1 Introduction

The demand for organ transplants has consistently outpaced the supply of available organs, leading to a significant organ shortage crisis. This disparity has resulted in thousands of patients dying each year while waiting for a suitable organ donor (Sykes and Sachs, 2019). According to the United Network for Organ Sharing, more than 113 000 candidates are currently on the U.S. national waiting list, but only a fraction of these patients receive the transplants they need annually (Wolf et al., 2019). The increasing prevalence of chronic diseases and end-stage organ failure has exacerbated this issue, making the search for alternative sources of organs more urgent than ever (Deng et al., 2022).

In response to the organ shortage crisis, researchers have turned to xenotransplantation, specifically the use of genetically modified pigs, as a potential solution. Pigs are considered ideal organ donors due to their anatomical and physiological similarities to humans, as well as their size compatibility (Hryhorowicz et al., 2017). Advances in genetic engineering, particularly with CRISPR-Cas9 technology, have enabled the modification of pig genomes to reduce the risk of immune rejection and other complications associated with xenotransplantation (Cooper et al., 2016). These genetically modified pigs have shown promising results in preclinical studies, with transplanted organs surviving for extended periods in non-human primate models (Kemter et al., 2020). Despite these advancements, several challenges remain, including immunological barriers, coagulation dysregulation, and the risk of zoonotic infections (Lu et al., 2020).

This study is to explore the ethical considerations surrounding the use of genetically modified pigs for organ transplants. As the field of xenotransplantation progresses towards potential clinical trials, it is crucial to address the ethical implications of this technology. These considerations include the welfare of genetically modified pigs, the potential risks to human recipients, and the broader societal impacts of adopting xenotransplantation as a standard medical practice. By comprehensively reviewing the ethical landscape, this study expects to provide a balanced perspective that can inform future research, policy-making, and clinical applications in the field of xenotransplantation.

2 Background on Genetically Modified Pigs in Organ Transplantation

2.1 Scientific advancements in genetic modification technologies

The field of genetic modification has seen significant advancements, particularly with the development of CRISPR-Cas9 and other gene-editing tools. These technologies have enabled precise modifications to the pig genome, which are crucial for overcoming immunological barriers and physiological incompatibilities in xenotransplantation. For instance, genetic modifications can delete pig genes responsible for the synthesis of specific antigens or insert human regulatory genes to prevent immune rejection and coagulation dysfunctions (Lei et al., 2022). Additionally, the ability to knock down genes related to porcine endogenous retroviruses has reduced the risk of zoonotic infections, making genetically modified pigs safer for clinical applications (Kemter et al., 2020).

2.2 Current status of xenotransplantation research and trials

Xenotransplantation research has made considerable progress, particularly in preclinical studies involving non-human primates. Genetically modified pigs have been used to achieve clinically significant graft survival times in these models, demonstrating the potential for future human trials. Recent studies have reported successful pig-to-baboon heart transplants (Figure 1) (Reichart et al., 2022) and even a compassionate use case where a genetically modified pig heart was transplanted into a terminally ill human patient, who survived for two months (Lu et al., 2020). These advancements suggest that the first-in-human clinical trials for xenotransplantation could be imminent, provided that regulatory and ethical frameworks are adequately addressed (Cooper et al., 2019; Anwar et al., 2022).

