Introduction

Despite the 46,632 organ transplant surgeries performed in 2023, as of March 2024, there were 103,223 candidates for organ transplants in the U.S. The evident paucity of viable organs for transplantation leads to the death and removal of 17 people off the organ transplant list every day.¹ Though there were over 170 million registered organ donors as of 2022, only 0.3% of people die in a manner permitting organ procurement.² The numbers dwindle further as proxies and/or durable power of attorneys, unaware of the patients’ wishes, object to the procurement of the latter’s organs. Over the years, experts have proposed several ideas to increase organ availability, but many proved ineffective, some caused serious medical complications, and others brought about ethical concerns. Thus, interest and research into xenotransplantation has grown significantly since the 60s.

Among the various organs under study for xenotransplantation, the liver has become a particular area of focus due to the pressing need for life-saving liver transplants. 9,862 patients awaiting an organ transplant urgently needed a liver. Current research in hepatology has recently focused on examining xenotransplantation from pigs as a viable means to combat liver organ shortage and save patients suffering from chronic and/or irreversible liver failure, which accounts for more than 44,000 deaths annually in the U.S. and 2 million deaths globally.³ Although still in preliminary phases, current xenotransplantation efforts have focused on pigs as the organ xenograft donor because of similar physiological metabolism and immune system functioning to humans as well as ease of cloning and genetic engineering.⁴ Pigs also vary in size, with those weighing 70 to 90 kilograms—comparable to the average human weight—having organs that can be a good fit for human recipients. It takes about 6 months for a pig to grow and develop a transplantable organ.^4,5,6 Given the national average waiting time of 11 months for a life-saving liver transplant, and the fact that many patients die before receiving one, genetically modified pig livers could help sustain patients with liver failure until a human liver becomes available.⁷ Although early attempts at pig-to-human liver transplants resulted in complications such as thrombocytopenia (low blood platelet count) and graft rejection, which led to abnormal blood clotting in recipients, advances in biotechnology and genetic engineering have recently helped scientists overcome these challenges. These developments have made it possible to bypass the pig's coagulation system and mitigate immune responses that would normally trigger rapid rejection of the transplanted organ.^8,9

The purpose of this article is threefold: first, providing an overview of genetically modified pig liver transplants from historical, cost/benefit, and medical perspectives; second, examining the procedure using basic bioethics principles; and third, offering recommendations on the next steps towards liver xenotransplantation becoming a globally recognized solution to shortages in livers available for patients with severe liver damage and/or failure.

Xenotransplantation: An Overview

The recently expanding field of xenotransplantation is in the early stages of providing a means of revolutionizing organ transplantation. Xenotransplantation can be defined as “any procedure that involves the transplantation, implantation or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs.”¹⁰ “Xenotransplantation,” therefore, is an umbrella term that encompasses a broad range of human-nonhuman transplants including the use of genetically modified pig livers. While humans are genetically closer to monkeys and baboons, ethical and ecological restrictions limit their use, making pigs the primary animal source for organ transplantation.¹¹

History

While xenotransplantation has become an increasingly popular area of interest in medicine, its origin dates back to the 19th century, when skin transplants from animals such as sheep, rabbits, cats, and dogs were attempted.¹² The first solid organ xenotransplantation was performed in 1906 by French surgeon Mathieu Jaboulay, who performed a heterotopic kidney xenotransplant from both sheep and goats.¹³ However, both of these transplants failed due to vascular thrombosis from hyperacute rejection of each organ graft. Similar issues plagued other early attempts, such as those of Dr. Ernst Unger, a German surgeon, who transplanted a Macaque monkey kidney that survived for 32 hours before resulting in the death of the transplanted individual.¹⁴

With progressions in immunosuppression, organ transplants became more feasible in the late-half of the 20th century. In 1964, Dr. Keith Reemtsma transplanted chimpanzee kidneys into 13 patients, and despite most failing over 4-8 weeks, one patient eventually survived for 9 months without experiencing any rejection of the kidney. That same year, Dr. Hardy of the University of Mississippi implanted a chimpanzee heart into a human male, which lasted for 90 minutes before failing due to inadequate circulation. In 1969, Dr. Tom Starzl performed the first liver xenotransplantation with a chimpanzee liver that lasted for 9 days in the transplant recipient. By the 1990s, with advancements in immunosuppressive drugs like Tacrolimus, Starzl extended survival times in liver xenotransplants using baboon livers, with one patient living nearly 70 days.¹²

Thanks to advancements in genome editing, researchers and surgeons are pushing for more clinical trials in xenotransplantation, particularly on brain-dead patients with family consent. In late 2023 and early 2024, the world witnessed significant milestones in porcine liver transplants.

In December of 2023, a research team at the Perelman School of Medicine at the University of Pennsylvania completed the world’s first successful external blood perfusion of a porcine liver. The study, part of the PERFUSE-2 project, explored the possibility of external liver perfusion as a liver dialysis-like machine. The study was done in collaboration with eGenesis (a biotechnology company pioneering genome editing for the creation of human-compatible animal organs), OrganOx, Inc. (a pioneer in normothermic machine perfusion), and the Gift of Life Donor Program (the organ procurement organization in Pennsylvania, New Jersey, and Delaware). eGenesis developed the genetically modified porcine liver while OrganOx supplied the extracorporeal liver cross-circulation (ELC) device needed to circulate the patient’s blood through the porcine liver. After obtaining informed consent from the family of a brain-dead patient, the research team connected the porcine liver to a brain-dead patient’s bloodstream while leaving the original liver intact. After 72 hours, the pig liver showed no signs of rejection or damage, and the patient remained stable. This success has prompted Penn Medicine to explore the potential of using this technique in patients with recoverable liver injuries, similar to ECMO machines used for heart and lung support.^15,16

