University Medical Center of Groningen
The University Medical Center of Groningen
Besides providing clinical care and educating students, the UMCG performs cutting-edge research. The UMCG’s research focus is on the theme ‘healthy and active aging’ and aims to develop personalised health care and prevention strategies. Important activities developed within this focus are the Lifelines population cohort (Lifelines.nl) and the European Research Institute for the Biology of Ageing (ERIBA; eriba.umcg.nl).
Added value for hDMT
See Expertise and Facilities. The UMCG will bring in the researchers, the expertise and infrastructure highlighted in bold.
Added value for UMCG
The added value for the UMCG is that it will become part of an internationally known consortium in the field of organs-on-chip. The expertise that is shared within this consortium will greatly synergise the work that is ongoing or will be starting in this field at the UMCG.
The Lifelines project and its ‘add-on’ studies
The Lifelines project (Lifelines.nl) involves the collection of samples and medical data of 165,000 individuals living in the northern part of the Netherlands while aging (follow-up of 30 years). Questionnaires (e.g.demographics, lifestyle) are collected every 1.5 years and physical measurements and biological samples (e.g.blood, urine, biomarkers) every 5 years. Currently, hundreds of phenotypes can be linked to each individual subject. Individual research groups at the UMCG collect samples or data from Lifelines or contribute to the biobank by performing extra analyses in vitro or in silico. Examples of such studies are:
- For the LifelinesDeep project molecular data (e.g. genotypes, transcriptome, epigenome, microbiome,metabolites) was obtained (n=1,500) leading for example to a publication in Science describing ~150 environmental and clinical factors that shape the human microbiome (Zhernakova et al., 2016).
- The LifelinesNext-BabyVir project (ERC Starting Grant to Sasha Zhernakova, UMCG, Dept. of Genetics, 2016) aims to determine how the human bacterial microbiome is shaped by the virome (viruses and bacteriophages) during the first year of life of 1,000 babies of Lifelines mothers.
- LifelinesDAG3 (started 2017) aims to determine the microbiome of 10,000 Lifelines subjects. New aspects are the virome and the collection of the culturome that can be added to a ‘gut-on-chip’.
- LifelinesGSA (GSA = Genomewide Screening Array) aims to genotype 60,000 Lifelines subjects. Using the trio design of the cohort, genotypes of the subjects that are not analysed can be imputed.
- LifelinesCBSC (CBSC = Cord Blood Stem Cells) aims to create a cord blood derived stem cell bank.
Systems biology analyses on data acquired in these studies, generate hypotheses which can be tested on ‘organ-on-chip’. Moreover, when cells are collected these could be used to generate organs-on-chip.
In 2016 an NWO Zwaartekracht grant was awarded to the Netherlands Organ-on-Chip Initiative led by Christine Mummery (LUMC). Co-PI on this project is Cisca Wijmenga (Dept. of Genetics, UMCG) who applies systems biology approaches to study the effect of genetics on homeostasis of the gut and the immune system. The Dept. of Genetics houses the Genome Analysis Facility of the UMCG (rug.nl/research/genetics/genomeanalysisfacility/) and the Groninger Genomics Coordination Center (umcg.nl/EN/Research/Researchers/Facilities/GCC). Utilizing the Lifelines cohort and the 500FG cohort (FG = Functional Genomics; humanfunctionalgenomics.org) her group, in close collaboration with Mihai Netea (Radboud UMC), is characterizing the interaction between genetics, microbiome composition, and the consequences of the aforementioned on the immune response, on cognitive function and on other systems. Second line investigators on the Zwaartekracht proposal are Jingyuan Fu (Genetics & Pediatrics; liver metabolomics & liver-on-a-chip), Sasha Zhernakova (Genetics, microbiome, gut-on-a-chip, gut-brain axis), Iris Jonkers (Genetics , Celiac disease, gut-on-a-chip), and Lude Franke (single cell RNA sequencing of immune cells and stem cells).
