In 2022, surgeons transplanted the first genetically engineered pig heart into a human. Fifty-seven-year-old David Bennett, a patient with heart failure, survived almost two months with a pig heart beating in his chest, one of five people who have received pig organs as a part of an experimental procedure called xenotransplantation — the transplanting of living cells, tissues, or organs from one species to another.

Some scientists view these pig organs transplants as potentially lifesaving for many like Bennett.

In the US alone, more than 100,000 people are waiting for an organ transplant, and almost 20 people die every day because they can’t get one in time. But a major challenge remains in making xenotransplantation work: scientists haven’t figured out how to get a human body to accept a pig organ for very long. None of the five patients who received these pig organs have survived beyond two months, though researchers believe they’re making progress toward overcoming rejection and eventually moving to clinical trials.

This push to make pig organs viable for humans also comes with enormous ethical implications — from concerns surrounding the use of humans in an experimental procedure that they’re highly unlikely to survive, to the impacts on animals who are supplying the organs themselves. At first glance, the pursuit can feel like hubris. I wanted to better understand these questions, so I spoke with bioethicist L. Syd Johnson, author of a 2022 paper on the ethics of xenotransplantation, for Unexplainable, a Vox podcast that explores unanswered scientific questions. A portion of our conversation, edited for clarity, is included below.

Mandy Nguyen: Before you started doing this research, what were your general impressions of xenotransplantation?

L. Syd Johnson: My initial impressions of it were, ”Boy, this doesn’t really sound like something that’s going to work.” It’s something that in theory might be possible, but there have actually been experiments in xenotransplantation going back to the 1960s, and some of the first experiments involved hearts from chimpanzees.

One of the reasons why doctors were looking to get organs from other animals was because there wasn’t a supply of [human] organs at the time. Transplantation was sort of just starting out and they were just starting to have success with figuring out how to do it, but there was no legal mechanism at that time to obtain organs from humans who had died. So they were looking at animals, which they could kill and take their organs.

I think the first time I ever heard of xenotransplantation involved a case in the 1980s, which was a pretty famous case involving an infant named Baby Fae, who received a baboon heart. She was born with hypoplastic left heart syndrome, which is a fatal condition, and then, as now, it was very difficult to obtain organs that were the right size for an infant.

That was a really famous case where the doctor involved was actually sort of notorious and was criticized for what he had done. And of course, baby Fae also died.

From those initial experiments that failed, how did we suddenly get to this being done in living people today? What was that jump?

The leap was that we have this relatively new genetic editing technology, CRISPR Cas9, and it has enabled scientists and investigators to perform lots of gene edits on an animal.

Several decades ago, the US Public Health Service essentially told investigators that it was too dangerous to try to transplant organs from monkeys, baboons, chimpanzees [into humans], because they were so similar to humans and had a lot of viruses that could be transmitted to a human patient through an organ. That took organs from non-human primates off the table.

The effort to use pigs comes about because of the ability to genetically modify those pigs. We are not nearly as closely related to pigs as we are to the nonhuman primates, so the development of CRISPR, the ability to do lots of gene edits on an animal, is what has led to the current optimism on the part of scientists about the possibility that xenotransplantation using organs from pigs might be able to work.

Right. And now to temper that optimism — what do you see are the biggest ethical concerns or potential harms when it comes to the people who get the transplant?

The biggest concern is that we haven’t figured out how to make this work. It’s very possible that xenotransplantation will never work, that no animal’s organs could be made to support life in a human being, that the risk of xeno-zoonotic transmission of viruses from pigs to humans is still a live possibility.

That for me is a major concern. We’re in the middle of a zoonotic pandemic right now, the Covid pandemic. We are still dealing with another zoonotic pandemic in AIDS, which is a worldwide problem. There is a concern that putting an organ from an animal that has a virus into a human, and that human is immunosuppressed [as organ transplant recipients are], will result in the mutation of a virus that might plausibly be transmitted to other humans, and who knows what the results of that could be.

