Human organ transplantation is a crucial medical technology for saving critically ill patients. The greatest obstacle to organ transplantation is the shortage of organs available for transplant, and xenotransplantation using pigs as organ donors is bringing new hope.
On November 22, the Asian Transplantation Society Symposium (TSS), an international academic conference formally recognized by the International Transplantation Society (TTS) and hosted by Zhongshan Hospital of Fudan University, was held in Shanghai. Renowned experts in organ transplantation and related disciplines from both China and abroad gave keynote speeches and engaged in discussions on hot topics and difficult issues in the field of organ transplantation.
Zhongshan Hospital of Fudan University is one of the few comprehensive hospitals in China qualified for heart, liver, kidney, and pancreas transplantation, and has taken the lead in carrying out numerous technological innovations in the field of organ transplantation. (Photo provided by Zhongshan Hospital)
The shortage of organs available for transplant is a medical challenge faced globally. Public information shows that since the pilot program for organ donation was launched in China in 2010, significant achievements have been made in institutional design, social mobilization, and standard procedures, resulting in dual improvements in both the quantity and quality of organ donations and transplants. However, according to the China Organ Transplantation Development Report (2021), the organ donation rate per million population is 3.73, which still lags behind international advanced levels.
According to a Xinhua News Agency report in April 2024, data from the non-profit organization “Organ Sharing United Network Organization” in the United States shows that over 100,000 people in the US alone are waiting for organ transplants, with an average of 17 people dying each day while waiting.
At the symposium, Zhou Jian, the president of Zhongshan Hospital of Fudan University, said that China has made significant progress in the field of organ transplantation but still faces a severe shortage of organs. This not only requires further improvement of the existing organ donation and allocation system to ensure fair, transparent, and efficient operation, but also highlights the indispensable role of technological innovation.
Zhou Jian believes that adopting advanced medical technologies and methods is currently one of the measures to address the shortage of organs. For example, Zhongshan Hospital has implemented the world’s first case of combining “discarded liver” liver transplantation with ALPSS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy), which can effectively expand the source of donors and improve surgical success rates, thereby alleviating the current tense supply-demand contradiction.
The Paper’s (www.thepaper.cn) reporter noted that xenotransplantation using pigs as donors was frequently discussed at the meeting.
John Fung, the current president of the International Transplantation Society, believes that China is a leader in the field of organ medicine. He has observed liver transplantation surgeries using original Chinese techniques in Chinese hospitals. “There are many impressive medical technological innovations in China,” he said, adding that China is also making rapid progress in the field of xenotransplantation.
On March 21, 2024, Massachusetts General Hospital announced that its transplant center’s surgical team successfully transplanted a gene-edited pig kidney into a 62-year-old male. This was the world’s first transplantation of a pig kidney into a live recipient. Two months after the surgery, the patient died of heart disease in May.
China soon achieved a breakthrough as well. In early April, Xijing Hospital of Air Force Medical University announced that on March 25, its team performed a xenotransplantation surgery, successfully transplanting a kidney from a multi-gene edited pig into a brain-dead recipient.
On May 24, the First Affiliated Hospital of Anhui Medical University announced that on May 17, its team, in collaboration with Yunnan Agricultural University, successfully transplanted a genetically modified pig liver into a 71-year-old male patient with a huge right lobe hepatocellular carcinoma at the First Affiliated Hospital of Anhui Medical University. This was the world’s first xenotransplantation of a liver into a live human.
Research on xenotransplantation using pigs as donors is rapidly emerging.
Zhu Tongyu, vice president of Fudan University Shanghai Medical College and professor at the Renal Transplantation Department of Zhongshan Hospital, told The Paper that the greatest obstacle to organ transplantation is the shortage of organs. Taking kidney transplantation as an example, each patient may have to wait for 5 to 10 years to receive a precious donor organ. Data from the China Organ Transplantation Response System (COTRS) in 2023 shows that over 140,000 people in China are registered as waiting for organ transplantation, but the number of patients receiving organ transplants each year is less than 20,000, indicating a significant gap between supply and demand. In recent years, driven by new technologies such as gene editing, significant progress has been made in xenotransplantation using pigs as donors.
