Biomedical Science

Research – Selected Highlights in 2012–2013

Research at the ZMB is structured into four programmes, which are presented below in selected projects.


Essen University Hospital’s Department of Medical Oncology, headed by Prof. Martin Schuler, is the largest academic institution for medical oncology in Germany. For more than 40 years the department has been dedicated to research into the diagnosis and therapy of tumour diseases as well as mechanisms of tumorigenesis, tumour progression and resistance to therapy. The Department of Medical Oncology comprises 4 independent grant-funded reseach groups: The Laboratory for Molecular Oncology (headed by Prof. Martin Schuler/Dr. Frank Breitenbücher), the Laboratory for Translational Sarcoma Research (headed by Prof. Sebastian Bauer), the Molecular Risk Profile Research Group (headed by PD Dr. Andreas-Claudius Hoffmann) and the Laboratory for Thoracic Oncology (headed by Dr. Daniel C. Christoph). Alongside laboratory-based, preclinical and translational research, clinical research at the department centres around the scientifically controlled application of new cancer pharmacotherapies. In this context, the department’s dedicated Oncology Phase I Unit, established more than 15 years ago, plays a major role. This unit is one of the most active of its kind in Europe in conducting early clinical studies (First-in-man, phase I, early phase II studies), most of which enroll ­patients based on specific biomarker profiles. The Oncology Phase I Unit constitutes a bridge between translational oncological research and clinical application to the benefit of patients.

Every patient with advanced cancer who is treated at the Department of Medical Oncology is offered determination of an individual biomarker profile from a tumour biopsy. The results of these analyses guide the selection of the most appropriate cancer therapy or clinical study to ensure the highest probability of a therapeutic effect. Scientists of the Department of Medical Oncology and the Institute of Pathology have thus established an internationally leading programme for biomarker-stratified clinical drug development.

The leading role of Essen University Hospital in this field is exemplified by recent findings on biomarker-stratified therapy of metastatic lung cancer. The novel drug Afatinib was found to be considerably more effective than standard chemotherapy in patients with lung cancers ­harbouring a so-called EGFR gene mutation. ­Afatinib blocks signal transduction pathways in these tumour cells. Similar results have recently been obtained in a phase I study of the novel drug Ceritinib in patients with metastatic lung adenocarcinoma exhibiting a mutation in the ALK gene.

Such studies provide evidence of the direct benefit to patients of the systematic biomarker screening offered by the West German Cancer Center of Essen University Hospital. The biomarker programme provides the basis for selection of a patient-specific targeted therapy.

Another extraordinary success in oncology was achieved by a research group led by Prof. H. J. Schulte, like Prof. Schuler a member of the ZMB. Prof. Schulte is head of Paediatric Oncology ­Research at Essen University Hospital. Research in his group aims to analyze the pathogenesis of embryonal tumours (neuroblastoma, medulloblastoma, retinoblastoma) as a basis for the ­development of rational individualized therapies with an improved cure rate in children with ­malignant embryonal tumours. The team was able to demonstrate that LIN28B expression in a model of tumour formation induced development of neuroblastomas. This finding provides a basis for targeted neuroblastoma therapy and was published in Nature Genetics in 2012. In recognition of the discovery, Prof. Schulte was awarded the Kind-Philipp Award 2012 of the Society of Paediatric Oncology and Haematology.

The Department of Dermatology, Venerology and Allergology of Essen University Hospital and the West German Cancer Center headed by Prof. Dirk Schadendorf focuses in particular on experimental and clinical research into the diagnosis, therapy and therapy resistance of malignant skin cancer, melanoma. A “biobank” comprising tissue samples of currently more than 10,000 patients including documented patient histories has been set up as a vital basis for translational research projects. Until just a few years ago, no life-prolonging therapy option had been available to patients with melanoma at an advanced stage. In 2010, the immune-modulatory antibody CTLA-4 (Ipilimumab) was shown to have a survival benefit in advanced-stage melanoma. Since that time, major advances in the clinical development of new antibodies have been made. As in Medical Oncology, high priority is given to setting up gene mutation profiles for every cancer to be treated  in skin cancer research  at Essen University Hospital. The goal of this approach is to determine the best possible therapy for each patient.

