Crazy attempts – the path of xenotransplantation

In 1984, American doctors transplanted a baboon heart into a 25-day-old baby girl with left heart hypoplasia.

Surgeons at the University of Maryland Medical Center in the United States carried out a special organ transplant operation, for the first time transplanting the heart of a genetically modified pig into a patient with advanced heart disease, the patient did not have a serious rejection reaction, and the pig heart began to function normally. This is the first time that humans have successfully transplanted a genetically modified pig heart into a patient, which has aroused widespread attention and discussion among the public and the media. In fact, xenotransplantation is not a new thing that has appeared recently, its history can be traced back to more than three hundred years, which is full of bravery and fanaticism, deception and ignorance, and finally gradually embarked on the right path of science.

Early madness

After several attempts at blood transfusions between dogs and dogs, cattle and dogs, Jean-Baptiste Dennis, the imperial physician of King Louis XIV of France, became confident in the transfusion of humans and beasts. In June 1667, a 15-year-old male patient had a severe high fever due to an unknown infection, and the doctors used the then popular bloodletting therapy on him, which was released 20 times, resulting in severe ischemia in his body. Dennis and his assistants injected fresh lamb blood into the patient's veins, and soon the patient's body returned to normal. Dennis then underwent several similar xenotransfusions, including lamb blood and calf blood. Doctors in other European countries followed suit, but soon Dennis's patients died after multiple transfusions of lamb's blood, which directly led to the French government banning blood transfusions in 1670, and Germany, Britain and other European countries also banned.

In the mid-to-late 19th century, xenotransfusions resurfaced, and doctors in European countries performed hundreds of xenotransfusions, but most patients experienced serious side effects or even died. Until 1900, austrian immunologist Carl Landsteiner first discovered that there are blood group differences in humans, and found that blood transfusions with the same blood type are not easy to cause serious side effects, thus opening the era of human homogeneity transfusion and ending the frenzy of animal xenotransfusion.

During this period, European doctors also became interested in xenodermal skin transplantation, trying to transplant the skin of animals such as frogs, sheep, rabbits, dogs, cats, mice, chickens and pigeons into patients with severe burns or skin loss, but only a short "improvement" was achieved, and none of the xeno skin grafts showed sustained efficacy.

What is even more bizarre is that some people actually hope to achieve rejuvenation and sexual function improvement through xenotransplantation, of course, some people use it to defraud money. In the late 1920s, Russian surgeon Serge Voronov proposed the idea of cell transplantation, which provided ideas for islet cells to treat diabetes. However, Voronov was passionate about xenotransplantation, and he developed a "rejuvenation" cell transplant therapy in which chimpanzees or baboon testicles were cut into slices, not for stir-frying, but for inserting into human testicles. There are reports that these patients quickly regain their youthful vitality after surgery, as if they are rejuvenated. This grotesque operation was sought after by some rich people in France, and the rich in other countries also admired it, and at one time Voronov performed hundreds of surgeries and made so much money that he chartered the floor of the most luxurious hotel in Paris for himself. Soon, other scientists proved that Voronov's surgery did not play a positive role, at most like a placebo, giving patients some psychological comfort.

Coincidentally, an American impostor doctor named John Brinkley claimed to be able to improve men's sexual function with goat testicular slices, and even to cure all diseases, he also used the emerging form of radio advertising to conduct crazy circular ads on the border between the United States and Mexico, defrauding a large number of patient trusts and millions of dollars. However, due to the large number of patient deaths caused by related xenografts, Brinkley suffered a series of lawsuits, declared bankruptcy in 1941, and then died of heart failure without any money, leaving a large number of compensation lawsuits that had not been heard.

A return to reason

The fanatical fireworks are gradually extinguished, but they reflect the rational brilliance of science. Despite the controversy surrounding xenotransplantation, some scientists and doctors who have dared to explore have insisted on conducting relevant research, laying a scientific foundation for the true clinical application of subsequent xenotransplantation.

Kidneys are the most in demand organ donors, with more than 100,000 kidney donors needed in the United States alone. Originally, Serge Voronov, who was addicted to "rejuvenation" therapy, had the opportunity to become the first person to perform a human allogeneic kidney transplant, and he applied for a kidney transplant from a death row prisoner, but was preempted by his compatriot Dr. Yuri Vorno, who performed the first human kidney transplant in 1933, which was successful, but the patient died two days later. Xenotrans kidney transplantation is earlier. Back in 1906, French surgeon Matthew Jabrey transplanted a pig's kidney to a 49-year-old female patient with kidney dysfunction. In the following 50 years, doctors intermittently tried to transplant animal kidneys to human patients, but the results were not ideal, and most of the patients died within a few days or even a few hours of transplantation.

According to the theory of Nobel laureate in physiology or medicine, Pete Medawar and others, because there is immune rejection between different species and even different individuals of the same species, it often leads to rapid failure of transplantation. Medavo et al. immediately discovered acquired immune tolerance, that is, the use of some immunosuppressants can alleviate immune rejection, which opened a new era of organ transplantation and revived the hope of xenotransplantation. From 1963 to 1964, Kesse Remcima, a professor at Tulane University in the United States, with the help of immunosuppressants, transplanted the kidneys of chimpanzees into 13 patients with advanced renal failure, most of whom survived for no more than 2 weeks, and only one female teacher was lucky enough to live for 9 months. At the same time, American doctor Thomas Stazel also performed 6 xeno kidney transplants from baboons to humans, but none survived for more than 2 months.

