This Little Piggy

Organ transplants have become a staple of modern medicine with 9 types of transplants approved in the United States: cornea, heart, kidney, liver, lung, pancreas, skin, trachea, and vascular tissue. These transplants are usually highly successful at both extending and improving the quality of life in the recipients, with about 40,000 performed yearly in our country. Nonetheless, there are still major limitations with transplants including lack of donor organs, the need for tissue compatibility between the donor and the recipient, and the need for the recipient to stay permanently on anti-rejection medication. All of these factors limit the quantity and quality of transplants that can be performed each year, leaving many desperate patients unable to receive the needed organs. By some estimates, as many as 10 potential transplant recipients die each day because a suitable organ is not available. Clearly, rather than human donors, other organ sources are needed to meet the unfulfilled demand. Creating human organs in the laboratory through bioengineering is a promising approach, but this technology is still being developed and is likely years from clinical application. Another alternative is to use animals rather than humans as the source of the donor organs, a process known as xenotransplantation.

Because their physiology and size of organs are similar to that of humans, domestic pigs are often used to test medical devices such as artificial hearts. These same attributes make pigs attractive animals for xenotransplantation if three major obstacles can be overcome. First, pig genomes harbor 25 endogenous retroviruses (PERVs) that could potentially spread from the transplanted organ into human cells where they could cause genetic disruptions leading to immunodeficiency or cancers. Second, pig cells express certain surface molecules that are not found on human cells. These unique pig molecules are recognized as foreign antigens by the human immune system and would elicit an immune response leading to rejection of the grafted organ. And lastly, there are some incompatibilities between the pig and human blood-coagulation systems that could cause dangerous clotting in the transplanted pig organs. Until all these issues are resolved, the use of pig organs in humans is not possible.

A recent publication in the journal Nature Biomedical Engineering used CRISPR-Cas9 and other genome editing technologies to alter the pig genome to make pig organs more suitable for xenotransplantation into humans. These investigators knocked out all 25 PERVs, inactivated the 3 pig enzymes that produce the rejection-inducing cell surface molecules, and inserted 9 human genes to improve immune compatibility and reduce the coagulation problem. In animals with such extensive genome modifications, there may be unexpected consequences, and it is never certain if the animals will be healthy and able to reproduce. However, these “humanized” pigs had normal physiology and fertility and could pass on the genetic modifications to their offspring. Importantly, transgenic pig cells behaved like human cells and did not suffer immune damage or clotting issues during in vitro testing in the lab. The next phase will be testing the pig organs for rejection in a living system by doing xenotransplants into nonhuman primates. While further modifications may be necessary to create clinically viable donor pigs, this study shows that complex and extensive genome modifications are tolerable and can correct the critical tissue differences between pigs and humans. Even if they need more genetic alterations, these modified pigs are a tremendous step forward towards solving the organ shortage dilemma.