Neural stem cells forming rosettes, stained against the forebrain transcription factor PAX6 (red) and the intermediate neurofilament Nestin (green).
Courtesy of Bachmann lab (Affef Abidi)
|Ruxandra Bachmann-Gagescu||Wolfgang Berger||Christian Grimm|
|Edna Grünblatt||Sebastian Jessberger||Magdalini Polymenidou|
|Gerhard Schratt||ChristianTackenberg||Janos Vörös|
SNF Assistant Professor
Institute of Medical Genetics and Department of Molecular Life Sciences, University of Zurich
Research Focus: Our research focuses on a group of human Mendelian disorders called ciliopathies, which are unified by shared genetic causes resulting in primary cilium dysfunction. Primary cilia are small non-motile organelles present on the surface of most vertebrate cells where they are involved in transduction of sensory, mechanical or chemical signals and in regulation of signaling pathways during development and cell homeostasis. Typical clinical presentations of ciliopathies include neurological involvement, retinal degeneration and renal fibrocystic disease, as illustrated by Joubert syndrome (JS), an iconic ciliopathy, which is the main focus of our research. To understand the consequences of mutations in JS-associated genes at the molecular level, we are developing iPSC-based neuronal 2D and 3D models using CRISPR/Cas9 genome editing, imaging and –omics approaches such as RNAsequencing and proteomics. In parallel, we are differentiating the iPSC lines harboring mutations in the genes of interest into further cell types affected in ciliopathies such as renal tubular cells.
Methods: CRISPR/Cas9 genome editing, next generation sequencing for clone selection and quality control, 2D cortical neuronal differentiation, 3D cerebral organoids
Keywords: ciliopathies, primary cilia, Joubert syndrome, iPSCs, neurons
Topics: Neuroscience, Disease Modelling
Full Professor of Medical Molecular Genetics
Director, Institute of Medical Molecular Genetics, University of Zurich
Research Focus: Our research focuses on disease modelling of Mendelian eye disorders by making use of induced pluripotent stem cells and genome editing. Diseases include monogenic retinal dystrophies (IRDs), which are generally progressive and may lead to blindness due to dysfunction and gradual loss of photoreceptors and/or supporting retinal pigment epithelial cells. This disease family is characterized by a significant genetic heterogeneity and clinical variability and involves more than 300 associated genes and mapped loci (https://sph.uth.edu/retnet). The second group of diseases includes optic nerve hypoplasia (ONH), persistent hyperplastic primary vitreous (PHPV) and Norrie Disease (ND), the latter two of which are characterized by a maldevelopment of the neuroretina and retinal vasculature.
Our disease modelling is performed using 3D retinal organoids, which are chemically differentiated from human induced pluripotent stem cells (iPSCs). In order to study the impact on vascular development, our retinal organoid model is complemented by endothelial cells differentiated from iPSC-derived mesodermal progenitors. Developmental and functional consequences of CRISPR/Cas9-mediated gene knockout or patient variant introduction in the organoid model is studied by morphologic and histologic techniques as well as gene expression approaches (mRNA sequencing (mRNA-seq) and single-cell RNA sequencing (scRNA-seq), where the latter technique provides the benefit of investigating individual subtypes of retinal cells). Other cell-based assays, including minigene assays for characterization of splicing and Luciferase reporter assays for detection of transcriptional activation, allow us to study novel genotype-phenotype associations and possibly lead to the identification of new therapeutic targets.
Methods: CRISPR/Cas9 genome editing, next generation sequencing, iPSC-derived 3D retinal organoids, iPSC-derived mesodermal progenitors and endothelial cells, mRNA-seq, scRNA-seq, minigene assay, luciferase reporter assay
Keywords: ATOH7, ABCA4, NDP, monogenic/Mendelian retinal diseases, vitreoretinopathies
Topics: Retinal development and disease modelling
Professor for Experimental Ophthalmology, University of Zurich
Head of Lab for Retinal Cell Biology, Dept. Ophthalmology, University Hospital Zürich
Research Focus: Our research focuses on blinding diseases of the retina with a special focus on age related macular degeneration (AMD) that affects up to 25% of people above the age of 75. We use various animal models to understand specific aspects of disease etiology and progression, and develop therapeutic strategies that are based on neuroprotection and AAV-mediated gene therapy. Photoreceptor neurons form a functional unit with the underlying cells of the retinal pigment epithelium (RPE) that not only form the outer blood/retina barrier but also are crucial for photoreceptor function and survival through the regulation of metabolic support and oxygen delivery from the choroidal blood vessels to photoreceptors. Part of this regulation is the transport and recycling of lipids that originate from the daily process of photoreceptor renewal. We are using iRPE cells differentiated from iPSCs derived from patients carrying genetic variants that confer either increased or decreased risk to develop AMD. These cells closely resemble the in vivo situation in patients and are ideal to study their function in response to various stimuli and conditions that include exposure to neuronal debris with a high cholesterol load and hypoxia, an important factor for disease development. We also use CRISPR editing to inactivate genes in isogenic cells in order to study specific genetic factors for RPE function.
