DNA mutations driving cancer development are caused by different mechanisms, each of them leaving behind specific patterns, or “scars” in the genome. Using CRISPR-Cas9 technology, researchers at CeMM and the Wellcome Trust Sanger Institute at Cambridge, UK were able to show for the first time in cell culture that specific genetic alterations indeed lead to the predicted pattern of mutational signatures observed in human cancers. The results were published in Nature Communications (DOI: 10.1038/s41467-018-04052-8).
When a cell develops into a tumor, something has gone terribly wrong: the uncontrolled growth, invasion of nearby tissues and finally metastasis are the result of many consecutive DNA mutations. Such an accumulation of demolished genetic material often derives from initial environmental exposures, enzymatic activities or defects in DNA replication or DNA repair mechanisms. Each of those initial mutagenic conditions creates their own pattern of DNA damage called mutational signature. Deciphering them could theoretically allow us to trace back the initial cause of a tumor, profile its properties and help find a therapeutic strategy.
However, reading those mutational signatures in tumor samples is a difficult task, as the large amount of mutations that a patient acquires during its lifetime create a noisy and uncontrolled system – even the best clinical data will, at most, provide only associations. Therefore, the group of Joanna Loizou, Principal Investigator at CeMM in collaboration with researchers from the Wellcome Trust Sanger Institute, developed an experimental setup to validate the concept of mutational signatures in cell culture.
The findings of this study not only confirm an analytical principle that describes mutational processes and cancer development, mutational signatures are a direct mechanistic read-out of specific dysfunctions of a cell. Thus, even if the underlying gene defect is unknown, mutational signatures could be used as biomarkers for the molecular characterization of tumors – a new diagnostic tool to improve the precise and personalized treatment of cancer.
Xueqing Zou*, Michel Owusu*, Rebecca Harris, Stephen P. Jackson, Joanna I. Loizou#, Serena Nik-Zainal# (*These authors contributed equally to this work # Corresponding authors). Validating the concept of mutational signatures with isogenic cell models. Nature Communications 9, 2018. DOI: 10.1038/s41467-018-04052-8.
The study was funded by the Austrian Academy of Sciences, the European Commission (Marie-Curie Career Integration Grant), the Austrian Science Fund FWF and the Wellcome Trust.
The 8th CeMM S.M.A.R.T. Lecture held by architect and urban design consultant Jan Gehl was exceptionally entertaining and inspiring. It illustrated with many captivating examples the problems cities developed in the 20th century by pursuing an object- instead of a people-centered city planning and how simple measures can make cities livable.
“We knew more about the natural habitat of the mountain gorilla or the Siberian tiger than about the Homo sapiens’ living space” – with this provoking citations, Jan Gehl displayed the vast lack of knowledge that lead to some of the 20th centuries biggest challenges for modern cities. By building in an objects- and road-focused manner, a typical approach for the era of modernism and “motorism” in architecture, urban planners forgot about creating livable spaces for people. Instead, huge buildings and vast roads were built for cars, a now outdated and inefficient transportation technology, as Jan Gehl pointed out.
In consequence, many modern cities today are not only ugly and unpleasant to live in, but also unhealthy. The emphasis on mobility, meaning the use of automobiles, lead to the so-called “sitting syndrome”, a lack of physical exercise that has become a mayor health threat. To counteract those developments, Jan Gehl pioneered an observation-based city planning by systematically documenting urban spaces, making gradual incremental improvements, then documenting them again.
His results are impressive: measures like banning cars from city centers, creating extensive and coherent biking lanes and designing nice and “sticky” places that people like to use, turned Copenhagen, where Jan Gehl was involved in the urban planning for over 40 years, from a car-dominated city into one of the most livable places in the world. Many other cities, including New York and Moscow, sought advice from Jan Gehl and improved their urban space with his help.
A crowded seminar hall at CeMM with an audience of somewhat 150 people with all kinds of backgrounds followed this S.M.A.R.T. Lecture eagerly and engaged in lively discussions afterwards. Artist, architects, city planners and scientists met Jan Gehl in the brain lounge for an intense discussion round. We are proud, honored, and most thankful that Jan Gehl followed our invitation, and supports our efforts to foster the interdisciplinary discourse, widen our horizons and establish a dialogue with the broader public. The quality of our research is strongly influenced by the quality of our environment and creativity flourishes in inclusive, integrative and livable cities.
His take home message will remain firmly etched into our memories: The world is not about getting from A to B, the world is about having nice places to be!
