Completion of the genomes of humans and several other organisms creates the foundation for translating this rich knowledge base into new products for the improvement of human medicine. A critical component of realizing the promise of genomics efforts is access to well-characterized chemical compounds that bind to and alter the activities of specific gene products. To this end, modern technologies for genome-wide expression profiling and high throughput proteomics provide the enabling foundation for large-scale chemical biology initiatives, using chemical compounds as discovery tools to probe biological pathways, thereby revealing new protein targets that alter cellular phenotypes in potentially beneficial or insightful ways. It is becoming recognized that many critical points of biological pathway regulation are predicated on protein-protein interactions rather than enzyme-based catalysis of cellular products to substrates. Thus, traditional methods of drug discovery are limited in the scope of targets they can adequately address. Screening scientists are finding that elucidation of cellular responses to chemical compounds at critical points of biological pathway regulation can be enabled by image-based cellular assays that automatically measure protein dynamics via computer vision of pattern and organelle translocations. Subunits of membrane and intracellular receptors often respond by reorganization or translocation. In addition, cellular heterogeneities that are both physiological (e.g., cell division cycle phase-specific) or apparently random can overwhelm whole-well conventional high throughput screening HTS readouts. These are examples of the ways that cell-image-based instruments can dramatically increase the information content of automated assays. The drawback of cell-image-based screening has been that instruments imaging at medium microscopy resolution (approximately 0.5 - 2.0 mu/m with 10-40x objectives) are typically limited to about 25,000 wells per day as compared with rates of 100,000 or more wells/per day for HTS conventional whole-well plate-reader HTS systems. While higher rates have been reported, these increases have been typically achieved by sacrificing resolution (e.g., even lower magnification objectives or substantial camera binning). Here we propose to increase the fundamental image scanning bandwidth (measured in pixels/s) by 10- fold over the current Beckman Coulter IC-100 instrument, the prototype of which was developed in Dr. Price's academic laboratory and first commercialized by Q3DM Inc. This increase will be gained by application of fundamentally new principles that parallelize auto-focus and image acquisition to scan slides and microtiter plates in long, unbroken continuous-motion multi-color strips. This will result in screening speeds of over 100,000 wells per day using medium resolution objectives (10-40x dry magnification).
