SELECTBIO Conferences High-Content and Phenotypic Screening Europe 2018


Co-Located Conference Agendas

High-Content and Phenotypic Screening Europe 2018 | Stem Cells and Antibodies in Drug Discovery Europe 2018 | 

Thursday, 24 May 2018


Conference Registration, Materials Pick-Up, Morning Coffee, Tea and Breakfast Pastries

Session Title: Conference Opening Session Framing the Key Topics and Opportunities in these Fields


Robert WilliamsKeynote Presentation

Partnering in the Discovery & Development of Novel Biotherapeutics: A Perspective from Cancer Research UK
Robert Williams, Chief Drug Development Scientist, Cancer Research UK, United Kingdom

Cancer Research UK is the world's largest charitable funder of cancer research. The organization has a long history of supporting the discovery and development of novel anti-cancer medicines. CRUK works extensively with academic institutes, biotechnology and pharmaceutical companies utilising a wide range of partnering arrangements and business frameworks. This presentation will describe examples of innovative collaborations in the discovery and development of new antibody-based therapeutics.


Gary GintantKeynote Presentation

Title to be Confirmed.
Gary Gintant, Research Fellow, Abbvie, United States of America


Morning Coffee and Tea Break and Networking


Matthew DanielsKeynote Presentation

iPSC-based Models of Heart Disease - How to Make Them and Study Them Properly
Matthew Daniels, Wellcome Trust Intermediate Clinical Fellow, Honorary Consultant Cardiologist, University of Oxford, United Kingdom

Many iPSc based models of inherited heart disease are now available, but very little has been done to improve the way they are analyzed. I will demonstrate an example of iPS to validate a whole genome sequencing result, and show how various contemporary phenotyping strategies fail but can be improved.


Cisbio BioassaysHTRF Assays + Reagents for Biologics Drug Discovery
Louise Affleck, UK Team Leader, Cisbio Bioassays

The HTRF assay platform is robust and flexible and can be applied to a large range of drug targets for small and large molecule drug research. This presentation highlights PPI assays, ADCC binding assays, IgG quantification assays.


Networking Lunch -- Meet the Exhibitors and View Posters

Session Title: Stem Cells for Drug Discovery - Current Status


Human Stem Cell Research for Potential Drug-induced Cardiac and Neuronal Side Effects
Hua Rong Lu, Senior Principal Scientist, Discovery Sciences, Janssen Pharmaceutical NV, Belgium

Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) and HiPS-neurons are increasingly used as a new source of human based-cells for drug safety assessment.  Indeed attention to this field may increase in response to the FDA's CiPA proposal for long QT and pro-arrhythmias and HESI-MEA for drug-induced seizures. Within Janssen, we are currently investigating the effects of different reference compounds in different types of hiPS-CMs and hiPS-neurons using different high content screen assays, and establishing potential assay (s) using HiPS-cells for early drug discovery and development.


Human Stem Cell-Derived Renal Cells and High-Throughput Nephrotoxicity Prediction
Jacqueline Chuah, Lab Officer, Institute of Bioengineering and Nanotechnology, A*Star, Singapore

The kidney is a major target for compound-induced toxicity. Animal-free alternative methods are required by governmental agencies and various industries to decrease costs and increase the throughput of nephrotoxicity prediction. We have developed the first accurate and pre-validated in vitro models for predicting compound-induced nephrotoxicity in humans (Loo and Zink, 2017; Chuah and Zink, 2017; Kandasamy et al., 2015; Li et al., 2014; Li et al., 2013; Su et al., 2014; Su et al., 2016). Our models include the first and only pre-validated and predictive stem cell-based renal in vitro models (Li et al., 2014; Kandasamy et al., 2015; Chuah and Zink, 2017). The most advanced of these models is based on induced pluripotent stem cell (iPS)-derived renal proximal tubular (PTC)-like cells. A rapid one-step protocol has been established for the generation of PTC-like cells in 8 days of differentiation, and these cells can be directly used for compound screening (Kandasamy et al., 2015). Alternatively, PTC-like cells can be applied after cryopreservation. By combining iPS-derived renal cell-based assays with machine learning methods, a test balanced accuracy of 87% could be achieved with respect to nephrotoxicity prediction (Kandasamy et al., 2015; Chuah and Zink, 2017). In addition, underlying mechanisms of drug-induced cellular injury could be correctly identified. We have also established a high-content screening (HCS) platform that combines high-content imaging of renal cells with automated phenotypic profiling and machine learning methods (Su et al., 2016). The automated HCS platform has a test balanced accuracy ranging between 82%-89%, depending on the human renal cell type used (Su et al., 2016; Loo and Zink, 2017). Based on these technologies we are currently developing a portfolio of platforms for the prediction of compound-induced toxicity to various organs. In addition, a kidney-on-chip platform for repeated dose testing is under development. This platform appears to be suitable for the assessment of the human dose response.


