Epigenetic modifications are an important factor in cancer development and a promising target for its treatment. With red glowing cells, CeMM researchers in collaboration with groups at Oxford University and IMP Vienna found new small molecules, which trigger specific epigenetic modifications and thus are promising compounds for the treatment of blood born cancers. Their study was published in Nature Chemical Biology.
For Stefan Kubicek, red light means hitting the bull´s eye: His research group at CeMM developed fluorescent cell lines which signal the inhibition of specific epigenetic modifications by bright red radiance. When a substance behaves like a so-called “BRD4 bromodomain inhibitor”, those engineered cells start to glow. Nearly 90.000 chemical compounds could be tested by this method in CeMM’s highly automated facilities, 22 out of them showed BRD4 bromodomain inhibitor-like properties. Notably, this set contained all previously known BRD4 inhibitors, plus 13 novel chemical structures.
The two most promising novel compounds were examined in detail – one of them turned out to be a promising candidate for future cancer therapies. It affects a protein called TAF1, which has not previously been linked to BRD4 biology. “We could show that TAF1 directly interacts with BRD4 and that our new TAF1 inhibitor has the same effect as a BRD4-inhibitor” says Sara Sdelci, PostDoc in Kubicek’s Lab and first author of the study.
In further studies, Stefan Kubicek’s team, in collaboration with Susanne Müller and Stefan Knapp from Oxford University, Johannes Zuber from the Vienna Institute for Molecular Pathology (IMP), Giulio Superti-Furga and Christoph Bock from CeMM, could show that TAF1 inhibitors and BRD4 inhibitors synergize in leukemia cells. When the newly discovered compound is used in combination with BRD4 Inhibitors, its cancer-killing effect is strongly increased.
Sara Sdelci, Charles-Hugues Lardeau, Cynthia Tallant, Freya Klepsch, Björn Klaiber, James Bennett, Philipp Rathert, Michael Schuster, Thomas Penz, Oleg Fedorov, Giulio Superti-Furga, Christoph Bock, Johannes Zuber, Kilian V. M. Huber, Stefan Knapp, Susanne Müller and Stefan Kubicek. Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk. Nature Chemical Biology. DOI: 10.1038/nchembio.2080
This project was supported by SFB grant F4710 of the Austrian Science Fund (FWF). Sara Sdelci acknowledges support by JDRF postdoctoral fellowship 3-PDF-2014-206-A-N “Reprogramming by Loss of Function”.
Emmanuelle Charpentier held the 10th CeMM Landsteiner Lecture on May 6, 2016, in the festive hall of the Austrian Academy of Sciences, which was filled up to the last place. Her magnificent talk on the CRISPR technology delighted scientists and lay audience alike and was also broadcasted via live stream.
"A fast and easy tool was needed - and that's was CRISPR brought. The CRISPR-Cas technology allows precise gene surgery in any cell and organism" – with those almost casual sounding phrases, Emmanuelle Charpentier summed up her discovery which has revolutionized biomedical research within only a few years and will have a fundamental impact on the future of medicine. In front of some four hundred people, she explained the molecular basis of this ingenious genetic tool and the story of its development.
Welcomed by Anton Zeilinger, President of the Academy, and introduced by Giulio Superti-Furga, CeMM Director and initiator of the Landsteiner Lecture Series, Emmanuelle Charpentier’s talk was an extraordinary event in the baroque hall of the Academy. With the musical framework provided by the ensemble “Karat-Apart” and the subsequent cocktail reception, the 10th CeMM Landsteiner Lecture was in every aspect a memorable and joyful jubilee.
We would like to thank Emmanuelle Charpentier for coming to Vienna to give this wonderful lecture, and also for taking her time to spend a day at CeMM. Her energetic personality, as well as her unswerving dedication to science left an unforgettable and remaining impression to all of us. Thank You Manue!
