You may have heard in the news recently that back in March, a 62-year old patient received a donor kidney from a genetically engineered pig. This was one of six cases in the past few years of pig organs being transplanted into humans as part of a “compassionate-use” protocol. The act of using animal organs for transplant in human patients (called xenotransplantation) has been a topic of research for decades with a significant increase in traction in the past few years. So since this likely won’t be the last time you hear about this topic, let’s talk about what xenotransplantation is, why it could be so significant, and what obstacles still remain.
The Promise
As of 2023, there were over 100,000 people on the organ transplant list in the United States alone, with an additional 65,000 added to that list per year. That same year, there were only 45,000 transplantable organs made available to recipients on this list from living and deceased donors. Demand so far outstrips supply that seventeen people die per day waiting for organs that never come. While the number of registered organ donors is rising, only 0.3% of these donors die in such a way to leave their organs transplantable. Additionally, because transplanted organs often spend some time disconnected from a body and because the recipient’s immune system does attack the foreign organ, transplanted organs don’t last as long in the recipient’s body as they would in their original body. Depending on the organ and the amount of time it spent outside the body, transplanted organs can last between ten and twenty years on average. As such, 25% of patients on the transplant list for donated kidneys have already received a kidney that has since stopped working. This has all necessarily resulted in a triage situation; organ donor lists have to carefully consider a number of factors when deciding who receives the limited number of organs. Therefore, people don’t make transplant lists because they are too old or too sick for a donated organ to contribute as much quality of life as it would for a younger or healthier person. Compared to the 89,000 people in the US on the organ transplant list for a new kidney, there are over 500,000 patients on dialysis with late-stage renal failure who don’t qualify for transplantation, as a new kidney would only buy them a few additional years but could buy someone else additional decades. This is what ethics has to look like when one is dealing with this degree of scarcity.
With all this in mind, finding ways to create organs or otherwise make new organs available has been a major research topic ever since the first organ transplants were performed. Xenotransplantation, transplanting tissues or organs between members of different species, has been explored as a concept for about as long. Transplanting animal tissue into humans is fairly common practice, from transplanting pig heart valves* to wound dressings developed from samples of pig bladder or fish skin. Transplanting whole animal organs is significantly harder. The first humans to receive interspecies organ transplants did so in 1963, when six terminally-ill patients received kidneys from chimpanzees. The organs did function normally in human bodies, but all six patients would die from complications of organ rejection within the next few months. Future attempts with animal hearts, kidneys, and lungs would all meet the same fate. Tissue rejection, where a patient’s immune system recognizes proteins on donated tissue as “not-self” and attacks it, has been observed ever since the earliest experiments with organ transplants were performed in 1902 (all with animal donors and recipients). Transplant patients have to take immunosuppressive drugs to prevent tissue rejection, and even these only slow tissue damage from rejection. That is what happens with human donors, even when the donor is the recipient’s sibling. If the organs of someone with the same parents are different enough to cause rejection, imagine the case where your last common ancestor with the donor lived 80 million years ago. So, ever since scientists began genetically modifying animals, there have been proposals to use genetic engineering to “humanize” animals, making their organs more molecularly similar to human organs so they will last longer in the human body.
Pigs are the most commonly considered animal for xenotransplantation today, as their organs are roughly the same size as human organs, their long history of close proximity to humans means there are very few diseases that could jump species that haven’t already, and they are extremely easy to breed, raise, and farm. To make pig organs work in humans, however, requires several modifications. Tissues contain several proteins which downregulate the immune system and communicate with immune cells, the human versions of which have to be added to the pig organs. There is a sugar on the outside of pig cells (and the cells of most mammals besides apes) called alpha-gal that has been known to cause allergic reactions in humans.** And the pig genome is known to carry several endogenous retroviruses (ERVs). Retroviruses, like herpes and HIV in humans, are viruses that, upon infecting a cell, incorporate their genes into the host’s genome such that they can remain there indefinitely, waiting for the right opportunity to emerge (more here). This is why diseases like herpes and AIDS are currently incurable; if there were a drug or immune response that kills the viruses, they would just wait inside their infected cells until the danger passed. And if a mutation were to ever break the gene which allows these viruses to re-emerge, then the genome of that virus would remain trapped in the host’s DNA indefinitely. These viral genes can then be passed down the generations until another mutation fixes the broken gene and allows the virus to randomly re-emerge. Porcine endogenous retroviruses (PERVs) are of serious concern to scientists exploring xenotransplantation because of the risk of these viruses jumping species to humans through transplanted organs.
