In light of the importance of research on precision, molecular, and personalized medicine, CeMM and the Medical University of Vienna hosted on March 6, 2017 a kick off meeting to celebrate the start of Pharmacoscopy, a novel high-content screening and imaging platform to break resistance of relapsed and refractory hematological malignancies - a true bench-to-bedside circle.
This meeting presented and celebrated the collaborative project between the Superti-Furga and Kubicek laboratories at CeMM and the Division of Hematology and Hemostaseology, Department of Internal Medicine I of the medical University of Vienna. The Pharmacoscopy platform is funded with the precision medicine grant from the WWTF (Wiener Wissenschafts-, Forschungs- und Technologiefonds / Vienna Science and Technology Fund) awarded to Giulio Superti-Furga and Ulrich Jäger.
The meeting began by reviewing the importance of the strong CeMM and MedUni Wien collaborative atmosphere that has propelled basic and translational science, as reiterated by the Vice Rector for Research and Innovation Michaela Fritz. Christoph Zelinski, Director of the Department of Internal Medicine I, touched upon ongoing precision medicine programs in the MedUni Wien such as the EXACT trial. Ulrich Jäger, Head of the Division of Hematology and Hemostaseology, further spoke about the need for personalized and precision medicine in the hematological space, where functional testing that will be used to meet the aims of the WWTF grant can synergize with genetic testing that is clinically routine.
CeMM scientific Director Giulio Superti-Furga and his Senior Postdoctoral Fellow Gregory Vladimer outlined the image-based screening platform that is the backbone of this program, and how the technology is currently being used for clinical utility. The meeting was finished by Ulrich Jäger presenting interim results of an ongoing clinical study aimed at describing the benefits of data generated through this collaboration for the treatment of patients.
The Pharmacoscopy project aims to break resistance of refractory blood cancers through ex vivo automated image-based analysis of drug action, and potentially drive clinical trials of already approved drugs in off-indication blood cancers. The approach provides a very concrete and actionable platform for precision medicine and the use of off-indication approved drugs for late stage hematological malignancies. The collaboration is tuned directly to unmet clinical needs of resistant blood cancer patients.
With the first breath, the lungs require to develop immunological defense mechanisms while maintaining the gas exchange. The postnatal immunological development of the lungs remained largely unknown until the group of Sylvia Knapp at CeMM and the Medical University of Vienna shed light at a complex immune program that starts right after birth: the study published in Cell Reports reveals how first breath-induced interleukin-33 signaling shapes the performance of pulmonary immune cells and influences anti-bacterial defenses.
(Vienna, February 21, 2017) The lung is an important interface between the body and the outside environment: with each breath, a surface of roughly 100 square meters exchanges oxygen for carbon dioxide. More than 10,000 liters of air pass adult lungs every day and with this come numerous viruses, bacteria and pollutants, which need to be prevented from entering the body.
To defend the organism from these intruders, the lungs harbor their own arsenal of highly specialized immune cells that are equipped to maintain the balance between host defense and tissue quiescence. However, how this balanced immune homeostasis in lungs emerged after birth, was largely unexplored. Now, for the first time, the group of Sylvia Knapp showed with the help of mouse models that the very first breath of a newborn releases crucial signals that shape the lifelong immunological milieu of lungs.
The study, published in Cell Reports (DOI:10.1016/j.celrep.2017.01.071), reveals that the mechanical forces of spontaneous ventilation at birth lead to the release of interleukin (IL)-33, a cytokine with a wide-range of effects: So-called “type 2 innate lymphoid cells” (ILC2s) follow the IL-33 signal and migrate into the lung tissue, where they release IL-13, another cytokine. This second signal determines the faith of alveolar macrophages by inducing the anti-inflammatory M2 phenotype.
The described mechanisms are crucial in achieving lung quiescence after the first contact with the outside world. However, these processes at the same time increase the susceptibility to bacterial infections, such as bacterial pneumonia - the primary cause of death by an infectious disease in Western countries.
