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Clinical Challenges in Transplant Surgery: How Xenotransplantation Will Change Our Lives · Behind The Knife: The Surgery Podcast

• finalxxxeno_mixdown === [00:00:00] Hi everyone. Thanks for joining us. My name's Dr. Maddie Clonan. I'm a general surgery resident at the University of Nebraska Medical Center, and today we're talking about one of the most fascinating ideas in transplantation, and that's xeno transplantation, the possibility of using organs from other species to help save human lives. This idea has been around for decades, but to date, it feels closer than ever before. To understand where the field might be going, we really have to understand the story of transplantation itself. So today for the behind the knife. Transplant series. We're doing something a little bit different. I'm joined today by Dr. Jo Rich. She's a professor of surgery and abdominal transplant surgeon at at the University of Wisconsin. Before we get started in the actual podcast, can you tell us a little bit of why you decided to pursue a career in the field of transplantation? Absolutely. Well first of all, it's just wonderful to be on this podcast. I feel really honored in a lot of ways. I stumbled into the field of transplant. I was sort of an unlikely person to even go into surgery. I, I kind of was a [00:01:00] messy kid, sort of disorganized and, uh, I wanted to be Hawkeye Pierce, so that was the one connect I had to surgery. But I went into medical school not really knowing much about surgery and. This is almost too good to be true. It sounds like it, it sounds cliche, but it was my first day on my surgery rotation and I found out I was on call. Um, I was running around like crazy. I was too nervous to eat or drink. Um, felt like I was doing everything wrong and. I was in New York City, it was the winter, and I remember in the evening I was scrubbed on a bowel obstruction and I was watching these bowels move around and I was starting to feel sick myself. And I actually remember I was hanging off of the bowels and was like, can you stop doing that? And um, I just, you know, was sweating and somehow I got through that case and around midnight. My resident said, Hey, go scrub in the case next door. And all I wanted to do was go to bed. I was so tired. I felt like really outta place in the operating room. I was already thinking, this is not for [00:02:00] me. But I went in the room and it was a kidney transplant and the classical music was playing. It was very, very calm and quiet. I scrubbed in and they already had the iliac vessels dissected out. I didn't know what I was looking at. Uhhuh. I'll never forget they opened this cooler and they took out what, to me, looked like a lump of fat. I was thinking, when, when are they gonna get the kidney? And they sewed it in and it just seemed very beautiful and simple. And when they released the clamps, it turned pink and. A couple of moments later, urine started squirting out and I thought, oh my gosh, I can't believe this is real. Like, how could this work? And I remember having a lot of thoughts, uh, you know, one just being amazed, how, how does this work? Who figured this out? How, how, how could anyone think this would work? I really wondered who was that donor. I knew it was a deceased donor, and I wondered like, who, who gave this gift? And maybe like, the third thing I really wondered was. Like, [00:03:00] is this something I could ever do? I, even though I think I was unlikely to be a surgeon, I always liked the idea that if I work really hard at something, could I possibly master it that? Mm-hmm. That was very exciting to me. And really from that night on, not only did I decide I wanted to be a transplant surgeon, but I decided I wanted to understand this whole field and who the people were that made it happen. So it was an epiphany, it was an amazing night in my life. Yeah, it's so cool how, you know, small moments can really change your whole career and your whole life, and that's a really neat story. Transplant feels like it's this established field in medicine and I think we often take for granted just how young the field is. Can you walk us through how transplant evolved, um, from science fiction in the 1950s to standard therapy today? Absolutely. I think this story is incredible and, um, I think people sometimes don't, don't remember or forget how new a field transplant is. 'cause as you described in the fifties, it really was science fiction in the sixties and seventies. It was this highly experimental field with really [00:04:00] awful outcomes. Um, with a few crazy fools that were conducting transplants. And then in 1983 with the approval of Cyclosporine, it became a legitimate, repeatable, you know, non-experimental field. And, you know, one of the reasons I wanted to write my first book is that I knew that a lot of those pioneers were still alive and, um. How, how rare does that feel to be in a field where the people who actually made that happen were still alive? And, um, I, I just like remind people that in the seventies, which I mean, I was alive in the seventies, a lot, a lot of people remember the seventies, like transplant was really, really tough. I mean, 50% one year survival, maybe a little better than that. Patients doing terribly horrible infections and people were just gutting it out and, there were a number of pioneers. You know, the, the most well known Joe Murray, Tom Starzl, uh, a Num, uh, Roy Ka, a number of other people all of whom have died in the last few [00:05:00] years, who just had the courage to make this field happen. They just knew it was gonna work