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Piecing together antibodies

Institute Scholar Christopher Barnes on his path to ChEM-H, antibody jigsaw puzzles, and the importance of mentorship.


Christopher O. Barnes
Christopher Barnes. Image credit: Matt Harbicht/HHMI

Stanford ChEM-H Institute Scholar Christopher Barnes is a structural biologist who studies the three-dimensional shapes of biomolecules that are critical for vaccine development: virus-neutralizing antibodies and the proteins that stimulate their production, called antigens.  Barnes, who is also an assistant professor of biology in the School of Humanities and Sciences, talks about his path to ChEM-H, putting together antibody-antigen jigsaw puzzles, and his drive to be a supportive mentor.

Did you always know that you wanted to be a scientist?

Growing up, I was fascinated by the world around me and in understanding just how things work. I was one of those kids who took apart things, always trying to figure out what items looked like on the inside. Back when I was eight years old, one of my favorite gifts was this little light microscope, which gave me my first insight into the microscopic world that drives everyday life.

As an undergrad interested in science, I went to UNC Chapel Hill with the intention of becoming a medical doctor, having no experience or understanding of what it meant to become a PhD scientist. I think this is very true for many students, especially in the African American community, where the term “doctor” usually refers to an MD, not a PhD scientist. I had no idea that becoming a professor who leads a research group was even a possibility.

I would not be here today without my first academic mentor, Gary Pielak. Gary took a chance on me and gave me an opportunity that many others would not. I was double-majoring while also playing on the football team as a wide receiver, and my grades suffered. Gary changed my view about the possibility of a career in research. He instilled in me a belief that I could be the one behind the scenes, the one in the lab tackling the biggest challenges of the day, making discoveries and finding treatments that doctors would use. He saw that I had what it takes to become a scientist. “We just have to show others that you have it,” he said, and my scientific career took off from there.

What did you study in your graduate and postdoctoral labs?

After first obtaining a master’s in chemistry with Gary, where I used NMR spectroscopy to study protein dynamics inside living cells, I entered a PhD program at the University of Pittsburgh. As a graduate student in Guillermo Calero’s lab, I used different structural biology techniques to study transcription, the process a cell uses to make RNA from a DNA template. It was a lot of fun, but I found myself asking the question: what projects would allow me to solve problems in human health?

That brought me to Pamela Bjorkman’s lab at Caltech, where I immediately jumped to studying broadly neutralizing antibodies, antibodies that target many different strains of HIV, and their epitopes, the features on the surface of the virus that these antibodies bind to. These are exactly the kind of antibodies we would want to elicit when designing a vaccine. If we can understand antibody-epitope interactions, then maybe we can design epitope mimics that, when used as a vaccine, would bring about these antibodies.

Your work pivoted in the last year and a half. Can you tell me about it?

Back in January 2020, our collaborators at Rockefeller University reached out and asked if any of us wanted to work on SARS-CoV-2. Having solved several HIV protein structures by that time, I volunteered, eager to work on new viral protein complexes. Little did I know it would blow up from there.

There were a lot of long hours and missed holidays last year trying to understand how antibodies targeted viral spike proteins to prevent virus entry and replication. We actually found two antibodies that are now in clinical trials, one of which has a really unique mechanism for neutralizing the virus. This antibody clamps down on the spike protein, stapling it and preventing access to a receptor on the cell surface, leading to ultrapotent SARS-CoV-2 neutralizing activity.

What goes into solving the structure of a protein? What kinds of tools do you need to use?

To be a good structural biologist, you first have to be a good biochemist, because it doesn’t matter how good your tools are if the sample—the protein, the antibody, the DNA or the RNA—isn’t stable, pure, and in a biologically-relevant conformation. Then you can use a technique, something like X-ray crystallography or cryogenic electron microscopy (cryo-EM) to analyze the sample.

What you get from these tools is what’s called an electron density map, a three-dimensional outline of your whole protein or other molecule, that you can build into. By knowing the sequence of the protein or DNA and understanding the shapes or outlines that bits of those sequences leave behind, you can begin to model how those pieces fit together. And then comes the fun part, when I put on my headphones and go into this zone where I place pieces into the 3D-puzzle until I come out with the full structure.

Once you have that complete picture, you can apply chemistry and physics knowledge to see what interactions present at the interface between, for instance, the antibody and the virus, are important for function.

What are you planning to research in your new lab?

An HIV vaccine is still much needed, so I will be turning my immediate focus back to that. When I was a postdoc, I identified a new epitope on HIV called the “silent face.” This epitope sits adjacent to the site on the virus that recognizes proteins on the host cells. Antibodies that target the silent face work by attaching to that epitope and then, because of their bulkiness, blocking the interactions necessary for viral attachment. We think that this epitope would be more amenable to vaccine design relative to other candidates, and that antibodies engineered to target the silent face will be a useful addition to the repertoire of HIV therapies, so we’re going to start there.  

Thus, there will be a mixture of projects in my lab, from pushing the boundaries of methods and instrumentation, to developing antibody therapeutics and vaccines. This will bring together trainees from all different fields like immunology, engineering, synthetic chemistry, and structural biology.

What drew you to ChEM-H?

The environment at ChEM-H is so unique. Having experts in so many fields under one roof lowers the energy barrier to starting impactful collaborations. I can walk upstairs and talk to Polly Fordyce about microfluidics, or down the hall to talk to Chaitan Khosla about making molecules or to Carolyn Bertozzi to discuss glycobiology, without ever leaving the building. That is unlike the experience you would get in traditional departments. Beyond the collaborative environment, I am also looking forward to having senior experts who can provide knowledge and mentorship during the beginning of my academic career.

If you weren’t a structural biologist, what would you be?

A coach. Getting the best out of your players on the field is the same thing as getting the best out of your trainees in the lab. Helping my trainees reach and then exceed their potential is my number one driving force. I want to provide an environment that is conducive to learning by building relationships based on communication and trust, offering encouragement, and ensuring that their physical, emotional, and mental health is taken care of.

There were times throughout my career where I felt I had to hide parts of myself, times when I was the only Black scientist in my building. I want to make sure that my trainees understand that they have a voice, that I’m listening, and that they belong. Developing these mentoring relationships and helping my students get to moments of discovery are what I am excited about and look forward to the most. Everything else is just icing on the cake.

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