Ep 66 The Outs and Ins of Organ Transplantation

00:00:01
Speaker 1: I'm Carol often and fourteen and a half years ago I donated a kidney to my son Paul. He was in college when he was diagnosed with kidney disease, and it came totally out of left field.

00:00:16
Speaker 2: He was not someone with risk factors.

00:00:19
Speaker 1: He didn't have high blood pressure, diabetes, he was an obese, he was a skinny college kid, and he was otherwise healthy. What he had was a lingering strip infection, but he was otherwise healthy, and they said, well, we'll monitor it, you know, but it could be years, it could be twenty years before it ever got to kidney failure. And by that time, you know there's going to be a cure or some great treatment, you know, So let's just watch it and you know, put it on the back burner, which we did, and a couple of months after college graduation, he went for his normal lab work and found out that his kidneys were failing and that within a few months he was a need dialysis but ultimately a transplant, and we were just blindsided. Everyone in the family said they wanted to be tested, but my husband had had kidney stones. They eliminated him. Our daughter was barely fifteen at the time. And they wouldn't even consider her. I was the only one who was healthy enough and the right blood type. But anyone who knows me knows that I was not an obvious choice. I'm a whimp.

00:01:28
Speaker 2: I fainted flu shots.

00:01:30
Speaker 1: I've been known to pass it out thinking about a blood test. So you know, the idea of giving voluntarily giving up a bodily organ, you know, was not something that anybody thought that I would ever do. But you know, when your kids kidneys are failing and there's something that you can do to change it, you know, I think any parent would want to. And so we started the testing, and I mean, you name it. They did lots of lab work, chest X ray and EKG and a lung function test and stress test and sent me home with a big receptacle for a twenty four hour year in collection. So it was incredibly thorough. I mean, most of the tests are to make sure that you're healthy enough for yourself and that it's not going to jeopardize your health. The testing went on for months, and so I kind of went through all of the phases of.

00:02:31
Speaker 2: You know, really want to do this, Yes I do, No, I don't.

00:02:35
Speaker 1: Kind of but by the time we went through advanced testing.

00:02:39
Speaker 2: I was pretty sure, and I.

00:02:41
Speaker 1: Kind of wondered, you know, would I secretly be relieved if I found out that I couldn't. I mean, hey, I tried, you know, I did everything I could. And you know, Paul my Son, wouldn't you know, think ill of me if it you know, if it couldn't be. And I don't know when, but certain point I realized no, I wanted to do this. The fact is he had no other options and he'd been on dialysis. He was on dialysis for twenty months, and it was help for him.

00:03:13
Speaker 2: He was depressed. It dominated his life.

00:03:17
Speaker 1: It was really rough, and we watched him going through this feeling like there was no light at the end of the tunnel. And he was on the list for a deceased donor. But the wait for a deceased donor is then and I think still is in our state five to seven years, and the thought that this could go on and on longer was just unthinkable. And so, yeah, if I could turn things around for him, you bet I wanted to.

00:03:53
Speaker 3: And.

00:03:55
Speaker 2: I did.

00:03:57
Speaker 1: And June twenty seven to two thousand and is still the proudest day of my life. And it was not only easier than I expected. It's made or surgery, of course, but it's laparoscopic. I was walking the next day. I bounced back quicker, and it was even more gratifying than I'd expected. I mean, I knew i'd be relieved, god, you know, and I knew i'd be thrilled because of the difference it was going to make for my son, but I had no idea what an incredible high it was going to be. That It's just an indescribable feeling to know that you have made such an incredible difference in somebody's.

00:04:41
Speaker 2: Life, whether whether it's a loved one or not, just.

00:04:44
Speaker 1: Anybody, another human being. And I wanted to shout it from the rooftops. I'm an editor and writer by profession, but I was intimidated by the subject.

00:04:56
Speaker 2: And it was years.

00:04:57
Speaker 1: Before I wrote anything about it, and years before I became an advocate, but I wanted to spread the word and tell anybody who listened and reached out to Betsy. Betsy and I knew each other from when our girls were in Girls Scout. I knew that not only that she'd had a transplant, but she was kind enough to come talk to our son when he was on dialysis and give him some sense of how much better his life was going to be. When it finally happened and I reached out to her, I remember you mentioning years ago that you were thinking of, you know, someday writing about donation, and I kind of wanted too, you know, I want to talk, and she did, and that was over six years ago. The title is The Insider's Guide to Live in Kidney Donation. Everything you need to know if you give or get the greatest gift, and it should be out in late Spring Way.

00:05:53
Speaker 2: Help and Anyway.

00:05:56
Speaker 1: But that also led to my wanting to widen while we were working on the book my impact and created a website and started advocating more and more, not just through writing, but through involvement with the National Kidney Foundation and Donate Life and You Knows.

00:06:16
Speaker 3: And.

00:06:18
Speaker 1: Wanting to make people aware not just about donation, but of kidney disease. And basically I want people to understand that what happened to our family can happen any family.

00:06:32
Speaker 4: My name is Elizabeth Kray. Most my friends and families call me Betsy, and I am a professor at the University of North Carolina Chapel Hill and like Carol, have a linked kidney story, and that is that I needed a kidney some years ago. I needed a kidney in two thousand and three. I have family history of polycistic kidney disease, so my kidneys began to get bigger and bigger and bigger. By the time I had my transplant, both kidneys were about five pounds of each, So just imagine two bags of sugar carrying around. So people frequently asked me when my baby was due, and if they were strangers and I didn't know them, I would just say I would just make a guess, oh July or something like that. Some people wanted to touch my belly. It was very strange at the time. You know, back then in two thousand and three, two thousand and four, there just wasn't much information about kidneys. And I went to the library because that's what you did. We didn't have the Internet, and you know, all the things that I read were just technical texts and not really personal or practical things. And now it seems like with the Internet we have lots of things and it's really hard to kind of read between the lines or you know, know what to read or what to follow and so that's really what Caroline put this book together for to help both donors and recipients kind of know the steps. From my own family, I'm into the police kidney disease. The best thing is that I had two sisters who had polycistic kidney disease in addition to my mother, and so we really were our own support group. And so when I had my transplant, one of my sisters had already had a transplant. She came helped me through the transplant process, and you know, it was invaluable in terms of her own experience. So again, you know, I think it motivated us to think about putting this book together for people. My own donor is a colleague and we still work together. Her name was Linda Watson. She was very concerned and didn't know that she could be a donor because she wasn't a family member, and so that was one of the things she found out early on in the donor process. The other thing that's important to know is that even if we hadn't been a match for each other, now they're programs, kidney pairing programs where if you're not a match for your donor or DONEE, you can get in a computer system and sign up for this matching process, and they can find other people who can be a donor or a donee. And so this donation happened. I had both my kidneys taken out in two thousand and three because they were so big. And in two thousand and four, my friend, good friend, Linda Watson stepped up and went through donor testing and became a donor. And she did great too. Within a few days she was up walking around. I think she took off a couple of weeks from work, but she said that even that was not necessary. I had felt like I didn't know how I was going to express my gratitude. I mean, who can thank someone enough for giving a kidney? I mean, that's incredible that somebody would be willing to do it. And yet at the time afterwards, I was kind of struggling with this responsibility that I had this other person's kidney, and what if I didn't take care of it, and what if, you know, what if I didn't eat well or something. And it was really great that the transplant staff really helped me come to realize, you know, that I was a good patient, that I was followed the rules, I took my meds, I did all the right things, and they were saying, you know, you're a great person to receive a kidney. You're going to be very careful and take care of it. Linda also wrote me a note afterwards when I was trying to express my gratitude to her, and wrote me this beautiful note. I probably go with Tierry and said that her giving to me was sort of a coming back to a hole for her and making her feel hole that she had done this extraordinary thing for someone else and really changed my life. So I've had her kidney for almost seventeen years. Next month it'll be seventeen years. So it's been quite a while. But unfortunately, kidneys last about fourteen fifteen years. But there are people who have had their kidney's twenty thirty years. And so a couple of years ago, her kidney began to begin to have less kidney function and back on dialysis. And I'm also going to need a kidney and a liver. So I'm listed for a kidney and a liver transplant. And but yet, you know, I'm having a good life. I work full time, I'm happy, I'm healthy and feeling really good. About it.

00:11:59
Speaker 5: M thank you so much Carol and Betsy. It was so great to chat with you and thanks for taking the time and heads up. So, their book, The Insider's Guide to Living Kidney Donation Everything you need to Know if you give or get the Greatest Gift, will be released sometime spring this year, twenty twenty one, So put that on your pre order list and check it out. It's fantastic.

00:12:26
Speaker 3: Oh that's awesome.

00:12:28
Speaker 2: Hi.

