His research lab at Yale University, Newhouse Group, is pioneering the synthesis of natural molecules that lie at the heart of human biological functions and potential medicines. This month, he will receive the American Chemical Society’s Arthur C. Cope Scholar Early Career Award—the latest of many accolades.
A molecular chess game
At Yale, Newhouse leads a group of undergraduate, graduate, and postdoctoral researchers in making complex small molecules that have been isolated from natural sources so that they can be engineered for medicine. His group focuses on neurologically active compounds that play a role in diseases such as Alzheimer’s or Parkinson’s; others could be useful in treating cancer or diabetes. To synthesize such molecules, researchers must successfully predict and then carry out a series of chemical reactions.
“In many ways, it’s like a chess game, where one needs to plan out a series of maneuvers ahead of time and then react to the information that one obtains,” Newhouse said.
Sometimes, like an unanticipated checkmate from an opponent, a late step in the synthesis process fails after months or years of work. To counter this risk, Newhouse’s lab uses computational chemistry, performing calculations ahead of time to help identify likely pathways to success.
“It’s much faster to make a prediction than it is to do the experiment,” he said. Computational chemistry—specifically, a modeling method called density functional theory—recently helped Newhouse and colleagues synthesize a cancer-fighting molecule called paspaline A in nine steps rather than the 25 steps as reported previously. The team is now working on ways to integrate machine learning, which involves training a computer to use what is known about certain molecules and reactions to evaluate potential synthesis pathways.
Newhouse liked chemistry in high school and intended to major in this subject along with German literature, but he didn’t have a specific career path in mind when he enrolled at Colby. He grew up moving among small towns and rural areas of New Hampshire, Massachusetts, and Maine, a Boy Scout who spent a good part of his childhood outside. At Colby, he competed on the Woodmen’s Team when he wasn’t studying.
“Growing up in an economically disadvantaged community, one doesn’t have much opportunity,” Newhouse said, and that changed when he went to college. “Being at Colby, there was a huge amount of possibility.”He took an accelerated general chemistry course with Whitney King, the Dr. Frank and Theodora Miselis Professor of Chemistry, who encouraged students to conduct their own research—an unexpected and welcome option for Newhouse. An organic chemistry class with Professor of Chemistry Das Thamattoor led him to join Thamattoor’s lab, conducting his honors research on syntheses of highly reactive compounds.
“It was doing experimental research as an undergraduate that was transformative for me,” Newhouse said. “I began to love not just organic chemistry, but the process of generating hypotheses and being able to test those hypotheses with an experiment.”
Thamattoor remembers how Newhouse thrived in the notoriously difficult organic chemistry field. “It’s almost an unteachable quality, his ability to see things that most people wouldn’t right off the bat,” Thamattoor said.
After Colby, Newhouse took a year to work at a free health clinic in New Orleans, helping to fill a gap in care left after Hurricane Katrina. He wanted to have an impact on healthcare, but his time in New Orleans was no detour: by then, he was already set on pursuing organic chemistry. During that year, he also taught high school chemistry at United World College of the Adriatic in Italy, which cemented his desire to teach. He went on to earn his doctorate at the Scripps Research Institute and spent three years as a postdoctoral research fellow at Harvard University before starting at Yale in 2013.
“It was doing experimental research as an undergraduate that was transformative for me. I began to love not just organic chemistry, but the whole process of running reactions, generating hypotheses, and being able to test those hypotheses with an experiment.” —Timothy Newhouse ’05
As a teacher, he thinks all the time about the challenges of getting people to love organic chemistry rather than fearing it. To him, organic chemistry is an appealing mix of scientific logic and visual problems that require creativity and analysis on several levels to solve.
“I love seeing and facilitating that ‘a-ha’ moment when someone is struggling with a problem,” he said of teaching. “Eventually one can direct a student to have the epiphany that they were trying to have.”
The Cope Award comes with an unrestricted $40,000 in funding for research. Newhouse doesn’t yet know to which project the funds will be directed, but he does know that he wants to keep advancing the combination of organic synthesis and computational chemistry to accelerate discovery. He noted the funding is important for “high-risk, high-reward projects” that federal funding agencies aren’t typically able to support.
His former professor and mentor is excited to see the direction Newhouse’s research is taking. “He has just really blossomed as a chemist,” Thamattoor said. And when Newhouse came back to campus for a visit a few years ago, Thamattoor offered him a turn teaching a session of the same organic chemistry course he had taken as an undergrad: “I just sat in the back with a camera, puffing out my chest.”