Xenotransplantation promises to solve organ shortage and to reshape how we think about human longevity, but it also raises a host of questions
Shards of electricity burned through Mr P’s flesh. Layers upon layers of subcutaneous fat unraveled, filling the operating room with a pungent, metallic odor, like singed hair at the neighborhood barbecue. Within a few minutes, the pearly white bone of the sternum stuck out before a vein split open, filling the operative field with blood.
Zap! Maroon juice turned into a crackly black mass.
Transplant surgery is all about timing, says Dr Brandon Guenthart, a cardiothoracic surgeon at Stanford University School of Medicine. Anesthesiologists put the patient to sleep after the retrieval team confirms the donor heart looks good. Two surgeons start operating an hour before the donor heart arrives in the hospital. They don’t begin cutting the patient’s heart out until the donor heart has landed safely at the local airport.
And if the plane crashes? “Knock on wood,” says Guenthart. There’s unfortunately no wood in the operating room.
I was at Stanford hospital watching this heart transplant because of my interest in David Bennett, a 57-year-old man who had died back in March. On 7 January 2022, at the University of Maryland Medical Center, Bennett had received a landmark heart transplant from an unusual donor: a genetically modified pig.
In 2021, a record 41,354 human-to-human organ transplants were performed, but over 100,000 Americans are still stuck on the transplant list. Every day, 17 people die waiting because there simply aren’t enough organs to go around.
Xenotransplantation – or transferring cells, tissues and organs between species – promises to solve this shortage and to reshape how we think about human longevity.
Lost in this boundless potential, however, is the significance of the human-animal divide. People walking around with pig organs melded into their bodies – human-animal cyborgs of sorts – can seem dystopian. And with the zoonotic Sars-CoV-2 virus having killed more than 6 million people, violating the interface between humans and animals may just promise more catastrophe.
This tortuous relationship is nothing new, but it’s often sanitized and hidden from sight – think grinning cows on milk cartons and secret bunkers for animal research. Left open is a whole host of questions, starting with the most complex of all: what does it mean to be human?
Humans are animals. But animals are not humans. And yet, our history is rife with a cultural imagination of hybridity. The ancient Egyptian god of the sky, Horus, was depicted with a falcon head and the goddess of war, Sekhmet, that of a lioness. Similarly, the Hindu god Ganesha was beheaded and then resurrected with an elephant head grafted on to his body. In ancient Greece, fantastical creatures roamed the myths, from the bull-headed Minotaur to the snake-haired Medusa.
Within this wealth of options, the International Xenotransplantation Association chose a more obscure mascot: the Lamassu, an Assyrian deity with the body of a bull, the wings of a bird, and the head of a man – a grounding wisdom.
Xenotransplantation, as a research field, started only with cells and tissues. In 17th-century France and England, blood was transfused from animals to humans to cure a whole host of medical conditions. Spiritual meaning was imbued into the act: “Since Christ is the lamb of God,” one recipient wrote in a letter to the Royal Society, “sheep’s blood possess[es] a symbolic relationship with [his] blood”. One patient’s violent fever was purportedly cured, as was another patient’s paralysis, but at least two others died soon after these “xenotransfusions”.
Other early xenotransplants would follow, including ones with the bone, cornea and skin. Perhaps most infamously, the French surgeon Serge Voronoff transplanted slices of chimpanzee and baboon testicles into men, and ape ovaries into women, to rejuvenate his patients’ “zest for life”. Thousands of these operations were performed around the world, but any reported benefit, such as reduced fatigue or increased sex drive, was probably only the placebo effect and quickly faded.
While cell and tissue xenotransplants have been performed for centuries, whole organ transplants were more difficult to figure out. Sewing all the blood vessels together is a tricky business. You have to put two floppy tubes together “mouth-to-mouth”, tying them tight enough that the patient doesn’t bleed out, but delicately enough that the patient doesn’t have major clotting either.
This was a Nobel prize-level problem that the French surgeon Alexis Carrel solved with a small embroidery needle and fine silk suture, and was recognized for in 1912. He’s sometimes known as the father of transplant surgery.