About the CeMM Landsteiner Lecture: Once a year, usually at the beginning of May, CeMM is organizing its Karl Landsteiner Lecture for the scientific community and an interested lay audience. It is named after the Viennese discoverer of the blood groups and is given by a prominent scientist whose molecular research has a strong impact on medicine. The lecture is held in the stunning 18th century frescoed festive hall of the Austrian Academy of Sciences (where Haydn and Beethoven conducted premieres of their work) and is accompanied by a small ceremony, music and a cocktail. Former CeMM Landsteiner lecturer: 2007 John Kuriyan, University of California; 2008 Kari Stefánsson, deCODE Genetics; 2009 Vishva Dixit, Genentech Inc.; 2010 Helen Hobbs, University of Texas; 2011 George Daley, Howard Hughes Medical Institute Boston; 2012 Ruslan Medzhitov, Yale University; 2013 Hans Clevers, Hubrecht Institute Utrecht; 2014 David Sabatini, MIT; 2015 Laurie H. Glimcher, Weill Cornell Medical College NY; 2016 Emmanuelle Charpentier, Max Planck Institute for Infection Biology Berlin;
Extracting DNA of strawberries, observing your own cells under the Microscope or building “DNA strands” with gummy bears: The CeMM booths at the long night of science presented molecular medicine’s basics and methods in an interactive and playful way – especially to children.
On Friday, 22nd of April, the seventh “long night of science” / “Lange Nacht der Forschung”, organized by the Federal Ministry of Science, Research and Economy, took place all over Austria. In Vienna, CeMM was represented in two different places: The Ministry’s tent at the Heldenplatz, and the Medical University at the AKH campus. While in the first district the focus was on CeMM, at the Medical University of Vienna, Genom Austria was presented to the public, as well as the Center for Rare and Undiagnosed Diseases (CeRUD).
In the tent of the Ministry our Scientific Director, Giulio Superti-Furga, gave a talk on the Genom Austria project in front of some hundred and fifty people, emphasizing the importance of an open discussion about genome sequencing and its impact on medicine, culture and society. Meanwhile, Principal Investigator Christoph Bock and PostDoc Matthias Farlik talked about the project at the Medical University in front of a well-filled auditorium. We were amazed by the curiosity and interest of our audience, the willingness to participate in our games and to discuss basic science, new technologies and precision medicine with us. It was a wonderful opportunity to present our daily work, the relevance of the CeMM projects and our future goals to a broad public.
The long night of science was a huge success – more visitors than ever attended this year´s event, our booths on both sites were crowded with spectators and participants, and our games and hands-on science enthused young and older visitors alike. We are very grateful to the CeMM helpers, and appreciate the interest of so many visitors who will hopefully continue to support science and stay connected with CeMM.
DNA damage frequently occurs during cell division, its repair is essential for survival for every organism. Scientists at CeMM have now discovered new mechanisms that maintain genetic material during cell division. Their study was published in Cell Reports and provides new potential approaches for cancer and Alzheimer's therapy.
Reproducing is stressful, a fact well-known to all parents. Yet, it also applies to the smallest units of life: The cells. Each cell division requires a duplication of its entire genetic material, frequently resulting in damage to the enormous DNA molecules – the cell is experiencing "replication stress". In collaboration with the Max Planck Institute of Biochemistry in Martinsried, Germany, the University of Sheffield, UK, and the John Hopkins University School of Medicine in Baltimore, USA, Joanna Loizou, Principal Investigator at CeMM, and her team have now discovered previously unknown mechanisms that protect cells from damage.
Previous experiments have shown that ATM, a kinase that is actually known for other DNA repair processes, also plays a decisive role in DNA repair during replication. This discovery led the scientists to trace the precise reaction paths of ATM and its cofactor ATMIN within a large-scale study. With resounding success: "For the first time, the complete workings of this important kinase and its activation protein is now understood," says Joanna Loizou. For her study, the scientist and her team compared both the complete RNA set – and thus the gene activity – as well as all proteins from cells that were missing the gene for ATM or its activation protein ATMIN with RNA and proteins from normal cells.
