Despite challenges, human-pig chimeras could boost regenerative medicine

This mouse was created by injecting rat pluripotent stem cells into a mouse blastocyst. Credit: Courtesy of Juan Carlos Izpisua Belmonte, Salk Institute.

Scientists at the Salk Institute generated plenty of buzz on January 26 when they announced they had successfully grown embryos containing cells from both pigs and humans. They were quick to report that the effort was more challenging than expected, and that the human-pig chimera embryos were not allowed to fully develop. But they are certain their invention could prove valuable for a range of scientific pursuits, from drug development to regenerative medicine.

"The ultimate goal is to grow functional and transplantable tissue or organs, but we are far away from that," said Juan Carlos Izpisua Belmonte, lead investigator and a professor in the Salk Institute of Biological Studies' Gene Expression Laboratory, in a press release. The research was published in the journal Cell.

Izpisua Belmonte and his team started by creating a rat-mouse chimera and then using CRISPR gene editing tools to eliminate certain genes in fertilized mouse eggs. They found that if they deleted the gene for a critical organ, like a heart, and then introduced rat stem cells into the embryo, those cells would develop into the needed organ, in essence filling in the gaps so normal development could occur. The rat stem cells were even able to create mouse gall bladders, even though rats themselves don’t have that particular organ.

Then they tried introducing human cells into cow and pig embryos, and that’s where it got challenging. They zeroed in on pigs, and over a four-year period searched in vain for human cells that could survive in pig embryos. Then they found a specific population of human cells that survive and develop in pigs: pluripotent stem cells that are in an “intermediate” stage of development, meaning they’re at the beginning of the development path, but they still have the ability to form any tissue in the body. Embryos containing these cells were implanted in cows and allowed to develop for about a month.

"This is long enough for us to try to understand how the human and pig cells mix together early on without raising ethical concerns about mature chimeric animals," Izpisua Belmonte said in the statement.

The Salk researchers see a host of potential applications for their technology. In the Cell paper, they point out that CRISPR-edited rodents may offer a more efficient platform for medical research than models that are currently used, which are often cross-bred mice with various gene mutations. They also suggest that human-pig chimeras could help researchers better understand embryo development and the progression of human diseases. They might also prove to be a good platform for testing human drugs, they write.

The Salk announcement came on the heels of new research out of Stanford University and the University of Tokyo, where scientists showed they could reverse diabetes in mice with pancreatic cells that were grown in rats. They hope the method will eventually be translatable to people—and that it will prove to be more practical than implantable insulin pumps currently on the market.

CRISPR gene editing methods are being tried in multiple experiments around the world, in both animal and human health. The U.K.’s Roslin Institute has used the technique to create pigs that are resistant to African swine fever, for example. And in October, a multi-institution team of researchers showed they could correct genetic mutations in stem cells taken from people with sickle cell disease. A few weeks later, China became the first country to announce it was testing gene-edited cells in people, starting with a lung cancer patient.

The next step for the Salk researchers is to see if they can use CRISPR to create pigs that are lacking key organs, and then use human cells to fill in the gaps—just as they did with the rat-mouse chimera. And they’re working on understanding how the cells develop into particular organs, so they can ensure that the chimeras won’t be “too human,” meaning they won’t have human brains.

"At this point, we wanted to know whether human cells can contribute at all to address the 'yes or no' question," said Izpisua Belmonte in the statement. "Now that we know the answer is yes, our next challenge is to improve efficiency and guide the human cells into forming a particular organ in pigs."