out and, um. I, I wanted to have that opportunity to talk to them and understand how they could do that. Mm-hmm. I, I don't think I could do that. I can do what other people teach me, Uhhuh, but in general, if you're, if you're operating and you're doing something no one has ever described before, like you should be a little cautious mm-hmm. That, you know, be a little humble about that. But that's what these people did. Yeah, it is pretty amazing that they, they push past, 'cause it seems so crazy, right? To push past the outcomes that they had in the beginning. But I mean, now, today, it changes people's lives every single day. Yeah. I mean, I, I think when I spoke to them, I, and I, I wanted, I didn't wanna know like what they did because I knew what they did. I'd read everything. You know, that they'd written and that others had written. But I wanted to know, like, how, how could they persist when people were calling them murderers? Were not sending them patients. There were petitions with Starzl in [00:06:00] particular, you know, petitions to have him fired from basically every place he ever worked. Someone wrote a book about about these early surgeons, and the book was titled, uh, the Courage to Fail. Mm-hmm. Uh, and I do, uh, agree. It was written by a sociologist who followed them around, and I agree that they had the courage to fail, but I kind of think a lot of us have that in our field and in other fields. But to me, there's something subtly different, which is that they had the courage to succeed. They, they knew it was gonna work out e with each failure. They said, I, I'm gonna learn from this and this is why I didn't work, and I'm gonna keep going. And, you know, when you talk to Starzl. He said like it had to succeed. I mean, it, it just, my entire life would be a farce if it didn't. I just knew it was gonna succeed and, um, you know, each one of them was different, but they all had this belief that no matter what, it was worth persisting. Mm-hmm. I love the history of transplant and I also, I think Xeno transplant is a really nice, it seems crazy and it's always seemed crazy, but it's kind of gone along with the whole history of transplant. So I know [00:07:00] in your, in your new book you describe, um, Xeno transplant as kind of a unfolding in several eras. So should we start with the primate era? I think that that makes sense. You know, in a lot of ways, like the idea that you could take an organ from someone who had died and, and back then they didn't have like preservation solution. Mm-hmm. They didn't have brain death. That wasn't defined until 1968. Um, so, so these were like. True cadaver organs. I mean, the thought that that would work seemed totally crazy. And actually in those early days, because they, they, you know, living donor was, uh, risky. They didn't really have immunosuppression, so primarily they were doing like identical twins, but the idea of using a primate as a donor, you know, was not hard to get your head around. Mm-hmm. I mean, primates look like humans. Um, they share a lot of, uh, genetic similarities, particularly chimpanzees. So really since the earliest days of transplant, people were thinking about xeno transplant and you know, maybe the. [00:08:00] Maybe the father or, or the patriarch of Xeno transplantation would have to be Keith Rema. Okay. Who was a, a larger than life figure. He was, uh, chair of surgery at Columbia in New York for many, many years. But he, uh, he actually, his parents were missionaries and he grew up in, out in the southwest, he always wore a cowboy hat and cowboy boots and cowboy, you know, he was a larger than life figure. He was in the Korean War. Actually shared a tent with Frank Spencer, who was a very famous, uh, heart surgeon in New York. Okay. The two of them were residents, like second and third year residents. They operated like crazy. They flouted the rules. The, the military had these rules that when there was a vascular injury in the leg, they, they were, they had to do an amputation because Oh, interesting. Yeah. That was from World War ii because they didn't have helicopters and by the time patients got brought out, their legs were dead. Still was in the rule book. You know, in Korea they had to do amputations and Rema and Spencer were like, we're not following these rules. So they were just doing [00:09:00] bypasses, almost got court marshed. And I think Rema developed this attitude of like, I I don't care about the rules. Mm-hmm. I'd rather ask for forgiveness than permission. He was mm-hmm. As an, as an aside uh, uh, many people think Hawkeye Pierce was based on Keith ResMan. He showed up. Oh really? Yeah. He showed up with a crate of scotch, uh, and apparently was always mixing martinis. And, uh, Alan Alda went and visited him when he was, uh. You know, first uh, filming his Hawkeye peers, Uhhuh, sort of part of the legend. But when he got down to Louisiana, he wanted to start a heart surgery program. He was down at Tulane. Um, but there were no patients because, well, they weren't doing bypasses and he wanted to do something new and impactful. And he wanted to do kidney transplant, but there were like no donors other than identical twins. So he got the idea if a patient has no donor and they couldn't do long-term dialysis, I'm gonna offer them a, a, a primate transplant. He did one monkey and that went badly. So then he switched to chimpanzees, he transplanted uh, six [00:10:00] patients and the only immunosuppression they had was, uh, steroids. Mm-hmm. Uh, radiation and they had Imuran, uh, just by that point, Uhhuh. Um, so not very much. And many of those patients did badly. But