By Rivka Galchen

In the early hours of January 7th, the cardiothoracic surgeon Bartley Griffith, unable to sleep, went to his kitchen to make coffee. It was about 2 a.m. His usual mug is tall, and he had to remove the stand from his Krups machine in order to fit it. “Next thing I realized, I had coffee all over the floor. I had forgotten to put the cup under,” Griffith told me. “You get a bit wiggly, a bit superstitious.” He asked himself, “Do you know what you’re about to do?” Griffith has forty years of surgical experience. But later that morning he was scheduled to perform a surgery that would be unusual even for him: the world’s first transplantation of a pig’s heart into a human.

Griffith’s team, at the University of Maryland Medical Center, had received confirmation from the Food and Drug Administration only seven days earlier, on the evening of December 31st, that the experimental surgery was approved. “It was just two lines or so,” Griffith said. “It read, ‘Good luck with the surgery!’ ” But Griffith and his colleague Muhammad M. Mohiuddin, who jointly run the school of medicine’s Cardiac Xenotransplantation Program, had been working together toward this goal for five years. “So then, there we were in the hospital on January 1st, thinking how to make this actually work.” The medical center had to decide that it was willing to pay for the procedure—insurance tends not to cover xenotransplantation. The patient, David Bennett, Sr., a fifty-seven-year-old man with severe heart failure, had to undergo four psychiatric evaluations, to make sure he could give consent. All the staff who might work on the experiment had to be given permission to opt out. “So many people are involved with the care of a patient,” Griffith said. “We have a binder of four hundred or so consents—people wanted to participate.”

Mohiuddin, who led the lab work that studied the transplantation of the pig heart, lives an hour from the hospital. There was a snowstorm on January 6th, so he spent the night on the sofa in his office. “My wife has given up on me for a while—she knows what I am going through,” he told me. “I spent thirty years just driving for this.” On the morning of January 7th, he headed the surgery that extracted the heart from a year-old genetically modified pig, which had been raised at a facility in Virginia run by the company Revivicor. (Revivicor is a spinoff of PPL Therapeutics, known for making Dolly the sheep, the first mammal cloned from an adult cell.) Pigs have about thirty thousand genes. Ten of those genes in the donor pig had been altered, through a time-consuming gene-editing process. (crispr technology has recently sped up similar processes.) Three genes largely responsible for making sugars that a human body would consider foreign were “knocked out”; a gene that controls how large and how fast the heart grows was also deleted; and six genes that help regulate antibody function, inflammation, and coagulation cycles in humans were “knocked in.” The pig heart was now, in theory, more likely to be taken on by the patient’s body as “self” rather than as “foreign.”

After Mohiuddin’s team extracted the pig heart, they placed it in a box resembling a high-end automatic breadmaker; the box keeps a transplant heart cold and metabolically active. It pumps a fluid through the heart that is made up of saline, cocaine, and a few other components. The box and the solution were developed by researchers in Sweden. “Every time we import one of these boxes, I have to fill out special forms from the D.E.A.,” Mohiuddin said.

The cold pig heart was delivered to the operating room. “Some people like to blast music in an O.R., but I like to hear pins drop,” Griffith said. “I like to hear the sound of the heart-and-lung machine.” Griffith estimates that he has performed more than a thousand heart transplants, but this one called for a different start: before he made the first incision, he suggested that everyone pause for thirty seconds to “think about what this man is entering into.” He described the transplantation as an opportunity to learn. Griffith told me, “We don’t usually take a moment like that. But I think it relaxed everyone. And then we went to work.” The process of transplanting a heart is both brutal and precise. An eight-inch incision is made in the chest. The breastbone is cut in half with a bone saw. The ribs are opened outward to expose the heart. One large vein and one large artery are connected by tubes to a cardiopulmonary-bypass machine; a third tube washes the organ with a heart-stopping fluid. That’s the beginning.

