May 23, 2017

A CLOUD of possibilities: Finding new therapies by combining drugs

(c) Nature Chemical Biology / Stefan Kubicek

The CeMM Library of Unique Drugs (CLOUD) is the first condensed set of FDA-approved drugs representing the entire target and chemical space of all clinical compounds. Its potential was shown in a combinatorial high throughput screen at the CeMM chemical screening platform and published in Nature Chemical Biology: A pair of hitherto unrelated drugs proved to be highly effective against multiple prostate cancer cell lines. 

(Vienna, May 22, 2017) The synergy of two combined pharmaceuticals assessed in an experimental setting can reveal completely new therapeutic options. Nevertheless, finding a novel combination of drugs for a given disease within the more than 30,000 drug products approved by the regulatory agencies was hitherto a big challenge for scientists.To facilitate systematic screening for synergistic interactions of drugs, CeMM PI Stefan Kubicek and his colleagues established a collection of 308 compounds (CeMM Library of Unique Drugs, CLOUD) that effectively represent the diversity of structures and molecular targets of all FDA-approved chemical entities. 

Moreover, the scientists proved the potential of the CLOUD with CeMM´s highly automated chemical screening platform by identifying a novel synergistic effect of two drugs (flutamide and phenprocoumon (PPC)) on prostate cancer cells. The results of Kubicek´s team with Marco Licciardello as first author where published in Nature Chemical Biology (DOI:10.1038/nchembio.2382) “The combination induced massive cell death in prostate cancer cells. We then went back to the entire approved drug list, and indeed, we could show that all drugs from the clusters that flutamide and phenprocoumon represent synergize. Thereby we validated the reductionist concept underlying the CLOUD library,” Stefan Kubicek explains. 

With their experiments, Kubicek´s team in collaboration with scientists from the Medical University of Vienna, the Uppsala University, Enamine Kiev and the Max Planck Institute for Informatics in Saarbrücken proved that the CLOUD is the ideal set of compounds to develop screening assays and discover new applications for approved active ingredients. At CeMM, a number of key discoveries on new applications for approved drugs have already been made with the CLOUD. Furthermore, as shown in the current issue of Nature Chemical Biology, the CLOUD is ideal for finding new drug combinations. “In view of these successes, I would predict that this set of compounds will become world standard for all screening campaigns”, Stefan Kubicek emphasizes.

Publication:

Marco P Licciardello, Anna Ringler, Patrick Markt, Freya Klepsch, Charles-Hugues Lardeau, Sara Sdelci, Erika Schirghuber, André C Müller, Michael Caldera, Anja Wagner, Rebecca Herzog, Thomas Penz, Michael Schuster, Bernd Boidol, Gerhard Dürnberger, Yasin Folkvaljon, Pär Stattin, Vladimir Ivanov, Jacques Colinge, Christoph Bock, Klaus Kratochwill, Jörg Menche, Keiryn L Bennett & Stefan Kubicek. A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor. Nature Chemical Biology, May 22, 2017. DOI:10.1038/nchembio.2382

Funding:

This study was supported by a Marie Curie Career Integration Grant, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development and the Austrian Science Fund (FWF).

May 16, 2017

Taking out the Cell Garbage with Chemical Degraders

The 11th CeMM Landsteiner Lecture, held by James “Jay” Bradner, President of the Novartis Institutes for BioMedical Research (NIBR) on May 15, 2017, was a truly memorable event: with enthusiasm and with great incisiveness, Dr. Bradner illustrated for the audience principles and examples of medical innovation and eloquently argued about their impact on the whole of humankind.

This year’s CeMM Landsteiner Lecture was accompanied by the wonderful accordionist Otto Lechner, whose music evoked many stimulating emotions in a short time and left the audience of more than 400 people prepared for more virtual adventures. CeMM Scientific Director Giulio Superti-Furga introduced Dr. Bradner as a pivotal figure of the chemical biology community and a visionary innovator, praising the paradigm-changing contributions of Dr. Bradner to drug discovery from a scientific and social point of view. On stage, starting with an historical overview, Dr. Bradner recalled the giants on whose shoulders every medical new modern achievement in drug discovery is built on. From vaccines to antibiotics to biomolecules like insulin – real medical progress was always achieved by radically new ideas and incisive execution. 

