Is Raising Genetically Modified Pigs A Way to Solve the Organ Transplant Shortage?

By Breanne Kincaid and Rebecca Critser | August 8th, 2024

THE TRANSPLANTATION CONUNDRUM

A national shortage of organs for transplant has left tens of thousands of patients in limbo, waiting for a lifesaving transplant that may never materialize. United Network for Organ Sharing (UNOS), the federal contractor that operates the nation’s organ donation and transplant system, reports that 103,868 patients are currently on the organ transplant waiting list as of July 2024. Each day, 14 of these patients become too sick for transplant or die before being able to receive a donor organ. Transplantation is often the only remaining intervention for these patients’ conditions, and post-graft outcomes are generally favorable, with five-year survival rates topping 70% for most organs.

In short, sourcing additional viable organs is a necessity. Utilizing humanized pig tissue has been suggested as a means of alleviating this shortage. However, this strategy carries significant public health and ethical concerns, and ultimately may not be necessary if minor adjustments in the existing organ procurement model are implemented.

Organ Shortage Challenge

Numerous biological and logistical considerations go into whether an organ is matched for transplantation. Generally, donors and recipients must have a matched blood type and tissue type. Much like blood donation, people with blood type O are universal donors but may only receive organs from a type O donor, while those with blood type AB are universal recipients but may only donate to other type AB patients. In tissue typing, matches between several immune recognition proteins on the surface of the cells in the organ – called or human leukocyte antigens or HLAs – have been found to be particularly important to avoid the recipient’s body rejecting the donor organ. Matching all 6 antigens is rare outside of identical twins and Certain organs fare better than others when it comes to partial HLA matches. The organs must also be properly sized: children typically need to receive organs from other children, and adults from adults. Proximity also matters, since many organs can only survive outside the body for several hours.

Organs for transplant are identified from donor registries and inpatient hospital deaths reported to regional organ procurement organizations (OPOs), which operate as government-granted monopolies for on-the-ground organ recovery and distribution. UNOS oversees OPO operation and performance. Inefficiencies in the organ transplant system are responsible for additional complications that result in only 30 to 40 percent of organs available for transplant being utilized. For instance, OPO performance is assessed based on the number of organs procured per donor. This metric disincentivizes pursuing organs from donors who are only able to supply a single organ or tissue, meaning many thousands of otherwise viable donations are left unpursued. Similarly, the focus on post-operative multi-year success metrics used to evaluate transplant centers incentivize risk aversion, which means that organs procured for transplant are discarded if they are anything short of perfect.

Logistical challenges persist as well. Just 12% of inpatient hospital deaths are even reported to OPOs, allowing for any organ evaluation to occur. Investigations from Congress and the National Academies have also revealed substantial organ loss due to delays in transportation.

The Power of Shifting Policies

External watchdogs have pointed to UNOS’ monopoly as a primary factor in poor performance of the transplant system. The rate of OPOs losing or damaging organs during transportation is relatively high. Transplant coordinators currently enter, update, and validate patient and donor data by hand into an outdated computer system that is prone to crashing.

Research from the University of Pennsylvania Perelman School of Medicine identified roughly a half dozen policy changes to the existing organ procurement system that would result in 28,000 additional transplants every year – enough to entirely eliminate the waiting list for lungs and livers. These changes include empowering hospital staff to report inpatient deaths to OPOs, changing OPO reporting metrics to donors per death rather than organs per donor, and increasing oversight of poorly performing OPOs. Additional, more substantive changes also have the potential to address the organ shortage. Updating the outdated, manual workflow to include automation and linkages to electronic health records would reduce the time it takes to identify and alert matches, as well as reduce inequities in recipient selection. While UNOS has operated without competition since the organization first received its federal contract in 1984, improvement is expected to follow the 2023 disbanding of its monopoly. Experts hope that by introducing competition into the awarding of regional contracts, organ procurement entities will be more incentivized to improve their performance.

The theoretical need for pig organ transplantation

Utilizing pig organs would potentially present a near limitless supply of donor tissue. Companies that produce these organs are using gene editing techniques to address the biological constraints of patients rejecting grafts from foreign animals. By inserting genes that encode the cell surface markers that allow a human immune system to recognize a tissue as “self,” and removing genes that encode those which act as a red flag targeting the tissue for immune system attack, researchers have engineered pig tissue that is more human-like.

Sporadic human trials are already underway. In China, pig pancreatic islet cells have been grafted in diabetic patients whose own pancreas no longer produces insulin. In the US, gene-edited pig skin was successfully used as a temporary graft for a burn victim and performed as well as human skin. Transplantation of more complex organs hasn’t yet been as successful. Two recipients of genetically modified pig hearts, experimentally transplanted under compassionate use laws, survived just 40 and 60 days post-operation. However, numerous independent research groups across the globe are nearing readiness for transplanting gene-edited pig hearts into infants born with severe congenital heart defects.

Identifying the Public Health Risks

The primary concern with modifying pig genes to make their tissues and organs more human-like is the risk of making it even easier for pathogens to jump from pigs to humans.

