Iit was 4 a.m. on a damp 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 been dead, Ostrander recalls. She was in her early fifties.
She would spend the next five years clinging to an oxygen tank, the ropes tangling around her as she slept. The incurable disease worsened until she had only 25% of her lung capacity left. It was so hard to breathe that she could barely haul groceries from her car to her kitchen, let alone be the “avid camper” she once was. She had to stop working and was placed on the waiting list for a lung transplant. When the Covid-19 pandemic hit, she said to herself, “I will never have my lungs.
She finally did, on November 13, 2021, but it took almost two years of waiting and three false alarms.
Ostrander was in the same situation as many people awaiting transplants. His blood type, B positive, did not match many donor organs, and an incompatible transplant would be catastrophic and deadly. But new research suggests that this barrier could disappear if donor organs were treated with special enzymes that made them compatible with recipients of any blood type.
“This research is truly a game-changer in organ transplantation,” said Aizhou Wang, lead author of a paper published Wednesday in Science Translational Medicine. “For modern transplant medicine, matching is always part of the criteria when trying to find the right organ for a recipient.”
And blood type is always one of the first considerations that limits which organs a patient can receive, she said. A hospital might have a donor organ, and it’s healthy, it’s the right size for the patient, and it’s geographically close, 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 a network of immune system foot soldiers on the surface of red blood cells and blood vessels, is a problem for all three major blood types: A, B, and O. For patients with blood type O, who cannot receive an organ from another donor O, their risk of dying while waiting for a transplant is 20% higher than for those with other blood types. Blacks and Latinos are more likely than whites to have type O blood.
In the fall of 2018, Wang sat down with Marcelo Cypel, his supervisor and a lung transplant specialist at the Toronto General Hospital Research Institute. They were looking for a project that Wang could focus his postdoctoral research on, and a corner of the scientific world was abuzz with enzymes. Specifically, people were talking about the work done 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 it extremely well, far more efficiently than any other similar enzyme previously found.
The enzymes move like a pair of sharp scissors, carefully shearing a sugar called GalNAc from the A antigens that line the surface of red blood cells, as well as cells in the lungs, until they resemble blood type O. This transformation, Withers realized, could neutralize any conflict that may arise when warring antigens and antibodies meet during an incompatible organ transplant. In Cypel and Wang, Withers found researchers eager to explore this hypothesis.
Their research shows proof of concept: the lungs of a type A donor could be treated with the enzymes for a few hours and emerge with the cellular appearance of a blood type O. And, the treated lungs were not damaged when they came into contact with O blood plasma during a transplant simulation. “Like camouflage,” Cypel said. The antibodies “will no longer recognize cells as being of a different blood type”.
About 85% of people have blood type A or O, so engineering organ compatibility between the groups would greatly expand transplant options for these patients, Cypel said. If doctors could remove ABO blood type matching entirely from the equation, it would remove a major logistical hurdle and get organs to the patients who need them more quickly.
“He has the potential – and I would underline ‘potential’ – to expand the donor pool significantly. And we have to think of any way to do that, given that there is still significant mortality on the lung transplant waiting list,” said David Weill, former director of the lung transplant program at the ‘Stanford University.
Despite a marked increase in organ donations over the past decade, the demand for lung transplants is often unmet, according to Annual Report of the Organ Procurement and Transplantation Network. More than 20% of patients on the waiting list for donor lungs wait longer than a year.
Each year, “hundreds of patients die while waiting for lung transplants due to lack of availability of matching organs,” said Nirmal Sharma, medical director of the lung transplant 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 keeping the lungs at body temperature in an incubator that mimics the environment of the human body. EVLP has also proven to be an effective way to treat less healthy lungs and test their performance in the human body. After trying the enzymes on human red blood cells and aortas, Cypel’s multidisciplinary Canadian research group used EVLP to treat human lungs and then expose them to O blood plasma. It was a clever workaround which came out of necessity. The researchers couldn’t go the usual route – from small animal (rodent) models that were easy to control, to large animals and then to humans – because there is no comparable list of blood types in animals.
“I had never thought of using the technology of these devices in this way. In other words, I knew all about the type of treatment you can do to the organs while they are on the devices. I didn’t know not that we could change ABO compatibility,” said Weill, who sits on the board of TransMedics, creator of a competing organ storage machine.
Cypel is founder and shareholder of Traferox Technologies, which develops alternative methods of lung storage, including an EVLP machine. He is also a consultant for Lung Bioengineering and inventor of a patent for the use of these sugar-cutting enzymes to alter blood types in human organs.
The main limitations of the study stem from the fact that the treated lungs were not implanted in a real person, several lung transplant specialists told STAT. Passing O blood plasma through EVLP can trigger an interaction comparable to what would happen in the human body. But the body’s immune system is much more complex in real life and could present additional challenges.
“It’s still isolated plasma. It’s not related to an actual recipient who has active bone marrow, may have active antibody production because T-cells and B-cells may be activated,” said Matthew Bacchetta, chairman of the Department of Thoracic Surgery at the Vanderbilt University Medical Center.
The next step will be to test this organ treatment against the full arsenal of tools a human body uses to destroy the unknown. Additionally, the enzyme haircut is not permanent; antigens, like hair, reappear on cell surfaces at some point, raising questions about whether the body might have a negative response to an incompatible transplant sometime after the initial 24-hour post-transplant window. Wang, the lead author, agrees that more research is needed.
“We recognize that we are only suppressing the antigen, not the body machinery that makes those antigens,” Wang said. “So over time we expect them to gradually grow back. But how fast? We are currently trying to study this.
For people like Ostrander, who waited two years for new lungs, the universal organs would make a huge difference – giving them back years of their life. “It would have changed my whole life,” she said. “I could have done more back then instead of being so limited.”
Correction: An earlier version of this story misrepresented the status of a patent for the use of sugar-cutting enzymes in the new research.