Part 2: A legacy of leadership, celebrating 50 years of discovery with Dr. Donald R. Branch

In this second installment of our series celebrating career milestones in transfusion science, we turn the spotlight to Dr. Donald R. Branch, senior scientist at Canadian Blood Services and Professor at the University of Toronto. With over 200 published papers, numerous prestigious awards, and a research career spanning five decades, Dr. Branch has shaped the fields of transfusion medicine and transplantation through groundbreaking research, mentorship, and innovation.

We invited him to reflect on his proudest achievements, the evolution of the field, and his advice for the next generation of researchers. His insights offer a glimpse into a career defined by curiosity, perseverance, and leadership.

Dr. Donald (Don) R. Branch

Canadian Blood Services senior scientist who celebrated 40 years of service on December 5, 2025.

Looking back over your 50-year career, what research contribution are you most proud of and why?

I have many contributions for which I am proud and grateful, in several different disciplines: transfusion medicine, virology (including HIV, hepatitis B, Ebola, coronavirus), signal transduction and cancer. However, for me to have real pride in what I’ve accomplished, others in the scientific world must acknowledge my work as seminal. Unfortunately, although I am proud of my work on HIV pathogenesis, Ebola and signal transduction, I will only describe my proudest contributions to transfusion medicine which have been recognized worldwide.

1. My discovery of mixed hematopoietic chimerism in bone marrow transplantation.

This was the first time that, due to my work, it was revealed that in marrow ablative bone marrow transplantation, engraftment of donor bone marrow could not be confirmed by simply monitoring the return of hematopoietic cells. In fact, my discovery showed that the host’s cells (the recipient of the bone marrow transplantation) often came back showing both donor and host hematopoietic cells in the engraftment. The return of endogenous blood cells, mixed with the transplanted cells, resulted in systemic tolerance and a negative effect on graft-vs-host disease in the transplanted patients. We suggested that trying to achieve mixed hematopoietic chimerism could alleviate rejection of transplants, bone marrow or solid organ. 

This finding has led to other transplants trying to obtain a “mixed” cell status to create tolerance to graft rejection. If one checks the PubMed database, there are more than 1500 publications that relate to my original discovery. In one of the latest publications in 2025, the authors say, “Mixed hematopoietic chimerism after allogeneic hematopoietic cell transplantation (HCT) promotes tolerance of transplanted donor-matched solid organs, corrects autoimmunity, and could transform therapeutic strategies for autoimmune type 1 diabetes.” That my original discovery led to this statement after 40+ years makes me very proud.

2. My invention of a reagent that has multiple applications in transfusion medicine.

The reagent, which I named ZZAP, was shown to remove antibody that was coating patient red blood cells (RBCs) in conditions called autoimmune hemolytic anemias. Removal of the coating antibody resulted in some RBC antigens able to be determined, but more importantly, it allowed for the autoantibody to be removed from the patient’s serum so that potentially clinically significant alloantibodies, that could cause hemolytic transfusion reactions when donor blood was transfused, could be identified; thus, the safest blood could be transfused.

My invention of this reagent was translated by a commercial company into a reagent called Warm Autoantibody Removal Medium (WARM), and blood banks and transfusion services throughout the world now use this medium to remove autoantibodies in the investigation of patients with direct antiglobulin test (DAT) positive autoimmune hemolytic anemias, to provide the safest donor blood for transfusion. Indeed, my invention has likely minimized morbidity (and perhaps mortality) in many hundreds of patients.  For this invention, I was awarded the Dale A. Smith Memorial Award by the Association for the Advancement of Blood and Biotherapeutics in 2022.

3. My use of DTT which led to my discovery that the Kell blood group system was not a carbohydrate antigen system like ABO, but instead was a protein antigen.

I found that ZZAP treatment of RBCs resulted in the denaturation of all Kell blood group system antigens. Because ZZAP contained a proteolytic enzyme and a disulfide bond-breaking agent, and we already knew that proteolytic enzymes do not denature Kell antigens, I investigated whether the disulfide bond-breaking component, called dithiothreitol (DTT), was doing this. In fact, I showed that DTT could denature all Kell blood group antigens in a dose-dependent manner, allowing for me to not only prove that the Kell blood group antigens were proteins, but that the system contained multiple disulfide bonded antigens. 

Years after my claim, the Kell blood group gene was cloned, and my early work was confirmed. The person who cloned the Kell blood group gene told me that my paper was “a seminal paper” that helped him with his work as he was searching for a gene that would translate into multiple disulfide bonding. In addition to my elucidation of the Kell protein structure, I also advocated for the use of DTT in routine antibody investigations. DTT is now standard use in blood banks and transfusion services in their investigations of RBC alloantibodies. For this work, I received the Morten Grove-Rasmussen Memorial Award in 2003, the Tibor Greenwalt Memorial Award and Lectureship in 2019, and the Sally Frank Memorial Award and Lectureship from the Association for the Advancement of Blood and Biotherapeutics in 2014.

4. The MMA assay.

I was one of the pioneers of the so-called monocyte monolayer assay (MMA). The MMA was developed as a means of predicting transfusion outcomes in incompatible transfusions. I have been using and advocating for the use of this assay for over 40 years to aid transfusionists in understanding the reason for transfusion reactions and whether certain RBC alloantibodies would be dangerous or clinically insignificant if donor blood that had the corresponding antigen was transfused. 

