In a press conference on November 25th, 'Genom Austria' was announced as a joint Citizen Science Project of CeMM, the Medical University of Vienna, and the PersonalGenomes.org foundation. Genom Austria will explore the scientific, educational, philosophical, ethical, and social implications of personal genome sequencing. Following the model of Harvard’s Personal Genome Project, Genom Austria provides qualifying volunteers the opportunity to sequence their personal genomes and to share the data with the public. An important aim is to start a public debate on the opportunities and risks associated with whole genome information and contribute to the genomic literacy of as many Austrians as possible, particularly young people. Genom Austria is backed by an outstanding team of experts from biology, medicine, ethics, sociology and other disciplines, and it is under the patronage of Margit Fischer, chairwoman of the Science Center Network foundation and wife of the Austrian National President. For more information, please visit the project websites.
Viruses can predispose the host to bacterial superinfection, and secondary pneumonia is considered to play a major role in the morbidity of seasonal as well as pandemic influenza. Despite the significant clinical and socioeconomic impact, the molecular mechanisms of how influenza virus causes superinfection have been poorly understood. Scientists from Andreas Bergthaler´s Group at CeMM now succeeded in finding a new molecular mechanism, which may explain why influenza virus infections increase the susceptibility to bacterial pneumonia. Their discovery of a novel crosstalk between the antiviral molecule interferon and the enzyme Setdb2, which weakens the antibacterial response has been published advanced online on November 24th, 2014 in the scientific journal Nature Immunology.
During seasonal flu epidemics, respiratory infections with influenza virus lead to a sudden onset of high fever, cough, headache, runny nose, sore throat and other signs of fatigue and general discomfort. High-risk groups such as very young, elderly or chronically ill people may develop severe disease, which results in approximately 500.000 deaths annually (WHO). These severe influenza cases are often associated with secondary bacterial infections, so-called superinfections. Past studies suggested that the virus is not the primary cause of disease. Instead, the trigger for disease seems to be the suppression of the immune system by the virus.
Using a superinfection model of influenza virus and streptococci, Bergthaler´s group could now show that interferon, which plays a central role in the antiviral response, induces the enzyme Setdb2. Subsequently they found that Setdb2 blocks the expression of antibacterial genes such as the chemoattractant Cxcl1, which is crucial for the recruitment of immune cells to the lungs and the control of bacterial infections. This mechanism may avoid excessive inflammation during viral infection. At the same time, however, it renders the organism more vulnerable to bacterial superinfection. Future research aims to elucidate the complex molecular interplay between the virus, Setdb2, the bacteria and the immune system. This may open new potential therapeutic avenues for patients at risk of superinfections.
Setdb2 mediates virus-induced susceptibility to bacterial superinfection.
Christopher Schliehe, Elizabeth K. Flynn, Bojan Vilagos, Udochuku Richson, Savitha Swaminanthan, Berislav Bosnjak, Lisa Bauer, Richard K. Kandasamy, Isabel M. Griesshammer, Lindsay Kosack, Frank Schmitz, Vladimir Litvak, James Sissons, Alexander Lercher, Anannya Bhattacharya, Kseniya Khamina, Anna L. Trivett, Lino Tessarollo, Ildiko Mesteri, Anastasiya Hladik, Doron Merkler, Stefan Kubicek, Sylvia Knapp, Michelle M. Epstein, David E. Symer, Alan Aderem and Andreas Bergthaler. Nature Immunology AOP, Doi: 10.1038/ni.3046
The study has been funded by CeMM, the Austrian Academy of Sciences (ÖAW), the Austrian Science Fund (FWF), the German Academic Exchange Service (DAAD), the Swiss Foundation for Grants in Biology and Medicine (SSMBS), the Swiss National Science Foundation (SNF) and the US National Institutes of Health (NIH).
