Cell News—Could GMO Xenotransplants Break the Donor Bottleneck?

Could xenografts genetically-modified to reduce immune reactivity ease the shortage of transplant organs? Photo: Official U.S. Navy

Could xenografts genetically-modified to reduce immune reactivity ease the shortage of transplant organs? Photo: Official U.S. Navy

The name may evoke images of “The Island of Dr. Moreau” or of countless comic book superheroes who are human-animal hybrids but the reality of xenotransplants is a lot less macabre and a lot more promising. Xenotransplants, which are organ or tissue grafts from one species to another, could be a way to break the organ supply bottleneck for transplants. The U.S. Department of Health & Human Services says that every day 79 Americans receive transplants while 22 die waiting for a suitable donor organ.

Xenografts could supply more of those needed organs. But in all organ transplants, human or not, the chief problem after surgery is manipulating the recipient’s immune system, which is primed to reject all foreign objects whether bacteria, other infectious agents, or transplanted organs. A lifelong regime of powerful immune suppressing drugs is the current method to avert host-graft disease after human-to-human transplants. But a different strategy is emerging in xenotransplant research: could organs from non-human donors be genetically modified to decrease immune reactivity?

A new article by Muhammad Mohiuddin, Keith Horvath, and colleagues at the NIH National Heart, Lung, and Blood Institute (NHLBI), published in Nature Communications, reports exciting progress using a genetically modified xenotransplant, leading to a new survival record for baboons with pig heart transplants. The NHLBI researchers used pigs genetically engineered with a knockout of their alpha 1-3 galactosyltransferase gene and expressing two human proteins, CD46 and thrombomodulin. The overall goal of using this genetically-modified pig as an organ source was to lower the baboon host’s immune response to the new xenograft hearts and prevent blood clotting, a common mediator of transplant rejection.

In addition, the NHLBI researchers used a new regimen of drugs to suppress the baboon’s immune system, deploying an antibody against CD40, a key protein activating antigen-presenting cells that trigger the immune system. The baboons did extremely well with the genetically modified pig hearts. It was the removal of the anti-CD40 component from their medications that finally triggered rejection of the transplanted pig heart, say the researchers, confirming their hypothesis about the role of the novel antibody. Importantly, baboons that received the pig hearts along with this novel drug regimen survived an average of 298 days, with some animals surviving more than two years (945 days to be exact). This shatters the old survival record for the longest functional xenotransplant, a record held by the same NIH group of 100 days on average.

It is important to note that in these studies, the pig hearts were transplanted into baboons that had functional hearts, the new organs working along with the baboon’s original heart. But the researchers say this study is a proof of concept for genetically modified xenotransplants while the next stage will test a fully “life-supporting” system where the transplanted xenograft organ will be on its own. This study moves the field of organ transplant forward into the realm of cross-species transplants, something that could provide life-saving organs for many patients in the future.

About the Author:


Hashem is a Postdoctoral fellow in the laboratory of Dr. Melanie H. Cobb, studying regulation and interactions of WNK protein family members. Email: Hashem.Dbouk@UTSouthwestern.edu
Christina Szalinski is a science writer with a PhD in Cell Biology from the University of Pittsburgh.