November 13, 2019

Novel mathematical framework provides a deeper understanding of how drugs interact

First author Michael Caldera and last author Jörg Menche © Franzi Kreis / CeMM

Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have developed a new methodology characterizing more precisely how drugs influence each other when combined during treatment. Their analysis of over 30k drug pairs applied to cell lines identified 1,832 interactions between 242 different drugs and sheds new light on how drugs perturb the underlying molecular networks. The findings have now been published in the scientific journal Nature Communications.

Combining two or more drugs can be an effective treatment of diverse diseases, such as cancer. Yet, at the same time, the wrong drug combination can cause major side effects. Currently there is no systematic understanding of how different drugs influence each other. Thus, elucidating how two given drugs interact, and whether they have a beneficial effect, would mean a major step towards drug development to treat diseases more effectively in the future.

On a molecular level, drugs cause complex perturbations of various cellular processes in our body. These processes are orchestrated by an intricate network of molecular interactions, the so-called interactome. Over the last decade, numerous studies have revealed a close relationship between the structure of the interactome and the functional organization of the molecular machinery within the cell. This opened exciting opportunities for using network-based approaches to investigate the foundations of both healthy and disease states. Following this trend, Principal Investigator Jörg Menche and his group at CeMM developed a novel mathematical framework for mapping out precisely how different perturbations of the interactome influence each other.

The new study performed by Caldera et al., represents the first general approach to quantifying with precision how drugs interact with each other, based on a mathematical model that considers their high-dimensional effects. Their research reveals that the position of targets of a given drug on the interactome is not random but rather localized within so-called drug modules. They found that the location of a drug module is linked to the specific cell morphological changes induced by the respective treatments, making morphology screens a valuable resource for the investigation of drug interactions. Further they identified various factors that contribute to the emergence of such interactions. Most notably, the distance between two drug modules on the interactome plays a key role: Certain types of interactions are more likely depending on the exact proximity between the two respective drug modules. If the modules are too far away from each other, it is rather unlikely that an interaction will take place.

“We developed a completely new methodology to classify drug interactions. Previous methods could characterize interactions only as synergistic or antagonistic. Our methodology is able to distinguish 12 distinct interactions types and also reveals the direction of an interaction”, says Michael Caldera, first author of the study and PhD student at Jörg Menche’s Group.

The study of the Menche group has broadened the understanding of how drugs perturb the human interactome, and what causes drugs to interact. Moreover, the introduced methodology offers the first comprehensive and complete description of any potential outcome that may arise from combining two perturbations. Finally, this methodology could also be applied to address other key challenges, such as dissecting the combined impact of genetic variations or predicting the effect of a drug on a particular disease phenotype. Their research forms a solid base for understanding and developing more effective drug therapies in the future.

 

The study “Mapping the perturbome network of cellular perturbations” was published in Nature Communications on 13 November 2019. DOI: 10.1038/s41467-019-13058-9

Authors:
Michael Caldera, Felix Müller, Isabel Kaltenbrunner, Marco P. Licciardello, Charles-Hugues Lardeau, Stefan Kubicek and Jörg Menche

Funding:
This work was supported by the Vienna Science and Technology Fund (WWTF) through project number VRG15-005.

November 12, 2019

3rd RESOLUTE Consortium Meeting 6-8 November 2019

RESOLUTE partners that participated at the 3rd RESOLUTE Consortium Meeting in Milan, Italy

On 6-8 November 2019, the 3rd RESOLUTE Consortium Meeting took place near Milan, Italy, and was hosted by Axxam within OpenZone. RESOLUTE is a public-private partnership, funded with a grant from the Innovative Medicines Initiative (IMI) and coordinated by CeMM and Pfizer, with 13 partners from academia and industry.

The first day of the meeting kicked off with updates from several RESOLUTE partners, which showcased the progress achieved since the last consortium meeting in Krems, Austria, in June 2019.

The second day was dedicated to a “Data Integration workshop”, where participants discussed insights and tools to extract knowledge from the combination of diverse data types generated within the RESOLUTE project. The workshop included keynote talks by Avner Schlessinger (Mount Sinai, New York, USA), Rob Russell and Francesco Raimondi (BioQuant Heidelberg, Germany), and Patrick Aloy (IRB, Barcelona, Spain). EFPIA representatives Andreas Steffen (Bayer AG), Robert Stanton (Pfizer Ltd), and Karsten Quast (Boehringer Ingelheim), as well as CeMM members Enrico Girardi and Eva Meixner, shared specific examples and tools related to data integration.

On the last day, RESOLUTE external collaborators presented several strategies to develop high-affinity binders for Solute Carriers (SLCs), which will help boost research on this protein class. This was followed by project-specific discussions leading to the definition of current priorities and plans for the upcoming year of RESOLUTE.

We would like to thank OpenZone and Axxam for the smooth organisation, and all participants and partner institutions for their enthusiasm and fruitful discussions!