As a follow-up to the publications on the initial draft of the human proteome that appeared in Nature in May this year, Bernhard Küster and Akhilesh Pandey were invited to CeMM to present their key research findings. As part of their presentations, the speakers described the broad range of applications of their research, such as the use of protein identification to aid forensic teams at crime scenes, or a large-scale malarial study in India. They also discussed the future of this research field, including the aim to produce a more refined map of the human proteome and also the development of proteogenomic centers to complement upcoming organism-wide sequencing efforts.
The presentations were followed by an interactive and lively round table discussion on the next frontier in human proteome research, and what it may mean for us to perform research in a post-proteomic era. Karl Mechtler (Head of Mass Spectrometry & Protein Chemistry at the IMP), Thomas Helbich (Professor of Radiology at the Medical University of Vienna), Keiryn Bennett (Head of Mass Spectrometry & Proteomics at CeMM) and Giulio Superti-Furga (Scientific Director at CeMM) joined the two speakers on the panel.
The team of Kaan Boztug, Principal Investigator at CeMM and Assistant Professor at the Department of Pediatrics and Adolescent Medicine of the Medical University of Vienna discovered the molecular origin of a new rare disease and succeeded in deciphering the essential role of the NFkB-inducing kinase (NIK) for an efficient immune response in humans. The findings have been published online, on November 19th, 2014, in the open access journal Nature Communications.
Primary immunodeficiencies are inherited disorders resulting in malfunction of the immune system. The identification of the molecular defects underlying these disorders is crucial not only to diagnose patients and enable targeted therapies, but also highlights essential components and pathways in human immunity in general. The research team under the supervision of Kaan Boztug has now uncovered a novel, rare form of primary immunodeficiency, and identified a loss-of-function mutation in the gene NIK as the underlying genetic cause for this disorder.
In their publication, first author Katharina Willmann and her colleagues at CeMM and the Medical University decipher the essential role of NFkB-inducing kinase (NIK), a central kinase involved in non-canonical NFkB signaling, for an efficient immune response in humans. Usually, the signaling molecule NIK is expressed in lymphoid cells of the immune system. However, the variant they found in the patients is enzymatically inactive and therefore unable to transmit signals necessary to mount an appropriate immune response. Human NIK deficiency not only leads to defective B-lymphocytes that cannot produce antibodies appropriately. The scientists discovered that also T-lymphocytes, which specialize in memorizing and recognizing specific pathogens, as well as the so-called natural killer cells, which specialize in killing virus infected body cells, were affected in their functions. Together, these defects have a profound and devastating effect on the defense mechanisms of the patients.
By identifying the signaling molecule NIK as a crucial player in a functional immune defense, the team of Kaan Boztug uncovered a central molecular mechanism of the human immune system. These findings will not only help to understand signaling in the human immune system better but will, in the long run, also enable scientists to develop molecular therapeutic approaches.
