Ethical Considerations in Islet Xenotransplantation

ABSTRACT

For the management of type 1 diabetes, islet xenotransplantation has emerged as a potential alternative to lifelong insulin therapy or islet allotransplantation. However, this progress raises significant ethical questions that warrant further exploration. This article will examine the ethical landscape of islet xenotransplantation, highlighting points of convergence and distinction with solid organ xenotransplantation. We focus on four key areas: (i) animal welfare, including the ethical implications of sourcing large numbers of pigs per recipient; (ii) pediatric considerations, given the lifelong impact of early interventions, and the increasing prevalence and burden of pediatric diabetes; (iii) informed consent and obligations for long‐term monitoring including sample retention; and (iv) strategies for inclusive public and patient engagement to build trust and transparency.

Abbreviations

IDDM

Insulin‐dependent diabetes mellitus

NIDDM

Non‐insulin dependent diabetes mellitus

T1D

Type 1 diabetes

T2D

Type 2 diabetes

1. Introduction

Researchers estimate that over 8 million people worldwide live with type 1 diabetes (T1D), a chronic autoimmune disorder in which the body's immune system mistakenly destroys the insulin‐producing pancreatic beta cells [1]. Type 2 diabetes (T2D) affects 462 million people worldwide and while this is usually non‐insulin dependent diabetes mellitus (NIDDM), up to 30% of these patients also become insulin dependent [2]. The standard of care when a patient develops either T1D or insulin‐dependent T2D is lifelong dependence on exogenous insulin, a therapy that, while life‐sustaining, imposes a persistent burden on the patient.

The burden of insulin‐dependent diabetes mellitus (IDDM) extends far beyond the physical act of administering insulin via multiple daily injections or an insulin pump. It can manifest as a constant cognitive load, requiring continual blood glucose monitoring, complex carbohydrate counting, and dose adjustments for every meal, exercise, or illness. Patients live under the dual threat of acute glycemic episodes: (i) the immediate danger of hypoglycemia (low blood sugar), which can lead to confusion, seizure, or death, and (ii) the long‐term, debilitating micro‐ and macrovascular complications of hyperglycemia including blindness, kidney failure, nerve damage, and cardiovascular disease. The burden is manifest in reviewing emergency room usage and affects both the individual with diabetes and the health system writ large given the resource utilization—up to 72 visits per 1000 adults are related to diabetes, nearly doubling when comparing 2012 to 2021, with significant socioeconomic disparities noted [3, 4]. This constant management, coupled with the fear of both acute events and future complications, may contribute to psychosocial distress, anxiety, and a diminished quality of life [5]. Individuals with T1D have an average life expectancy approximately 10 years shorter than that of individuals without T1D [6].

For a subset of patients, insulin therapy does not prevent recurrent severe hypoglycemia or restore their quality of life. In one recent study, upwards of 20% of patients with T1D report having had at least one severe hypoglycemic event in the past 12 months, and upwards of 30% having impaired awareness of hypoglycemia, which can be life‐threatening [7]. The “dead in bed syndrome” due to severe hypoglycemia is the most feared complication in young patients. For these individuals, pancreas transplantation has been a focus for reinstating islet function, however it remains invasive and risky. Thus, rather than transplanting the pancreas itself, transplanting islets from deceased donors represents a more effective strategy. Indeed, islet allotransplantation has emerged as an effective therapeutic strategy. Studies have established its capacity to substantially decrease or even eliminate the need for daily insulin following islet allotransplantation, with an insulin independence rate of about 50%‐60% at 5‐years [8, 9, 10, 11, 12, 13, 14, 15]. It is considered less risky and invasive than a pancreas transplant with, however, the same need for standard immunosuppression [16, 17]. Of note, even in patients not fully insulin‐independent after islet transplant, the resolution of hypoglycemia unawareness is durable and approaches a rate of 100%. One caveat is that these islets must still come from the pancreases of deceased donors; scarcity of cadaveric pancreases remains a significant challenge [18].

