Chemical Screening Center at UCSC will search for new drugs

Scott Lokey, assistant professor of chemistry and biochemistry, shows off one of the robotic instruments in the new Chemical Screening Center. Photo by Hugh Powell.

Researchers at the University of California, Santa Cruz, will shift their search for potential drugs into high gear on September 21, when a new Chemical Screening Center opens for business. The center will allow researchers to perform up to 30,000 experiments per day as they test chemical compounds for usefulness in fighting disease or understanding fundamental aspects of a cell's life. A half-day symposium and reception will mark the opening day.

The screening center will be shared by UCSC faculty in the Departments of Chemistry and Biochemistry; Molecular, Cell, and Developmental Biology; and Environmental Toxicology. Researchers will use its six robots and library of 55,000 compounds to study cancer, malaria, Parkinson's disease, cholera, and the mechanics of inflammation, among other ailments. Additional projects include studies of cell division, DNA transcription, and the ways in which genes regulate cell life.

The $500,000 center gives an enormous boost to UCSC's capability in the field of high-throughput screening. "It's where robotics meets biotechnology," said Scott Lokey, assistant professor of chemistry and biochemistry and lead investigator of the center. "We harness the ability of robots to do thousands of tedious manipulations in parallel, so we can focus on analyzing data."

Scientists searching for new disease treatments have an embarrassment of riches, Lokey said. Hundreds of thousands of chemical compounds look promising on paper. But with so many possibilities, testing each compound's activity against a welter of diseases, metabolic pathways, and reaction conditions can quickly fill up a lifetime's to-do list.

The answer is automation. "We're sort of taking the shotgun approach," Lokey said. "We throw tens of thousands of compounds at a problem until we find one that hits."

The new center consists of six robots. Three act as steady-handed lab technicians that unerringly handle tiny droplets of chemicals down to one-tenth of a microliter, or about four millionths of a fluid ounce. Needles flit across a plate containing 384 pen-cap-sized reaction wells, adding a variety of solutions to eight wells at a time. An automated stacker hovers over the machine holding another 49 plates, each awaiting the same treatment.

A fourth machine handles cleanup between reaction steps. The fifth and sixth measure experimental results by either detecting a light signal or recording an image through an automated 60-power microscope. Image-recognition software then identifies basic characteristics of the cell's life cycle and assembles preliminary results overnight to greet the researcher in the morning.

The new devices mark a huge improvement over the old method, Lokey said, which included manual equipment and a used machine that a pharmaceutical company had donated years earlier.

"We were doing 10 plates in a day, maximum, and it was very painful," he said. "And the way we were doing it led to a lot of inaccuracies because it was so tedious. With robots, you have a lot of inherent reproducibility in the manipulations that you don't have when you're doing it all by hand. Now you can put in 50 plates, come back after a cup of coffee, and have your compounds added. It lowers the barrier for biologists who want to do screening."

Drug companies routinely use high-throughput screening to test perhaps a million samples per day, Lokey said. Although the UCSC center is smaller, it's not as concerned with sheer volume.

"Instead of focusing on finding a blockbuster drug, we can be a bit more broad and discover compounds that could be used for basic research as well," Lokey said. "We are also going after infectious diseases like malaria and cholera that are still big health issues in the developing world. Drug companies have tended to shy away from these diseases, and it's up to academic screening centers to pick up the slack."

The diversity of research being performed at UCSC helps accomplish the center's broader goals. For example, typical drug discovery centers often focus on synthetic chemicals that are easy to produce and to modify; Lokey has a freezer full of more than 40,000 synthetic compounds to choose from when conducting analyses.

Added to this number are naturally occurring products with very different chemical structures and properties, compounds that have been painstakingly collected and purified by the research teams of Phil Crews, professor of chemistry and biochemistry, and Roger Linington, assistant professor of chemistry and biochemistry.

"About half of all drugs on the market come from natural sources," Lokey said. "Plants and many marine organisms have this uncanny ability to create diversity and complexity in terms of the molecules they produce. These molecules are much, much more complex and interesting from a chemical point of view than synthetic compounds. We've got two world-class natural-products chemists right down the hall from us, and we're hoping our work together will stimulate a lot of new discoveries."

Over several decades of work with marine sponges, Crews has compiled a screening library of 1,000 natural compounds that are unlike the substances produced in any other organisms. The UCSC group also has plans to collaborate with natural-products chemists at the Eijkman Institute of Indonesia and the Russian Academy of Sciences, among others.

The symposium will begin at 2:30 p.m., September 21, in room 240 of the Physical Sciences Building on the UCSC campus. A keynote address at 3 p.m. by Professor Jim Wells of the Small Molecule Discovery Center at UC San Francisco will be followed with a tour and ribbon cutting at the new center. A reception and scientific poster session will be held in the building's atrium.

The Chemical Screening Center was funded by grants from the National Institutes of Health, the U.S. Department of State, and the California Institute for Quantitative Biomedical Research.

In addition to Lokey, Crews, and Linington, other UCSC professors using the new center include Manuel Ares, Jr., professor of molecular, cell, and developmental (MCD) biology; Grant Hartzog, associate professor of MCD biology; Ted Holman, professor of chemistry and biochemistry; Tony Fink, professor of chemistry and biochemistry; Melissa Jurica, assistant professor of MCD biology; Douglas Kellogg, professor of MCD biology; John Tamkun, professor of MCD biology; Karen Ottemann, associate professor of environmental toxicology; and Fitnat Yildiz, assistant professor of environmental toxicology.

Note to reporters: You may contact Lokey at (831) 459-1307 or