We study the genetic factors that contribute to complex diseases in order to gain a better understanding of disease mechanisms, hoping that this will lead to novel prevention and treatment strategies.

We do this by incorporating the genetic background of disease into model systems that represent human disease tissues. Our focus is oriented towards movement disorders and complex and immune-mediated diseases. Our research areas include:

  • Genetic screening and editing
  • Induced pluripotent stem cell–derived organ-on-chip models of disease
  • Functional genetics and genomics
  • A focus on brain, intestine, liver and immune system
Relevance

How our research benefits to society

The different research lines in our group focus on determining the biological mechanisms that translate genetic predisposition and environmental influences into disease. Understanding these mechanisms will enable the development of new ways to screen and advise at-risk individuals and new forms of treatment for patients.

  • “The dream of the organ-on-chip field is to create personalized tissue models for every organ and for every individual with a disease. These models can then be used to test drug efficacy in a patient-specific manner.”

    Our ultimate aim is to develop personalized tissue models of disease to improve our understanding of disease mechanisms and test novel treatments for both complex and monogenic disorders.

    Our starting point will be iPSC cells from individuals with a specific genetic background, either patients or Lifelines participants with a particular polygenic risk score. These iPSC cells can then be differentiated into different types of tissues. Initially, we have focused on the gut and developed models for celiac disease (https://tinyurl.com/k3xc424y). We will challenge these mini-guts with gluten peptides, cytokines and other (microbial) metabolites associated with celiac disease to investigate how both disease-affected and healthy guts respond to these stimuli.

    This work is done in the context of the Netherlands Organ-on-a-chip Initiative (NOCI), funded by NWO, and in collaboration with Emulate Inc., Boston, USA. More recently we have developed a liver-on-chip system as well that we will use to study the role of the gut-liver axis in drug metabolism and to study NAFLD/NASH biology.

    Gut-on-a-chip

    We currently have an operational gut-on-a-chip system through our active collaboration with Emulate. We initially intend to use this platform to study celiac disease, an immune-mediated disease that affects the gut. Here we can utilize organ-on-a-chip to study how gluten peptides affect the immune system and microbiome and how the gut interacts with these factors in very high detail.

    Liver-on-a-chip

    We have also generated a liver-on-a-chip to study the role of the intestine-liver axis in drug metabolism and their response to nutrients and drugs.

    Brain-on-a-chip

    We dream of generating multiregional brains-on-a-chip as well, again by taking advantage of PBMCs stored in liquid nitrogen for 20,000 Lifelines participants. Since we have polygenic risk scores for each of these samples, we can use PBMCs from individuals strongly susceptible to brain disorders such as Alzheimer’s & Parkinson’s diseases, multiple sclerosis or ALS.

    Connecting different organs-on-a-chip

    By connecting these systems, we will be able to ascertain how the gut and liver interoperate and gain highly detailed insights into the metabolism of nutrients and drugs. We expect that the genetic makeup comprises a very strong factor in food and drug metabolism. Because we have PBMCs and polygenic risk scores for more than 20,000 participants, we can select those individuals with strongly increased or decreased risks for e.g. cardiometabolic disorders, which will enable us to study the effects on metabolism in unprecedented detail.

    Leveraging existing multi-omics Lifelines cohorts

    The PBMCs that have been stored in liquid nitrogen for more than 350 Lifelines Deep samples make it is possible to derive iPS cells that we can differentiate into a gut-on-a-chip. Additionally, as we have already generated a tremendous amount of multi-omics data on these samples, we can also integrate these in-vivo measurements with extremely well controlled organ-on-a-chip measurements. This will allow us to obtain extremely detailed insights into the interplay between the genome and environmental exposures.

  • We study autoimmune disease as a representative model of complex diseases. Celiac disease has our particular interest as it is the only autoimmune disease for which the direct trigger – dietary gluten – is known. Gluten intake causes severe inflammation in the small intestine in genetically pre-disposed individuals. To date, researchers in our department have identified >40 genetic risk loci for celiac disease, and we are now investigating how these loci contribute to disease-onset and exacerbation. Other autoimmune diseases on which our research focuses are multiple sclerosis (MS) and inflammatory bowel disease (IBD).

    Multiple cell types are involved in the disease process of autoimmunity, making it truly complex. We therefore use innovative genomics technologies to directly and functionally identify the genetic modifications that play a role. We also carry out computational (single-cell) genomics and genetic studies to understand the function of the genes and pathways modified by the genetic risk loci.

    We do this using the cell types and circumstances most applicable for the disease in order to capture the true genetic effect under disease conditions. For instance, in celiac disease we use patient derived samples and advanced models like gut-on-a-chip to infer the role of genetic risk loci. Ultimately, we aim to bridge the gap between genome-wide association studies and precision approaches to auto-immune disease.

