Courtesy of the Researchers
Mice with two fathers have been born—and have survived to adulthood—following a complex set of experiments by a team in China.
Zhi-Kun Li at the Chinese Academy of Sciences in Beijing and his colleagues used CRISPR to create the mice, using a novel approach to target genes that normally need to be inherited from both male and female parents. They hope to use the same approach to create primates with two dads.
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Humans are off limits for now, but the work does help us better understand a strange biological phenomenon known as imprinting, which causes certain genes to be expressed differently depending on which parent they came from. For these genes, animals inherit part of a “dose” from each parent, and the two must work in harmony to create a healthy embryo. Without both doses, gene expression can go awry, and the resulting embryos can end up with abnormalities.
This is what researchers have found in previous attempts to create mice with two dads. In the 1980s, scientists in the UK tried injecting the DNA-containing nucleus of a sperm cell into a fertilized egg cell. The resulting embryos had DNA from two males (as well as a small amount of DNA from a female, in the cytoplasm of the egg).
But when these embryos were transferred to the uteruses of surrogate mouse mothers, none of them resulted in a healthy birth, seemingly because imprinted genes from both paternal and maternal genomes are needed for development.
Li and his colleagues took a different approach. The team used gene editing to knock out imprinted genes altogether.
Around 200 of a mouse’s genes are imprinted, but Li’s team focused on 20 that are known to be important for the development of the embryo.
In an attempt to create healthy mice with DNA from two male “dads,” the team undertook a complicated set of experiments. To start, the team cultured cells with sperm DNA to collect stem cells in the lab. Then they used CRISPR to disrupt the 20 imprinted genes they were targeting.
These gene-edited cells were then injected, along with other sperm cells, into egg cells that had had their own nuclei removed. The result was embryonic cells with DNA from two male mice. These cells were then injected into a type of “embryo shell” used in research, which provides the cells required to make a placenta. The resulting embryos were transferred to the uteruses of female mice.
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It worked—to some degree. Some of the embryos developed into live pups, and they even survived to adulthood. The findings were published in the journal Cell Stem Cell.
“It’s exciting,” says Kotaro Sasaki, a developmental biologist at the University of Pennsylvania, who was not involved in the work. Not only have Li and his team been able to avoid a set of imprinting defects, but their approach is the second way scientists have found to create mice using DNA from two males.
The finding builds on research by Katsuhiko Hayashi, now at Osaka University in Japan, and his colleagues. A couple of years ago, that team presented evidence that they had found a way to take cells from the tails of adult male mice and turn them into immature egg cells. These could be fertilized with sperm to create bi-paternal embryos. The mice born from those embryos can reach adulthood and have their own offspring, Hayashi has said.
Li’s team’s more complicated approach was less successful. Only a small fraction of the mice survived, for a start. The team transferred 164 gene-edited embryos, but only seven live pups were born. And those that were born weren’t entirely normal, either. They grew to be bigger than untreated mice, and their organs appeared enlarged. They didn’t live as long as normal mice, and they were infertile.
It would be unethical to do such risky research with human cells and embryos. “Editing 20 imprinted genes in humans would not be acceptable, and producing individuals who could not be healthy or viable is simply not an option,” says Li.
“There are numerous issues,” says Sasaki. For a start, a lot of the technical lab procedures the team used have not been established for human cells. But even if we had those, this approach would be dangerous—knocking out human genes could have untold health consequences.
“There’s lots and lots of hurdles,” he says. “Human applications [are] still quite far.”
Despite that, the work might shed a little more light on the mysterious phenomenon of imprinting. Previous research has shown that mice with two moms appear smaller, and live longer than expected, while the current study shows that mice with two dads are overgrown and die more quickly. Perhaps paternal imprinted genes support growth and maternal ones limit it, and animals need both to reach a healthy size, says Sasaki.
