The Longest-Running High-Content Analysis Event 

High-Content Analysis

CHI’s Thirteenth Annual High-Content Analysis meeting, the premier event showcasing the latest advancements in HCA applications and technologies, will return to San Diego with a new program. Over the years we have observed the technology mature and its adoption spread into many areas of compound screening/evaluation and functional analysis. The High-Content Analysis meeting will focus on the next steps of technology development, including screening of 3D and physiologically relevant complex models, ultra-high resolution and high-throughput imaging, more advanced image analysis and data management, and new assays and applications.

Final Agenda

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Wednesday, February 10

5:00-6:00 pm Short Course Registration and Main Conference Pre-Registration

6:00-9:00 pm (SC1) DINNER SHORT COURSE: High-Content Phenotypic Screening

The ever-increasing demand for improved productivity in research through the generation of robust analysis outputs has driven both the development and deployment of automated high-content analysis (HCA) and phenotypic cell-based approaches to drug discovery. In contrast to the more traditional cellular analysis and target-based approaches, here the researcher is able to evaluate the efficacy of potential therapeutics by monitoring the physiological state of cells through the simultaneous analysis of multiple cellular parameters in the context of an intact biological system. This course will cover the key features of HCS/A technologies and the best approaches to using these technologies for phenotypic cell-based screening.

Instructor: Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

Separate registration required.

Thursday, February 11

7:30 am Conference Registration and Morning Coffee

Phenotypic and High-Content Screening in 3D Cellular Models

8:00 Chairperson’s Opening Remarks

Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

8:15 The Trials and Tribulations of Complex Phenotypic Screening

Shane Horman, Ph.D., Research Investigator, Advanced Assays, Genomics Institute of the Novartis Research Foundation

With the emergence of new biomimetic phenotypic screening platforms comes the inevitable complexities and technical challenges associated with such initiatives. Side-stepping assay-related landmines on the road to drug discovery is an iterative process, characterized by repeated trial and error. Herein I present benefits and potential pitfalls of complex and multi-culture 3D cell models currently used for drug discovery in the pharmaceutical industry.

8:45 The Challenges of Identifying Cellular Phenotypes in 3D in vitro Cellular Assay Systems

Anthony M. Davies, Ph.D., Center Director, Translational Cell Imaging Queensland (TCIQ), Institute of Health Biomedical Innovation, Queensland University of Technology

Currently, one the biggest drivers in the field of translational research is the need to improve the relevance of cell-based assays. To achieve this goal many investigators are turning their attention to high-content analysis used in conjunction with primary cells and/or 3D cell assay models. Despite the potential benefits that these new experimental approaches may offer, their use has not been without both technical and practical difficulties. In this presentation we will discuss the challenges we have encountered here at TCIQ and the solutions that we have arrived at to meet our research objectives.

Beckman Coulter Life Sciences9:15 Automated 3D Culture and Sample Preparation for Imaging and Flow Cytometry Analysis

Jennifer MacFarland, Field Marketing Manager, Automation and Genomics, Beckman Coulter Life Science

Spheroid cultures can be challenging to manipulate and are amplified as sample throughput increases. We will demonstrate how the Biomek FXP was used to automated steps include the plating of cells, media exchange, and compound and staining reagent addition within the hanging drops.

Persommics9:30 High Content Discovery with Persomics Technology: Reduction of Scale and Cost with Turnkey Printed Libraries.

Neil Emans, Ph.D., CEO, Persomics

RNAi is routinely used in High-content and Phenotypic screening. However, set-up and operational costs exceed the scope of individual labs. Persomics technology miniaturizes, accelerates and de-industrializes screening. Preprinted libraries integrate with High-content imaging platforms, removing barriers to entry and lowering costs. This presentation will introduce Persomics technology and future applications.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

High-Content Analysis for Immunotherapy Development

10:30 A Paradigm Shift in Immune Cell-Mediated Immuno-Modulatory Responses Using High-Throughput FACS Analysis

