A medical team at the University of Maryland Medical Center announced Monday that it had accomplished a world-first: its surgeons had transplanted a heart from a genetically engineered pig into a human. The doctors performed the eight-hour procedure Friday evening. As of Monday night, the man, 57-year-old David Bennett, is awake and breathing on his own, and his new heart is pumping away, according to his doctors.
Bennett had terminal heart failure and was too sick to qualify for a human heart transplant or a mechanical assist device, the lead surgeon said. The pig heart, from an animal created by a Virginia biotech company, was the only option to try to prolong his life. “It was either die or do this transplant,” Bennett said in a hospital news release. “I know it’s a shot in the dark, but it’s my last choice.”
The groundbreaking procedure raises hopes that animal organs might one day be routinely used for human transplants, which would shorten waiting lists — where thousands of seriously ill people languish and die every year. But it’s also raising a few eyebrows and a lot of questions from bioethicists.
“There’s still relatively little known about how safe this is to try in humans, so I’m viewing this with a little apprehension,” said Arthur Caplan, the founding director of New York University School of Medicine’s Division of Medical Ethics.
The transplant was not performed as part of a formal clinical trial, as generally required for experimental treatments. And the immunosuppressive drugs the patient was administered are also novel and have not yet been tested for this use in non-human primates.
It’s also renewing a debate about pigs and other animals as the source of human organs. Animal rights activists have condemned the surgery as dangerous and unethical. In a statement released Monday evening, PETA raised the potential for xenotransplantation to transmit animal viruses to humans and urged researchers to look elsewhere for solutions to organ shortages. “Animals aren’t toolsheds to be raided but complex, intelligent beings,” the organization said.
Scientists have been toying with animal-to-human tissue grafting and organ donation, collectively known as xenotransplantation, for centuries. Throughout the 1800s, doctors treated wounds with skin grafts from a variety of animals — most popularly, frogs. In the 1960s, 13 people received kidneys from chimpanzees. One lived an additional nine months, but the others died within weeks.
In a more controversial episode, doctors at Loma Linda University Medical Center in California transplanted a baboon heart into a premature baby born with a fatal cardiac defect in 1983. She lived for 21 days. It was later revealed that the surgical team had not sought out a human heart before opting for the riskier (and more headline-worthy) primate option.
After these and other failures, the medical community largely turned away from xenotransplantation. The human immune system was just too robust, too good at expelling alien intruders. But the arrival of new and better methods for altering DNA to create designer animals optimized for the purpose of producing human-compatible organs revived the dream. Now there are a handful of labs and companies chasing cross-species transplantation, including Harvard biologist George Church and eGenesis, a CRISPR-focused company that spun out of his lab.
The heart that Bennett received came from a pig created by Revivicor, a biotechnology company spun off in 2003 from PPL Therapeutics, the U.K. firm that produced Dolly the Sheep, the first mammal cloned from a cell from another animal. In 2011, Revivicor was acquired by United Therapeutics, the pharma company founded and helmed by xenotransplantation enthusiast and futurist Marthine Rothblatt.
In December, Revivicor won approval from the Food and Drug Administration for its GalSafe pigs, which have been genetically engineered not to produce a sugar that triggers organ rejection as well as an increasingly common meat allergy caused by a tick bite.
Revivicor is also raising a small herd of more extensively engineered pigs, containing 10 genetic changes intended to make their organs better suited to residing within a human body. The company has not disclosed what methods it has used to achieve these changes, which include inactivating a growth gene — so the porcine heart won’t continue to expand after transplantation — and other modifications to remove molecules most likely to provoke an immune attack.
It was an animal from this herd that was loaded into a van last week and driven five hours northeast to the University of Maryland Medical Center in downtown Baltimore. A few hours before the surgery began, surgeons removed the heart from the pig and placed it in a perfusion box — a mechanical device that pushed fluid through the organ to keep it preserved until the surgical team, led by Bartley Griffith, director of the cardiac transplant program at the medical center, could settle it into their patient’s open chest.
This dramatic bid to save Bennett’s life came after he had been in the hospital for more than a month, being kept alive by an artificial breathing machine, and his medical care team determined that he was too sick to be a candidate for either a human heart or an artificial ventricular assist device. Without either, he wouldn’t live long. “This was the only option available for an existing inpatient, already within UMMC hospital, who was facing near certain death from heart failure,” Griffith told STAT.
In December, Griffith contacted the FDA to obtain an emergency authorization through the agency’s expanded access, or compassionate use, pathway to use Revivicor’s pig heart. On New Year’s Eve, the FDA said yes. It also okayed the use of an experimental anti-rejection drug manufactured by Kiniksa Pharmaceuticals, and the perfusion device.
The medical team then notified the hospital’s institutional review board, which must sign off on all experimental treatments, which it did in this case. An informed consent was obtained from the patient after a thorough ethics review and psychiatric evaluation, Griffith said in written answers to STAT’s questions.
Caplan said that those would be the minimum conditions under which it might be ethically permissible to try something as new as putting an unapproved genetically engineered animal organ into a patient. But there are other things to consider. For example, what will the hospital team do if the patient’s immune system rejects the heart in the coming days and weeks? “You need to think hard about what you’re going to do if the patient is not succeeding and lay those options out during the consent process,” Caplan said.
In 1982, when another critically ill man named Barney Clark received the first artificial heart, no such options had been considered. Clark died a slow, torturous death, wracked by convulsions and kidney failure. His suffering may have advanced science, but bioethicists today consider it a lesson in what not to do.
Griffith did not say what sorts of options were discussed during the consent process with Bennett. “He was informed of the risks and that there were no proven benefits to this,” Griffith said via email. “He was told it was comparable to the care he was currently getting in terms of potential lifesaving benefits.”
There’s also the question of what exactly scientists can learn from a procedure like this one, taking place outside the framework of a clinical trial, and with a patient who is on his deathbed. Trials take months, sometimes years, to set up because they’re designed to gather a bevy of biochemical and physiological information to say conclusively whether or not a treatment is safe and effective. According to Griffith, Bennett, if he survives, will be closely monitored in the hospital for several weeks or even months, until he can be sent to a rehabilitation center. He did not provide specific details about what sorts of data they plan to collect.
Caplan has argued that before clinical trials of engineered animal parts can proceed, researchers need more information. At his home institution, New York University, which is also in the race to xenotransplant, he proposed testing these types of organs first in newly deceased humans — to gain preliminary insights about how to safely proceed. Beginning late last year, NYU Langone has done two experiments testing genetically modified pig kidneys in the donated bodies of people who had recently died and were being maintained on a ventilator. That research showed that organ rejection of a xenotransplant can be prevented during the first few days.
Griffith said that work gave his team more confidence in proceeding. But he acknowledged that the longer-term outcomes are unknown. “Rejection of the organ can occur any time after transplant,” he wrote. The surgeon added that while organ rejection, which can be life threatening, is the greatest risk Bennett faces, there are also risks from the drugs used to suppress the immune system to prevent rejection. “The intensity of immune system suppression required is higher with a xenotransplant than with a traditional transplant from a human donor,” he said.
It’s still unclear when a formal test of engineered pig organs might move forward. When asked about the company’s plans to test its pigs organs in a clinical trial, Dewey Steadman, a Revivicor spokesman, declined to share any details. “We are continuing to work with the FDA on a clinical and regulatory path forward,” he said via email.
https://www.statnews.com/2022/01/10/first-transplant-of-genetically-altered-pig-heart-into-person-sparks-ethics-questions/
