Translational Technologies

Development of Metrics for Heterogeneity in Drug Discovery and Development

 

One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, it is not routinely evaluated or reported. To address this need we have developed the Pittsburgh Heterogeneity Indices (PHI) (Gough, A.H., N. Chen, T.Y. Shun, T.R. Lezon, R.C. Boltz, C.E. Reese, J. Wagner, L.A. Vernetti, J.R. Grandis, A.V. Lee, A.M. Stern, M.E. Schurdak, and D.L. Taylor; PloS one, 2014, 9:e102678) to measure reproducibility in heterogeneity (QC-KS), and to identify, quantify and characterize heterogeneity in cellular and small organism assays, to guide decisions during drug discovery and experimental cell/tissue analysis.

 


 

One of the benefits of the PHI is the ability to browse cellular distributions in large scale experiments. In the Heterogeneity Browser, the distributions are organized by shape as characterized by the PHI. The browser allows the user to drill down into a subset of the distributions selected by shape, PHI, compound name, plate, concentration, IC50 or dose relative to IC50 (Gough, A., T.Y. Shun, D. Lansing Taylor, and M. Schurdak;Methods, 2016, 96:12-26). Standardizing methods and providing tools for the analysis of Heterogeneity will enable a better understanding of the relationships between compound mechanisms, cellular pathways and variation in cellular response and drive the development of combination therapies that address whole population of cells, rather than just a subpopulation.