The world witnessed a groundbreaking surgical procedure just earlier this month, one that appeared to most lay observers something straight out of science fiction. On January 10, the University of Maryland School of Medicine (UMSOM) announced that a 57-year-old terminally ill patient had received a successful heart transplant from a genetically modified pig. In the days that followed, it emerged that Karachi-born Dr Muhammad Mansoor Mohiuddin, as the scientific and programme director of the Cardiac Xenotransplantation Programme at UMSOM, was directly involved in the cutting-edge transplantation procedure.
For almost as long as the science of transplantation has been known, doctors and scientists have been searching for means to transplant animal organs into people, a field that is known xenotransplantation. The scarcity of suitable organ donors and difficulty in arranging organs for patients in desperate need of transplantation has spurred on the search for a sustainable surgical alternative.
The Express Tribune was able to reach out to Dr Mohiuddin, who is one of the leading experts on xenotransplantation, to demystify animal-to-human organ transplantation and explain what this watershed surgery could mean for the future of medicine.
ET: The heart transplant surgery has been termed as a medical breakthrough. How long did it take to get to the point of performing it?
Dr Mohiuddin: It took me 30 years of research to get to this point. Initially, a lot of work was done in small animal models – that focused on translating a heart from one small animal to another. We recorded great success, but when you move to a large animal model, which is required before transitioning to humans, we had some setbacks. We discovered that humans have antibodies that will attack the pig’s heart and will reject it very quickly.
After intense research we were able to identify the culprits in the pig’s heart that would trigger the rejection and we slowly started knocking these genes out with the help of our collaborator, Revivicor, the biotechnology company that cloned Dolly the sheep. Through newer genetic techniques we started knocking out some of these molecules and then finally we managed to edit parts of the genome. That was done and during this research, mostly at the National Institute of Health (NIH), and then for the last five years at my current institution, we have demonstrated that we can we can avoid rejection by genetically modifying these pigs by putting in multiple genes and taking out a few. On the other end, we modified immune suppression in a way that it's not using a generalised immunosuppression that suppresses, every cell in your body.
So, with that, first at the NIH before I moved here, we used an abdominal transplant model, while leaving the baboon’s heart in place and we got survival up to three years. The survival was only terminated because we withdrew the antibody to see if there's some kind of tolerance. When we moved here, we tried to see if the same combination of genetics and drugs could help us prolong the heart in its original position and that heart is able to support life. We have been able to do that and on the basis of that, me and my partner, Bart Griffith approached the regulatory agencies in US, asking them for permission to help a patient who had no other options and would have died in few days.
After vigorous back and forth communication with them, we were able to convince them to let us try this in one patient only, and finally on the New Year's Eve, we got the permission for the procedure. So, that’s how it led this experiment, which is still is an experiment because nobody knows – it has never been done before so nobody knows how it will progress. We are taking every day as a new day, and we are managing everything as it come along.
ET: What challenges did you and your team face during this procedure?
Dr Mohiuddin: This patient was suffering from heart failure for long period of time and his heart had grown considerably, its muscles becoming flaccid. When we opened his chest and took this heart out and matched the pig’s heart with it, we noticed that because his had already dilated, the match was not possible. The pig’s heart was not the exact fit so, we had to modify the recipient connection point to ensure the plumbing system comes together in a manner that we can proceed. That was a one challenge that we faced, but besides that, I mean the surgery was as if you're doing any other surgery.
ET: In medical terms, how is the patient doing now with a new heart?
Dr Mohiuddin: David Bennett, our patient, is improving. We have not witnessed any problem with the heart. It is contracting and functioning as we had expected. I explain it by telling people it is like installing a BMW’s engine in an old car. So, there is no issue with the heart. But, you know, this patient, who has been severely deconditioned because of his prolonged illness he was on bed for two months in our hospital. And out of those two months, he was on this machine called the ECMO machine, also known as extracorporeal life support, which functions as a heart. Though his kidneys and other organs were functioning fine, overall, this person was in a very bad shape. So, our major concern was, based on our previous experiments, we were sure that this heart will, you know, work well. But our main concern is whether or not his body will be able to support this heart.
ET: What challenges will the patient face in the future?
Dr Mohiuddin: One of the major challenges is a compliance. At 57, he came to us with a failing heart because he was not taking blood pressure medications. We were even asked by the Food and Drug Administration (FDA): If the hospital cannot trust this patient with a human heart, how can he be trusted with a pig’s heart and whether he would even take prescribed medications,which would be required as long as the heart is functional.
