On December 25, 2002, Louis Kaye was in his lab at the University of Toronto, devising a new way to observe the invisible workings of life. At least that’s what I try to do.

The macromolecules that Kay has spent his career studying are as dynamic, unruly, and slippery objects as cells. Understanding how these proteins work may be the key to repairing them when they are broken, potentially enabling treatments for diseases ranging from Alzheimer’s disease to cancer.

Accompanied by a postdoctoral researcher, Kay took advantage of the quiet Territory University campus on Christmas Day to revisit a problem that had defied two years of sophisticated experimentation.

It worked this time.

but why? A few hours later, while swimming with my son, the equation popped into my head. He spent the rest of his winter break furiously scribbling away, planning the physics of how to capture short-lived molecular signals before they disappear.

“Basically, it was just the results of the experiments that spoke to me,” says the now senior scientist at Sick Kids Hospital. university professor He completed his master’s degree at T’s Temerty University School of Medicine and was appointed to the Department of Molecular Genetics, Biochemistry and Chemistry.

“It’s about getting a little bit lucky and then knowing that you were lucky and being able to explain your good fortune.”

This breakthrough allows scientists to study protein complexes on an unprecedented scale. But Kay went further. Then he found a way to watch them undulate, bend, and deform. Using nuclear magnetic resonance spectroscopy (NMR), a decades-old technology, Kay revealed the world of molecules in motion. Other methods freeze the proteins in place, but Kei was able to capture the proteins as they were, meaning they were still alive.

Today, Kay’s techniques are used around the world to understand how the movement of molecules causes health and disease, and as a result, he has amassed a growing collection of science’s highest honors. These include Canada’s Gardner International Prize, also known as the “Baby Nobel,” and the Gerhard Herzberg Canadian Gold Medal.

After more than 30 years at U of T, he remains the type of researcher happiest behind the lab, exploring new ideas and trying to move the field forward.

“Why do we have to let people in the lab do all the fun?” he says. “I want to experiment with my own hands and think about it myself.”

magnetized molecules

Tucked away in the back of U of T’s medical building, Kaye’s Nuclear Magnetic Resonance Center laboratory resembles a boiler room, filled with giant tanks, metal piping, and the low hiss of a cooling system. At its center stands a white cylindrical magnet several meters high, extending almost to the ceiling through a grid of steel beams and yellow safety rails.

The magnet, kept cooler than space by liquid helium and nitrogen, never stops, humming with a magnetic field hundreds of thousands of times stronger than Earth’s.

Kay climbs a narrow staircase to feed the magnet with molecules, carrying a sample from the SickKids lab across the street. Inside that powerful field, he attacks molecules with bursts of radio waves. The show begins.

“The molecules start dancing,” Kay says. “They begin to sing for us. Each atom produces its own frequency, its own nuclear song.”

That “song” is the basis of NMR. By listening to how atoms resonate in a magnetic field, scientists can map molecules into three-dimensional space, atom by atom.

For decades, NMR has worked well for small molecules. But larger ones posed a challenge because their songs faded too quickly to be recorded, disappearing into noise before scientists could capture them.

This was a problem. The most important functions of the cell, such as destroying damaged proteins, folding new proteins, and packaging DNA, are carried out by giant protein complexes that are too large to be heard by NMR.

Kay’s 2002 discovery changed that. By developing new physics to extend signal lifetimes, scientists can now study complexes an order of magnitude larger than previously possible with NMR. But seeing larger molecules was only part of Kay’s vision. He also wanted to see them in action.

Traditional methods in structural biology, such as X-ray crystallography, cryoelectron microscopy, and even early NMR, can only capture snapshots of molecules frozen at a single moment in time. But Kay knew that the action happens between frames.

“Photographs tell us something about molecules, but they don’t tell us how they dance and wiggle, which is important for understanding how molecules work,” Kay says.

Consider a car engine. The photo shows its parts and construction. But to understand how it works, you need to observe it in action.

Proteins constantly bend, twist, and move between different shapes. Most of the time they exist in the “ground state”, or low energy state. But momentarily, perhaps for a few milliseconds at a time, they assume an “excited state,” a high-energy form that represents less than 1 percent of the molecules at any given time.

These fleeting forms are often key to their functionality. Anticancer drugs may bind to the excited state rather than the ground state. Disease-causing mutations can affect how proteins transition between states. Without looking at these invisible 3D structures, scientists miss important information.

Throughout his career, Kaye developed techniques to detect these elusive conditions and measure their properties even when they do not emit a visible signal. Measurements combined with computational approaches reveal atomic details of shapes that exist over fractions of a second.

“If we don’t see these conditions, we can’t understand how drugs work or why resistance develops in certain cases,” Kay says.

That’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 is littered with open binders, haphazard stacks of books, and scribbled formulas, creating a productive mess of workers. On one wall hangs a poster commemorating his 500 publications, his face assembled from tiny images from each paper. Nearby, an Edmonton Oilers hockey puck is a reminder of home.

Kay excelled in mathematics and physics, and studied biochemistry at the University of Alberta, where her father was a professor. He received his PhD in molecular biophysics from Yale University and is a postdoctoral researcher at the National Institutes of Health. There, he collaborated with NMR pioneer Adrian Bax to develop the technology that became the foundation of the field.

When it was time to make their next move, Kaye and his wife, biophysicist Julie Forman Kaye, had to make a choice. They have both secured positions in Toronto, he at U of T, she at SickKids (she is currently a senior scientist and professor of biochemistry at Temerty Medical School), and have offers from Johns Hopkins University in Maryland.

They decided to toss a coin to decide. Heads, Hopkins. Tails, Toronto. It attracted attention.

“I told her to flip the coin again.”

He never looked back. At 64 years old, Kay shows no signs of slowing down.

More recently, NMR techniques have been combined with artificial intelligence approaches like AlphaFold, combining experimental data and computational predictions about molecular dynamics to create a more complete picture of how proteins behave.

Nor does he see himself as a supervisor above his trainees, but as an equal partner in discovery.

“I just want to be like Peter Pan,” he says. “Like the postdocs, I want to play with molecules.”

One of his postdocs, Rasik Ahmed, is using Kay’s techniques to study how proteins are organized in cells, the way oil separates from water. He says it’s not unusual for Kay to squat next to him and help troubleshoot.

“This is a one in a million chance,” Ahmed said. “If I’m interested in something I want to pursue, he’s always there to support me. Sometimes I fail, sometimes I succeed. But he facilitates that independent learning.”

For Kay, that is his true legacy.

“More important than my research is passing on the excitement to the next generation so they can far exceed what I was able to accomplish.”