Animal-to-human transplant could be the key to tackling the organ donor shortage

"The other is that there aren't enough animal organs to go around in the short term, so they are also added to the illegal trade. And then, people who are on the waiting list for organs — but way down — may go abroad to get pig kidneys or hearts as they're ineligible for human organs but also not sick enough to be enrolled in a clinical trial in their country," he says.

And that would be riskier, as people would be receiving such organs without proper clinical procedures.

"My fingers are crossed - one day, it could alleviate the need for illegal organs, but in the short term, it could make it worse," says Parent.

Last year, surgeons at N.Y.U. Langone Health attached a genetically modified pig kidney to a brain-dead patient sustained on a ventilator. In another breakthrough move, surgeons at the University of Alabama in Birmingham transplanted two genetically modified pig kidneys inside the abdomen of another brain-dead human after removing the recipient's native kidneys. 

Earlier this year, in a groundbreaking procedure, surgeons from the University of Maryland transplanted a genetically altered pig heart into a living person - a 57-year-old patient called David Bennett. Although Bennett passed away two months after receiving the porcine heart, the transplanted pig heart performed well for several weeks, suggesting that xenotransplantation may be the future of organ transplantation.

Who gets a pig organ?

According to the Organ Procurement and Transplantation Network, U.S Department of Health and Human Services, more than 100,000 Americans are currently on transplant waiting lists, most of whom — around 92,000 — need a kidney. Approximately twelve people on the waiting lists die each day.

In such circumstances, xenotransplantation offers numerous prospects - an unlimited supply of organs and cells for clinical transplantation, thereby ending waiting lists and the critical shortage of human tissues. It may even stop organ trafficking. Cross-species transplantation, even though centuries-old, essentially led to failure, organ rejection, and the patient's death. However, the idea gained steam after scientists figured out why the human body fiercely rejected animal organs and how to outwit that process.

But what makes someone a potential suitor for xenotransplantation?

"Regarding the eligibility, there are no standards or expectations right now because this is all research. There are no guidelines that are codified in law or rules. Currently, all the rules apply solely to human organ transplants. And the people who are performing the procedure with nonhuman animal organs are pioneering the space," says Parent. 

People who will be receiving the first animal transplants are, of course, ineligible for other organs. "We cannot justify giving a pig heart or a pig kidney to a person who could potentially have their life saved by human organs. So that means we have to start with people who have no other options," he continues.

Bennett had been terminally ill with severe heart failure and had ended up on an artificial heart machine. He was ineligible for a conventional heart transplant and was offered the experimental option of a genetically modified pig heart.

But that can be tricky, Parent feels. This very group of people is vulnerable and subject to the possibility of undue influence.

"If you tell someone who is actively dying that we could perform an animal transplant that could save their life, they're going to say that they want that. We have to make sure that the people who receive such transplants are adequately informed - engaging them in a way where they retain control over the medical care that they understand as research," explains Parent.

The procedure, he says, cannot be termed as a treatment, per se, as there isn't sufficient data available.

Evaluating the impact of transplanted animal organs

While a living person, Bennett, received the pig heart, the pig kidneys were transplanted into humans who were already brain-dead and where there was no hope of recovery. 

And so, naturally, the first thing I asked Dr. Jayme Locke, MD, Director of the Comprehensive Transplant Institute in the University of Alabama’s Department of Surgery, was how much useful information her team receives when xenotransplantation is performed on someone who is brain-dead. After all, bodily functions tend to deteriorate rapidly after brain death, making it difficult to assess the full impact of transplanted organs. 

For more context, it was Dr. Locke's team that had transplanted the genetically modified pig kidneys inside the abdomen of the brain-dead recipient. 

"Really great question," Dr. Locke tells me. "One of the things we had to do was develop a flow cross-match (a standard technique for evaluating the compatibility of potential kidney transplant recipients and donors) that would be specific for the pig kidney going into a human. And that had not been done before."

If the tissues do not match (confusingly known as a positive cross-match), the kidney turns black and fails - known as a hyperacute reject. "So we developed that cross-match and predicted ahead of time that this deceased donor would have a negative cross-match with the pig. But the only way to validate that was to do the transplant and make sure that the kidney turns pink [and stays pink] and doesn't get rejected. This happens within the first few minutes of the transplant," explains Dr. Locke.

As a practicing transplant surgeon, she says it was crucial to understanding this before performing the transplant on a living person.

"To perform the surgery on a living person and not to know whether or not it was going to be immediately rejected just seemed like the wrong thing to do. If it did immediately reject, that would have been a futile transplant. And I don't think subjecting a living person to a futile surgery is the right thing to do," she says.

Is an animal organ a permanent solution?

Can transplanted organs from animals provide a lasting replacement? Or are they a temporary option - intended to last just long enough to keep the patient alive until human organs are available?

