On Dec. 25, 2002, Lewis Kay was in his lab at the University of Toronto, devising new ways to observe the invisible machinery of life. Or trying to, at least.
The large molecules Kay has spent his career studying are slippery subjects, as dynamic and unruly as the cells they power. Understanding how these proteins work could be key to fixing them when they break, potentially unlocking treatments for diseases from Alzheimer's to cancer.
Accompanied by a postdoctoral researcher, Kay was taking advantage of a quiet U of T campus on Christmas Day to make another run at a problem that had defied two years of sophisticated experiments.
This time, it worked.
But why? Hours later, while swimming laps with his son, the equations floated into his mind. He spent the rest of his winter holiday scribbling furiously, mapping out the physics of how to capture short-lived molecular signals before they vanish.
"It was basically just allowing the results of the experiment to speak to me," says Kay, now a senior scientist at the Hospital for Sick Children (SickKids) and a University Professor in U of T's Temerty Faculty of Medicine with appointments in the departments of molecular genetics, biochemistry and chemistry.
"It's about getting a little bit lucky, then knowing that you've gotten lucky to be able to explain your luck."
The breakthrough allowed scientists to study protein complexes on an unprecedented scale. But Kay went further. Next, he found ways to watch them wriggle, bend and transform. Using a decades-old technology - nuclear magnetic resonance spectroscopy, or NMR - Kay revealed a molecular world in motion. While other methods freeze proteins in place, Kay was able to capture them as they truly are: alive.
Today, Kay's techniques are used worldwide to understand how molecular movements drive health and disease - and he has collected a growing collection of science's highest honours as a result. They include: the Canada Gairdner International Award - often called the 'baby Nobel' - and the Gerhard Herzberg Canada Gold Medal.
After more than 30 years at U of T, he remains the type of researcher who is happiest behind the lab bench, exploring new ideas and trying to push the field forward.
"Why should I let people in my lab have all the fun?" he says. "I want to do experiments with my own hands and figure things out myself."
Molecules, magnetized
In the bowels of U of T's Medical Sciences Building, Kay's Nuclear Magnetic Resonance Centre lab resembles a boiler room - filled with hulking tanks, metal piping and the low hiss of cooling systems. At its centre, a white cylindrical magnet stands several metres tall, rising almost to the ceiling through a lattice of steel beams and yellow safety rails.
Kept colder than outer space by liquid helium and nitrogen, the magnet never shuts down, humming with a magnetic field hundreds of thousands of times stronger than that of Earth.
With samples from his SickKids lab across the street, Kay climbs a narrow staircase to feed molecules into the magnet. Inside that powerful field, he hits the molecules with bursts of radio waves. The show begins.
"The molecules start to dance around," Kay says. "They start to sing for us. Each atom produces its own frequency - its own nuclear song."
That "song" is the foundation of NMR. By listening to how atoms resonate in a magnetic field, scientists can map molecules in three-dimensional space, atom by atom.
For decades, NMR worked well on small molecules. But larger ones posed a challenge because their songs fade too quickly to record, disappearing into noise before scientists can capture them.
This was a problem. The cell's most important work - destroying damaged proteins, folding new ones, packaging DNA - is carried out by massive protein complexes that were simply too large for NMR to hear.
Kay's 2002 discovery changed that. By developing new physics to extend signal lifetimes, he allowed scientists to study complexes by NMR an order of magnitude larger than ever before. But seeing bigger molecules was only part of Kay's vision. He also wanted to watch them move.
Traditional methods in structural biology - X-ray crystallography, Cryo-electron microscopy, even early NMR - could only capture snapshots of a molecule, frozen at a moment in time. But the action, Kay knew, happens between the frames.
"A picture tells you something about a molecule," Kay says, "but what it doesn't tell you is how the molecule dances and wiggles. That's important for understanding how it works."
Think of a car engine. A photograph shows its components and structure. But to understand how it works, you need to watch it run.
Proteins constantly flex, twist and shift between different shapes. Most of the time, they exist in a "ground state," a low-energy form. But briefly, perhaps for milliseconds at a time, they adopt "excited states," higher-energy shapes that might represent less than one percent of molecules at any moment.
These fleeting forms often hold the key to their function. A cancer drug might bind to an excited state, not the ground state. Disease-causing mutations might affect how proteins shift between states. Without seeing these invisible conformations, scientists miss crucial information.
Over his career, Kay developed techniques to detect these elusive states, measuring properties even when they produce no visible signal. Combined with computational approaches, the measurements reveal atomic details of shapes that exist for fractions of a second.
"If you can't see those states," Kay says, "you can't understand how drugs work or why resistance develops in certain cases."
It's why he describes his life's work as "seeing the invisible"- capturing not just what molecules look like, but how they behave as living systems.
The 'Peter Pan' of biophysics
Kay's office has the productive chaos of a working mind, strewn with open binders, haphazard book piles and stray scrawls of equations. On one wall hangs a poster commemorating his 500 publications, his face assembled from tiny images of each paper. Nearby, a pair of Edmonton Oilers hockey pucks remind him of home.
With a head for math and physics, Kay studied biochemistry at the University of Alberta where his father was a professor. He went on to complete a PhD in molecular biophysics at Yale University and conduct postdoctoral research at the U.S. National Institutes of Health. There, he worked with NMR pioneer Adriaan Bax, developing techniques that would become foundational to the field.
When it came time for their next move, Kay and his wife, biophysicist Julie Forman‑Kay, faced a choice. Together they had positions lined up in Toronto - his at U of T, hers at SickKids (where she's now a senior scientist, as well as a professor of biochemistry at Temerty Medicine) - and had offers from Johns Hopkins University in Maryland.
They decided to let a coin flip decide. Heads, Hopkins. Tails, Toronto. It turned up heads.
"I told her to flip the coin again."
He never looked back. At 64, Kay shows no signs of slowing down.
These days, he's combining his NMR techniques with artificial intelligence approaches like AlphaFold, bringing together experimental data about molecular dynamics with computational predictions to create a more complete picture of how proteins behave.
Nor does he see himself as a supervisor standing above his trainees, but rather as an equal partner in discovery.
"I just want to be sort of like Peter Pan," he says. "I want to play around with my molecules, just like the postdocs do."
One of his postdoctoral researchers, Rashik Ahmed, is using Kay's techniques to study how proteins organize in cells like oil separating from water. He says it's not unusual for Kay to plop down next to him and help troubleshoot.
"It's a one-in-a-million opportunity," Ahmed says. "If I'm curious about something I want to pursue, he's always supportive. Sometimes I'll fail, sometimes I'll succeed. But he's catalyzing that self-directed learning."
To Kay, that's his real legacy.
"More important than my research is being able to convey a sense of excitement to the next generation so that they can go far beyond whatever I've been able to achieve."