The human heart being replaced was, of course, an ill one. It was dilated from being unable to pump properly. The cardiac chambers to which the pig heart would be attached were large. The team had to stitch the small “O” of the pig part to a much larger “O” on the human’s. Griffith was accustomed to making modifications, but less drastic ones. When he first pulled the pig heart out of its container, it looked small and pale. “It had an opaqueness that was off-putting,” he said. “I wondered, Did we do something wacky?” He connected the pig heart to the patient’s vessels. He released the clamp, allowing human blood to flow into the organ. “It was as if we’d turned on a light. And it was a red light. The heart just brightened up. And it went from trembling to pumping.” He demonstrated the movement with his hands. “Hearts don’t just squeeze when they beat, they kind of twist, and this heart—it was doing the hoochy-coochy. It was one of the best hearts I’ve ever seen after transplantation.”

An Irish tale tells of a ruler who loses an arm in battle. Once maimed, a king cannot rule. But a doctor shows up at the king’s door. The doorkeeper, who is half-blind, won’t let him in. The doctor replaces the doorkeeper’s blind eye with a cat’s eye, curing his sight. The doctor then replaces the ruler’s missing arm with a swineherd’s. The doorkeeper with the cat’s eye is said to stay awake at night thereafter, looking for mice.

Have our feelings about the extraordinary weirdness of transplants changed much over the centuries? The history of transplantation has its horrors. In eighteenth-century England, the poor would sell their teeth; the rich would have those teeth implanted. A reasonably eminent twentieth-century scientist transplanted second heads onto dogs. The physician Charles-Édouard Brown-Séquard was thought by his neighbors to be a sorcerer; his back yard had chickens with rats’ tails affixed to their heads, and other mutilated and altered creatures. Brown-Séquard made serious contributions to the field of neurology, and a syndrome is named for him, but he may be better remembered for having claimed, at the age of seventy-two, that injecting himself with parts of dog and guinea-pig testicles had sexually revived him. For a few decades, “gland grafting” was all the rage, especially in France.

In 1906, a French physician had two patients dying of kidney disease; he gave one a goat kidney and the other a pig kidney. Both kidneys lasted three days. It was years before even those dismal results were matched. Doctors were working without any substantial knowledge of the human immune system and its role in accepting or rejecting transplants; it was as if one were trying to treat diabetes without knowing about insulin.

Transplanting human parts (other than teeth and patches of skin) didn’t really get going until the middle of the twentieth century. How could fresh organs be ethically obtained? A kidney, unlike a heart, can be taken from a living donor, and kidney transplants developed earlier. The first kidney transplant with long-term success was performed on the identical twins Ronald and Richard Herrick, two days before Christmas in 1954, by Joseph Murray, in Boston. Richard, the recipient, married one of the nurses who had cared for him; Ronald, with just one kidney, lived another fifty-six years. Murray performed kidney transplants in non-twin subjects for the next ten years, but the patients didn’t do well. It was only with the advent of effective immunosuppressants that transplants began to work consistently. In 1990—thirty-six years after the twin transplant—Murray received the Nobel Prize in Physiology or Medicine.

More than twenty-four thousand kidney transplants were performed in the United States in 2021, and more than three thousand eight hundred heart transplants. These surgeries are considered routine, and outcomes are generally very good. The median survival time following a heart transplant is about twelve years; for kidney transplants, that number is nearing twenty years. In the U.S., there are typically more than three thousand people waiting for a heart and more than ninety thousand people waiting for a kidney. The development of the Uniform Donor Card in the U.S., a legal document that was recognized in all states, made organ donation more straightforward, and the 1984 National Organ Transplant Act established some legal ethics for the field, prohibiting the sale of organs and providing a framework for trying to distribute organs fairly.

