Xenotransplantation has the potential to solve organ scarcity and transform how we see human longevity, but it also poses several questions.
Mr. P’s flesh was ravaged by shards of electricity. Layers upon layers of subcutaneous fat peeled away, filling the operating room with a strong, metallic odor reminiscent of hair charred on a neighborhood barbeque. Within a few minutes, the bone of the sternum protruded before a vein ruptured, flooding the surgical site with blood.
Zap! The maroon liquid transformed into a brittle black lump.
Timing is everything in transplant surgery, according to Dr. Brandon Guenthart, a cardiothoracic surgeon at the Stanford University School of Medicine. The patient is put to sleep by anesthesiologists after the retrieval team verifies that the donor’s heart is in good condition. Two surgeons begin surgery an hour before the heart donor arrives at the hospital. The patient’s heart is not removed until the donor’s heart has landed safely at the local airport.
What if the aircraft crashes? “Knock on wood,” Guenther says. Unfortunately, there is no wood in the surgery room.
Due to my interest in David Bennett, a 57-year-old man who died in March, I was at Stanford hospital to observe this heart transplant. Bennett had a groundbreaking heart transplant on 7 January 2022 at the University of Maryland Medical Center from an unusual donor: a genetically engineered pig.
In 2021, a record number of 41,354 human-to-human organ transplants were done, but more than 100,000 Americans remain on the transplant waiting list. Every day, 17 people die waiting for organ transplants because there are simply not enough available.
Xenotransplantation, or the transfer of cells, tissues, and organs between species, has the potential to alleviate this scarcity and alter our conceptions of human longevity.
However, lost in this limitless possibility is the significance of the human-animal difference. People with pig organs grafted into their bodies, like human-animal cyborgs, can appear dystopian. And given that the zoonotic Sars-CoV-2 virus has killed over 6 million people, a breach of the link between humans and animals may only portend further disaster.
This torturous relationship is not new, but it is frequently cleaned and concealed from view – think gleeful cows on milk cartons and underground laboratories for animal experimentation. A multitude of questions remain unanswered, beginning with the most complex: what does it mean to be human?
Humans are animals. However, animals are not people. Yet, our history is replete with hybrid cultural imagination. Horus, the ancient Egyptian god of the sky, was represented with the head of a hawk, while Sekhmet, the goddess of war, had the head of a lioness. Similarly, the Hindu god Ganesha was decapitated and reborn with an elephant’s head grafted onto his body. Myths of ancient Greece were filled with extraordinary creatures, such as the bull-headed Minotaur and the snake-haired Medusa.
The International Xenotransplantation Association opted for a more esoteric mascot: the Lamassu, an Assyrian deity with the body of a bull, the wings of a bird, and the head of a man — a symbol of grounded knowledge.
As a scientific field, xenotransplantation began with merely cells and tissues. In France and England throughout the 17th century, animal blood was transfused into humans to treat a variety of medical ailments. A receiver said in a letter to the Royal Society, “Since Christ is the lamb of God, sheep’s blood has a symbolic affinity with [his] blood.” Supposedly, one patient’s high fever and another patient’s paralysis were cured, but at least two more died shortly after these “xenotransfusions.”
Other early xenotransplants would include bone, cornea, and skin transplants. Possibly most infamously, the French surgeon Serge Voronoff inserted chimpanzee and baboon testicles into male patients and ape ovaries into female patients to restore their “want for life.” Thousands of these procedures were conducted across the globe, but any reported benefits, such as reduced weariness or enhanced sex desire, were likely due to the placebo effect and shortly disappeared.
While cell and tissue xenotransplants had been performed for centuries, figuring out how to perform organ transplants was more challenging. Connecting all the blood vessels is a difficult task. You must connect two floppy tubes “mouth-to-mouth,” tying them tight enough so the patient doesn’t bleed out but carefully enough so the patient doesn’t clot excessively.
This was an issue worthy of the Nobel Prize, which the French surgeon Alexis Carrel solved in 1912 using a small embroidery needle and delicate silk suture. He is occasionally referred to as the father of transplant surgery.
