How Xenotransplantation Moved From Failed Experiments To Lifesaving Reality

Once defined by unsuccessful early trials, xenotransplantation has evolved into a field with real clinical potential. Advances in genetics, immunosuppression, and pathogen control bring cross-species organ transplantation closer to reality, highlighting its role in addressing the critical shortage of human donor organs and positioning it as a potential long-term therapeutic option.

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What Is Xenotransplantation?

Xenotransplantation refers to the transplantation of living cells, tissues, or organs from a nonhuman animal source into a human recipient, or their use in ex vivo procedures involving human fluids or cells.¹

Organ transplantation remains the primary life-saving therapy for most patients with end-stage organ failure. However, the growing demand for transplantable organs has widened the supply–demand gap, highlighting xenotransplantation as a potential alternative.²

The clinical application of xenotransplantation is highly complex, necessitating a comprehensive assessment of immunological compatibility, precise genetic modification of donor organs, and stringent measures to prevent cross-species pathogen transmission.^1,2

Beginnings of Xenotransplantation

Xenotransplantation originated several centuries ago and is defined by key experimental milestones.

In 1667, the first documented attempt to transfuse sheep blood into humans was made. By the 19th century, experimental corneal transplants using porcine tissue were performed, alongside the use of animal skin grafts as biological dressings.^1,3

During the early to mid-20th century, xenotransplantation was extended to kidney, heart, and liver grafts, mainly sourced from primates, although graft survival was very short due to rejection and infection.^1,3

These early efforts introduced the use of animal-derived organs to address shortages and laid the foundation for further research in xenotransplantation. In subsequent years, the development of immunosuppressive therapies and improvements in donor–recipient compatibility, along with the use of porcine models for their physiological similarity to humans and amenability to genetic editing, has led to the emergence of clinically relevant xenotransplantation protocols.^1,3

More recently, genetic engineering has enabled targeted modifications to reduce graft rejection. At the same time, progress in pathogen screening has enhanced safety, further advancing xenotransplantation as an investigational approach to expand the donor pool.1,^3,4

Overcoming Immunological Barriers

A significant challenge in cross-species transplantation is the host immune response, which often mounts a rapid attack against xenografts, resulting in graft failure.

In xenotransplantation, hyperacute rejection (HAR) occurs within minutes to hours. It is driven by preformed natural antibodies, primarily against the galactose-α-1,3-galactose (α-Gal) epitope expressed on porcine vascular endothelium, leading to complement activation, thrombosis, and rapid graft loss.²

Subsequent immune responses also remain critical barriers, with acute vascular rejection (AVR) developing over days to weeks through humoral and cellular mechanisms, and chronic rejection, characterized by vascular and interstitial fibrosis, reducing long-term graft survival.²

These sequential immunological barriers highlight the need for integrated strategies addressing immediate and delayed xenograft rejection. Current approaches targeting donor and recipient, through immunosuppressive therapy, genetic engineering, and immune tolerance induction, have improved graft survival outcomes in experimental models.^1,3

On the recipient side, emerging strategies focus on modulating the immune system to promote long-term graft tolerance. One example is mixed chimerism, which involves introducing donor hematopoietic cells to create a coexisting donor–recipient immune system. In addition, regulatory cell therapies, utilizing T cells and myeloid-derived suppressor cells, further support durable graft tolerance by suppressing immune responses and controlling inflammation. Although these approaches remain experimental, they are being actively tested in preclinical models as bridges toward future clinical translation.^1,3

Advances in Genetic Engineering

Genetic engineering has enabled the targeted modification of immunogenic antigens in porcine models, reducing antibody-mediated rejection and enhancing graft compatibility.

