It was 4 a.m. on a humid night in St. Catharines, Ontario, and Elizabeth Ostrander couldn’t breathe. Chronic obstructive pulmonary disease, complicated by pneumonia, was suffocating her, doctors told her that day in 2016. If she hadn’t gotten to the hospital when she did, she would have died, Ostrander remembers them saying. She was in her early 50s.
She would spend the next five years hooked to an oxygen tank, cords tangling around her in her sleep. The incurable disease worsened until she had just 25% of her lung capacity left. It was so difficult to breathe that she could barely lug groceries from her car to her kitchen, much less be the “avid camper” she was before. She had to stop working, and was placed on the lung transplant waiting list. When the Covid-19 pandemic hit, she thought, “I’m never going to get my lungs.”
She finally did, on Nov. 13, 2021, but it took nearly two years of waiting and three false alarms.
Ostrander was in the same bind as many people awaiting transplants. Her blood type, B positive, wasn’t a match for many donor organs, and a mismatched transplant would be catastrophic and deadly. But new research suggests this barrier could disappear if donor organs were treated with special enzymes that make them compatible with recipients of any blood type.
“This research is really a game-changer in organ transplantation,” said Aizhou Wang, the lead author of a paper published Wednesday in Science Translational Medicine. “For modern transplant medicine, matching is always part of the criteria when you are trying to find the suitable organ for a recipient.”
And blood type is always one of the first considerations that limits what organs a patient can receive, she said. A hospital could have a donor organ, and it’s healthy, it’s the right size for the patient and geographically nearby, but if it’s an incompatible blood type, the recipient’s immune response would destroy the organ within the first 48 hours.
This mismatch, determined by an array of immune system foot soldiers on the surface of red blood cells and blood vessels, is a problem across the three main blood types: A, B, and O. For patients with type O blood, who can only receive an organ from another O donor, their risk of dying while waiting for a transplant is 20% higher than for those with other blood types. Black and Latino people are more likely than white people to have type O blood.
In the fall of 2018, Wang sat with Marcelo Cypel, her supervisor and a lung transplant specialist at the Toronto General Hospital Research Institute. They were seeking a project for Wang to focus her postdoctoral research on, and a corner of the scientific world was abuzz with enzymes. More specifically, people were talking about work led by Stephen Withers at the University of British Columbia. His team had discovered a new pair of enzymes in the human gut that could change blood type from A to O — and do so extremely well, way more efficiently than any other, similar enzymes that had been previously found.
The enzymes go around like a sharp pair of scissors, neatly shearing off a sugar called GalNAc from A-antigens that line the surface of red blood cells, as well as cells in the lungs, until they resemble O blood type. That transformation, Withers realized, could neutralize whatever conflict might arise when warring antigens and antibodies meet during a mismatched organ transplant. In Cypel and Wang, Withers found researchers willing to explore that hypothesis.
Their research shows proof-of-concept: Lungs from a type A donor could be treated with the enzymes for a few hours and emerge with the cellular appearance of having O blood type. And, the treated lungs weren’t damaged when they came into contact with O blood plasma during a transplant simulation. “Like a camouflage,” Cypel said. Antibodies “won’t recognize the cells anymore as being a different blood type.”
About 85% of people have either A or O blood type, so engineering organ compatibility between the groups would vastly expand transplant options for these patients, Cypel said. If doctors could remove ABO blood type matching from the equation entirely, that would remove a major logistical hurdle and get organs to patients in need more quickly.
“It has the potential — and I would underline ‘potential’ — to expand the donor pool in meaningful ways. And we have to think of any way that we can do that, given there’s still significant mortality on the lung transplant waiting list,” said David Weill, former director of the lung transplant program at Stanford University.
Despite a marked increase in organ donations over the last decade, the demand for lung transplants is often unmet, according to annual reports from the Organ Procurement and Transplantation Network. More than 20% of patients on the waitlist for donor lungs wait more than a year.
Every year, “hundreds of patients die waiting for a lung transplant due to lack of availability of compatible organs,” said Nirmal Sharma, medical director of the Lung Transplantation Program at Brigham and Women’s Hospital.
A thoracic surgeon, Cypel was one of the researchers who developed ex vivo lung perfusion (EVLP), a method of preserving lungs at body temperature in an incubator that mimics the environment of the human body. EVLP has also been found to be an effective way of treating less healthy lungs and testing how they might perform in the human body. After trying the enzymes on red blood cells and human aortae, Cypel’s multidisciplinary Canadian research group used EVLP to treat human lungs, and then to expose them to O blood plasma. It was a clever workaround that came out of necessity. The researchers couldn’t take the usual route – from easy-to-control small animal (rodent) models, to large animals and then humans — because there is no comparable slate of blood types in animals.
“I just had never thought of using the technology of these devices in this way. In other words, I knew all about the kind of treatment you can do to the organs while they’re on the devices. I did not know we could change the ABO compatibility,” said Weill, who serves on the board of directors of TransMedics, creator of a competing organ storage machine.
Cypel is a founder and shareholder of Traferox Technologies, which develops alternative lung storage methods, including an EVLP machine. He is also a consultant for Lung Bioengineering, and an inventor on a patent for the use of these sugar-cutting enzymes to change blood types across human organs.
The study’s key limitations stem from the fact that treated lungs weren’t implanted in a real person, several lung transplant specialists told STAT. Running O blood plasma through EVLP can trigger a comparable interaction to what would happen in the human body. But the body’s immune system is far more complex in real life, and could present some additional challenges.
“It’s still plasma in isolation. It’s not connected to an actual recipient that has an active bone marrow, may have active production of antibodies because T cells and B cells may get activated,” said Matthew Bacchetta, chair of Vanderbilt University Medical Center’s Department of Thoracic Surgery.
The next step will be testing this organ treatment against the full arsenal of tools a human body uses to destroy the unfamiliar. Plus, the enzymatic haircut isn’t permanent; antigens, like hair, reappear on cell surfaces at some point, raising questions about whether the body could have a negative response to a mismatched transplant sometime after the initial 24-hour window post-transplant. Wang, the lead author, agrees more research is needed.
“We do recognize we’re removing just the antigen, not the machinery in the body that makes these antigens,” said Wang. “So, over time, we do expect that they grow back gradually. But how fast? We are currently trying to study that.”
For people like Ostrander, who waited two years for new lungs, universal organs would make a huge difference — giving them back years of their life. “It would’ve changed my whole life,” she said. “I would’ve been able to do more back then instead of being so limited.”
Correction: An earlier version of this story misstated the status of a patent for the use of sugar-cutting enzymes in the new research.
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