Xenotransplantation

26:20All right. Tell us the story. All right. So Sergei Varnov in the 1920s and 1930s. He was doing these experiments. He was a Russian émigré living in Paris, and he was implanting slices of chimp and baboon testicles into human males as an anti-aging thing. Where into human males? Like near the testicles. It would be like you'd get a little slice of chimp nard behind yours. Sorry, everybody. And there were some people who reported afterwards that they felt more virile and alive and i suspect that that was entirely uh placebo effect and they're lucky they didn't get massive infections in their testicles from these foreign cells being placed in that so delicate of an area but were they like wired up with blood vessels and stuff so they could live or it was just like a chunk of dead flesh yeah it was a chunk of dead flesh that was definitely going to die uh super gross uh it was not going to be like producing more testosterone or anything like that, the way they had done it.

27:22And if you went to the U.S., there was like a charlatan who I believe he was pretending to be a medical doctor and he was giving folks testicles from like super virile goats. This is like zombie goat testicles. This is not good. I don't understand why anybody would say yes to this. So, I mean, I don't feel like this is a metaphor we need to double down on, but I would say these goat testicles aren't like coming back to life inside of this human. You know, I think they're Just like they're in there and they decay away. And if you're lucky, it won't cause a massive infection. And that's the best case scenario.

27:56All right. So then this got dropped for a while because this wasn't really working out. In the 1960s, we tried transplanting chimpanzees and bonobo kidneys into humans directly. One woman lived with a chimpanzee kidney for about nine months. Wow. Which was a pretty long time to have your life extended. But in general, these surgeries don't work because human immune systems reject these foreign organs. And so some people, the rejection takes a little longer. Others, it happens more quickly. But it becomes clear that just straight-up implantation of kidney and bonobo organs into a human is not going to solve our problems.

28:32Well, we heard earlier that not even all human kidneys work, right? If I need a transplant, I can't just get a random human. I need a specific human that's probably not going to trigger my immune system. So that makes it sound very unlikely that any chimp would work. But when they do this, do they like choose a chimp that's less likely to trigger an immune system? And do you have like a chimp match? You know, some chimps who are better for donating kidneys. So at this point, we didn't really understand blood types. And so we were just kind of hoping that chimpanzees were closely related enough to humans that this would work.

29:03It was a little bit after this where we started to figure out that, oh, hey, even within species, like with dogs, if you transfer organs from one dog to another, sometimes it works, sometimes it doesn't. And it took a while for us to figure out that that all depended on blood types. And so once we figured that out, I think it was in dogs. I read this great book called Spare about the history of organ transplantation. They talk about blood type and how we figured that stuff out in more detail if anybody's interested. But once we figured it out in humans, we realized, okay, so this isn't going to work with chimpanzees.

29:35They're too distantly related. Same with bonobos. Even with humans, you need to figure out blood types. But I told you at the start of the episode that we've made some progress in xenotransplantation. And the way that we've done that is by genetically engineering pigs so that they look more human. That's really interesting, Kelly. I wouldn't choose pigs necessarily. Tell me, why would we choose pigs to be our organ farmers? That's such a great question, Daniel. So chimpanzees and bonobos are more closely related to us. So they seem like a more obvious choice. But they've got a couple problems.

30:09So first of all, they're smaller than us. So their organs are smaller. And that was a problem in some of the surgeries that were tried earlier. The chimp kidneys were too small, chimp hearts too small. But additionally, people feel much more uncomfortable about euthanizing chimpanzees and bonobos because they're more closely related to us. So there was this idea that there would be more of an ethical backlash. But perhaps even more than that, chimpanzees and bonobos take a long time to reach sexual maturity, and then they only have a few babies at a time. So you'd have to scale up in a way that would be very difficult and we've never really done before to have enough chimpanzees and bonobos to meet the need.

