Episode 35: Could a pig save your life? Discussing xenotransplantation with Dr. Mohiuddin of University of Maryland School of Medicine

Definitively Speaking is a Definitive Healthcare podcast series recorded and produced in Framingham, Massachusetts. To learn more about healthcare commercial intelligence, please visit us at definitivehc.com. Hello and welcome to another episode of Definitively Speaking, the podcast where we have data-driven conversations on the current state of healthcare. I'm Justin Steinman, chief marketing officer at Definitive Healthcare and your host for this podcast. More than 130 million pigs are slaughtered each year in the United States, roughly 350,000 each day according to animalequality.org. Now, don't go anywhere, don't think I've lost my mind and don't question why I am leading with the fact on a podcast dedicated to healthcare in the United States about 130 million pigs slaughtered each year. Because what if I told you that every year nearly 120,000 people are in need of a healthy organ for a transplant in the United States? Every 10 minutes, a new name is added to the list, while on average, 20 people die each day waiting for an organ to become available according to Georgetown University Press, that's more than 6,000 people per year. Now, what if I told you that there might be a way to use pig organs to address this organ shortage? Not a pig valve, mind you, but a whole pig heart. Now, before you go and dismiss this idea as sheer lunacy, what if I told you that a pig heart had already been transplanted into a human and that patient lived for 60 days? If I've got your curiosity peaked by now, then you're interested in something called xenotransplantation. And my guest today is one of the global thought leaders, if not the global thought leader in this dynamic and rapidly emerging field. Dr. Muhammad Mohiuddin is the director of Cardiac Xenotransplantation Program at the University of Maryland Medical School. In January 2022, Dr. Mohiuddin led the team that did the first ever transplant of a pig heart into a human body. And the patient, David Bennett, lived for 60 days with that pig heart. Named as one of the 10 people who helped shape science in 2022 by the world renowned scientific journal "Nature." Dr. Mohiuddin has a fascinating perspective on how we could use animal organs to address the organ shortage in the United States and around the world. Dr. Mohiuddin, welcome to Definitively Speaking. We are honored to have you here.

Thank you for having me.

All right, so let's get started here. Just Cesco rattles. Can you define for our listeners exactly what xenotransplantation is?

Sure. Xenotransplantation is transplanting either organs cells from one species to another, either from, you know, rat to mouse. It's also called xenotransplantation. In our case, we are talking about non-human organ or cell into humans.

And so you've led this field in transplanting organs from pigs into humans, correct?

Yes, so there's only one that has been done in a live human, which was done by us from a pig. Earlier, there have been a few cases where organs have been transplanted from non-human primates like baboon or chimpanzees into humans but that did not last for long.

Got it. And so why are pigs a better fit than other primates? I would expect, you know, you always hear about, you know, we're related to the apes and baboons and the primates are closer, but it sounds like you've had more success or more interested in pigs. Why is that?

So phylogenetically. We are close to non-human primates. So in an ideal condition, those organs will fit better with us and will not reject as vigorously as the pig organ. Pig is definitely not close to us phylogenetically. It's in fact, very distant. However, you may know that all the organs that have been transplanted from non-human primates did not survive for long. And also the diseases like HIV have been transmitted from these organs, it was decided. And in fact, there's a moratorium in England for doing these kind of transplantation. So what would be the next best organ or the species? We thought about pig because of several reasons. The major reason is that we are now know the pig genetic very well, and we can modify the genetics to our liking. And then these pigs are farm animals. They grow well in captivity, they grow very fast. So the pig that we used for Mr. Bennett, our first and only patient, was only one year old and was about 110 kilograms. And Mr. Bennett was about 85 kilograms. And also these pigs give birth very quickly, have a short gestational period, so you can expand the colony very quickly and the organ can grow very quickly to the size that's required for humans. So these are some of the reasons that made pig our next choice after non-human primate.

Yeah. How do you genetically modify a pig heart? Are you using the gene-editing tool CRISPR, how does that work?

So yes, we are using this technique, but this technique is relatively new, right? So before we used to take one gene out or insert one gene and then cross breed the pigs and then get pigs with multiple, you know, genetics. But with the discovery of this new technique of CRISPR-Cas9, we are able to now take out as many genes as possible and insert as many human genes as possible at one time. And so within about few months, you have a pig ready that has your desired genetics. So that's a huge advantage and that has helped greatly in xenotransplantation.

And are you genetically modifying it for humans or if like, "God forbid I needed a transplant, you take some of my DNA and transplant it into a making kind of custom genetically modify it?