Lymphocytic choriomeningitis virus (LCMV) served as an indispensable model system for chronic viral infections over the last 80 years; two Nobel prizes were awarded for its exploration. However, the molecular interactions during the life cycle of the virus were hitherto poorly understood. In a new study, published in PLOS Pathogens, CeMM scientists revealed the comprehensive set of cellular proteins that physically interact with the LCMV polymerase – a key enzyme for the development of a chronic infection.
Chronic viral infections like HIV or hepatitis are among the biggest threats to human health worldwide. While an acute viral infection usually results in a full recovery and effective immune memory, chronic viruses evade the immune system and remain permanently in their host´s body. Treating such a disease is a difficult task, as the molecular events during the development of a chronic infection remained largely elusive.
With their latest study published in PLOS Pathogens (DOI 10.1371/journal.ppat.1006758) the team of Andreas Bergthaler, Principal Investigator at CeMM, in cooperation with the University of Basel and the MRC Laboratory of Molecular Biology Cambridge made an important contribution to the understanding of chronic viral infections: the scientists established the first comprehensive overview of cellular proteins interacting with the LCMV polymerase, a crucial enzyme for the replication of the virus and for chronic infection. By mapping them in the human proteome, they revealed various viral strategies and potential targets for future antiviral therapeutics.
In order to perform the study, the researchers – with CeMM PhD student Kseniya Khamina as first author – developed a novel approach to tag viral proteins. Therewith, the interactions of the LCMV polymerase with the proteins of the host cells were determined. Combined with publicly available data from other RNA viruses’ polymerase interactomes, the generated dataset allowed a mapping of the cellular pathways targeted by different viral polymerases. Some of the proteins found to interact with the LCMV polymerase turned out to be essential for the viral life cycle.
Kseniya Khamina, Alexander Lercher, Michael Caldera, Christopher Schliehe, Bojan Vilagos, Mehmet Sahin, Lindsay Kosack, Anannya Bhattacharya, Peter Májek, Alexey Stukalov, Roberto Sacco, Leo C. James, Daniel D. Pinschewer, Keiryn L. Bennett, Jörg Menche, and Andreas Bergthaler. Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein. PLOS Pathogens, December 20, 2017. DOI: 10.1371/journal.ppat.1006758
The study was funded by the City of Vienna and the Austrian Academy of Sciences.
We congratulate Barbara Mair to the highest possible honor for achievements in university studies - the promotion sub auspiciis praesidentis rei publicae, Alexander Van der Bellen. The ceremony was held in the Van Swieten Hall of the Medical University of Vienna.
Straight A´s from high school until the end of the doctorate, graduation within a given time scale, accompanied by exemplary moral character – in order to qualify for the honor of a promotion sub auspiciis praesidentis, an individual has to meet the highest possible demands. Since 1952, slightly more than 1000 students graduated sub auspiciis. Barbara Mair now belongs to this academic elite, as well as Eliana Montanari, former PhD Student at the Medical University of Vienna, who was also honored today.
Federal President Alexander Van der Bellen presented the graduates with the gold ring, engraved with the words "sub auspiciis praesidentis" and the emblem of Austria, as a sign of recognition from the Republic of Austria. In his speech, he expressed his admiration for the exceptional endurance and curiosity, which are necessary – besides exceptional talent and intelligence – for such outstanding achievements. Rector of the Medical University Markus Müller, who himself graduated sub auspiciis, welcomed the audience with a brief historical overview of the sub auspiciis tradition.
CeMM Scientific Director Giulio Superti-Furga emphasized in his laudation Barbara Mair’s stellar impression she made from the very first moment: she applied for a PhD position at CeMM with an already impressive CV, especially with respect to her achievements and top grades during high school and undergraduate studies, with distinction in Molecular Biology (Mag.rer.nat.) and in Spanish literature and linguistics (BA). In 2011, she started her Ph.D. studies at CeMM, in Sebastian Nijman’s group as the top ranked student from over 400 applicants and continued to impress with her sharp and critical intellect paired with ambition, diligence, persistence, and hard work. Barbara stayed at CeMM until Sebastian Nijman’s lab moved to Oxford (December 2014), still registered with Medical University of Vienna continued her studies. Barbara completed her PhD with an excellent thesis and an impressive public defense of her work. Her ambition also expands into her spare time, where she – among others - competes in Austria’s and Great Britain’s first and second handball leagues and won the All British University Handball Championships in 2016.
