compiled | Qi
In January this year, a team at the University of Maryland Medical Center transplanted pig hearts into living people for the first time. The 57-year-old man named Bennett became the first human in history to undergo a gene-edited pig heart transplant. However, because the transplanted organ carries the pig herpes virus, the new heart only helped him maintain his life for 8 more weeks, but for the "xenotransplanted animal organ", these 8 weeks are of epoch-making significance.
Several months after Bennett's operation, different research groups independently reported related studies on the legal transplantation of pig kidneys and pig hearts into brain-dead individuals. A growing number of U.S. research teams are applying to the FDA to continue formal clinical trials of xenografts. Data from hundreds of baboons show they can survive for up to three years after receiving pig organs. The researchers believe clinical trials are needed to confirm issues such as which pigs are the best type to use and how to ensure that animals do not carry infections. "I think we need to take a step forward," said Wayne Hawthorne, a surgeon at the University of Sydney, Australia. However, it has to be considered that Bennett's death has brought unprecedented attention to the topic, accompanied by fear.
In fact, as early as 1960, people had begun to test the organs of chimpanzees and baboons on humans, but the results were very little. In the early 1990s, an important problem faced by pig organs was "immune rejection." The breakthrough point is . The transplant surgeon David Cooper of Massachusetts General Hospital . The immune system of humans and other primates mainly reacts to , a sugar molecule on the surface of pig cells. If it is genetically mutationed, it can prolong its survival time in the human body. Until 2010, the emergence of CRISPR-Cas9 "catalyzed" the development of this field, not only making it easier to modify genes involved in α-Gal production, but also many other genes that may help the human to tolerate pig organs. Bennett's transplanted pig heart contained 10 gene-edited .
Human research has just begun, and each genetic modification has been specially tested and optimized in non-human primates. It is not clear which modifications are crucial for human transplants. Despite the differences between human and non-human primates, the FDA asked the research team to provide more data on how pig organs perform in non-human primates. "It's like saying a drug shows that it can do what we want in humans, but not in monkeys - but we still have to test it in monkeys," Cooper said. "It's totally illogical to do this." Currently, transplanting into a brain-dead person can provide an intermediate step. NYU surgeon Robert Montgomery, who led one of the teams to implant the pig kidneys this year, plans to perform more transplants for brain-dead patients before applying for clinical trials involving living people, as trials on living people will be the best way to determine whether the body rejects organs in a few months after the transplant.
In addition to the heart and kidneys, Hawthorne believes that various tissues, including insulin islet cells, may not trigger too many immune responses at all, and a simpler set of genetic modifications may be enough. His team designed a series of pigs for islet cell production that lack α-Gal and contain two additional genes that inhibit human immune response. In June, his team reported that transplanted islets cured five baboons who survived for nearly two years without insulin or immunosuppressive drugs. Hawthorne is now planning a clinical trial of pig islet cells in patients with severe type 1 diabetes who have caused a sharp drop in blood sugar.
In addition to the issue of immune rejection, one of the biggest concerns of regulators about this technology is whether there are infectious diseases in pigs.In addition, there is the endogenous retrovirus (PERV), which is a viral element embedded in the pig genome. These are not obtained from the environment, but are inherited fragments of viral DNA. They are not harmful to pigs, but it is still debated whether they can jump from organs into human cells. Church and Yang of of Harvard Medical School founded eGenesis to commercialize CRISPR technology for xenografts. One of the macaque kidney transplanted from a pig that knocked out dozens of PERVs and has survived for nearly a year. Despite this, some scientists believe that unknown harmful pathogens may still exist.
Figure 1. Biotechnology company eGenesis transforms animal pancreatic islet cells
FDA recommends that to minimize public health risks, only pig organs are transplanted to those who have no choice but whose quality of life will be significantly improved through surgery. In addition, they have developed policies to monitor patients for a long time and prohibit people with pig organs from donating blood because of the risk of disease transmission. Bennett's heart was found to contain swine cytomegalovirus, and researchers at the University of Maryland Medical Center noted that there was no evidence that the virus damaged the heart, and they were convinced that the virus did not spread to other parts of Bennett's body. Despite this, it is still impossible to determine whether the virus caused Bennett's death.
Bennett's death is not the end, and if successful, this effort may rescue many patients who will die while waiting for organ donation.
original link:
https://www.nature.com/articles/d41586-022-03794-2
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