Transplanting islets from genetically engineered pigs is one potential solution [18, 19, 20, 21, 22, 23, 24]. Xenotransplantation has made significant scientific progress to the point that the Food and Drug Administration (FDA) has approved the first kidney xenotransplantation clinical trials from genetically engineered pigs in the United States [25, 26]. Society guidelines on appropriate potential candidates have been formulated and the priority categories include diabetic patients with end‐stage renal disease [27, 28]. This is a milestone as, historically, major barriers to xenotransplantation have included hyperacute rejection, the risk of transmitting porcine endogenous retroviruses, and physiological incompatibilities [28]. However, recent breakthroughs in genetic engineering, particularly using CRISPR‐Cas9 technology, have enabled the creation of donor pigs with multiple genetic modifications that address these obstacles.

This article examines the ethical landscape of islet xenotransplantation, highlighting points of convergence and distinction with solid organ xenotransplantation. Navigating these ethical dimensions is not merely a secondary academic exercise; it is foundational to the clinical translation of this potential therapy. Because xenotransplantation introduces unique risks (e.g., xenozoonosis), rigorous ethical oversight is required to maintain the social license necessary for its clinical implementation. Herein, a background of clinical application of islet xenotransplantation is provided first. Then, the paper turns to ethical issues. We focus on four key areas of concern for ethics: (i) the use and welfare of animals, particularly the number of pigs required per patient treated; (ii) pediatric considerations; (iii) informed consent and long‐term monitoring; and (iv) the need for more inclusive public and patient engagement.

1.1. Background of Clinical Application

For islet xenotransplantation, the goal is to provide a therapeutic solution for patients with IDDM so that they no longer need exogenous insulin. Two methods are being explored: free (nonencapsulated) and encapsulated islet xenotransplantation [29, 30, 31]. Groth first conducted clinical trials of free islet xenotransplantation in 8 patients with T1D from 1990–1993 [32, 33]. In each case, insulin production was insufficient to affect the patient's insulin requirements [34]. Normoglycemia has been maintained in a small number of streptozotocin‐induced diabetic, immunosuppressed nonhuman primates with free porcine islets for periods >1 year [35]. However, few instances of clinical application using free islets have been conducted since Groth [18, 36].

Additional substantial clinical evidence informing the ethics of pig islet xenotransplantation comes from two parallel programs using alginate‐microencapsulated neonatal porcine islets (DIABECELL) sourced from designated pathogen‐free Auckland Island pigs and delivered intraperitoneally without immunosuppression. In New Zealand, Elliott and Matsumoto's phase I/IIa trial in 14 patients with unstable type 1 diabetes demonstrated reductions in unaware hypoglycemic events across all dose groups, with four patients reaching HbA1c below 7% and no detectable PERV DNA or RNA in any recipient [31]; a follow‐up efficacy study in 8 patients showed that the higher‐dose cohort sustained HbA1c below 7% for more than 600 days alongside meaningful reductions in severe hypoglycemia [30]. The Argentine program led by Abalovich and Matsumoto transplanted 21 patients and similarly found no evidence of PERV transmission through 113 weeks of monitoring [37], and a decade‐long follow‐up survey reported durable glycemic improvement (mean HbA1c 7.4% versus 8.5% pre‐transplant), reduced insulin requirements, and improvement in severe hypoglycemia for 86% of respondents, with 85.7% expressing a desire for booster transplantation and 76% willing to recommend the procedure to others [38]. Taken together, these data establish a baseline ethical case that encapsulated porcine islet xenotransplantation can deliver clinically meaningful, durable benefit without the principal infectious harm, cross‐species retroviral transmission, that has long anchored objections to xenotransplantation, while the strong patient endorsement at ten years speaks to the recipients' own retrospective valuation of the trade‐offs involved [20, 39].