30:49You're talking about chimp farming, right? You're saying that it's hard to get a big population. Yeah. Wow. So you want something that grows quickly and has babies young so that you can get that exponential factor going early. Yikes. Right. And your face is telling me that you feel uncomfortable about this suggestion, which almost everybody else did. the final nail in the coffin is that those more closely related organisms are more likely to have diseases that could jump from them to us making this a little bit scarier so pigs are an organism that we already know how to grow in like sort of production level yeah so they reach sexual maturity when they're young they have lots of babies we know how to keep them alive we understand these organisms fairly well.

31:35We've got like their genome and their organs are like fairly similar in size to humans in a lot of ways. And so we've sort of settled on pigs as our best bet as starting material to tinker with to make organs to keep us alive. I don't know if that logic really holds. It's like this is ethically dubious. So let's do it on a creature we're already mistreating ethically, right? Like we already treat pigs as if they're objects. And so therefore it's okay to treat them as objects, where it's not okay to treat chimps as objects because we don't do that already? Yes. Or is it just about being closer to us?

32:12Is this another like speciesism thing? Like how much of humanity's rights do you get? Chimps get a little bit and pigs get almost none? Yes. I mean, I think everything that you just said is uncomfortable, but true. But you've told me in a previous episode that you have accepted that humans are just sort of like a level above the other animals and you are okay with eating them. And I feel like you're not consistently applying that philosophy right now. No, you're right. Because consistently applying that philosophy means arbitrarily labeling humans as better. And the point you just made with chimps and bonobos is that there's a spectrum, right?

32:47And like, where do you draw the line? And now you have to have a fuzzy delineation of how much of this like special glowy rights do you put on people and how much do you not? And what if somebody had a half pig, half human hybrid, what would they get? you know and so yes I'm not prepared to answer these questions my philosophical framework here is quite naive yeah I do think a lot of this stuff is complicated like you know if you go to some countries they eat guinea pigs and it's like nothing but if you told a child in the U.S. that you were going to have guinea pig for dinner they'd probably be very upset because we think of those animals as pets and not food and so I think a lot of it depends on what you grew up feeling comfortable with.

33:29Like I know some people who won't eat bunnies because they're too cute, but they will eat pigs because they think they're not cute. But I think pigs are cute. And I think anyway, humans have very complicated feelings, but pigs are an organism that I think a lot of people have decided is OK to eat. Although I know that there are cultures and religions for which that's not the case. And at least we're not committing any more crimes. We're committing more crimes on each individual, but we're not committing crimes on more individuals. We're already raising these folks for meat. And so might as well harvest their organs.

33:59Yeah, it's not that easy, actually. So in the U.S., we're very uncomfortable with eating genetically modified foods. And in the European Union, I think it may even be completely prohibited. And so I don't actually know if these pigs, after having their organs harvested, would be sent out to become bacon, for example. I will say that if the companies that made these pigs said, you know, we're going to sell pork from these animals that we used, their organs for transplants, and it's safe, we eat it ourselves, then that would be the pork that I would buy. But I don't actually know that that's how it would play out.

34:38All right. So then the key concept is that these aren't just normal farm pigs. These are pigs that have been genetically engineered to make their organs better for transplanting into humans. How do you do that? Do you just like randomly breed pigs? Or can we actually go in and tinker with the DNA. Yeah. So you're going to have to tinker with the DNA because if you don't tinker with the DNA, you're always going to have this immune system problem. And so recently we got this major advance in tinkering with DNA. I'm sure just about everybody has heard of this. This is the CRISPR-Cas9 system. So CRISPR stands for clustered, regularly interspaced, short palindromic repeats.

35:12I'm sure everybody's going to remember that. The women who found this, Jennifer Doudna and Emmanuel Chapadier. Wait, you do French stuff, right? How do you say that name? That sounded pretty good, yeah. Okay, fantastic. You know, I've been working on French and Duolingo. Kudos to your microbiome. Okay. So they got the Nobel Prize for this work. And so essentially this system is snagged from bacteria's immune system. So the way this works is that bacteria remember, not the same way that we remember things, but they remember a virus that has infected them by essentially when they find that virus, they grab a piece of the virus's genetic material and they stick it into their own genome.

