Hi Michael, it is great to talk to you today! You have been involved with D2R’s training activities for a couple of years as a D2R Doctoral Scholar in Prof. Masad Damha’s lab in the Department of Chemistry. Many people I have spoken to in this series discovered RNA therapeutics while in grad school, but it sounds like you had a very specific goal to work in this field while in undergrad?
Yes, definitely. I did my Bachelor’s in Medicinal Chemistry, and I always knew I was going to do a PhD. In 2019 I came across a documentary on Netflix called Unnatural Selection about gene editing and CRISPR and I just fell in love with it; I enjoyed the balancing of the power of science with the ethical debate around the technologies. So, when pursuing grad school, I tried to find a research group that had published on the chemistry side of CRISPR.
And that’s what led you to Prof. Damha’s group?
Yes. During my Bachelor’s at Trinity College in Dublin, I did an exchange at McGill. When I was looking at the CRISPR literature, a paper with Prof. Damha popped up, so I reached out by email. And then I reached out twice more. Eventually, since I was at McGill at the time, a guy who I was playing intramural Ultimate Frisbee with who was in Prof. Damha’s group, James, helped set up a first meeting. I feel that graduate studies are a gamble on the field itself as much as they are a gamble on your supervisor or the university you're going to; I am very happy with the area of research I chose to pursue.
Other than your exchange at McGill, did you have other research experience from your Bachelor’s?
Definitely not, no. I see undergrads here who are very driven to do research, but in Ireland that’s not the case at all. You use your summers to travel or work and save up, but there are not significant opportunities to get funding to join a lab for the summer. For your undergraduate thesis, you take a full semester to fully dedicate to a project. I wanted to do this semester abroad and that’s what led me to McGill and Prof. Scott Bohle’s group in Chemistry. Despite my lack of research experience at the start of my PhD, I have learned that the reality is that there’s always going to be a learning curve, no matter what lab you join or the experience you have.
I know you are working on CRISPR-related research but what specifically is your project focused on?
The concept of CRISPR, when you break it down, is surprisingly simple and only has two components. There is a Cas enzyme, which acts as a pair of scissors that allow you to edit DNA. And then you have a CRISPR RNA, which acts as a guide or the hands that guide the scissors. So, by changing the sequence of the CRISPR RNA, you can tell where in the DNA to bind, and then the Cas enzyme cuts it. My work specifically is focused on chemically modifying the CRISPR RNA to improve their therapeutic potential in vivo.
Are these modifications needed because of RNA’s high susceptibility to degradation?
Yes, exactly. There are many strategies being developed to modify RNAs for increased stability, such as the N1-methylpseudouridine used in mRNA vaccines. I am trying to do that for CRISPR RNAs through using bases with modified sugars, such as replacing hydroxyl groups with fluorine, while still ensuring that the function as a guide RNA is retained. That’s the real challenge – to be able to synthesize an RNA strand to still be recognized by the Cas enzyme, but to not be recognized by other enzymes, like nucleases, which will break it down. And what is great with this project, is thanks to D2R’s support, we are collaborating with Eli Lilly who are taking our best designs and testing them in vivo to see impact on stability and potentially improved potency.
What methods do you typically use day-to-day in the lab?
The vast majority of my work is using solid-phase synthesis to generate RNAs with different modification patterns. We then use HPLC to purify the strands and other biophysical characterization steps to determine how stable these sequences are. And now we are transitioning to doing some of the cell work ourselves as well.
You already spoke about the Eli Lilly collaboration, but how else have you been impacted by being part of the D2R community?
It’s very easy for researchers who are working on similar problems in the nucleic acid space to be separated, to be working in silos. But if you don’t take advantage of all the knowledge, equipment, and resources around you, your research will be slower and not as impactful. The real power of what D2R is doing is bringing together researchers with overlapping interests from across different disciplines. Since I started being involved with D2R, I now have a much better idea of what other research is going on and who I can reach out to if I need advice, guidance, or collaboration on a specific project.
In addition to your research, you are also a Venture Manager at Front Row Ventures and, in this role, you collaborated with D2R on a trainee-founder event earlier this year. Why are you interested in being involved in research commercialization?
I have always had a passion for startups and commercializing research. The research that I am most interested in often borders academia and industry and I love being able to sell and think about the applications. This interest led me to join the Quebec Scientific Entrepreneurship Program a couple of years ago and this was a great introduction to entrepreneurship as a graduate researcher. And through this experience, I met another grad student at McGill who was involved with Front Row. Despite wanting to stay in academia long term, I wanted to get involved to support student founders and to gain the knowledge to one day be able to commercialize my future research projects or spin off a company. Last year I was an Investment Associate where I was helping decide who to invest in, but now I’ve moved to the Portfolio Management team which is focused on supporting the companies we invest in to help them grow.
Despite this interest in commercialization, you want to stay in academia. Why?
I know there are many challenges to staying in academia, but in its purest form, it is a career where you get to pursue your own ideas. The freedom to do that continues to motivate me. And I also really enjoy teaching. The combination of both being able to do research and teach is a career that I know will be fulfilling for me.
Is there anything that you would like the D2R community to know about you that we haven’t touched on?
I really enjoy any kind of activity where I get to know people, be it playing intramural frisbee or a simple chance to talk outside of an academic setting and form real relationships with people. One of the things that has helped me in academia is enjoying the people you get to meet and not just the science.
This conversation with D2R Training Program Officer, Anthony Van Kessel, has been edited for length and clarity.