This is also true for what regards therapy of one of the most intensively researched diseases of our time: cancer. Jay presented the highly significant progress that has been made in cancer therapy the last decades, particular by targeted therapy, exemplified by imatinib/Glivec and and T-cell-based immunotherapy, such as the one involving chimeric antigen receptors (CAR-T cells)

Jay then presented briefly the breakthrough discovery of bromo-domain inhibitors able to reprogram the transcriptional program of cancer cells, such as JQ1, from his own laboratory as associate director of the Broad’s Center for the Science of Therapeutics and as hematologist at Dana-Farber Cancer Institute. The central part of his talk dealt with a yet different, unprecedented approach able in principle to overcome the difficulty presented by so-called “undruggable” part of the human genome. If a protein is difficult to inhibit, how about taking it out of the equation altogether? In other words, to “destroy” it by a chemical strategy? The approach presented, called “targeted protein degradation”, attacks cancer proteins not by inactivating single parts of them, but by dragging them in their entirety to the garbage removal of the cell – the proteasome - where they are destroyed and recycled. Georg E. Winter, now a Principal Investigator at CeMM and present in the audience, has been critically involved in the discovery of these “degronomids” drugs while a postdoctoral fellow in the Bradner laboratory.

While other methods try to find the right key to unlock a given door shut in cancer cells, targeted protein degradation is comparable to an explosive charge that tears the door away completely – with this impressive image, Jay pointed out the game changing difference of his approach. The results of this method speak for themselves: blood cells of leukemia patients treated with JQ1-mediated targeted protein degradation seemed to have “forgotten” that they are cancer cells and thrived like healthy, normal cells again.

The last part of the talk was dedicated to the presentation of a new collaborative paradigm by which Dr. Bradner, now heading NIBR, wants to engage the scientific community. He effectively argued that by sharing tools, reagents and ambitious goals, a new era of public-private partnerships could accelerate the identification of solutions to important challenges in a manner that neither industry alone, nor academia, could achieve alone. 

After his talk, Jay answered the many questions from the audience and continued the discussion at the subsequent cocktail reception, meeting literally hundreds of young as well as more senior participants and exchanging views, selfies and coordinates. We want to warmly thank Jay Bradner for his enlightening talk and this wonderful evening!

May 11, 2017

Celebrating the 10th Anniversary of the European Research Council in Vienna with ERC President Jean-Pierre Bourguignon

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On May 10, 2017 Austria celebrated the 10th Anniversary of the European Research Council (ERC) in Vienna in the presence of ERC President Jean-Pierre Bourguignon. The festive program “Cultivating Talents - the next ERC Decade” organized by the Federal Ministry of Science, Research and Economy (BMWFW), the Austrian Research Promotion Agency (FFG) and the Austrian Science Fund (FWF) and masterfully moderated by former ERC President and Chair of the ERA Council Forum Austria Helga Nowotny, took place in the “Haus der Europäischen Union”, and the celebration continued with a networking event in the “Börsensäle Wien” afterwards.

The program started with a welcome speech by Barbara Weitgruber, Director General for Scientific Research and International Relations of the BMWFW, followed by congratulations by Wolfgang Burtscher, Deputy Director General for Research & Innovation, European Commission, Paul Rübig, Chair Science and Technology Options Assessment Unit, MEP, Henrietta Egerth, Managing Director, Austrian Research Promotion Agency, and Klement Tockner, President of the Austrian Science Fund.

Giulio Superti-Furga, ERC Scientific Council Member since January 2017, led a discussion round with ERC Grantees on the ERC effects and visions for the future, and Helga Nowotny spoke with Heinz Engl, Rector of the University of Vienna, Thomas Henzinger, President of IST Austria and Anton Zeilinger, President of the Austrian Academy of Sciences about the view of ERC host institutions.