Simona Saluzzo, Anna-Dorothea Gorki, Batika M. J. Rana, Rui Martins, Seth Scanlon, Philipp Starkl, Karin Lakovits, Anastasiya Hladik, Ana Korosec, Omar Sharif, Joanna M. Warszawska, Helen Jolin, Ildiko Mesteri, Andrew N. J. McKenzie und Sylvia Knapp. First-breath induced type-2 pathways shape the lung immune environment. Cell Reports, February 21, 2017. DOI:10.1016/j.celrep.2017.01.071
This study was supported by the Austrian Science Funds (FWF, DK CCHD), the Vienna Science and Technology Fund (WWTF) and grants from the Medical Research Council and the Wellcome Trust.
We congratulate CeMM PI Christoph Bock on being awarded the 2017 Overton Prize of the International Society of Computational Biology (ISCB). Each year, this prestigious award is given to one early to mid-career scientist from any country who is recognized as an emerging leader in computational biology and bioinformatics.
Christoph Bock has been one of the first computational biologists who dedicated his career to understanding epigenetics and the human epigenome. During his PhD in the lab of Thomas Lengauer at the Max Planck Institute for Informatics (2004-2008), he developed pioneering methods and software for analyzing and interpreting DNA methylation data. As postdoc in the laboratory of Alexander Meissner at the Broad Institute (2009-2011), he conducted large-scale epigenome analyses of stem cells and contributed to the Roadmap Epigenomics project.
Since 2012, Christoph Bock has been a Principal Investigator at CeMM and a Visiting Professor at the Medical University of Vienna. His research on epigenetic biomarker development helped established the practical value of epigenetics for personalized medicine. He has also been one of the lead bioinformaticians in the BLUEPRINT epigenome project and the International Human Epigenome Consortium. Christoph Bock received an ERC Starting Grant in 2015 and a New Frontier Group award by the Austrian Academy of Sciences in 2013.
In the light of these achievements, the ISCB’s announcement of the 2017 Overton Prize highlights Christoph Bock as “a rising star in epigenetic data analysis.”
The Overton Prize was instituted in 2001 to honor the untimely loss of G. Christian Overton, a leading bioinformatics researcher and a founding member of the ISCB Board of Directors. Over the last 16 years, the prize has been awarded to an outstanding group of computational biologists (https://www.iscb.org/iscb-awards/overton-prize).
The ISCB is the world’s leading professional society for computational biology and bioinformatics. It seeks to communicate the significance of computational biology to the larger scientific community, to governmental organizations, and to the general public; the society serves its members locally, nationally, and internationally; it provides guidance for scientific policies, publications, meetings, and distributes information through multiple platforms.
(Modern) civil societies rely on the sharing of goods and information that allow the best use of resources and labor for the common good and well-being of the people. At the heart of all innovation in human civilization is the scientific research process.
No Ideas – No Scientific Progress: Progress in all scientific disciplines, whether in the natural sciences, or humanities, mathematics, engineering or medicine, dramatically relies on the free circulation of ideas within a large and dynamic community of individuals and between the individuals and the cultural environment. Circulation and exchange of ideas, in turn, rely on the free exchange of people across nations. People move to visit schools and universities, to refine training in laboratories and institutions, to attend conferences, workshops, short visits, or sabbatical leaves. Avicenna (Ibn-Sīnā), Leonardo, Erasmus, Darwin, Marie Skłodowska Curie, Einstein are just famous examples of scientist that travelled intensively and made some of their most important contributions away from the environment they were born in.
For all scholars and students, the ability to travel freely should be a fundamental right. CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, issues a plea to all politicians and policy makers in the world to do everything in their power to promote the freedom to travel and to enter countries. We express solidarity with all colleagues worldwide who currently suffer from travel restrictions and tell them that we are committed to engage society until these fundamental rights are (re-)installed. For the sake of knowledge, diversity, science and humankind.
