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Welcome to the Knoblich lab

“What I cannot create, I do not understand”
(Richard Feynman)

Everything that makes us human is located within 1.4kg of yellowish tissue that we call the human brain. Our brain is where we feel love or hate and where our most imaginative and most evil thoughts arise. Scientists in the Knoblich lab are fascinated by this enormously complex structure. We study, how it is formed when embryos develop. Our ability to recreate the process of human development in the lab allows us to ask what goes wrong when patients develop severe neuro-psychiatric disorders like epilepsy or autism.

Vision

We aim to understand the principle mechanisms of human brain development. We identify basic principles by analyzing the simple brain of Drosophila. Using three dimensional cerebral organoids, we transfer our ideas to human patients and recapitulate neuro-psychiatric disorders in the lab.

Approach

We take a unique, multidisciplinary approach that bridges the stringency of Drosophila genetics with the application and physiological relevance of human disease. We use Drosophila as a model to explore new mechanisms of brain patterning and tumor biology. In parallel, we use a new generation of brain organoid culture to address key mechanisms of brain development or dysfunction such as neuronal migration, neuronal networks, brain tumors, arbovirus infections.

Cerebral organoids

To transfer our knowledge from animal models to the developing human brain, and to link it to human neurological disorders, we have developed a three-dimensional culture method (cerebral organoids) that allows us to model the early steps of human brain development. We generate organoids from human embryonic stem cells or patient-derived induced pluripotent cells. Our 3D culture model recapitulates the formation of a layered human cortex with distinct ventricular zone and cortical plate. We can see the migration of neurons along radial glia fibers and can observe their neuronal activities by Calcium imaging and electrophysiology.

Cerebral organoid technology can generate various parts of the human brain. By fusing two separately patterned organoids, we can observe and measure interactions between distinct brain areas, such as the long-distance migration of interneurons or generation of the major axon tracts. This allows us to identify defects in patients suffering from epilepsy or autism. We can repair genetic aberrations in patient cells and see whether they were responsible for the defect. We can also edit DNA regions encoding for disease relevant genes to test their effect on brain development. By using large scale CRISPR/Cas9 screening approaches directly in human organoids, we aim to identify complete gene sets involved in disease relevant biological processes. The goal is to develop the organoid system so that we can carry out genome-wide genetic screens directly in human tissues -  like we are used to from Drosophila.

Tumor biology and Metabolism

Many scientists don’t know that Drosophila is actually one of the oldest model systems for tumor biology. In the early 1970’s already, multiple tumor suppressors were identified in fruit flies. We found that many of those genes are involved in a process called asymmetric cell division. Normally, asymmetric cell division allows neural stem cells to maintain a precise balance between self-renewing and differentiating daughter cells. Tumor suppressor mutants often affect differentiation in stem cell lineages so that stem cells proliferate exponentially. In vertebrates, such cells are called tumor stem cells and our work will help clarifying, what distinguishes normal from tumor stem cells. Identifying features specific to tumor stem cells will help the development of intervention strategies for fighting tumor growth without affecting normal stem cells.

Our work benefits greatly from a huge collection of transgenic RNAi lines that we have at our hands via the Vienna Drosophila RNAi Center (VDRC) and that allows us to knock out any fly gene in any tissue and cell type. Using those unique tools, we found exciting connections between tumor stem cells and metabolism. We identified a metabolic switch that occurs when stem cells stop proliferating. How tumor stem cells escape the metabolic control mechanisms that limit proliferation in normal stem cells is a key question we are trying to answer. In parallel, we are developing organoid culture systems to model human brain cancer.

Impact

Our research is expected to provide novel insights into early human brain development and to uncover new mechanisms underlying brain tumorigenesis, neurodegeneration and neurological disorders. The ability to regenerate human organogenesis in the lab has initiated a new era of disease research and drug discovery and we are confident that the tools we generate will help to fight neurological and psychiatric diseases.

Selected Publications

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

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

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

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

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

Funding