That's a very distant thought. There's a vigorous rejection process when you transplant an unmodified pig heart into a human or its surrogate, which we use for experimental purpose than non-human primate. So our first goal is to get to a level where we can use the same kind of immunosuppressive regimen that we are using in a human-to-human transplant. So when we transplant this pig organ with certain gene modifications, we will give the same level of immunosuppression and get the long-term survival. However, these gene modification techniques, you know, sky's the limit. You can modify as many genes as you want. And theoretically what you're saying could happen in future that, you know, you can customize a pig for yourself and keep it somewhere, you know, breeding or you get it cloned and at one time when you need it, you know, you have organ ready for yourself.

Yeah, I feel like we're talking about a science fiction movie here or an episode of "Black Mirror" on Netflix. I can just see at somewhere there's a pig out there with a backup heart for me.

Yeah, it's practically possible in the future.

Practically possible in the future? All right. I'm going home and telling my wife today that we're gonna get a pig ready for me. So talk to me about David Bennett, your first patient. How did you find him? What was that process like? How did the transplant go? Give us that story. It's a fascinating story.

Yeah, so we had Mr. Bennett admitted to our hospital for heart failure. His heart was, you know, completely not working and we had to put him on an artificial support called ECMO support, that's a machine that takes over the function of the heart. So he was bedridden for about 60 days before this transplant happened, totally dependent on this machine. The day we would have taken this machine off, Mr. Bennett would have died. Before that, I've been working in this field for 30 years. We have produced some very good results in non-human primate model as a proof of concept to show that a pig heart can sustain the life of a baboon for up to nine months. So we presented this idea to Mr. Bennett that would you be interested in experimenting using a pig heart, which is genetically modified. And we offer no hope to him. We said that this will be the first time we will do it. You know, we don't have any data to show you that in humans, but we have data in non-human primaries, like in baboons. So he agreed to it when he gave us, you know, some agreement. Then the main thing was to convince our regulatory agencies, which is the FDA. So FDA usually have a provision which they call expanded access, that used to be called compassionate use. In this provision, when there is a patient who's close to dying and you have tried every means available to save him and it's not possible to save his life, then they allow you to use an experimental technique, drug or machine to save his life. We presented Mr. Bennett's case and asked FDA to approve us to use a 10-gene modified pig heart, we also asked permission to use a preservation system of heart that was also not approved. And the third thing we also asked was a novel drug that I've been working with for years and have shown to be very helpful in xenotransplant experiments. So FDA, you know, came back to us. We went back and forth for 10 days. In this provision, FDA has to take a quick action because the patient's life is online and you know, that they cannot delay their response. So within that 10 days back and forth conversation, they asked us, you know, a lot of questions, lot of details about our non-human primate experiments, because those were the reasons they were even thinking of giving us permission. And finally, we were able to convince them. This is a valid option. And on the New Year's Eve, they actually gave us the permission to go ahead. So once we got that permission, we asked our institution, "Okay, we got the permission and we are ready to do it." So our institution said, "Who's gonna pay for it?" Because the xenotransplantation is not covered by any insurance. And these insurance companies are very farsighted because in Mr. Bennett's insurance, there was a clause that his insurance cannot be used for xenotransplantation. So somebody thought about it even before us, but finally convincing my institution finally, you know, agreed to take responsibility of the financial responsibility. And on January 7th of 2022, we were able to do this transplant for which it was a snowy day. So I had to stay back in my office to make sure that... I am president here and my partner, Dr. Bartley Griffith, who was the main surgeon in the transplantation, he was also here. So the pig was brought in a few days before because we were going back and forth with our institution. So that morning, you know, we harvested the pig heart, put it in this fancy machine that preserves the heart. And this was done in my ORs in my lab. And then it was taken into the human side of our hospital where in the human, or Dr. Griffith was ready to receive this heart. And then with his help, the heart was transplanted into Mr. Bennett. Although, the pig was much bigger in weight than Mr. Bennett, the heart was a little smaller and we had some difficulty doing the anastomosis. However, the heart immediately after finishing this anastomosis started to work. However, we found our anesthesiologist indicated that somehow one of the major vessels has developed a dissection, which means that instead of blood flowing through the central part of his vessels, there was a nick in the wall of those vessels inside. And it was flowing through the sidewalls and you know, it was creating two channels instead of one. So we had to top the heart again and repair that, that took not more than half an hour. And then we restarted the heart, and the heart restarted. So that was the time when we all felt, you know, some relief and we knew that this is going to work. And at that time we were not even sure. And we had told this to Mr. Bennett also that you cannot expect anything with this heart. We don't even know if we can get past the surgery. But luckily the heart started beating very well, performing all the functions it was supposed to do, and then did that for 50 days after this surgery until the heart started to fail. And finally we had to, you know, stop all the treatment around like day 60.