CeMM is a supporter of the following EMBO initiative, offering temporary bench or desk space for US-based scientists who are stranded abroad:
Researchers at the St. Anna Children’s Cancer Research Institute (CCRI) and CeMM observed unexpected variety in the epigenome of Ewing sarcoma, an aggressive childhood cancer. This finding, published in Nature Medicine, supports the importance of epigenetics in pediatric tumors and provides new perspectives for developing personalized therapies.
Tumors of the elderly, such as breast cancer and colon cancer, accumulate thousands of DNA mutations. These genetic defects contribute to cancer-specific properties including uncontrolled growth, invasion in neighboring tissues, and evasion from the immune system. Similar properties are also found in childhood cancers, although those tumors carry much fewer genetic defects, making it difficult to explain their clinical heterogeneity.
This is particularly true for Ewing sarcoma, an aggressive bone cancer in children and adolescents. A team of scientists by Eleni Tomazou from the St. Anna Children’s Cancer Research Institute in Vienna found that the disease’s clinical diversity is reflected by widespread epigenetic heterogeneity. Using novel bioinformatic methods developed by Nathan Sheffield at CeMM, the scientists studied the tumors’ DNA methylation patterns.
Ewing sarcoma showed unique characteristics that differ markedly from others cancers, and the DNA methylation patterns also varied between patients. Moreover, the researchers found that Ewing sarcoma tumors appear to retain part of the characteristic DNA methylation patterns of their cell-of-origin. Thus, the diverse clinical courses observed among Ewing sarcoma patients may be explained by the combination of Ewing sarcoma specific and cell-of-origin specific DNA methylation patterns.
“From these new insights into the biology of Ewing sarcoma we expect new impulses for personalized therapy of this aggressive cancer”, Heinrich Kovar, Scientific Director of St. Anna Children’s Cancer Research Institute, optimistically states. “Our findings also provide an interesting concept for other cancer with low genetic complexity. In the era of precision medicine, understanding the causes and consequences of tumor heterogeneity will be crucial to treat in a targeted way”, Christoph Bock, Principal Investigator at CeMM, adds.
Nathan C Sheffield, Gaelle Pierron, Johanna Klughammer, Paul Datlinger, Andreas Schönegger, Michael Schuster, Johanna Hadler, Didier Surdez, Delphine Guillemot, Eve Lapouble, Paul Freneaux, Jacqueline Champigneulle, Raymonde Bouvier, Diana Walder, Ingeborg M Ambros, Caroline Hutter, Eva Sorz, Ana T Amaral, Enrique de Álava, Katharina Schallmoser, Dirk Strunk, Beate Rinner, Bernadette Liegl-Atzwanger, Berthold Huppertz, Andreas Leithner, Gonzague de Pinieux, Philippe Terrier, Valérie Laurence, Jean Michon, Ruth Ladenstein, Wolfgang Holter, Reinhard Windhager, Uta Dirksen, Peter F Ambros, Olivier Delattre*, Heinrich Kovar*, Christoph Bock*, and Eleni M Tomazou* (*jointly directed this work). DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nature Medicine, 30 January 2017. DOI:10.1038/nm.4273
This work was partly funded by the Austrian National Bank (OeNB), a charitable donation from Kapsch Group (http://kapsch.net/kapschgroup), the Austrian Science Fund (FWF), the Human Frontier Science Program, and the Austrian Academy of Sciences.
On January 26, 2017, a LIBRA Workshop on “Best Practice in Gender-Inclusive Recruitment Processes” with representatives of the partner institutes took place at CeMM in Vienna. It provided expert insights into the topic of unbiased recruitment with the goal to start discussions on best practices, and to define recommendations to remove gender barriers in hiring processes at the LIBRA partner institutes, especially for leading positions.
