Biomolecular Screening Branch

Warren Casey, Ph.D.
Acting Chief, Biomolecular Screening Branch

Tel 984-287-3118
warren.casey@nih.gov

P.O. Box 12233

Mail Drop K2-16

Durham, N.C. 27709

Delivery Instructions

Research Summary

The Biomolecular Screening Branch (BSB), headed by Warren Casey, Ph.D., develops and carries out programs in medium and high throughput screening of environmental substances for rapid detection of biological activities of significance to toxicology.

The Branch develops analysis tools and approaches that integrate its assessment with findings from traditional toxicology.

The Branch also administers the National Toxicology Program (NTP) High Throughput Screening (HTS) Initiative called Tox21, a major initiative within NTP's Roadmap to achieve its vision for Toxicology in the 21st Century. Tox21 places an increased emphasis on the use of alternative assays for targeting the key pathways, molecular events, or processes linked to disease or injury, and attempts to incorporate them into a research and testing framework. In support of this Program, the Biomolecular Screening Branch represents the NTP in the Toxicology in the 21st Century Partnership.

Tox21 is a unique collaboration between several federal agencies to research and test chemicals in a new way. The goals of the Tox21 partnership are to:

• Identify patterns of compound-induced biological response in order to characterize toxicity/disease pathways, facilitate cross-species extrapolation, and model low-dose extrapolation
• Prioritize compounds for more extensive toxicological evaluation
• Develop predictive models for biological response in humans

The Branch’s involvement in Tox21 complements the support the Biomedical Screening Branch provides NTP in programmatic needs to evaluate the adverse effects of chemical exposure on human health. Branch scientists strive to improve the relevance of assay findings to human health outcomes, providing data from a variety of high throughput and/or high content approaches and developing computational approaches to best analyze those data.

The goals of the Biomolecular Screening Branch are carried out by 3 groups and adjunct staff from the Division of the National Toxicology Program and the Division of Intramural Research:

• Genetic Toxicology Group
• Molecular Toxicology & Genomics Group
• Spatiotemporal Health Analytics Group
• Toxicoinformatics Group