Mohanraj Dhanabal, Ph.D., Group Leader, Lead Discovery Technology, EMD Serono

11:00 High-Content Imaging Assays to Elucidate Antibody Mediated Antigen Endocytosis

Ming Lei, Senior Scientist, Lead Discovery & Optimization, Bristol-Myers Squibb

Understanding the mechanisms of antibody mediated antigen endocytosis is essential for new biologics drug discovery. We developed a multifaceted internalization assay platform to deliver a comprehensive kinetic data package that offers quantitative information on the various aspects of cellular activities of drug-target interactions. We applied high-content internalization assays to a number of immuno-oncology drug discovery programs and identified novel mechanism of action.

11:30 Phenotypic Drug Discovery: The Use of 3-D Culture and Image-Based Multi-Parametric Profiling

Steven Rust, Senior Manager, R&D, MedImmune

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

Machine Learning and Systems Biology Applied to High-Content Screening

1:25 Chairperson’s Remarks

Vance Lemmon, Ph.D., University of Miami

1:30 Combining Phenotypic Screening and Biochemical Profiling Data to Identify Kinase Targets and Anti-Targets

Vance Lemmon, Ph.D., Professor and Chair, Developmental Neuroscience, The Miami Project to Cure Paralysis, University of Miami

Mammalian central nervous system (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple factors underlie this regenerative failure. This suggests a need for drugs that engage multiple molecular targets. Although multi-target drugs are often more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, the identities of these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened a collection of kinase inhibitors in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds' kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound that inhibited 5/7 targets and 0/3 anti-targets was found to promote axon growth in a rodent spinal cord injury model. Our approach is generalizable based on its ability to deconvolve known targets for a breast cancer cell line as well as targets that mediate drug resistance.

2:00 Quantifying Complex Phenotypes Using Open Source Machine Learning Tools

David J. Logan, Ph.D., Computational Biologist, Imaging Platform, Broad Institute of Harvard and MIT

Biologists increasingly use more complex, physiologically relevant systems for high-throughput drug screening. We have successfully devised image analysis workflows for complex systems using machine learning in multiple stages of the image analysis pipeline. We expect this combination of free, open-source tools to be broadly useful across difficult image analysis domains.

2:30 Discovery of Cardiac Signaling Networks by High-Content Imaging

Jeff Saucerman, Ph.D., F.A.H.A., Associate Professor, Biomedical Engineering, University of Virginia

Biochemical and mechanical cues can cause the heart to remodel in a variety of ways, involving changes in cardiac myocyte size and shape, proliferation, apoptosis and fibrosis. While it is well recognized that these responses are coordinated by signaling and gene regulatory networks, their complexity has prevented an integrated understanding of how these responses are coordinated at the network level. In this talk, I will provide several examples of how we have combined high-content imaging and systems biology modeling to identify signaling networks that control cardiac myocyte phenotypes. These include morphological analysis to identify pathways that regulate myocyte elongation, texture analysis for automated measures of sarcomere organization, and cell cycle analysis to quantify cardiac myocyte proliferation.

PerkinElmer NEW 20093:00 Towards an Integrated Phenotypic Screening Worklflow

Alexander Schreiner, Biological Applications, PerkinElmer

Seungtaek Lee, Product Manager, Informatics, PerkinElmer

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

Organoids and 3D Organotypic Cell Culture

4:00 Phenotypic Screening to Accelerate Lead Discovery and Drug Repositioning

Zhuyin Li, Ph.D., Translational Biomarker Team Lead, Lead Discovery & Optimization, Bristol-Myers Squibb

Potential leads from high-throughput screening (HTS)-based drug discovery approaches often result in a high lead attrition rate, due in part to lack of disease relevant in vitro cellular models and predictive assay technologies. Recent developments in phenotypic screening using disease-relevant cellular models and advanced assay technologies have reduced attrition rate and improved in vitro to in vivo connectivity. In this presentation, three examples will be highlighted: 1) identification of potent inhibitors of tumor growth and metastasis for an anaplastic thyroid cancer in vivo model using in vitro phenotypic screening; 2) phenotypic screening for potential drug repositioning to promote functional remyelination in vivo; 3) phenotypic screening using 3D organotypic cellular models that mimic omental tissue for the identification of ovarian cancer metastasis inhibitors with demonstrated efficacy in vivo.