We are more than proud, and want to express our warmest congratulations to Barbara Mair her truly exceptional achievements!
Congratulations to Giulio Superti-Furga, CeMM´s Scientific Director, Miriam Unterlass, Technical University of Vienna, and Stefan Kubicek, CeMM for winning one of the WWTF 2017 Life Science Grants on Chemical Biology. In the project called “3C - Cellular color chart” the research team aims to generate new fluorescent molecules that probe intracellular processes with a full molecular understanding of their biological specificity.
This proposal is made possible by the existing expertise and infrastructure of the project partners. The laboratories of Giulio Superti-Furga and Stefan Kubicek, especially the Platform Austria for Chemical Biology at CeMM, have extensive experience in the handling of compound libraries and phenotypic screening using automated high-content microscopy. And Miriam Unterlass is an expert in chemical synthesis and provides knowledge and infrastructure for the efficient generation of analogs of the fluorescent molecules identified from chemical screening. CeMM is looking forward in entering this research collaboration with a member from the Technical University of Vienna.
Giulio Superti-Furga, CeMM
Miriam Unterlass, TU Vienna
Stefan Kubicek, CeMM
The next PhD Program at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna will start in October 2018. We offer 15 fully funded PhD positions and are looking for exceptionally motivated PhD candidates with a keen interest in genomics, medicine and interdisciplinary teamwork.
+++ Apply now! The application deadline is 2nd February 2018 +++
The 2018 CeMM PhD Program will focus on the thematic areas of Infection, Immunity, Metabolism, Cancer and Network Medicine. These areas are built on the pillars of epigenetics and genome integrity, bioinformatics and systems biology, chemical biology, high-throughput genetics, genomics and proteomics, and molecular and cell biology.
CeMM is an international research institute of the Austrian Academy of Sciences. The mission of CeMM is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an international and creative team of scientists and medical doctors pursues free-minded, basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM operates in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future.
CeMM is located at the center of one of the largest medical campuses in Europe, within walking distance to Vienna’s historical city center. Vienna is repeatedly ranked as the world’s best city to live in and is a United Nations city with a large international, English-speaking community. The official language at CeMM is English, and more than 40 different nationalities are currently represented at the institute.
The successful candidates will be awarded a generous scholarship, which covers all research costs, university fees, work-related travel expenses, salary and health insurance for 4 years. The PhD degree will be awarded by the Medical University of Vienna.
To be eligible to enroll in the CeMM PhD Program, all candidates are required to have a final degree (minimum requirement is a four-year Bachelor’s degree) in medicine, biology, chemistry, bioinformatics, computer science, engineering, physics, mathematics or a similar subject. The working language at CeMM is English, i.e. excellent written and oral communication skills in English are mandatory.
For further information about the PhD Program, and to apply through the online system, please visit:
What impact do the nuclear components of metabolism have on gene expression? And how does the distribution of metabolites contribute to the emergence of cancer? To answer those key questions, a Consolidator Grant of the European Research Council ERC was awarded to Stefan Kubicek, Principal Investigator at CeMM.
Genes need to be controlled. This very basic principle for a well-functioning cell – and thus a healthy organism – has been investigated thoroughly during the last decades. Huge progress in disciplines like epigenetics has revealed that in the cell´s nucleus various kinds of biomolecules are highly compartmentalized to occupy distinct regions of the chromatin – the material chromosomes are made of – and contribute to the regulation of genes. In contrast, small molecules and cellular metabolites are generally considered to lack a distinct subnuclear localization and not directly influence gene expression.
This assumption is challenged by Stefan Kubicek, Principal Investigator at CeMM: based on preliminary results from his laboratory, he hypothesizes that chromatin-bound enzymes of central metabolism and subnuclear metabolite gradients contribute to gene regulation and cellular identity – and also to the emergence of cancer. To address this hypothesis, Stefan Kubicek was awarded with a ERC consolidator grant with the project title “chromabolism” (from chromatin and metabolism) worth ~2 Million Euro.
Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein’s group at the IMP in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010, and is also head of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives.
