After studying Molecular and Cellular Biology at the University Heidelberg, Germany and the University of Bergen, Norway, I obtained my Ph.D. from the EMBL and the Combined Faculty of Natural Sciences and Mathematics of the University of Heidelberg for work on primary cell culture development and tissue patterning based on phase-encoding using molecular oscillators.
In 2014, I moved to Karolinska Institutet as a MarieCurie fellow to work on the development and characterization of physiological hepatic model systems and became Group Leader in Personalized Medicine and Drug Development in 2017.
My research group uses 3D cell culture systems of primary human cells, microfluidics and integrative bioinformatics approaches to identify novel therapeutic strategies for complex metabolic diseases, such as non-alcoholic fatty liver disease and type 2 diabetes. In addition, we develop algorithms to improve personalized pharmacological therapy and establish novel methods for the prediction of drug toxicity.
We put major emphasize on the dissemination of our discoveries in order to make innovations available to the public. To this end, we founded HepaPredict AB (www.hepapredict.com) a contract research organization (CRO) that got admitted into Karolinska Innovations DRIVE program. We offer in-house evaluations of drug metabolism, pharmacokinetic properties and safety as well as various liver disease models for drug discovery based on our novel long-term stable microphysiological 3D spheroid culture platform.
Since 2018: Associate Professor in Personalized Medicine and Drug Development (Karolinska Institutet, Stockholm, Sweden)
Since 2018: Director of the Micro- and Nanofabrication Core Facility (https://ki.se/en/fyfa/micro-and-nanofabrication-core-facility-mcf)
Since 2018: Docent in Pharmacology
2017 - 2018: Assistant Professor in Liver Function and Regeneration (Karolinska Institutet, Stockholm, Sweden)
2014 - 2016: Postdoctoral Research Associate and MarieCurie Fellow (Karolinska Institutet, Stockholm, Sweden)
2013 – 2014: Bridging Postdoctoral Research Associate (EMBL Heidelberg, Germany)
2007 – 2009: Scientific Assistant in Molecular Genomics and Evolution (University of Heidelberg, Germany)
2016 – 2018: Master of Science in Business Administration and Economics (University of Hagen, Germany)
2012 – 2016: Bachelor of Science in Business Administration and Economics (University of Hagen, Germany)
2009 – 2013: Dr. rer. nat. / PhD studies (EMBL Heidelberg, Germany)
2007 – 2009: Master of Science in Molecular Biosciences (University of Heidelberg, Germany)
2004 – 2007: Bachelor of Science in Molecular and Cellular Biology (University of Heidelberg, Germany and University of Bergen, Norway)
Development of microphysiological 3D tissue models.
We previously established an integrated 3D spheroid cell culture system for primary human hepatocytes (PHH) in which cells faithfully mimics hepatic phenotypes in vivo and can be utilized for long-term analyses of drug metabolism, liver function and regulation. In addition we develop 3D tissue models for human adipose tissue, pancreatic islets and skeletal muscle and carefully benchmark the cultured cells to their corresponding counterparts in situ using an array of omics techniques.
Integrated microfluidic models for studies of complex diseases.
Type 2 diabetes mellitus (T2DM) affects 435 million patients globally and is characterized by insulin resistance of muscle, liver and adipocyte tissue in combination with progressive failure of pancreatic β‑cells, together resulting in loss of glycemic control. Due to the complexity of interactions between cells and tissues that are involved in the maintenance of human metabolic homeostasis, there is a lack of experimental tools to study T2DM. Pharmacologic therapy only allows for the management of T2DM and its sequelae and no cure is currently available, at least in part due to the lack of physiologically relevant and high-throughput compatible model systems.
We develop microfluidic chips using innovative polymers in which we can co-culture tissue models with relevance for T2DM. Specifically, we integrate human microphysiological and long-term stable 3D tissue models of liver, pancreas, adipose tissue and skeletal muscle and utilize this platform to investigate T2DM biology and to screen for novel anti-diabetic medications.
Development of hepatic disease models for drug discovery.
Non-alcoholic fatty liver disease (NAFLD) constitutes a clinicopathological condition that accounts for the majority of chronic liver disease cases in the Western world. Onset of NAFLD is hallmarked by the accumulation of lipids within hepatocytes (hepatic steatosis), which arises from an imbalance between triglyceride import, production and extrusion primarily caused by obesity and a hypercaloric diet. In some patients steatosis can progress to non-alcoholic steatohepatitis (NASH), an inflammatory condition that can further develop in liver fibrosis. Despite its significant importance, no pathophysiologically replicative model systems exist. Based on our 3D primary human hepatocyte spheroid model, we develop and extensively characterize novel in vitro platforms that are suitable to model human NASH and fibrosis.
Hepatic spheroids as model system for liver regeneration.
Strikingly, during spheroid aggregation stages, PHH first dedifferentiate, followed by rapid redifferentiation, providing an ideal ex vivo experimental paradigm to study the full spectrum of differentiation state changes that occur in vivo during liver regeneration. Besides extending our mechanistic understanding, this finding opened possibilities for the development of therapeutic approaches as a substitute for orthotopic liver transplantations. To this end, we work on the establishment of protocols in which PHH isolated from patients proliferate and, after cells sufficiently multiplied, are induced to redifferentiate into functional hepatocytes using our 3D spheroid culture system. We recently showed that miRNAs are important driving forces in the hepatic dedifferentiation process; knowledge which, besides being of mechanistic importance, can be useful for the optimization of hepatic redifferentiation.
Evaluation of the importance of rare genetic variants on hepatic metabolism and drug response.