4:30 A 3D Phenotypic Screening Platform to Mimic Tumor Microenvironment and Tissue Architecture

Malin Akerfelt, Ph.D., Senior Research Scientist, High-Content Screening Laboratory, Institute of Biomedicine, University of Turku

5:00 High-Throughput Imaging: Focusing in on Cancer Drug Discovery in 3D

Daniel V. LaBarbera, Ph.D., Associate Professor, Drug Discovery and Medicinal Chemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado

High-throughput imaging drug discovery using 3D tissue culture and organoids has been limited due to practical and technical hurdles. This presentation will describe recent advances that we have developed for volumetric high-content analysis using multicellular tumor spheroids suitable for high-content screening drug discovery.

AxioGenesis5:30-6:30 Welcome Reception in the Exhibit Hall with Poster Viewing

5:30 Short Course Registration

6:30-9:00 (SC2) Dinner Expert ThinkTank: How to Meet the Need for Physiologically Relevant Assays

It used to be adequate to build target-specific and robust assays to drive lead optimization. These assays were relatively inexpensive and reliable and could be counted on to provide chemists with usable results. However, with time, it has become apparent that it is not enough to be robust and target specific. To build therapies for patients, we need to have assays that are more predictive of patient outcome. The current buzz words are “physiologically relevant assays.” This session will explore the need for physiologically relevant assays and explore the ways that we can achieve this endpoint.

Moderator: Lisa Minor, Ph.D., President, In Vitro Strategies, LLC

Separate registration required.

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Friday, February 12

7:45 am Breakfast Presentation (Opportunity Available) or Morning Coffee

Phenotypic Drug Discovery: Lessons Learned

8:25 Chairperson’s Remarks

Ulrich Schopfer, Ph.D., Novartis Institutes for BioMedical Research

8:30 Lessons from Phenotypic Lead Discovery

Ulrich Schopfer, Ph.D., Executive Director and Head, Integrated Lead Discovery, Novartis Institutes for BioMedical Research

Phenotypic screening in in vivo or ex vivo models has been the historic origin of drug discovery. When advances in molecular biology enabled target-based screening, these origins lost popularity in favor of more reductionist approaches. Over the last several years, there has been a renaissance of phenotypic discovery approaches in academia and the pharmaceutical industry. It is time to take stock and assess the successes and the difficulties that were encountered. We will discuss the experience with phenotypic lead discovery at Novartis and look out to the integration of phenotypic and target-based approaches that we predict to be the strategy of the future.

9:00 High-Content Cell-Based Assays for Receptor Internalization and Intracellular Trafficking

Regis Doyonnas, Ph.D., Senior Principal Scientist, High-Content Screening and HTS-Flow Cytometry, Primary Pharmacology Group, Pfizer

9:30 Know Your Target, Know Your Molecule

Erik Hett, Ph.D., Team Leader, Senior Scientist, Chemical & Molecular Therapeutics, Biogen

I will pose some key questions about the characteristics of protein targets and small-molecule drugs that may be important to consider in drug discovery projects and could improve prospects for future clinical success. This includes questions such as what is your target, where does it localize, does it have multiple isoforms, as well as, how does your molecule bind, where does it distribute, what are the consequences of it binding your target, and how much occupancy is required to drive your phenotype?

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

Innovation in HCA Assay Development

10:55 Chairperson’s Remarks

Alan Waggoner, Ph.D., Carnegie Mellon University

11:00 Fluorescent Biosensors for Live Cell Protein Trafficking

Alan Waggoner, Ph.D., Professor, Biological Sciences, and Director, Molecular Biosensor and Imaging Center, Carnegie Mellon University

Live cell health and function is controlled by interactions between thousands of types of proteins that are parts of regulatory pathways. We are developing a toolkit of fluorescent probes (biosensors) for quantifying these regulation pathways. Emphasis will be placed on high-throughput quantification of membrane surface channels, transporters and signaling receptors. I will, as well, cover new, targeted physiological indicators for membrane potential, calcium, sodium, potassium and pH.

