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By the time Louise Tilley got to the blood sample, it had already been puzzling scientists for more than 30 years. In 1972, a pregnant woman had her blood taken, and doctors noticed that her red blood cells seemed to lack a surface marker, known as an antigen, that everyone else seemed to have. No one knew why. These antigens are vitally important because they define blood groups. If you ever receive blood that is a mismatch to your own, with the wrong antigens, it could kill you.
Not long after Tilley started working for NHS Blood and Transplant in the early 2000s, a colleague suggested to her that she might try to solve the decades-old mystery of this very unusual blood. A handful of other blood samples with the same missing antigen had emerged over the years, meaning it was possible to compare these rare cases. “We thought it was going to be easy,” Tilley recalls. “It didn’t quite work out like that.”
In the end, it took her and her colleagues 19 more years to discover the genetic basis that causes someone to have blood like this. The results of their work have finally been published in the journal Blood—more than half a century since that first perplexing blood sample was taken. The findings mark the discovery of the 47th blood group system. Each such system refers to whether a person has particular antigens on their red blood cells. You’ll likely have heard of the best known systems, ABO and Rh. But there are now known to be 46 others, though most of them affect a very small number of people. Your blood will have a classification in each of these 47 systems. It’s possible to have type A blood that is also Rh positive, for instance, and so on.
The antigen that was missing in the blood samples studied by Tilley and her colleagues has been dubbed AnWj, an obscure reference to the names of two individuals known to have blood lacking this antigen. The vast majority of people are AnWj-positive, while those who are AnWj-negative are extraordinarily few and far between. Nicole Thornton, a coauthor of the study who also works at NHS Blood and Transplant, can’t give a specific estimate, but suggests there could be fewer than tens of thousands of such people on the planet: “There’s probably more than we realize, but it’s still super, super rare.” Just eight AnWj-negative blood samples caused by a person’s genetics are listed in the paper, and some of those came from members of the same families.
For these individuals, knowing they have AnWj-negative blood is potentially life-saving—for example if they ever require a blood transfusion in a hospital. “We have to give them […] compatible blood. Otherwise there’s a high likelihood that they will have a transfusion reaction that could be fatal,” says Thornton.
In order to better understand this blood group system and be able to identify potential AnWj-negative blood donors, Tilley, Thornton, and their colleagues sought to find the underlying genetic cause. But at first, it was far from obvious which gene, out of the many thousands in the human genome, was responsible for a person being AnWj-positive or -negative. However, the team had a hunch that a gene called MAL, important for various blood cell functions, might be involved. Genetic sequencing revealed that the AnWj-negative individuals they knew about all shared an unusual change in this important gene. Through extensive tests, the researchers eventually proved that a mutation in MAL could result in someone having AnWj-negative blood. They also noted that some people with certain cancers can develop a form of AnWj-negative blood, in cases where those cancers affect expression of the MAL gene in a particular way.
There were many challenges in the process of confirming the role of the MAL gene, including a study by rival researchers that suggested a completely different gene could be responsible. “We suddenly thought, ‘Oh no, maybe all this work we’ve been doing has been wasted,’” recalls Tilley. “That was a real low point.” Thornton chimes in: “But we were convinced we were right.”
In the end, the other study turned out to be wrong, and one of its authors later joined forces with Tilley, Thornton, and their colleagues. Together, the group was subsequently able to prove the significance of the MAL gene in some key experiments. First, following painstaking efforts to find antibodies that would react with it, they established that the crucial AnWj antigen (encoded by the MAL gene) was indeed present on the surface of most people’s red blood cells. Then, they took AnWj-negative blood cells, lacking said antigen, and inserted a complete MAL gene into those cells. This had the hoped-for effect of generating the antigen on the cell surface, turning the cells AnWj-positive. That was definitive proof that the researchers had found the gene responsible for this rare red blood cell variation.
Now that they know the gene in question, it should make it much easier to find AnWj-negative people who could become blood donors so that, if people affected by this blood group ever need a transfusion, they can have one safely.
“What they did was really clever,” says Sara Trompeter, a consultant hematologist and pediatric hematologist at University College Hospitals London. Trompeter also works for NHS Blood and Transplant but was not involved in the AnWj study. “They presented it at a conference, some of their early work. It was like watching one of those detective shows where they’re just picking up on tiny clues and testing hypotheses—things that other people might have ignored.”
Mark Vickers, a hematologist at the University of Aberdeen, who also was not involved in the study, agrees that the results are robust. “They’ve really gone to town and done some very nice work,” he says. “As far as this blood group is concerned, this is going to be the unequivocal landmark paper.”
There are few indications as to what factors might influence someone to have genes that make their blood AnWj-negative. One family of AnWj-negative individuals in the paper was Arab-Israeli, but the authors stress that there is no clear link to ethnicity at this stage. The vast majority of people who are AnWj-negative are not genetically predisposed to it. Rather, they have such blood because of a hematological disorder or because they have one of the cancers that can affect their MAL gene. “It’s not truly negative. It’s just suppressed,” says Thornton, referring to those cases.
There are questions remaining though. Babies don’t actually develop the AnWj antigen on their red blood cells until they’re seven days old. The mechanisms as to why that is remain murky. Vickers suggests it could be something to do with the variety of changes that happen in a fetus’s blood around the time of birth—for example, when its dependence on nutrition and oxygen from its mother’s blood ends.
Tilley, Thornton, and colleagues were also responsible for discovering the genetic basis for the 44th blood group system, called Er, in 2022, as well as the MAM blood group system in 2020, among others. During the past decade or so, blood researchers around the world have described roughly one new blood group system every year, on average. “We’ve got some more in the pipeline,” teases Thornton.
There are still a handful of enigmatic blood samples—blood that reacts to other people’s blood in unexpected ways—out there, tucked away in lab storages. Scientists—mindful of the patients whose lives are affected by this, who will struggle to find matching blood donors, or who, in some cases, may suffer devastating complications during pregnancy—regularly pore over those samples, hoping to explain them one day.
At least one more mystery has been solved. Describing how she feels upon seeing her and her colleagues’ paper published at last, and reflecting on nearly 20 years of work, Tilley just says: “It’s a huge relief.”