two of those patients left the hospital. And young, one young woman not only left the hospital, but she went back as a teacher and lived for nine months with perfectly functioning kidney, and unfortunately died, uh, from an electrolyte disturbance at nine months. So to this day, that's the longest surviving Xeno transplant. Uh, but I hope that record gets broken soon. What do you think the early primary era taught the field of transplant? Yeah, I mean, I think it taught them a number of things. Uh, number one, it taught them that it pro it probably could work if immunosuppression got better. It probably could work. It taught them that genetic matching, which was very much in its infancy, probably mattered a lot because, um, Starzl got involved in this [00:11:00] too. And he analyzed baboon results and chimpanzee results and the, the chimpanzee results were so much better which he ascribed to the genetic matching. It also taught them. Importance of public trust and mm-hmm. The risk of pushing the ethics of using animal organs mm-hmm. For humans. And you know, SMA in my opinion, was a very ethical man. He was very open about what he was doing. He was very clear with his patients about the risk and really not knowing if this was gonna work out. And he. Strongly felt it was okay to use chimpanzee kidneys. I don't think the public really had a huge problem with it. 'cause I don't think they associated kidney from a chimpanzee that it would necessarily kill the chimpanzee. Oh, sure. Mm-hmm. I mean, of course it would. We know that, but I don't. Yeah. Think that the public knew that, and it wasn't until the Baby Faye case mm-hmm. In 1984, which was the baboon heart mm-hmm. Where the public [00:12:00] exploded. With a protesting, you know, the idea of using a primate organ for a human. Can we talk a little bit more about that story, the Baby Faye story? Yeah. I think, um, baby Faye is still the most famous Xeno transplant case around, and certainly I think anyone who is. Uh, alive and of age, uh, in 84. Might, might remember that case or something about that case. It's really interesting. It was, the surgeon was a man named Len Bailey who had trained in Toronto. He was a, you know, an excellent heart surgeon and he, like, he wanted to do pediatric heart surgery and he really believed in transplant. He thought the reconstructive surgeries on pediatric hearts were terrible. Primarily it was talking about hypoplastic left hearts, and those kids would just die. And it was just at the very beginning where surgical options, um, were coming around. Uh, the, the staged, uh, procedures, uh, for hypoplastic left heart, but they, they hadn't even done like the second stage yet. Mm-hmm. Like, pretty much it was [00:13:00] a death sentence. Len Bailey had this idea that since infants have you know, lack a really well developed immune system that, you know, maybe a heart transplant, uh, could work for those kids. He actually did research in the lab with goats and sheep, and he wasn't having good outcomes. But then when Cyclosporine got approved in 83, he got hold of some and he had good results like between goats and sheep, uh, with cyclosporine. With baby goats and sheep. He thought that was a big difference. He got referred this patient whose name was baby Stephanie. Mm-hmm. And she, she was, you know, blue, she was dying and it was past the point where they could even possibly offer some sort of stage reconstruction because, um, she was just too sick for that. And he had a long discussions, seven hour discussion with, I guess, Stephanie's mom. And they, and he was very honest about everything, and they ultimately decided to move forward with a baboon heart transplant. There's some challenges [00:14:00] there. Mm-hmm. I mean, no one was doing infant heart transplants in any way. Mm-hmm. And he wanted to do a human one, but it was like literally impossible. To get a, a baby heart, like he couldn't. So it basically was do nothing and let Stephanie die or do the transplant. They decided to use a moniker, a fake name, uh, because they knew that a lot of press about this, so they went with her middle name, which was Faye. I see. Okay. They, they did the cross matching that they could. Interestingly baboons are mostly blood type. AB Faye was not compatible with that, but, but he thought because Faye was a baby, uh, she probably wouldn't have, you know, significant antibody. Mm-hmm. Chimpanzees, there are blood type O and A chips, but they're very few baboons interestingly. Um, so we went in with that transplant and actually the surgery went like. Amazingly well. Mm-hmm. And Baby Faye initially did amazing. There were all these amazing pictures of her, like, uh, you know, just around the nursery and with this big phone next to her. 'cause her mom was sick and so they kept her outside. Oh. [00:15:00] But the public like, went crazy. Massive protests, threats. Glen Bailey had to wear bulletproof vests. He was always with police, uh, protection. The police would open his mail. His kids couldn't go outside. People were like calling him, you know, a, a murderer for baboon donor. Mm-hmm. Who happened to be named Ubers probably not ideal to name the donors. That's something I think people learned. But the, but the baby was doing great. And then unfortunately, after about three weeks, she ultimately got sick and did die. Mm-hmm. But Len Bailey wrote some very beautiful. Things, uh, very beautiful papers and, um, press releases, you know, discussing and thinking about this idea of using animal organs for humans. Mm-hmm. You know, he said he did struggle with it, but he kind of thought, you know, the lion eats