00:12:28
Speaker 3: I'm Erin Welsh and I'm Erin alman Updyke.

00:12:32
Speaker 5: And this is this podcast will kill you.

00:12:34
Speaker 3: And today if you haven't figured it out yet, we're talking about organ transplantation.

00:12:41
Speaker 5: Like of all different kinds.

00:12:43
Speaker 3: It's gonna be so big, it's very large, and it's also it's a hard one in some ways to fit into our normal format. Yeah, so heads up, this episode is going to be a little more different than tradish.

00:13:03
Speaker 5: I think it'll be good though. I think it'll be I'm very excited to lesten all about the mechanics and immunology of organ transplantation.

00:13:12
Speaker 3: Great. I'm glad you said immunology because like we're not going to talk about mechanics.

00:13:16
Speaker 5: I mean, you know, vein to vein artery.

00:13:19
Speaker 3: Yeah, that's not I don't know anything about that.

00:13:22
Speaker 5: So well, before we begin, I guess we have some business to take care of.

00:13:29
Speaker 3: We always do. Let me check it's quarantin any time.

00:13:33
Speaker 5: Quarantin any time. What are we drinking this week?

00:13:36
Speaker 3: Nothing other than on ice on ice?

00:13:40
Speaker 5: And as you can guess, on ice is a drink served on ice on ice. It is made of whiskey and pomegranate juice and lime juice and some bitters and a little splash of club soda. And guess what it is served on ice on ice. And we will post the full recipe for the quarantine as well as the non alcoholic Placybrita on our website. This podcast will kill you dot Com as well as all of our social media channels, so be sure to follow us.

00:14:13
Speaker 3: There absolutely any other business to attend to.

00:14:18
Speaker 5: There's the usual things. We have transcripts now, and we are getting so many of the back ones, we're getting so many of the current ones. So if you want to check out any of these transcripts, go to our website and click on the transcripts tab and you will see what is there.

00:14:34
Speaker 3: Also on our website you'll find a link to our bookshop dot org affiliate account, as well as our Goodreads list and merch merch.

00:14:44
Speaker 5: I was like, what else do we have there?

00:14:46
Speaker 3: I forgot, Yeah, I forgot for a second. But we have incredible merch.

00:14:49
Speaker 5: We really do. Okay, Well, I'm kind of like ready to get down.

00:14:54
Speaker 3: Me too, business, Me too. It's a big one, so let's take a quick break and then dive in.

00:15:00
Speaker 2: That's great.

00:15:21
Speaker 3: So, like I said, this is a different sort of episode. So the biology section is going to be a little bit different in that we are going to focus on very broad strokes themes that are involved in all organ transplantation.

00:15:38
Speaker 5: I'm excited, me too.

00:15:41
Speaker 3: So in dealing with organ transplants, whether we're talking about solid organs like lungs and livers and kidneys and hearts like the organ part that you probably think of, as well as tissue transplants like heart, valves and skin and bone, there are kind of a few big categories of issues that might arise or things that might become complications. So, of course there are medical complications, especially because in the case of organ transplantation, a person who's undergoing organ transplantation is probably pretty sick, right, and so there are likely other medical complications aside from just the organ that needs replacing, and there also could be complications with the donor, depending on whether it's a living donor or a deceased donor and what medical conditions they may have had or what the cause of death may have been. So that's like a whole category is medical complications. Okay, we're not going to talk about those. They exist. That's all we need to know for the purposes of today. Additionally, because we're talking about literally moving organs or tissues from one person to another, for the vast majority of organ and tissues transplants, there are major surgical complications to contend with, and the degree of surgical complication is going to vary very widely, like bone marrow relatively small versus entire face transplant or entire hand transplant Oh my gosh, right, and there's everything in between, from skin grafts to livers to partial livers to single kidneys, et cetera. So there's a huge potential for surgical complication. Again, I don't know anything about that, so we're not going to talk about like how you hook up one artery to another. However, there is at least one category that I do feel that I can talk about, and it happens to be, by and large, one of the biggest hurdles. And what I suspect based on I don't know much about the history, but I suspect that most of the history of organ transplantation, the biggest issues were in fact this hurdle exactly. Okay, Yeah, and that is neither medical nor surgical, but immuneologic right now, all right, So that's what we're going to focus on. We're going to talk through these immune logic complications, both in the short term and the long term, how we can actually recognize them, prevent them from happening now, and then how we can also manage in the long term.

00:18:22
Speaker 5: Sounds great, all right.

00:18:24
Speaker 3: So first we'll touch on the big immune system components that we have to take into consideration in order to find a matching donor, like what does it mean to be a matching donor? Yeah, and then we'll briefly go through what happens if things don't go exactly according to plan or aren't perfectly match and different kinds of rejection that can happen. So the first big hurdle, and the easiest one to cross, in fact, is blood type boom okay standard, so blood type as an abab or O. So a donor in general has to have a matching blood type in order for an organ not to be rejected. The question is what are these blood types exactly and why is it so important that they match? So I can't believe we've never have we ever talked about blood types.

00:19:13
Speaker 5: We briefly touched on it in the Hepatitis C episode and then but really what we did We spent most of the time being like, we should do an episode on blood and bloody Yeah.

00:19:25
Speaker 3: Well, here we go, a promise finally realized. So basically A and B represent antigens, which are glycoproteins, little proteins that are found on the surface of our red blood cells. However, these antigens are also on the surface of a huge variety of our cells, including the lining of our blood vessels. So we think of them as your blood type, like your red blood cells, but these proteins are found on the surface of a whole bunch of cells. If you have type A blood that means that your cells have that A antigen on their surface, And what naturally happens in everyone who is type A is shortly after birth, you start to produce antibodies against the b antigen. If you have type B blood, it's the opposite. You have the B antigen and you make natural antibodies against the A antigen.

00:20:26
Speaker 5: How does your body know what the b antigen looks like if you have type A blood.

00:20:32
Speaker 3: It's a good question. So our bodies are constantly making antibodies against all kinds of different things, and whether or not they kind of keep them in our memory and continue making antibodies against them just depends on whether we recognize them as actually foreign. Why it is that we all make antibodies against the one protein that we don't have, I don't really know. It's a good question.

00:20:58
Speaker 5: And so I'm AB right. Does that mean I don't make antibodies against exactly?

00:21:05
Speaker 3: So you, as a type AB are a universal exceptor right for blood and things like that because you don't make any antibodies. I, on the other hand, am type OH, which means I make antibodies against A and B. So your blood would kill me erin, but you could take my blood any day.

00:21:26
Speaker 5: Wow. I don't like the metaphors that are that are being implied by this.

00:21:33
Speaker 3: That is really funny. Actually, Okay, listen. In the case of organs, if you have a mismatch of blood type ABO, when you try to put in that new organ that's of a different blood type, those pre formed antibodies that you already have will immediately recognize this new organ as non self and will attack it, resulting in what we know as hyper acute rejection. So that means it's not just in the short term, but it's within less than twenty four hours the organ will fail. And a lot of times, I mean, essentially this should never happen in modern times, but if it ever did, a lot of times it's so instant that, like if you try to say, hook up a kidney, as you're waiting where it should pink up, it will then depinkify.

00:22:25
Speaker 5: Oh interesting, okay, yeah.

00:22:27
Speaker 3: So our AH, which is the positive and negative in your blood type, is reesis factor, and people either have it and then their RH positive, or they don't have it and then their RH negative. There's two reasons that it does not matter as much for organ transplantation whether you're positive or negative, and one is that while A and B antigens are expressed on a wide variety of tissues, the RH factor is only on red blood cells.

00:22:56
Speaker 5: Okay.

00:22:56
Speaker 3: And so when you're doing an organ transplant, you flush that organ to get rid of all of the blood, so you're not giving that person any red blood cells directly, okay. And the other reason is that because unlike A and B, we don't automatically make antigens against RH if you're RH negative unless you've been previously exposed to it. Okay.

00:23:18
Speaker 5: So that's the whole like where you hear about it during pregnancy and.

00:23:21
Speaker 3: Right, that's why it's important and pregnancy. Yeah, okay, yeah, exactly interesting.

00:23:26
Speaker 5: Okay.

00:23:27
Speaker 3: So that's AB and O. And that's a really easy one to deal with because there's only three blood types, right, they're four, there's a B, AB and O. If you get those right, you're good. The next one is more complicated. The next big immuno logic hurdle are the HLA proteins, or human leukocyte antigen proteins. So to understand these, and I'm going to be one hundred percent honest researching this episode was the first time I actually understood what HLA was.

00:24:03
Speaker 5: I am so excited to hear you explain them because I kept coming across this kind of thing in my readings, and I was just like, I can't. I don't know. I don't know what the relevance is.

