Tiny Matters
Take a dive into the genes, microbes, molecules and other tiny things that have a big impact on our world with Tiny Matters. Join scientists Sam Jones and Deboki Chakravarti as they take apart complex and contentious topics in science and help rebuild your understanding. From deadly diseases to ancient sewers to forensic toxicology, Sam and Deboki embrace the awe and messiness of science and its place in the past, present, and future. Tiny Matters releases new episodes every Wednesday and is brought to you by the American Chemical Society, a non-profit scientific organization advancing chemistry and connecting the broader scientific community. Tiny Matters is produced by Multitude.
Tiny Matters
Pig hearts in people: Xenotransplantation's long history, current promise, and the ethical use of people who are brain-dead in research
In the early hours of January 7, 2022, David Bennett was out of options. At just 57 years old, he was bedridden, on life support, and in desperate need of a heart transplant for which he was ineligible. Yet Bennett would go on to live for two more months — not with a human heart, but with a heart from a pig. David Bennett was the first case of a pig heart being transplanted into a human, an example of xenotransplantation — when the cells, tissues or organs from one species are transplanted into another. In the United States, over 100,000 kids and adults are currently on the national transplant waiting list, and every day around 17 people on that list die while waiting.
In today's episode, we cover the science and historical research that made Bennett’s transplant possible, and what doctors learned from him that helped the next heart xenotransplant recipient, Lawrence Faucette, live even longer. We also get into some of the ethics conversations surrounding xenotransplantation work — not just questions about the use of animals like pigs and baboons, but experiments with recently deceased, i.e. brain dead, people.
Check out Jyoti Madhusoodanan's Undark story, "The Allure and Dangers of Experimenting With Brain-Dead Bodies" here. Her JAMA story we mention, also on xenotransplantion, is here.
Send us your science stories/factoids/news for a chance to be featured on an upcoming Tiny Show and Tell Us episode and to be entered to win a Tiny Matters coffee mug! And, while you're at it, subscribe to our newsletter at bit.ly/tinymattersnewsletter.
Links to the Tiny Show & Tell stories are here and here. Pick up a Tiny Matters mug here! All Tiny Matters transcripts are available here.
In the early hours of January 7th 2022, David Bennett was out of options. At just 57 years old, he was bedridden on life support and in desperate need of a heart transplant, for which he was ineligible. Yet Bennett would go on to live for two more months, not with a human heart, but with a heart from a pig. Welcome to Tiny Matters. I'm Sam Jones, and today I'm joined by my co-host, science communicator and producer, George Zaidan. George, welcome to Tiny Matters.
Speaker 2:Thank you so much for having me. I'm especially glad to be here because this is such a fascinating story. David Bennett was the first case of a pig heart being transplanted into a human, an example of xenotransplantation, when the cells, tissues or organs from one species are transplanted into another. In the US, over 100,000 kids and adults are currently on the national transplant waiting list, and every day around 17 people on that list die while waiting.
Speaker 1:So today on the show we're going to talk about the science and history that made Bennett's transplant possible and what doctors learned from him that helped the next heart xenotransplant recipient, lawrence Fawcett, live even longer. We'll also get into some of the ethics conversations surrounding xenotransplantation work not just questions about the use of animals like pigs and baboons, but experiments with recently deceased people. Throughout history you'll find stories of human-beast hybrids, for instance, the ancient Egyptian god Anubis body of a man with a head of a dog, or the Sphinx in ancient Greece, who was part woman, part bird, part lion. Starting centuries ago, there are records of taking the blood and skin from other animals and using them in humans blood and skin from other animals and using them in humans.
Speaker 3:Even in the early 1600s, they tried to put a dog's skull in a nobleman just to repair a defect there. However, the church disallowed it and they took it out and the nobleman died.