Applications of Human Pluripotent Stem Cells for Neuromuscular Diseases: Advances and Challenges
Masatoshi Suzuki, Associate Professor, Department of Comparative Biosciences and Stem Cell & Regenerative Medicine Center, University of Wisconsin-Madison, United States of America

Neuromuscular diseases are caused by functional defects of skeletal muscles directly via muscle pathology or indirectly via the nervous system. Extensive studies have been performed to improve the outcomes of therapies; however, effective treatment strategies have not been fully established in any major neuromuscular disease. Human pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, have a great capacity to differentiate into skeletal muscle progenitor/stem cells (or called myogenic progenitors) and skeletal myocytes for use in treating and modeling neuromuscular diseases. Particularly, recent advances allow us to create patient-derived stem cells, which can be used as a unique platform for comprehensive study of disease mechanisms and drug screening in vitro. In the last decade, a number of protocols (including ours) have been established for derivation of skeletal muscle cells from human pluripotent stem cells. These protocols have been developed by following the process of myogenesis controlled by the expression of transcription factors and signaling molecules to specify cellular lineage during muscle development. This presentation overviews recent progress of the protocols for skeletal muscle derivation using human pluripotent stem cells. We also discuss the potential limitations and promise of these approaches for future applications of myogenic progenitors and myocytes in neuromuscular diseases.


Afternoon Coffee and Tea Break and Networking


Bridging the Translational Gap: A hiPSC Model of Marfan Syndrome for Drug Discovery
Sanjay Sinha, BHF Senior Research Fellow, University of Cambridge, United Kingdom

Marfan syndrome is a connective tissue disorder, caused by mutations in FBN1, with pleiotropic manifestations including aortic aneurysms and dissection. Although the angiotensin II receptor blocker, losartan, was effective in treating the disease in mouse models, clinical trials have been much less successful. In this presentation, I will discuss the use of a hiPSC model of aortic disease in Marfan syndrome to understand the molecular basis of this disease and why the mouse studies may not have translated well to patients. I will also describe how this complex in vitro system can be used for novel drug screening for this devastating clinical disorder.


Modeling Endoderm Development and Disease Using Human Stem Cells
Nicholas Hannan, Assistant Professor, University of Nottingham, United Kingdom


David HayKeynote Presentation

Automated Hepatocyte Differentiation From Pluripotent Stem Cells and Their Use in Drug Screening
David Hay, Professor, University of Edinburgh, United Kingdom

In both preclinical and clinical testing, drug induced liver injury (DILI) is the major cause of drug attrition, costing pharmaceutical companies millions of dollars every year (Ware & Kehtani 2017, Trends in Biotechnology).  It is therefore essential to rapidly identify and remove drug candidates that pose a risk, decreasing development costs and improving post market success. Currently primary human hepatocytes (PHH) are the most widely used cell type for the prediction of DILI. However when cultured in vitro PHH do not proliferate, rapidly lose their phenotype, in particular drug metabolism. Furthermore, sources are limited and usually isolated from diseased tissue limiting their utility in large scale drug screening. The cost effective delivery of human tissue from a renewable resource, such as pluripotent stem cells (PSCs), offers a possible solution to the issues associated with human somatic cells for in vitro testing. Of note, PSC derived hepatocytes have previously been shown to be as sensitive and predictable as the pharmaceutical 'gold standard' PHH (Szkolnicka et al 2014, Stem Cells Translational Medicine and Szkolnicka et al 2016, Stem Cells Translational Medicine). More recently, improvements in culture methods and protocols have led to further improvement in hepatocyte function and stability. The focus of our recent research has been to combine defined differentiation with automation to deliver reliable and stable liver models at scale. In order to multiplex our cell based screening tool we have used a cytological assay that 'paints the cell', specifically marking intracellular components of the cell, allowing high through put and multi-parametric analysis (Gustafsdottir et al 2013, PLoS One; Bray et al 2016, Nature Protocols). PSCs were differentiated into hepatocyte like cells (HLCs) using a previously published protocol (Cameron et al 2015, Stem Cell Reports). Once mature HLCs were incubated with a pharmaceutical grade compound library provided by AstraZeneca. Following 48 hours exposure, we scored for drug toxicity, using multiple endpoints and correctly identified drug toxicity in compounds tested. In conclusion, we have developed an automated, reproducible, and scalable platform to generate functional hepatocytes for human drug screening. Importantly, the production method is GLP compliant and cost effective (Cameron et al 2015, Stem Cell Reports). Going forward our automated system will be further miniaturised and fine-tuned to study genetic variation in the human population.


