Science Spotlight: Immune Repertoire Sequencing

A Conversation with Miranda Byrne-Steele, Ph.D.

The immune system is a complicated network of processes that protect us from diseases. The adaptive immune system creates a living memory of pathogens you’ve encountered by learning to recognize antigens. Upon infection, antibodies are quickly created to recognize pathogenic antigens for elimination. The adaptability of antibody production is driven by V(D)J recombination in antigen receptors that are uniquely expressed on B cells and T cells.

iRepertoire specializes in immune system investigation with its proprietary adaptome sequencing technology. They provide a snapshot of the functional status of the immune system. iRepertoire enables researchers to amplify all V(D)J sequences in either B cells or T cells and has the only technology available with the ability to profile all seven adaptive immune chain receptors.

We spoke with iRepertoire’s Director of R&D and Operations Management Miranda Byrne-Steele, Ph.D., to discuss how her expertise facilitates the development of iRepertoire’s groundbreaking technology.

Miranda earned her Ph.D. from the University of Alabama, Huntsville, where she studied the structure and function of archaeal DNA replication proteins in extremophiles.

How did you transition from your dissertation work on DNA replication proteins to immunology? 

Miranda Byrne-Steele: I had the good fortune of meeting Dr. Jian Han, MD, Ph.D., [founder and CSO of iRepertoire] about a month before I was to defend my dissertation. He gave a talk at our lab group about the immune system. I already knew that I wanted to do something related to human health next, and here was somebody locally who was examining at a systems biology, big picture view these immune receptors and disease. And I was like “oh, this is what I want to do.” My advisor must have noticed this sparked something in me and invited Dr. Han to my dissertation defense, and I had a job offer two days later. I joined that January in 2010.

How did you come to be Director at iRepertoire, and what are some of your favorite parts of your position?

Miranda: When I first began [at iRepertoire], I was purely doing research and development and it was the most fun I ever had. I was trying to identify antigen specific responses within this immune repertoire sequencing data and developing new methods. We were doing the research and development and having a lot of fun with it. Then I saw that if we were to continue to grow, somebody needed to step in and begin to manage all these projects and make sure they were completed appropriately. I kind of stepped into that role and was officially promoted later. So having the freedom to do the research and see something no one else has ever seen was the most fun I’ve had. As Director, I get to see people use what I developed in their projects. That’s really incredible because I get to see my methods work in a whole different realm, which is a different kind of joy than doing the research myself.

Since you joined iRepertoire almost at its founding, what can you tell us about Dr. Jian Han’s motivation for taking this research to industry?

Miranda: He’s got an entrepreneurial spirit. When he sees a really good idea, he wants to figure out how to translate it into a product and service to share with somebody else. I think that happens a little bit faster in industry than academia. Academic labs are very focused on a single question, whereas he wants the tool that answers all the different questions. So instead of working to answer one question, we’re perfecting a way to view the entire immune repertoire.

Learn more about iRepertoire in this video:

Given the boom in single cell sequencing products and services, how does iRepertoire set itself apart from competitors?

Miranda: Immune repertoire single cell sequencing specifically is still a nascent a field, and we have the founding members of the field. We developed the technology from scratch. We’re not buying off-the-shelf kits and applying it to samples, then returning data. Also, you can’t find the breadth of knowledge and databases we have anywhere else because we’ve accrued and developed that over the last twelve years. We’re also flexible and willing to collaborate. With our collaborators we’re open to doing research and development to get the perfect method for a specific project before running the actual specimens. I think that willingness to find the right method and our deep databases really set us apart.

You recently published an article in Nature Communications on a malaria neutralizing antibody. What drew you to this project?

Miranda: To back up a bit, I did my post-doc at iRepertoire while I was with Hudson Alpha Institute for Biotechnology, and I was searching the immune repertoire data for neutralizing antibodies to the flu. At the time, our datasets consisted of short sequences and no information on which heavy chain matched with which light chain to make a full receptor. And I remember asking “where’s the rest of the receptor?” and we decided to sequence them on a longer platform. So now we have all these long sequences, and I developed a method that allowed us to match heavy and light chains that at the time was arduously done by hand. This led us to develop our single-cell sequencing platform called iPair where we can retrieve the cognitive pairing of the heavy and light chains without pulling down individual antigen specific antibodies by hand.

We happened to have just finished developing iPair when we got a call from Camila Coelho, Ph.D., MBA, who at the time was working with NIAID. She wanted to know the repertoire of 50 antigen specific B cells, and I thought “she needs to do single cell.” It came full circle – she had the method to pull down antigen specific B cells and we had the method to provide the paired sequencing.

You can read the publication here or see the webinar here or blog here.

Sequencing the immune repertoire is still a new space, and iRepertoire seems to focus on two broad areas – immunotherapies and infectious diseases. What kinds of questions are you investigating in these areas?

Miranda: What’s amazing about the immune system is that it touches on every aspect of disease, so there are many different questions we still need to answer. There are a lot of people working on the immune response to immunotherapies. It may be that there’s a specific response to each regimen and maybe there’s a general repertoire as well. It’s a very active area of research because it can change how patients are treated.

We’re also asking whether we can find disease signatures – biomarkers to diagnose different types of disease with just one or two immune repertoire snapshots. And we have information coming about research on COVID and antigen specific responses to the vaccine in addition to ongoing research on flu vaccine responses. We also are moving into the autoimmunity space, primarily rheumatoid arthritis and lupus, so keep an eye out for those publications.

I think that in the future single cell sequencing the immune system can provide insight into the dynamics of the immune repertoire. We won’t just show that an immune response is being induced; we could also show the extent of the response and whether it’s B cell or T cell driven. There are lot of questions we will be able to ask.

A look inside the advanced technology of iRepertoire:

You’ve had incredible experiences in your career: working with a start-up at the very beginning and watching it grow into an industry leader. What do you think helped you most when you were an early career researcher?

Miranda: There’s a quote that I really like and it goes “in the field of observation, chance favors the prepared mind.” That really resonates with me as I was always very studious in areas I was interested in so I had a prepared mind when opportunities arose. So I think that is a really important piece of advice. Another important piece of advice I would give is that if you’re ever asked to give a talk, always say yes. You never know who’s going to be in that room. I can’t tell you how many times having that exposure and being prepared has had a huge impact on my career path.

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