LIBRA is an EC funded project which brings together ten research institutes in life sciences in ten European countries. They all are members of the alliance EU-LIFE, which aims to build and promote excellence in life sciences throughout Europe. Their commitment to excellence is also a commitment to diversity and gender equality. CeMM in collaboration with the Max-Delbrück Center for Molecular Medicine Berlin coordinates LIBRA's centralised activities to recruit without gender bias including the dissemination of gained knowledge. Additional topics within LIBRA focus on career development and training, work-life balance, and sex and gender dimensions of research.
We are grateful to our guest speakers who shared their expertise with us on why diversity matters, how job advertisements can make a difference, and what to consider to make a fair assessment of candidates possible.
Anna Beninger, Director, Research at Catalyst Inc., USA
Saher Ahmed, Athena SWAN Project Manager, Wellcome Trust Sanger Institute, UK
Eva Lübke, Project Manager at the Chair of Econometrics at the University of Mannheim, Germany
We would also like to thank Petra Unger for a very interesting guided tour “Female Traces” through the first district of Vienna the evening before the workshop started. It reminded us that history was made by both women and men alike, although it is hard to find memorials or texts in history books commemorating women.
Gaucher D et al. Evidence that gendered wording in job advertisements exists and sustains gender inequality, J Pers Soc Psychol., doi: 10.1037/a0022530
A new cell screening method combines two revolutionary tools of biomedical research: Scientists at Christoph Bock’s lab have integrated CRISPR genome editing with single-cell RNA sequencing. Their study, published in Nature Methods, establishes a method for studying gene regulation in unprecedented scale and detail.
(Vienna, 19 January 2017) Genome editing using CRISPR/Cas9 “gene scissors” is a powerful tool for biological discovery and for identifying novel drug targets. In a new article published in Nature Methods (DOI: 10.1038/nmeth.4177), a team of CeMM scientists led by Christoph Bock now present a method that combines the strengths of pooled and arrayed CRISPR screens: By integrating CRISPR genome editing with single-cell RNA sequencing, they were able to determine the gene-regulatory impact of many genes in parallel, studying thousands of individual cells in a single experiment.
Bock’s team succeeded with an elegant design that takes advantage of cutting-edge molecular technologies: The study’s first author Paul Datlinger created a viral vector for making the CRISPR guide-RNAs visible in single-cell sequencing experiments, and the latest droplet-based methods for single-cell RNA sequencing provided sufficient throughput to characterize the effect of thousands of genome editing events in individual cells.
Combining two of the most promising fields of genomics, the CROP-seq (for “CRISPR droplet sequencing”) method enables high-throughput analysis of gene regulation at a scale and detail that would be difficult to achieve with other methods. Furthermore, with falling single-cell sequencing costs, this technology could give rise to the first comprehensive maps of the regulatory effects for each of the 23,000 genes in the human genome.
“We will use CROP-seq to study the interplay of genetic and epigenetic factors in leukemia development”, says Christoph Bock, advancing the laboratory’s European Research Council (ERC) funded project on epigenome programming. “If we understand what it takes to make a cancer cell in the test tube, we can find new ways to interfere and revert cells to a less harmful state”.
CROP-seq was developed as an open source method. All data, protocols, reagents and software that are part of CROP-seq will be freely shared by CeMM, enabling other scientists to use and extend the method in their own work. The ambition to make new methods as widely available as possible is part of CeMM’s commitment to advancing biomedical research.
Paul Datlinger, André F Rendeiro, Christian Schmidl, Thomas Krausgruber, Peter Traxler, Johanna Klughammer, Linda C Schuster, Amelie Kuchler, Donat Alpar and Christoph Bock. Pooled CRISPR screening with single-cell transcriptome readout. Nature Methods, 18 January 2017. DOI: 10.1038/nmeth.4177.
The study was partly funded by a New Frontiers Group award of the Austrian Academy of Sciences and by an ERC Starting Grant.
