Blood Bonus Episode: What is a Blood group?

Summary

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Blood Podcast Bonus Episode: What Is a Blood Group?

Published March 31, 2025
Host: Dr. Erica Wood (Associate Editor, Blood; Monash University, Melbourne)
Guest: Nicole Thornton (Head, International Blood Group Reference Laboratory, Bristol, UK)

Episode Overview

This bonus episode dives deep into the groundbreaking research published in Blood on the definition and molecular basis of the rare inherited ANWJ negative blood group. Dr. Erica Wood interviews lead author Nicole Thornton, exploring both the challenges of identifying the genetic underpinnings of rare blood groups and the significant clinical implications for transfusion medicine.

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Key Discussion Points & Insights

1. Background and Significance of the Study

• Discovery and Complexity:

  • Nicole Thornton’s team has been working to identify the gene responsible for the ANWJ antigen, a challenge dating back nearly 20 years.
  • The ANWJ antigen was first identified in the early 1970s, but its molecular genetics remained a mystery until this work.
  • This discovery not only solves a longstanding puzzle but opens doors for further hematological research.

  • “ANWJ has been a long standing mystery... The gene responsible for encoding that antigen hasn’t been known until we set to work on it.” — Nicole Thornton [03:13]

• Clinical Relevance:

  • The presence of antibodies against the ANWJ antigen can cause hemolytic transfusion reactions, making safe transfusions difficult for affected patients.
  • The genetic identification of the antigen therefore has immediate clinical importance.

  • “The antibody involved does cause hemolytic transfusion reactions. So we wanted to get an answer to this one, especially because it would have a patient impact.” — Nicole Thornton [03:47]

2. Major Findings of the Paper

• Genetic Basis of ANWJ Negative Blood Group:

  • The research team identified deletions in the MAL gene as the cause of the absence of the ANWJ antigen.
  • They also noted that being ANWJ negative can occur by two distinct mechanisms: true genetic lack (via MAL deletion) and a “suppression effect” where antigen expression is reduced, often in hematologic malignancies.

  • “There is more than one way to be an ANWJ negative individual. There is the genetic way, which we’ve discovered, but there’s also another way and that’s a suppression effect.” — Nicole Thornton [05:16]

• Suppression of Antigen Expression:

  • The suppression type, associated with certain blood cancers, results in reduced or absent antigen expression, complicating diagnosis and treatment:

  • “The suppression type... is generally when a patient has sort of a hematological malignancy. We see now that the ANWJ antigen is reduced or very, very much suppressed.” — Nicole Thornton [07:58]

3. Implications for Research and Medicine

• Impact on Blood Group Genetics and Transfusion Medicine:

  • The newly clarified genetic basis will improve genotyping accuracy, guiding safer transfusion strategies.
  • The work sets a foundation for studying suppression phenomena, with potential implications for cancer biology and therapy:

  • “We know that in this suppression type we see hemolytic transfusion reactions occurring... it means that this molecule has an important role. Why is it suppressed in these situations? Can we maybe exploit that information for targeted therapies in these malignant states?” — Nicole Thornton [08:35]

• Wider Scientific Value:

  • The discovery enables broader investigation into the function of the MAL protein in hematological diseases and potentially other tissues.

  • “We’re describing a molecule that we don’t know a lot about the function of it. And now having a blood group marker may be able to help other areas in hematology also look at what this molecule is doing in certain disease states.” — Nicole Thornton [04:23]

4. Defining a Blood Group & the Rigorous Validation Process

• What Constitutes a Blood Group:
  • Multiple lines of evidence are required to define a blood group, including genetic, serological, and clinical proof.
  • The international working party (International Society of Blood Transfusions) reviews and rigorously challenges each proposal to ensure accuracy.

  • “It goes through a very stringent process when it comes to ratification... we do make sure that we have proven this in several different ways, not just one. Which is the approach we took in this study…” — Nicole Thornton [10:31]

  • “The rule of thumb is they don’t exist until there’s an antibody that defines them... and that was the case for us with ANWJ.” — Nicole Thornton [11:31]

5. On the Function of the MAL Protein

• “The function of it in the red cell is very unknown. But the name itself is myelin and lymphocyte protein, so that’s obviously been known to be important in lymphocytes… we find that a lot of the molecules in red cells, we don’t know the biological function. But what we do know is when we have these natural knockouts... then that tells us a lot.” — Nicole Thornton [12:43]

6. The Power of Collaboration

• The study’s success depended on global collaboration, with patient samples sent from around the world.