the zebra, the, you know, there's a natural order of things, and if he can save. A human with an animal, he thought that was appropriate. Other people may disagree with [00:16:00] that. There's some people who use this term speciesist. Mm-hmm. Uh, which is similar to like, um, I guess racism, but between species. That was, that was not really a term that was used then, but mm-hmm. Became popularized later. Ultimately, after Faye died, Len Bailey was, think had another baby that he was going to considering doing this on, but he didn't wanna put his own family through everything they went through, but amazingly. He got a call, he had a baby who was dying of hypoplastic left heart, and this surgeon from elsewhere said, Hey, I know what you did with Faye, believe it or not, we have this baby with, I think it was a, a hypoxia or anencephaly or something. And he was able to get that heart and performed the first infant. Heart transplant. And that baby who they nicknamed baby Moses because they knew is still alive today. Oh, very cool. Yeah, he really, and he basically created the field of pediatric heart transplant. Mm-hmm. He did 350 infants in his career with amazing [00:17:00] outcomes. So he's sometimes gets vilified, but, um, I believe he was courageous. He gets accused of not having done the work and have had the data, but actually he had quite a lot of data, but he didn't have a lot of publications and he thought Cyclosporine was gonna be a game changer for infants, which is not the craziest idea. Mm-hmm. Like I think it's likely that in this era, if one were able to use chimpanzee organs with the immunosuppression we have right now, we probably could make it work. However, the ethics of like. Trying to breed chimpanzees. Uhhuh, yeah, totally. Uh, for humans is quite dystopian. Yeah. Yeah. And then I, I, I have to, so the person that like maybe put the fork in pri in the primate era. Mm-hmm. Believe it or not, I think this is in the book, I, I should do it as a teaser, but like, I just gotta tell this story. Of course. Like Jane Goodall mm-hmm. Who just died recently. The primatologist, the absolutely brilliant. A fascinating trailblazer. Mm-hmm. Um, who studied [00:18:00] chimpanzees, uh, and other primates over her career was probably the person who ended the primate era at the, was it the 25th anniversary of Rems MA's, uh, uh, Xeno transplants. They had a conference in New York and the organizer decided to invite Jane Goodall. He was a, he's a transplant surgeon, and I got to talk to him and I Hey, would you, yeah. You know, those are like celebrating Xeno and they're all pro, like, why would you invite. This is Jane Goodall. This is 1989. And he was like, well, I thought she was a part of the story. He just wrote a letter to her organization, Uhhuh, and she agreed to come and she showed up and they all presented their data. Starzl was there and Reams move Uhhuh. And uh, then they were presenting the basic science and the immunology assays. And then in the last session they had Jane Goodall come and she gets up and she says, you know what? I'm not gonna talk to you guys about any data. Uh, I'm not gonna talk to you about [00:19:00] whether what you're doing is right or wrong. I'm just gonna tell you a story about the family I've been living with for the last, you know, 30 years. These chimpanzees had names, they had emotions, they had love and hate and envy. They use tools and you know, every, everything you would equate with a conscious being. I mean, you have to remember back in this period, people would argue, are these animals like conscious? It's sort of crazy. Yeah. Right at the end of this talk, basically everyone was like, we can't do this anymore. Mm-hmm. And that was the end of chimpanzee transportation. That's fascinating. I love, yeah, I love that story. Afterwards, she was in an interview and she goes, I just thought those people were so crazy. That's So as after the primate era ended, can you take us through the next era? Yeah. So interestingly, um, even before the primate era was over, there were a number of, you know, very brilliant researchers who knew that it, that primates weren't ultimately gonna work out. And they knew that for a number of reasons. Number [00:20:00] one. Well size. I mean, chimpanzees get up to like a hundred pounds. But the other, you know, monkeys um, baboons, they're really small and mm-hmm. They would transplant both kidneys on block, kind of similar to how we do mm-hmm. A peds on block transplant now, but they still were way too small, you know, a 30 pound. Baboon or whatever. And so that was number one problem. Number two problem was they breed like we breed. And so, not only would it be, as I said, kind of dystopian to have like an island of breeding. Mm-hmm. Chimpanzees don't, you know, breed well in captivity, but then even beyond that. They already were understanding that ultimately they would need to do a gene, uh, modification and gene editing. And they kind of were aware that without a faster breeding cycle that was gonna be impossible. And then infectious risk, I mean, HIV uh, came from chimpanzees. Some of the hepatitises are in, uh, uh, chimpanzees and a lot of other diseases. So that was a concern. And then the public response to it. So, pigs, [00:21:00] uh, became a natural choice for a number of reasons. Number one, we sacrificed so many pigs for food that nobody, you know, a billion a year. Nobody seems to mind that. So it's kind of hard to argue not arguing against that. Number two, they breed very quickly. They have big litters. You know, you can have a litter up to eight pigs. Uh, they can breed again and again. So