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--:-- Sean Rameswaram: Kelly Cervic, reporter at Science Magazine. we've put a pig heart into a human being. Yes, we have. Is that a first? It feels like a first. It is a first. Yeah, this is something that researchers have been working towards for decades. A transplant from one species to another, also called xenotransplantation, has the potential to make up for this really severe shortage of organs for people who need them. And happily, pig organs are roughly the same size as ours, but getting them to work in a human body has been really challenging. And this is the first time that surgeons have tried to swap a pig heart into a human. And at least in the first few days after that attempt, it seems to have worked.
--:-- Sean Rameswaram: Okay, give me the details of this xenotransplantation. How did it happen? Paint me a picture.
--:-- Kelly Cervic: This patient's name is David Bennett. He's 57 and he had terminal heart failure and an arrhythmia that kept him in the hospital for more than a month, pretty much incapacitated him. Our patient looked like a pretty healthy 57-year-old except that his heart was failing. Doctors decided that he was not a candidate for a heart transplant from a human donor, in part because he hadn't taken steps to control high blood pressure and other health issues that he had. And so that left him with a terminal diagnosis and really no other established treatments available to him. And that is when these surgeons in Maryland decided that he could be the one to test this idea that they had been studying for many years of transplanting a heart from a genetically modified pig into a human.
--:-- Kelly Cervic: He said to me two very important things. He said, I don't want to die. And he said, if I do, maybe you'll learn something to help others. So they approached the Food and Drug Administration to ask for permission to try this under a pathway called compassionate use, which is designed to let patients try something unproven in a life-threatening situation like this. And they got the go-ahead. So this happened at the University of Maryland Medical Center. And this team at the University of Maryland School of Medicine has been collaborating on xenotransplant research with a Virginia-based company called Revivacor.
--:-- Kelly Cervic: Revivicor. Revivicor. These are genetically engineered pigs or GE pigs. That company has been developing pigs, especially for this purpose. Their organ cells and tissues are resistant to rejection when transplanted. The big challenge in this field is that the human body is really good at recognizing when something foreign gets in. Thank goodness. That's kind of how our immune system fends off harmful viruses and bacteria and keeps us alive. And that's great. And so even human-to-human organ transplants come with a risk of rejection when the immune system sort of attacks the new organ and the organ fails. And it's an even bigger problem, as you would imagine, for a pig organ.
--:-- Kelly Cervic: And so what Revivacor and others are trying to do is create genetically modified pigs that won't set off the immune system in the same way. So, for example, they lack certain sugars on the surface of their cells that human antibodies would recognize as foreign. And the pig used for this transplant actually had 10 different genetic modifications. Four of them were genes that were removed, and six of them were human genes that were inserted. And all of that was just to try to make this heart sort of play nice with its new body.
--:-- Kelly Cervic: So this is a pig that was genetically modified, basically made in a lab. Whose heart they wanted to put in a 57-year-old human who had a terminal heart condition. Is that all right? That's right. And they had reason to think that it would work. This approach has been tested in baboons who were getting these same types of pig hearts. And in some recent experiments, baboons with the pig hearts lived up to nine months before they died of an infection that was unrelated to the transplant.
--:-- Sean Rameswaram: Where are all these genetically modified pigs living? Is there some like Maryland Revivacore pig farm filled with scientifically engineered pigs?
--:-- Kelly Cervic: There is a facility in Virginia, a Revivacore facility. Oh, it's in Virginia. Yeah, where these pigs are reared. Snowball led the other animals in organizing a new society, which they now named Animal Farm. My understanding is that there are, you know, different pigs of different ages being kept and sort of raised in this facility. Tending farm by themselves posed problems for the animals, but the pigs could think of a way around every difficulty.
--:-- Sean Rameswaram: Do we know how Mr. Bennett responded when these doctors and scientists came to him and said, hey, you're probably going to die, but we have this pig we made in a lab and we can hook you up to its heart?
--:-- Kelly Cervic: From the statements that he made about his choice before the transplant, we know that he saw this as a chance at life and that he wanted to live and didn't have really another avenue to pursue. My dad's only 57 years old, so that was very important to him and he didn't feel like he was ready to die. I think it the New York Times has a really wonderful quote from him along the lines of will I oink Which was one of the questions that he had for his doctor before going into this We also know that he went through an informed consent process to opt into the procedure.
