Bartley Griffith is a cardiac surgeon at the University of Maryland, Baltimore, who says he’s probably done over a thousand heart transplants over a career that has spanned four decades. But on January 7 of this year, Griffith performed an operation unlike any other. He transplanted a pig heart into a human for the first time.
When Griffith released the clamp off of his 57-year-old patient’s new heart, blood rushed through David Bennett’s coronary arteries and transformed the pale lifeless pig organ into a vivacious scarlet pump. “The heart fired right up,” Griffith says.
But 60 days later, Bennett passed away, and doctors could not identify a specific cause of death. Answers have only now begun to emerge after Griffith’s team published their report of the historic operation in The New England Journal of Medicine. Considering the reasons why Bennett may have died will help doctors as they prepare for future pig heart transplants.
“Cardiac xenotransplantation,” or the transfer of a heart between species, was first performed in 1964 with a human recipient: University of Mississippi surgeon James Hardy implanted a chimpanzee heart into the 68-year-old Boyd Rush. At least eight other similar cardiac xenotransplants took place over the next half-century, none of them quite successful.
With the gene-editing possibilities of CRISPR though, this time was different. Biotech company Revivicor designed pigs with ten genetic changes, deleting four pig genes and adding in six human ones, so that their organs would be more compatible with humans. Bennett, who had end-stage heart failure, was not eligible for a human heart because of his history of not following his doctors’ orders. So, on his deathbed and without any other options, Bennett got a heart from one of Revivicor’s pigs under the Food and Drug Administration’s (FDA) “compassionate use” authorization, allowing experimental treatments for emergency cases.
Currently, 17 individuals die every day on the transplant waiting list, and xenotransplantation, if fully realized, could end the national shortage of 100,000 organs with an almost unlimited supply of pigs. If these pig organ transplants are to one day replace human-to-human transplants, scientists will have to learn how to make xenotransplantation safe, accessible and truly life-extending.
As such, attention has naturally shifted away from the novelty of Griffith’s operation toward trying to understand Bennett’s cause of death. Griffith’s report clearly lays out the facts of the case. Capillaries around Bennett’s heart exploded, which caused fluid to leak out and his heart to double in size. Because those busted capillaries fed the heart with oxygen, cardiac muscle cells began to die in their absence. On day 60, Griffith’s team withdrew life support because Bennett’s heart had been irreversibly damaged.
But why’d this happen? “We still don’t really know,” Griffith admits. His paper considers three major possibilities, but a fourth unifying explanation exists as well.
Organ Rejection May Have Occurred
One of the biggest concerns with any transplant is the risk of rejection where the body’s immune system sees the donor organ as foreign and destroys it. Unless the donor and recipient are identical twins, some rejection is inevitable, but doctors can usually limit organ rejection with drugs that suppress the patient’s immune system.
In Bennett’s xenotransplant, Revivicor’s genetic changes “humanized” his pig heart to evoke less of an immune response, and Griffith’s team gave him a cocktail of immunosuppressive drugs for additional protection. Consequently, Bennett tolerated his new organ fairly well over the first month, and the biopsies never showed evidence of acute rejection, according to Griffith.
But evidence exists that rejection did in fact occur, according to xenotransplantation pioneer David Cooper, whose early work helped kickstart the genetic engineering effort to make pig organs more human-like. Griffith’s report declares that damaged capillaries and a swollen heart are “not consistent with typical rejection,” but Cooper, who is also a senior investigator at Massachusetts General Hospital, says that these findings are classic signs of organ rejection from xenotransplant experiments 30 years ago. Cooper believes that not keeping immunosuppression levels high enough over time, perhaps because of medical professionals’ lack of experience with this novel experiment, may have contributed to organ rejection in Bennett’s case.
Anti-Pig Antibodies May Have Attacked the Heart
On day 43 after surgery, Bennett was given something called intravenous immunoglobulin (IVIG) in order to treat a potential infection. Prepared from blood donations from thousands of individuals, IVIG is a highly concentrated antibody therapy that is given to boost a patient’s debilitated immune system.
