Xenograft: A Transplant From One Species to Another

A xenograft is a living tissue or organ transplanted between two different species, and the version that matters most today is the pig-to-human transplant. For decades, the idea of placing an animal organ inside a person sat firmly in the realm of science fiction or failed experiment. That changed dramatically in 2022, when surgeons at the University of Maryland transplanted a genetically modified pig heart into a living patient who survived for 60 days with the organ beating in his chest. The field has moved fast since then, with pig kidneys now being tested in both brain-dead and living recipients, and the first regulated clinical trial of a gene-edited pig kidney underway in the United States.

A Long History of Trying

Cross-species transplantation is not a new idea. In the 1920s, a French surgeon named Serge Voronoff grafted slices of chimpanzee testicular tissue into elderly men, convinced the hormones would rejuvenate them. The modern era of xenotransplantation began in the early 1960s, when Keith Reemtsma transplanted chimpanzee kidneys into 13 patients who had no access to dialysis or human donors. One of those patients returned to work for nearly nine months before dying suddenly from what was likely an electrolyte problem. In 1964, James Hardy performed the first-ever heart transplant in a human using a chimpanzee heart; the patient died within two hours. Thomas Starzl attempted the first chimpanzee-to-human liver transplant in 1966, and decades later, in 1992, he kept a patient alive for 70 days with a baboon liver.¹

These early cases made two things clear. First, animal organs could function inside humans, at least temporarily. Second, the human immune system was ferociously hostile to them. Every attempt ended the same way: rejection, infection, or both. The field needed to understand exactly why cross-species organs failed so violently before it could move forward.

Why the Body Attacks a Pig Organ

When a pig organ is connected to a human blood supply, the immune response is almost instant. Human blood contains preformed antibodies that recognize a sugar molecule found on the surface of pig cells. This sugar, commonly called the alpha-gal epitope, is produced by an enzyme that coats pig blood vessel linings with it in abundance. Within minutes, those antibodies latch onto the pig tissue, trigger the complement system (a cascade of proteins that punch holes in cells), and kick off rapid blood clotting inside the organ. The result is hyperacute rejection, where the transplant can turn dark and stop working in less than an hour.²

Even if hyperacute rejection is avoided, the immune system mounts a longer-term campaign. Pig proteins that carry the alpha-gal sugar get swallowed up by human immune cells, which then present fragments of those proteins to helper T cells. Those T cells activate antibody-producing B cells, which churn out large quantities of high-affinity antibodies specifically targeting the pig tissue. This secondary wave is harder to suppress than the initial blast because it involves the adaptive immune system learning and remembering the foreign tissue.³

Rewriting the Pig Genome

The breakthrough that made modern xenotransplantation possible was gene editing. Using tools like CRISPR-Cas9, researchers can now delete the genes responsible for producing the sugar molecules that trigger rejection. The most common approach targets three genes at once: GGTA1 (which makes the alpha-gal sugar), CMAH (which produces another sugar called Neu5Gc), and β4GalNT2 (which makes a third called Sd(a)). Pigs with all three genes knocked out, known as triple-knockout pigs, show dramatically reduced binding of human antibodies across most organs. In testing, the alpha-gal, Neu5Gc, and Sd(a) sugars were barely detectable in triple-knockout pig tissues, and human antibody binding to the heart, lungs, kidneys, and corneas dropped significantly compared to unmodified pigs.⁴

Some research groups have gone further, knocking out a fourth gene called CIITA that plays a role in activating human CD4 T cells, the immune cells that coordinate the longer-term rejection response. Four-gene-knockout pigs are designed to blunt both the immediate antibody attack and the slower adaptive immune response at the same time.⁵ On top of gene knockouts, many donor pigs also carry inserted human genes, such as those coding for human complement-regulatory proteins or proteins that help manage blood clotting. The goal is to make the pig organ’s surface look less foreign and more human to the recipient’s immune system.⁶

The Virus Problem

Immune rejection is not the only barrier. Pigs carry viruses embedded in their own DNA, called porcine endogenous retroviruses, or PERVs. Unlike a regular infection that can be treated or prevented with hygiene, PERVs are part of the pig genome itself. Every pig cell contains them, and there was genuine concern that these viral sequences could reactivate after transplantation and infect the human recipient, potentially even spreading to the wider population.

In 2017, a team led by Luhan Yang and George Church used CRISPR-Cas9 to inactivate all PERV copies in a pig cell line by disrupting a critical part of the viral machinery needed for replication. They then cloned live piglets from those edited cells, producing the first PERV-free pigs.⁷ Follow-up work confirmed that 100% of the PERV elements could be knocked out in a single cell line.⁸

But PERVs are not the only viral risk. Porcine cytomegalovirus, a herpesvirus common in pigs, turned out to be a serious practical threat. In preclinical studies, transplanting organs from PCMV-infected pigs drastically shortened graft survival in primates. The virus disrupted the clotting system and suppressed the recipient’s immune function.⁹ By contrast, using PCMV-free pig hearts in the same experimental setup prevented consumptive coagulopathy entirely and extended graft survival.¹⁰ This finding became painfully relevant in the 2022 Maryland pig heart case, where rising PCMV DNA was detected in the patient’s blood before his death, and the virus likely contributed to the graft’s decline.