In the U.S., as of 2019, the rate of opting in to organ donation is around fifty per cent, though ninety per cent of people express support for the idea. In some countries, people have to opt out, rather than opt in. Spain has been a global leader in organ donation for decades; in addition to having an opt-out system, it trains professionals in talking to families about organ donation. Croatia adopted a similar model and raised its donation rate to one of the highest in the world. Japan has one of the lowest rates of organ donation, a situation attributed in part to gotai manzoku, a belief that the body should be intact. This idea connects to a fear that, if a corpse is cremated without all its organs, it cannot be properly put to rest. Some Japanese stories feature a ghost whose head is separated from its body, and this is sometimes interpreted as a disturbed soul.

Mohiuddin moved to the United States from Pakistan in 1991, when he was twenty-six, to train in cardiac surgery. His first mentor asked him to think about how many patients he could help as a cardiac surgeon, and then asked what he would think if he was told about a field that would help a hundred times more patients. “That was the first fish thrown at me,” Mohiuddin told me. He began research work transplanting organs from hamsters to rats. “And, since then, I have not looked back.”

There were long periods when funding for xenotransplantation research seemed almost nonexistent. Mohiuddin used to work at the National Institutes of Health. “When we underwent the external review, which happens every five years, they said what we were doing was a waste of time and that we should be shut down,” he said. He secured outside support from Revivicor. Its C.E.O., Martine Rothblatt, has a daughter with pulmonary arterial hypertension, and the company has funded research on lung xenotransplantation. At his lab’s next external review, Mohiuddin said, the assessment was glowing. It’s difficult for him to explain to others, even to his wife of nearly thirty years, exactly what he does. He says he asked her just to believe in him. “This was not an easy road,” he said. “There were many occasions where I thought, Did I make the right decision?” Mohiuddin’s work eventually led to transplants of pig hearts into baboons; after nine hundred and forty-five days, the baboons were still thriving. This work helped persuade the F.D.A. to approve the recent heart transplantation.

Pigs are a preferred xenotransplantation animal for several reasons: their circulatory system is similar to the human one, their organs are about the right size, they grow up fast, they breed easily, and, well, although they’re as sweet and emotional as our pet dogs—and often smarter—they aren’t closely related to us. Mohiuddin, however, is a religious Muslim. On his drive to and from work, he typically listens to the Quran and calls his mother, who lives in Karachi. “For me, as a Muslim, of course, pork is a big no-no,” he said. “We don’t eat pork or talk about pork.” He encountered some resistance from his family when he began to work with pigs. Mohiuddin said, “I talked to religious leaders—not only Muslim leaders but also Jewish and Christian leaders—and the consensus was that saving lives takes precedence over everything. That is what I base my belief on—that what I am trying to do will help save lives.”

Using baboons in scientific research is itself anathema to many people. Protesters sometimes demonstrated outside the N.I.H. when Mohiuddin worked there. His current lab has no direct entrance from outside the building, and there is security. In 1984, a baboon heart was transplanted into Baby Fae, an infant with congenital heart defects. Baby Fae lived for only twenty days afterward. One reason for the rejection was an unavoidable blood-type incompatibility—there were no Type O baboons available. The doctor who performed the procedure, Leonard Bailey, stated, regarding the choice of a baboon, that he did not believe in evolution. The year after Baby Fae’s procedure, Bailey transplanted a human heart into a four-day-old infant: Eddie Anguiano, known as Baby Moses, who in 2014 visited the man who had transplanted his heart.

In the late nineteen-eighties, Jane Goodall gave a talk to an international congress on xenografts. “They were all talking happily about breeding pigs for xenotransplant, dogs, and so on,” Goodall said. “I felt like an alien in a world full of people with no empathy.” The audience was moved by her speech; baboons are now hardly, if ever, used as a source of organs, though they are still used in research. Mohiuddin has been celebrated and criticized in Pakistan, where organ transplantation from dead people is relatively recent and rare.

When David Bennett, Jr., visited his father after the transplant, David, Sr., in terrible pain, said desperately, “I can’t take this anymore.” By the end of the day, the pain medications were working. David, Jr., said, “He was able to say thank you to the doctors. That was a huge sigh of relief and peace to everyone.”