00:24:13
Speaker 3: Let me break it down so simply for you. I'm really thrilled to do this. So to understand what HLA proteins are, we have to think back for a second to our vaccines episode. In that first part of our Vaccines episode, we went through the immune system play right, yeah, and we talked a lot about how the immune system responds to things like pathogens or any other non self what we call antigens, which is just non self material. In Act one of our play, our white blood cells, like macrophages, are the first ones to recognize this non self, whether that's pathogens or whatever, bits and bobs of little pieces of protein and stuff that they find. Those white blood cells then engulf this material, they go, hmm, this isn't me. I don't recognize this, and then they present it on their surface to T cells who are there waiting like a flag. Right. So it turns out that the proteins that are on the surface of our white blood cells that actually do this process, that actually present those antigens to the T cells, those are HLA proteins. So You can think of HLA proteins as like the flag poles that our cells use to present different flags, different little peptides or antigens or whatever to our immune system to start the process of our immune system mounting a response.

00:25:45
Speaker 5: Okay, cool, very cool. Why are there different.

00:25:51
Speaker 3: Like, let me, we'll keep going. I know what question you're going to ask. Let me preempt you and continue going. So, as it turns out, the immune system is a little more complicated than our immune system play was. Oh well there are I know, who knew? There are two different classes, So two different entire classes of HLA proteins. HLA class one is found on a huge range of our cells, like almost every cell, and it presents all kinds of intracellular material. So like if a virus infects let's say, your epithelial cells in your nose, then those epithelial cells will present on HLA class one. They'll be like, hey, I found this piece of a virus. Can you come check this out? Okay, So that's HLA class one. HLA class two are the ones that we kind of talked about already and that we talked about more in our Vaccines episode. Those are found on the surface of white blood cells that in gulf foreign material and then present it to the T cells. Okay, okay, this is very complicated. Within those two classes of HLA proteins, there are six different subgroups. So there's a B and C for class one, and then there's I think it's like d R, DQ and DS. I might have gotten that wrong and someone's gonna yell at me for it. And then within those six subgroups there are tons of additional variations, like person to person differences. I think we found a couple thousand different individual variations, and so unlike the ABO system where you have four things to contend with, now we have six different subgroups and lots more individual variation within that that we have to contend with. Yes, Erin, I can tell by your intake of breath that you have a question.

00:28:04
Speaker 5: And so how do we recognize other like non self.

00:28:10
Speaker 3: HLA great passion. Yeah, So what you're kind of getting at gets into the time course of these types of rejection that we see. Okay, because what you're kind of asking is, so, in the case of an ABO incompatibility, we already have antibodies against that foreign blood type. Right in the case of HLA, you may or may not already have anti HLA antibodies. So when we are looking and this is totally jumping ahead from my notes, but that's fine. When we look at trying to match someone for organ transplantation, we have to look not only at their HLA profile and the donor's HLA profile, but you also have to look at do the recipient or the donor have any anti HLA antibodies against any of those other classes You may or may not. So if you've ever had a blood transfusion, if you've ever had any other tissue transplantation, then you'd be at much higher risk of having those. If you haven't, then there's a good chance that you might not have any hr antibodies got free formed. That doesn't mean that you couldn't then form them, but we'll talk about how we deal with that in a second. Okay, gotcha, great question. So, because these HLA proteins are proteins that are found on cell surfaces that are directly involved in invoking immune responses, there are two different ways that a recipient's body can react to a mismatch in donor HLA. They can do so either directly by recognizing that foreign HLA on, for example, a donor white blood cell, just like they would respond to their own white blood cell, except they say, Hey, that whole HLA protein, m I don't like that, and then respond to that whole protein. Or alternatively, some of those proteins on the surface of the donor cells might get broken at some point, and then the recipient's antigen presenting cells or white blood cells would pick up little bits of donor HLA that they find and then present those very much in the same way that they would present any other pathogen or whatever to T cells.

00:30:35
Speaker 5: Okay, So that.

00:30:37
Speaker 3: Indirect response is thought to be something that's more important later, like later in the course of a graft rejection, for example, whereas that direct response is thought to be more important earlier okay, after transplantation m hm, Oh my gosh. There's a lot of acronyms and immunology, but essentially from there, once a recipient's immune system recognizes that foreign HLA, they do exactly what their immune system is supposed to do. They respond in any number of different ways, either by making a bunch of antibodies against it, or activating natural killer cells or cytotoxic T cells. Whatever they just mount an immune response to try and kill anything with that HLA protein, which means the brand new organ that you just transplanted.

00:31:30
Speaker 5: So you can match blood types, how close can you get to matching HLA can you?

00:31:37
Speaker 3: You can match subgroups, definitely, like the six different subgroups you can match. Certainly, siblings are the easiest to match. You have a twenty five percent chance of having a perfectly matched sibling just based on genetics. But those individual little polymorphisms I think would be a lot harder to match. How much those matter in the grand scheme of antibodies I don't actually know, okay, but for those six six groups, and it also varies organ to organ exactly how close the match has to be to ensure good graft survival.

00:32:16
Speaker 5: Ooh, that is very interesting.

00:32:18
Speaker 3: Yes, please don't ask me any more details than that.

00:32:20
Speaker 5: Oh you're killing me.

00:32:23
Speaker 3: I know, I'm sorry, but if you also think about it. So, HLA class one that's the one that's found on the majority of cells, So that's for most transplants going to be the most important. HLA class two is found on white blood cells. So if you're transplanting something with white blood cells involved, then that one's going to be more important, okay, et cetera, et cetera. There are also non HLA proteins called minor histocompatibility proteins, which also vary, but they aren't major players in solid organ transplantation. That's why they're minor histoic add ability.

00:33:00
Speaker 5: Gotcha, all right.

00:33:03
Speaker 3: So that's the basic underlying immunology. But now the question is what happens if there is a mismatch, Like, what does transplant rejection actually look like. I'm not going to go into a ton of detail because the truth is, the exact symptoms that you see very a lot based on organ, and exactly what symptoms you're going to have will depend on what type of transplantation you're talking about. But there are a few large scale ways that we classify it, either by time course or by immune response. So by time course, you have hyper acute rejection, which we kind of already talked about, and that's if you have pre formed antibodies that immediately within twenty four hours go ahead and attack that new organ. You can also have acute rejection anywhere from six to ninety days. There is a little window period those first few days where if things go really wrong, it's like a whole different classification accelerated rejection, but acute rejection is sort of that in those first couple of months, and that can actually be either antibody or cell mediated, So it could be mostly an antibody response or it can be a cell mediated response either way, and then you have chronic rejection. And so this is what can happen. If someone has a transplant, seems fine for several months, but then later, could be months later, could be years later, that graph starts to get rejected, and this again can also be either sell or antibody mediated, and to some degree, there's going to be chronic damage in essentially every graph eventually, and exactly when that happens depends in part on how well those organs are matched, so how well each hl and everything matches, and also on how good of immune suppression you get and kind of everything overall.

00:35:08
Speaker 5: Does that make sense, Yeah, it's like a it's a tricky line to walk.

00:35:13
Speaker 3: Right, Yeah, So every recipient and donor has to be checked for their blood type as well as their HLA profile as well, like we said, if they have any pre formed anti HLA antibodies in their blood, and then like I said too. How strict you have to be depends in part on the organ that you're transplanting. But no matter what organ, and no matter how well you are matched, basically everyone who undergoes an organ transplant of any kind is going to be on at least some immunosuppressive drugs. I'm not going to get into all the different types of immunosuppressive drugs, because that is who that's a whole thing. There's a lot of different ones, and we've come very far in the amount of immunosuppression that we can do. However, all of our immunosuppressants are still very general. They're not specific. So in general the goal is to just reduce overall white blood cell activation, growth or downstream effects, which means that because these are acting on our entire immune response, they make people more susceptible to infectious disease as well as cancers, since our immune system normally helps fight off infection and take care of any mutated cells that could turn into cancer in our own body. So usually immunosuppression is very high right after the transplant, or even sometimes starting before the transplant, and then can be tapered down, but is usually for the entire life of the graft, which is the new organ. So yeah, that's the biology of organ transplantation. Oh wow, okay, yeah, oh, I did want to give a quick shout out to graft versus host disease. Yes, soft versus host disease is what it sounds like. The graft is the new like donor tissue versus host, which is the recipient. And so that is when the donor tissue is an immunologically active tissue that then recognizes and attacks recipient cells. So this is a problem most commonly in bone marrow transplantation, where you're literally giving someone stem cells that become white blood cells whose job it is to find and eliminate non self, and they are now surrounded by non self.

00:37:45
Speaker 5: Oh boy, it's like the trojan horse of right.

00:37:48
Speaker 3: Yeah. But it's also a problem in the case of intestinal transplantation as well, which is not surprising considering how immunologically active intestines are.

