Challenges of Xenotransplantation

  On January 7, 2022, David Bennett, a 57-year-old heart patient, made the last-ditch effort to receive a pig heart transplant, becoming the first patient in history to receive a pig heart transplant. On March 8, two months after surgery, Bennett died at the University of Maryland Medical Center.
  Bennett’s porcine heart transplant is regarded as the most successful xenotransplantation surgery to date, and is an important milestone in the human race towards xenotransplantation. However, in general, the survival period of the recipient of the organ transplant reaches more than one year, and the operation is considered to be an initial success. At present, xenotransplantation still faces many major challenges in terms of survival time, cross-species safety, and immune rejection.
  On May 5, 2022, researchers at the University of Maryland Medical Center revealed the cause of Bennett’s death. A very common virus, porcine cytomegalovirus, may have been a factor in Bennett’s death. In addition, Bennett was very weak before, during and after the transplant.
  The newly revealed findings suggest that there were more complex causes of Bennett’s death. On June 22, a paper published in the New England Journal of Medicine pointed out that after Bennett transplanted pig hearts, not only did porcine cytomegalovirus appear in his body, but the weight of his heart almost doubled after his death, from 328. grams increased to 600 grams. Fibrotic tissue appeared in the heart of the deceased, with extravasation of red blood cells. At the same time, doctors also found human herpes virus in Bennett’s lungs. These results suggest that the cause of Bennett’s death is very complex, but may still be mainly related to porcine cytomegalovirus.
  Bennett transplanted a gene-edited pig heart. The pre-transplantation test found that it only carried porcine endogenous retroviruses PERV-A and PERV-B, but did not detect PERV-C, porcine cytomegalovirus and porcine lymphotropic herpesvirus. However, on the 20th postoperative day, doctors detected a small amount of porcine cytomegalovirus in Bennett’s blood. In addition, human herpes virus was also found in Bennett, but the source of the virus could not be determined, and it was not clear whether it existed before surgery or was infected after surgery. The coexistence of porcine cytomegalovirus and human herpesvirus results in cross-reactivity of the two viruses, which may lead to xenograft rejection. The combined effect of the above factors caused Bennett to have side effects and abnormal reactions after transplanting pig hearts.
  As the level of porcine cytomegalovirus in Bennett’s blood increased, doctors treated him for cytomegalovirus infection, which was originally used in AIDS patients, and also gave him an injection of human immunoglobulin to boost his resistance. These treatments allowed Bennett to feel better and even get out of bed 48 days after surgery. However, over the next few days, Bennett’s health took a turn for the worse. The researchers found that the heart wall of the transplanted heart was abnormally enlarged, the size of the ventricle was reduced, and the level of antibodies against the pig tissue in the body was also rising. These circumstances suggest that an antibody-mediated atypical immune rejection occurred in Bennett, apparently related to porcine cytomegalovirus. However, whether the patient’s heart increased from 328 grams to 600 grams was caused by porcine cytomegalovirus, researchers cannot give a definite answer at present. Because the patient’s heart enlargement is not consistent with the typical organ transplant rejection.
  The researchers believe that the enlarged heart is mainly due to signs of leaky blood vessels and partial myocardial fibrosis. However, these symptoms are not associated with typical rejection. Therefore, Bennett’s exact cause of death will require more in-depth research to determine.
  The short survival time of patients is the primary challenge facing xenotransplantation, and the issue related to porcine cytomegalovirus discovered this time demonstrates another important challenge facing xenotransplantation—cross-species safety, also known as biological barrier risk.
  Humans are pinning their hopes on xenotransplantation because it can expand the source of donor organs to save more lives. In China, there are hundreds of thousands of patients queuing up for donor organ transplants every year. However, due to differences in species, including differences in genes, immune systems and biological barriers, xenotransplantation represented by pigs is destined to be extremely difficult.
  In terms of cross-species safety alone, there are many risks involved in using animal organs for transplantation. Taking pig organ transplantation as an example, porcine cytomegalovirus is only one of the risks. Various pathogens hidden in pigs, such as viruses, bacteria, parasites, etc., have created many difficulties for xenotransplantation. Pigs have both swine flu virus, swine fever virus, swine Japanese encephalitis virus, and even some parasites (such as tapeworms), which can make transplant patients sick and cause xenotransplantation to fail.
  How to build a strong biological barrier to protect people’s health and safety is also an important issue worthy of attention. Whether it is the severe acute respiratory syndrome (SARS) that appeared in 2002 or the new coronavirus pneumonia that appeared in 2019, the pathogens have broken through the biological barrier between humans and animals. Now, monkeypox virus found in many countries is also transmitted from animals to humans, and it has become a typical zoonotic disease.
  Statistics show that 75% of emerging infectious diseases that cause major harm come from cross-species transmission that breaks through biological barriers. Wild animals are important microbial storage and transmission hosts in nature. They have great microbial diversity and are also an important source of new and sudden infectious diseases for humans. Ebola, Marburg, and HIV come from non-human primates. There are more than 1 million species of arthropods in the world, and more than 100 arboviruses can cause human diseases, including yellow fever, dengue fever, Japanese encephalitis, forest encephalitis, etc.
  Today, environmental and climate change has resulted in both increased human-wildlife contact and the adaptive evolution of microorganisms. This is a newer, larger challenge to break through biological barriers. Although the adaptive evolution of many microorganisms to new hosts takes months or years to complete, the current situation shows that when humans and animals have intimate contact conditions (such as human active transplantation of animal organs), this leapfrog The process of the barrier does not actually take much time.
  Using a model of mammalian virus-sharing patterns, researchers from the Department of Biology at Georgetown University used a model of virus-sharing patterns in mammals to predict the chances of future cross-species virus transmission among 3,139 animal species. The researchers found that under a climate warming scenario of 2°C, at least 15,000 new cross-species virus sharing events are expected to occur by 2070 due to the reorganization of mammalian distribution driven by climate change. Geographical migration of animal species facilitates virus exchange between previously disjoint species and may contribute to zoonotic “spillover,” the transmission of pathogens from wild animals to humans. At the same time, the research has not yet addressed the possibility of birds and marine mammals transmitting the virus between animals and humans.
  A warming climate will lead to new contacts between mammal species, which could occur anywhere in the world, but will be concentrated in areas with high population densities in tropical Africa and Southeast Asia. The coldest regions on Earth will also experience new species contacting and sharing bacterial and viral events. For example, some species will be forced to relocate to higher elevations in response to rising temperatures, eventually congregating in mountains and highlands to come into contact with each other.
  Therefore, climate change creates the conditions for the breakthrough of biological barriers between humans and animals. It also means that future xenotransplantation should be more tightly controlled in animal-derived organs, including testing them for viruses, bacteria and parasites. At the same time, various measures should be taken to slow climate warming, reduce close contact between humans and wild animals, protect biological barriers and prevent the emergence of new zoonotic diseases.