"We were able to examine the functionality of ATM and ATMIN in a very unbiased manner based on these enormous datasets," emphasised Joanna. "We have gained insights in proteins involved in cancer and Alzheimer's disease." One result was of particular interest: ATMIN chemically changes a protein (CRMP2) in the same manner as observed in the nerve cells of Alzheimer's patients. “It is well-known that neurodegenerative diseases are frequently associated with an accumulation of DNA damage in the brain. Thus, an interesting connection between ATMIN and Alzheimer's disease has been established that can perhaps help us better understand disease progression," says PhD student Abdelghani Mazouzi, first author of the study.
Abdelghani Mazouzi, Alexey Stukalov, André C. Müller, Doris Chen, Marc Wiedner, Jana Prochazkova, Shih-Chieh Chiang, Michael Schuster, Florian P. Breitwieser, Andreas Pichlmair, Sherif F. El-Khamisy, Christoph Bock, Robert Kralovics, Jacques Colinge, Keiryn L. Bennett, and Joanna I. Loizou. A Comprehensive Analysis of the Dynamic Response to Aphidicolin-Mediated Replication Stress Uncovers Targets for ATM and ATMIN. Cell Reports 15, 1–16. DOI: http://dx.doi.org/10.1016/j.celrep.2016.03.077
This study was partly funded by the Austrian Science Fund FWF and a DOC fellowship from the Austrian Academy of Sciences.
Giulio Superti-Furga, scientific director at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor of Medical Systems Biology at the Medical University of Vienna is to receive the Advanced Investigator Grant of the European Research Council ERC in the amount of approximately 2.5 million euro. The term for the prestigious grant is 5 years.
"ERC Grants are the most important promotions for life sciences in Europe. Unfortunately, the situation is becoming increasingly competitive due to budget cuts," says Giulio Superti-Furga who has built up and is leading CeMM at the campus of the Medical University of Vienna and the Vienna General Hospital: "I am all the more delighted to receive this extraordinary distinction as it also confirms the relevance and quality of CeMM research." The goal of CeMM is to prepare the precise medicine of the future by decoding molecular causes for important diseases such as cancer, inflammation and immune disorders. Giulio Superti-Furga already received an ERC Advanced Grant in 2009 for the exploration of basic immune system mechanisms. In 2011, he also received the first ERC Proof of Concept Grant in Austria.
The molecular system biologist has been granted the present ERC funding for research into existing components in cell membranes that transport dissolved substances into cells. Previous studies have shown that these "cell gates", so-called SoLute Carrier Proteins (SLCs) perform an important task in regulating the cellular metabolism and are responsible for accepting medications. The goal of the research project with the title "Game of Gates" is to decode the previously unknown rules according to which cells open or close their gates, either permitting or preventing the entry of substances. Giulio Superti-Furga: "Thus far, SLCs were treated more or less as second-rate by the scientific community. However, we expect that insights from our study will significantly contribute to a new, fundamental understanding of cellular physiology and thus prepare the way for the development of new, targeted therapies for various illnesses."
The ERC Advanced Investigator Grant is being awarded to Giulio Superti-Furga after two ERC Starting Grants had been given to Andreas Bergthaler and Christoph Bock in the autumn of 2015. Moreover, CeMM Principal Investigator Kaan Boztug won the bid – also in the autumn of 2015 – for founding the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. The "Vienna Research Groups for Young Investigators" grant of the Vienna Science and Technology Fund WWTF had also been awarded to the CeMM PI Jörg Menche. All of these promotions once again emphasize the excellent work being performed at the CeMM.
Excessive LDL cholesterol in the blood is dangerous as it penetrates vascular walls, causes chronic inflammation and leads to atherosclerosis and liver inflammation. A group of antibodies, present in the body from birth, counteracts these inflammations and the resulting illnesses.
A certain group of white blood cells – B-1 cells – work against the life-threatening damage to vessels that can lead to heart attack and stroke: These cells produce naturally occurring antibodies that bind oxidised LDL and neutralise it, disrupting the inflammation. A discovery made by scientists from the lab of Christoph Binder, group leader at the CeMM and Professor for Atherosclerosis Research at the Medical University of Vienna in cooperation with Lars Nitschke from the University of Erlangen and Ronit Shiri-Sverdlov from Maastricht University.
