Ethical Issues Involved in Solid Organ Xenotransplantation

ABSTRACT

Xenotransplantation (specifically, genetically modified pig‐to‐human transplant of organs, tissues, or cells) clinical trials are set to begin in the United States after decades of pre‐clinical studies and recent decedent and compassionate use investigations. This article provides a primer on the key ethical issues attendant with this emerging therapy. We explore four central areas of concern: (i) the use of animals to meet human transplant needs, as well as their welfare since they are housed in non‐natural conditions, (ii) the risk of infectious disease transfer from the porcine graft to the human recipient, known as xenozoonosis, (iii) patient selection criteria for initial clinical trials when an unknown risk/benefit ratio exists, and (iv) the necessity of public engagement in order to increase acceptance and trust of this novel potential therapy. The article argues that the long‐term success and social acceptance of xenotransplantation are contingent not only on overcoming immunological hurdles but also on thoughtfully considering the ethical issues.

1. Introduction

In the United States, over 100,000 individuals are on an organ transplant waitlist, with approximately 13 dying each day waiting for an organ that does not arrive (U.S. Department of Health and Human Services ²⁰²⁵). The supply of healthy transplantable human organs is not enough to meet the demand. Because of this, researchers have been exploring allotransplantation (human‐to‐human) alternatives. Xenotransplantation—the cross‐species transplantation of organs, cells, or tissues—is one such alternative that has been attempted in various ways for centuries, though there have been significant advances in the last few decades (Cooper et al. 2015; Khush et al. ²⁰²⁴).

While most of the early attempts at clinical solid organ xenotransplantation used a nonhuman primate (NHP) model as the source of the organ, today the focus is on genetically modified pigs (Cooper et al. 2015). This is due to several reasons, including the ready availability of pigs in comparison to NHPs, knowledge of breeding, large litter sizes, rapid organ growth, and the mature size of the organ (Cooper et al. 2015). Anatomically, a pig kidney is remarkably similar to the human kidney. Although the pig heart and pig liver are not identical anatomically to their human counterparts, their overall anatomy is similar, and the differences are not considered insurmountable barriers to pig‐to‐human transplantation (Ekser et al. 2015). For example, while the pig liver has three lobes compared with four in humans, this variation does not impair its ability to perform essential liver functions in humans.

Since 2021 in the United States (US), there have been at least 12 decedent studies (in which an individual declared dead by neurological criteria receives a porcine kidney or heart) or expanded access uses (in which a patient who was not a candidate for an allograft or, in the case of cardiac transplantation, was not a candidate for a mechanical circulatory device receives a porcine kidney or heart). Expanded access, which is often referred to as “compassionate use,” is a potential pathway through the US Food and Drug Administration (FDA) for a “patient with a serious or immediately life‐threatening disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.” (U.S. Food and Drug Administration ²⁰²²) As of early 2025, the FDA has approved two biotechnology firms to begin kidney xenotransplantation clinical trials. What is more, one biotechnology firm has expressed their desire to begin cardiac xenotransplantation studies in pediatric patients with congenital heart disease (Hamzelou 2023).

While immunological, anatomical, and physiological considerations are critical to the success of xenotransplantation as a clinical alternative to allotransplantation, ethical considerations cannot be overlooked. This article, while not intending to be exhaustive, provides a primer on the ethical issues that are attendant with solid organ xenotransplantation. Herein we discuss animal use and welfare, risk of zoonosis, patient selection for clinical trials, and public engagement.

2. Animal Use and Welfare

The use of animals in science, be it for research purposes in pre‐clinical studies or for xenotransplantation, raises significant ethical questions. Many of these questions center on the moral status of animals and the responsibilities that humans have toward them. Globally, pigs are routinely raised for food; yet, the pigs used in xenotransplantation are different from farm or factory‐raised pigs. The pigs used for xenotransplantation are genetically modified to, at a minimum, delete expression of the three known pig xenoantigens as well as introduce human transgenes for human protective proteins (Cooper and Hara 2023). These modifications reduce the risk of organ rejection and disease transmission in the human recipient. It is essential that these pigs are raised in highly controlled, pathogen‐free environments.

These genetic modifications and living conditions, while necessary for the safety of the human recipient, may have a significant adverse impact on the animals' welfare. The pathogen‐free environments they are raised in, while protecting them from specific microorganisms, could plausibly deprive them of the ability to engage in natural behaviors, such as rooting and socializing with other pigs. The procedures involved in organ procurement, including anesthesia and surgery, also carry risks of pain and distress for the animals, not to mention death subsequent to organ retrieval. These concerns have led some to question whether it is morally permissible to use animals in this way, especially when it involves significant alterations to their genetic makeup and a highly medicalized life (Johnson 2022).

