Where is the future of xenotransplantation headed?
Xenotransplantation, akin to Prometheus’ fire, bringing new hope in addressing the shortage of organs available for transplantation. Remarkably, on May 17, 2024, our colleagues at the First Affiliated Hospital of Anhui Medical University completed the world’s first liver xenotransplantation surgery of a living person (1), marking the first such procedure in China. The patient was a 71-year-old patient with giant liver cancer in the right lobe. After obtaining informed consent from family members and patients, the team transplanted a 514-gram liver of a 10-gene-edited pig (11 months old, 32 kg, male) obtained from the Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation of Yunnan Agricultural University into the right hepatic fossa of the patient. The operation went very smoothly and bile was secreted immediately. As of May 24, the seventh day after the operation, the patient was in good condition, had walked freely, and his liver function had returned to normal. The transplanted pig liver secreted about 200 ml of golden bile every day, and computed tomography (CT) and B-ultrasound confirmed that the blood flow in the hepatic artery, portal vein, and hepatic vein of the transplanted pig liver was completely normal. This indicates that clinical trials of xenotransplantation, excluding those involving brain-dead recipients, have now commenced outside the United States.
Surprisingly, the history of xenotransplantation is even longer than that of allotransplantation (2). Due to the inability to effectively address serious rejection in recipients, research on xenotransplantation remained stagnant for a long time. It was not until the emergence and development of gene editing technology, particularly CRISPR/Cas, that xenotransplantation experienced significant advancements over the past 2 years. In 2021, Locke et al. from the University of Alabama first attempted pig kidney xenotransplantation in brain-dead patients (3). This milestone was followed by Kawai et al. from the Massachusetts General Hospital of Harvard University, who completed the first pig kidney xenotransplantation on a living person in 2024 (4). In 2022, Mohiuddin et al. from the University of Maryland Medical Center achieved the first pig heart xenotransplantation on a living person (5). Moreover, Dou et al. from the Xijing Hospital of Air Force Military Medical University of China attempted pig liver xenotransplantation in a brain-dead patient in 2024 (6). To date, all human xenotransplantation procedures have been performed in the USA and China. The field of xenotransplantation is dominated by the USA and China, owing to their substantial investment and leading positions in genetic engineering. Additionally, as predominantly secular countries, the USA and China face fewer religious restrictions on xenotransplantation, such as the prohibition of pig organ transplants in Islamic doctrine.
However, there are still technical risks in xenotransplantation. Firstly, gene editing techniques represented by CRISPR/Cas, pose a risk of off-target and extensive intervention in the genome. In the future, artificial intelligence may be able to accurately simulate genome editing scenarios and design more powerful genome editors to address these issues. Furthermore, the application paradigm of nucleic acid-guided systems may also evolve, perhaps toward more transient editing approaches to minimize the risk of unintended long-term genetic changes, or transient delivery to minimize genome disruption and immune response (7). Secondly, there may be some unknown or difficult-to-detect pathogens in animals that pose biosafety risks. For example, the failure of the world’s first xenotransplanted heart was most likely caused by porcine cytomegalovirus (PCMV) (8). Metagenomic next-generation sequencing (mNGS) may be an effective tool to deal with this challenge. Especially for the diagnosis of unknown pathogens, a bioinformatics analysis process based on assembly algorithms can be established. Additionally, there is no precedent for clinical trials that have survived acute immune rejection (3 months). Therefore, the supporting long-term immunosuppression program remains to be explored. Despite the genetic alteration of surface markers in pig livers, the production of pig-derived proteins remains a concern. These proteins can potentially provoke immune responses in the recipient. While genetic modifications aim to minimize the immunogenicity of porcine organs, residual immune responses to pig proteins can still occur, particularly in sensitized individuals. This sensitization may lead to complications post-transplantation including graft rejection. To mitigate these risks, ongoing research is exploring strategies such as further genetic engineering of pig proteins to reduce their immunogenic potential or the use of immunosuppressive therapies post-transplantation to manage any adverse immune responses. While significant advancements have been made in the field of liver xenotransplantation, the role of pig-derived proteins in eliciting hypersensitivity reactions remains a critical area of investigation. It is worth noting that cultivating human organs in animals for transplantation is also a potential optimization alternative that cannot be ignored (9).
It is expected that xenotransplantation will make further progress in the future, with developed countries in Western Europe, which process high technological levels and relatively open societies, also beginning to explore this field. Therefore, it is urgent to improve the public’s scientific understanding, acceptance, and compliance of xenotransplantation. Especially for those patients who cannot maintain or replace the function of failed organs through other means and have limited waiting time for donor organs, xenotransplantation based on the principle of compassion is a preferred choice. However, it is necessary to guard against ethical risks or even violations of the law caused by blindly following the trend, which is particularly important in a competitive research system.
Acknowledgments
Funding: This study was supported by
Footnote
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-382/coif). T.X. reports grants from the National Natural Science Foundation of China (No. 82373932), Natural Science Foundation of Anhui Province (No. 2208085MH203), Anhui Province University outstanding youth research project (No. 2024AH020006), Department of Education of Anhui Province Outstanding Young Teacher Training Project (No. YQZD2023023), Research Fund of Anhui Institute of Translational Medicine (No. 2022-zhyx-C09) and Anhui Medical University Youth Shuangpei Program (2024). The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article. A copy of the written consent is available for review by the editorial office of this journal.
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