• “It takes bringing all of those samples together to be able to study them in the way that we did. And that really does rely on quite an amazing international collaboration.” — Nicole Thornton [06:58]

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Notable Quotes & Memorable Moments

• On Persistence in Science:
  “It did take us quite a while because it’s a really complicated molecule... it takes an awful, awful lot of work to actually get enough evidence to prove a new blood group.” — Nicole Thornton [02:48]

• On Future Blood Group Discoveries:
  “There are some antigens that are still unknown, we don’t know the genetic basis of. But it’s not just the known antigens. We’re going to discover new ones.” — Nicole Thornton [05:54]

• On the Gravity of Blood Group Definition:
  “The consequences of it being wrong and a blood group being ratified incorrectly could mean that then genotyping platforms are going to predict the wrong blood group phenotype.” — Nicole Thornton [10:12]

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Key Timestamps

• 00:25–01:11: Dr. Erica Wood introduces Nicole Thornton and the paper’s background
• 01:11–06:58: Thornton discusses the path to discovering the genetic basis, clinical significance, and the collaborative process
• 07:26–09:17: Discussion on genetic and suppression mechanisms for ANWJ negativity and their implications
• 09:49–12:11: Defining a blood group and the robust validation process
• 12:11–13:48: Exploration of the potential biological function of the MAL protein
• 13:48–14:44: Closing remarks and reflections on the impact of the research

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Conclusion

This episode offers a rare view into the scientific detective work behind defining a blood group, highlighting the rigor, collaboration, and patient impact that drive advances in transfusion medicine. Listeners come away with a deeper appreciation for the complexities of blood group genetics, the vital importance of accurate diagnosis for patient care, and the exciting frontiers still ahead in hematology.

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Transcript

[A]

Welcome to this week's bonus episode of the Blood podcast. Your source for innovative ideas and cutting edge information. In this episode, Associate Editor Dr. Erica Wood discusses deletions in the malgene result in loss of malprotein. Defining the rare inherited NWJ negative blood group with senior author Nicole Thornton.

[B]

I'm Erica Wood. I'm a haematologist at Monash University and Monash Health in Melbourne, Australia. I've been an associate editor at Blood this last couple of years and my particular area of interest and expertise is in transfusion medicine. Dr. Thornton and her colleagues submitted a paper for consideration to the journal and it came to me as the associate editor in that field. Field and then we called upon some of our expert reviewers to evaluate the paper and to give feedback to the authors which was incorporated prior to acceptance and I'm very pleased to see the final result.

[C]

My name's Nicole Thornton and I'm head of the International Blood Group Reference Laboratory in Bristol, uk and our lab gets to investigate some of the most complex immunohematology cases in the world. Very lucky. Our most recent article, which we're really excited about, was accepted by Blood. We first came to study the ANWJ antigen because we come across cases that come through our lab. These, these cases are patient cases where the patient has made an antibody and then it makes it a difficult transfusion situation. Our research is mainly what we try to focus on is things that are clinically significant and we need to find an answer in order to make the treatment possibly better for these patients. And ANWJ has been a long standing mystery. It was discovered in the early 70s, the antigen itself, but the gene responsible for encoding that antigen hasn't been known until we set to work on it. It did take us quite a while because it's a really complicated molecule. So yeah, we had to spend a lot of time on the proof work, which I think a lot of people don't know that it takes an awful, awful lot of work to actually get enough evidence to prove a new blood group. This antigen is one of the last remaining known blood group antigens that the molecular basis isn't known, the genetic basis isn't known, there are very few left. We have worked on others as well, other new blood group systems as well, and this one had really eluded us. We have been working on it for many years and it's not an exaggeration. We first started looking at it around 20 years ago. We obviously went looking at it continuously, but we as we were working on other things, but this one was a particularly difficult one, but it was also one that we knew was very important because the antibody involved does cause hemolytic transfusion reactions. So we wanted to get an answer to this one, especially because it would have a patient impact. Knowing, knowing the answer, knowing what gene was responsible. The primary goal was to share what we had learned with the rest of the transfusion community. And it's also of interest to possibly other areas of medicine because it's. We're describing a molecule that we don't know a lot about the function of it. And now having a blood group marker may be able to help other areas in hematology. Also look at what this molecule is doing in certain disease states. So it's not just about transfusion. It has a much wider application when we make these discoveries. So it can have an impact in other areas as well. The main takeaway is that we now know the gene responsible for the AWJ antigen. And one thing I hope that we addressed and I think we addressed in the article is that there is more than one way to, to be an ANWJ negative individual. There is the genetics, the genetic way, which we've discovered, but there's also another way and that's a suppression effect. And so I think one take home that I hope those in the transfusion field will appreciate is that although we've found the gene responsible, it doesn't answer all the questions about this very complicated blood group. And it does open up the doors for us to be able to study it in much more detailed way now, because we know molecule responsible. So we can look at the other aspect, the suppression aspect as well. The contribution that our article makes to our knowledge base around blood group genetics is significant. We now know that we're adding another gene to the mix when it comes to blood group genes. I think there are more discoveries. We're already working on things that it's going to be exciting, some of the discoveries that we're going to make. There are some antigens that are still unknown, we don't know the genetic basis of. But it's not just the known antigens. We're going to discover new ones. We already know that this is possible, that we've seen some of the newer blood group systems coming through were brand new antigens and brand new blood group systems, not just solving a long standing mystery. So I think we're going to continue to discover new blood groups, new blood group systems, but it will all come down to our patients and the patients that come through the door with antibodies that we have to investigate and go through the whole process of getting to a point where we think this is something new. The powerful tools we have now when it comes to studying the genetics and the genes is what we've seen a bit of a boom for some of the new blood group systems. And I think it's because of the power of the genetic tools that we have now. It's really exciting times for that aspect of blood group discovery. I think one thing that I'd really like to highlight is that this article was a really big collaboration effort. It wasn't just my team, we collaborated with other colleagues. And for us, one of the really important things is to recognize that samples are sent to us from patients that need answers. They have come from different parts of the world and that's what these types of discoveries, that's what it takes. It takes bringing all of those samples together to be able to study them in the way that we did. And that really does rely on quite an amazing international collaboration. We can't do any of these things without that. It's something that we're really proud of that we can do that as well.

