Faculty of Biology
Medical Biology Research
The “Medical Biology” research focus is associated with the Centre for Medical Biotechnology (ZMB), which also includes research groups from the Faculty of Medicine and the Faculty of Chemistry. The ZMB’s eleven biological research groups support the BSc and MSc degree programmes in “Medical Biology,” as well as contributing to the Bachelor’s and Master’s programmes in Biology and the Lehramt [teaching certification] in Biology. The Medical Biology research area has the following core facilities at its disposal: Analytics Core Facilities (ACE), the Imaging Centre Campus Essen (ICCE), the Imaging Center Essen (IMCES), and NMR Spectroscopy. Furthermore, the ZMB also has its own mouse facility at the Essen-based site. The research here centres on the subjects of “Oncology”, “Immunology, Infectious Diseases and Transplantation” and “Molecular and Chemical Cell Biology”. The biological research groups of the ZMB play a prominent role in SFB 1093: Supramolecular Chemistry on Proteins, as well as in the Transregional Collaborative Research Centre 60, four research training groups, and research group 2123.
The Structural and Medical Biochemistry research group (Prof. Peter Bayer) deals with the interaction between and the post-translational modification of proteins. As part of Collaborative Research Centre 1093: Supramolecular Chemistry on Proteins, and in collaboration with the Molecular Biology I research group led by Hemmo Meyer, the past two years have seen this research group structurally investigate the interaction of p97 with its cofactor UBXD1 at the molecular level with the aid of NMR (1). Also known as VCP, p97 is an AAA-ATPase involved in cell cycle regulation, DNA repair and protein degradation. Mutations in p97 that affect the interaction between this AAA-ATPase and UBXD1 could lead to the development of neurodegenerative diseases. With this in mind, a cooperation involving Thomas Schrader (Organic Chemistry) has made it possible to successfully inhibit this disease-related interaction by means of supramolecular ligands. Similarly, the interaction of the apoptosis-related protein survivin is investigated with supramolecular forceps in collaboration with Shirley Knauer’s Molecular Biology II research group. In the field of peptidyl-prolyl isomerases (PPIase), it was possible to show for the first time that PPIases are endogenously expressed in archeal organisms, as well as to explain the structures, localisation and cellular function of representatives of these enzymes with NMR, TEM and enzyme assays (2).
The research group of Prof. Hemmo Meyer explores cellular defence strategies against stress-induced damage, and how these are mediated by the ubiquitin-proteasome system to ensure the survival and functioning of the cells. Somatic cells are constantly exposed to stresses that can damage their organelles, their DNA and their proteins. These stresses include radiation, oxidative substances, pathogens, and cell-specific factors that can accelerate ageing and degenerative processes. A particular focus of research in this field is a molecular machine known as p97. In cooperation with neurologists from Washington University in St. Louis, the group has now discovered that p97 reacts to defective lysosomes and, with the help of other factors, ensures that these organelles are efficiently disposed of, once damaged, by the process of autophagy. It is now assumed that this is the way forward in regards to preventing the degeneration of muscle and nerve cells, which not only occurs when p97 mutates in humans, but also plays a role in a variety of other degenerative diseases. In collaboration with molecular biologists at Rockefeller University, the group has also been able to show that p97 reacts to DNA damage caused by dangerous double-strand breaks. To this end, p97 exploits its amazing ability to unfold proteins in order to subtract repair factors from DNA after repair, allowing the DNA to perform its function once again. The aim of both projects is now to further understand the underlying molecular mechanisms, not least to uncover possible strategies for therapeutic intervention in these processes.