Principal Investigators at CeMM so far received 2 ERC Advanced Investigator Grants, 4 ERC Starting Grants and 2 Proof of Concept Grants. Stefan Kubicek is now awarded with CeMM’s first ERC Consolidator Grant. ERC Consolidator Grants are designed to support excellent Principal Investigators at the career stage at which they may still be consolidating their own independent research team or programme. Applicant Principal Investigators must demonstrate the ground-breaking nature, ambition and feasibility of their scientific proposal. Consolidator Grants may be awarded up to a maximum of 2 Million Euro for a period of 5 years. erc.europa.eu/funding/consolidator-grants
The severe and debilitating genetic disease Xeroderma pigmentosum impedes cells to repair UV-induced DNA damage. Scientists from CeMM found a drug approved for diabetes treatment to alleviate the impact of the gene defect in cell culture, which led to the discovery of a previously unknown DNA repair mechanism. The study was published in Molecular Cell.
The destructive force of UV radiation on DNA molecules is only fully visible, when repair mechanisms fail: patients with the rare genetic disease Xeroderma pigmentosum – also known as “Moon children’ - develop inflammations upon exposure to only small amounts of sunlight, rough-surfaced growths and eventually skin cancer occurs often in early age. The severe condition is caused by mutations in the genes for the nucleotide excision repair (NER) pathway – the only known mechanism that deals with UV-induced DNA damage in human cells. Although first described in 1874, Xeroderma pigmentosum to date lacks any curative treatment.
Led by Joanna Loizou, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and together with collaborators from the Medical University of Vienna and the IRB Barcelona, the scientists at CeMM found in their most recent publication that the FDA-approved diabetes drug acetohexamide significantly improves the resilience of NER deficient cells against UV radiation in vitro. Above that, the study published in Molecular Cell (DOI: 10.1016/j.molcel.2017.10.021) identified the responsible molecular mode of action – a hitherto unknown, NER-independent repair mechanism for UV-induced DNA damage. The study has not tested the use of acetohexamide in Xeroderma pigmentosum patients.
For their study, the scientists of Loizou’s team developed a special chemical screening approach for compounds that would allow Xeroderma pigmentosum-disease cells to survival UV treatment better. Using the CLOUD (Cemm Library of Unique Drugs), this approach led to the identification of acetohexamide: By treating Xeroderma pigmentosum-disease cells with the diabetes drug, these cells could now repair UV-induced DNA damage more efficiently. A multitude of subsequent experiments eventually led to the elucidation of the underlying molecular mechanism: acetohexamide leads to the degradation of the DNA repair enzyme MUTYH, triggering an hitherto unknown NER-independent mechanism for removing UV-induced DNA damage.
Abdelghani Mazouzi, Federica Battistini, Sarah C. Moser, Joana Ferreira da Silva, Marc Wiedner, Michel Owusu, Charles-Hugues Lardeau, Anna Ringler, Beatrix Weil, Jürgen Neesen, Modesto Orozco, Stefan Kubicek and Joanna I. Loizou. Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Molecular Cell, November 16, 2017. DOI: 10.1016/j.molcel.2017.10.021
The study was supported by the Austrian Academy of Sciences, the European Commission, the Austrian Science Fund, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development, the Spanish Ministry of Science the Catalan Government, the Instituto de Salud Carlos III-Instituto Nacional de Bioinformática, and the European Research Council ERC.
Researchers at CeMM and the Medical University of Vienna presented a preliminary report published in The Lancet Hematology on the clinical impact of an integrated ex vivo approach termed pharmacoscopy. The interims analysis of the first-ever clinical trial with the approach shows that pharmacoscopy can assist decision-making of the responsible clinicians effectively and thus represent a powerful tool for practical precise and personalized medicine.
Patients suffering from refractory and relapsed blood cancers often have few treatment options and short survival times. At this stage, identifying effective therapies can be challenging for doctors. Even state-of-the-art genetic analyses, due to the high heterogeneity of cancer cells and the impact of the various mutations on their drug response, do often not suffice to instruct personalized treatments. Pharmacoscopy, a technology developed by scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and tested for its clinical efficacy by clinicians of the Medical University of Vienna, offers a functional approach: hundreds of drug options can be quickly pre-tested ex vivo in small liquid biopsy samples collected from individual patients.
The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy. In combination with specially developed analysis methods and machine learning and other unique algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first presented last April in Nature Chemical Biology (doi:10.1038/nchembio.2360).
While the clinical study is still recruiting, interim analysis of the program showed that 88.2% of the patients recruited (15 out of 17) who received pharmacoscopy-monitored personalized therapies achieved partial or complete remission, while only 23.5% (4 out of 17) responded similarly well to their previous respective treatments.
