Volker Lauschke

Volker Lauschke

Professor
Telephone: +46852487711
Mobile phone: +46704926778
Visiting address: Solnavägen 9, Biomedicum, 17165 Solna
Postal address: C3 Fysiologi och farmakologi, C3 FyFa Individanpassad medicin och läkemedelsutveckling, 171 77 Stockholm
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About me

  • Volker M. Lauschke (V.M.L.) is Professor in Translational Pharmacology at Karolinska Institutet (KI), Stockholm, Sweden and Director of the Biofabrication and Tissue Engineering Facility at KI. He is also Deputy Head of the Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, Germany and holds Guest Professorships at Changsha Central South University and Lanzhou University.

    His research group integrates 3D cell culture systems of primary human cells, microfluidics and comprehensive molecular profiling technologies to discover novel therapeutic strategies for inflammatory conditions (NASH), infectious diseases (COVID-19 and hemorrhagic fevers) and complex metabolic diseases (type 2 diabetes). In addition, we use population-scale genomics and machine learning tools to map the ethnogeographic variability in genes involved in drug absorption, distribution, metabolism and excretion, as well as drug targets with a specific focus on the contribution that rare genetic variations play in drug response and toxicity and how this information can improve personalized medicine and precision public health.

    V.M.L. has authored over 180 papers in peer-reviewed journals and is the recipient of multiple awards in the area of genetics, pharmacology and drug discovery, including the Malin and Lennart Philipson Prize 2016, the AAPS High Impact Award 2020 and the ISSX Karl Netter Award 2023. Furthermore, he is among the Clarivate Highly Cited Researchers in Pharmacology 2022 (1 of 3 in Sweden). Besides his academic work, he is co-founder and CEO of HepaPredict AB, a biotech company offering 3D human liver models for drug discovery and development, as well as co-founder and CSO of PersoMedix AB, providing services for personalized drug response predictions.


    Professional Experience
    Since 2023: Professor in Translational Pharmacology (Karolinska Institutet, https://ki.se/en/fyfa/lauschke-lab)
    Since 2021: Deputy Head of the Margarete Fischer-Bosch Institute of Clinical Pharmacology (Stuttgart, Germany, http://www.ikp-stuttgart.de/content/language1/html/16655.asp)
    Since 2018: Director of the Biofabrication and Tissue Engineering Core Facility (https://ki.se/en/research/research-infrastructure-and-environments/core-facilities-for-research/the-biofabrication-and-tissue-engineering-core-facility-biofab)
    Since 2018: Docent in Pharmacology
    2018 - 2023: Associate Professor in Personalized Medicine and Drug Development (Karolinska Institutet)
    2017 - 2018: Assistant Professor in Liver Function and Regeneration (Karolinska Institutet)
    2014 - 2016: Postdoctoral Research Associate and MarieCurie Fellow (Karolinska Institutet)
    2013 - 2014: Bridging Postdoctoral Research Associate (EMBL Heidelberg, Germany)


    Education
    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)


    Fellowships, Prizes and Awards
    2023 ISSX Karl Netter Award
    2022 Clarivate Highly Cited Award in Pharmacology
    2020 High Impact Award by the American Association of Pharmaceutical Scientists (AAPS)
    2017 Lennart Philipson Prize
    2014 Marie Curie Fellowship
    2009 Top Master of Science (M.Sc.) Award
    2006 Erasmus Fellowship


    Current and recent funding
    NovoNordisk Project grant, NovoNordisk Pioneer Grant, Data-driven Life Science Program, ERC Environment & Health Grant NEMESIS, ERC Synergy Grant SPHERES, IMI2 EUbOPEN, VR Project Grant, VR Consolidator Grant, KI Consolidator Grant, Rolf Luft Grant in Diabetes Research, SFO Stem Cells and Regenerative Medicine, Lennart Philipson Research Grant.
    We furthermore acknowledge support from Merck KGaA, Eli Lilly and Company and the Robert Bosch Foundation.


