Xenotransplantation and the organ shortage: evaluating policy priorities

Abstract

Purpose of review

Xenotransplantation has emerged as a popular potential solution for increasing organ supply, but it comes with formidable public health risks and ethical harms. The purpose of this review is to evaluate xenotransplantation and other strategies for addressing the organ shortage, pointing toward the most promising policy priorities.

Recent findings

Advances in genetic engineering, paired with increasing financial support, have positioned xenotransplantation in its first ever clinical trials. Rejection remains a formidable challenge, and caution prevails as the full breadth of zoonotic infectious potential remains to be determined. Meanwhile, strategies have been implemented around the world to bolster allotransplant organ supply and practices and to better treat chronic diseases to reduce demand for organs.

Summary

With more support and broader global adoption, these alternative strategies can address the organ shortage more effectively, safely, and ethically than xenotransplantation and should be prioritized by policymakers.

INTRODUCTION

Today, organ transplantation is the most effective treatment for end-stage organ failure. But increases in chronic diseases and organ failure, plateaued donations, and weaknesses in organ procurement and preservation systems cause the demand for organs to outpace supply. This review discusses solutions to address these fail points that have been pursued to varying degrees of success around the world, such as government organ procurement and transplant systems, programs to build public awareness and trust, organ preservation technology, disease prevention and management improvements, and cross-species organ sourcing and transplantation, or xenotransplantation. Public and private financial support for xenotransplantation is discussed, along with regulatory oversight and recent clinical trial green lights. The purpose of this review is to situate xenotransplantation amongst other approaches to the organ shortage, highlighting areas with the most potential for reducing organ demand and increasing supply and pointing toward policies that could benefit from broader adoption and further bolstering. 

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THE GLOBAL ORGAN SHORTAGE

Since the creation of modern allotransplantation, countries worldwide have implemented various strategies to ensure well tolerated, equitable, and efficient organ procurement and distribution [1–3]. In the United States, for example, the Uniform Anatomical Gift Act of 1968 and the National Organ Transplant Act of 1984 established the legal and regulatory framework for organ donation, creating the foundation for a coordinated national system [2,4^▪▪,5].

Despite these advances, the most pressing challenge in transplantation is the persistent gap between organ demand and supply [1–3]. In the United States alone, tens of thousands of patients remain on waiting lists, and thousands die before receiving a transplant [2,6]. In Europe, as many as 30% of patients on waiting lists die each year without receiving a transplant [2]. This disparity arises from multiple factors. Globally, the surge in conditions such as diabetes, cardiovascular disease, and hypertension has led to higher rates of organ failure, amplifying the need for transplants [2,3,4^▪▪]. Yet this growing demand has not been met with a corresponding increase in supply. Stagnant donor rates – combined with the impact of these same chronic diseases and longer life expectancy – have further diminished the availability of high-quality organs from deceased donors [7]. Finally, although transplantation technologies have advanced significantly in recent decades, such as the development of perfusion techniques, the viability of organs after death remains limited. Once outside the body, organs can only maintain optimal quality for a short period, resulting in potential organ loss if suitable recipients are not identified and matched in time [8]. With the number of patients waiting for lifesaving organs continuing to rise worldwide, urgent action is needed by countries and healthcare systems to address the widening disparity between organ availability and demand.

XENOTRANSPLANTATION AS A POLICY SOLUTION TO THE ORGAN SHORTAGE

The increasing demand for organs, paired with advances in genetic engineering, has led to significant attention in xenotransplantation as a possible solution. There has been an interest in xenotransplantation since ancient times, although the practice of transplanting whole organs from animals into humans did not reach experimental clinics until the 1900 s [9,10^▪]. Organs were initially sourced from nonhuman primates, namely chimpanzees and baboons, but over time, pigs became the donors of choice due to various claimed ethical and biological advantages [9,10^▪]. Concerns over infectious risks, particularly after porcine endogenous retroviruses (PERVs) were shown to infect human cells, led to brief moratoriums on xenotransplantation in the USA, Australia, UK, and elsewhere in the 1990 s and 2000 s [10^▪]. To this day, international and national regulatory guidance on xenotransplantation includes the need for pathogen-free pig donors and infectious disease surveillance of donors and recipients, but regulatory entities may not be able to provide sufficient oversight beyond clinical trials [11–13]. Genetically modified source pigs have been created in an attempt to reduce the risk of PERV transmission, prevent organ growth and rejection, and protect from coagulation dysregulation, inflammation, and other damages [14]. Despite these interventions, rejection is still a formidable barrier and extensive immunosuppressive regimens are required; the full breadth of infectious risk is still unknown; and long-term xeno-organ survival and transplant success have yet to be demonstrated [15,16^▪].

