June 04, 2019

Petition #DEALFORSCIENCE: Keep the EU and UK collaborating in science

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EU-LIFE, EuroScience and Wellcome launched a campaign to urge the EU and UK to continue supporting scientific collaboration and to asap sign a research and innovation agreement. www.openpetition.eu/dealforscience  #dealforscience

Researchers need certainty on scientific collaboration between the UK and EU. 
Science has been a key success of the EU and must remain a priority to keep Europe competitive. International collaboration makes science stronger and we should not let Brexit disrupt this.

Researchers need a long-term solution to allow them to continue working together on the big challenges our societies face, transforming peoples’ lives for the better. It’s essential that politicians quickly find a way to keep this collaboration as easy as possible.

We call on the EU and the UK to sign a research and innovation agreement as soon as possible. This should include:

  • A commitment by European countries to work together to make the European Research Area a world leader in science;
  • Full researcher mobility between the UK and the rest of Europe for all levels and career stages;
  • A commitment to collaboration, including UK associate membership of Horizon Europe;
  • Co-operation on regulations that support science.

If you agree with the statement above, please support the petition with your signature, and by disseminating it to your network. www.openpetition.eu/dealforscience

June 03, 2019

Robert Kralovics becoming CeMM Adjunct Principal Investigator

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On June 1st 2019, Robert Kralovics and team members moved to the Medical University of Vienna, to join the Department of Laboratory Medicine (KILM) at the Anna Spiegel Building, which means Robert is now becoming an Adjunct Principal Investigator of CeMM. 

Robert Kralovics was one of the very first internationally recruited Principal Investigators who started at CeMM in June 2006. At that time CeMM was still a virtual institute, with rented lab space, a PhD Program that just started, and a long way to go in terms of reputation and scientific recognition. We are grateful to Robert and his team for taking the risk of joining CeMM at that early stage, and for contributing to its success story, in a scientific sense, but also by being a pioneer and reliable partner in CeMM’s IP and commercialization efforts. 

In 2013, the research group of Robert in collaboration with Heinz Gisslinger´s group at the Medical University of Vienna was able to decode a genetic mutation (CALR, Calreticulin) responsible for about 15% of myeloproliferative neoplasia cases. This newly identified mutation filled the gap in the molecular pathogenesis of MPN and brings hope to many MPN patients. The findings had been published in the New England Journal of Medicine (Klampfl et al, NEJM 2013, DOI: 10.1056/NEJMoa1311347). In 2014, the company QIAGEN obtained an exclusive license from CeMM, and started to develop a diagnostic test for the CALR mutation offering patients/physicians a clearer prognostic profile and guiding disease management. The CALR diagnostic test is highly complementary to QIAGEN’s kits for a key mutation of the Janus kinase 2 (JAK2) gene, therefore a partnership between CeMM and QIAGEN was the preferred solution by both sides from the very beginning. In 2016, QIAGEN and CeMM were able to announce the market launch of the CALR kit. And in December 2015, Robert co-founded the company Myelopro in order to follow up on the therapeutic use of the Calreticulin mutation. 

This is not a goodbye. It is a natural development, as CeMM does not offer tenure. After several years of successful collaboration, our relationship now enters into a new phase. As Adjunct PI, Robert will stay connected with CeMM through its PhD Program, Friday Seminars, Faculty Meetings and established networks and research collaborations. We wish Robert all the best for his new position at the Medical University of Vienna.

May 30, 2019

EU-LIFE Strategy Meeting 2019

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Thanks to the Babraham Institute for hosting the annual EU-LIFE Strategy Meeting, bringing together directors and main representatives from the 13 member institutes. CeMM is a proud member of EU-LIFE, profiting from the exchange of best practices and contributing to European research policy. 