Cisca Wijmenga and Rinse Weersma (Gastroenterology) are leading the Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI). The PIs involved in 3GI (amongst others Hermie Harmsen, Dept. of Medical Microbiology; Rinse Weersma, Dept. of Gastroenterology; Klaas Nico Faber, Dept. of Gastrointestinal and Liver Diseases; Sven van Ijzendoorn, Dept. of Cell Biology) have a shared interest in intestinal stem cells, iPSC cells, and organ-on-chip technology. Hermie Harmsen collects the Lifelines microbiomes which can be cultured (culturomics) and has, together with Klaas Nico Faber, already developed a macro-sized, closed system in which gut bacteria can grow on and interact with epithelial cells. Klaas Nico Faber and Sven van Ijzendoorn are working on intestinal biopsy and urine derived iPS cells. Rinse Weersma is the head of the Dept.of Gastroenterology and uses genomics to study Inflammatory Bowel Disease (IBD). Moreover, he collects biopsy samples from IBD and Celiac disease (CeD) patients. Together with Cisca Wijmenga, Rinse Weersma is applying single cell RNA sequencing (scRNAseq) to study the cell populations present in these biopsies. All the stem cell work, iPSC work and scRNAseq work performed by these groups is performed at the iPSC/CRISPR Facility of the UMCG, the Next Generation Sequencing Center of the UMCG and the single cell DNA sequencing facility of ERIBA. Cisca Wijmenga is currently setting up a cord blood stem cell biobank (LifelinesCBSC) in close collaboration with Floris Foijer who heads the iPSC/CRISPR Facility. The iPSC/CRISPR facility has already developed standard operating procedures for the generation of urine-derived iPSCs and is engineering the genome of these iPSCs using CRISPR technology. In the next year, the iPSC/CRISPR centre will focus on differentiating iPSCs into neurons (with Bart Eggen, Molecular NeuroScience and Aging Research), cardiomyocytes (with Peter van de Meer, Cardiology) and hepatocytes (with Sven van Ijzendoorn). Altogether, these efforts will benefit the organ-on-chip projects at the UMCG (and the hDMT as a whole), as they will allow for ‘personalized organ-on-chip’ approaches.
Other UMCG researchers interested in organ-on-chip technology which were not mentioned above are Jon Laman (Molecular NeuroScience and Aging Research; neuroinflammation and gut-brain axis), Rob Coppes (Radiation Oncology & Cell Biology, salivary gland organoids), Jan Meilof (Dept. of Neurology, collects skin fibroblasts from Multiple Sclerosis patients to create iPS cells), Cor Calkhoven (ERIBA, cancer-on-chip), Vinod Kumar (Genetics, endothelium-on-chip), Folkert Kuipers (Pediatrics, liver-on-chip), Barbara Bakker (Pediatrics, intestinal organoids), Maaike Oosterveer (Pediatrics; iPS hepatocytes/microfluidics), and Peter van den Akker (Dermatology & Clinical Genetics, skin-on-a chip).
Several additional facilities are available at the UMCG for performing state-of-the-art molecular biology and cell biology research, including The Microscopy and Imaging Center, the Facility for Proteomics and Metabolomics, and The Flow Cytometry Facility (umcg.nl/EN/Research/Researchers/Facilities).
Embedding of Organ-on-Chip technology in research policy
The UMCG’s research focus is ‘healthy and active aging’. The aim is to develop personalised health care and prevention strategies. Organ-on-a-chip technology is an extremely interesting tool to use for such studies as the organs can be personalised by developing them starting from a patient’s stem cells.
- NWO Zwaartekracht grant Netherlands Organ-on-Chip Initiative to Prof. Cisca Wijmenga and co-investigators, aimed at designing and coupling of gut-on-a-chip, heart-on-a-chip, and brain-on-a-chip (NOCI, NWO-024.003.001; €18.800.000).
- ERC Starting Grant to Sasha Zhernakova (UMCG, Dept. of Genetics). Goal of this grant is to study how the microbiome develops during the first year of a child’s life with a focus on how the bacterial microbiome is shaped by the virome (BabyVir; ERC-2016-STG-715722; €1.500.000).
- ERC Starting Grant to Lude Franke (UMCG, Dept. of Genetics). For this grant more than 1,000,000 cells obtained from blood will be subjected to single-cell sequencing in order to investigate the cell type specificity of eQTLs (ImmRisk; ERC-2014-STG-637640; €1.500.000).
Relevant key publications
1. Zhernakova A et al., Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016 Apr 29;352(6285):565-9. PubMed PMID: 27126040.: http://dx.doi.org/10.1126/science.aad3369
2. Li Y et al., A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans. Cell. 2016 Nov 3;167(4):1099-1110. PubMed PMID: 27814507. http://dx.doi.org/10.1016/j.cell.2016.10.017
3. Li Y et al., Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi. Nat Med. 2016 Aug;22(8):952-60. PubMed PMID: 27376574. http://dx.doi.org/10.1038/nm.4139