35:53And now whenever that viral sequence is found in their body again, CRISPR goes and cuts it to break it up. So it's like a little bacterial immune system. They have like a library of viral codes that they've seen before that they're like, this is bad, kill it. Right. So you essentially have a system that can recognize certain sequences of genetic code and then it goes in there and it cuts it. And so it's like targeted molecular scissors. And so we can use this. We can say, okay, here's a pig and here is the code for a gene that we want to tinker with. And so you can tell CRISPR, like go in there and cut it at the spots where we want you to cut it.

36:29And now you can deactivate a gene. Or when it cuts a gene, the way the DNA responds is it repairs itself by sort of joining the two ends back together after you've made the cut. But you can, before it joins itself back together, sort of slip in a new gene or some new genetic code. And so in that way, you can both remove things or add things in specific locations that you want. Man, biological engineering is incredible. I can't believe this ever works. I know. Because it's not like, I imagine you'd need like tiny little tweezers and you're like moving it into place just right. But you can't do that, right?

37:03You just have like a test tube with solution and you jiggle it and you hope everything lines up. It's crazy. It's so crazy. I cannot believe that it works, but it does. Amazing. It's absolutely amazing. But so the next step from there, I found sort of confusing. And I was reading the scientific papers I wasn't following. So I wrote eGenesis, which is a company that makes genetically modified pig organs in addition to making a bunch of other stuff. This is not science fiction. They exist in our world. eGenesis exists in our world. That's right. Wow. And I wrote them. I wrote for their media contacts or whatever.

37:36And I was like, I don't speak molecular biology. I can't figure out exactly what was done here. Can you connect me with someone who can explain it? And so they connected me to Wenning Chin, who was the senior author on the Nature paper describing how they made these genetically modified pigs. Wow. Amazing. She was so fantastic to talk to and so excited about this research. So she told me that there's three different classes of genetic changes that they made. So first... Wait, hold on. Did you talk to her and see a video or just over the phone? Over Zoom. And did you see her only like, you know, chest up or full body?

38:12Chest up. Okay. So she could have had like, you know, pig legs under the table and you wouldn't even know. I had no idea where you were going with this. I was like, the hell are you asking me, Dan? I mean, you're talking to somebody at a company who's like doing cutting edge, like human animal weirdness. So like, I mean, you're not curious? I had no reason to believe that she was anything other than a, you know, woman with no animal parts. Okay. And she was wonderful. So, okay. They had made three different classes of edits. The first thing they did was they removed all the pervs. The what? The pervs.

38:48Pervs are porcine endogenous retroviruses. So the pig genome has some viruses in it. And most of the time, those viruses are either helpful, for example, they help with things like placenta formation. And we're going to have Kat Bohannon on the show in the future to talk about how that works. But they also have some other viruses that are able to start replicating themselves at like sort of random times that we don't really understand how they choose when they want to start replicating themselves. And we've put these viral particles in plates with human cells, and it looks like they can infect those human cells.

39:25Yeah. So you really don't want to get a pig organ and then discover that you are filled with pervs and that you are going to die from those viruses. Nobody wants a pervy organ for sure. No, no, absolutely not. No, there's so much material we could work with here. But anyway, we won't get too gross. And so they cut out the porcine endogenous retroviruses to make it so that that wouldn't be a problem. They had to be pretty clever about how they did the cutting, but they made it so that they feel like this is no longer a risk to people who get these organs. Then the next thing they had to do was remove stuff on the pig cells that our immune system could use to say, hey, that doesn't belong to me.

40:09So pig cells have some sugars on them. And that's because pigs and humans, you know, diverged something like 80 million years ago. We've gone on very separate paths. And so our cells look different. And so what they did was they went in and they removed these sugars from the cells. They essentially de-pigged these cells so that our immune system would be less likely to see it and be like, you don't belong here. And then the next set of changes that they made were essentially humanizing the pig cells. So now on the cells, they added stuff to make them look more human, again, so that the immune system wouldn't respond.