In March of 2024, the transplant team at Xijing Hospital of the Air Force Medical University in Xi’an conducted the world’s first porcine liver transplant for a brain-dead person. The genetically modified liver, developed by Clonorgan Biotechnology, underwent six genetic modifications to reduce immune rejection and was transplanted into a 50-year-old man. One of the lead-surgeons on the transplant team reported no signs of immediate rejection, and the transplant team confirmed the liver was functioning, secreting about 30 mL of bile a day.¹⁷ Two months later, surgeons at the First Affiliated Hospital of Anhui Medical University in east China reported the world’s first successful auxiliary transplantation of a porcine liver into a living recipient. A 71-year-old man with a large liver tumor underwent surgery where his right liver lobe was removed. A genetically modified pig liver, designed to complement the remaining left lobe, was successfully transplanted at a 45-degree angle. This liver, created by Yunnan Agricultural University, had ten genetic modifications to prevent rejection. The operation marked a major milestone in the field of xenotransplantation surgery and research.^18,19

Benefits and Concerns

Benefits

In regard to the advantages of xenotransplantation, the biggest immediate benefit would be to practically eradicate organ shortages, with the ability to offer transplantation to all who need it. Aside from anatomical similarity to human organs, pigs are specifically easy to breed and have large litters making them ideal for transplantation. Pigs have also been found to be suitable for genetic engineering which allows for tighter control on reducing pig organ rejection and helps address the immune barriers to xenotransplantation. Genetically altered pigs are able to evade the human immune system from recognizing the foreign organ because the pigs are altered to have human DNA to produce human specific proteins.²⁰

The primary advantage of xenotransplantation is its potential to virtually eliminate organ shortages by making transplants available to everyone in need. Pigs are particularly suited for this purpose due to their anatomical similarity to humans, ease of breeding, and large litters. They can also be genetically engineered to reduce organ rejection by incorporating human DNA to produce human-specific proteins, helping to overcome immune system barriers. Additionally, using animal organs would lessen reliance on human donors, which is especially beneficial in cultures where using organs from deceased humans is unacceptable. Furthermore, using transgenic pig organs holds potential to reduce human trafficking for organ harvesting, an illegal industry generating an estimated $1.5 billion annually from 12,000 transplants.²¹

Xenotransplantation would also allow for the scheduling of transplant procedures, giving patients more time to prepare, as opposed to the often sudden and urgent nature of human organ transplants. Pre-scheduled procedures would enable pretreatment with immunosuppressive drugs, lowering the risk of organ rejection.

From a financial standpoint, porcine organ transplants could drastically reduce the costs associated with the existing transplant process, eliminating the need for the current organizations that facilitate the acquisition and distribution of human organs. With the success of pig organs, demand for life-prolonging treatment—such as chronic dialysis for patients with renal failure—would decrease. Additionally, the substantial costs that are needed to maintain patients with end stage lung, kidney, and liver disease, can be drastically reduced as access to pig organs becomes more immediate and widespread.²²

Concerns

Despite the benefits of xenotransplantation, there are also some significant concerns. One major issue is rejection of the transplanted organ, especially hyperacute rejection, which occurs when the recipient’s antibodies recognize the transplanted organ as foreign and attack it.^23,24 Hyperacute rejection requires immediate removal of the organ to prevent irreversible organ failure. In pig kidney xenotransplantations, survival has generally been limited to less than 100 days, even with recent advancements in immunosuppression and gene editing. High levels of anti-pig antibodies and white blood cells called CD4 T-cells further reduce the survival time of xenotransplanted organs.²⁵

Along with rejection, xenotransplantation poses a risk of infection to transplant recipients. Pigs carry viruses known as porcine endogenous retroviruses (PERVs) that pose significant risk to human sources.²³ One of the most well-known PERVs, the H1N1 virus, caused a pandemic of swine flu in 2009, leading to an estimated 284,400 human deaths that year.²⁶ As with traditional organ transplants, xenotransplants require rigorous microbial surveillance to prevent infection by bacteria, viruses, parasites, and fungi.²⁷

There are also ethical concerns regarding animal welfare. While the killing of animals itself for organs is controversial, a bigger issue is the living conditions of donor animals. Pigs used for xenotransplantation must be kept in sterile laboratory conditions, which are detrimental for their biological and psychological well-being.²³ Donor pigs endure a lifelong process of invasive procedures and monitoring before being euthanized for organ harvesting. Furthermore, animal welfare regulations are extremely inconsistent. In the United States, standards vary between institutions and are influenced by funding sources. When projects involve international collaboration and private and public funding, this can complicate matters even further, as it becomes unclear which animal welfare regulations apply. Given past issues with animal welfare violations in xenotransplant research, some might argue that researchers have an incentive to produce pigs for xenotransplantation in the U.S. to avoid stricter regulations in other countries.²⁸ This concern was highlighted in 2000 when the Swiss drug company Novartis moved its xenotransplantation subsidiary from the U.K. to the U.S., allegedly to bypass tougher welfare standards.²⁹

Medical Analysis

Research indicates that pig organs bear striking similarities to human organs, rendering them viable for xenotransplantation. This medical analysis section will comprehensively explore the pre-transplantation, transplantation, and post-transplantation phases involved in genetically modified pig liver transplants. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable.³⁰

