Complex Cellular Phenotype Analysis

BII - Computer Cellular Phenotype Analysis Group Photo

Research

We are a computational biology research group with members coming from different scientific disciplines, including chemistry, cell biology, computer science, and bioinformatics.

The overall goal of our research is to understand the modes of action (MoAs) of xenobiotics, such as environmental agents and drugs; and predict their human efficacy and/or toxicity. We develop and use novel phenotypic and molecular profiling methods to elucidate the MoAs of xenobiotics, and build computational models that can predict the in vivo effects of these agents.

We collaborate with different academic, clinical, industrial, and governmental research groups, including Institute of Molecular and Cell Biology (IMCB), NanoBioLab (NBL), Institute of Bioengineering and Nanotechnology (IBN) (all three from A*STAR), Singapore General Hospital (SGH), the United States Environmental Protection Agency (US EPA), and the Netherlands National Institute for Public Health and the Environment (RIVM).

Our current research is focused on three major areas, namely phenotypic profiling and digital pathology, toxicodynamics of xenobiotics, and pulmonary effects of xenobiotics (Fig. 1).

BII - Complex Cellular Phenotype Analysis Figure 1

Figure 1: Our current research areas

Phenotype Profiling and Digital Pathology

Phenotypic profiling is a computational procedure to construct quantitative and compact representations of cellular or tissue phenotypes based on images obtained from high-throughput microscopy (Bougen-Zhukov et al., 2017). We have developed several phenotypic profiling methods, including the Drug-Profiling (“D-profiling”) algorithm (Loo et al., 2007) and the Protein-localization Profiling (“P-profiling”) algorithm (Loo et al., 2014). We also develop a user-friendly and efficient phenotypic profiling software called “cellXpress” (Laksameethanasan et al., 2013), which can handle terabytes of image data collected under large numbers of experimental conditions. Phenotypic profiles constructed using these methods have been used to classify the effects of small molecules (Loo et al., 2007, 2009), or assess potentially toxic effects of environmental agents (Friedman et al., 2019; Lee et al., 2018; and Su et al., 2016). Recently, we have also developed a new digital histopathology platform based on phenotypic profiling for cancer diagnosis and prognosis (Fig. 2). The platform can help researchers and clinicians to rapidly and accurately quantify the effects of cancer therapeutic agents, resulting in more systematic clinical decision-making processes.

BII - Complex Cellular Phenotype Analysis Figure 2

Figure 2:  Our digital histopathology platform is based on the new cellXpress 2.0, which can now handle and quantify highly-multiplexed and large microscopy images obtained from human tissue microarrays (TMA).

Toxicodynamics of Xenobiotics

Many xenobiotics have unknown and/or non-specific intracellular targets. To study the toxicodynamics of these chemicals, unbiased approaches that do not require prior information about the targets or mechanisms of the chemicals are required. Together with eight other research teams from A*STAR, we are developing the Toxicity Mode-of-Action Discovery (ToxMAD) Platform to elucidate the modes of action of xenobiotics in major target cell types using advanced phenotypic, signaling, and genomic profiling methods. Our focus is to study chemical analogs with related structures but differential cellular effects, and develop fit-for-purpose assays that will be used by regulatory agencies and industrial research laboratories to assess chemical safety. In 2019, we participated in an international case study that demonstrates the utility of in vitro bioactivity as a lower bound estimate of in vivo adverse effect levels in risk-based prioritization (Friedman et al., 2019).

Pulmonary Effects of Xenobiotics

Human lungs are exposed to inhaled or blood-borne soluble xenobiotics that may originate from the environment, food, consumer products, and/or pharmaceuticals. We are broadly interested in the understanding the biological targets and pathways affected by these chemicals in the lung cells. We have recently developed a high-throughput and predictive in vitro pulmonary toxicity assay (Fig. 3; Lee et al., 2018). We found that the resulting assay based on two phenotypic features of a human bronchial epithelial cell line, BEAS-2B, can accurately classify 33 reference chemicals with human pulmonotoxicity information (88.8% balance accuracy, 84.6% sensitivity, and 93.0% specificity). We also studied the effects of talc particles, a sclerosis agent commonly used in the management of malignant pleural effusions, in human lung cancer cells (Bougen-Zhukov, et al., 2019). We found a novel role of the PI3K pathway in talc-induced cell death and IL-6 secretion, which are key cellular events known to drive pleural fibrosis. This provides a better understanding of the mechanisms of talc sclerosis in the malignant pleural space.

BII - Complex Cellular Phenotype Analysis Figure 3

Figure 3: Immunofluorescence microscopy images of human lung cells showing different phenotypic responses to non-toxic (blue) and toxic (red) chemicals.

Members

 Senior Principal Investogator  LOO Lit Hsin   |    [View Bio]  
 Senior Post-Doctoral Research Fellow MILLER James Alastair
 Senior Post-Doctoral Research Fellow  HTWE Su Su 
 Post-Doctoral Research Fellow ZHONG Guorui
 Senior Research Officer LEE Jia Ying Joey
 Research Officer FU Shufeng Oscar
 Research Officer KONG Jia Wen Carmen 
 Web programmer DONG Jiahui 

Selected Publications