Our research aims to enhance the physiological relevance and functionality of human brain in vitro models, deepening our understanding of human brain development, function, and dysfunction.

Our expertise lies in generating iPSC-based human brain cell models and utilizing microelectrode arrays, high-content imaging, and data analysis to assess the functional and cellular properties at multiple levels.

Our ambition is to bridge the gap between in vitro models and clinical applications by studying the effects of drugs on brain cell function and identifying mechanisms for dysfunction.

From immaturity towards functional human brain activity: What does it take?

With the discovery by Sebastian Illes and Jelena Ban in 2007 that neurons generated in vitro from pluripotent stem cells self-organized into synchronously active neuronal networks, it was demonstrated that in vitro generated brain cells can mimic key principles of brain functionality. However, it also raised important questions: How far can we push the boundaries? How far should we push them? When aiming to replicate the function of the human brain in vitro, what truly defines brain function?

Human brain function is intimately linked to its electrophysiological characteristics. The brain's electrical activity, driven by the coordinated firing and communication of billions of neurons, forms the foundation of cognitive processes such as perception, attention, memory, and decision-making. The study of emergent electrical signals recorded from the brain and its cells provides a path towards unraveling the intricacies of brain function and ultimately gaining a deeper understanding of ourselves.

Our research approach is to utilize the most primitive cells, human pluripotent stem cells, to direct their neural developmental trajectories by mimicking their in vivo dynamic environment while simultaneously measuring the emerging electrical signals generated by populations of human brain cells. Through this approach, we aim to contribute to a better understanding of the development and function of the human brain. Additionally, we use our expertise in human brain in vitro models for pre-clinical drug testing, target identification and CNS disease modelling collaborative projects.

Related collaborations

Extracting and analysis of the full spectra of brain cell activity from MEA recordings: Stephan Theiss (Heinrich-Heine-University Duesseldorf, Germany)
Analysis and modelling of subthreshold activity from MEA recordings: Måns Henningson, Chalmers

Related publications

Ontogeny of oscillatory slow-wave and neuronal population activity in human iPSC-3D cortical circuits
Julia Izsak, Stephan Theiss, Sebastian Illes
bioRxiv. (2022)
Human Cerebrospinal Fluid Promotes Neuronal Circuit Maturation of Human Induced Pluripotent Stem Cell-Derived 3D Neural Aggregates
J. Izsak, H. Seth, S. Theiss, E. Hanse, S. Illes
Stem Cell Reports. (2020)
Robust Generation of Person-Specific, Synchronously Active Neuronal Networks Using Purely Isogenic Human iPSC-3D Neural Aggregate Cultures
Izsak J, Seth H, Andersson M, Vizlin-Hodzic D, Theiss S, Hanse E, Ågren H, Funa K, Illes S.
Frontiers in Neuroscience. (2019)

Drug effects on human brain cell functionality

Beyond demonstrating that human neuronal network function involves glutamatergic and GABAergic transmission, we are uncovering the contribution of other mechanisms, including neurotransmitter and ion channel receptors, in regulating and driving human neuronal circuit function. Through communication and collaboration with other academic groups and pharmaceutical companies, we are revealing the functional effects of drugs that modulate targets relevant to ongoing drug discovery projects or approved novel drugs focused on neurological diseases. For example, the project funded by EISAI serves as an example of how we combine human brain in vitro models with MEA technology to assess the potency, efficiency, and adverse effects of drugs, allowing us to better predict their impact on human brain activity.

Related collaborations

Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, University of Gothenburg.

Related publications

Differential acute impact of therapeutic effective and overdose concentration of lithium on human neuronal single cell and network function
Izsak J, Seth H, Theiss S, Hanse E, Ågren H, Funa K, Aigner L, and Illes S.
Translational Psychiatry. (2021)

Identification of new CNS disease targets and mechanisms

While the combination of human iPSCs and MEA technology is powerful, the discovery of new mechanisms underlying CNS diseases and the identification of novel drug targets require complementary technologies and human biosamples. Therefore, we engage in several collaborations where core expertise is combined, with the aim of gathering knowledge about new disease mechanisms and discovering novel targets.

Related collaborative projects

Exosome and Stroke: Georg Kuhn (Sahlgrenska Academy at GU)
Pathological CSF and its functional role in neurodegenerative diseases: Eric Hanse, Henrik Zetterberg (Sahlgrenska Academy at GU)
Pathological CSF and its functional role in psychiatric disorders: Eric Hanse (Sahlgrenska Academy at GU), Laurent Groc (CNRS - Université Bordeaux, France & Sahlgrenska Academy at GU)
Target identification and validation in Bipolar disorder: Kenji Hashimoto (Chiba University, Japan), Keiko Funa (Sahlgrenska Cancer Center, emeritus), Hans Ågren (Sahlgrenska Academy at GU, emeritus)

Related publications

Abnormal gene expression of BDNF, but not BDNF-AS, in iPSC, neural stem cells and postmortem brain samples from bipolar disorder
Ishima T, Illes S, Iwayama Y, Dean B, Yoshikawa T, Ågren H, Funa K, Hashimoto K.
Journal of Affective Disorders. (2021)
Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages
Vizlin-Hodzic D, Zhai Q, Illes S, Södersten K, Truvé K, Parris TZ, Sobhan PK, Salmela S, Kosalai ST, Kanduri C, Strandberg J, Seth H, Bontell TO, Hanse E, Ågren H, Funa K.
Translational Psychiatry. (2017)

Publications

Making research results accessible to everyone as quickly as possible is important to us. Therefore, starting from 2021, all manuscripts in which Sebastian Illes leads the project and is the senior author will be published on bioRxiv and subsequently submitted to peer-reviewed journals for review.

Click on the bioRxiv and PubMed symbols to access all preprints and peer-reviewed publications.