4th Keynote Speaker Announced

Murat Cirit

Director of Translational Center of Tissue Chip Technologies

(Massachusetts Institute of Technology)

Paper presenting: Translational applications of microphysiological systems

Murat Cirit, PhD, is a Research Scientist at MIT & director of the Translational Systems Pharmacology Team. Murat completed his PhD at NCSU focusing on systems biology of growth factor-mediated signal transduction pathways. After completion of his PhD, he worked in the pharmaceutical industry focusing on preclinical drug discovery for oncology. He brings an interdisciplinary and systematic approach through his extensive experimental knowledge and computational modeling with an understanding of biological, physiological, and physical processes. His main research experience is systems pharmacology, systems biology, applied tissue engineering, cell biology and signal transduction networks. His current focus as the scientific lead is integrating various scientific fields to build interacting MPSs by interfacing platform engineering & tissue engineering for pharmacology studies.

Translational applications of microphysiological systems

Abstract: A large percentage of drug candidates fail at the clinical trial stage due to a lack of efficacy and unacceptable toxicity, primarily because the in vitro cell culture models and in vivo animal models commonly used in preclinical studies provide limited information about how a drug will affect human physiology. The need for more physiologically relevant in vitro systems for preclinical efficacy and toxicity testing has led to a major effort to develop “Microphysiological Systems (MPS)”, aka tissue chips (TC), based on engineered human tissue constructs. Translational Center of Tissue Translational Center of Tissue Chip Technologies (TC2T) has been established to bridge between academic research and development and industrial application of MPS technologies via providing unbiased testing and validation of MPS technologies. TC2T takes a holistic and mechanistic approach—based on quantitative systems pharmacology (QSP)— to achieve unbiased characterization of these complex systems and translation of experimental insights to clinical outcomes. Our team at MIT includes tissue engineers, experimentalists, and computational biologists and serves as the core of the testing center to identify adverse effects of pharmaceutical compounds and environmental toxin on human organs.

Title Sponsor

2nd Keynote Speaker Announced

Dr Paul Walker

Head of Toxicology


Paper presenting: Combined in silico and 3D in vitro approaches for the accurate prediction of human drug induced liver injury

Paul Walker is the Head of Toxicology at Cyprotex where he is responsible for the development of new assays and management of client work performed within the Toxicology Group. 

Paul obtained his Ph.D. from King’s College London in Molecular Toxicology being awarded the Tadion-Rideal prize for molecular sciences (2004). Paul further developed his understanding of molecular biology and toxicology during his post-doctoral years at the University of Manchester with a keen interest in the application of high content screening within this field. 

Paul joined Cyprotex in 2010 with his research interests focused on the role of drug metabolism in drug toxicity and in vitro assays to predict toxicity in early drug discovery.

His team are focused on:

1. Developing and evaluating novel cellular systems to improve the prediction of toxicity.

2. Evaluate current industry utilised mechanistic endpoint assays in predicting toxicity.

3. The importance of drug metabolism and appropriate cellular models in our mechanistic understanding of toxicity.

4. Integrating in vivo exposure in interpretation of in vitro data, and 5. Modelling approaches combining ADME, PK and in vitro Tox assays to predict toxicity.

Combined in silico and 3D in vitro approaches for the accurate prediction of human drug induced liver injury

Abstract: Utilising 3D in vitro approaches to de-risk drug induced liver injury (DILI) is an emerging trend. These approaches primarily use primary human hepatocytes (PHH) and kupffer cells to form microtissues (MTs). Various studies have now illustrated the advantages of these approaches over traditional 2D assays utilising a single biochemical endpoint ATP1. We have further developed this approach by applying multiparametric confocal high content imaging to determine mitochondrial membrane potential, reactive oxygen species formation and GSH content in addition to ATP and have evaluated PHH in co-culture as well as HepaRG 3D human liver MTs2. CYP450 characterisation of MTs showed significantly higher activities in HepaRG MTs compared to PHH MTs (CYP3A4: 210pM/min/MT HepaRG, 80pM/mn/MT PHH). Following characterisation DILI reference compounds were screened through each model and confocal high content imaging was used in addition to ATP activity to determine DILI risk.

Prediction of human DILI was improved in the HepaRG MT when compared to the overall response in the PHH MTs, with hepatocyte donor differences observed. In addition the accuracy of the prediction of DILI was increased further using a multiparametric approach compared to measurement of ATP alone. Furthermore, incorporation of in silico human liver exposure data further enhanced the sensitivity of this approach.

Our research has demonstrated that 3D MTs enhances our ability to predict DILI risk over traditional 2D techniques. This prediction of DILI is also significantly improved by using multi-parametric approaches and in silico human exposure data. In vitro models such as the system detailed above are amendable to high throughput screening, are cost effective and as such could play an important role in the pharmaceutical strategies for mitigating DILI risk early in drug discovery.

Title Sponsor