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UK Scientists Identify New Blood Type and Crack 50-Year-Old Mystery

Findings could lead to new clinical laboratory tests to screen for individuals with increased risk of blood transfusion complications

Pathologists and clinical laboratory scientists who understand the complexities of blood typing from one human to another will be interested to learn that a 50 year-old mystery has brought about an exciting new discovery—a new human blood group.

British and Israeli scientists led by the UK’s NHS Blood and Transplant (NHSBT) and the University of Bristol discovered the meaning behind a missing protein molecule found in a pregnant woman five decades ago. This anomaly has now been given its own blood group identification called MAL, according to a University of Bristol new release.

“Some people can lack this blood group due to the effect of illness, but the rare inherited form of the AnWj-negative phenotype has only been found in a handful of individuals—though due to this discovery it will now be easier to find others in the future,” the news release notes.

This is important because receiving mismatched blood can be fatal.

“AnWj is a high-prevalence red blood cell (RBC) antigen in the ISBT 901 series. Only nine reports of anti-AnWj have been published since it was first documented in 1972,” according to a 2012 article published by the American Association of Blood Banks, now known as the Association for the Advancement of Blood and Biotherapies (AABB).

For even the small proportion of the population with this new blood group, diagnosing its presence can have a major impact while preventing unwanted harm.

“The work was difficult because the genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified wasn’t an obvious candidate and little is known about Mal protein in red cells,” said Louise Tilley, PhD, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release.

The researchers published their findings in Blood, a journal of the American Society of Hematology, titled, “Deletions in the MAL Gene Result in Loss of Mal Protein, Defining the Rare Inherited AnWj-Negative Blood Group Phenotype.”

“The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career,” said Louise Tilley, PhD (above), Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release. “It represents a huge achievement, and the culmination of a long term effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients,” she added. Clinical laboratory scientists involved in blood banking will want to keep updated as further research into this new blood group is published. (Photo copyright: NHS Blood and Transplant.)

Unraveling the Mystery

In 1972, scientists were stumped by a pregnant woman with a blood sample that was “mysteriously missing a surface molecule found on all other known red blood cells at the time,” Science Alert reported. The AnWj antigen that was missing in that patient’s blood is present in 99.9% of human blood samples.

“Researchers found that the AnWj antigen is carried on the Mal protein. While illness can cause some people to lose the AnWj antigen, inherited cases of the AnWj-negative phenotype are extremely rare. Using whole exome sequencing on five genetically AnWj-negative individuals, researchers confirmed that, in these cases, the participants lacked the antigen due to homozygous deletions in the MAL gene,” an AABB news release stated.

The researchers named the group with the missing antigen the MAL blood group (short for Myelin and Lymphocyte Protein) which is where the antigen resides.

Genetic sequencing enabled the scientists to locate the gene when they “inserted the normal MAL gene into blood cells that were AnWj-negative. This effectively delivered the AnWj antigen to those cells,” Science Alert noted.

Mutated MAL genes result in the AnWj-negative blood type. The team discovered three patients with the blood type and no mutation, “Suggesting that sometimes blood disorders can also cause the antigen to be suppressed,” Science Alert added. The researchers also discovered that AnWj isn’t present in newborns but arrives sometime after they are born.

“Interestingly, all the AnWj-negative patients included in the study shared the same mutation. However, no other cell abnormalities or diseases were found to be associated with this mutation,” Science Alert said.

The discovery that “the Mal protein is responsible for binding AnWj antibodies” could lead to new clinical laboratory tests to screen for patients at risk from blood transfusions, AABB noted in its news release.

Facing the Challenge

Scientists had to overcome many challenges to uncover the details of this blood type. The complexity of the protein further hindered their efforts.

“MAL is a very small protein with some interesting properties which made it difficult to identify, and this meant we needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system,” said Tim Satchwell, PhD, senior lecturer and cell biologist at the University of the West of England, in the University of Bristol news release.

“Resolving the genetic basis for AnWj has been one of our most challenging projects,” Nicole Thornton, head of IBGRL Red Cell Reference at NHSBT told the AABB. “There is so much work that goes into proving that a gene does actually encode a blood group antigen, but it is what we are passionate about, making these discoveries for the benefit of rare patients around the world.”

It’s hard to pinpoint how many individuals will benefit by testing for the blood group, Tilley told the BBC. Nevertheless, “the NHSBT is the last resort for about 400 patients across the world each year,” the BBC reported. 

While more research needs to be done, the initial discovery is promising and may lead to new clinical laboratory tests to identify individuals who could be severely harmed should they receive the wrong blood type during a transfusion.                    