40:44And so my question when she told me about that was, well, if we have to worry about our immune system attacking cells with pig sugars, why don't you have to worry about the pig bodies attacking the human sugars when the pigs are growing these organs? That was my question, too. Yeah. But it's such a cool answer. And I should have known the answer as someone who works sort of adjacent to immunology. But anyway, the answer is that if you are a fetus, the things that you're exposed to when you're a fetus are what your body expects. And so if you grow a pig from the starting point, like as an embryo with these human sugars, its immune system is like, oh, sweet, these sugars belong here and it doesn't attack them.

41:28There's no ingrained knowledge in the immune system. It's just trained on examples from when your fetus. It's like a blank neural network. That's right. That's amazing. Yeah. And so like if fraternal twins, so twins that aren't exactly identical, like if they share a blood supply, you're more likely to be able to do transplants between them because they had that stuff in the environment. So their immune system is less likely to attack it. Incredible. Okay. So those are the three changes that were made. Let's take a break. And when we come back, I'll tell you about what they did once they had crispered all of that stuff into existence.

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46:02All right. So what eGenesis did is they collected cells from the ears of 100 different pigs. They ran their CRISPR magic to make all of those three different classes of changes we talked about. They ended up making 69 changes total. They took an egg from pigs. They pulled out the nucleus in the egg and they put in the genetic material that they had just created. So with all of the changes and then they grew that up into a pig. All right. So because before we're talking about genetic information sort of in the abstract, It's just like you have DNA in a vial, but it's not part of a cell. You're just like writing the code.

46:41Now you've got to load that code into the hardware so like the whole pig cell runs it. Yes. Cool. And so they did that. And so now they have pigs that are adults and are growing these organs. And they have all the genetic changes that they put in there. And now when these pigs have babies, they will also have these genetic changes. So now you have lines of pigs that are making organs that should be able to go into humans. All right. So the first pig is an adult, has the normal like piggy pervy organs, but you've put cells into it that have the edited DNA and its children will have that edited DNA and they will grow up and generate the organs without the pervy bits.

47:24Is that right? Yeah. So you could take a cell from that pig's ear, use CRISPR-Cas9 to make a bunch of edits inside of that cell, then take the nucleus out of that cell and put it in an egg from any pig, really. Could be the same one that you took the ear stuff from. Oh, I see. And then you use that egg to grow up new pigs. All right. Wow. And so does it work? Do we have baby pigs growing human kidneys or human-ish kidneys? Well, so the way that you test this stuff, so first you tend to try these organs out in like macaques or baboons. So you try them out in closely related primates. And if it works okay in them, then you can say, all right, maybe we're ready to jump to humans.

48:05Sometimes you have an additional step in between where you have a human who has had an accident and they've experienced brain death, but their organs are still working. And so then you put them on life support and you can put a genetically modified organ in them and see how their body responds. And so that's a way to see. You treat them as like a science experiment. Wow. Yeah, that's a not so nice way of putting it. But I would say, you know, if I were in that situation and someone has to decide, does Kelly's body get used to try to, like, figure out this life-saving technique and that's her last contribution to the world, like, I would hope that somebody would say yes.

48:42Because that, I mean, that feels like it sucks that I died. But it would be amazing if I could help build the argument that was needed so that we could start using this amazing life-saving technique in other people. And so. So yes, basically. So yes, yes. But, you know, families get asked ahead of time. You know, it's all of this stuff. Fascinating. It has complicated ethical approvals that are needed ahead of time. But so eGenesis did get permission from the Food and Drug Administration to try these organs out. I believe that they're still getting tried out under what's called compassionate use.

49:15So it's getting tried out on patients who I believe are not able to get on the wait list for one reason or another. Like, you know, for example, they have a blood type that is pretty rare. It's hard to find someone who's compatible. the probability that they will be on the wait list for longer than they're likely to survive is high. And so we're trying it out on these folks because it's a good option for them, given the options they have. And so these folks tend to be 55 to 70 years old, and they're unlikely to get an organ in the next five years. So two of these surgeries have been done. And so far, both of the people have survived.