That's just an absolutely like, amazing story. What was like his quality of life during those 50 days? I read somewhere that he actually able to watch a Super Bowl with his family?

Yeah. And he sang the song during the Super Bowl. Every day, he used to ask me one question, "Can I walk to the bathroom myself?" I used to give him assurance that one day you will, because we were very enthusiastic about his recovery. We were impressed. Even all the cardiologists in our team were very, very impressed to see the function of this pig heart in this patient. Because according to them, it was functioning even better than the human heart. The heart as you know, is a pump. We have put like a Ferrari pump in a Ford car. So everyone was very optimistic about him. And around like day 20, we were even talking about moving him from an ICU to a Step Down Unit where less intensive care is required. And then in a stepwise manner, we were planning his discharge from the hospital until, you know, things fell apart a little bit.

And what was the cause of those things falling apart? Was it organ rejection?

So we recently published in "Lancet Magazine." It came out last month where we took about a year to reflect back on this experiment and see, you know, what could have possibly gone wrong and, you know, how could we improve this post-procedure in the future. So the major thing that we have found during this investigation, and you'll find it in the in the "Lancet Magazine," is that the patient condition itself, so this patient was so weak, you know, by staying in the bed for 60 days, not even coming out of the bed and totally dependent on the machine to perfuse his circulation. And his immune system was down to an extent that the white blood cells which are supposed to fight your infections were so low at the time of transplantation that we had to give some extra blood and to build that up to an extent that we were allowed to proceed with the transplantation. But even after transplantation, you know, his immune system stayed very depressed. And as you know, in transplantation, you have to give immunosuppression to prevent rejection. And we have this unique immunosuppressive regimen that has worked wonders for us in the baboon model. And that has helped us prolong the graft for a significant period of time. You know, we were not able to use that to full extent in this patient. At one time, we had to stop one of the major immunosuppressive drugs with the fear of over suppressing his bone marrow. And we could not restart that immunosuppression for another 30, 40 days. So first thing that we think that led to the failure of this heart was the patient himself. And in the future, we are thinking of getting a patient with a better immune system. The second thing was, as you all have heard, and was much publicized, was the discovery of a porcine virus in the heart. So this porcine virus was porcine cytomegalovirus or CMV. So this virus was a latent virus that sleeps very deeply in the cells of the pig. You know, it is not pathogenic to the pig. It doesn't cause any disease in the pigs. At the time of transplantation, all the testing that we had, we were not able to find this virus in the pig heart or in the pigs any other organ. But however, when Mr. Bennett was alive through his 60-day course, we started seeing some remnant of DNA from this virus in his blood, which started to increase over a period of time. Then we realized that maybe this heart may have carried this virus. However, all our studies so far have indicated that no disease transmission from this pig heart was to human. None of the virus that was detected affected human cells or organs. So that was very reassuring because if this virus did anything wrong? It did only to the pig heart that was transplanted. However, you know, there were several overlapping causes. So we cannot be sure that this virus was, well, the cause of heart dysfunction. At one time when his immunoglobulins was low, we have to give this pooled immunoglobulins, which is called IVIG, which is pooled immunoglobulins from thousands of healthy human beings. However, something that I have not mentioned before, all of us have antibodies against pig antigens. So in the 10-gene modified pigs, we have been identifying these antigens and kind of knocking out those antigens. But when we gave this IVIG, it has a large number of antigens, which we found out later, after, you know, testing it with the same pigs cells that it bound to pig cells very strongly. So we believe that this antibodies that we give, which is a normal treatment for decreased immunoglobulins in humans in allotransplantation, you know, may have instigated this damage of the cells and this virus may be sitting there, you know, not doing anything. And when the cells break, this virus particles were detected in the blood. No active virus was detected, and somehow this antibody-mediated graft rejection happened. It's like a chicken or the X story whether the virus caused the cell to die or the antibody-mediated rejection caused the cell to die and release the virus particles in the blood. But the reassuring thing, as I mentioned before was, that we have no evidence of this virus infecting Mr. Bennett or causing any disease in Mr. Bennett, which is always a major concern by all the regulatory agencies.