Molecular pathological findings have now led to the development of novel  substances and allowed the development of a targeted therapy building on tyrosine kinase inhibitors. This new approach is based on the knowledge that black skin cancer presents certain alterations in its tumour cells, known as BRAF mutations. The Clinic of Dermatology in Essen participated in clinical studies with Vemurafenib and Dabrafenib, two kinase inhibitors specifically inhibiting kinase activity of mutated BRAF, which demonstrated the therapeutic efficacy of the kinase inhibitors and also a survival benefit for patients with brain metastasis. The corresponding results of a multicentre Phase II study led by Prof. Schadendorf with Dabrafenib were published in Lancet Oncology at the end of 2012.

Another spectacular discovery by the Schadendorf group in collaboration with the German Cancer Research Center Heidelberg (Prof. R. Kumar’s group) is the identification of mutations in the promotor of the telomerase reverse transcriptase (TERT) gene in skin tumour samples. The mutations and the resultant increased expression of telomerase appear to be an important trigger for skin tumour formation. The analysis was performed in a multitude of melanoma tissue samples and TERT was identified as the most frequently mutated gene. Metastasized tumours carry the mutation in as many as 74 percent of cases. On the basis of these findings, which were published in Science in 2013, telomerase is now seen as a new potential target in skin cancer therapy.

Regulatory mechanisms of immune responses represent the focal point of the Molecular Infection Immunology group of Prof. Wiebke Hansen. During the reporting period, a surface receptor called Neuropilin-1 was identified in collaboration with the Clinic of Dermatology as an important regulatory component of immune ­responses against melanoma. Neuropilin-1 expression is enhanced in regulatory T-cells, a ­subgroup of CD4+ T-lymphocytes. This type of cell exhibits immune suppressive activity and is thought to contribute to a compromised immune response against tumour cells. The ­researchers were able to show that Neuropilin-1 is responsible for the infiltration of regulatory ­T-cells in tumour tissue. As published in 2012 in the Journal of ­Experimental Medicine, elimination of  Neuropilin-1 results in the formation of a reduced number of tumours and a deceleration in tumour growth in corresponding studies in mice.

Important findings were also achieved in eye tumour research.  An interdisciplinary team of researchers led by Dr. Michael Zeschnigk in ­cooperation with the group for Genome Informatics at the Institute of Human Genetics (Prof. Sven Rahmann) and the UDE have succeeded in identifying two key genes relevant for the development of uveal melanoma, the most common primary tumor of the eye. Mutations found in the genes called EIF1AX and SF3B1 are restricted to the tumour and are responsible for its formation. The relevant results, which were published in a leading international journal, could only be obtained by applying the latest DNA sequencing and genome-bioinformatics technologies, which have only recently become available at Essen University Hospital.

Pioneering work on the origin of tumour cells in chronic lymphatic leukemia (CLL) was performed at the Institute for Cell Biology, Tumour Research, headed by Prof. Ralf Küppers. Using large-scale gene chip analysis of differential gene expression and genetic analysis of immunoglobin genes, the researchers were able to prove that CLL originates from a special sub-group of mature B-cells, the CD5-positive B-cells. This finding makes it possible to identify deregulated genes in CLL specifically.

The group of Dr. Cyrus Khandanpour (Clinic for Haematology headed by Prof. Ulrich Dührsen) in cooperation with Prof. Tarik Möröy (Montreal, QC, Canada) and Prof. Heighton L. Grimes (Cincinnati, OH, USA) was able to demonstrate that Growth factor independent 1 (Gfi1) is an important survival factor for acute lymphatic leukemia cells. The results arise from studies using mouse models and evaluation of patient data and suggest that Gfi1 could be a new target in leukemia therapy.

The Lysin-specific Histondemethylase LSD1 is seen as a promising target for the therapy of solid tumours. The group of Dr. J. Göthert in collaboration with Prof. J. Schulte (Paediatric Oncology Research at Essen University Hospital) could recently show that LSD1 exhibits an essential function in haematopoietic and progenitor cells. The results imply that efficient pharmacological blockade of LSD1 could cause reversible haematological side effects.

The Oncology research programme also includes molecular studies of cellular processes which, if malfunctioning, may lead to the development of cancer. The group of Professor George Iliakis at the Institute of Medical Radiation Biol­ogy trains young scientists as part of DFG-funded Research Training Groups GRK 1431 and 1791 and focuses on the mechanisms of cellular responses to DNA damage. DNA damage, especially DNA double strand breaks (DSB), is generated as a ­result of replication errors, from reactive oxygen species, or by ionizing radiation, and may have grave consequences for the integrity of the genome. Cells have therefore developed an impressive arsenal of repair pathways to preserve genomic integrity by removing DSB. Research activities in Professor Iliakis’ group centre on elucidating these repair mechanisms and analyzing their coordination in the cell cycle. Their findings have been published in high visibility scientific journals, including the respected magazine Science in 2013.

