The BBZ is an internationally competitive center which promotes research and development as well as teaching and advanced training in the areas Protein Engineering & Bioanalytics, Molecular Medicine & Therapeutics as well as Biomedical and Cell Engineering. Platform technologies and methods in biotechnology, biomedicine and nanotechnology are offered as services for academic institutions and industry. Here, the BBZ strengthens and supports collaborations between institutional and university research teams but also forms a unique interface between academia and industry in Europe. With expertise and competence, innovations are transferred to industrial utilization.
With a focus on red biotechnology and following the motive “From the molecule to the patient” the BBZ develops and offers chemical compounds, proteins and other biomolecules, cells as well as tissues as instruments and products for a wide variety of biotechnological and biomedical applications. To this end, novel analytical methods and preparative procedures are developed.
The center collaborates closely with the University Hospital and the Interdisciplinary Centre for Bioinformatics (IZBI) at the University of Leipzig. A central office for management and acquisition supports the networking between science and business.
In the BIO CITY LEIPZIG six academic research groups from the chemical, biological and medical sciences work under one roof with innovative biotechnological companies including many startups. In addition, 37 life science research groups in the Leipzig area are currently members of the BBZ.
Chairs at the BBZ
- Bioanalytics
- Molecular Biological-Biochemical Processing Technology
- Molecular Pathogenesis
- Molecular Cell Therapy
- Structural Analysis of Biopolymers
- Cell Techniques and Applied Stem Cell Biology
Independent junior research groups at the BBZ
- Applied Molecular Evolution
- Molecular Diagnostics - Microarray Techniques
- Molecular Medicine of Contagious Diseases
- Protein Engineering
- Protein-Ligand Interaction by Ion Cyclotron Mass Spectrometry
The research projects of the Chair of Bioanalytics (Prof. Ralf Hoffmann) have the overall goal to develop new analytical tools to identify posttranslational modifications as well as to characterize proteins for their phosphorylation, hydroxylation, methyllation, glycosylation, desamidation and glycation sites. These mostly reversible but partially irreversible modifications regulate both the structural and functional characteristics of proteins in response to cellular or extracellular signals. The research projects were supported by a total of six grants from the DFG, BMBF, and SMWK. The following results were obtained in close collaborations with several international research groups, i.e., three research groups in the United States, two research groups in Russia and two research groups in Australia. As part of these collaborations, two predoctoral students worked abroad for four weeks each, whereas two predoctoral students and one postdoctoral fellow visited us for one month each. In the field of Alzheimer’s disease several new monoclonal antibodies (mAbs) were published that recognize several disease-specific phosphorylation patterns of the Tau-protein. This specific binding and the resulting diagnostic potential was further evaluated and finally confirmed by enzyme-linked immunosorbent assays (ELISA), immunoblots and immunohistochemistry using brain samples. The results were published in two peer-reviewed journals. Furthermore, we could show that these disease-specific phosphorylation patterns are not present in-vivo in normal Tau, although the phosphorylation pattern of normal Tau appears more complex than generally expected. Protein glycation (or glycoxidation) by glucose was linked to Alzheimer’s disease and diabetes for example and it appears to be the cause of many clinical symptoms. A simple solid phase synthesis for glucose-, fructose-, and ribose-derived Amadori-products and their mass spectrometrical analysis (ESI- and MALDI-MS) to identify and characterize accordingly glycated peptides and proteins were published. In a third project related to antibiotic resistance the structures of several substances with antimicrobial activities were characterized. Some compounds were synthesized and are currently tested against several clinically important bacteria, viruses, and fungi. These tests focus on bacterial strains resistant to one or several standard antibiotics.