00:37:58
Speaker 5: Yeah.

00:37:59
Speaker 3: So h and especially HLA class two, which is the white blood cell HLA matching and pre treatment with immunosuppression in the recipient is really important in these cases because graph versus host it's pretty easy to prevent, but it's very difficult to treat once it's established, and it's atrocious. It's a horrible disease. Yeah.

00:38:27
Speaker 5: Yeah, Obviously we've come a long way since early transplants. How often does that happen? Now, that's a good question.

00:38:35
Speaker 3: I don't actually know the statistics on it, Okay, Yeah, I think it's pretty rare, because I don't think we'd be able to continue doing transplants if this was something that was super common. There may be some degree of it a little bit, and I actually remember learning that in a very small amount in a disease like for example, leukemia, if you have those graft those donor cells actually helping to eliminate the last bits of any cancer that might still be there. It could a little bit of graph versus host might not be a terrible thing, Okay, but in general, graph versus host is not not good. Yeah, yeah, yeah, And so immunosuppression is really important to prevent that. They also, I will say, the other thing that they do to prevent it is if you transplant just stem cells and not any already activated T cells. So you make sure that when you transplant you flush out any active tea cells that also greatly reduces the risk of graph versus host.

00:39:37
Speaker 5: That makes sense.

00:39:38
Speaker 3: Yeah, so that now is truly the biology of work in transplantation. Aaron, I don't know anything about this history, and I can't wait to learn it.

00:39:51
Speaker 5: Let's take a quick break first, Okay, okay, Erin, let's talk organ transplantation. Yes, I actually have a little note in here that I wrote, put on your grafting boots, Erin. I think that's just because we've been watching too much Love Island.

00:40:42
Speaker 3: Oh my god, that's the best use of that phrase.

00:40:45
Speaker 5: I love it.

00:40:47
Speaker 3: My rafting boots are on.

00:40:50
Speaker 5: Okay, here we go. So, as you can imagine, there are many early myths and traditional tales that tell stories of body parts being replaced, of limbs regrown or reattached. There are tales of a magic glue from tortoises that is strong enough to reattach human body parts, noses and ears being removed and then replaced by wax, a heart replacement from the underworld. Ooh, grafting a premature baby onto a god's thigh until it grows large and strong enough to be born.

00:41:25
Speaker 3: Oh okay, Yeah.

00:41:29
Speaker 5: At the core of some of these stories was like a philosophical question. Can a heart or head or hand replacement make the recipient take on the feelings or thoughts or personality of the donor in other words, like what makes you you? It was a question of identity, while other stories use the instance of organ or limb replacement as simply like a plot point or to demonstrate the power of a god or goddess or saint. But whatever the reason, there's one thing that unites these early stories and myths, and that is that in them, body part replacement was pretty much just symbolic. It was not seen as a medical operation or like something that could actually happen.

00:42:15
Speaker 3: Right. It wasn't real. It was mythology, right, Yeah.

00:42:18
Speaker 5: And what I want to do in this section is to trace the history of organ transplantation from the first people who looked at these myths or thought of limb replacement and thought, I wonder if we could actually do this, like really, And then I'll start there, and then I want to take us all the way through like the first big burst of successful transplantation in the mid twentieth century, Like I want to talk about the immunological and surgical developments that led to that period, being the period of organ transplantation. Why then?

00:42:52
Speaker 3: Why now? Yeah?

00:42:54
Speaker 5: Yeah, this is a massive history, as I've said, and not just because of the incredible growth of technologies that allowed for transplantation to become this almost everyday reality, but also because of the ethical conversations that were happening alongside and were often outpaced by these developments. So just a warning, this won't be an entirely comprehensive history, just an overview, but don't worry, I will recommend lots of further reading. The story of organ transplantation starts earlier than you might expect, and it doesn't start with a reattached hand or a transplanted kidney. It starts with skin grafts. Skin grafts and their widespread use in ancient and then Renaissance times led to building a lot of the knowledge base on how our bodies heal themselves and how our immune systems often reject tissue that is not ours. The ancient Hindu Sanskrit text Susrudo Samhita from around the sixth century BCE It's like a long time Ago, lays out in impressive detail how to perform tissue replacements using skin flaps from the person who was injured, and this type of plastic surgery was practiced with regularity for hundreds of years in India before the knowledge spread more widely to East Asian cultures Arab surgeons, and then to Europe by the Renaissance.

00:44:24
Speaker 3: Say in the sixth century.

00:44:26
Speaker 5: Sixth century. Yeah, and so I want to specify, I want to clarify hear, I mean autographs, so like from the person's thought, yeah, yeah, there's like schematics and like here's how you you know, fix a nose. It's that's pretty amazing, amazing. Yeah, and it like it was pretty much went like unnoticed until the Renaissance in other places, and then there in the Renaissance it was especially in Europe, it was taken up by a lot of different surgeons and expanded upon because of the increased demand caused in part by syphilis and the spread of syphilis. Because tertiary syphilis can cause your nose to fall apart. But using skin flaps from someone to surgically repair facial disfigurements on that same person is you know, that's not whole organ transplantation, like we would consider that plastic surgery. So from the seventeen hundred to the eighteen hundreds, there was a shift in scientific research trends from observation, which had been made possible through advancement in technology like microscopes and like stethoscopes and other tools, and so it went from observation to experimentation, where researchers could test hypotheses to learn the things that might not be as easily observed. And among this new era of experimentation was of course, transplantation. Skin graphs became increasingly popular, and not just autographs, so like from one person to that same person, and not just on humans. Researchers began playing around with allographed so skin from another individual of the same species on humans and animals, so like within you know, from one dog to another, and then also some xenographs, so like skin from another species entirely, or organs from another species entirely, like.

00:46:33
Speaker 3: Put a pig organ into a dog.

00:46:35
Speaker 5: Or exactly et cetera happened a lot pigs or a goat's kidney into a dog, whatever, anyway, you know, there were lots of kind of out there experimentations, and some of them, most of them, all of them were unsuccessful, but there were several key things learned during this time up to the nineteen hundreds. That'll just kind of go over. Number one was that blood flow could become re established with autographs.

00:47:08
Speaker 3: Okay.

00:47:08
Speaker 5: Number two, diseases could be transplanted along with the tissue. Ooh, that's an important one, hugely important. So, like doctors were finding syphilis, for example, pop up in the recipients of tooth transplants. Tooth transplants, Yeah, that were really popular in seventeen and eighteen hundreds. I don't think they actually worked, but I don't think no, but you could still give someone syphilis that way, So even if the transplant itself didn't work. Wow.

00:47:41
Speaker 3: Okay.

00:47:42
Speaker 5: Number three xenographs, so like from one species to another, just they don't work. The heart of a pigeon can't really replace the heart of a rabbit. And this kind of reinforced the idea that there were significant biological differences between species, which, even though it sounds sort of self evident to us now, like that was still kind of up for debate.

00:48:06
Speaker 1: Yea.

00:48:07
Speaker 5: And number four, very thin skin grafts worked better than whole chunks of skin.

00:48:13
Speaker 3: Okay, yeah, just those first few layers.

00:48:16
Speaker 5: Yeah, exactly. The growth in experimental transplants during this time meant that transplantation also was no longer just a fascination for the medical community. The vast possibilities that transplantation seemed to present bled into the public arena, where some of these possibilities were laid out in fiction books such as Frankenstein by Mary Shelley or The Island of Doctor Burreau by H. G. Wells.

00:48:46
Speaker 3: I haven't read that one.

00:48:48
Speaker 5: It has a bunch of like composite animals monstrous animals.

00:48:53
Speaker 3: Oh yeah, how fun.

00:48:56
Speaker 5: And ethical questions were raised as to owner willingness, for example, so like prisoners and other disenfranchised individuals were often quote unquote like volunteered as donors, and philosophical questions were asked about transferable personality characteristics or the unnatural extension of life. Some snake oil salesmen took advantage of the public's fascination with transplantation as per usual, and they promised renewed virility or manliness by transplanting. Get this small slices, well close, just quite close, small slices of goat testes into human testes. Like that doesn't I don't know why.

00:49:49
Speaker 3: Coat it's easily accessible.

00:49:51
Speaker 5: Yeah, maybe maybe there's like a size thing to them too, I don't know.

00:49:56
Speaker 3: Goat testicles, yeah, just bits of them, Yeah, just slices, just little bits into your testicles.

00:50:06
Speaker 5: This it didn't work, obviously, and this misguided procedure misguided as an understatement, But it wasn't the only bit of misinformation that remained from this period, with the biggest one being that most people seemed to believe, like researchers seemed to believe that allographs between humans worked and there was no issue, no issue, Which is very interesting that that was like the prevailing thought. Maybe it's because expectations weren't very high to begin with, or the definition of a successful transplant was not how like you or I would define it or people would define it nowadays. But yeah, doctors in surgeons from this time seemed to think that skin graphs with donated tissue were largely successful.

