Former NIEHS Scientific Director and Nobel Laureate the late Martin Rodbell, Ph.D., was best known for his work on understanding how a large family of receptors for GTP-binding proteins, or G-proteins, transmit signals in cells.
Bryan Roth, M.D., Ph.D., the 2017 speaker for the lecture series named in Rodbell’s honor, studies the same family of signaling proteins. By focusing his research on how these proteins interact with drugs, Roth hopes to find treatment options for neuropsychiatric disorders.
During his May 16 presentation on "How Chemical and Synthetic Biology Are Revolutionizing Biomedical Science," Roth concentrated on three aspects of his work — new drug discovery technologies, G-protein coupled receptors (GPCRs), and a chemogenetic technology his group invented called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs).
"DREADDs have become instrumental for many of the new advances in neurobiology," said Serena Dudek, Ph.D., deputy chief of the NIEHS Neurobiology Laboratory and host of the talk. "Much of Bryan's work involves G-protein coupled receptors, and so I can’t think of a more fitting or distinguished speaker for this lecture named after Dr. Martin Rodbell," she said.
What a long, strange trip
Roth said his interest in how chemical compounds exert their effects on the brain began in the late 1990s when he was an associate professor of psychiatry at Case Western Reserve University in Cleveland. A student came to him for advice after experiencing a terrifying episode from smoking a marijuana substitute. He was afraid he’d have lasting psychiatric damage.
The young man had used the herb Salvia divinorum, a plant discovered in the early 1960s. The active ingredient, Salvinorin A, is the world’s most potent naturally-occurring hallucinogen, rivalling D-lysergic acid diethylamide (LSD) in potency.
Roth said that many drugs and medicines on the market are sold without knowing their mechanism of action or targets, and he wanted to find those answers for S. divinorum and similar drugs. To do so, he had to develop a new screening method.
Roth's proposal to create libraries of molecular targets and then screen small molecules against them is the opposite of how screening is usually done. But he and his team tried it. They screened Salvinorin A, along with LSD as a control, against a small number of targets. LSD had multiple targets, while Salvinorin A had just one. Their proof of principle experiment worked.
"Although our assay platform was great, it didn’t have the breadth of targets we'd like to achieve," Roth said. "My dream was to set up a platform where we could screen all of the druggable targets in the genome simultaneously. We’re not there yet, but we're getting there."
Because GPCRs are the largest family of druggable targets, with about 900 members, Roth expanded his original platform to screen all of the GPCRs in the genome simultaneously in a 384-well plate. The method, called PRESTO-Tango, is available from Addgene, a nonprofit organization dedicated to making it easier for scientists to share small, circular pieces of DNA called plasmids.
Roth's innovative thinking led to a contract from the National Institute of Mental Health Psychoactive Drug Screening Program. He serves as the screening program's director at his current institution, the University of North Carolina at Chapel Hill School of Medicine. It is the only resource of its kind at an American university.
Controlling behavior with DREADDs
Scientists in the 1940s observed that turning on electrodes that were inserted into the hypothalamus of animals elicited certain behaviors, such as aggression. Turning the electrodes off eliminated the behavior. Roth and others wanted to create a genetically-encoded chemical switch for neurons that could turn on or off specific behaviors.
Roth was successful in developing these switches, called DREADDs, which can activate, inhibit, or regulate neuronal signaling.
"Ultimately, we hope the technology will lead to therapeutics for neuropsychiatric diseases," Roth said.
During his days as an M.D.-Ph.D. student at St. Louis University, Roth was fortunate to meet and talk science with Martin Rodbell. Roth was studying opiate receptors in the late 1970s and early 1980s, a time when half of his biochemistry department did not believe receptors existed. The few occasions he and Rodbell spoke helped affirm to Roth that his work was important.
"I was an unknown graduate student, and he was very kind to me," Roth said. "He listened intently to what I had to say and gave some really insightful ideas on where the research would ultimately go."