We have great hopes that this person has received a new lease of life. We are trying to educate him, and we will follow him, even if we have to visit his house to make sure that he's taking his medicine because this is a very precious experiment and a lot of experiments coming later will depend on the success of this experiment. To me, being able to conduct this experiment is a success. Every passing day is a success, but for long-term use of this heart, this patient has to be compliant, and a strict check needs to be done. So, I think that is the biggest challenge before us.
ET: When do you think this patient will be able to live a normal life right now?
Dr Mohiuddin: He was on support. We have managed to remove the support he was on That was done gradually. When we were confident that his heart can support his life other breathing machines were also removed. He is talking at this point and receiving all the required medical attention. But even if it was a human-to-human transplant, the normal transplant, it takes a while for the patient to be able live on his / her own. It will take at least a month ICU care, and then maybe a month of rehab, because all his muscles have become very weak due to inactivity. So, at this point he cannot even walk by himself. But with a lot of physiotherapy, rehab and if all goes well, we are hoping he should be back home in the next two months.
ET: How far are we from seeing such lifesaving transplants being performed regularly across the developing world?
Dr Mohiuddin: Even in the developed world it's not going to be a routine procedure very soon. We had to request for special permission to conduct this experiment. They may give us the same kind of permission to do another one or two or three. But they insist on going through a regular path that includes doing more animal-related research, providing safety data, drug safety data, the pig heart safety data, and proving that there is no disease transmission. So, all that will lead to clinical trials and the clinical trials when they start, they start with less people and slowly you can increase the number. Once the clinical trial is satisfactory, only then the FDA give the green light for the procedure. Even in the United States, the procedure would take two more years of research and vigorous testing before it becomes available. The cost of this procedure is a major factor. This patient was not covered under any insurance, the hospital paid for his transplant. It will take a considerable time before such procedures can be taken to countries like Pakistan because we are not even performing the normal heart transplant procedure there. We need to establish that first, before we think about this. Getting a donor in a country like the US is very difficult, I can imagine it is even more difficult in a country like Pakistan. Once the genetic modification of pigs is permitted, these companies will be producing these animals in a large number. So, there will be no issue of the availability of the organs. The only issue will the countries that will be performing it – whether they have the capacity to afford such transplants. So, to become a routine procedure in any of the developing countries, it will take a while.
ET: What was the decision to take a pig’s heart based on?
Dr Mohiuddin: The biggest reason among several others was that a pig’s heart was easy to edit genetically. Since we know the genome of the pig, it was easy to edit the gene. A lot of research has already been done on pigs. A lot of modifications have been done to produce more meat etc. So, we know a lot about its gene structure. Earlier, a baboon’s kidney and heart were used, but those organs were rejected very fast. Even while baboons are much closer to humans than the pigs, it didn’t work. To get the right size of a baboon’s heart, you probably have to wait for twenty years for the organ to be compatible for a human. Whereas the heart that we used was from a pig that was only one year old. The heart matched exactly to our recipients. The third factor is ethics. Pigs are consumed widely across the western world. So, sacrificing a pig for its heart tends to raise less issue than if you were to utilize a baboon’s heart – which is considered an endangered species. Pigs, on the other hand, not only breed fast, but also grow very fast. These pigs that will be used for transplantation will come from a very clean facility, and they won’t transmit any infection to humans. So, these are some of the some of the factors that led the xenotransplantation community to choose a pig as a donor.
ET: In most Muslim countries, the pig will not be considered as an acceptable donor. What do you think about that?
Dr Mohiuddin: I've been working in this field for last 30 years and I’ve consulted innumerable religious leaders, not just Muslim, but Christians and Jews. Orthodox Christians and Jews have the same issue. I am the president of a society that oversees all the xenotransplantation, and, in that group, we have been trying to get a consensus statement from Muslim, Christian and Jewish scholars. Islamic scholars have said that in dire situations where an individual’s life is threatened, such a procedure can be performed to prevent death. Our job, in this case, was to save the patient’s life and that is what we did with the best advise available to us and with the best guidance from scholars on the subject. And prior to this, patients have been using porcine insulin and heart valves. So, it is not entirely new. Again, our job was to save the patient’s life and he wouldn’t have survived much longer without a replacement. In the absence of a regular human heart, this was our best option. And in dire situations, even eating pork is permissible to save one’s life. So, I’ve applied the same principle here and ensured that I did everything possible to save the patient’s life.
ET: How promising is this surgery?
