Following the Molecular North Star

Our molecules are always in motion; our understanding of them must also be. That's where tech like NMR spectroscopy comes in.

 |  Transcript [PDF]

“We’re made up of molecules. We’re looking at what it is about them that makes them special: what it is about them that makes them work when they work properly, and what it is about them that makes them malfunction in the course of, say, disease.”

Biophysicist Lewis Kay, professor of molecular genetics and biochemistry at the University of Toronto, works to understand health and disease at a molecular level. And to do this he needs to understand how molecules interact with each other and evolve over time, because our molecules are anything but static.

“Just like if I take a picture of somebody, I get a static entity: I learn something about that person — what they look like, how big they are, perhaps — but I don’t learn a lot about them,” explains Kay.

Going beyond a snapshot to something more like a video requires Kay to develop new technology. His go-to experiment uses a method called nuclear magnetic resonance (NMR) spectroscopy. To better conceptualize how it works, Kay likens molecules to collections of bar magnets.

Just like life-sized bar magnets, which each have a north and a south pole, molecules can be arranged in ways that place north poles with north poles, or south poles with south poles — but because like poles repel each other, this is a high-energy configuration. Conversely, north poles being next to south poles represent low-energy configurations.

In an NMR experiment, forces are applied that raise the energy in the system to bring like poles together. Pushed into a high-energy configuration, Kay then monitors the system to see how the applied forces impact molecules as they return to their lowest energy states.

“I really have to learn about the nuances of these molecules. And to do that we have to develop the technology which not only allows us to have a picture of these molecules, but to understand how they evolve in time in response to various stimuli,” adds Kay.

Depending on the disease, some molecules need a boost, and others are already too active. By understanding each molecule and its interactions, Kay hopes to pinpoint whether their functionality needs to be turned up or down to restore health. He also develops tools that may help manipulate molecules to achieve the effect that a patient needs.

“We’ve got to be able to understand these biological molecules at a very fundamental level if we really want to address practical questions that come from disease,” says Kay.

“Molecules are at the root, and we want to be able to understand these molecules fundamentally. So that’s my North Star, that’s where we want to be now, that’s where we’re going to be working towards in the future.”

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Lewis Kay is professor of molecular genetics, biochemistry, and chemistry at the University of Toronto and a Senior Scientist at the Hospital for Sick Children. He received his BSc in biochemistry from the University of Alberta in 1983 and his PhD in biophysics from Yale University in 1988, pursuant to which he spent three years as a postdoctoral fellow in chemical physics at the NIH.

Appointed Assistant Professor at the University of Toronto in 1992, he was promoted to Professor three years later. In 2012, in honour of his scholarly achievements, he was named University Professor by the University of Toronto, the highest academic distinction bestowed by the institution.

Kay’s research cuts across the interface of physical chemistry and medical sciences. His work focuses on transforming the techniques of nuclear magnetic resonance (NMR) spectroscopy as applied to the study of large proteins and their complexes, in particular those that are involved in health and disease.

NMR methods established by Kay now allow for the study of protein complexes in the one million Da molecular weight range. He has applied these techniques to study the proteasome, the nucleosome, p97, and protein machines involved in disaggregation that serve as critical targets for drug discovery. In addition, Kay has developed and advanced NMR methods used to study protein dynamics and how these dynamic properties change upon ligand binding or folding.

In related accomplishments, Kay has improved methods to study protein folding, and has applied these new techniques to study protein aggregation in numerous disease-related systems. His research has led to a reliable framework by which to explore sparsely-populated, transiently-formed conformations of proteins that are implicated in protein function and disease. He now applies this methodology to a wide spectrum of protein systems.

Kay has published close to 450 research papers, including several cited more than 1,000 times. His work has earned approximately 50,000 citations and his h-index exceeds 100. He has been identified by ISI as being among the top 0.5 percent of authors in chemistry in the world (since 2005). The tools developed in his laboratory are disseminated freely, used extensively worldwide, and have far-reaching impact not only for current research, but also for future discoveries.

Kay is a Fellow of both the Royal Society of London and the Royal Society of Canada. In 1997, he was appointed an International Research Scholar of the Howard Hughes Medical Institute, and since 2000, he has held a Canada Research Chair in Proteomics, Bioinformatics and Functional Genomics. Included among numerous awards he has received are the Anfinson Award from the Protein Society, the Khorana Prize of the Royal Society of Chemistry, the Founders Medal of the International Society of Magnetic Resonance in Biological Systems, the Steacie Award of the Canadian Society for Chemistry, and the Flavelle Medal of the Royal Society of Canada. Most recently, he was named a Canada Gairdner International Award laureate (2017); he received the Nakanishi Prize from the American Chemical Society (2018); and was awarded Canada’s most prestigious science prize, the Gerhard Herzberg Canada Gold Medal for Science and Engineering (2018).

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