00:50:56
Speaker 3: Well, that skin graphs yeah yeah, yeah.

00:50:59
Speaker 5: But they did didn't work like what would happen, They just didn't work like what would often happen is that it may have appeared to work in that the donor skin would wither away and become shrunken and then eventually fall off. In the meanwhile, if the wound was not severe enough the person's own skin would recover. But I see, besides that, like people were barely blood typing at this time.

00:51:27
Speaker 3: Yeah, yeah, I thought they might have just got lucky, or you know, it's possible populations where there's like a lot of one blood type, so maybe they just sure.

00:51:38
Speaker 5: I mean, it's possible. You know, even a broken clock is right twice a day. But I don't know about how that applies to allographs skin grafts. Anyway, this wide belief in the fact that like allographs were easypasy aokay for skin, that caused a bit of a hurdle later on in immunological advancements. And that being said, there were some types of transplantations or graphs that were successful, including bone grafts, which because basically the bone just provided like a surface where the host cells could grow, and corneal graphts, and those were successful often because rejection is uncommon. Host cells can't reach corneas because there are no blood vessels that nourish the cornea, et cetera. And these promising advancements overall encouraged surgeons to expand their horizons a bit. In terms of transplantation. Surgeons attempted whole gland transplantation, which was met with mixed results because I see mixed because often spontaneous improvement in gland function was incorrectly attributed to the transplanted glands, which were like thyroid, oh right, yeah, but these transplanted glands were like almost without a doubt rejected. Yeah there's yeah. And then other whole organ transplantation began to take place, with allographs of human to human kidney but also xenographs of all kinds, so like goat to human. None of these transplants was ultimately successful, and the recipient often died within a few days of the surgery.

00:53:27
Speaker 3: And these are often recipients. Are these in this case who actually need a new organ to survive or are these medical tortures that are being.

00:53:38
Speaker 5: From what I could read, it was people who this was the last resort type of surgery. Now the donor, on the other hand, were there wasn't necessarily consent and this was like pre legal discussion of what consent would mean from someone who was deceased. Okay, but yeah, from what I can tell, at least I did not come across any medicalized torture. I'm sure that they happened, but I don't think that they contributed to the body of knowledge, and so they maybe just didn't make it into the history if that makes sense.

00:54:15
Speaker 3: Yeah, yeah, yea, yeah, definitely.

00:54:17
Speaker 5: So the question at this point is what would it take for successful transplantation to occur? So in the history we're around the early twentieth century right now, and we're still five decades away from the first successful whole organ transplant, and there are some major hurdles to overcome before we get there. These next decades are largely spent asking and answering what I like to think of as the how and the why of organ transplantation. So the how meaning basically the technical or mechanical aspects of the procedure, how to best suiture the vessel, where organ should be placed in the body, how to prolong organ life outside of the body. And the why is what I take to basically mean the immunology. Why does rejection happen? Because if we can understand that, we can maybe prevent it from occurring. Oh fun, Yeah, So I talk a lot on this podcast about the huge impact that germ theory had on sanitation infrastructure, microbiology techniques, vaccine development, and overall public health. I bet you didn't think I was going to mention germ theory in this, did you.

00:55:36
Speaker 3: I didn't expect it, honestly.

00:55:39
Speaker 5: Well I didn't either, But as I was reading, it occurred to me that one thing that I don't really mention either ever, or at least as often as I should, is the huge implications that germ theory had for the field of immunology. Essentially like creating it created it.

00:55:58
Speaker 3: Yeah, yeah, because if these are you know, things that can be passed from human to human, our body is taking them in and doing something with them. What is our body doing.

00:56:07
Speaker 5: That's exactly exactly? Disease is not just an imbalance in the body's humors, but like if we use the battle lingo that a lot of people often use in describing infectious disease, you know, it's due to tiny invaders attacking the body's organs. So it stands to reason, or it stood to reason that if there were tiny invaders, there must also be like tiny defenders, right. So this recognition that there was a biological basis for non self material and then a subsequent attack mounted against it would prove to be a huge step forward in transplant science.

00:56:47
Speaker 3: Wow.

00:56:48
Speaker 5: And this also, I find this really interesting. This wasn't a one way transfer of knowledge. It wasn't just from immunologists telling transplant surgeons this is what works, this is what doesn't work, this is how whatever. These experimental transplants gave immunologists the opportunity to study the body's immune response. Oh yeah, leading to the observation that rejection was not just this passive response with the donor tissue or organ dyeing, but a very active immune reaction. Yeah it's cool.

00:57:22
Speaker 3: I'm gonna chills a little bit ooo yay.

00:57:28
Speaker 5: And in some ways these observations led to a changing paradigm of immunity where it wasn't all dictated just by antibodies, this humoral immune response, and also a more complete understanding of, especially in the case of transplant science, what the lymphocite actually does, which was like previously it was just thought to be a stationary thing that didn't do anything.

00:57:54
Speaker 3: Really, Yeah, oh, here's this cell. It just hangs here.

00:57:57
Speaker 5: It just hangs here and waits.

00:57:59
Speaker 3: It was like a more thing.

00:58:00
Speaker 5: Yeah yeah. So in the early twentieth century, the first couple of decades did see a lot of progress, particularly in this realm in experimental transplantation and in observations on the immune response to a transplanted skin or transplanted organ. But the overall rate of progress in transplant science slowed to a near crawl during and after World War One. Really the only field of transplant science that didn't experience a decline due to the war was, as you might guess, skin, allographs and humans because of you know, lots of disfigurements from bombs and battle wounds. So the nineteen thirties then began this slow climb back towards methodical research in transplant science and experimental transplants of whole organs began in earnest. It was more like, let's measure this, not just like, hey, you know what, like let's spin in the what do you call those things at a casino roulette? No, not roulette. Let's do the slot machine of like a dog kidney and you know, monkey heart into a pig or something like that.

00:59:17
Speaker 3: I see what you're saying.

00:59:18
Speaker 5: Yeah, So it was more like, okay, let's like let's take careful notes at the very least, and part of this was helped along because technical advancements in surgical procedures had been developed in the previous decades, so suturing in vascular surgery techniques developed by French surgeon Alexis Carroll, which eventually earned him the Nobel Prize in nineteen twelve. These techniques allowed for the mechanics of transplant surgery to become a reality during this time.

00:59:53
Speaker 3: That makes sense. Yeah, it makes sense too that that like stayed as being important during the war, because that would be very necessary, right.

01:00:03
Speaker 5: And another key mechanics development that I'll mention is the perfusion pump, developed in the nineteen thirties, also by Alexis Carroll, who had teamed up with Charles Limberg of all people. Also in doing the research, I learned that they were both eugenicists and Nazi sympathizers and typical.

01:00:23
Speaker 3: Yeah, so anyway, I'm not even surprised anymore, Aeron, I know, and this person was a Nazi and this person.

01:00:31
Speaker 5: I mean, yeah, that's the history of scientific research in the nineteen thirties and forties for the most.

01:00:37
Speaker 3: Part, especially medical research.

01:00:39
Speaker 5: Yes, yeah, a lot, a lot. But anyway, the perfusion pump allowed organs to survive outside the body during surgery, which was a crucial development for transplants as well as for open heart surgery, and other technical advancements during this time, such as like how coal the organ should be kept and how long it could be considered viable. All of these contributed to surgeons having the tools and technical knowledge that would allow them to perform whole organ transplants by the nineteen thirties and nineteen forties. Okay, so, like the technical stuff is down.

01:01:19
Speaker 3: Right, They've got the surgery complications done. That's why I didn't talk about them. They were easy.

01:01:26
Speaker 5: Oh yeah, super dupre easy. In nineteen thirty three, Ukrainian Uri Vorinoi performed the first human alligraphed kidney transplantation from a cadaver donor. So six hours after death.

01:01:43
Speaker 3: What it's nineteen thirty three?

01:01:46
Speaker 5: Well okay, I didn't say successful.

01:01:49
Speaker 3: Oh god, I got it.

01:01:49
Speaker 2: You ready?

01:01:50
Speaker 5: Yeah, So pump the braker.

01:01:53
Speaker 3: This is the first human cadaveric transplant where we know how to do this surgically. Is it going to work otherwise? Like, we know that the surgery wasn't the issue here, so if it didn't work, it wasn't because of that, whereas any previous ones would have just been like a crap shoot.

