Zachary Knight is turning the study of hunger, thirst, and thermoregulation on its head. How do we “know” when we’re full, for example? His research team at the University of California, San Francisco (UCSF), is racing to finding out – studying neural circuits in mice that underpin behaviors critical to maintaining the body’s homeostasis.

Knight didn’t go to college with aspirations of becoming a scientist. When he started at Princeton University, Knight was an economics major. But many of his friends were chemistry majors, and he was, in a word, jealous. “I was blown away by how fascinating their research was, and I switched majors,” he says.

By the time Knight took up chemistry, late in his junior year, there was only one chemical biology lab with space, and it belonged to HHMI Investigator Kevan Shokat, then a junior faculty member.

“I set up a time to meet and talk with Kevan about the possibilities,” Knight recalls. But when Knight arrived, Shokat wasn’t there. Instead, he found a single Post-it note on Shokat’s office door saying, “Yes, you can join the lab.”

That Post-it note, and the research opportunity it represented, changed Knight’s life.

Knight eventually followed his mentor across the country to UCSF for his doctoral work. The two worked together for a decade, discovering some of the first inhibitors of PI3 kinase and mTOR – enzymes involved in metabolism and cell growth. Knight and Shokat co-founded a biotech company, Intellikine, with the goal of developing cancer drugs based on Knight’s graduate work and moving them into clinical trials.

As a postdoc at the Rockefeller University, Knight learned how to delve deep into the brain, identifying neuron clusters controlled by the hypothalamus that play a role in hunger and other behaviors. Afterward, he brought this passion back to UCSF and started his own lab focused on physiology.

Knight says he approaches every neuroscience question with his chemist’s goggles on. His team is now tackling the mystery of how neurons assess the body’s internal state – and challenging long-held assumptions in the process.

Previously, scientists thought neurons that control hunger became activated gradually when the body was deprived of food and then were inhibited with the onset of satiety. But Knight’s team found that, as soon as a hungry mouse smelled food, the hunger neurons shut off – before the mouse even started its meal. “These neurons use sensory cues to make a prediction about how many calories the mouse is about to eat and then shut themselves off in proportion to that prediction,” he says. “This was incredibly surprising.”

The discovery earned Knight the Novo Nordisk Helmholtz Young Investigator in Diabetes Award in 2016, one of several early-career awards he has received. But for Knight, this finding was just the beginning. “As soon as we saw that result, we realized how much we don’t know about these systems,” he says.

When he needs to clear his mind, Knight heads north to ski at Lake Tahoe. On the slopes, he gets to step away from the big questions that dog his time in the lab. He knows that more progress could yield exciting dividends, like a better design for obesity treatments or a drug that could assist with weight loss. “That’s not the reason for my research,” he says. “But imagine a pill that left you feeling full without eating a thing.”