Speaker 2:That's Mohamed Mahyuddin, a professor of surgery and the director of the cardiac xenotransplantation program at the University of Maryland School of Medicine. He co-led the team that performed both David Bennett and Lawrence Fawcett's surgeries. He told us that in the early 1900s there was a rise in xenotransplantation attempts using organs from a number of species, but the survival rate was low, like hours, not even days. That's not that surprising, given what we now know about the immune system and the role it plays in an organ being rejected by a transplant recipient's body after what may have looked like a successful surgery. Muhammad has dedicated his life to understanding the immune response to xenotransplantation and how to temper it, and we're going to get into that a little bit later in this episode. But first let's talk about a few milestones in the xenotransplantation world. Because immunosuppressant drugs weren't available in the early 1900s, doctors were at a loss, and by the mid-1920s many had moved away from xenotransplantation, and it stayed that way for decades.
Speaker 1:A big turning point came in 1963, when surgeon Keith Reemsma at Tulane University transplanted the kidneys of chimpanzees and in one case a Reese's monkey into people. One of the chimpanzee kidney recipients survived an astonishing nine months. That huge jump in survival time was attributed to new immunosuppressive drugs that kept the immune system from immediately flaring up and rejecting the organ. Unfortunately, the other xenotransplant recipients died within a couple of months, either due to immune rejection or because their immune system was so depleted that they developed an infection that they would have typically been able to fight off.
Speaker 2:A year later, in 1964, a doctor tried the first cardiac xenotransplantation in humans using a chimpanzee heart. Unfortunately, the patient died within a couple of hours. But 20 years later, baby Faye really put cardiac transplantation on the map. In 1984, a surgeon named Leonard Bailey at Loma Linda University Medical Center in California transplanted a baboon heart into 12-day-old Stephanie Faye Beauclair, better known as Baby Faye. Baby Faye was born with hypoplastic left heart syndrome. This is a condition where the left side of the heart is so underdeveloped that it has trouble pumping blood. In Baby Faye's case, it was so severe that she wouldn't have survived as her heart failed. Bailey performed the surgery. Just hours later her new baboon heart began beating. Sadly, just a few weeks after that, baby Faye's immune system rejected the heart and she passed away. But in the years since then, researchers have made huge strides in immunosuppression medications and treatment approaches have also moved away from using organs from non-human primates.
Speaker 3:We found out that the chimpanzees, or baboons, do very similar to humans. There are several disadvantages of transplanting their organs.
Speaker 1:One disadvantage is that they carry diseases that can easily transmit to us, including simian immunodeficiency viruses, or SIV, notorious for crossing into humans and causing HIV, mohamed told us, the focus soon began to shift to pigs.
Speaker 3:They are domestic animals raised well in captivity. They grow very fast. So for a human of about 80 kilograms you need a pig of only one year of age and that heart or other organs will be compatible with the human organ size.
Speaker 1:Researchers also know a lot about the pig genome, which means that we can tinker with their genetics.
Speaker 3:So with the technology now we have to modify genes. We can alter their genes and take out the genes that are kind of immunogenic to humans and then put in some human genes to make them more compatible to humans.
Speaker 1:This is a huge deal because it means pig heart xenotransplant recipients are no longer fully reliant on immunosuppressants. Researchers are able to remove the genes in pigs that code for the production of molecules that trigger the human immune system. At the same time, researchers can now insert genes that make a pig's heart appear to be more human to our immune system.
Speaker 2:This is possible thanks to cloning. The company Muhammad and his colleagues work with is called Revivacor, which is a spinoff of PPL Therapeutics, which is the company that cloned Dolly the sheep. Revivacor retrieves eggs from the ovaries of female pigs, removes the DNA and replaces it with new DNA, and in that new DNA, the researchers removed three genes that are responsible for rejection of pig organs by human immune systems. The gene for a growth hormone receptor was also removed to prevent the pig heart from growing too much once transplanted.
Speaker 1:Six human genes were also inserted into the new DNA, which would help with immune acceptance. They then placed the eggs now fertilized back in the pig's uterus, where they developed into embryos. There can still be some variation in genes even with these genetic modifications, but the team is ultimately working to create a stable breeding line where pigs who show stable genetics would then be bred with each other, so that you'd always get these 10 desired genetic mutations in their offspring. You'd no longer need cloning. So by 2021, muhammad and his colleagues had not only genetically modified pigs, but were using better immunosuppressants, including a new anti-CD40 antibody, which targets an incredibly important immune pathway in humans.