The Chair of Molecular biological-biochemical Processing Technology (Prof. Dr. Andrea A. Robitzki) could realize a further great technological effort in the field of semiconductor technology. Establishing a new semiconductor clean room of the class 100 novel fabrication processes as well as first micro-structures could be developed in the field of micro-implants and medical micro-devices (biosensors). A novel 3D cavity chip was fabricated and validated for the real time monitoring of 3D in vitro tissue models, e.g. for an online and real time detection (bio-impedance spectroscopy) of myocard ischemia in 3D cardiomyocytes or physiological changes in 3D melanoma. This biosensor platform was successfully adapted to a microlaser manipulation platform for studying neural regeneration of e.g. dorsal root ganglion cells or for realizing the proof of principle of therapeutical concepts. A further focus of the research was (i) the development and validation of 2D/3D in vitro tissue models for bioelectronic drug screening in the cardiovascular field and (ii) first design studies for an endoluminal micro-implant for a controlled drug delivery. In the first case a concept of system biology funded by an STREP project of the European Commission will result in the development of an in silico cell and tissue model for efficient drugs and therapies against cardiovascular diseases. In the last case a project of the Centre for Translational Regenerative Medicine funded by the Federal Ministry of Research and Technology (BMBF) a drug delivery micro-implant will be developed for a molecule based regeneration in vivo e.g. within the central and peripheral nervous system.
The Chair of Molecular Pathogenesis (Prof. Manfred Blessing) investigates the function of growth factors and cytokines. The research is focused on members of the „Transforming Growth Factor-beta“ (TGF-beta) family. TGF-beta is a pleiotropic factor. TGF-beta is a central regulator of the immune system promotes proliferation and differentiation of mesenchymal cells but strongly inhibits epithelial cell prolixferation and modulates angiogenesis and apoptosis. Because of this broad spectrum of activities which may be quite opposite in different cell types, changes in TGF-beta activity or TGF-beta responsiveness strongly affect tissue homeostasis and tissue function. It is thus not surprising that modifications of the TGF-beta system are found in a variety of diseases including cancer, immune system malfunction and impaired regeneration. For functional analysis we generated a series of transgenic mice with local and cell-type specific modifications in TGF-beta activity or TGF-beta responsiveness. A correlation between these modifications and altered susceptibility towards cancer and immune system malfunction has been established. For example, loss of TGF-beta responsiveness in skin, gut and liver quite differently affected tumor incidence in these tissues and reflected the frequency of respective mutations in tumors of skin, gut and liver from patients. In addition, we demonstrated that loss of TGF-beta responsiveness in T-cells augmented susceptibility towards asthma, hepatitis and arthritis, whereas increased TGF-beta secretion by T-cells rendered resistance towards asthma. Recently, cell-type specific target genes of this central regulator have been identified in these models using high density DNA-chip arrays and proteome analysis. These new candidate genes are now being analyzed in patients for the development of new diagnostic, prognostic and therapeutic tools.
The Chair of Molecular Cell Therapy (Prof. Dr. Peter Seibel) develops methods and technologies to correct genetic defects in human cells. As a model for human diseases, mitochondrial DNA disorders were chosen, because they display a wide variety of symptoms and are known as multisystem disorders. To develop a treatment regime for these diseases, knowledge on the genetic defect as well as the understanding of mechanisms involved in mitochondrial biogenesis are essential. Fission and fusion events of mitochondria support the equal distribution of genetic material within the mitochondrial network of a cell. To study these molecular events, a highly specified imaging platform was set up. The fluorescence imaging microscope was upgraded to a confocal multiphoton/laserscanning system that allowed already in its test phase important discoveries: when we studied fluorescently labeled mitochondria, we were able to visually detect the mitochondrial membrane topology. Fission and fusion events of mitochondrial membranes could be detected for the first time in living cells. Moreover, fluorescently labeled single-strand-binding-proteins of mitochondria and mitochondrial transcription factor A were detected when acting on the mitochondrial genome so that time and location of mitochondrial transcription and replication events were recorded. These observations will have a direct impact on the development of new treatment regimes and therapeutic approaches.
The main research interest of the Chair of Structural Analysis of Biopolymers (Prof. Norbert Sträter) is the study of the relationship between the three-dimensional structure of proteins and their function by using biochemical and biophysical methods, mainly protein crystallography. Here, currently enzymes are being studied, mostly metalloenzymes, but also other proteins of medical or biotechnological relevance. Aside from the study of the structure of the native protein, a prime interest is the characterization of the catalytic mechanism or function of a protein on a molecular basis. Current projects focus on metallohydrolases, pharmacologically relevant extracellular receptor proteins and proteins involved in signal transduction. The place of the group’s research is at the interface between chemistry and life sciences: Prominent examples are the analysis of the chemical catalytic mechanisms of enzymes or the molecular mode of action of synthetic drugs on the biological targets by structural analysis of the complex structures.