Methods: differentiation of iPSC into iRPE cells, CRISPR/Cas9 genome editing, cholesterol efflux, phagocytosis, transepithelial resistance, single cell sequencing, transcriptomics, proteomics, AAV-based gene therapy.
Keywords: RPE, lipids, hypoxia, iPSC, neurons, gene therapy
Topics: neurodegeneration, gene therapy
Head of the Translational Molecular Psychiatry, University Hospital of Psychiatry (PUK), Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zurich
Chair of the ECNP Thematic Working Group iPSCs platform for Neuropsychiatry
Research Focus: The main research focus of the Translational Molecular Psychiatry Research group, part of the University Hospital of Psychiatry Zurich, is on neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD), Autism spectrum disorders (ASD), psychosis, early onset obsessive-compulsive disorder (OCD) and environmental /stress effects. The lab includes research at the pre-clinical as well as at the basic molecular neuroscience, integrating both research fields in a translational manner. The techniques used include molecular genetics, epigenetic, psychopharmacology, neuronal cellular models and biochemical measures. The goal of the research is to elucidate the etiopathology of the disorders discovering biomarkers for early diagnosis and precision personalised medicine, predicting treatment response and outcomes. Currently, the research group has established patient specific iPSC (induced pluripotent stem cell) neuronal modelling to enable personalized medicine, via studies of the neuronal/molecular alterations in a dish of the disorders using 2D techniques. This will provide a non-invasive approach to investigate etiopathology of neurodevelopmental disorders as well as test drug therapy effects.
Methods: Hair follicle Keratinocytes, Prick blood cells culturing, Reprogramming via Sendai, Monolayer Neural Progenitor cells generation, cortical neuronal differentiation
Keywords: ADHD, ASD, biochemistry, child and adolescent psychiatry, iPSC, molecular biology, NPC, OCD, psychosis, transcriptomics
Topic: Neuroscience, Psychiatry
Professor of Neuroscience
Brain Research Institute, University of Zurich
Research Focus: We use a multipronged, interdisciplinary approach to study the molecular and cellular framework of neural stem cell (NSC) biology in the developing and adult brain. We use state-of-the-art imaging-, genome editing-, and transgenesis-based approaches as well as cellular models of human diseases using pluripotent stem cells with the aim to further our understanding of NSC behavior in health and disease.
Methods: Mouse and human embryonic stem cells, genome editing, regionalized forebrain organoids, single cell RNA-sequencing, longitudinal imaging.
Keywords: brain development, neurogenesis, asymmetric cell divisions, imaging
Topics: Stem cells, neuroscience, brain development, disease modeling
Associate Professor of Biomedicine
Department of Quantitative Biomedicine, University of Zurich
Research Focus: We study the molecular mechanisms of neurodegenerative diseases, focusing on amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS and FTD are characterized by the accumulation of RNA-binding proteins, such as TDP-43 and FUS, as well as non-canonically translated dipeptide repeat proteins (DPRs). The molecular mechanisms that trigger aggregation of ALS/FTD-linked proteins, the basis of disease heterogeneity and the mechanisms of neurotoxicity remain elusive. The aim of our research is to address these important questions using a multidisciplinary approach, working at the molecular, cellular and organismal level. Our vision is to gain deep mechanistic understanding of ALS and FTD to inspire rational design of target-based therapies for these devastating diseases. To explore the disease mechanisms in the context of mature human neurons, we generated highly homogeneous, unmodified, human neural stem cells from iPSCs, along with a robust differentiation method that yields functional, interconnected and long-lived neurons within 3D neural cultures. Inducible expression of ALS/FTD-linked proteins in this system is routinely used to understand their behavior and functional consequences in human neurons, as well as evaluate the therapeutic efficacy of antibodies and other compounds. We are currently expanding our efforts to patient-derived neural systems.
Methods: Generation of homogeneous and unmodified human neural stem cells, differentiation to cortical neurons and pure astrocytes, 3D neural cultures, lentiviral generation for inducible expression in neurons, single cell RNA-seq, superresolution microscopy, protein aggregation assays.
