There were many challenges in the process of identifying the role of the MAL gene. Research by rival researchers That suggested a different gene might be to blame entirely. “Suddenly we thought, ‘Oh, maybe all this work has been for nothing,'” Tilly recalls. “That was rock bottom,” 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 collaborated with Tilly, Thornton, and their colleagues. Together, the groups were then able to prove the importance of the MAL gene in several key experiments. First, after painstaking work to find antibodies that react to this gene, they found that the important AnWj antigen (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 that lacked this antigen and inserted the complete MAL gene into those cells. This produced the antigen on the cell surface, which had the expected effect of making the cells AnWj-positive. This was conclusive evidence that the researchers had found the gene responsible for this rare red blood cell mutation.
Now that we know the gene in question, it should be much easier to find potential AnWj-negative blood donors, so that affected people who need a transfusion can receive it safely.
“The way they’ve done it is really clever,” says Sarah Trompeter, a haematologist and paediatric haematologist at University College London Hospital, who also works at NHS Blood and Transplant but was not involved in the AnWj work. “They presented some of their early work at the conference, and it was like watching a detective show where they were picking up little clues and testing hypotheses – things that other people might have missed.”
Mark Vickers, a haematologist at the University of Aberdeen who was not involved in the study, agrees that the results are solid: “They’ve worked really hard and done a really impressive job,” he says. “This is definitely going to be a landmark paper as far as this blood type is concerned.”
There is little evidence about what factors influence a person to carry the gene that makes their blood AnWj-negative. One family of AnWj-negative people in the paper was Arab Israeli, but the authors emphasize that there is no clear link to ethnicity at this time. The vast majority of people who are AnWj-negative are not genetically predisposed; rather, they have that blood because of a blood disorder or because they have one of the cancers that can affect the MAL gene. “It’s not really negative, it’s just suppressed,” Thornton says of these cases.
But questions remain: Babies don’t produce the AnWj antigen on their red blood cells until the seventh day after birth. The mechanism behind why is unclear. Vickers suggests it could have to do with various changes that occur in the fetal blood around the time of birth, such as it becoming less dependent on the mother’s blood for nutrients and oxygen.
Tilly, Thornton and colleagues discovered the genetic basis of a 44th blood type, called Er, in 2022, as well as MAM Blood Group System in 2020Over the past decade or so, hematology researchers around the world have published, on average, about one new blood group system per year, and “we have a few more on the way,” Thornton says.
Mysterious blood samples — blood that reacts unexpectedly with that of other people — still sit in lab vaults, and scientists periodically scrutinize them in hopes of one day explaining the causes for patients whose lives could depend on them, who struggle to find matching donors, or who, in some cases, suffer dire complications during pregnancy.
At least one more mystery has been solved. Looking back on nearly two decades of research, Tilly says, “It’s just a huge relief.”
