Cameron Myhrvold is using ‘spectacular’ new technologies to seek and destroy viral pathogens

Research
Posted on November 24, 2021

Coronavirus and RNA expert Cameron Myhrvold, an assistant professor of molecular biology, straddles the boundary between fundamental research and groundbreaking technological developments. “His spectacular new technologies enable him and his collaborators to solve fundamentally important problems of current biomedical urgency,” said department chair Bonnie Bassler. (Photo by Denise Applewhite, Office of Communications)

 

Myhrvold, a 2011 alumnus, was working as a postdoctoral researcher at the Broad Institute of MIT and Harvard, where he’d been neck-deep in coronavirus research for years before the pandemic brought his work into global significance.

His fascination with viruses started young, he said. His dad, Nathan Myhrvold, a 1983 Ph.D. alumnus from Princeton, had told him about Ebola. “I was really fascinated by viruses — how they could make us so sick, but they’re so simple, with so few genes,” he said. “And I’ve always had an interest in technology, so I think it was inevitable that there would be a technology component to the work that I was doing.”

In January 2021, Myhrvold joined the department of molecular biology as one of Princeton’s newest COVID-19 experts and part of a growing cohort of researchers who straddle the boundary between fundamental research and groundbreaking technological developments.

“Cameron uses genome editing technologies to learn about, monitor, diagnose and destroy viral pathogens with pandemic potential,” said Bonnie Bassler, the Squibb Professor in Molecular Biology and chair of the department. “His spectacular new technologies enable him and his collaborators to solve fundamentally important problems of current biomedical urgency.”

A key weapon in his arsenal is CRISPR-Cas13. If that sounds familiar, it’s probably because in 2020, the Nobel Prize in chemistry went to the scientists behind CRISPR-Cas9, a gene-editing tool that allows precise cuts in DNA. Not as much attention has been paid to CRISPR-Cas13, the tool that Myhrvold uses to detect and cleave RNA (DNA’s lesser-known, single-helix cousin).

Myhrvold and others in the field have identified four technologies based on Cas13 that work in slightly different ways. One works like a scalpel, carefully snipping single RNA strands much like Cas9 cuts DNA. Another variant tags RNA strands with other proteins, including a fluorescent protein that can track RNA. A third one uses a protein called ADAR to edit one “letter” at a time in RNA — a very exciting biomedical development, as so many diseases arise from a single letter “misspelled” in the genetic code.

The fourth variant is more like a ninja star than a pair of scissors; it has an “overdrive” mode that can destroy all nearby strands of a harmful RNA. “I often use the analogy of a paper shredder, because you feed in specific things that you want to get destroyed, and then boom, they get thrashed,” said Myhrvold.

Some simple organisms, including many viruses, encode their blueprints in RNA. This means that Myhrvold’s paper-shredding Cas13 application could become an antiviral treatment for diseases including HIV, the common cold, influenza and COVID-19.

“A Cas13-based antiviral medication is still many years away, but that’s definitely an area we’re excited about,” said Myhrvold. “It’s an exciting approach because, as long as we can deliver it to the right parts of your body to be effective, we can eventually treat any virus that’s infecting that part of your body. Maybe the next outbreak is a flu again, like in 1918, or maybe it’s Ebola or something else entirely different. We want to have versatile tools at our disposal.”

Tapping the versatility of RNA

The secret to the versatility is RNA itself. Unlike DNA, which maintains a constant size and shape, RNA occurs in a variety of lengths and shapes, to perform its many roles to build and maintain your body’s various systems.

DNA, the double-helixed strands holding the blueprint for every tiny component of your body and brain, has captivated geneticists for years. But a growing number of biologists are shifting their focus to single-stranded RNA. If DNA is your body’s blueprint, proteins are the contractors and bricklayers and plumbers bringing the blueprint to life. For decades, RNA was seen as a simple translator, delivering the DNA instructions in a form that the proteins can read. Now, scientists are discovering a host of other jobs RNA can perform, including doing the work of some proteins.

If you look at the last decade or so, we have all these great tools for studying DNA that have been really transformative, including Cas9. I would like to see us say, ‘Let’s do all that again, but at the RNA level,’” said Myhrvold. “And then maybe in a few decades, we’ll be talking about doing this for proteins.”

That technology doesn’t yet exist for proteins, but Myhrvold hints that that may change. His career has been marked by his refusal to be stymied by the limitations of technology; he holds seven patents and has another three pending.

Myhrvold’s lab already has people working on technology development, and he’s looking for students and researchers with wide-ranging expertise to build that out.

“A lot of the best science we do at Princeton is interdisciplinary,” he said. “When I studied here, I was part of the Integrated Science Curriculum, and that has very much shaped how I like to operate as a scientist. I love these interdisciplinary, collaborative projects.”

In addition to his primary placement in the Department of Molecular Biology, Myhrvold is affiliated with the Department of Chemical and Biological Engineering as well as the Department of Chemistry. As he builds his lab, Myhrvold is looking for students and researchers from any — or all — of those departments, as well as quantitative and computational biology, the Lewis-Sigler Institute for Integrative Genomics, even physics, he said.

“Cameron is a great mentor,” said Shruti Sharma (right), a graduate student in Myhrvold’s lab. “You really feel that someone’s there to champion you and help you succeed.”Photo by Denise Applewhite, Office of Communications)