--:-- Sean Rameswaram: Tell us how this procedure, this xenotransplantation went.
--:-- Kelly Cervic: Yeah, so I understand it was an eight-hour operation, and the surgeons were quite straightforward with Mr. Bennett beforehand that they really couldn't guarantee even that he was going to wake up from that surgery. But he did wake up from that surgery with the pig heart beating in his chest. And a few days later, he was off the heart-lung machine, breathing on his own. He's able to talk. His recovery is expected to be very slow because of his prior condition, but he continues to be monitored in the hospital.
--:-- Sean Rameswaram: Okay, and Bennett wakes up with a pig heart, and it's working, it's functioning, and he doesn't oink. He doesn't oink. So far, so good. Yeah, that's where we're at now. That'll do a pig.
--:-- Sean Rameswaram: One thing that I thought was a bit unusual was that before the transplant, this pig heart was sort of bathed in this special broth containing cocaine.
--:-- Kelly Cervic: Cocaine like the drug? Yes, the illicit drug, a dissolved form of powdered cocaine, as I understand it. The problem that they were trying to solve here is that, at least in baboons, the pig heart tended to sort of sputter out in a few days for reasons that are not clear. And the researchers found that perfusing the heart with this circulating sort of nutrient broth fixed that problem.
--:-- Sean Rameswaram: Cocaine is a hell of a drug. So this was a liquid cocktail developed by a team in Sweden for preserving organs, and it contains hormones like adrenaline and also cocaine. It did create a little bit of a challenge because this team had to get approval from the DEA every time they wanted to import a new batch from Sweden. And Sweden has cornered the legal cocaine for pig heart market?
--:-- Kelly Cervic: It seems like this company, yeah, has this sort of proprietary solution. I think cocaine has had a variety of medical uses throughout the world, but the innovation here happened to come from Sweden. So that's where it has to ship from for the moment. So they needed to like bathe this heart in cocaine to make sure it was going to work for Mr. Bennett.
--:-- Sean Rameswaram: Does he have to like do lines in the bathroom once a day or something to keep it going?
--:-- Kelly Cervic: What's next for him? To my understanding, Mr. Bennett was never directly exposed to cocaine, right? That was just sort of prepping the heart. But he is on a strong immune suppressing drug that's meant to keep his immune system from attacking the heart. And that is actually an experimental drug that helps shut down the antibody response, which is of particular concern here. And it's being developed actually to treat rheumatoid arthritis and is still in clinical trials for that use.
--:-- Sean Rameswaram: So what does this mean for Mr. Bennett? Is he good to go? Is he is he not allowed to go on roller coasters? What's what's the prognosis for him?
--:-- Kelly Cervic: Yeah, Mr. Bennett is being monitored very closely and is not able to leave the hospital yet, although he is breathing on his own and able to speak. We don't know how well this heart is going to work for him or how long it's going to work. When I asked different researchers in this field whether we should call this transplant a success at this point, I really got different answers. So for the team that did the transplant, it was a success when he woke up from the surgery and every additional day that the heart is working, that's a success because it's all new. But if this approach is going to someday be approved for use in large numbers of people, will it be considered worthwhile if the patient gets an extra month or an extra six months to live? Or if this sort of holds them over until a human heart is available, is that a success?
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--:-- Sean Rameswaram: Megan Molteni, you're a reporter at Stat News. We've been talking about how a pig's heart saved the life of one man, Mr. Bennett, who needed a new thumper. How many people in the United States are in that position waiting for an organ transplant right now?
--:-- Megan Molteni: Every year there about 100 people waiting for an organ transplant not just hearts kidneys liver other organs. And a lot of them die waiting for those organs. And in 2020, 6,000 people on the transplant waiting list died. So we're talking about a lot of people who could potentially benefit from something like this.
--:-- Megan Molteni: You know, that being said, like anything in the healthcare system, there are disparities in who's eligible to get a new organ. So people who can travel really far to get to these medical centers where these transplants are performed, people, you know, who have more money, who have private insurance, who can take paid time off from work to have these procedures and recuperate from them. You know, those are the people who are most likely to receive these organs. And so we know that patients from underrepresented and historically marginalized groups, Black people, as well as other minority groups, they're just much less likely to receive organs.