"I think we can only answer [that question] when we move this into the living," says Dr. Locke. 

"The pig was, in part, chosen as the animal source because we know pigs have a lifespan of about 30 years, so we would expect the kidney, in theory, to last that long. But, until we put one of these in a living person, we're not going to really know whether this is going to be a bridge to allow human to human [transplantation] or whether this will be the destination - you get that pig kidney for the rest of your life," she says.

Dr. Locke is hopeful that a Phase One clinical trial in living people can be conducted in the next year or so.

"In the U.S., the pig kidney is regulated by the Food and Drug Administration. We have to get the approval of the pig kidney as a product to be able to put that into a living person. That's what we're working on now," she says.

Since the pig kidneys have undergone a 10-gene genetic edit to make them compatible with humans, concerns about blood type have been eliminated.

"The pigs have been genetically engineered to be a universal blood donor. The next test is that, in my opinion, at least in the early stages, [the recipient needs] to be compatible with the pig kidney. And in some early studies, we've found that somewhere between a third and two-thirds of humans are completely compatible with this pig kidney. So, I think that will be the subset that we need to start this with," says Dr. Locke.

An unethical space, given free rein

Since the first recorded xenotransplantation, critics have questioned the ethics behind rearing animals only to kill them for their organs and give them to humans.

"But people usually respond to this and say, 'we eat animals all the time. We could raise them in a nice facility with quality care because we're going to give their organs to people and eventually kill them to save a human's life," says Parent.

"But, maybe, it's the opposite. We need to rethink the whole enterprise of rearing animals, which are living, breathing, sentient beings for human use," he tells me.  

And then, there is also the possibility of a zoonotic virus transfer.

"We're living in a pandemic right now, one that probably resulted from the transfer of a virus from a nonhuman animal to a human. The possibility of taking an endogenous porcine organ that may have a virus and putting it into a human could have catastrophic consequences, not just for the recipient of that organ, but for the rest of the world," says Parent.

Another ethical issue would be developing adequate global regulations for the procedure.

Because of organ shortages, all of the authorities concerned need to be very deliberate and careful about guidelines for how the organs would be allocated and the recipient's well-being. "All these outcomes are usually monitored. But as xenotransplantation involves nonhuman animal organs, it doesn't fall under the purview of these regulations," points out Parent.  

Without adequate oversight, there is always the potential for significant safety issues and rogue transplant procedures. 

People who aren't certified to do transplant surgery could be performing them, and we may not be able to know what happens to the recipients. "So we have to make sure to monitor who's doing it, what the outcomes are, and publish the results. This has to be researched in clinically regulated trials," says Parent.

The future: More animal, less human

Although humans are just like every other organism in that we have evolved from other organisms, some philosophers and others have argued that humans are "elevated above nature for their capacity for deliberation and ability to judge and comprehend meanings."

But what happens when if xenotransplantation were to become commonplace - when humans can merge animal and human?

"That's an interesting question. What are the lines between being human and being a nonhuman animal? Do we breach some sort of ethical barrier when we make animals have more human parts? Or do we dehumanize a person when we give them a nonhuman animal organ?" asks Parent.

However, the gap between nonhuman animals and humans is far smaller than many people might think.

"Because we do know that nonhuman animals have complex reasoning - some of them suffer, they experience pain, fear, and in some cases, even depression. And so, I don't think there's a problem per se to acknowledge that we are closer than we thought we were. But, at the same time, maybe the problem is that we don't have a right to take these organs from these creatures, which are closer to us than maybe people previously thought," says Parent.

Not a quick fix, but a bridge

From what it looks like, if we go down this route and start rearing animals, in all probability, we could get comfortable with xenotransplantation as the final solution to organ transplant shortage - as a renewable and sustainable organ source.

"But is it really right?" Parent asks me. "Because if we do so, you could imagine a future where every person has their own pig waiting somewhere in a factory. And then we could end up exploding the animal agricultural industry, which would increase environmental pollution," he says.

Xenotransplantation using nonhuman animals can't just be the end, argues Parent.

Instead, it is a stepping stone for organ transplants. "It has to be a bridge to bioengineering, which can be the solution to this problem," he says.

"But, even more important than bioengineering humans, we need to address the social determinants of health that lead to organ failure in the first place. Why are people's organs failing? Why do we need a transplant? It's because our diets aren't good, we're not getting enough exercise, our medical care isn't efficient, and many of us don't have access to shelter and water," says Parent.

If these problems are addressed in the first place, our organs won't fail too early or nearly as often - which means we won't need as many organs.

The processes of transplantation and bioengineering could also be too easy, "a band-aid to the [main] problem, which is making sure that people have access to basic needs," he says. "We're too fixated on the scientific and technological progress to create solutions to fairly simple problems that we could solve with better health care and better equality or distribution of wealth in society," adds Parent.