The world's first case of pig heart transplant patients have been able to go to the ground to move, how about China's xenotransplantation technology?

"Why don't fireflies light up?" This is a sentence that the little bug asked his father before he fell ill.

In the movie "Manslaughter 2" released at the end of the year and the beginning of the year, the son of the male protagonist in the film, Xiao Worm, was diagnosed with dilated cardiomyopathy and needed to undergo heart transplant surgery in order to survive. Due to insufficient heart resources, my father took a risk, which led to a tragedy.

The little worm in the film did not replace the heart in the end, but the dream shone into reality. On January 7, 2022, the University of Maryland School of Medicine in the United States successfully transplanted the heart of a gene-edited pig into a 57-year-old male heart failure patient after obtaining an urgent authorization from the U.S. Food and Drug Administration (FDA), with a 7-hour operation.

At present, the patient has been more than a month after the operation, the transplanted pig heart is functioning well, the patient has been able to move to the ground, and more importantly, so far, the transplanted pig heart has not shown signs of rejection.

The success of pig heart transplantation, on a global scale, has aroused the general attention of the public and the strong response of the scientific and technological community, and the study of xenotransplantation (xenotransplantation, referring to the transplantation of pigs' organs to the human body and solving the shortage of organs) has once again become the focus.

In the battle for xenotransplantation, why is this the United States winning the world's first?

What are the key techniques for swine heart transplantation?

In addition to pig heart transplantation, what other organs are currently being tried?

What efforts has the mainland made to catch up with the gap with foreign xenotransplantation technologies? And how to overtake in curves?

In response to these problems, the health community interviewed Professor Deng Shaoping, member of the Standing Committee of the International Xenotransplantation Association and director of the Organ TransplantAtion Institute of Sichuan Provincial People's Hospital. As a researcher who has been engaged in organ transplantation for a long time, especially in the field of xenotransplantation, and a witness to the development of 30 years, Professor Deng Shaoping has paved us with the tortuous and magnificent development path of organ transplantation.

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The success of "pig heart transplantation" is inseparable from three core technologies

"Either die or have a transplant." That was my last resort." The day before receiving this swine heart transplant, Bennett said.

Before the operation, he was bedridden for six weeks, in the advanced stages of heart disease, and relied on ECMO to sustain himself. He was not disappointed by the xenotransplantation surgery at the University of Maryland School of Medicine, and he has now gotten out of bed and walked as he wished.

"First of all, the perfection of surgical technology is the soil in which this operation can be carried out." Professor Deng Shaoping told the health community. Clinically, since the late 1980s, after the emergence of cyclosporine immunosuppressants, organ transplantation has developed in a comprehensive and explosive manner. The first development is kidney and liver transplant technology, and later the heart and lung technology follows. Clinically, heart transplantation also has decades of development experience, so from the surgical technology, there has been a full preparation.

Secondly, the "gene-edited pig" is the core of this operation, which is divided into two aspects:

On the one hand, in response to immune rejection, the main antigen gene of the donor pig was knocked out. As early as 2002, two teams in the United States simultaneously made gene knockout pigs, which did not occur ultra-acute immune rejection.

On the other hand, in this pig heart transplantation, 3 glycoprotein gene antigens that can cause rejection were knocked out, and 6 human genes were introduced, which can make the donor more suitable for human transplantation.

Third, the drug optimization of immunosuppressants is the condition that ensures the success of the operation. For xenotransplantation, even for organs that use gene editing, some special immunosuppressive drugs are added to ensure the success of xenotransplantation.

There is a gap of more than 300,000 organ transplants each year

Organ transplantation is the most effective treatment for end-stage organ failure.

However, it is difficult for women to cook without rice, and there is a serious shortage of human organ sources, which greatly limits the clinical application of organ transplantation technology.

At present, the mainland has become the second largest organ transplant country in the world, but there is still a big gap compared with developed countries. The number of patients waiting for organ transplantation in the United States reaches 110,000 every year, and about 30,000 cases of transplantation are completed, and the supply-demand ratio is close to 1:4, while about 300,000 patients in the mainland need organ transplants every year, less than 20,000 organ transplant surgeries, and the supply-demand ratio is close to 1:15, in other words, the United States is nearly 4 times that of the mainland, and the problem of organ shortage in China is more severe.

How to balance such a large supply and demand relationship has become a big problem. The needs of patients do not decrease, and the supply of matched organs is even more difficult to find. Gene editing technology offers new ideas – if human organs are difficult to find, can other animal organs close to humans continue their function in the human body?

In fact, xenotransplantation is not a new concept proposed in recent years, as early as the beginning of the last century, scientists have begun to try xenotransplantation. In 1905, France performed the world's first xenotransplantation, implanting rabbit kidneys into children with renal failure. The surgery was successful, but 16 days later the child died of a lung infection due to rejection.