Genetic variants primarily in drug and metabolite transporters, phase I and phase II drug metabolizing enzymes and nuclear receptors can influence drug response by modulating drug absorption, distribution, metabolism and excretion (ADME). Importantly, while in the past decades an ever-growing arsenal of genetic variants with demonstrated impacts on human drug response has been identified in these pharmacogenes, a substantial fraction of the heritable variability in drug response remains unexplained. Rare genetic variants that only occur in very few individuals and are hence missed in genome-wide association studies have been proposed to contribute to this missing heritability. We integrate data from recent population-wide Next-Generation Sequencing (NGS) projects to quantify the extent of genetic variability in pharmacogenes on a population level and, using an arsenal of in silico techniques, quantify the impact on hepatic metabolism and pharmacokinetics and -dynamics.
- At KI I teach courses in local anaesthetics, cardiovascular pharmacology, pharmacokinetics and receptor pharmacology.
- MSc projects are available upon request.
Academic honours, awards and prizes
2017 Lennart Philipson Prize
Rolf Luft Grant in Diabetes Research
2016 VR Starting Grant
VR 3R Grant
KI Fonder Grant
VR Proof-of-concept Grant (Co-applicant)
KI Early Verification Grant
2015 Lars Hierta Research Grant
Sigurd och Elsa Goljes Minne Research Grant
Eva och Oscar Ahréns Grant for Medical Research
2014 Marie Curie Fellowship
2013 Dedicated Research Highlight article in Nature Reviews Genetics
Dedicated News and Views article in Nature
2009 EMBL International PhD Program Graduate Fellowship
Top Master of Science (M.Sc.) Award
2006 Erasmus Fellowship
Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews
Journal of medical genetics 2018;55(9):617-627
Computational Methods for the Pharmacogenetic Interpretation of Next Generation Sequencing Data
FRONTIERS IN PHARMACOLOGY 2018;:1437-
Current Statistical Metrics Are Pragmatic Measures to Compare the Predictive Quality of Preclinical Assays
Toxicological sciences : an official journal of the Society of Toxicology 2018;165(1):4-5
Functional characterization of CYP2D7 gene variants
Global genetic diversity of human apolipoproteins and effects on cardiovascular disease risk
Journal of lipid research 2018;59(10):1987-2000
How to Consider Rare Genetic Variants in Personalized Drug Therapy
Clinical pharmacology and therapeutics 2018;103(5):745-748
Human hepatic 3D spheroids as a model for steatosis and insulin resistance
Scientific reports 2018;8(1):14297-
Human liver spheroids in chemically defined conditions for studies of gene-drug, drug-drug and disease-drug interactions
Integrating rare genetic variants into pharmacogenetic drug response predictions
Human genomics 2018;12(1):26-
Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation
Novel copy-number variations in pharmacogenes contribute to interindividual differences in drug pharmacokinetics
Genetics in medicine : official journal of the American College of Medical Genetics 2018;20(6):622-629
Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities
Annual review of pharmacology and toxicology 2018;58():161-185
Prediction of Drug-Induced Hepatotoxicity Using Long-Term Stable Primary Hepatic 3D Spheroid Cultures in Chemically Defined Conditions
Toxicological sciences : an official journal of the Society of Toxicology 2018;163(2):655-665
Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions
Genetics in medicine : official journal of the American College of Medical Genetics 2018;():-
A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
Archives of toxicology 2017;91(3):1385-1400
Dysregulation of miR-223 constitutes a promising biomarker that informs about clinical outcomes of acute liver failure
Clinical science (London, England : 1979) 2017;131(15):2059-2062
Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics
FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2017;31(6):2696-2708
Pharmacogenomic Biomarkers for Improved Drug Therapy-Recent Progress and Future Developments
The AAPS journal 2017;20(1):4-
Pitfalls and Opportunities for Epigenomic Analyses Focused on Disease Diagnosis, Prognosis, and Therapy
Trends in pharmacological sciences 2017;38(9):765-770
Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response
Genetics in medicine : official journal of the American College of Medical Genetics 2017;19(1):20-29
The role of microRNAs in liver injury at the crossroad between hepatic cell death and regeneration
Biochemical and biophysical research communications 2017;482(3):399-407
Transcriptional, Functional, and Mechanistic Comparisons of Stem Cell-Derived Hepatocytes, HepaRG Cells, and Three-Dimensional Human Hepatocyte Spheroids as Predictive In Vitro Systems for Drug-Induced Liver Injury
Drug metabolism and disposition: the biological fate of chemicals 2017;45(4):419-429
Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects
Clinical pharmacology and therapeutics 2017;102(4):688-700
Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease
Scientific reports 2016;6():25187-
Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation
Hepatology (Baltimore, Md.) 2016;64(5):1743-1756
Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates
Chemical research in toxicology 2016;29(12):1936-1955
Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
Clinical pharmacology and therapeutics 2016;99(2):172-85
Precision Medicine and Rare Genetic Variants
Trends in pharmacological sciences 2016;37(2):85-86
Requirements for comprehensive pharmacogenetic genotyping platforms
Single base resolution analysis of 5-hydroxymethylcytosine in 188 human genes: implications for hepatic gene expression
Nucleic acids research 2016;44(14):6756-69
The Importance of Patient-Specific Factors for Hepatic Drug Response and Toxicity
International journal of molecular sciences 2016;17(10):-
Genetic variation in the human cytochrome P450 supergene family
Pharmacogenetics and genomics 2015;25(12):584-94
Scaling of embryonic patterning based on phase-gradient encoding