that. Works uh, for gene therapy. If, you know, they didn't know how to do it then, but they knew eventually that would work. And we'd already been exposed to pigs for so many years with our interaction with food that the thought was mm-hmm. That the infectious risk would be lower. Um, so there were a number of researchers and they found out very quickly that if you just put a pig organ into a human or into. Really into a primate as a model for a human, uh, into a baboon or a monkey. Mm-hmm. Uh, they would rapidly reject, uh, the organ. Mm-hmm. And people like David Sachs, David Cooper David White, weirdly, like, they're like five Davids as these it's apparently you have to be named David to be a [00:22:00] transplant. But they ultimately were able to identify that humans. And primates, old world monkeys have natural antibodies against any animal below that on the evolutionary scale. Okay. And, um, they kind of sorted out that the, that antibody actually evolutionarily probably was very important. Probably a virus or bacteria came around where those primates, like 28 million years ago, that had alpha gale antibody. Uh, survived this, uh, epidemic or pandemic. Mm-hmm. And then ultimately we evolved from old World Monkeys. Interestingly, new world monkeys, which had already migrated elsewhere, uh, uh, don't have Alpha Gallo antibody, which is thought to be that they weren't exposed to this. So it really, really fascinating. Interesting. Yeah. Um, so then they spent like the next many years trying to figure out how can you make a transplant work when you have tons of natural antibody, uh, you know, is there a way to get rid of it? Mm-hmm. And ultimately it became obvious that they were gonna have [00:23:00] to find a way to get rid of this sugar molecule from these pigs, and that was gonna require gene therapy. Mm-hmm. So that, yeah, the late 1990s and early two thousands were also the era of cloning. Um, how did these. Advances influence, um, Xeno transplant? Yeah. I mean, I, I will, I, maybe we'll talk about this more, but I, I think like most scientific advances there's incremental hard work. And, um, I don't say that in a belittling way. The incremental work is critical and it's fascinating and it takes hard work. And then there are these episodes of quantum improvements. Mm-hmm. So like, I don't know, I think in human transplant, the incre, you know, the, maybe the quantum was the. Identical twin transplant. 'cause it proved to people in 54 because that proved to people it could happen. Then the incremental work of trying to make it work, trying to make it work. And then cyclosporine was like the quantum leap in 83. Mm-hmm. That made human aloe transplant work. I think for a Xeno and many other areas of science. Being able to clone [00:24:00] Dolly the sheep mm-hmm. Was a massive quantum jump because before cloning, they had these very primitive ways of doing gene therapy where you literally. Would take some DNA and you would inject it into like a fertilized egg. And this worked well with mice and actually David White was able to do it with a pig. He made a transgenic pig, but you'd like inject DNA into tons of fertilized eggs, just hoping. Mm-hmm. It would get somewhere that it would get made and not disrupt something else. Uh uh And then, you know, just put this fertilized egg into. So, and then you do this for years and maybe you'd get one pig that had one gene. Mm-hmm. But you couldn't do a knockout like that. Okay. There was no technology to do it. And people understood that you would need to be able to do your gene editing in cells in a dish that were dividing. Mm-hmm. And then you would need to be able to take those cells and clone an animal without being able to clone. You couldn't do anything in a dish. With dividing cells, it was just impossible. And people thought they were able to clone [00:25:00] mice actually back in the eighties 'cause they found stem cells, uh, that would divide, that were really easy, but in large animals they couldn't. And then, um, there were a number of different groups, but the group in Edinburgh, they figured out how to clone dolly the sheep. They took mammary cells and they got them to divide in culture. And basically, um, they sucked out the nucleus of the mammary cell and they, um, put that into an egg cell that didn't have a nucleus. So that's like nu nuclear transfer. Mm-hmm. So you take this nucleus out, squirt it into the egg, and then, you know, and then put it into a sow. And, and they were able to clone Dolly the, she. Then shortly thereafter they made poly the sheep where they actually took that mammary cell and they put in a gene for enzyme in the milk that could cure human disease. And that's where their idea of like, oh my gosh, we can use cloning to generate a transgenic animal that can make something that can cure disease. The group that did this, they were scientists, but they had a funding [00:26:00] arm that recognized. That cloning was gonna be huge. And they also recognized that it might lead to Xeno and which they knew was gonna be a big market. Novartis was already pretty interested in Xeno at this point, so they, they started a company called PPL Therapeutics that ultimately down the road, was bought eventually by United Therapeutics, which is one of Okay. There are companies in Xeno, so like I I, there's a great story of a guy, another David, David Ayers, who's now this, the head of, of one of these companies, and he was a gene editor. He was working in mice and he, he was looking for a new job and he got invited to PPL in Edinburgh and they wanted to open a branch in Virginia. And they, um, he was like, this was before Dolly was cloned. And he was like okay, yeah, maybe this'll be interesting. And he was, he was trying to decide whether to take the job and he was on vacation back in the States and he was reading Jurassic Park and he was like laughing to himself like, this book is so stupid. This would be done. Halfway through [00:27:00] the book, the New York Times article came out about cloning of Dolly, the she, and, you know, the world's gonna change. And he said he just like. Closed the book and threw it out. 