Several encouraging preliminary results have brought new hope to patients anxiously awaiting allogeneic organ transplants, but whether they can ultimately be successfully applied to clinical treatment cannot be fully predicted. Written by Guo Xiaoqiang (Hebei Institute of Physical Education) On March 26, 2025, London time, a research team from the Xijing Hospital of the Chinese Air Force Medical University published a paper online in the journal Nature, reporting the world's first successful case of transplanting a gene-edited pig liver into a brain-dead human (completed in March 2024), which will help solve the shortage of transplanted organs. The research team said that this study explored the feasibility of "gene-edited pig-human" liver xenotransplantation for the first time, and made original breakthroughs in scientific theory innovation, core technology research, and military medical applications. Nature published online the world's first research on gene-edited pig liver transplantation in humans. Academician Dou Kefeng of Xijing Hospital is the corresponding author of the paper, Professor Tao Kaishan is the first author, Professor Wang Lin and Professor Dong Hailong are co-corresponding authors, and Associate Professor Yang Zhaoxu , Doctor Zhang Xuan , and Doctor Zhang Hongtao are co-first authors. Following this experiment, the team successfully conducted the second pig-to-human liver transplant experiment on January 7 this year. Unlike the first time, when the human liver was not removed but the pig liver was transplanted into the human body, this time the pig liver was transplanted into the brain-dead patient in situ replacement mode (i.e., the patient's liver was removed). Looking around the world, since November last year, there have been three successful cases of gene-edited pig kidneys being transplanted to kidney disease patients. The first two were completed by American scientists, and the third was also completed by Xijing Hospital. All patients are currently surviving well. Faced with the frequent success of pig-human xenotransplantation, people can't help but ask, do these advances indicate that the day when humans can use pig organs to maintain life or even improve the quality of life is no longer out of reach? As we all know, organ transplantation is the fundamental method for treating many debilitating diseases (such as heart failure, kidney failure, etc.). With the advancement of technology, the clinical effect has become more ideal, but it also faces a huge problem, that is, the imbalance between supply and demand. Data from the World Health Organization show that donor organs can only meet the needs of about 10% of patients waiting for transplantation each year, and most patients can only leave this world while waiting for organs. Faced with this problem, scientists have envisioned many strategies, such as stem cell transplantation, which was once highly anticipated, but this solution has not yet solved many bottleneck problems. Xenotransplantation has therefore become another important option. The so-called "xenotransplantation" is the transplantation of organs between different species, as distinguished from the transplantation of organs between the same species. The idea of transplanting organs from other species to humans has been around for a long time. Since the 1960s, it has been tried and screened many times. After comprehensive consideration, pigs were selected as the best donors in the 1980s. The reason is that the size, structure and physiological function of pig organs are similar to those of humans (scientific considerations). In addition, pigs have strong fertility, relatively low prices, and better ethics (compared to primates) (feasibility considerations). Subsequently, scientists conducted extensive animal experiments, but failed to make major breakthroughs due to problems such as immune rejection and safety risks. However, in recent years, the emergence and improvement of efficient gene editing tools have provided a major turning point for pig-human xenotransplantation. The rejection reaction of pig organs that have undergone gene editing (knocking out or knocking in genes, etc.) is greatly reduced after being transplanted into other animals (generally monkeys), thereby extending the maintenance time of the transplanted organs in the body. For example, the record for heart transplantation is 945 days, the record for kidneys is 758 days, and the record for liver is 29 days. These gratifying results have undoubtedly boosted the confidence of researchers. Starting in 2022, the medical community will begin to try to transplant pig organs directly into humans and evaluate the efficacy. Pig-to-human organ transplantation makes progress despite difficulties Let's first look at the attempts and results of pig-to-human xenotransplantation of organs other than the liver in the past few years: On January 7, 2022, the world's first pig-to-human heart transplant was completed at the University of Maryland Medical Center in the United States. The patient, David Bennet, survived for more than two months (died on March 9) On September 20, 2023, the second pig-to-human heart transplant was also completed at the University of Maryland Medical Center. The patient, Lawrence Faucette, survived for 6 weeks (died on October 30). In 2023, a research team from NYU Langone Medical Center and the University of Alabama at Birmingham transplanted a pig kidney into a brain-dead patient. On March 16, 2024, the first pig-to-human kidney transplant was completed at Massachusetts General Hospital in the United States. The patient, Richard Slayman, survived for 52 days (died on May 12). On May 29, 2024, the second pig-to-human kidney transplant was completed at NYU Langone Medical Center, and the patient, Lisa