[B]

Dr. Sanchez, we all read your article with great interest. Could you expand a little bit perhaps, on the fact that there's a genetic component to this, which you've nicely described. In some people there is a transient or longer suppression of the expression. Can you tell us a bit more about that and what might be its implications?

[C]

Yeah, sure. Because that's like. That was the big complication for us when it came to studying this blood group. So the suppression type is what we call it the suppression type. It's generally when a patient has sort of a haematological malignancy of some sort of. We see now that the ANWJ antigen is reduced or very, very much suppressed. And what's really intriguing about this situation with AWJ is that these individuals can make an alloa. It's an antibody. It appears as an allo antibody, but essentially it should really be an autoantibody because they're not genetically negative. But in this situation, the antibody can be clinically significant. We know that in this suppression type we see hemolytic transfusion reactions occurring. And that's unusual, but it's intriguing as well because to me it means that this molecule has an important role. Why is it suppressed in these situations? Can we maybe exploit that information for targeted therapies in these malignant states? That's the really exciting aspect of it, I think, what it could mean for looking at what the molecule is doing in these situations.

[B]

Yes. For the expression to be both suppressed and then to return, the mechanics of that and the control of that will be very interesting to understand in the future. You've talked about this in the paper and the title speaks to defining the rare inherited ANWJ negative blood group phenotype. What is the definition of a blood group and how is that determined?

[C]

It sounds like such a simple question. What defines a blood group? So as I mentioned before, the work that has to go into providing evidence a gene does actually encode a blood group is quite a significant amount of work. And the reason it is is because that information and the gene that we're proposing, the proof work, has to be undeniable because the consequences of it being wrong and a blood group being ratified incorrectly could mean that then genotyping platforms are going to predict the wrong blood group phenotype. So that's why we go to the ends of the earth to make sure that that evidence is undeniable. And it goes through a very stringent process when it comes to ratification. So there's the working party responsible for doing this and that's the International Society of Blood Transfusions working party on red cell immunogenetics and blood group terminology. It's a long name, but it's an important working party. And we have many experts who are members of this working party. And when we have a proposed new blood group antigen or blood group system, we have to present the evidence to the working party and we can be grilled, have lots of questions. So we, we do make sure that we have proven this in several different ways, not just one, which is what the approach we took in this study, we had proven it in three, essentially three different ways so that it was undeniable. So yeah, for us, a blood group, I guess you could define it as. When it comes to red cell antigens, we basically say the rule of thumb is they don't exist until there's an antibody that defines them. And that's a really important criteria. An allo antibody that defines them. And that was the case for us with anwj. We had patients who had made these antibodies. So the antigen was defined, so the antigen was actually ratified many, many years ago. It was just the genetic basis that was missing. And now we have that answer.

[B]

Can I ask a question about the possible function of this molecule? These blood group antigens aren't there to entertain you and me. Many of them have a biological function, but many of them have taken a long time to be discovered. Is there anything known about the function or possible function of this molecule?

[C]

I think the function of it in the red cell is very unknown. But the name itself is myelin and lymphocyte protein. So that's obviously been known to be important in lymphocytes. I think there are still lots of questions about this molecule. It's not very well known, but it clearly has an important function when it comes to malignant cells and the changes that we see. But I think that's where the work needs to be done, is to really look into the function of it. Probably in other tissues, it's going to be more important to know what the function is. I think in red cells, we find that a lot of the molecules in red cells, we don't know the biological function and the importance of it in the red cell. But what we do know is when we have these natural knockouts, if you like people that are lacking them and they're not sick or there's not a problem, then that tells us a lot. That's why these individuals are very important for when we're studying such molecules.

[B]

Dr. Thornton, thank you for joining us for this podcast. It was a pleasure to accept your article on deletions in the MAL gene resulting in the loss of the protein which defines the rare inherited ANWJ negative blood group phenotype. A lot of work has been done. There's more work to do in the future. For now, I think people will enjoy reading the manuscript, thinking about its implications, and being reminded of how fascinating transfusion medicine is. I think it's a wonderful addition to to the publications in Blood for this year. And I congratulate you, Dr. Tilley, your whole team, and your collaborators on very nice work. And I commend the paper to the readers of Blood. Thank you.

[A]

Thank you for listening to this bonus episode of the Blood podcast. To read these articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.