Design and implementation of cell-based assays to model human disease

Cell-based assays, if appropriately designed, can be used to rapidly identify molecular mechanisms of human disease and develop novel therapeutics. In the last 20 years, many genes that cause or contribute to diverse disorders, including cancer and neurodegenerative disease, have been identified. With such genes in hand, scientists have created numerous model systems to dissect the molecular mechanisms of basic cellular and developmental biology. Meanwhile, techniques for high-throughput screening that use large chemical libraries have been developed, as have cDNA and RNA interference libraries that cover the entire human genome. By combining cell-based assays with chemical and genetic screens, we now have vastly improved our ability to dissect molecular mechanisms of disease and to identify therapeutic targets and therapeutic lead compounds. However, cell-based screening systems have yet to yield many fundamental insights into disease pathogenesis, and the development of therapeutic leads is frustratingly slow. This may be clue to a failure of such assays to accurately reflect key aspects of pathogenesis. This Review attempts to guide the design of productive cellular models of human disease that may be used in high-throughput chemical and genetic screens. We emphasize two points: (i) model systems should use quantifiable molecular indicators of a pathogenic process, and (ii) small chemical libraries that include molecules with known biological activity and/or acceptable safety profiles are very useful.