Keywords: ALS, FTD, TDP-43, FUS, DPRs, LLPS, RNA misregulation, protein aggregation, prion-like
Topics: Neuroscience, Neurodegeneration, Brain Diseases, Disease Modelling, RNA biology
Professor of Systems Neuroscience
Institute for Neuroscience, ETH Zurich
Research Focus: Despite extensive research, there is up to date no final explanation for the unique cognitive abilities of the human species. Whereas most of the genetic, molecular and cellular components in mammalian brains are quite similar, human neurons seem to display an increased potential for synaptic plasticity. This might be due to a generally higher number of synapses or a prolonged maturation of these in comparison to other mammals and even primates.
Non-coding RNAs and especially miRNAs play a significant role in synaptic development and plasticity. Furthermore, particularly the regulatory part of the genome distinguishes humans most from their closest relatives. Nevertheless, the contribution of non-coding RNA dependent mechanisms to human synapse development and plasticity is poorly understood.
To study the role of non-coding RNAs in human synapse development, we established a defined human neuronal differentiation protocol without the need for the addition of animal glia cells on two different human induced pluripotent stem cell (iPSC) lines. We show that these neurons are electrophysiological active and investigate synapse formation in detail by analyzing confocal images of pre- and postsynaptic markers at distinct developmental time points. Furthermore, the glia-free differentiation protocol allows us to perform small-RNA sequencing in combination with proteomics and long-RNA sequencing at these same stages.
These characterizations are essential for a more detailed functional analysis in the future. By manipulating the expression of specific candidate RNAs, we plan to investigate their role in synaptic maturation as well as effects on neuronal morphology and electrophysiological properties. Newly identified pathways can further be studied in the context of neuropsychiatric diseases using patient-derived iPSC lines.
Methods: induced-pluripotent stem cell derived neuron differentiation, imaging, transcriptomics, proteomics, electrophysiology, genome editing
Keywords: iPSC, iNeuron, Crispr/Cas9, non-coding RNA, lncRNA, microRNA, synapse, neurodevelopmental disease
Topics: Neuroscience, brain development, neuropsychiatric disease
Scientific Head of Stem Cell Research and Teaching
Research Focus: We use stem cells, especially induced pluripotent stem cells (iPSCs), for regenerative therapy and for modeling human brain diseases. Currently, we focus on Alzheimer’s Disease (AD) and Stroke.
AD is the most common type of dementia with the apolipoprotein E4 (APOE4) allele as major genetic risk factor. Using either AD patient-derived iPSCs or isogenic cells that differ only in their AD risk genes, we aim to better understand AD pathomechanisms in differentiated human cortical neurons and astrocytes.
Stroke causes a permanent disability to five million people each year. This is largely due to the lack of effective medical treatment that promotes long-term recovery. Therefore, we are developing a regenerative therapy for stroke based on transplantation of iPSC-derived cells.
Methods: Induced pluripotent stem cells (iPSCs), differentiation into cortical neurons, astrocytes and neural progenitor cells, 2D and 3D cell culture, photothrombotic stroke mouse model, cell transplantation, deep neural networks (DeepLabCut), in vivo bioluminescence imaging, Laser-Doppler imaging.
Keywords: Alzheimer’s disease, Stroke, induced pluripotent stem cells (iPSCs), neurodegeneration, neurons, astrocytes, neural progenitor cells, disease modeling, cell transplantation
Topics: Neuroscience, Neurodegeneration, Brain Diseases
Laboratory of Biosensors and Bioelectronics Institute for Biomedical Engineering
Research Focus: We are promoting a new, bottom-up approach to neuroscience. We create well-defined in vitro neural networks with oriented connections and study their behavior. We use both rat primary hippocampal neurons and human iPSC-derived neurons to build such circuits. We interact with these networks by stimulating selected neurons and record the resulting activities of the networks using optogenetic means and microelectrode arrays (MEAs) including high-density CMOS arrays. We collect TBytes of data that we analyze using machine learning means. We also try to build computational models of the produced living neural networks with the aim to predict the expected behavior of the network.
In addition, we also develop stretchable microelectrode arrays to study the strain response of neural networks and the neuro-muscular junction.
Methods: Stretchable microelectrode arrays; Optogenetics; Microfabrication; Soft lithography; iPSC-derived neurons
Keywords: Neuronal circuits; Induced pluripotent stem cells (iPSCs); Deep learning
Topics: Bottom-up Neuroscience; Electrophysiology;