Pretransplant phase

The pretransplant phase encompasses identifying the optimal donor match for the patient and genetically modifying the pig to achieve compatibility. Given the scarcity of human organ donors, this has spurred exploration into xenotransplantation, particularly using genetically modified pig livers. Once a suitable pig donor liver is identified, the initial step involves genetically modifying the liver to mitigate immediate immune responses and reduce potential complications.³¹

Miniature pigs are considered ideal to better match the size of human organs. Pigs with the universal blood group O are selected. Also, all pigs have endogenous retroviruses incorporated in their DNA. There are 3 types: PERV A, PERV B, and PERV C. All pigs have PERV A and PERV B in different amounts, but not all pigs have PERV C.³⁰ No transmission of PERVs has been reported in the recent clinical trial involving xenotransplantation.³² Studies done in NPH in xenotransplantation have suggested that the production of α1,3-galactosyltransferase gene-knockout (GTKO) donor pigs is a major milestone of the field. The gene for α1,3- galactosyltransferase enables this enzyme to add galactose-α1,3-galactose (Gal) oligosaccharides to various underlying glycoproteins and glycolipids in the pig.³³ Gal is the major target for human and nonhuman primate anti-pig antibodies,³⁴ and its deletion from pigs has greatly reduced the incidence of hyperacute rejection of pig grafts in nonhuman primates.³⁵ There is data suggesting the addition of human complement regulatory proteins, such as CD55 (decay-accelerating factor), to donor pigs may decrease post-transplant complications.

After obtaining the genetically modified pig liver, the recipient undergoes preparation, which includes preoperative assessments such as blood typing, cross-matching, and evaluation of any existing medical conditions. In some cases, immunosuppressive therapy may be initiated prior to the surgery.

Transplant Phase

The surgical process of pig liver transplantation closely resembles that of human liver transplantation, consisting of several crucial stages. Firstly, the donor liver harvesting involves preparing the genetically modified pig under general anesthesia and using standard surgical methods to remove the liver. The organ is then preserved in a cold storage solution to maintain its functionality. Next, the recipient's diseased liver is removed, and the pig liver is transplanted. This procedure includes making vascular anastomoses to connect the donor liver's blood vessels with those of the recipient. Additionally, biliary reconstruction is performed to ensure proper drainage of bile.³⁰

Following successful transplantation, close monitoring of the liver includes observing changes in its color, bile production, signs of hyperacute rejection, platelet aggregation, bleeding tendencies, infection, and any delayed immune responses.

Post-transplant phase

After the transplant, the recipient undergoes close monitoring with daily assessments of liver enzymes, coagulation parameters (including prothrombin time, D-dimer, fibrinogen, international normalized ratio, and partial thromboplastin time), bile drainage, albumin and total protein levels, and liver biopsy if required. The xenotransplant, which was done at Xijing Hospital of the Air Force Medical University in Xi’an, China, reported that, after the transplant, the pig liver’s color remained normal, bile production was around 30 ml/day, and there was an absence of evidence of rejection on biopsy.³¹

Due to the recognition of the pig liver as foreign tissue by the human immune system, the patient requires rigorous immunosuppressive therapy to deter rejection. This treatment entails a meticulously controlled regimen of medications aimed at suppressing immune responses. Immunotherapy is initiated to preempt immune reactions and rejection. Various combinations of induction immunosuppressive medications were employed to achieve this goal, with the most frequently used being anti-thymocyte globulin, azathioprine (AZA), bone marrow (BM), CD154mAb (a monoclonal antibody for a protein member of the TNF superfamily which is expressed on activated T cells), cobra venom factor, mycophenolate mofetil, cyclophosphamide, corticosteroids, tacrolimus, and rituximab.³⁶

Because of immunosuppression, patients are at risk for developing infection. Monitoring for signs of infection and taking preventive measures are essential during the post-transplant period. It is important to provide education to the patient and their caregiver on managing medications, recognizing signs of complications, and maintaining a healthy lifestyle post-transplant. Coping with the emotional and psychological aspects of a transplant can also be challenging. Research and clinical trials on xenotransplantation, including pig-to-human liver transplants, are ongoing to improve outcomes and address challenges such as rejection and infection risks.

Safety/Efficacy:

Hyperacute rejection (HAR) is the first barrier faced in any organ transplant, especially in xenotransplants. It occurs within minutes to hours when natural (preformed) antibodies in the recipient recognize and bind antigens expressed on the pig vascular endothelium, triggering the complement cascade. HAR is histologically observed as diffuse interstitial hemorrhage, edema, and thrombosis of graft’s small vessels. It is also associated with a very high frequency of mortality. The generation of GTKO pigs has largely overcome the barrier of HAR and shifted the primary concern to a delayed form of antibody-mediated rejection—termed acute humoral xenograft rejection (AHXR, also known as delayed xenograft rejection or acute vascular rejection)—in which the injury develops within days to weeks.³⁷ Prevention of HAR and early acute rejection is a key safety consideration, and recent data from xenotransplant trials in China supports this.³¹

The second current safety problem is platelet activation, aggregation and/or phagocytosis, which can cause immediate and severe thrombocytopenia and hemorrhage. There is evidence of platelet phagocytosis by pig liver sinusoidal endothelial cells, hepatocytes and Kupffer cells. Platelets aggregate, bind to white blood cells in the blood, become sequestered in the liver xenograft, and are removed from circulation in the native lungs. There is evidence that initial tissue factor expression on platelets and peripheral blood mononuclear cells cause platelet aggregation without the need for liver sinusoidal endothelial cells activation.