Xenotransplantation research has benefited from public and private funds, including efforts like the US National Institutes of Health's Immunobiology of Xenotransplantation Cooperative Research Program and other government grants around the world [17–19]. In 2024, the global xenotransplantation market was valued at $16 billion, expecting to reach $31 billion by 2032 [20]. This growth reflects the ever-expanding genetic modifications in source pigs and the growing number of compassionate use cases and green lights for clinical trials, including two approvals from the US Food and Drug Administration to proceed with small clinical trials of xeno-kidney transplantation [21^▪,22]. United Therapeutics’ trial will begin with just six patients, expanding to up to 50 if safety and efficacy results are supportive; there will be a cautious 12-week waiting period between the first and second transplants; safety endpoints include zoonotic infections; and participants will be monitored for the rest of their lives [23].

At this stage, governments and companies seem to be primarily concerned with how to proceed rather than whether to proceed, failing to consider questions unanswerable by clinical trials, like what the environmental impact of a new form of industrialized pig farming would be or how the commodification of xeno-organs might exacerbate health disparities [24^▪]. Ethical principles related to public health risks and animal use suggest that alternative approaches should be exhausted before xenotransplantation pursuit [24^▪,25]. It is thus our view that support for xenotransplant research and development – in the absence of robust programs promoting more sensible and proven alternative strategies for reducing organ demand and increasing allograft supply – is a policy pitfall. Examples of such programs across the globe are expanded on below.

ALTERNATIVE STRATEGIES, SYSTEMS, AND INNOVATIONS FOR ADDRESSING THE ORGAN SHORTAGE

Establishing robust government-led systems to support organ transplantation has proven to be one of the most effective strategies for addressing organ shortages worldwide [2,3,4^▪▪]. Although many countries have developed frameworks to optimize transplantation, the number of procedures performed annually varies considerably. The US leads the world in total transplants performed, while countries across Africa report some of the lowest figures [4^▪▪]. Despite the US’ high transplant volume, Spain is widely recognized as the global leader in transplantation systems, with one of the highest rates of deceased donors (46.03 per million) and transplants (115.31 per million) [3,4^▪▪,26].

Spain's success can be attributed to multiple interventions, the most notable being its multitiered structure that integrates national, regional, and local governance under the Organización Nacional de Trasplantes (ONT) [3,4^▪▪,26]. ONT collaborates with regional offices across Spain's 17 autonomous communities to develop policies, assess standards, and set long-term strategies [4^▪▪]. Since ONT's establishment in 1989, the country's annual donation rate has more than tripled, rising from 14 to 46 per million [3]. Spain has also implemented policies and protocols that strengthen donor rates and streamline transplantation processes. One important measure is the reimbursement of costs associated with living organ donation, which helps reduce the financial burden on donors and encourages higher donation rates [26]. Additionally, Spain employs dedicated, specially trained transplant coordinators within hospitals who oversee donor evaluations, manage transport logistics, and coordinate with procurement teams to ensure a seamless donation process [3,26].

International collaborations, such as Eurotransplant and Scandiatransplant, have been key in contributing to higher rates of organ transplantation [3,4^▪▪]. These cooperative networks enable smaller countries to expand their donor and recipient pools, reducing organ wastage and shortening waiting times for patients. Currently, Eurotransplant coordinates transplantation activities across eight countries, while Scandiatransplant serves six.

The approach to organ donor registration, specifically “opt-in” versus “opt-out” systems, differs between countries but can impact donor rates [27,28]. In the United States, individuals must explicitly indicate their willingness to donate organs after death – an “opt-in” system – which operates under the assumption that people do not wish to be donors unless they state otherwise [5]. While opt-in systems were historically common, many countries have recently transitioned to “opt-out” systems, in which all citizens are presumed to consent to organ donation unless they have formally registered their refusal [5,27,28].

While governments can implement policies and systems to improve the efficiency of organ transplantation, public trust and education are essential for these measures to be effective [3,29,30]. For instance, in Germany, the absence of mandated specialized transplant coordinators, limited organ donation education, and past scandals have contributed to families often being unaware of the deceased patient's wishes and mistrust in donation systems, resulting in relatively low donation rates compared to neighboring European countries [3]. In contrast, Spain's high levels of public trust in its healthcare system, combined with widespread family discussions about donation preferences prior to death, have been major factors in its transplantation success.

Technological progress can complement policy efforts in addressing the global organ shortage. One notable development is ex-situ perfusion technology, which preserves organs outside the body for extended periods and helps reduce organ wastage by prolonging organ viability after donor death and enabling more thorough assessment and even repair of organs prior to transplantation [31,32^▪]. Another example is drone delivery, which has innovative applications across public health, including organ transportation [33].