Speaker 3:So at that time we thought that, you know, this is the right time to take this to human and save millions of people throughout the world who cannot get a human heart, either because of the shortage or because of certain conditions these patients have which make them ineligible for a human heart.
Speaker 2:So they approached the FDA, and although xenotransplantation surgery is not yet approved, it falls under compassionate use rules for emergency situations, similar to how new cancer drugs that are not FDA approved can be used in a terminal patient, with their consent, of course. And that brings us back to David Bennett.
Speaker 3:Muhammad told us that, after going back and forth several times with the FDA, they were granted compassionate use approval and then we presented this idea to Mr Bennett and he graciously accepted it, saying that you know, even if it doesn't help me, you know it may help other people. So he volunteered his life for this purpose.
Speaker 2:On January 7, 2022, cardiothoracic surgeon Bartley Griffith, alongside Muhammad and the rest of the team at the University of Maryland Medical Center, performed the first successful xenotransplantation surgery, placing a genetically modified pig heart into a person.
Speaker 3:When we were doing this transplant, nobody knew what to expect because there was no precedence. So we even told the patient. And the patient understood that there is not even a guarantee that he will recover from this transplant. He will wake up. So every day from that point on we took it as success and finally he lived for 60 days.
Speaker 2:Now for context the first person to receive a heart transplant from another human only lived for 18 days Over the course of David Bennett's 60 days before his immune system ultimately rejected the pig heart. He not only got more time with his family, mohammed and the team were also learning from him At one point.
Speaker 3:we had to stop one of the major immunosuppressive drugs for a little bit. We did not know that what levels of the CD40 that we'd used very successfully in baboons is enough for this particular patient, because of course he's not a baboon and also there were so many other issues going on simultaneously that we had difficulty maintaining the levels of that drug.
Speaker 1:At one point, David Bennett's immune system took such a dip that they actually needed to give him intravenous immunoglobulins, or IVIG, which is an antibody serum from healthy volunteers.
Speaker 3:But what we didn't realize at that time, that poor serum also had antibodies against pigs. So we believe that those antibodies, kind of you know, attacked the pig heart and caused the graph to fail.
Speaker 1:In addition, the pig heart David Bennett received was unknowingly infected with a latent virus called CMV.
Speaker 3:We do look for the viruses in these donors. However, we were not able to detect this virus because it was very deep-seated. Since this patient we have developed a lot of new techniques to detect even these deep-seated viruses and in the second case we were able to, you know, screen that virus out. So we did not see any issue with any virus in the second case. So if you say what were the reasons the first patient lived for only 60 days, not 100 days I would say the number one was his own condition, a very vulnerable condition, where we could not maintain the immunosuppression that we wanted to give to protect the heart from rejection. Number two was the IVIG that we gave acted against the heart. And number three, the virus may have, you know, caused some kind of initial damage or immune reaction that may have caused the destruction of the heart cells, causing the rejection or the graft failure.
Speaker 1:Right now, the team at the University of Maryland is continuing to evaluate patients for future pig heart transplants, while also optimizing their approach.
Speaker 3:I mean every transplant. We will learn something patients for future pig heart transplants, while also optimizing their approach. In every transplant we will learn something, but we want to improve and not repeat. So everything that we learned in the first transplant that we thought had gone wrong, we never repeated it.
Speaker 1:The second patient, 58-year-old Lawrence Fawcett, received a genetically modified pig heart on September 20, 2023, and lived for nearly six weeks before his body rejected it. Fawcett, a retired US Navy veteran and histology technician at the NIH, was able to spend that time with family members and even begin physical therapy.
Speaker 2:There has been so much work to get to this point and people like David Bennett and Lawrence Fawcett have been invaluable in that progress. But there are also many other species, including pigs, but also many non-human primates that have played an essential role in understanding immune rejection. One of the main reasons the FDA granted compassionate use approval for David Bennett's surgery was a landmark study done by Muhammad and his team, in which a pig heart was transplanted into a baboon who went on to survive for nearly three more years.