    Editorial Activities
    - Editorial roles: The Pharmacogenomics Journal (Associate Editor since 2022, Board Member 2020-2022), Human Genomics (Executive Associate Editor since 2024, Associate Editor 2020-2022, Board Member 2017-2020), Computational & Structural Biotechnology Journal (Associate Editor since 2020), Annals of Human Genetics (Senior Editor since 2019)
    - Editorial Board Member: Pharmacological Reviews (Since 2023), Frontiers in Pharmacology (Since 2017), Frontiers in Medicine (Since 2018), Drug Metabolism Reviews (Since 2019), Current Drug Metabolism (Since 2019), Current Research in Pharmacology and Drug Discovery (Since 2020), Pharmacogenomics Research and Personalized Medicine (Since 2020), Precision Cancer Medicine (Since 2020)
    - Guest Editor of Special Issues in Human Genomics ("Pharmacogenomics beyond single common genetic variants", June 2023), Journal of Clinical Medicine ("Importance of Genetic Variants for the Hepatic Metabolism of Xenobiotics", June 2020) and Frontiers in Genetics ("Population Pharmacogenomics: From Variant Identification to Clinical Implementation", Dec 2020)


    Current group members
    Sonia Youhanna (Postdoctoral Researcher)
    Shane Wright (Postdoctoral Researcher)
    Nayere Taebnia (Postdoctoral Researcher)
    Sabine Willems (Postdoctoral Researcher)
    Yi Zhong (Postdoctoral Researcher)

    Yoomi Park (Postdoctoral Researcher)
    Reza Zandi Shafagh (Postdoctoral Research Engineer)
    Xuexin Li (Senior Researcher)
    Isabel Barragan (Senior Researcher)
    Nuria Oliva-Vilarnau (PhD Student)
    Aurino Kemas (PhD Student)
    Jibbe Keulen (PhD Student)
    Mahamadou Camara (PhD Student)
    Stefania Koutsilieri (PhD Student)

Research

  • 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.

    Novel therapeutic strategies against non-alcoholic steatohepatitis (NASH)
    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease with a global prevalence of 24% in the general adult population. Onset of NAFLD is hallmarked by the accumulation of lipids within hepatocytes. This initially benign steatosis can develop into NASH, an inflammatory condition in which liver macrophages (Kupffer cells) are increasingly activated and secrete excessive amounts of pro-inflammatory cytokines, which further progresses into liver fibrosis and cirrhosis in approximately 20% of NASH patients. Despite substantial efforts, there are very limited treatment options for NASH. Furthermore, the lack of validated biomarkers in NASH that predict the development of liver-related morbidity and mortality hinder progress in drug development. 
    We have previously established a 3D spheroid culture system for primary human liver cells in which hepatocytes and non-parenchymal cells (NPCs), including stellate and inflammatory Kupffer cells, remain viable and functional for ≥5 weeks in culture. Importantly, physiological crosstalk between hepatocytes and NPCs is maintained in vitro and we could show that nutritional perturbations can induce hepatic insulin resistance and steatosis. We have recently succeeded in extending the system by directly using cryopreserved hepatocytes and NPCs from NASH patients and could show that key disease aspects including extensive oxidative stress, inflammation and fibrosis are recapitulated in vitro. Furthermore, using chemogenomic screening of a library of chemical probes with well-characterized specificity profiles accessible via the Structural Genomics Consortium, we could identify multiple novel pharmacologically accessible targets that reduce steatosis or fibrosis. Mechanistic follow-ups investigations into hits are currently ongoing.

    Facilitating the development of micro- and nanofabrication technologies for scalable drug development
    For nearly three decades, microfluidic and organ-on-a-chip models are still heavily reliant on polydimethylsiloxane (PDMS) soft lithography. While these methods allow the easy fabrication of cell compatible devices, PDMS soft lithography suffers from long cycle times, limited scalability and substantial absorption of hydrophobic molecules. As a consequence, the translation of micro- and nanodevices from the research setting to industrial applications remains limited. 
    To overcome these limitations, we develop micro- and nanofabrication technologies using novel polymers in our on-site state-of-the-art cleanroom facilities. We have developed nanoimprint lithography (NIL) and Nano Reaction Injection Molding of a novel polymer with low drug absorption, off-stoichiometry thilo-ene (OSTE), that allow for rapid and cost-effective fabrication of polymer micro- and nanodevices. By uncoupling ultra-high resolution multiplanar polymer structuring from complex processing conditions, we provide accessible and versatile technologies for the fabrication of devices for a wide range of applications in biology, medicine and physics that already support a multitude of research groups at Karolinska.