Recent Pig-to-Human Transplants

The modern clinical era of xenotransplantation began in September 2021 at NYU Langone Health, where surgeons transplanted a kidney from a single-gene-knockout pig into a brain-dead person. The kidney started producing urine immediately and showed no signs of hyperacute rejection over the 54-hour observation period.¹¹ In a subsequent experiment with two brain-dead recipients, the xenograft kidneys substantially improved kidney function. In one recipient, the estimated filtration rate nearly tripled, from 23 to 62 ml per minute. In the other, it roughly doubled, from 55 to 109. Creatinine levels fell in both cases, and biopsies taken at multiple time points found no evidence of hyperacute or antibody-mediated rejection.¹²

The most dramatic case was the January 2022 pig heart transplant at the University of Maryland. The patient, David Bennett, had end-stage heart disease and was not eligible for a human donor heart. The genetically modified pig heart functioned well for over 40 days, sustaining his cardiovascular system. Around day 47, diastolic heart failure set in. Biopsies showed damaged blood vessels, clotting abnormalities, and complement deposits. Rising levels of porcine cytomegalovirus DNA were detected, and antibodies against pig tissue increased after the patient received intravenous immunoglobulin for low antibody levels. He died on day 60.¹³ The case raised a difficult question: did the pig virus, the immunoglobulin treatment, or something else trigger the decline? Researchers have described the cause of death as overlapping and uncertain, with the virus, immune reactions, and the patient’s fragile baseline health all playing a role.¹⁴

Blood Clotting Mismatches Between Species

Beyond immune rejection and viral risk, there is a subtler problem: pig and human blood clotting systems do not work together smoothly. Pig von Willebrand factor, a protein involved in clotting, interacts abnormally with human platelets, which can trigger unwanted clots. Pig thrombomodulin, which normally helps activate protein C (a natural anticoagulant), does not work efficiently with its human counterpart. The result is a one-two punch: too much clotting inside the transplanted organ and a dangerous depletion of clotting factors throughout the recipient’s body, a condition called consumptive coagulopathy.¹⁵ In primate studies, rejected pig organs almost always show blood clots and trapped platelets, and recipients frequently develop this systemic clotting disorder.¹⁶

This is partly why some gene-edited pigs now carry human genes for thrombomodulin and other clotting regulators. The idea is to make the pig organ’s blood vessel lining respond to human blood more like a human vessel would. It is an active area of engineering, and one where the stakes are high: clotting problems have been implicated in most xenograft failures to date.

The Organ Overgrowth Problem

Even if the immune system is controlled and clotting works properly, pig organs can keep growing inside a human body. Pigs grow fast, and a pig heart transplanted into a primate can enlarge to the point of compressing surrounding structures or developing diastolic failure simply because it gets too big. To address this, researchers created pigs with a growth hormone receptor knockout, which limits organ size. In preclinical heart transplants, these growth-limited grafts showed normal function, with recipients surviving up to 264 days. The heart’s mass increased only modestly over six months, and the recipients remained symptom-free with no signs of heart failure from overgrowth.¹⁷ Using growth-limited donor pigs also allows transplantation at a more mature age, past the steepest phase of their growth curve, which further reduces the risk of the organ outpacing the recipient’s body.¹⁸

How Long Pig Organs Have Lasted in Primates

Before pig organs go into human patients, they are tested in non-human primates. These preclinical results set the benchmarks that regulators look at. A pig kidney graft with multiple human transgenes and a knockout of the alpha-gal gene survived 136 days in a baboon, with generally stable kidney function throughout.¹⁹ More recently, a study of genetically engineered pig hearts transplanted into non-human primates reported life-supporting function for up to 225 days, with an average survival of about 128 days across ten transplants.²⁰ Ongoing studies are now analyzing these long-surviving grafts at the molecular level to understand which immune pathways stay active over time and which eventually quiet down.²¹

Keeping the Immune System in Check

Xenotransplant recipients need aggressive immunosuppression, more than what is typically used for human-to-human transplants. One of the most effective strategies targets a signaling pathway called CD40-CD154, which T cells use to activate B cells and ramp up antibody production. In baboon studies, blocking this pathway with an anti-CD40 antibody extended pig heart graft survival to a median of 84 days, with the longest survivor reaching 149 days.²² Follow-up work confirmed that this co-stimulation pathway is central to how the primate immune system drives xenograft rejection.²³

In kidney xenotransplantation studies, a combination approach has shown promise: anti-thymocyte globulin and anti-CD20 antibodies to deplete T and B cells upfront, followed by anti-CD40 antibody maintenance therapy that keeps those immune cells from bouncing back.²⁴ The challenge is that such deep immune suppression leaves patients vulnerable to infections, cancer, and other complications. Finding the right balance, enough suppression to protect the pig organ but not so much that the patient’s defenses collapse, remains one of the field’s hardest problems.

