Mice with Two Fathers? Researchers Develop Egg Cells from Male Mice

For the first time, researchers have created mice with two biologically male parents by manipulating the chromosomes inside a stem cell. Katsuhiko Hayashi, a stem cell biologist at Kyushu University in Japan, presented the new research on March 8 at the Third International Summit on Human Genome Editing at the Francis Crick Institute in London.

The new announcement marks the first time that researchers have managed to turn a stem cell from an adult male mouse into an egg. It’s a new variation on what scientists call in vitro gametogenesis. During in vitro gametogenesis, researchers create gametes (sperm and egg cells) from induced pluripotent stem cells, which are unspecialized cells converted from body tissue that researchers can then manipulate into, say, blood cells or neurons. Although the advance raises the possibility that men may someday be able to have biological children together, any such attempt remains a long way off, researchers emphasize.

Previously egg cell creation began with stem cells from a female animal. But Hayashi and his team used stem cells from a male mouse instead. The researchers discarded the Y chromosome and duplicated the X chromosome. They then embedded it in an artificial ovary that was also produced from stem cells. In the ovary, the manipulated cell developed into an egg cell, or oocyte. Hayashi and his colleagues transplanted 630 embryos formed from such egg cells into surrogate mice. This resulted in seven living pups that grew normally and were fertile as adults, he said in the March 8 presentation.

“I think it’s clearly very preliminary research,” says Evelyn Telfer, a reproductive biologist at the University of Edinburgh in Scotland, who was not involved in the new research. She says she found the work compelling and appreciates the insight it offers into how organisms reproduce, but she notes that the research has not yet been published in a scientific journal and that the presentation skimmed over technical details.

Telfer is particularly concerned by how few of the artificial egg cells grew into living mice. “Although they get quite a lot of eggs, these eggs are clearly not fully competent because they really get a very, very small proportion of them that are capable of being fertilized and forming embryos,” she says. “It’s a huge achievement, but it’s still an indication that there are problems with these in vitro–derived oocytes from the stem cells, so there’s a lot of work that has to be done.”

And attempting the technique in humans would be significantly more difficult than the mouse work Hayashi described, as he noted during the presentation. “There is a big difference between a mouse and a human,” he said. (Hayashi did not respond to Scientific American’s request for comment.)

Human cells develop much more slowly than mouse cells, and scientists have honed advanced processes for artificial mouse reproduction in the lab, Telfer says. For human cells, these systems aren’t as developed. Telfer notes that in her own work, which relies on natural precursors to human egg and sperm cells, successfully growing mature gametes remains difficult.

“I think we’re at a stage where the mouse work is fabulous, but moving this area along to other species has proven to be a lot more difficult,” Telfer says. “There are challenges at every stage.”

And researchers haven’t yet successfully produced human egg and sperm cells from stem cells, says Kotaro Sasaki, a biomedical scientist at the University of Pennsylvania, who has worked with Hayashi in the past but was not involved in the new research. “In humans, we’re still so behind,” he says, although he thinks that producing human gametes will become technically feasible within perhaps a decade.

Mimicking in humans the chromosome-swapping feat that sets Hayashi’s new work apart would require additional development time. Sasaki expects that deleting Y chromosomes and duplicating X chromosomes won’t happen nearly as smoothly in human cells. Hayashi’s team manipulated the chromosomes by adding a compound that encourages chromosomal changes, but Sasaki says that the same approach in humans could cause many additional mutations along the way—some of which could be dangerous.

Sasaki would also like to see Hayashi’s technique tested in monkeys before any attempts are made using human cells, much less before scientists create any human embryos. He cautions that some safety issues could become apparent only in a second generation. “Using this for reproductive purposes … comes with lots and lots of ethical and legal issues, which we need to seriously address,” he says.

I. Glenn Cohen, a law professor at Harvard Law School who specializes in medical ethics, says that the new research suggests that society as a whole needs to have conversations about in vitro gametogenesis, its regulation and its ethical implications sooner rather than later.

Those conversations may depend on the precise uses of the technology. During his presentation, Hayashi specifically referenced only Turner syndrome, a rare condition associated with infertility in which someone’s cells contain only one X chromosome, as a potential human use case for the technique. But facilitating childbirth for LGBTQ+ people may be a potential application with higher demand, says Telfer, who works with patients with Turner syndrome.

And the way the technique could open reproduction to couples without an XX-XY chromosomal pair raises a unique question, Cohen said in an e-mail to Scientific American. “To what extent does [in vitro gametogenesis] represent the ultimate in equality for same-sex couples?” he wrote. “Should this become technologically feasible for human beings,” he asked, “should same-sex couples have a right to do so?”