The immune cells also carry a molecular regulator that reduces their activity – the researchers were able to show that the deactivation of this regulator, the so-called 'Siglec-G' protein, caused an increased propagation of B1-cells and antibodies, which protect vessels and the liver from inflammation. This was proven with special laboratory mice that lacked the gene for Siglec-G. In those animals, the development of atherosclerosis, which is frequently accompanied by inflammation of the liver, was massively reduced despite an extremely fat-rich diet and consistently high cholesterol values.
The study clearly shows that increased levels of these naturally occurring antibodies prevent atherosclerosis and inflammation. These mechanisms could be used in a therapy by, e.g., blocking Siglec-G with a specific medication. A completely new and promising approach that strengthens the body's own defensive mechanisms and thus counteracts the deadly consequences of a fatty diet that leads to cardiovascular diseases. The results were published in the journal "Cell Reports".
Sabrina Gruber, Tim Hendrikx, Dimitrios Tsiantoulas, Maria Ozsvar-Kozma, Laura Göderle, Ziad Mallat, Joseph L. Witztum, Ronit Shiri-Sverdlov, Lars Nitschke, and Christoph J. Binder. Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells, Cell Reports
This study was partly funded by the Austrian Science Fund (FWF F43-B09, FWF W1207-B09).
On Tuesday, March 1, Rector Markus Müller, Vice Rector Michaela Fritz, and the CeMM Directors Giulio Superti-Furga and Anita Ender have signed a framework agreement which allows the mutual usage of specific infrastructure and further strengthens scientific collaborations and common projects.
CeMM’s research is strongly oriented towards medical needs and integrates research on fundamental biological processes with clinical expertise to gain new insights into human pathophysiology and develop innovative diagnostic and therapeutic approaches. The research focus is on cancer, inflammation, infection and metabolism. The Medical University of Vienna is the most important research partners of the Austrian Academy of Sciences Institute and plays a key role in the career development of the CeMM students and Faculty. The MedUni Vienna is a highly dynamic research organization, competent in treatment of a very wide area of human ailments with a tradition of innovation going back centuries. It provides a perfect environment for modern research initiatives on precision medicine centered around CeMM’s cutting edge technologies.
Several common projects of strategic importance have already been established between CeMM and the Medical University of Vienna in the past years. A highly productive collaboration has been established over the years with the University Clinic for Internal Medicine I, for example with the pioneering personal medicine project EXACT lead by the chairman Christoph Zielinski, or with very intensive and productive set of studies involving the Clinical Division of Hematology and Hemostaseology, that already resulted in some forty joint publications. Another centerpiece of the CeMM-MedUni Vienna partnership is the joint Biomedical Sequencing Facility (BSF), that is a critical component of most precision medicine initiatives on campus. The Vienna Center for Rare and Undiagnosed Diseases (CeRUD) has been established by the two institutions to pool resources and competencies required to provide individual suffering from rare conditions with the best possible interdisciplinary diagnostic analysis and care. This includes interdisciplinary clinical care involving many disciplines that are represented at the campus of the General Hospital Vienna and the Medical University Vienna and in future will expand to involve a yet larger network of researchers. In 2014 “Genom Austria”, a Personal Genome Projects, has been started to contribute to the public discussion about genomes in science, medicine and society, preparing the cultural ground for informed citizens facing genomic information including and beyond the personalized medicine prospect.
CeMM is looking forward to continuing this highly successful relationship on many more collaborative projects with the clear goal of improving medical practice for the benefit of patients and training researchers in molecular medicine.
From 19th to 20th February 2016, rare and undiagnosed diseases were illuminated from many different angles with a terrific selection of speakers at the first Symposium of the Vienna Center for Rare and Undiagnosed Diseases (CeRUD).
