This story was originally published in our Jul/Aug 2023 issue as “Breaking the Interspecies Barrier.” Click here to subscribe to read more stories like this one.

On a warm fall day in 2021, University of Alabama at Birmingham (UAB) surgeon Jayme Locke peered into a sliced-open abdomen and braced for the task ahead of her: transplanting two pig kidneys into a brain-dead human recipient for the first time in history. Locke had done experimental surgeries before, even putting pig kidneys into baboons. But this new procedure danced closer to the edge of the surreal, and unknowns leapt out at her.

She had no idea, for example, if the porcine organs would survive the rigors of stronger human blood flow. And though the pig kidneys had been genetically tweaked for cross-species compatibility, she feared the recipient’s body might still reject them. Setting her doubts aside for the moment, Locke stitched one pig kidney’s main vessels to the patient. She removed the steel clamps that pinched the human vessels shut. Then she and the rest of the operating team waited. “We were almost in suspended animation,” she recalls. “We all were just standing there, hoping the kidney was going to turn beautiful and pink.”

As human blood thrummed through the new organ, its color ripened from blue-gray to mauve and then to bright coral — the first sign the kidney was settling in as it should. Twenty-three minutes after Locke removed the vessel clamps, human urine began to flow from the pig kidney into its ureter, the tube that shunts urine from the kidney to the bladder.

“It was probably the most remarkable thing I’ve ever seen,” she says. Watching the dark-yellow fluid drip from the ureter into a clear cup, Locke knew things could easily go south later on. Still, she let herself contemplate how much this moment could mean for the thousands of end-stage kidney patients facing a wait for a new organ with no end in sight.

Demand exceeds supply

That day at the operating table — when Locke and her team leapt into medically uncharted deep space — came to fruition not just through dogged scientific legwork, but through the muscular force of necessity. As long as organ transplants have existed, there’s been a glaring mismatch between the number of people needing transplants and the number of human donor organs available.

In the U.S. alone, more than 500,000 people now live with end-stage kidney disease, meaning they require dialysis therapy or a kidney transplant to survive. Another 6.2 million people live with heart failure, their hearts unable to pump enough blood to their bodies, and 4.5 million have chronic liver disease. Yet donor organs are incredibly scarce.

On average, just 3 in 1,000 people can donate their organs after they die, since causes of death ranging from disease to accidents often make organs unusable for transplant. In 2021, for the first time ever, U.S. surgeons performed more than 40,000 organ transplants — but that number is nowhere near enough. Everyone else is forced to languish on the waitlist, and more than a dozen people die each day because their hoped-for organ didn’t arrive in time. “The demand far exceeds the supply that we have,” Locke says. “To meet these patients and know that they are more likely to die from their disease than they are to get a transplant — it’s just extremely devastating.”

That’s where porcine kidneys and hearts, and a series of other organs, come in. Using techniques they’ve refined in the lab, scientists are now breeding organ-donor pigs in germ-free conditions and genetically engineering the animals so their organs produce less rejection in human recipients. “It’s a source of organs that’s sustainable and can be scaled exponentially,” says Robert Montgomery, a transplant surgeon at New York University’s Langone Health.

Five days before Locke and her team transferred pig kidneys into a brain-dead human patient — a setup conceived as a way station between primate studies and full-scale human transplants — Montgomery and his NYU colleagues pulled off a similar procedure, attaching a pig kidney to a brain-dead recipient’s body.

Should modified pig organs pan out for recipients in the long term, these organs could feed an inexhaustible cross-species transplant pipeline. But pig kidneys that filter human urine and pig hearts that beat inside human bodies haven’t yet fulfilled xenotransplantation’s promise. Researchers must still prove that these donor organs function reliably in humans over the long term, and that drugs and shrewd gene edits can keep the threat of organ rejection at bay.

Locke, Montgomery and others hope the U.S. Food and Drug Administration will soon approve human clinical trials of xenotransplants. But, so far, the FDA has held back. Xenotransplantation’s potential may be great, but the risks are just as significant: Not only could botched procedures cost people their lives, but they could also potentially deal the entire field a death blow. “One wrong step,” warns University of Pittsburgh Associate Professor of Surgery Mohamed Ezzelarab, “may jeopardize a great future for patients.”

Mythology to gene modifications

Cross-species transplantation first proceeded in a series of ill-advised flying leaps. Like Greek mythology’s Icarus, whose faux bird wings allowed him to soar across the sea, early xenotransplant surgeons foundered after flying too close to the sun. French doctor Jean-Baptiste Denys started transfusing sheep blood into humans in the late 1600s — and while a few recipients survived, many others died. In the 19th century, doctors attempted to graft sheep, rabbit or frog skin onto injured humans, but the recipients’ bodies rejected these skin transplants, their immune systems attacking the foreign cells.