Pisano, survived for 40 days (died on July 7). On November 25, 2024, the third pig-to-human kidney transplant was completed at NYU Langone Medical Center. The patient, Towana Looney, is currently alive, which is the longest record (more than 4 months). On January 25, 2025, the fourth pig-to-human kidney transplant was completed at Massachusetts General Hospital, and the patient, Tim Andrews, is currently undergoing health testing. On March 6, 2025, the fifth pig-to-human kidney transplant was completed at Xijing Hospital in China. The patient was a 69-year-old female patient with end-stage renal disease, who is currently in good condition. From these facts, it can be seen that the global medical community has now carried out clinical trials of pig-to-human heart and kidney transplants, including 2 heart transplants (the patients have died) and 5 kidney transplants (3 of which are currently alive). FDA approves pig-to-human kidney transplant clinical trial Pig-to-human organ transplantation trials are currently only being conducted in China and the United States. The few cases carried out in the United States are mainly based on the "compassionate use" policy of the Food and Drug Administration (FDA), which means that critically ill patients can implement new therapies that have not yet been clinically approved when there is a lack of existing satisfactory treatment options. On February 4, 2025, the FDA officially approved clinical trials to transplant pig kidneys into patients with renal failure. Two biotechnology companies, United Therapeutics and eGenesis, will start their research this year. If successful, it will hopefully solve the problem of severe shortage of donors in organ transplantation. Of course, due to the many uncertainties of the technology itself, even if the clinical trial is approved, I am cautious about the results of the subsequent trials. Public information shows that Yiyuan’s clinical trial will start with three patients with renal failure who may not be able to obtain human organs within five years (the kidneys for several surgeries in the early stage were mainly provided by the company). United Healthcare decided to start the trial in mid-2025, first recruiting six patients with end-stage renal disease for transplantation and a 12-week observation period. An independent committee will evaluate the safety and effectiveness of the surgery before expanding it to a larger group of up to 50 subjects. From this preliminary information, it can be seen that the selection of participants for clinical trials is critical and must meet one of two criteria: not meeting the conditions for human kidney transplantation, or being unlikely to obtain a human kidney within five years (including being able to obtain one within five years but being likely to die by then). In layman's terms, the patient's condition is relatively serious and should not be delayed any further, or is not serious at present but the chances of obtaining a human organ are slim. In addition, all participants must be between 55 and 70 years old, have end-stage renal disease, and have been on dialysis for at least six months. These harsh conditions indicate that most of the patients who receive transplants are in serious condition and pig kidneys are the only hope. This reality also poses a huge challenge to the evaluation of transplant effectiveness, because sometimes even if the transplant is successful, the patient dies later due to other diseases, and it is difficult to distinguish the cause of death from transplant failure. But in any case, the approval and subsequent implementation of clinical trials are undoubtedly of great significance in promoting pig-to-human transplantation, because clinical trials are the gold standard for evaluating the safety and effectiveness of new treatments, and only after comprehensive verification can they be approved for clinical use. Major breakthrough in pig-to-human liver transplantation The first pig-to-human liver transplant trial completed in my country in March 2024 has brought new hope to patients with advanced liver disease. The liver is more complex than the heart and kidneys, and the various pig proteins produced by the pig liver may stimulate the human body to produce a strong immune response that is difficult to suppress, ultimately leading to transplant failure. This additional difficulty makes many scientists even less optimistic about pig liver transplants. In this regard, Dr. Zhang Xuan from Dou Kefeng's team at Xijing Hospital also said in an interview with Fanpu: "Pig liver transplantation is much more difficult than heart and kidney transplantation." "It involves the compatibility of the physiological functions of proteins. For example, the coagulation factors synthesized by pig livers are not completely compatible with humans, and coagulation abnormalities are more likely to occur." Therefore, "In the next 2-3 years, we may first use auxiliary liver transplantation for human transplantation, just like this time." Assisted liver transplantation | Source: Xijing Hospital The so-called "assisted liver transplantation" method is to not remove the patient's own liver, but to place a pig liver in another location in the abdominal cavity. Under the premise of reasonable use of immunosuppressants, the patient did not have a serious rejection reaction. Ten days after the transplant, the experiment was terminated at the request of the family. At this time, the removed pig liver still maintained normal structure and function. During the transplant, the pig liver continued to maintain normal blood flow, and produced bile and porcine albumin, showing some functions of a normal liver. Because the patient still has a healthy liver, it is not yet possible to determine whether relying solely on the implanted pig