#EULIFEScience #researchexcellence #sciencepolicy
>7000 scientists and support personnel, >500 group leaders, >4000 publications, >100 running ERC Grants

Partner Institutes: CRG Barcelona, VIB Flanders Institute for Biotechnology, Institute Curie Paris, MDC Berlin, Institute Gulbenkian Oeiras, European Institute of Oncology Milan, CEITEC Brno, NKI Amsterdam, FIMM Helsinki, BRIC Copenhagen, Babraham Institute Cambridge, FMI Basel, CeMM of the Austrian Academy of Sciences

May 27, 2019

Epigenetic study provides new approaches to combination therapies for aggressive cancers

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First author Sara Sdelci, last author Stefan Kubicek (c) CeMM/Franzi Kreis

A recent study by CeMM reveals how the interaction of the epigenetic protein BRD4 with the metabolic enzyme MTHFD1 controls gene expression and cell proliferation. The results of the study have now been published in the renowned journal Nature Genetics. They suggest novel approaches for the development of combination therapies for aggressive cancers. 

Epigenetic processes enable cells to respond to changes in their environment by regulating the activity of their genes. One of the proteins that plays a key role in gene activation is BRD4, a well-characterized "epigenetic reader" that binds to acetylated lysine residues on both histone and non-histone proteins. To measure cellular BRD4 activity, the laboratory of Stefan Kubicek at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences had generated a cellular reporter system in 2016. Now the researchers were able to apply this model to systematically test whether loss of any of the approximately 23,000 human genes resembles BRD4 inhibition. Surprisingly, they discovered an interaction of folate metabolism with gene regulation. The results of the study, which among others included scientists from the Institute of Molecular Pathology (IMP) and the Medical University of Vienna, have now been published in the journal Nature Genetics (DOI: 10.1038 / s41588-019-0413-z).

Modern genome-wide screening techniques enable the generation of populations of mutagenized cells, in which a single gene is disrupted in each cell. The BRD4 reporter cells enabled Stefan Kubicek's laboratory at CeMM to precisely select from these cell populations those cells that behave as if BRD4 were inhibited. Next generation sequencing was then used to identify which genes were switched off. "We had expected to find one of the classic epigenetic factors," said Kubicek, "so we were all the more surprised that the best hit was MTHFD1." This enzyme is involved in folate metabolism, a process that had not previously been connected to BRD4. In addition, MTHFD1 is located predominantlyin the cytoplasm, while BRD4 resides in the nucleus.

Coincidence and serendipity provided first author Sara Sdelci another piece of the puzzle, which confirmed the results. At a conference, she met Philipp Rathert from Johannes Zuber's laboratory at the IMP, who was also working on BRD4. Sara Sdelci: "Philipp Rathert had generated data showing that MTHFD1 also physically binds to BRD4." In subsequent experiments, she could show that the small portion of the MTHFD1 protein found in the nucleus interacts with BRD4. This interaction recruits MTHFD1 to the DNA, where the enzyme contributes to gene regulation.

The study by Sara Sdelci is of clinical relevance for BRD4-dependent tumors. This includes tumors that harbor genetic aberrations leading to BRD4 overexpression, but also many other cancers in which BRD4 contributes to cell growth by its gene regulatory function. Accordingly, pharmaceutical companies have developed highly active BRD4 inhibitors, which are currently being tested in clinical trials. In clinical oncology, monotherapy with a single chemical agent is rarely successful due to the development of drug resistance. The discovery of the interaction of BRD4 and the enzyme MTHFD1 from the folic acid metabolism promises new approaches in cancer combination therapy, in the treatment of aggressive tumors. Antifolates, substances that inhibit the folate cycle, have been used for more than 70 years in cancer therapy and against diseases such as rheumatoid arthritis. The new study shows that antifolates can be combined with BRD4 inhibitors to more effectively combat tumors. The results may also help to stratify patients to ensure therapy success. "In the best case, based on our findings, patients can also be selected who, because of their folic acid level and their genetics, respond particularly well to BRD4 inhibitors," says Stefan Kubicek.

The study “MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation” was published in Nature Genetics on 27 May 2019. DOI: 10.1038/s41588-019-0413-z.

The study was funded by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF), and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme.

Sara Sdelci conducted this research project as Senior Postdoctoral Fellow at CeMM. Since January 2019 she has been group leader at the Center for Genomic Regulation (CRG) in Barcelona. She holds a PhD in Biomedicine from the Institute for Research in Biomedicine, Barcelona, and a BSc and MSc in Medical Biotechnology from the University of Florence.