    Microfluidic human ex vivo models for complex metabolic phenotypes
    Type 2 diabetes (T2D) is the most prevalent metabolic disorder that manifests due to a dysfunctional interplay of multiple tissues and organs. T2D constitutes a globally increasing health problem that affects 450 million individuals worldwide, which is expected to rise to 592 million by 2035. Although diabetes care has improved, complications are still common, and diabetes remains a leading cause of cardiovascular morbidity, visual loss, amputation, and end-stage renal disease. 
    By integrating our custom-designed microfluidic systems with human tissue models, we develop MPS in which 3D microtissues can be cultured with in vivo-like molecular phenotypes and tissue-specific functionality for multiple weeks, thus allowing to investigate tissue interactions upon nutritional and pharmacological perturbations. Specifically, we have developed devices with pneumatic actuation that allow for long-term communication between 3D primary human tissue models. We furthermore integrate 3D tissue models of liver, pancreas, adipose tissue and skeletal muscle to develop integrative human MPS to study mechanisms underlying glycemic control.

    Rational drug biasing
    Bioluminescence resonance energy transfer (BRET)-based biosensors have been used extensively to characterize signal transduction events using recombinant expression in human cell lines. While these experiments are useful to reveal possible ligand and receptor bias, they do not allow to study signaling in a physiological context. We have established a battery of biosensors for all human G-proteins as well as a suite of organelle markers to investigate signaling in primary human 3D tissue cultures. We observed that clinically approved compounds targeting the receptors differ with regards to signaling dynamics and their signatures of downstream G-protein/β-arrestin activation. Dual incretin receptor agonism constitutes an emerging strategy for the treatment of diabetes and obesity that has recently been demonstrated to also improve NASH. Combining our BRET biosensors with patient-derived material aspires to provide much needed insight into the intra- and inter-patient variability of drug action and offers the potential to develop better and more targeted therapies that effectively balance insulin stimulation with the hyperglycemic effects of GCGR agonists. Furthermore, by combining these tools with structural approaches we aim to develop compounds with specific bias, which opens new avenues to optimize drug efficacy and minimize side effects also for other G-protein coupled receptors.

    Individualized precision drug development
    Inter-individual differences in drug response constitute major challenges for drug development and clinical therapy. We will profile the differences in molecular phenotypes of 3D human tissue cultures and compare pharmacological effects between donors. For these efforts, we focus on high-throughput compatible models of liver, adipose tissue and pancreatic islets to screen for hit compounds across donors. For instance, the GLP1R agonists semaglutide and liraglutide are used in type 2 diabetes to increase insulin secretion to control glycemia; however, effects differ considerably between patients. By treating human islets from non-diabetic, prediabetic and diabetic individuals ex vivo, we investigate response biomarkers that can facilitate patient stratification and the development of companion diagnostics. Similar assessments of inter-individual differences in drug response are planned for insulin sensitizers and sulfonylureas, as well as for treatments for NASH and infectious diseases.

    Mechanistic analysis and pharmacological modulation of human liver regeneration
    To study the molecular biology of liver regeneration, particularly the rodent hepatectomy model serves as the main experimental paradigm. In this model, the majority of remaining hepatocytes re-enter the cell cycle within 24 hours, which is in stark contrast to homeostatic conditions, under which hepatocytes are quiescent with an average lifespan of 200-400 days. By integrating organotypic 3D spheroid cultures of primary human or murine hepatocytes with chemogenomic screening, we have revealed striking species differences in the molecular control of hepatocyte regeneration. Specifically, we found that growth factors are the main mitogens in rodents, while activation of Wnt/β-catenin signaling is the major driver in human hepatocytes. We furthermore identify TGFβ inhibition and inflammatory signaling via NFκB as essential steps for the quiescent-to-regenerative switch that allows Wnt/β-catenin-induced proliferation of human cells. High-throughput chemogenomic screening furthermore revealed critical roles of the Polycomb Repressive Complex 2 (PRC2), as well as of the bromodomain families I, II and IV in controlling cell cycle re-entry and proliferation of primary human hepatocytes. These results are conceptually important as they extend our mechanistic understanding of human liver regeneration, demonstrate the potential of organotypic human culture systems for the chemogenomic interrogation of complex physiological processes and open new possibilities for the development of therapeutic approaches as a substitute for orthotopic liver transplantations. 

