You are interested in a master or a student project? Great! Below you will find some general research topics of our group with potential projects to work on. You can also check our Research and Methods section to learn more about our ongoing projects and the respective techniques applied. If you want to know more please reach out to us. We look forward hearing from you!
Cryo-EM is a mature and powerful method that is amazingly productive. Nevertheless, it has its limitations, if the samples are too small, or if the samples are too flexible. If the atomic structure of such particles should still be determined, more contrast in cryo-EM would be needed. The projects below aim at increasing contrast in cryo-EM of single particle proteins.
In this project, the master student will participate in the development of an automated toolchain for high-throughput data collection via ptychography, using a prototype cryo-EM instrument that is tailored to this task. Ptychography is a method, in which a focussed electron beam is stepped over the sample in a 2D raster, while 2D electron diffraction patterns are recorded with a very-high-speed camera. This method is therefore also called 4D STEM (4D = 2D + 2D).
Method development is required at various parts in the development of this novel workflow for life sciences cryo-EM. Involved disciplines are electron optics, instrument automation, hardware remote control, high-volume / high-speed data processing, deep learning, computer algorithms (matlab, python).
In this project, the prototype CryoWriter that is installed in our lab, will be adapted and specialized towards becoming able to target individual locations in tissue slices and extract fibrillar samples from those locations for subsequent cryo-EM investigations. The CryoWriter is a microfluidic device that is developed and produced by the CryoWrite AG.
This technology is based on developments in our former lab at the University of Basel, done by the Group of Thomas Braun.
Our lab purchased the first prototype of the commercially available CryoWriter, which will be the basis of this research project. Involved disciplines are microfluidics, mechanical engineering, 3D printing, python programming.
Are you interested in solving the three-dimensional structure of proteins or fibrils? You will learn a lot about the biological relevance of the protein in question, sample preparation and computational aspects.
In this project, the master student would prepare an in-vitro protein sample for cryo-EM structure determination. The workflow involves optimizing protein expression and purification using liquid chromatography, EM grid preparation and plunge freezing, screening and imaging your samples (at the DCI Lausanne), and computational structure determination.
In this project the student would prepare BSL-2 fibril samples for structure determination. This involves learning EM grid preparation, negative staining, data acquisition, sample processing to final structure determination. You would also learn the biological foundation of neurodegeneration and the link to fibril structures. Please note that due to the type of work involved this project is only suited for full master thesis projects.
In these projects, the master student would prepare chemically fixed human brain tissue for high-resolution imaging with electron microscopy. For this, a continuous workflow from tissue sectioning, fluorescent and heavy metal staining, resin embedding, and serial sectioning with ultramicrotomy is needed. You will collect light and fluorescent microscopy images and high-resolution electron microscopy images to assess the ultrastructure of different types of inclusions. We work on different disease types, outlined below.
The presence of pure characteristic disease pathology for any neurodegenerative disease is the exception rather than the rule, with the majority of brains showing multiple pathologies (co-morbidity). In this project, we aim to gain morphological and ultrastructural information from the post-mortem human brain on these pathological inclusions across a variety of neurodegenerative diseases.
The main neuropathological hallmark of Parkinson’s Disease are Lewy bodies, however, there exists a wide spectrum of alpha-synuclein inclusions in the human brain. These different inclusions are thought to represent various stages of Lewy body formation. Apart from the presence of alpha-synuclein, very little is known about their molecular components or structural organization. In this project, we aim to use CLEM to gain ultrastructural information on these different pathologies in order to gain insight into the mechanism of Lewy body formation.
Parkinson’s disease is the second-most common neurodegenerative disorder. Its main pathological hallmarks are Lewy bodies and alpha-synuclein inclusions in the brain and peripheral tissues (skin, gut, salivary glands) of affected patients. Interestingly, peripheral tissues are easily accessible and believed to play a crucial role in Parkinson’s disease, especially in its early stages. In this project, we aim to gain high-resolution morphological and biochemical insights into alpha-synuclein deposits in the skin from Parkinson’s disease donors.
Dementia with Lewy bodies (DLB) is another synucleinopathy where the onset of dementia precedes the onset of Parkinsonism. The neuropathological inclusions include Lewy bodies in the cortical and limbic regions alongside Alzheimer’s disease-related pathologies. In this project, we aim to gain high-resolution ultrastructural insights into alpha-synuclein deposits in the post-mortem human brain from DLB donors.
Multiple systems atrophy belongs to the group of synucleinopathies and is a rapidly progressing neurodegenerative disease. A central hallmark of neurodegenerative diseases is the observation of tissue inclusions that are positive in alpha-synuclein. We aim to understand the morphology, temporal development, and fibril dependency of these structures. This project is directly linked to adjacent in-vitro and in-situ fibril research and is linked to the development of a cryo-CLEM approach.
Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are two diseases of the same spectrum. While one Transactive response DNA binding protein 43 (TDP43) protein is the main protein component in the aggregates, observed in 97% of aggregates in ALS and 50% of aggregates in FTD. In this project, we aim to gain structural insights into the role of TDP43 pathological plaques in these diseases. To this end, we will apply correlative light and electron microscopy approach to a post-mortem patient brain.