During the last year we determined the crystal structure of the cAMP-dependent phosphodiesterase 4A. In cooperation with industrial partners new drugs against inflammatory diseases will be developed within the project. Within DFG-funded projects we study the structure and function of other proteins of the pharmacologically relevant extracellular nucleotide metabolism. Procedures for expression, refolding, purification and in part crystallization of these proteins have been developed. A further aim is the structure determination and structure based development of inhibitors. In another DFG-funded project the structure-function relationships of the domain movement of 5'-nucleotidase and its role in catalysis are studied.
The research projects of the Chair of Cell Technology and Applied Stem Cell Biology (Prof. Dr. Augustinus Bader) are centred on the development and characterization of bioreactors to produce autologous implants (bone, cartilage and skin grafting), and as bioartificial liver replacement systems for drug screening and as a bridge to transplantation and to support autologous liver regeneration. The department is also involved in unravelling the mechanisms involved in tissue regeneration. At the heart of the work on liver bioreactor development for drug screening (STREP-project LIVEBIOMAT) is the testing of various biomaterials for long-term cultures of primary hepatocytes. In the process the regulation of the expression of liver-specific genes using microarray technology has been successfully investigated. Within the research cooperation, the platform concept of cell biology - systems biology, proteins of the signalling pathways which play an important role in liver regeneration, could partly be identified by adding certain cytokines in primary hepatocyte cultures. Furthermore, the immunological responses to allogenic hepatocytes in a liver bioreactor included investigations into the biotolerance of various materials for the encapsulation of primary hepatocytes (IZKF – partial project of the University of Leipzig). The EFRE-project ²Liver² (SMWK) has tested with some success various bioreactor models using human hepatocytes which were developed as a production system for proteins. The BMBF-project in the field of skin replacement is concentrating on the colonizing behaviour of various skin cells on different membranes in static cultures and also in bioreactor cultures. Analysis of the cell-cultivated matrices was carried out using metabolic investigations and illustrative processes to quantify cell viability. The aim was to achieve reproducible adequate skin cultures on different 3D polymers. The SMWK-sponsored project on the “Development of a sterile bioreactor system for individual cartilage cultivation with NMR quality control/quality assurance (QC/QA)-analysis” could be completed. The “proof of concept” was set up in which the aseptic production of autologous cartilage replacement materials in the bioreactor was investigated using NMR spectroscopy and MALDI-TOF spectrometry on joint cartilage parameters. The future of this research and development project is secured by a BMBF-sponsored cooperation project established in the medical faculty. Its aim is an “Automated production and supervision of three-dimensional cartilage replacement tissue from mesenchymal stem cells” in which the department will incorporate new technologies / developments from the Institutes of Experimental Physics I and II, the Institute of Medicinal Physics and Biophysics and the Interdisciplinary Centre for Bioinformatics into the existing bioreactor system. The department has succeeded in being granted two DAAD projects. In the one case there is a cooperation with the department of Dr. Meng at the University of Zhejian, China, in the development of tissue-like cultures of primary hepatocytes in a hollow fiber bioreactor, and in the other case a cooperation with Dr. Diaz at the Institute of Sevilla, Spain in the field of synthesis and development of nanostructured biomaterials for cell culture systems in the area of orthopaedic, regenerative medicine. For the successful clinical application of the cell biological results and the animal experimental studies of this project, a necessary clean room system for the manufacture of so-called Advanced Medical Products (AMP) or Tissue Engineered Products (TEP) was created and put into use. Now it is possible for the department to produce cell-based autologous human transplants in accordance with the German Law Governing the Manufacture and Prescription of Drugs, and also to test and validate extracorporeal organ support and bioreactor systems.
The junior research group Applied Molecular Evolution (PD Dr. Susanne Brakmann) employs techniques of directed evolution for the functional optimization of nucleic acid polymerases and also, is concerned with the realization of DNA sequencing on the single-molecule level. In the past year, active variants of HIV reverse transcriptase with increased error rate were identified using a two-step genetic selection approach (1. complementation of deficient polymerase I activity, 2. reversion of tryptophane auxotrophy). Kinetic analyses supported that the variants identified so far differ significantly from wildtype enzyme with respect to turnover numbers and substrate acceptance. However, we were not able to corroborate a hypothesis on improved incorporation of non-natural nucleotides by error-prone polymerases. Further, we established a combined selection/screening system for identifying variant enzymes that preferably incorporate 2’-modified nucleotides instead of natural ones. Using genetic selection (marker: GFP), active variants of T7 RNA polymerase were isolated from a mutant library and then assessed with regarding their acceptance of modified nucleotides (molecular beacon assay). First results showed the emergence of variants with improved activity. These enzymes are currently studied in detail. Regarding the realization of single molecule sequencing, DNA labeled with high density was immobilized on cover slides and submitted to degradation by exonuclease III. Experiments with detection on the single molecule level were performed together with Prof. Christian Hübner, MLU Halle.
Aim of the junior research group Molecular Diagnostics – Microarray Techniques (Dr. Peter Ahnert) is the identification of biomarkers for complex diseases. Identification of biomarkers is one tool in the investigation of etiology and pathogenesis of complex diseases with usually undetected onset. The development of markers for early diagnosis and better classification become possible. Focus of the group is autoimmune diseases, especially rheumatoid arthritis (RA), and brain tumors. Autoimmune diseases like rheumatoid arthritis are complex diseases with various causative factors. It is well accepted that genetic predisposition plays a role in disease susceptibility and disease progression. Most likely, not just the well known HLA locus is involved. However, to date it is unclear which other genes and their variants may be important. The study of candidate genes and their polymorphisms appears to be a promising approach to elucidate this problem. Likely, combinations or patterns of low penetrance gene variants are important here and for complex diseases in general. This points in the direction of systems biology. The goal of this project is to contribute to the elucidation of the genetic component in the etiology and pathogenesis of RA and to further the development of methods for investigating the genetics of complex diseases in general.
Diffuse astrocytoma are among the most deadly types of cancer. Prognosis and treatment options depend heavily on the type and grade of a given tumor. In collaboration with the Department of Neuro Surgery of the University Hospital of Leipzig, molecular signatures of different tumors are being investigated, especially with cytogenetic methods and proteomic profiling.
The research projects are supported by the „Sächsische Aufbaubank“, the „HWP”, “EFRE” and the “DFG”. We work in close collaboration with the group of Dr. Francois Cornélis (University of Evry and University Paris VII) as well as with several partners in Germany.
The junior research group Molecular Medicine of Infectious Diseases (PD Dr. Reinhard Straubinger) dealt with following during the last years: description of molecular mechanisms that allow spirochetes to persists in the host with a specific emphasis on the host-spirochete-interactions observed during Lyme borreliosis and characterization of the infection-induced modulation of extracellular communication factors such as cytokines.
Borrelia burgdorferi organisms are able to change their shape and simultaneously can halt their metabolism when they encounter specific unfavorable environmental conditions. We were able to show, that during this process neither the lipid nor the protein composition of the outer membrane, which is accessible to the host’s immune system, are changed. This is not a process that is primarily regulated by genes within the bacterium, but rather a passive reaction to environmental conditions. As a consequence, it will be difficult to develop therapeutic strategies, that aim at a complete elimination of a dormant agent. This project was carried out in collaboration with the Department of Nephrology/Rheumatology, University Hospital Göttingen, Germany and with the Institute of Veterinary Anatomy, College of Veterinary Medicine, University of Leipzig). Despite this ability to hide from the immune system, the infection with Borrelia burgdorferi, nevertheless induces early after the transfer of the bacterium into the host’s skin the release of the cytokines interleukin 23 and interleukin 17 by immune cells. In vitro cultured dendritic cells, which encounter and process as one of the first cell types foreign material during the course of an infection, communicate with surrounding T-cells via IL-23. T-cells on the other hand function as switches and forward this information via IL-17 to cells of downstream processes. This way the host initiates an intercellular signal cascade, which effectively amplifies the signal and ultimately leads to the inflammation of specific organs, especially the joints, heart and brain.
