Xenotransplantation

00:00:00
Speaker 1: Hey, friends, just a heads up that we're talking about organ shortages today and will touch on topics like death and animal research. So decide if this is an appropriate episode for you or your kiddos. According to Donate Life America, over one hundred thousand people are on the organ transplant waitlist. Approximately every eight minutes, another person is added to this list, So while you are listening to our show, approximately five people will have been told that their life depends on receiving a new organ. That weight might be quite long. Some folks will wait years before that organ becomes available, and during that weight the quality of their life could be quite poor. And unfortunately, not everyone on this waitlist is going to get an organ in time. Every day, about thirteen people on the waitlist will pass away because an organ was not made available soon enough. So what are our options. Well, today we're going to talk about one of those options that's looking more and more promising every day, and that option is zeno transplantation. That is taking organs from a non human animal pigs in this case, and implanting them into humans. This requires a fair bit of genetic engineering, and today we'll chat about how that's done. Welcome to Daniel and Kelly's Extraordinary Universe.

00:01:43
Speaker 2: Hi, I'm Daniel. I'm a particle physicist, and me and my microbes consider myself one hundred percent human.

00:01:49
Speaker 1: Hi, I'm a Kelly Wiener Smith. I study parasites and space, and yes, the community that makes up me is all me, and I feel great about it.

00:02:00
Speaker 2: Some one wonder and ask Katrina this question whether my microbes would be offended to be considered human because you know, they don't have the human DNA, but they are part of me.

00:02:09
Speaker 1: Yeah, you know, I feel like you could actually have a pretty interesting philosophical argument about what you really means, because you know, when we had Katrina on the show, she was talking about how bacteria sort of communicate with our brain via the vagus nerve vegas nerve. We both know I don't pronounce things correctly, ever, and so you know, I had to what extent your well being and behavior is influenced by what kinds of bacteria you have at the moment. I think it is a fascinating question. And so I contain multitudes.

00:02:39
Speaker 2: And maybe if you had different multitudes, you could pronounce things differently or better. Even right, I don't.

00:02:44
Speaker 1: Think anything could help me with that. Ever, I've always been this way no matter what my microbiome was up to.

00:02:51
Speaker 2: I'm going to ask Katrina to engineer some superbug to help you with your pronunciation.

00:02:57
Speaker 1: I would happily pay for that. That would be a So when I have to do the audiobook readings for my books, I'm always like, ah, this is going to be a disaster.

00:03:07
Speaker 2: But in general, I love when questions in science bump up against philosophical issues, you know, that make us ask questions like what do we really mean by your body? And it's not that hard to get there, you know, you can just even ask like, well, where does your body end? You know, is it at your skin, at your hair, a millimeter past it? It's your fuzzy personal space boundary. You know, it's not that hard to get stuck in weird philosophical questions.

00:03:33
Speaker 1: Yeah, and organ transplants, whether it's from one human to another or zeno transplantation, which we're talking about today, which is when you take organs from a non human animal and put them into a human. You know, causes a lot of philosophical questions or at least a lot of sort of emotional turmoil. There are stories about people who have gotten face transplants, for example, just feeling very uncomfortable looking at their face in the mirror. There's a story of one person who had a hand transplant and he ended up wanting the hand remove moved because he just was like, this is not my hand and it's just too weird. I'm not emotionally, I can't handle this.

00:04:06
Speaker 2: You can't handle it nice.

00:04:08
Speaker 1: Oh I didn't even get how clever even when I'm not trying.

00:04:12
Speaker 2: Man, Well, I was just going to raise that issue, like it's really a ship of theseus question. You know, if you get somebody else's liver, you feel like you're still you. What if you've got somebody else's liver and pancreas and heart and legs and arms and everything else except the brain, would you still be you? I think we mostly consider ourselves to be our brain, which is I don't know if that's philosophically naive or sophisticated or not. But the face is weird. Right to be in somebody else's face. That must feel strange.