GTKO pigs have brought liver xenotransplantation a step closer to the clinic, by preventing HAR and early AHXR, and enabling normal or near-normal liver function and coagulation in recipient nonhuman primates after xenotransplantation. However, coagulation dysregulation results in the development of thrombotic microangiopathy in the graft. After the xenotransplantation, due to localized inflammation and endothelial cell injury, activation of tissue factors leads to activation of extrinsic coagulation pathway. Features of thrombotic microangiopathy include fibrin deposition and platelet aggregation, resulting in thrombosis within the vessels of the graft and eventual ischemic injury. Systemic consumptive coagulation can cause death. To address this, further genetic modifications may be well required to avoid platelet activation and phagocytosis. These may include expression of thromboregulatory genes (e.g. CD39, thrombomodulin, endothelial protein C receptor), knockdown of specific proaggregatory elements (e.g., asialoglycoprotein receptor-1, CD18), or expression of a specific protein (e.g., human signal regulatory protein-α).³⁶ If immediate platelet activation and severe thrombocytopenia can be prevented, a clinical trial on genetically engineered pig liver xenotransplantation as a ‘bridge’ to allotransplantation in patients with acute liver failure may be justified.

A third barrier is delayed xenograft rejection, which is similar to cellular rejection seen in allotransplants, but is much stronger and requires additional immunosuppressive agents, some of which are not approved by the US Food and Drug Administration (FDA) for human use. Manipulation of the swine leukocyte antigen (SLA) class I and SLA class II may be beneficial, but most researchers believe this will come later, after the initial success of pig-to-human xenotransplantation. Other gene manipulations, such as adding human CD47 and HLAE, can also help improve outcomes by preventing innate immune system responses. Specifically in livers, massive thrombocytopenia can be caused by internalization of platelets on liver sinusoidal endothelial cells. This can be minimized by knocking out, or erasing, ASGR1.³²

The fourth, final, and most important safety concern alongside HAR is prevention of zoonotic virus transmission upon liver xenotransplantation. Transmission of porcine endogenous retroviruses (PERV) has been researched extensively in the transplantation of pig tissues into NPH and humans. Although genetic modifications are done to prevent virus transmission and no PERV transmission has been reported in recent clinical trials, the risk during liver xenotransplantation into humans remains unclear. To mitigate this risk, PERV-free pigs are being developed for use in xenotransplants.³⁰

Liver xenotransplantation presents unique challenges due to the complexity and critical functions of the liver, making it more difficult than heart or kidney transplants. The liver is responsible for hundreds of vital processes, including metabolism, detoxification, and blood clotting, which means any failure can have widespread consequences. Current research in nonhuman primates has shown limited survival rates after liver xenotransplants, highlighting the need for further advancements. As a result, pig-to-human liver transplants remain in the early stages of development comp the early stages of development comp strategies could pave the way for future success.

Cultural Considerations

Xenotransplantation raises complex ethical questions that vary across different cultural perspectives, highlighting the need for a nuanced approach to the ethics of xenotransplantation, considering religious beliefs and values. Many cultures, regardless of religion, are increasingly sensitive to animal rights and welfare. Ethical objections lie in animal rights advocates seeing the genetic modification, breeding, and harvesting of pig organs as exploitative and inhumane. Many cultures also have deep-rooted beliefs about the distinction between humans and animals, and the idea of transplanting animal organs into humans can challenge this boundary. Once study found a deep, cross-cultural repugnance toward violating species boundaries. This reaction reflects a broader societal discomfort with blurring the natural distinctions between humans and animals, often expressed through the 'yuck' response, a visceral reaction to perceived contamination or transgression.³⁸

To further understand the ethics of xenotransplantation (and specifically porcine xenotransplantation), we must explore how specific religious traditions approach this issue. We will cover Hinduism, Buddhism, Christianity, Judaism, and Islam.

Hinduism

Devout Hindus believe that the body must remain whole to pass into the next life, and therefore generally do not believe in transplantation. Furthermore, there are broader principles of ahimsa (non-violence) and respect for all life that could influence opinions on using animals for medical purposes. However, religious law does not prohibit Hindus from donating their organs or accepting an organ, both of which are an individual’s decision. There is nothing in the Hindu religion indicating that parts of animals cannot be used to alleviate the suffering of humans, with the exception of the cow, which is held as sacred. Therefore, attitudes may vary depending on individual beliefs and the urgency of the medical need.³⁹

Buddhism

Buddhism also shares this principle of ahimsa, as using animals for human benefit, especially in ways that involve killing or harming them, may conflict with these values. However, many Buddhists also recognize the importance of reducing human suffering, which may lead to acceptance in some cases. Ultimately, there is no written resolution on this issue and Buddhists believe this is a matter that should be left to an individual’s conscience.³⁹

Christianity

Christianity (similar to the other monotheistic religions), emphasizes the special place man holds in the hierarchy of Creation.⁴⁰ While humans have the power to use other creatures in Creation to heal, the ‘‘creative responsibility in making reasonable use of the power that God has given to him’’ is essential.³⁹ The Christian tradition supports the use of animals for human well-being, but done in such a way to avoid abuse and exploitation. This is particularly pertinent when considering the suffering animals may endure during rearing and preparing them for organ transplantation. Another ethical consideration of Christians is the number of animals needed to meet patient demand. A potential solution could involve identifying a subset of patients who would benefit most from xenotransplantation, while recommending alternative treatments to others.⁴⁰