In 1964, James Hardy of the University of Mississippi performed the world’s first cardiac transplant by implanting Bino the chimpanzee’s heart into 68-year-old Boyd Rush, whose health was fast failing. Rush only lived for 90 minutes, since his chimpanzee heart provided insufficient support and his body was swiftly shut down by rejection.
Baby Fae established the true stakes for xenotransplantation. She was a 12-day-old newborn with hypoplastic left heart syndrome, a congenital defect in which the left side of the heart is just a fraction of its normal size. The condition carried the death penalty.
In 1984, doctors at Loma Linda University in California transplanted a baboon heart the size of a walnut into Baby Fae’s chest. The conditions were nearly ideal. Baby Fae’s immune system was immature (and sympathetic), and the immunosuppressive drug cyclosporine could prevent attacks on the baboon’s heart.
Following the operation, Baby Fae appeared to be in good health. According to the hospital spokesperson, the infant was resting in her crib with a gauze-covered scar spanning her chest while gulping down her formula and sobbing with a “lusty cry.” Additionally, the hospital posted photographs of Baby Fae “speaking” with her mother, the phone receiver being larger than her entire torso.
Her immune system refused to tolerate the infant-baboon hybrid and she passed away 21 days after her surgery. Physicians and the general public were soon outraged, with animal-rights advocates protesting and bioethicists writing papers with titles such as “Baby Fae: The ‘Anything Goes’ School of Human Experimentation.”
Xenotransplantation died with Baby Fae, although temporarily.
“When the curtains are up during operation, it’s not a person,” Guenthart remarked. It’s a challenge.
Technically, a heart transplant is rather simple. It requires only five incisions to remove the failing heart and five connections to replace it. With electrocautery in one hand and scissors in the other, the superior vena cava, the blood vessel that returns blood to the heart from the head, neck, arms, and chest, is typically removed first, as it is the most accessible structure.
Next is the inferior vena cava, which returns blood from the south but is difficult to access. So, you remove a part of the right chamber of the heart where this vessel drains.
The aorta and pulmonary arteries are then removed by rather uncomplicated incisions. The pulmonary veins are more challenging because they consist of four tiny vessels that are nearly impossible to rejoin. The solution is to elevate the heart and remove a rim of left heart tissue from beneath. Guenthart stated, “You build a swimming pool or a small crater.” He stopped. “I am simply providing a description. They do not refer to it as a swimming pool.”
Regardless of whether a human or pig heart is being transplanted into a patient, the procedures are fundamentally identical.
“If you questioned 99 out of 100 doctors, they couldn’t identify the difference between a human chest and a pig chest,” Guenthart stated.
Pigs are filthy creatures, according to traditional thinking. In Judaism and Islam, pork and other filthy meats are forbidden. The epithet “police are swine” is indisputable. The sorceress Circe converts Odysseus’ gluttonous men into pigs in the Odyssey.
Pigs are also very intellectual and emotionally expressive. Before 11,000 years ago, wild pigs may have self-domesticated after discovering the benefits of the human alliance. According to IQ tests, they enjoy playing fetch, are adept at navigating mazes, and are smarter than dogs and chimps.
After the Baby Fae experiment, primates lost favor as a model organism for xenotransplantation, and pigs became the new organism of choice for researchers.
If you ask xenotransplantation experts today, they’ll give you a laundry list of reasons why pigs are superior to baboons: they can be genetically modified more easily, they can be reared in a sterile environment to prevent infections, and they can be bred to provide organs of any size.
Dr. Brad Bolman, a science historian at the University of Chicago, argues that sheep, goats, or some other animal could have been deemed more suitable. Bolman stated that it was first unclear if pigs were the best replacement for non-human primates. However, when pigs were picked, scientific ideals were established retroactively to make them appear to have been the obvious option the entire time.
According to Bolman, pigs were chosen due to their social and economic use. They produce big litter rapidly, and piglets reach adult size within six months. As agricultural animals, they are not governed by the Animal Welfare Act, and there is a nearly endless supply of them (700 million worldwide).
