"Pig heart" becomes "human heart"

On January 7, 2022, local time, Maryland, USA, Bennett became the first person in the world to receive a heart transplant from a genetically modified pig. Courtesy of Visual China

The author | Qiu Yunuo

Editor| Yang Jie

Recently, Mr. Bennett, a 57-year-old patient with advanced heart disease in the United States, underwent a heart transplant in a gene-edited pig. To figure out why you want to transplant a pig's heart, you must first understand why you can't use a human heart.

According to the Global Donation and Transplant Database, a total of 129681 organ transplants were performed worldwide in 2020, with an average of 17.5 cases per hour. With 40,608 organ donations, less than 10% of the global transplant needs are met.

Heart transplants are even more special. Unlike organs such as the liver, lungs, and kidneys, the donor for a heart transplant must be someone who has been judged to be brain dead and has been successfully matched. In addition, among all organs, the heart is most sensitive to ischemia during organ removal and refrigeration, and it is relatively difficult to preserve.

This gradually shifted people's attention from humans to animals.

The history of xenotransplantation is beyond imagination. As early as 1682, surgeon Job Janszu van Mikren installed a dog's bone on a Russian nobleman who had been wounded in battle and had a missing skull. In the centuries that followed, many experiments were carried out out in a vacuum: the skin of frogs, the eyes of rabbits... But in the end, they all ended in failure.

Serious xenotransplantation still began in the 20th century. At the beginning of the 20th century, the Frenchman Karel invented vascular suture, and organ transplantation finally saw hope, but the ending was not good.

The obstacle that runs between animal organs and the human body is mainly immune rejection. The organ is transferred from the donor to the recipient, and the recipient's body finds the foreign organ, which will treat it as an invading enemy, triggering an immune response to attack the organ, and the patient's body becomes a fierce battlefield, and the weak patient is difficult to bear.

The farther a species evolves, the greater the risk of transplantation. In this way, it seems that the best donor choice should not be pigs, but primates that are more closely related to humans. Why not choose "Master Brother", but use "Second Master Brother"?

Since the 1960s, people have been experimenting with transplanting the hearts, kidneys and livers of primates such as baboons. In 1983, an American cardiologist transplanted a baboon heart for a baby girl who had a congenital heart disease and could not get other baby organ donations. At first everything was normal, and at a press conference at the hospital, she was described as a "beautiful, healthy baby." But eventually due to immune rejection, the baby died after 21 days.

Due to the scarcity of numbers, differences in organ size, and huge ethical problems caused by too close relatives, primates such as chimpanzees are no longer allowed for xenotransplantation procedures and research.

The size of the organs of pigs is similar to that of humans, and the number and reproduction rate are not to be mentioned. Gene editing technology can achieve "camouflage pig hearts as adult hearts" by editing key points of the pig's immune system, thereby reducing the risk of immune rejection.

The swine heart transplant went through 10 gene edits. 3 genes were knocked out to avoid immune rejection, one gene was knocked out to avoid overgrowth after transplantation of pig heart tissue, and 6 human genes responsible for "camouflage" were inserted into the genome of donor pigs to prevent human blood from clotting in the pig heart and reduce the risk of immune rejection.

"It's been over a few weeks since the operation, and it can be said that the operation itself was a success." Wu Ning, an associate professor at Tsinghua University School of Medicine, said, "In the ultra-acute stage within 24 hours after surgery, the immune rejection that patients will experience is mainly due to the huge genetic differences between heterogeneous species, and the treatment team has carried out a number of gene edits on donor pig hearts, and it can be said that the problem of gene differences has been roughly solved." "This is followed by an acute phase of about 2 weeks, and the patient has passed it safely, and what needs to be waited for now is the long-term effect of the chronic phase in months and then in years." The more acute the more dangerous, the next danger period is about two to three months, and if successfully passed, the risk of subsequent immune rejection is greatly reduced, but it still needs to be closely monitored. ”

Wu Ning said: "In addition, it is also necessary to observe some problems that are not related to the operation itself for a long time, such as people walking upright, which is very different from other mammals, and whether pig hearts can bring long-term efficacy to patients is still unknown." ”

The researchers had applied to the U.S. Food and Drug Administration (FDA) for clinical trials of swine heart transplants in humans, but were rejected. The FDA wanted the researchers to transplant hearts into 10 baboons before proceeding to humans. This is also a necessary process for the development of medical technology, first animal experiments, obtaining enough data support before acting on the human body.

Prior to this exceptional surgery, the patient's heart had lost its basic function, had repeated arrhythmias, and could no longer wait for a traditional heart transplant or artificial heart pump surgery. The heart of the pig is "the only viable option at the moment". The FDA has approved an urgent authorization for Bennett's surgery, but that doesn't mean the technology could go to homes from now on.

"Whether it's an extra day, a week, a month or a year, I don't know." Bennett's attending physician Griffith said in an interview with the Daily Mail.

"Nevertheless, even if it takes half a year, it is worth the efforts of doctors and doctors." Wu Ning said.

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