In a plastic-domed case at the Toronto General Hospital Research Institute, researchers gave a pair of lungs a new identity. When the lungs first arrived in the lab, they were from someone with type A blood, meaning that there were certain tiny markers, called antigens, attached to the lung tissue and blood cells. But when the lungs left the lab, those antigens were almost entirely gone. In just one hour, the researchers had effectively transformed the lungs into type O.
“This is absolutely amazing,” says Aizhou Wang, a researcher in the Cypel Lab at the University of Toronto and first author on a paper published this week in Science Translational Medicine that describes the transformation. The experiment is an important step toward giving more people access to life-saving organ transplants. More than 100,000 people in the United States are currently waiting for organs, but often those most in need can’t get help because of one big problem: Their blood type doesn’t match the organs that are available.
Wang works in a lab run by Marcelo Cypel, lead author on the paper and a thoracic surgeon who’s spent years figuring out ways to increase the number of lungs available for transplants. One of his previous innovations was creating ex vivo lung perfusion (EVLP), that plastic-domed apparatus in which this study’s lungs got their new identity.
The device allows doctors to feed donated lungs nutrients and oxygen in a protected environment, which improves their transplant viability. Unlike organs that are put on ice after being harvested from a donor and then go straight to the operating room, lungs inside the EVLP warm up and their metabolism restarts before they're transplanted. Doctors can then reassess the lungs’ function and use EVLP to administer drugs that improve the quality of the organ, saving slightly damaged lungs that might have been ineligible for use before. “We put the lung back to life on this machine,” says Cypel, who thought this technology could also be used to modify the organ, transforming it into one that can be received by a person of any blood type.
There are four major blood type groups: A, B, O, and AB. Think of type O as the base model. It has no antigens that attach to it. The A and B blood types each have extra antigens that attach to that core, and AB blood has both types of antigens.
For an organ transplant to work, the donor and recipient have to have compatible blood types. If someone with type O or B blood receives a donation from someone with type A blood, for example, those A antigens will trigger the recipient’s immune system to attack the transplanted organ, which is perceived as a foreign invader. This process, called rejection, can be deadly.
But because type O blood has no antigens, people with O are considered “universal donors.” Their blood and tissue won’t set off an immune response for recipients of any blood type.
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Increasing the number of universal donors, Cypel hoped, would make more lungs available to more people, and make the process more equitable. “Today we have a separate list of A patients, B patients, O patients, and we don’t necessarily transplant [to] the sickest one,” he says. And even if a pair of donor lungs match the person’s blood type, they might be the wrong size for them. Too small and they won’t provide enough oxygen. Too big and they won’t fit correctly into the chest.
Even worse, only about 20 percent of donor lungs are healthy enough to be used. Some are too damaged from being on prolonged ventilation, others are infected, or the donor is simply too far away for their organs to get to the patient in time. But Cypel thinks that technologies like the EVLP and blood type conversion can improve transplant rates dramatically. “Right now in North America we do about 2,500 lung transplants a year. I think we could double that number,” he says.
To test their idea, Wang, Cypel, and their collaborators worked with Stephen Withers, a chemist at the University of British Columbia, to identify a specific set of molecular tools. Withers tested thousands of enzymes in the human gut and found two, FpGalNAc deacetylase and FpGalactosaminidase, that normally help the body create energy by digesting sugar antigens on the gut wall. Those sugars are similar to the A antigens, which means these enzymes are uniquely suited to performing a highly specific task: Working like molecular editors, they track down these antigens on cells, slice them off, and leave behind that core O structure.
Using a set of donated lungs that had once belonged to a person with type A blood, Wang and Cypel administered a small dose of those enzymes to the tissue. Then the team performed an antibody stain, which marked the remaining antigens so they could see how successful the enzymes had been. Within an hour, over 90 percent of those A antigens had been chopped away. After four hours, 97 percent were gone.
Next, the team assessed the lungs using the same parameters a transplant team would use, evaluating factors like airway pressure, blood gasses, and lung inflammation. Despite their transformation, the lungs were healthy. “To have something work so well in such a short amount of time at a dose that’s feasible—it’s absolutely mindblowing that it happened,” says Wang.
This study is just a proof of concept, meant to show that such a feat is possible, cost-effective, and takes effect quickly enough to work in a real-life transplant scenario. But they didn’t try transplanting the tissue, and they focused their work on only the A antigen. (The team is currently looking for the right enzymes to perform that same search-and-snip function on B antigens.) One question is whether the body will immediately reject the modified lung. Another is whether those A antigens will regrow and trigger that dangerous immune response when they do.
“This research and the results reported are particularly important, since graft diseases caused by antibodies directed against the donor are among the most difficult to treat,” says Marilia Cascalho, an immunologist at the University of Michigan who was not involved with the study.
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But, she adds, even if the antigens do regrow, there’s some evidence that the body will accept the organ. Already, research in kidneys suggests that the body can adjust to using organs from a different blood type if doctors suppress the recipient’s immune system before and immediately after surgery, giving the body time to adjust. “It is possible that if this treatment is followed by a slow return of the blood group antigens, that the organ will ‘adapt’ to those antibodies—a process called accommodation,” says Cascalho. She adds that being able to treat the organ would be better than weakening the immune system of an already-sick patient. “This would be a major advance in solid organ transplantation,” she says.
Before the new approach can advance to human clinical trials, the next step will be to test it on animals. The team is trying to find the right animal models and is working on experiments in mice and pigs. Cypel says they’re also considering transplanting altered lungs into someone who is brain dead but being kept alive on life support, similar to a procedure done at New York University to test the feasibility of transplanting pig organs.
Albert Rizzo, chief medical officer for the American Lung Association, says it will be hard to assess how well these modified lungs work until they’re actually transplanted into human patients. “There may be lungs that do better than others, depending on how the lungs were prior to the process,” he says. “Time is going to tell.”
Rizzo points out that a changed blood type will just be one factor that surgeons consider, alongside issues like whether the lung is the right size and whether the patient is too sick to wait for a better one to come along. “You’re weighing the benefit of getting the lung sooner against the likelihood of rejection,” he says. Surgeons want to make sure they’re getting the best lungs possible before they subject ill patients to an invasive and risky procedure.
Still, he’s hopeful that this process will make more lungs viable for transplant. “I do think this is very promising research,” he says.
Update 3-18-2022 11:31 am ET: This story was updated to correct the spelling of Aizhou Wang's name.
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