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for SLAS High-Content Screening Conference 2017
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Tuesday, September 19 • 2:30pm - 5:00pm
Session 2: Screens
Thanks to recent advances in cell culture and imaging technologies, high content screenings are now reaching a critical point where they can be realistically deployed at large scale, opening exciting opportunities for industry and academia. This section aims to gather worldwide experts involved in every aspects of this promising field to share their recent achievements and vision of the future.

2:30 - 3:00
Filling the Drug Discovery Gap: Is HCS the Missing Link?
Jean-Philippe Stéphan, SERVIER

Despite the fact that many drugs on the market today were discovered through phenotypic screens, this approach is considered by many investigators as a “black box” and in many cases target centric biochemical or cellular assays are preferred to support the initial drug discovery steps. Nevertheless, this “white box” approach clearly does not deliver all the expected success in term of drug developments, mostly due to the lack of pathophysiological relevance of the models. Now, the pharmaceutical industry is implementing new discovery paradigms to try to solve the current disconnect between the drug discovery process and the human clinical trials. Among the myriad of new technologies and approaches currently considered, High Content Screening combined with biosensors technologies, genome-editing and stem cell-derived cellular models offer the opportunity to drastically transform phenotypic screening, linking target engagement and phenotypic impacts in more relevant in vitro models. This new generation phenotypic screens combined with the current drug discovery strategies represent a true opportunity to fulfill the gap between the screening dish and the patients. Despite the tremendous potential of HCS, researchers have to carefully consider various aspects of the projects before deploying the technology and this presentation will go through several examples highlighting the current strengths and weaknesses of the approach.    
3:00 - 3:30  
Imaging Phenomics for the Discovery of Next-Generation Anti-Virals
Steffen Jaensch, Janssen Pharmaceutica

Several proof-of-concept studies have demonstrated that unbiased pheno-signatures derived from high-content imaging data provide a powerful tool to characterize the mechanism-of-action of small molecules in a cellular context. Such signatures can be generated at an early stage of the drug discovery pipeline and provide valuable information to guide, for example, the selection of lead compounds from high-throughput screening hits. We have employed such a phenomics approach for the discovery of novel anti-viral compounds. We established an imaging assay and computational pipeline to generate pheno-signatures that capture the infection state and morphological characteristics of single cells under compound treatment. The signature of non-infected untreated cells describes the most desirable phenotypic state that an ideal inhibitor should revert infected cells back to. We validated our approach with annotated reference compounds and found that we can distinguish host-factor targeting from direct anti-viral compounds with near perfect accuracy. Our method can also distinguish several sub-categories of direct anti-viral mechanisms such as replication vs. entry inhibitors. This greatly reduces the need for costly and time-consuming follow-up assay cascades.

3:30 - 4:00 
High-content phenotypic screening using disease relevant, human, primary cells – Identifying and profiling diverse compounds for cardiac regeneration
Erik Müllers, AstraZeneca

Heart failure is incapacitating and currently incurable. It is thought that activation and proliferation of resident cardiac progenitor cells, i.e. EPDCs has therapeutic potential to help repair the heart after injury. However, drug discovery approaches have so far been impeded by lack of well-defined screening platforms and poor understanding of the molecular mechanisms regulating EPDC activation, proliferation and differentiation. In areas of novel and complex pharmacology high-content phenotypic screening is particularly attractive to identify starting points for potential therapeutics in an unbiased fashion, as well as to aid target deconvolution and mechanism of action activities. We developed and validated a high-throughput, phenotypic screen for compounds selectively proliferating EPDCs while maintaining the progenitor phenotype. Following from the primary screen and respective counter screens we identified and validated hits representing more than 20 different chemical clusters. For a few of these cluster we could identify primary targets. To further aid target identification and mode of action studies we applied a high-content image-based assay for morphological profiling, i.e. Cell Painting, to our EPDC screening campaign. The assay was implemented in 384-well format, using automated liquid handling, high-throughput microscopy, and automated image analysis on a high-performance computing cluster. Building on available image analysis pipelines for nucleus, cell and cytoplasm we developed additional segmentation of endoplasmic reticulum and nucleoli. From the segmented objects thousands of cellular features were extracted and analysed using clustering algorithms resulting in morphological fingerprints of donor populations, and effects of compound treatment. In summary, we developed a high-throughput phenotypic screen as well as a high-content phenotypic screen using relevant human primary cells. We used the assays to identify starting points for drug discovery projects, to better understand mechanism of action, and to deconvolve primary drug targets.