Right. So in my mind, there are two big buckets of potential harm to people. One is the infectious disease aspect, and one is the danger to the patients themselves and the ethics around informed consent. I’d love to hear a little bit more about that. What are the concerns there?

The living patients that they have attempted these organ transplants in have been individuals who are quite sick, who are in organ failure, and who are not able to get an organ from a human. So those are all patients who have few good options. Some of them are facing almost certain death if they don’t get a transplant of some kind. So the worry is that we are making these patients an offer they just can’t refuse because their alternative is that they are going to die.

You have to be concerned about whether or not they’re truly providing voluntary informed consent under those circumstances, whether they really understand the risks of xenotransplantation — which so far has never worked and has never actually saved a human life in all the decades of experimentation — and whether or not those patients understand the difference between being part of an experiment and receiving therapeutic treatment. This is something called the therapeutic misconception, where patients believe that being part of an experiment, that experiment is actually intended to benefit them. And we can’t say that at this point about xenotransplants.

But unfortunately, the patients who have agreed to these transplants have all said in media interviews that it was their last chance at survival, that they really had to do this because they had no other options. And that suggests that they did truly believe that these transplants would save their lives, and that is, unfortunately, a misconception. And unfortunately, all of these patients so far have died.

I’ve spoken to scientists and ethicists who are working with scientists to try to make sure informed consent is really tight and transparent. Do you think that’s a possible solution?Is it possible to get informed consent from someone who’s put in this position?

Of course it’s possible, and someone might go into this thinking, well, it’s never worked before and it’s really a long shot and It’s probably not going to work for me, but a one in a million chance is better than a zero in a million chance, so I’m going to take it. We can provide patients with all of the information that they need in order to make an informed choice.

There’s been lots of research showing that despite our best efforts, lots of people who are enrolled in clinical trials or enrolled in experimental therapies do still misunderstand what might happen and that the purpose of the experiment is not to benefit them, but to benefit others, to, to acquire more scientific knowledge that will be a benefit to patients in the future.

But I think people are complex and they can understand both of those things at the same time, and still have this hope that this might work for them.

You’ve done a lot here on animal research and the use of animals as models for humans. How are you thinking about xenotransplantation here?

So two things. One is, there are questions about what’s happening to the pigs, and the welfare of these pigs. And the other is that we are actually still doing research transplanting monkeys with these pig organs.

So far the longest that monkeys have been kept alive with a pig organ is two years. There’s not a lot of information about what happened to that monkey, what that monkey had to undergo in order to get it to survive for that long. Any time we’re talking about experimenting on animals, there are welfare concerns about what happens to those animals and how we’re using them. But there’s also the fact that having a monkey living in a laboratory in a cage where we can do just about anything we want to that monkey is very different from the circumstances in which human patients exist.

A human patient doesn’t want to spend the rest of their life in a hospital bed. They want to be able to go home and, and go on with their lives. So we’re not replicating the conditions of a human life or a human existence in a laboratory animal. So I have concerns that what we’re doing with those monkeys actually isn’t really telling us anything very useful about whether or not this will work in humans and whether it will provide the kinds of benefits that we’re hoping it would provide to humans.

So one question is whether what we are doing with other animals is telling us anything useful about long-term survival for humans with pig organs.

For the pigs themselves, there are a few concerns here. One is what the effects of the genetic modifications are on those pigs, on their health, on their survival, and on their wellbeing. Of course, those pigs are not actually created to survive. We are creating them to produce organs so that they can be killed and those organs can be used in humans.

With gene editing, we’re trying to sand off the edges of pig organs to force it to fit into a human and to work in a human. So what are we doing to the pigs under those circumstances? What are the conditions under which they are bred or cloned and raised? Much of it requires them to stay in unnatural environments in isolation, with multiple invasive medical procedures and tests, and that’s before they’re killed for their organs.