This assay is most useful in patients who have an antibody that is reactive with >95% of all donor bloods to determine if the specific antibody can be ignored so that rare and difficult to obtain blood that would lack the antigen doesn’t have to be used. Though it has been more than 40 years since I first described my assay, I am still using it in my laboratory to help in making decisions about transfusion, and I have assisted many other blood bank labs in setting up my assay in their institution, such as Héma-Québec and Canadian Blood Services in Edmonton.

How has the field of transfusion and transplantation medicine evolved during your time, and what changes have most surprised or inspired you?

Early in the 1970s, I was hired to build a transfusion service from the ground up in the wine country of California. At the time, transfusion medicine considered all antibodies as potentially clinically significant, this included antibodies only reactive at room temperature, so testing for these antibodies was being routinely performed by transfusion laboratories. 

When I set up my transfusion service, one thing I did immediately, based on the literature and discussions, was to drop any room temperature testing and focus my compatibility testing only on warm reactive antibodies. This is now the norm. Eluates – liquids that carry substances rinsed from a material, were done with ether and due to its flammability and possibility of explosion, all ether containers needed to be stored in a separate building from the hospital. When we needed to make an eluate, we had to go to the shed yards away from the hospital, open the container and transfer some of the ether into another container and bring it back to the lab to use it. It was a very scary situation, as opening the top of the ether container was when it was most possible for an explosion. I made it through those days and decided a new elution method was needed. I described a new method which encouraged others to look for new methods and finally a great method was developed called “acid elution” which is the method of choice today having no adverse potential. Methods for the detection of potentially clinically significant alloantibodies has greatly evolved over my 50 years. When I started, detection of antibodies was using RBCs suspended in normal saline or saline with some added albumin. 

When I set up my lab in California, I switched immediately to using a “new” method called low-ionic strength saline (LISS). This method was far superior to saline alone or saline/albumin, in detection of antibodies and allowing much shorter incubation times. I was the first transfusion service in the world to drop the room temperature test and use LISS routinely for compatibility testing. This resulted in an article published in Medical Laboratory Observer claiming my transfusion services should be the model for the world. Since LISS, the evolution continued with the development of gel technology and solid-phase antibody detection. LISS is still used but not as often.

Fifty years ago, antibody detection required serum and use of antihuman globulin sera (AHG) that contained both anti-immunoglobulin (anti-IgG) and anti-complement. Now, plasma and only anti-IgG are generally used. Of course, transplantation of hematopoietic stem cells and solid organs has changed immensely over the past 50 years and many other interesting things have happened, too. 

When I started, there were no computers, no cell phones, no Microsoft Word. Manuscripts had to be typed out using electric or manual typewriters, changes in manuscripts required white out and re-typing. There was no Google or PubMed. You had to go to conferences to learn about new stuff. Other evolutions included induced pluripotent stem cells (iPSCs), recombinant proteins and monoclonal antibodies, freeze dried blood products, CAR-T and -NK cells, viral inactivation technology, etc. Therapeutics have also changed over the years as one might imagine immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) treatment used to be steroids, then intravenous immunoglobulin (IVIG) was discovered, and it surprises me how well IVIG works in so many different diseases. I was hoping to be most surprised by successful propagation of RBCs and/or platelets in vitro for transfusion but still waiting for that, maybe within the next 10 years.

What advice would you offer to emerging researchers who hope to make a lasting impact in this field?

The best advice I can offer to emerging researchers is to have passion for science in general and your chosen field in particular. Also, they will need perseverance in maintaining new ideas/hypotheses as these are often met with resistance (e.g., H.pylori causes ulcers). Don’t be a linear thinker, think outside of the box and have fun doing that. 

A career in science not only requires a strong motivation and an ability to take criticism, but it also often involves a lot of rejection. I often say that in a scientific field where you need to write grants, papers and give presentations, where you get reviews, is that you need to be somewhat of a masochist as there will be a lot of negative stuff and you need a strong constitution to take the criticism, learn from it, and move on. 

Also, you need to remember that serendipity is your friend. Don’t be so focused on one question that something important is missed. Science is a pathway that may have many different alternative pathways and, unlike in Lewis Carroll’s book where Alice asks the cheshire cat which pathway to take, in science the pathways do not all lead to the same place. Have fun!

What keeps you curious and motivated after five decades in science?

What doesn’t? Science and especially biological science provide a gold mine of questions and explorations. Questions translate into hypotheses and hypotheses can be tested. There are so many questions, so many hypotheses, so much still to do. Also, having different trainees, year after year, undergraduate and graduate students, interns, etc. Kids around 20-25 years old keep you young and alert and motivates one to make sure they are well trained and can survive in the real world of scientific discovery.

As we celebrate Dr. Donald R. Branch’s remarkable 50 year career in transfusion medicine, we reflect on a legacy defined by scientific breakthroughs, fearless innovation, and a deep commitment to mentorship. From pioneering techniques that reshaped clinical practice to inspiring the next generation of researchers with his curiosity and resilience, Dr. Branch’s contributions continue to shape the field and remind us that progress is driven not only by knowledge, but by passion, perseverance, and the courage to challenge convention.

Canadian Blood Services – Driving world-class innovation 

Through discovery, development and applied research, Canadian Blood Services drives world-class innovation in blood transfusion, cellular therapy and transplantation—bringing clarity and insight to an increasingly complex healthcare future. Our dedicated research team and extended network of partners engage in exploratory and applied research to create new knowledge, inform and enhance best practices, contribute to the development of new services and technologies, and build capacity through training and collaboration. Find out more about our research impact.  

The opinions reflected in this post are those of the author and do not necessarily reflect the opinions of Canadian Blood Services nor do they reflect the views of Health Canada or any other funding agency.