Here’s a perennial health problem facing humanity: We don’t have enough organs for those in need. In the U.S., more than 100,000 people are on the waitlist for a new organ; every day, around 17 die waiting for one. But even with a life-saving transplant, most people have to be on immunosuppressive drugs to prevent rejection, compromising their body’s ability to fend off infections and cancer.
One solution to the limited supply of organs is xenografts — a tissue or organ transplanted from one species into another or, in our case, from an animal like a pig or chimpanzee into humans. Since our immune systems would definitely recognize a xenograft as non-human, this doesn’t make the challenge of ensuring the success and survival of an organ transplant any better.
Enter gene editing. By removing or modifying genes for certain proteins, scientists are modifying animal organs — from hearts to kidneys — to make them more compatible for human use. In a proof-of-concept surgery revealed on Wednesday, surgeons at New York University Langone Health took one such genetically modified kidney from a pig and transplanted it into a brain-dead patient whose family consented to the procedure. The pig kidney, which contained additional tissue from an organ called the thymus, appeared to work just as well as a human kidney and wasn’t rejected in the month following the surgery.
It’s the latest milestone in the “journey to create an unlimited sustainable source of organs for transplantation,” Robert Montgomery, director of the NYU Langone Transplant Insitute, told reporters during the press conference.
What’s new about this transplant?
The procedure, performed on July 14, is the fifth xenotransplant performed at NYU Langone in the last few years.
Prior efforts involved a genetically modified pig kidney transplanted onto a brain-dead patient's leg, outside the abdomen, in September 2021 and again on a separate patient in November 2021. In the summer of 2022, surgeons transplanted genetically modified pig hearts into two brain-dead patients — one in June, the other in July – whose bodies were donated to science. These transplants followed a procedure done by the University of Maryland in January 2022 where a genetically modified pig heart was transplanted into a living human who died two months after. The cause of death wasn’t organ rejection but was believed likely from a porcine virus in the xenograft.
As with the prior efforts, the kidney xenotransplant came from a pig whose herd descends from an ancestor genetically altered not to have alpha-gal, a sugar molecule humans lost during our evolution but which remains in mostly mammals like pigs, cows, and deers. Known as a GalSafe pig, it was supplied by Revivicor Inc., which was granted federal approval to make the genetically modified animal in 2020.
“Humans have high levels of antibodies against [alpha-gal], which causes hyperacute rejection,” said Montgomery, explaining that deleting its gene prevents this undesirable reaction.
In addition to editing out alpha-gal, a layer of tissue from an organ called the thymus was nestled right under the outer layer of the kidney. The thymus is a small gland located in the upper chest, and its job is to train immune cells, specifically T cells, to recognize proteins that are innate to our bodies from those that aren’t.
“Transplanting the thymus from the pig allows new developing cells in the recipient’s body to recognize the pig’s antigens as their own,” Adam Griesemer, associate professor of surgery at NYU Grossman School of Medicine, told reporters during the press conference. “It can potentially lead to a decreased immune response and decreased risk of rejection of the xenograft.”
Promising results
Montgomery said that with this fifth xenograft, the surgeons hoped to answer two questions unanswered with their previous attempts: whether the pig kidney would last long enough without being rejected (previous efforts evaluated organ and recipients for 54 to 72 hours after transplant), and whether the pig kidney could do the same job as a human one.
The kidney was transplanted into a 57-year-old man diagnosed with glioblastoma who fell unconscious after a biopsy confirming his cancer and later declared brain dead. His family elected to donate his body since his organs weren’t eligible for organ donation due to his cancer.
Both of the deceased’s kidneys were removed and replaced with one genetically modified pig kidney, which was screened for any potential pathogens like porcine cytomegalovirus. The new kidney immediately produced urine after the surgery. During the 32-day observation, while the deceased was on a life support system, there were no signs of organ rejection based on regular tissue biopsies, and the pig kidney continued to work pretty well, said Montgomery.
More research before clinical trials in humans
The study remains ongoing as the researchers continue to monitor the kidney for the next two months. By then, they say they will have a better idea of how effective the whole procedure is, especially whether including that bit of thymus is truly helpful toward minimizing the immune response. If it is, it could lead to strategies for other organs like the liver and lungs, which are notoriously more immunologically challenging than the kidney.
“I think there’s compelling [evidence] at this point that should give further assurances about starting some initial phase one clinical trials in living humans,” Montgomery said.
But the success in deceased recipients doesn’t mean human clinical trials are forthcoming any time soon. Montgomery and his colleagues are hopeful, however, that further research in more deceased recipients and success with longer observation periods will set up a foundation for carrying the research over to the thousands awaiting an organ.
