Is there still hope for xenotransplantation after the death of the world's first pig heart transplant patient?

In January 2022, David Bennett, a 57 year old patient with advanced heart disease, received a pig heart with gene editing, becoming the first patient to receive pig Heart transplantation in human history. Unfortunately, Bennett passed away two months after surgery at the University of Maryland Medical Center in the United States, and the cause of death was not announced at that time

In January 2022, David Bennett, a 57 year old patient with advanced heart disease, received a pig heart with gene editing, becoming the first patient to receive pig Heart transplantation in human history. Unfortunately, Bennett passed away two months after surgery at the University of Maryland Medical Center in the United States, and the cause of death was not announced at that time. Recently, a study published by the famous medical journal The Lancet revealed some reasons for the failure of pig Heart transplantation, and the virus hidden in the pig heart may be the main reason.

In fact, scientists have been studying xenotransplantation for many years. So, what is the difficulty of xenotransplantation? Can we really find a breakthrough in animals in the plight of human organ transplantation? We invite renowned science popularization author Zhang Tiankan to give us a talk.

(1) Why the first patient to receive pig Heart transplantation died

Mohammed Moxidin, professor of surgery at the University of Maryland School of Medicine and director of the heart xenotransplantation project, and Bartley Griffith, a pig Heart transplantation surgeon, led the investigation of the cause of death.

According to the medical team's investigation, the main cause of Bennett's death was sudden heart failure. There are several overlapping factors that cause Bennett to experience heart failure, including his poor health condition before transplanting the pig heart, which severely reduces his immune function and makes it impossible to use an effective anti rejection medical plan for xenotransplantation. In this situation, Bennett's immune system is difficult to accommodate the transplanted pig heart. The patient's histology, immunohistochemistry staining, and single cell RNA analysis all revealed symptoms of rejection. The direct evidence comes from the autopsy, which showed extensive endothelial damage in Bennett's body, indicating the presence of antibody mediated rejection. This further indicates that the transplanted pig heart is rejected by antibodies produced by the patient's immune system.

In addition, the use of Immunoglobulin therapy (IVIG) (a drug containing antibodies) by patients after transplantation may also cause myocardial cell damage. In order to prevent infection, in the second month after transplantation, the patient received two injections of immunoglobulin, which triggered his immune activation response to the pig heart.

Another obvious reason is the presence of porcine cytomegalovirus/porcine Roseola virus in pig hearts, which may lead to dysfunction of transplanted hearts. After the patient reduces the intensity of the antiviral treatment regimen, the virus is activated, triggering an inflammatory response that leads to cell damage.

Other causes of patient death have been previously proposed, such as a paper published in the New England Journal of Medicine on June 22, 2022, which pointed out that after Bennett transplanted a pig heart, not only did he discover a previously unknown porcine cytomegalovirus, but his heart weight almost doubled after death, from 328 grams to 600 grams. The deceased's heart also showed fibrosis tissue accompanied by red blood cell extravasation. At the same time, human herpesvirus (HHV-6) was also found in Bennett's lungs. The MIT Technology Review in the United States published an article saying that the cause of death of the patient may be the presence of virus in the heart of the transplanted gene editor pig. The author believes that porcine cytomegalovirus is a preventable infection, meaning that the failure of this transplantation could have been avoided.

All of the above factors may lead to Bennett's death, but the virus hidden in the pig heart may be a more important cause. At present, researchers have not fully confirmed the cause of the patient's death, but have only proposed various related factors to let everyone know that the human body still cannot accommodate the pig heart. Nevertheless, Bennett's surgeon Griffith still expressed the hope that the next patient will not only survive for a longer time through transplantation, but also be able to return to normal life for months or even years.

(2) Heterologous organ transplantation starting from non-human primates

Organ transplantation can be divided into homologous and heterologous types. The former involves transplanting organs from individual A of the same type of animal to individual B, which is known as allogeneic transplantation. The earliest well documented allogeneic organ transplantation in humans occurred in the late 16th century, when Italian surgeon Gaspar Taliacozi transplanted parts of the skin from different individuals. However, the official and successful allograft transplantation took place in December 1954, when Dr. Joseph Murray of the United States successfully performed the first identical twin kidney transplantation without using anti rejection drugs. In 1990, Murray shared the Nobel Prize in Physiology or Medicine in Physiology or Medicine with E. Donnall Thomas for his contributions to "organ and cell transplantation".

Xenotransplantation refers to the mutual transplantation of organs from different types of animals, with the earliest recorded being in 1905 when French doctor Princeteau sliced a rabbit's kidney and implanted it into a child with renal failure. Although the transplanted kidney urinated well after surgery, the child still died of lung infection caused by rejection 16 days later.

In recent years, the call for xenotransplantation has become increasingly strong, mainly due to the scarcity of human organ donors of the same species, while animal organs are relatively easy to obtain and subject to less ethical constraints. To this end, researchers conducted a large number of experiments.

There are many animals that can perform xenotransplantation on humans, such as non human primates such as baboons and orangutans. Initially, non human primates were indeed the first choice for xenograft research, as they were close relatives of humans and humans had better adaptability and acceptance of their organs. Under this approach, some research teams have conducted experiments and achieved certain results.

In 1964, Dr. Keith Reemtsma of the United States transplanted the kidney of a chimpanzee to a teacher with renal failure. At the same time, he gave immunosuppressive treatment such as Azathioprine, glucocorticoid, and whole-body irradiation. After the operation, the patient recovered and returned to his teaching post. But the patient only survived for 9 months due to electrolyte disorders caused by immune rejection. In 1984, Dr. Leonard Bailey of the Medical School of Roma Linda University in the United States gave a Heart transplantation of a baboon to an infant with hypoplastic left heart syndrome 12 days after birth. However, the infant developed Tachypnea and obvious myocardial damage 11 days after the operation. At the same time, his immune system produced serious rejection reaction to the baboon's heart, and died 21 days after the operation.