Speaker 1:Xeno transplantation is, in my opinion, really important, but it's not like you can just go from pig to human and not do a lot of things in between. And a pig heart, it's still a pig and some people might get upset that it's a pig. And so how do you navigate those conversations surrounding? Is it ethical to have all of these pigs that are being raised for this purpose or working with baboons? I'm just kind of curious how you manage that or how you view that in your work.
Speaker 3:You know, every single drug that we use these days or every single procedure has been tested in an animal before we used it. Right, so it's unfortunate. I mean, you know we all love animals and we don't want to use them for this purpose, but we don't have any computational models or anything else to replace a live human biology, and I've been doing it for the past 33 years. You know we do receive a lot of you'll say hate mails, or you know we've been questioned a lot. But I was very surprised when we did these two humors. You know 99% of the mail or the communication I received was very positive. A lot of people said that you know where were you 10 years ago when we lost our dear one.
Speaker 3:It's unfortunate that to keep one human alive, we have to kill one pig. But again, 90,000 pigs are killed per day in the United States for our dietary needs. That's one of the reasons that you know pigs were chosen, because they are already being sacrificed every day for other purposes. There are about 105 products that we use. Even maybe the makeup you're using was derived from the pig products. To me, saving one life takes precedence over everything, and just imagine, you know, if this becomes a routine. Every 80 minutes, a patient dies waiting for an organ. So you can save millions of lives throughout the world just within a year. So you can save millions of lives throughout the world just within a year.
Speaker 2:But baboons and other non-human primates are not the only option for studying xenotransplant rejection. Another approach is experimenting in people who are recently deceased. In 2022, surgeons at NYU made headlines when they transplanted pig hearts with the same 10 genetic changes as David Bennett's donor pig heart into two recently deceased people who were then monitored for three days.
Speaker 1:I came across this side of xenotransplantation research in a story titled the Allure and Dangers of Experimenting with Brain-Dead Bodies, written by Jyoti Matusudanan, who's a freelance science journalist based in Portland Oregon. A couple years before writing the story, jyoti was working on an article about xenotransplantation for the Journal of the American Medical Association. David Bennett had just received his pig heart transplant.
Speaker 4:There was a lot of news and excitement about it, and I was speaking with researchers about not just the transplant itself but this massive body of work they had done leading up to that moment. And in the course of that conversation it came about that some of that research had been done in people who were recently deceased.
Speaker 2:Recently deceased people are sometimes referred to as brain dead people or decedents, and, although they're legally dead, machines keep their blood pumping and air flowing into and out of their lungs. What Jyothi soon learned was that using recently deceased people opens up a massive can of worms when it comes to regulation. In the US, since 1991, we've had the Federal Policy for the Protection of Human Subjects, which is also known as the Common Rule.
Speaker 4:And the Common Rule is basically a set of federal policies that are meant to protect people who participate in scientific research. So the Common Rule covers things like making sure that protected classes of people, like children, or communities that are especially vulnerable, like people who are in prison or pregnant people, are protected from experiments that could be harmful to them or that might in some way violate their freedoms, for instance, and over time the common rule has expanded and shifted to be more encompassing of different kinds of research.
Speaker 4:It also covers biospecimens, which are things like blood or tissue or organs, and essentially for all of these things that are done with people who are living, whether they are minors or not, or whether they're tissue samples or not, you have things like informed consent, meaning no one can use your tissue, your blood sample from you for a genetic test or whatever, without your consent. There's also institutional review boards, which offer oversight within institutions, which offer oversight within institutions.
Speaker 1:Researchers proposing to do work with living people have to get approval from an institutional review board, or IRB, before moving ahead with a project.
Speaker 4:And there's also another set of rules about research involving tissues or bodies of people who are deceased, but what I discovered while reporting this is that recently deceased people people who have been declared brain dead are in this gray area, so there's not a lot of regulation about how to do research with recently deceased subjects. There are groups of researchers and ethicists who have developed guidance to help the community, but none of that is formal regulation per se, and what that does is open things up to a range of treatment, both good and bad.
