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Neuronal Cell Types and Circuit Engineering - Future projects and goals

1. Human neuronal circuit engineering: In order to understand how parts of the human brain function in health and disease, our major aim is to reverse engineer functional human neuronal circuits from scratch combining neuroscience with stem cell research and bioengineering. We plan to generate the basic parts, namely electrically active neurons, from adult-derived human stem cells. Next, we need to understand and control the biology to connect these cells in a reproducible way into defined functional neuronal circuits in vitro. The lab will apply an interdisciplinary approach combining molecular biology, human stem cell differentiation, 2D neuronal pattern cultures, imaging techniques, optogenetics and electrophysiology to engineer and analyze the fabricated human neuronal circuits. Disease-causing mutations will be introduced to some circuit members trying to model brain diseases in a human setting to explore novel therapeutic interventions. Furthermore, from an engineering point of view, we aim to create biological computers using living cells to compute signals as our brain does with extreme efficiency. The Volkswagen Foundation generously funds this project.

 

2. Neuronal cell fate engineering: The discovery of pluripotent stem cells has expanded the working modes in biology towards the reverse engineering of specific cell types. Unlike studying developmental phenomena in vivo, we are now theoretically able to mimic some of these processes in a dish. The use of human iPS cells facilitates studying the genesis of human cell types in an ethically approved setting. However, exploiting the full potency of stem cells is only possible with very few differentiated cell types. In particular, the generation of neurons is in its infancy: of the many neuronal types present in the brain, only a few types have been generated in vitro. So far, neuronal differentiation protocols are multifaceted and tailored to individual cell types. The molecular events that occur during reprogramming remain enigmatic. Hence, we cannot confer these protocols easily on producing different neurons of interest. Therefore, we plan to induce transcription factors as differentiation control buttons in human iPS cells in order to explore in vitro neurogenesis systematically. First, we will apply transcription factor libraries to conditional fluorescent iPS reporter lines, facilitating high-throughput isolation and analysis of induced neurons. Second, the underlying gene regulatory networks will be revealed using RNA-sequencing over the entire differentiation period to identify the biological rules of in vitro neuronal differentiation. We will combine these in-depth transcriptomic analyses with morphological, anatomical, and functional characterizations. Conceptually, our systems biology approach paves the way for targeted “forward” programming of human iPS cells to neurons. The European Research Council (ERC) generously funds this project.

 

3. Precise gene editing: Within a collaboration with Professor Knut Stieger’s lab (Uni Giessen, Germany), we are first assessing the DNA repair pathways in postmitotic retinal neurons. We aim to discover ways to harness genomic engineering technologies to precisely repair mutations that cause retinal diseases leading to blindness. Our joint project is funded by the DFG within the priority program SPP2127 “Gene and Cell Based Therapies to Counteract Neuroretinal Degeneration”.

 

4. Subcellular optogenetic stimulation: Within a collaboration with Professor Juergen Czarske (TU Dresden, Germany), we are developing holographic stimulation devices to stimulate optogentically-tagged neurons. Our focus is to facilitate subcellular stimulation as well as multiple areas per plane. Our work is funded by the DFG.

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