--:-- Megan Molteni: And you mentioned there's 100,000 people who are waiting for a transplant from another human. I'm not sure how many of those are waiting for a heart, but I imagine the numbers in the thousands, at least in this country. Is this potential to have a pig heart transplant a game changer for that list?
--:-- Megan Molteni: Not in the immediate future. The medical care team at the University of Maryland that performed this procedure we're talking about with Mr. Bennett, They got a one-time clearance from the Food and Drug Administration to do this, but it is kind of emblematic of the momentum that is behind moving xenotransplantation into clinical trials, which would be the first step toward making it a reality for patients more broadly.
--:-- Megan Molteni: How long has science been considering xenotransplantation? What's the genesis of that term even? Xeno transplantation, xenos from the Greek meaning foreign or strange or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Scientists have been toying with animal to human donation for centuries. Organs are a more recent evolution of that. In the 1800s, doctors treated wounds with skin grafts from a variety of animals. Frogs were very popular for this.
--:-- Megan Molteni: Before that, there was infusions of blood from different animals to humans, going back even further. But in kind of the modern era, you know, in the 1960s, there were a series of experiments where people received kidneys from animals. In this case, they were chimpanzees. 13 people received this organ, and only one of them lived an additional nine months. The others died within weeks. So it wasn't seen as, you know, a great success.
--:-- Megan Molteni: This is what we heard from Kelly earlier in the show, that the human body has a tendency to reject a foreign entity. Yeah, that's right. And so there were those failures. There were a few other ones later in the 80s. And after that, the medical community largely turned away from this idea because the thinking was that the human immune system was just like too good at keeping, you know, things that don't belong inside your body outside of your body.
--:-- Megan Molteni: So what changed? How did we get here? Yeah, there's a couple of things that change, but I think the big one technologically is that scientists develop tools that are more adept at editing animal genomes to make organs more compatible with human bodies. So we have tools coming along like CRISPR. CRISPR is a tool for editing DNA, and that can sound really abstract. So I like to picture a Word document that has a million pages in it. Basically what CRISPR does is it adds a find and replace function to that document so that scientists can essentially type in the sequence of DNA that they want to find and then make the edit at that point.
--:-- Megan Molteni: And those kind of revive the dream because you can make very discreet and precise changes to the genome. And what that does is it allows you to delete surface proteins that maybe the immune system recognizes. It allows you to make other changes like making these organs not grow as fast so that they don't outgrow a human body. And so those technological advances made it feasible. And then if you think about from kind of a societal perspective, times have changed and opinions have changed. Like there have been a series of recent surveys that suggest that xenotransplantation is just more acceptable to the public than it was 15 years ago.
--:-- Megan Molteni: It doesn't seem quite as sci-fi and there's a real medical need for it. And, you know, I think what we've seen in this most recent case with Mr. Bennett was there wasn't a massive backlash against this experiment. You know, and so the thinking is that, you know, maybe this is something people are more willing to get behind than they were in the 80s and the 60s.
--:-- Sean Rameswaram: The hurdle to get over wasn't really the ethical quandary of, say, raising a pig for the sole purpose of killing it and giving its heart to some Mr. Bennett type candidate. It was more so would Mr. Bennett want the heart of a pig to save his life? It's still an open question whether or not we should be raising animals solely to kill them to use their organs, making them essentially organ farms. You know, we saw statements from PETA after the transplant, you know, to that effect.
--:-- Megan Molteni: But, of course, you know, plenty of Americans are totally fine with killing animals to eat them. So the question of is this actually maybe a more noble use or is feeling a more dire need is certainly a conversation people are starting to have right now with a little bit more urgency given the amount of movement in this field.
--:-- Sean Rameswaram: And are there ethical questions about what to do if something goes wrong with the pig heart once it's in the human? I mean, it sounds like Mr. Bennett could die at any point here.
--:-- Megan Molteni: The ethicists that I spoke to were most curious to know what sorts of conversations during the consenting process they had with Mr. Bennett and his family in the event that things went bad. Because if you don't think about these things carefully while he's, you know, awake and can make decisions for himself, you could wind up in a situation where, you know, physically he's alive, they can collect data on how the heart is doing, but he might be in a lot of pain, he might not be able to communicate that.
