Why recent animal-to-human organ transplants are just stunts – for now

For two months, a genetically engineered pig heart kept 57-year-old David Bennett alive. He received the organ during a historic transplant surgery at the University of Maryland Medical Center after being deemed ineligible for a human donor heart.

The experimental procedure, along with recent test transplants of genetically engineered pig kidneys into brain-dead people, has renewed decades-old hopes that animals could help meet the need for donor organs. The latest advances have been driven by the development of powerful and easy-to-use gene editing tools.

But significant hurdles remain before animal-to-human transplants could become anything other than one-off experiments. Doctors and scientists would need to conduct extensive clinical trials to win regulatory approval for such procedures. Part of that process would involve learning how to make sure that human bodies wouldn’t reject organs from other species over the long term. There are also ethical concerns — from how to equitably distribute any new supply of organs to more fundamental questions about whether harvesting animals for transplants can be justified.

“That’s groundbreaking success,” said David Mulligan, director of the Yale New Haven Transplantation Center. “But as you can imagine, it’s only a fraction of all of the people waiting for lifesaving organ transplants.”

Altering animal genes

To address the organ shortage, biotechnology companies have turned to xenotransplantation, the process of transplanting cells, tissues or organs between different species — in this case, moving pig organs into humans. The genetically modified pig that served as Bennett’s donor was engineered by Revivicor, a subsidiary of United Therapeutics Corporation.

In all those cases, the kidneys showed signs of normal function, including the production of urine.

Revivicor scientists modified a gene in the GalSafe pigs to block the production of a sugar molecule called alpha-gal. It’s found on the surface of cells in most mammals, except for monkeys, apes and humans. Human bodies see alpha-gal as a foreign invader, which is one of the reasons why a person’s immune system rejects transplanted organs from other species. By eliminating alpha-gal in pigs, a human recipient’s immune system is much more likely to accept a porcine organ.

The company also modified nine other genes, including one controlling the pig’s growth hormone receptor, to make the animal “more human-like and less pig-like,” said Mulligan.

The Food and Drug Administration approved the pigs in late 2020 for food consumption by people who are allergic to the alpha-gal sugar molecule, and potentially for tissue and organ transplants. Other biotech companies, including eGenesis, are using the gene-editing tool CRISPR — essentially, a kind of molecular scissors — to make pigs whose organs can be transplanted into people.

Organs from genetically modified pigs might eventually be able to function for many years, or they might only be able to serve as a bridge until a patient can receive a human organ transplant. There is wide variation in how long organs from human donors last. Another big question, Mulligan said, is whether a pig heart can withstand the physiological demands of a human when they are moving or exercising.

Transplanting other organs like kidneys and livers is even more complex, he noted. Unlike the heart, which is essentially a muscular pump, the kidney removes waste and extra fluid from the body and produces urine through a series of highly complex steps. Similarly, the liver filters out toxins in the blood, regulates blood sugar levels and creates essential nutrients.

A regulatory puzzle

Bennett’s heart transplant was conducted under emergency authorization from the FDA, which regulates any live cells, tissues and organs from nonhuman sources. That meant it took place outside the purview of UNOS, which is responsible for overseeing all human organ donations and transplants. But if animal-to-human transplants ever become routine, there will need to be a set system to oversee the process.

After the pig heart surgery, Mulligan, the former president of UNOS, got a call from the director of the University of Maryland transplant program, Daniel Maluf. Maluf said, “David, we did this transplant, and I don’t know how we are going to be able to report this to UNOS,” Mulligan recalled. The pig donor did not exist within the UNOS system, and because the recipient, Bennett, had been deemed ineligible for a human heart, he was not registered either.

If more surgeries like this are going to happen moving forward, whether as proofs of concept or through clinical trials, “we’re going to have to figure out how can we oversee the care of these patients so that their safety is maintained,” Mulligan said.

When it comes to distributing pig organs, “who is going to be in charge of that? Will it be a panel or committee who will decide their distribution? And what kind of factors will be taken into account?” said Keisha Ray, a bioethicist at the University of Texas Health Science Center at Houston who studies issues related to biomedical enhancements. “How are we going to make sure that the people who need it the most have access to it?”

Globally, countries’ regulatory frameworks are already diverging, creating siloed markets for these commercially tradable organs. “Markets create inequities,” said Nils Hoppe, director of the Center for Ethics and Law in the Life Sciences at Leibniz University Hannover in Germany.

“I think xenotransplantation is a wonderful thing,” said Hoppe. However, “we have a unique opportunity now to create a regulatory framework that fixes some of the problems that we normally have in this field.”

An ethical quandary

There is also a major ethical question at play: Whether humans can morally alter pigs’ genomes to harvest the animals’ organs.

Bioethicist Julian Koplin at the University of Melbourne Law School finds this line of thinking deeply problematic. Just because xenotransplantation may involve better treatment of pigs than factory farming doesn’t provide enough reason to accept it, he said — especially when many people agree that industrial farming is inhumane.

The way in which the surgeries are performed and how the data is employed are also important considerations.

“I have a lot of conflicting feelings, and I think, like every other ethical challenge, the details really matter,” said Lisa Moses, a veterinarian who teaches medical ethics at Harvard Medical School. “It’s really dependent upon the way in which it’s done and the context and what kind of guidelines we use.”

One thing that concerned Moses about the recent pig heart transplant is the fact that it was done under an emergency authorization, meaning the findings cannot be used to evaluate the overall risks and benefits of such procedures.

“It was not done in the context of a research trial, it was done as a private individual without any intent to generate generalizable knowledge,” said Moses. “We have basic research regulations in this country that have to be followed in order for collected knowledge to be published and verified, and that’s not being done here.”

Moses wishes more energy, money and time would be put toward solutions that don’t require growing and harvesting animals. “My ideal world would be that we would redirect a lot of our money and efforts toward the giant promise that was made of growing human organs completely in a lab,” she said. “We simply haven’t devoted the resources and intellectual power and will toward finding other options. It keeps just being cheaper and easier to just keep using animal bodies.”

The weight of big promises

There is nothing wrong with this process taking longer than expected, as safe, ethical science requires ample time. But for those on the waitlist for a new organ, this can be devastating.

“With transplants, you’re going to die if you don’t get the organ,” said Jordan Rogers. When Rogers was 11 years old, his 7-year-old sister needed a liver transplant due to a genetic disorder that caused severe liver damage. After around four years of waiting, she finally got the transplant. “It’s very black and white,” he said.

The often-lengthy wait for a transplant may also lead to people putting off other necessary surgeries or medical treatments because they’re waiting on a life-changing procedure that may never come, Rogers noted. Biotech companies “need to think long and hard about the difference between the marketing that they need to do and the decisions people might be making in their medical lives because of that marketing,” he added.

There is also the emotional toll that comes with this anticipation. “They’re waiting for better health and all of the things that come with health,” said Ray. “I feel heartbroken for these people.”

Biotech companies’ big promises are often prompted by a need to find investors. ”In order to get funding, these institutions want you to talk a big game,” said Ray.

And it’s worked — in 2021, eGenesis raised $125 million and MiroMatrix Medical, a biotech company that’s working to combine pig and human cells to create new organs, raised $27 million. Revivicor was bought by United Therapeutics back in 2011 for $7.6 million.

There is no question that xenotransplantation has the potential to address the organ shortage crisis. However, if the science pans out, it will likely take years before pig organs are produced on a large scale. Many patients who are currently on the organ transplant waitlist will die before that day comes.

For biotech companies focused on promoting their work — no matter how vital — that’s worth considering, too.