00:04:42
Speaker 1: Yeah, that must feel strange. I still feel like, you know, for a lot of people, it must be a huge relief, depending on what happened to them to put them in the position where they needed a face transplant.

00:04:50
Speaker 2: Oh right, Yeah, I thought you were just saying, like, I'm not that happy with my face either, so would be a relief to have somebody else's face over here.

00:05:00
Speaker 1: I spent too much time in the sun. I could use a face with less evidence of that. But this is the face I got, and I'm going to stick with it. But yeah, you know, I as somebody who is working their way through paramenopause, and there are days where I'm feeling grumpy. I'm so interested in this question about like what makes you who you are, and like how your hormones influence the way that you behave or maybe how the bacteria that are releasing stuff, how that influences the way you behave. I think it's a really fascinating question that ties in with this question of like, you know, to what extent does it matter if the you parts have your genome in their nucleus or not. It's complicated. What do you think if you had lungs, hearts, kidneys, liver from somebody else, how would you feel about that?

00:05:46
Speaker 2: I would feel a little bit like I had some of them inside of me. Yeah, and I wonder how parents feel when their children's organs are reused after a tried to accident. Do they feel like, you know, little Timmy's heart is still beating and so we have still some part of him, I wonder, or if they just feel like that was a gift to help somebody else live. I don't know.

00:06:11
Speaker 1: It's fascinating, yeah, yeah, no, fascinating, And it must be very emotionally complicated. I imagine lots of people have different feelings. I think if I was in that situation, I would be glad that other families were spared the pain that I was going through and that, you know, our family was able to give that to them. But it would be, yeah, really complicated. So today our topic is a bit of a downer, But a lot of.

00:06:33
Speaker 2: Those philosophical issues can be partially sidestepped if you're not talking about a human to human gift, right, If you're talking about getting an organ from another animal, and this different set of philosophical issues, right, if you're getting it from a pig or from a baboon, and are they sentient and can they consent? And do they have rights and all this sort of stuff, But you do avoid the question of like taking organs from another person and then being part of you. So tell us, Kelly, how do we get started on this question?

00:07:00
Speaker 1: Well, the reason we got started on this question is because a listener, Jane, who's a pastor, wrote and wanted to know what kind of philosophical issues come up when you're using you know, pig organs, transgenic pig organs to keep people alive. So let's go ahead and listen to Jane's question and then we'll jump into talking about what xeno transplantation is and how it works.

00:07:20
Speaker 3: Hi, Daniel and Kelly, this is Jane from Redcar, England. I've got a question which is more philosophical and scientific. There's been a lot of news about transgenic pigs created for transplantation. The idea is that their genome becomes more and more human so that they trigger less rejection. My question is, at what point do we need to start treating them as human and therefore with more respect. Not that we always treat other humans with the respect, but that's a different question. I'm excited by the opportunities this offers, but I'm also conflicted by the ethics. I look forward to hearing your take on this. Thank you, for a great show.

00:08:02
Speaker 1: All right, So Jane and I had a pretty interesting conversation over email about the you know, the ethics of this question. And I guess I'm a little bit of a negative Nelly. I'm not sure anything is going to put a dent in the way we treat animals that we also eat. But it made me want to do a whole episode on zeno transplantation because there has in the news recently been some pretty exciting updates in this field, and so I thought this would be a great chance to sort of catch up on that research.

00:08:32
Speaker 2: All right, so let's get started. Why do we even consider taking organs from pigs? I mean, obviously I would prefer human organ if I'm going to receive a transplant. Why do we consider other species?

