Patrick McDonough has been interested in microscopy and cell biology, through out his career. Pat’s initial interests were focused on marine organisms, and he received his Ph.D., in Marine Biology from Scripps Institution of Oceanography, in 1984. Realizing that his true passion was experimental biology, Pat switched to research on cell biology/physiology, joining the UCSD School of Medicine, Department of Pharmacology, as a post-doctoral fellow. Pat has always been fascinated with the physiology of cardiac and skeletal muscle cells, and the role of intracellular calcium in contraction and gene expression. Since the late 1980’s Pat has used fluorescent calcium indicators (e.g., fluo-4, invented by Roger Tsien), to visualize and quantify calcium transients that underlie cellular phenomenon in cardiac myocytes, skeletal muscle, neurons, and other cell types. The evolution of digital cameras, computers, automated microscopes and image analysis algorithms, set the stage for development of high throughput methods for visualizing calcium and voltage transients in excitable cells. Pat joined Vala Sciences Inc in 2004 (founded by Jeffrey Price, a pioneer in the automated microscopy and “high content analysis”), to develop cell-based assays for drug-discovery and toxicology. With funding from NIH STTR/SBIR grants, Vala Sciences, in collaboration with academic researchers at the Sanford Burnham Prebys Medical Discovery Institute, developed the Kinetic Image Cytometer (KIC), a purpose-built instrument to quantify calcium or voltage transients, for cells plated in 96- or 384-well formats. Pats current research develops KIC methods to enable high-throughput screening of chemical compounds/genomic constructs for beneficial or harmful effects relevant to heart failure, arrhythmias, and neurobiology.
Kinetic image cytometry (KIC) creates single cell measurements of dynamics of events such as action potentials and calcium transients in all cells, and is especially compelling for fast-acting cells such as cardiomyocytes and neurons. Kinetic plate readers (e.g., FLIPR and FDSS) provide well-averaged readouts that require synchronized cellular behaviors, whereas our novel KIC parameterizes Ca2+ transients and action potentials on each cell; e.g., typically on 300-500 cardiomyocytes in a field of view simultaneously. Developed collaboratively by Vala Sciences and Jeff Price’s and Mark Mercola’s academic labs at Sanford-Burnham-Prebys Medical Discovery Institute (SBP), KIC has been used to detect arrhythmogenic and toxic effects in early drug discovery, and for drug discovery for heart failure. The presentation will primarily report on the accuracy of KIC for predicting arrhythmia from kinetics of the calcium transients in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and will also include some examples of application to hiPSC-derived neurons.
This continuing medical laboratory education activity is recognized by the American Society for Clinical Pathology for 1 CMLE credit. ASCP CMLE credits are acceptable for the ASCP Board of Registry Certification Maintenance Program.