Giulio Superti-Furga, Scientific Director of CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor for Medical Systems Biology of the Medical University of Vienna has been appointed Member of the Scientific Council of the ERC, on the 10th anniversary of its existence, for a function period of 4 years.
The European Research Council is the most important and prestigious funding institution for basic research in any field conducted within the European Union. Excellence is the sole criterion for selection; there are neither thematic priorities, nor geographical or other quotas for funding. Perhaps the most important funding programme of the ERC is the ERC Starting Independent Research Grant, promoting early scientific independence of promising talents with 2 million Euros over a period of 5 years. It has created a very positive impact on the attractiveness of Europe as research area. But the ERC has also other programmes, such as the ERC Advanced Investigator Grant, which fosters innovation carried out by established scientists with a proven scientific track record of excellence. Having been awarded two ERC Advanced Investigator Grants over the years and two ERC Proof-of-Concept Grants, to explore the application potential of research ideas, Giulio Superti-Furga, who also acted as ERC panel member in the past, knows the ERC well and is well suited to offer his experience to the organization that this year celebrates its 10th anniversary.
The ERC is governed by the Scientific Council, consisting of eminent European scientists and scholars including Nobel Prize laureates. Members are nominated by an independent search committee and appointed by the European Commission. Since 2014 Professor Jean-Pierre Bourguignon, a renowned French mathematician, is President of the European Research Council. From 2010 to 2013 Professor Helga Nowotny, a Viennese Professor of Social Studies of Science held this prestigious position. She was also a founding member of the ERC in 2007. In 2017 the European Research Council is celebrating its 10th anniversary.
The ERC Scientific Council acts on behalf of the scientific community in Europe to promote creativity and innovative research. Giulio Superti-Furga: “It is a great honor to accept this important responsibility, which has had a tremendously positive impact on basic research in Europe. My aspiration is to contribute to a more science and innovation-friendly climate in Europe by promoting excellence in research and ensuring that politicians protect and promote the ERC as the most successful research funding scheme of the EU. Results from basic research accompany us at every step and should therefore become a core theme in everyday life - in education, in the media and in public discussions. Society and politics must have the courage to invest in new projects, to keep pace with scientific developments and associated implications. It is important to understand science as a fundamental component of our culture and of our future and a motor for innovation and competiveness also for the European industry."
CeMM Adjunct PI Thijn Brummelkamp and his team discovered a surprising role of a host enzyme in Picornavirus life cycle. Their study, published in Nature, offers a completely new approach for antiviral therapies, which are soon anticipated to enter preclinical development.
Polio, hepatitis A, but also the common cold – Picornaviruses cause a broad range of human diseases. Their structural and genetic diversity made it difficult to develop effective antiviral therapies against this large family of viruses. Lacking the membrane envelope present in other types of viruses, Picornaviruses have developed a sophisticated – and largely unknown – mechanism to safely deliver their RNA packaged into protein shells called capsids into the cytoplasm of their host cells.
In this crucial step of Picornavirus infection, CeMM Adjunct Faculty Member Thijn Brummelkamp, group leader at CeMM’s EU-Life partner institute NKI, and his team identified a hitherto unknown and surprising role of a protein called PLA2G16: Located at the host’s cell membranes, PLA2G16 is essential for poliovirus entry, acting at a previously unknown step between pore formation and translation of viral RNA (published in Nature, doi:10.1038/nature21032).
The scientists didn´t leave it with that: Cells in which the PLA2G16 gene was deleted were resistant to virus infection, and mice lacking the gene were protected from a dose of a virus that would normally be lethal. Inhibition of the drugable PLA2G16 Protein surrenders picornavirus particles to a clearance mechanism normally associated with bacterial infections.
“These findings suggest that PLA2G16 can be exploited as novel antiviral target for diseases caused by picornaviruses. Furthermore, as such drugs would target a host factor rather than a viral protein, there would be a high barrier for the virus to develop drug resistance”, explains Dr Thijn Brummelkamp.
