Many challenges were encountered in confirming the role of the MAL gene, including a study by rival researchers that suggested an entirely different gene might be responsible. “We suddenly thought, ‘Oh no, maybe all the work we’ve done is wasted,'” Tilly recalls. “That was a real low point,” Thornton interjected, “but we were convinced we were right.”
Eventually, another study was proven wrong, and one of the authors later joined forces with Tilley, Thornton, and their colleagues. Together, the team then demonstrated the importance of the MAL gene in some key experiments. First, after working hard to find antibodies that reacted with it, they determined that the key AnWj antigen (encoded by the MAL gene) is indeed present on the surface of red blood cells in most people. They then took AnWj-negative blood cells lacking the antigen and inserted the intact MAL gene into these cells. This has the desired effect of producing antigen on the cell surface, making the cells AnWj positive. This is clear evidence that researchers have discovered the gene responsible for this rare red blood cell mutation.
Now that they know the genes involved, it should be easier to find AnWj-negative people who can become blood donors, so that if someone affected by that blood type needs a transfusion, they can do so safely.
“What they’re doing is very clever,” said Sara Trompeter, a consultant hematologist and pediatric hematologist at University College London Hospital. Trompeter also works for NHS Blood and Transplantation but was not involved in the AnWj study. “They presented some of their early work at a conference. It was like watching a detective show where they were just picking up tiny clues and testing hypotheses — things that others might have overlooked.
Mark Vickers, a hematologist at the University of Aberdeen who was not involved in the study, also believes the results are reliable. “They did go into town and do some really good work,” he said. “This will be a definite landmark paper for this blood group.”
There is little indication of what factors might affect someone’s blood AnWj-negative gene. One family of the AnWj-negative individuals in the paper is 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 have no genetic predisposition. Rather, they have it because of a blood disease or because they have cancer that may affect the MAL gene. “It’s not really a negative impact. It’s just suppressed,” Thornton said of the cases.
But questions remain. Infants do not actually produce AnWj antigen on their red blood cells until they are 7 days old. As for why this occurs, the mechanism remains unclear. Vickers believes this may be related to various changes that occur in the fetus’s blood at birth, such as when the fetus is no longer dependent on the mother’s blood for nutrients and oxygen.
Tilley, Thornton and colleagues are also responsible for discovering the genetic basis of the 44th blood group system Er in 2022 and the MAM blood group system in 2020. Over the past decade or so, blood researchers around the world have described an average of about one new blood group system every year. “We have more plans in the works,” Thornton joked.
There are still mysterious blood samples—blood that reacts in unexpected ways with other people’s blood—hidden in the lab’s storage rooms. Scientists often study these samples closely in the hope of one day explaining them. Sexual complications.
At least one mystery has been solved. Describing his feelings after seeing his and his colleagues’ paper finally published and reflecting on nearly 20 years of work, Tilley simply said: “It’s a huge relief.”