Dr. Lisa Moses, a bioethicist and veterinarian at Harvard Medical School, stated, “We treat pigs in ways we would never treat humans, but we also understand they are so similar to us that they are our models.” “You cannot make sense of that because it is illogical. It is a gigantic conundrum.” Pigs are close enough to us to sacrifice themselves for us, but not so close that their predicament causes us to halt.
Perhaps it should. If you belong to Kantian ethics, it is unethical to use others as a means to an end, thus genetically modifying a pig and killing it for its heart feels exploitative. People for the Ethical Treatment of Animals (Peta) has therefore denounced pig-to-human transplants as “unethical, harmful, and a great waste of resources,” arguing that “animals are not toolsheds to be looted, but rather sophisticated, intelligent people.” Kathy Guillermo, a senior vice president at Peta, even went so far as to declare, “pigs are people.”
These ethical issues are not novel. In the 1999 New York City Halloween Parade, members of the Campaign for Responsible Transplantation protested while appearing as genetically produced monsters. As millions of Americans watched the parade on television, these attendants with snouts lifted a 13-foot-tall puppet of a crazy scientist wearing a dollar sign tie and grasping a pig-human hybrid.
However, the xenotransplantation specialists I met with frequently ignored these ethical issues by emphasizing the global pork industry’s structural reality. If pigs are going to be consumed nonetheless, they might as well be employed for science, a more worthwhile and honorable endeavor.
“If you look about eating in a somewhat broader sense,” said Bolman, “eating is actually about consuming and making creatures vulnerable to destruction.” Primarily, the edible nature of pigs justifies their use in xenotransplantation and research in general.
Bolman stated, “Science consumes animals, even if they are not consumed.” “Science remains carnivorous.”
Guenthart was zigzagging and zagging a tiny thread over the arc of two vessels to tighten them together when Mr. P’s replacement heart arrived in the operating room half an hour ago.
Six o’clock, then seven, then eight… Guenthart sewed one part of the artery together before grabbing a second needle to run counterclockwise. Once the two sutures had circled and met at midday, he tied a right-handed knot, followed by a second. Then, left-right-left-right-left-right-left-right, with each opposing throw tying the previous one into a square knot, Guenthart’s hands danced with the tiny thread.
Throughout the operation, everyone in the operating room was conversing, but now it was so quiet that you could faintly hear the music that had been playing the entire time. Guenthart sewed as quickly as he could to restore the heart’s blood flow at this vital moment, during which the donor’s heart was actively dying. Every second was crucial.
Guenthart finally announced, “Stop!” With the aorta’s pressure reduced, blood surged into the coronary arteries and nourished the heart.
Guenhart, who graduated from medical school a decade ago, said that “xenotransplant is the promise that is always 10 years away.” However, he also considers Bennett’s 60-day survival to be an “incredible milestone” and xenotransplantation to be the most promising solution to the organ shortage that is killing his patients.
Mr. P’s new heart began beating on its own after approximately 30 seconds, like a zombie rising from the grave. Guenthart had not attached any nerves or anything else to his brain. The intrinsic pacemaker of the heart is the ringmaster of its performance.
Xenotransplantation needs to humanize a pig selectively. Simply transplanting a pig heart into a person will result in rejection. According to Dr. Richard Pierson, director of the Center for Transplantation Sciences at Massachusetts General Hospital, the organ would specifically turn a hideous shade of black and become clogged with blood clots. (I spoke with Pierson as he sped to the hospital for a human-to-human lung transplant, with the sound of ambulance sirens in the background.)
Because our immunological police force is so effective at its job, the Virginia-based biotechnology firm Revivicor utilized the gene-editing technology Crispr to develop a line of pigs with ten changes. Four genes are “knocked out” and six are introduced.
So, what is the formula for preparing pig hearts for human consumption?
Remove three sugar genes found exclusively in pigs. “The majority of us believe that having a pig with these three genes knocked out is preferable to having just one. “We do not know for certain,” stated Pierson.