By the mid-20th century, Tulane University surgeon Keith Reemtsma, driven by the dire shortage of human donor kidneys, tried his hand at transplanting chimpanzee kidneys into people. Though he gave his dozen or so patients drugs that staved off rejection in human-to-human transplants, almost all the transplants failed within weeks as recipients’ bodies rejected the animal organs.

Xenotransplant specialists began to make more meaningful advances in the late 20th century, most notably by transplanting pig heart valves into humans. In the 1990s and 2000s, that success helped to focus attention on the benefits of using pigs as donor animals; not only were they easy and cheap to breed, but their organs were fortuitously similar in size to human organs.

Even so, transplanting an entire donor pig organ — a complex biological machine unto itself — remained an elusive feat for decades. This is in part because of the pathogen cargo such organs can transfer: Most pigs carry endogenous retroviruses, which can in theory lead to unpredictable illnesses in human recipients. Cross-species transplants also pose a distinct set of immune compatibility issues. For one, pig cells express certain types of carbohydrates, including one called alpha-gal, which is found in most mammals but not in human cells. Without intervention, human immune cells treat these foreign molecules like invading guerrillas, resulting in swelling or blood clotting that can grind organ functions to a halt.

To address the retrovirus issue, researchers turned to so-called pathogen-free facilities for raising organ donor animals. In 2016, for example, UAB opened a germ-free pig-breeding facility in Birmingham in collaboration with the biotech company Revivicor. There, technicians conduct stringent tests to verify that no harmful pig viruses are present. “That was an important step in the right direction,” Locke says.

Scientists have also made a flurry of genetic tweaks to donor animals to fend off the threat of organ rejection. After zeroing in on animal molecules like alpha-gal that provoke a strong human immune response, researchers used gene-modification tools like CRISPR to engineer pigs whose cells do not produce these molecules. In late 2020, the FDA approved Revivicor’s so-called GalSafe pigs, which do not express alpha-gal at all. Experimental Revivicor pigs at the UAB boast a total of 10 different gene modifications geared toward dialing down human immune responses.

A Reason For Hope

Technical tweaks like these successfully laid the groundwork for transplant pioneers, many of whom aim to make organ waitlists a thing of the past. But after years of testing xenotransplant techniques in lab animals, researchers set their sights on the next level: transferring modified pig organs into humans. Most experts, understandably, were wary of utilizing live human recipients right away.

Still, Locke says, “we needed a new model to really test our engineering.” That prompted her team, as well as Montgomery’s, to try placing animal organs into human patients with nonexistent brain function and no chance of recovery. This way, they thought, they could assess how the pig organs performed in humans without the risk of losing sentient patients on the operating table.

As the UAB researchers prepared to test this model in September 2021, they looked for a family who would allow a loved one who’d suffered brain death to receive a pair of pig kidneys. They found one prospect in Jim Parsons, a 57-year-old man severely injured in a motorcycle crash days before; doctors had confirmed that Parsons’ brain no longer showed any activity, even though his organs were still functioning. “They ultimately decided,” Locke says of the family members, “that this is what Mr. Parsons would have wanted.”

For Locke, the trust the family placed in her amped up the stakes of the transplant. She wanted to succeed not just to honor Parsons, but to give thousands of waitlist patients a new reason to hope. That also meant she had a hard time relaxing — even after the transplanted pig kidneys pinked up in the operating room. She and other surgical team members took turns camping out by Parsons’ bedside after the procedure. “It was three days of not a lot of sleep,” she says, during which time Locke watched the pig kidneys’ surface closely for signs that Parsons’ body was starting to reject the organs.

But as she sat by her patient hour after hour, Locke also tried to focus on the positive. Each drip of urine felt like a victory — proof that the kidneys were filtering waste the way they were supposed to. Then, after more than 70 hours with no major signs of organ rejection, the team took Parsons off life support, confident they’d taken a big step toward showing that animal parts could work inside people. “It was extraordinary,” Locke says. “We were just ecstatic.”

Following a procedure in which they attached a pig kidney to a brain-dead recipient’s body, Montgomery and his NYU team carried out another barn-burning achievement: transplanting two Revivicor pig hearts into brain-dead recipients. The cross-species transplants felt especially poignant for Montgomery, who had received a donor heart himself years before. As part of the surgical team, he even got to work with the same surgeons who had done his own transplant. “That was very deeply personal,” Montgomery says. “Standing at the head of the bed and seeing this pig heart pounding away in the chest of a human — I just never imagined that in my lifetime I would see that.”