    Bioprinting
    3D bioprinting in which biocompatible materials together with cells and supporting components are patterned into complex functional tissue constructs is enabling new applications in many areas of research. Bioprinting facilitates the high-throughput generation of biomimetic tissue models for personalized medicine, drug discovery, and toxicology using patient-derived material. 3D bioprinting is also applied in regenerative medicine to address the scarcity of tissue and organ transplants. 
    We have received infrastructure support for the acquisition of a state-of-the-art bioprinter to facilitate spatially controlled biofunctionalization and the reconstitution of relevant anatomical structures, such as fine-patterned liver sinusoids. Bioprinting will complement our high-throughput 3D microtissue methods with capabilities that allow to emulate vascularization, spatial organization of tissue microdomains, as well as immune cell patterning. Furthermore, by combining 3D bioprinting with live cell biosensors, we aspire to reveal human cell crosstalk at the single cell level within a physiological microenvironment.

Teaching

  • - At KI I am the Director of the Bioinformatics course within the International Master's Program in Translational Physiology and Pharmacology. In addition, I teach courses in local anaesthetics, cardiovascular pharmacology, pharmacokinetics and receptor pharmacology.

    - MSc projects are available upon request.

Articles

All other publications

Grants

  • Swedish Research Council
    1 December 2024 - 30 November 2027
    Primary human hepatocytes rapidly lose their functionality in conventional 2D cultures, which significantly limits their usefulness as an in vitro model to study hepatotoxicity, particularly of biological and nanoparticle therapeutics, which commonly accumulate and exert their effects over prolonged periods of time. Thus, in the absence of relevant in vitro systems, animal models constitute a cornerstone to predict the toxicity of newly developed biologics. The liver is however an organ with pronounced species differences with regards to expression and catalytic activities of factors involved in drug absorption, distribution, metabolism and excretion. This is further amplified for nucleotide- and antibody-based therapeutics where sequence and epitope differences between species are common problems during preclinical development.We have previously developed a 3D human liver model that accurately predicts the hepatotoxicity of small molecules, which is by now widely used in industry. Here, we aim to extend this work and develop and benchmark a platform that can predict hepatotoxicity and liver biodistribution of biologics (antisense oligonucleotides, siRNAs, therapeutic antibodies) and different nanoparticles (lipid-based, polymeric and inorganic). This system aspires to improve the predictability and translatability of findings as well as to mitigate the need for animal models, thus reducing the number of animals needed in pre-clinical discovery and development.
  • Swedish Research Council
    1 January 2024 - 31 December 2028
    Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons. NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH. NASH is closely linked to obesity, sarcopenia, dyslipidemia and insulin resistance and it has become clear that multiple extrahepatic tissues, including pancreas, skeletal muscle and adipose tissue produce signals that orchestrate hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans remain poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver, pancreas, skeletal muscle and fat to comprehensively map human metabolic crosstalk. By analyzing the secretome from healthy and diseased individuals, we will identify novel endocrine signals that contribute to NASH etiology and progression. Moreover, we will use the established platform to screen chemogenomic libraries to identify compounds that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.
  • Chemogenomic profiling of nuclear hormone receptors as targets for NASH
    Novo Nordisk Foundation
    1 November 2023 - 31 October 2025
    Non-alcoholic steatohepatitis (NASH) is a very common liver disease that affects around 1/3 of all obese persons worldwide. NASH is caused by buildup of fat in the liver, which results in inflammation and liver damage. Despite its prevalence, there are currently no approved treatments for NASH._x000D_ In this project we aim to facilitate the development of novel drugs against NASH by targeting a protein family called nuclear receptors (NRs). Specifically, we will culture liver cells isolated from NASH patients as 3D liver microtissues and treat those micro-livers with hundreds of different substances that specifically target NRs. This approach will allow us to directly identify which substances reduce fat buildup, inflammation or liver injury. Such “hit molecules” will then be validated in animal models of NASH and provide good candidates to finally develop effective treatments for this prevalent disease._x000D_
  • Swedish Research Council
    1 January 2023 - 31 December 2026
