The surgery demonstrated that gene editing can control hyperacute (minutes to 24 hours postoperatively) rejection, representing the promise of xenotransplantation for patients with transitional surgery for the possibility of obtaining a human donor heart
Although the prospect of solving the imbalance between supply and demand of organs through xenotransplantation is promising, the medical risks and ethical risks that exist make it still need to be cautious
"Life from birth to death is a natural law, in order to prolong life, what scientific and technological means can be used, where the boundaries are, it is worth pondering."
Wen | Yu Xue, Wei Yuhong, and Shuai Cai, reporters of the "Lookout" news weekly
After surviving for about two months, David Bennett, the patient who underwent the world's first swine heart transplant, died on March 8.
The University of Maryland Medical Center, which implemented the operation, released a message on the 9th that in the weeks after the operation, the transplanted heart in Bennett's body was working well and there was no sign of rejection. He lived with his family and received physical therapy to help restore his strength. But a few days ago Bennett's condition began to deteriorate. The hospital gave Bennett palliative care after it became clear that he had no hope of recovery. Bennett was still able to communicate with his family for hours before his death.
The news of Bennett's successful implantation of xeno-organs was seen by some as a hope to alleviate the shortage of human donor organs, and his sudden death has re-examined this beautiful vision. What are the prerequisites and criteria for choosing a xenotransplantation (a type of xenotransplantation)? What are the potential medical risks of xenotransplantation? What ethical controversies do you face?
Although there are still many places to be carefully observed for xenotransplantation, every failure in the field of medical technology is an important attempt for humanity to move forward.
On June 13, 2020, Liu Jincheng (first from the left), director of the Cardiovascular Surgery Department of Xijing Hospital of the Air Force Military Medical University, and team members jointly performed a pig-monkey xeno heart transplant zhang Yinan photo/this journal
The principle of "taking risks"
According to the University of Maryland Medical Center, Bennett first visited the center last October and was bedridden, relying on extracorporeal membrane oxygenation (ECMO), an in vitro life support system. His condition was unsuitable for a routine heart transplant. Prior to receiving a swine heart transplant, Bennett was fully informed of the risks of transplant surgery, which was experimental and had unknown risks and benefits.
The risks and benefits of Bennett's xenotransplantation are unknown, and what is the principle of "risk-taking" for doctors?
Guo Kequan, deputy chief physician of the Beijing Heart Transplant and Valvular Surgery Diagnosis and Treatment Center of Beijing Anzhen Hospital affiliated to Capital Medical University, said that the access criteria for clinical same-species organ transplantation are generally that patients may die within one year if they do not do organ transplantation, and the corresponding situation of heterogeneous organ transplantation access is definitely more urgent, "If you don't do it, you will die soon." He said that there are also patients who have done the same organ transplant, the immune system is activated, and then do it will soon appear immune rejection, which can also be considered for xenotransplantation.
Professor Zhou Xinmin of the Department of Cardiovascular Surgery of the Second Xiangya Hospital of Central South University believes that the following conditions should be met when choosing to initiate the emergency procedure of xenotransplantation for patients: 1. The patient has irreversible terminal end-stage organ failure, which cannot be cured by systematic internal medicine treatment or conventional surgery; 2. In the case of contraindications or serious complications, patients cannot be temporarily assisted or long-term treatment by implanting artificial kidneys, artificial livers, artificial hearts and other therapies 3. Lack of suitable all-donor organs in the same period; 4. The life expectancy of patients is calculated in hours or days.
Xenotransplantation remains an experimental treatment in the United States. Bennett was able to use the therapy under the U.S. Food and Drug Administration's (FDA) "compassionate use" provision, which applies when a patient is facing a serious or life-threatening medical condition and there is only one option, experimental therapy.
