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Interview with Dr. Andrew Bennet
Professor, Department of Chemistry
Dr. Bennet’s group has a knack for synthesizing carbohydrates and their mimics, and fine-tuning their reactivity in order to understand how bonds are made during catalysis by carbohydrate processing enzymes. Their work has unraveled a variety of exquisite mechanisms via precision techniques, revealed new inhibitors that can affect human diseases, and changed the way people think about the consequences of using substrate analogues versus real transition state mimics.
What early life experiences may have foretold your path into science?
Mathematics was like a first language for me. From a very early age I would follow my mother around the grocery store and at the check-out tell the cashier how much we owed. Mind you, it was all shillings and pence, no decimals. I loved mathematics at school and would do it very fast because then the teachers would give me more math to do – except one teacher who would give me English; I would slow up then. In high school, we started doing science and that's when Chemistry took over.
What was it about chemistry that became more appealing than mathematics?
The majority of chemistry taught in school in England was very mathematical. The patterns of chemistry intrigued me. There is a logic to it such that you can predict what will happen.
What part of your research gives you the most satisfaction?
Sitting down and putting ideas together on paper and then six months later, seeing them begin to work in the lab. The most exciting bit is starting to see results come in from your initial idea. I now find writing grants more interesting than writing papers because you have to sit and think about your new ideas.
What is the overarching goal of your current research program?
One goal is to work out how biological catalysts perform their functions so efficiently, how they take something that is kinetically stable and break it down in milliseconds. How does Nature perform such catalysis? We design compounds that slow this process or stop it completely in order to understand how it works. Using insight gained from this, we can design new inhibitors.
The other major part of my program involves kinetic isotope effects. Using NMR spectroscopy as a tool, we follow individual atoms and examine how bonds are made or broken during catalysis. Once we know how this process works, we have a handle on how we can slow it down or accelerate it.
What are the major projects in your lab right now?
Projects that focus on the development of carbocyclic compounds as inhibitors of certain carbohydrate processing enzymes and studies using kinetic isotope effects to probe the mechanics of enzyme function. For example, in collaboration with my departmental colleagues David Vocadlo and Rob Britton we are looking at enzymes that have been linked to various disease states. We are working mainly with carbohydrate cleaving enzymes (i.e., glycosidases), but we are starting to work with some of the transferases as well. Many of the isotopically-labelled compounds we synthesize can be used to investigate several different enzymes, which gives more bang for each research dollar.
Which features of sugar molecules or their analogs do you get most excited about?
I love to incorporate cyclopropyl groups into sugar molecules, because the strain energy in the three-membered ring can be used to increase reactivity toward the carbohydrate processing enzyme.
Not all sugars are created equal, so how do you decide on which one to use in trying out a new structural modification?
Initially, these choices were based on knowledge we had about an enzyme we were already working on. This is why we've been working mainly with galactose and glucose, although we are going to move on to more sugars. The ease of synthesis is a factor as well, in terms of cost and expertise required.
How much time do your graduate students spend on synthesis versus characterization of their new compounds?
Most students in my lab are doing synthesis, which occupies about 90% of their work, followed by kinetic studies on how effective the compounds are as inhibitors. Right now, I also have a biochemistry trainee as well as an incoming student who is going to be doing mainly enzyme kinetics.
What traits are shared by your most successful trainees?
The willingness to try new things, to be unafraid of taking on projects for which there is no precedent, and to be open to the unexpected. Those who are willing to take on really tough projects have done very well.
What exciting possibilities are currently brewing in your lab?
We have some new structural motifs that we can put into molecules to make new inhibitors. These involve cyclopropyl groups put into different positions of the sugar ring to fine-tune the enzyme reactivity. I would love to turn some of our motifs into more structurally complex carbohydrates. For example, I would love to take our most recent inhibitors and use that motif on a sialic acid scaffold; though this is a challenging synthesis.
Congratulations on your funding increase from NSERC last year. What is the funding landscape like for your particular research program?
In general, funding has gotten tougher. In cases where there is not significant preliminary data, with the exception of NSERC, more collaboration is required in the early stages of a project to obtain the preliminary results needed to get funding. In the carbohydrate research community, things changed when the GlycoNet (the Canadian Glycomics Network) was funded, though the funding is for applied rather than fundamental research. GlycoNet is also a good source for fellowships and it offers training courses for grad students.
If you could improve just one thing with regard to the funding of science in Canada what would you do?
With the recent federal budget announcement, the future of science in Canada looks more promising than it has in a long time. I would like to see funding agencies such as NSERC link good students – scholarship students – with cutting-edge research.
As it is now, undergrads who apply for NSERC scholarships decide who to work with. These students have an impact on what research gets supported because they take their scholarship money to those labs. The problem is, they choose labs based on knowledge of the subject gained from undergraduate chemistry curriculum rather than innovative science.
I would like to see a way to take advantage of the NSERC review process to link strong faculty and student applications together to push toward the goal of making Canada a world leader in science.
Interview by Jacqueline Watson with Theresa Kitos