Networking Reception with Beer and Wine. Engage and Network with Your Colleagues, and Connect with the Exhibitors


Close of Day 1 of the Conference

Friday, 25 May 2018


Morning Coffee, Tea, Breakfast Pastries and Networking

Session Title: High Content and Phenotypic Screening


Using Patient-Specific Induced Pluripotent Stem Cells to Model Retinal Diseases
Alice Pebay, Associate Professor, Principal Research Fellow, University of Melbourne & Centre for Eye Research Australia, Australia
Maciej Daniszewski, PhD Student, University of Melbourne, Australia

Age-related macular degeneration (AMD), primary open-angle glaucoma (POAG) are leading ageing neurodegenerative diseases of the eye. Although phenotypically distinct, their respective pathophysiologies do share similarities. They are chronic, progressive, and lead to the degeneration of neurons key to the function of the retina or optic nerve. If no treatment is found, the direct and indirect costs associated with these conditions will drastically increase. But Despite enormous research efforts, treatment options are still limited, with no current definitive treatment for AMD and POAG. This paucity of treatment options can be attributed to a fundamental absence in the knowledge around what causes these conditions and how they progress. We use of patient-specific induced pluripotent stem cells (iPSCs) to obtain the key cells involved in these diseases.  To increase power of analysis, we use automation of cell culture to allow large-scale modelling of AMD and POAG. Those methods will be discussed. Ultimately, we aim to improve our molecular understanding of those neurodegenerative diseases, and ultimately facilitate preclinical trials, and translatable outcomes.


Phenotypic Discovery Using Machine Learning and Image Analysis Methods
Peter Horvath, Finnish Distinguished Professor, Fellow FIMM Helsinki and Group Leader, Hungarian Academia of Sciences, Switzerland

In this talk I will give an overview of the computational steps in the analysis of a single cell-based high-content screen. First, I will present a novel microscopic image correction method designed to eliminate vignetting and uneven background effects which, left uncorrected, corrupt intensity-based measurements. I will discuss the Advanced Cell Classifier (ACC) (, a software tool capable of identifying cellular phenotypes based on features extracted from the image. It provides an interface for a user to efficiently train machine learning methods to predict various phenotypes. We developed the Suggest a Learner (SALT) toolbox, which selects the optimal machine learning algorithm and parameters for a particular classification problem. For cases where discrete cell-based decisions are not suitable, we propose a method to use multi-parametric regression to analyze continuous biological phenomena. Finally, to improve the learning speed and accuracy, we recently developed an active learning scheme which automatically selects the most informative cell samples.


High-Content Screening for Adverse Cytologic Effects
Peter O'Brien, Head of Clinical Pathology, University College Dublin, Ireland

The first, highly-effective, high-content-screening (HCS) for adverse cytologic effect was reported a decase ago (Arch Toxicol 2006, 80, 580). Success was attributed to simultaneous measurement of multiple "cytobiomarkers", use of human cells that can metabolise drugs, 72 h exposure for slow toxicants, exposure to wide-ranging concentrations,  and normalizing toxic  to efficacious concentration. Many HCS studies now support this approach as necessary in predictive toxicology, as does review of literature since the ?rst cytotoxicity assay was reported 100 years ago.  A subset of the original toxicants was reanalyzed using the original HCS confirming high sensitivity and speci?city across locations, technologies, sta?, laboratories, and time. A protocol is demonstrated for operational validation of the HCS within labs to document pro?ciency and quality management.