--:-- Megan Molteni: And so having a clearly laid out set of options about what his family can do in that event is really important. And this kind of stems out of a particular case from history where there was this guy named Barney Clark Barney Clark was near death when doctors rushed him into surgery He had end-stage congestive heart failure and was out of options. And so he volunteered to receive a early version of a mechanical heart that was experimental, you know, had not been tested in clinical trials.
--:-- Megan Molteni: He's breathing on his own and has spoken his first words since surgery. He wanted a glass of water. And when he woke up, he said, this feels good. I'm glad I'm a beating. And then he looked at his wife, and she leaned down, and he said, I want to tell you that even though I don't have a heart, I still love you. And that wasn't a dry eye in the house.
--:-- Megan Molteni: And the stories about what that process was like for him was that he suffered terribly. He was having convulsions. He was in a terrible amount of pain. But he had kind of committed to being a part of the experiment for as long as they could keep him alive. His lungs failed. Next, his brain failed. And lastly, when the key was turned off, his heart failed. And bioethicists hold up that story today about an example of what not to do.
--:-- Sean Rameswaram: And so making it clear to the family that they need to be able to make some decisions around that, you know, is both good ethics. And it clarifies that this is most likely a short term terminal experiment and, you know, not a Hail Mary, like, let's try to save this guy's life.
--:-- Sean Rameswaram: Okay. So for now, this is a quote unquote success, though, a tentative one. Everyone's probably thrilled about that. But then to add a wrinkle to this whole heart transplant from a pig situation. Last week, this woman came out and said, this man, Mr. Bennett, stabbed my brother, paralyzing him, destroying his life. And my brother suffered and tortured for 19 years. And I feel that there's a lot more deserving people.
--:-- Sean Rameswaram: What do you make of that situation and the ethical quandaries there?
--:-- Megan Molteni: It was certainly a twist that I did not see coming. But I will say that, you know, doctors in every country in the world are sworn to treat patients who need care equally. And it would be really bad ethics to exclude people convicted of crimes, you know, or even accused of crimes from receiving medical treatment, including a potentially life-saving organ transplant. Like, that's a very dangerous precedent just that I don't think we want to live in a society where people can be refused treatment if they have a record.
--:-- Sean Rameswaram: Do you have any sense of where we go from here? Are, you know, are we going to continue to experiment this way irrespective of how this experiment goes with Mr. Bennett?
--:-- Megan Molteni: So I think it's important to note that, you know, Mr. Bennett received this organ not as a part of a clinical trial. So it's not necessarily going to, you know, advance the science in a serious way. But I do think that the fact that he didn't die on the table kind of catalyzes, you know, some more excitement about pushing this to actual human trials. The company Revivacor that has developed these pigs and is raising them in a herd on their farm in Virginia is not just working with the University of Maryland, they're also working with a couple other academic centers.
--:-- Megan Molteni: And we know that at least one of them, which is the University of Alabama, Birmingham, has built its own pig facility, rearing facility on campus with the goal of trying to get a clinical trial started sometime by the end of this year or early next year. And their estimations are if everything goes well and the first phase looks good and the second phase looks good, and in phase two we're talking about treating a couple hundred patients, that they could be offering this to patients at their hospital within five years.
--:-- Sean Rameswaram: One night to be confused One night to speed up truth We had our promise paid For I'd send that away
--:-- Sean Rameswaram: Megan Molteni is a reporter at Stat News. You can find her work at statnews.com Earlier in the show, you heard from Kelly Cervic. She's at Science Magazine. You can find them at science.org. Our show today was produced by Miles Bryan, edited by Matt Collette, engineered by Efim Shapiro and Paul Mounsey, fact-checked by Laura Bullard. If you want to spend a little more time with the ethical questions surrounding xenotransplantation, let me go ahead and recommend a recent episode from a humble audio program called Radiolab. The episode is titled Return of Alpha Gap.
--:-- Sean Rameswaram: I'm Sean Rameswaram from It's Today Explained. And here, he knew the hand of the devil And here, he kept us awake with mulch tears Sharing different heartbeats in one eye To call for hands above To lean on Would it be good enough For me now To call for hands above To lean on Would it be good enough That's all, folks.