So what's your prognosis for finding a second patient?

So we took our time right to find our next patient. So we are narrowing down on few patients right now. We want these patient, our next patient to be immunocompetent meanings that he should have intact immunity. So when we give our immunosuppressive drugs, you know, he should be able to withstand that those heavy immunosuppressive drugs. The second thing we wanted was our next patient should have his disease limited to the heart and shouldn't have any other organs affected. And that is our priorities and we want that the patient to be mobile. So our next patient would be someone who would walk into our hospital for this operation. Not like Mr. Bennett who was already admitted and was bedridden for 60 days and had massive, you know, loss of muscle mass during that period. So all these factors, you know, combined together will bring us our next patient. And that's why it's taking a little bit longer because we are being very selective. We are already the first in the field. Our next goal is to make it a viable option for all these patients waiting for the heart transplant.

But you know, just to ask a question for a second, like you said, you're looking for someone to literally walk in, who's looking for a pig heart transplant like, this still seems, like, a pretty risky procedure if you'd only be the second person in the world has ever ever had this done, don't you kind of have to be sort of like, you know, at your last resort to sign up for this procedure?

Of course, so the patient who will sign up for this procedure is probably already told that you are not eligible to receive a human heart. You are not eligible to receive a mechanical device. So there are no other options available to you that will be the patient who will opt in for a xenotransplant. And trust me, since we have done this transplant, you know, many patients and their family members have reached out to us. Even the transplant surgeon who works in our own hospital who's a kidney transplant recipient reached out to us and said that, "Where were you when I needed an organ, right?" So a lot of these patients are saying that, "You know, could we be your next patient?" And these family members are telling us, if you had done this before, you could have saved a loved one for us. At least, I thought of a lot of, you know, bad rap after doing this, especially from animal right groups. I did get some, but response was overwhelmingly positive from everyone. And I'm really surprised to see how many people are opting in for this because, you know, those people understand that they have no other option.

That's amazing. So when do you think this will happen? Are we talking like a matter of months? Are you talking like sometime in 2024? 2025?

So there are two pathways that we can go. The pathway we adopted from Mr. Bennett was a single patient approval from our regulatory agency, FDA and that we are trying to seek again with patient number two. But FDA has also shown us a way to go to a clinical trials in that pathway. We have to have some consistent xenograft survival in the baboon for a certain period of time in a very protected environment. And we have to develop the measures to monitor all these viruses and also monitor the patient and his close contacts in the future. So we are taking both the pathways, we will try to do another patient using the single use option and we are also doing what FDA has asked us to do in terms of generating this data from non-human primate experiments for us to get permission for a clinical trial. So the single cell patient option can happen like within a month, but the other option that may happen in a year or two because we have to generate certain amount of data that is required by the FDA.

Got it. So you mentioned a few minutes ago about a kidney surgeon or someone, a surgeon who needed a kidney, and I actually saw recently that surgeons at NYU Langone Health transplanted a pig kidney into a brain dead pig, brain dead patient, excuse me. And the kidney has been working for 32 days and counting. Are you working on hearts only? Are you exploring other organs like these folks at NYU Langone? Will we see a kidney implanted into a live human before the next heart? How are you thinking about this?

I mean, there are more people in line for kidney than hearts for sure. However, kidney has a backup in form of dialysis. So if your kidney fails, you can only always go on dialysis. But if your heart fails and you are not eligible for a transplant, not eligible for a mechanical device, you don't have any other option. Even if you do a kidney transplant and the kidney fails, you can still go back on dialysis. So we think that the heart patients need this procedure more desperately than the kidney patients. However, what has been done at NYU and they have done it before also for fewer days. And by keeping this kidney functioning for 32 days is significant and you know, I appreciate anyone producing results that will progress this field, all these experiments done at NYU and also at University of Alabama who have done similar experiments and have kept the kidneys alive. You know, these are all, you know, helping us progress towards clinical reality of xenotransplantation. So I don't know exactly what are the conditions at NYU. They have not published a scientific paper yet. So, you know, once I know that, you know, what was the background of the patient they have used, whether it was like a cancer patient who all was already on immunosuppressive regimens, they were, you know, how they were maintaining the patient, what drugs they were go giving. It's very hard to comment on, you know, the status of that kidney. But it's very encouraging to even find out that you can do that for 30 days and they intend to keep it even longer up to 60 days. The xenotransplantation field is a very close net field. We all know each other, we all help out each other. So, you know, with all these collaborations and helping out each other, this field with progress because we all believe in making this a clinical reality.

