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Scientists discover enzymes that convert type A, and B blood into universal donor

Blood transfusions save lives. In the US alone, people receive around 10 million units each year. But blood banks are always short in supply—especially when it comes to the “universal donor” type O.

Surprisingly, the gut microbiome may hold a solution for boosting universal blood supplies by chemically converting other blood types into the universal O.

Infusing the wrong blood type—say, type A to type B—triggers deadly immune reactions. Type O blood, however, is compatible with nearly everyone. It’s in especially high demand following hurricanes, earthquakes, wildfires, and other crises because doctors have to rapidly treat as many people as possible.

Sometimes, blood banks have an imbalance of different blood types—for example, too much type A, not enough universal O. This week, a team from Denmark and Sweden discovered a cocktail of enzymes that readily converts type A and type B blood into the universal donor. Found in gut bacteria, the enzymes chew up an immune-stimulating sugar molecule dotted on the surfaces of type A and B blood cells, removing their tendency to spark an immune response.

Compared to previous attempts, the blend of enzymes converted A and B blood types to type O blood with “remarkably high efficiencies,” the authors wrote.

Wardrobe change
Blood types can be characterized in multiple ways, but roughly speaking, the types come in four main forms: A, B, AB, and O.

These types are distinguished by what kinds of sugar molecules—called antigens—cover the surfaces of red blood cells. Antigens can trigger immune rejection if mismatched. Type A blood has A antigens; type B has B antigens; type AB has both. Type O has neither.

This is why type O blood can be used for most people. It doesn’t normally trigger an immune response and is highly coveted during emergencies when it’s difficult to determine a person’s blood type. One obvious way to boost type O stock is to recruit more donors, but that’s not always possible. As a workaround, scientists have tried to artificially produce type O blood using stem cell technology. While successful in the lab, it’s expensive and hard to scale up for real-world demands.

An alternative is removing the A and B antigens from donated blood. First proposed in the 1980s, this approach uses enzymes to break down the immune-stimulating sugar molecules. Like licking an ice cream cone, as the antigens gradually melt away, the blood cells are stripped of their A or B identity, eventually transforming into the universal O blood type.

The technology sounds high-tech, but breaking down sugars is something our bodies naturally do every day, thanks to microbes in the gut that happily digest our food. This got scientists wondering: Can we hunt down enzymes in the digestive track to convert blood types?

Over a half decade ago, a team from the University of British Columbia made headlines by using bacterial enzymes found in the gut microbiome to transform type A blood to type O. Some gut bugs eat away at mucus—a slimy substance made of sugary molecules covering the gut. These mucus linings are molecularly similar to the antigens on red blood cells.

So, digestive enzymes from gut microbes could potentially chomp away A and B antigens.

In one test, the team took samples of human poop (yup), which carry enzymes from the gut microbiome and looked for DNA that could break down red blood cell sugar chains.

They eventually discovered two enzymes from a single bacterial strain. Tested in human blood, the duo readily stripped away type A antigens, converting it into universal type O.

The study was a proof of concept for transforming one blood type into another, with potentially real-world implications. Type A blood—common in Europe and the US—makes up roughly one-third of the supply of donations. A technology that converts it to universal O could boost blood transplant resources in this part of the world.

“This is a first, and if these data can be replicated, it is certainly a major advance,” Dr Harvey Klein at the National Institutes of Health’s Clinical Center, who was not involved in the work, told Science at the time.

There’s one problem though. Converted blood doesn’t always work.

Let’s talk ABO+
When tested in clinical trials, converted blood has raised safety concerns. Even when removing A or B antigens completely from donated blood, small hints from earlier studies found an immune mismatch between the transformed donor blood and the recipient. In other words, the engineered O blood sometimes still triggered an immune response.

There’s more to blood types than classic ABO. Type A is composed of two different subtypes—one with higher A antigen levels than the other. Type B, common in people of Asian and African descent, also comes in “extended” forms. These recently discovered sugar chains are longer and harder to break down than in the classic versions. Called “extended antigens,” they could be why some converted blood still stimulates the immune system after transfusion.

The new study tackled these extended forms by again peeking into gut bacteria DNA. One bacterial strain, A. muciniphila, stood out. These bugs contain enzymes that work like a previously discovered version that chops up type A and B antigens, but surprisingly, they also strip away extended versions of both antigens.

These enzymes weren’t previously known to science, with just 30 percent similarity when compared to a previous benchmark enzyme that cuts up B and extended B antigens.

Using cells from different donors, the scientists engineered an enzyme soup that rapidly wiped out blood antigens. The strategy is “unprecedented,” wrote the team.

Although the screen found multiple enzymes capable of blood type conversion, each individually had limited effects. But when mixed and matched, the recipe transformed donated B type cells into type O, with limited immune responses when mixed with other blood types.

A similar strategy yielded three different enzymes to cut out the problematic A antigen and, in turn, transform the blood to type O. Some people secrete the antigen into other bodily fluids—for example, saliva, sweat, or tears. Others, dubbed non-secreters, have less of these antigens floating around their bodies. Using blood donated from both secreters and non-secreters, the team treated red blood cells to remove the A antigen and its extended versions.

When mixed with other blood types, the enzyme cocktail lowered their immune response, although with lower efficacy than cells transformed from type B to O.

By mapping the structures of these enzymes, the team found some parts increased their ability to chop up sugar chains. Focusing on these hot-spot structures, scientists are set to hunt down other naturally-derived enzymes—or use AI to engineer ones with better efficacy and precision.

The system still needs to be tested in humans. And the team didn’t address other blood antigens, such as the Rh system, which is what makes blood types positive or negative. Still, bacterial enzymes appear to be an unexpected but promising way to engineer universal blood. Singularity Hub

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