www.newyorker.com /magazine/2022/02/28/the-medical-miracle-of-a-pigs-heart-transplant-in-a-human-body

The Medical Miracle of a Pig’s Heart in a Human Body

Rivka Galchen 9-12 minutes 2/17/2022

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.”

“Ordered fifty-eight days ago and it’s here already!”
Cartoon by Julia Suits

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.