Xenografts Already in Clinical Use

While whole-organ xenotransplantation grabs headlines, simpler forms of xenografts have been used in medicine for years. Porcine skin grafts are widely used as temporary wound dressings for severe burns. They function as a biological barrier, reducing fluid and heat loss, blocking bacteria, and decreasing pain. A systematic review of clinical outcomes found that porcine grafts required fewer dressing changes and provided effective temporary coverage.²⁵ Genetically modified pig skin grafts (with the alpha-gal gene knocked out) have been shown to provide wound coverage for up to 11 days, roughly equivalent to human donor skin, making them a viable alternative when human allografts are not available.²⁶

Pig heart valves have also been used for decades after being chemically treated to remove living cells, leaving behind a scaffold of structural tissue. These are not living xenografts in the strictest sense, but they are animal-derived implants that millions of people walk around with. The newer frontier is cellular xenotransplantation, particularly for diabetes. In clinical trials, encapsulated pig islet cells (the insulin-producing cells of the pancreas) were transplanted into patients with type 1 diabetes without immunosuppression. In the higher-dose group, all four patients improved their blood sugar control, maintaining HbA1c below 7% for more than 600 days with a significant drop in dangerous hypoglycemic episodes.²⁷ The capsules protect the pig cells from immune attack, which is why no anti-rejection drugs were needed. Improvements in capsule biocompatibility, transplant location, and pig genetics are expected to push efficacy further.²⁸

Religious and Social Attitudes

Public acceptance of xenotransplantation varies along cultural and religious lines. A nationwide U.S. survey found that the two biggest concerns across all religious groups were the lack of long-term evidence and the risk of animal viruses crossing into humans. On average, about a quarter of respondents across all faiths flagged the zoonotic infection risk as a concern. Catholic and Muslim respondents were the most comfortable with pig-to-human transplantation overall. Orthodox Christians expressed the highest rate of negative feelings about recent xenotransplantation experiments. Perhaps surprisingly, people who reported no religion were the most likely to have negative feelings about killing pigs for human organs.²⁹

Racial disparities also shape attitudes. In one study of kidney patients, white patients were substantially more willing to accept a pig organ transplant if results were shown to be comparable to human-to-human transplants. Black kidney patients were more likely to express concern that receiving a pig organ could change their personality or alter their social interactions.³⁰ Among adolescent patients who actually received porcine islet cell transplants, the dominant feeling was pragmatism: they saw pigs as an unlimited resource and focused on the autonomy the treatment gave them. Those whose transplants worked best reported the biggest improvements in quality of life, while non-responders experienced mainly frustration.³¹

The Regulatory Path Forward

Xenotransplantation in the United States is moving from emergency one-off cases into structured clinical trials. The EXPAND study, sponsored by United Therapeutics Corporation, is the first regulated multicenter clinical trial evaluating a 10-gene-edited pig kidney in patients with end-stage kidney disease who are ineligible for or unlikely to receive a human donor kidney within five years.³² Previous cases relied on the FDA’s expanded access (compassionate use) pathway, which allows seriously ill patients to receive investigational treatments outside formal trials. Moving into a registered clinical trial means standardized protocols, larger patient numbers, and the kind of systematic data collection that regulators need to evaluate safety and effectiveness.

One of the thorniest regulatory questions involves long-term monitoring. Recipients of pig organs, along with their close contacts, may need to be followed for years to watch for delayed viral transmission or other unforeseen complications. The most difficult legal and public health questions may center on what happens when individual patients or their contacts do not comply with monitoring requirements.³³ This is not a hypothetical concern. Organ transplant recipients already struggle with medication adherence, and xenotransplantation adds an entirely new surveillance layer that has no precedent in medicine.

Growing Human Organs Inside Animals

While gene-edited pig organs represent the near-term path, some researchers are pursuing a more radical strategy: growing fully human organs inside animal embryos. The approach, called blastocyst complementation, involves disabling a specific organ-development gene in an animal embryo and then injecting human stem cells that fill the developmental gap. In theory, the animal grows normally except that one organ, the one whose gene was knocked out, is built entirely from human cells. Early experiments in rodents have demonstrated the concept, and efforts to scale it up to larger animals are underway.³⁴ If it works in pigs or sheep, this could eventually produce transplantable organs that are genetically matched to a specific patient, eliminating the need for immunosuppression altogether. The technical and ethical hurdles remain steep, but the concept illustrates just how far the boundaries of cross-species medicine are being pushed.