Figure 1 Mechanisms of xenograft rejection and strategies to overcome them (Adopted from Reichart et al., 2022) Image caption: (A) Hyperacute rejection of pig-to-primate xenografts (HAR) is triggered by the binding of recipient’s preformed natural antibodies to specific carbohydrate antigens [αGal, Neu5Gc, Sd(a)] on the surface of pig cells and subsequent activation of the complement system. In addition, bound antibodies activate natural killer (NK) cells via Fc-receptors (FcR) causing antibody-dependent cellular cytotoxicity (ADCC) by the release of lytic granules. (B) Responses of NK cells and macrophages. In addition to ADCC, NK cells exhibit direct cytotoxicity of pig cells because swine leucocyte antigens (SLAs) do not effectively bind to inhibitor receptors of human/NHP NK cells (KIRs) to prevent their activation. Additionally, activating signals, resulting from activating NK cell ligands (ALs) on pig cells with their corresponding activating receptors (ARs) on primate NK cells may be involved. NK cell activation may be prevented by expressing HLA-E/beta2-microglobulin (B2M) in transgenic pigs. HLA-E binds the inhibitory NK cell receptor CD94/NKG2. Macrophages are activated by FcRs binding the Fc portion of anti-pig antibodies. In addition, they are activated by galectin-3 binding αGal on pig cells. Porcine (p) CD47 does not activate the ‘don’t eat me’ receptor signal regulatory protein-α (SIRPα) on human macrophages. (C) Activation of T cells against xenotransplants may occur directly via porcine antigen-presenting cells (APCs) or indirectly via human/primate APCs presenting porcine peptides. In addition to the interaction of the peptide-presenting major histocompatibility complex (MHC) with the T-cell receptor (TCR), costimulatory signals are required, most importantly CD40—CD40L (CD154), which can be blocked by treatment with anti-CD40 and/or anti-CD40L antibodies to prevent T-cell activation. Another costimulatory pathway, CD80/CD86—CD28, can be blocked by treatment with CTLA4-Ig or its affinity-optimized variant LEA29Y. Another strategy is the involvement of the coinhibitory pathway PD1-PD-L1 expressing hPD-L1 in transgenic pigs. Finally, pigs lacking SLAs or expressing SLAs with reduced activating capacity have been produced to reduce T-cell activation via the direct pathway (Adopted from Reichart et al., 2022)

2.3 Potential benefits of using genetically modified pigs for organ transplants

The use of genetically modified pigs for organ transplants offers several potential benefits. It addresses the critical shortage of human organ donors, providing an alternative and potentially unlimited source of organs (Deng et al., 2022). Genetic modifications can be tailored to reduce or eliminate immune rejection, thereby increasing the likelihood of successful transplantation and long-term graft survival (Xi et al., 2023). Additionally, pigs are anatomically and physiologically similar to humans, making them ideal candidates for xenotransplantation (Wolf et al., 2019). The ability to engineer pigs to express human proteins further enhances the compatibility of pig organs with the human immune system, reducing the need for immunosuppressive therapies and their associated complications (Sykes and Sachs, 2019).

3 Ethical Frameworks and Theories

3.1 Utilitarian perspectives on xenotransplantation

Utilitarianism, which emphasizes the greatest good for the greatest number, provides a compelling framework for evaluating the ethical implications of xenotransplantation. The primary utilitarian argument in favor of xenotransplantation is the potential to save numerous human lives by addressing the chronic shortage of transplantable organs. The use of genetically modified pigs as organ donors could significantly reduce wait times and mortality rates for patients with end-stage organ failure (Hryhorowicz et al., 2017; Montgomery et al., 2022). However, utilitarianism also requires a careful consideration of the risks involved, such as the potential for zoonotic diseases to cross species barriers and the long-term health impacts on recipients (Lu et al., 2020). Additionally, the welfare of the donor animals must be weighed against the benefits to human patients, as the ethical treatment of pigs used in xenotransplantation is a significant concern.

3.2 Deontological ethics and the moral status of animals

Deontological ethics, which focuses on the adherence to moral rules and duties, offers a different perspective on the ethical considerations of xenotransplantation. From a deontological standpoint, the moral status of animals and the inherent rights they possess are central issues. The genetic modification and use of pigs for organ transplants raise questions about the objectification and instrumentalization of animals (Rémy, 2009). Deontologists argue that animals should not be treated merely as means to an end, regardless of the potential benefits to humans. This perspective emphasizes the need to respect the intrinsic value of animal life and to ensure that their welfare is not compromised by invasive procedures and unnatural living conditions (Johnson, 2022). The ethical tensions between the rights of human research subjects and the welfare of donor animals highlight the complexity of applying deontological principles to xenotransplantation.

3.3 Virtue ethics and considerations of human character and behavior

Virtue ethics, which focuses on the character and virtues of moral agents rather than on rules or consequences, provides a unique lens through which to examine the ethical dimensions of xenotransplantation. This approach emphasizes the development of moral virtues such as justice, courage, temperance, and practical wisdom in the context of medical research and practice (George, 2022). Virtue ethics encourages researchers and clinicians to reflect on their motivations and the moral purpose (telos) of their work, fostering a sense of responsibility and ethical integrity. The virtues of justice and compassion are particularly relevant, as they guide the fair allocation of resources and the humane treatment of both human patients and donor animals (George, 2022). By cultivating these virtues, medical professionals can navigate the ethical challenges of xenotransplantation in a manner that promotes the well-being of all parties involved.

