The first pig heart transplant recipient survived only 60 days! The Lancet published the reasons for the failure. Is there still hope for xenotransplantation?

According to new research published in The Lancet, multiple factors may have combined to cause heart failure in patients.

Written by reporter Li Jing, Photo and text editor Chen Yongjie

On January 7, 2022, 57-year-old David Bennett received the world's first pig heart transplant at the University of Maryland Medical Center (UMMC). After 7 hours, a gene-edited pig heart began beating again in his body. However, two months later, on March 8, David Bennett died. At that time, the hospital did not announce the exact cause of death. The death of the world's first pig heart transplant recipient was extremely regrettable, and people were full of questions about the cause of his death.

Only survived 60 days, the Lancet published the reason for failure

On June 30, 2023, according to the University of Maryland website, the famous medical journal "The Lancet" published a study revealing the possible reasons for the failure of the world's first genetically modified pig heart transplant.

▲The world's first pig heart transplant to humans (Photo source: University of Maryland School of Medicine website)

Mohammed Mohidin, professor of surgery at the University of Maryland School of Medicine and director of the cardiac xenotransplantation program, and Bartley Griffiths, a pig heart transplant surgeon, are the lead authors of the study. According to the new study published in The Lancet, there may be multiple reasons that lead to the patient's heart failure. First, the patient's poor health before the transplant caused his immune system to be severely damaged, which also limited the use of effective anti-rejection regimens used in preclinical studies of transplantation. The researchers found that as a result, the patient's organs may be more susceptible to rejection by antibodies produced by the immune system. Then, the patient's use of intravenous immunoglobulin (IVIG), a drug containing antibodies, after the transplant may also cause damage to the myocardial cells. In the second month after the transplant, the patient received two injections to help prevent infection, which may also trigger an immune response to the pig heart. Finally, the new study believes that there may be a latent virus called porcine cytomegalovirus (PCMV) in the pig heart, which may lead to transplant dysfunction. After the patient reduced the antiviral treatment regimen, the virus may have been activated, triggering an inflammatory response that caused cell damage. However, there is no evidence that the virus infected the patient or spread to organs outside the heart.

Griffiths said: "We hope that the next patient will not only be able to survive longer through the transplant, but also be able to return to normal life for months or even years." Although the first xenotransplant patient unfortunately died, in the face of the reality of tight human organ supply, this operation still brought new imagination space for xenotransplantation.

Can xenotransplantation be revived?

There are two main branches of organ transplantation: one is "allogeneic organ transplantation", which means that the recipient and the donor are of the same species, such as organ transplantation between humans; the other is "xenogeneic organ transplantation", such as transplanting animal organs into humans. At present, the vast majority of organ transplantation surgeries performed clinically are allogeneic organ transplantation, but due to the shortage of donors, many people cannot wait for a suitable organ until the last moment of their lives.

According to expert estimates, there are about 300,000 patients in my country who need organ transplants to save their lives every year. In 2020, the ratio of organ donors to recipients in my country is 1:15. One in every 15 waiting patients can get a life-saving organ. Although the situation has eased, a large number of patients still die while waiting. In order to alleviate the serious contradiction of "supply and demand" in organ transplantation, scientists have long tried animal organ replacement methods, and xenotransplantation has become an important way recognized by the world to solve organ shortages. Which animals can serve as organ transplant donors? The first thing people think of is monkeys, gorillas and baboons, which are closely related to humans. They belong to the same primates as humans, and their organ structure, physiological function, and metabolism are similar to those of humans.

▲ Illustration of a human, a monkey, and a pig under an X-ray machine (Photo source: Visual China)

As early as the 1960s, surgeons tried to transplant orangutan organs into humans. The recipient's immune system quickly rejected the transplanted organs, causing them to fail in a short period of time, leading to the death of the recipient. The repeated failures of the initial exploration made people realize that primates' "close relatives" might not be ideal organ transplant donors. Listing primates as organ donor candidates also faces many problems, including technical and ethical issues.

Most of the smaller primates have organs that are smaller in size and cannot meet the metabolic needs of humans. Primates have a low reproduction rate, and the larger gorillas and baboons are endangered, making it difficult to meet the human demand for organ transplants. As "close relatives" of humans, they may also carry some viruses that humans are susceptible to, such as simian immunodeficiency virus and Ebola virus. Once these organs are transplanted into the human body, they may produce more harmful viruses after recombination. All these unfavorable factors have dimmed the "halo" of primate candidates. Scientists have turned their attention to animals whose external indicators such as body size, diet, and metabolic level are similar to those of humans. After layers of "screening", pigs are considered to be the best choice for xenotransplantation at this stage because of their advantages such as organ size similar to that of humans, lower risk of infectious diseases, and relatively more sufficient numbers.

From the performance parameters, the body temperature of pigs and humans is 36℃～37℃, and the heart size, duct distribution and power output, and even heart rate (human heart rate is 60～100 times/minute, pig heart rate is 55～60 times/minute) are similar. The foreseeable scope of organ transplantation includes cornea, skin, pancreatic islets, joints, tendons, ligaments, kidneys, heart, liver and many other aspects. In the medical field, pig heart valves implanted with human cells have been used to treat patients, and pig ligament tendon transplantation has also matured.