In addition, the median progression-free survival of patients who were treated in accordance to pharmacoscopy-guided therapy increased from 5.7 week to 22.6 weeks compared to their last line of treatment. Further, in a retrospective study organized to specifically determine the ability of the method to stratify responding and non-responding newly-diagnosed patients with acute myeloid leukemia (AML), resulted in 90% accuracy. Before, such accuracy in prediction of treatment outcome was unachievable, with or without genetic assays.
Berend Snijder*, Gregory I Vladimer*, Nikolaus Krall, Katsuhiro Miura, Ann-Sofie Schmolke, Christoph Kornauth, Monika Sabler, Oscar Lopez de la Fuente, Hye-Soo Choi; Emiel van der Kouwe; Sinan Gültekin, Lukas Kazianka, Johannes Bigenzahn, Gregor Hörmann, Nicole Prutsch, Olaf Merkel, PhD; Anna Ringler; Georg Jeryczynski, Marius Mayerhöfer, Ingrid Simonitsch-Klupp, Katharina Ocko, Franz Felberbauer, Leonhard Müllauer, Gerald W Prager, Belgin Korkmaz, Lukas Kenner, Wolfgang R Sperr, Robert Kralovics, Heinz Gisslinger, Peter Valent, Stefan Kubicek, Ulrich Jäger, Philipp B Staber, and Giulio Superti-Furga. (*co-first authors) Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study. The Lancet Haematology, November 13, 2017. DOI: 10.1016/S2352-3026(17)30208-9
The study was supported by the European Research Council (ERC), the Austrian Science Fund (FWF), Austrian National Bank, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology and Development, the MPN Research Foundation, the Swiss National Science Foundation and the European Molecular Biology Organization (EMBO)
Defective DNA repair mechanisms can lead to diseases like Fanconi anemia. Utilizing a concept called “synthetic viability”, researchers at CeMM, in international collaboration, found additional gene disruptions that rescue the phenotype of this disease in cell culture and identified the responsible protein complex. The study, published in Nature Communications, intriguingly demonstrates the potential of synthetic viability screens to identify genetic interactions rescuing cells with defects in the DNA damage response.
Sunlight, cellular metabolism or simply faulty DNA replication: DNA damage occurs tens of thousands of times per day in every cell of the body. Hence, a whole arsenal of molecular machineries stand by to repair various forms of damage and maintain cellular function. If those repair mechanisms fail, it can lead to serious diseases, as in the case of the Fanconi anemia pathway: named after the disease, it´s failure leads to impaired repair of DNA interstrand crosslink damage.
The research group of Joanna Loizou at CeMM, in international collaboration, showed with a so-called “synthetic viability” screen that cells with defects in the Fanconia anemia pathway can be rescued by introducing additional genetic defects, targeting genes of the BLM helicase complex. The study was published in Nature Communications (DOI: 10.1038/s41467-017-01439-x).
Using CRISPR/Cas9, the scientists produced a library of viruses able to disrupt almost all of the genes in the human genome individually. Millions of cells with Fanconi anemia defect were infected with those viruses, introducing a single additional gene defect in each cell. Subsequently, DNA interstrand crosslink damage was generated – the kind of DNA damage that should kill the diseased cells. With a high throughput assay, the researchers searched for cells that survived better after disrupting additional genes and found that upon loss of a functional BLM helicase complex, cellular survival of Fanconi anemia cells was increased and the cells behaved more like healthy ones.
This work demonstrates that genome-wide CRISPR/Cas9 screens are suitable to identify genetic “synthetic viable” interaction partners that increase the survival of cells with defective DNA damage repair mechanisms. Above that, the now published study clearly shows that the loss of both components (BLM & Fanconi anemia pathway) is less detrimental for cells than a deficiency of only the Fanconi anemia pathway – an important contribution to the elucidation of this rare genetic disease.
Martin Moder*, Georgia Velimezi*, Michel Owusu, Abdelghani Mazouzi, Marc Wiedner, Joana Ferreira da Silva, Lydia Robinson-Garcia, Fiorella Schischlik, Rastislav Slavkovsky, Robert Kralovics, Michael Schuster, Christoph Bock, Trey Ideker, Stephen P. Jackson, Jörg Menche and Joanna I. Loizou. Parallel genome-wide screens identify synthetic viable interactions 3 between the BLM helicase complex and Fanconi anemia. Nature Communications, November 1st, 2017. DOI: 10.1038/s41467-017-01439-x.
This study was supported by the European Molecular Biology Organization (EMBO) and the Austrian Science Fund (FWF).