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 Assistant Professor and group leader in Liver function and Regeneration with Emphasis on Drug Development in 2017. My research is focused on physiological and pathophysiological hepatic in vitro models for drug toxicity, mechanisms underlying hepatic plasticity and regeneration and on the genetic basis of drug response.
The commercialization of relevant discoveries constitutes one of the key aims of EU’s Horizon 2020 program and I am very enthusiastic about making innovations available to the public. To this end, we founded HepaPredict AB, providing 3D hepatic model systems for hepatotoxicity testing, pharmacokinetic applications and mechanistic studies of drug candidates to the pharmaceutical industry.
Since 2017: Assistant Professor in Liver function and regeneration with emphasis on drug development (Karolinska Institutet, Stockholm, Sweden)
2014 - 2016: Postdoctoral Research Associate and MarieCurie Fellow (Karolinska Institutet, Stockholm, Sweden)
2012 – 2016: Bachelor of Science in Business Administration and Economics (University of Hagen, Germany)
2013 – 2014: Bridging Postdoctoral Research Associate (EMBL Heidelberg, Germany)
2009 – 2013: Dr. rer. nat. / PhD studies (EMBL Heidelberg, Germany)
2007 – 2009: Scientific Assistant in Molecular Genomics and Evolution (University of 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)
My research interests are focused on liver metabolism and function as well as hepatic pathologies. We previously established an integrated 3D spheroid cell culture system for primary human hepatocytes (PHH) in which cells remain viable and functionally stable for multiple weeks. Importantly, we recently showed that PHH in this model exhibited superior sensitivity to hepatotoxic agents compared to other emerging cell models, such as HepG2 and HepaRG cells, and were faithfully reproducing in vivo drug toxicity mechanisms in man. Furthermore, using a combination of untargeted and targeted metabolomics, we showed that the endogenous and xenobiotic metabolic signatures of PHH were maintained in 3D spheroids, thus allowing to comprehensively study drug-induced molecular effects on cellular metabolism and to investigate mechanisms of drug action. The results indicate that the 3D PHH spheroid system faithfully mimics heptic phenotypes in vivo and can be utilized for long-term analyses of drug metabolism, liver function and regulation.
In vitro toxicity models.
We aim to establish the spheroid model as a platform for the prediction of drug-induced liver injury (DILI) using a large panel of compounds that are hepatotoxic in man. Integration of histological, transcriptomic and metabolomic signatures during different stages of DILI will allow in-depth analyses of toxicity mechanisms. Matching these toxicity profiles to the suggested mechanisms of toxicity observed in vivo, will systematically reveal which molecular frameworks that underlie hepatic toxicity can be recapitulated using the 3D culture system in vitro. Furthermore, these studies facilitate the elucidation of biomarkers and yet unknown mechanisms of toxicity that can guide future in vivo studies and can aid targeted compound optimization to prevent toxicity while retaining biological activity.
Development of hepatic disease models.
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 aim to develop and extensively characterize a novel in vitro platform that is suitable to study liver biology during steatosis, NASH and fibrosis, as well as to screen compounds either for steatotic side effects or for anti-steatotic action.
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
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