My writing assignments for Medscape Medical News tend to be formulaic: summarize the findings of an interesting new paper, enabling busy health care professionals to stay on top of the literature. I knew immediately the importance of an assignment from a few weeks ago – a team from the University of British Columbia had found a way to convert type A blood to type O. The report, in Nature Microbiology, details how they commandeered a pair of enzymes from a human gut bacterium.
Type O blood is the “universal donor.” An individual of any ABO blood type can receive it without suffering a rejection reaction, until supplies of the matched type become available. That’s because the surfaces of red blood cells (RBCs) that are type O lack certain glycoprotein molecules that festoon cells of types A, B, or AB.
Because more people have type O blood (45%), finding a way to make more of it could help address the ongoing shortage of human blood. The American Red Cross recently began offering gift cards to entice type O donors, warning that unless supplies extend from 2-days to 5-days, some emergency departments will be without blood and some types of surgeries delayed.
I guessed that the researchers had found some way to denude types A, B, or AB RBCs – shake them, zap them, bathe them in enzymes – but I didn’t imagine that beaver dams would be an inspiration. My Medscape article had only a sentence on the beaver connection, so I thought I’d elaborate here at DNA Science, where inquiring minds gravitate to the weird.
The ABCs of ABO Blood Types
The billions of cells that make up the human immune system zero in on the topographies of other cells, noting the molecular features, called antigens, that define “self” – the person – and launching attacks against “non-self” cells, such as those of infecting microbes or cancer cells.
Karl Lansteiner discovered and described the ABO blood types in 1900 at the University of Vienna. He was investigating why some transfusions worked and others killed.
The idea to create more type O blood simply by stripping away the A or B antigens isn’t new. A report from 1981 described using an extract (alpha galactosidase) from green coffee beans to convert type B to type O, which chemical supply companies sold to researchers. The media at the time heralded a coming solution to blood shortages. But even though the doctored type B-to-O blood worked in transfusions, the green coffee bean approach couldn’t provide enough to stock clinics.
Over the next few years, a sprinkling of other papers touted variations on the coffee bean theme. Then in 2007 researchers at a biotech company deployed two types of bacteria that make enzymes that can denude type A RBCs, which are more resistant to stripping than type B cells. But again, there wasn’t enough of the stuff to significantly boost type O blood supplies.
Other strategies couldn’t get clean enough blood cell preps to prevent mismatches, which can be deadly. In 2015, another approach, “directed evolution” to tinker with the gene that encodes an enzyme in Streptococcus pneumonia that removes A or B antigens, couldn’t up supplies enough either.
Then Stephen Withers, PhD, professor of chemistry at UBC, thought about the work his group had done on how beavers build dams.
Borrowing from Beavers
“The North American beaver (Castor canadensis) has long been considered an engineering marvel, transforming landscapes and shaping biological diversity through its dam building behavior,” begins the researchers’ paper in the ISME Journal from December 2018.
While it’s easy to see how a beaver’s teeth and tail would help to process wood, the animal’s microbiome also plays a major role. A thriving community of gut microbes cranks out wood-degrading enzymes, releasing nutrients while weakening tree branches so the animals can build.
To get a closer look at how beavers do it, the researchers took a “metagenomics” approach – sampling a slice of the environment, such as a New York City subway railing, a deep-sea thermal vent, or an armpit – cataloging all the microbes and analyzing their biochemical repertoires.
In beaver poop, the team found the enzymes that “deconstruct” wood, releasing its carbohydrates and then breaking them down. That’s a clue, for the “glyco” part of the glycoproteins that dot human RBCs are sugars, the simplest carbs. Where in a human body might microbial residents offer up enzymes that might strip the sugars from type A, B, or AB blood?
Dr. Withers thought of the gut, like in the beavers. Particularly the slimy mucin smeared on the inner lining, which is rich in sugars that coincidentally resemble those on RBCs. Bacteria clinging to mucin aren’t flushed out of their comfy human host, so natural selection would have favored the skill.
“We reasoned the human gut would be a good place to look for enzymes that could degrade the A and B antigens, in the context of mucin,” Dr. Withers told me.
Like in the beaver experiments, the researchers started with stool, from a man with type AB+ blood so that they’d have a source of RBCs dotted with A and B antigens. Of the 19,500 or so species in the gut bacterial library that they established from the sample, they found Flavonifractor plautii, which thrives in the oxygen-free environs of the human intestines and has a pair of enzymes that strip type A RBCs down to type O. Not much was known about the microbe because it doesn’t show up in clinical specimens.
To scale-up production of the enzymes, the researchers transferred the requisite genes to recombinant E. coli, which mass-produces the enzymes. And it worked, converting the blood of 26 type A volunteers to type O, as well as converting a unit of blood. Afterwards, the routine step of centrifuging blood effectively stripped away any bacterial enzymes.
The Beaver Blood Story Solved a Mystery
Once the bacterial conversion of human blood types worked with the help of gut microbes, the researchers realized that they’d explained a medical mystery.
In the “acquired B phenomenon,” a person with blood poisoning (sepsis) can transiently change ABO blood type, then revert when the infection is treated. A dismembered body found in the River Thames also seemed to have switched blood types.
“When forensic scientists pulled out body parts, depending on where they sampled tissue, they got different blood types. The bacteria in the Thames were doing the same thing as the bacteria causing sepsis,” Dr. Withers explained, eating away at the antigens on some RBCs, turning types A, B, and AB into O – partly.
The researchers are working on improving their process and exploring applications of the technology in organ transplantation. Hopefully it won’t be too long until the bacterial enzyme stripping helps to bolster type O blood supplies.
In the meantime, the message, again, is that basic research is important. We never know when and how practical benefits will arise. The beaver paper dealt with effects of its microbiome on landscapes and ecosystems. It took the minds of scientists who could make connections to think of the application to the human blood shortage.