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23 November 2018

The Quest for Universal Blood

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Each year about 112 million units of donated blood are collected around the world. Its use in transfusions, operations, transplants, complications surrounding pregnancies, and massive trauma injuries represents one of the remarkable achievements of modern medicine, a line of research launched 350 years ago and for which one great challenge remains. Researchers are today finding new techniques that bring us closer to the Holy Grail of transfusions: universal blood that is safe for any patient regardless of their blood type.

The most useful blood for transfusions is type-O negative as it bears no A or B antigens and no Rh protein, which are rejected in people who don’t carry them in their own blood. These antigens act like a bullfighter’s red cape, inciting the immune system to attack, causing severe reactions in the event of a transfusion error. People with type-O negative blood are, therefore, universal donors and their blood is in high demand by blood banks (9% of the Spanish population are type-O negative, though among Basques the percentage is much higher).

Diagram of ABO blood groups and the IgM antibodies present in each. Credit: InvictaHOG

Because type-O negative blood is universally safe, it’s often used in emergency situations when there’s no time for blood type matching, so at times it can be in short supply. Researchers around the world have long sought methods to convert A, B and AB blood into type-O, thereby helping blood banks to better manage their supplies.

Creating O blood with gut bacteria

One way to make type-O blood is to cleave off the A or B antigens from the blood cells so the immune system doesn’t recognise the blood as being foreign. Researchers at the University of British Columbia (Canada) led by Stephen Withers, professor in the Department of Chemistry and Biochemistry, have been searching the human gut microbiome for enzymes that can do just that. As the intestines are lined with glycoproteins containing sugar structures, including A and B antigens, it follows that some gut bacteria have evolved the ability to cleave off these sugars in order to feed on them.

Using a technique called metagenomics, Withers and his team screened 20,000 faecal extracts and was able to identify a powerful new enzyme that can cleave A antigens 30 times more efficiently than previous enzymes, meaning that much less of the enzyme needs to be added to the blood to convert it to type-O, greatly reducing the cost of the process. In laboratory tests, the enzymes successfully converted 100% of type-A blood to O.

Blood type compatibility table.

The next step, before the enzyme-treated blood can be used in patients, is to ensure that no other changes have been produced in the red blood cells during the modification process. Withers explained to OpenMind that he anticipates that “lab-based tests will take another two years while the subsequent clinical trials at least another three years beyond that. If all works out with the safety trials then this technology should be fairly easily incorporated into the current blood processing stream, providing broader access to O-type blood when needed.”

Early attempts

The history of blood transfusions goes back to the English physician Richard Lower (1631 – 17 January 1691), who demonstrated by some rather grisly experiments carried out in 1665 and 1666 on some unfortunate dogs that it was possible to transfuse blood from one animal to another.

When news of this spread to France, scientists there began their own experiments, leading to the first successful animal-to-human blood transfusion (called a xenotransfusion) being performed in 1667 by Jean-Baptiste Denys, physician to King Louis XIV, between a lamb and a 15-year-old boy. The teenager survived the procedure, likely due to the small quantity of blood transfused, as did Denys’ second patient a few weeks later.

Back in England, Richard Lower, having heard of Denys’ successes, and with the support of the Royal Society, hired an eccentric man named Arthur Coga, whose brain was “a little too warm,” to accept a transfusion of lamb’s blood. Coga survived the procedure and was even persuaded to undergo a second transfusion three weeks later before crowds of curious spectators. Meanwhile Denys’ xenotransfusions in France were no longer going well: the death of two patients and the subsequent publicity led to the procedure being banned in France and condemned by the Vatican. Following a few more unsuccessful experiments in England, the Royal Society also abandoned the idea.

An image attributed as Lower and King’s 1667 transfusion of Arthur Coga. Source: Matthias Goffried Purmann

Blood transfusions go modern

Although there were some (mostly fatal) attempts at human-to-human transfusions in the nineteenth century, the modern scientific era of blood transfusions was ushered in with the discovery of the main blood groups in 1900 by Karl Landsteiner (14 June 1868 – 26 June 1943), which earned the Austrian biologist and physician the Nobel Prize in Physiology or Medicine in 1930.

Landsteiner also learned that transfusions between people with different blood types result in the destruction of the donor blood cells in the recipient. As a result of his discoveries, in 1907 the first successful ABO matched blood transfusion was carried out at Mount Sinai Hospital in New York.

The quest continues

More than a century has passed since then and the quest for universal blood continues. Some researchers are focused on manufacturing artificial blood from stem cells, but even if they are successful, it’s doubtful that enough could be manufactured in the lab at a low enough cost to eliminate the need for blood donations in the foreseeable future.

For their part, Withers and his team, who have achieved a promising advance along another path—that of efficiently transforming A-type blood into O-type—aren’t resting on their laurels. After presenting the discovery at the meeting of the American Chemical Society in Boston in August 2018, the Canadian researcher told OpenMind: “We are looking for other A-cleaving enzymes and will shortly be searching for better B-cleavers too.”

If everything goes well, this new technique could see itself in general use in the 2020s, with great advantages for patients of whatever blood type—not to mention the community of type-O negative blood donors, taking some of the pressure off them during moments of crisis when supplies of their valuable blood start to run low.

 

Neil Larsen

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