01:02:11
Speaker 5: I think it might have been that. In the literature, this seems to be what people often point towards as being the first one. Okay, yeah, And then there were a bunch of additional transplants performed throughout this time in the thirties and forties, not like tons, but you know, a good number. Yeah, And of course, just like for noise transplant, they all failed. The surgeons and the transplanted organs were all losing this fight against the immune system and it was starting to look like a lost cause until World War Two. So unlike World War One, the need for applied surgical and medical research was very clear in the mid of the Second World War, and the high rate of burns really highlighted the importance and potential of skin graphs in treating those burns. During World War Two, a young zoology graduate student at Oxford named Peter Metowwar saw firsthand the horrible pain and excruciating experience that a burn victim could go through when a British pilot's plane crashed into his neighbour's garden. The pilot survived the crash, but sixty percent of his body was covered in burns. Oh no, and Metowar knew about skin graphs and how allographs were used as short term treatments for burns in the hopes that the body could start the healing process before the graft was rejected, and Metowar attempted to heal the fallen pilot with tissue culture slurries or tiny slices of skin basically like painted on the raw areas, but nothing worked, and the pilot eventually died of infection. But this experience would then launch Metawar onto a research path that laid the groundwork essentially for the future as of successful transplantation.

01:04:10
Speaker 3: Wow.

01:04:11
Speaker 5: Yeah, because he at the time he was a zoology student, he wasn't really sure what exactly he wanted to do, and then he was like, had this experience and was like, if the pilot could have survived if those skin grafts weren't rejected, So how can I prevent rejection? So pretty cool, yeah, But answering those questions would require like a lot of untangling of these immune system mysteries that had long been like untouched in a way, And now that he had landed on a career path, Metowar sought opportunities to explore these questions using both clinical and laboratory experiments, which made him like kind of unusual in that respect. He teamed up with a Scottish plastic surgeon named Tom Gibson, and that's where he got opportunity to observe first hand the use of allographs to treat burns as a graduate student, and together they made the observation that a second graft from the same donor was rejected more quickly than the first. Very interesting, very this finding, and it was also, i have to say, more of a rediscovery since it had been observed before, but then it was lost to the lost era of organ transplantation. With this finding was published in a nineteen forty three paper, and it would end up being hugely instrumental in the field of transplant science since it firmly established rejection as an immune response. Metawar continued his research by looking at skin grafts between rabbits, like the timing of rejection, pigment spread, and the immunological basis of rejection. Then came a very fortunate meeting that would end up paving the way for successful transplantation. At an international conference in Stockholm in nineteen forty nine, a Scottish veterinarian asked Metowar if he knew how to distinguish between fraternal and identical cattle twins, and Metowar was like, yeah, of course, you just need to like exchange skin graphs between the twins and see how long they last. If they last forever, you've got identical twins, if they slip off fraternal. The vet called him up later and was like, hey, can you demonstrate this in person? And so Metowar drove up and performed a bunch of graphs and none of them were rejected, which was absolutely not what they were expecting. Like even all of the fraternal twin graphs took, suggesting that the twins shared some sort of blood flow in utero where they got used to one another. This eventually led him to realize that tolerance could be acquired, that the immunological barrier could be broken, and that the comingling of fluids between two unborn organisms in utero would allow them, or could allow them later as adults, to accept each other's foreign tissues and have their body and fail to recognize it as non self. I'm speechless, I mean, and it's like, yeah, there's more about these cows in particular and why they are important. But like I try to do as like succinct as possible, and then this like suddenly here was a way, if like at least a suggestion that you could manipulate immunity and then you could bypass this enormous hurdle that had so far prevented organ transplantation from being an actual viable option.

01:07:47
Speaker 3: And just as a refresher on the time that we are here, do we know yet about blood types? Do we know anything about what it is that's causing the incompatibility?

01:07:59
Speaker 5: We know about blood types, and so there was at least that so like that the vor and OI the first kidney transplant that was also a mismatched blood type, which could have contributed of course to the failure, But that was about it. Like there was some inkling of these other major histocompatibility complex type things. But I don't really know exactly how much we knew about that as it related to things other than infectious disease, Okay, because I think that was the larger context that we understood the immune system at that time for the most parts, right, Yeah, so yeah, okay, thanks, no problem.

01:08:44
Speaker 3: And so.

01:08:46
Speaker 5: After finding this out, After this cattle experiment, Metawar, along with colleague Rupert Billingham and graduate student Leslie Brent, began experimenting with different methods of immune supporse on mice, using spleen cells to induce chimerism in order to prevent rejection, and they met with some success, some limited success, and eventually Metowar was awarded a Nobel Prize in nineteen sixty for all of his efforts.

01:09:16
Speaker 3: Wow.

01:09:17
Speaker 5: And the key take home from all of this research that he did was that rejection was not inevitable. You could overcome it. So while Metowar was hard at work at untangling the mysteries of the human immune system, many surgeries were still tinkering away at transplantation, and they seemed to focus in particular on kidneys. Why are the kidneys, you might ask, Well, for one, most people have two of them, so replaces Yeah, we have two, so we have one, so yeah, so replacing one didn't It seemed like as much of a death sentence as something like trying to replace a liver or heart, almost ensuring death at that point. The other thing is that kidney disease was really common in the first half of the twentieth century with conditions like crushed syndrome thanks to all of the bombings and people trapped under the rubble in World War Two, like bringing that to light, Bright's disease, acute renal failure, chronic nephritis, all of these things occurred quite frequently. And the other thing is that in these pre antibiotic times, infections were often likely to cause lasting kidney damage, and so.

01:10:41
Speaker 3: I never thought that.

01:10:42
Speaker 5: Yeah, And so there was a substantial amount of like focus on the kidneys and on kidney disease, and in terms of transplants, kidneys happened to be more available because a common treatment for hydrocephalus was to remove one kidney so that cerebra spinal fluid could be drained to the bladder like through the vessel, Yeah, exactly, through the eurator, so there'd be like spare kidneys.

01:11:13
Speaker 3: Yeah, that's really interesting. I never knew that.

01:11:19
Speaker 5: So also the importance of kidney disease during this time is also kind of illustrated by the fact that artificial kidney machines were developed during World War Two, and those represented this enormous step forward for treatment of kidney disease that long ago, that long ago. Yeah, but a lot of people at the time when these machines were first developed saw them as prolonging misery and not increasing the quality of life at all, and so throughout the late nineteen forties and into the early nineteen fifties, several experimental kidney transplantations were attempted, and though none were ultimately successful, these transplants did do a couple of things though. They demonstrated that a kidney could be transplanted into another person and regain functionality as evidenced by urine production, okay, and they illustrated that as always, the immune system stood in the way of a successful transplant. Enter surgeon Joe Murray Okay. Before training as a plastic surgeon, Murray had worked as an Army doctor in Valley Forge Hospital, where he treated wartime burn victims and developed firsthand experience in the potential power of skin allographs. He happened to treat someone whose skin whose allographs took really well, like kind of stayed on there for a lot longer. So I wonder if it was just a fortuitous match in some way, But that kind of like really lit the fire under him. And after his time and the Army was up, he decided to become a surgical resident with a focus on transplants of all kinds. In addition to studying transplant surgical techniques and tracking the timeline for rejection, he also studied Peter Metawar's research, and Murray, who was then a surgeon at Brigham Hospital, came to the conclusion that while there were several barriers that needed to be addressed in order for there to be long term transplant success, there was at least one solution for all of them that he could think of. Identical twins.

01:13:30
Speaker 3: Ooh good, one yep.

01:13:34
Speaker 5: On October fifteenth, nineteen fifty four, the Brigham transplant team received a phone call about a twenty two year old patient, Richard Herrick, who was close to death with Bright's disease and was seeking dialysis, and they called Brigham because Brigham had an artificial kidney machine.

01:13:52
Speaker 3: Initially, there was.

01:13:53
Speaker 5: Some hesitation from Brigham, with the doctor in charge of the artificial kidney feeling that this would just be a way to prolong a long and painful death. But just as the phone call was about to end, the doctor who had called added, by the way, this patient has an identical twin, and for Joe Murray. This was the opportunity that he had been waiting for. He had been training for this for over ten years, and for Ronald Herrick, Richard's twin brother, the decision to donate was absolutely a no brainer. It was unbearable to watch his brother and best friend slowly die, and he said he would do anything to help him, even giving him his own kidney. Joe Murray, the surgeon, wasn't entirely without reservations, like what if the twins weren't actually identical and the kidney was rejected? What if Richard's condition left him too sick to survive surgery. There were many, many what ifs to consider, but the one that overruled them all was but what if this works? The questions about the twins identical status were laid to rest with ample genetic screening and a test skin graft, and the kidney transplant was scheduled for December twenty third, nineteen fifty four. For hours, the transplant team worked removing a kidney from Ronald to replace his twins diseased ones, suturing artery to artery, vein to vein, and once every stitch was finished, came the moment of truth. For an hour and twenty two minutes, the transplanted kidney had been entirely without blood flow. The clamps on the arteries were then released, allowing blood to flow into the new kidney, which promptly turned pink and began producing urine, so much urine that they were the surgeons were laughing about it because it had to be mopped up from the surgery floor.

