The human immune system is essential for the prevention of infections and the detection of tumor cells, and severe congenital allergic (atopic) diseases can be the result of a genetic disorder effecting the immune system. An international team of researchers from the USA, UK and Kaan Boztug's research group at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) in Vienna has now discovered a novel genetic defect that leads to infections and severe atopic reactions.
This new study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3 and ZNF341, genes encoding different components of the IL-6 signalling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R. The results were published on June 24, 2019 in the Journal of Experimental Medicine.
The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was launched by the Ludwig Boltzmann Gesellschaft in April 2016 together with its partner institutions CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, the Medical University of Vienna, and the Children’s Cancer Research Institute (CCRI) of the St. Anna Children’s Hospital Vienna. Its research remit is the thorough analysis of rare diseases of the hematopoietic system, the immune system and the nervous system – as such not only dedicated to provide research for the development of personalized therapeutics for affected patients, but with similar efforts dedicated to unravel novel insights into human biology. Benefitting from full access to the infrastructure of its partner institutions, LBI-RUD has established a coordinated research programme, integrating and considering scientific, sociologic, ethical and economical aspects of rare diseases. http://rud.lbg.ac.at/
Publication:
Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses, Journal of Experimental Medicine, DOI 10.1084/jem.20190344.
Funding:
The study has been supported by the European Research Council (ERC StG 310857), the Austrian Science Fund (FWF 29951-B30), the Austrian Academy of Sciences (ÖAW DOC Fellowship), the Medical Research Council und Cancer Research UK.
A research group from MedUni Vienna and CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences has discovered a new mechanism by which cells communicate in inflammatory processes. This involves endogenous mitochondria released from white blood cells turning into initiators of inflammation. It is as if friends turn into enemies. The results have been published in the journal Circulation Research.
In collaboration with other partners, Christoph Binder from the Department of Laboratory Medicine of MedUni Vienna and CeMM, and his group members Taras Afonyushkin and Florian Puhm have investigated how monocytes (a subset of white blood cells) belonging to the immune system react under stress. Monocytes shed parts of their cell membrane in the form of so-called microvesicles. These microvesicles are capable of transmitting alarm signals to other cells. The scientists discovered that a subset of these microvesicles contains mitochondria. Normally mitochondria are an important component of cells and are known as cellular power plants. However, compared to conventional mitochondria, these mitochondria released by stressed monocytes have an increased potential to trigger inflammation.
There are two factors that render these monocytic "stressed mitochondria" dangerous. The tumour necrosis factor (a messenger molecule of the immune system) associated with them and modified mitochondrial RNA (ribonucleic acid). Via these two factors, "stressed mitochondria" trigger tumour necrosis factor and Type 1 interferon signaling pathways in recipient cells. Notably, these are two of the major signaling pathways in chronic inflammatory diseases.
"We were able to demonstrate that activated monocytes release certain stressed mitochondria, which - even in small quantities - trigger dangerous pro-inflammatory responses in recipient cells" explains Taras Afonyushkin, one of the study's first authors.
These findings give rise to two new potential therapeutic approaches. "On the one hand, one could specifically stimulate the immune system to enhance the clearance of these released mitochondria (e.g. by means of antibodies) and thereby diminish their activity in the blood," explains Christoph Binder, "on the other hand, a better understanding of the mechanisms leading to the release of these mitochondria could help to identify molecules that specifically prevent this."
The Study: “Mitochondria Are a subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells” was published in Circulation Research in May 2019, DOI: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.314601
Authors: Florian Puhm*, Taras Afonyushkin*, Ulrike Resch, Georg Obermayer, Manfred Rohde, Thomas Penz, Michael Schuster, Gabriel Wagner, Andre F Rendeiro, Imene Melki, Christoph Kaun, Johann Wojta, Christoph Bock, Bernd Jilma, Nigel Mackman, Eric Boilard, and Christoph J Binder.
Funding: The study has been supported by the Special Research Program SFB-54 “InThro” of the Austrian Science Fund (FWF), the Doctoral Program CCHD “Cell Communication in Health and Disease” of the FWF, and the Christian-Doppler Laboratory for Innovative Therapy Approaches in Sepsis.
On June 5, 2019, the “1st Vienna Symposium on Machine Learning in Medicine & Biology” took place at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences bringing together the diverse crowd of Austrian researchers in this rapidly growing field. The event was organized by Georg Langs (Medical University of Vienna) and Christoph Bock (CeMM), with support by the Austrian Platform for Personalized Medicine.
Invited talks covered new methods and exciting applications of machine learning – including deep neural networks and interpretable AI, cancer and drug toxicity, the social dimension of machine learning, and what machine learning can learn from the way our brains work.
Finally, a keynote lecture by Thomas Lengauer (Max Planck Institute for Informatics & University of Cologne) demonstrated how machine learning predicts drug resistance in HIV and improves the treatment of patients with HIV in very concrete ways.
The event was heavily oversubscribed, testimony of the great interest and strong community in this field. Indeed, (bio)medicine is consistently ranked among the areas where machine learning will have most impact – but it is among the most challenging fields and requires dedicated technology to be applicable and acceptable in the context of biomedical research and clinical practice.
Following the success of this first symposium, a follow-up event is planned for 2020. Please feel free to e-mail Christoph Bock (cbock@cemm.at) and Georg Langs (georg.langs@meduniwien.ac.at) if you have any feedback or suggestions for improvements. Thank you!
RESOLUTE, an European Union IMI2 funded project with 13 partners, CeMM as academic coordinator and Pfizer as EFPIA leader, celebrated the 2nd RESOLUTE consortium meeting from June 3-5, 2019 in Krems an der Donau, near Vienna.
More than 65 participants coming from all over Europe and the US joined the meeting. This was a great chance to review the current status of the RESOLUTE project right before completing the first year of collaborations. This edition featured many young investigators presenting their progress in the generation of reagents, data and assays for solute carriers. Additionally, strategies were developed for tackling the challenges of the second year of RESOLUTE. Participants as well enjoyed the excellent weather and cultural amenities of the beautiful vineyards of the Wachau area.
Learn more about the RESOLUTE (Research Empowerment on Solute Carriers) Project: https://re-solute.eu/
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:
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
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.
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
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.
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!
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.