Publication: Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity. Katharina L. Willmann, Stefanie Klaver, Figen Doğu, Elisangela Santos-Valente, Wojciech Garncarz, Ivan Bilic, Emily Mace, Elisabeth Salzer, Cecilia Domínguez Conde, Heiko Sic, Peter Májek, Pinaki P. Banerjee, Gregory I. Vladimer, Sule Haskoloğlu, Musa Gökalp Bolkent, Alphan Küpesiz, Antonio Condino-Neto, Jacques Colinge, Giulio Superti-Furga, Winfried F. Pickl, Menno C. van Zelm, Hermann Eibel, Jordan S. Orange, Aydan Ikincioğulları & Kaan Boztug. DOI:10.1038/ncomms6360
It is with great sadness that we learn of the decease of Prof. Dr. h.c. mult. Max L. Birnstiel, of Wollerau, Switzerland. Max Birnstiel was the founding director of the Institute of Molecular Pathology (IMP) in Vienna and can be held responsible for kicking off the renaissance of the life sciences in Austria in the last 25 years. As a mentor of the CeMM director Giulio Superti-Furga, who in the late eighties had followed him as a PhD student together with his PhD supervisor Meinrad Busslinger, from Zurich to Vienna, Max Birnstiel provided important advice for the making and leadership of CeMM. Max Birnstiel will long remain a towering figure in molecular biology. Trained at the ETH in Switzerland with Frey-Wissling, he moved to Caltech to work with James Bonner. In 1966, together with his wife Margaret Chipchase, he first purified ribosomal RNA genes from vertebrates. He moved to Edinburgh where he physically isolated the histone genes of the sea urchin, before the invention of molecular cloning. Ernst Hadorn called him to the University of Zurich where for 15 years he led a world-renowned research program that determined gene-regulatory processes of eukaryotes. He was recruited by Boehringer Ingelheim and Genentech to conceive and lead the new IMP in Vienna, as a rather risky and innovative experiment, recruiting internationally and fostering world-class basic research in molecular biology in an environment that initially was a waste-land. He insisted on having the biochemical institutes of Vienna University to settle next to the IMP, to create the nucleus of the Vienna Biocenter. During his period as head of the IMP, he founded Intercell, a successful pioneering biotechnology company that helped put Vienna on the world map of research and business excellence in the life sciences. In his life, Max Birnstiel has earned numerous awards, prizes and honorary doctorates. He was a member of numerous academies, including the Austrian Academy of Sciences and the United States Academy of Sciences, as a foreign associate. In recognition of his pioneering work and immense contributions, the Austrian community of life scientists gave him the Achievement Award Medal during the EMBanniversary meeting in July 2014. In no possible way can the importance of Max L. Birnstiel for the life sciences in general, and for the Austrian molecular biology, be overstated. He will be dearly missed.
It is our great pleasure to congratulate the Medical University of Vienna on their 10 year anniversary! The Medical University of Vienna is one of our key research partners and plays a major role in the education and scientific development of CeMM’s PhD students, and postdoctoral fellows. We truly value the strong collaborative relationship with our neighbours, and we would like to thank the rectorate, our collaborators and the administrative staff of the Medical University of Vienna for their cooperation. Several members of CeMM Faculty are also affiliated with the Medical University and thus represent a successful “marriage” of ideas and objectives. In recent years we have published a number of co-authored papers in top journals and have shared some very promising research results. We are looking forward to continuing this successful relationship on many more collaborative projects to come.
Giulio Superti-Furga, Director CeMM
The 4th Vienna Next Generation Sequencing Symposium & Workshop brought together over 150 current and future users of next generation sequencing technology. Six invited speakers described exciting applications of NGS technology in basic biology and in biomedical research. And the keynote speaker Bart Deplancke (École Polytechnique Fédérale de Lausanne, EPFL) presented a biologically interesting and methodologically advanced study on the massive-scale characterization of the genome regulatory code in Drosophila. The meeting was organized by Christoph Bock (Coordinator of the BSF Biomedical Sequencing Facility of CeMM and MedUni Vienna) and Andreas Sommer (Coordinator of the CSF NGS unit at the Vienna Biocenter), who also gave an overview of the technological support and opportunities for collaboration that are available to researchers in Vienna, Austria and beyond. The symposium was followed by an interactive workshop that allowed all participants to go into further detail and to discuss practical approaches and challenges of using NGS technology in their research. The success story of the Vienna NGS Symposium & Workshop will continue with 5th event in winter 2015/2016.
Giulio Superti-Furga, Scientific Director and Kilian Huber, Senior Postdoctoral Fellow at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, have been selected as winners of GlaxoSmithKline plc’s (GSK) 2014 European Discovery Fast Track Challenge, which is designed to accelerate the translation of academic research into novel therapies. CeMM will partner with scientists in GSK’s Discovery Partnerships with Academia (DPAc) and Molecular Discovery Research (MDR) teams to screen the target against GSK’s compound collection. Active compounds could then form the basis of full drug discovery programmes that may ultimately lead to innovative medicines for cancer.
