From The Quarterly, Spring 2011
“What’s most hopeful about our field today is the fact that we have the technologies in hand that will get the answers to mental illness in ways never before possible,” says Bryan Roth, M.D., Ph.D., and member of the Brain & Behavior Research Foundation Scientific Council. “We’re going to know all the genes involved, and the circuits that regulate complex behaviors. And from the intersection of those two areas, I believe new treatments will become obvious. The insights we obtain will lead to discoveries that will transform the lives of people with these illnesses.”
Dr. Roth speaks from the perspective of one who spends long hours in the lab, conducting research on how to design more effective drugs, based in part on technologies that he and his protégés have invented. NARSAD Grants have helped support new projects conceived by some of the lab’s most promising doctoral students.
One technology invented by Dr. Roth and colleagues, based on Dr. Roth’s 2008 NARSAD Distinguished Investigator Grant, goes by the acronym DREADD, for Designer Receptors Exclusively Activated by Designer Drugs. These manmade receptor molecules can be genetically introduced into any cell in mice, which are used to model human illnesses. The DREADDs enable scientists to switch “on” and “off” specifically selected nerve cells in the brain. In this sense, DREADDs are akin to a revolutionary method devised by another Brain & Behavior Research Foundation Scientific Council Member, Dr. Karl Deisseroth, whose ‘optogenetics’ technology enables researchers to activate and deactivate specific neurons with beams of colored light.
Dr. Roth’s DREADDs which his lab has synthesized and bred into a line of mice, now available to researchers worldwide provide a means of determining precisely which effects of a drug to attribute to the drug’s action on its intended target(s), and which (if any) are generated by socalled ‘off-target effects,’ i.e., impacts on parts of the cell or neural circuitry that are not expected. Using DREADDs, Dr. Roth’s team recently reported success in teasing out the details of neural circuitry that had long eluded scientists’ best efforts one that connects several brain regions involved in the biology of addiction.
Another of the lab’s major efforts addresses the problem of how to optimally design drugs that hit multiple targets the ‘shotgun approach.’ In designing a drug to hit a single target, it’s relatively simple to set up screens that will show which molecules adhere best to the target. Multiple target drugs present a much deeper challenge, since rational design implies biological knowledge of interactions among multiple parts of one or more neural circuits. The Roth team’s approach turns the traditional drug discovery process on its head.
“Rather than screen every proposed drug molecule against every known target, we asked, ‘Is there a way to predict the target?’ With some colleagues, including my longtime collaborator Brian Shoichet at UCSF and his brilliant student Michael Keiser, we came up with computer programs that explore possible drug interactions mathematically.” It’s part of a field called chemo-informatics, and what excites Dr. Roth is that with it his team was able in a 2009 demonstration to sift 3,665 known drugs against hundreds of known targets and identify many interactions that no one had ever seen or anticipated. Even better, he said, the team actually validated 23 of these experimentally, and one was successfully tested in a mouse model.
Bryan L. Roth, M.D., Ph.D.
Scientific Council Member
Michael Hooker Distinguished Professor
Department of Pharmacology, School of Medicine
Department of Medicinal Chemistry and Natural Products, School of Pharmacy
Director, NIMH Psychoactive Drug Screening Program
University of North Carolina Chapel Hill Medical School