After the surgery, Griffith and Mohiuddin had two worries that they were trying to balance: rejection and infection. Immunosuppressants could stave off rejection, but they left Bennett vulnerable to infection. Early on, an abdominal infection required an additional surgery to clear. Later, Bennett had an unusual response to one of the immunosuppressants, causing his white-blood-cell count to fall perilously low; his medications were changed. The heart was beating too powerfully for its fragile new owner, and it had to be chemically slowed. By the end of day eighteen, Bennett had outlived the first human-heart-transplant patient. By the end of day twenty-one, he had survived longer than Baby Fae. That day, he remembered to wish Griffith a happy birthday. He was able to speak to his son on the telephone, something he had not been strong enough to do for the ten days before the transplant. “My dad wants to go home,” David, Jr., said. “He wants to see his dog, Lucky.”

Bennett had been on a heart-lung machine for months before the transplant, leaving him very weak. Even learning to stand on his own again would take time. The transplants in Mohiuddin’s lab had been into young, healthy baboons; this transplant was a different experiment altogether. But, Mohiuddin noted, “we also know so much more about how Mr. Bennett is doing than we can ever know in the lab.” Griffith said that in the early days, when he went to check on Bennett, he’d often find ten experts outside his room, collaborating on his care: “There’ll be two infectious-disease specialists, a transplantation pharmacist, an I.C.U. nurse. It’s such a team effort—everyone wants to contribute.”

Transplants of human organs and of pig organs may seem like very different procedures, but the problem of rejection is the central issue in both cases. Your body decides what is alien and what is self. If you get a tiny splinter, your body will likely mount an inflammatory reaction that extrudes it over time. If you get infected by a virus, your immune system will attack it.

But it’s tricky. The bacteria Helicobacter pylori can move into your gut and evade detection, because it camouflages itself with surface sugars that resemble our own. In a disease such as lupus or rheumatoid arthritis, by contrast, the immune system erroneously attacks native cells, as if they were invaders. If you think of immunity as a battle, which it basically is, H. pylori is a case of enemy soldiers wearing the uniforms of your own side; lupus is your soldiers being knocked out by friendly fire.

There are several ways your body can reject an organ. Hyperacute rejection can happen within minutes of transplantation when the body has preëxisting anti-donor antibodies; it has met this enemy, or something similar, before, and is ready to attack immediately. In hyperacute rejection, large blood clots rapidly form, obstructing the blood supply of the donor organ. This is what would happen if a “regular” pig organ were used for transplant; all humans have roughly one per cent of their antibodies devoted to attacking what are called alpha-gal sugars. Most mammals have these sugars, but humans don’t. The alpha-gal gene is one of the genes that were knocked out in the transplant pig.

Besides gene-editing—which became practicable only recently and is not an option for donated human organs—the main approach to getting a patient’s body to accept a donor organ has been to suppress the immune system. This is dangerous. The first heart transplant that had some success took place in 1967 in South Africa. Thanks to immunosuppressants, the patient did not immediately reject the organ; also because of immunosuppressants, the patient died of pneumonia eighteen days later. Even when a recipient makes it past both hyperacute rejection and postoperative infections, transplant organs can fail later, owing to what is called chronic rejection, a process that is not entirely understood.

One pioneer of heart-transplant surgery said, “We were excited about sewing in the heart, which is . . . when you think about it technically, quite a simple plumbing job.” The history of advances in transplantation is, arguably, more accurately understood not as a history of surgery but as a history of immunobiology. The transplant surgeons saw that rejected organs were infiltrated by cells; trying to understand the mechanism prompted the tremendous bloom in immunobiology. To return to the limited but apt battle analogy, immunobiology is the science that develops diplomats, who suggest that there are alternative ways to respond to the presence of the foreign agent—that there’s a way to get along.

