Xenotransplantation and Gene Editing in Pigs

Source: https://cdn.modernfarmer.com/wp-content/uploads/2014/03/pig-organ-hero.jpg

Source: https://cdn.modernfarmer.com/wp-content/uploads/2014/03/pig-organ-hero.jpg

Xenotransplantation, the transplantation, implantation, or infusion into a human recipient from an animal donor, has been attempted for more than 300 years with little to no success [1]. The possibility of an essentially unlimited pool of organs to choose from has taunted many transplant surgeons and researchers alike. Beginning with blood xenotransfusion, then the grafting of animal skin to humans, and organ transplantation between different animal species in recent years, there have been many attempts to devise a feasible procedure to make organs and cells viable for human utilization. So far, none of these transplantations have succeeded enough to allow the recipient to live long after [1]. If successful, however, xenotransplantation could provide an abundant supply of the organs or cells required by individuals while providing the particular product in favorable conditions [3]. The growing organ wait list, currently with an estimated 117,000 Americans in which 22 die every day, could be potentially diminished to zero waits [4]. Currently, with expanding technologies in gene editing through CRISPR-Cas9, advancements have been made toward a pig to human transplantation that has the potential to terminate the waitlist itself and produce the boundless supply of organs and cells that would be available to all in need.

Pigs, relatively easy to breed with similar organ size and physiology to humans, are ideal candidates for growing organs for human use. One of the greatest obstacles with xenotransplantation was the presence of porcine endogenous retroviruses, or PERVs, in the pig genome [2]. Endogenous retroviruses are facets of animal genomes that have existed through thousands of years of evolution and are now “fossilized” viruses. These fossilized viruses remain in pig genomes and have the potential to adversely affect the human cell. Although some researchers argue that PERVs are a negligible factor when developing the xenotransplantation process, there is evidence that PERVs can spread to human cells, and those human cells can infect other human cells [4]. Although exactly what effects these PERVs have on human cells is unknown, there is a possibility that like other retroviruses, PERVs may produce immune responses that detrimentally affect human cells in an already immuno-incompetent individual, like an organ recipient [2].

In August of this year, a group of researchers led by Luhan Yang published an article illustrating the success they had with removing all 25 functional PERV genes from the pig genome using CRISPR-Cas9. CRISPR-Cas9 is a revolutionary method to manipulate and change DNA sequences in organisms [5]. In short, an inserted RNA sequence attaches to the target area of DNA and in turn, an enzyme called Cas9 also attaches to the RNA and cuts the DNA at that particular site. After the cut, the cell’s repair machinery can be utilized to make changes to the target location in the DNA. In this way Dong Niu et al. eliminated the PERV sequences from pig genomes [2]. The PERV free pig genome in nuclei were then transferred to pig embryos which were, in turn, implanted in normal pig mothers with PERVs. After birth, the surviving baby piglets were found to be healthy with fully deactivated PERVs. Although these piglets require long term study to detect ramifications of PERV inactivation and CRISPR-Cas9 editing, this strain of PERV free piglets has great potential to serve as organ and cell donors.

With the issue of PERVs seemingly resolved, researchers must now focus on pig tissue and blood compatibility with the human counterparts. Since humans and pigs express different blood group antigens, humans may produce antibodies against the pig antigens which could lead to a compromised immune system [1]. There is also the matter of ethics, and whether growing and genetically engineering pigs for organ harvesting is right. That matter may lie in the choice of the recipients, who will also have an opinion on whether they even want an organ from a pig in the first place. In addition, unknown viruses or other adverse health effects may plague the recipient years after the transplant, requiring a long term and careful monitoring of the recipient [2].

If each matter can be settled and if the xenotransplantation process becomes feasible, kidneys, hearts, livers, pancreatic islet cells, skin, corneas, and even embryonic neural precursor cells may be able to be produced to benefit not only those on the organ wait list, but also those with currently incurable diseases, like Parkinson’s or Huntington’s disease. Organs from pigs can also be a better option than organs donated by deceased individuals after brain death. For one, the organ would be taken out of the donor pig while the pig is still alive, essentially providing a fresh organ that is known to be superior to an organ taken after brain death [1]. The pigs would also be strictly monitored throughout their growth and inspected for any known viruses, which often is unable to be done on human organs as the transplant must happen immediately after death [2]. The benefits of a pig to human xenotransplantation is eminent and the implication that successful gene edited pigs holds is far reaching: not only would these pigs provide a limitless organs supply, but they can be the means for contribution to genome engineering in various other organisms and a source of specialized cells that have the potential to reverse many degenerative diseases.

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