Mouse Born to Two Fathers and No Mother Survives to Adulthood

Scientists in China have successfully created and raised a mouse with two biological fathers, marking a breakthrough in genetic research that could enhance understanding of reproductive biology and genetic disorders.

The study, conducted by Zhi-kun Li of the Chinese Academy of Sciences, utilized advanced stem cell techniques to generate egg-like cells from male embryonic stem cells. These artificial eggs were subsequently fertilized with sperm from another male and implanted into a surrogate female.

In previous experiments, attempts to create offspring using male cells resulted in severe developmental defects. However, the new method has produced healthier mice that have survived into adulthood. Despite this progress, the mice remain sterile, and many embryos still fail to develop properly.

Overcoming a major reproductive barrier

Scientists have struggled to bypass the biological need for an egg in mammalian reproduction for decades. Unlike sperm, which are highly specialized and cannot divide into other cells, eggs contain essential nutrients and cellular mechanisms required for early development.

Efforts to create embryos using only male cells encountered a significant genetic challenge: imprinting abnormalities. Normally, when a sperm fertilizes an egg, specific genes from each parent are naturally activated or deactivated to ensure proper development.

But when two sperm contribute genetic material, these genes can be mistakenly silenced, leading to severe defects.

Li’s team overcame this challenge by modifying 20 imprinting genes before fertilization, ensuring that only one copy of each gene remained active. This correction significantly increased the survival rate of embryos compared to previous attempts.

Higher success rates, but challenges remain

The study represents a significant advancement over previous attempts. In 2023, Japanese researchers conducted a similar process with a success rate of merely 1.1%, resulting in only a small fraction of embryos developing into live mice. With the new technique, 13% of embryos survived to birth, marking a notable increase.

Despite this progress, the process is still far from perfect. Nearly 90% of embryos failed to develop, and half of the surviving mice did not reach adulthood. Scientists suggest that refining the technique could further improve these outcomes.

Implications for medicine and genetic research

While the prospect of applying this method to humans remains distant, researchers believe it could provide valuable insights into congenital disorders and reproductive medicine. By understanding how imprinting genes function, scientists could develop treatments for diseases caused by similar genetic errors.

“This work will help to address a number of limitations in stem cell and regenerative medicine research,” said Wei Li, a stem cell researcher at the Chinese Academy of Sciences.

Chinese scientists use genetic engineering to make mice with two male parents.

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Co-author Qi Zhou emphasized the fundamental challenges of unisexual reproduction in mammals. “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,” Zhou said.

A long road ahead

The breakthrough comes nearly two decades after Japanese researchers successfully created mice with two mothers in 2004. That process was easier since some species in nature can reproduce without sperm, effectively cloning the mother. However, no known animal has ever naturally been born with two fathers.

Further modifications may one day allow scientists to create viable, fertile mammals with two male parents. “Further modifications to the imprinting genes could potentially facilitate the generation of healthy bi-paternal mice capable of producing viable gametes,” Li said.

For now, the study represents a major step forward in understanding how genes shape early development. The findings were published in Cell Stem Cell.