The CeMM spin-off company Haplogen, of which three CeMM faculty members were scientific founders, is developing drugs targeting PLA2G16 in partnership with Evotec which are anticipated to enter pre-clinical development in the course of 2017.
Jacqueline Staring, Eleonore von Castelmur, Vincent A. Blomen, Lisa G. van den Hengel, Markus Brockmann, Jim Baggen, Hendrik Jan Thibaut, Joppe Nieuwenhuis, Hans Janssen, Frank J. M. van Kuppeveld, Anastassis Perrakis, Jan E. Carette & Thijn R. Brummelkamp. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature, Jan 2016. DOI: 10.1038/nature21032.
This work was partially funded by the Swiss National Science Foundation (SNF), the Cancer Genomics Center (CGC), the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NOW) and the European Research Council (ERC).
Diet-related diseases like non-alcoholic fatty liver disease (NAFLD) are known to have a major inflammatory component. However, the molecular pathways linking diet-induced changes with inflammation remained elusive. In a new study, Christoph Binder’s Group at CeMM and the Medical University of Vienna identified crucial inflammatory processes in NAFLD and found that malondialdehyde (MDA), a biomarker for oxidative stress, plays a key role in the development of NAFLD and can be neutralized by specific natural antibodies – a novel approach towards a potential therapy for the prevalent disease.
Worldwide, the incidences of obesity, hypertension or insulin resistance are alarmingly high. As a consequence, risk of developing inflammation-associated diseases like type 2 diabetes, NAFLD and cardiovascular disease increased accordingly. However, the exact pathways that link the eating habits with the ensuing inflammation were so far not well understood.
The team of Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM, in collaboration with Ronit Shiri-Sverdlov at the Maastricht University, Christoph Reinhardt at the University Medical Center of the Johannes Gutenberg University Mainz and the German Center for Cardiovascular Research Mainz was not only able to shed light on the biological processes that lead to the development of chronic inflammation upon a nutrient rich diet in mice. Moreover, the Scientist found MDA to be a key player in hepatic inflammation which can be neutralized with natural antibodies. Their results were published in Hepatology (DOI: 10.1002/hep.28970). Shared co-first authors of the study are Clara Jana-Lui Busch, PhD Student at CeMM and the Medical University of Vienna, and Tim Hendrikx, PostDoc in the group of Christoph Binder.
“This study shows how the close collaboration of CeMM and the Medical University Vienna fosters the development of a future precision medicine”, says senior author Christoph Binder. “With cutting edge RNA sequencing methods and bioinformatic analyses of transcriptome data, we discovered key mechanisms in some of the most prevalent diseases and we confirmed those findings in mice models.” Binder explains, and adds: “Above that, the administration of specific antibodies for MDA epitopes provide a promising new approach for the development of therapeutic strategies.”
Clara Jana-Lui Busch*, Tim Hendrikx*, David Weismann, Sven Jäckel, Sofie M. A. Walenbergh, André F. Rendeiro, Juliane Weißer, Florian Puhm, Anastasiya Hladik, Laura Göderle, Nikolina Papac-Milicevic, Gerald Haas, Vincent Millischer, Saravanan Subramaniam, Sylvia Knapp, Keiryn L. Bennett, Christoph Bock, Christoph Reinhardt, Ronit Shiri-Sverdlov and Christoph J. Binder (*shared first author). Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice. Hepatology, Dec 16 2016. DOI: 10.1002/hep.28970
This study was supported by the Austrian Science Fund (FWF, SFB Lipotox F30), Boehringer Ingelheim (PhD Fellowship), Austrian Academy of Sciences (Doc Fellowship), EMBO (Short Term Fellowships), The Netherlands Organisation for Scientific Research (NWO), German Center for Cardiovascular Research (DZHK), German Federal Ministry of Education and Research, and the German Research Foundation (DFG).