49:51I think these surgeries were done in like February or March, and it's June now. And as far as I could tell, searching through Google, the folks who received these organs are still alive and still doing well. Amazing. Which is so amazing. And then there's another company called United Therapeutics, and they also have used CRISPR to modify pig organs. They only did 10 edits. It sounds like maybe they're keeping their fingers crossed that those retroviruses aren't a problem. I don't think they did as many edits to those, but this is all sort of information that isn't made public exactly what edits you make probably.

50:26So anyway, they've also done some transplant experiments using their organs. One of the patients who had one of these genetically modified organs had it for four months and then her body started to reject it for unknown reasons and it had to be removed. So it's possible some more tinkering is going to need to get done with the pig organs, or we need to do a little bit more work figuring out the right amount of immunosuppressive drugs. But, you know, these organs are being trialed out. And if these initial trials go well, then the pool of people who could join trials to test these organs out will expand.

51:00And so that's where we are right now. We're kind of trying it out to see if we figured out all the changes we need to make. This feels like we're on the cusp of something really big. I mean, if this works, it could really change what it means to wait for an organ, how many people die waiting for organs. Yeah. It could really change the experience of being human and the experience of being pig, unfortunately. Yeah, yeah, yeah. So these pigs need to be grown in facilities where they are absolutely not going to encounter additional viruses. So for example, sometimes the flu can jump from birds to people.

51:32Sometimes it can jump from pigs to people. So you want to make sure that your pigs are not encountering any new flu strains. So they need to be in these like incredibly biosecure facilities. But yes, once you grow up enough of them and you expand the facilities, hopefully, you know, with a lot of procedures that are ethically, you know, compassionate for the lives of the pigs, you could have organs that are ready at just about any time. So, you know, somebody who has kidney issues wouldn't have to face down a few years of dialysis where the quality of their life is much lower. You know, they could discover they need a new kidney and they could, you know, have it a month later or something like that.

52:09Yeah, but these kidneys are not tailored to an individual human, right? They're generically modified so that they're more acceptable to humans broadly. But we know the humans are different, right? And some humans reject or accept different kidneys. Is it possible that some kinds of people will be able to accept pig kidneys and others won't? I think, yes, I think that is a live option. So the woman who had the United Therapeutics kidney, who eventually rejected it, I think we don't understand why she rejected it. It could be that there's some incompatibility issue that, you know, might be specific to her.

52:42Maybe we will need to personalize these organs a bit more. And I'm sure the 3D printing people are saying, if you print with your own cells, this will never be a problem. But, you know, that technology isn't here yet either. So yes, it could be that more tinkering needs to get done. It would have been beautiful if everyone who got these genetically modified pig organs accepted them with no problems right from the start. But that's not where we are right now. And are pigs the only place this is happening? Is there any other species that's in contention? Nope, just pigs. Wow. As far as I can tell.

53:14Yeah. So maybe society will get divided in the future into people who can accept pig organs and people who can't, the piggy people and the non-piggy people. That's right. That's right. A little bit of levity in our otherwise sort of bummer of an episode. But so I've got a question you might not know the answer to. So there are some cultures that can't eat pork. So my husband is Jewish and he's a vegetarian, too. So it's sort of a nonstarter. But do you think there'd be any rules about accepting organs? That is a great question. And what I don't know the answer to. And one reason that it's a great question is that I'm sure the rabbis will have a lot of fun arguing about it.

53:49Because rabbis have a lot of fun arguing about stuff like this. Can you turn on the light switch on Saturday? No. Can you hire someone to turn on the light switch? No. But can you pay them to do something else and then they turn on the light switch? Yes. So there's all these creative ways to find loopholes to satisfy all the requirements. and I think they get a lot of joy in arguing about it. So this seems like a really juicy question for them. That's right. That's right. And I have to admit, like, I feel a bit uncomfortable. Okay, so since I moved on a farm, I have had a much harder time eating meat because I encountered the animals that I'm eating a lot more.

