Dr. Bondy-Denomy went to the University of Waterloo for his undergrad in Biology (Microbiology specialization) and attended the University of Toronto to complete his Ph.D. in Alan Davidson's lab where he focused on the effects of lysogeny and the CRISPR-Cas immune system. In the spring of 2015, he started his lab at UCSF where he is now an Assistant Professor in the Department of Microbiology & Immunology.
Molly: Thanks for taking the time to talk with us today. Could you start by providing a general overview of your lab and the work your group is doing?
Dr. Bondy-Denomy: My lab is in the Department of Microbiology and Immunology at the University of California, San Francisco (UCSF). I started my group here five years ago and currently have about 11 people in the lab. We focus primarily on microbes and bacteria and are trying to understand how they interact with the viruses that infect them.
These viruses are known as bacteriophages and are very common on the planet -- and in your body. Bacteria are constantly being bombarded by viruses and have come up with ways to protect themselves and in turn, viruses have come up with ways to counteract what bacteria do to protect themselves. Much like with viruses that infect us, there is an immune and anti-immune arms race between these two entities. One particular bacterial immune system that people may have heard of is called CRISPR/CAS, which has become a gene-editing tool, but in nature, it’s what bacteria use to protect themselves from phage attacks. Then, in this specific microbial arms race, phages encode proteins called anti-CRISPRs that sort of push back against the bacterial CRISPR system. Our lab is interested in dynamic for two reasons: the potential applications of bacteriophages in the design of therapeutics and the potential for using anti-CRISPR proteins to improve CRISPR as a gene-editing tool.
Molly: You mentioned the study of the immune system to help build better biotherapies. So how exactly does this work translate to biotherapies for genetic or infectious diseases?
Dr. Bondy-Denomy: Sure, I think that there are two separate answers there. For infectious diseases, when a bacterium is the cause of infection, antibiotics have been our go-to resource for a long time. But as those become less effective, people are interested in using these viruses to kill harmful bacteria in our bodies. There have been clinical trials and even compassionate use examples of phage therapy, so anything that we can understand about how they kill bacteria in nature could help design better drugs in the future.
On the genetic disease side, there is a more counterintuitive use case where a protein called an anti-CRISPR that can effectively turn off CRISPR is a useful gene-editing tool. The idea here is that CRISPR will be deployed in your body and be going around cutting DNA to fix mutations, and, at some point, turning that off would be logical to do. This is where an anti-CRISPR protein may be useful to prevent these CRISPR scissors from saying, “Hey, how about we cut over here, how about we got over here?” or at any off-target location. Stopping these off-target events is a big problem a lot of people are working on solving. So that’s just one area we're plugged into, and it’s because people discovered these anti-CRISPR proteins in nature and wondered, “How could this be useful?”
So we assume that there is a novelty, that there's new stuff that we just can't even predict.
Molly: Generally speaking, is this where the field of biotherapies and microbial research is going?
Dr. Bondy-Denomy: The areas of CRISPR gene editing and bacterial phage therapeutics are both active right now. These are the lion’s share of applied areas where our work could help. On the other hand, we have no way to predict where or what we might discover in the future and how that discovery could be useful. That's what excites me most about the basic science; is that we don't necessarily have a clear goal, we have a question about how some part of nature works. For example, just trying to figure out how bacteria and their viruses battle each other led to the discovery of CRISPR only 13 years ago. And you may have heard of restriction enzymes which fuel modern molecular biology, those were discovered in the 60s and 70s because researchers asked the same question: “How do bacteria and viruses battle each other?” So we assume that there is a novelty, that there's new stuff that we just can't even predict.
Jordan: Could you describe your decision to pursue a Ph.D. and go down the road of Academia?
Dr. Bondy-Denomy: Definitely! The decision wasn’t how do I want to spend my life for the next 5 years or 10 years, it was “What do I want to do tomorrow and every day?” Being at Waterloo as a coop student undoubtedly changed my life. The ability to have a position that wasn't in the summer where I'd be competing with everybody meant I was able to get full-time lab jobs at Western and McGill. Even though I wasn't very good at it at the start, just spending 8, 9, or 10 hours in the lab in a day and doing experiments showed me what research was. I enjoyed being able to create things and learn things that nobody else knew at that moment. So although I was a very small piece of a lab project, I got to move something forward, and that appealed to me greatly. I also liked how you could walk around in the lab and talk to other young people, you didn't have to wear nice clothes, you didn't have to fall into some certain pillar of how you're supposed to be, you got to be yourself and it was a fun environment. As far as going to grad school, that was suggested to me by the professors at Waterloo like Dr. Dupont, Dr. Butler, and Dr. Charles. They encouraged me that I could do this and it wasn't solely based on marks. Once I went to grad school I got to do more of bumming around the lab doing a lot of experiments talking to people about ideas and trying to think about where you can carve out a niche for yourself. I came to enjoy that, and I still do that. I don't feel like I have a real job though I work a lot, I don't feel like it's any different than my first undergrad job where I was just hanging around the lab trying to figure out something cool to do.