Stefan Kubicek is Principal Investigator at CeMM and Head of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives. He also leads the Chemical Screening and PLACEBO (Platform Austria for Chemical Biology) program and the Proteomics and Metabolomics Facility at CeMM.

May 24, 2019

Wilhelm Auerswald Prize 2019 awarded to Michel Owusu

On May 21, 2019, Michel Owusu, former PhD Student at Joanna Loizou´s group at CeMM, has been awarded the Wilhelm Auerswald Prize for the Best Doctoral Thesis at an Austrian Medical University. Michel convinced the jury with his study "DNA damage and DNA repair in cancer genomes" and reached the first place in the ranking. Six candidates have been pre-selected and invited to present their work at the Society of Physicians, Billroth House Vienna. 

The Wilhelm Auerswald Prize is sponsored by Sanofi-aventis GmbH and was awarded for the 28th time in appreciation of the meritorious work of the Dean of the Medical Faculty of the University of Vienna, Wilhelm Auerswald (1917 - 1981). Botond Ponner, Country Medical Chair of Sanofi-aventis GmbH handed over the award, and the jury was chaired by Helmut Sinzinger, Institute Athos Vienna.

Congratulations to Michel Owusu for his success, and all the best for his postdoctoral work at the IRB Barcelona! 

May 23, 2019

Niki Lauda (1949-2019)

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Niki Lauda: "Being competent, professional, and very concentrated on one's goals, are key factors to success in sports, business and, I am sure, also in science. From what I know, CeMM is a formula one racing house in medical research that we are already proud of."

With great sadness we learned about the decease of F1 Champion and Airline Founder Niki Lauda. We are grateful to Niki Lauda for being a CeMM testimonial and supporter. Our thoughts are with his family and friends.

May 22, 2019

CeMM Scientific Advisory Board Meeting 2019

We thank the Scientific Advisory Board (SAB) Members Carl-Henrik Heldin (Uppsala University and Chairman of the Board of the Nobel Foundation), Emmanuelle Charpentier (MPI Berlin), Janet Kelso (MPI Leipzig), Hidde Ploegh (Harvard University) and Richard Flavell (Yale University) for visiting CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences from May 19-22, 2019, for listening to more than 30 talks, and for their critical feedback and advice, which is highly appreciated and an important source of motivation for the entire Institute.

The overall set-up of the SAB meeting was similar to previous years, which means we had presentations of PhD Students and PostDocs of every research group, and on the second day there were 1:1 meetings with Principal Investigators and Management. We asked our new Adjunct Principal Investigators who joined in Autumn 2018 to introduce themselves and their research focus, and there was also an update on CeMM’s business and tech transfer activities, as well as an introduction to the virtual reality holodeck project of the Menche group. 

We are looking forward to the written SAB report, and are going to publish the general comments as part of the next research report, as we did in previous years. 

On Monday evening, we had the pleasure to visit the Ephesos Museum in the Imperial Palace with our guests, and we thank its Director Georg Plattner for an exclusive tour and introduction to the valuable collection, which we enjoyed very much. 
Picture Gallery Ephesos Museum  

And we would especially like to thank City Councillor Veronica Kaup-Hasler and her team, for hosting us for a great SAB Dinner with Stakeholders and CeMM Friends at the Vienna City Hall on Tuesday. It was a real pleasure and privilege to be able to spend an evening in the Wappensaal (coat of arms hall).
Picture Gallery Vienna City Hall

May 20, 2019

Withering Away: How Viral Infection Leads to Cachexia

First author Hatoon Baazim, PhD student at CeMM, last author Andreas Bergthaler, Principal Investigator at CeMM

Cachexia is a multifactorial syndrome that occurs in patients suffering from chronic infections such as HIV, tuberculosis and malaria. In addition, 50% to 80% of cancer patients are affected by cachexia (Argiles JM et al. Nature Reviews Cancer 2014). Due to reduced food intake and altered metabolism, patients unintentionally lose body weight and lose their strength. Their fat reserves and skeletal muscle mass are progressively depleted, which cannot be reversed by nutritional supplementation. Cachexia severely impacts the patient’s quality of life and worsens the outcome of ongoing therapies. Despite this tremendous clinical need the standards of diagnosis and care for cachectic patients remain insufficient and effective treatment options are elusive so far.