Allan D. Kirk, a transplant surgeon in the Duke University Department of Surgery, who has worked in the field for more than thirty years, said, “In the nineteen-seventies, every transplant case was like a miracle. To decide to be a transplant surgeon was like saying you wanted to be an astronaut.” Until recent advances, he said, enthusiasm about xenotransplantation had not been scientifically justified. “It was driven by companies that would drop a bunch of money without knowing the science. But this is the first time I think the enthusiasm is scientifically credible.” Kirk attributed the change to genetic engineering and to better immunosuppressive drugs. “crispr has made it logistically more reasonable to change all the genes you need to change,” he said. “And immunosuppressive drugs are not as brutal as they once were. We can make more refined interventions.” There are even some transplant patients walking around who no longer take any immunosuppressive drugs, or who take them once a month. At some point, their bodies learned to accept the foreign organ as self. “The problem is that no one knows how it happened,” Kirk said.

Kirk then turned philosophical, while apologizing for doing so. “All of us were allogenic tumors at one point,” he said. “Allogenic” refers to being foreign, but from the same species. “That’s called a fetus. Our mothers didn’t reject us—at least not until we turned thirteen and burned down the garage. So we know as a species how to not reject foreign organs. Our biology already knows how to do that, and we need to catch up.”

When news of the pig-heart operation was announced, one transplant surgeon found it especially meaningful. Robert Montgomery, the director of the N.Y.U. Langone Transplant Institute, had received a heart transplant in 2018. He had a genetically linked heart condition, which he learned about when his brother Richard died suddenly at age thirty-five. Montgomery, a surgical intern at the time, connected this to his father’s death, some years earlier, from what was erroneously attributed to a virus-induced heart condition. Three of Robert’s children have the same condition, as do Richard’s two daughters.

I met Montgomery on November 23rd, the day after he completed the transplant of a pig kidney to a human, the third such operation ever; the first had also been performed by Montgomery’s team, two months earlier. (The University of Alabama at Birmingham did a similar operation in between.) Montgomery had a mustache that made him look like Wyatt Earp, though it was less dramatic than the one he had had before covid; he had trimmed it for heightened hygiene protocols. Nikki Lawson, a transplant-research nurse coördinator who has been on his team for almost two decades, “was so upset when I had to trim it,” he said, laughing. “She said she thought it was the source of my power.” Montgomery’s team’s kidneys also came from Revivicor; they were attached to brain-dead human bodies, demonstrating that they would not be hyperacutely rejected. The kidneys were monitored for more than fifty hours, after which the experiment ended.

“To do a trial in a living human, you need to know that it’s reasonable to believe the trial will give the patient over all a better outcome than not being in the trial,” Montgomery said. People in need of a kidney who are otherwise relatively healthy have a decent chance of receiving a human kidney; people less likely to do well with a transplant are lower on the list, but that also means they are less likely to do well with an experimental procedure, such as a pig-kidney transplant. In the case of the pig-heart transplant, the patient, David Bennett, Sr., had been rejected by several centers for a heart transplant, owing in large part to a history of not being good about taking medications—a necessity for transplant success. In the case of a kidney transplant, many patients can be sustained by dialysis, a miserable but often effective treatment. Of the pig-heart transplant, Montgomery said, “It was stunning. It was incredibly inspiring and exciting, and my nieces and kids called me. It was very personal in that way.”

The fourth of four boys, Montgomery was seen by his elementary-school teachers as undisciplined and a slow learner: “The nun called in my mom to say she shouldn’t expect the same from me as from my brothers.” He was also, in his words, a magnet for wounded animals. Robins, squirrels, beavers: he was obsessed with trying to nurse creatures back to health. One year, for Christmas, an older brother gave him a box of miniature tombstones, “with the names of all the creatures that had died under my care.” His mother put him in a different school, but still had him work with some nuns, who offered therapy of a sort. It was decided that the problem was that he had been “a butt-scooter,” he said. “I had never crawled. So these nuns would get on the floor with me and we would all crawl around.”

When he was fourteen, his father fell very ill with heart troubles. The family was told that the only thing that could save him was a heart transplant—a new procedure at the time—but that he was too old (fifty!) to qualify. Montgomery recalls doing his homework in his father’s hospital room.