01:15:57
Speaker 3: Oh goodness, they forgot to put a catheterin.

01:16:01
Speaker 5: Maybe it overflowed, who knows. At least at the outset, the transplant seemed entirely successful, and it was for eight years. Richard lived with his brother's donated kidney until that kidney, too, developed Bright's disease and he passed away, very sad. But this was huge, like monumental.

01:16:28
Speaker 3: Oh my goodness. Yeah, nineteen fifty.

01:16:32
Speaker 5: Four, nineteen fifty four, December twenty third, And for his work on the surgery, Joe Murray was awarded a Nobel Prize in nineteen ninety.

01:16:41
Speaker 1: Wow.

01:16:42
Speaker 5: Yeah. And it's kind of it's interesting because in retrospect, this first successful organ transplantation was hugely important, not because it necessarily opened the doors to more transplants, because in many ways this transplant was seen as kind of a one off, like so many things had to align in order for it to happen. Identical twins young, you know, one very healthy, one sick. Yeah, But what it did was it breathed life into the field of organ transplantation, which and it injected a much needed dose of optimism after what seemed like years and years of near winds but overall like losses.

01:17:27
Speaker 3: Yeah, absolutely, just that sense of hope like it's been done once, yep.

01:17:33
Speaker 5: And popular support as well for organ transplantation which had definitely waned.

01:17:39
Speaker 3: Yeah yeah, yeah, yeah, especially with like twenty two year old then saved doing it.

01:17:44
Speaker 5: That would that would be oh my god. There are some very cute pictures of them, like in the hospital and afterwards they're just like, ye, it's very very sweet. After the success of nineteen fifty four, there was a bit of a lag in terms of transplants. You know, there were more twin transplants that were performed, but there wasn't this huge upswing in transplants overall, mostly because the issues with rejection still remained right, but progress in that realm was also being made. Bone marrow donation seemed in some cases to help prevent rejection before like an organ was transplanted, and experiments involving total body irradiation prior to transplantation also showed limited success. So for instance, one recipient of a kidney from his fraternal twin lived for twenty years after receiving some limited irradiation, and this surgery was in a way in even more successful accomplishment than the first kidney transplant.

01:18:45
Speaker 3: Right.

01:18:46
Speaker 5: But as you may remember from our radiation episode, radiation is not harmless, no, and people began to look for other ways to minimize the immune system reaction following transplantation. So next came chemical immunosuppression. The ability for certain chemicals to suppress the immune system was not a new discovery or a new concept at the very least. During World War One, researchers had observed mustard gas was able to reduce the immune system, and some drugs used in cancer therapy, like six MP, were found to reduce immune responses. Tissue typing and the importance of blood type were also key in developing a protocol for preventing rejection, but for much of the nineteen fifties and into the nineteen sixties' success following a transplant was absolutely not guaranteed or like even likely.

01:19:42
Speaker 3: So by the sixties they also knew, okay, it's not just blood type, right, also have these tissue aigens.

01:19:49
Speaker 5: We have to deal with tissue antigens. But it was still like, even with that knowledge, it doesn't Yeah, it's not enough. Yeah, it's like it's a small thousands, Yeah, it's a small it's a small step. And so yeah, so, you know, the glow of the nineteen fifty four and then the limited success of like the later nineteen fifties transplants, you know, started to kind of fade away a bit. But then in nineteen sixty three there was a conference organized by the National Research Council to review the status of human kidney transplantation. Many of the surgeons at the meeting were reporting low success rate, low success rate, everyone's dying. People were like, should we even be doing this anymore? The mood was just like incredibly incredibly grimy, grim. And then a young surgeon named Thomas Starzel spoke up and he was like, Hi, actually, I have survival rates in patients that are, you know, actually kind of decent. And they were so high, in fact, that the rest of the surchens were like, we don't, we don't believe you. How are you doing this? So then he was like, okay, well what I'm doing is I give azathia prene and prednizone the.

01:21:13
Speaker 3: Steroid I was waiting for you to say.

01:21:18
Speaker 5: And steroids had tried been tried on their own before, but they didn't really seem to work. And so it was this combination that had led Starzel to stumble upon this greater than seventy percent survival rate like one year following the surgery for kidney transplantation, whereas like everyone else was like, yeah, I've had one in like ten patients live for a month or something like just really really really remarkable.

01:21:45
Speaker 4: Wow.

01:21:46
Speaker 5: And so this protocol absolutely revolutionized the field of kidney transplantation. Transplant units were started in hospitals around the world like it was, it was huge. And this also opened the door for other whole organ transplants. Surgeons started to consider other organs to transplant, like liver, lung, intestines, pancreas, and of course the heart. The first heart transplant was performed in early December nineteen sixty seven in Cape Town, South Africa by a Christian Barnard this first attempt had limited success, so the patient died after eighteen days due to the immunosuppression regimen. But the second attempt, the recipient lived for two years, which is pretty amazing. Yeah, and then not many people had success after him, Like I don't know what he did that was like so magical. But yeah, and so, you know, with these developments, especially once Starzl's immunosuppressive cocktail was out and about, you know, that sort of really like opened the door for everything. That really like broke the dam for transplants, and so the transplant science like at this point, it wasn't quite off and running, you know, but it was steadily walking, like incrementally growing in knowledge, refining surgical and immunosuppressive technique. And that actually did leap a bit forward with the development of cyclosporian in nineteen seventy six. But the next few decades are just sort of like a list of firsts, right, So we see like the first pancreas, the first liver, the first intestine, the first lung, and other organs successfully transplanted. And before I handed over to you to talk about where we are today, I want to talk about how alongside the steady growth of transplant science, there's one thing that lagged far behind, or at least a little behind, and that was the ethics of transplantation. And this is where science had definitely outpaced the law. I had touched on this a little bit earlier, but questions like who was in charge of the body after death, who at the next of kin were the deceased person's wishes like during life legally binding, And then later when artificial ventilation had been developed, there was this new ethical dilemma of how to define life and death for legal purposes, Not to mention the philosophical implications, was someone on a ventilator but without brain activity considered alive And this was a crucial question for successful transplantation of organs other than kidneys, like the heart, or the liver or the lungs, organs that became rapidly damaged after death. When transplantation first became a reality, many of these questions didn't yet have legal answers, and it would take some time not only for the legality to be sorted out, but also the public perception. But eventually rulings came out that did address some of these things. So it was ruled that permission could be given from the donor's relatives after death, and that if someone wanted to donate tissue after death, they could put that in writing. And also brain death was defined medically and legally in nineteen sixty eight by a Harvard committee, and then advancements in organ storage and long distance transport also gave rise to the formation of a transplant waiting list, and naturally criteria had to be developed about who gets on the list and their place on the list. So when I looked it up, I found the different you know, criteria were medical urgency, blood and tissue type and size, match with the donor, time on the waiting list, and then the proximity between the donor and the recipient were just some of the criteria. And some of these ethical debates around organ transplantation have definitely continued through today, just as the technology for transplantation has developed enormously. And I think in reading this, I realized I had kind of taken organ transplantation for granted in some ways, Like obviously, you know, we know, like I knew that it was this huge, incredible surgical feat, but I don't think it was until this episode that I realized just how much baseline knowledge needed to be built, how many surgeons and scientists were involved in these developments I only mentioned like a handful of them, and how brave some people were to say, yeah, I volunteer to give my kidney, or I volunteer to have my heart replaced. Like some there are some things I feel like in medical science that seem inevitable, some discoveries, some developments, but organ transplantation really doesn't seem that way to me. Seems like pushing forward in an incredible way, Like this is not very long ago at right, it's incredible. At the same time, it feels so recent and also surprising to me that it, like nineteen fifty four was the first successful Like that's incredible, that's yeah, we've come a long way since that first kidney transplant. And Aaron, I'm excited for you to tell me now where we stand.

01:27:17
Speaker 3: Oh, I'll try, I'll try my best. We'll take a quick break. So why don't we start with kind of the best news.

01:27:50
Speaker 2: Oh?

01:27:50
Speaker 3: Yeah, I think overall the best news and that is how much better we do with overall survival than many of the scenarios that you said overall and I'll again just kind of keep this broad. For all transplant types of entire organs and partial organs, there is an initial pretty rapid decrease in survival, and that is because of the things that we talked about in the biology section, that kind of acute onset of graft failure. But overall, about seventy percent of graphs will be functioning at ten years. When you look at the overall transplant numbers.