So speaking of making it a clinical reality, what do you think the timeline for mass adoption of xenotransplantation is? Is this something I'll see in my lifetime?

I hope so, like I said, I'm working in the field for 30 years. I started for a rat model of xenotransplantation and I've never had imagined that I would be able to do a human transplant. So I have seen what I have had never expected and you know, helped me become more bold in this field and to say that, you know, definitely this is a definite option. In next few years, you will see a huge development in this field and I sincerely hope within my lifetime I see this procedure becoming an actual process to help all these people.

Do you see any ethical issues with xenotransplantation?

Of course, I mean, you know, like I mentioned, you know, using an animal organ to save a human life, people don't like it. Although, like you mentioned in your introduction, we are sacrificing a lot of pigs for other purposes, not only for our dietary purposes, but, you know, the different parts of the pig is used in different products also. But again, you know, the animal rights and other concerns about viral transmissions and you know, just using and sacrificing an animal to save the life of a human, for some it is hard to digest. You know, I've even been asked, right, "That would you put a human heart in a pig to save a pig life?" So these kind of questions, you know, we do have to answer that. I have to answer a question like, you know, why do even have to save a life, right? I mean, you know, if if it's meant to die, you know, why you are extending it. But you know, I've taken, you know, an oath to save life and that's my job to save life, right? So I'm trying every measure to find a way to do that.

What's the role of drug companies in xenotransplantation? Are you working with them to develop, you know, new age or next generation anti-rejection drugs?

So one that I can proudly say that my development was that using a different drug from the conventional immunosuppressive drugs used in the human-to-human transplantation. My earlier studies have shown that one of the other drugs that we have used in xenotransplantation has, you know, changed the field completely and has helped prolong the xenograft significantly. So there are several companies, so this is a costimulation blockade antibody, and there are several companies who are working to get FDA approval for this kind of antibodies. And I think this antibodies has a lot of potential and for your information, you know, the FDA considers this genetically modified pig as a drug also. So these pigs are being produced by our industry partners who are, you know, modifying these pigs for us. And of course, they'll be used later for commercial purposes also. So yes, I mean, you know, there are other, you know, agents also that we think are very critical, the pharmaceutical agents that may help us in the future. But genetic engineering by itself, you know, in the future could reduce the use of these immunosuppressive drugs also.

So this has been just absolutely fascinating. And before we go, I have to get a little bit of like the personal side of things for you. You said you've been in this field for more than 30 years. How did you get into it? And then what did it feel like after 30 years when it finally came time to do this transplant?

Well, that's the feeling you cannot even describe. You know, when I came to this country in the early '90s to become a cardiac surgeon, one of my mentors, early mentors sat me down and said, "Let's calculate how many lives you're gonna save by becoming a cardiac surgeon." And he put down a number and then he suggested to me, "You know what if you work on something that may exponentially save hundreds of thousands or more life than you expect to save as a cardiac surgeon." And that was xenotransplantation that he suggested to me, which was in his infancy at that time. And I didn't know what future it holds, but some things at that time strike me that this may be the future of transplantation. And I had like several roadblocks or what you can say, you know, discouraging experiences during this journey. But finally, you know, you cannot describe the feeling when you see your lifelong, you know, work materializing form of this transplantation. So definitely it was like a dream come true for me.

Just amazing. Fascinating. Dr. Mohiuddin, thank you very much for your time today. I've really enjoyed talking with you.

Thank you very much.

And for all our listeners out there, thank you for listening to Definitively Speaking, a Definitive Healthcare podcast. Please join me next time for a conversation with Russ Thomas, CEO of Availity. As one of the nation's largest health information networks, Availity facilitates billions of clinical administrative and financial transactions every year. They work to solve communication challenges in healthcare by providing a richer, more transparent exchange of information among health plans, providers and technology partners. Russ and I are gonna take an in-depth look at the payer provider collaboration. A job I'd say is never done. We'll talk about what's working, what's not, and why payers and providers have a love-hate and a love to hate but I need you relationship. I hope you'll join us. If you like what you've heard today, please remember to rate, review, and subscribe to the show on Apple Podcasts, Google Podcasts, Spotify, or wherever you get your podcasts. To learn more about how healthcare commercial intelligence can support your business, please follow us on X, formerly known as Twitter @DefinitiveHC or visit us at definitivehc.com. Until next time, take care. Please stay healthy and remember that one day there might just be a pig out there with your name and your DNA on it.