“We are now seeing the dawn of a new era, with several cases worldwide where pig kidneys, hearts, and other organs have been transplanted into humans and have survived for several months,” said Zhu Tongyu. “It is now globally recognized that pigs are one of the best suppliers for humans, and their role is becoming increasingly important.”
At the same time, Zhu Tongyu emphasized that there are still many challenges to overcome with pigs as organ donors. There are significant differences between pigs and humans. Humans have 23 pairs of somatic cell chromosomes, while pigs have only 19 pairs. Pig organs as donors require gene editing through technological means. Additionally, zoonotic diseases and immune rejection are challenges faced in organ transplantation. Further research is needed to enable transplant recipients to survive longer.
According to a Xinhua News Agency report, since the 1960s, the medical community has conducted multiple human xenotransplantation surgeries, choosing primates such as chimpanzees and baboons as donors for kidneys, livers, and other organs. However, due to severe rejection reactions, the recipients had very short survival times after transplantation.
In recent years, pigs have come into the medical community’s view as donors because their organ structure, physiological functions, and size are similar to human organs. Additionally, pigs are distantly related to humans and have fewer zoonotic diseases, making them one of the ideal donors for human xenotransplantation. Scientists use gene editing to “knock out” genes in pigs that may cause rejection reactions and insert some human genes to increase the likelihood of long-term survival for transplant recipients. Currently, the use of multi-gene edited pigs as xenotransplantation donors is being widely studied and validated.
For example, in May 2024, the team of Academician Dong Jiahong from Beijing Tsinghua Changgung Hospital, Affiliated to Tsinghua University, the team of Zeng Zhong from the First Affiliated Hospital of Kunming Medical University, and the team of Wei Hongjiang from Yunnan Agricultural University successfully transplanted the liver and kidney of an 8-gene edited pig into a brain-dead patient.
At that time, scientists performed 8-gene editing on the donor pig through gene editing technology and somatic cell nuclear transfer technology. They knocked out three xenogeneic glycosyl antigen synthesis genes (GGTA1, CMHA, β4GalNT2) in pigs to eliminate hyperacute rejection reactions; they transferred three human complement regulatory proteins (hCD46, hCD55, hCD59) to effectively alleviate acute rejection caused by human complement system activation; and they also transferred regulatory proteins that inhibit coagulation (hTBM, hCD39) to effectively avoid rejection caused by coagulation disorders.
Apart from the issue of organ sources in organ transplantation research, experts such as Zhou Jian also discussed the hidden dangers posed by immunosuppression for transplant recipients. Typically, transplant recipients must continuously take immunosuppressants to prevent rejection reactions, but this also weakens their resistance to external pathogens, making them more susceptible to infections. How to improve the immunity of post-transplant patients and reduce the risk of infections is an urgent problem to be solved.
In response to this problem, Zhu Tongyu’s team proposed the “Innovative Diagnostic and Treatment Model for Severe and Special Infections in Organ Transplantation” for the first time. This model includes developing a new diagnostic system for precise diagnosis of pathogens, using bacteriophage therapy to treat refractory bacterial infections after transplantation, and developing BK virus vaccines to prevent viral infections. These measures can effectively enhance patients’ ability to resist infections.
Since 2018, Zhu Tongyu’s team has initiated China’s first clinical trial of bacteriophage therapy, achieving a clinical improvement rate of 78.3%. During this period, the team published the first case report of bacteriophage therapy in China, as well as the world’s first case series and case paper on bacteriophage therapy for secondary bacterial infections caused by the new coronavirus and RNA bacteriophage therapy. In 2022, Zhu Tongyu’s team initiated the establishment of the China Bacteriophage Research Alliance and released expert consensus and group standards for the quality of bacteriophage therapy and bacteriophage preparations. “With the advancement of this research, the survival time and quality of life of post-transplant patients will be improved in the future,” said Zhu Tongyu. Bacteriophage therapy will be used for the prevention, diagnosis, and treatment of super bacterial infections, and has great application potential in the field of organ transplantation.