Liu Ruishuang, deputy director of the Department of Medical Ethics and Law at Peking University Health School, told Lookout Newsweek that xenotransplantation must meet the requirements of procedural compliance. First of all, we must consider the indications, that is, the scope and standards of surgery. Second, patients should be clearly informed of the risks and benefits of surgery and obtain their consent. Third, the ethics committee should be organized to evaluate, not only clinicians, but also members involved in the evaluation should include experts in sociology, ethics, law, etc., to conduct a comprehensive and comprehensive assessment.
At present, many countries and international organizations have set limits on clinical trials of xenotransplantation. The most important of these is to ensure that the transplantation of non-human animal organs into the human body has a favorable risk-benefit ratio for patients, that is, the transplanted animal organs can perform normal physiological functions, and cross-species infections and immune rejection can be well resolved to benefit patients. A consensus is that to strengthen the supervision of clinical trials of xenotransplantation, administrative or judicial measures must be used to punish clinical trials or clinical applications of xenotransplantation that violate the rules.
It is understood that at present, the mainland pig heart valve has been widely used in human clinical practice, the clinical application of pig cornea has been opened, and pig islet and skin xenograft have also entered the human clinical trial stage. The transplantation of large organs such as the heart and kidney of pigs faces more difficulties, and it is still in the stage of animal experimentation, and the relevant regulations involving clinical xenotransplantation have not yet taken shape.
Liu Ruishuang said that although there is no clear legal provision on xenotransplantation in the mainland, there are still corresponding principles and ethical principles for medical clinical trials and experimental treatment. In the future, on the basis of confirming the biosecurity, transplant effectiveness and technical feasibility of xenotransplantation, setting more detailed procedures and rules and effectively supervising the whole chain and the whole process will be a booster to promote the standardization of xenotransplantation.
The world's first inbred cloned pig born in Yunnan (january 19, 2010). Its successful cultivation is of great significance for the establishment of animal models of diseases, the development of xenotransplantation research and other fields
"Bright Prospects"
Exploring xenotransplantation has an urgent and practical need.
According to incomplete statistics, about 2 million people around the world need organ transplants every year, and the number of organ donations is much lower than the demand. On the mainland, the ratio of waiting for and receiving organ transplants has reached 30:1, and hundreds of thousands of patients die every year because they cannot wait for organ transplants.
The surgery at the University of Maryland Medical Center is the world's first use of gene-edited pig organ transplantation to treat end-stage human disease. This has given some patients who have to face death due to the lack of human donor organs to see the hope of life.
"Swine-human heart transplantation is a medical revolution." Professor Wang Wei, a Chinese scientist who presided over the breeding of medical donor pigs and the chief expert of the Third Xiangya Hospital of Central South University, told this reporter that the death of the patient is regrettable, but the operation will provide extremely valuable scientific data for further heterogeneous organ transplantation research.
Many of the experts interviewed said that compared with the same organ transplant, xenotransplantation faces difficulties such as xenovirus transmission, more serious immune rejection of implanted organs by recipients, risks caused by the amount of multiplication of immunosuppressants, and functional compatibility of implanted organs.
For porcine-human organ transplants, the pig genome carries endogenous retroviruses, which may be "toxic" when transplanted into humans. In 2015, Yang Luhan's team, a young scientist engaged in genomic research at Harvard University, used CRISPR technology to knock out 62 potentially harmful genes in the pig genome, and in 2017 announced the cultivation of the world's first batch of "pig 1.0" that does not carry endogenous retroviruses, solving the risk that pig organ transplantation into the human body may lead to viral infection.
In addition, pig organs may trigger severe immune rejection in the patient's body. At present, scientists can knock out the genes that cause immune rejection through gene editing technology, and insert related genes for human immunity, coagulation, and inflammation regulation, in order to effectively inhibit the rejection of xenotransplantation.
Zhou Xinmin told reporters that the receptor's rejection of grafts can be divided into three types according to speed: ultra-acute rejection, which occurs within a few minutes to 24 hours after surgery, which will inevitably lead to transplant failure; acute rejection, which occurs within days to months after surgery; chronic rejection, which occurs in months to years after surgery.
