By Suherman Candra Maholtra 
In a landmark achievement for hematology and transfusion medicine, a global collaborative effort led by scientists at NHS Blood and Transplant (NHSBT) in Bristol has finally unraveled a mystery that persisted for over half a century. By identifying the genetic source of a mysterious marker on human red blood cells, researchers have established MAL as the world’s 47th human blood group system. This breakthrough provides a definitive molecular explanation for the AnWj antigen, a marker first discovered in 1972, and offers a life-saving diagnostic pathway for an exceptionally rare subset of the global population.
The research, conducted in partnership with the International Blood Group Reference Laboratory (IBGRL) and the University of Bristol, resolves a scientific puzzle that had frustrated experts for decades. While the ABO and Rh systems are household names, the discovery of the MAL system underscores the immense biological complexity of human blood, where hundreds of antigens reside on the surface of red blood cells. For the vast majority of people, these markers go unnoticed, but for the tiny fraction of individuals who lack them, a routine blood transfusion can become a life-threatening event.
The Fifty-Year Search for the AnWj Antigen
The story of the MAL blood group begins in 1972, when clinicians first identified a patient whose blood lacked a specific, near-universal antigen. This marker was named AnWj. For decades, the presence of AnWj was a statistical certainty for almost every human on Earth; more than 99.9% of the population is AnWj-positive. However, the biological "home" of this antigen—the specific protein that carried it and the gene responsible for its production—remained unknown.
The challenge in identifying the source of AnWj lay in its scarcity. Because so few people lack the antigen, scientists had a vanishingly small pool of genetic material to study. The rarity of the "AnWj-negative" phenotype meant that researchers could not easily perform the large-scale comparative studies typically used to map genetic traits.
Clinical interest in the antigen persisted because of the danger it posed to the few individuals who lacked it. If an AnWj-negative person is exposed to AnWj-positive blood—either through a previous transfusion or during pregnancy—their immune system recognizes the antigen as a foreign invader and develops antibodies against it. Subsequent transfusions of standard blood can then trigger a hemolytic reaction, where the recipient’s immune system systematically destroys the donor’s red blood cells, potentially leading to organ failure or death.
Deciphering the Genetic Code: The Role of the MAL Gene
To crack the case, the research team turned to whole exome sequencing, a sophisticated genomic technique that focuses specifically on the protein-coding regions of the DNA. By sequencing the entire exome of the few known AnWj-negative individuals, including members of a specific Arab Israeli family and samples preserved since the 1970s, the researchers looked for a common thread—a genetic mutation shared by all who lacked the antigen.
The analysis pointed to the MAL gene. This gene is responsible for producing the Mal protein (Myelin and Lymphocyte protein), a small, highly hydrophobic membrane protein. The study found that individuals with the inherited AnWj-negative phenotype carried homozygous deletions in the MAL gene, meaning they had inherited a defective or missing version of the gene from both parents.
The discovery was unexpected because the Mal protein had not previously been associated with red blood cell antigens. It was known to play a role in stabilizing cell membranes and facilitating the transport of molecules within cells, but its presence on the surface of red blood cells as a blood group marker was a revelation. To confirm their findings, the scientists used advanced gene-editing techniques to introduce the normal MAL gene into laboratory cell lines. These cells immediately began expressing the AnWj antigen. Conversely, when the gene was absent or mutated, the antigen disappeared, proving that the Mal protein is both necessary and sufficient for AnWj expression.
Clinical Implications and Rare Donor Identification
The establishment of the MAL blood group system is not merely an academic milestone; it has immediate practical applications for patient safety. For the first time, blood centers can move beyond reactive testing—identifying antibodies after a patient has already had a reaction—to proactive genetic screening.
"The genetic background of AnWj has been a mystery for more than 50 years," said Louise Tilley, Senior Research Scientist at IBGRL. "It represents a huge achievement to finally establish this new blood group system and be able to offer the best care to rare, but important, patients."