A half-century later in 1964, the University of Mississippi surgeon James Hardy attempted the world’s first cardiac transplant, transferring Bino the chimpanzee’s heart into the chest of the rapidly deteriorating 68-year-old Boyd Rush. Rush survived for only 90 minutes, with the chimp heart offering insufficient support and rejection quickly shutting down his body.
It was Baby Fae who truly set the stakes for xenotransplantation. She was a 12-day-old infant with hypoplastic left heart syndrome, a congenital abnormality where the left side of the heart is a sliver of its full form. The condition was a death sentence.
So, in 1984, surgeons at Loma Linda University, California, transplanted a walnut-sized baboon heart into Baby Fae’s chest. The conditions were almost perfect. The heart was well-sized, Baby Fae’s immune system was immature (and sympathetic), and the immunosuppressive drug cyclosporine could suppress attacks on the baboon heart.
After the operation, Baby Fae seemed to be doing well. Resting in her crib with a gauze-covered scar traversing her chest, she was “just gulping down her formula” and wailing with a “lusty cry”, according to the hospital spokeswoman. The hospital also released photos of Baby Fae “talking” with her mother, the phone receiver bigger than her entire torso.
She died 21 days after her operation, her immune system refusing to accept the new infant-baboon hybrid. Outrage from physicians and the public soon followed, with animal-rights activists protesting and bioethicists publishing articles like “Baby Fae: The ‘Anything Goes’ School of Human Experimentation.”
Xenotransplantation died with Baby Fae, if only for a little while.
“During surgery when the drapes are on, it’s not really a person,” Guenthart said. “It’s a task.”
Technically speaking, a heart transplant is pretty easy. It takes only five incisions to cut out the failing heart, and only five connections to put in the new one. Electrocautery in one hand, scissors in the other, you usually first cut out the superior vena cava – the vessel bringing back blood to the heart from the head, neck, arms and chest – because it’s the most accessible structure.
Next is the inferior vena cava, which brings back blood from down south but is a bit hard to reach. So, you cut off a portion of the heart’s right chamber where this vessel drains into.
Then comes the aorta and pulmonary arteries in fairly simple, straightforward incisions. More difficult are the pulmonary veins, because these are four delicate vessels that are almost impossible to reconnect. The way around that is to lift the heart up and cut out a rim of left heart tissue from underneath. “You create a swimming pool, or a little crater,” Guenthart said. He paused. “That’s just me giving a description. They don’t actually call it a swimming pool.”
Regardless of whether you’re transplanting a human heart or pig heart into someone, the steps are essentially the same.
“If you asked 99 doctors out of 100, they wouldn’t be able to tell you if they were looking at a human chest or pig chest,” Guenthart said.
Pigs are filthy animals, as conventional wisdom goes. Judaism and Islam prohibit consumption of pork and other unclean meat. The insult “cops are pigs” bears undeniable teeth. And in the Odyssey, the sorceress Circe transforms Odysseus’s gluttonous men into swine.
Pigs are also highly intelligent animals, capable of showing emotions. Some 11,000 years ago, wild pigs may have domesticated themselves, recognizing a benefit to allyship with humans. They like playing fetch, are whizzes at navigating mazes, and can outsmart dogs and chimpanzees, according to their IQ tests.
Following the Baby Fae experiment, primates fell out of favor for xenotransplantation, and pigs became the new model organism for researchers to develop.
If you ask xenotransplantation experts today, they’ll give a laundry list of reasons why pigs are better than baboons: they are more easily genetically manipulated, they can be raised in a sterile environment to reduce infections, and they can be grown to give organs of any size needed.
It’s a nice packaged narrative, but Dr Brad Bolman, historian of science at the University of Chicago, argues that sheep, goats or some other animal could have been deemed suitable instead. At the outset, Bolman said, “it wasn’t obvious that pigs were the right replacement for non-human primates”. But when pigs were chosen, the scientific ideals were constructed retroactively to make them seem like the clear choice all along.
Bolman says that pigs were chosen because it was socially and economically convenient. They produce large litters quickly, with piglets reaching adult human size in six months. There’s also an almost unlimited supply of them – 700 million worldwide – and as agricultural animals, they aren’t covered by the Animal Welfare Act.