In recent years, studies using experimental models of cancer-associated cachexia greatly improved our understanding of how inflammation may trigger cachexia and the associated metabolic alterations. These studies showed that secreted inflammatory factors can induce weight loss through either direct or indirect mechanisms that affect appetite and alter fat and muscle metabolism. In the context of infectious diseases, the knowledge of cachexia is lagging behind, and it is not understood whether the same or different mechanisms of cachexia occur during infection and cancer.

The research group of Andreas Bergthaler, Principal Investigator at CeMM, together with collaboration partners from the University of Graz, the Medical University of Vienna as well as international collaboration partners from Germany, Switzerland and the USA elucidated a novel mechanism of how chronic viral infection leads to cachexia. These results are published in the recent issue of Nature Immunology (DOI: 10.1038/s41590-019-0397-y) and describe the organism-wide pathophysiological changes associated with cachexia during chronic viral infection.

By using well-controlled animal infection models, the researchers identified the key molecular players that lead to cachexia. Viral infection resulted in a reduction of body weight. This weight loss could only partially be explained by decreased food intake and it was not prevented by nutritional supplementation.

The researchers went on to show that the viral infection led to a severe reorganization of the architecture of the fat tissue which coincided with the activation of lipolysis, a molecular cascade of processes that the body uses to melt its fat depots. Yet, none of the inflammatory mediators known to induce cachexia in cancer seemed to play an important role during infection. “This came as quite a surprise to us”, says first-author of the study, PhD student Hatoon Baazim.

The researchers continued to study other potential mechanisms and realized that CD8 T cells were responsible for triggering cachexia. CD8 T cells are important cells of the immune system, which are able to recognize and kill virus-infected cells or cancer cells. In this study the researchers could show that in order to trigger cachexia, the CD8 T cells required additional signals from the antiviral cytokines type I interferons and needed to recognize the virus.

This study by Baazim et al. elucidates the inflammatory drivers of infection-associated cachexia and offers a valuable model for future investigations about the mechanisms of infection-associated cachexia to the international research community. This will allow for new molecular insights into how infectious pathogens including HIV, mycobacterium tuberculosis or various parasites cause cachexia. In addition, as last-author Dr. Andreas Bergthaler puts it, “We are convinced that future studies that compare cachexia in the context of both infection and cancer, ideally through the integration of experimental models and clinical patient data, are going to provide much needed advancements for our understanding of this still very mysterious disease.” Such new insights from basic research may stimulate the development of innovative therapeutic strategies to alleviate the burden of cachexia and associated life-threatening chronic diseases.  

The study „CD8+ T cells induce cachexia during chronic viral infection“ was published in Nature Immunology, on May 20, 2019. DOI: 10.1038 / s41590-019-0397-y

Authors:
Hatoon Baazim, Martina Schweiger*, Michael Moschinger*, Haifeng Xu, Thomas Scherer, Alexandra Popa, Suchira Gallage, Adnan Ali, Kseniya Khamina, Lindsay Kosack, Bojan Vilagos, Mark Smyth, Alexander Lercher, Joachim Friske, Doron Merkler, Alan Aderem, Thomas H. Helbich, Mathias Heikenwälder, Philipp A. Lang, Rudolf Zechner, Andreas Bergthaler

Funding:
The study has been supported by the European Research Council (ERC), the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the German Research Foundation (DFG) and the US National Institutes of Health.

May 15, 2019

New IDK Board of ÖAW

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The conference of the 28 institute directors (Institutsdirektorenkonferenz, IDK) of the Austrian Academy of Sciences (ÖAW) have elected their new board members for the next 2 years (May 15, 2019 to May 15, 2021). The IDK advises on common concerns of the ÖAW institutes and assists the Academy with its planning.

