Advances In Pig-To-Human Organ Transplantation Hold Promise

IRA FLATOW: This is Science Friday. I’m Ira Flatow. Earlier this year, in a cutting edge medical experiment, a pig heart was successfully transplanted into a human for the very first time. Unfortunately, the patient lived for just under two months, but it marks a big milestone in the field of xenotransplantation. That is, interspecies organ transplantation.

What went wrong and what went right, and how might these scientific advances help solve the problems of thousands of people in the US waiting on organ donation lists? Joining me now to talk more about it is Dr. Muhammad Mohiuddin, professor of surgery and director of the Cardiac Xenotransplantation Program, University of Maryland School of Medicine based in Baltimore. He’s part of the team that performed this historic pig heart transplant. Welcome to Science Friday.

MUHAMMAD MOHIUDDIN: Thank you very much. Thank you for having me.

IRA FLATOW: You’re welcome. How could transplanting pig organs into humans help those waiting on organ transplant lists?

MUHAMMAD MOHIUDDIN: I mean, no matter what we do, how much awareness we have about organ transplantation, there will never be enough organs available from humans to transplant in the patients who are waiting for the organs, that there are about 150,000 of them waiting right now just in the United States. And unfortunately, most of them will die waiting for those organs. So xenotransplantation, if successful, will provide an unlimited supply of organs for not only these patients, but we can intervene at an earlier time point before these patients reach the end stage heart failure.

IRA FLATOW: As I mentioned in the introduction, the recipient of the first pig to human heart transplant, David Bennett, survived for just about two months. Have you been able to determine why his heart failed?

MUHAMMAD MOHIUDDIN: The cause of the heart failure or the patient death is not one, but there are multiple causes that overlapped. The major cause of why his heart did not function well in the later part of his life was his own preconditions. As you may know, this patient was very sick to begin with. And his immune system was very, very weak.

So that prevented us from giving him the immunosuppression or the antiviral treatment that we wanted to give, and in fact, had to terminate one of the major immunosuppressants and the antiviral therapy around, like, 20 days. His heart, however, survived or functioned for 50 days without any issues and, in fact, worked better than an elder transplant, like a human-to-human transplant.

IRA FLATOW: No kidding. Why is that?

MUHAMMAD MOHIUDDIN: I mean, because most of the heart donors are not healthy, unless that you get a young person in traffic accident or something like that. This pig was a young one-year-old pig without any issues so that the heart function was better than we expect from an elder transplant.

IRA FLATOW: You also detected fragments of porcine cytomegalovirus in the patient as well. Do you think that may have contributed to the heart failing?

MUHAMMAD MOHIUDDIN: We are still trying to determine what part of this virus may have played. We accept that our detection methods at the time of transplantation were not sensitive to detect this virus in the pig, which was in a very latent form.

However, after Mr. Bennett passed away, we have developed very sensitive tests to detect this virus, and we have not seen any sign of this CMV disease in the patient. So somehow the virus was there in a latent form. Whether something else that caused the cell death and led to release of virus or the virus itself caused the cell death is very debatable at this time.

IRA FLATOW: You recently published an article about how the pig heart changed its electrical signals once implanted in a human. Is that a cause for concern?

MUHAMMAD MOHIUDDIN: No, it is not, at least for these 60 days this patient lived. There are some conduction delays or changes that are observed in patients after transplantation. In this patient also, we did see difference in conduction compared to the pig heart in pig or pig heart in baboon or human heart in human. However, I would stress here that these changes did not affect the function of the heart. Whether or not they will affect in the long run, that remains to be seen.

IRA FLATOW: So given all that you’ve learned from this transplant, how is it going to shape your approach going forward? I’m sure you must be trying this again.

MUHAMMAD MOHIUDDIN: No matter whether virus caused any damage or not, we don’t want a virus to be transmitted. So we are making every effort to develop testing, sensitized testing, to eliminate this virus from our donors. So the next one we will do will make sure that this virus is not transmitted. It is not 100% guaranteed that that will happen. So we are also trying to see if we can develop antiviral therapies. And we also are looking at patients who are not as sick as Mr. Bennett because most of the issues we saw was because of his pre-transplant condition.