00:08:43
Speaker 1: Well, there's just not enough of the human organs. So last year there were forty eight thousand transplants that happened in the United States, and so that's a lot, and that's fantastic, but it's less than fifty percent of the number of people who are on the list and need organs. So there's this massive difference between the number of people who get organs and the number of people who need them, and there's probably even more people who need them, but they're not on the weight list for a variety of reasons. It could be that it just seems unlikely that an organ that's the right match will come through for them on time, and so some people who would like new organs, you know, don't even put themselves on the weight list. So if we had a lot of organs, then there's a lot more people who would be in a good position. So where do we get the organs we have now? So this is something we've already sort of hinted at in this episode. When somebody passes away, for example, in a car accident, they're organs. The organs that you know are still in good shape can be given to other people who need them if you can find people who are a good match. So being a good match. We have different blood types, you know, if you go in to donate blood, they'll tell you what your blood type is. Essentially, we've got stuff that stick out on our cells, and if your stuff that sticks out on your cells looks different the stuff that sticks out on someone else's cells, then your body's going to recognize that as foreign and the immune system is going to go after it and kill it. So the organ that you get needs to look like an organ that would have been in your body to begin with. Otherwise the immune system is going to go nuts.

00:10:15
Speaker 2: Fascinating, And then does having a good match guarantee that the immune system is going to be cool or do you still need to take immune suppressants your whole life.

00:10:24
Speaker 1: You still need to take immunosupressants your whole life, which means you might be at greater risk of things like infections. Also, I think immunosuppressants make it slightly more likely that you could get cancer later in your life. But you know, if the surgery goes well, then your life will be extended, even though you'll have these problems to deal with.

00:10:42
Speaker 2: I remember, in our conversation about type one diabetes, Katrina was saying that you could cure type one diabetes by getting a pancreaus donation. But then you have immunosuppression, and that's pretty hard for somebody who's very young.

00:10:54
Speaker 1: Yeah, and even today sometimes we don't get that immunosuppression level completely correct. And so if you give people too many immunosuppressive drugs, then you know, people can get horrible diseases and then they can pass away from those diseases. It's a very delicate balance, and so a fair bit of your life from then on out goes towards trying to like modulate your immune systems so that you don't get sick, but you don't reject this organ.

00:11:17
Speaker 2: And what organs are mostly the ones being donated? Is it mostly like kidneys and livers?

00:11:21
Speaker 1: Yeah, mostly kidneys, and then after that livers, and sometimes you'll get lungs or hearts. I think kidneys are so common because if you have a problem with your kidney, you can stay on dialysis. So dialysis is essentially a machine that cleans your blood, does the job that kidneys would have done, and so you can stay alive for years on this machine. It's not a great quality of life, but you can wait for years for an organ to come along, whereas it's harder to get machines that replace our heart or our lungs or our liver. You can do that, but it's not the kind of thing that you can do for like years at a time. And so kidneys are an easy ish organ to deal with or to wait for replacement. And another way that we get organs are through living donors, and so if you happen to have an identical twin who you get along with, and they're willing to give you one of their kidneys. If you two are a blood match, which you would be if you were identical twins, then they can donate one of their kidneys to you and they can still live with just one kidney, and then you get one of their kidneys. But say you don't have an identical twin and it turns out that your siblings and no one in your family is a good match, then for a while there you were kind of out of luck. But recently this system has been created called matching markets. So essentially, if I needed a kidney and Zach was like, I'll give you one of mine, and he's not that nice, I'm not sure he would, but no, I'm kidding, No, I'm kidding, he'd give me his kidney. But so if Zach was like, well, I'll give you my kidney, but it turned out we weren't a match, we could enter our names into a matching market and if somebody else had a you know, a sibling, a boyfriend, whatever, who was a match to me, And it turned out that Zach was a match to them, then we could create that loop and we could switch the kidney, so I would get you know, that boyfriend's kidney, Zach would give his kidney to you know, the other boyfriend, and then we would manage to make the loop that way. And you can get really complicated loops where people are swapping organs and you know, I think more than twenty of these pairs have gone through these loops. And so by having a bunch of people who are willing to donate, you can make a lot of matches in this system, and so some of the matches come from that, but those can be a little bit complicated because if everybody owes a kidney to somebody else, then you want to try to do those surgeries as much as possible at the exact same time, so that nobody wakes up in the morning and is like, never mind, I'm too nervous, I'm not going to do it, and then one person's gotten a kidney, and now somebody else is sort of left in the lurch.

