In the latest of decidedly very sci-fi but crucial bids for life-saving organs, scientists created a pig kidney that has survived for two years in another animal, the longest amount of time thus far. The new feat brings this type of genetic engineering — known as xenotransplants — one step closer to human use.
In a study published Wednesday in the journal Nature, researchers led by Boston-based biotech company eGenesis made a total of 69 different edits to the genomes of Yucatan miniature pigs that appeared to make the animals’ kidneys more compatible with non-human primates, in this case, an animal known as the crab-eating macaque. The monkeys, who had their own kidneys removed and replaced with one of the minipigs’ genetically modified kidneys, survived for up to 758 days — roughly a little over two years — while also on immunosuppression.
“These results are unprecedented and signify a monumental step forward in achieving human compatibility,” Mike Curtis, a study co-author and chief executive officer at eGenesis, told reporters in a press conference on Tuesday. “Our study underscores the pivotal role of genome engineering in cross-species transplantation… [it] gives us hope for a future where organ transplantation can save lives of all patients suffering from organ failure.”
Altered to the max
For the last sixty years, scientists have experimented with animal-to-human organ transplants with varying levels of success, and nothing long-term. With the advent of the gene-editing tool CRISPR-Cas9, the idea is to purposefully manipulate an animal’s genome, deleting problematic genes — including those for viruses native to the animals — and incorporating desirable ones related to target species. The end goal is to essentially trick the recipient’s immune system into believing the foreign organ is its own and allow it to work business as usual once inside the body.
Pigs are often considered ideal donors because their organ size, physiological metabolism, and immune system are similar to humans. To breed more similarity and compatibility, biotech companies are playing around with the porcine genome. Revivicor, a competitor to eGenesis, designed a pig with 10 genetic changes where six human genes were added and four pig genes were deleted, including one for alpha-gal, a sugar molecule humans lost during our evolution but which remains in mostly mammals like pigs, cows, and deer. Known as a GalSafe pig, it was granted federal approval for commercial and experimental use in 2020 and has been used for heart and kidney transplant xenotransplant trials.
The new eGenesis pig has a leg up in terms of genetic edits — it’s got 69 changes. These changes resulted in a deleted alpha-gal gene as well as two sugars found on the surface of animal cells. Researchers think deleting these sugars will significantly reduce or prevent immediate organ rejection. Other gene edits involved removing 59 copies of the porcine endogenous retrovirus as a safeguard against the off chance the virus activates once in the new animal (or potential human recipient).
Scientists also added seven human transgenes (a fancy science word for a gene introduced from one organism to another) that play a role in how the immune system modulates inflammation, immunity, blood coagulation, and overall organ rejection.
To see how well genetically modified kidneys stacked once in another animal, the researchers transplanted the genetically altered kidneys into crab-tailed macaques (after having their own kidneys surgically removed). For comparison, some macaques got donor kidneys where only offending sugar molecules were stamped out. Both groups only got one kidney replaced.
Compared to the comparison group, the monkeys with the more altered kidneys survived longer — a median of 24 versus 176 days. A third of monkeys even survived for longer, up to a little more than two years, and are still being monitored. The pig kidneys also appeared to function just as normally.
More research needed
The company, eGenesis, plans to investigate the efficacy and safety of their genetically modified xenotransplant for other organs like the heart and liver. But for now, the CEO of eGenesis, Mike Curtis, gave no timeline of when human clinical trials would be forthcoming. He told reporters that the company is working with the U.S. Food and Drug Administration to provide more pre-clinical data in animal studies, especially for organs like the heart and liver (which are slightly more challenging to modify and transplant), and that the company’s intention was “to work with the agency over the next few months to set the path to the first human trial.”
Jeffrey Stern, a transplant surgeon at New York University Langone Health, who was not involved in the study, tells Inverse one of the most important questions further research will need to answer is whether xenotransplants with so many different genetic modifications may have any unintended immunological consequences for recipients. For example, in knocking out one gene for a molecule at a cell’s surface, there’s the chance you’re exposing other foreign molecules hidden beneath to the recipient’s immune system and, in turn, inadvertently riling it up.
“We could test these [genetic modifications] all day long and then realize that knocking out three more things makes it work a lot better in primates but actually, in fact, make it worse for humans,” says Stern. “There a lot of testing that we can try to do to hopefully not let that happen, but there are certainly situations that, until you cross-circulate with an actual human immune system, you may not know the answers to some of those [changes].”
There’s the hope that with genetically tailored xenotransplants, we may one day cast aside the need for immunosuppressant drugs, which transplant patients need to be on lifelong, Mohamed Ezzelarab, a research associate professor of surgery at the University of Pittsburgh School of Medicine, who was not involved in the study, tells Inverse.
A present concern is that immunosuppression can sometimes be a double-edged sword: in dampening cells and molecules in the adaptive (or acquired) immune response, you might instead activate ruthless others in the body’s first line of defense, also known as the innate immune response. This can be a problem for xenotransplants, says Ezzelarab, since the innate immune system, more so than the adaptive one, can be a formidable barrier in species-to-species organ donation. While genetic modifications done in the new study may take care of some of the hurdles, it’s still yet to be seen how the immunosuppressants used in this study — some of which are not clinically approved for humans and have been known to cause severe side effects — will play out in future clinical trials.
Despite being a work-in-progress, both Stern and Ezzelarab say this new study advances the field of organ transplantation, offering insight into new directions and avenues that could solve the organ supply crisis at hand.
“We are constantly advancing our technology and our ability to modify organs to better with organ failure,” says Stern. “Hopefully, the day will come when the organ shortage will be able to be answered by xenotransplants.”
