With the completion of the Human Genome Project in 2003, scientists have a basic blueprint of our DNAand the genes it contains. While the project answered many questions, it also left many unanswered. How and why are genes turned on and off? What proteins do specific genes produce? What do those proteins do, and how does their activity affect our health?The Conrad Prebys Center for Chemical Genomics (Prebys Center) seeks to answer these and other questions by finding small molecule chemical compounds that selectively bind to a specific protein and turn it on or off. Small molecules are valuable because they help scientists determine a protein’s function in a cell. These are the first steps toward understanding how a dysfunctional protein can cause disease—important knowledge that can lead to new treatments.

After investigators isolate a protein implicated in disease, they can use the Center’s ultra high-throughput robotic systems to search for chemical compounds that alter that protein’s function. Small quantities of biological material (measured in nanoliters or one billionth of a liter) are combined with reagents and chemical compounds in a series of tiny wells arrayed on a plate. The goal is to find the compounds that most effectively alter the activity of the protein. These active compounds are called “hits” and are the starting points for drug discovery. With more than 700,000 compounds in various chemical libraries, the Prebys Center has the raw materials to make an enormous impact on the global hunt for new medicines.

In addition to its four ultra high-throughput screening robots, the Prebys Center features image-based screening systems, which use robotics to produce images of individual cells using high-throughput microscopes and computer-based image analysis. The Center uses this capability to identify compounds that change the cell by interfering with cellular function. Hits from these experiments provide new avenues to explore how complex cellular functions are performed. They can also find compounds that alter the characteristics of a diseased cell.

Once active compounds are found, medicinal chemists and pharmacologists collaborate to refine them further by making small alterations in their chemical structures. Transforming a hit into a lead compound means creating a molecule that has a greater affinity for a protein and more effectively regulates its function.

For researchers, the active compounds that come from these assays are like tweezers to dissect a cell’s biology. They can be used to investigate what happens to an organism when a protein is altered, to study how an aberrant protein causes disease and to influence how stem cells develop and differentiate. In some cases, a promising lead compound can be refined further to create a new drug to treat disease. Sanford-Burnham is one of only a handful of nonprofit research institutes to have these advanced drug screening capabilities, a critical first step toward translating basic research into new medicines.