54:28And I have been very surprised by how dynamic their personalities are and how good they are with their babies and how... They obviously feel joy and pain. That's right. Yes. Yes. Seeing like goats get zoomies and frolic around a field, you're like, ah, I really enjoy you in my Euro. And now I feel complicated about that. But, you know, if my daughter needed an organ and it was between a pig and my daughter, I wouldn't have a hard time with that choice. And I guess same with me. Mm-hmm. So Jane, at the start of this episode, asked if we would start treating pigs with more respect if they became a major source for our organs.

55:11I don't see that happening, to be honest. I think the opposite is true. No, I think the more useful they are, the more we convince ourselves that they're just things and not like people. Yeah. So for me, the more I encounter farm animals, the more I want to either not eat them or only eat animals that had really good lives. Like I feel more and more uncomfortable about factory farms. But I think that most of us are not seeing or engaging with these animals that we end up eating or, you know, that are part of the various processes for products that we use in our lives, like leather or whatever.

55:47And so I don't see us treating animals nicer as long as we are not encountering them more and like needing to see what it looks like to get this done. I hope that we'll treat them ethically. It does seem like over time there have been more rules for treating animals ethically and trying to give them a nice life for as long as they've got it. But I don't think this is going to change things. Well, let's take a positive view. if we have pigs that can grow organs for humans, it means more humans survive and it means more jobs for philosophers to figure out whether or not we are bad people and jobs for rabbis to answer these questions.

56:25So everybody wins except the pigs, I guess. Yeah, okay. Well, so I'd like to end on a slightly high note. So first of all, I don't know if this is a high note, but we already eat a lot of pigs. So this is apparently something we're, for the most part, already comfortable with. but let's focus for a second on how much amazing stuff we had to learn to get where we are today you know like we are harnessing bacteria's immune response to create organs that could save the lives of like over a hundred thousand people who are on the wait list right now it is amazing to me that we have figured out how to get this far like just the many giants whose shoulders we had to stand on to get to where we are today.

57:07And if this works, the suffering of many, many, many people could be alleviated. A lot more people could survive and the people who are waiting for organs would have a much higher quality of life. I can't help but be inspired, even though, you know, everything that has to do with humans seems like it's ethically complicated. It does. Yeah. On the other hand, I want to live and I want my kids to live. Yes. Amen. And this might be a path towards making that happen for a lot of people. So I'm wishing them luck. And thank you to Wenning Chin for chatting with me and for making me even more excited about this.

57:41Your enthusiasm was contagious. And thank you very much to Jane for sending us your question. And if you have a question about any kind of science you'd like to hear us break down, please write to us, questions at danielandkelly.org. And let's close out by seeing what Jane thought about our episode. Hi, Daniel and Kelly. I'm so glad that my question sparked such a super interesting discussion. Did you answer my question? Well, yes, but by giving me even more ethical and philosophical conundrums to worry about. I can't comment on the rabbi's response, but as a Christian pastor, I hold a high view of humanity.

58:20I've been on the UK organ donor register for decades, and it really saddens me that there are not enough people willing to donate organs that they've finished with. I just worry that this will be one more exciting scientific breakthrough, which is pushed through without serious ethical consideration. Thank you so much, Kelly, for looking into this and sharing your wonder and enthusiasm with us all.

58:54Daniel and Kelly's Extraordinary Universe is produced by iHeartRadio. We would love to hear from you. We really would. We want to know what questions you have about this extraordinary universe. We want to know your thoughts on recent shows, suggestions for future shows. If you contact us, we will get back to you. We really mean it. We answer every message. Email us at questions at danielandkelly.org. Or you can find us on social media. We have accounts on X, Instagram, Blue Sky, and on all of those platforms, you can find us at D and K universe. Don't be shy. Write to us. Aging is real. And so are the benefits of new vital proteins, collagen, sparkling water, because around the age of 30, your body needs backup to keep your collagen up.

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1:01:40Get started at ChatGPT.com by selecting Work Mode. Available on Plus and Pro Plans. This is an iHeart Podcast. Guaranteed human. Thank you.