4 Animal Welfare Considerations

4.1 Ethical implications of genetic modification on animal welfare

The genetic modification of pigs for xenotransplantation raises significant ethical concerns regarding animal welfare. The process of genetic engineering can lead to unintended health issues in pigs, such as arthritis and lung problems, as seen in earlier experiments with genetically modified livestock. These health issues highlight the potential for suffering and reduced quality of life for the animals involved. Moreover, the ethical debate extends beyond physical health to include broader welfare considerations, such as the animals’ ability to express natural behaviors and their overall well-being throughout their lives (Bovenkerk, 2020). Critics argue that the genetic modification of animals, even when intended to solve human health problems, can compromise the integrity and natural state of the animals, leading to moral objections.

4.2 Standards for the humane treatment of genetically modified pigs

To address the welfare concerns associated with genetically modified pigs, it is crucial to establish and adhere to stringent standards for their humane treatment. These standards should encompass not only the physical health of the animals but also their psychological well-being. For instance, the prevention of infectious diseases in source animals often necessitates isolation and ethologically inappropriate housing, which can severely impact the well-being of social creatures like pigs (Johnson, 2022). Therefore, humane treatment standards must ensure that genetically modified pigs are provided with environments that allow for social interactions, natural behaviors, and minimal stress. Additionally, invasive reproductive procedures used in the genetic modification process should be carefully regulated to minimize pain and distress.

4.3 Balancing animal welfare with human health benefits

The potential human health benefits of using genetically modified pigs for organ transplants must be carefully weighed against the welfare of the animals involved. On one hand, xenotransplantation offers a promising solution to the critical shortage of human organs available for transplantation, potentially saving countless lives (Sykes and Sachs, 2019; Kemter et al., 2020; Lei et al., 2022). On the other hand, the welfare of the genetically modified pigs used in these procedures cannot be overlooked. It is essential to find a balance that maximizes human health benefits while minimizing animal suffering. This balance can be achieved through rigorous ethical review processes, the development of less invasive genetic modification techniques, and the implementation of comprehensive welfare standards that prioritize the well-being of the animals throughout their lives (Johnson, 2022). By addressing both the ethical implications and the practical welfare concerns, the field of xenotransplantation can progress in a manner that respects the dignity and welfare of all living beings involved.

5 Human Health and Safety

5.1 Potential risks and benefits to human recipients

The use of genetically modified pigs for organ transplants presents both significant potential benefits and notable risks to human recipients. One of the primary benefits is the potential to alleviate the chronic shortage of human organs available for transplantation, which could save countless lives (Cengiz et al., 2019; Kemter et al., 2020). For instance, recent advancements have demonstrated the viability of pig kidney xenotransplantation in brain-dead human recipients, showing promising renal function without signs of hyperacute rejection (Montgomery et al., 2022). Additionally, pig heart xenotransplantation has shown success in non-human primate models and even in a terminally ill human patient, suggesting a viable alternative to mechanical assist devices for patients with advanced heart failure (Reichart et al., 2022).

However, the risks associated with xenotransplantation are substantial. These include the potential for cross-species infections (xenozoonosis), immune rejection, and other unforeseen complications (Johnson, 2022). The need for lifelong immunosuppression to prevent graft rejection also poses significant health risks, including increased susceptibility to infections and malignancies. Moreover, the long-term effects of xenotransplantation on human health remain largely unknown, necessitating rigorous monitoring and research (Hurst et al., 2019).

5.2 Ethical implications of unforeseen long-term effects

The ethical implications of unforeseen long-term effects in xenotransplantation are profound. One major concern is the requirement for lifelong monitoring of recipients, which raises questions about the right to withdraw from follow-up studies, especially in pediatric cases where parents or guardians must consent on behalf of the child (Hurst et al., 2019). This lifelong commitment can impinge on the autonomy of the recipient as they grow older and gain the capacity to make their own medical decisions.

Furthermore, the potential for unforeseen long-term health effects, such as the development of new diseases or chronic conditions, poses ethical dilemmas. These effects could significantly impact the quality of life of recipients and their families, raising questions about the fairness and justice of subjecting individuals to such risks. The balance between the potential benefits of increased organ availability and the ethical responsibility to protect recipients from harm is a critical consideration in the development of xenotransplantation protocols.