Because pigs are already genetically relatively similar to humans – a primary rationale for using the species for human transplants in the first place – they can act as amplifying hosts that transmit zoonotic diseases – viruses, bacteria, and parasites – to people. This shared infectivity is particularly risky when disease agents that previously could not infect humans make the intraspecies leap, as happens with some degree of frequency with swine influenza (flu) variants. In fact, numerous regional and global pandemics over the past century have resulted from emergent zoonotic diseases, including ebola (primates), MERS (camels), and Zika (primates/mosquitoes).

The facilities where gene editing and pig rearing take place go through great lengths to remain germ-free, conceiving gene-edited animals in vitro, delivering the animals by ceasarian section, isolating individual animals, and requiring an extensive scrubbing in and out for all personnel entering the laboratory and animal housing facilities. With more facilities comes additional risk of a failure point along the zoonotic disease risk mitigation pipeline.

WHAT ABOUT ANIMAL WELFARE?

Current Systems in Place to Ensure Animal Welfare

One of the main ethical frameworks used in research with animals is known as the three Rs: replacement, reduction, and refinement. This phrase was coined by Russell & Burch in their 1959 text “The Principles of Humane Experimental Technique” in order to “diminish[] or remove[]” the “inhumanity” surrounding the use of animals in science and research.

Although not necessarily the original intent, today the term “replacement” is understood to mean a substitution of an animal model for a non-animal alternative. This is the most aspirational of the three Rs and as a result is harder to implement and less likely to be incorporated into laws and regulations.

The second term, “reduction” represents the need to use fewer animals while maintaining scientific and statistical significance. This is in part a reflection of the desire not to “unnecessarily” harm an animal subject.

The third and final term is “refinement.” This term is implemented when an experiment necessarily calls for animal subject and where there is the belief that the subjects may be caused physical pain. Under the principle of “refinement” researchers should make procedures as pain free as possible.

In addition to the 3Rs, the use of animals in research is subjected to ethical review. In the United States, that ethical review is conducted by the Institutional Animal Care and Use Committee (IACUC). Oversight by these committees are is legally required by facilities that are subject to the Animal Welfare Act or the PHS Policy.

The role of the IACUC is to review procedures that use animal subjects prior to the start of the work. The Committee’s exact purview is legally proscribed in the United States but contains a list of requirements consistent with the 3Rs framework. It is worth noting that under the Animal Welfare Act the IACUC’s role is limited by language that states “nothing in this part shall be deemed to permit the Committee or IACUC to prescribe methods or set standards for the design, performance, or conduct of actual research . . . .”

Many countries outside of the United States have mandated ethical reviews for research using animal models. Some take very different shapes. For example, Switzerland has an external review board that is the responsibility of the government. As you can imagine, an external review creates a very different type of process (and potentially outcome) than an internal institutional review. Some of these countries apply a harm-benefit test to measure the benefit of the science to humans, weighed against the harm it would inflict on animals.

Shifting Objectives

In pharma, toxicology and in basic research, traditional animal model uses have had three main goals: the acquisition of general knowledge, a check on product safety, and a check on product efficacy. For example, basic research tends toward the acquisition of general knowledge while environmental toxicology testing serves as a check on chemical safety. The use of animals in these cases is a way to gather data that will have in decision-making; therefore the use of these animals can be replaced with other non-animal, human-relevant means that also provides this information, or information that is even better.

However, the goals for companies who raise genetically modified pigs in order to harvest their organs for human use is markedly different. The goal here is to (1) address the organ shortage, (2) enhance human quality of life, (3) and prolong human life. Animal-use in this context is no longer secondary to the goal but the primary mode by which the goal is achieved. It can be argued that these companies are not investing in the development of GMO pigs in order to gain information about pig hearts or human hearts.  It is a business set up to use pig hearts to help humans. Once the decision is made to use animals as the primary vehicle by which the goal is accomplished, it becomes much more difficult to envisage an off ramp to a non-animal model.

Consequently, these solutions are inconsistent with the 3Rs. Companies can implement pain reduction techniques, but they will never strive to reduce the number of animals used since that is the merchandise they are creating. In fact they will most likely ramp up production, which will equate to ramping up animal use. Further, once they fully invest and the general health care system invests in products such as modified-for-humans pig hearts, it will be very hard to replace the animal use or think about other solutions to the organ transplant problem.

It is difficult to imagine what type of a review should be conducted by an IACUC or by the USDA in these situations. The GMO pig model requires a highly clean, bordering on sterile environment, necessarily limits social interactions between animals, and removes the child from the mother at birth. Further, the exact slaughter method is unknown but is almost guaranteed to be driven by the scientific needs which may run counter to general accepted “humane slaughter” practices.

THE WAY FORWARD

Healthcare is a finite resource, and its allocation is a reflection of societal values. Given the public health risks, welfare concerns, and relative ease with which human organ procurement solutions can be implemented, is a multi-billion dollar investment in the research and infrastructure required to make gene-edited pig organs necessary or appropriate?  We think better, less risky, ways of tackling the transplant organ shortage can be implemented. and would represent a much better use of healthcare resources.

The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.