Furthermore, the group is engaged with the detailed characterization of novel borrelia species, especially the molecular description of B. persica. The project is carried out in close collaboration with Prof. Gad Baneth, Hebrew University, School of Veterinary Medicine in Israel. Supported by the companies IDEXX Inc. and Merial GmbH, the group additionally determines the prevalence of specific antibodies against the tick-transmitted bacteria Anaplasma phagocytophilum and Borrelia burgdorferi in dogs throughout Germany. These data will help to get an impression of the epidemiological situation for these two infections and to assess the infection risk for humans living in this area. Further medically relevant infectious disease projects are dealt with in collaboration with the Institute for Animal Hygiene and Veterinary Public Health (Pathogenic plants: characterization of virulence markers in Prototheca originating from human and animal samples; supported by the DFG) and together with the Institute of Food Hygiene and Institute for Parasitology of the College for Veterinary Medicine in Leipzig (Toxoplasmosis in humans and animals in Germany: pathogenesis, risk factors, and control - TOXONET 01; supported by the BMBF).
The research field of the junior research group Protein Engineering (Dr. Thomas Greiner-Stöffele) was the application and development of methods for the rational protein design and for in vitro evolution of proteins. Two areas were in the focus of the group. On the one hand the work on exonuclease III of E. coli and two thermostable proteins from A. fulgidus und M. thermoautotrophicus has been continued. Derived from the x-ray structure of both thermostable proteins probably stabilizing mutations were introduced in exonuclease III of E. coli. Additionally the catalytic centers of all three enzymes were analyzed using mutagenesis studies and first hints for the basis of the different specificity regarding endo- or exonucleolytic activity of these nucleases could be found.
Within a collaboration project new systems and assays for the screening of new restriction endonucleases inside genomic DNA libraries were developed. The generation of a “proof of concept” starting from a strain with a known restriction endonuclease was started.
The techniques developed in the junior research group Protein-Ligand Interaction by Ion Cyclotron Resonance Mass Spectrometry (PD Dr. Andrea Sinz) for investigating low-resolution three-dimensional structures of protein complexes by chemical cross-linking and high-resolution mass spectrometry are steadily being improved. Isotope-labeled cross-linking reagents have proven to be advantageous for a rapid identification of cross-linked products based on their characteristic isotope patterns in the mass spectra (ESI-FTICR-MS und MALDI-TOF-MS). Another promising strategy relies on a selective enrichment of cross-linked products by using trifunctional reagents that contain a biotin moiety, thus allowing to enrich cross-linker-containing species by affinity chromatography on avidin beads.
The following research projects were conducted in the junior research group. The projects marked with an asterisk will be continued at the Institute of Pharmacy, Martin Luther University Halle-Wittenberg: Interaction studies of the annexin A2 / S10010 (p11) heteroteramer (Cooperation with Prof. Arnold and Dr. Zschörnig, University of Leipzig), *Investigation of laminin self aggregation (Cooperation with Prof. Meiler, Vanderbilt University, Nashville, USA, and Prof. Paulsson and Dr. Smyth, University of Cologne, DFG-Schwerpunktprogramm SPP 1086 ‘Genetic and molecular analysis of basement membranes and basement membrane anchoring’, DFG-Project Si 867/7-1, finished Sept. 30, 2006), *Expression and purification of the Peroxisome Proliferator-Activated Receptor a (PPARa) (Cooperation with Prof. Sträter, University of Leipzig and Prof. Schubert-Zsilavecz, University of Frankfurt) and *Analysis of phosphorylated peptides using a hybrid mass spectrometer (linear ion trap and ICR cell) (Cooperation with K. Mechtler, IMBA, Vienna, Austria).
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