The project is one of nine challenge winners, chosen from 232 entries across 24 European countries. Research between CeMM and GSK will focus on a new drug which prevents tumour growth by inhibiting the nucleotide pool sanitizing enzyme MTH1.
"We are very happy to see our studies carried on in the fast track programme together with GSK. It is really a rare stroke of luck that in our underlying studies we have not only found a previously unknown sore spot of aggressive cancers, but that by chance we simultaneously identified a chemical substance that is a mirror image of one of the best new anticancer agents in the clinic."
Launched in the U.K. in late 2010, DPAc is a new approach to drug discovery that enables academics to marry their scientific excellence with the drug discovery insight of GSK. For projects that progress to full DPAc programmes, GSK and the academic partner share the risk and reward of innovation; GSK funds activities in the partner laboratories and provides in-kind resources to progress a programme from idea to candidate medicine. Currently GSK has ten active DPAc collaborations in ten disease areas, of which six are with academics based in European institutes.
CeMM Scientific Director Giulio Superti-Furga was recently elected member of the Academia Europaea – the Academy of Europe. The election followed a recommendation of the Academic Sections and a peer review by the Nominations Committee of the academy.
The Academia Europaea is a registered not-for-profit charity founded in 1988 as an international, nongovernmental association of eminent, individual scientists and scholars from across the continent of Europe who are experts and leaders in their own subject areas as recognized by their peers. Currently 3000 academy members span the full range of academic disciplines comprising the humanities, social, physical and life sciences as well as mathematics, engineering and medicine.
The appointment represents an honor recognizing Prof. Superti-Furga’s international scholarship and major achievements, including the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers, the discovery of fundamental organization principles of the proteome of higher organisms and the development of integrated approaches to understand the mechanism of action of drugs at the molecular level. CeMM congratulates him on this distinguished achievement.
Congenital immunodeficiencies comprise a group of disorders characterized by an abnormal immune system. The body’s ability to fight infections is impaired and infections can have life-threatening consequences for those affected. Analysis of patients with a disease characterized by an inherited lack of neutrophil granulocytes termed severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling differentiation, maintenance, and decay of neutrophils. The team of CeMM Principal Investigator Kaan Boztug in collaboration with the group of Christoph Klein, Director of the Dr. Von Hauner Children’s Hospital Munich, identified mutations in the gene JAGN1 as a novel subtype of SCN in 14 patients bearing 9 distinct JAGN1 mutations. JAGN1 deficiency accounts for approximately 10% SCN for which the underlying genetic defect had previously been unknown. The researchers could show that JAGN1 mutations lead to aberrant function of the endoplasmic reticulum, defective protein glycosylation and increased neutrophil apoptosis. SCN patients are usually treated with the cytokine G-CSF, however for JAGN1-deficient patients the treatment response was unsatisfactory. In a second study IMBA Director Josef Penninger and his team generated Jagn1 knock-out mice and could show that GM-CSF, but not G-CSF, treatment rescues the defects of JAGN1-deficient neutrophils in mice.
Kaan Boztug, first author of one of the studies, identified the first patients with JAGN1 mutations: “The discovery of the JAGN1 deficiency illustrates that inborn errors of immunity can be caused by mutations in genes that were previously not even known to play a role in the immune system. It would be a wonderful result of this CeMM-IMBA-Munich collaboration if treatment with GM-CSF also works for human patients – this will now be assessed in further clinical studies. This is also a perfect example that not only new drugs lead to better therapies. An enhanced molecular understanding of diseases may enable targeted use of existing drugs and can thus fulfill the promise of patient-oriented medicine."
The findings of both studies have been published on August 17, 2014, in the journal Nature Genetics:
Boztug, K. et al. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. (2014).
Wirnsberger, G. et al. Jagunal-homolog 1 is a critical regulator of neutrophil function in fungal host defense. Nat Genet. (2014).