Dr Mohiuddin: Initial xenotransplantation experiments were done without any background, experimental data. I'm not saying that this heart will function for long, long time. But we have solid experimental data I’ve based all my research on for all these years, that indicates that it is time for us to move from an animal transplantation model to human model. There are several things that we couldn't study in the animal model, and this kind of experimentation that we have done would tell us what we have missed in that model. You can work on the baboon model for your entire life, but there may be a few things that you could never study in that model -- until you to do it in a human. So based on my animal models, where we consistently got over six months of survival, I'm hoping that this heart will at least support life for six months. I cannot guarantee that if the other organs or other parts of the body will cooperate with that heart because this patient was very, very sick, and very decondition. So, that's the bigger challenge more than thinking of whether this heart will be rejected or not.
ET: You receive special dispensation from the US medical regulator in Dave Bennett's case. Do you do think the world and other doctors even in the western world are willing to walk that extra mile?
Dr Mohiuddin: Of course, you know, as we speak, several other institutions, based on our success are trying to get permission for kidney or eyelid or other procedures. So, I'm sure the FDA will be bombarded with applications like ours -- at this time or, or soon will be bombarded with such requests. But the advantage we had was that we had the solid data that's supported our case. So not all applications will have that kind of data available. And, in the entire United States in Northern America, we are the only medical facility that has the kind of data for the heart. There's only one center in Germany who has similar data than ours or are compatible data. So, they are trying, and I know for sure because I've spoken to them. But you know, the regulations in Germany are a little bit stricter than here. It was a tough call for us as well. But we were convinced that it would work based on our primary data and the FDA believed us.
ET: What does the success of this surgery or this procedure mean for the future of organ transplantation?
Dr Mohiuddin: This procedure is the game changer. We see patients who have no hope and die waiting for an organ. If this process is approved, we will have unlimited supply of organs. No one will have to wait for an organ. And we won’t even have to wait for the stage at which Mr. Bennet is. That means if you know or if you anticipate organ failure, you can get a transplant way earlier. Of course, I am biased because I did it. But this is a great service to humanity.
So, sky's the limit. We have done only 10 Gene modifications. Fast-forward a few years, this technique will be so advanced that you may even be able to get a customized organ for yourself. All by giving a simple blood sample. This addresses many issues that we currently face, including organ shortage and so on and so forth. You will be able to create organs that are not rejected as foreign by the body. This technique has a lot of potential – the potential to help everyone who needs an organ. That is the beauty of this technique.
ET: You and your team took a chance on a patient who only had one last chance. What was it like? the pressure the responsibility, what did you feel?
Dr Mohiuddin: It was tremendous because this is not the perfect time for any experimental procedure. We are suffering from Covid, and the hospitals are struggling due to the enormous cost that came with the pandemic. So, it was not only a difficult task for us to get the permission from the regulator, but perhaps more difficult to convince our own hospital. We had to justify the cost of this procedure at this time and why so much was being spent on a single patient when there are so many other expenses. Since the patient was already occupying a bed, it made things a little easier. At first the entire hospital was reluctant, then everyone came together and provided everything that was needed to conduct this procedure. When this surgery was being performed, we were about 20-30 people in the operation room, and the combined surgical experience was about 100 years among all of us present at the time.
So, that much expertise was available at our disposal to make this successful.
ET: What does it mean for you personally?
Dr Mohiuddin: It means a lot. It is 30 years of my work becoming a reality. It was an awesome moment for me to see this heart beat in a human. I've seen it beating in in a baboon for years, but to see it beat in a human and every single day is amazing. I never thought I would see this happen in my lifetime. And again, it is not just my work, it is a team effort. I had tremendous support from Dr Bartley P. Griffith, and the entire extended team.
ET: Has anyone reached out to you from Pakistan asking for any support to introduce this in Pakistan?
Dr Mohiuddin:
I’ve been contacted by Dr Adeeb Rizvi who has been successfully carrying out kidney transplants in Pakistan. I am from DOW University of Health Sciences. I have received considerable support from that institution. Several other doctors have reach out, and so has our ambassador. I hail from Pakistan, and I am here to help in any way I can. My goal is to transfer whatever we have learned here to make things easier for institutions in Pakistan. A lot of good will come out of this experiment. I am very optimistic about the future.
ET: There has been a lot of talk about your patient's past, where apparently, he was convicted of stabbing somebody, and then there are all these ethical questions. The Washington Post has written an editorial. What are your thoughts about that? Did he deserve it?
Dr Mohiuddin: Our job as doctors is to save lives. We don’t conduct background checks on our patients. And neither does the hospital. I don’t think anyone at the hospital was aware about it. Whoever comes to us, irrespective of his or her past, if they need help, we provide them with that help. And that is exactly what we did in Mr. David Bennett’s case. So, even if someone at our institution had known about the background, it wouldn’t have mattered in terms of providing the medical support he needed.