00:13:51
Speaker 2: You want to like them all in beds in a row. You're just like, ask the kidney.

00:13:54
Speaker 1: Over to the left, right, Yeah, something like that, And so I think two percent of the time, you do have an instance where somebody will come in and you know, it's not necessarily that they like they've changed their mind or they got too scared to go through with it. Sometimes it's just like, hey, actually, it turns out that we discovered they have I don't know, some disease, and so they can no longer donate that organ. And so there's good reason for not being able to do it. But every once in a while you get a good Samaritan who doesn't necessarily know somebody who needs a kidney, but they're just willing to donate one, and then you can get this whole match set off and you can start doing a bunch of kidney transfers between people. So anyway there is a bunch of people who are alive and donate their kidneys, and because we only need one, you can do this. It happens less often with livers, so you can live with just part of a liver, so you could donate part of it. But this surgery is a little bit more high risk, and so it's asking a lot more than just asking someone to give you one of their kidneys.

00:14:50
Speaker 2: And what are the ethics around this because people have these very valuable resources which can save somebody else's life. But obviously you need their consent, but it feels like they could all be pressured into it. It reminds me of the questions people raise around end of life stuff. Or it's like, yeah, it's great if people get to decide when they exit, but do you want grandma to be pressured into the grave by her nephew who needs the inheritance? Right? Right? And so there's tricky issues.

00:15:16
Speaker 1: There, aren't there, Yeah, really tricky issues. And there was for a while, all right. So I'm pulling way back in my memory from when I was writing soonish, I think I'm going to get all of this right. But I ran used to allow legal selling of organs, and it did seem to be the case that the poor were getting exploited, and they were often not getting paid very much for their organs, and then when they had trouble of their own, for example, maybe they had a problem with their remaining kidney, they couldn't afford the care that they needed, oh gosh, And so that system was not working very well. There are folks who recommend, you know, in the US, for example, you had a system where if somebody is willing to donate their kidney, it doesn't go to a person in particular, Like some super rich person couldn't say I want Daniel's kidney in particular, but Daniel could say, you know, for a million dollars, which is about the cost of dialysis for a year. So like you can imagine a insurance company maybe saying, all right, we'll give Daniel a million dollars so that this other patient of ours doesn't have to be on dialysis for three years, and we promise that if Daniel ever has a problem with his remaining kidney, he goes to the top of the list and he always gets free medical care for anything related to kidney problems. But there's this concept of repugnance in economics, and there's some trades that people feel comfortable with and some trades that people don't feel comfortable with, and trading organs sort of falls into the category of repugnant. People just kind of feel uncomfortable about it. For the reason that you identified. There's so many ways to do it that feel ethically complicated, and you can absolutely imagine that people who are the most likely to donate their organs, or people who are in financial straits and wouldn't be doing it otherwise, but absolutely feel like they need to do it to like, you know, pay their bills or something. So it gets complicated. But in the US you are not allowed to pay for organs.

00:17:11
Speaker 2: And do you think it happens anyway?

00:17:13
Speaker 1: Probably?

00:17:14
Speaker 2: I mean, it definitely happens in the dystopian science fiction that I read. I don't know if that means it happens in reality.

00:17:20
Speaker 1: Yeah. Well, you know, when I was reading the Space Settlement literature, they cited the expanse a lot as though that was actually happening. So if it's happening in dystopian science fiction, it's probably happening in real life.

00:17:29
Speaker 2: Well, since we're talking about science fiction, why can't we avoid this problem by figuring out how to grow organs ourselves? Like why do you need a whole human being just to create a human kidney. Why can't you just grow a kidney in a vat somewhere or like three D print a kidney or something like that.