And the third thing is the IVIG that you must have heard that we had to give to build up his immunity. That IVIG is a pooled immunoglobulin from many patients, thousands of patients, and some of them have reactivity to pig cells. We all do. So we will try not to give IVIG again. So these are the three major things that we intend to do in our future experiments.

IRA FLATOW: You know, I think many listeners might be a little uncomfortable with the idea of pig organs becoming the norm in organ transplants. Are there perception barriers to overcome for patients to consider this a viable option in the future?

MUHAMMAD MOHIUDDIN: Yeah, we are trying our best to bring awareness, and you will be surprised to know that how many emails, phone calls, and communications I have received from patients who are on the waiting list, and they are offering themselves for this procedure. So a young healthy person may have some reservations. But the person who’s at the deathbed and have been told that there is no alternative left for him or her may have a different perception.

IRA FLATOW: Do you think other surgeons, other people who are doing xenotransplantation with other organs, maybe liver or kidneys, are they watching your success and learning from it and rooting along with you?

MUHAMMAD MOHIUDDIN: Of course. I mean, this success, not only this, but a few years ago, when I was in NIH, having survival of pig heart in a baboon for a long period kind of revived this field. And now, with this success, we’ve made a lot of believers out of people who thought that this was not possible.

IRA FLATOW: Dr. Mohiuddin, thank you for taking time to be with us today. And good luck to you.

MUHAMMAD MOHIUDDIN: Thank you very much. Thank you for having me.

IRA FLATOW: Dr. Mohammed Mohiuddin, professor of surgery and director of the Cardiac Xenotransplantation Program at the University of Maryland School of Medicine, of course, that’s based in Baltimore. I mentioned that pigs are being studied as donors for other organs besides hearts. But how did scientists decide that pig organs were suitable for use in humans in the first place? And what are the benefits and drawbacks of interspecies organ transplantation?

Joining me now to continue our conversation about the latest in pig-to-human organ transplantation is my guest, Dr. Megan Sykes, professor and director of the Center for Translational Immunology at Columbia University, based in New York City. How did the scientific community land on pigs as the ideal animal for organ transplants?

MEGAN SYKES: Well, pigs are a good choice because they’re quite close to humans in their organ function and physiology. A lot of pigs are quite a bit bigger than humans, and that’s something that might become a concern if their organs grow in a young person, for example. But there are certain kinds of pigs that are closer to humans in size, like miniature pigs that we use in our research. They breed well in captivity, have large litter sizes in a relatively short gestational period. So that also makes it easier if you want to inbreed them for certain purposes relative to their use as organ sources.

IRA FLATOW: Why is it that we did not go right to primates? I mean, we are primates. Pigs are not primates. Aren’t they more genetically similar to humans? And why are they not good choices?

MEGAN SYKES: Primates certainly are more genetically close to humans, and the way that you’re thinking about it is the way that many researchers thought about it. And in fact, there were attempts at primate organ and bone marrow transplants to humans in the 1980s and the 1990s even. But what people realized when that was tried was it’s ethically challenging to be using non-human primates that are so close to humans, but secondly that infections can be more easily transmitted from non-human primates to human primates, particularly viral infections, than they can be from a species as different as a pig to a human.

IRA FLATOW: Do you genetically modify the pigs that you’re using?

MEGAN SYKES: Well, the first genetic modification that really provided a breakthrough in the field in the early 2000s was to remove the gene that produces a sugar that decorates many proteins and lipids in most species, but not humans. And the consequence of not having that enzyme that produces that sugar in humans and old world primates is that we make natural antibodies against it. We have antibodies that recognize that sugar.

