Jennifer Zhong, 12th Grade

In the United States, over 100,000 patients are on the national organ transplant waiting list in hopes to receive the necessary transplant to save their lives [10]. However, with the growing demand for organ transplants, only one-third of those on the waitlist will receive a transplant, and it is estimated that 40% will die before an organ donor is available [2, 10]. Xenotransplantation, the transplantation of animal organs or tissues into human recipients, is becoming an increasingly possible solution to this organ shortage crisis. By genetically engineering organ sources to remove the threat of harmful antigens and by utilizing immunosuppressive therapies to limit immune rejection, xenotransplantation becomes an extremely viable option for many clinical applications [9]. In addition to combating the organ shortage, xenotransplantation has the potential to treat many diseases that result in organ or cell failure, but it also raises many health-related and ethical concerns.

In order for xenotransplantation to succeed, many pathobiological barriers including the activation of immune responses and coagulation need to be mitigated [3]. Pig organs express certain antigens such as Galactose-alpha-1,3-galactose that trigger the production of antibodies and the activation of complement proteins in the human body, causing hyperacute rejection, the rapid destruction of an organ [3, 9]. Scientists can now genetically engineer pigs with unexpressed immunogenic antigen molecules using CRISPR/Cas-9 gene-editing technologies to prevent this immune response [8]. Human genes can also be introduced into the pig genome in order to reduce rejection and coagulation [3]. Currently, there are pigs that express up to 5 or 6 of these genetic manipulations [3, 5]. The increased availability of multiple-gene pigs with these genetic modifications has led to the survival of an orthotopic pig kidney in a non-human primate (NHP) for over 90 days [5]. In addition, immunosuppressive agents such as costimulation blockade-based regimens that decrease antibody and T-cell responses are available and have the potential to aid in xenotransplantation [3].

Recently, there has been much success in xenotransplantation. In a clinical study of two cases of pig-to-human kidney transplantation, both brain-dead human recipients had kidneys that remained functional and continued to produce urine throughout the 54-hour study [10]. The kinetic eGFR which estimates kidney function increased in both recipients from 23 to 62 ml per minute in Recipient 1 and from 55 to 109 ml in Recipient 2. Both recipients showed a low risk of hyperacute rejection [10]. These xenotransplantation clinical trials have culminated in the first successful transplant of a gene-edited porcine heart to a human performed on January 7th, 2022 [11, 12]. A pig heart was genetically modified to remove 3 immune rejection-related genes and introduce 6 transgenes and 1 growth gene [6, 12]. The patient, David Bennett, was unable to receive a transplant from a human donor because he was not on the transplant waiting list, so xenotransplantation was a necessary option approved by the FDA to save his life [11]. Although Bennett died 2 months later, this success provides increased knowledge to make xenotransplantation a feasible and accessible option in the future [12].

In addition to immunological barriers that prevent accessible xenotransplantation, many ethical issues persist. Many believe the transplantation of an animal organ into the human body is unethical, a disruption to the natural order of life, and view xenotransplantation as animal mistreatment [1]. Because xenotransplantation sacrifices the life of a sentient animal and manipulates an animal’s genes where less than 1% of modified embryos survive, many consider it to be morally wrong [6]. Additionally, the grafting of tissues from different species creates a chimera, an organism with a mix of genetically different tissues, and some believe the creation of a new form of life that has not previously existed is unethical as well [6]. Many considerations need to be made regarding limiting the number of animals killed and genetic manipulations that can harm the animal.

Xenotransplantation also raises other ethical questions concerning the potential risk of zoonosis, the spread of viral diseases from donor animals to humans [7]. Transplanted organs can carry infectious diseases such as the porcine endogenous retroviruses (PERVs) present in the pig genome [6]. However, only PERV-A and PERV-B of the three main PERVs have infected in vitro human cells and have not been found in clinical studies of NHPs or humans [6]. Although the risk is low, immunosuppression therapies which are often used to prevent rejection of non-human organs in xenotransplantation may increase the risk of infection [7]. With the suppression of T lymphocytes that regulate immune response, the transmission of zoonosis with viable cells can occur [7]. Xenograft recipients need to be aware of all possible associated risks and should be closely monitored in order to prevent a public health crisis [7]. Still, other ethical questions need to be considered, such as if transplant status should be publicly disclosed, what to do if xenotransplantation patients do not adhere to necessary treatments, and who should regulate xenotransplants [7].

Although ethical dilemmas exist, the potential for xenotransplantation to become a viable treatment option for many diseases is growing. Xenotransplantation has the potential to solve the organ shortage and reduce the number of patients waiting for a human organ donor. With the ability to create a virtually unlimited supply of organs from animal sources, organ transplantation can become more accessible to all patients, especially those who face issues becoming transplant candidates [2]. Furthermore, xenotransplantation can aid those with diseases unrelated to organ failure with the transplantation of neuronal cells for neurodegenerative diseases, corneas for those with blindness, and islets for diabetes [4]. Xenotransplantation holds the potential to save lives around the world, but many ethical considerations still need to be made in order to ensure the safety and welfare of both humans and animals.

Citations:

1. Cengiz, Nezerith and Wareham, Simon. “Ethical Considerations in Xenotransplantation: A Review” Current Opinion in Organ Transplantation 25(5) (2020): 483-488.
2. Cooper, David, et al. “Pig Kidney Xenotransplantation: Progress Toward Clinical Trials” Clinical Transplantation 35(1) (2020): 1-11.
3. Cooper, David, et al. “Xenotransplantation – The Current Status and Prospects” British Medical Bulletin 125 (2018): 5-14.
4. Ekser, Burcin, et al. “Clinical Xenotransplantation: The Next Medical Revolution?” The Lancet 379 (2012): 672-683.
5. Ekser, Burcin, et al. “Xenotransplantation: Past, Present, Future” Current Opinion in Organ Transplantation 22(6) (2017): 513-521.
6. Entwistle, John, et al. “Clinical Xenotransplantation Seems Close: Ethical Issues Persist” Artificial Organs 46 (2022): 987-994.
7. Fishman, Jay “Infectious Disease Risks in Xenotransplantation” American Journal of
Transplantation 18 (2018): 1857-1864.
8. Goerlich, Corbin, et al. “Regulatory Barriers to Xenotransplantation” Current Opinion in Organ Transplantation 24(5) (2019): 522-526.
9. Lu, Tianyu, et al. “Xenotransplantation: Current Status in Preclinical Research” Frontiers in Immunology 10 (2020): 1-19.
10. Montgomery, Robert, et al. “Results of Two Cases of Pig-to-Human Kidney Xenotransplantation” The New England Journal of Medicine 386(20) (2022): 1889-1898.
11. Sade, Robert and Mukherjee, Rupak “Ethical Issues in Xenotransplantation: The First Pig-to-Human Heart Transplant” The Annals of Thoracic Surgery 113(3) (2022): 712-714.
12. Wang, Wei, et al. “First Pig-to-Human Heart Transplantation”​​ The Innovation 3(2) (2022): 100223.