Scientist Spotlight: David Bryson, CRISPR Base Editors, and Beam Therapeutics
“These early papers combined biology and chemistry to solve big problems. It was really inspiring, and it flipped a switch in my brain to this whole unexplored territory that is ripe for study.”
David Bryson’s scientific journey is speckled with moments of fascination just like these—fascination with the chemistry and biology that explain “how the world works and how nature engineers itself to support life.” David is a Senior Scientist at Beam Therapeutics, where he leads a team using groundbreaking CRISPR technology to treat genetic diseases one nucleobase at a time.
David Bryson’s research career began in Dr. Alice Haddy’s lab at UNC Greensboro, where he studied the biochemistry of the photosystem II complex in higher order plants. Given the university’s small undergraduate and master’s program, he was able to get into a research lab early, learn directly from Dr. Haddy, and have ownership of his own research project. “It was at that point when I realized that I could do this as a career,” recalls David as he explains the importance to develop as a scientist and get experience early on.
At the end of college, David wasn’t sure if he wanted to go straight into industry. Instead, he opted to stay at UNC Greensboro to get his master’s in biochemistry. “It was then that I really got inspired by some of the seminal papers of the time. That led me to go into chemical biology,” and ultimately led David to pursue a Ph.D. In Dr. Webster Santos’s lab at Virginia Tech, David focused on the design, synthesis, and screening of unique branched peptide libraries for inhibiting RNA secondary structures that are integral to the HIV life cycle.
“Don’t just rely on whatever your mentors say about academia versus industry. Especially if they’re telling you that there’s only one correct choice: there’s not.”
Leaning toward a career in academia, David decided to continue his academic work as a postdoc in Dr. David Liu’s lab at Harvard. “As I was going through [my postdoc], I realized what my values were, and what type of work makes me happy and what would make a fulfilling career for me,” said David. “About halfway through, I changed my mind and decided I would be happier in an industry setting. I was happiest in front of the bench, solving problems.” David notes the importance of keeping an open mind and soliciting a variety of opinions: “Don’t just rely on whatever your mentors say about academia versus industry. Especially if they’re telling you that there’s only one correct choice: there’s not.”
Base Editing and Beam
In David Liu’s lab, David Bryson completed his postdoctoral research project, performing phage-assisted continuous evolution (PACE) on orthogonal aminoacyl-tRNA synthetase enzymes. His goal was to improve activity and specificity and ultimately to enhance site-specific installation of unnatural amino acids into designer proteins. While at Harvard and later the Broad Institute, David supported the research of his Liu Lab colleague Nicole Gaudelli. This research would go on to become one of the core base-editing technologies that drives Beam. With the science behind Beam developing in the laboratory, David Bryson’s mentor, David Liu, was outside the lab working with current Beam CEO John Evans, other co-founders (Feng Zhang and Keith Joung), and venture capital groups (F-Prime and ARCH Venture Partners) to translate their science into therapy.
Though similar in nature to some other base-editing techniques, Beam uses RNA-guided Cas proteins to bind specifically at a desired locus in the genome. Instead of generating a double-stranded break in the DNA, members of the Liu lab including Nicole and Alexis Komor developed a way to circumvent the need for homology-directed repair entirely. Rather than cut DNA at the locus of interest, Beam uses base-editing domains (deaminases) fused to the Cas protein that chemically transform a single letter of the genome directly to another letter, a process known as single-base conversion. This technology and a similar approach developed in the Zhang lab allows scientists to intentionally perform all possible transition mutations in DNA (C-to-T, G-to-A, and vice versa) as well as A-to-G conversions in RNA. Though some individual diseases may necessitate DNA cutting (and CRISPR nucleases are more advantageous), homology-directed repair is a generally disfavored process. Thus, base editing is the more efficient route if a precise, single base change is all that is required.
Over half of all genetic diseases result from point mutations, most of which—about two thirds—are transition mutations.
Over half of all genetic diseases result from point mutations, most of which—about two thirds—are transition mutations. This editing technology represents an incredible opportunity to directly repair many pathogenic point mutations that drive genetic disease. Bryson explains, “We can install mutations that are clinically known to compensate for the presence of an otherwise pathogenic allele. We can also install stop codons or edit gene regulatory elements to alter gene expression levels and gene splicing. Finally, we can install mutations that alter a gene’s function.”
As Beam co-founders David Liu, Feng Zhang, and Keith Joung built a company, Bryson found himself posed with the exciting opportunity to transition his passion for genome engineering from academia to industry. “Knowing the capabilities of the technology, it was an opportunity that I couldn’t pass up. In addition, this would give me the ability to see how a company is built from the ground up, as I was only the second scientific employee at the company, ” said Bryson. “We didn’t even have a lab space at the time. We were just working out of office space at the venture capital firm.”
Using Benchling in Academia and Industry
From his postdoc in the Liu Lab to his CRISPR work at Beam Therapeutics, Benchling has been there throughout. A fellow postdoc in the Liu Lab, Ben Thuronyi, introduced David to Benchling while they worked on a research project together. Using Benchling to share plasmid maps and notes, David “became familiar with Benchling and understood how powerful it could be.”
When David began his career in industry, he took Benchling with him. According to David, “We knew that Benchling already had all of the kit technologies that we want as a company, whether it’s lab notebook, entry witnessing, or molecular biology tools (like the cloning toolkit that’s incorporated). It checked all of those boxes for us in one product.”
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