“What I cannot create, I do not understand”
Everything that makes us human is contained within 1.4kg of yellowish tissue that we call the human brain. Our brain is where we feel love or hate, and from where our most imaginative and most evil thoughts arise. In the Knoblich lab we are fascinated by this enormously complex structure and study its formation during embryonic development. Our unique combination of model organisms allows us to study the mechanism of human brain development in a powerful way: We take basic principles from analysis of the simple brain of Drosophila, and transfer them to a human model using three-dimensional cerebral organoids. Our ability to recreate the process of human neurodevelopment in the lab using the organoid system allows us to investigate what goes wrong when patients develop neurodevelopmental disorders like microcephaly, or severe neuro-psychiatric disorders like epilepsy or autism.
Electronic reprint of the following publication:
- Christopher Esk, Dominik Lindenhofer, Simon Haendeler, Roelof A. Wester, Florian Pflug, Benoit Schroeder, Joshua A. Bagley, Ulrich Elling, Johannes Zuber, Arndt von Haeseler, Jürgen A. Knoblich: “A human tissue screen identifies a regulator of ER secretion as a brain size determinant”.
Jürgen Knoblich talks about the latest research on elucidating human-specific mechanisms of disease using brain organoids in this webinar:
We aim to understand the unique form and function of the human brain, and to decipher how genotypic changes associated with brain-related disease cause phenotypic malformations and misfunctions. Toward this, we investigate the mechanistic principles of human brain development across a broad scale: from molecules to cells to complex tissues.
We take a distinct, multidisciplinary approach that bridges the stringency of Drosophila genetics with the power and physiological relevance of a human model. Mechanisms of brain patterning and tumor biology that have been established in Drosophila are now being expanded upon in a new generation of brain organoid culture.
Cerebral organoids, developed from human embryonic stem cells or patient-derived induced pluripotent cells (iPSCs), provide a three-dimensional model to understand the early steps of human brain development. The system recapitulates the formation of a layered human cortex with distinct ventricular zone and cortical plate, along with other regions of the brain, and allows us to observe and investigate the generation, migration and activity of neurons in a three-dimensional tissue environment. We can apply genetic technologies to the organoid system to mimic and repair aberrant DNA sequences in patient cells and identify genes responsible for observed neurodevelopmental defects. In addition, large scale CRISPR/Cas9 screening approaches directly in human organoids enables us to identify sets of genes involved in disease-relevant biological processes. Further study of these genes allows us to propose underlying mechanisms and potential therapies for the disease. Ultimately, our goal is to develop the organoid system to the point where we can carry out genome-wide genetic screens directly in human tissues, as was done in the Drosophila model.
Esk, C., Lindenhofer, D., Haendeler, S., Wester, RA., Pflug, F., Schroeder, B., Bagley, JA., Elling, U., Zuber, J., von Haeseler, A., Knoblich, JA. (2020). A human tissue screen identifies a regulator of ER secretion as a brain size determinant. Science.
Bonnay, F., Veloso, A., Steinmann, V., Köcher, T., Abdusselamoglu, MD., Bajaj, S., Rivelles, E., Landskron, L., Esterbauer, H., Zinzen, RP., Knoblich, JA. (2020). Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis. Cell. 182(6):1490-1507.e19
Bian, S., Repic, M., Guo, Z., Kavirayani, A., Burkard, T., Bagley, JA., Krauditsch, C., Knoblich, JA. (2018). Genetically engineered cerebral organoids model brain tumor formation. Nat Methods. 15(8):631-639
Lancaster, MA., Corsini, NS., Wolfinger, S., Gustafson, EH., Phillips, AW., Burkard, TR., Otani, T., Livesey, FJ., Knoblich, JA. (2017). Guided self-organization and cortical plate formation in human brain organoids. Nat Biotechnol. 35(7):659-666
Bagley, JA., Reumann, D., Bian, S., Lévi-Strauss, J., Knoblich, JA. (2017). Fused cerebral organoids model interactions between brain regions. Nat Methods. 14(7):743-751
Eroglu, E., Burkard, TR., Jiang, Y., Saini, N., Homem, CC., Reichert, H., Knoblich, JA. (2014). SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells. Cell. 156(6):1259-73
Homem, CC., Steinmann, V., Burkard, TR., Jais, A., Esterbauer, H., Knoblich, JA. (2014). Ecdysone and mediator change energy metabolism to terminate proliferation in Drosophila neural stem cells. Cell. 158(4):874-88
Lancaster, MA., Renner, M., Martin, CA., Wenzel, D., Bicknell, LS., Hurles, ME., Homfray, T., Penninger, JM., Jackson, AP., Knoblich, JA. (2013). Cerebral organoids model human brain development and microcephaly. Nature. 501(7467):373-9