Exploring in vitro Vibrational Microspectroscopy for High Content Analysis
Hugh Byrne, Professor, Dublin Institute of Technology, Ireland

The potential of vibrational spectroscopy, but infrared absorption and Raman scattering, in the fields of biological and biomedical applications has been well demonstrated. The techniques provide molecular based profiles of the biomolecular content, in a label free, non-destructive manner, which, in the microscopic mode, can have subcellular resolution. Multivariate statistical analysis is commonly employed to extract high content information concerning cellular metabolism and response pathways. The presentation provides an over view of efforts to advance the application of vibrational spectroscopy for high content cellular analysis, using examples of exposure to model nanoparticles and chemotherapeutic agents. This progress is discussed in the light of emerging technologies in the field of spectroscopic microscopy.


Collaborative Phenotyping at King's: HipSci and the Stem Cell Hotel
Davide Danovi, Director, Cell Phenotyping Platform, Kings College London, United Kingdom

We work in the framework of the Human Induced Pluripotent Stem Cells Initiative (HipSci) project, funded by the Wellcome Trust and MRC. We provide a dedicated laboratory space for collaborative cell phenotyping to study how intrinsic and extrinsic signals impact on human cells to develop assays for disease modeling and drug discovery and to identify new disease mechanisms.


GE Life SciencesHigh-Content Screening of Complex Biological Models
Ben Haworth, Cellular Imaging Application Specialist, GE Life Sciences

Exploring how the IN Cell Analyzer Platforms delivers image quality and speed in high-content Analysis workflows.  We will look at how the systems can be used to optimize assays using both 3D and live models.


CYTOO SAEnabling Early Stage Muscle Drug Discovery with MyoScreen™, a High-throughput High-content Phenotypic Screening Platform Deploying Micropatterned Human Primary Skeletal Myotubes
Joanne Young, Senior Scientist, CYTOO SA

CYTOO has recently developed a disease relevant phenotypic muscle drug discovery platform to fully leverage the characterization of compounds at an early stage of the drug discovery pipeline. MyoScreen™ deploys imaging and image-analysis methodology along with a micropatterned plate system that allows the precise control of myotube length and the formation of highly aligned myotubes.
In this seminar, I will discuss the robust performance of the MyoScreen™ platform and show how it exploits the improved architecture and maturity of micropatterned myotubes, which are superior to standard 2D culture, to quantitatively analyze drug effects on proliferation, hypertrophy/atrophy, acetylcholine receptors, as well as providing a screening index of contractile force. I will also describe actual use of MyoScreen™ in a primary screen with secondary hit validation, focusing on two intriguing hits that were identified to enhance myotube function by distinct mechanisms of action.


Paul FrenchKeynote Presentation

Multidimensional Fluorescence Imaging For High Content Analysis and Preclinical Applications
Paul French, Professor, Department of Physics and Photonics Group, Imperial College London, United Kingdom

We are developing multidimensional fluorescence imaging technology with a particular emphasis on fluorescence lifetime imaging (FLIM) across the scales to contrast different molecular species and to map variations in the local fluorophore molecular environment, particularly due to Forster resonant energy transfer (FRET) in order to assay protein interactions or read out genetically expressed FRET biosensors. For high content analysis (HCA) we are implementing automated time-gated FLIM for multiwell plate assays of protein interactions or cellular metabolism. We have applied FLIM FRET HCA to study signalling and disease mechanisms in 2-D and 3-D cell-based assays, including the intracellular measurement of KD to quantify protein interactions. For in vivo preclinical studies, we are combining optical projection tomography (OPT) with FLIM, particularly applied to live zebrafish - from larvae up to adults - and are developing FLIM endoscopy to read out FRET biosensors in murine disease models. We aim to implement our multidimensional fluorescence imaging technology using open source software tools for instrument control, data acquisition, analysis and management and to provide lists of equipment components to enable other users to replicate our instrumentation for application to their own biological questions. Our open source FLIM analysis software, FLIMfit which provides rapid global fitting capabilities and is available as an OMERO client and our FLIM HCA and OPT instrumentation are controlled by uManager.