There have been some clinical applications using encapsulated islets [18, 36]. One possible benefit of encapsulated islets is not needing to use immunosuppressive regimen. Nonetheless, some researchers worry that encapsulation may not be entirely effective at eliminating the need for immunosuppressive therapy and may detrimentally alter the effectiveness of islet cells [40, 41]. Some believe that “despite the need for effective immunosuppressive therapy, the transplantation of ‘free’ islets will prove more successful than that of encapsulated islets.” [18] Still, as Cooper et al. note, free islet xenotransplantation “has not undergone clinical testing,” and the few studies involving encapsulated islet xenotransplantation have not been “totally successful.” [18]

Additional clinical trials of islet xenotransplantation may be near. Because of this, it is important to understand the ethical issues attendant with islet xenotransplantation. While the scientific literature is now replete with articles on the ethical issues of xenotransplantation, much of this literature has focused exclusively on solid organs. Only a small minority has focused on the ethical issues of islet xenotransplantation specifically [42, 43]. Furthermore, public attitude studies have largely ignored the question of how the public views islet xenotransplantation. A reason might be that islets are perceived as “less invasive” as they fall in the “cell transplantation” category and not organs. A recent scoping review of studies assessing viewpoints toward islet xenotransplantation found a notable lack of data specifically from patients with T1D [44]. The overwhelming majority of existing viewpoint data originated from student populations, whose perspectives may not adequately reflect the considerations of those who live with the disease. While we recognize there is considerable convergence in the ethical issues that are present with solid organ and islet xenotransplantation, nuance and difference exist, which this paper will help to clarify.

An important feature distinguishes islet xenotransplantation from most other organs being pursued for clinical xenotransplantation. Whereas heart, lung, or liver xenografts would typically be implanted into recipients without other failing organs, beta‐cell replacement is most often considered for patients whose diabetes has already produced end‐stage renal disease. In current allotransplantation practice, roughly 95% of pancreas transplants are performed either simultaneously with a kidney or after a prior kidney transplant. Although isolated islet allotransplantation is more common in current practice, reflecting the post‐Edmonton shift toward hypoglycemia unawareness as the primary indication, the early candidate population for islet xenotransplantation, patients with type 1 diabetes and diabetic nephropathy, is precisely the group already receiving combined or sequential kidney‐and‐beta‐cell grafts. For any given patient in this population, then, islet xenotransplantation will most likely be performed either concomitantly with, or after, a kidney transplant. This sequencing is ethically consequential: many of the central concerns raised by xenotransplantation–for example, informed consent for novel and uncertain risks, lifelong infectious‐disease surveillance, the acceptability of porcine source animals, and the regulatory framework for first‐in‐human trials–will already have been worked through in the context of kidney xenotransplantation, which is further advanced clinically and is widely expected to reach routine use first. Moreover, the small minority of pancreas transplants performed in isolation (∼5%, pancreas transplant alone) are reserved for highly selected patients in whom a favorable risk‐benefit ratio can be established; meeting this threshold will be considerably more difficult, if not impossible, in the xenotransplantation setting, and the same constraint applies with equal or greater force to any proposal for isolated islet xenotransplantation.

2. Animal use and Welfare

The use of animals in science, be it for research purposes in pre‐clinical studies, or as donors for xenotransplantation, presents significant ethical challenges. Xenotransplantation as a field actually requires both, as non‐human primates are needed as organ recipients for XTx research prior to clinical trials, and porcine donor animals are needed for the organs themselves. This ethical challenge in xenotransplantation that we will focus on centers on the question of whether humans should genetically modify, breed, and raise pigs as a source of organs, cells, or tissues for humans or instead seek to increase their supply through non‐animal alternatives (e.g., policy changes; bio‐printing). Whether it is ethically permissible is one question but further, given questions about seeking alternatives, whether it is ethically balanced and prudent is another. People will come to varying conclusions on this question based on their own moral frameworks and how they balance opposing values in animal rights, resource utilization, and human health. As the solid organ xenotransplantation literature is replete with debate on the issue [45, 46, 47], we will not be reviewing this in depth. The issues that will be covered in this section are: (i) the pig‐to‐patient ratio needed for islet xenotransplantation, (ii) the principle of proportionality, and (iii) a comparison of islet xenotransplantation to alternative therapies