    We work closely with population (Lifelines) and patient cohorts (CeDNN) and are involved in developing and applying new technologies like induced pluripotent stem cell models (organoids and organ-on-chip platforms) and gut-on-a-chip to answer critical questions about celiac disease, MS, IBD and the overlap and differences between them.

  • From population-based cohorts to infectious disease patient

    As part of the Human Functional Genomics Project, we have studied the capacity of blood leucocytes to produce cytokines in response to different infectious agents using healthy population-based cohorts. This has revealed remarkable variability in individual’s capacity to produce cytokines and shown that 40–80% of the variability in leucocyte response between individuals can be explained by genetic differences. We now aim to extend these studies to different cell types and infectious agents. We have also shown that the same genetic variants confer differential susceptibility to fungal infection in sepsis patients. Our aim is to develop diagnostic markers and identify therapeutic targets based on the individual genetic variation that affects sepsis outcome.

    We are conducting these human functional genomic studies in other diverse populations from Tanzania, Indonesia, Guinea-Bissau and Vietnam to identify genetic risk factors for tuberculosis (TB) and TB meningitis.

    Genetic susceptibility to sepsis survival

    In addition to immune cells, our recent functional genomic studies have revealed a crucial role for endothelial and epithelial cells in sepsis pathogenesis. By making use of genetic data of multiple sepsis patient cohorts and iPSC lines, we are developing a ‘sepsis-on-chip’ model to unravel the contribution of different cell types in sepsis survival.

    Multi-omics approach to COVID-19

    The ongoing pandemic with the new SARS-CoV2 virus shows the desperate and urgent need for better strategies to predict and treat Coronavirus disease 2019 (COVID-19). A subset of COVID-19 patients develop very severe respiratory symptoms, whereas others experience mild flu-like symptoms. To determine how differences in molecular response patterns affect COVID-19 severity and outcome, we will use cohorts of COVID-19 patients in the Netherlands to profile longitudinal multi-omics data. This will allow us to 1) characterize the role of plasma metabolites, inflammatory markers and circulatory proteome variability in explaining COVID-19 outcome, 2) pinpoint causal molecular networks using dynamic changes in host multi-omics data and 3) provide the genetic support for multi-omics variability that determine COVID-19 outcome in prospective independent cohorts. By conducting systematic longitudinal systems biology analyses, we can establish causal relationships between omics-networks and COVID-19 clinical phenotypes.

  • We identify and functionally characterize disease genes involved monogenic movement disorders such as ataxia, dystonia and Parkinson’s Disease. These diseases affect specific brain regions involved in the execution and coordination of movements, including the cerebellum or basal ganglia. However, recent data show that multiple brain regions of the cerebello-thalamo-cortical network are also involved in these disorders, but it remains unknown how dysfunction of this network causes these different disorders. Over the past few years, we have identified several new disease genes, including genes for dominantly inherited ataxia, dystonia and chorea, and we are now investigating the mechanisms of disease in different model systems representative for these diseases.

    Generating new disease model systems

    We use CRISPR-Cas9 base-editing or prime-editing technology to edit specific genes. We genetically deplete genes or introduce human mutations in cell model systems of different origin. Additionally, we use CRISPR-mediated tagging of endogenous proteins to discover the cellular localization and interacting partners of novel disease proteins to better understand their functionality and the corresponding biological pathways in which the disease gene operates.

    Shared disease mechanisms

    We are also working on identifying disease mechanisms that are shared between different movement disorders and between different genetic subtypes of specific movement disorders. We also are exploring the underlying genetics and mechanisms of mixed phenotypes of various movement disorders. In the end, we aim to obtain a better understanding of the shared disease pathogenesis and identify putative common treatment targets.

    This work is carried out in close collaboration with the Expertise Centre of Movement Disorders of the UMCG, which involves a multi-disciplinary group of clinicians and researchers.

    • Dr. Kieu Le, Postdoctoral researcher
    • Aarón D. Ramírez-Sánchez, Postdoctoral researcher (ORCID)
    • Dr. Jelle Slager, Postdoctoral researcher (ORCID)
    • Rutger Modderman, Research Analyst
    • Jody Gelderloos-Arends, Research Analyst
    • Astrid Mattman, Research Analyst
    • Michiel Fokkens, Research Analyst

Contact

Secretariat Genetics

Telephone: +31 50 361 71 00
Email: secr@medgen.umcg.nl

Department of Genetics

University Medical Center Groningen
Postbus 30.001
9700 RB Groningen
The Netherlands

Location in UMCG

Department of Genetics

University Medical Centre Groningen
Medical Faculty building (building 3211), 5th floor
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands