Thursday, January 12, 2006
Presented by the Predictive Toxicology Discussion Group and Systems Biology Discussion Group
Organizer: David de Graaf, Pfizer
Systems approaches are showing early promise in helping bridge the gap between pathophysiological processes and their molecular determinants. Systems toxicology promises to deliver in this area. This meeting will showcase comprehensive approaches touching on experimental, computational, and regulatory aspects.
Mikhail Gishizky, Entelos, "Mechanistic Biosimulation Modeling to Predict Drug Efficacy and Safety."
Linda Griffith, Massachusetts Institute of Technology, "Human Body on A Chip: Microscale Tissue Engineering for Drug Discovery."
Yvonne Dragan, National Center for Toxicological Research, FDA, "Integrating OMICs Data for Systems Toxicology."
"Human Body on A Chip: Microscale Tissue Engineering for Drug Discovery"
The most visible applications of tissue engineering are in creation of new tissues and organs in patients. However, the need for better models of drug efficacy and safety in humans are driving the field of tissue engineering toward the creation of accessible in vitro 3D tissue models for drug discovery and development. Although animal models can capture important facets of human responses, they fail to capture others; for example, a leading cause for failure of new drugs in clinical trials is liver toxicity that was not predicted by animal or in vitro models. And while significant progress has been made in "humanizing" mice by transplanting human cells, such models are currently challenging and expensive to adopt for routine use in an assay format. 3D tissue models are likely to play an increasingly important role in screening new drugs for efficacy and safety in humans before clinical trials. This talk will focus on current efforts to create the "human body on a chip" for drug development with an emphasis on predictive liver toxicology.
"Integrating OMICs Data for Systems Toxicology"
Systems toxicology is the integrative assessment of the adverse effects of a compound as determined across multiple levels of biological complexity. These toxicity profiles provide biomarkers of the indicated toxicity and can be determined across chemical or pharmacological class. The assessment of toxicity profiles needs ultimately to be performed in accessible biofluids for applications to bridge preclinical and clinical development. Microarray analysis can be applied to tissues from animals treated with compounds with selected toxicity profiles to determine gene expression signatures that are indicative of that toxicity or that demonstrate pharmacological class. Tissue-derived transcripts provide information on the target tissue response. Alternatively and in keeping with the use of accessible biofluids, microarray analysis can be performed on white blood cells from animals that demonstrate liver toxicity or are in the same chemical or pharmacological class. Altered gene expression profiles can be indicative of tissue response to agent exposure. Since the tissue is in equilibrium with the blood supply and the urine, these biofluids provide a surrogate matrix to indicate changes in the liver itself. Proteomics is generally applied to both tissue and blood. Proteomic based approaches provide a useful mechanism of biomarker development that can be performed in preclinical and clinical models. Changes in protein may be reflected in the gene expression profiles, but differences in protein levels (and turnover), post-translational modifications, protein-protein, and cellular protein localization can also contribute to biomarker pattern development at the protein level. Metabolomics analyses can be performed on tissue, blood, or urine. Analysis of small molecule metabolites in tissue is the primary indicator of a toxic response. Metabolites in ser