00:17:44
Speaker 1: Yeah, so people are working on that. So the idea here is that you extract some cells from a person, you grow up their own cells, and then you like extrude them through a three D printer or do some other sort of complicated technique to create an organ out of their own cells. If this worked, you wouldn't need to be on immunosuppressive drugs. It would be amazing. But the problem is that our organs are exquisitely complicated, and even just things like delivering nutrients and removing waste, which you know we usually do with our vasculature our blood vessels, is really hard to recreate with a three D printer, like on the microscale, And so right now we're good at printing what are called organoids. They're like slabs of organ and so that's good for like testing out drugs and stuff. So you know, if your liver drug kills your little liver slab, you probably don't move on to the stage where you're trying it out on humans. But at the moment, it's not good enough to replace any organs. People are working on that. There's some really amazing work to create like vasculature out of like sinered sugar, So you fuse the sugar so it looks like vasculature, and then you seed it with blood vessel cells and those blood vessel cells grow around the sugar and then you put hot water through there and you dissolve the sugar away, and your left with vasculature whoa, and then you can put like liver cells around that.

00:19:04
Speaker 2: But all this talk of sugar, I'm just imagining like a cotton candy kidney or something.

00:19:09
Speaker 1: Yum. Oh, we got to we kind of got to cannibalism. I think you know.

00:19:15
Speaker 2: I tricked you into it.

00:19:16
Speaker 1: That's all right, that's right, Okay, So let's take a break, and then when we come back from the break, we'll talk about xeno transplantation, where you're forgetting about human organs altogether and instead we're just seeing if we can use organs from other animals. Okay, So, xeno transplantation, which is when you use organs from other animals in human bodies, has a pretty long history. We're going to stick with the history in the twentieth century. And you know, I should say that the history of this field is august and amazing, and the scientific work that's been done is fantastic. But I am going to start with the guy who was implanting testicles for anti aging, because I'm me and that's obviously where I had to start.

00:20:18
Speaker 2: But you're saying these experiments are maybe not representative of the scientific calimber of the whole field.

00:20:23
Speaker 1: I mean, it was pretty representative of science in the nineteen twenties. But you know, I don't want you to judge the whole field based on this story I'm about to tell, all right, tell us the story, all right. So Sergey Varnoff in the nineteen twenties and nineteen thirties, he was doing these experiments. He was a Russian emigray living in Paris, and he was implanting slices of chimp and baboon testicles into human males as an anti aging thing.

00:20:49
Speaker 2: Where into human males, like.

00:20:51
Speaker 1: Near the testicles, it would be like you'd get a little slice of chimp nard behind yours and sorry everybody. And there were some people who reported afterwards that they felt more virile and alive, and I suspect that that was entirely 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.

00:21:19
Speaker 2: But were they like wired up with blood vessels and stuff so they could live or it was just like a chunk of dead.

00:21:24
Speaker 1: Flesh yeah, it was a chunk of dead flesh that was definitely going to die, super gross. It was not going to be like producing more testosterone or anything like that the way they had done it. And if you went to the US, 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 viral goats.

00:21:42
Speaker 2: This is like zombie goat testicles. This is not good. I don't understand why anybody would say yes to this.

00:21:48
Speaker 1: 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 they're in there and they decay away and if you're lucky, it won't cause a massive infection, right, and that's the best case scenario. All right. So then this got dropped for a while because this wasn't really working out. In the nineteen sixties, we try transplanting chimpanzees and bonobo kidneys into humans directly. One woman lived with the 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 banobo organs into a human is not going to solve our problems.

00:22:43
Speaker 2: Well, 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 were better for donating kidneys.

00:23:05
Speaker 1: 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. It 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. They're two 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 zeno transplantation, and the way that we've done that is by genetically engineering pigs so that they look more human.

00:24:03
Speaker 2: That's really interesting, Kelly. I wouldn't choose pigs necessarily. Tell me, why would we choose pigs to be our organ farmers.

00:24:09
Speaker 1: 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. So 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 they 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 knee.

00:25:00
Speaker 2: You're talking about chimped 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 go it early.

00:25:12
Speaker 1: 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. We'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.

00:26:01
Speaker 2: 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? Is 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?

00:26:29
Speaker 1: 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.