2.1. Pig‐to‐Patient Ratio

One important aspect of the ethics of islet xenotransplantation that does seem to depart from solid organ xenotransplantation is the pig‐to‐patient ratio that would be needed to treat one human. Imagine solid organ xenotransplantation in an idealized situation: one pig could provide one heart, two kidneys, one liver, and so forth for multiple patients. However, for islet xenotransplantation, even under ideal conditions, this ratio may differ. If adult pigs are used, 2–3 pigs may be sufficient to treat one diabetic patient. Some have proposed the use of newborn piglets to minimize the occurrence of disease transmission after birth, minimize the costs of breeding, and address the relative difficulty of isolating islets in adult pigs. In the case that piglets are used, Ekser and colleagues have estimated that “a single patient would require islets from approximately 25–50 piglets.” [40] Cooper and colleagues provide a similar estimate based on islet equivalents (IE), a standardized unit used to quantify islet volume where one IE represents a single islet with a diameter of 150µm [18]. These estimates may exclude piglets who were non‐viable donors for genetic or breeding reasons. While there have now been a number of viewpoint studies assessing the public's outlook on xenotransplantation [48, 49], only one study with a limited number of participants has addressed the number of pigs needed to benefit one human being [50]. Traditional medical innovations seek to minimize the number of animals required, and islet xenotransplantation based on piglets would necessitate a vast expansion of animal production, which might not be realistic in the context of genetic modifications since the pigs are obtained by cloning methods. Also, this higher number of piglets per patient would demand a more rigorous justification of proportionality. We must also account for the hidden welfare costs, including the attrition rates inherent to producing medical‐grade, genetically modified pigs. If the moral footprint of a single human treatment involves the sacrifice of high numbers of animals, the field must demonstrate that the clinical benefit is sufficiently transformative to outweigh this unprecedented level of animal use. It bears emphasizing that this high ratio applies specifically to the piglet‐based approach; an adult‐pig strategy (2‐3 pigs per patient) would bring islet xenotransplantation into a range comparable to solid organ xenotransplantation, and would substantially reduce the animal welfare footprint of the field. The choice of donor age is therefore itself an ethically significant design decision, not a fixed feature of islet xenotransplantation. A further aspect regarding the ratio of animals used to humans who benefit is provided by the ethical assessment in the late 1990s, which concluded that the continued use of non‐human primates as donors for xenotransplants was excluded, in part, on the grounds of their human‐like properties. It was considered unethical to take the life of one non‐human primate to benefit a single human. By contrast, the use of non‐human primates as human proxies in experimental trials was deemed ethically permissible, as each animal was assumed to benefit multiple humans. For pigs, no such ratio was applied, and their use as source animals was therefore considered justified. However, more recent research attributes cognitive, social, and emotional capacities to pigs that are comparable to those of non‐human primates, thereby calling into question the validity of these earlier ethical judgments [51].

2.2. The Principle of Proportionality: Weighing Patient Benefit Against Animal Harm

From an ethical perspective, the move toward clinical application of islet xenotransplantation necessitates a rigorous justification for the extensive use of animals. This justification typically rests on the principle of proportionality, which requires that the potential benefits to human health outweigh the moral cost of animal sacrifice, though this justification is not uncontested [52]. Preliminary economic analysis (though, the analysis is quite dated now) suggests that islet xenotransplantation may prove to be a cost‐effective therapy for T1D compared to standard insulin management [53]. While this analysis requires updating to reflect current healthcare costs, the long‐term economic argument is straightforward: replacing lifelong exogenous insulin, continuous glucose monitors, and expensive insulin pump supplies with a one‐time (or infrequent) cellular transplant could significantly reduce the financial strain on both the patient and the healthcare system.

Beyond economics, the primary ethical justification lies in the clinical utility for the recipient. For patients suffering from brittle diabetes or impaired hypoglycemia awareness, islet xenotransplantation offers more than just convenience; it offers a restoration of physiological stability that exogenous insulin cannot replicate. If this therapy proves safe and effective, it would eliminate the constant cognitive load of glucose management and the fear of severe hypoglycemic events. By significantly decreasing the burden of disease, xenotransplantation could fundamentally transform a patient's quality of life. However, for this net benefit to remain ethically sound, the field must demonstrate that these clinical gains are sufficiently transformative to justify the high‐volume animal use described previously.