Fortunately, with the development of CRISPR-Cas9 into a tool for relatively easy genetic engineering, this kind of significant genetic alteration of an organism has become far more feasible in just the past decade. In 2020, the FDA approved a line of pigs developed by the company Revivicor that had been genetically modified to remove alpha-gal from their cells. The primary purpose of these GM pigs are as a testing bed for xenotransplantation of organs and tissue. Removing alpha-gal drastically reduces the possibility of hyperacute rejection, where the immune system tries to kill the new organ within seconds of it being connected to the body, so this is arguably the most important gene edit to make. In 2022, the first transplant was done with one of these organs, when a patient with terminal heart disease received a heart transplant from one of these pigs. This was approved by the FDA under a compassionate use provision, designed for giving experimental treatments to patients with no other options. This pig had ten gene edits; three to remove alpha-gal and similar antigens, six to add human immune regulation genes, and one to prevent the heart growing too large. The patient only lived an additional two months (tests showed the presence of a porcine virus that likely weakened the heart in an already very weak patient), but it provided researchers with useful data. In 2022, a pig kidney with the same ten gene edits was transplanted into a brain-dead patient as part of a clinical study. The study only lasted for three days, but this was long enough to confirm the kidney wasn’t immediately rejected. Two similar studies have since been performed, with the third one lasting two months without signs of rejection. A second heart xenotransplant was done in late 2023 and a first kidney xenotransplant into a non-brain-dead patient was done in early 2024, though both of these patients would die months later of complications. Data is still being gathered and scientists are still learning how to refine this process.
Concerns and Obstacles
If xenotransplantation could be refined to the point of reliability, it would revolutionize transplant medicine. Not only could existing patients be rapidly given their much needed new organs, but patients who don’t currently qualify for transplants due to age or chronic illness would suddenly qualify. There are 75 million pigs in the United States as part of the pork industry; if just 1% of these pigs were to double as organ donors, we could provide kidneys for everyone in the country with renal failure and still have over a hundred thousand left over. Human longevity would likely increase as donor organs become plentiful enough to be used to treat age-related illness and overall quality of life would increase dramatically. That said, we are not yet near this point where pig organs will begin saving lives.
The biggest moral objection that has been raised to xenotransplantation has been one of animal rights. At its heart, the entire concept of xenotransplantation is predicated on the idea that an animal’s life is fundamentally worth less than a human’s life. I won’t comment on the relative moral standing of animals compared to humans, mostly because thinking about it causes me to fall down a rabbit hole that ends with me questioning how laws can exist if we don’t know what consciousness is. But I will say that killing pigs for their organs strikes me as significantly less unethical than killing them for their meat, and as a society we seem pretty insistent on the latter.
The more practical concerns for xenotransplantation are also plenty. So far, none of the test patients I described above survived longer than two months. Now to be fair, all of these patients were terminally ill and received these organs under a compassionate use provision (no one agrees to highly experimental medicine unless they are very close to death), so they already weren’t in the best position to contend with recovery. It’s possible a younger, healthier person could recover more easily, but we won’t be able to test that until we can reliably save the sickest patients. In at least one of these test cases, the cause of death was acute tissue rejection, where the immune system sees the new organ as foreign tissue and attacks it. While genetic engineering has reduced the chances of hyperacute rejection, where antibodies and the complement system attacks the organ after only minutes in the body, the risk of acute rejection, where immune cells attack the organ over the course of weeks, is still a risk. The strategy we’ve used since organ transplants became possible is drugs that suppress the immune system so they can’t attack the new organs. But as you can imagine, suppressing someone’s immune system has its own side effects, and patients with animal organs will require far greater immunosuppression to prevent their immune system attacking non-human tissue. All of the kidney recipients listed above received one other experimental treatment to potentially prevent rejection; a thymus co-transplant. The thymus is the organ responsible for training immune cells not to attack one’s own body, which I’ve talked about before if you want more details. The hypothesis behind the co-transplant is that by taking tissue from the donor’s thymus and implanting it in the recipient (either in the transplanted kidney or near the recipient’s own thymus), one can add the donor’s tissues to the list of tissues the immune system is trained to not attack. The first of these thymus co-transplants was performed in 2022 with a human-to-human transplant, and while that patient is still alive, it is still too early to determine its long-term success. While potentially revolutionary in its own right, this technique of preventing rejection without suppressing the immune system is just as experimental as xenotransplantation.