Montgomery eventually became a better student (though, as far as I know, no randomized-controlled trial exists that can fairly assess the impact of the crawling therapy). He attended medical school at the University of Rochester, and then started a surgical residency at Johns Hopkins. In his first year there, after his brother Richard died, Montgomery arranged to have a colleague in the pathology department of Hopkins examine his brother’s heart. The colleague detected familial dilated cardiomyopathy, or FDC. One aspect of FDC is sudden death; another is episodes of ventricular tachycardia. Montgomery began to wonder how he could continue in the surgical field.

He wasn’t sick enough to qualify for a heart transplant, but he had a defibrillator put in. “It was just a dumb box,” he said. If something sets the defibrillator off, it administers a shock directly to the heart; the shock is so powerful that the fear of it going off is too much to bear, some patients have told him, and they wanted theirs taken out. Montgomery took a break after his second year of residency to get a Ph.D. in immunology at Oxford. He learned to live with the Sword of Damocles, and returned to his surgical training. “I taught myself to stay calm,” he said. “Let’s say I was going to give a talk in front of people, I would think to myself, O.K., what’s the worst thing that could happen? That would be dying—that would be pretty bad. But everything below dying began to seem not so important. That produced a benevolent cycle, where I would perform better because I was relaxed.”

Montgomery became a celebrated transplant surgeon. At Johns Hopkins, he was named the chief of transplant surgery and directed the team that developed so-called domino kidney transplants. A fellow-surgeon, Dorry Segev, had studied computer science. One day, Montgomery was looking at their whiteboard of data on kidney patients and donors, as a way of seeking out matches: “I said, ‘There must be a better way to do this.’ And Dorry said to me, ‘Of course there is.’ ” That weekend, Segev and his wife, Sommer Gentry, who was an M.I.T. mathematician, wrote a computer program, and, not long afterward, Hopkins began lining up multiple surgeries instead of a single swap. Imagine you want to donate a kidney to your partner, but you’re not a match. In a domino transplant, several partner donors donate, and all the patients receive a kidney, but, for purposes of matching, a donor’s kidney goes to someone she doesn’t know, just as her partner receives a kidney from someone he doesn’t know. In 2009, the Hopkins team did a twelve-person, multistate procedure, working in conjunction with hospitals in Oklahoma City and St. Louis.

The team also helped expand the pool of kidneys that would be considered viable for transplantation. “I had this colleague, Niraj Desai, and he was very early thinking about, What if we used hep-C-positive kidneys?” Montgomery recalled. Every year, hundreds of organs were deemed unusable because their donors had hepatitis C. “This was when there was early treatment for hep C, but it wasn’t very effective,” Montgomery said. But, a couple of years later, antiviral drugs were developed that could cure hepatitis C. Desai’s idea had come of age. A trial was conducted of patients who would otherwise not have received kidneys but who consented to receive hep-C-positive organs, and were subsequently treated for hep C. Later, the trial was expanded to hep-C-positive hearts. Four years ago, Montgomery received a hep-C-positive heart. “I think I was the seventeenth patient in the trial,” he said. “If I’m going to ask others to do it, I have to be willing to do it myself.”

An unexpected reprieve from mortality—the most poignant example of this that comes to mind is the one in which it is a pig whose life is indefinitely spared. In “Charlotte’s Web,” by E. B. White, Charlotte, a spider, makes Wilbur, the pig, more valuable to the farmer as a beloved individual than as pork. Charlotte, though, having completed her egg sac, will die very soon, in the natural cycle to which her species is condemned. She says to her friend:

"Christmas will come, then the snows of winter. You will live to enjoy the beauty of the frozen world, for you mean a great deal to Zuckerman and he will not harm you, ever. Winter will pass, the days will lengthen, the ice will melt in the pasture pond. The song sparrow will return and sing, the frogs will awake, the warm wind will blow again. All these sights and sounds and smells will be yours to enjoy, Wilbur."