5.3 Informed consent and patient autonomy in xenotransplantation

Informed consent is a cornerstone of ethical medical practice, and its importance is magnified in the context of xenotransplantation due to the novel and uncertain nature of the procedure. The process of obtaining informed consent must ensure that potential recipients fully understand the risks, benefits, and unknowns associated with receiving an organ from a genetically modified pig (Padilla et al., 2022). This includes the possibility of lifelong health monitoring, restrictions on reproductive rights, and the potential need for quarantine in the event of xenozoonosis.

Patient autonomy is another critical ethical consideration. Recipients must have the freedom to make informed decisions about their participation in xenotransplantation trials without coercion. This is particularly challenging in cases where the patient is in acute need of a transplant and may feel pressured to accept the risks due to the lack of alternative options (Hurst et al., 2021). Ensuring that patients have the capacity to withdraw from the trial at any point, while balancing public health concerns, is essential to maintaining ethical standards.

6 Public Perception and Societal Impact

6.1 Public attitudes towards the use of genetically modified animals

Public attitudes towards the use of genetically modified animals, particularly pigs, for organ transplants are complex and multifaceted. There is a general lack of understanding and awareness about the scientific principles underlying xenotransplantation, which can lead to misconceptions and fears. For instance, societal ignorance of science can foster spurious ethical concerns, such as the belief that xenotransplantation violates natural or divine laws (Rollin, 2020). Additionally, the ethical tensions surrounding the genetic modification of pigs, including concerns about zoonotic diseases and animal welfare, contribute to public apprehension (Johnson, 2022). Despite these concerns, the potential of genetically modified pigs to address the chronic shortage of human organs is recognized, which may positively influence public perception over time.

6.2 Societal and cultural considerations in acceptance of xenotransplantation

Societal and cultural considerations play a significant role in the acceptance of xenotransplantation. Different cultures and religions have varying views on the use of animal organs in humans. For example, some religious groups may oppose xenotransplantation on the grounds that it interferes with the natural order or divine will. Additionally, societal concerns about animal welfare, particularly the conditions under which donor pigs are kept, can influence public acceptance. The ethical implications of keeping animals in deprived laboratory conditions that do not meet their biological and psychological needs are significant societal concerns (Rollin, 2020). Addressing these cultural and societal issues is crucial for the broader acceptance of xenotransplantation.

6.3 Strategies for addressing public concerns and fostering informed debate

To address public concerns and foster informed debate about the use of genetically modified pigs for organ transplants, several strategies can be employed. Improving public understanding of the science behind xenotransplantation is essential. This can be achieved through educational campaigns that explain the genetic modifications involved and their purpose in preventing immune rejection and reducing the risk of zoonotic diseases (Hryhorowicz et al., 2017; Wolf et al., 2019; Lei et al., 2022). Meanwhile, transparent communication about the ethical considerations and the measures taken to ensure animal welfare can help alleviate public fears. Highlighting the rigorous ethical standards and welfare practices in place for donor pigs can address concerns about animal treatment. In addition, engaging with diverse cultural and religious groups to understand their perspectives and address their specific concerns can help build broader societal acceptance. Creating platforms for open dialogue and debate can ensure that all voices are heard and considered in the development of xenotransplantation policies.

7 Regulatory and Legal Considerations

7.1 Current regulatory frameworks governing xenotransplantation

The regulatory landscape for xenotransplantation is complex and varies significantly across different regions. In the United States, the Food and Drug Administration (FDA) oversees the use of genetically modified pigs for organ transplants, treating these organs as medicinal products for human use. This classification subjects them to stringent regulatory requirements, including compliance with “current good practices” from the generation of the xenogeneic organ to its transplantation and lifelong follow-up of the recipient (Schuurman and Hoogendoorn, 2020). Similarly, in Europe, the European Medicines Agency (EMA) and national competent authorities regulate xenotransplantation, ensuring that all procedures adhere to established guidelines for genetically modified organisms and xenotransplantation products. These frameworks are designed to ensure the safety and efficacy of xenotransplantation while minimizing risks to patients and the broader community.

7.2 Legal implications of using genetically modified pigs

The use of genetically modified pigs for organ transplants raises several legal issues, primarily related to patient safety, ethical considerations, and the potential for zoonotic disease transmission. Legal frameworks must address the liability of medical practitioners and institutions in the event of adverse outcomes, including organ rejection or infection. Additionally, there are concerns about the long-term monitoring of recipients and the legal responsibilities for managing any complications that arise post-transplant (George, 2006; Reichart et al., 2022). The legal landscape must also consider the intellectual property rights associated with the genetic modifications made to the pigs, which can complicate the commercialization and widespread adoption of this technology (Wolf et al., 2019).