When it comes to the social acceptability of genetic modification, acceptance rates are generally high when the benefits to humans are clear—particularly in health and medical contexts—and lower when perceived risks are complex or may affect areas such as environmental safety or animal welfare. As xenotransplantation encompasses several of these dimensions, including human health, animal welfare, and risks that are difficult to assess, it is particularly complex to evaluate and calls for more nuanced, comparative analysis [54, 55].

2.3. Comparison to Alternative Therapies

However, there is room for further ethical reflection. To determine if the use of pigs for islet xenotransplantation is ethically tenable, we must thoroughly evaluate it against existing T1D treatments. This assessment should include a direct comparison with novel therapies in development that do not require the extensive use and death of animals. For example, there is ongoing research on the use of human embryonic and pluripotent stem cells to generate transplantable islet cells [56, 57, 58]. Recently, Reichman et al. reported a study in which “allogeneic stem cell‐derived, fully differentiated islets” were transplanted into 14 patients with T1D [59]. The intervention “produced endogenous insulin, and restored the physiologic function of islets, leading to improved glycemic control, elimination of severe hypoglycemic events, and insulin independence.” [59] This success represents a meaningful alternative pathway that islet xenotransplantation will need to be compared against. If a non‐animal alternative can achieve comparable clinical utility, the moral footprint of xenotransplantation, specifically the use of multiple sentient animals, will require stronger justification, though stem‐cell‐derived islets still require immunosuppression and have their own risk profile.

Aside from not having to use animals, the primary area for this potentially superior benefit likely lies in the management of recipient risk. Megan Sykes has previously recognized,

“Islet xenotransplantation, an alternative to insulin therapy, may represent a more challenging arena to justify immunosuppression than with heart or kidney recipients. Treatment of severe conditions such as hypoglycemic unawareness should be evaluated and measured against the risk of general immunosuppression. Protocols aimed at tolerizing the recipient toward the donor, thus reducing the need for systemic immunosuppression may significantly and positively impact the focus for islet xenotransplantation.” [60]

This must be balanced with additional considerations. For instance, Cooper and colleagues write that, as the field progresses, they foresee that for free islet xenotransplantation, “the intensity of immunosuppressive therapy that is required will not be prohibitive.” [18] Encapsulated islet cell xenotransplantation presents the theoretical possibility of islet transplantation without immunosuppression [18, 60].

Yet, this is where the competing potential of stem cells (or other alternatives) and xenotransplantation meet. While stem‐cell based therapies have a different risk profile including the risk of developing cancer, elevated costs, and the persistent need for immunosuppression, their clinical emergence may shift the burden of proof onto xenotransplantation to demonstrate a unique, superior clinical benefit that justifies the use of animals. Other alternatives such as advanced insulin pumps and closed loop system, new therapies for diabetes [61], may further reduce the number of candidates for islet xenotransplantation, yet more research is needed before we can confidently assess the feasibility of these alternatives.

3. Pediatric Considerations

The pediatric population introduces several nuances and can shift several of the ethical analyses. It is worth noting that even islet allotransplantation remains exceptional in children as we usually wait for secondary complications to occur (e.g., end‐stage renal disease) to consider beta cell replacement along with kidney transplant. Even classifying diabetes simply as type 1 or 2 in children can be challenging as obesity is common in both groups and on the rise [62]. Indeed from 2001 to 2017 the prevalence of T1D in children rose by 45%, while T2D increased by 95%, with significant further increases predicted by 2050 [63]. The most recent estimates in the United States find a prevalence of T2D of 18 cases per 100 000 children, and for T1D there are 304 000 children in the United States [64]. Globally, it is estimated that 1.5 million of the approximately 8.4 million individuals with T1D are younger than 20 [1]. Because clinicians frequently diagnose T1D during childhood or adolescence, the population naturally includes a high proportion of vulnerable patients and the increase in T2D has shifted the most common form away from T1D. Clearly there is a significant need for multi‐faceted approaches to their care, but integral in this is restoring insulin function while other diet, exercise, and insulin sensitization strategies are employed. This vulnerability in children is an important consideration because their limitations in legal and cognitive capacity for informed consent make novel therapies like islet xenotransplantation all the more controversial and raise other harm‐benefit analyses. In this section we consider (i) autonomy and vulnerability, (ii) therapeutic misconception, and (iii) distribution of risks and benefits.