01:28:41
Speaker 5: That's amazing, yeah, isn't it. That is amazing.

01:28:47
Speaker 3: Yeah, it's really really incredible. And for some particular organs, you know, it can be a little bit better and a little bit worse. For example, lungs tend to be overall the worse, with maybe a five year survival of only fifty to sixty percent at most institutions, But for example, in infants who need a heart transplant, they can have a ninety percent ten year survival.

01:29:19
Speaker 5: Holy cow.

01:29:20
Speaker 3: Right, Yeah, So it really varies still, but we've definitely come an incredibly long way in terms of overall survival. If we look at the global numbers, which I think is really interesting to do, there is a global database it's literally called the Global Database on donation and transplantation, and according to that database, at least from two thousand and seven. They do have some more updated data, but this was synthesized nicely. So in two thousand and seven there were around one hundred thousand solid organ transplants worldwide. I think the number from twenty eighteen was a little higher, around one hundred and forty something thousand, so not a huge increase, but an increase. Of those in two thousand and seven, sixty eight thousand were kidney transplantations. Okay, so kidney by far is the largest, and the numbers for kidney transplantations I actually do have the more recent numbers for that. So in twenty nineteen there were ninety eight thousand kidney transplants worldwide. Ninety eight thousand kidney transplants, and that's out of one hundred and fifty thousand total organ transplants.

01:30:39
Speaker 5: Wow. Yeah, So what do you think happened in between two thousand and seven and twenty nineteen to lead to so many more? Because it's just infrastructure?

01:30:50
Speaker 4: Is it?

01:30:50
Speaker 5: Need?

01:30:51
Speaker 4: Is it?

01:30:51
Speaker 3: I would guess that it's infrastructure because there are certain countries that disproportionately do a lot of the transplants. So I wonder if are is it a wider geographic range of where transplants are being done, and that is what is causing those numbers to go up because it was unavailable in some parts of the world and now it is becoming available. I don't know for sure if that's the case, but my guess would be that would be at least part of it. Okay, yeah, let me let me throw some other numbers out at you. For liver transplants total worldwide thirty four thousand in twenty nineteen. Heart transplants eighty five hundred and twenty nineteen, So by far, kidney is the biggest, but there's pancreas, there's hearts, there's lungs. You can do partial livers, you can do entire livers, and then there's also differences in how many of those come from living donors versus deceased donors. Right, So, yeah, we do a lot of transplants overall, although I had to say it was also a smaller number than what I expected. Really Okay, yeah, yeah, it was like one hundred and fifty thousand. That's a lot, but there's a lot of people. So another thing that we could talk about is how many people need organs. Yeah, and there is a huge discrepancy in the number of people who need organs who are on waiting lists who don't ever actually get an organ. In the US, according to US Organ Donation statistics, there are one hundred thousand people that are on the transplant waiting list as of September twenty twenty, for only less than forty thousand transplants generally performed in a year. And so in the US at least seventeen people die every day waiting for an organ transplant. Oh my gosh. To look at some other countries, I have statistics on the UK as well. So in the UK, for example, in twenty ten, it's a little older statistic, but there were eight thousand people on the waiting list for an organ transplant in general. And if you look at heart transplants, which are one of the less commonly performed transplants, while sixty two percent of people who need a heart would get a transplant within a year, twelve percent will die on the waiting list and another seven percent will be removed from the waiting list for some other medical reason, like they're no longer a candidate. And that's for hearts. For lungs, it's even worse. Twenty seven percent of people will either die or be removed from the waiting list, and only thirty one percent will be transplanted. So we definitely have a big mismatch in terms of need even in the countries that do a ton of transplants. That's not even mentioning places where this just isn't even possibility, where a kidney failure is either dialysis if that's available, or a death sentence.

01:34:07
Speaker 5: I have a question about the makeup of the list in terms of like, like does it follow proportionately the transplants that are actually performed? Like do you see most of the lists being made up of people who are on the list for a kidney?

01:34:22
Speaker 3: Oh? Good question, that's a really good question. I actually don't know. They don't have those particular statistics off the bat on. Let's see here we go. Okay, they actually have a graph here. No interesting, I mean, well, yes and no. So kidneys are by far the biggest need. However, even though it's the most commonly performed, there's the biggest gap by far between needed and received.

01:34:55
Speaker 5: For king Oh okay, okay, so a.

01:34:58
Speaker 3: Lot more people need kidneys than get them especially, and then it goes down proportionally from their liver, heart, lung, and then other is all infrequent enough that it's just combined on this graph. So I can't tell you more data, but if you want to know more, you could go to organdonor dot gov and they have a lot more statistics there.

01:35:17
Speaker 5: Gotcha.

01:35:18
Speaker 3: But yeah, so I guess the biggest question is kind of where do we go from here? We've come a very long way, like you kind of walked us through Aaron, It's still far from perfect, but in general there's kind of two big gaps that at least that I see. One is long term tolerance of graphs, and the other is organ availability. Right right there, like we already said, are thousands of people who die every year on waiting lists. And on top of that, no organ from another person can function precisely as well as the original. So there's a lot of room for improvement in both of those regards, and it's kind of a question of where where do we go from here? Like what direction do we take? I will say there are people doing work on all fronts. There was a paper from nineteen ninety eight that was published in Nature that was like new directions for organ transplantation. We figured it out. Here's how you're going to use animal tissues. Xenographs are the way of the future. We still don't really do xenographs with the exception of tissues not full organs, and so the research on using animal organs is still well within like animal model stages. We have a very long way to go before we're using pig hearts in a human. But there is another kind of technology that has the potential to ensure not only organ availability, to overcome that hurdle, which we know is huge, but to also overcome essentially all immunologic barriers. And that would be it is twilight zone. It's using your own stem cells to three D print a new organ.

01:37:23
Speaker 5: It is the coolest thing, one of the coolest things.

01:37:29
Speaker 3: It is ever. I still every time I think about it, I get reblown away all over again. We're not there, It's the long and short of it. But there is proof of concept in at least some of this, Like we can induce cells to become pluripotent stem cells, which is what you would in theory need, and then we can induce those to differentiate into specific cell types, and at least in mouse models that's been shown to potentially help a mouse live longer even with a disease.

01:38:08
Speaker 5: That's amazing.

01:38:09
Speaker 3: And there are a lot of different companies across the globe that are working on three D printing with like bioengineered tissue things like ears, because it turns out ears are kind of a good starting point. But even as far as those go, we still do have a really long way to go before we're three D printing new hearts or kidneys for people. But I do think it's kind of the way of the future, and the future is now.

01:38:43
Speaker 5: It absolutely is, like it really is, I think, I mean, and it all seems very promising in like just a matter of time kind of a thing.

01:38:53
Speaker 3: It does, it does. There's a couple of great articles out there that we'll link to that have a lot more detail on kind of where we are at in this process, So if you'd like to read more. Speaking of which should we talk about our sources.

01:39:06
Speaker 5: Sources, let's do it. I want to shout out a couple of books. One is by David Hamilton and it is called History of Organ Transplantation Appropriate. Yes, it is thorough, it is great. Another one is called Borrowing Life by Shelley Fraser Michel and that is more specifically about the first kidney transplantation. Very interesting read and I have a few papers and I will post those to the website.

01:39:35
Speaker 3: Excellent. A couple of resources that I want to especially shout out. One is the Immunology of Organ Transplantation Article in Surgery twenty seventeen by Phillips and Callahan, and another is Transplantation Immunology, Solid Organ and Bone Marrow in the Journal of Allergy and Clinical Immunology twenty ten by China and Buckley. There's a bunch of other resources, including more detail on the global database on donation and transplantation. You can find the list of all of our sources for this episode and every single one of our episodes on our website This Podcast will Kill You dot Com under the episodes tab.

01:40:17
Speaker 5: Absolutely. Thank you again so much Carol and Betsy. It was so much fun. And again, keep an eye out for their upcoming book.

01:40:27
Speaker 3: I can't wait to read it. I wish I got to talk to them too.

01:40:30
Speaker 5: Oh my gosh, they were great. And we will also link to Carol's website where you can find more information about the book as well as some great resources that she links to for especially like living donors for kidneys and so on.

01:40:44
Speaker 3: Excellent, awesome.

01:40:46
Speaker 5: Thank you to Bloodmobile for providing the music for this episode and all of our episodes.

01:40:51
Speaker 3: Thank you to Exactly Rate Network, of whom we are very proud to be a part, And.

01:40:55
Speaker 5: Thank you to you listeners for sitting through this veryvery long episode on organ transplantation.

01:41:03
Speaker 3: I hope that you guys had fun, because I did.

01:41:05
Speaker 5: I did too. Okay, Well, until next time, wash your hands

01:41:10
Speaker 3: You filled the animals