Innovative Electron Microscopy
Nanoscale characterization is essential for progress of modern nanotechnology, energy science, biology, and biomedical sciences. The Program Division Innovative Electron Microscopy conducts interdisciplinary research at the interface of physics of electron microscopy, cancer research, biophysics, materials science, and image processing. Our main aim is to better understand the molecular mechanisms behind drug resistance development in HER2-overexpressing cancer. This research could lead to predictive markers for personalized medicine. We develop forefront in situ electron microscopy methods for the study of functional materials and biological samples at realistic conditions, with a focus on liquid-phase electron microscopy (LP-EM). We are also exploring new routes for three-dimensional (3D) data acquisition using intelligent software. We have extensive experience with image processing and particle detection methods, and with developing protocols for specific labeling of proteins with nanoparticles. Various research collaborations exist both with academia, and industry. Students and users obtain high-quality training on modern electron microscopy in our group.
Our main research topic involves the role of epidermal growth factor receptors in cancer cells. Of key interest is to analyze differences in protein function between individual cancer cells (cancer cell heterogeneity) and between distinct functional membrane regions within the same cell. With our approach it is possible to study the effect of cancer drugs on small sub-populations of cells, with the goal to better understand the molecular mechanism behind drug-resistance development aiming to develop predictive markers that increase the effectiveness of drugs in a personalized approach.
A research project on HER2 overexpressing breast cancer is funded by the Else Kröner-Fresenius-Stiftung. Projects partners are Prof. Wiemann of the German Cancer Research Center, Heidelberg, and Prof. Solomayer of the Saarland University Hospital. Together with Prof. Gaiser of the Medical Center Mannheim we also investigate gastric cancer, which is funded by the Deutsche Krebshilfe. More information.
Figure: Liquid STEM image of a membrane region of a cancer cell showing the locations of HER2 receptors labeled with quantum dots. The overlay reflects a molecular model. From: Peckys et al., Sci. Adv. 1:e1500165, 2015.
Together with Prof. Niemeyer, Molecular Biophysics, Saarland University, Homburg, Germany, we explore the stoichiometry of ORAI Ca2+ channels. This research is funded by the Deutsche Forschungs Gemeinschaft (DFG) and is part of the Collaborative Research Centre 1027 entitled “Physical modeling of non-equilibrium processes in biological systems”. More information.
Electron microscopy of liquid specimens offers unique options to study the nanometer-scale dynamic processes occurring at liquid interface. New fundamental insights are gained in nanoscale dynamics, and local van der Waals interactions. We discovered that nanoparticles in close proximity of a surface do not move as predicated by Brownian motion but many orders of magnitude slower. This research is funded by the DFG in the project: “Probing nanoscale interactions at the solid-liquid interface via liquid-phase electron microscopy”. More information.
We are partner in the MARIE SKLODOWSKA-CURIE ACTIONS Innovative Training Network (ITN) project “A multiscale approach towards mesostructured porous material design, MULTIMAT”. This consortium uses in-situ analysis to unravel the mechanisms of multiscale assembly. More information.
We have developed a novel electron microscopy technology to image whole eukaryotic cells in their native liquid state, so-called liquid-phase electron microscopy. Proteins are specifically labeled with electron dense nanoparticles. The atomic number (Z) contrast of scanning transmission electron microscopy (STEM) is then used to image the nanoparticles within a layer of liquid containing the cells. Labels of different sizes and compositions can be distinguished. LP-EM is also used to study protein complexes and nanomaterials in liquid. Correlative fluorescence microscopy and LP-EM is possible using quantum dot nanoparticles as protein labels. Our latest research involves graphene liquid enclosures. More information.
Figure: Liquid STEM principle. From Jonge et al., Proc. Natl. Acad. Sci. 106, 2159-2164 (2009).
We are also developing intelligent data acquisition strategies for 3D electron microscopy together with Dr. Dahmen of the German Center for Artificial Intelligence and funded by the DFG in the project: “TFS-STEM: Combined tilt- and focal series for STEM tomography with a computational correction for beam blurring.”
The INM houses a state-of-the-art aberration corrected scanning transmission electron microscope (STEM, ARM200, JEOL, Japan), with a combined energy filter and an electron energy loss analyzer (Gatan). This microscope has a cold field emission source (CFEG) with low energy spread. The microscope combines a spot size of 0.08 nm with a probe current of 200 pA and an energy spread of only 0.3 eV. This microscope is used for various areas of research at the institute and also at the Saarland University.
Research projects are conducted together with scientific partners in the areas of functional nanomaterials, energy-related materials, and catalytic materials. The properties of functional materials are closely related to the atomic structure and especially dislocations of atoms within the bulk structure, and at interfaces. Aberration corrected STEM is capable of atomic-resolution chemical mapping using EELS, X-ray elemental analysis, and Z-contrast, such that dislocations of single atoms can be studied within the atomic matrix.
Figure: Picture of the JEOL ARM200F.