Selected Publications

1. Innes CL, Hesse JE, Morales AJ, Helmink BA, Schurman SH, Sleckman BP, Paules RS. DNA Damage Responses in Murine Pre-B Cells With Genetic Deficiencies in Damage Response Genes. Cell Cycle 2019; doi: 10.1080/15384101.2019.1693118 [Online 22 November 2019]. [Abstract Innes CL, Hesse JE, Morales AJ, Helmink BA, Schurman SH, Sleckman BP, Paules RS. DNA Damage Responses in Murine Pre-B Cells With Genetic Deficiencies in Damage Response Genes. Cell Cycle 2019; doi: 10.1080/15384101.2019.1693118 [Online 22 November 2019].]
2. Ramaiahgari SC, Auerbach SS, Saddler T, Rice JR, Dunlap PE, Sipes NS, DeVito MJ, Shah R, Bushel PR, Merrick BA, Paules RS, Ferguson SS. The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals using High-throughput Transcriptomics and Benchmark Concentration Modeling. Toxicological Sciences 2019 [Abstract Ramaiahgari SC, Auerbach SS, Saddler T, Rice JR, Dunlap PE, Sipes NS, DeVito MJ, Shah R, Bushel PR, Merrick BA, Paules RS, Ferguson SS. The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals using High-throughput Transcriptomics and Benchmark Concentration Modeling. Toxicological Sciences 2019]
3. Ryan, K. R., Sirenko, O., Parham, F., Hsieh, J.-H., Cromwell, E. F., Tice, R. R., & Behl, M. Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high- throughput screen for developmental neurotoxicity or neurotoxicity. NeuroToxicology. [Abstract Ryan, K. R., Sirenko, O., Parham, F., Hsieh, J.-H., Cromwell, E. F., Tice, R. R., & Behl, M. Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high- throughput screen for developmental neurotoxicity or neurotoxicity. NeuroToxicology.]
4. Hsieh, J. H., Sedykh, A., Huang, R., Xia, M., & Tice, R. R. (2015). A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays. J Biomol Screen, 20(7), 887-897. [Abstract Hsieh, J. H., Sedykh, A., Huang, R., Xia, M., & Tice, R. R. (2015). A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays. J Biomol Screen, 20(7), 887-897.]
5. Chen S, Hsieh JH, Huang R, Sakamuru S , Hsin LY, Xia M, Shockley KR, Auerbach S, Kanaya N, Lu H, Svoboda D, Witt KL, Merrick BA, Teng CT, Tice RR. Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library. Toxicological sciences: an official journal of the Society of Toxicology 2015 147(2):446-457. [Abstract Chen S, Hsieh JH, Huang R, Sakamuru S , Hsin LY, Xia M, Shockley KR, Auerbach S, Kanaya N, Lu H, Svoboda D, Witt KL, Merrick BA, Teng CT, Tice RR. Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library. Toxicological sciences: an official journal of the Society of Toxicology 2015 147(2):446-457.]
6. Behl, M, Hsieh, JH, Shafer, TJ, Mundy, WR, Rice, JR, Boyd, WA, Freedman JH, Hunter III ES, Jarema KA, Padilla S, Tice, RR. 2015. Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicology and Teratology, 52, Part B: 181-193. [Abstract Behl, M, Hsieh, JH, Shafer, TJ, Mundy, WR, Rice, JR, Boyd, WA, Freedman JH, Hunter III ES, Jarema KA, Padilla S, Tice, RR. 2015. Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicology and Teratology, 52, Part B: 181-193.]
7. Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. (2015). Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect., 123(5):458-466. [Abstract Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. (2015). Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect., 123(5):458-466.]
8. Adler, M., Ramm, S., Hafner, M., Muhlich, J. L., Gottwald, E. M., Weber, E., Jaklic A., Ajay A.M., Svoboda D., Auerbach S., Kelly E.J., Himmelfarb J., Vaidya, V. S. (2015). A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. [Abstract Adler, M., Ramm, S., Hafner, M., Muhlich, J. L., Gottwald, E. M., Weber, E., Jaklic A., Ajay A.M., Svoboda D., Auerbach S., Kelly E.J., Himmelfarb J., Vaidya, V. S. (2015). A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol.]
9. Attene-Ramos M. S., Huang, R., Michael, S., Witt, K. L., Richard, A., Tice, R. R., Simeonov A., Austin C.P., Xia, M. (2015). Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect, 123(1), 49-56. [Abstract Attene-Ramos M. S., Huang, R., Michael, S., Witt, K. L., Richard, A., Tice, R. R., Simeonov A., Austin C.P., Xia, M. (2015). Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect, 123(1), 49-56.]
10. French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, et al. (2015). Diversity outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect, 123:237-245. [Abstract French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, et al. (2015). Diversity outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect, 123:237-245.]
11. Huang R, Sakamuru S, Martin MT, Reif DM, Judson RS, Houck KA, Casey W, Hsieh JH, Shockley KR, Ceger P, Fostel J, Witt KL, Tong W, Rotroff DM, Zhao T, Shinn P, Simeonov A, Dix DJ, Austin CP, Kavlock RJ, Tice RR, Xia M. Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. Scientific reports 2014 4():5664-. [Abstract Huang R, Sakamuru S, Martin MT, Reif DM, Judson RS, Houck KA, Casey W, Hsieh JH, Shockley KR, Ceger P, Fostel J, Witt KL, Tong W, Rotroff DM, Zhao T, Shinn P, Simeonov A, Dix DJ, Austin CP, Kavlock RJ, Tice RR, Xia M. Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway. Scientific reports 2014 4():5664-.]