With the genetic sequence identified, laboratories can now design genotyping tests to screen for the MAL mutation. These tests can be integrated into existing blood-typing platforms, allowing for the rapid identification of AnWj-negative patients and the recruitment of compatible donors from the general population. Given that AnWj-negative blood is one of the rarest types in the world, having a genetic "search warrant" is a game-changer for international rare donor registries.
The Complexity of Acquired vs. Inherited Phenotypes
One of the most significant aspects of the research is the distinction between inherited and acquired AnWj-negativity. While the inherited form caused by MAL gene mutations is incredibly rare, a larger number of patients can become "transiently" AnWj-negative.
Medical data indicates that certain hematological disorders and cancers can suppress the expression of the AnWj antigen on red blood cells. In these cases, the patient’s MAL gene is perfectly healthy, but the disease prevents the protein from reaching the cell surface. This nuance is critical for clinicians.
Recent clinical reports from 2026 highlight the stakes. In one instance, a 75-year-old man with severe anemia developed an anti-AnWj autoantibody. Because no compatible AnWj-negative blood was available, doctors had to perform an unmatched transfusion. Genomic testing confirmed his MAL gene was normal, suggesting his condition was acquired. In another complex case involving a patient with B-cell lymphoma, clinicians utilized sutimlimab—a drug designed to inhibit the immune system’s complement pathway—to mitigate the destruction of red blood cells following an incompatible transfusion. These cases emphasize that understanding the molecular basis of the MAL system allows for more tailored, precise interventions in emergency hematology.
A Growing Map of Human Biology
The ratification of MAL as a blood group system comes at a time of rapid expansion in the field of transfusion science. The International Society of Blood Transfusion (ISBT) formally listed MAL as ISBT 047 in its 2026 terminology report. It was joined by other recently discovered systems, including ER, CD36, and ATP11C. By September 2026, the discovery of the JAMA system brought the total number of recognized blood group systems to 49.
Each new system represents a new layer of understanding regarding how the human immune system interacts with blood. The designation of a "blood group system" requires rigorous proof that an antigen is linked to a specific gene, a threshold that the MAL research team met through multiple lines of experimental evidence.
"There is so much work that goes into proving that a gene does actually encode a blood group antigen," noted Nicole Thornton, Head of IBGRL Red Cell Reference. "Now genotyping tests can be designed to identify genetically AnWj-negative patients and donors… making these discoveries for the benefit of rare patients around the world."
Chronology of the MAL/AnWj Discovery
- 1972: The AnWj antigen is first discovered after a patient exhibits a mysterious antibody reaction. The genetic source remains unknown.
- 1970s–2010s: Rare cases of AnWj-negative individuals are identified globally, but the scarcity of samples prevents genetic mapping.
- 2015: A key sample is donated by the original 1970s patient, providing vital material for future genomic study.
- 2020–2023: Researchers at NHSBT and the University of Bristol apply whole exome sequencing to samples from an Arab Israeli family and other rare donors.
- 2024: The MAL gene is identified as the source of the AnWj antigen. Gene-editing experiments confirm the Mal protein’s role.
- 2026: The ISBT formally ratifies MAL as the 47th blood group system. Clinical cases involving sutimlimab and anti-AnWj autoantibodies further refine the medical understanding of the system.
Future Outlook for Transfusion Medicine
The resolution of the MAL mystery marks the end of a long scientific journey, but it also signals the beginning of a new era in precision transfusion medicine. As genomic sequencing becomes more accessible and integrated into standard hospital care, the ability to identify rare blood types will move from specialized reference laboratories to the bedside.
For the rare individuals who lack the AnWj antigen, the world has become a slightly safer place. The ability to identify compatible donors across international borders, supported by the genetic certainty provided by the MAL gene discovery, ensures that "the needle in the haystack" can finally be found when a patient’s life is on the line.
As Ash Toye, Professor of Cell Biology at the University of Bristol, concluded: "It’s really exciting we were able to use our ability to manipulate gene expression… to help confirm the identity of the AnWj blood group, which has been an outstanding puzzle for half a century. This development will help identify these rare donors and help patients in the future."
