When Dr. Griffith removed the clamp from his new heart, the blood flowed through the patient's coronary arteries and the organ began to function properly.
But 60 days later, a 57-year-old patient, David Bennett, died, and the doctors were unable to determine the exact cause of death; the answers began to appear only now, after Griffith's team published their report on the operation in the New England medical journal, which will help doctors prepare for future heart transplants.
How did such an operation become possible?
A biotech company, Revivicor, raised pigs with an edited genome: they removed four genes of pig and added six human beings to make the organ more compatible.
Bennett had a terminological state of heart failure, he was not entitled to a human heart transplant because he had failed to comply with doctors' orders in the past, so that Bennett received a heart from a pig, Revivicor, and the transplant procedure was approved by the Food and Medicine Health Inspectorate.
Today, 17 people die every day on the transplant waiting list; if doctors complete xenotransplantation, it will put an end to the shortage of about 100,000 organs a year.
Xenotransplantation or inter-species transplantation is the transplantation of organs, tissues and/or cellular organoids from the organism of one species to the body or part of another species.
The first surgery failed, and now the doctors want to understand the reasons.
Why did the first patient die?
Griffith's report clearly stated what was happening to the patient's body before he died. The capillaries around Bennett's heart exploded, causing a leak of fluid, and his heart doubled. Because these bursting capillaries supplied the heart with oxygen, the heart muscle cells gradually began to die. On the 60th day after the operation, the Griffith team shut down the life support system, because Bennett's heart was permanently damaged.
- The organ was rejected
One of the biggest problems associated with any transplant is the risk of rejection, when the immune system perceives the organ as an alien and destroys it. If the donor and the recipient are not identical twins, a small risk of rejection is inevitable. Doctors try to minimize this risk with medication that suppresses the patient's immune system.
Before the surgery, the pork heart was genetically redacted to be closer to human beings, and Griffith's team added an immunosuppressive cocktail to it for additional protection, so Bennett lived quite well with his new organ for the first month, and, according to Griffith, the biopsy showed no signs of acute rejection.
But there's evidence that rejection could actually have happened, says the innovator in the xenotransplant, David Cooper. The Griffith report says that damaged capillaries and a swollen heart "didn't look like a typical rejection." But Cooper says that these are classic signs of organ rejection. Cooper thinks that this was due to insufficient maintenance of immunosuppression.
- The antibodies attacked the heart.
On the 43rd day after Bennett's surgery, an I.V. administered a drug called immunoglobulin to cope with a potential infection.
During the transplant surgery, you need to balance two risks: organ rejection and infection development. If the immune system is too strong, it will destroy the organ, but if it's too weak, the patient will die of infection. In this case, Griffith's team may have overreacted initially, so they had to introduce IVIG to strengthen Bennett's immune system and help him fight infection.
The problem is, among the different kinds of antibodies used, there might be those that target pigs, and these antibodies could in theory attack Bennett's heart, and according to Griffith, when testing Revivicor IVIG, they probably didn't kill pig cells, but he also admits that in real life, antibodies against pigs IVIG could destroy the heart.
- The pig virus destroyed the heart.
One of the most dangerous infections that Bennett contracted was the cytomegalovyrus of pigs. The virus is found only in pigs and usually has no effect on their health except for small cold symptoms. But if a pCMV hits a person, it could in theory cause a fatal pandemic. In Revivicor, it took all precautions in the cultivation of pigs for xenotransplantation, for example, they were held in biosecurity rooms and tested for pathogens with regular nose swabs.
But this test may not have been rigorous enough. Mike Curtis, CEO of eGenesis Xenotransplantation, says that nose swabs can't detect a hidden infection in adult pigs, so he was surprised why they were used in Revivicor. Instead, Curtis said he had to run a blood test to make sure that the pig donor didn't have any type of pCMV.
Griffith believes that the porcine heart may have been infected with an activated pCMV form that entered Bennett's immune system, then the pCMV woke up, blew up a few capillaries and killed the heart.
- The patient was too sick to live even with a new organ.
Perhaps the reason was not one, but a combination of all the factors.
Cooper thinks there's a simpler explanation. "The patient was too weak to go through this procedure," he says.
Bennett was chained to a hospital bed for two months prior to surgery, and his condition was so severe that he needed ECOME to restore the function of the heart and lungs. ECOM is a procedure for maintaining life, but with prolonged use it causes gradual organ destruction. Bleeding in the digestive tract and bacterial infection in the blood also probably weakened Bennett's body before surgery.
Griffith also admits that David was too sick, so he says that this xenotransplantation should be seen as an opportunity for learning. Further testing is expected to help learn more about the causes of Bennett's death. Griffith is confident that regardless of what happened, they will learn to correct it.
What happens next?
Griffith estimates that it will take at least a year and a half before the FDA approves clinical trials of xenotransplantation, but he does not intend to wait so long and intends to continue these one-off operations.
According to him, the best way to learn is to do so, so each additional Xenotransplant over the next 18 months will enable him to optimize the survival of patients.