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, Zhang, 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, Zhang 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 Zhang.
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.
