Fight Aging!

In principle, engineering pig organs to survive in humans is a viable project for this age of biotechnology. Pig organs are the right size, and strategies exist to address the known issues in rejection of tissues, transfer of retroviruses, and the like. An entire industry is coming into being based on enabling cells and tissues from one individual to be introduced into another without rejection. Much of the work needed to make that possible between individuals of the same species also enables transplantation between species.

In a world in which organs fail, and transplants are in limited supply, there are several roads ahead towards providing an unlimited, on-demand supply of replacements. Xenotransplantation is one of them, farming engineering pigs for their organs. Secondly, there is decellularization, taking a donor organ and stripping it of cells, leaving the extracellular matrix and all of its chemical cues, before introducing the recipient's cells to repopulate the empty organ. Further, researchers are working to be able to build organs from scratch, from a cell sample. This is a challenging process in which the major hurdle remains the establishment of complex small-scale capillary networks. Lastly, there is the longer-term prospect of entirely artificial, machine organs, a field that receives less attention and seems likely to fall behind given advances in biotechnology.

It has hard to say which of the biological approaches will win out in the next few decades. Many of the difficulties are yet to be discovered in each case. Xenotransplantation is running at ahead of the others at this stage, but equally, as the first human studies are conducted, this is where the unknown difficulties start to arise.

Developing pig-to-human organ transplants

Over 100,000 people in the US are currently waiting for organ transplants. Because the human organ donor pool cannot keep pace with this demand, many patients die without receiving the life-saving transplant they need. Pigs are similar to humans in organ size and physiology, so the transplantation of pig organs to humans offers a potential solution to this problem and raises the prospect of scheduled, elective transplantation of quality-controlled organs, even for patients who would not currently meet the criteria for allocation of a scarce human organ. Although other technologies, such as tissue engineering, may eventually offer alternative solutions to this shortage, there is currently no substitute for transplantation of a fully formed, functioning organ. Several developments in the past year, most notably the first pig-to-human transplants, bring this promising solution closer to fruition, but challenges remain.

Transplants from one species to another are called xenotransplants. Because nonhuman primates (NHPs) are closest to humans phylogenetically, early human xenotransplantation efforts used NHP organs. However, graft survivals were short, and the use of NHPs for xenotransplantation was later deemed to be unsafe owing to potential virus transmission, impractical because of limited animal availability, and more ethically challenging than the use of pigs, which consequently became the xenograft source animal of choice. However, transplantation of pig organs into NHPs resulted in rapid "hyperacute" rejection (HAR) owing to the binding of preexisting "natural" antibodies (NAbs) in the NHP to targets on endothelial cells lining the transplant organ's blood vessels. Activation of complement and coagulation cascades then resulted in ischemic organ death within minutes to hours.

NAbs exist in the absence of any known exposure to pig tissues owing to cross-reaction with antigens that are shared by common microbes. During the 1990s, pigs transgenically expressing human complement regulatory proteins were developed, and it was discovered that most human and NHP anti-pig NAbs recognize a single carbohydrate, α-galactose-1,3-galactose (Gal), making it possible to remove these antibodies by adsorption. These advances extended the survival of pig organs to days or weeks in NHPs. Enthusiasm for xenotransplantation was nevertheless dampened by the identification of porcine endogenous retroviruses (PERVs) and concerns about the possibility that new viral illnesses might arise in humans as a result.

Guidelines have been developed to mitigate the risk of pathogen transmission from pigs to humans. Notably, PERV infection has not been detected in any pig-to-human or pig-to-NHP transplant recipient, although PERVs may have lower affinity for NHP forms of its receptor than of the human receptor. PERV loci have also been suppressed or deleted from some pigs, further improving safety. Consequently, there is broader acceptance of the likely safety of pig-to-human xenotransplantation with appropriate animal husbandry and microbial surveillance of the source animals, recipients, and their close contacts.

These encouraging developments have set the stage to proceed with clinical xenotransplantation. The first trials of pig-to-human organ xenotransplantation took place in 2021.