Jordan: For those students who are interested in figuring out where to do their Ph.D., can you walk us through how you figured out that Toronto is the place to be for you to go?
Dr. Bondy-Denomy: I think it was a combination of being 22 and wanting to live in the city, and it's helpful that Toronto has the best medical research enterprise in the country. For me, it wasn't moving too far away from home and going to a highly regarded graduate program. The day-to-day decision was not that am I going to live in Toronto for the rest of my life, it was just let's go to Toronto.
It's important to make your work and yourself known, and in that sense, it's very entrepreneurial.
Jordan: What does a day look like as you enter into the world of being a professor?
Dr. Bondy-Denomy: In my world, your currency, or what makes you stand out is publications, your network, and the conferences you go to. It's important to make your work and yourself known, and in that sense, it's very entrepreneurial. I'm surprised at how much of a small business I'm running in running a lab. As a grad student, you need to figure out how to promote yourself in a non-arrogant or excessive way. That means you have to publish papers, you have to show that you're doing something to publish those papers, you need to work harder than others, you need to talk to people and engage and think about your ideas. You publish a paper by reading the work of others at talking to people about your work and doing your own experiments. You need to have the credibility to go to a conference and introduce yourself to people and talk about your work confidently and start to build a CV and a reputation for yourself, similar to an entrepreneur. A big part of how you learn how to write research proposals and get funding is to develop your niche and your elevator pitch, and all the stuff that the business world loves to talk about. You've got to communicate and you've got to be productive. Now, I'm helping people in my lab, and that requires those skills to move their projects and careers forward. But it's still the same, we're still trying to think of good ideas, I'm still reading papers, talking to people constantly and that's continuous for the rest of your life in this area.
Molly: What advice would you give to students who are aspiring researchers?
Dr. Bondy-Denomy: Oftentimes when looking for research opportunities people are very focused on the kind of work that a lab does what kind of science they work on. If you can learn and get excited about anything, my advice is to find a good interpersonal fit more than anything. Having a supervisor that you click with and labmates that you enjoy being with is really important because you spend a lot of time together. That feeling of waking up and being excited to go somewhere is really important. There's stuff to discover everywhere and there's so much we don't know. I would rather enter into an area that I'm less familiar with, but in a lab where I can find a friend and have people that want to talk to me about the work. Try to find a lab with a history of supporting young people and producing people who graduate and go on to do something else that's great because you're going to do one thing for your whole career. Get a good research experience, get good mentorship, and you'll carry with you the emotional and mental experience and the learning you've done more so than the nitty-gritty details of the science.
Just as much time as people spend reading papers from a potential lab, they should spend just as much time talking to the people who are currently in that lab or where I left that lab and figuring out what it's like day-to-day. The political and interpersonal interactions are important wherever you are and you don't want to work in a toxic environment. It's important to figure that all out before you jump in. Linkedin and lab websites are great tools to go about finding and contacting students.
Molly: Is there anything else that you would like to highlight from your journey?
Dr. Bondy-Denomy: The first real shift for me was learning about how bacteria make people sick in the third year of my undergrad. I thought that was just the craziest thing and of course, you know that going in, but these little single-celled microbes can do so much damage on the planet yet are also fundamental for the planet's ability to live. The second shift came after the halfway point in grad school when I was working a lot but I hadn't published papers. Then three to four years in we had a bit of a breakthrough and I started to really enjoy it. Switching from the Masters to the PhD program was another key point, I'd be going down the road to maybe be a professor but again I just focused on the day-to-day and I realized that it seemed like an okay thing to do no matter where it took me. I realized I'm developing a lot of skills along the way that is very translatable. For example, I would record myself in lab meetings and listen to myself and hate what I was saying because I just wasn't clear. So I wasn't wasting my time, I was learning how to speak and write and study science. So no matter where it took me it would be okay.
Molly: Thank you for your time!