That the ERC is the most important and successful institution promoting research excellence in Europe is a common view. It has created a very positive impact on the attractiveness of Europe as research area, and has proven to be a catalyst for innovation and top scientific research. As such, we urge politicians from all members states and the European Union institutions to unequivocally support the ERC namely by increasing its budget in the next framework programme the FP9 and clearly endorsing its guiding principles of scientific merit and independence.

CeMM has also had the pleasure to host ERC President Jean-Pierre Bourguignon in the morning of the celebration day. It was a great privilege to welcome Professor Bourguignon in the CeMM Brain Lounge and to engage the ERC President in discussions with ERC grantees and young scientists from CeMM and befriended institutes.

As ERC Scientific Council Member, Giulio Superti-Furga considers himself a spokesperson of- and for- good science and will continue discussions and an active dialogue with scientists and host institutions in Austria: “The ERC is a wonderful project for scientists by scientists and lives of the energy and input of the scientific community. The ERC will always be as good as we can imagine it to be.” 

 

May 10, 2017

LBI-RUD opening celebration

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Kaan Boztug with LBI-RUD SAB members William Gahl, Cynthia Morton, Barbara Prainsack and Matthias Baumgartner (from left to right)

On May 9, 2017 the opening celebration of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) took place at CeMM with keynote speaker and LBI-RUD Scientific Advisory Board Chair Prof. William Gahl (NIH) and special guest Prof. Jean -Pierre Bourguignon (ERC President).

We thank Kaan Boztug and his LBI-RUD team for the wonderful party and wish them all the best for their research endeavours!

LBI-RUD will establish coordinated research efforts on the genetic and functional basis of rare diseases. The Ludwig Boltzmann Gesellschaft, 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 of St. Anna Children’s Hospital (CCRI) are official partners of LBI-RUD. LBI-RUD is located within the medical campus to maximize synergies and to enable truly translational research activities.

http://rud.lbg.ac.at/

April 24, 2017

Next-Generation Microscopy with Pharmacoscopy

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A novel microscopy method, developed and patented by scientists from CeMM, allows unprecedented insights into the spatial organization and direct interactions of immune cells within blood and other liquid multi-lineage tissues. The assay, called Pharmacoscopy and published in Nature Chemical Biology, is able to determine the immunomodulatory properties of drugs within large libraries on immune cells in high resolution and high throughput. 

The search for new drugs, small molecule or biologicals, that influence the immune system in a desired manner is challenging: immune signaling, often a combination of communication via soluble proteins and direct interaction by cell-cell contacts, is subtle and hard to track in all its nuances. So far, there has been a lack of fast and robust technology to measure the effect of a potential immunomodulatory drug in particular in a cell-cell contact dimension. 

By combining state-of-the-art high-throughput fluorescent microscopy with single cell image analysis and novel analysis algorithms, Pharmacoscopy provides a powerful solution. Developed by a group of scientists at CeMM led by Director Giulio Superti-Furga and tested in collaboration with the Medical University of Vienna, Pharmacoscopy can quantify the overall spatial patterning and direct interactions of immune cells within blood with unprecedented speed and accuracy. The method was introduced in Nature Chemical Biology (DOI:10.1038/nchembio.2360).

Combined single cell resolution and fully automated platform control, Pharmacoscopy can test large drug libraries, as available in Stefan Kubicek’s PLACEBO (Platform Austria for Chemical Biology) laboratory, for compounds with immunomodulatory potential. With this method, the scientists identified Crizotinib, an FDA approved drug for non-small cell lung cancer, to have a previously unknown immunomodulatory potential.

Publication:

Gregory I. Vladimer, Berend Snijder, Nikolaus Krall, Johannes W. Bigenzahn, Kilian V.M. Huber, Charles-Hugues Lardeau, Kumar Sanjiv, Anna Ringler, Ulrika Warpman Berglund, Monika Sabler, Oscar Lopez de la Fuente, Paul Knöbl, Stefan Kubicek, Thomas Helleday, Ulrich Jäger, and Giulio Superti-Furga. Global survey of the immunomodulatory potential of common drugs. Nature Chemical Biology, April 24, 2016. DOI:10.1038/nchembio.2360

Funding: 

This study was supported by the European Research Council, the Austrian Science Fund (FWF), Swiss National Science Foundation, European Molecular Biological Organization, the Austrian Federal Ministry of Science, Research and Economy, The National Foundation for Research, Technology and Development, The Swedish Cancer Society, the Kunt and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, and the Marie-Sklodowska Curie Fellowships.