Judaism

The issue of XTx from a Jewish bioethical perspective is a matter of halakhah, Jewish law. Jews consider pigs to be unclean (treif), and are forbidden to raise pigs or eat their meat. However, while Judaism prohibits the consumption of pork, it does not forbid deriving benefit from pork. Some interpretations of religious law allow for exceptions in life-saving medical cases, the use of pig organs for transplantation could still be contentious. The Torah states it is a religious obligation of a physician to heal. In fact, this principle of pikuach nefesh (saving a life) overrides most other prohibitions in Judaism, and many Jewish authorities may permit xenotransplantation in life-saving situations.⁴⁰ In fact, Dr. Moshe Freedman, a senior London rabbi on the UK Health Department's Moral and Ethical Advisory Group says receiving a pig heart is "not in any way a violation of the Jewish dietary laws. Since the primary concern in Jewish law is the preservation of human life, a Jewish patient would be obligated to accept a transplant from an animal if this offered the greatest chance of survival and the best quality of life in the future."⁴¹

Islam

Similar to Judaism, Islam considers pigs to be unclean (haram), pork consumption is strictly prohibited, and to a majority of scholars, pigs cannot be used for medical purposes. In the context of xenotransplantation then, some Muslim experts limit their approval to cases involving non-porcine animals. Some scholars, however, argue for permissibility based on the concept of ḍarūrah (dire necessity), which allows for the suspension of a normative prohibition in situations where life is threatened, no other alternatives exist, and the proposed solution does not cause greater harm than the benefit provided. Certain Muslims permit the use of porcine products under ḍarūrah, or when the pig undergoes istiḥala (essential transformation), meaning it is no longer considered a pig but a completely new substance.⁴⁰ Egypt's Dar al-Ifta, the country's central authority for issuing religious rulings, has said in a fatwa that pig heart valves are allowed if “there is fear for the patient's life, the loss of one of his organs, exacerbation or continuation of the disease or an overwhelming deterioration of the body.”⁴¹ It is important to note, though, that this viewpoint has encountered opposition from more traditionalist Muslim religious scholars, and some scholars predict that it is unlikely the wider Muslim community will eagerly accept using pig organs for transplantation, even if someone’s life is at stake.⁴²

Ethical Analysis

The issue of xenotransplantation has raised serious interdisciplinary concerns. Many have called for a continued public debate on the issue of xenotransplantation, especially genetically modified pig livers for human transplants, that would examine all aspects of it, including the crucial ethical and moral implications. These issues include the safety of the technology, animal welfare issues and the claim by some that genetic engineering is a technology that should not be advanced by humans. However, some have warned that the agenda of the debate, especially the moral debate, should not be wholly framed within the aspirations of the practitioners. All parties need to be consulted—clinicians, recipients, and society as a whole. The surgeons involved are still talking in terms of how we should proceed rather than should we proceed. If this is going to be an open debate with all parties participating, then all options must be placed on the table, including the option that we should not proceed with xenotransplantations and in particular, genetically modified pig livers in humans. To determine if this procedure is ethical, the principles of respect for persons, beneficence, nonmaleficence and justice will be applied to this procedure and its consequences.

Respect for persons

Respect for persons refers to the right of a person to exercise self-determination and to be treated with dignity and respect. Proponents argue that genetically modified pig kidneys have the potential to save hundreds of lives. We know that currently 9,862 patients are awaiting a liver transplant and more than 44,000 die annually and 2 million die globally.³ Experimental transplants at the University of Pennsylvania Hospital and Xijing Hospital in Xi’an, China suggest that major barriers to human xenotransplantation have been surmounted and identify where new knowledge is needed to optimize xenotransplantation outcomes in humans.⁴³ Opponents argue that there is not enough information available for recipients to give informed consent. Safety concerns exist in regards to porcine endogenous retroviruses (PERV A, PERV B, and PERV C) carried by pigs that could transfer to the recipient and be not only detrimental to the recipient but possibly become a public health crisis. Furthermore, immunosuppressants have serious side effects and genetic modifications pose serious medical and ethical concerns. Proponents argue that respect for persons is protected because any participant in this experimental surgery would give their informed consent and be made well aware of the animal trials and previous human trials that have preceded this surgery, as well as the potential risks, benefits, and alternatives. In addition, they would know that the surgery has met the conditions of being ethically justified research by the local Institutional Review Board (IRB). The problem is that in the United States and many European countries, a new surgical technique requires no formal regulatory approach and is controlled primarily through surgeons’ self-regulation that is not always supplemented by local control over research (i.e. peer review and IRB approval of a formal protocol).⁴⁴ The conditions for approval by an IRB are:

1) a reasonable prospect that the research will generate the knowledge that is sought;

2) the necessity of using human subjects;

3) a favorable balance of potential benefits over risks to the subject; and

4) a fair selection of subjects.⁴⁵

Proponents argue that the duty of the IRB is to check that researchers have not overestimated the potential success and underestimated the possible risks. Their duty is also to ensure that the risk-benefit ratio of undergoing this surgery is reasonable.⁴⁴ Approval by the IRB would be an added assurance to potential recipients and to society as a whole.

To give valid informed consent to be a subject in an experimental surgery, two conditions must be met: the consent must be freely obtained from a competent person and the individual must be adequately informed regarding all aspects of the experimental surgery.46 First, from the recipient’s perspective, the option open to patients with severe liver disease is an “extracorporeal” liver or a possible liver transplant. The Perelman School of Medicine at the University of Pennsylvania “marked a milestone in the quest for a more effective option to “bridge” critically ill patients to liver transplant. The research team today announced the first successful completion of an experiment to circulate a recently deceased donor’s blood through a genetically engineered pig liver outside their body-an effort they plan to study further in hopes of providing options to save patients from dying while waiting for transplants.”¹⁵ This “extracorporeal” or outside-the-body liver- “is designed to help people survive acute liver failure, which can be caused by infection, poisoning, or (most commonly) too much alcohol.”⁴⁷ Individuals involved were made aware of the chances of success and knew this was a “bridge” until a human liver was available. Patients knew that this procedure was temporary to either give the liver time to recover or wait until a transplant is possible. This information is vital so the patient can give informed consent.