'cause he was like, it's so banal, it's not even worth reading anymore. And that's how big this was. I mean, people knew immediately that the world was gonna change. Dolly was cloned. 'cause they knew even with their, they at this point, they could do homologous recombination, they could do some very primitive gene editing. And they knew once they could clone, they could make knockout animals. Mm-hmm. They, it was gonna be painstaking, but they knew it could happen. Mm-hmm. You talk about quantum leaps in, um, the field of transplantation. What is the next big thing that changed, you know, transplant? Yeah. So, um, there were a couple of, like, there was the good and there was the bombshell. Mm-hmm. I think the good is that two groups one David Sachs's group, uh, at ultimately at Mass General. And I worked in his lab mm-hmm. But not a little bit before that. Um, as well as the David Ayers group working for, you know, that PPI. Which ultimately became United [00:28:00] Therapeutics. Mm-hmm. Were able to make an alpha go knockout pick. Mm-hmm. And they made that kind of 2002 into 2003 and they did it, um, using homo homologous recombination, so early version of gene editing and clotting. And it was like a huge effort. And it, it seemed like it was gonna be a world changer. But at the same as they were doing this, there were problems rising and maybe the biggest problem, two problems. Number one, animal protests. So the UK has a very strong history of like animal rights groups for hundreds of years, much more so than the US. On top of that. They actually went through like the, the whole mad cow, uh, sort of epidemic I guess you'd call it, where, you know, people were getting really, really sick from cow meat. And so this combination of thinking that it was a bad. Idea to use animals for humans, both. Mm-hmm. Because it was unethical, but also because it was risky. Actually kind of ended, [00:29:00] uh, Zeno in the uk. So David White, who was working in the uk got kind of like run outta town and Zeno moved over to the us. The other kind of bad thing that happened to Zeno is this. Endogenous retrovirus. Mm-hmm. Sadly called perv pit, you know, porcine, endogenous retrovirus is identified. So people may not realize that we all have viruses that are embedded into our genome which some people call endogenous. Mm-hmm. Or fossil, uh, uh, retrovirus. And they actually are important in evolution. So like. The fact that humans can make a placenta or women can make a placenta. Mm-hmm. Came from, uh, an endogenous virus. So those viruses, some people say 8% of our genome comes from, uh, viruses and they get passed down from generation to generation. Um, but these viruses laid dormant, but they can wake up. Rip Van Winkle, that was written by Spike. Mm-hmm. And so. A, uh, researcher, a very high end researcher who was doing a lot of HIV research. Mm-hmm. Published a paper showing [00:30:00] that pig cells can have this virus and in culture. The cells can checked other cells. So that was a big headwind that, wait a minute, if we do, if we actually put pig organs into humans and immunosuppress them, it could unleash a pandemic. Nevertheless, these two Davids pushed on and you know, got to the point where they had these alpha G knockouts and they at the time were being funded by big companies like Novartis, and actually Pizo and Pittsburgh were funded. Mm-hmm. The other group, and they got to the point where they were able to transplant these pig or organs into um, primates. Mm-hmm. And while the outcomes were dramatically better. Than ever seen before. Like they were able to get a heart sewn into the belly of a primate to last, Hmm. You know, almost 200 days. And they got a kidney to last close to a hundred days. It wasn't like so dramatic that mm-hmm. It was gonna enter the clinic anytime soon. And so this is around 2003, 2004. The big companies, like Novartis said, between animal rights. This [00:31:00] infectious risk of perv. Mm-hmm. Outcomes aren't moving quick enough. We're pulling all our money. Zino went into the wilderness. Okay. I mean, with, with still incremental work funded, NIH, you know, funded by other government, you know, agencies, UK still funded some research, although not at the level it used to. Zeno kind of went into the wilderness. Um. And was, you know, had the risk of like not advancing. Mm-hmm. And, you know, I would say the next people made incremental progress, but probably the next quantum leap would have to be Crispr Cas nine. Mm-hmm. Mm-hmm. Um, because by this point they had better gene editing techniques, um, the like, um, they had this thing called zinc, uh, finger endonuclease where they. They could actually do gene editing a lot better than homologous recombination. They could have a guide and they could cut genes out, but it was still highly inaccurate. Mm-hmm. Took a lot of effort. They [00:32:00] didn't always know if it would hit the right spot, so they were still doing gene editing and cloning. They actually made more knockout pigs, but nothing was like. Kind of really exciting industry. Mm-hmm. And really generating a lot of interest. But then