Growing up in California, Bill Zagotta loved architecture, art, and science. He developed an interest in science from his father, a physicist at Lawrence Livermore National Laboratory. Though physics seemed a likely career path for Zagotta as well, two summers of work at Lawrence Livermore during his college years dissuaded him.
"The kind of physics I wanted to do was very big science, like a thousand people working on one experiment," Zagotta remembers. "I realized that would be a limitation for me, because I wanted more control."
As an undergraduate at University of California, Davis, Zagotta created his own major in biophysics, which allowed him to study the physics and math he loved while working on biological problems. His first foray into biophysics involved studying muscle mechanics, but in graduate school Zagotta began searching for a different challenge. When he learned about ion channels, he was hooked.
"They're the transistors of the brain—they do the same thing a transistor does in a computer," he says. "I became fascinated by trying to figure out how they worked, and that's what I continue to work on."
He started with a potassium channel called Shaker. When the gene for this channel is mutated in fruit flies, their legs shake constantly, even under anesthesia. In Richard Aldrich's lab, Zagotta used this channel to prove the "ball-and-chain" hypothesis, which described how this channel becomes inactivated.
A stretch of amino acids hangs off the end of the channel inside the cell. The first 20 amino acids are crumpled into a ball, which is connected to the rest of the channel by a stretch of amino acids called the chain. "The ball swings up on the chain, and plugs the channel closed," Zagotta says.
As a postdoctoral student at Stanford, Zagotta then became interested in the channels that help convert light to electrical signals in the eye. He unraveled how these channels are regulated by the direct binding of molecules called cyclic nucleotides. He has found that a similar mechanism occurs in the channels involved in regulating heartbeat.
The bulk of projects in his lab at the University of Washington focus on cyclic nucleotide–regulated channels, of which the channels in the eye and the heart are a subset. "While we are primarily focused on this one family of channels, we're quite diverse in the techniques we use to try to understand them," he says.
One technique is x-ray crystallography. In 2001, Zagotta used a sabbatical to live in New York City and learn as much about x-ray crystallography as he could from fellow HHMI investigator Eric Gouaux. Previously at Columbia University, Gouaux is now at Oregon Health & Science University.
"It's a tough discipline to learn," Zagotta says. "It requires knowledge and skills that I didn't have."
Working with Gouaux, Zagotta managed to capture the crystal structure of one HCN channel that's important for the human heartbeat. He also fell in love with New York. The year there was "the perfect compromise between being a tourist and moving there permanently," he says. He and his wife fly back every year to visit.
Zagotta has also begun using fluorescence to study ion channels. "You attach fluorophores, and they will change the way they fluoresce when the channel opens or closes," he says. "I believe this is a super-powerful idea, but its full potential has not yet been reached."
When he's not working, Zagotta and his wife go to as many Seattle Mariners games as possible. They discovered a mutual love of theatre during their New York stint and now attend shows in Seattle. But Zagotta doesn't differentiate between work and play: to him, it's all play.
"[My job] is the kind of thing I'd do even if I wasn't being paid," he says. "You get an idea and play around and solve a problem . . . . I don't think of that as work. I'm not sure I could do anything else other than what I do."