Immunology, Infectious Diseases and Transplantation

The immune system responds to various pathogens, including viruses and bacteria, in ­different ways to prevent severe disease and persistence in the host. Many pathogens, however, have developed mechanisms to evade immune defence. Groups at the ZMB analyze the molecular and cellular interactions of pathogens with the immune system as part of this research programme. The objective is to gain a fundamental understanding of the mutual interaction of pathogens and the immune system, which can then be used to develop strategies for immunotherapy and vaccination. In transplantation, ­research aims to understand triggering of the immune response in order to prevent rejection.

Core themes of research in this area are ­reflected by the objectives of the collaborative ­research projects mentioned above. They are SFB/TRR60 and its Research Training Groups GRK 1045 and GRK 1949. Several of the research highlights from the 2012–2013 period have been published in important journals.

The group of Prof. Carsten Kirschning, Institute for Medical Microbiology, investigates the recognition of bacteria by host cells. Pathogens are detected by cellular sensors, the toll-like receptors (TLR), which recognize molecular patterns of pathogens. An international research team led by Prof. Kirschning analyzed the complex detection of bacteria and found that TLR13 recognizes a specific segment of bacterial ribosomal RNA. The new findings, which were published in Science in 2012, are important for the treatment of bacterial infections and understanding antibiotic resistance. The results could furthermore help in treating immunological overreactions and provide options for new vaccination strategies.

Innate or unspecific immune response belongs, like adaptive immune response, to the spectrum of reactions of the immune system in all organisms to foreign matter or pathogens. The innate immune system limits virus replication on infection. The study of molecular and cellular mechanisms of the immune reaction is the focus of the group of Prof. Karl Sebastian Lang, head of the Institute of Immunology at the UDE.  The group has recently described the mechanism of “enforced viral replication”, which refers to the deliberate replication of viruses in specialized macrophages  in the spleen and lymph nodes. Without enforced viral replication (e. g. in the absence of the specialized macrophages or certain genes), immune activation after infection is limited, which strongly influences the onset of virus-induced diseases. The new findings were published in the renowned journals Nature Immunology and PLOS Pathogens in 2012 and 2013 and provide a basis for further studies within the frame of SFB/TRR60.

Genetics, Developmental, Molecular and Cell Biology

The expertise and research activities of the groups working in this particular programme lie in chromosome organisation, gene expression, gene silencing, cell biology, cellular interactions, ­developmental biology, and clinical and molecular genetics. Their main topics are reflected in the objectives of the collaborative research projects mentioned above. The international visibility and recognition of ZMB research in this area is documented by publications in prestigious science journals.

The group of Prof. Hemmo Meyer (Molecular Biology I, ZMB) focuses on the function of a ­molecular nano-machine in human cells, termed VCP/p97, which facilitates the controlled disposal of cellular components in processes that are ­relevant for degenerative diseases and genomic stability. Their research has recently revealed a mechanism that forms the basis of a human muscle disease and contributed to understanding aspects of the cellular response to DNA damage.  Current efforts form part of the DFG Research Training Groups GRK 1431 “Transcription, Chromatin Structure and DNA Repair in ­Development and Differentiation” and 1739 “Molecular determinants of the cellular radiation response and their potential for response modulation”, the newly established Collaborative ­Research Centre SFB 1093 “Supramolecular Chemistry on Proteins” and the national DFG Priority Programme SPP1365 “The Ubiquitin Family Network”. In 2013, Prof. Meyer organized the EMBO workshop “AAA+ Proteins – from mechanism and disease to targets”, which brought together leading scientists from top institutions worldwide.

Prof. Anke Hinney leads the group for Molecular Genetics at the Department of Child and Adolescent Psychiatry, Psychosomatics and ­Psychotherapy at the UDE. The group explores the molecular genetic basis of early-onset extreme obesity, eating disorders and attention deficit/hyperactivity disorder (ADHD). It is engaged in relevant competence networks such as the Obesity Network, which was BMBF funded within the National Genome Research Network (NGFN) and coordinated by Prof. Johannes Hebebrand (UDE). Research highlights include participation in studies to identify gene loci associated with obesity or leading to identification of a gene associated with an increased risk of ADHD in children. The studies were published in Nature Genetics and Molecular Psychiatry in 2012.