Proponents of xenotransplantation argue that, generally, the potential benefits to humans outweigh the harms to animals (Bobier et al. 2023). They point to the thousands of people who die each year while waiting for a transplant, and they argue that xenotransplantation could provide a life‐saving solution in the foreseeable future, whereas as non‐animal alternatives (e.g., bio‐printing) are nowhere close to clinical trials, and some policy alternatives (e.g., regulated kidney market) remain highly debated. They also argue that the pigs used in xenotransplantation are treated humanely—more humanely than pigs in factory farms, for example—and that their welfare is a top priority for researchers. The use of pigs, as opposed to nonhuman primates, is often seen as a more ethically acceptable choice, given the greater genetic and social complexity of primates.

The ethical debate over animal use in xenotransplantation is multifaceted, and different people will come to different conclusions based on their own moral frameworks. However, there is universal agreement that if xenotransplantation is to proceed, it must be done in a way that minimizes animal suffering and maximizes animal welfare. The “3Rs” principle—Replacement, Reduction, and Refinement—a guiding framework in the context of animal ethics that was developed by Russell and Burch in the mid‐20th century, urges researchers to replace animal use with alternatives where possible, reduce the number of animals used, and refine procedures to minimize suffering (Russell and Burch 1959). While there is ongoing debate regarding where xenotransplantation aligns with the totality of the 3R framework, there are certain ways to more closely align xenotransplantation. For instance, reducing the number of pigs needed for xenotransplantation could look like using multiple organs, cells, and tissues from a single pig to treat multiple human patients, rather than, for instance, only transplanting the heart from the pig and disposing of the remainder of the animal. Refinement might include continuing to improve methods for genetic modification, which may also have the effect of reducing the total number of pigs needed. Further, refinement may include improving housing conditions and ensuring that all procedures are carried out with the utmost care for the animal. The use of designated pathogen‐free herds could also be considered a refinement, insofar as it improves animal welfare by reducing disease burden and associated suffering, even though it does not address the underlying ethical issue of breeding and killing animals for xenotransplantation. Replacement is likely the principle from which xenotransplantation most clearly deviates from the original intention of the 3Rs, since it presupposes that additional animals will be bred and killed for their utility to humans (Rodger et al. 2024). Because of this, some may argue that xenotransplantation is only one potential solution to the human organ shortage, and researchers ought to continue to explore solutions that do not require animals (e.g., 3D bioprinting).

3. Risk of Xenozoonosis

One of the most significant patient safety and public health concerns associated with xenotransplantation is the risk of xenozoonosis—the transmission of diseases from animals to humans. Because the organ donor is a different species, there is some level of risk that the pig could carry microorganisms that are harmless to the source animal but are pathogenic to the human xenograft recipient (Fishman 2022). This is particularly concerning in the context of xenotransplantation, as the recipient's immune system is suppressed to prevent organ rejection, making them more vulnerable to infection.

This is not a hypothetical risk, as the first recipient of a genetically modified porcine heart, who died on day 60 post‐transplantation, was found to have contracted porcine cytomegalovirus—a porcine virus that attacks porcine cells (Griffith et al. 2022; Mohiuddin et al. ²⁰²³). This is significant, as it is unclear how certain porcine microorganisms might react in the human body and, should a human xenograft recipient contract a porcine microorganism, if they might be able to transmit that to other close contacts (e.g., members of the healthcare team, caregivers, household members, sexual partners) (Hurst, Padilla, Rodger, et al. ²⁰²⁴). To mitigate the risk of xenozoonosis, researchers are taking several precautions. Source animals are raised in designated pathogen‐free facilities to prevent them from acquiring infections. They are also extensively screened for a wide range of known pathogens. In addition, the development of CRISPR‐Cas9 gene‐editing technology has made it possible to inactivate certain viruses in the pig genome, which could significantly reduce the risk of transmission (Denner 2024).

