Hardware Development
Advancements in live-cell imaging technology are driving significant improvements in the fields of biology and medicine. The hardware development stream is focused on implementing and evaluating new hardware modalities with the goal of advancing research in neuronal biology, stem cell biology, and drug development.
Neurophysics Laboratory
Physics drives quantitative biology by contributions in two main areas: through theoretical understanding of biological phenomena and through methodologies for observation and control of biological entities. The Laboratory Neurophysics is active in both areas. We establish theories of information encoding, at subcellular structure and in whole neuron networks. Where these theories depend on precise knowledge of biological parameters, we advance or create methods to measure properties of molecules in-situ, of neurons, or entire brain circuits. One challenge posed by a stochastically operating system such as a brain circuit is the need for vast amounts of observations. We address this by optically stimulating and electrically recording networks inside cell culture incubators for days and weeks. Within QuCellAI, we will fuse this approach with the non-invasive imaging capabilities of the Incucyte® Live-Cell Analysis System, generating large datasets of optically stimulated, optically recorded neuron activity.
Contact: Dr. Andreas Neef
Biophysics
Mechanical properties have been recognized as key elements for many biological processes, such as cell migration and fate decision, embryogenesis or disease progression. To better understand these, experimental access to the biomechanics of cells and tissues is essential but still challenging. Since many mechanical measurements are based on microscopy, live cell fluorescence imaging is crucial for their studies.
The Betz lab combines optical tweezers, traction force microscopy and fundamental force probing techniques with tissue engineering to decipher the biomechanical influences during cancer metastasis, cell division, embryo development and muscular disorders.
In particular, they found that cells highly regulate their stiffness during cell division and soften their cytosol for a short time, probably to facilitate chromosome segregation (Hurst et al. 2021, Nature Physics). This emphasizes the immense importance of mechanical properties in biological systems, since cell division is one of the most essential principals in biology.
Using 3D tumor models, they further observed that the internal tumor pressure, that rises during tumor growth, eventually drives metastasis outburst which is initiating the coordinated cell migration (Raghuraman et al. 2022, Advanced Science).
Hence, they believe that healthy cells and tissues actively establish a highly orchestrated mechanical homeostasis which they further study in the context of the most common inherited muscular disease: Duchenne Muscular Dystrophy. For this purpose, they developed a tissue engineering platform that enables mechanical measurements and real-time high resolution fluorescence microscopy at the same time (Hofemeier et al. 2021, eLife).
Finally,they aim to use these novel insights into healthy and diseased biomechanical fingerprints to interfere in and treat the mechanical homeostasis. Therefore, they use live imaging-based screening approaches to discover therapeutical targets.
Contact: Prof. Dr. Timo Betz
Phenotypic Drug Screening
Systematic phenotypic drug screening of novel cardioactive compounds relies on model systems that faithfully represent the in-vivo situation of failing human heart. Past screening campaigns were typically based on either oversimplified biochemical essays or misleading animal models, causing numerous false negative and, worse, false positive results in pre-clinical screens leading to high attrition and enormous cost in clinical drug development.
Novel screens based on human cardiomyocytes derived from induced pluripotent stem cells open new alleys to systematic drug screening including genetic and chemically or biomechanically induced disease phenotypes. Common technics are either cell-based screens at sub-cellular resolution or macroscopic, tissue-based models.
The Meyer group is keen to bridge the microscopic and macroscopic view on live cells embedded into a bona-fide, native 3D environment. Their established Mastermix consisting of cardiomyocytes, fibroblasts, and collagen hydrogel is cast into a novel 96-well tissue plate format. Initial tissue formation is monitored during 3 days at 4h timepoints for all 96 wells at high (20x) resolution. During three week maturation buildup of contractile force and sarcomere synthesis is quantified by brightfield video analysis at 30fps of macroscopic pole deformation and microscopic evaluation of fluorescence emitted from citrine-labelled sarcomeres. Functional outcome a is finally evaluated by online recording of concentration dependent response to pharmacologically active substances.
Contact: Dr. Tim Meyer