“We treat pigs in ways that we would never treat people, but we also recognize they’re so similar to us that they’re our models,” said Dr Lisa Moses, a bioethicist and veterinarian at Harvard Medical School. “You can’t make sense of that because it doesn’t make sense. It’s one giant paradox.” Pigs are close enough to give their lives for ours but not close enough that their plight gives us pause.
Maybe it should. If you subscribe to Kantian ethics, it’s wrong to use others as a means to an end, so it feels downright exploitative to genetically modify a pig and kill it for its heart. People for the Ethical Treatment of Animals (Peta) has thus decried pig-to-human transplants as “unethical, dangerous, and a tremendous waste of resources”, asserting that “animals aren’t toolsheds to be raided but complex, intelligent beings”. Kathy Guillermo, a senior vice-president at Peta, went even further to proclaim, “pigs are people”.
These ethical concerns aren’t new. In 1999, the Campaign for Responsible Transplantation protested in New York City’s famous Halloween Parade, with members dressed up as genetically engineered monsters. As millions of Americans watched the parade on TV, these snout-wearing attendants hoisted a 13ft-tall mad scientist puppet, sporting a dollar sign tie and clenching a pig-human hybrid.
But the xenotransplantation experts I spoke to often dismissed these ethical concerns by citing the structural fact of the global pork industry. The thinking goes that, if pigs are going to be eaten anyway, they might as well be used for science, a more valuable and noble pursuit.
“If you think about eating in a slightly more capacious sense,” Bolman said, “eating is really about consumption and rendering animals destroyable.” More than anything else, the edibility of pigs justifies their usage for xenotransplantation and research at large.
“What science does is consume animals, even if they aren’t literally eaten,” said Bolman. “Science remains carnivorous.”
Mr P’s new heart had arrived in the operating room a half-hour ago, and Guenthart was zigging and zagging a fine thread across the arc of two vessels to cinch them together.
Six o’clock, seven o’clock, eight o’clock … Guenthart stitched together one half of the artery before he grabbed another needle to run around counterclockwise. Once the two sutures had circled around and met at noon, he threw a right-handed knot, and then another. Then left-right-left-right-left-right, each opposing throw locking the last one into a square knot, Guenthart’s hands dancing with the fine thread.
During the entire operation, everyone in the operating room was chatting away, but now it was so silent you could hear the faint music that had been playing all along. This was the crucial moment where, with the donor heart actively dying, Guenthart was sewing as fast as he could to restore blood flow to the heart. Every second counted.
“Clamp off,” Guenthart finally announced. With the pressure released off the aorta, blood rushed into the coronary arteries and fed the heart.
Having graduated from medical school a decade ago, Guenhart joked that “xenotransplant is the promise that’s 10 years out – and always will be”. But he also sees Bennett’s 60-day survival as an “amazing milestone” and xenotransplantation as the most promising solution for the organ shortage killing his patients.
After about 30 seconds, Mr P’s new heart started beating on its own, like a zombie rising from the dead. Guenthart hadn’t connected any of the nerves and definitely nothing to his brain. The heart’s internal pacemaker is the circus master of its own show.
Xenotransplantation requires selective humanization of a pig. If you transplant a pig heart into a human, just like that, it will get rejected. Specifically, it’ll turn an ugly black and be flooded with blood clots, according to Dr Richard Pierson, director of the Center for Transplantation Sciences at Massachusetts general hospital. (I spoke with Pierson as he was speeding down to the hospital for a human-to-human lung transplant, ambulance sirens hollering in the background.)
Because our immune police force is so good at its job, the Virginia-based biotech company Revivicor used the gene-editing technology Crispr to create a special line of pigs with 10 modifications. Four genes are “knocked out”, and six genes are added in.
So, what is the recipe for making a pig heart fit for humans?
1. Knock out three sugar genes that are only found in pigs. “Most of us think if you have a pig with those three genes knocked out, that’s probably better than just one. We don’t know that for sure,” Pierson said.
2. Knock out a growth hormone gene to prevent the pig heart from overgrowing its new home. Pierson said, “Is growth at the graft going to be a problem? We don’t know.”