- Remove the growth hormone gene to prevent the pig’s heart from outgrowing its new environment. Pierson questioned, “Will growth at the graft be a problem? We cannot say.”
Add two complement inhibitor genes that prevent the patient’s antibodies from killing the pig heart and two anti-clotting genes that prevent the patient’s blood from coagulating within the foreign organ.
Add two anti-inflammatory genes to the pig heart to prevent enlargement. One of these genes informs the immune system that the pig heart is a buddy (self) rather than a food source (nonself). Pierson stated, “That may or may not be essential.” It is likely beneficial, but this has not been demonstrated.
After all of this copying and pasting, the next obstacle is keeping the pig “clean.” The last thing you want is to transplant a pig heart with human-infecting viruses, germs, and parasites.
Therefore, these pigs are raised in facilities devoid of pathogens. “There are no windows present. They never venture outside. According to Dr. Leo Buhler, editor-in-chief of the journal Xenotransplantation and professor of surgery at the University of Fribourg, the air is filtered and sanitized.
After the genetically modified embryos are implanted, cesarean sections must be performed on the surrogate sows (a vaginal birth is more likely to cause an infection.) The piglets are then placed in isolation boxes with infrared lighting and are only permitted to nurse their mother every two hours under the supervision of scientists.
The sows are removed from the facility after twenty-four hours, and the piglets are artificially fed using a “motherless rearing system” and formula. When interacting with humans, the highest level of personal protective equipment must be used.
With this “pig-in-a-bubble” strategy, you should obtain a line of pigs that have never been exposed to the outside world and in which all exogenous, or external, viruses have been eradicated. Then, these pig hearts are okay for human implantation, correct?
Not quite At least in Petri dishes, Bennett’s heart remained positive for pig endogenous retroviruses (PERV) – viruses built into the swine genome that can infect human cells. It is a concerning case of zoonosis that could result in a pandemic similar to Covi-19.
It remains to be seen whether these viruses can infect people, but Pierson does not believe this will be a significant obstacle to xenotransplantation. HIV medications appear to be pretty effective against them, and the Boston-based biotechnology company eGenesis has already created a pig devoid of 60 PERV genes.
Consequently, what concerns Pierson about xenotransplantation?
He said, “The unknown.” You can do a series of tests to seek for viruses, but you may only find the one you’re looking for. And with a mix of immunosuppressants required to quiet our overactive immune system, any infection that crosses the pig-human barrier might have catastrophic effects.
“Doesn’t it feel a touch premature at this point?” I ask Pierson.
“Worry is not an excuse not to act. You need to move forward with caution. If an issue arises, you devise a solution. You don’t just go home.”
The facts of Bennett’s transplant, which had been kept secret for months, were finally revealed in a mid-June report in the New England Journal of Medicine. Bennett’s infection with a pig virus was one of the groundbreaking findings of the study. The article itself is neutral on Bennett’s cause of death, but the cardiothoracic surgeon and lead author of the study, Dr. Bartley Griffith, is “somewhat betting” that Bennett was killed by a pig virus.
However, the pig virus he’s referring to is not a PERV; it’s porcine cytomegalovirus, an external virus (pCMV).
pCMV is a member of the herpes virus family, and its human version causes mononucleosis, also known as the kissing illness. However, do not be deceived. “Cytomegalovirus induces inflammation and organ damage,” explained Pierson. Numerous damages.
pCMV is also one of the viruses that Revivicor claimed to have removed from pigs; it has been a known hazard to xenotransplantation for decades.
On the 20th day after surgery, a routine blood draw revealed a little blip. “When it first appeared, we thought it was a mistake or something,” Griffith explained.
Griffith’s team found the possibility of a pCMV infection so inconceivable that they weren’t even seeking this pig virus and discovered the infection by mistake. Griffith told me, “We immediately went to the corporation and asked, ‘How could we possibly be witnessing this?'”
A xenotransplantation expert who requested anonymity for legal reasons believes that Revivicor may have slacked off on their protocol. He asserts that the research is conclusive that pigs do not contract pCMV if they are weaned early and other safeguards are taken.