a combination of like the Human Genome project, understanding that we were getting our heads around the genome, and then this idea of Crispr Cas nine, where people realize we can really easily edit genes. We can do it at will, we can do it accurately, we can do it quickly. And then with Crispr Cas nine, all these big companies, all these big investors were like looking for people and companies to invest in. And Xeno became one of those things. I, I don't think it's fair to give all the credit to Crispr Cas nine because I think some of the really good gene editors of that era will say, oh, we were doing pretty good uniting already. Mm-hmm. Uh, that was a game changer. Mm-hmm. And I mean, a bunch of really big names got into the game. So, like George Church, who many people will have heard of the mm-hmm. Broad Institute, uh, Harvard researcher who I describe. [00:33:00] Um, he's this tall, lanky guy. He has a deep voice and the person he most resembles is God. Like he, he looks like God, but he, um, he's done a lot of amazing things. He's the guy who's trying to bring the woolly mammoth back, so I'm okay. My, my brother actually wrote a book about him and that. Oh, really? Um, he spun off like tons of big companies, but he got interested. He was a gene editor, not a transplanter. Mm-hmm. But he was like, what cool things can I do with crispr? Mm-hmm. And he cut out the entire perv virus, which was like, oh. Mm-hmm. 59 edits. Uh, and added 10 additional edits, um, that were both knocking out Alpha Gal and a few other things, and then adding things in. So he has a pig that has 69 gene edits. Mm-hmm. It's the most edited, most edited uhhuh on earth. Some other fascinating figures. God in the game and who I write. Mm-hmm. So it's funny, the book, like the first half. Goes through the primate era, the history, the incremental work, the Davids mm-hmm. You know, gets us to that [00:34:00] point. The second half is almost like a movie where it's like, you know, give me like some amazing characters that are gonna make this happen. So you got George Church, you got Martine Rothblatt, who in my opinion, could be the most interesting human being in the world. Many listeners will know Bob Montgomery kind of ultimate pioneer also on the short list of most fascinating people in the world. So Bob is a transplant surgeon, was really big in desensitization and pared exchange. He himself had a, has a, uh, congenital, uh, heart, uh, malady. He actually had like, I don't know, seven cardiac arrests, including at a Broadway show where they did CPR for like an hour. And then he woke up and looked around and like waved his hand and the whole theater erupted. He like arrested in Patagonia on a hunting trip and somehow he lived through all of this and. Ultimately got a heart transplant from a Hep C donor. He was like one of the first, and when he was lying in the [00:35:00] ICU, he was, you know, he thought he might die and he felt bad taking a heart from someone else. And he said, if I get through this, we need to find a new paradigm. We can no longer live under this paradigm where someone has to dive for someone else to live. We have to do something different on all in, on Xeno as well, so. Mm-hmm. I think like the quantum weep was, CRISPR was this ability to make really complex, amazing pigs. Now there are multiple pigs out there with anywhere from three to 10 to 69 gene edits. Mm-hmm. And in primates were able to have those organs, whether they be hearts or kidneys, last multiple years. Mm-hmm. And this work has now led to humans getting transplants. Mm-hmm. Our first ever human trials. We have two human trials that are happening now. Can you talk a little bit more about where Zeno is today? I, I get goosebumps thinking about this, that we finally reached this point. Yeah. I have to say, when I was in the lab, like [00:36:00] in 19, 19 99, I, I thought this would actually come quicker, but just a foolish. So I kind of thought the first Alpha gal would be like, game changer. But, um, we finally got to a point where the primate, the pig to primate data was good enough, you know, with, with people last, with primates lasting more than a year that it became time to try in humans. And the FDA has, although I think they've been overall supportive, challenging in many ways too. So they did approve a number of transplants through compassionate use, and I think there were two heart transplants, uh, performed at University of Maryland, um, with Bart Griffith and Mohamed Udin, who's another. Fascinating. Mm-hmm. Character, they were able to do two humans who, uh, were turned down for various reasons for human heart transplant were really, really sick. Mm-hmm. And, um, some ethical challenges there, whether that's appropriate in people that were turned down for human transplants. Um, and they received hearts. Their hearts lasted a couple of months. They worked really well. [00:37:00] Initially, they got off the breathing tube off. I mean, these were really, really sick patients, but. They died of various things. Um, and then a number of kidneys were done. I think Mass General did the first, uh, kidney, which was an genics kidney into an African American man re-transplant. He actually, his kidney worked really well for a month and then he suddenly died of a heart, maybe a heart arrhythmia. Mm-hmm. Which may or may not have been related to the transplant. And then, um, Bob, Bob performed a kidney into a patient that got a vad. You can't get a VAD in renal failure. So it was the only one and it was very fascinating. She did really well initially and also unfortunately died. Then Bob did a, they did a second kidney