In addition to implementing systems designed to expand the organ donation supply, many governments have introduced public health policies aimed at reducing the overall need for organ transplantation. High rates of smoking, obesity, alcohol consumption, and longer life expectancy all contribute to organ failure and, consequently, greater demand for transplants [26,34^▪▪]. The rising prevalence of chronic conditions such as hypertension, diabetes, and cardiovascular disease further compounds this demand [34^▪▪]. Public health initiatives targeting these behaviors and conditions – such as antismoking and alcohol reduction campaigns, as well as programs that promote healthy diets and physical activity – play a critical role in mitigating some of the root causes of organ failure. In the United States, for example, strategies to reduce smoking, the nation's leading cause of preventable death, have included workplace and public smoking bans, tobacco taxation, expanded access to cessation treatments, and large-scale media campaigns [35]. Collectively, these interventions have contributed to a more than 50% decline in smoking prevalence over the past five decades [35].

ONGOING CHALLENGES AND POLICY RECOMMENDATIONS

Collectively, the above policies, systems, and technological advances have made substantial progress in narrowing the gap between organ supply and demand, ultimately saving the lives of many patients without resorting to the yet unproven, risky approach that is xenotransplantation. Challenges remain and waitlists linger, though. Any single strategy – be it opt-out policies or public health interventions – is insufficient to significantly impact organ supply and demand; a holistic approach should thus be pursued and must further be mediated by robust social programs [28,34^▪▪]. Crosstalk between nations should be prioritized to share best practices and research into further means of fine-tuning allotransplantation and disease prevention and management should be expanded.

It is also important to consider the wide variation in cultural, social, and structural issues across regions, not only globally but also within individual countries [2,4^▪▪,30,36,37]. New systems and policies cannot be applied as a universal, “one-size-fits-all” model. For example, cultural and religious beliefs are among the most significant barriers to increasing organ donation rates in many Asian, African, and Latin American countries, a challenge far less pronounced in most European and North American contexts [4^▪▪,30,36,37]. Limited public education about organ donation often leaves families unaware of its importance or uncertain about the wishes of their deceased relatives [3,4^▪▪]. Mistrust of governing bodies further complicates the issue, as seen in Germany following transplantation scandals and in India due to the history of illegal organ trafficking [3,4^▪▪]. While Spain has one of the highest rates of deceased donors, its living kidney donor rate has been historically low and is now only slightly above the European average, partly due to a shifting cultural belief that living donation is not ethically justified or should be a last resort because of the risks posed to donors [26,38,39].

Beyond these cultural and trust-related barriers, disparities in funding and access also play a critical role in stagnant waitlists: in many countries, particularly across Africa, transplant services are limited or absent, and insufficient funding prevents the implementation of supportive measures such as donor reimbursement or subsidized healthcare costs [4^▪▪]. Taken together, these challenges underscore the need for recommendations, policies, and resources that are carefully tailored to the specific cultural, social, and structural realities of the populations they are intended to serve.

Below are some policy recommendations which are intended for broad, universal application but should be adapted to meet the specific needs and contexts of individual countries and regions:

• (1)Develop government systems to ensure efficient, well tolerated, transparent, and equitable allotransplantation: Establishing government-run programs with clear guidelines significantly enhances the efficiency of allotransplant systems. Successful initiatives worldwide include the use of trained and mandated transplant coordinators, national or international donor and recipient databases, and coordinated governance through national and regional transplant authorities.
• (2)Reduce stigma and increase public awareness of organ donation: Cultural and religious beliefs, as well as mistrust of government institutions, remain major barriers to increasing organ donation. Expanding education on the importance of organ transplantation and improving communication between healthcare professionals, patients, and families can help change perceptions and increase donation rates.
• (3)Reinvest funds for xenotransplantation programs into allotransplant technologies and strategies aimed at decreasing demand: Public funds slated for xenotransplantation research and programming should be shifted toward other, more promising initiatives. Investments in technologies to improve organ preservation, viability, and availability can further expand the organ supply for patients in need. Additionally, investment in medical research can lead to better prevention and treatment of diseases, delaying or preventing the need for transplants. Finally, public health measures that promote healthier lifestyles – such as reducing smoking, alcohol consumption, and obesity – can lower rates of organ failure and, in turn, reduce the demand for transplants. These interventions can range from educational programs and media campaigns to subsidized healthcare and support for healthy diet and exercise programs.

CONCLUSION

Solving the organ shortage is one of the great medical problems of our time. Driven by recent advances in genetic engineering and supported by public and private funds, there is a renewed focus on xenotransplantation to meet organ demand. Policymakers worldwide should reassess this priority given its many risks and harms and the availability of proven and more promising options, like multitiered government-run programs, specially trained hospital coordinators, innovative preservation and delivery modes, and biomedical advancements to decrease the demand for organs. Together, these and other strategies can narrow, if not close, the supply-demand gap for organs without imposing risks to patients and public health. Future research should conduct a thorough assessment of successful strategies to reduce organ waitlists around the world to present with policy implications as we have briefly done here.

Acknowledgements

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Financial support and sponsorship

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Conflicts of interest

J.K., J.B., and C.E.K. are employed by the Physicians Committee for Responsible Medicine, a 501(c)(3) nonprofit organization dedicated to saving and improving human and animal lives through plant-based diets and ethical and effective scientific research.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest