FIRST. Mouse pups born to two fathers without a biological mother – Science et Avenir

Are mothers no longer needed? For the first time in the world, Japanese researchers have succeeded in creating functional eggs from cells taken from a male mouse, resulting in the birth of young mice without the need for a biological mother. Their feat, published March 15, 2023 in the magazine Natureadded to 2018 Chinese Academy of Sciences Researcherswho managed to produce viable and fertile fatherless mice. Advances that open the door to the (still remote) possibility of allowing male or female couples to have biological children genetically related to both parents.

Male cells are manipulated to become female

Previous attempts to obtain viable eggs from male cells have always failed in the past. Some were partially successful, but the young that emerged as a result of these experiments died quickly, showing the limitations of their approach. But the mice, created by the team of Katsuhiko Hayashi from the University of Kyushu in Fukuoka (Japan), were healthy and managed to reproduce themselves. They managed to avoid another setback by causing male cells to lose their Y chromosome and duplicate their X chromosome to produce female cells (XX, as opposed to male XY cells).

To do this, they used cells from the tails of male mice, which they reprogrammed to become pluripotent stem cells, which can then become any type of cell in the body. These stem cells were then grown in the laboratory, allowing them to multiply many times over. Because during this cell reproduction, sometimes a male cell (with XY chromosomes) can naturally lose its Y chromosome (keeping only the sex X chromosome, a phenomenon that has happened to about 1% of cells). The researchers selected these cells that had lost their Y chromosome and treated them with a product that disrupts chromosome segregation during cell division. At this stage, the chromosomes are duplicated and then redistributed in two daughter cells resulting from this cell division. This drug, called reversin, disrupts this process and increases the chance that a daughter cell will end up with both copies of the X chromosome made during chromosome duplication.

This method works in mice, but is not yet ready for humans.

So cells that were male (XY) become female (XX). Then all you have to do is program them to become germ cells from which oocytes will emerge. These oocytes were then fertilized with normal spermatozoa, resulting in embryos that were transferred to female mice for gestation. In this experiment, the mouse was born in about 1% of attempts, which is slightly lower than with normal eggs (5%). But all of these mice from the two fathers were in good health and were able to reproduce in turn, showing that these male-derived eggs were fully functional.

However, there are still several technical barriers to replicating these experiments in humans (not to mention the ethical dilemmas that can arise from such an approach). For example, researchers have genetically manipulated cells to make it easier to detect cells that have received two X chromosomes, so first we would need to find ways to track these cells without these genetic manipulations to avoid any unintended consequences for the embryonic genome. To do this, the researchers propose to track the expression of a gene that appears to be more pronounced in these cells with two X chromosomes.

In addition, the researchers warn that their method resulted in some differences in gene expression, such as the Parp8 gene, which was more active in eggs from male cells compared to normal eggs. Differences that may have unpredictable consequences and therefore should be well understood in advance. Finally, they acknowledge that their genome analysis method was not robust enough to rule out any off-target genome modification that might have occurred with their method. A better understanding of these possible unwanted modifications is necessary before attempting human experimentation. However, study leader Katsuhiko Hayashi told reporters that Guardian that he is convinced that the technique could be used on humans in about a decade. At least for research purposes, it is not necessary to allow two men to have children, even if he declares himself for such use, while claiming that it should be the choice of society.

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