To give informed consent for a genetically modified pig liver, recipients would have to be made aware of the risks, benefits and alternatives available to them. They would need to understand and comprehend that the pig liver has ten genetic modifications to prevent the organ from being rejected by the recipient’s body. They would need to be informed that the team would deactivate three genes that contribute the production of sugars on the surface of pig cells, which the human immune system attacks, and introduce seven genes that express human proteins.¹⁷ The gene edits made to the pigs “seem to protect the organs from severe rejection in the short term.” Here there is no complex immunology. We eliminate the rejection question because we don’t use the organ for long. It is more like a piece of machinery.”⁴⁷ The problem is that besides the risk of rejection, which would mean removal of the liver, the patient would also have to be on immunosuppressant drugs for the remainder of his or her life, which are expensive and have serious side-effects such as increased chances of serious infections. The patient would need to be given all this information at a level he/she could adequately comprehend.

In addition to understanding the “extracorporeal” liver experiments, the patient would also have to be made well-aware of the Chinese transplants at Xijing Hospital, in which the surgeons transplanted a genetically modified pig liver into a dead patient in March 2024. Then in May 2024, surgeons in China removed a live patient’s left lobe of the liver and replaced it with a 514-gram liver from an 11-month old miniature pig that weighed 32 kilograms. The pig had 10 gene modifications to prevent rejection in the recipient’s body.¹⁷ Patients must understand that this is still an experimental procedure with serious risks, but with additional research, genetically modified pig livers for humans have the potential to be lifesaving and to give individuals with liver failure a far better quality of life. Under these circumstances, it is questionable whether the recipient is really free to give consent for such a procedure. Research has shown that whenever a new form of surgery is proposed, patients tend to dwell more on the benefits than the risks. “If potential patients are desperate for a procedure, the question arises whether it is feasible for them to assess if possible improvements in quality of life outweigh the potential morbidity and mortality caused by long-term immunosuppression.”⁴⁶ It is very difficult to determine if informed consent can be freely obtained with the way the media has sensationalized this surgery and the hype by various surgeons about its potential benefits. The consent may appear to be free, but, unfortunately, it may be based upon unrealistic expectations. At the present time, what this procedure realistically offers these patients is the possibility of improvement in the quality of their life.

Second, for a patient to give informed consent, he or she must have the necessary information to make such a decision. The basic elements of informed consent are:

1) A fair explanation of the procedures to be followed, including an identification of those which are experimental;

2) A description of the attendant discomforts and risks;

3) A description of the benefits to be expected;

4) A disclosure of appropriate alternative procedures that would be advantageous for the subjects;

5) An offer to answer any inquiries concerning the procedures;

6) An instruction that the subject is free to discontinue participation in the project or activity at any time.⁴⁸

In a specific sense, the surgeons who want to transplant genetically modified pig livers into humans have an ethical obligation to give an objective, unbiased assessment of all materially relevant information pertaining to the animal studies and the human trials so that the patient can give informed consent. In addition, the rates of rejection, the costs and side-effects of the immunosuppressant drugs, the psycho-social issues, and other risks must be clearly stated and explained to the patient. The surgeons are also responsible to verify, to the best of their ability, that the patient can comprehend and has comprehended the information and has not engaged in “selective hearing.” This means, surgeons should explain the risks, benefits and alternatives at a 5th grade level so that all patients can comprehend the information. Under the circumstances, it is not uncommon for patients to engage in “selective hearing,” that is, taking in all information about potential benefits and filtering out all information about potential risks. To overcome “selective hearing” the surgeon should invoke the “teach-back method,” which means the patient repeats back to the surgeon what he/she heard and understands. In addition to this, surgeons must be vigilant against their influence over subjects, who may unwittingly treat the surgeon with the same deference as they treat their primary care physicians. Dr. Robert Levine, professor of Medicine at Yale University, describes the surgeon/researcher’s obligation as one of “forthright disclosure.” This includes preliminary evidence and data from animal studies and previous human clinical trials that indicate the risks and benefits as well as the safety and efficacy of these controlled studies.⁴⁹ Patients need to have information that a reasonably prudent person would require to make well-reasoned decisions that will protect their personal interest.

The problem is determining what sort of knowledge translates to what degree of risk to patients. This is a value judgment that must be made by the surgeons. The concern is that the judgment of some surgeons may be biased by considerations of career self-interest and even financial gains.⁵⁰ “The potential for coercion can be difficult for surgeons. On the one hand, most accept that the final choice for surgery should be left to the patient. On the other hand, surgeons want what they believe to be best for their patients. Therefore, there is ample room for unintentional coercion through selecting information for disclosure that overtly reinforces the surgeon’s beliefs.”⁵¹ There is also the problem of forming an “innovative alliance.” Patients may encourage their surgeons to try any new and promising technique to improve their quality of life or prospects for survival and surgeons also may be eager to apply a promising new technique for the same reasons. It is the duty of the surgeons to decide whether responsible behavior lies in attempting an innovative technique or in concluding that the background research is not sufficient to warrant its use, even when the patient consents.⁴⁴