into a woman who actually had been a kidney donor. Uh, really. Uh, down in Alabama and then was very sensitized and she got a kidney, uh, did really well, got outta the hospital, but unfortunately lost it after a couple of months. And then Mass General did a [00:38:00] guy from New Hampshire and he did amazing for just under nine months, perfect kidney function out of the hospital. Mm-hmm. And, uh, he did a CNN did a piece on him with Sanjay Gupta. They were taking a walk together really good, but unfortunately he lost his kidney and he lost it. Like one week before he beat the record from Keith. Oh, really? From Keith. So Uhhuh, it's sort of ironic, but anyways two trials have been approved so far. Mm-hmm. One with United Therapeutics, which is Martine Roth Letz. Company and Bob Montgomery's, one of the surgeons doing the transplant, uh, he's the chair at NYU and they haven't like announced how many they've done, probably a couple. The, the trial is they have to do at a couple centers, six transplants, and as long as, as they have, then they're gonna see how they do for a few months. And as long as they do well for something like six months, it's gonna go to a multicenter 50 person trial. And then Egen SSIS also has. Started a trial with Mass General being the lead center, and they've also [00:39:00] done some, and it's a similar trial. I think they have to do three more transplants and then they'll go to a 20 person multicenter. So hopefully in this calendar year, hopefully we'll get into the multicenter. Trial. Like I, I'll just my, I think that right at this moment with, and there are a few different pigs being used. The 69 gene edit without perf the 10 gene edit that United Therapeutics uses, which has knockouts and some knockins of Immunomodulary genes. I think realistically we can get six months to a year mm-hmm. Survival of these kidneys and they can function well as a bridge. I am unsure that. We can get longer than that. Both between the challenges of how much immunosuppression they need and still the potential for increased risk of rejection. Mm-hmm. That said you know, there are some newer pigs out there. Joe Teter has a newer pig that's kind of hot off the press, so probably not yet. Ready to, he probably wouldn't want me to talk about it too much, but seeing some like, amazing [00:40:00] results. And so like my gut feeling prediction here could be wrong. Mm-hmm. Is that I could see this iteration of pigs and there's a few other things going on. I, I couldn't get into everything. Right. This version maybe could see FDA approval as a bridge. Um, you know, what are the scenarios? Someone who couldn't tolerate dialysis. Mm-hmm. Maybe someone who's highly sensitized. Mm-hmm. Uh, maybe pediatric heart transplant because they don't have VADs or mechanical hearts for peds patients. Yeah. So that could be an area, I think next iteration, like in the next five to 10, you know, hopefully less than that is gonna be significantly better, I hope. Like a decade from now, we've got xeno transplants that can be similar to humans, I hope in our lifetime, or maybe your lifetime, 'cause I'm editing rapidly in this career. But, um, you know, we can have pig organs that require less immunosuppression. Mm-hmm. Maybe even tolerance. Mm-hmm. That can last [00:41:00] longer than humans. Um, that can be cha, you know, ordered. That can even be matching genomes or at least matching class two. Mm-hmm. I think all of that is possible 'cause our ability to gene edit and cloning has just gotten so much better so quickly. It's such an exciting time to be in transplant. I mean, it's just it, it still feels a little bit like science fiction, but it is happening today. It's happening today. Like there's so much, I just want your listeners to know, like mm-hmm. This is like one area. I'm a xeno optimist. That's a my point. And I love Xeno. I think it's like, um, I think you can't think of transplant as what it is now. If we got to a point where we had unlimited organs, it would be such a different field. Like now. We only list people that can get really good outcomes, you know, but there are, you know, what, five, 6 million people that have heart failure in the United States, you know, there, you know, countless people with cirrhosis, with lung failure that we don't even consider for transplant. So, I think the sky's the limit, but there's so much buzz going on in the field of transplant. This is just one of [00:42:00] many innovations. Mm-hmm. I think transplant's a really new field, but there's so many exciting things going on. That it's sort of electric actually, to practice in this field right now. Will you tell listeners a little bit about your upcoming book and, um, where they can find it? Absolutely. So, um, the book is slated to come out April 7th. I, people may not know, books always come out on Tuesdays. That's sort of a relic of. Of times when people would go to the bookstore and buy books. So April 7th is the release date and uh, you can pre-order it now either through MIT press or Penguin Random House or Amazon. Mm-hmm. Uh, always the easiest one. Or from your local bookstore. Um. And then you can actually buy the hardcover on April 7th. This has been a really interesting conversation and I'm so excited for all the listeners to check out your book. Yeah, I mean, just thank you so much for having me on here. And, uh, there are a million more stories, uh, a million more people that are part of this. And I think the future, uh, is gonna be really [00:43:00] exciting in our field. Um, despite all the crazy things going on in the world, I still remain excited about transplant, dominate the.