Loren Looger makes intensity-based fluorescent biosensors from GFP and periplasmic binding proteins. When these proteins bind their small molecule ligand (maltose, glutamate, etc.), fluorescence increases by about 5-fold. Looger's group is making sensors for other neurotransmitters by using periplasmic binding proteins that already have the desired specificity and by designing new periplasmic binding proteins to accommodate ligands for which natural binding proteins do not exist. Loren uses both computational protein design and library-based protein design (phage display and high throughout screening).
Loren Looger trained to be a mathematician, but switched to chemistry after deciding that a mathematician's life might be too solitary. The shift took courage, because everything about his background suggested that Looger was a math prodigy of considerable promise. Looger recalls solving long multiplication problems in the back of his parents' car when he was very young. "My mom claims that I was doing multiplication problems when I was three," he said. Years later, he spent his teenage summers shuttling between math and chemistry olympiads—where he was one of the top 20 students nationally—and his spare time as a research associate at the NASA Space Sciences Lab in his hometown of Huntsville, Alabama.
Looger studied at Stanford University, where he received a B.S. degree in chemistry and an M.S. degree in mathematics in just four years. But after another year of mathematics in a University of California, Berkeley, graduate program, he realized that his true passion was biochemistry. So Looger trekked back across the country to Duke University to study biochemistry, with Homme Hellinga, an internationally recognized protein biochemist, as his advisor.
Looger began exploring a combined computational and experimental approach to protein design, a goal he summarizes with deceptive simplicity: "I take proteins that nature has evolved for a specific job and try to modify them—through a lot of computer modeling—to do jobs that I want them to do." A 2003 Nature paper by Looger, Hellinga, and colleagues illustrated the power of an algorithm they developed to redesign bacterial receptors that normally bind sugars or amino acids. The scientists redesigned these receptors to recognize the explosive TNT, an analog of the nerve agent soman, the groundwater pollutant MTBE (a gasoline additive), and neurotransmitters and metabolites.The computer-intensive nature of his research often requires Looger to spend months writing computer code to solve a set of problems. "For months at a time I live the life of a computer programmer," he says. "Then I emerge to test my ideas in the lab." With his own small research group, Looger says he'll be able to accomplish more in less time at Janelia.
When asked how he first heard about Janelia, he says: "My wife assures me that she told me about Janelia first, although a colleague of mine also claims credit. My wife was eager to move to the D.C. area, so she searched on the internet for 'Washington…D.C.…Institute.' Janelia popped up in the search, and after some further investigation and thinking, Janelia seemed like a great fit." That's putting it mildly. Looger says that about 18 months ago, he had virtually excluded any job option but Janelia. "This was a really high-risk endeavor for me," he says, referring to the lack of a safety net. Janelia appeals to him because he does not like teaching and hates bureaucracy and the pure profit motive of industry.
It's also high risk in an intellectual way. Looger freely admits that he is likely to buy lots of neuroscience textbooks on Amazon.com this summer. "I have a lot of catching up to do," he jokes.
For a neuroscience neophyte, his ambitions are large: He wants to use his protein design and computation background to engineer and construct novel biosensors that can be used in living organisms and cells. The sensors will sit inside cells looking for specific chemicals, such as metabolites or neurotransmitters. When the biosensor encounters those chemicals, it will transmit a signal that can be observed with an instrument. He envisions using this approach to build glutamate, dopamine, GABA, and serotonin sensors, which could be deployed simultaneously inside neurons and provide researchers a wealth of new information about how neurotransmitters work.
Another project under consideration is using the tools of his trade to "start tinkering" and redesign neurotransmitters that have slight chemical variations on nature's design. He would then work with other researchers at Janelia to see how the synthetic neurotransmitters and pathways influence the behavior and development of fruit flies and worms. The big question: Can the function of the brain be systematically altered?
In his opinion, Janelia is truly set apart from other academic research institutions. His 20-year dream would be to run a program like Janelia—possibly on a smaller scale—that would be devoted to studying neglected diseases. "I got really excited when Gerry Rubin told me Janelia almost studied malaria," he says."
"I see Janelia as a crack team of scientists—almost like a SWAT team—that comes together to solve difficult problems. Everyone is really playing together. Not like in academia, where they say they play together, but in reality it does not always work that way."
Not one to sit idle, Looger is also founder of a biotech company that applies the principles of protein design to real-world problems. Although he cannot say much about the projects he's working on for bigger companies, he allows that some very large clients are looking to him to design kill switches for genetically modified organisms. His company is called Molecular Engineering, LLC, and is based in San Francisco.