Transplant surgery is about balancing the dual risks of organ rejection and infection: if the immune system is too strong, it will destroy the organ, but if it is too weak, the patient will die of infection. In this case, Griffith’s team may have initially overdone the immunosuppression, so they had to give IVIG to bolster Bennett’s immune system and help him fight off his infections.
The problem is that, among a diverse collection of antibodies, IVIG naturally contains anti-pig antibodies that could’ve attacked Bennett’s heart. Griffith is quick to point out that, in Revivicor’s testing, IVIG didn’t appear to kill pig cells. But he also recognizes that, in real life, IVIG’s anti-pig antibodies could have nonetheless targeted and destroyed the pig heart, killing Bennett in the process.
A Pig Virus May Have Blown Up the Heart
One of the more dangerous infections Bennett contracted was porcine cytomegalovirus (pCMV). The virus is found only in pigs and usually has no bearing on their health beyond sneezing and a runny nose. But if pCMV makes it into humans, it could theoretically cause a deadly pandemic. Revivicor thus takes extensive precautions in raising pigs for xenotransplantation, for example housing them in biosecure facilities and testing them for pathogens with regular nasal swabs.
But this viral testing may not have been stringent enough. Mike Curtis, CEO of the xenotransplantation company eGenesis, says that nasal swabs can’t pick up dormant infections in adult pigs, so he was surprised why Revivicor had used them. Instead, actual blood testing should have been done to ensure the donor pig didn’t have any type of pCMV, Curtis says.
Griffith thinks the pig heart may have been infected with an inactivated form of pCMV that, when inside Bennett’s immunosuppressed body, “woke up, blew up some capillaries, and killed the heart,” he says.
Bennett May Have Been Too Sick to Benefit from the Organ
“Which one of these things was the cause?” Curtis asks, referring to the three possibilities considered in the report. “Maybe it wasn’t any one thing, but it was a combination of all.”
Cooper thinks a simpler explanation exists. “They chose a patient who was too debilitated to undergo this procedure,” he says.
Bennett had been confined to his hospital bed for two months before his operation, with his condition so bad that he needed ECMO (extracorporeal membrane oxygenation) to replace the function of his heart and lungs. While ECMO is a life-sustaining technology, over long periods of usage, it causes organs to gradually deteriorate. Bleeding in his digestive tract and a bacterial infection in his blood also probably weakened Bennett before the operation. “The odds were stacked against them from the beginning,” Cooper says about Griffith’s team. “You have to choose a patient that has a realistic chance of doing well.”
Griffith similarly recognizes that “David was almost too sick to benefit,” but he frames this xenotransplant as a learning opportunity. With further testing expected to provide more clarity over Bennett’s death, Griffith is confident that, whether it was because of rejection, IVIG, infection, or all the above, they will learn to fix it.
What Comes Next?
Bennett’s postoperative course was filled with numerous attempts to save his life. He needed continuous dialysis because his kidneys were failing. He needed emergency abdominal surgery because he had unexplained belly pain. He needed ECMO restarted when his heart started to deteriorate. “This patient's two months must have been a nightmare for him, as well as the medical team,” says Cooper. He doesn’t think putting another similarly sick patient through a pig heart transplant has much value. Instead, Cooper thinks that surgeons should go straight to clinical trials with patients “who are in reasonably good shape and have a realistic chance they will do well.”
Griffith estimates that it will take at least a year-and-a-half before the FDA approves a clinical trial for xenotransplantation, but rather than wait that long, he intends to continue these one-off surgeries in the interim. Because the best way to learn is by doing, Griffith feels that every additional xenotransplant over the next 18 months will allow him to better optimize patient survival in the ultimate trial. Of course, the only way to get more experience at this point is through operating on “compassionate use” patients who, like Bennett, have no other options left.
“Patients are a remarkable source of courage; they make us, the physicians, courageous because they’re willing to go forward, even though they don’t have a snowball's chance maybe,” Griffith says. “They still go for it because it’s better than certain death.”