    The availability of relevant in vitro models of tissue units would be highly valuable for our struggles to understand human biology and physiology to obtain better health solutions. In the native tissue, cells are organized by a supporting extracellular matrix (ECM) in various types of microenvironments. ECM proteins build up the frameworks of these different environments, e.g. interstitial fiber networks in connective tissue and basement membranes in biological barriers. It has lately become clear that cells in culture are largely affected by their microenvironment, and especially mechanotransduction and the availability of cell-cell and cell-matrix connections. We will herein use a functionalised recombinant spider silk protein to construct relevant ECM-mimics, both networks for parenchymal and support cells in tissue compartments, and membranes for their biological barriers. These we will use to survey the effect of different parameters of the environment for cells in culture. For investigations of biological processes, it is essential to include a combination of cellular compartments and biological barriers. We will use our obtained knowledge to construct physiologically relevant tissue units of 1) tumours in stroma with blood vessels, for investigations of the interplay between cancer cells and vasculature, as well as 2) tumours behind blood brain barrier (BBB), for investigation of treatment strategies of brain tumours.
  • Deutsche Forschungsgemeinschaft
    1 January 2023
    Non-alcoholic steatohepatitis (NASH) is a serious liver disease characterized by fat accumulation, inflammation, and fibrosis. It affects ~6% of the global population but lacks effective treatment options and is thus a severe medical and healthcare challenge. Pharmacological treatment options are urgently needed to address this unmet medical need. Therapeutic modulation of nuclear receptors (NRs), many of which crucially regulate hepatic metabolism and inflammation, is increasingly recognized as potential avenue to hepatoprotective NASH treatment. However, only a minor fraction of the 48 human NRs has been evaluated in this context and comprehensive understanding of the entire NR family’s involvement in NASH pathology is lacking. Growing evidence supports remarkable potential of many (orphan) NRs to mediate beneficial therapeutic effects in NASH. For example, relevant sex-specific differences in NASH incidence point to an involvement of steroid hormones which act via NR activation. The role of hormone sensing and other NRs in the disease complex urgently requires systematic and comprehensive evaluation for therapeutic potential. This project aims to close this gap by systematically probing NR modulation for therapeutic effects in a primary patient-derived tissue model following a chemogenomics (CG) strategy. To meet its main objective of achieving comprehensive understanding of the pharmacological role of NRs in NASH, the project will assemble a custom CG compound set to cover ≥40 of the 48 human NRs and systematically assess the phenotypic outcomes of NR modulation in liver spheroids generated from primary human hepatocytes and non-parenchymal liver cells. Using such sophisticated in vitro model to mimic relevant disease characteristics aims to overcome incomplete translation from rodent model to patient in NASH and to capture individual and sex-specific differences. Primary evaluation will focus on anti-steatotic, anti-inflammatory, anti-fibrotic, and anti-oxidative effects in a global, sex-specific, and genotype-dependent manner. Subsequently, beneficial effects resulting from NR modulation will be orthogonally validated and analyzed in-depth for sex- and patient-specific roles, dependence on metabolic parameters, potential synergies of dual modulation, and signaling networks. This unprecedented systematic and comprehensive approach to explore NRs as therapeutic targets for NASH treatment will reveal uncharted potential of this protein family and address an urgent unmet medical need. Additionally, new insights into the roles of steroid hormones as well as sex- and patient-specific differences in NASH will offer significant biological advance and may suggest personalized treatment strategies.
  • Swedish Research Council
    1 January 2022 - 31 December 2025
    Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons. NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH. NASH is closely linked to obesity, dyslipidemia and insulin resistance and it has become clear that that the adipose tissue produces many signals that control hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans are poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver and fat to comprehensively map human fat-liver metabolic crosstalk. By analyzing the secretome of adipose tissue from lean insulin-sensitive and obese insulin-resistant individuals, we will identify novel endocrine signals of human fat that promote or prevent NASH. Moreover, we will use the established platform to screen libraries of lead-like molecules to identify compounds that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.
  • Swedish Research Council
    1 December 2019 - 31 December 2022
  • Swedish Research Council
    1 January 2017 - 31 December 2020
  • Swedish Research Council
    1 January 2017 - 31 December 2019
  • Swedish Research Council
    1 January 2016 - 31 December 2016

Employments

  • Professor, Department of Physiology and Pharmacology, Karolinska Institutet, 2023-

Degrees and Education

  • Docent, Karolinska Institutet, 2018

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