A heavily modified pig lung survived for 216 hours inside a brain-dead human recipient. Reported in Nature Medicine, it’s the first trial of a cross-species lung transplant in humans.
The hope is that the approach, known as xenotransplantation, could one day address today’s donor organ shortage. Pig organs are about the same size as human organs, but they’re laden with proteins that ignite immune rejection. Over the years, scientists have meticulously identified these proteins and the genes that give rise to them and, in the process, fine-tuned their strategy to make pig organs more human-friendly through gene editing.
These efforts are starting to pay off. Thanks to courageous volunteers, people have received genetically altered pig hearts, livers, and kidneys. Now, a Chinese team from the First Affiliated Hospital of Guangzhou Medical University and colleagues have shown that lung xenotransplantation is also possible—with caveats.
Although the organ worked for over nine days, it also sparked inflammation that damaged the transplant, even with an extensive cocktail of drugs to suppress the immune system.
However, the study “paves the way for further innovations in the field,” wrote the team.
Why Pigs?
Roughly 13 people die each day waiting for an organ transplant. The reason is heartbreakingly simple: There aren’t enough donor organs available.
For a transplant to take, the organ has to be carefully matched with the recipient’s blood type and other immune markers to lower the chances of rejection. This results in a painfully long wait. As of late September 2024, nearly 90,000 people were on the waiting list for a kidney transplant, and over 3,000 people were waiting for a new heart.
Pig organs could be an alternative, but unaltered, they’re toxic to the human body.
The organs often carry viruses called porcine endogenous retroviruses (PERVs) embedded in their genes. These are harmless to their hosts, but they can infect humans. Also, integrating a donor organ into a new body triggers the host’s immune system. Donor organ cells, whether from a person or a pig, are dotted with protein markers, like a fingerprint. When the body doesn’t recognize the fingerprint, it launches a full immune onslaught. Killer T cells, B cells, and a cascade of toxic molecules called cytokines attack the new organ.
The trick is to make pig organs more like ours, so they escape immune surveillance.
Over the years, scientists have painstakingly searched out the pig genes behind immune-triggering proteins and snipped them out using the gene-editing tool CRISPR-Cas9. But the genetically stripped-down organs have other issues. Lacking protein signals that would mark them as normal cells or organs, they still look suspicious to roaming immune cells. So, scientists have added three human immune-regulating genes as a form of immune disguise.
After years of refinement, Chinese scientists developed an altered Bama Xiang pig—a minipig that lives in south China—with six edited genes that make its organs more human compatible.
At least in theory.
Breathe In
In the new trial, researchers removed the left lung of a fully grown, edited Bama Xiang pig and transplanted it into a brain-dead recipient. The 39-year-old wasn’t eligible for organ donation, and his family gave full consent for the procedure.
Before transplantation, the team carefully screened the organ for pathogens. The tests came back negative. The transplantation procedure was similar to a human-to-human lung transplant, though some air tubes and vessels from the pig had to be trimmed for a better fit.
Compared to solid organs, like hearts and kidneys, lungs are squishy and especially vulnerable to injury. When tissues are deprived of blood, they go into a sort of molecular shock mode. Rapidly reinfusing blood during a transplant jolts organs back to life but also causes extensive damage. Some lung cells are especially sensitive to this type of injury.
Against the odds, the condition of the transplanted lungs was improving within a day. Pressure between blood vessels shuttling oxygen into and out of the lungs stabilized. In other words, the transplanted lung was functional.
It wasn’t all good news. A day later, part of the transplanted lung swelled up dangerously due to an onslaught of immune cells and cytokines, indicating a sharp immune response. Three and six days after the transplant, tests showed a surge of antibodies. Though this activity eventually died down, it suggests a “secondary immune activation,” wrote the team.
Although the immune tsunami damaged the transplant, the lung appeared to have partially healed by day nine. It had integrated with the host and was steadily supporting oxygen exchange with the blood. Medical imaging also showed the transplant healing. However, the team ended the experiment that day at the request of the recipient’s family.
Throughout the study, the lung tested negative for pig viruses, and the host didn’t experience any common infections, even when treated with immune-suppressing drugs.
Long Road Ahead
Unlike previous xenotransplants, such as those involving hearts and kidneys, lungs are especially tricky due to their anatomy and role.
Like water mains, they have to sustain high pressure as the heart pumps large quantities of blood into the organs for oxygenation. Unlike the heart or kidneys, lungs are also exposed to environmental pathogens, making them especially vulnerable to infection. And the blood vessels lining the lungs contain lots of proteins that can easily trigger rejection.
Despite the fact immune-triggering genes were removed from the implanted lungs, they were still subjected to multiple types of immune attack. The immune reaction was more severe and occurred earlier than in previous experiments in baboons, wrote the team, highlighting the need for better strategies to prevent immune attack or more tweaks to the pig genome.
Finally, the recipient’s right lung, which was still working, might have altered the transplant’s function and the immune system. This makes it difficult to predict how a full lung transplant would work in the long term.
For now, the team is looking into drugs that are already used to support human lung transplants to more completely head off the immune system in the future.
“A more refined approach tailored for the lung’s immunity,” such as adding blood thinners or anti-inflammatory drugs could better control the immune response, they wrote.
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