3. Add two complement inhibitor genes that prevent antibodies from destroying the pig heart and two anti-clotting genes that stop the patient’s blood from curdling inside the foreign organ.
4. Add two anti-inflammatory genes to prevent the pig heart from swelling up. One of these genes signals to the immune system that the pig heart is a friend (self), not food (nonself). “That may or may not be necessary,” said Pierson. “It probably is helpful, but we haven’t proven that.”
After all this cutting and pasting, the next challenge is to keep the pig “clean”. The last thing you want is to transplant a pig heart with viruses, bacteria and parasites that cause infections in humans.
Therefore, these pigs are raised in pathogen-free facilities. “There are no windows. They don’t go outside. The air is filtered and sterilized,” said Dr Leo Buhler, editor-in-chief of the journal Xenotransplantation and professor of surgery at the University of Fribourg.
After the genetically engineered embryos are implanted, the surrogate sows have to undergo caesarian sections (a vaginal birth is more likely to cause an infection.) The piglets are then immediately taken to isolation boxes under infrared lights, allowed to suckle their mother only every two hours under scientist supervision.
After 24 hours, the sows are all removed from the facility, and the piglets are artificially fed with a “motherless rearing system” and formula. Any interaction with humans must happen with the highest level of personal protective equipment.
With this “pig-in-a-bubble” approach, you should get a line of pigs that has never had any contact with the outside world and whose exogenous, or external, viruses have all been eliminated. These pig hearts are safe to implant into humans then, right?
Not exactly. Bennett’s heart still tested positive for pig endogenous retroviruses (PERV) – viruses built into the porcine genome that can jump into human cells, at least in a Petri dish. It’s an alarming example of zoonosis that could lead to a pandemic like Covid-19.
Whether or not those viruses can infect humans remains to be seen, but Pierson doesn’t think it will be a major barrier to xenotransplantation. HIV drugs seem to be relatively effective against them, and Boston-based biotech company eGenesis has already made a 60-gene PERV-free pig.
So what does worry Pierson about xenotransplantation?
“The unknown unknown,” he said. You can run a battery of tests in search of viruses, but you might only find what you’re looking for. And with a cocktail of immunosuppressants required to sedate our trigger-happy immune system, any infection that crosses the pig-human barrier could wreak devastating consequences.
“Doesn’t this all feel a bit premature, then?” I ask Pierson.
“Worry is not a reason not to do things. You need to take cautious steps forward. If the problem presents itself, you figure out a way to solve it. You don’t just go home.”
For months, Bennett’s transplant had been shrouded in secrecy, but the details of the operation were finally unveiled in a mid-June report of the New England Journal of Medicine. One of the study’s blockbuster findings was that Bennett was infected with a pig virus. The paper itself is neutral on the cause of death, but the cardiothoracic surgeon and study first-author Dr Bartley Griffith is “slightly betting” that a pig virus killed Bennett.
The pig virus he’s referring to is not a PERV, however; it’s an external virus called porcine cytomegalovirus (pCMV).
pCMV is a member of the herpes family, and its human form is known for causing mononucleosis, the kissing disease. Don’t let that fool you though. “Cytomegalovirus causes inflammation and damage to the organ,” Pierson told me. “A lot of damage.”
pCMV is also one of the viruses that Revivicor had supposedly eliminated from pigs through all their precautions; it has been a well-recognized threat to xenotransplantation for decades.
“When it first showed up, we thought maybe it was just an error or something,” Griffith said, discussing how a routine blood draw on the 20th day after surgery returned a tiny blip.
Possible pCMV infection was so unimaginable to Griffith’s team that they weren’t even looking for this pig virus and discovered the infection only on accident. Griffith told me, “The first thing we did is we went to the company and said, ‘How can we possibly be seeing this?’”
One xenotransplantation expert who wished to remain anonymous for legal reasons thinks that “Revivicor may have gotten a bit slack” about their protocol. He says the evidence is clear that, with early weaning and all other precautions, pigs don’t get pCMV.