Naturally, Revivicor checked the donor pig multiple times using nasal swabs and PCR, obtaining negative findings each time. Buhler wrote to me, “It appears that PCR is insufficient to exclude silent pCMV that can reactivate in an immunosuppressed milieu.” He argues that Revivicor made a genuine error by not employing a more specific test. (Revivicor did not react to the Guardian’s persistent inquiries.)
Regardless of why pCMV was overlooked, the autopsy results were horrific. After traveling into Bennett, the virus appears to have caused the rupture of many capillaries and the death of the heart.
Griffith hopes to perform another xenotransplant within the next three months, even though he does not yet know why Bennett died. He is convinced that whatever it was can be overcome. An infection by pCMV? Exclude it. Too much immunosuppression? Lessen it. The anti-pig antibodies they administered to Bennett? Don’t repeat that action.
“This is how progress is made,” Griffith stated. “You acknowledge where you have made mistakes and attempt to limit them. But you proceed.”
In a world where Crispr humanizes pigs and xenotransplantation “piggifies” people, what does it even mean to distinguish between humans and animals?
The word “division” is problematic in various senses. In the end, there is no distinct dividing line between humans and other animals. Humans and pigs share 98 percent of genes, and the remaining 2 percent is crucial. But it’s also merely 2 percent.
The Harvard bioethicist Moses argues that the distinction between humans and animals is an artificial construct. “Ever since Descartes and Francis Bacon, the biomedical science community has made a concentrated effort to improve the awareness of this difference,” she said.
The distinction between animals and humans has been solidified over millennia despite its fragile base. Consider the absurdly cheap sticker price on a package of bacon, which conceals environmental externalities and cruel conditions behind a cellophane wrapper. It is easier to not overthink the situation.
However, we cannot ignore xenotransplantation. If its promise is to be fulfilled, we will have to construct a whole new economy of factory farming, in which pigs will be mass-produced and slaughtered to provide us with life.
Yes, 1.5 billion pigs are already slaughtered annually. Moreover, if your closest loved ones were suffering from heart failure, with their lungs progressively filling with fluid and their dilated heart twisting in agony, you would likely opt for the pig heart over the transplant list. I would, at minimum. However, this should not eliminate the need for caution.
The executive director of the Wildlife Conservation Society, Dr. Chris Walzer, believes that xenotransplantation could benefit from the OneHealth paradigm — the notion that human, animal, and environmental health are interconnected.
Use the Nipah virus as an illustration. Nipah is a zoonotic disease that has produced epidemics in Malaysia, Singapore, Bangladesh, and India. The transmission link between fruit bats – the virus’s natural hosts – and people was a mystery to epidemiologists for years, as they were unable to decipher how these outbreaks occurred. And finally, a broader perspective was required to solve this problem, which involved tracing how date palm trees blossomed in the winter, how fruit bats contaminated tree sap with saliva and urine, and how humans ingested the infected sap and contracted Nipah.
It is overly simplistic to suggest that pigs are human. And it is overly simplistic to assert that pigs are an endless source of organs. Every day, seventeen individuals pass away while waiting for a transplant, but xenotransplantation is about much more than just saving these lives.
We all participate in a shared ecology. And denying our connectivity is dangerous.
Guenthart had informed Mr. P earlier that day that he was receiving a new heart. Mr. P began to cry. He is in his early twenties, and three months ago, for no apparent reason, his heart began failing. His doctors are still unsure about the cause.
It was difficult for me to refrain from crying, Guenthart said.
A heart transplant is a highly technical procedure, but for the recipient, it represents a second chance at life. When David Bennett had his xenotransplant, he not only received a pig heart, but also two additional months of life. The Los Angeles Rams won the Super Bowl while he was present. His therapist and he sang America the Beautiful together. He spent time with his five grandchildren, pleading with his surgeons every day to be allowed to return home to his dog Lucky.
Now that the operation was complete, Guenthart called Mr. P’s mother.
“The operation went quite well. The replacement heart is wonderful, and he is doing exceptionally well. He is currently asleep, and we are sending him to the ICU to sleep.
