Watercolour portrait of Denise P. Barlow by artist Lisl Spurny-Schwarzmüller
(c) CeMM/Klaus Pichler
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
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
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.
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.
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.
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.
On May 6, 2019, some 350 participants enjoyed the inspiring as well as entertaining 13th CeMM Karl Landsteiner Lecture, delivered by Luke O´Neill, Chair of Biochemistry at Trinity College Dublin.
In his talk “Will we cure all diseases by targeting Inflammation?” which addressed scientists as well as lay people, Professor Luke O´Neill pointed out the desperate need for new treatments for important diseases. 7,000 distinct diseases are currently only faced with 500 available treatments!
Many socially important illnesses, like neurodegenerative diseases, cancer, neuropsychiatric disorders, many inflammatory disease, osteoarthritis, inflammatory bowel disease, and lupus desperately need new medicines. Considering a timeline of at least 10 years from the discovery of a new, disease-causing molecular mechanism, to the development of an effective drug, he emphasized that one cannot overestimate the importance and urgency of basic research to grow the fundaments of our understanding.
Luke O´Neill highlighted the five discoveries in medicine with the largest impact, which are vaccines, penicillin (antibiotics), anesthetics, insulin and birth control and gave an insight into his own research focusing on inflammation at the root of most diseases.
Vividly, he described the inflammatory process and pathways as a domino game and the importance of searching for the first targetable domino stone piece to effectively interfere with the process.
He forged a bridge from the discovery of NLRP3 as one main pathway for pathology in multiple inflammatory diseases, to the detection of effective small molecules, from the most valuable basic research, to the impact on drug discovery and development.
Luke O´Neill reminded the scientists among the audience about the importance of their work, he stood up for funding and support through the responsible politicians and policy-makers. He also stressed the importance of science communication with the wider public and, at the same time, raised hopes for the future with many new treatments at the horizon.
After the talk and a cocktail reception, he rocked the Haus der Industrie as lead singer and guitarist of his band “The Metabollix”.
Thank you to Luke O´Neil for his excellent talk and a brilliant concert.
Thank you to the participants of the Alumni Kick-Off Event, who joined the treasure hunt and the dinner on Sunday, May 5, despite the cold and rainy weather. We hope you had a good time, solving the criminal case around the disappearance of our Scientific Director, and also thank the cast of the company www.nesterval.at for their great performance and the team of www.stiftstpeter.at/ for the nice hospitality. On Monday, May 6, our exchange with Alumni at CeMM continued. In discussions with the Alumni Board, Members and CeMMies we collected suggestions and ideas to further improve our institute and its network. Please do not hesitate to also send written feedback.
Picture Gallery: cemm.at/media/
If you are an Alumnus and have not received the invitation for the event or CeMM’s recent Research Report, please help us to stay connected by providing your current postal and mail address: alumni(at)cemm.oeaw.ac(dot)at
A big thank you from CeMM to the Alumni Board members for their voluntary support and dedication in setting up a CeMM Alumni Club: Ferran Fece de la Cruz, Adriana Goncalves, Tatjana Hirschmugl, Katrin Hörmann, Evren Karayel, Erika Schirghuber, Christopher Schliehe, Christian Schmidl.
Watercolour portrait of Denise P. Barlow by artist Lisl Spurny-Schwarzmüller
(c) CeMM/Klaus Pichler
CeMM, IMP, IMBA and MFPL hereby launch a PhD Thesis Award in memory of our former colleague and formidable researcher Denise P. Barlow.
Denise P. Barlow (1950-2017) has been an excellent researcher who inspired the molecular biology community in Austria and beyond. In Vienna, she has been associated with four institutions: IMP, where she was a group leader, MFPL, where she has been a professor, IMBA, which has provided laboratory space for some time, and CeMM, where she has been ten years as principal investigator. In 1991, Denise P. Barlow made her first major breakthrough discovery by identifying the first imprinted gene in mammals to show parental specific gene expression. Denise continued to work relentlessly to uncover many fundamental details of the imprinting mechanism. Her group’s subsequent finding that epigenetic silencing of this imprinted gene is induced by expression of an unusually long non-coding (lnc) RNA has led the team to investigate how lncRNAs act throughout the mouse and human genome as regulators of gene expression in development and disease.
The Denise P. Barlow Award intends to promote the academic career of young scientists, strategically addressing the transition of graduated PhD Students to PostDocs, by offering a small financial help that will alleviate the costs associated with relocation or career development. The Denise P. Barlow Award amounts to € 5000 and will be given once a year. The topic of the thesis can vary and cover basic cell biological, biochemical, molecular biological, structural and computational work, with an emphasis on insight on new biological mechanisms, something Denise P. Barlow was fond of.
Deadline for applications: June 30, 2019. For any IMP, MFPL, IMBA, and CeMM student who has submitted her/his PhD thesis between July 1, 2018 and June 30, 2019. The Award Ceremony will take place end of October 2019.
An independent jury chaired by Reinhard Jahn, Director of the Max Planck Institute for Biophysical Chemistry in Göttingen, selected and announced CeMM Principal Investigator Georg Winter as the 2019 winner of the Eppendorf Award for Young European Investigators. Congratulations to Georg!
Georg Winter receives the prize for his pioneering work developing a method for targeting specific proteins for degradation. The award ceremony will take place on June 27, 2019 at EMBL Heidelberg.
Since 1995 the Eppendorf Young Investigator Award is granted annually to European researchers not older than 35 years. It acknowledges outstanding contributions to biomedical research based on methods of molecular biology, including novel analytical concepts. The prize reflects the wish of the company’s founders, Heinrich Netheler and Hans Hinz, to show the close links of Eppendorf to the biomedical fields. The award includes prize money of € 20.000 and the coverage of the awardee’s work by the scientific journal Nature.
Georg Winter studied Biotechnology and performed his undergraduate studies with Thomas Jenuwein at the IMP in Vienna. He undertook his graduate studies with Giulio Superti-Furga at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences and continued his training as a postdoctoral fellow with James Bradner at the Dana Farber Cancer Institute/Harvard Medical School. In 2016 Georg joined CeMM as Principal Investigator.
Congratulations to Julia Pazmandi, CeMM and LBI-RUD PhD Student at Kaan Boztug’s laboratory, for winning the Falling Walls Lab Austria competition with her talk “Breaking the Wall of Science and Fiction”, a project in collaboration with CeMM’s VR Holodeck platform.
The virtual reality (VR) platform devised and constructed in Jörg Menche´s group at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, allows scientists to dive deep into the massive molecular networks behind genetic diseases. The unique VR experience provides a first glimpse at how humans and machines will interact in the future to visualize and explore complex medical data.
The goal of the Falling Walls Lab is to advance scientific and entrepreneurial visions, and to initiate and promote exchange between outstanding talents and innovative thinkers across disciplines. At Falling Walls Lab Austria, 14 young talents from a wide variety of disciplines were selected to present their ideas and projects in 3 minutes talks in front of a top-class jury under the direction of Hans Sünkel, former Rector of the Graz University of Technology. The winner qualifies for the International Falling Walls Conference on Future Breakthroughs in Science and Society on November 8, 2019 in Berlin.
Read more about the event, and Julia’s project in collaboration with the Menche lab.
picture © Lunghammer, TU Graz:
TU Graz Rector Harald Kainz, Julia Pazmandi and Hans Sünkel, Chair of the Jury
We are happy to introduce the CeMM Research Report 2018 to you.
Learn more about the Science, Life and Facts of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences. In this report we not only present you our scientific highlights, we took the discussions of the Directors, CeMM Principal Investigators and our Adjunct PIs outside of CeMM into the city of Vienna. We hope you enjoy the little tour of “CeMM-related” Kaffeehäuser/coffeehouses as a stage for multicultural communication. Rather than thinking of researchers as being confined to an ivory tower, relate to us as members of civic society, sitting next to you, drinking coffee, exchanging ideas and discussing how the future may look.
We thank our mother organization the Austrian Academy of Sciences, and all stakeholders, funding organizations and research partners for their steady and valuable support and trust.
And we would like to thank our CeMM employees and our affiliated members from the MedUni Vienna, LBI-RUD, MedUni Innsbruck, University of Vienna and TU Vienna for their hard work and passion for science. This report tells of their success and collaboration spirit!
Giulio Superti-Furga, Anita Ender
Congratulations to Kaan Boztug (CCRI and LBI-RUD Director, CeMM Adjunct PI and Associate MedUni Wien Professor), Elisabeth Salzer and Bernd Boidol (former CeMM PhD Students) for winning three individual Johann Wilhelm Ritter von Mannagetta Awards!
Kaan received the Mannagetta Medicine Prize as recognition for his research on inherited defects of the immune system, and Lisi and Bernd the Mannagetta Advancement Awards for their excellent publications and PhD studies in the field of medical research.
Salzer E. et al. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol. doi: 10.1038/ni.3575.
Boidol B. et al. First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia. Blood. doi: 10.1182/blood-2017-05-785683.
The Mannagetta Prize for Medicine and the Advancement Awards have been awarded for the first time by the Austrian Academy of Sciences in a festive event which took place on March 21 in the Johannessaal of the ÖAW. The awards are named after the physician Johann Wilhelm Ritter von Mannagetta (1588-1666), who served as Rector of the University of Vienna and was personal physician to the Emperor Ferdinand II, Ferdinand III. as well as Leopold I. In 1661 he set up a foundation that exists to this day and supports prizes and scholarships in medicine, in the humanities, and social sciences.