In fact, Thomas Stazel's most notable achievement was a human liver transplant. In 1963, Stazel and colleagues performed the first human liver transplant, but it was unsuccessful, and it was only four years later that the allogeneic liver transplant was successful. During this period, Stazel did not abandon the study of xenotransplantation, and he and his colleagues repeatedly transplanted baboon livers to liver disease patients, but unfortunately did not survive more than 10 days. Using new immunosuppressants, Stazel performed several more xeno liver transplants in the 1990s, including chimpanzees and baboons, and one of the patients who received a baboon's liver survived 70 days, the longest survival time for xeno liver transplants.

The scientists who first performed xenotransplantation are not generalists. In 1963, American physician James Hardy successfully performed the first human lung transplant, although the patient survived only 18 days. Motivated by the results of the Keith Remcima trial, in 1964 Hardy performed the first human heart transplant, also the first xenomic heart transplant, because the heart donor came from a chimpanzee. But due to severe immune rejection, the patient died less than two hours after the operation. After that, doctors performed several xenotransplantations, with donors chimpanzees, baboons, sheep and pigs, and most of the patients survived for no more than 1 day. Only in 1984 did American physician Leonard Bailey transplant a baboon heart into a newborn baby girl with left-sided hypoplasia syndrome, who survived for 20 days.

It can be seen that most of these early xenotransplantation operations were personally operated by well-known organ transplant experts, who conducted rational and scientific explorations of unfortunate patients in the face of organ shortages and serious conditions. Although these patients were ultimately doomed, they used their lives to bring xeno organ transplant research into the right path of science.

The solution

These experimental xenotransplantations have made scientists increasingly aware that immune rejection remains the biggest obstacle to organ transplantation, and that immune rejection between xenoparties is much greater than between allogeneic organs. Since the mid-1990s, doctors have not rushed to conduct human trials of xenotransplantation. Without new, more scientific measures, immune rejection will be an insurmountable obstacle to xenotransplantation, and xenotransplantation will always be a myth.

Of course, scientific problems have their own scientific solutions. Some doctors with scientific literacy and scientific exploration spirit and some scientists interested in xenotransplantation have come together, and through careful research and analysis of the reasons for the failure of xenotransplantation, they have gradually realized that for xenotransplantation to be successful, it is necessary to withstand multiple tests such as ultra-acute rejection, acute vascular rejection and cell rejection, because there is a natural barrier between different species, and transplant recipients will do their best not to let grafts "take root" in their own territory. Further analysis found that there are special protein molecules on the cell surface of different animals, which are the main markers of the immune system to distinguish between "their own people" and "enemies", which was originally an important defense mechanism of the organism against pathogenic microorganisms, but now it has become the main obstacle to xenotransplantation.

Immunosuppressants reduce the sensitivity of the immune system so that the patient's body can accommodate foreign grafts, making organ transplantation the ultimate means of saving the lives of patients with organ failure. With the rise of gene modification technology, scientists suddenly have a bright eye, if the use of gene modification technology, the organ donor animal cells are transformed close to human cells, it is expected to escape the attack of the human immune system.

Because the organ mechanism, function and metabolic characteristics of pigs are similar to those of humans, and pigs have strong reproductive ability, convenient feeding, and there is no ethical controversy faced by primates, they have been selected by scientists as the chief representative of heterogeneous organ donors. At the beginning of the new millennium, German scientists took the lead in transferring human-specific genes into pig cells and breeding transgenic pigs for organ transplantation, and two years later, American scientists announced in the journal Science that they used gene knockout technology to successfully destroy the protein molecules in pig cells that are most likely to cause xenomic immune rejection. The study also announced that xenotransplantation would become one of the mainstream areas of life science research. Since then, scientists have continued to use gene modification technology to transfer human genes into pig cells, and at the same time destroy the specific genes that cause rejection in pigs to breed genetically modified pigs for xenotransplantation.

After obtaining this genetically modified pig, the scientists did not rush to transplant the organs of these pigs into humans, and established and followed the new rules of xenotransplantation, that is, preclinical trials must be conducted on primates before clinical trials. As of the end of August 2019, after scientists transplanted organs from genetically modified pigs into primates such as chimpanzees, baboons or monkeys, the survival time of grafts is constantly extending, of which kidney transplantation can survive up to 405 days, liver transplantation can survive up to 200 days, ectopic heart transplantation can survive more than 900 days, isotopic heart transplantation can only live less than 60 days, and cornea, neuron and islet cell transplantation can survive for more than 1 year.

On December 14, 2020, the U.S. FDA officially approved a α-galactose-free genetically modified pig for potential uses such as producing food and pharmaceutical products, which is the world's first approved genetically modified pig product and the first approval of a genetically modified animal for both edible and medical uses, which is of landmark significance. Since then, clinical trials of xenotransplantation in pigs have accelerated. In October-December 2021, a research team from NYU Langone Health at New York University announced that two experimental xenografts were successfully performed on patients who died of brain using genetically engineered pig kidneys. Not only did the kidneys continue to filter waste products and produce urine at normal rates, but they also returned the patient's abnormal creatinine levels caused by poor kidney function to normal levels. On January 10, 2022, the world is paying attention to an explosive scientific news, three days ago, surgeons at the University of Maryland Medical Center in the United States performed a genetically modified pig heart transplant for a patient with advanced heart disease, and the patient is currently in good condition after surgery, with normal heartbeat, pulse and blood pressure detected, and there is no obvious rejection.

With the development of the world's first clinical trial of pig heart xenotransplantation, marking the beginning of a new era of xenotransplantation, it is expected that more xenotransplantation clinical trials will be carried out in the next few years, which is expected to bring new hope to a large number of critically ill patients who lack human organ donors and have no other treatment options.

Southern Weekend Contributing Writer Tombo