Using Physical Techniques To Solve Biological Problems: Professor Lewis Kay Wins the Gairdner
Written by Anastassia Pogoutse
Artwork by Nikko Torres
The Canada Gairdner International Award is given yearly to five individuals for outstanding contributions to medical science. 84 of its 388 recipients have gone on to win the Nobel Prize. Dr. Lewis Kay, a Professor in the Departments of Biochemistry, Molecular Genetics, and Chemistry, received the Gairdner International Award this year “for the development of modern NMR spectroscopy for studies of biomolecular structure dynamics and function, including applications to molecular machines and rare protein conformations.” He is the first Canadian to win this award in nine years. Unlike many scientists, Dr. Kay is known not only for providing insights into central questions in biology and medicine, but also for developing the methods that led to these breakthrough discoveries.
“It’s a dream come true”, he says. Dr. Kay had already accumulated a number of honours prior to receiving the Gairdner: He is a Tier I Canada Research Chair in Proteomics, Bioinformatics and Functional Genomics. He has also been a recipient of the Merck Frosst Award, the Steacie Prize from the National Research Council of Canada, the Flavelle Medal from the Royal Society of Canada, and the Founders Medal from the International Society of Magnetic Resonance in Biological Systems, to name a few. In 2006, he was elected to the Royal Society of Canada and four years later, to the Royal Society (London). In 2005, he was listed in the top 0.5% percent of most highly-cited chemists in the world. Earlier this year, he became an Officer of the Order of Canada.
A Tension Between Biology and Physics
Dr. Kay’s fascination with understanding the physical world started early. “I always wondered whether you could combine very quantitative science with biology to solve problems,” he says, “But, and this is the important thing, I had no interest in biology.” He recalls how during his early school days, sitting in non-math-related classes, he would hide textbooks under his desk and solve math problems.
He became acquainted with NMR while completing his undergraduate degree at the University of Alberta, working summers in the lab of Dr. Brian Sykes. Dr. Kay went on to complete his PhD at Yale and a postdoc at the National Institutes of Health (NIH). He says that in the beginning of his career he was “not so interested in applications but deeply interested in the theory.” He started at the University of Toronto in 1992, studying large molecular machines.
I always wondered whether you could combine very quantitative science with biology to solve problems. But, and this is the important thing, I had no interest in biology.
Massive Molecules and Rare States
Biomolecular NMR (nuclear magnetic resonance) spectroscopy is used to determine protein and nucleic acid structures and to study dynamics. It relies on quantum mechanical properties of atomic nuclei and the effect they have on each other in solution. By putting molecules in a strong magnetic field and hitting them with radio waves, NMR spectroscopists can glean information about chemical bonds, the relative positioning of atoms in space, and how rapidly atoms move relative to each other. It is the ability to monitor motion in biological molecules that makes NMR stand out from other methods in structural biology.
For many years, protein size was a limiting factor in NMR experiments. The signals produced by large proteins disappear quickly, which makes the signal peaks in NMR spectra less sharp and decreases measurement sensitivity. Early in his career as a professor, Dr. Kay, along with Dr. Cheryl Arrowsmith, pushed the size envelope by solving the structure of a 37 kDa ternary complex. Over the years, Dr. Kay and colleagues were able to further extend the size limit of proteins that could be studied with NMR to approximately 1 MDa.
Dr. Kay’s lab currently has two areas of focus: studying supra-molecular machines and characterizing low-populated conformational states. They have continued to develop techniques to study large systems and have been applying them to important biological molecules, such as the proteasome. They’ve been able to explore the mechanism of proteasome gating, shed light on how substrates enter the 20S proteasome’s catalytic chamber, and identify sites that could potentially be targeted with therapeutics.
When you get older you want to do something important, something that could be the beginning of making an impact.
Method development has also gone into the Kay lab’s study of rare protein conformations. High-energy protein conformers, which sometimes make up less than 1% of a total protein population, can be stepping stones to a misfolded or aggregated state. The Kay lab has developed methods to probe these rare conformations, which remain invisible to conventional structural biology techniques. They found a powerful application of these methods in studying SOD1, a protein linked to the development of amyotrophic lateral sclerosis (ALS). The group discovered that exposed surfaces found only in some high-energy conformational states cause SOD1 molecules to stick together in new and potentially aberrant ways. These sites are considered to be potential drug targets.
From Method Development to Application
With a research program that is increasingly collaborative, Dr. Kay stresses that he wants more scientists to take advantage of his techniques. “Many technologies were developed 15 years ago,” he says, “but no one used them then.” Explaining his interest in biological applications, he touches on funding agencies and his postdocs’ job searches, but ultimately admits, “When you get older you want to do something important, something that could be the beginning of making an impact.” According to him, part of his shift in research direction stemmed from the “unconscious desire…to leave some sort of legacy”.
Work on things that are not hot in science, and make them hot.
Despite his turn towards addressing big biological questions, Dr. Kay encourages students who want to make a name for themselves in science to stray off the beaten path. “Work on things that are not hot in science, and make them hot,” he advises. He also mentions that he hasn’t had a grad student in over 10 years. “There are some really talented biochemistry grad students out there but they don’t like the physics end of things,” he says. “If there are new graduate students applying, tell them to come by my lab. I’m not that scary.”
When it comes to the future of his lab, Dr. Kay says that there is a lot more work to be done on the rare conformational states his lab has learned to detect. But, as he points out, research is full of unpredictability:
When I became a professor I thought I’d have to work on applications because there are no more methods to be developed, but then I began to work on methods that form the basis of what I’m working on now…If tomorrow I come up with an idea that’s drop-dead, I’m happy to drop everything to work on it. But tomorrow hasn’t happened yet.