Speaker 4:There were some truly wonderful stories from the US actually, where it was moving to see how much researchers cared about doing things the right way. They sort of adhered to the highest standards they could find because there weren't any other standards for them, which was really heartwarming and wonderful to see. At the same time there was this one instance from India that really stood out. It started out as a US-based company that wanted to conduct experiments with trying to revive brain-dead subjects and they didn't get the consent they needed in the US. So then they moved out of the US to, they say, a few different countries Didn't really get off the ground because of the pandemic. But there is one institute in India where the researcher says they have been continuing that sort of work on their own, without the US company being involved, and they are using a combination of stem cells and other treatments to literally revive brain activity in people who've suffered brain injuries during traffic accidents.
Speaker 1:Although they're not working in the xenotransplantation space, at least to our knowledge, it gives you a sense of how so much gray area surrounding this regulation means that things can get real dicey, real fast.
Speaker 4:All the researchers that I spoke with about that work described it as premature. Ethicists have published review articles, opinion pieces describing how that work is essentially exploitative of grieving families by giving them false hope that their loved ones might come back to life. And if you contrast that with the xenotransplantation work, where there has been decades of work in animal models to see what needs to be done to make that process feasible for humans. And then they carried out the work in recently deceased subjects and then went into a living human, which is a very methodical, systematic way of bringing the research to a point where it's acceptable to experiment on a human being.
Speaker 2:The 2022 NYU study where pig hearts were transplanted into two recently deceased people was a great example of decedent work being done ethically. One of the people in that study was a woman named Alva Capuano.
Speaker 4:Alva Capuano had dealt with so many health issues over the course of her life that really epitomized the need for xenotransplant research.
Speaker 2:In her reporting, Jyoti had the opportunity to speak with Alva's son, Tim.
Speaker 4:The conversation I had with Tim really framed for me how, when research is done well, how it can really build trust with people who participate. His mom had signed up to donate her own organs because of her complicated life experience and knowing the value of a donated organ and unfortunately, it turned out that, because of her complicated medical history, when they were trying to arrange this gift at the end of her life, the family kept running into rejection of people telling them they can't use this organ or that organ or the other, and it was this really traumatizing, grueling process for them. And they were really reaching the end of that process when they heard about the possibility of her participating in this study, in this experiment.
Speaker 2:The medical team at NYU explained the process to the Capuano family and they decided it was the right move. Alva wanted to contribute to research that could ultimately save the lives of people like her who were in need of a transplant.
Speaker 4:And apparently Tim said during our interview that at the time, during those two days that they were conducting the experiment, the researchers would call them, so they had frequent updates about how things were going, what the researchers were learning from what they were doing and things like that, which is just a really sweet example of how science that engages the people that it hopes to help can do so much more when it's done well.
Speaker 1:In this country. Every eight minutes, someone is added to the transplant waiting list. As of March of this year, over 3,000 children and adults were waiting for a new heart, and now cardiac xenotransplantation is no longer some sci-fi pipe dream. There are a lot of patients and doctors out there with a lot of hope. Let's tiny show and tell.
Speaker 2:All right, let's do it.
Speaker 1:What do you think George First tiny show and tell yeah.
Speaker 2:I know, does that mean, I should go first or second?
Speaker 1:You decide.
Speaker 2:Normally I do rock paper scissors, but I'll just go first.
Speaker 1:Okay, go for it.
Speaker 2:So my tiny show and tell has to do with a disease called progeria. Have you ever heard of it?
Speaker 1:I've heard of it, but I can't quite remember, so remind me.
Speaker 2:So it's basically it's kids with super accelerated aging, so it's like a 10-year-old who looks like a 50-year-old, a 27-year-old who looks like an 85-year-old, that kind of thing. And interestingly, I didn't know this, but it's caused by a single point mutation in one gene. It's a really really rare disease. It only affects I think there's only like 18 living patients in the US, and the thing that was highlighted by this article that I was reading about this is that there are about 7,000 genetic disorders for which we know the mutation. 85% of those disorders are super, super rare and only a few hundred of the 7,000 currently have any sort of treatment, and progeria is one of those. There was no treatment, right. So researchers created a protein that actually fixes this point mutation. They tested it in mice. It showed a lot of promise, and this is where you get to guess, like can you guess how they created this protein that fixed the problem in mice?