To investigate DNA replication in humans, Prof. Dominik Boos and his research group are currently investigating the cellular functions and regulations of the treslin, MTBP and TopBP1 protein complex, which is a main regulatory platform of the first step of replication – initiation (Boos and Diffley 2011 and 2013). In a bid to ensure the consistency of the genetic information over many generations of cells and organisms, each cell must be given a complete, error-free set of genetic information upon being generated by cell division. Prof. Boos and his research group are aiming to find out how human cells are able to duplicate their DNA correctly by means of DNA replication so as to have a set of genetic information available for both daughter cells. Issues with the DNA replication can lead to cancer and the transmission of diseases as a result of mutations. As part of a North Rhine-Westphalian returnee project, the Boos research group has been investigating the molecular and cellular functions of treslin and MTBP since 2015. What’s more, the involvement of this group in GRK1739 since 2016 has facilitated a natural extension of its research objectives, which include investigating the regulation of the replication process following the induction of DNA damage by radioactive cell irradiation. Also since 2016, Boos and the team have been investigating how the treslin MTBP-TopBP1 protein complex is involved in cancer predisposition. Supported by the Josep Carreras Leukaemia Foundation, this is a collaborative project with the Kratz research group in Hanover.
The research in Prof. Perihan Nalbant’s “Molecular Cell Biology” workgroup focus on the study of signalling cascades that control the actin cytoskeleton during dynamic cellular processes. In particular, the group is interested in the proteins of the Rho GTPase family known as key regulators of cell protrusions (Rac1 and Cdc42) and actin-based cytoskeletal contractions (RhoA). To understand the regulation of the individual cytoskeletal structures and to uncover their biological relevance, the group uses cutting-edge fluorescence microscopy techniques and cellular and molecular biology methods. Using TIRF (Total internal reflection fluorescence) microscopy, the group has recently revealed dynamic sub-cellular actin-myosin contractions in adherent cells and was able to identify key components of the regulatory signal network. Building on those findings, the group are currently investigating a potential sensory role of dynamic contraction patterns in the control of cell fate as a response to distinct physical properties of the extracellular matrix.
The research group of Prof. Shirley Knauer (Molecular Biology II) is interested in the oncologically and developmentally relevant proteins survivin and tapsase 1, a protease. Their work focuses on understanding the regulation of nucleo-cytoplasmic transport and its impact on cellular homeostasis, especially the cell cycle and decisions impacting cell fate, as well as its impact on the malign transformation in cancer development, and as potential target for new therapy strategies. The work over the last few years could shed light on the evolution of the proteolytic repertoire of taspase 1. Its evolutionary divergence leads to species-specific substrate recognition, which is attributed to a less stringently-defined consensus sequence as well as a missing nucleolar localization in other species, demonstrated by studies on the homologous enzyme from the Drosophila fruit fly. In a long-standing cooperation with the Organic Chemistry group of Prof. Carsten Schmuck, also as a member of the Center for Nanointegration Duisburg-Essen (CENIDE), we have been successfully developing novel gene transfection reagents, which are also suited for the downregulation of survivin in different cancer cell lines. Recently, significant progress could be achieved by the incorporation of tailor-made anion-binding motifs and of non-natural amino acid analogues, which led to the formation of nanotubes.
Bioactive, chemical active ingredients are valuable starting substances for the development of new chemotherapeutics, as well as tools for basic biological research. The Chemical Biology research group (led by Prof. Markus Kaiser) seeks to synthesise innovative, structural, chemical agents, test their biomedical properties, and explain the underlying molecular action mechanisms with promising biological activity. Within the scope of this research, for example, it has been possible to chemically present the polyacetylene natural substance of callyspongynic acid for the first time, and characterise its molecular action mechanism in detail by means of modern mass-spectrometry-based proteomics. Although polyacetylenes represent a large family of potentially interesting natural products from a bioactive and chemotherapeutic perspective, their molecular action mechanisms are still largely unknown. Using a substitute polyacetylene class of natural substances, this work has shown for the very first time that these have a polypharmacological effect on many different biological processes.
The group led by Prof. Michael Ehrmann studies evolutionarily-conserved cellular factors that are involved in key aspects of quality control, such as the detection of misfolded proteins, signal recognition and integration into the unfolded protein response pathways, and regeneration of the functional state. These studies aim to reveal the general concepts governing the underlying molecular mechanisms of protein diagnosis, repair and degradation. The research focuses on the widely-conserved HtrA family of serine proteases that are involved in all aspects of ATP-independent protein quality control. We demonstrated that a protein can combine the antagonistic functions of chaperone and protease activities within a single polypeptide. Furthermore, in collaboration with Tim Clausen (IMP Vienna), it was shown that HtrAs can switch between various oligomeric states and has elucidated the mechanism of activation by oligomerisation. In recent years, work on human HTRA1 has revealed its involvement in cancer (as a tumor suppressor), in arthritis (in remodelling of the extracellular matrix) and in Alzheimer’s disease (in disaggregation and proteolytic degradation of amyloid fibrils that are hallmarks of the disease). Chemical biology approaches have been used for a number of years, mainly in collaboration with Prof. Markus Kaiser, by biotech and pharmaceutical companies, to generate tools for basic research and for drug development purposes.