Gene-editing technologies, particularly CRISPR-Cas9, allow precise inactivation of key xenoantigen genes (e.g., α-1,3-galactosyltransferase [GGTA1] knockout to eliminate the α-Gal epitope), reducing immunogenicity and improving graft survival. Additional edits like CMAH and B4GALNT2 knockouts further diminish human antibody recognition. Targeted edits are also being explored to promote tolerance, such as modulating major histocompatibility complex (MHC) expression to better align with human immune recognition.⁴

Genetic interventions also target coagulation dysregulation, inflammation, and interspecies cellular incompatibilities. For example, transgenic expression of human complement-regulatory proteins, anticoagulant factors, and anti-inflammatory molecules has been introduced into porcine genomes to enhance physiological compatibility with human recipients.⁴

Another key safety concern in xenotransplantation is the transmission of pathogens from porcine donors, which may carry asymptomatic agents that threaten immunosuppressed recipients. Of particular concern are porcine endogenous retroviruses (PERVs), which are integrated into the pig genome and not detectable by conventional pathogen-screening methods.⁵

To address this, a major advance in genetic engineering has been the inactivation of PERVs using multiplex CRISPR-Cas9 editing, which enables the simultaneous disruption of numerous viral sequences. This approach reduces the risk of retroviral transmission while enhancing biosecurity and graft safety, and maintaining the functional integrity of xenografts.⁴

Clinical Breakthroughs in Xenotransplantation

Recent achievements in xenotransplantation highlight the clinical potential of genetically modified pig organs, with several important procedures demonstrating their translational feasibility.

In January 2022 and September 2023, the University of Maryland Medical Center performed the first two pig-to-human heart transplants in patients with end-stage heart failure, using genetically modified porcine hearts with ten gene edits to mitigate immune rejection.^6,7

In March 2024, Massachusetts General Hospital performed the first clinical-scale pig-to-human xenograft of a genetically modified kidney, followed in November by NYU Langone Health, marking key milestones in renal xenotransplantation.^8,9

In August 2025, researchers in China reported the first pig-to-human lung xenotransplantation in a brain-dead recipient. The lung, sourced from a genetically engineered pig carrying six gene edits, maintained ventilatory function for nine days without evidence of hyperacute rejection. However, antibody-mediated injury and inflammatory changes were observed after the third day.¹⁰

In 2025, the U.S. Food and Drug Administration (FDA) approved the first formal clinical trials of xenotransplantation involving genetically modified pig kidneys, marking a significant milestone and establishing a framework for broader clinical studies. These trials represent the shift from one-off compassionate-use procedures to regulated clinical evaluation.¹¹

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Alternatives and Complementary Approaches

While xenotransplantation is advancing rapidly, it is not the only strategy being pursued to address the global shortage of donor organs. Regenerative medicine approaches, including stem-cell–derived organoids, bioengineered tissues, and 3D bioprinting, offer parallel pathways for creating transplantable tissues. For example, kidney organoids derived from pluripotent stem cells have shown early promise in preclinical models. Advances in bioprinting enable the generation of vascularized tissue constructs that could one day replace damaged organs.¹²^,13

However, these technologies face significant barriers to near-term clinical translation, including challenges in achieving full organ-scale function, long-term vascular integration, and regulatory approval. By contrast, xenotransplantation uses whole organs with intact physiology, supplied by genetically engineered pigs, providing an immediately scalable option for patients with end-stage organ failure.

Regenerative medicine and xenotransplantation are likely to be complementary rather than competing. Engineered tissues may be best suited for repairing localized injury or supporting organ regeneration, while xenotransplantation offers a near-term solution for complete organ replacement. Over the longer term, hybrid strategies, such as seeding porcine scaffolds with human cells, could further integrate these fields and expand therapeutic possibilities.

Challenges and Future Directions

Despite recent advancements, xenotransplantation continues to face major challenges in modern medicine. Critical issues such as immune rejection and the risk of zoonotic infections remain, alongside profound ethical questions, including animal welfare, cross-species morality, long-term health risks, equitable access, and societal acceptance. Regulatory agencies like the FDA and EMA are developing frameworks to balance innovation with safety. At the same time, ethical debates increasingly focus on public trust and the acceptability of genetically engineered animal donors.⁴

Meanwhile, ongoing research to optimize genetic modifications that balance graft survival, long-term function, and patient safety rapidly advances the creation of humanized animal donors, bringing xenotransplantation closer to meeting clinical immunological and safety requirements.

Collectively, these developments have the potential to overcome existing barriers, making xenotransplantation a viable, lifesaving option for patients in urgent need of organ transplants.