—Kristin Althea O’Connor

Related Information:

Deletions in the MAL Gene Result in Loss of Mal Protein, Defining the Rare Inherited AnWj-Negative Blood Group Phenotype

British Researchers Discover New Blood Group

NHS Blood and Transplant-Led Team Discovers New Blood Group System MAL

Researchers Discover New Blood Group System—MAL

New Blood Group Solves Half a Century of Mystery

Scientists Crack a 50-Year Mystery to Discover a New Set of Blood Groups

The Discovery of the MAL Blood Group: A Breakthrough in Understanding Rare Blood Types

Anti-AnWj Causing Acute Hemolytic Transfusion Reactions in a Patient with Aplastic Anemia

Scientists Identify New Blood Group after a 50 Year Mystery

Scientists Find New Blood Group after 50-Year Mystery

Cambridge University Researchers Develop and Administer Lab-developed Red Blood Cells in Clinical Study with Promising Results for the Blood Supply

Sickle cell patients and others who need long-term blood transfusions provided by clinical laboratories and others would benefit most from successfully lab-grown blood

Administering lab-developed red blood cells in humans in a clinical study conducted in the United Kingdom (UK) is being hailed as a significant step forward in efforts to supplement the supply of whole blood through the development of synthetic blood products. Of interest to those clinical laboratory managers overseeing hospital blood banking services, researchers were able to create this new blood product from normal blood pints collected from donors.  

What caused this clinical study to gain wider attention is the fact that previous attempts to create synthetic whole blood products have proved to be unsuccessful. For that reason, this new research has raised hopes that lab-grown blood may be just around the corner.

The initiative, known as RESTORE, is a joint research project conducted by scientists from the UK’s:

According to the researchers, it is the first such clinical trial performed in the world. Partial funding for this clinical study was provided by an NIHR grant, according to an NHS press release.

Most hospital laboratories also manage a blood bank. Thus, this breakthrough will be of interest to many clinical laboratory managers and blood bankers who are concerned about the shortage of blood products. Plus, blood products are quite expensive. This research could develop solutions that both ease the tight supply of blood and lower the cost of these critical products while improving patient care.

Neil O'Brien

“This research, backed by government investment, represents a breakthrough for patients and means treatment could be transformed for those with diseases including sickle cell,” said Neil O’Brien (above), Minister of State for Health, in an NHS press release. “Once again this shows the UK is leading the world when it comes to scientific innovation and collaboration while delivering high quality care to those who need it the most,” he added. If the lab-grown products prove clinically viable, medical laboratories in the UK may soon suffer less from a shortage of available blood. (Photo copyright: UK Parliament.)

Manufacturing Blood from Stem Cells

“This world-leading research lays the groundwork for the manufacture of red blood cells that can safely be used to transfuse people with disorders like sickle cell,” hematologist Farrukh Shah, MD, Medical Director Transfusion, NHS Blood and Transplant, told BBC News. “The need for normal blood donations to provide the vast majority of blood will remain. But the potential for this work to benefit hard-to-transfuse patients is very significant.”

The process of manufacturing blood cells starts with a normal donation of a pint of blood. The researchers then use magnetic beads to single out flexible stem cells that can become red blood cells. Those flexible stem cells are grown in large quantities in the lab and then guided to transform into red blood cells.

“This challenging and exciting trial is a huge stepping stone for manufacturing blood from stem cells,” said Ashley Toye, PhD, Professor of Cell Biology at the University of Bristol in the NHS press release. “This is the first-time lab grown blood from an allogeneic donor has been transfused and we are excited to see how well the cells perform at the end of the clinical trial.”

The process to create the lab-grown blood cells takes about three weeks, and a pool of approximately half a million stem cells can result in 50 billion red blood cells. These cells are then clarified further to reap about 15 billion red blood cells that are at the optimum level to transplant into a human patient.

“Some blood groups are extremely rare, to the point that only 10 people in a country can donate blood,” Toye told BBC News. “We want to make as much blood as possible in the future, so the vision in my head is a room full of machines producing it continually from a normal blood donation.”

Transforming Care for Patients Who Need Long-term Blood Transfusions

To date, only two patients have taken part in the clinical trial. Next, the researchers plan to perform two mini transfusions on 10 volunteers at least four months apart. One transfusion will contain traditional donated red blood cells and the other will consist of the lab-grown cells. This experiment will show which blood cells last longer in the body. The findings could ultimately allow a patient to receive fewer transfusions and prevent iron overload, which can be a side effect of blood transfusions.

“We hope our lab-grown red blood cells will last longer than those that come from blood donors,” said Cédric Ghevaert, MD, Senior Lecturer in Transfusion Medicine at the University of Cambridge, in the NHS press release. “If our trial—the first such in the world—is successful, it will mean that patients who currently require regular long-term blood transfusions will need fewer transfusions in the future, helping transform their care.”

More research and clinical trials will be necessary to validate the efficacy and safety of these lab-grown blood products. However, such a breakthrough could potentially revolutionize treatments for patients with blood disorders, complex transfusion needs, and rare blood types, as well as reduce healthcare costs and curb blood shortages.

At the same time, this technology would also contribute to expanding the supply of useful blood products, a development that would be welcomed by those pathologists and clinical laboratory professionals overseeing the blood banks in their respective hospitals and integrated delivery networks (IDNs).   

JP Schlingman

Related Information:

First Ever Clinical Trial of Laboratory Grown Red Blood Cells Being Transfused into Another Person

Lab-grown Blood Given to People in World-first Clinical Trial

Lab-grown Red Blood Cells Transfused into People in First Trial—NHS

Laboratory-Grown Blood Has Been Put into People in a First Clinical Trial

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