Rejection aside, there are other practical matters to consider with xenotransplantation. For one of the patients listed above, death appears to have been at least partially caused by a porcine virus that had been carried over during the transplant and weakened the heart when it needed its strength. While this wasn’t a case of a virus truly jumping species (there’s no evidence the virus spread to the patient’s human tissues), having a reservoir for a virus inside your body creates about the best opportunity possible for said virus to figure out how to infect humans. While gene edits can remove PERVs from a pig’s genome, that still leaves non-retroviral infections that could infect a donor pig and hitch a ride into a human host. All of the pigs whose organs were used for the xenotransplants above were grown in a sterile environment with filtered water, feed, and even air to ensure viruses can’t reach them. But these techniques are apparently imperfect and would be very difficult to scale up. Additionally, we have the various physiological differences between pigs and humans. Pigs only live about fifteen years, so it’s unlikely their organs would last a human’s lifetime. Pig’s organs are larger than human organs; transplant organs would come from juvenile pigs whose organs are the right size, but there’s a possibility these organs might continue to grow inside the recipient. Pigs have higher body temperatures than humans and they have lower blood pressures than humans, meaning a pig organ in a human body would experience a lower temperature and higher blood pressure than it’s used to. While all of these issues could be solved with further gene editing, it would be genetic engineering far more complicated than what’s been done so far, not to mention the pigs would have to remain viable and healthy with all these modifications in order to live long enough to donate.
Finally, I’d be remiss if I didn’t touch on the competition xenotransplantation has as a research topic; bio-printing. You’ve probably heard of this one as well, bio-printing is the concept of using 3D printers that lay down cells and proteins to create tissues or even organs for therapeutic purposes. Versions of this have been used to create heart valves and outer ears, as well as tissue samples for drug testing, but creating a fully functional organ has so far eluded researchers. Organs are incredibly complex and their structure needs to be perfect in order to work properly, not to mention it is hard to get oxygen and nutrients to a cell when it’s deep inside a half-printed organ. But if we could figure it out, bioprinting would be the holy grail of transplant medicine, able to produce organs on demand from a patient’s own cells with no risk of rejection whatsoever. It is an incredibly complex research topic that we are nowhere close to being able to use practically, but the same is true for xenotransplantation. This has been one last criticism that scientists have had for xenotransplantation; is it worth investing time and funding into an intermediary solution to organ production when the perfect solution doesn’t appear to require that much more effort? While xenotransplantation seems like a lower-hanging fruit compared to bioprinting, enough progress has been made in the latter to challenge that assumption. Determining how close an emergent technology is to regular implementation is nearly impossible, which makes allocating funding for these kinds of projects similarly difficult. The development of CRISPR-Cas9 and the resultant simplification of genetic engineering does seem to have removed some of the obstacles for xenotransplantation and thus made it a safer investment, so there may yet be a window of time where pigs become the best source of donor organs. But xenotransplantation will almost certainly not be our permanent solution to the problem of organ failure, and the permanent solution might come soon enough to make us question if this effort was worth it.
There are a lot of questions that need to be answered before we can determine if xenotransplantation is a possible solution to our organ shortage. Should we someday have a patient who survives with an animal organ longterm, the next big step will be to monitor how the organ behaves in their body over years and decades. We won’t really know if this is a viable solution until we know how long these organs last. We also need to know what genetic modifications these pigs need to make their organs viable in humans and what growing conditions would they need to improve the health outcomes. All of these are questions it will take time to answer and there’s no guarantee that this will be the solution to our problems. But the amount of effort being put into xenotransplantation, and other fields of medical experimentation, should make you confident that we will find a solution to this problem.
For More Details
*Transplanted pig valves don’t have any risk of rejection because they are treated with glutaraldehyde. This permanently binds together the surface proteins the immune system would react to and makes this reaction impossible. This also kills the cells in the heart valve, but it preserves the valve’s physical properties so it remains functional as a valve. This does mean glutaraldehyde treatment isn’t a viable solution to prevent rejection of more complex organs since they do require still-living cells to perform the chemical or nanoscopic functions needed for a functioning organ.
**Fun fact; the allergy to red meat caused by tick bites is itself an allergy to alpha-gal. Several tick species produce alpha-gal in their saliva and the antibody response to it is also activated in response to the alpha-gal in red meat. One of the other proposed uses for these alpha-gal-less pigs is as meat for those with this allergy.
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