3.1. Autonomy and Vulnerability

Legally and ethically, in most contexts, a minor cannot provide informed consent for medical procedures or research purposes except if certain exceptions apply. Examples of exception may be treatment for sexually transmitted infection, prenatal care, or that the patient is an emancipated minor. Unless an exception applies, a parent or legal guardian must consent on behalf of the minor using a best interest standard. In a research context, the parent/guardian receives and reviews the detailed information about the study's purpose, procedures, and potential risks and benefits. They must weigh the burden of their child's participation, such as additional blood draws or clinic visits, against the possibility of direct benefit to their child or the broader benefit of advancing medical knowledge. As one may expect, there is a high threshold for participation in research in this context. However, this threshold should not be insurmountably high because we risk robbing the child of a potentially effective therapy, a life‐changing intervention, and sometimes a life‐saving novel treatment. While consent of the parent/guardian is an ethical requirement, many jurisdictions, as well as the pediatric ethics literature, recognize the concept of pediatric assent due to the child's burgeoning autonomy. Assent is the minor's affirmative agreement to participate in the research; it is not merely the absence of an objection and its role in research can be overlooked especially when not assessing the child's comprehension directly. The process of obtaining assent must be tailored to the child's age, maturity, and developmental level and is an ongoing process, not a one‐time event. In the context of allotransplantation and xenotransplantation, the weight of the decision is particularly heavy; a child's assent and their guardian's consent to a trial today may bind them to a lifetime of monitoring that they may not fully comprehend. For this reason and others (e.g. need for lifelong immunosuppression, the relative absence of other end organ complications caused by diabetes in children), beta cell replacement by the way of transplantation is rarely considered in children. As children develop understanding or experience the burdens, their feelings may change significantly. As well, parental consent does not occur in a vacuum and is informed by what they expect their child will tolerate and what benefit they will experience—thus as the child's feelings change, parental regret for consent may occur. Transparency and ongoing support is integral in xenotransplantation where significant benefit may occur but uncertainty and significant questions remain. Some research exists demonstrating that adolescent motivation to participate in islet xenotransplantation is centered on autonomy [65]; more empirical data is needed.

At present, the combination of clinical risk, the availability of safe and effective insulin therapy, and the lifelong surveillance requirements discussed in the following section make pediatric islet xenotransplantation difficult to justify outside of exceptional cases. This calculus may shift if disease burden, alternative therapies, or surveillance protocols evolve substantially.

4. Informed Consent and Long‐Term Monitoring

Several guidance documents recommend that xenotransplantation recipients submit to long‐term monitoring due to the potential for xenozoonosis. For instance, the FDA 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 [66].

In a recent kidney xenotransplantation clinical trial approved in the United States, the biotechnology company stated in a press release that, post‐xenotransplant, patients “will continue to be followed for the rest of their lives, including for survival, UKidney function, and monitoring for zoonotic infections.” [25] Although the risk of zoonosis may be minimal and is generally considered lower than in solid organ xenotransplantation, islet xenotransplantation is not exempt from concerns about zoonotic transmission [37, 39, 67].

4.1. Privacy and Biological Archiving

Beyond the physical burden of surveillance, the recommendation to archive tissue and body fluid specimens indefinitely introduces privacy concerns. Unlike traditional clinical trials where researchers typically destroy samples after a set period, xenotransplantation protocols may mandate the creation of permanent biological archives. These archives serve as a public health safety net to trace potential xenozoonotic outbreaks decades after the initial procedure.