References and Further Reading

1. Lu, T., Yang, B., Wang, R., & Qin, C. (2020). Xenotransplantation: Current Status in Preclinical Research. Frontiers in Immunology, 10. doi: 10.3389/fimmu.2019.03060
2. Peterson, L., Yacoub, M.H., Ayares, D., Yamada, K., Eisenson, D., Griffith, B.P., Mohiuddin, M.M., Eyestone, W., Venter, J.C., Smolenski, R.T., & Rothblat, M. (2024). Physiological basis for xenotransplantation from genetically modified pigs to humans. Physiological Reviews, 104(3), 1409-1459. doi: 10.1152/physrev.00041.2023
3. Arabi, T.Z., Sabbah, B.N., Lerman, A., Zhu, X-Y., & Lerman, L.O. (2023). Xenotransplantation: Current Challenges and Emerging Solutions. Cell Transplantation, 32. doi:10.1177/09636897221148771
4. Ryczek, N., Hryhorowicz, M., Zeyland, J., Lipiński, D., & Słomski, R. (2021). CRISPR/Cas Technology in Pig-to-Human Xenotransplantation Research. International Journal of Molecular Sciences, 22(6):3196. doi: 10.3390/ijms22063196
5. Zhou, Y., Zhou, S., Wang, Q., & Zhang, B. (2024). Mitigating Cross-Species Viral Infections in Xenotransplantation: Progress, Strategies, and Clinical Outlook. Cell Transplantation, 33. doi: 10.1177/09636897241226849
6. University of Maryland Medical Center. (2022). University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic Transplant of Porcine Heart into Adult Human with End-Stage Heart Disease. [Online]. Available at: https://www.umms.org/ummc/news/2022/pioneering-transplant-of-porcine-heart-into-adult-human-heart  (Accessed on 5 September 2025)
7. University of Maryland Medical Center. (2023). UM Medicine Faculty-Scientists and Clinicians Perform Second Historic Transplant of Pig Heart into Patient with End-Stage Cardiovascular Disease. [Online]. Available at: https://www.umms.org/ummc/news/2023/um-medicine-clinicians-perform-second-historic-transplant-of-pig-heart-into-patient (Accessed on 5 September 2025)
8. Mass General Brigham Communications. (2024). In a First, Genetically Edited Pig Kidney Is Transplanted Into Human. Harvard Medical School News. [Online]. Available at: https://hms.harvard.edu/news/first-genetically-edited-pig-kidney-transplanted-human (Accessed on 5 September 2025)
9. NYU Langone Health. (2024). Gene-Edited Pig Kidney Gives Living Donor New Lease on Life. [Online]. Available at: https://nyulangone.org/news/gene-edited-pig-kidney-gives-living-donor-new-lease-life (Accessed on 5 September 2025)
10. He, J., Shi, J., Yang, C., Peng, G., Ju, C., Zhao, Y., Liu, H., He, P., Liu, X., Zhang, Z., Chen, C., Pan, D., Yang, Z., Guang, W., Li, H., Chen, Z., Liu, M., Liang, H., Huang, W., Jeon, K., Chen-Yoshikawa, T.F., Rucker, A.J., Lal, A., Zhong, N., Zhang, K., Liu, X., & Xu, X. (2025). Pig-to-human lung xenotransplantation into a brain-dead recipient. Nature Medicine. doi: 10.1038/s41591-025-03861-x
11. Brooks, A. (2025). FDA clears first xenotransplant trial for gene-edited kidneys. HCPLive. [Online]. Available at: https://www.hcplive.com/view/fda-clears-first-xenotransplant-trial-gene-edited-kidneys (Accessed on 5 September 2025)
12. Hunsberger J, Harrysson O, Shirwaiker R, et al. (2016). Manufacturing road map for tissue engineering and regenerative medicine technologies. Stem Cells Transl Med. ;5(10):1370–1375. doi:10.5966/sctm.2015-0394
13. Takebe, T. & Wells, J.M., (2019). Organoids by design. Science, 364(6444), pp.956–959. doi:10.1126/science.aaw7567

Last Updated: Sep 15, 2025