4:00 - 4:30
Genome-wide RNAi screening combined with high content imaging to dissect membrane traffic pathways in mammalian cells
Jez Simpson, University College Dublin

The endomembrane system of mammalian cells has a unique architecture allowing it to carry out a large number of specialised biochemical reactions in parallel. The function of these organelles is dependent on highly regulated intracellular transport events between them. We are using a systematic approach of genome-wide RNA interference screens combined with high-content screening (HCS) microscopy, specifically applying texture feature analysis and machine learning, to quantitatively map these transport pathways and identify their regulators. In this seminar I will describe how this approach has revealed novel regulators of the endomembrane system, and regulators of how nanoparticles (as surrogate drug delivery vectors) enter and traffic through cells. I will also discuss some of the challenges associated with transitioning membrane traffic assays between 2D and 3D cell culture formats.
Overall, the information that we gather provides a deeper systems-level view of how cells are organised, and provides knowledge fundamental to the design of next generation drug delivery vectors and biomedical devices. 

[1] Galea G, Bexiga MG, Panarella A, O'Neill ED & Simpson JC (2015). A high-content screening microscopy approach to dissect the role of Rab proteins in Golgi-to-ER retrograde trafficking. J. Cell Sci., 128(13), 2339-2349.
[2] Panarella A, Bexiga MG, Galea G, O' Neill ED, Salvati A, Dawson KA & Simpson JC (2016). A systematic High-Content Screening microscopy approach reveals key roles for Rab33b, OATL1 and Myo6 in nanoparticle trafficking in HeLa cells. Scientific Reports, 6, 28865.

4:30 - 5:00 
Presentation Title Forthcoming
Michael Boutros, Deutsches Krebsforschungszentrum

Speakers
avatar for Steffen Jaensch

Steffen Jaensch

Senior Scientist, Johnson & Johnson
Dr. Steffen Jaensch works at Janssen Pharmaceutica, Pharmaceutical Companies of Johnson & Johnson, in Beerse, Belgium. He is responsible for the analysis of imaging assay development and screening data for drug discovery and target identification projects with a focus on establis... Read More →
avatar for Jez Simpson

Jez Simpson

Jeremy Simpson carried out his PhD at the University of Warwick (UK). After post-doctoral work at the Scripps Research Institute (San Diego, USA) and the ICRF (London, UK), a long term EMBO fellowship took him to the EMBL (Heidelberg, Germany), where he developed and applied novel high-throughput imaging approaches to study protein localisation and membrane traffic. In 2008 he was appointed as Professor of Cell Biology at University College Dublin, Ireland. His lab applies high-throughput imaging technologies to study intracellular trafficking pathways, the internalisation routes taken by synthetic nanoparticles on exposure to cells, and how cells respond to nanomaterials and nanosurfaces. He has authored over 90 peer-reviewed articles, including articles in Nature Cell Biology, Nature Communications and Nature Methods, and runs the UCD Cell Screening Laboratory (www.ucd.ie/hcs). He is currently the Head of School of Biology... Read More →
avatar for Jean-Philippe Stephan

Jean-Philippe Stephan

Head of Models & HTS department, Institut de Recherches Servier
Jean-Philippe Stéphan, originally from Rennes, Brittany, France, received his Ph.D. in Developmental Biology from Pierre and Marie Curie University (Paris VI, France). After a postdoctoral fellowship at Genentech, he was hired as a Research Scientist in the Assay and Automation Technology department (AAT) at Genentech, Inc. Over his 17 years tenure at Genentech, Dr... Read More →


Tuesday September 19, 2017 2:30pm - 5:00pm
Rosales I Courtyard by Marriot Madrid Princesa Hotel
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