Chemical Biology, Neuroscience
Janelia Research Campus
Dr. Sternson is a group leader at the Janelia Research Campus.
Scott Sternson is reverse engineering the mouse brain in order to understand how neural circuits control innate behaviors. He combines synthetic chemistry with genetics to deliver molecular switches to small groups of neurons in mice. By "flipping" these switches with chemicals or light, he maps neural circuitsand measures the contribution of neurons to innate behaviors such as feeding.
Scott Sternson is, quite literally, a born chemist. Both of his parents are chemists, and some of his earliest memories are of being in the lab. He was drawn to the logic of the periodic table early on, recognizing its power to predict the properties and reactivity of molecules.
Sternson earned an undergraduate degree in chemistry at Bowdoin College, then set out to apply the power of chemistry to biological questions. The Harvard University lab of HHMI investigator Stuart Schreiber was a hotbed for the relatively new science of chemical biology, and it seemed like a good place to start. As a PhD student in Schreiber's lab, Sternson synthesized thousands of molecules and studied how they altered biological pathways. He succeeded in creating a chemical that could interfere with the ability of yeast—a popular organism for laboratory study—to sense the amount of glucose in its environment. "It turned out to be a nice story and we published it," Sternson said, "but I was a little disappointed that there was no next step that would be relevant for human health."
Eager to pursue research that had a more direct connection to human biology, Sternson considered a variety of fields after completing his PhD. "Coming from chemistry it really was not apparent how big biology was. But once I got to Stuart's lab," he said, "I realized that biology was extremely broad and, if I wanted to work on a problem that was ultimately relevant to human health, I would need to focus further." What intrigued him most, he decided, was the puzzle of how neurons control the complex range of behaviors exhibited by humans and animals.
But for a synthetic chemist this meant starting at the beginning: an introductory neuroscience course at nearby Harvard Medical School. That class equipped Sternson with the language and basic concepts he needed to explore the world of neurobiology on his own, through reading and discussions with other scientists. The next step was to unite his interest in neuroscience with the work he had done in Schreiber's lab—and again, he found a perfect fit.
His work on the glucose-sensing pathway had opened his eyes to the tremendous amount of genetic resources that even a relatively simple organism like yeast devotes to balancing its energy intake. "Once I started thinking about that, I got really interested, because the process is so fundamental to life," he said. Thinking about how higher organisms deal with the same problem led Sternson to the lab of HHMI investigator Jeffrey Friedman at the Rockefeller University.
When Sternson came calling, Friedman's lab was busy studying a hormone called leptin—an important regulator of food intake and energy expenditure—that Jeff Friedman discovered in 1994. Sternson soon learned that leptin exerts its effects in the brain, and he became interested in the neural circuits that leptin acts on to regulate feeding.
Sternson was new to biology, but he dove right into postdoctoral research in the Friedman lab. "So in the lab, I learned molecular genetics and mouse physiology from Jeff. And I learned neuroscience through a combination of courses at the Marine Biological Laboratory in Woods Hole, Massachusetts, and by spending time in the lab of HHMI investigator Karel Svoboda [now a Janelia lab head] at Cold Spring Harbor."
He combined what he learned in Friedman's lab with technology developed in Schreiber's lab to begin to tease apart how leptin influences feeding behavior by acting on groups of neurons in the brain. The challenge, he says, is being able to manipulate neurons rapidly. "Most techniques for perturbing neuron function involve genetic methods, which operate on a timescale of days to weeks to months—whereas neuron activity occurs on the timescale of milliseconds to seconds," he explained.
"You want to develop a quick switch for the neurons. That's tricky, because the cells already express switches, but those are not unique to any one cell population. If you flip that switch, you might activate very large populations of cells, or entirely different brain systems. So it is difficult to learn anything specifically about the neurons that you are focused on," Sternson said.
To get around this problem, Sternson designed artificial receptors, or switches, that will respond only to synthetic chemicals. He used genetics to target these artificial switches to the precise neurons he wanted to study. This gave him complete control over their activation. By applying the synthetic molecule, he could turn on these neurons and watch what happens. During his research in the Friedman lab, this meant activating subsets of neurons that are normally under the control of leptin, then observing how that activation influenced feeding behavior.
As he delves into neurobiology, Sternson retains a chemist's sensibility, with its emphasis on rigorous detailed analysis and quantitative thinking. "When I think about problems of biology, I think about them as a chemist would; I take a reductionist approach. I like to break down a neural circuit into its component parts—just like you would break down a molecule into its component atoms, electrons, and bonds to analyze it," he said.
In setting up his own lab at Janelia, Sternson will use a similar approach to continue exploring how populations of neurons control behavior. "I aim to combine molecular biology with chemistry to develop new tools to answer hard questions in neuroscience," he noted.
He plans to develop mutant ion-channel receptors that can be genetically introduced into specific neurons. He will also design synthetic molecules that activate those receptors. He expects to work closely with lab head and fellow chemist Loren Looger to design these tools. He also anticipates interacting extensively with lab heads Karel Svoboda and Alla Karpova, and other Janelia researchers who share his goal of developing and applying techniques to modulate neuronal activity.
At Janelia, Sternson will focus on the hypothalamus, a region of the brain that governs innate behaviors such as feeding, reproduction, and the aggressive and defensive behaviors associated with the fight-or-flight response. "Because of the complexity of neural circuitry, when I thought about the types of problems I wanted to work on, I decided to focus on behaviors that are more innate, that are encoded within the circuitry," he said.
Sternson's goal is to integrate his knowledge of these neurons, so that he can map the intricate hypothalamic circuitry. While he will approach his studies by targeting groups of neurons that he suspects control a specific behavior, he thinks his work can also help reveal those cells' roles in other behaviors.
"You can turn neurons you think are involved in feeding behavior on or off, and it's pretty simple to determine how much the animal eats over the next half hour," he said. "But what if a group of neurons winds up being responsible for heart rate instead?" To help him detect unexpected effects like these, Sternson will set up a battery of tests for behaviors that are likely to be controlled by the hypothalamus. These tests will be an important resource for colleagues at Janelia who are exploring similar questions, as well.
Sternson says that being at Janelia offers a unique opportunity to tackle the questions he's interested in. "Had I not come to Janelia, in order to work on these types of projects, I would have had to focus on a specific behavior so that I could write a targeted grant with appropriate preliminary data. When I got the opportunity to come to Janelia, it opened up the possibility of taking a wider view of this problem. Instead of saying, 'Let me just try to find the neurons that control feeding,' I started thinking, 'Why don't I actually set up a whole battery of tests?' This will take a decent amount of resources, and outside of Janelia that could be tough, especially when you are just starting out," he said.
Sternson was first drawn to Janelia by an evocative question posed on its Web site: "How do you look at a problem differently?" The question caught his attention, because it echoed his own approach to research.
"This question really spoke to me, because I had come at problems of neuroscience like a chemist, and this is different than the rest of the field," he said. "Under these circumstances, sometimes you feel like an outsider. I was attracted to the personal fit with Janelia because there are all sorts of characters with exciting and unusual backgrounds coming together there. If I didn't come to Janelia, I thought I would be missing out on a once in a lifetime opportunity."