Research at the Institute for Human Genetics led by Prof. Bernhard Horsthemke considers questions of clinical and molecular genetics.

The Institute is currently engaged in nationwide networks to advance highly relevant topics in medicine. Prof. Horsthemke coordinates the BMBF “Network Imprinting Diseases” project and since 2012 his group has been contributing to the BMBF’s German Epigenome Programme (DEEP). The programme is receiving 16 million euros in funding. 1.5 million euros are allocated to the institution in Essen in the five-year timeframe. Award of the grant reflects the expertise of the Human Genetics unit in Essen in DNA methy­lation as well as its state-of-the-art equipment for next-generation sequencing and genome bioinformatics.

Prof. Gunther Wennemuth, head of Anatomy at the University Hospital, became a new member of the ZMB in 2013. His research focus is on the study of the signal transduction pathways and signalling molecules that play an essential role in male and female reproduction. One projectis dealing with bicarbonate and its role in activating sperm. The group successfully identified membrane-localized and cytoplasmic carboanhydrases as key enzymes of sperm motility.

Another main topic of research concerns the search for oncogenes relevant in the pathogenesis of prostate carcinoma.

Biomolecular Structure and Function

The Biomolecular Structure and Function research programme combines expertise in biochemistry, biophysics, and chemical synthesis to elucidate molecular structures and interactions at atomic resolution, and to develop molecules that specifically interact with biological factors for use as research tools or leads for future medical drugs.
The goals of the research programme are ­represented by the Collaborative Research Centre “Supramolecular Chemistry on Proteins” and the Research Training Groups GRK 1431 and 1739.
Protein homeostasis is one key topic. It comprises control and repair mechanisms that have evolved in nature to ensure that all proteins are biologically active, localized to the proper cellular compartment and present in appropriate quantity. This functional state must be maintained under normal conditions as well as under stress. The failure of quality control can influence cell growth and cause severe diseases ranging from bacterial infections to neurodegenerative and arthritic diseases or cancer. One protein family, the HtrA serine ­proteases, is a focus of their research. hHtrA is a bifunctional protein, exhibiting protease and chaperone activity. By definition HtrA protein family members contain one catalytic unit and at least one domain, the so-called PDZ domain, which mediates the interaction with other proteins. Recent investigations in the Department of Microbiology and a group of researchers under Prof. Michael Ehrmann have produced new information on the mechanism of action of PDZ proteases. For the protease DegQ the group was able to show that protein repair and degradation proceed simultaneously in a hollow “reaction chamber”, independent of energy. Crystal structure analysis of another protease, CtpB, in different states of ­activity showed the molecular mechanism of signal transduction, which controls spore formation in Gram positive bacteria, at atomic resolution. The work was published in Nature Structural Biology and in Cell in 2013.

The Department of Structural and Medical Biochemistry headed by Prof. Peter Bayer is engaged with other partners in the BMBF project “Structure based design of MRI probe molecules for the highly sensitive detection of metastases”. The group succeeded in designing a protein-based MRI contrast agent for tumour diagnostics. A patent was filed on the probe and its clinical application.
In collaboration with the University of ­Aberdeen (GB), the mechanism of penetration of Oomycetes such as Phytophtera or Saprolegnia into their host was deciphered. Sulfated protein receptors serve as an anchor for docking and penetration. The data were published in the ­renowned science journal Proceedings of the ­National Academy of Science (PNAS) in 2012.
The Bioinformatics research group (Prof. Daniel Hoffmann) has developed new methods of computational diagnostic characterization of HIV-1 in the BMBF-funded collaboration “Corus: Co­receptor usage as a marker for specific HIV ­diagnostics with high sensitivity”. Currently, the virus-related research of the group in the trans­regional collaborative centre SFB/TRR60 focuses on computational sequence analysis of Hepatitis C Virus (HCV) ­genomes to pinpoint interactions between the virus and the immune system.

The interdisciplinary makeup of the ZMB as the representative of the Main Research Area of Biomedical Sciences is further consolidated by three members from the Center for Nanointegration (CENIDE). The group leaders, Professors Stephan Barcikowski and Matthias Epple and Dr. Nils Hartmann, are working on the development of new materials for medicine and medical technology based on nanotechnology. As just one example, Prof. Matthias Epple and his team have developed a nano-calcium phosphate paste for the treatment of bone defects.