The process of confirming the role of the MAL gene has been fraught with challenges, including work by rival researchers suggesting that an entirely different gene may be responsible. “All of a sudden we thought, ‘Oh, maybe all we’ve done is wasted,'” Tilley recalls. “That was a really low point,” Thornton agreed, “but we knew 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. The group then worked together and was able to prove the importance of the MAL gene in several important experiments. First, painstaking efforts to find antibodies that react with it proved that the key AnWj antigen (encoded by the MAL gene) is indeed present on the surface of most people’s red blood cells. Next, they took AnWj-negative blood cells that lacked the antigen and inserted the entire MAL gene into those cells. This had the expected effect of producing antigen on the cell surface and making the cells positive for AnWj. It was conclusive evidence that researchers had discovered the gene responsible for this rare red blood cell mutation.
Now that we know the gene in question, it will be much easier to find AnWj-negative potential blood donors, making it safer for people with this blood type if they ever need a blood transfusion. You will be able to receive blood transfusions.
“What they did was really clever,” says Sarah Trompeter, consultant hematologist and pediatric hematologist at University Hospitals London. Mr Trompeter also works in the NHS Blood and Transplant Department but was not involved in the AnWj study. “They presented some of their early work at conferences, and it was like watching a detective drama where you test your hypothesis by finding little clues that others might ignore.”
Mark Vickers, a hematologist at the University of Aberdeen who was not involved in the study, agreed the results were robust. “They really went to town and did a really great job,” he says. “This is definitely a landmark paper as far as this blood type is concerned.”
Little is known about what factors influence people who carry the gene that makes their blood negative for AnWj. One of the AnWj-negative families in the paper was Arab-Israeli, but the authors stress that there is no clear link to ethnicity at this stage. The majority of people who are AnWj negative are not genetically predisposed to AnWj. Rather, it’s there because you have a blood disease or one of the cancers that can affect the MAL gene. “It’s not really a negative thing. It’s just being suppressed,” Thornton says, referring to these incidents.
However, questions remain. Babies don’t actually produce the AnWj antigen on their red blood cells until the seventh day of life. The mechanism why this happens remains unclear. Professor Vickers suggests that it may be related to various changes that occur in the fetus’s blood before and after birth, for example when it ceases to rely on the mother’s blood for nutrients and oxygen.
Tilly, Thornton and colleagues were also responsible for discovering the genetic basis of the 44th blood group system, called Er, in 2022, and the MAM blood group system in 2020. For the past decade or so, blood researchers around the world have described, on average, approximately one new blood group system each year. “We have some more plans in the works,” Thornton teases.
Several mysterious blood samples (blood that reacts in unexpected ways with other people’s blood) are still sitting in the lab’s warehouse. Scientists are mindful of the patients whose lives will be affected by this, who may struggle to find compatible blood donors, and who, in some cases, may suffer devastating complications during pregnancy. I am regularly examining these samples in the hope that one day I will be able to explain them.
At least one more mystery solved. “It was such a relief,” Tilly said only, describing how it felt to see her and her colleagues’ paper finally published, looking back on nearly 20 years of research.
