Germ cell production in genetically modified hybrid animals is now a reality rather than science fiction, as recently demonstrated by researchers at ETH Zurich.
Stem cell biologist Ori Bar-Nur, PhD, and his team used genetically engineered rat-mice chimeras to show that sterile mice could support the development of rat spermatogenesis.
“In the distant future we would like to adapt this technique to try to produce critically endangered animal germ cells inside more common animals such as mice or rats,” said Bar-Nur. Though it’s not his team’s goal, others are using this technology with a more medical purpose. “The overarching purpose of this technology, eventually, with respect to therapeutics, is to generate human organs inside animals for transplantation.”
The ETH researchers used a process called blastocyst complementation, tweaking the technique to exclusively produce rat gametes inside of mice. To start the process, the researchers injected rat stem cells into mice embryos that had gene knockouts designed to cause infertility.
The process was “quite spontaneous,” according to Bar-Nur. The mice embryos incorporate the rat stem cells and the whole development occurred in tandem. “The mouse and rat grow, they’re born, and they have both mouse and rat cells.”
The chimera has predominantly mouse cells, but the researchers were able to generate exclusively rat spermatozoa inside the mice.
It was surprising how easy it was to generate a mouse-rat chimera, said Bar-Nur. “The rat cells that we injected into mouse embryos became part of these mice. And they were very, very viable,” he said. The chimeras lived for more than a year, carrying cells from both ancestral species.
The success of the mice producing rat sperm cells was also a surprise.
“The rat germ cells, the produced sperm, had to develop inside these mice and mature, and eventually differentiate,” said Bar-Nur. “This was quite surprising — that even the action of a mouse that was believed to be sterile, they could still support the development of rat spermatogenesis.”
The researchers hope the proof-of-principle experiment could be used for conservation efforts in the future. “In theory, if we have a biopsy from a critically endangered species, we can convert them into stem cells, then inject those stem cells into more prevalent animals that are sterile to produce germ cells of the critically endangered species,” Bar-Nur explained.
There are medical applications as well, though Bar-Nur stressed that this research is never meant to be extended to producing human germ cells inside of other animals. That would bring about a large and complex set of ethical and moral questions, he said. Rather, scientists have been developing this technology to generate human organs inside of surrogate animals.
Researchers have used this technique to show that you can generate a mouse pancreas inside a rat — or a rat pancreas inside a mouse — and then use the pancreas to treat diabetes inside mice and rats, said Bar-Nur. More recently, people have shown chimeras between a human and a pig.
There are still mysteries to explore, and Bar-Nur and his team are investigating them. So far, the sperm produced in the chimera are morphologically indistinguishable from rat sperm cells and have a half set of chromosomes like they should. But they’re immobile and haven’t yet produced live offspring.
The researchers hypothesize that, somewhere in the process, there is something not completely normal in the development of the sperm. Another theory is that there was some degradation or damage from using frozen sperm.
For next steps, Bar-Nur and team have some ideas. “We would like to bring the rats to term from germ cells that are produced in mice, that’s one thing.”
Stem Cell Rep. Published online August 4, 2022. Full text
Bar-Nur reports no relevant financial relationships.