After that, countries have carried out xenotransplantation exploration and experiments, especially the research and development and preclinical experiments of DAF transgenic engineered pigs, which have also achieved a more obvious effect of prolonging graft generation, so that everyone seems to see a good prospect for xenotransplantation applications.

By the late 1990s, however, xenotransplantation research had fallen into a trough.

First, due to the limitations of the times and technology, the genetic modification technology is not mature enough to carry out multi-gene and multi-target knockout to overcome ultra-acute rejection after xenograft.

Second, the social ethics of xenotransplantation has been raised and widely discussed. The reason was that in the case of unclear animals carrying pathogens, concerns about the safety of xenotransplantation exceeded the enthusiasm for research at the time.

Third, between the public opinion concerns, many companies have stopped investing in xenotransplantation research. High cost and high risk have deterred many enterprises, and the special social funds and investment projects have also been significantly reduced.

As a result, xenotransplantation has experienced a special period of low.

From a big country for organ transplantation to a strong country for organ transplantation

From the perspective of same transplantation, the mainland is already the second largest country in the world in terms of transplantation, and all kinds of organ transplantation can be done, and lung transplantation and heart transplantation have also achieved rapid development in recent years, reaching the international advanced level. Another place to be proud of is that the surgical techniques in the mainland are very sophisticated, especially experts in the field of liver and lung transplantation, which are unanimously recognized by their international counterparts.

Professor Deng Shaoping believes that clinical organ transplantation is proud of the data, but in fact there are some gaps: the mainland is not precise in the long-term follow-up of patients after surgery, and the statistical data method is not perfect. If the follow-up system can be optimized, it will further improve long-term efficacy (long-term survival).

In addition, for multidisciplinary participation and patient management, there is also a big gap with foreign countries. In foreign countries, postoperative patient management is a team of physicians and surgeons, imagists, clinical pharmacists, infection experts, etc. to discuss the implementation work together. In recent years, the concept of multidisciplinary consultation has sprouted in China, but it is really implemented as a regularization and standardized management, and the country is still very inadequate.

Therefore, from a clinical point of view, the gap in management level cannot be ignored.

In addition, organ donation in the mainland has yet to be developed. Before 2015, there were still some problems in mainland organ donation, which have been completely improved in recent years, forming a standardized, standardized and internationally recognized organ donation system, but so far, there is still a big gap between the quantity and quality of organ donation in the mainland and developed countries. Therefore, in the future work, we must vigorously strengthen the work of citizen organ donation, hoping to increase the number of our organ donations by at least 2 to 3 times to partially alleviate the pressure of organ supply and demand.

Although the mainland has many achievements in same-species organ transplantation, there is also a certain gap between the basic research and preclinical experiments of xenotransplantation technology and developed countries.

Catching up with the United States, what efforts has China made

Xenotransplantation is the dawn of human beings' "change of life against the sky" and is a palpable means to solve the shortage of organs. Many scientists in foreign countries have chosen to return to China to develop, and China has provided these scientists with a broader platform and more abundant resources to show their magic.

After Professor Deng Shaoping returned to China in 2009, he established an organ transplant research institute and organ transplant center in the Sichuan Provincial People's Hospital of the Sichuan Academy of Medical Sciences, and began to introduce teams, and at the same time sent the team of provincial doctors abroad for further study.

With the lofty ambition of carrying out xenotransplantation research in China, Professor Deng Shaoping returned to his homeland from the United States and brought back the organ transplantation techniques he learned abroad.

Before returning to China, Professor Deng Shaoping wanted to bring the best-bred Harvard genetically engineered pigs in the United States back to China for research. David Sachs, an expert on the Harvard xenotransplant team at the time, director of the Organ Transplant Institute, and globally recognized leader in xenotransplantation, expressed his support. He visited Chengdu and for the first and only time named the xenotransplantation laboratory after himself.

Because of biosecurity issues, genetically engineered pigs have not been introduced to China, which has become a historical regret.

However, the failure to successfully introduce pigs abroad has also inspired domestic experts and scholars to make continuous progress in this field, including Professor Pandenko and his team. As an expert in genetically engineered pigs, Professor Pan Dengke also joined the research and development team of Sichuan Provincial Medicine a few years ago.

Professor Pan Dengke brought China's best genetically engineered pig-related team and technology to Sichuan for development, and received support from all walks of life, such as major national projects, provincial science and technology departments, hospitals, social capital support, etc., in Sichuan to establish a special breeding experimental base for genetically engineered donor pigs, and a clinical-level ultra-clean level base was also established in Neijiang, Sichuan.