Speaker 1:How they created it. It's like an enzyme. Did they do something in pigs?
Speaker 2:Actually I don't know what animal they did it I was, so this is actually maybe maybe you're the wrong person to ask because you know about these things, but I feel like most people would just be like CRISPR. They used CRISPR right, and the shocker is they did not. They used directed evolution. So not all work being done in genetics and proteins is CRISPR, which I thought was cool. So the next step is to do a clinical trial in humans, which they want to do in the next two years, and the NIH director is actually he's one of the labs that did this work. So I thought that was also very, very cool. And that's the limit of my like. I'm a chemist by training, so that's the limit. Everything I just told you is the limit of my biology knowledge that's really fascinating.
Speaker 1:Well, we'll link in the episode description. We always link to the article or the paper so that if someone is listening and they want a really deep dive then they know where to go for it.
Speaker 2:Great, it's a nature paper, so it'll be fun.
Speaker 1:Today I have something very different for you. Okay, I have a cool cicada fact for you that was actually brought to my attention by a colleague's five-year-old daughter named Ellie. So thank you, Ellie. Before I get to Ellie's fact, I'm going to talk a little bit about cicadas. So just bear with me, George, I know you're not a big fan. Yeah.
Speaker 2:I'm not. Insects are not my jam, but go ahead.
Speaker 1:Well, you're going to have to suck it up for a sec.
Speaker 2:So all right.
Speaker 1:There is, of course, been a lot of cicada talk in recent years, with people particularly excited about the Magi-cicada genus. Those are the ones that hang out underground in their nymphal stage for up to 17 years and then have this big emergence right. They're what are called periodical cicadas, and groups of them, called broods, will emerge all at once in a specific area and year, based on a very predictable cycle of development, which is kind of cool that you can say, okay, they're back underground, but they're actually going to come out now in 13 years or 15 years or whatever it may be. So after female cicadas mate, they go to lay their eggs, and when they do that, they use something called an ovipositor to cut through wood typically trees where they then lay those eggs. So this ovipositor kind of looks like a serrated sword, great, and it sticks out of the female cicada's abdomen.
Speaker 2:Love it.
Speaker 1:Yeah, it's a great visual and you would think you know to cut through wood must be pretty strong, right? So a few years back, researchers hypothesized that it might contain different inorganic elements to make it strong, including different metals. So they used a couple of different techniques. They used energy dispersive X-ray spectroscopy and electron microscopy to identify and quantify the elements that were actually present in the ovipositor and then be able to map their locations as well, and so they found 14 inorganic elements, including silicon, iron and zinc. So cicadas are part metal, and that was Ellie's fact, that's amazing.
Speaker 1:And then I went a little bit deeper, but don't worry, I'm almost done with these insects. So something else that I really found fascinating was that a lot of these, what are called cuticles on insects so this is technically it's called the ovipositor is a cuticle. A lot of them are reinforced with metal, including spider fangs oh no, insect mandibles, which are the appendages that are near the mouth that help them crush or bite or cut things, and also the jaws of marine polychaetes, which are these like very creepy looking worms that you find in the water. So just a fun little fact. I hope you sleep well tonight, george.
Speaker 2:I guarantee you I will not Thanks Sam. Thanks for tuning in to this week's episode of Tiny Matters, a production of the American Chemical Society. This week's script was written Matters, a production of the American Chemical Society. This week's script was written by Sam, who is also our executive producer, and was edited by me, george Zaidan and by Michael David. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode's sound design is by Michael Simonelli and the Charts and Leisure team.
Speaker 1:Thanks so much to Mohamed Mahouddine and Jyoti Mathusudanan for joining us.
Speaker 2:Thank you.
Speaker 4:Please don't share insect stories anymore Only insect tiny show, and tell us, from now on, no insect stories.
