There were many challenges in the process of confirming the role of the MAL gene, including A study by rival researchers suggesting that a completely different gene might be responsible. “We suddenly thought, ‘Oh no, maybe all this work we’ve been doing has been for nothing,’” Tilley recalls. “It was a really low point.” Thornton chimes in: “But we were convinced we were right.”
In the end, the other study turned out to be flawed, and one of its authors subsequently joined Tilley, Thornton, and their colleagues. Together, the group was subsequently able to demonstrate the importance of the MAL gene in some key experiments. First, after a painstaking effort to find antibodies that reacted with it, they established that the crucial antigen AnWj (encoded by the MAL gene) was indeed present on the surface of most people’s red blood cells. Next, they took AnWj-negative blood cells, which lacked such an antigen, and inserted a full-length MAL gene into those cells. This had the expected 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 be much easier to find AnWj-negative people who can become blood donors, so that if people affected by this blood type ever need a transfusion, they can receive it safely.
“What they did was really clever,” says Sara Trompeter, a consultant haematologist and paediatric haematologist 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, part of their early work. It was like watching one of those detective shows where they just pick up on little clues and test hypotheses – things that other people might have ignored.”
Mark Vickers, a haematologist at the University of Aberdeen who was also not involved in the study, agrees that the results are robust. “They have really worked hard and done a very good job,” he says. “As far as this blood group is concerned, this will be a landmark paper.”
There is little evidence of what factors might influence whether a person has 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 that blood because of a blood disorder or because they have one of the cancers that can affect their MAL gene. “It’s not really negative. It’s just suppressed,” Thornton says, referring to such cases.
However, some questions remain. Babies do not develop the AnWj antigen on their red blood cells until they are seven days old. The mechanisms explaining this remain unclear. Vickers suggests it might have something to do with the variety of changes that occur 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 their colleagues were also responsible for discovering the genetic basis of the number 44 blood group system, called Er, in 2022, as well as The MAM blood group system in 2020among others. Over the past decade, blood researchers around the world have described about one new blood group system each year, on average. “We’ve got a few more in the pipeline,” Thornton jokes.
There are still some enigmatic blood samples – blood that reacts unexpectedly to other people’s blood – stored in laboratories. Scientists, aware of the patients whose lives are affected by this, who will have difficulty finding compatible blood donors or who in some cases may suffer devastating complications during pregnancy, periodically examine these samples in the hope of one day finding an explanation for them.
At least one more mystery has been solved. Tilley describes how it feels to see that his and his colleagues’ papers have finally been published and reflects on nearly 20 years of work: “It’s a huge relief.”
