A mouse with no biological mother has survived to adulthood in China – a major scientific achievement that’s been years in the making.
The feat was pulled off by a team of researchers in China, led by molecular biologist Zhi-kun Li from the Chinese Academy of Science (CAS), using precise stem cell engineering.
This isn’t the first time that scientists have created a mouse with two male parents. In 2023, researchers in Japan managed a similar feat using a different technique.
Before that, attempts to generate eggs from male stem cells proved unsuccessful. The motherless offspring, born through a female surrogate, are typically nonviable and show severe developmental defects.
Not so for the ‘bi-paternal’ mice recently created in China. These adult mammals are not capable of reproducing themselves, but they are healthier than their predecessors, without fatal feeding or respiratory difficulties.
That said, roughly half of their siblings failed to make it to adulthood, and nearly 90 percent of the viable embryos did not make it to birth, which means the success rate for the process can still be improved upon.
There’s still a long way to go before the same sort of technique could be achieved in our own species, but the authors of the study say their work helps scientists better understand human congenital disorders caused by similar genetic issues.
Usually, when a male sperm fertilizes a female egg, there is a double-up of genes which means that one half of each pair needs to be silenced.
When genetic material comes from two sperm, however, it can often result in a double silencing effect, whereby both copies of a gene are canceled out by mistake, leading to developmental disorders.
This is called an imprinting abnormality, and it occurs because the regulation of certain genes or chromosomal regions depends on contributions from a male and female parent.
Li and his colleagues have figured out how to correct for 20 of these special cases, using a range of genetic techniques, including gene deletions, region edits, and the insertion or deletion of genetic base pairs.
“This work will help to address a number of limitations in stem cell and regenerative medicine research,” claims stem cell researcher Wei Li from CAS.
“The unique characteristics of imprinting genes have led scientists to believe that they are a fundamental barrier to unisexual reproduction in mammals,” says cooauthor Qi Zhou from CAS.
“Even when constructing bi-maternal or bi-paternal embryos artificially, they fail to develop properly, and they stall at some point during development due to these genes.”
Researchers in Japan created mice with two mothers and no biological father for the first time way back in 2004, but reproduction without the need for sperm is easier to pull off than reproduction without the need for an egg.
That’s because an egg holds key cellular machinery, nutrients, and the power to induce every cell type in an adult organism. In nature, some animal species can even reproduce without sperm, making the fatherless offspring essentially clones of the mother.
By contrast, there is no natural example of an animal with two fathers and no mother. Compared to an egg, mature sperm cells are highly specialized, and they can’t divide into other cells.
To get around this, scientists had to create egg-like cells from male embryonic stem cells, and then fertilize those eggs using sperm from a different male.
Before fertilization, imprinting genes were modified by researchers to ensure only one copy of each gene was expressed in the offspring.
The technique has improved the success rate for bi-paternal mice. In 2023, researchers in Japan reported that 1.1 percent of their bi-paternal embryos made it to a live birth. Using this new technique, around 13 percent of embryos produced live offspring.
Unlike the mice in Japan, however, the ones in China seem to be sterile.
“Further modifications to the imprinting genes could potentially facilitate the generation of healthy bi-paternal mice capable of producing viable gametes and lead to new therapeutic strategies for imprinting-related diseases,” says Zhi-kun Li.
The study was published in Cell Stem Cell.