Barbara Horejs (Chair), OREA 
Jürgen Eckert (Vice-Chair), ESI 
Brigit Kellner, IKGA 
Anita Ender, CeMM

The Austrian Academy of Sciences is Austria’s central non-university research and science organization. It is a learned society, and also consists of several research institutes in the field of innovative basic research - in the arts and humanities and the social and natural sciences. In these institutes, ~1700 employees are dedicated to top scientific research, training, the exchange of knowledge and the dissemination of new insights, with the aim of contributing to progress in science and Society.

Learn more about the 28 different ÖAW research Institutes.

May 09, 2019

New immunotherapy targets for MPN patients

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Robert Kralovics and Fiorella Schischlick (c) CeMM/Franzi Kreis

Myeloproliferative neoplasms (MPNs) are blood cancers characterized by excessive blood cell production, frequent thrombosis and transformation to acute leukemia. Oncogenic mutations in the JAK2, CALR and MPL genes have been identified as drivers of the disease along with many other MPN-associated mutations. While detailed knowledge of disease mechanisms is available, stem cell transplantation is still the only curative treatment but only for a small subset of eligible patients. Using cutting-edge technologies, scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, together with researchers from the Medical University of Vienna and the University of Pavia were now able to identify possible targets for immunotherapy which could also serve as a blueprint for cancer vaccine production. 

Recent advances in T-cell based immunotherapy have raised hopes for curative treatments, capable of eliminating the cancer cell. A key requirement for targeted immunotherapy is the identification of antigens that are present in tumor cells but absent in healthy cells. These antigens are mutated parts of proteins present in the tumor cells of the patient. Traditionally, tumor antigen identification has been limited by either high costs or low sensitivity depending on the implemented methodology.

In this study, spearheaded by scientists at CeMM Research Center for Molecular Medicine in collaboration with researchers from the Medical University of Vienna and the University of Pavia, a novel RNA-based methodology has been developed for the systematic identification of cancer antigens for each patient. Fiorella Schischlik, first author of the study and PhD student at CeMM; reflects: “As a bioinformatician, with a particular interest in data analysis, I was excited to find how much useful information can be extracted from a single RNA sequencing data set.”

Using RNA sequencing performed on the tumor biopsy as a basis for target discovery is particularly efficient. First, only targets are identified that are expressed and therefore relevant and second, a variety of different mutation classes can be addressed. Fusions and splicing-related aberrations are examples of mutation classes, where RNA sequencing is the preferred method of their systematic discovery. In this study, the researchers were able to demonstrate that especially patients with mutations in the splicing factor SF3B1 and CALR genes produce a variety of tumor specific peptides. These altered peptides could serve as a blueprint for cancer vaccine production. 

Robert Kralovics, Principal Investigator at CeMM and corresponding author of the study is excited to start the next step in target validation: “We want to show that these tumor-specific antigens are capable of eliciting an immunogenic response in the patients and are, therefore, suitable to serve as bona fide targets for T-cell directed killing of the cancer cell. Finding immunotherapy targets in 62% of MPN patients – as a conservative estimation - is raising hope that many MPN patients might benefit from this approach.” 

The study “Mutational Landscape of the Transcriptome Offers Putative Targets for Immunotherapy of Myeloproliferative Neoplasms” has been published in Blood

Authors: Fiorella Schischlik, Roland Jäger, Felix Rosebrock, Eva Hug, Michael Schuster, Raimund Holly, Elisabeth Fuchs, Jelena D. Milosevic Feenstra, Edith Bogner, Bettina Gisslinger, Martin Schalling, Elisa Rumi, Daniela Pietra, Gottfried Fischer, Ingrid Faé, Loan Vulliard, Jörg Menche, Torsten Haferlach, Manja Meggendorfer, Anna Stengel, Christoph Bock, Mario Cazzola, Heinz Gisslinger and Robert Kralovics

The Study was funded by the Austrian Science Fund (FWF) and the Associazione Italiana per la Ricerca sul Cancro.