00:26:46
Speaker 2: 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 and 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 that 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 am not prepared to answer these questions. My philosophical framework here is quite naive.

00:27:18
Speaker 1: 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 US that you were gonna 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. Like 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 okay to eat, although I know that there are you know, cultures and religions for which that's not the case.

00:27:59
Speaker 2: 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.

00:28:10
Speaker 1: Yeah, it's not that easy actually, So in the US 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, all right, So.

00:28:48
Speaker 2: Then the key concept is that these aren't just normal farm pigs. These are pigs have been genetically engineered to make fair 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?

00:29:03
Speaker 1: Yeah, so you're gonna 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 CRISPER CAST nine system. So CRISPER stands for clustered regularly interspaced short palindromic repeats. I'm sure everybody's going to remember that the women who found this Jennifer Dudna and Emmanuel Chapatier. What you do French stuff? Right? How do you say that name?

00:29:33
Speaker 2: That sounded pretty good.

00:29:34
Speaker 1: Yeah, okay, fantastic. You know I've I've been working on French and du a lingo.

00:29:37
Speaker 2: To your microbiome.

00:29:38
Speaker 1: Okay. So they got the Noball 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. And now whenever that viral sequence is found in their body again, Crisper goes and cuts it to break it up.

00:30:10
Speaker 2: So it's like a little bacterial immune system that like a library of viral codes that they've seen before that they're like.

00:30:15
Speaker 1: 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 Crisper like, go in there and cut it at the spots where we want you to cut it, and 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.

00:31:03
Speaker 2: Man, biological engineering is incredible. I can't believe this ever works 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. You just have like a test tube with solution and you jiggle it and you hope everything lines up. It's crazy.

00:31:19
Speaker 1: It's so crazy. I cannot believe that it works, but it does. 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 e Genesis, which is a company that makes genetically modified pig organs in addition to making a bunch of other stuff.

00:31:38
Speaker 2: This is non science fiction. They exist in our world.

00:31:40
Speaker 1: E Genesis exists in our world. That's right.

00:31:42
Speaker 3: Wow.

00:31:43
Speaker 1: And I wrote them. I wrote for you know, their media contacts or whatever. And 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 described how they made these genetically modified pigs 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.

00:32:13
Speaker 2: 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 chest up? Okay, So she could have had like you know, pig legs under the table and you wouldn't even know.

00:32:27
Speaker 1: I had no idea where you were going with this.

00:32:31
Speaker 2: 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.

00:32:39
Speaker 1: I had no reason to believe that she was anything other than a you know, woman with no animal parts, and she was wonderful. So all right, okay, they had made three different classes of edits. The first thing they did was they removed all the pervs.

00:32:56
Speaker 2: The what's pervs.

00:32:58
Speaker 1: The pervs. Pervs are poor sign anddogenous 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 cap Ohannan 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.

00:33:36
Speaker 2: Yeah, so you.

00:33:37
Speaker 1: 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.

00:33:44
Speaker 2: Nobody wants a purview organ for sure.

00:33:46
Speaker 1: No, no, absolutely not. No. There's so much material we could work with here, but anyway, we won't get to too gross. And so they cut out the poor sign anddogenous retroviruses to make it so 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. So pig cells have some sugars on them, and that's because pigs and humans, you know, diverge something like eighty 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 depigged 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. And so my question when she told me about that was, well, if we have to worry about our immune s 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.

00:35:09
Speaker 2: That was my question too. Yeah, well, but it's such a.

00:35:11
Speaker 1: 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, it's immune system is like, oh sweet, these sugars belong here, and it doesn't attack them.

00:35:38
Speaker 2: There's no ingrained knowledge in the immune system is just trained on examples from when your fetus. It's like a blank neural network.

00:35:45
Speaker 1: 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 vironments, so their immune systems 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 crispired all of that stuff into existence. All right. So what Egenesis did is they collected cells from the ears of one hundred different pigs. They ran their crisper magic to make all of those three different classes of changes we talked about. They ended up making sixty nine 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.