March 28, 2017

7th CeMM S.M.A.R.T. Lecture with Hermann Hauser

In CeMM’s 7th S.M.A.R.T. Lecture, Hermann Hauser held a fascinating talk on how “Machine learning is changing everything” – from every day communication technologies to transportation habits to business strategies. 

“Machine learning is the most powerful tool that mankind developed so far” – with these words, Hermann Hauser, physicist and extremely successful serial entrepreneur at Cambridge, opened his Lecture on one of the fastest developing technologies of our times. In contrast to similar sounding but refuted predictions on artificial intelligence, Hermann Hauser emphasized, the progress of machine learning clearly shows the real impact that this tool soon will have and already has on everyone’s life. 

Speech recognition in mobile phones, face recognition programs or recommender systems of commercial platforms are just some recent examples for the capabilities of machine learning. A key feature of this technology responsible for its outstanding success: instead of following pre-programmed rules, the system learns from big data. Overruling the deterministic character of classic programming, machine learning is based on probabilities that allow to make guesses and decisions. As quality, size and availability of data is constantly increasing, machine learning will improve and pervade more and more areas of our life, Hermann Hauser is convinced. Moreover, it will change the way business is made and affect a broad range of industries. 

While this new technology will offer humanity a broad range of innovations and advantages, Hermann Hauser also pointed out the risks: “The genie is definitely out of the bottle – now we must figure out how to ensure that super intelligent machines embody human values” he emphasized. Furthermore, they pose a major challenge for society: intelligent machines might put more than 50 % of jobs be in danger. However, at the same time machine learning opens up unique business opportunities, especially in the service and health care sector with its dramatic increase in high-throughput and sensor technologies.

Having funded more than 20 technology companies, including outstanding success stories like Advanced RISC Machines (ARM) that licenses the architecture for the most widely used microchips for smart phones, Hermann Hauser is an expert in identifying and foreseeing future trends. With his S.M.A.R.T. lecture on machine learning, he gave us a thrilling overview of the latest developments and presented some eye-opening features of this revolutionary technology. Our warmest thanks to Herman Hauser for a wonderful and illuminating evening at CeMM! 

March 13, 2017

ERC’s 10th anniversary: EU-LIFE statement on the need for increased ERC budget

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EU-LIFE, the alliance of research centres in life sciences congratulates the European Research Council (ERC) on its 10th anniversary and wishes to acknowledge publicly the key role of this European Commission initiative in promoting excellent basic research.

In only a decade, the ERC has become a flagship for excellent scientific research in - and for - Europe which is key to innovation.  This is particularly relevant because even though- and mainly because of- its impact is initially unpredictable, basic research is the most certain way to major innovation for the benefit of the society.

The ERC has proven very successful in attracting top researchers to Europe and in increasing the competitiveness of Europe’s research on a global scale. The ERC allows the brightest scientists to perform excellent research that sooner or later will pave the way to disruptive innovation from all scientific fields. Coupled to professional technology transfer, basic research is of utmost importance to boost innovation. The ERC Proof of Concept Grants are indispensable for the translation of disruptive innovation from basic research results. 

Without ERC grants, research institutions would not be able to attract many of the best scientists in the world. However, Europe’s scientific potential is still not being fully realised due to lack of funding, many great research ideas fully fitting ERC evaluation criteria are put on hold, simply because of the current ERC budget limits. With an increased ERC budget excellent research will further flourish in Europe, making it even more attractive for top researchers. 

As such, we urge politicians from all Members States and the European Union institutions to unequivocally support the ERC namely by increasing its budget in the next framework programme the FP9 and clearly endorsing its guiding principles of scientific merit and independence.

March 07, 2017

Kickoff for Pharmacoscopy – a novel tool for precision medicine

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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.

February 21, 2017

First breath shapes the lung’s immune system

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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.

Publication

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

Funding:

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.

February 10, 2017

Christoph Bock receives Overton Prize

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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.