In a feat that sounds like the plot of a sci-fi B-movie but is actually real science, researchers in Japan have deliberately transformed male mouse embryos into females for the first time. Using a CRISPR-based technique they call Y-CUT, the team removed the Y chromosome from male cells, creating female clones of male mice.
"No one has done this before," says Monika Ward, a reproductive biologist at the University of Hawaii, who wasn't involved in the research. Well, that's reassuring - because the next thing you know, they'll be cloning dinosaurs.
The findings, published as a preprint on bioRxiv and not yet peer-reviewed, could upend the long-held belief that reproduction requires both sexes. "There's a fixed concept in our scientific field that we need both females and males for reproduction," says co-lead Takashi Ishiuchi of the University of Yamanashi. "I think we could change this concept." Because who needs males, really? They're only good for one thing, and now we've got CRISPR.
The Y-CUT tool targets a section of the Y chromosome that ensures the chromosome is passed on during cell division. By eliminating it in early-stage embryos, the researchers produced female pups with XO chromosomes - that's one X instead of the usual two. Surprisingly, these females grew up healthy and fertile, which is more than can be said for the male ego.
In a second experiment, the team applied Y-CUT to cloned cells, creating female clones from male mice. The females are genetically identical to the original male, minus the Y chromosome. "It's like sci-fi," says Ishiuchi. Indeed, because the only thing more sci-fi than cloning is cloning with a twist of gender-bending.
The inspiration came from the Okinawa rubble goby, a fish that can change sex when the situation calls for it. If no males are around, a female can switch to male to reproduce. The researchers thought, "If a fish can do it, why not a mouse?" And why not a ferret, or a horse, or any endangered species that's down to its last males?
Cloning has already helped bring species back from the brink, like black-footed ferrets and Przewalski's horse. But cloning a male only gives you more males. Now, with Y-CUT, you could create females from those precious male cells, doubling the reproductive potential. "It's exciting to see," says Ben Novak of Revive & Restore, a conservation organization. "I am confident there will be plenty of applications, particularly for conservation purposes."
The technique isn't perfect, of course. It still requires egg cells from a female of the same or closely related species. And while XO female mice are fertile, other mammals with XO chromosomes tend to be infertile, which limits the approach to certain species - like the 355 endangered and vulnerable rodent species. So, if you're a rodent, your future just got brighter.
But there are complementary technologies on the horizon. In 2023, Katsuhiko Hayashi of Osaka University showed he could turn male mouse cells into egg cells, which could provide the hollowed-out eggs needed for Y-CUT. And Sayaka Wakayama of the University of Yamanashi recently demonstrated inserting rat chromosomes into mice, which could potentially create male embryos. "It's a complementary story," says Matoba.
So, what's next? Ishiuchi is working on adding a second X chromosome to restore fertility in the female clones. And for those situations where you have females but need males, there's a work-around in the works. "It's really exciting to see more diverse tools being developed," says Novak. "There are so many different scenarios in which they could be used for rare and endangered species."
In the meantime, we're just glad the mice are happy, and we're one step closer to a world where sex ratios are a thing of the past - at least in the lab.