Research Dr. Matthias Meier
Matthias Meier received his Diploma in Biochemistry from the University of Regensburg, Germany. For his PhD work in Biophysics he joined the lab of Joachim Seelig at the University of Basel. He pursued his postdoctoral studies in chemical engineering and bioengineering in the laboratories of Rustem Ismagilov (University of Chicago, now Caltech) and Stephen Quake (Stanford), respectively.
Matthias Meier has been awarded the prestigious Feodor-Lynen-Fellowship from the Alexander v. Humboldt Foundation (2008) and received an Emmy-Noether Fellowship from the German Research Society in 2012. Matthias Meier is recipient of an ERC Consolidator Grant (2017). He joined the Helmholtz Pioneer Campus in May 2018.
The Group aims to develop and use microfluidic Large-Scale Integration (mLSI), molecular and cellular bioengineering technologies for:
Quantitative Biology: Investigation of biomolecular interactions thermodynamics and kinetics with in situ sequencing.
Physical Chemistry: Development of biological and microsystems sensors for small molecules and high content cell analysis.
Synthetic Biology: Rebuilding cellular and tissue microenvironments to model in vivo conditions. Organs-on-chip
Our group is developing and using microfluidic large-scale integration chip technology for characterizing biomolecules and their interactions within regulatory signaling networks of cells and whole organisms. The hallmarks of our technology are pneumatic membrane valves for fluid routing, metering, and to control reaction kinetics in small volumes. Compared to conventional platforms, mLSI-based chips provide several advantages such as full automation and multiplexing, enhanced precision, control and throughput, as well as high spatial and temporal resolution. We are designing new fluid circuitries, investigate new materials compatible with mLSI applications. We further accelerate the interface of chips to standard lab ware as well as the integration of high throughput readout instrumentation (imaging, sequencing etc.).
Bio-Sensors: Our engineering vision is to build plug-and-play microfluidic devices to obtain customized fluorescence reporters for in vitro and in vivo detection of metabolites. Effective engineering requires detailed information about molecular structures and thermodynamics of binding and stability landscapes of the sensor and its target. We are able to screen hundreds of sensors designed with a range of structural modifications in various conditions on microfluidic large-scale integration platforms. Conceptually, we engineer biological sensors through systematic reconstruction of natural proteins (e.g. transcriptional factors) or nucleic acids (e.g. riboswitches) to quantitatively read-out biological activity. Synthetic biosensors optimized through our platforms, are subsequently deployed to investigate a variety of cell signaling pathways or to enable high-throughput analytics, respectively.
Microsystems-Sensors: We are engineering thin metal film oxygen, carbon dioxide and glucose sensors compatible with mLSI chip platforms for characterizing metabolic rates of human cell cultures on chip. Preferentially, the microsystems sensors are designed for live time monitoring of the cells with fluorescence readout technologies. The goal is to control and monitor fluctuations of the micro-environments to understand cell signaling responses.
Cell signaling is the process, by which cells detect changes within their micro-environment and elicit an appropriate response, e.g. a change in metabolic activity and signaling to other cells. Understanding the underlying molecular mechanisms is one of the main quests of biology, but cell signaling studies remain difficult due to the high number of involved factors and their interdependent actions.
The main biological interest of our group here is the activity of the AKT/mTOR pathway in the differentiation and growth process of adipocytes and pancreas cells. The AKT/mTOR pathway is a major pharmaceutical target to combat insulin resistance in adipocytes and insulin production of pancreas cells occurring during diabetes mellitus. We apply automated microfluidic cell culture chip technologies to precisely control stem cell differentiation on chip by activating or silencing the AKT/mTOR pathways. In contrast to standard cell culture technologies we modulate the simulation pulses over short and long term in their frequency, amplitude and duration on chip to simulate the natural and disease cell micro-environments.
To reveal cellular signal transduction in situ, we either use our biological and micromechanical sensor systems or immuno-based PCR methods for proteins. With these sensors we aim to measure changes in physical-chemical properties (pH, or oxygen) and small molecules (glucose, amino acids) in the surrounding volume or directly within the cells. With the immuno-PCR based technologies, including the proximity ligation assay, we aim to detect changes in abundance, modification and localization of signaling proteins on a single-cell level with high sensitivity and specificity. Specifically, we are highly interested in monitoring the whole AKT/mTOR signaling pathways in response to insulin.
Our group is working on microfluidic chip technologies to integrate two very different organ types, namely spheroid cultures and plant roots:
- Spheroids-On-Chip: Spheroids are clusters of cells, which mimic physiological tissues while retaining the advantages of in vitro cell culture in terms of simplicity and reproducibility. Within a spheroid, a few hundred cells form strong cell-cell contacts and synthesize extracellular matrix and thus, spheroids resemble the mechanical and communicational microenvironment of a tissue. Spheroids are therefore becoming popular 3D in vitro tissue models for high throughput pharmacology and toxicity studies. My group is focusing on culturing, stimulating, and differentiating spheroids formed by pre-adipocytes or pancreas progenitor cells into cell types of the corresponding tissue on chip. Our goal is to understand signal transduction and the contribution of the 3rd dimension in differentiation processes. Finally, spheroid cultures should be used to obtain cells to tackle diabetes with replacement therapies. To obtain signaling data we adopt the same technologies as for 2D cell cultures (see signaling topic) for deep tissue analysis.
- Plants-On-Chip: For the concept Plants-On-Chip we developed a microfluidic chip capable to germinate, grow and stimulate in parallel fashion roots of the model organism Arabidopsis thaliana. Integration of the living root system on chip allows to simulate and screen rapidly environmental conditions as drought- and salt stress or nutrient deprivation. Furthermore, the platform allows high-throughput imaging of the roots over a time period of hours to a week. Currently, we couple this platform to next generation sequencing to identify genes related to drought stress and enable new engineering approaches for crops.
T. Santisteban Silva, O. Rabajania, I. Kalinina, S. Robinson, M. Meier, ‘ Rapid spheroid clearing on a microfluidic chip’, LabChip, 18, 153-161 (2018)
X. Wu, N. Schneider, A. Platen, I. Mitra, M. Blazek, R. Zengerle, R. Schüle, M. Meier, “In situ Characterization of the mTORC1 during Adipogenesis of Human Adult Stem Cells on Chip”, PNAS, 113, E4143-50 (2016)
M. Blazek, R. Zengerle, M. Meier. “Analysis of fast phosphorylation kinetics in single cells on a microfluidic chip”, Lab Chip, 15, 726-34 (2015)
S. Ketterer, D. Hoevermann, W. Weber and M. Meier, “Transcription factor sensor system for parallel quantification of metabolites on chip”, Anal. Chem. 86, 12152-8 (2014)
M. Meier, R. Sit, and S. Quake. “Physical interaction map of conserved bacterial proteins of unknown function”, PNAS 110, 477-82 (2013)
L. Martin, M. Meier, M. Lyons, R. Sit, W, Marzluff, S. Quake, H. Chang. “Systematic reconstruction of RNA functional motifs with high-throughut microfluidics” Nat. Methods 9, 1192-94 (2012)
M. Meier, R. Sit, W. Pan, and S. Quake. “High-performance binary protein interaction screening in a microfluidic format” Anal. Chem. 21, 9572-8 (2012)
G. Grossmann, W.J. Guo, D.W. Erhardt, W.B. Frommer, R.V.Sit, S.R. Quake and M. Meier. “Root- Chip: An integrated microfluidic chip for plant science” Plant Cell 12, 4234-40 (2011)