12. Tice RR, Austin CP, Kavlock RJ, Bucher JR. Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 2013; 121(7):756-765. [Abstract Tice RR, Austin CP, Kavlock RJ, Bucher JR. Improving the human hazard characterization of chemicals: a Tox21 update. Environ Health Perspect 2013; 121(7):756-765.]
13. Attene-Ramos MS, Miller N, Huang R, Michael S, Itkin M, Kavlock RJ, Austin CP, Shinn P, Simeonov A, Tice RR, Xia M. The Tox21 robotic platform for assessment of environmental chemicals - from vision to reality. Drug Discovery Today 2013; 18: 716-723.
14. Huang R, Cho M-H, Sakamuru S, Shinn P, Houck KA, Dix DJ, Judson RS, Witt KL, Kavlock RJ, Tice RR, Austin CP. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 2011; 119(8): 1142-1148. [Abstract Huang R, Cho M-H, Sakamuru S, Shinn P, Houck KA, Dix DJ, Judson RS, Witt KL, Kavlock RJ, Tice RR, Austin CP. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 2011; 119(8): 1142-1148.] [PDF Huang R, Cho M-H, Sakamuru S, Shinn P, Houck KA, Dix DJ, Judson RS, Witt KL, Kavlock RJ, Tice RR, Austin CP. Chemical genomics profiling of environmental chemical modulation of human nuclear receptors. Environ Health Perspect 2011; 119(8): 1142-1148.]
15. Xia M, Huang R, Sun Y, Semenza GL, Aldred SF, Witt KL, Inglese J, Tice RR, Austin CP.  Identification of chemical compounds that induce HIF-1α activity. Toxicological Sciences 2009; 112(1): 153–163. [Abstract Xia M, Huang R, Sun Y, Semenza GL, Aldred SF, Witt KL, Inglese J, Tice RR, Austin CP.  Identification of chemical compounds that induce HIF-1α activity. Toxicological Sciences 2009; 112(1): 153–163.] [PDF Xia M, Huang R, Sun Y, Semenza GL, Aldred SF, Witt KL, Inglese J, Tice RR, Austin CP.  Identification of chemical compounds that induce HIF-1α activity. Toxicological Sciences 2009; 112(1): 153–163.]
16. Parham F, Austin C, Southall N, Huang R, Tice R, Portier C. Dose-response modeling of high-throughput screening data. Journal of Biomolecular Screening 2009; 14:1216-1227. [Abstract Parham F, Austin C, Southall N, Huang R, Tice R, Portier C. Dose-response modeling of high-throughput screening data. Journal of Biomolecular Screening 2009; 14:1216-1227.]
17. Kavlock RJ, Austin CP, Tice RR. Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment. Risk Analysis 2009; 29(4): 485-487. [Abstract Kavlock RJ, Austin CP, Tice RR. Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment. Risk Analysis 2009; 29(4): 485-487.] [PDF Kavlock RJ, Austin CP, Tice RR. Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment. Risk Analysis 2009; 29(4): 485-487.]
18. Huang R, Southall N, Xia M, Cho, M-H, Jadhav A, Nguyen, D-T, Inglese J, Tice RR, Austin CP. Weighted Feature Significance (WFS): a simple, interpretable model of compound toxicity based on the statistical enrichment of structural features. Toxicological Sciences 2009; 112(2): 385-93. [Abstract Huang R, Southall N, Xia M, Cho, M-H, Jadhav A, Nguyen, D-T, Inglese J, Tice RR, Austin CP. Weighted Feature Significance (WFS): a simple, interpretable model of compound toxicity based on the statistical enrichment of structural features. Toxicological Sciences 2009; 112(2): 385-93.] [PDF Huang R, Southall N, Xia M, Cho, M-H, Jadhav A, Nguyen, D-T, Inglese J, Tice RR, Austin CP. Weighted Feature Significance (WFS): a simple, interpretable model of compound toxicity based on the statistical enrichment of structural features. Toxicological Sciences 2009; 112(2): 385-93.]
19. Xia M, Huang R, Witt KL, Southall N, Fostel J, Cho MH, Jadhav A, Smith CS, Inglese J, Portier CJ, Tice RR, Austin CP. (2008) Compound cytotoxicity profiling using quantitative high-throughput screening. Environ Health Perspect. 116(3):284-91. [Abstract Xia M, Huang R, Witt KL, Southall N, Fostel J, Cho MH, Jadhav A, Smith CS, Inglese J, Portier CJ, Tice RR, Austin CP. (2008) Compound cytotoxicity profiling using quantitative high-throughput screening. Environ Health Perspect. 116(3):284-91.]
20. Huang, R., Southall, N., Cho, M. H., Xia, M., Inglese, J., & Austin, C. P. (2008). Characterization of diversity in toxicity mechanism using in vitro cytotoxicity assays in quantitative high throughput screening. Chem Res Toxicol, 21(3), 659-667. [Abstract Huang, R., Southall, N., Cho, M. H., Xia, M., Inglese, J., & Austin, C. P. (2008). Characterization of diversity in toxicity mechanism using in vitro cytotoxicity assays in quantitative high throughput screening. Chem Res Toxicol, 21(3), 659-667.]
21. Collins, F. S., Gray, G. M., & Bucher, J. R. (2008). Toxicology. Transforming environmental health protection. Science, 319(5865), 906-907. [Abstract Collins, F. S., Gray, G. M., & Bucher, J. R. (2008). Toxicology. Transforming environmental health protection. Science, 319(5865), 906-907.]