The Scientific Program Committee has coordinated the virtual presentation of three Scientific Sessions that were scheduled for the 2020 SOT Annual Meeting, which has been canceled owing to the 2019 coronavirus (COVID-19). For each of the three webinars, space is limited to 1,000 participants.
Genome Editing in Drug Discovery: Using the Cas9 Protein to Explore Target-Mediated Toxicity
Monday, March 16, 2020
1:00 PM–2:30 PM (ET)
Chair(s): Jeffrey Willy, Vertex Pharmaceuticals; and Myrtle Davis, Bristol-Myers Squibb Company.
Primary Endorser: Molecular and Systems Biology Specialty Section
Other Endorser(s): Mechanisms Specialty Section
The Cas9 protein is an emerging and powerful tool for engineering the genome in preclinical models for studying disease progression. Recent advances in CRISPR/Cas9 technology has enabled biomedical research to advance rapidly on multiple fronts, including target identification and on- and off-target mediated toxicities, as well as the implementation of genome editing for innovative therapeutic approaches. The first presentation will introduce novel advances in genome-wide high-throughput CRISPR/Cas9 screens to identify unique targets for RAS-driven cancers. The second talk will provide mechanistic insight into novel applications of the Cas9 protein for identification of on- and off-target toxicities during drug development of small molecules. The final talk will focus on the immunotoxicity of Cas9 in preclinical models with the goal of understanding implications on current genome-editing therapeutics. The collective content of this session will highlight both the advances and the challenges of CRISPR/Cas9 technologies during the different stages of drug development in a rapidly emerging field.
Functional Genomic CRISPR/Cas9 Modifier Screens Unveil Novel Therapeutic Targets in the Context of RAS-Driven Cancers. Jason Kwon, Broad Institute, Cambridge, MA.
Using CRISPR/Cas9 to Explore Mechanisms of Toxicity. Jeffrey Willy, Vertex Pharmaceuticals Incorporated, San Diego, CA.
Exploring the Toxicity of Cas9 Systems for In Vivo Editing in the Central Nervous System. Elizabeth Stahl, University of California Berkeley, Berkeley, CA.
New Frontiers in Dynamic Toxicology
Tuesday, March 17, 2020
1:00 PM–3:00 PM (ET)
Chair(s): John Wambaugh, US EPA; and Kim Anderson, Oregon State University
Primary Endorser: Exposure Specialty Section
The evolution of toxicity over time has often been characterized with serial observations and models based upon differential equations. New techniques are becoming available that allow additional insight into the dynamics of toxicology from various perspectives. In addition to addressing when, the speakers in this session describe tools for understanding who, what, where, how, and/or why chemical toxicity and exposure may occur to specific, susceptible populations. Depending upon the mechanism of action, windows of susceptibility exist as part of biological development and aging during which the effect of toxic perturbations may be greatly increased. The timing and magnitude of chemical exposures add a layer of complexity on top of biology, as exposures are subject to human activities and whims. Passive samplers can provide a record of exposure to a variety of chemicals over a time interval of activity. Alternatively, exposomics projects can provide snapshots of diverse biometric and chemical exposure information. Mathematical modeling and dynamic machine learning can allow inferences to be drawn from both time-integrated and instantaneous information. Affect modeling can help address the why of human behavior—what drives patterns of product use and chemical co-exposure? Meanwhile, machine-learning methods for time-series data can draw powerful inferences about what goes on between the sampling intervals. All the new approach methodologies (NAMs) presented can inform modern toxicological assessment of the chemical effects on public health. The Workshop will conclude with a moderated panel discussion where speakers will address audience questions on how to apply the methods presented to toxicology. In this session, each speaker will (1) provide example systems, made relevant to toxicologists, in which important aspects change over time; (2) describe the key challenges in understanding the example systems; (3) characterize which aspects change over time and which are constant; (4) describe publicly available tools or methods for analysis of their examples; and (5) consider how better characterization of dynamics can inform toxicology and chemical risk assessment.
Introduction. John Wambaugh, US EPA, Research Triangle Park, NC.
Windows of Susceptibility. John Wambaugh and Annie Lumen. US EPA, Research Triangle Park, NC; and US FDA/NCTR, Jefferson, AR.
Time-Integrated Exposures to Identify Chemical Profiles between Healthy and Dysphagic Foals. Brianna Rivera, Oregon State University, Corvallis, OR.
Modeling, Machine Learning, and Time-Series Data. Ann Pitruzzello, Northrop Grumman Corporation, Morrisville, NC.
E-cigarette, or Vaping, Product Use-Associated Lung Injury (EVALI): Outbreak Analysis from Epidemiological, Clinical, Forensic, and Mechanistic Perspectives
Wednesday, March 18, 2020
1:00 PM–3:45 PM (ET)
Chair(s): Matthew J. Campen, University of New Mexico; and Michael J. Kosnett, University of Colorado School of Medicine.
In the past year, a surge of hospitalizations and deaths occurred that were found to be associated with the usage of e-cigarette and vaping products. Termed e-cigarette, or vaping, product use-associated lung injury, or EVALI, this syndrome led to an estimated 2,500 hospitalizations and over 50 deaths in 2019. EVALI involves symptoms of fever, cough, sore throat, shortness of breath, muscle aches, fatigue, nausea, or vomiting. Efforts from the National Institute for Occupational Safety and Health and US Food and Drug Administration indicate a potential contaminant of vitamin E acetate in lavage fluid samples from EVALI patients (94% of samples) compared with healthy e-cigarette users and non-users (0%). While the EVALI syndrome has subsided in recent months, the present session will highlight important lessons learned in addressing the outbreak and concerns in moving forward with e-cigarette usage. Four talks will cover the epidemiology, clinical manifestations, forensic examination, and toxicological mechanisms underlying the EVALI outbreak.
Epidemiology: An Outbreak of E-cigarette, or Vaping, Product Use-Associated Lung Injury (EVALI)—2019. Paul Melstrom, ATSDR, Atlanta, GA.
Clinical: Presenting Signs and Symptoms, Diagnosis, Treatment, and Outcomes in EVALI. Laura E. Crotty, University of California San Diego, San Diego, CA.
Forensic: Forensic Approach to Evaluation of Vaping Liquids Associated with Lung Injury of Unknown Origin—2019. Catherine Dasenbrock, US FDA/ORA/ORS, Cincinnati, OH.
Mechanistic: Vaping-Related Toxicities—Potential Mechanisms and Current Knowledge Gaps. Ilona Jaspers, University of North Carolina at Chapel Hill, Chapel Hill, NC.