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Looger doesn’t wait for collaborators to come to him. He takes every opportunity—hallway run-ins at Janelia Farm or emails to unfamiliar researchers—if he thinks he can help.
Each project has its own quirks, but the modular nature of proteins makes the job easier, Looger says. If nature has evolved a protein that lets an ocean coral glow red far beneath the sea, the relevant parts of that protein can be borrowed and adapted to bring the same fluorescent hue inside the lab. Likewise, a brittle star whose predator-dazzling luminescence triggers fluorescence that lingers for days offers clues to a longer-lasting “integrator” that could record a history of neural activity. By changing the genetic sequence that encodes any protein, Looger, using “intuition and a relatively easy bag of tricks,” can alter the molecule in predictable ways, shifting its shape so it becomes more stable or binds more tightly to its target, for example.
Marveling at the opportunities he has to affect science by solving biochemical puzzles, Looger says he can imagine few careers that could be as invigorating, satisfying, and just plain fun. “Science,” he says, “is an absolute scream.” Yet he insists that his path to Janelia Farm has been almost entirely haphazard. “If any one of 10 different things hadn’t happened, I wouldn’t be here.”
Wanted: Tool Builders
For much of his life, Looger assumed his future was in mathematics. But when he realized as a graduate student that a career in the field would be less about the puzzle-solving camaraderie of youth math camps and more about a solitary pursuit of knowledge, he altered his course. He fled to biology, he says, selecting a biochemistry program at Duke University largely because his girlfriend, Covington Brown (now his wife), was working nearby. Four years later, he left Duke with a Ph.D. in biochemistry and no plan for the future. An unexpected phone call determined his next step: Wolf Frommer, a plant scientist at Stanford University, about 45 minutes south of San Francisco, had read about the protein biosensors Looger designed as a graduate student. He wanted a reagent to detect glucose inside living plants. Looger, who happened to be traveling on a train outside San Francisco, told Frommer he would come to his lab to discuss the matter straight away. By the end of the day, he had accepted a postdoctoral position.
"Loren is not out to prove anything, he just wants to get the right tool to the right person so they can learn something new about biology.”
In Frommer’s lab, Looger grappled for the first time with the challenges of creating sensors that function inside living cells, helping to engineer not just sugar sensors (the main task) but also a protein that would detect a different plant metabolite, glutamate. As a side project, Looger helped test the glutamate sensor in neurons, which use the molecule as a key signal transmitter. Soon after that first dabbling in neuroscience, he set out to land a job at HHMI’s nascent Janelia Farm Research Campus.
As Janelia Farm began recruiting its very first lab heads, HHMI leaders had made clear that they wanted tool builders to be an integral part of the scientific community, where they would contribute to an anticipated synergy between technology development and biological research. When Looger stood before the selection committee in red bell bottoms and a flowered shirt to convince its members he had the skills and creativity they needed, he unabashedly announced that he knew nothing about neuroscience that he hadn’t read in the past two weeks. The roomful of accomplished neuroscientists listened with undisguised skepticism to his proposed plan to “reengineer the brain,” and Looger began to regret not applying for other jobs.
That’s when Svoboda approached him to consider developing new calcium sensors. And Janelia group leader Scott Sternson, who was also applying for a job at Janelia, asked Looger if he could help design ion channels that would respond to novel drugs so biologists could manipulate brain activity (see February 2012 HHMI Bulletin Web Extra, “Cowboy Chemistry”). Looger was game. So when Janelia Farm director Gerry Rubin, impressed by Looger’s bravado and open mind, surprised him with a job offer—as long as he promised not to work on the project he had proposed in his seminar—Looger didn’t hesitate.
Six years of immersion in the Janelia Farm community have given Looger a new perspective on the complexity of the brain. “My naïve idea, until I actually got here, was that a bunch of neurons hook together to make a brain, and they all basically do nothing until they decide to signal something. That turns out to be absolutely not the case.” Working alongside neuroscientists—huddling in a tiny room searching for glimmers of activity in a zebrafish brain, or witnessing unexpected behavior in a worm expressing a slightly toxic protein sensor—has given him an understanding that textbooks and journal articles could not. “In the beginning, I was clueless about what people wanted tools to really do, but now I get it.”
To generate and evaluate their tools, biologists and chemists work side by side in Looger’s lab. Graduate students, technicians, and senior scientists pursue their own projects with considerable autonomy and independence—an advantage, they say, of the lab’s diverse portfolio. Their airy, glass-walled workspace, where bacterial DNA is manipulated and three-dimensional protein structures are examined, feels industrious but calm. Step into a smaller windowless back room, however, and it becomes immediately apparent that Looger’s team is churning out high-volume science. Plastic plates, each sectioned to contain 96 populations of bacteria, are stacked high on counters and incubators. Looger says the system is set up to isolate as many as 10,000 different proteins from bacterial colonies and crudely characterize their biophysical properties—fluorescence, stability, and light absorption, for example—in a day. Yet there is no bustle inside this room. Robotic instruments handle the more tedious tasks of protein design with quiet precision.
Photo: Dustin Aksland