The surgeon has the responsibility to act in the best interest of the patient. The belief that this experimental surgical procedure will not cause too much harm to too many people or that society will benefit at the possible expense of particular individuals violates the duty of the surgeon/researcher to act in the patients’ best interest. To determine whether that duty has been breached, a surgeon/researcher’s actions should be measured against the accepted practice as set by professional norms. Those researchers whose treatments fall below the professional standards and cause harm to patients may be held civilly liable for that failure.⁵² Various ways have been proposed that ensure individuals going into research protocols are giving informed consent, these include: written and oral forms of consent so that the patient has time to read and reflect on the risks and benefits; someone other than a member of the surgical team obtains the informed consent; obtaining second opinions from other knowledgeable physicians regarding the feasibility of such a procedure; and appointing an objective advocate who would accompany the patient during the decision-making process. These advocates would ensure that the patient is capable of understanding the information and comprehends all the information, that researchers do not overestimate potential benefits and underestimate potential risks, and that all viable options are given, even the option of no transplant. These are not only excellent ideas; they should be implemented with every research protocol.

The complexity of this experimental surgery and its multileveled physical, psychological and social dimensions, make informed consent very complex. Since this surgery has been performed on a limited basis, it would be hard for surgeons to evaluate the potential risks and then adequately inform the patient of them to satisfy informed consent. Therefore, information that is necessary for informed consent is limited at the present time. In fact, the obstacles to informed consent in this situation seem almost insurmountable. In addition to weighing the risks and benefits, we are also asking individuals considering a transplant from a genetically modified pig to weigh just as many psychologically demanding variables. These issues only highlight the complexity of a patient giving informed consent under the circumstances. However, if the previously mentioned safeguards are enacted, it may be possible for patients to give informed consent, but this must be done objectively, comprehensively and honestly by a team of medical professionals.

Beneficence

Beneficence involves the obligation to prevent and remove harm and to promote the good of the person by minimizing the possible harms or risks and maximizing the potential benefits. Beneficence includes nonmaleficence, which prohibits the infliction of harm, injury, or death upon others. In medical ethics this principle has been closely associated with the maxim Primum non nocere: “Above all do no harm.”

Proponents argue that xenotransplantation and in particular, transplant of a genetically modified pig liver into a human has the potential to save thousands of lives. Proponents contend that the risks are present as they are with any form of transplantation, but that if a patient comprehends the risks, benefits and alternatives and consents freely and knowingly to the surgery, then that individual should be given the right to make that informed decision. To delay the inevitable when the knowledge, technology and skills are available and when patients believe this surgery is in their best interest, is not only standing in the way of scientific advancement but is failing to promote the good of the patient and the good of society as a whole.

Opponents argue that the safety concerns regarding xenotransplantation are a major factor. The most significant concern is the immunological rejection of the organ by humans. The human system will recognize the organ as foreign and correlatively reject it. To date, the 10 genetic modifications have been successful, on a limited clinical trial basis of avoiding the hyper-acute rejection. The use of immune-system-suppressing drugs has also reduced the probability of rejection. The immunosuppressant drugs do have serious side-effects, but the patient would need to weigh the side-effects against the potential of a lifesaving transplant. The costs of the drugs must also be factored into the patient's consent process.

Second, there are safety concerns for endogenous retroviruses carried by pigs, which could be capable of making humans very ill. This is not only a recipient concern but also a public health concern. Porcine endogenous retroviruses (PERV A, PERV B and PERV C) could impact the common good of society. Proponents will argue that the pigs used in xenotransplantation are not raised under the traditional husbandry conditions. “Rather they are kept much in the manner of laboratory animals, under confined, sterile conditions that minimize the risk of pathogen proliferation and keep the animals sufficiently healthy to provide a (relatively) safe source for transplantation. Although such conditions are far better than agricultural conditions in terms of animal health, they are equally deficient in accommodating the animal’s biological and psychological natures.”⁵³ Most ethicists would argue that the good of humanity would take priority in this regard. Another ethical issue concerns the limited privacy of recipients of a genetically modified pig liver. These patients would need to be monitored for pathogens dangerous to them and others for extended lengths of time, which in turn would impact the privacy of not only the patient but also the patients’ family, friends, work associates and others who are in contact with the patient. Due to the experimental nature of these transplants, it would be difficult to protect the anonymity and confidentiality of the recipient and their respective families from the public and the press. These patients may be looked upon as “freaks of nature.”⁵⁴ Critics fear the large amount of publicity will place unrealistic expectations on the recipient thus creating additional psychological stress and pressure. This could result in discrimination, alienation and exploitation of the patient and his/her family. To imagine or even calculate the psychological impact on the recipient and his or her family seems almost impossible.

The final issue regarding the risk/benefit ratio has to do with the genetic modification of the pigs with human stem cells. To date, the process seems very regulated and controlled but some critics raise the issue of the human stem cells migrating to the brain of the pig and creating medical and ethical concerns. This is an issue that has been advanced in regards to all genetic engineering pertaining to xenotransplantation. This is a valid concern, but it is not enough of a concern to limit all genetic engineering technology. Researchers are also moral agents and we must respect their integrity in regards to following proper human research protocols. There are also many safeguards in place to verify this integrity.

No one will dispute that balancing the benefits and risks is difficult. Some will say that the value of life will take precedence over potential risks. After reviewing the facts concerning the state of our knowledge regarding xenotransplantation, the effects of immunosuppressant drugs and the inevitable psychological impact on the recipient and the recipient’s family, it seems reasonable to argue that the transplant of a genetically modified pig liver into a human person could maximize the benefits and minimize the risks incurred by these patients. This is still an experimental surgery and more research in this area will need to be done. Unless more research is done, we will never know conclusively if the benefits outweigh the burdens. Arguably, this form of xenotransplantation has the potential to pass not only the test of beneficence, but also that of nonmaleficence.