00:37:02
Speaker 2: 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. Now you got to load that code into the hardware, so like the whole pig cell runs it.

00:37:15
Speaker 1: 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.

00:37:38
Speaker 2: All right, So the first pig is an adult as 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. Is that right?

00:37:54
Speaker 3: Yeah?

00:37:54
Speaker 1: Yeah, So you could take a cell from that pig's ear, use Crisper cast nine to make a bunch of edit it's 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, and then you use that egg to grow up new pigs.

00:38:12
Speaker 2: All right, wow, and so does it work? Do we have baby pigs growing human kidneys or or human is kidneys.

00:38:19
Speaker 1: 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. Sometimes 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.

00:38:52
Speaker 2: You treat them as like a science experiment. Wow.

00:38:55
Speaker 1: Yeah, that's a not so nice way of putting it. I would say, you know, if I were in that sea 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, because 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.

00:39:24
Speaker 2: And so so yes basically.

00:39:26
Speaker 1: 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 E Genesis 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. So 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, to 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 and they're likely to survive is high. And so we're trying it out on these folks, yeah, because it's a good option for them given the options they have. And so these folks tend to be fifty five to seventy 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. I 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, which is so amazing. And then there's another company called United Therapeutics, and they also have used Crisper to modify pig organs. They only did ten 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, so 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 suppressive 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. And 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.

00:41:35
Speaker 2: 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.

00:41:49
Speaker 1: 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. Sometimes 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 with 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.

00:42:39
Speaker 2: Yeah, 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 pigkinnys and others won't.

00:42:56
Speaker 1: I think yes. I think that is a live option. So the 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. Maybe we will need to personalize these organs a bit more. And I'm sure the three D printing people are saying, if you print with your own cells, this will never be a problem, when 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 that's not where we are right now, and.

00:43:36
Speaker 2: Our pig's the only place this is happening. Is there any other species that's in contention?

00:43:41
Speaker 1: Nope, just pigs. Wow, as far as I can tell.

00:43:43
Speaker 2: Yeah, 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.

00:43:50
Speaker 1: That's right, that's right, a little bit of levity and 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 non starter. But do you think there'd be any rules about accepting organs?

00:44:09
Speaker 2: 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, because Rabbis have a lot of fun arguing about stuff like this, you know, like, can you turn on the light switch on Saturday? No? Can you hire someone to turn on the light switch?

00:44:27
Speaker 3: No?

00:44:28
Speaker 2: But can you pay them to do something else and then they turn on the light switch. Yes, so there's all these like creative ways to like 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.

00:44:45
Speaker 1: 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 encounter the animals that I'm eating a lot more, and I have been very surprised by how dynamic their personalities are, and how good they are with their babies, and how.

00:45:07
Speaker 2: They obviously feel joy and pain.

00:45:09
Speaker 1: 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. So Jane at the start of this episode asked if we were to start treating pigs with more respect if they became a major source for our organs. Don't. Actually, I don't see that happening, to be honest, I think the.

00:45:44
Speaker 2: 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.

00:45:51
Speaker 1: 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. And 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, yeah, I don't think this is going to change things.

00:46:40
Speaker 2: 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. So everybody wins except the pigs. I guess.

00:46:57
Speaker 1: Yeah. Okay, Well, so I'd like to end on a slightly high notes. 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 where 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 one 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. And 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.

00:47:54
Speaker 2: It does. Yeah. On the other hand, I want to live and I want my kids to live.

00:48:00
Speaker 1: 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 Wenningchin for chatting with me and for making me even more excited about this. Your enthusiasm was contagious.

00:48:13
Speaker 2: 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 breakdown, please write to us questions at Daniel and Kelly dot org.

00:48:23
Speaker 1: And let's close out by seeing what Jane thought about our episode.

00:48:28
Speaker 3: Hi, Daniel and Kelly, I'm so glad that my question spot 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. I've been on the ukogn done a register for decades, and it really suddens 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.

00:49:17
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