There were many challenges in confirming the role of the MAL gene, including: study conducted by competitive researchers suggesting that a completely different gene might be responsible. “We suddenly thought, ‘Oh no, maybe all this work we’ve done has been for nothing,’” Tilley recalls. “That was really the worst moment.” Thornton chimes in: “But we were convinced we were right.”
Eventually, another study turned out to be flawed, and one of its authors joined forces with Tilley, Thornton, and their colleagues. Together, the group was able to prove the importance of the MAL gene in several key experiments. First, after painstakingly trying to find antibodies that could react with it, they determined that the key AnWj antigen (encoded by the MAL gene) was indeed present on the surface of most human red blood cells. Next, they took AnWj-negative cells lacking the antigen and implanted the complete MAL gene into those cells. This had the expected effect of generating the antigen on the cell surface, changing the AnWj-positive cells. This was the final proof that the scientists had found the gene responsible for this occasional red blood cell variant.
Now that scientists know the gene in question, finding AnWj-negative people to donate blood should become easier. This will ensure that people with this blood type, if they ever need a transfusion, can safely accept one.
“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, some 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 ignore.”
Mark Vickers, a haematologist at the University of Aberdeen who was also not involved in the study, agrees that the results are solid. “They’ve really come on board and done a great job,” he says. “This is going to be a clear landmark paper for this blood type.”
There are few clues as to what factors might influence someone to have genes that make their blood AnWj-negative. One family of AnWj-negative people in the paper were Arab-Israelis, but the authors emphasize that at this point there is no clear link to ethnicity. The immense majority of people who are AnWj-negative are not genetically predisposed to it. They have it because of a hematological disorder or because they have a cancer that can affect their MAL gene. “It’s not really negative. It’s just suppressed,” Thornton says, referring to these cases.
But questions remain. In infants, the AnWj antigen does not develop on red blood cells until the seventh day of life. The mechanisms for why this happens remain unclear. Vickers suggests that it may be related to a variety of changes that occur in the fetal blood around birth—for example, when it ends its dependence on the mother’s blood for nutrition and oxygen.
Tilley, Thornton and colleagues were also responsible for the discovery in 2022 of the genetic basis of the 44th blood group system, called Er, as well as MAM blood group system in 2020among others. Over the past decade or more, blood researchers around the world have described an average of about one novel blood group system per year. “We have more in the pipeline,” Thornton jokes.
There are still a handful of mysterious blood samples—blood that reacts with other people’s blood in unexpected ways—hidden away in lab storage. Scientists—aware of patients whose lives are affected, who will have difficulty finding suitable blood donors, or who in some cases may suffer devastating complications during pregnancy—regularly dissect these samples, hoping to one day explain them.
At least one mystery has been solved. Describing how she feels about finally seeing her and her colleagues’ work published, and reflecting on nearly 20 years of work, Tilley says simply: “It’s a huge relief.”