7.3 International standards and harmonization of regulations

Given the global nature of medical research and the potential for international collaboration in xenotransplantation, there is a pressing need for harmonized international standards. Currently, regulatory frameworks differ significantly between countries, which can hinder the progress of clinical trials and the adoption of best practices. Efforts are underway to establish international guidelines that would standardize the regulatory requirements for xenotransplantation, ensuring that all procedures meet high safety and ethical standards regardless of where they are performed (Schuurman and Hoogendoorn, 2020). Such harmonization would facilitate the sharing of data and resources, accelerating the development of safe and effective xenotransplantation therapies.

8 Environmental and Ecological Impact

8.1 Potential ecological consequences of genetically modified pigs

The introduction of genetically modified pigs for xenotransplantation raises several ecological concerns. One of the primary issues is the potential for these pigs to escape into the wild and interbreed with native pig populations, which could lead to unforeseen genetic consequences and disrupt local ecosystems. The genetic modifications intended to make these pigs suitable for organ donation, such as alterations to immune system genes, could potentially spread to wild populations, leading to unknown ecological impacts (Sykes and Sachs, 2019). Additionally, the risk of zoonotic diseases, which are diseases that can be transmitted from animals to humans, is a significant concern. Genetically modified pigs could potentially harbor and spread new pathogens, which could have devastating effects on both human and animal populations (Cengiz and Wareham, 2019).

8.2 Measures to mitigate environmental risks

To mitigate the environmental risks associated with genetically modified pigs, several measures can be implemented. One approach is to ensure that these pigs are kept in highly secure and controlled environments to prevent any possibility of escape. This includes physical barriers, as well as monitoring and tracking systems to ensure that all animals are accounted for at all times (Wolf et al., 2019). Additionally, rigorous health screening and quarantine protocols should be established to detect and manage any potential zoonotic diseases before they can spread. Another important measure is the development of genetic containment strategies, such as creating pigs that are sterile or have limited reproductive capabilities, to prevent them from breeding if they do escape (Hryhorowicz et al., 2017).

8.3 Long-term sustainability considerations

The long-term sustainability of using genetically modified pigs for organ transplants depends on several factors. One key consideration is the ethical and public acceptance of this technology. Public concerns about the safety and morality of genetic modifications must be addressed through transparent communication and robust regulatory frameworks (Xi et al., 2023). Additionally, the continuous monitoring of ecological impacts and the effectiveness of mitigation measures is crucial. This includes long-term studies to assess the health and behavior of genetically modified pigs and their interactions with the environment (Cooper et al., 2016). Meanwhile, advancements in genetic engineering techniques should focus on minimizing any potential negative impacts on both the pigs and the ecosystems they may interact with, ensuring that the benefits of xenotransplantation can be realized without compromising environmental integrity (Kemter et al., 2020; Lei et al., 2022).

9 Ethical Case Studies and Precedents

9.1 Review of notable case studies in xenotransplantation ethics

The field of xenotransplantation, particularly involving genetically modified pigs, has seen significant advancements and ethical considerations over the past decade. Notable case studies include the transplantation of genetically modified pig kidneys into brain-dead human recipients, which demonstrated the potential for these organs to function without hyperacute rejection (Figure 2) (Montgomery et al., 2022). Another landmark case involved the first life-supporting pig-to-human heart transplantation in a terminally ill patient, which highlighted both the potential and the ethical complexities of such procedures (Anwar et al., 2022).

Figure 2 Photomicrographs of Biopsy Samples from Pig Kidneys Explanted from the Recipients 54 Hours after Reperfusion (Adopted from Montgomery et al., 2022) Image caption: Immunofluorescence microscopy did not reveal C4d deposition in the xenograft for Recipient 1, but focal C4d deposition was present at 54 hours in the xenograft for Recipient 2. Arteritis and interstitial hemorrhage were not present in either case. Electron microscopy revealed normal thickness of the glomerular basement membrane and uneffaced podocyte foot processes in the two xenografts (Adopted from Montgomery et al., 2022)

9.2 Lessons learned from historical and contemporary examples

From these case studies, several key lessons have emerged. For instance, the importance of genetic modifications in donor pigs to prevent immune rejection has been underscored. The deletion of the alpha-1,3-galactosyltransferase gene in pigs has been crucial in preventing hyperacute rejection in kidney transplants (Wolf et al., 2019). Additionally, the compassionate use of a genetically modified pig heart in a terminally ill patient demonstrated the potential for xenotransplantation to save lives, albeit with significant ethical considerations regarding patient consent and the experimental nature of the procedure.