Zhou Xinmin said that in the most critical 48 hours after the operation, the patient did not have abnormalities and successfully passed the ultra-acute rejection stage. "It seems to give people a bright future. As for judging whether other rejection reactions have occurred, follow-up research and detailed academic reports are required."
Wang Wei said that in addition to immune rejection, whether the function of implanted xeno organs can be maintained for a long time also requires long-term observation. In addition, severe damage to the recipient's immune system due to excessive immunosuppressive therapy and double the amount of immunosuppressants must be prevented. It is worth looking forward to the fact that this surgery represents the promise of a transient surgery for patients, buying time for possible access to a human donor heart.
Guo Kequan believes that the evaluation of the success of clinical xenotransplantation is difficult to evaluate horizontally with the standards of all-species organ transplantation that have been developed and mature, and it is necessary to compare vertically to see the progress of this result in previous xenotransplantation. "Against the backdrop of a shortage of human donor organs, this surgery is a very meaningful exploration in the field of organ transplantation."
On March 28, 2018, at the Kowloon Experimental Animal Base in Guangzhou, researchers took a group photo with the "Huntington's disease" gene knocking into the pig. After four years of efforts, an international research team led by mainland scientists used gene editing technology (CRISPR/Cas9) and somatic cell nuclear transplantation technology for the first time to successfully breed the world's first case of Huntington's disease gene knocking into pigs Courtesy of the Guangzhou Institute of Biomedicine and Health of the Chinese Academy of Sciences
Step by step
The shortage and shortage of organs available for transplantation is a common problem around the world. In this context, although the prospect of xenotransplantation is promising, its medical risks and ethical risks still require caution.
"Scientific research is always a spiral." Zhou Xinmin said that this pig heart transplant fully shows that human beings still have a very difficult road to go in xeno organ transplantation.
International research on xenotransplantation in pigs has been studied internationally since the 1990s. Pigs as domestic animals and humans coexist for a long time, the probability of carrying microorganisms that seriously harm humans is relatively small, and the tissue structure, physiological function and size of pigs are similar to human organs, so the international scientific community generally believes that the use of pig organs for xenotransplantation is more operable.
Guo Kequan believes that different tissues and organs, based on their immunogenicity and functional differences, have great differences in the difficulty of xenotransplantation. The sequence of domestic xenotransplantation into the clinical stage is first islets and corneas, followed by the heart that may have a more urgent need for transplantation, followed by the kidneys, and lung xenotransplantation is more difficult to overcome.
Wang Wei said that heart and kidney transplantation in domestic xenotransplantation is expected to take the lead in clinical research. Xenotransplantation experiments from transgenic pig organs to monkeys have shown that the pumping function of the transplanted heart and the urinary function of the transplanted kidney can exist in the recipient for a long time, and the anti-rejection regimen used is also clinically acceptable. Due to the large number of genes that need to be edited, the liver is more difficult to transplant, and preclinical studies showing that the transplanted liver survives in primate recipients for more than 6 months before clinical studies can be carried out. Xenotransplantation of the lungs and small intestine is more difficult.
"Experiments in primates have shown that pig organs can theoretically achieve human organ function without rejection occurring." Guo Kequan said.
But Zhou Xinmin said that the kidneys and heart are not only "dialysis" or dynamic organs, but also endocrine organs, "whether there is this function after the implantation of heterogeneous organs, it is still unclear."
Zhou Xinmin said that for now, if xenotransplantation is to be further promoted, the following problems need to be solved: stereotyped and more mature gene-edited animals are introduced, making animal organs more similar to human organs; perfecting skilled transplant surgery techniques; drug optimization of immunosuppressants, with judgment of the best immunosuppressants and the best dosage to use; proper monitoring and treatment of immune rejection and endogenous viruses; and improvement of relevant ethics and laws.