However, maintaining these repositories creates a permanent link between the recipient's biological identity and a centralized database, raising the stakes for data security. A breach could expose not only the patient's xenotransplantation history but also sensitive genomic data inherent in the archived specimens. Because authorities hold these specimens for public health purposes, recipients may lose the right to request the destruction of their samples, even if they withdraw from the clinical study. This biological tethering represents a significant concession of privacy that researchers must explicitly detail during the informed consent process.

4.2. The Right to Withdraw and Public Health

The view that recipients be subject to long‐term or lifelong monitoring is intended to protect public health, but it is not without ethical concern. Since the Nuremberg Code, the international research community has recognized that participants in a research study should have recourse to end their participation in the study. Yet, if a xenograft recipient in a clinical trial wants to stop the monitoring component of the trial, it is uncertain whether they would be allowed to or not and, if not, how this would be enforceable [68, 69, 70]. The prospect of forcing otherwise healthy participants to comply with lifelong surveillance protocols is ethically troubling [71]. This highlights the conflict between researchers’ obligation to respect participant freedom and their obligation to protect public health. Furthermore, as has been argued previously, it is uncertain how enforcement of long‐term monitoring might be mandated in a binding way. Some have recommended the use of a “Ulysses contract,” an agreement that a patient would sign prior to xenotransplantation that would, supposedly, bind them to a course of action post‐transplant [72]. Such contracts are frequent in psychiatry in order to dictate treatment decisions should a patient lose decision‐making capacity. Other researchers have recommended against the use of Ulysses contracts based upon: (i) the nature of Ulysses contracts are inapplicable in the context of xenotransplantation when a patient retains decision‐making capacity, (ii) the uncertain nature of enforcing Ulysses contracts in xenotransplantation which would seem to require police powers, and (iii) the ethical and regulatory hurdles that such enforcement would require [70].

For the very hypothetical pediatric patients, if they are subjected to long‐term or lifelong monitoring, as children have a longer potential lifespan ahead of them compared to adult recipients, this period of monitoring is correspondingly extended [71]. This will magnify the cumulative burden on the patient. Monitoring protocols may not be passive but rather could involve regular blood draws, tissue sampling, and stringent reporting of any febrile or unusual illness for the remainder of the recipient's life. This burden is imposed upon them at an age when they cannot provide true informed consent. While parents or guardians provide legal consent, the child themselves cannot fully comprehend the lifelong implications of these monitoring requirements and the potential social and personal restrictions that accompany them. Perhaps the most ethically significant aspect is the potential need for quarantine or behavioral restrictions. A mandatory quarantine would necessarily encompass both the patient and their immediate household, including caregivers, thereby amplifying the social and psychological burden of the procedure.

In addition to physical isolation if xenozoonosis is suspected, the potential for lifestyle modifications because of merely the risk of infectious disease is possible. These restrictions could be psychologically taxing and could include:

• Social Engagement: Would the recipient be advised against close physical contact with peers, participating in social gathers, or sharing personal items? Such limitations could lead to stigmatization, isolation, and impaired social development.

• Ongoing and Future Relationships: The protocol could necessitate forthright discussions with current and future intimate partners about the possible risk of transmitting an unknown pathogen. This could place an extraordinary psychological weight on the recipient, especially pediatrics ones during adolescence and early adulthood.

• Autonomy: The conflict between public health imperatives and the recipient's desire for autonomy could create intense familial and medical friction.

As can be seen, long‐term monitoring for a patient that never consented to it could have far‐reaching implications.

5. Public and Patient Viewpoints

5.1. Current state of Research

Social science literature extensively explores the ethical complexities and public attitudes surrounding solid organ xenotransplantation, such as heart and kidney procedures. Yet, researchers have devoted considerably less attention to how the public (e.g., general public, patients, family members, healthcare providers) views islet cell xenotransplantation. A recent scoping review highlighted a gap: most viewpoint data originates from student populations rather than patients living with T1D [44]. These perspectives may not adequately reflect the considerations of those who live with T1D. While these studies generally report positive attitudes, acceptance drops sharply when researchers disclose potential risks, such as zoonotic disease transmission.