Over the past two years, the Bioinformatics and Computational Biophysics group (Prof. Dr. Daniel Hoffmann) has been developing quantitative methods to research biological “populations”. “Population”, in the general sense, is central to many biological phenomena (evolution, ecology, immunology, etc.). It also enables the use of powerful statistical methods that can to provide hints of biological mechanisms. Some methods have been developed to make sense of “High-Throughput Sequencing” (HT-Seq) data, a set of revolutionary experimental techniques that are able to measure various biological aspects at the population level. Examples of our new methods are: the SeqFeatR and genphen methods for the discovery of genotype-phenotype relationships (e.g. between a virus mutation and its ability to evade the immune system), the AmpliconDuo method for the effective processing of HT-Seq amplicon data (e.g. of microbial communities), the MaxRank normalization method that allows the quantitative comparison of populations (e.g. gut microbiomes, B-cell receptor repertoires, viral quasispecies, etc.). The application of these new methods by us and others has led to a number of discoveries, for instance mutations that help Hepatitis B virus to evade recognition by the immune system, or the natural history of gut microbiomes in young children that diverges between USA and Malawi and Venezuela. Finally, we also looked at populations of molecules and their conformational states using computational methods, both well-known simulation methods (Molecular Dynamics) and faster screening approaches. These computational molecular methods helped us to discover links between diverse biological phenomena and the common language of molecules spoken by all life forms.
The Developmental Biology research group (led by Prof. Andrea Vortkamp) investigates the molecular mechanisms that control the chondrocyte differentiation of enchondral bones and lead to their misregulation as degenerative skeletal disorders such as osteoarthritis. At present, the group is focusing on the role of heparan sulphate (HS) as a regulator of extracellular signal forwarding and tissue homeostasis. A particular aspect of this research looks at how HS controls the distribution and activity of Indian hedgehog homolog, one of the main regulators of chondrocyte differentiation. The research group is also investigating the role played by HS in the degeneration of articular cartilage. A second focus is on the role of transcription factors and epigenetic modifications in the regulation of chondrocyte differentiation. To this end, the research group seeks to establish the chromatin methylation and acetylation profiles of defined chondrocyte populations using ChIP-sequencing (chromatin immunoprecipitation followed by high-throughput sequencing). Bioinformatic analyses carried out in cooperation with the Hoffmann group are intended to identify mechanisms that regulate direct differentiation processes – such as the differentiation of proliferating chondrocytes into their hypertrophic or articular counterparts – at the epigenetic level.
The genomic building plan of the organism needs to be exactly copied and distributed between cells during mitosis and meiosis. Prof. Stefan Westermann’s workgroup is seeking to understand how cells pass on their chromosomes with such remarkable precision. Our laboratory is trying to understand how the duplicated genome is passed accurately from one cell generation to the next. Two related lines of experiments are thus being pursued: 1. We are performing a detailed genetic and biochemical analysis of the budding yeast kinetochore, in order to understand how this molecular machine is constructed to move chromosomes. 2. We are investigating how microtubules are organized by molecular motors and other microtubule-associated proteins in order to form the mitotic spindle. To this end, dynamic microtubules will be examined in vitro, using highly-sensitive fluorescence microscopy methods. We were recently able to demonstrate how the microtubule-binding element of the kinetochore, the Ndc80 complex, is arranged from other conserved components of the inner kinetochore, providing insights into how the connection to microtubules is established. We have also described a novel molecular mechanism in which two components – a molecular motor and a plus-end binding protein – can co-operate to determine the direction of microtubule growth. This conserved mechanism is responsible for the formation of parallel microtubule bundles in many different cells.