In addition to immune rejection, safety issues are also of great concern, as transplanting organs from non human primates carries the risk of causing additional diseases. For example, monkeys have hidden diseases such as Ebola, Marburg virus and Simian immunodeficiency virus (SIV), and the well-known AIDS virus originates from Simian immunodeficiency virus. Therefore, even if primate organs can be transplanted to humans, the presence of pathogens in their organs is a significant safety issue.

(3) Gene editing of pig organs still not solved the problem of rejection

Due to the high cost of using non human primates for xenotransplantation, scientists have begun to explore the possibility of other animals, especially pigs, for xenotransplantation. Compared to humans, the organ size of pigs is relatively matched. In theory, most organs of pigs can be transplanted to humans, including the cornea, skin, joints, tendons, ligaments, kidneys, heart, liver, lungs, etc.

After a lot of exploration and accumulation by predecessors, the foundation of pig Heart transplantation for Bennett in January 2022 was laid. Researchers made 10 modifications to the genes of pigs using organs, including knocking out or inactivating 4 genes, while the other 6 genes were similar to human genes, only to make the transgenic pig organs more acceptable to the human body. However, the pig Heart transplantation failed with the death of the recipient.

Why has the heterologous organ transplantation represented by pigs, which is highly regarded by humans, not been successful yet? Summarizing the existing failure experience, the core issue of xenotransplantation is still rejection, which is even more severe than rejection in homologous organ transplantation. The reason is that genes and multiple antigens encoded by genes on pig organs can trigger rejection reactions, and pathogens and microorganisms on pig organs may be antigens that trigger immune rejection reactions, as well as cause zoonotic diseases or new diseases.

When summarizing the cause of Bennett's death, Dr. Griffith, the chief surgeon, stated that they plan to further study how to remove potential viruses from the pig heart, together with the company responsible for genetic editing of the pigs. This indicates that various antigens and pathogens in pig organs are obstacles to pig organ transplantation to humans. Prior to this, an important reason why they were able to obtain approval from the Medical Ethics Committee to carry out transplantation surgery was the use of genetically modified pigs, which experts had originally believed could solve the initial issue of immune rejection. The fact proves that this idea is too optimistic.

(4) The path of "cooperation" between human and animal organs is obstructed and long

Although the first pig organ recipient of gene editing died, this operation still left room for imagination in the face of the reality of tight supply of human organs.

Humans use pig organs for transplantation because this can expand the source of donor organs and save more people in urgent need of organ transplantation. Whether in China or the United States, the number of people queuing up for donor organ transplantation each year ranges from 100000 to several hundred thousand. In 2022 alone, the United States has carried out 41000 transplant operations, including about 3800 Heart transplantation operations. However, there are still more than 106000 people waiting for donor organs on the national waiting list. Every year, thousands of people die before obtaining organs, and thousands of people have never even been included in the list. According to the data from the China's National Health Commission of China, there are about 300000 people waiting for organ transplantation every year in China, but only 20000 people can complete the transplantation. Many patients are waiting in despair.

However, at this stage, due to differences in species, including genes, molecules, immune systems, and biological barriers, it is destined that xenotransplantation, represented by pigs, will be extremely difficult.

In terms of biological barriers between different species, the use of pig organs carries many cross species risks. In addition to porcine cytomegalovirus, pigs also harbor influenza viruses, swine fever viruses, Japanese encephalitis viruses, as well as parasites such as tapeworms. Porcine circovirus type 2 was also found in domestic pigs and wart pigs, and four major influenza virus subtypes were also isolated from pigs: H1N1, H1N2, H3N2 and H3N1. All of these can cause illness in humans and lead to the failure of xenotransplantation. Therefore, scientists need to focus on addressing the immune rejection response of pig organ transplantation, as well as the risk that pathogens in pigs may induce human diseases.

In addition, the use of pig organs also involves issues such as age. Due to being a heterologous organ, the lifespan and physiological functions of pigs are different from those of humans, making it difficult to ensure that pig organs transplanted into humans can fully play their desired role. For example, the lifespan of pigs and pig organs is much shorter than that of human organs, with a pig's lifespan not exceeding 15 years at most. If its organs are transplanted into humans, 15 years may be its limit.

At present, the longest Time to live of human liver transplant recipients has exceeded 33 years, and Kidney transplantation recipients can survive longer. The Time to live of known living related kidney transplant patients in the world is nearly 40 years. Based solely on survival years, it is estimated that transplanting pig organs will be performed several times more than transplanting human organs, which clearly brings more risks. In addition, due to being a heterologous organ, the dose of anti immune rejection drugs taken by the recipient after the rejection reaction occurs is also large, which may affect their quality of life and survival years.

Even if various technical issues can be fully resolved in the future, transplanting pig organs into humans will still face ethical and psychological acceptance issues. An obvious question is whether recipients of pig organ transplants will become an incomplete 'person' in their own or others' perceptions? So, before accepting pig organ transplants in the future, it is likely that there will be an additional process - doctors providing psychological counseling to the recipient and their relatives, at least eliminating ethical concerns.

In short, transplanting animal organs into humans is clearly much more complex and technically challenging than using human organs, and requires long-term and difficult exploration. According to the media, there are still dozens of people waiting in line to approve pig Heart transplantation in the United States. However, it may take a long time for pig heart or other organ xenotransplantation to succeed before a perfect solution is found.

Source: Beijing Daily

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