These are animals who would not exist at all, except for our human intervention. And I think we’re treating them just for the purpose of taking them apart to provide spare parts for humans. They don’t see the sky. They’re not going to touch grass. And we are attempting to undo 80 million years of evolutionary divergence in this way that involves the radical exploitation of an animal that we’ve created and built for a purpose. I think we really do need to reflect on what we’re doing there and on the harms that we’re causing to living, conscious, intelligent creatures, in part so that a handful of biotech companies can profit from their existence.

I was recently reading how GalSafe pigs, a kind of pig being used for xenotransplantation research, were recently FDA-approved for both consumption and therapeutic uses. I think there’s something really strange about the idea that someone could get a pig heart from this pig and also be eating the same pig. It’s very bizarre.

That does raise some weird issues. That I am now part pig, I have this heart that I got from a pig and it saved my life, so that I could go eat parts of that pig’s relatives.

Say we get into a future where xenotransplantation works, it becomes common. Is there a concern that we’re just replicating some of the environmental harm of, say, factory farming?

This would absolutely be factory farming. These would be animals grown and bred and raised in a facility. And you presumably have a fairly resource-intensive facility, even perhaps beyond what we see currently with pig farms.

These are pigs that are being grown and created and controlled by these private biotech companies with this hope that we might actually have on-demand organs for everyone who needs one at some point in the future. But we are talking about expanding the footprint of factory farming — expanding the use of resources to grow these animals. And we would be talking about growing perhaps millions of these animals rather than however many we are currently growing.

It has been really interesting to learn how much funding is coming from these biotech companies into all this research. Are there any other concerns around that that you have?

This is sort of what biotech companies do. They spend a lot of money and invest it in products that are speculative, that may or may not work, that may or may not improve human life for people in general. And part of my concern is that they are currently in control of what is being done experimentally.

They create the pigs, they create the organs, and they are paying investigators at academic research hospitals to do these experiments on their patients. You can’t just find patients on the street — you have to access them through doctors who have patients who are in dire straits and who don’t have good options So what we have now is this kind of private enterprise with lots of hype around it, but not enough attention, I think, to the profit motive behind this and how much that is driving research in xenotransplantation.

Do you think we’re moving too fast here? What needs to be done to be able to get to a point when it feels safe to do clinical trials? Or do you think that’s not really possible?

I think we’re not close to that yet. But I also think it’s important for us to think about what else we might be doing as an alternative to xenotransplantation. In some sense, xenotransplantation seems like the least likely technology to be used out of the gate as the solution to this problem.

We have other options that people are also working on, things like being able to grow a human organ from the cells of the actual recipient, which would be an organ that is made from that person’s own cells where they wouldn’t face problems of rejection. There is potential for therapeutics that would actually help address organ failure so that the patient doesn’t get to the point where they need an organ transplant.

There are opportunity costs in terms of the time and the effort and the resources that are being put into xenotransplantation, which, if it doesn’t work, is a lot of money and a lot of time and effort down the drain. There are other possibilities that we could be pouring more resources into that don’t require us to overcome 80 million years of evolutionary divergence between humans and pigs.

A really important option, one of the least glamorous ones, is what else could we be doing to prevent organ failure in the first place — because an organ transplant, whether that organ comes from an animal or comes from another human, is not a quick, easy fix. You’re looking at a patient who has a lifetime of immunosuppressive therapy ahead of them. There’s always going to be the potential for the rejection or the failure of that transplant for that individual where they may need another transplant somewhere down the line.

One of the major causes of kidney failure is diabetes, and another one is hypertension. And those are both illnesses that we have treatments for if we provided them to the people who actually need them. And so instead of pouring however many billions of dollars are being poured into xenotransplantation research, what if we put that money somewhere else where we might actually be able to prevent organ failure in the first place? That would truly benefit lots and lots of patients.