Revivicor, of course, tested the donor pig several times with a nasal swab and PCR, getting negative results every single time. “It looks like PCR is not sufficient to exclude silent pCMV that can reactivate in an immunosuppressed environment,” Buhler wrote to me. He suggests that Revivicor made an honest mistake by not using a more specific test. (Revivicor did not respond to repeated queries sent by the Guardian.)
Regardless of why pCMV was missed, the results were gruesome on autopsy. After hitchhiking into Bennett, the virus seems to have exploded some capillaries and killed the heart.
But Griffith is continuing to march along, hoping to do another xenotransplant in the next few months, even if he isn’t entirely sure yet why Bennett died. Whatever it was, he’s confident that it can be overcome. A pCMV infection? Exclude it. Too much immunosuppression? Reduce it. The anti-pig antibodies they gave Bennett? Don’t do that again.
“That’s how you make progress,” Griffith said. “You admit where you made errors, and you try to limit them. But you move on.”
In a world where we are humanizing pigs with Crispr and “piggifying” humans with xenotransplantation, what does it even mean for there to be a human-animal divide?
In some ways, the word “divide” is problematic. After all, there’s no bright red line separating humans from other animals. Pigs and humans share 98% of genes, and that 2% is critically important. But it’s also just 2%.
Moses, the Harvard bioethicist, believes that the notion of a human-animal divide is an artificial construct. “There’s been a concerted effort from the biomedical research community to enhance the perception of that divide, going back as far as Descartes and Francis Bacon,” she said.
Built on a shaky foundation, the separation between animals and humans has been reified over millennia. Look no further than the impossibly low sticker prices of a pack of bacon that hides environmental externalities and inhumane conditions under a crisp cellophane wrap. It’s easier to not think too hard about it.
But we can’t not think hard about xenotransplantation. If its promise is to be realized, we’ll have to, at the very least, create a whole new economy of factory farming, where pigs will be manufactured and slaughtered en masse to give us life.
Sure, 1.5 billion pigs are already killed each year. And sure, if the people you loved most had heart failure, lungs slowly drowning in fluid, their dilated heart twisting agonizingly, you’d probably take the pig heart instead of gambling with the transplant list. I would, at least. But that shouldn’t obviate the need to tread carefully here.
Dr Chris Walzer, executive director of the Wildlife Conservation Society, thinks xenotransplantation could benefit from the OneHealth framework – the idea that human, animal and environmental health are all connected.
Take the Nipah virus as an example. Nipah is a zoonotic disease that has caused deadly outbreaks in Malaysia, Singapore, Bangladesh and India. For years, these outbreaks were a mystery to epidemiologists, who couldn’t understand how the transmission chain worked between fruit bats – the natural hosts of the virus – and humans. And ultimately, it took a broadened perspective to solve this puzzle – tracing how date palm trees bloomed in the winter, how fruit bats infused tree sap with saliva and urine, and how humans consumed that infected sap and got Nipah.
It’s too simple to say pigs are people. And it’s too simple to say pigs are an unlimited supply of organs. Seventeen people die every day waiting on the transplant list, but xenotransplantation is about a whole lot more than just saving these lives.
We’re all part of a shared ecology. And there’s a danger to ignoring our interconnectedness.
Earlier that day, Guenthart had told Mr P that he was getting a new heart. Mr P started crying. He’s in his early 20s, and three months ago, his heart started failing without any apparent reason. His doctors still aren’t sure why.
“It was hard for me to not also start crying,” Guenthart said.
A heart transplant is a highly technical operation, but for the patient, it’s a chance at life. When David Bennett had his xenotransplant, he didn’t just get a pig heart; he got two more months of life. He watched the Los Angeles Rams win the Super Bowl. He sang America the Beautiful with his therapist. He spent time with his five grandchildren, every day begging his surgeons to let him go home to his dog Lucky.
Now that the transplant was over, Guenthart was calling Mr P’s mom.
“The surgery went really well. The new heart looks beautiful, and he’s doing amazing. He’s asleep right now, and we’re sending him over to sleep in the ICU.
“Yes, he’s going to be two floors above where he was before.
“Normal visiting hours are from 8am to 7pm, but you can call them at any time and get updates directly from his nurse.
“Of course, you’re so welcome, and I hope to see you tomorrow.”