The Aussie native originally thought of becoming an astrophysicist. Now, he’s exploring the intricate universe of protein structures.
CRISPR regularly graces health and medicine headlines, with no sign of stopping. Within the sprawling field, University of Rochester professor and researcher Mitch O’Connell is creating a niche by zeroing in on CRISPR-Cas13. His goal? To better understand prokaryotic antiviral immunity and RNA-mediated gene regulation, and to inform the development of RNA detection tools that could improve clinical diagnostics. The assistant professor of biochemistry and biophysics recently published two back-to-back Cas13-related papers in Nucleic Acids Research, and in a 2023 Science paper found that this same Cas13 protein partners with a unique membrane protein to stop viral infection.
O’Connell joined the University’s Center for RNA Biology in 2017. Get to know him better as he shares his professional and personal path to Rochester.
WHAT’S UNEXPECTED ABOUT YOUR TWO NEWEST PAPERS?
O’Connell: We went in trying to understand allostery—how something that happens at one site in a protein (say, a drug binding) affects what happens at a different, distant site in the same protein. We identified a central communications hub and discovered that single amino acid substitutions (in what is a huge protein) altered the transmission of information across the protein. We were shocked that such a simple change made a difference and were able to use this strategy to create new variants of Cas13 that are more sequence-specific with respect to RNA recognition, and show these can improve our ability to discriminate between closely related SARS-CoV-2 strains using a CRISPR-based diagnostic test.
How’d you get into the CRISPR field?
O’Connell: I’m originally from Australia and got my PhD in Sydney, but wanted to do a postdoc in the US. I contacted a bunch of people, including Jennifer Doudna, to get interviews. I didn’t hear back, so I emailed Jennifer again and she asked me to visit her at Berkeley. This was back in 2012, and a week after our correspondence she published the Science study on CRISPR-Cas9 that won her the 2020 Nobel Prize. I guess it was serendipitous that she replied to my email and I was able to join her lab; it was a really inspiring and invigorating time to be there.
Outside of your own, what areas of research do you find most interesting?
O’Connell: Many things! I loved learning about astrophysics and the universe as a kid and went to college with the hopes of becoming an astrophysicist. However, in my first year, I fell in love with protein structure and function and quickly decided that’s the path I wanted to take.
In terms of recent research, I’ve been fascinated with how we have greater than 1,000 different odorant receptor genes in our genome but each of our approximately 10 million olfactory neurons decides to randomly select and express just one gene from this gene family. How this regulation is thought to occur is fascinating and still a bit of a mystery, although scientists have made some exciting progress recently.
What’s your favorite thing about Rochester?
O’Connell: How easy it is to live and work here, thanks to the quick commute and affordable housing. In terms of the University, I think our collaborative nature, collegiality, and support from the institution stand out as our biggest strengths. As do all of our undergraduate and graduate students—they are excellent.
When you aren’t in your office or lab, where can we find you?
O’Connell: My two-and-a-half year old is obsessed with ice hockey, so I’m usually taking him to skating lessons. I’m also a big music head; I love seeing local bands in the area, or traveling to shows in Buffalo or Syracuse. I have a pretty extensive record collection, so I spend time buying and selling. I like most kinds of music, but have a particular penchant for anything that is dark, mysterious, and noisy.