9.3 Application of ethical principles to real-world scenarios

Applying ethical principles such as beneficence, non-maleficence, autonomy, and justice to these real-world scenarios is critical. The principle of beneficence is evident in the potential life-saving benefits of xenotransplantation, as seen in the successful functioning of pig kidneys and hearts in human recipients (Reichart et al., 2022). Non-maleficence is addressed through rigorous preclinical testing and genetic modifications to minimize the risk of rejection and other complications (Lu et al., 2020; Lei et al., 2022). Autonomy is respected by ensuring informed consent from patients or their families, as demonstrated in the case of brain-dead recipients and the terminally ill patient. Finally, justice is considered by addressing the organ shortage crisis and providing alternative solutions to patients in need (Sykes and Sachs, 2019; Xi et al., 2023).

10 Future Directions and Recommendations

10.1 Emerging trends and ethical challenges in xenotransplantation

The field of xenotransplantation has seen significant advancements, particularly with the use of genetically modified pigs to address the shortage of human organs for transplantation. Recent studies have demonstrated the potential of these genetically engineered pigs to overcome immunological barriers and physiological incompatibilities, making clinical xenotransplantation more viable (Ariyoshi et al., 2020; Cooper et al., 2020; Anwar et al., 2022; Xi et al., 2023). However, these advancements bring forth new ethical challenges. For instance, the genetic modification of pigs raises concerns about animal welfare, as these animals often undergo invasive procedures and are kept in isolation, which can severely impact their well-being (Bobier et al., 2022). Additionally, the risk of zoonotic diseases and the need for lifelong infectious disease surveillance for recipients pose significant public health concerns (Entwistle et al., 2022). The ethical tensions between individual consent and public health threats, as well as issues of justice and equity in organ transplantation, further complicate the ethical landscape of xenotransplantation.

10.2 Recommendations for ethical research and practice

To address these ethical challenges, several recommendations can be made for future research and practice in xenotransplantation. First, there should be stringent ethical guidelines and regulatory frameworks to ensure the welfare of genetically modified pigs, including appropriate housing and care practices that minimize suffering. Second, robust protocols for infectious disease surveillance and management must be established to protect both recipients and the public (Johnson, 2022). Third, informed consent processes should be enhanced to ensure that recipients fully understand the potential risks and benefits, including the long-term implications of receiving a xenograft. Additionally, efforts should be made to address issues of justice and equity, ensuring that access to xenotransplantation is fair and does not exacerbate existing healthcare disparities.

10.3 Call for interdisciplinary collaboration and ongoing ethical review

The complexity of ethical issues in xenotransplantation necessitates interdisciplinary collaboration among scientists, ethicists, clinicians, and policymakers. Such collaboration can help develop comprehensive ethical guidelines and address the multifaceted challenges of xenotransplantation. Ongoing ethical review is also crucial, as the field is rapidly evolving, and new ethical dilemmas are likely to emerge. Continuous monitoring and assessment of ethical practices can ensure that the benefits of xenotransplantation are maximized while minimizing potential harms (Johnson, 2022). By fostering interdisciplinary collaboration and maintaining rigorous ethical oversight, the field of xenotransplantation can advance in a manner that is both scientifically sound and ethically responsible.

11 Concluding Remarks

The ethical landscape surrounding the use of genetically modified pigs for organ transplants is complex and multifaceted. This study has highlighted several key ethical considerations, including the welfare of genetically modified pigs, the potential risks to human recipients, and the broader societal and ecological impacts of xenotransplantation. The genetic modification of pigs raises significant concerns about animal welfare, particularly in terms of their living conditions and the invasive procedures they undergo. Additionally, the risks associated with zoonotic diseases, the need for lifelong monitoring of recipients, and the potential for unforeseen long-term health effects present substantial ethical dilemmas. The balance between the potential benefits of alleviating the organ shortage crisis and the ethical responsibilities to both human recipients and donor animals remains a critical area of concern.