In September 2017, at the 14th International Xenotransplantation Society Conference held in Baltimore, the Emory University team in Atlanta announced that a macaque in their laboratory received a genetically modified pig kidney transplant for more than 400 days before rejection occurred, several months longer than the previous record. A team from the University of Munich in Germany performed a pig heart transplant on a baboon, and the transplant lasted for 90 days.

▲German researchers transplanted hearts from pigs to several baboons, and the baboons survived for 90 days (Photo source: Nature)

At the same time, a small number of bioengineering companies use gene editing technology to improve the immune compatibility of xenogeneic organs with the human body and reduce the risk of transmission of endogenous animal viruses by knocking out some pig genes and inserting human genes.

Genetic technology breaks down some barriers

Even though there are still many problems to be faced, with the support of gene editing technology, xenotransplantation seems to have opened a window for patients. The main obstacle faced by all organ transplants is the behavior of the human immune system to "eliminate foreign bodies". Once "foreign objects" enter the human body, the immune system will attack and reject the "foreign objects", and the transplanted organs may be destroyed within a few minutes. This hyperacute rejection reaction not only occurs in xenotransplantation, but is also difficult to avoid in organ transplantation between people.

To deal with hyperacute rejection, scientists have tried to conduct animal experiments by removing donor antigens or using hemodialysis to remove antibodies in the recipient, but these methods have had little effect. With the development of genetic technology, especially the emergence of gene editing technology CRISPR/Cas9, scientists can "knock out" certain genes to achieve more matching organ transplant donors.

At the same time, researchers also added human genes to pigs so that after pig organs are transplanted into humans, they can produce proteins that function normally, such as human thrombomodulin, which inhibits blood coagulation, and CD46, which protects organs from host antibody immune responses. The potential risk of viral transmission in xenotransplantation is quite tricky. Current research has identified 26 pathogens that pose a risk of cross-species infection, including porcine endogenous retrovirus (PERV).

Although there are no reports of PERV causing disease in humans, PERV is still one of the main concerns of global regulators. New viruses cannot be spread through xenotransplantation. To dispel concerns, scientists once again used the gene "knockout" method to achieve a one-time knockout of the PERV fragment hidden in the genome, reducing the virus infection rate to one thousandth of the original.

▲The organs of a pig can be widely used for transplantation of human cornea, skin, pancreatic islets, joints, tendons, ligaments, kidneys, hearts, livers and other organs (Image source: Nature)

In 2017, Harvard University professor George Church and Yang Luhan's team published their research results in the journal Science. They bred the world's first pigs without endogenous retroviruses, fundamentally solving the risk of viral transmission caused by pig organ transplantation to humans. The following year, the 2.0 version of the transgenic pig was born to further solve the problem of immune rejection of xenotransplantation. Since then, the 3.0 version of the transgenic pig, which combines the advantages of the first two generations, has made further progress in the safety and effectiveness of xenotransplantation.

▲ "Pig 3.0" genetically edited by Yang Luhan's team (Photo source: Nature)

Scientists can use gene editing to solve the problem through the known key gene sites of the pig and human immune systems. The pig heart used in the world's first pig heart transplant to human surgery mentioned at the beginning has undergone 10 genetic modifications, including knocking out 1 gene that controls organ growth, 3 genes for human immune rejection, and inserting 6 genes that make the pig heart better adapt to the human immune system. Of course, in order to obtain such an ideal organ transplant donor, it is necessary to keep their living environment completely sterile and virus-free "isolated". It can be imagined that in an ultra-clean pig house, they are equipped with electronic chips, monitored 24 hours a day, eat sterile and non-toxic feed and water, and undergo quarantine inspections on time... All of this will inevitably require a lot of financial and material resources.

Unavoidable ethical challenges

Of course, from the perspective of solving the contradiction between "supply and demand" of organ transplants, the technical and financial problems should be solvable. So how should we deal with the ethical controversy? Are humans who have pig organs considered "hybrids"?

Professor Dai Yifan of Nanjing Medical University once responded to this question from a personal perspective. He believed that "it's like changing the engine of a car, but it's still the same brand of car, the essence has not changed. If a person is replaced with a pig's heart, he becomes a pig-man. Then, does a patient with an artificial device in his body become a robot?" Can the memory of animal organs be transplanted to humans? In clinical experiments, the hair of the elderly who received a kidney transplant from a young person turned black, and the temper of a gentle person became irritable after receiving a heart transplant from a person with a bad temper... If organs really have "memory", what impact will xenogeneic organs have on people's physiology and psychology?

▲ "Producing" organs like producing sausages to supply humans for transplantation! This is not a fantasy, the plots in those science fiction movies are becoming a reality (Image source: Nature)

In addition, different animals have different life spans. Generally, pigs live about 15 years, so will transplanting pig organs accelerate the aging of the recipient? What is the maximum limit of gene editing for xenotransplantation? Animal organs have a certain proportion of human cells, so should they be called "it" or "him"?

(Source: Comprehensive from Yangcheng Evening News, Huanqiu.com, Jiemian News, Zhihu Column of Intellectuals, Zhihu Column of Science Association, Xinhuanet)