Only a few of the embryos that came from all-male cells developed into healthy mouse pups.Credits: Ciobaniuc Adrian Eugen/Alamy
Researchers have made eggs from the cells of male mice and have shown that, once fertilized and implanted in female mice, the eggs can develop into apparently healthy, fertile offspring.
The approach, announced March 8 at the Third International Summit on Human Genome Editing in London, has not yet been published and is a long way from being applied to humans. But it’s early proof-of-concept for a technique that raises the possibility of a way to treat some causes of infertility — or even make single-parent embryos possible. “This is a significant advancement with significant potential applications,” said Keith Latham, a developmental biologist at Michigan State University in East Lansing.
Researchers have been working on this feat for years. In 2018, a team reported using embryonic stem cells from sperm or eggs to generate pups with two fathers or two mothers. The pups with two mothers survived to adulthood and were fertile; the pups of two fathers only lived a few days1.
Mouse embryos cultured without eggs or sperm: why and what next?
In 2020, a team led by developmental biologist Katsuhiko Hayashi, now at Osaka University in Japan, described the genetic changes required for cells to mature into eggs in a laboratory dish2. And in 2021, the same researchers showed they could reconstruct the environment of mice’s ovaries to grow eggs that produce healthy offspring3.
With these tools in hand, Hayashi and his colleagues embarked on a project to make eggs using cells from an adult male mouse. They reprogrammed these to create stem cell-like induced pluripotent stem cells. The team grew these cells in culture until some of them had spontaneously lost their Y chromosome. (As in humans, male mice usually contain one X and one Y chromosome.) Then they treated the cells with a compound called reversine, which can promote errors in the way chromosomes are divided during cell division, and looked for cells that are chromosomally were female, with two copies of the X chromosome.
From there, the team provided the induced pluripotent stem cells with the genetic signals needed to form immature eggs. They then fertilized the eggs using mouse sperm and transferred the resulting embryos into the uterus of a female mouse.
The survival rate was low. Of the 630 embryos transferred, only 7 developed into pups. But the puppies grew normally and were fertile, Hayashi said at the meeting.
Earlier
The technique is far removed from any kind of medical application. “There are big differences between a mouse and a human,” Hayashi said. Such differences often complicate efforts to translate discoveries in mouse reproductive and stem cell biology to the clinic.
Specifically, Hayashi says his team will need to carefully characterize the pups from the experiment, looking for ways in which they differ from pups bred using conventional methods.
Embryos with DNA from three people develop normally in initial safety screening
It will also be interesting to see if the “epigenetic” chemical modifications to DNA that could affect gene activity are properly preserved in the eggs derived from male cells, says Fan Guo, a reproductive epigeneticist at the Chinese Academy of Sciences Institute. of Zoology in Beijing, which calls Hayashi’s results “illuminating.” Epigenetic marks on DNA can influence the development of the offspring well beyond the embryonic stage.
Another concern is that performing the same technique with human cells would require researchers to let the oocytes grow in the lab for longer than it took with mouse cells, says Mitinori Saitou, a developmental biologist at Kyoto University in Japan who works with Hayashi. “If the breeding period gets longer, both genetic and epigenetic abnormalities can accumulate,” he told the conference. “The shorter the better.”
Latham says that even if the approach is feasible in humans, researchers will have to make it more efficient and practical by increasing the number of embryos that produce offspring. “If you’re going to apply this to humans, you really want to go for safety, prudence and efficiency,” he says.
But if these hurdles are overcome, Hayashi’s approach to chromosomal engineering could one day provide a treatment for some forms of infertility caused by sex chromosome disorders, such as Turner syndrome, in which women are missing part or all of their X chromosomes.
What’s next for lab-grown human embryos?
The ramifications of Hayashi’s work could also take human reproduction into new territory, says bioethicist Tetsuya Ishii of Hokkaido University in Sapporo, Japan. If applied to humans, such research could help male couples have biological children together, using surrogate mothers, he says. “It also suggests that a single man could have a biological child in the distant future,” he says.
Such applications require more than technical sophistication of a biological method, Hayashi said, but also a broader societal discussion about the ethics and implications of its implementation: “I don’t know if this kind of technology can really adapt to human society.”