5.2. Why Patient Engagement Matters

Relying on convenience samples of the general population or student samples overlooks the unique risk‐benefit calculus a patient with T1D might employ. For patients with T1D, the prospect of eliminating daily insulin and preventing complications may outweigh risks that an individual without T1D would deem unacceptable. However, the opposite may also be found, for in a recent interview study with a small cohort of T1D patients (n = 7), participants viewed islet xenotransplantation as a last therapeutic option in case other therapies failed [73]. Because patient perspectives differ so significantly from the general public, direct engagement is the only way to ensure clinical goals align with patient realities.

5.3. Ethical Imperative for Inclusion

Involving the public is not just a practical step. Viewpoint studies are needed in order to fulfill the spirit of the Changsha Communiqué principle that the regulation of xenotransplantation “should be transparent, must include scientific and ethical assessment and should involve the public.” [74] To fulfill this principle, additional empirical data are needed to inform discussions on the responsible advancement of islet xenotransplantation toward clinical practice and the adequate handling of expectations regarding transparency [75]. While public engagement is poorly institutionalized and lacks adequate funding, it is pivotal for trust and social acceptance in biomedical technologies and innovation [76, 77]. Authentic engagement that is sensitive to patient needs, values, and concerns helps to build the social license and public trust necessary for emerging biotechnologies to gain acceptance. Without public engagement, the field risks not only failing to be patient‐centered but also risks alienating the very population of patients that it intends to serve.

5.4. Next Steps for Research

To responsibly advance islet xenotransplantation toward clinical practice, we need large‐scale empirical data that are currently missing from the literature. Future research must move beyond small, localized cohorts to capture cultural and global diversity. Understanding how different demographics perceive risk and benefit will allow for a more inclusive, patient‐centered approach to medical innovation. Aligning the development of these therapies with the diverse values and concerns of the international T1D community remains an urgent ethical priority.

6. Conclusion

While islet xenotransplantation holds potential for transforming T1D management in certain patients, its clinical implementation cannot proceed on scientific merit alone. We have argued that there are unique ethical aspects of islet xenotransplantation that are distinct from solid organ xenotransplantation. The ethical considerations, ranging from the scale of animal use to the long‐term public health implications and the unique vulnerabilities of the patient population, are important to thoughtfully consider.

The clinical emergence of stem cell‐derived islets represents a significant competing alternative to islet xenotransplantation. Unlike solid organs, where no viable stem‐cell‐derived alternative currently exists, islet xenotransplantation will need to demonstrate distinct advantages, such as the potential for immunosuppression‐free protocols via encapsulation, greater scalability, or lower cost, to justify its animal use. That said, stem‐cell‐derived islets still require immunosuppression, carry a theoretical risk of tumorigenicity, and remain unproven at scale, so both approaches are likely to remain complementary in the near term, with the optimal choice depending on patient‐specific factors.

A reassuring consideration is that, for any given patient, islet xenotransplantation will likely be performed either after or concomitantly with kidney xenotransplantation, allowing many of the key ethical challenges to be addressed in advance. Transparent public and patient discourse with meaningful input from the T1D community is a prerequisite for the responsible advancement of this potentially life‐changing therapy. Navigating this ethical terrain will be a critical step to ensure that islet xenotransplantation becomes an accepted and truly beneficial treatment option.

Author Contributions

Daniel J. Hurst conceived of the idea and drafted the initial manuscript. Alexa Tarzy conducted research and aided in manuscript drafting. Christopher A. Bobier, Luz A. Padilla, Johannes Kögel, Anthony Merlocco, and Raphael P. H. Meier aided in drafting specific areas of the manuscript. All authors reviewed and approved of the final manuscript.

Disclosure

DJH is Chair of the International Xenotransplantation Association (IXA) Ethics Committee and AM and LAP are members of the IXA Ethics Committee. RPHM is an IXA councilor. The viewpoints here are their own. The remaining authors have no relevant disclosures.