Phenotypical screening is a widely used approach in drug discovery for the identification of small molecules with cellular activities. However, functional annotation of identified hits often poses a challenge. The development of small molecules with narrow or exclusive target selectivity such as chemical probes and chemogenomic (CG) libraries, greatly diminishes this challenge, but non-specific effects caused by compound toxicity or interference with basic cellular functions still pose a problem to associate phenotypic readouts with molecular targets. Hence, each compound should ideally be comprehensively characterized regarding its effects on general cell functions. Here, we report an optimized live-cell multiplexed assay that classifies cells based on nuclear morphology, presenting an excellent indicator for cellular responses such as early apoptosis and necrosis. This basic readout in combination with the detection of other general cell damaging activities of small molecules such as changes in cytoskeletal morphology, cell cycle and mitochondrial health provides a comprehensive time-dependent characterization of the effect of small molecules on cellular health in a single experiment. The developed high-content assay offers multi-dimensional comprehensive characterization that can be used to delineate generic effects regarding cell functions and cell viability, allowing an assessment of compound suitability for subsequent detailed phenotypic and mechanistic studies.

/pdf/image-based-annotation-of-chemogenomic-libraries-for-2elk5z5z.pdf

Image-Based Annotation of Chemogenomic Libraries for Phenotypic Screening

Background The current COVID-19 pandemic has highlighted the need for new and fast methods to identify novel or repurposed therapeutic drugs. Here we present a method for untargeted phenotypic drug screening of virus-infected cells, combining Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. Results We show that the methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with Human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state. Conclusions The method can be used in drug discovery for morphological profiling of novel antiviral compounds on both infected and non-infected cells.

/pdf/a-phenomics-approach-for-in-vitro-antiviral-drug-discovery-4rr3o6tizb.pdf

A phenomics approach for in vitro antiviral drug discovery

Cell image analysis is crucial in Alzheimer's research to detect the presence of A$\beta$ protein inhibiting cell function. Deep learning speeds up the process by making only low-level data sufficient for fruitful inspection. We first found Unet is most suitable in augmented microscopy by comparing performance in multi-class semantics segmentation. We develop the augmented microscopy method to capture nuclei in a brightfield image and the transformer using Unet model to convert an input image into a sequence of topological information. The performance regarding Intersection-over-Union is consistent concerning the choice of image preprocessing and ground-truth generation. Training model with data of a specific cell type demonstrates transfer learning applies to some extent. 
The topological transformer aims to extract persistence silhouettes or landscape signatures containing geometric information of a given image of cells. This feature extraction facilitates studying an image as a collection of one-dimensional data, substantially reducing computational costs. Using the transformer, we attempt grouping cell images by their cell type relying solely on topological features. Performances of the transformers followed by SVM, XGBoost, LGBM, and simple convolutional neural network classifiers are inferior to the conventional image classification. However, since this research initiates a new perspective in biomedical research by combining deep learning and topology for image analysis, we speculate follow-up investigation will reinforce our genuine regime.

From augmented microscopy to the topological transformer: a new approach in cell image analysis for Alzheimer's research.

Measuring the phenotypic effect of treatments on cells through imaging assays is an efficient and powerful way of studying cell biology, and requires computational methods for transforming images into quantitative data that highlights phenotypic outcomes. Here, we present an optimized strategy for learning representations of treatment effects from high-throughput imaging data, which follows a causal framework for interpreting results and guiding performance improvements. We use weakly supervised learning (WSL) for modeling associations between images and treatments, and show that it encodes both confounding factors and phenotypic features in the learned representation. To facilitate their separation, we constructed a large training dataset with Cell Painting images from five different sources to maximize experimental diversity, following insights from our causal analysis. Training a WSL model with this dataset successfully improves downstream performance, and produces a reusable convolutional network for image-based profiling, which we call Cell Painting CNN. We conducted a comprehensive evaluation of our strategy on three publicly available Cell Painting datasets, discovering that representations obtained by the Cell Painting CNN can improve performance in downstream analysis up to 25% with respect to classical features, while also being more computationally efficient.

/pdf/learning-representations-for-image-based-profiling-of-16ps3xt5.pdf

Learning representations for image-based profiling of perturbations

Identifying genetic and chemical perturbations with similar impacts on cell morphology can reveal compounds’ mechanisms of action or novel regulators of genetic pathways. Research on methods for identifying such similarities has lagged due to a lack of carefully designed and well-annotated image sets of cells treated with chemical and genetic perturbations. Here, we create such a Resource dataset, CPJUMP1, where each perturbed gene is a known target of at least two chemical compounds in the dataset. We systematically explore the directionality of correlations among perturbations that target the same gene, and we find that identifying matches between chemical perturbations and genetic perturbations is a challenging task. Our dataset and baseline analyses provide a benchmark for evaluating methods that measure perturbation similarities and impact, and more generally, learn effective representations of cellular state from microscopy images. Such advancements would accelerate the applications of image-based profiling, such as functional genomics and drug discovery.

/pdf/three-million-images-and-morphological-profiles-of-cells-29bj2axv.pdf

Three million images and morphological profiles of cells treated with matched chemical and genetic perturbations

Drug discovery for Parkinson’s disease (PD) is impeded by the lack of screenable phenotypes in scalable cell models. Here we present a novel unbiased phenotypic profiling platform that combines automation, Cell Painting, and deep learning. We applied this platform to primary fibroblasts from 91 PD patients and carefully matched healthy controls, generating the largest publicly available Cell Painting dataset to date. Using fixed weights from a convolutional deep neural network trained on ImageNet, we generated unbiased deep embeddings from each image, and applied these to train machine learning models to detect morphological disease phenotypes. Interestingly, our models captured individual variation by identifying specific cell lines within the cohort with high fidelity, even across different batches and plate layouts, demonstrating platform robustness and sensitivity. Importantly, our models were able to confidently separate LRRK2 and sporadic PD lines from healthy controls (ROC AUC 0.79 (0.08 standard deviation (SD))) supporting the capacity of this platform for PD modeling and drug screening applications.

/pdf/deep-learning-and-automated-cell-painting-reveal-parkinson-s-3xjaeo1upq.pdf

Deep learning and automated Cell Painting reveal Parkinson’s disease-specific signatures in primary patient fibroblasts

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Deep learning and automated Cell Painting reveal Parkinson’s disease-specific signatures in primary patient fibroblasts