Guo Kequan believes that it is not easy to solve the above problems, and xeno organ transplantation needs to be cautiously promoted step by step to enter the clinical stage. First, transplantation should achieve satisfactory results in primate receptors, such as maintaining organ function for more than one year; second, it needs to be tested on brain-dead patients; and finally, it can be considered to push to the next step of clinical research or even application. In his view, the U.S. pig heart transplant surgery to carry out 10 gene edits on donor pigs, "it may not seem enough now", still to continue to promote relevant immune research.
The boundaries of technology
The in-depth development of xenotransplantation also requires confronting huge ethical controversies.
Since the British writer Mary Shelley wrote the famous science fiction novel "Frankenstein" in 1818, this book describing the "Frankenstein" made by biotechnology, has continuously aroused the thinking of future generations on the ethics of science and technology with the pursuit of the nature of life.
Li Xianliang, deputy chief physician of the Department of Hepatobiliary, Pancreatic and Spleen Surgery of Beijing Chaoyang Hospital affiliated to Capital Medical University, told this reporter that from the clinical experience of organ transplantation for many years, it will be found that some phenomena that cannot be explained at present, such as biological characteristics and habits that did not exist before the recipient, have changed after transplantation. This means that organs transplanted into the human body have the potential to carry certain genes from the donor, which may play a role in the recipient and even be further passed on to the next generation. "Although there is no conclusive evidence at present, in the face of doubt, the medical community must be soberly aware of all the ethical challenges and social risks it may face."
Liu Ruishuang believes that after receiving organ transplant surgery, the change of the recipient's temperament may be affected by multiple factors such as organ state improvement, medication, psychology, etc. At present, there is no evidence in science that the implanted organs cause patients to have abnormal changes, but there is no evidence to completely deny this.
Guo Kequan said that the current pig, cow valve transplantation to human clinical application cases can be counted in millions, whether it is animal heart, kidney and other organs or valves and other tissues, after transplantation into the human body, its cells "will only fall off, will not proliferate", there is no medical evidence to prove that these fall off cells will have an impact on the receptor, there is no evidence that human genes are affected by donor genes after surgery. Not only that, but the "free DNA" after shedding does not blend with sperm and eggs, so it does not involve the problem of inheritance to the next generation. "However, if some cells that can proliferate are transplanted, such as transplanting pig stem cells into the human body for bone marrow transplantation, then the entire immune system of the recipient will be affected by the pig's gene pool."
Zhou Xinmin believes: "When and in what way the genetic material from the xeno donor will be expressed in the host, whether it will be passed on to the offspring, and whether it will have a negative impact on human evolution, are all questions to be further explored." ”
For pig-human heart transplantation, there are also voices asking: Will receiving pig heart transplantation affect the recipient's definition of self?
In this regard, Liu Ruishuang said: "Transplanting a pig's organ does not change the essence of human beings, and human genes are the mainstream in the patient's body. In addition, he has the cognition that he cannot deny the essence of his human being just because of transplanting pig hearts. But there is an extreme case, such as transplanting a monkey brain, which moves the basis of human cognitive function. Therefore, from an ethical point of view, the brain cannot be transplanted. ”
Li Xianliang said that he himself would "maintain a very cautious attitude" about ethical issues such as self-perception of recipients after receiving xenotransplantation. He said: "Life from birth to death is a natural law, in order to prolong life, what scientific and technological means can be used, where the boundaries are, it is worth pondering." ”
In addition, xenotransplantation may be just one of the possible directions to solve the problem. The experts interviewed said that in addition to xenotransplantation, the use of "bioink" containing living cells to 3D print human organs, the use of patients' autologous cells to culture organs and other technologies are also developing simultaneously, will make useful attempts to solve the problem of imbalance between supply and demand of organs.
Guo Kequan further said that the expansion of human social knowledge means, to a certain extent, that a longer human lifespan is needed to inherit civilization. "As for whether it makes sense to use science and technology to break the limit on the original life length, the current technology is far from the time to discuss this issue." When humans can live to be 150 years old, it is not too late to discuss it." ■