For policymakers, the ethical considerations highlighted in this study underscore the importance of establishing robust regulatory frameworks that prioritize both patient safety and animal welfare. Researchers must continue to explore ways to minimize the risks associated with xenotransplantation, including developing less invasive genetic modification techniques and improving disease surveillance protocols. Clinicians, on the other hand, must ensure that informed consent processes are thorough and that patients fully understand the potential risks and benefits of receiving organs from genetically modified pigs. The collaborative efforts of these stakeholders are essential to advancing xenotransplantation in a manner that is both scientifically sound and ethically responsible.

As the field of xenotransplantation progresses, there is an urgent need for a concerted effort to ensure the responsible and ethical use of genetically modified pigs. This includes implementing stringent welfare standards for donor animals, enhancing transparency in patient consent, and fostering public understanding of the science and ethics behind xenotransplantation. It is imperative that all stakeholders, from policymakers to researchers and clinicians, work together to create a framework that maximizes the life-saving potential of this technology while safeguarding the welfare of both human and animal participants. By doing so, we can move toward a future where the benefits of xenotransplantation are realized without compromising ethical standards.

Acknowledgments

EcoEvo Publisher extends sincere thanks to two anonymous peer reviewers for their feedback on the manuscript.

Conflict of Interest Disclosure

The author affirms that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Anwar I., DeLaura I., Gao Q., Knechtle S., and Kwun J., 2022, Letter to the editor in response to: measuring success in pig to non‐human‐primate renal xenotransplantation: Systematic review and comparative outcomes analysis of 1051 life sustaining NHP renal allo-and xeno-transplants by Firl and Markmann, American Journal of Transplantation, 22.

https://doi.org/10.1111/ajt.17007

Ariyoshi Y., Takeuchi K., Pomposelli T., Ekanayake-Alper D., Shimizu A., Boyd L., Estime E., Ohta M., Asfour A., Arn J., Ayares D., Lorber M., Sykes M., Sachs D., and Yamada K., 2020, Antibody reactivity with new antigens revealed in multi‐transgenic triple knockout pigs may cause early loss of pig kidneys in baboons, Xenotransplantation, 28.

https://doi.org/10.1111/xen.12642

Bobier C., Rodger D., Hurst D., and Omelianchuk A., 2022, In defense of xenotransplantation research: Because of, not in spite of, animal welfare concerns, Xenotransplantation, 30.

https://doi.org/10.1111/xen.12791

Bovenkerk B., 2020, Ethical perspectives on modifying animals: beyond welfare arguments, Animal Frontiers: The Review Magazine of Animal Agriculture, 10: 45-50.

https://doi.org/10.1093/af/vfz055

Cengiz N., and Wareham C.S., 2019, Pig-to-human xenotransplantation: overcoming ethical obstacles, South African Journal of Bioethics and Law, 12(2): 66-70. 

https://doi.org/10.7196/SAJBL.2019.v12i2.00677

Cooper D., Ekser B., Ramsoondar J., Phelps C., and Ayares D., 2016, The role of genetically engineered pigs in xenotransplantation research, The Journal of Pathology, 238.

https://doi.org/10.1002/path.4635

Cooper D., Hara H., Iwase H., Yamamoto T., Li Q., Ezzelarab M., Federzoni E., Dandro A., and Ayares D., 2019, Justification of specific genetic modifications in pigs for clinical organ xenotransplantation, Xenotransplantation, 26.

https://doi.org/10.1111/xen.12516

Cooper D., Hara H., Iwase H., Yamamoto T., Wang Z., Jagdale A., Bikhet M., Nguyen H., Foote J., Paris W., Ayares D., Kumar V., Anderson D., Locke J., and Eckhoff D., 2020, Pig kidney xenotransplantation: progress toward clinical trials, Clinical Transplantation, 35.

https://doi.org/10.1111/ctr.14139

Deng J.C., Yang L., Wang Z.R., Ouyang H.S., Yu H., Yuan H.M., and Pang D.X., 2022, Advance of genetically modified pigs in xeno-transplantation, Frontiers in Cell and Developmental Biology, 10.

https://doi.org/10.3389/fcell.2022.1033197

Entwistle J.W., Sade R.M., and Drake D.H., 2022, Clinical xenotransplantation seems close: ethical issues persist, Artificial Organs, 46(6): 987-994.

https://doi.org/10.1111/aor.14255

George A., 2022, Ethics, virtues and xenotransplantation, Perfusion, 2676591221140767.