Justice

Finally, justice recognizes that each person should be treated fairly and equitably, and be given his or her due. The principle of justice can be applied to this situation in two ways. First, questions of justice have been raised about whether those patients who are desperate for liver transplants might be classified as vulnerable individuals and whether this type of experimental surgery is a form of exploitation. No one seems to dispute that surgeons have the skills and techniques needed to perform this experimental xenotransplantation. However, there also seems to be a competition present among the various transplant teams examining this form of xenotransplantation. This debate cannot and must not be framed within the aspirations of the surgeons. There must be equality between the surgeons and the possible recipients. To allow these charismatic surgeons to present this form of transplantation in the media in such a way that seems to trivialize the side-effects and downplays the possibility of rejection and even death, is to exploit these recipients and use them as a means to an end. At the present time the debate among the transplant surgeons is on how they should proceed. Most transplant surgeons see no need for a delay in increasing the surgery because there is nothing to be learned during this time of delay. With this attitude, how objective and unbiased will the information about the surgery and its possible benefits and risks be when disclosed to potential recipients? How will surgeons know when the potential vulnerability of some patients is unduly influencing their willingness to consent? These transplant surgeons have suggested ways they believe will ensure informed consent; however, since many of these potential recipients have no other viable options, one could say it is unjust to place these vulnerable individuals in this position now. However, if the safeguards to informed consent are enacted, and recipients clearly comprehend the benefits and risks of the xenotransplantation, then it would be just to allow these individuals to become involved in further research protocols.

Second, the issue of justice pertains to genetically modified pig transplants into humans specifically in regards to distributive justice, which concerns the fair and equitable allocation of medical resources. The main issue here is research priorities. Should funds be used to support xenotransplantation surgery now when the potential risks seem unreasonable and even deadly? The amount of money spent on these surgeries could certainly be invested in new ways to tolerate immunosuppressant drugs and primate experimentation to lessen the rejection rates. This would help to minimize the risks and maximize the benefits not only for recipients of xenotransplantation but for all transplant patients. Also, immunosuppressant drugs cost tens of thousands of dollars a year. Will this not limit the individuals who would qualify for this surgery? If so, this now becomes a social justice issue, because those who would have access to this technique would logically be those who are privileged. The poor, the uninsured, the underinsured, and many middle-class individuals would never be viable candidates for this surgery, because they could not afford the cost of a life-time supply of immunosuppressant drugs. As a matter of social justice, who this surgery would benefit and whether it is a fair and equitable allocation of medical resources is an important ethical issue. Medical professionals have an ethical obligation to use available resources fairly and to distribute them equitably.

In conclusion, transplanting genetically modified pig livers into humans could be considered ethically and morally acceptable under certain circumstances. If there is a standardization of outcomes and comprehensive inclusion/exclusion criteria for xenotransplantation and guidelines and safeguards for informed consent, then and only then would this surgery be ethically permissible. To make xenotransplantation a reality, physicians have an ethical obligation to perfect the safety and efficacy of this technique. This will entail additional research to overcome the unknown long-term prospects.

Conclusion and Recommendations

As liver xenotransplantation continues to develop, the medical community must prioritize areas of further research aimed at improving the safety and efficacy of these procedures. Future studies should focus on refining genetic modifications in donor pigs to reduce immune rejection and minimize comp coagulation disorders. Advancements in biotechnology, particularly in gene editing, can open new pathways for safer transplants, and exploring novel immunosuppressive therapies could enhance graft survival rates. Furthermore, the development of more sophisticated immunological monitoring tools will be critical to improving patient outcomes by helping monitor organ function in real time and intervening before rejection occurs. Expanding research into these areas is essential for ensuring that liver xenotransplantation becomes a viable long-term solution to organ shortages.

In preparation for widespread clinical trials, it is imperative to establish clear protocols that safeguard patient rights and ensure the responsible implementation of xenotransplantation. Patient selection should prioritize those with no viable alternatives, ensuring that those in critical need can benefit first. Given the complexity and potential risks, patients must receive comprehensive information about the procedures, allowing for fully informed consent. Emphasis should be placed on transparent communication about risks, benefits, and the experimental nature of the transplant. Clinical trials must also reflect equitable access, ensuring that participants are selected without bias based on socioeconomic status, race, or geographic location. Policymakers and healthcare institutions should work together to guarantee that access to these life-saving procedures is equitable.

Additionally, international collaboration will be pivotal in accelerating the implementation of liver xenotransplantation. By standardizing research practices, animal welfare regulations, and safety measures across borders, the global medical community can share findings and innovations more efficiently. This will also ensure that the benefits of xenotransplantation are distributed more equitably around the world, particularly in low- and middle-income countries where organ shortages are most dire. Creating a global framework for xenotransplantation can help synchronize ethical standards, maximize resource use, and expand the pool of knowledge necessary for rapid advancements.

Continuous monitoring of xenotransplantation outcomes is essential. Policymakers must create regulations mandating long-term data collection on patient survival rates, complications, and societal impacts, ensuring that future policy decisions are informed by comprehensive evidence. This ongoing oversight will help refine medical protocols, improve patient care, and address any unforeseen consequences of large-scale xenotransplantation use. In a world where the demand for livers far exceeds supply, pig xenotransplantation holds the power to not only save lives but reshape the future of medical science—if we dare to embrace it.