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A pair of gut enzymes in the microbiome could be key to universal organ donation

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As a transplant surgeon, Marcelo Cypel tells Inverse one of the hardest things about his job is seeing the often unfair way organs are allocated.

“Sometimes an organ will go to someone who could live maybe six more months instead of someone who has only a few days to live,” he says.

One of the major factors preventing recipients from receiving available organs is blood type. Patients need organs from someone with their blood type or type O blood (the universal blood donor).

What’s New — In a proof-of-concept study published Wednesday in Science Translational Medicine, Cypel, who heads up the Ajmera Transplant Center in Toronto, and his fellow researchers say they’ve found a way to make organs compatible for any recipient.

Roughly 45 percent of people in the United States have type O blood. There are 106,454 people in the U.S. on the national organ transplant list. If all goes well in future experiments, this technology could usher in a new, more equitable era of organ transplantation.

A little background — Humans have four main types of blood — A, B, AB, and O. Proteins called antigens that sit on the outer surface of our blood vessels determine our blood type. Those with type A blood have A antigens, and those with type B have B antigens. Those with A.B. blood have both, and those with O blood have none.

People with blood type O are often called “universal donors;” they can donate blood to every other blood type. The reverse, however, isn’t true: People with blood type O can only receive blood transfusions and organ donations from others with type O blood. Luckily, type O blood is by far the most common. But people with blood type O are still 20 percent more likely to die waiting for a pair of donor lungs than any other blood type. The stats for other organs are similarly dire.

The researchers sought to find a way to get rid of the A and B antigens from organs. This would effectively turn every donor organ into blood type O; something that could potentially go to someone with any blood type.

Lungs hooked up to a perfusion machine at Dr. Marcelo Cypel’s lab in Toronto, Canada.UHN

How they made the discovery —An essential piece of technology that enabled the discovery is called the Ex Vivo Lung Perfusion (EVLP) system.

“When we used to take an organ from a donor, we would cool [the body] down and shut down the organ metabolism,” Cypel says. “This does the opposite.”

The EVLP system pumps nourishing fluids through the lungs, which repairs them and keeps them at body temperature, extending the time they can exist outside the body before transplantation.

Cypel, who was instrumental in developing the EVLP system, says, “it’s like an ICU for the lungs.”

In 2018, Stephen Withers, a co-author and biochemist at the University of British Columbia, and his team found a group of enzymes produced by bacteria in the gut that — four years later — would prove to have an extraordinary capability.

“Enzymes carry out particular reactions,” Withers tells Inverse. “We discovered that two of these enzymes in combination could cut the sugars from A and B antigens on red blood cells. This functionally turns them into O blood cells.”

The researchers hypothesized that running the enzymes through the EVLC machine could “scrub” the antigens from lungs from a blood type A donor and turn them into lungs that could theoretically go to a recipient with any blood type.

Transplant surgeon Marcelo Cypel in an operating room. UHN

How they tested the theory— First, the researchers tested the ability of the two enzymes, FpGalNAc deacetylase, and FpGalactosaminidase, to remove A-antigens from five human red blood cell samples and three human aortae after static incubation. The enzymes removed over 90 percent of the A antigens from red blood cells and the human aortae.

​​Next, researchers placed eight human donor lungs not eligible for transplantation in the EVLC system. For each pair from the same donor, one lung was treated with fluid containing the enzymes; the other was not.

Over 4 hours, the enzymes removed more than 97 percent of A-antigens from epithelial lung cells. Crucially, the enzymes removed these antigens without any treatment-related damage to the lungs.

Next, the researchers simulated what would typically be an ABO-incompatible transplant. They added type O blood with a high concentration of anti-A antibodies to the system. The results showed that the enzyme-treated lungs tolerated the introduction of O blood well, while the lungs that weren’t treated with the enzymes showed signs of rejection.

What it means for the future— The goal of the treatment would be to get transplant patients through the critical 24 to48 hours after receiving an organ, when their body is most likely to reject it.

Both Withers and Cybel say they know there’s a long way to go before this treatment is proven safe for patients with standard A blood type (or type B, but the focus is on A for now).

In the lung that hasn’t been treated with the enzymes, pumping O plasma through them induced antibodies that inflamed the organ tissue, signaling lungs that the body would reject. The lungs that had been treated with the enzymes saw no such inflammation.

With these promising results, the researchers are considering jumping right into clinical trials. And if all goes well, organ transplants could save even more lives in the future.

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