https://doi.org/10.1177/02676591221140767

George J., 2006, Xenotransplantation: an ethical dilemma, Current Opinion in Cardiology, 21: 138-141.

https://doi.org/10.1097/01.hco.0000203183.81534.f9

Hryhorowicz M., Zeyland J., Słomski R., and Lipinski D., 2017, Genetically modified pigs as organ donors for xenotransplantation, Molecular Biotechnology, 59: 435-444.

https://doi.org/10.1007/s12033-017-0024-9

Hurst D., Padilla L., Cooper D., and Paris W., 2021, Scientific and psychosocial ethical considerations for initial clinical trials of kidney xenotransplantation, Xenotransplantation, 29.

https://doi.org/10.1111/xen.12722

Hurst D., Padilla L., Walters W., Hunter J., Cooper D., Eckhoff D., Cleveland D., and Paris W., 2019, Paediatric xenotransplantation clinical trials and the right to withdraw, Journal of Medical Ethics, 46: 311-315.

https://doi.org/10.1136/medethics-2019-105668

Johnson L., 2022, Existing ethical tensions in xenotransplantation, Cambridge Quarterly of Healthcare Ethics, 31: 355-367.

https://doi.org/10.1017/S0963180121001055

Kemter E., Schnieke A., Fischer K., Cowan P., and Wolf E., 2020, Xeno-organ donor pigs with multiple genetic modifications - the more the better?, Current opinion in genetics & development, 64: 60-65.

https://doi.org/10.1016/j.gde.2020.05.034

Lei T., Chen L., Wang K., Du S., Gonelle-Gispert C., Wang Y., and Buhler L., 2022, Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: the first clinical steps, Frontiers in Immunology, 13.

https://doi.org/10.3389/fimmu.2022.1031185

Lu T., Yang B., Wang R., and Qin C., 2020, Xenotransplantation: current status in preclinical research, Frontiers in Immunology, 10.

https://doi.org/10.3389/fimmu.2019.03060

Montgomery R., Stern J., Lonze B., Tatapudi V., Mangiola M., Wu M., Weldon E., Lawson N., Deterville C., Dieter R., Sullivan B., Boulton G., Parent B., Piper G., Sommer P., Cawthon S., Duggan E., Ayares D., Dandro A., Fazio-Kroll A., Kokkinaki M., Burdorf L., Lorber M., Boeke J., Pass H., Keating B., Griesemer A., Ali N., Mehta S., and Stewart Z., 2022, Results of two cases of pig-to-human kidney xenotransplantation, The New England Journal of Medicine, 386(20): 1889-1898.

https://doi.org/10.1056/NEJMoa2120238

Padilla L., Hurst D., Maxwell K., Gawlowicz K., Paris W., Cleveland D., and Cooper D., 2022, Informed consent for potential recipients of pig kidney xenotransplantation in the United States, Transplantation.

https://doi.org/10.1097/TP.0000000000004144

Reichart B., Cooper D., Längin M., Tönjes R., Pierson R., and Wolf E., 2022, Cardiac xenotransplantation: from concept to clinic, Cardiovascular Research, 118: 3499-3516.

https://doi.org/10.1093/cvr/cvac180

Rémy C., 2009, The animal issue in xenotransplantation: controversies in France and the United States, History and Philosophy of the Life Sciences, 31(3-4): 405-428.

Rollin B., 2020, Ethical and societal issues occasioned by xenotransplantation, Animals: An Open Access Journal from MDPI, 10.

https://doi.org/10.3390/ani10091695

Schuurman H., and Hoogendoorn K., 2020, Solid organ xenotransplantation at the interface between research and clinical development: regulatory aspects, Xenotransplantation, 27.

https://doi.org/10.1111/xen.12608

Sykes M., and Sachs D., 2019, Transplanting organs from pigs to humans, Science Immunology, 4.

https://doi.org/10.1126/sciimmunol.aau6298

Wolf E., Kemter E., Klymiuk N., and Reichart B., 2019, Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation, Animal Frontiers: The Review Magazine of Animal Agriculture, 9: 13-20.

https://doi.org/10.1093/af/vfz014

Xi J., Zheng W., Chen M., Zou Q., Tang C., and Zhou X., 2023, Genetically engineered pigs for xenotransplantation: hopes and challenges, Frontiers in Cell and Developmental Biology, 10.

https://doi.org/10.3389/fcell.2022.1093534