11:30 High-Content Analysis of CRISPR-Cas9 Gene-Edited Human Embryonic Stem Cells

Krishanu Saha, Ph.D., Assistant Professor, Biomedical Engineering, University of Wisconsin, Madison

CRISPR-Cas9 gene-editing of human cells and tissues holds much promise to advance medicine, drug discovery and biology, but standard editing methods require weeks of reagent preparation where much of the initial edited samples are destroyed during analysis. Here, a new approach is described that separates thousands of edited cell populations for automated, live high-content analysis. The approach lowers the time and cost of gene editing and produces edited stem cells at high efficiencies. This preclinical platform adds important capabilities to observe editing and selection in situ within complex structures generated by human cells.

12:00 pm Presentation to be Announced

12:30 Drug Discovery Using Kinetic Live-Cell Imaging of Primary Human Cells

Enrico Schmidt, Ph.D., Lab Head and Investigator, Center for Proteomic Chemistry, Integrated Lead Discovery, Novartis Pharma AG

Engulfment of apoptotic cells is a highly dynamic process regulated by a complicated network of extra- and intracellular pathways. In order to identify modulators of this process with a broad molecular mode of action, dynamic live-cell imaging is required. We have developed a fully automated imaging assay to measure uptake of apoptotic corpses using primary human cells in a 1536 multi-well format that allows monitoring of the complete dynamic range of the process and identifying modulators.

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

High-Content Screening in Animal Models

1:55 Chairperson’s Remarks

Andreas Vogt, Ph.D., University of Pittsburgh

2:00 High-Content Analysis and Multicellular Organisms in the Continuum of Quantitative Systems Pharmacology (QSP)

Andreas Vogt, Ph.D., Associate Professor, Computational and Systems Biology, University of Pittsburgh

Quantitative systems pharmacology (QSP) is an emerging drug discovery paradigm that aims to comprehensively understand the interaction of drugs across systems of increasing complexity and within the physiologic environment of the cell. An important part of QSP is the development and execution of clinically relevant discovery assays. I will present an example from zebrafish discovery to illustrate how high-content analysis impacts at different points of the QSP continuum.

2:30 Zebrafish-Based in vivo Screens for Selective Modulators of Developmental Pathways

Charles C. Hong, M.D., Ph.D., Associate Professor, Cardiovascular Medicine, Pharmacology, and Cell & Developmental Biology, Vanderbilt University School of Medicine

3:00 Discovering Small Molecule Neuro-Protectives through a Chemical Genetic Neurodegeneration Model in Larval Zebrafish

Su Guo, Ph.D., Professor, Bioengineering and Therapeutic Sciences, University of California, San Francisco

Neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) affect millions of people worldwide and are without cure. Here we report the assay development and a pilot screen for small molecule neuro-protectives employing a chemical genetic neurodegeneration model in larval zebrafish. We provide evidence that the neurodegeneration in this model is a result of oxidative stress and is necroptotic rather than apoptotic, mimicking neuronal loss in AD and PD. The compounds identified through our screen represent promising leads for future testing in preclinical and clinical settings.

3:30 Ultra-High-Content Screening of Live Parasitic Worms

Steven Chi-Ming Chen, Specialist, Pharmaceutical Chemistry, Small Molecule Discovery Center at UCSF, Mission Bay

HCS has the potential to provide deep insight into drug treatments by capturing feature-rich time-lapsed images of live organisms. We have developed an HCS method using bright-field imaging to interrogate the larval stage of the flatworm Schistosoma mansoni, the etiological agent of the endemic disease Schistosomiasis. By quantifying multiple static and kinetic features, we are able to define complex phenotypes; we also demonstrate the use of this method for high-throughput screening.

4:00 Close of Conference

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