenge. Still, developmental biologist Ali Brivanlou of The Rockefeller University in New York is optimistic. “The field is not far away.”

The more advanced these embryos are, the greater the ethical issues. A key question is whether these synthetic structures should be considered embryos, a point of contention in the field. The International Society for Stem Cell Research has long advised against culturing human embryos after day 14 (equivalent to day 6 in mice) – around the time “primitive steak” emerged, the structure that marked the beginning of gastrulation . In 2021, the society lifted the restrictions and issued a press guide saying such research should have a compelling scientific basis and should use the minimum number of embryos necessary to achieve the scientific goals.

Still, Pera sees a need to continue the conversation about the ethics of such models. Researchers have been studying human embryo models for years without much opposition. But he worries about backlash as researchers begin to develop models of human embryos that begin to develop organs. “A reaction to this could jeopardize the entire field of research,” he said. “It’s important that people know what’s being proposed and that it’s done with some sort of moral consensus,” Pella added. “We have to tread carefully.”

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