For the first time, researchers have created mice with two biologically male parents by manipulating the chromosomes inside a stem cell. Katsuhiko Hayashi, a stem cell biologist at Kyushu University in Japan, presented the new research on March 8 at the Third International Summit on Human Genome Editing at the Francis Crick Institute in London.

The new announcement marks the first time that researchers have managed to turn a stem cell from an adult male mouse into an egg. It’s a new variation on what scientists call in vitro gametogenesis. During in vitro gametogenesis, researchers create gametes (sperm and egg cells) from induced pluripotent stem cells, which are unspecialized cells converted from body tissue that researchers can then manipulate into, say, blood cells or neurons. Although the advance raises the possibility that men may someday be able to have biological children together, any such attempt remains a long way off, researchers emphasize.

Previously egg cell creation began with stem cells from a female animal. But Hayashi and his team used stem cells from a male mouse instead. The researchers discarded the Y chromosome and duplicated the X chromosome. They then embedded it in an artificial ovary that was also produced from stem cells. In the ovary, the manipulated cell developed into an egg cell, or oocyte. Hayashi and his colleagues transplanted 630 embryos formed from such egg cells into surrogate mice. This resulted in seven living pups that grew normally and were fertile as adults, he said in the March 8 presentation.

“I think it’s clearly very preliminary research,” says Evelyn Telfer, a reproductive biologist at the University of Edinburgh in Scotland, who was not involved in the new research. She says she found the work compelling and appreciates the insight it offers into how organisms reproduce, but she notes that the research has not yet been published in a scientific journal and that the presentation skimmed over technical details.

Telfer is particularly concerned by how few of the artificial egg cells grew into living mice. “Although they get quite a lot of eggs, these eggs are clearly not fully competent because they really get a very, very small proportion of them that are capable of being fertilized and forming embryos,” she says. “It’s a huge achievement, but it’s still an indication that there are problems with these in vitro–derived oocytes from the stem cells, so there’s a lot of work that has to be done.”

And attempting the technique in humans would be significantly more difficult than the mouse work Hayashi described, as he noted during the presentation. “There is a big difference between a mouse and a human,” he said. (Hayashi did not respond to Scientific American’s request for comment.)

Human cells develop much more slowly than mouse cells, and scientists have honed advanced processes for artificial mouse reproduction in the lab, Telfer says. For human cells, these systems aren’t as developed. Telfer notes that in her own work, which relies on natural precursors to human egg and sperm cells, successfully growing mature gametes remains difficult.

“I think we’re at a stage where the mouse work is fabulous, but moving this area along to other species has proven to be a lot more difficult,” Telfer says. “There are challenges at every stage.”

And researchers haven’t yet successfully produced human egg and sperm cells from stem cells, says Kotaro Sasaki, a biomedical scientist at the University of Pennsylvania, who has worked with Hayashi in the past but was not involved in the new research. “In humans, we’re still so behind,” he says, although he thinks that producing human gametes will become technically feasible within perhaps a decade.

Mimicking in humans the chromosome-swapping feat that sets Hayashi’s new work apart would require additional development time. Sasaki expects that deleting Y chromosomes and duplicating X chromosomes won’t happen nearly as smoothly in human cells. Hayashi’s team manipulated the chromosomes by adding a compound that encourages chromosomal changes, but Sasaki says that the same approach in humans could cause many additional mutations along the way—some of which could be dangerous.

Sasaki would also like to see Hayashi’s technique tested in monkeys before any attempts are made using human cells, much less before scientists create any human embryos. He cautions that some safety issues could become apparent only in a second generation. “Using this for reproductive purposes … comes with lots and lots of ethical and legal issues, which we need to seriously address,” he says.

I. Glenn Cohen, a law professor at Harvard Law School who specializes in medical ethics, says that the new research suggests that society as a whole needs to have conversations about in vitro gametogenesis, its regulation and its ethical implications sooner rather than later.

Those conversations may depend on the precise uses of the technology. During his presentation, Hayashi specifically referenced only Turner syndrome, a rare condition associated with infertility in which someone’s cells contain only one X chromosome, as a potential human use case for the technique. But facilitating childbirth for LGBTQ+ people may be a potential application with higher demand, says Telfer, who works with patients with Turner syndrome.

And the way the technique could open reproduction to couples without an XX-XY chromosomal pair raises a unique question, Cohen said in an e-mail to Scientific American. “To what extent does [in vitro gametogenesis] represent the ultimate in equality for same-sex couples?” he wrote. “Should this become technologically feasible for human beings,” he asked, “should same-sex couples have a right to do so?”