Decoding the Chemical Brain: The Newhouse lab’s unique approach to neuroscience

Whereas scientific discoveries of the past were usually made in discrete fields of study, researchers today often must draw from several knowledge bases to advance our understanding of the world. Chemistry, biology, and physics are increasingly interwoven in modern innovations. Timothy Newhouse, who joined the Yale Chemistry Department last summer as an Assistant Professor, brings this interdisciplinary spirit with him. Newhouse studied natural products with anticancer applications as a graduate student, while his postdoctoral work revolved around mechanistic organometallic chemistry. At Yale, he plans to embark on an ambitious research plan that will combine diverse fields from physical organic chemistry to neuroscience: the synthesis and use of neurologically active natural products to explore the mysteries of cognition.

Many of the most common drugs used today were first derived from natural sources, from the morphine found in poppy plants to the aspirin in willow bark. In fact, 34% of small molecule therapeutics introduced over the last three decades fall into this category. The Newhouse lab plans to focus on those natural compounds with less well-characterized biological activities. The first such molecule they will tackle is gingkolide B, one of the active ingredients in gingko. While the molecule is widely used in herbal remedies to enhance memory and combat dementia, its mechanism of action is unclear. Newhouse’s team hopes that elucidating these mechanisms will provide valuable insight into the neuroscience behind memory.

“We want to synthesize gingkolide B and its analogs to use these compounds as tools to enable the understanding of how memories are formed, stored, and recalled on a molecular level,” Newhouse explained.

To create their tools, the Newhouse lab will employ a powerful oxidation reaction that permits the formation of carbon rings found in most natural products in an efficient and environmentally friendly manner. They also plan to delve into computational chemistry, using Yale’s High Performance Computer Center to optimize the synthetic reactions. This massive computing power will allow them to not only model and improve the efficiency of natural product synthesis, but also to modify the reactions to produce derivatives with greater efficacy than the parent compounds.

“In synthetic neurochemistry we generate a variety of presently unknown structures related to the natural compounds — structures which may have improved biological properties or which are easier to access synthetically,” said Newhouse.

The Newhouse lab’s potential for synthesizing neuroactive natural products has not gone unnoticed by those at Yale wishing to study them. Alex Kwan, an Assistant Professor in the Psychiatry Department who studies neural circuits in mice, is interested in identifying changes in the brain caused by Newhouse’s compounds. By combining his techniques for imaging neural activity in live mice with synthetic small molecules, Kwan can identify their effects on neurotransmission in mouse models of psychiatric disorders. Another collaborator, Dr. Henry Huang at the Yale Positron Emission Tomography (PET) Center, Department of Diagnostic Radiology, might use radiolabeled versions of the Newhouse lab’s compounds as PET imaging tracers, which would allow him to study how these compounds distribute and interact with biomolecules in the living body in real-time.

These collaborations will help inform Newhouse and his group’s research. After optimizing the synthetic process, they plan to use cell-based assays to determine the mechanisms of action for natural products. They will start by screening their molecules against the National Institute of Mental Health’s library of transmembrane proteins that are targets for many neuroactive compounds. The proteins that bind the small molecules will be identified as potential targets for more intensive study in the lab. The screening process can also be combined with results of the imaging and PET studies from Kwan and Huang to select the neuronal cell types where the molecules may have the greatest effect.

Ultimately, Newhouse and his team want to use the cellular mechanisms they discover to decode the complexities of neuroscience. Through studies with gingkolide B and a range of neuroactive natural products, they plan to connect the mysterious chemical brain to our everyday experiences of memory and self.

“Neuroscience is a field at its infancy with respect to our understanding of many of the basic molecular aspects of its operation,” said Newhouse. “By bringing the tools of synthetic chemistry to this area, we are positioned to ask questions that researchers with alternative skill sets are not trained to consider.”