In order to develop the cause of xenotransplantation, Professor Deng Shaoping introduced many talents and established a strong team composed of excellent experts at home and abroad. In order to be in line with international standards, Professor Deng Shaoping organized the international conference on xenotransplantation in Chengdu, and invited several of the most active experts in xenotransplantation in the world, including David KC Cooper, as well as teams from Germany, South Korea, the United States, Belgium and other countries.

Leo Bühler, President of International Xenotransplantation, strongly supports this and joins the Xenotransplantation R&D team as a high-end talent introduced from Sichuan, and has been guiding related research work in recent years. At the same time, adhering to the concept of openness, Professor Deng Shaoping and Professor Pan Dengke will provide the pigs bred to major centers across the country. Among them, Academician Dou Kefeng of Xi'an did the research of transplanting pig liver to monkeys, Professor Chen Gang of Tongji did the kidney research, Professor Wang Yi of Hainan did the kidney research, and Academician Hu Shengshou of Fuwai Hospital did the national major project of xenotransplantation of the heart.

At least 50 transplants from pigs to baboons

Professor Deng Shaoping believes that this American xenotransplantation can become the world's first, which is closely related to the large number of preclinical trials they have conducted in the early stage.

None of the successes came overnight, and this time Professor Mohitin and Professor Deng Shaoping, chair of the research team at the University of Maryland School of Medicine, worked in the same lab at the University of Pennsylvania. He later went to NIH to start a xenotransplantation research project and did a large number of preclinical trials from pigs to baboons. A few years ago, he joined the Team at the University of Maryland and the Clinical Cardiac Surgery Team to do at least 50 cases of heart transplantation from pigs to baboons, and it is precisely with such a large amount of preparatory work in the early stage that there will be breakthroughs in the human body.

"Don't think that other people's results are very sudden, or that they are explosive, in fact, they are doing a lot of preliminary work in others. This is also a leading role of the United States, and if the mainland wants to vigorously develop it in the future, it should also do a lot of preclinical work similarly in a down-to-earth manner." Professor Deng Shaoping said.

Therefore, in addition to donor pigs, these preclinical trials are very necessary and important. For example, the gene expression of genetically engineered pigs is not the same, and whether it can meet the needs of transplantation requires a large number of clinical trials to verify and verify. Therefore, it is indispensable to pre-clinical work, and on this basis, different model experiments of different organs are developed.

Different organs may require different immune gene modifications, etc., which need to be verified by preclinical experiments. At present, major teams in the world are carrying out relevant research to verify the effect of the combination of clinical immunosuppressants and new immunosuppressants in inhibiting the rejection of xenotransplanted organs.

The long-cherished wish of Chinese xenotransplanted curve overtaking

At present, China has become the third leading country in xenotransplantation research after the United States and Germany.

Professor Deng Shaoping recalled that 10 years ago, he had organized and participated in many xenotransplantation demonstrations, and the Political Research Office of the State Council also sent people to Sichuan to conduct special research. At that time, the country began to think about how xenotransplantation should develop.

In terms of demand, the number of citizen organ donations in the mainland is only about 6,000 per year, and there is demand, pressure and urgency in the supply of organs. Ten years of grinding a sword, China's xenotransplantation is developing steadily, in the past 10 years, the state's investment in scientific research funds has increased significantly, and xenotransplantation research has also received corresponding support.

Professor Deng Shaoping believes: "In the field of xenotransplantation, the mainland can at least reach the international level, and even lead the international level."

The mainland has the ability to concentrate on doing great things, and can be the top in the industry in many fields. For this aspect, Professor Deng Shaoping believes that it is necessary to concentrate resources and give them to places and teams with foundation and strength, and the core team should concentrate on research, and do not "sprinkle pepper noodles", so that it is possible to achieve rapid development, and even the possibility of overtaking in curves and leading the international standard.

"I hope that xenotransplantation can get more attention from all walks of life, and That China's xenotransplantation can develop rapidly and catch up with and shorten the distance with the United States." This is Professor Deng Shaoping's wish, and in the future, he will lead the team to accelerate the research and development of xenotransplantation in Sichuan and strive to seize the international commanding heights.

Solving the shortage of organ transplants can save more patients' lives, and hopefully the tragedy of Manslaughter 2 will not happen again.

According to Professor Deng Shaoping, the International Xenotransplantation Association is also organizing experts to develop a guiding program for clinical trials of three large organs from pig to human kidney, heart and liver to ensure the standardization and standardization of future clinical trials. Professor Deng Shaoping hopes and expects that after the next five to ten years of hard work, xenotransplantation will become one of the most important and effective methods for the clinical treatment of patients with end-stage organ failure.

Source | The health community

Written by | Huang Meiqing Liu Ke