In seven sessions, many important aspects of research, therapeutic options and international collaboration were covered. A rich and diverse poster session allowed insights into ongoing projects and the generous framework program provided an ideal occasion for exchange of the nearly 300 participants. On the previous day, William Gahl, Director of the Undiagnosed Diseases Program of the National Institute of Health (NIH), and Kaan Boztug, Director of CeRUD, double affiliate at CeMM and the Medical University of Vienna, and main organizer of this symposium hosted the 3rd international rare and undiagnosed diseases meeting in an effort to foster worldwide collaboration and data exchange amongst researchers and clinicians.
One of the highlights of the symposium was the keynote lecture of William Gahl. He gave valuable insights in both, the research during the last eight years since the foundation of his program and the progress of the international collaboration network it promotes, with CeRUD as one of the prime drivers and coordinators of these collaborative activities outside of the US. He highlighted the importance of a standardized tool to find the genetic cause of observed phenotypes.
“The symposium was a wonderful opportunity to further tighten this network of experts, create synergies and improve the research and treatment of rare diseases”, says Kaan Boztug. We are certain that this first symposium of Vienna’s Center for Rare and Undiagnosed Diseases was not the last one, and we thank the organizing committee, all speakers, participants and sponsors for their contributions.
The Vienna Center for Rare and Undiagnosed Diseases has been established in 2014 through a joint initiative of the Medical University of Vienna and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, to concentrate biomedical, genetic and technology resources and competencies to advance the rare disease research in Austria and interconnect with the international rare disease network required to provide the affected individuals with the best possible interdisciplinary diagnostic analysis and care.
The sixth call for “Vienna Research Groups for Young Investigators”, a founding programme of the Vienna Science and Technology Fund (WWFT) addresses Vienna based research institutions that intend to hire an excellent young researcher from abroad. This year, it was awarded to Jörg Menche, who will establish a new research group at CeMM to promote the emerging field of network medicine to investigate rare diseases.
The topic of this year´s WWTF´s founding call “Computational Biosciences” appeared all but customized to Jörg Menche´s scientific focus: A theoretical physicist by training, he works since his postdoc period on computational methods to study molecular networks of biological systems that are involved in diseases. The well founded and prestigious grant will help him establish a research group at CeMM to study rare monogenetic and complex human diseases and develop new approaches for precise diagnostics and therapies.
Recent advances in high-throughput technologies like next-generation sequencing of genomes, epigenomes and transcriptomes, proteomics and chemical screening have created exciting new opportunities for this kind of research. The vast amounts of data they produce allow unpresented insights into molecular details of biological systems, but pose simultaneously a big challenge to bioinformatics to exploit its full potential.
Jörg Menche will address that problem with a newly emerging approach called ‘network medicine’: It applies tools and concepts from network theory, a discipline at the interface of mathematics, physics and informatics to analyze the biomedical data produced by high-through put methods. With this approach, Menche and his collaborators at CeMM and the medical university Vienna will study the molecular networks involved in rare diseases, focusing on the relationships between genes, proteins and metabolic processes which differ between healthy and diseased cells.
The scientific education of Jörg Menche started in Leipzig, where he studied physics. His interest in statistical and computational physics lead him to Recife and Berlin before starting PhD with Reinhard Lipowsky at the Max-Planck-Institute for Colloids and Interfaces in Potsdam. He was a postdoctoral fellow with Albert-László Barabási at Northeastern University and at the Center for Cancer Systems Biology at Dana Farber Cancer Institute in Boston. His newly founded group within the highly collaborative and translationally-minded environment at CeMM will prove as immense enrichment for the institute and constitute a broad and substantial contribution to network medicine.
“Thank you” to the organizers of the 2016 Science Ball and Dr. Michael Häupl for hosting the second Ball of Sciences in the City Hall of Vienna. It was again a wonderful event, which we hope will continue in 2017 and beyond. In Vienna, over 400 balls are staged each winter, and the Austrian ball culture has a long tradition. For CeMM, and our special guest, world-famous structural biologist Dr. Nieng Yan from the Tsinghua University in Bejing, it was a highlight of the ball season. It values our profession and the importance of science for society.
We enjoyed very much and promise to come again!