Despite these measures, the risk of xenozoonosis is not zero. There remains the possibility of an unknown or undetectable pathogen being transmitted. This has precipitated several ethical issues, most notably is the issue of long‐term surveillance of xenograft recipients. Several guidance documents on xenotransplantation recommend that xenograft recipients submit to long‐term or life‐long biosurveillance. For instance, the FDA's Center for Biologics Evaluation and Research states:

2.5.7. The importance of complying with long‐term or life‐long surveillance necessitating routine physical evaluations and the archiving of tissue and/or body fluid specimens for public health purposes even if the experiment fails and the xenotransplantation product is rejected or removed (US Department of Health and Human Services ²⁰²⁵)

This would likely involve regular monitoring (e.g., blood draws, imaging, tissue biopsy) for any signs of infection. In the event that a xenozoonotic infection is detected, it would be essential to have a plan in place to contain it and prevent its spread. While researchers must attend to these public health implications, prospective xenograft recipients must also understand that xenotransplantation will likely entail lifelong data sharing. This surveillance may include not only infectious disease monitoring but also the storage and analysis of recipients' genetic information, raising concerns about privacy, data security, and potential secondary uses of biospecimens. Questions about who controls access to these data, how long they are retained, and whether recipients may ever withdraw consent from the use of these biospecimens require resolution.

Morevoer, how to ensure a xenograft recipient's long‐term surveillance has been a continuous source of debate. If a xenograft recipient in a clinical trial wants to stop the biosurveillance component of the trial, it is uncertain whether they would be allowed to or not and, if not, how this would be enforceable. Some scholars have advocated for the use of Ulysses contracts, wherein xenograft recipients voluntarily agree to suspend or waive their right to withdraw from long‐term surveillance protocols prior to receiving a xenograft (Spillman and Sade 2007). This would allow researchers to then require xenograft recipients to comply with surveillance protocol even if they later decide they no longer want to comply with surveillance protocols. This would help mitigate potential public health risk. However, it has been recognized since the Nuremberg Code that participants in a research study should have recourse to end their participation in the study at any time and for any reason: participants should not be forced to continue participation; this is one outworking of the principle of respect for individual autonomy, which is central to modern medical ethics and the Principlism framework. Moreover, critics of Ulysses contracts in xenotransplantation observe that enforcement will be difficult given regulatory reluctance to force otherwise healthy and decisionally‐capacitated individuals to do something they do not want to do (Hurst and Bobier 2025; Hurst, Padilla, Schiff, and Parent ²⁰²⁴). Lastly, the inability to withdraw from an intervention violates the Belmont Report's principle of Respect for Persons, as it undermines a recipient's autonomy, voluntariness, and right to make informed decisions.

4. Patient Selection for Clinical Trials

In January 2022, the world's first gene‐edited pig heart was transplanted into a 57‐year‐old patient who had previously been denied a human heart transplant. The reason for this denial was the patient's history of not adhering to medical advice, which is a common disqualifier for receiving a scarce human organ, as it would be unethical to provide an organ to a patient who may not follow the necessary post‐transplant care, potentially wasting the organ and denying it to a more compliant patient (Griffith et al. 2022). Yet, this raises a crucial question: should a patient who was denied a human transplant due to non‐compliance be eligible for a pig heart transplant, especially when the latter requires strict adherence to medical protocols and likely some form of biosurveillance due to the risks it presents to the public? (Gyngell et al. 2023) Indeed, the fact that the first patient to receive a pig heart had a history of non‐compliance is particularly striking as, for years, the FDA has advised that xenotransplant candidates should be chosen based on their reliability to comply with biosurveillance (US Department of Health and Human Services, Food and Drug Administration ²⁰²⁵). This situation highlights the urgent need for a structured discussion on patient selection criteria for xenotransplantation. While some conversations are already happening, a broader deliberation is needed among patients, doctors, bioethicists, and regulators, with the goal being to reach a consensus on who should be eligible for these procedures.

In addition, there is debate on whether it would be ethical to proceed with cardiac xenotransplantation in pediatric patients in need of transplant prior to obtaining safety and efficacy data in adults (Kogel et al. 2025; Hurst, Merlocco, et al. ²⁰²⁵). The contention that pediatric xenotransplantation should not precede adult xenotransplantation finds its origins in the Nuffield Council on Bioethics' 1996 report on xenotransplantation, which states: “It would be difficult to justify the involvement of children in major and risky xenotransplantation trials before some of the uncertainties have been eliminated in trials involving adults.” (Nuffield Council on Bioethics ¹⁹⁹⁶) Yet, infants in need of a heart bear the highest organ waitlist mortality, and many have few options aside from allotransplant. Pediatric patients often do well if cardiac allotransplant is achieved, with a 5‐year patient survival > 80% (Hurst and Padilla 2024). Pediatric xenotransplantation may serve as a bridge therapy to cardiac allotransplantation. It is against this background of having few alternative options to transplant that we believe the ethics of pediatric cardiac xenotransplantation must be assessed.