liver in the future can provide sufficient function for patients with liver failure. This requires further determination through follow-up research. Judging from the second case of in situ replacement of gene-edited pig livers into brain-dead patients completed on January 7, 2025, the patient's vital signs were stable after the operation, and all indicators of liver function were basically normal, marking another big step forward. This second transplant was also terminated after 12 days of observation after the operation at the request of the family. Talking about the overall feeling and future risk points of concern, Dr. Zhang Xuan told "Return to Park": "The overall feeling is that it is still difficult for pig livers to completely replace human livers." He introduced that the next most severe challenges of xenogeneic liver transplantation include problems with postoperative coagulation abnormalities, immune rejection, and how to prolong the postoperative survival of transplant recipients. "The clinical application of pig livers for humans in the future should not be too far away. The first method may be assisted liver transplantation or in vitro perfusion of pig livers, because this will be safer." Everything will be verified by time In recent years, clinical trials of pig-to-human organ transplantation have provided encouraging preliminary results for the eventual application of this technology, bringing new hope to some patients anxiously awaiting allogeneic organ transplants, but whether it will ultimately be successful is still not fully predictable. The first challenge is still the problem of immune rejection. Even for allogeneic transplants, immune rejection is the most important reason for failure. Of course, with the understanding of the mechanism of action of the immune system and the application of immunosuppressants, this problem has been well solved. For pig-human organ transplants, the problem of immune rejection is even more difficult. At present, with the help of gene editing technology, some pig genes are removed on the one hand, and some human genes are added on the other hand, so as to minimize the occurrence of immune rejection reactions, but the ultimate extent is still unknown. Regarding the problem of immune rejection, Dr. Zhang Xuan also confirmed to "Fanpu" that there are more types of immunosuppressants used in xenotransplantation, some of which are unique to xenotransplantation and are rarely used in allogeneic transplantation. The same immunosuppressant will also be used in a higher dosage than in allogeneic transplantation, in order to better control the rejection reaction. The second is the compatibility issue. Pigs and humans are different, and whether pig organs can perfectly replace human organs to perform physiological functions is also a question that needs to be determined. If they are overloaded, the life of the organs will inevitably be shortened, resulting in unsatisfactory clinical results. Finally, there is the issue of cost-effectiveness. If we look at the effectiveness of transplant surgery based on the results of previous heart and kidney transplants, extending survival by a few months is also of great significance to desperate patients and is worth a try. Corresponding to this is the issue of price (current trials do not exist). From the current point of view, the cost of surgery will be relatively high, such as the cost of donor gene-edited pigs, the difficulty of the surgical process compared to human organ transplantation, and the use of immunosuppressants, which will push up the price (of course, if it can be approved for large-scale clinical application, the relevant costs will drop significantly). However, if the survival period is extended by several months or even years, it is also worth considering whether this technology should be used. There is a problem of comprehensive judgment and technical positioning here. It cannot be completely benchmarked against allogeneic transplantation. If the effect can meet some expectations, it is undoubtedly a more ideal treatment plan. Overall, the progress of pig-human xenotransplantation is being actively promoted. The driving force for the development of this cause mainly comes from the fact that this plan is expected to solve the practical problem of organ shortage and benefit mankind. It currently appears to be the most promising plan to supplement (or partially replace) human-human homologous organ transplantation. In particular, many difficulties that once seemed insurmountable have been partially resolved with technological advances. The successful implementation of several clinical trials has also brought great confidence to researchers. These have undoubtedly become a powerful driving force for the further development of technology. When we asked whether Xijing Hospital was preparing to conduct research on patients who needed liver transplants, Zhang Xuan said, "We have plans, but the specific time has not been determined." In any case, there is hope and the possibility of breakthroughs if we work hard. But at the same time, we must also recognize the complexity of life. I think it is too early to draw a conclusion on whether the era of pig-human xenotransplantation has arrived, because it has just entered the formal clinical trial stage and ultimately depends on a comprehensive evaluation of the overall effect. Special Tips 1. Go to the "Featured Column" at the bottom of the menu of the "Fanpu" WeChat public account to read a series of popular science articles on different topics. 2. Fanpu provides a function to search articles by month. Follow the official account and reply with the four-digit year + month, such as "1903", to get the article index for March 2019, and so on. 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