Like Locke’s transplanted pig kidneys, the pig hearts held out for days without signs of rejection. Even so, other recent xenotransplant attempts have highlighted the very real hazards involved. In an early 2022 case that made headlines worldwide, University of Maryland surgeons transplanted a Revivicor pig heart into 57-year-old David Bennett, who had lived with heart failure for years. Because Bennett didn’t qualify for a traditional heart transplant, xenotransplantation was his only hope to stay alive.

While Maryland doctors didn’t uncover evidence that Bennett’s immune system had rejected the pig heart, they did find that the organ was carrying porcine cytomegalovirus at the time of Bennett’s death two months later, raising questions about whether the virus was to blame for the heart swelling that killed him.

Unanswered Questions

It’s hard to draw any firm conclusions from Bennett’s case, as his longtime heart failure made him a less than ideal xenotransplant candidate to begin with. Yet his fate underscores what surgeons like Locke and Montgomery have long known: The real verdict on cross-species transplants will play out over the course of months and years, not days. As exciting as it is to watch a pig heart pound away in a human chest cavity, it doesn’t mean much unless the recipient goes on to lead a normal life — ideally for a decade or more. “How long do these [organs] actually last?” Locke says. “That’s going to be a really important question.”

To evaluate how well pig organs do in humans over the longer term, Montgomery, Locke and others plan to follow future brain-dead human recipients for up to a month, watching for signs of incompatibility. Though the lack of immediate rejection in human recipients has been encouraging, that story could easily change when doctors follow transplant patients for extended periods, says Columbia University immunologist Megan Sykes.

Over a weeks- or months-long interval, the human immune system will likely mount a whole new attack on a pig organ. Blood proteins called antibodies could react to animal cells by emitting compounds that cause clots near the transplant organ, for example, slowly but surely degrading its function. “We don’t know what happens in terms of longer-term antibody responses,” Sykes admits. Likewise, T-cells — white blood cells that help shield the body from infection — could attack transplanted organ tissue over time. While transplant recipients will receive immunosuppressive drugs to control these responses, scientists still don’t know how well these drugs will work on patients who receive animal organs.

The flood of unanswered questions helps explain why the FDA has so far declined to approve a full-scale human clinical trial of pig heart or kidney transplants, even though surgeons like Locke see such a trial as the next logical step. Last year, administration officials highlighted what they saw as the biggest risks of xenotransplants, citing a need for more studies on how to control pig organ rejection and how to keep pig viruses contained.

Should future discussions and legwork convince the FDA to greenlight a trial, a key initial step will be “sitting down and discussing how to select the right patients,” says Ezzelarab. A trial that enrolls severely ill subjects, he notes, could have very different results than one that recruits less severely ill patients.

Whichever way the research turns out, Locke has no illusions about the scale of the challenges ahead. But a flush supply of animal organs could end one of the hardest parts of her job: breaking the news to patients, sometimes dozens each week, that their odds of receiving a donor organ are slim. With that burden lifted, she could engage many more people in planning for an open-ended future.

“If you get a transplant,” she says, “older adults live long enough to see their grandchildren. It really does give people life.” For her, that chance is worth fighting for, even with the risk of flying too close to the sun.

Alternatives to the Alternative

Should cross-species transplant trials fail to pan out, Minnesota-based Miromatrix Medical has a possible backup plan in the works. The life sciences company is perfecting a process that involves pumping pig organs with chemicals to dissolve the living cells, leaving only a skeletal tissue framework behind.

Scientists then re-seed this framework with human heart, kidney or liver cells obtained from organs that aren’t suitable for whole transplant, populating the tissue shell with the precise kinds of organ cells needed to perform different organ functions. Regenerative medicine researcher Doris Taylor, one of Miromatrix’s co-founders, pioneered the process of creating these so-called “ghost organs” more than a decade ago, using rat hearts as experimental organ shells.

The latest hybrid organs theoretically pose no threat of rejection or disease. “In our approach, we’ve mitigated that risk,” says Jeff Ross, Miromatrix’s CEO. “We’re able to wash all the porcine cells out of that organ.” Since the new organs contain only human cells, doctors could be more confident that long-term compatibility issues won’t arise.

Miromatrix scientists have successfully implanted five bioengineered livers into pigs in a pre-clinical study, but questions remain about how well the cell-seeded organs will perform inside humans. The researchers hope to resolve some of these in a study awaiting FDA approval, which will assess how well their engineered livers cleanse the blood of people with acute liver failure. “This is not decades away,” Ross says. “We’re thinking years in terms of being in the clinic, because the need is so great.”