Networking Lunch -- Meet the Exhibitors and View Posters

Session Title: Antibodies in Drug Discovery and Emerging Areas


Nanobodies Against Influenza and Their Applications in Preparing For Future Pandemics
Simon Hufton, Section Head Molecular Immunology, National Institute for Biological Standard and Control (NIBSC), United Kingdom

Both seasonal and pandemic influenza continue to represent a formidable public health challenge. The constant evolution of new strains means the rapid availability of highly specific neutralising monoclonal antibodies are of considerable interest. Nanobodies are emerging as next generation antibodies with a number of well documented advantages which make them highly amenable to applications in the infectious disease area. This presentation will describe the isolation and characterization of nanobodies specific for key influenza subtypes including 'swine flu' A(H1N1), highly pathogenic avian influenza A(H5N1), highly pathogenic avian influenza A(H7N9), A(H3N2) and B lineage influenza viruses. The use of yeast display for mapping their epitopes on hemagglutinin will also be presented as will their potential applications in preparing for future influenza pandemics.


Exploiting the Multiple Functions of FcRn for Therapy
E. Sally Ward, Professor, Texas A&M University Health Science Center, United States of America

The central role of FcRn in regulating IgG persistence and transport provides opportunities for targeting this receptor in multiple different diagnostic and therapeutic situations. The engineering of IgGs with higher affinity for FcRn can be used to produce antibodies with longer in vivo half-lives, but only if the pH dependence of the IgG-FcRn interaction is retained. Conversely, engineered IgGs with increased affinity for FcRn at both acidic and near neutral pH act as potent inhibitors of FcRn. Consequently, such antibodies ('Abdegs', for antibodies that enhance IgG degradation) can lower the levels of endogenous IgG. Recent studies in our laboratory have also resulted in the generation of engineered Fc-fusions that selectively clear antigen-specific antibodies ('Seldegs', for selective degradation). Recent developments related to the modulation of IgG dynamics will be presented.  We have demonstrated that the loss of expression of FcRn in tumor cells results in increased intracellular albumin accumulation and tumor growth in mouse models. These observations have implications for tumor immunotherapy and indicate a novel function for FcRn as a metabolic regulator.


Stefan DubelKeynote Presentation

New Ways For Human Antibodies - From Intracellular Applications to Switchable Affinity
Stefan Dubel, Full Professor and Director, Technische Universitat Braunschweig, Germany

While the generation and optimization of human antibodies by phage display today allows to design fine specificity and kinetic parameters in detail, and CAR-T-cells, ADCs, bi-specific antibodies and many others creative derivatives of the original IgG molecule are approved or in clinical studies, the antibody molecule still offers many opportunities for new and innovative applications.  The access of intracellular antigens with biologicals would add a huge target space to therapeutic antibodies. We used intra-bodies in the first protein knock down mouse to demonstrate the in vivo function of this principle, but also analysed many strategies to insert antibodies from the outside of the cell.  On another end, using cyclic mutants of human calmodulin as an allosteric effector module, antigen binding affinity of different antibodies could be regulated. This allosteric effect was demonstrated for five different scFv fragments under physiological conditions on living cells without the need of pH or ion concentration changes.


Stephen HelliwellKeynote Presentation

Yeast as a Compound-Target Pair Discovery Tool
Stephen Helliwell, Senior Investigator, Novartis Institutes for BioMedical Research, Switzerland

I will briefly summarize our efforts at Novartis to identify yeast bioactive LMWs and identify their targets using uHTS screens and chemogenomic profiling - known as HIP HOP.


Overcoming Antigen-Mediated Antibody Clearance
Tristan Vaughan, Vice President, R&D, Antibody Discovery and Protein Engineering, MedImmune Ltd, United Kingdom

An antigen can act as a "sink" for antibody clearance if the antibody binds to an antigen which is rapidly eliminated. High levels of antibody clearance can impede and often halt the development of a novel therapeutic due to an impossibly large dose that would be required to overcome the sink for the drug to bring any patient benefit.  Here, an antibody engineering solution to rapid clearance will be described and a case study presented.


Enhanced Interrogation of the B Cell Repertoire For Antibody Discovery
Win-Yan Chan, Research Scientist, UCB, United Kingdom

An overview of the automated, high through-put antibody discovery platform at UCB and our single-cell recovery technology for antibody discovery. Using a sophisticated screening cascade at an early stage of antibody discovery, we are able to find high quality antibodies that will go on to make the best therapeutic candidates.


Close of Day 2 of the Conference

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