There are not enough organs for heart failure patients who need them, and cardiac xenotransplantation is one potential, albeit controversial, solution. Recent advances in the field came to light when the world’s first pig-to-human heart transplant was performed at the University of Maryland. A 57-year-old patient was in the end stage of heart disease, and survived several months after receiving a genetically engineered pig heart.1
“Every single ethical heart issue that you’d ever want to discuss, this touches on [those] in some way,” says Douglas L. Mann, MD, professor of cardiology, medicine, cell biology, and physiology at the Washington University School of Medicine in St. Louis.
The central ethical considerations with xenotransplantation mirror those in any clinical research involving significant or unknown risks of harm to the research subject — in this case, a patient with end-stage organ failure. “Xeno is unusual in that it involves some risk to the research subject’s close contacts and caregivers, and a risk to the general public,” says Richard N. Pierson III, MD, scientific director for the Center for Transplantation Sciences at Massachusetts General Hospital.
Although it is unlikely based on available evidence, an infection could occur in the research subject that turns out to be transmissible to other people. “Consequently, xeno clinical trial designs will involve careful surveillance for infection or illness in the recipient, and scheduled monitoring for sample collection and archiving from the subject — and perhaps also from their close contacts,” says Pierson, who has authored several papers on cardiac xenotransplantation.2-4
Ethical, humane treatment of the animals that will be the source of the organ or cell xenografts is an additional consideration. Some people believe using animals for this or other purposes is unethical. “This view is not widely held, and people who feel this way can opt out from participation in xenotransplant clinical trials,” Pierson says.
Is it ethically justifiable to purposely breed a species of pig to serve as a supply for human organs? “There seems to be less hesitation about using pigs than, say, primates. However, it does still raise issues when we talk with folks about xenotransplantation,” says Daniel J. Hurst, PhD, ThM, MSc, director of medical professionalism, ethics, and humanities at Rowan University School of Osteopathic Medicine in Stratford, NJ.
Additional data on the attitudes and viewpoints of key stakeholders toward xenotransplantation are needed.5 “We don’t know enough about what patients and the broader public think about xenotransplantation. Studying this is important, as it’s difficult for science to progress without public support,” Hurst offers.
The potential for xenozoonosis — the spread of an infectious disease from the pig organ to the transplanted patient — raises a larger ethical issue. It is unknown if the xenozoonotic disease could pass from the infected patient to others — close contacts, sexual contacts, or the wider public. This would, in turn, become a public health issue.
“There have been calls for xeno patients to be closely monitored for the remainder of their lives post-transplant, but there is no workable solution right now to do so,” says Hurst, who co-authored a paper examining this issue in the pediatric population.6 “It’s also suspect whether such a mandate is ethical.”
Access to effective, potentially life-saving experimental treatments, “or to any approved medical therapy — as we hope xeno will eventually become — that may be scarce or expensive, should be equitable and fair,” Pierson stresses. Currently, few U.S centers are developing plans for xenotransplantation clinical trials. “However, the time is now for IRBs to get up to speed on the issues involved,” Hurst argues. “Researchers need to be thinking about how to promote informed consent in their potential subjects.”7
In a recently published article, Hurst and co-authors noted three important issues for informed consent: A subject’s ability to withdraw from the trial, restrictions on their reproductive rights, and the possibility of the need for quarantine if there is a perceived risk of xenozoonosis.8 “There is also a philosophical question of how free consent truly is if a patient has no other options,” Hurst notes.
All of these ethical questions aside, the recent case brought to light just how far the field has come. “Of course, that always gets you more excited about what could be,” Mann says.
Mann is keenly interested in how scientific discoveries evolve into actual clinical treatments. In terms of cardiac xenotransplantation, says Mann, “that one’s a little tricky, because our therapies right now are pretty mature.”
Traditionally, researchers conduct randomized, controlled trials to test new treatments against existing therapies. In this case, current treatment is regular cardiac transplantation, which carries an 80% five-year survival rate. “It’s hard to imagine where an IRB would sign off on that,” Mann says.
Mann notes the original field of cardiac transplantation did not progress through randomized, controlled trials; rather, progress occurred through single-center experiences. “Eventually, the field matured, and everyone shared their outcomes. Now, you have a therapy that’s really amazing and offers good quality of life,” Mann observes.
The same trajectory could happen with cardiac xenotransplantation. “When the technology matures a little bit more, it may be applicable for individuals for whom no other option exists,” Mann suggests.
Once there are additional cases, researchers can better understand mortality and morbidity in those patients. “That’s slow going, though, because the patients are so sick they are going to get every single complication you can get. It will be a slow road,” Mann predicts.
The recent case involved a patient for whom a left ventricular assist device was not a possibility. Cardiac transplant was not a possibility, and the patient was clearly failing medical therapy. “The FDA signed off on that, and obviously an ethics committee signed off on it. As compassionate use, xenotransplantation may work its way into the clinic,” Mann offers.
However, if patients are offered a human organ donor’s heart vs. xenotransplantation, the patient would presumably choose the human donor heart because the survival rates are well-established. In contrast, cardiac xenotransplantation would be a reasonable choice only for people without other options. “If medical therapy is clearly failing and the patient can’t get out of the ICU, then a discussion about xenotransplantation might be warranted,” Mann says.
It would need to include a full informed consent discussion covering everything that is known. Importantly, not all potential risks are known. “Most patients would opt for life over death if they thought they could live longer, but it will raise a lot of questions. Informed consent that we develop in the field will be based on what we’ve learned from the limited human experience,” Mann says.
Notably, the recent pig-to-human transplant case would have been impossible without advances in gene editing. “We’re in a really interesting place, and we’ve always developed new technology slowly — and, I think, responsibly,” Mann says.
That does not mean each case in the foreseeable future will not come with thorny ethical concerns. “It will challenge ethicists, and I think for each case, an ethics committee should weigh in on this,” Mann says. “But as long as the patient and the family are aware of all the challenges, I think this can proceed in an ethical manner.”
REFERENCES
1. Wang W, He W, Ruan Y, Geng Q. First pig-to-human heart transplantation. Innovation (Camb) 2022;3:100223.
2. Pierson RN 3rd, Allan JS, Cooper DKC, et al. Expert opinion special feature: Patient selection for initial clinical trials of pig organ transplantation. Transplantation 2022; Jun 28. doi: 10.1097/TP.0000000000004197. [Online
ahead of print].
3. Chaban R, Cooper DKC, Pierson RN 3rd. Pig heart and lung xenotransplantation: Present status. J Heart Lung Transplant 2022 May 13;S1053-2498(22)01914-3. doi: 10.1016/j.healun.2022.04.010. [Online ahead of print].
4. Pierson RN 3rd. Progress toward pig-to-human xenotransplantation. N Engl J Med 2022;386:1871-1873.
5. Mitchell C, Lipps A, Padilla L, et al. Meta-analysis of public perception toward xenotransplantation. Xenotransplantation 2020;27:e12583.
6. Hurst DJ, Padilla LA, Cooper DKC, et al. Clinical trials of pediatric cardiac xenotransplantation. Am J Transplant 2021;21:433-434.
7. Hurst DJ, Padilla LA, Trani C, et al. Recommendations to the IRB review process in preparation of xenotransplantation clinical trials. Xenotransplantation 2020;27:e12587
8. Padilla LA, Hurst D, Maxwell K, et al. Informed consent for potential recipients of pig kidney xenotransplantation in the United States. Transplantation 2022; Apr 27. doi: 10.1097/TP.0000000000004144. [Online ahead of print].