So given that pigs have that sugar on so many proteins and lipids, it means that the sugar is expressed on the endothelial cells, the cells that line the blood vessels. And if you just put a pig organ into a human from a wild type unmodified pig, those natural antibodies would very quickly bind to the sugar on the endothelial cells. And they would initiate a whole cascade of events that would result in a very dramatic inflammatory process and very rapid loss of blood supply to the graft, and it wouldn’t survive more than a few minutes or hours.

IRA FLATOW: Pigs harbor something called porcine endogenous retroviruses, PRVs, and other pathogens that could be very harmful to people. So how do you make sure that those viruses don’t get into humans?

MEGAN SYKES: Well, fortunately, they don’t seem to do that very easily. Really, the fear about PRVs came up in the mid 1990s, but since then, people have looked very assiduously at humans and non-human primates who have received pig tissues or organs to see if that virus has spread into the recipient. And there’s been absolutely no evidence that it has.

IRA FLATOW: Are there other issues? I mean, why don’t we see this being used generally now? What other issues need to be worked out before pig organs can be used more widely in people?

MEGAN SYKES: Well, there are quite a few issues still. There are antibodies that recognize other targets in the pig. There are several genetic engineering approaches that are being used to eliminate those additional targets. But what we really don’t know right now is how many of those genetic modifications are needed and which ones are needed?

And it may be different in the context of different human recipients because different humans have different levels of each type of antibody. Some of the details of the physiologic compatibility of pig organs will really only be worked out with studies in humans and with longer term studies that have been performed so far. Patients are treated with immunosuppressive drugs. Some of those are metabolized in the kidneys, some in the liver, et cetera. If the kidney is from a pig, how will that affect the metabolism of the drug?

So there are many, many questions to address. It doesn’t mean we can’t go ahead and try it in people who don’t have any other options. But we still do have a lot to learn.

IRA FLATOW: This is Science Friday from WNYC Studios, talking with Dr. Megan Sykes from Columbia University. Some listeners might be thinking, hey, can’t we just skip all these complicated issues we’re talking about and put research money towards artificially grown organs, instead of getting them from the outside? Why not just grow them in the lab?

MEGAN SYKES: Well, that’s certainly an exciting possibility. And there are a lot of people working toward that. But we’re just not close to having a lab grown organ that can function like the real thing.

IRA FLATOW: You know, I said in my introduction to this story that the first pig heart to human transplant made a lot of news earlier this year. But this isn’t the only pig organ being studied for transplantation into humans, right? What other organs and structures are being studied?

MEGAN SYKES: Well, the one that is most widely studied right now, in addition to hearts, is kidneys.

IRA FLATOW: Hmm.

MEGAN SYKES: Our group is most interested in inducing immunological tolerance in the recipient to the donor so that lifelong immunosuppressive drugs will not be needed. And to do that, we’re also transplanting thymus from the pig. The thymus is the organ that generates and educates T lymphocytes. And we can educate primate T lymphocytes to think of pig itself. And the other way is to transplant bone marrow, which also educates the recipient immune systems.

And several groups are also working on transplanting islets of Langerhans, which are the structures that include beta cells, which are the cells that make insulin. And so this is a possible cure for diabetes that is very exciting because there aren’t that many potential islet donors from humans.

IRA FLATOW: That is cool. How close are we, then, to clinical trials and then pig-to-human organ transplantation becoming norm?

MEGAN SYKES: Well, there are a few groups that are working toward being able to do small trials of pig kidney transplantation to humans. So those are not far off at all, we hope. I suspect we’ll see trials of pig kidney transplantation in the next few years. Heart transplantation likewise. I think it’s at a stage, given that the first patient has actually received a pig heart, we’re really at the stage of needing to work with regulatory authorities to define the conditions and the type of patient who could be treated in that way.

IRA FLATOW: Dr. Sykes, we have run out of time. So much interesting stuff to talk about. Dr. Megan Sykes, professor and director of the Center for Translational Immunology, that’s at Columbia University in New York City. Thank you for taking time to be with us today.

MEGAN SYKES: Thank you. It’s been a pleasure.

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