ADVANCED METHODS, DATA AND ANALYSES TO UNDERSTAND LIVING SYSTEMS
‘Connecting the dots: novel approaches in biological measurement and analysis’
Erik van Nimwegen
Professor at Universität Basel, CH – The Center for Molecular Life Sciences
Erik van Nimwegen studied theoretical physics at the University of Amsterdam. He performed his PhD studies at the Santa Fe Institute (SFI) in Santa Fe New Mexico, receiving his PhD from the Faculty of Biology at Utrecht University in 1999. This was followed by a year of post-doc studies at the SFI, and three years as a fellow at the Center of Studies in Physics and Biology at the Rockefeller University, New York. Since 2003 he is Professor of Computational Biology at the Biozentrum of the University of Basel, and group leader at the Swiss Institute of Bioinformatics since 2004.
Erik van Nimwegen leads an interdisciplinary group of researchers with backgrounds ranging from theoretical physics to molecular biology that are studying the function and evolution of the regulatory networks that cells use to control the expression of their genes. Read more
Inferring gene regulatory landscapes from single-cell data
Single-cell transcriptomics provides us with detailed quantitative pictures of gene expression patterns across single cells. However, connecting the observed gene expression patterns to the underlying gene regulatory dynamics is still highly challenging. In this talk I will discuss some new methods for inferring, from scRNA-seq data, the transcription regulatory interactions that guide single-cell gene expression trajectories. These method combines three new ideas: First, a scRNA-seq normalization method that rigorously deconvolves sampling noise from true variations in transcription rates. Second, a Bayesian method that infers the ‘regulatory states’ of each single cell by modeling measured transcription rates in terms of genome-wide computational predictions of transcription factor binding sites. And third, a maximum entropy approach that infers an effective epigenetic landscape that guides the distribution of single cells in the space of regulatory states.
Professor at TU Eindhoven – Department of Biomedical Engineering
Dr. Sahlgren obtained her PhD at Åbo Akademi University (ÅAU; Turku, Finland) in 2002, focusing on intermediate filaments as signaling mediators. During her postdoctoral work at Karolinska Institutet (Stockholm, Sweden; 2005-2008) she studied Notch signaling and hypoxia-related cancer cell characteristics. She then returned to Finland to establish the Cell Fate Lab at the Turku Centre for Biotechnology, focusing on Notch in cancer and stem cells. Together with collaborators, she worked on developing nanoparticles and biomaterials for Notch-targeting and modulation of cell differentiation. In 2013, Dr. Sahlgren moved to the department of Biomedical engineering at Eindhoven University of Technology (TU/e; Eindhoven, the Netherlands). At TU/e, her group has created technological platforms to study cell fate decisions in the vasculature and in tumors as well as used computational modelling to predict Notch mechanosensitivity. In 2016, she returned to Finland to become professor of cell biology at ÅAU while also keeping her affiliation to TU/e. In 2017, Dr. Sahlgren was awarded a five-year ERC Consolidator Grant (2 M€) to investigate the interplay of mechanical forces and cell signaling in the vasculature and to clarify their effects on blood vessel architecture. Read more
The integration of cell signalling and mechanical forces in vascular morphology
Structural remodelling of the vasculature in response to changes in blood flow is important to maintain mechanical homeostasis, and many cardiovascular diseases are related to defects in tissue morphology and mechanical imbalance. Signalling between endothelial cells and vascular smooth muscle cells via the Notch pathway regulates the morphology and structural remodeling of the arterial wall. Notch offers handles for therapeutic control; however, we lack essential understanding of how hemodynamic forces integrate with Notch signalling. The complexity of the problem requires new tools and an interdisciplinary approach. Our project integrates engineering and computational modelling with cell biology and in vivo model systems to address the question. We have created and characterized two new tools to for studies on isolated vascular cells. The Artery-on-Chip allows the different vascular cell types to be co-cultured in their physiological 3D organization under strictly controlled hemodynamic conditions and to be monitored in real-time. The Dish-in-a-Dish is a platform designed for 2D shear stress experiments with uniform and optimized mechanical stress conditions. We have also generated both a 1D and a 2D computational model of mechanosensitive Notch signalling in the artery wall. The models predict the fate of vascular smooth muscle cells in a vessel of increasing thickness while taking into account Notch signalling changes induced by mechanical cues. Additionally, we have combined animal work, cell biological laboratory experiments and computational modelling to identify vimentin, an important structural component of vascular cells, as a mediator of mechanosensitive Notch signalling and arterial remodelling.