With a number of significant developments being made over the last few years, xenotransplantation, transplanting organs from animals into humans, could solve the organ shortage crisis. But what challenges remain? How will scientists overcome these? These are questions that must be answered in order to understand how far xenotransplantation has come, and how far it still has to go.
A major risk with xenotransplantation is the transmission of viruses, the most problematic of which is Porcine Endogenous Retroviruses (PERVs). By co-culturing immortalised pig epithelial cells with embryonic kidney cells, it has been shown that PERVs can in fact be transmitted to human cells (1). Transmission of PERVs to humans could lead to tumorigenesis and immunodeficiency. Although this is a concern, many believe that the gene-editing technology Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) should prevent PERV transmission. This can be achieved by gene knock-out or knock-in in pigs to prevent PERV expression. (2)
Arguably the greatest challenge facing xenotransplantation is that of rejection. Preformed human antibodies bind to the antigens on porcine endothelial cells, activating complement proteins, in turn causing lysis of these cells and destroying the vasculature of the transplanted organ. To tackle rejection, the antibodies specific to porcine antigens could be removed, or the activation of complement proteins could be inhibited (3). Alternative solutions include using inhibitors that control macrophage function, restricting the immune response.
One of the most significant developments in xenotransplantation in recent years was the transplant of a pig kidney to a brain-dead human patient, the results of which were published this year (4). The donor pig had 10 genetic modifications: 2 human complement inhibitor genes were inserted (reducing rejection); 2 human anticoagulant genes were inserted (reducing coagulation); 2 immunomodulatory genes were inserted (reducing the response of the immune system); the pig growth hormone receptor gene was removed (preventing the kidney from growing too large), and 3 carbohydrate antigens were removed. No hyperacute rejection was observed, and no PERVs were found to have been transmitted.
Another major breakthrough occurred earlier this year: a porcine heart was transplanted for the first time ever into a person able to recover (5). According to the surgeon, Bartley P. Griffith, this operation “brings us one step closer to solving the organ shortage crisis” (6). However, the patient passed away after 2 months. Whilst it cannot be certain, this was likely due to the transmission of a virus. The specific virus, called porcine cytomegalovirus, is known to have very damaging impacts on transplants, but it is also avoidable through more rigorous testing for viruses and so this issue could likely be corrected for future xenotransplants. (7)
On balance, what is clear is that xenotransplantation has great potential. Much progress has been made, and most concerns, including rejection, have been addressed. David Bennett’s transplant is likely the first of many xenotransplants into humans, with clinical trials aimed to proceed by the end of the year (8). But with the heart being the only organ to have been transplanted into a living patient successfully so far, it will be quite a few years before xenotransplantation can be used for other organs. As an NHS Blood and Transplant spokesperson said, “there is still some way to go before transplants of this kind become an everyday reality.” (9)
Author: Dylan Domb, Year 12
Further reading:
- https://www.sciencelearn.org.nz/resources/1214-history-of-xenotransplantation
- https://www.bbc.co.uk/news/world-59951264
- https://www.bbc.co.uk/news/health-60708120
- https://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1207&context=sjlcas
- https://healthmatters.nyp.org/how-xenotransplantation-works/
References:
1: Niu, D., Wei, H.J., Lin, L., George, H., Wang, T., Lee, I.H., Zhao, H.Y., Wang, Y., Kan, Y., Shrock, E., Lesha, E., Wang, G., Luo, Y., Qing, Y., Jiao, D., Zhao, H., Zhou, X., Wang, S., Wei, H., Güell, M., Church, G.M. and Yang, L. (2017). Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science, [online] 357(6357), pp.1303–1307. doi: 10.1126/science.aan4187
2: Ekser, B., Li, P. and Cooper, D.K.C. (2017). Xenotransplantation: past, present, and future. Current Opinion in Organ Transplantation. 22(6), 513-521. doi: 10.1097/MOT.0000000000000463
3: Lu, T., Yang, B., Wang, R. and Qin, C. (2020). Xenotransplantation: Current Status in Preclinical Research. Frontiers in Immunology 10:3060. doi: 10.3389/fimmu.2019.03060
4: Porrett, P.M., Orandi, B.J., Kumar, V., Houp, J., Anderson, D., Cozette Killian, A., Hauptfeld-Dolejsek, V., Martin, D.E., Macedon, S., Budd, N., Stegner, K.L., Dandro, A., Kokkinaki, M., Kuravi, K.V., Reed, R.D., Fatima, H., Killian, J.T., Baker, G., Perry, J., Wright, E.D., Cheung, M.D., Erman, E.N., Kraebber, K., Gamblin, T., Guy, L., George, J.F., Ayares, D. and Locke, J.E. (2022). First clinical-grade porcine kidney xenotransplant using a human decedent model. American Journal of Transplantation. 22: 1037-1053. doi: 10.1111/ajt.16930
5: Reardon, S. (2022). First pig-to-human heart transplant: what can scientists learn? Nature, [online]. vol. 601(7893), pp.305-306. doi: 10.1038/d41586-022-00111-9
6: Kotz, D. (2022). University of Maryland School of Medicine Faculty Scientists and Clinicians Perform Historic First Successful Transplant of Porcine Heart into Adult Human with End-Stage Heart Disease. University of Maryland School of Medicine, [online]. Available at: https://www.medschool.umaryland.edu/news/2022/University-of-Maryland-School-of-Medicine-Faculty-Scientists-and-Clinicians-Perform-Historic-First-Successful-Transplant-of-Porcine-Heart-into-Adult-Human-with-End-Stage-Heart-Disease.html
7: Regalado, A. (2022). The gene-edited pig heart given to a dying patient was infected with a pig virus. MIT Technology, [online]. Available at: https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/
8: Rabin, R.C. (2022). Patient in Groundbreaking Heart Transplant Dies. The New York Times, [online]. Available at: https://www.nytimes.com/2022/03/09/health/heart-transplant-pig-bennett.html
9: Wilson, C. (2022). How a pig heart was transplanted into a human for the first time. New Scientist, [online]. Available at: https://www.newscientist.com/article/2304167-how-a-pig-heart-was-transplanted-into-a-human-for-the-first-time/
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