Dr. Wiseman has 30 years of experience in drug discovery research in the pharmaceutical industry. He recently joined Edelweiss Connect as Senior Fellow in the team that is building computational tools to promote multiple facets of chemical safety – including toxicology, low environmental impact, and green manufacturing - in multiple industries He previously held positions as worldwide vice president and member of the Research Executive Council of the pharmaceutical company GlaxoSmithKline and then as Chief Technology Officer at the biotechnology company Locus Pharmaceuticals. At Locus he participated in raising $32 MM in financing and established research collaborations valued at $60 MM. Most recently, he served for 10 years as Executive in Residence, Senior Research Scientist, and Adjunct Professor of Chemistry and Biochemistry at Ohio University. In these roles he conducted independent research on natural products as therapeutic agents and was responsible for identifying and advancing life science technologies to commercialization. These efforts advanced 5 companies to the pre-seed funding stage. Dr. Wiseman holds a B.S. degree summa cum laude in chemistry from Ohio University and a Ph.D. in chemistry from Harvard University, with postdoctoral studies in biochemistry at Stanford and Brandeis Universities. He retired from Ohio University in 2022.
Development and Testing Strategies for Mechanistic Toxicology Models
Steatosis, which itself is benign, is of interest in toxicology because it is often a precursor to more serious steatohepatitis. Major efforts are currently underway to understand the biological mechanisms underlying steatosis and their relation to progression to serious liver injury. As a major result of these efforts, the nuclear receptor family of transcription factors have been identified as major regulators of lipid metabolism, and dysregulation of this family has been shown to lead to lipid accumulation, which is the hallmark of steatosis. It has been proposed that highly prevalent forms of toxicity will arise from promiscuous interactions, i.e. more dependent on compound physical or reactivity properties than structure-specific ligand-protein interactions. Some, but not all members of the nuclear receptor family can be considered promiscuous in their ligand profiles and therefore fit this paradigm. This presentation recognizes, however, that a majority of compounds that cause steatosis are lipophilic and partition into cellular membrane. It is hypothesized that cellular membrane disruption is a major alternative cause of steatosis. We outline the kinds of information that will be required to test this hypothesis and preliminary data to support the hypothesis. A major purpose of the presentation is to outline the data management system that is currently being assembled to support testing of this specific hypothesis and can be generalized for testing of any hypothesis of toxicity mechanisms. This system recognizes the need not just to mine existing data but also to identify the additional hypothesis-specific data required and new assays to generate this data.