Ultimately, patient selection for clinical trials raises questions of access. If xenotransplantation proves to be a safe and effective alternative to allotransplantation, concerns about access and equity will move to the forefront, much as they already are in allotransplantation. While xenografts may ease scarcity in some contexts, this will not be universal. Allografts may continue to function better or longer than xenografts, and some patients may express a preference for allografts over xenografts. How, then, will access be determined? Economic factors—including the relative costs of xenografts and allografts, and the policies of public and private insurers—will inevitably shape availability. From a global perspective, the World Health Organization has cautioned: “Because of the potential benefits of successful xenotransplantation, consideration should be given from the beginning to future equitable access to this therapy.” (World Health Organization ²⁰²⁵) Yet, the issue of global equitable access remains only lightly explored (Hurst 2024).

5. Public Engagement

The successful and ethical implementation of xenotransplantation as a clinical reality depends not only on scientific and medical advancements but also on public acceptance and trust. Given the novel nature of the technology and the ethical and safety concerns it raises, engaging the public in an open and transparent dialogue is crucial, which has been recognized by the xenotransplantation research community and the (World Health Organization ²⁰²⁵). Public perception can significantly influence policy decisions, regulatory frameworks, and the overall willingness of society to embrace this new form of treatment. Hence, engaging the public is an important step in introducing a novel medical therapy that has an unknown (though potentially significant) risk profile. Indeed, one of the main reasons public engagement is so important is the potential for the risks of xenotransplantation to extend beyond the individual recipient. As discussed above, the risk of xenozoonosis, while considered low by infectious disease experts, has implications for public health. This shared risk necessitates a broader societal conversation about whether and how to proceed with xenotransplantation (Hurst and Cooper 2024).

Effective public engagement involves more than just providing information. It requires a two‐way dialogue where the public's (including the general public, patients, caregivers, healthcare providers, and other stakeholders) values, concerns, and questions are heard and addressed. This can be achieved through various means, such as public forums, educational campaigns, formal surveys, and qualitative interviews, and engagement with community leaders and patient advocacy groups. The goal is to foster a more informed public discourse, correct misconceptions, and build trust in the scientific and medical communities.

Experience has shown that a lack of public engagement can be a significant barrier to the adoption of new medical technologies. In Australia, for example, public consultations in the early 2000s led to a moratorium on xenotransplantation clinical trials, in part because of public concerns that were not adequately addressed (Tallacchini 2023). This serves as a cautionary tale about the importance of taking public perspectives seriously. In the US, as clinical trials for xenotransplantation are beginning, there is a renewed focus on the need for public engagement, and there has been one large‐scale survey study conducted (Padilla et al. 2024; Hurst, Padilla, et al. ²⁰²⁵). Regulatory bodies like the FDA have a role to play in ensuring that the public is informed and that its concerns are considered in the regulatory process. Biotechnology companies and research institutions also have a responsibility to be transparent about their work and to engage in open dialogue with the public. Ultimately, building a strong foundation of public trust will be essential for xenotransplantation to fulfill its promise as a life‐saving therapy.

6. Conclusion

Xenotransplantation holds the potential to alleviate the shortage of healthy transplantable organs. Yet, as we have detailed, the path forward is not merely a scientific endeavor but one with ethical challenges that require careful consideration. The welfare of the genetically modified animals that serve as organ sources, the public health risk of xenozoonosis, patient selection criteria, and the need for public engagement are not peripheral issues. These issues are central to the ethical advancement of this emerging technology. Importantly, these ethical challenges resonate deeply with principles foundational to the practice and teaching of clinical anatomy. Themes long familiar from the discourse on body donation—the durability and scope of consent, the protection of donor dignity, the stewardship of gifted biological materials, and the imperative of biosafety—find parallel expression in xenotransplantation. This unique intersection positions the clinical anatomist to contribute meaningfully to the conversation. Anatomy educators can therefore use xenotransplantation as a practical case study, demonstrating how the core ethical principles of stewardship, dignity, and biosafety first learned in the anatomy lab are the essential foundation for governing novel biotechnologies.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Hurst, D. J. , Bobier C., and Padilla L. A.. 2026. “Ethical Issues Involved in Solid Organ Xenotransplantation.” Clinical Anatomy 39, no. 1: 55–59. 10.1002/ca.70036.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.