Find out more about RESOLUTE: https://re-solute.eu

October 18, 2019

Thomas Reiberger receives UEG Rising Star Award

Thomas Reiberger, LBI-RUD/CeMM Adjunct PI / Credit: CeMM

Congratulations to Thomas Reiberger, Associate Professor at the Division of Gastroenterology and Hepatology at the Medical University of Vienna, and Adjunct Principal Investigator at LBI-RUD and CeMM, for receiving the United European Gastroenterology Rising Star Award at the 2019 UEG Week in Barcelona!

Follow the Rising Star Talk of Thomas via live stream on 21 October 2019 at 4.20 pm: "Understanding pathophysiology in order to identify novel therapeutic strategies for chronic liver diseases”

Every year the National Societies Committee and the UEG Scientific Committee jointly select 6-8 emerging clinical scientists as Rising Stars. These are promising candidates under the age of 40 with an excellent scientific track record and internationally recognized and independent research.

The United European Gastroenterology (UEG), represents more than 30,000 medical specialists from every field in gastroenterology. The UEG Week attracts around 14,000 conference participants each year.

Thomas Reiberger, born 1982, joined the LBI-RUD and CeMM in 2018 as an Adjunct PI. After obtaining his MD at the Medical University of Vienna, he did a first postdoc at the Department of Pathophysiology at the Medical University of Vienna, where he performed his first studies in the field of Liver Cell Biology. During his residency for Internal Medicine at the Divison of Gastroenterology and Hepatology at the Medical University of Vienna, Thomas Reiberger followed the career of a physician scientist and focused his translational studies on portal hypertension and fibrosis in patients with viral hepatitis. Next to the clinic he established the Vienna Hepatic Experimental (HEPEX) Laboratory at the Medical University of Vienna. In 2011 he received his Venia docendi and 2012 he obtained his board certification for Internal Medicine. After another postdoctoral fellowship in the United States from 2012 to 2015, Thomas Reiberger was appointed as Associate Professor of Gastroenterology and Hepatology at the Medical University of Vienna. 

More information: https://www.meduniwien.ac.at/web/ueber-uns/news/

October 10, 2019

International Consortium with CeMM Principal Investigator Joanna Loizou receives prestigious ERC Synergy Grant

Steve P. Jackson (The Gurdon Institute, UK), Joanna Loizou (CeMM) and Jacob Corn (ETH Zurich)

Joanna Loizou, Principal Investigator at CeMM, together with Jacob Corn, Eidgenoessische Hochschule Zuerich (ETHZ), Switzerland and Steve P. Jackson, The Gurdon Institute, University of Cambridge, UK, are awarded ERC Synergy Grant for DNA-damage response systems. The prestigious funding worth round €8.86M for a period of six years, of which € 2.95M will go to Joanna Loizou´s group, will help provide major insights into human genome surveillance and speed the development of new therapies for cancer and other diseases.

ERC Synergy Grants are intended to enable a minimum of two and a maximum of four Principal Investigators and their teams to bring together complementary skills, knowledge, and resources in new ways that are more than additive, in order to jointly address ambitious research problems. In their project “Dna Damage Response: Actionabilities, Maps and Mechanisms” (Acronym: DDREAMM) Joanna Loizou, Jacob Corn and Steve P. Jackson team up to shed light on DNA-damage response (DDR) systems.

Within this ERC Synergy Grant, starting in January 2020, the three teams will devote the next six years to mapping and understanding how eukaryotic cells monitor and protect their genomes. To do this they will use cutting-edge technologies in gene editing and chemical biology. Hence, they will take multidisciplinary approaches to create deeply integrated genetic and physical maps of DNA repair pathways and interactions in many human cell types. This work will provide major insights into human genome surveillance in multiple cell types, yield powerful tools to precisely control DNA repair outcomes, and speed the development of new therapies for cancer and other diseases. In response to receiving this grant, Joanna says: ‘the ERC Synergy Grant allows Jacob, Steve and myself to bring together our unique expertise in an unparalleled manner, to tackle the fundamentally important question of how our genomes are maintained’.

In the research project, each individual lab will play to its strengths while also assimilating expertise from the other labs. As the ERC Synergy grant will be focused on rapidly evolving scientific arenas, the international partnership offers a possibility to collectively embrace and exploit the very latest technological developments and scientific opportunities, in ways that would not be possible if the three groups operated individually.

Joanna Loizou’s long-standing expertise is embedded in investigating the cellular pathways that respond to DNA damage, to maintain genome stability and suppress disease. Her important contributions within this field began during her PhD (2000-2004, UK) and continued during two postdoctoral positions (2004-2007, France and 2007-2011, UK). During these training posts, Joanna consistently made seminal discoveries, by identifying a novel kinase that regulates DNA repair (Loizou et al, Cell 2004), linking the DNA damage response to post-translational modifications and epigenetic regulation (Murr* & Loizou*, et al Nature Cell Biology 2006) and identifying and characterizing a novel tumour suppressor (Loizou et al, Cancer Cell 2011).

In September 2011, Joanna established her independent group at CeMM, Vienna, Austria. Her vision is to piece together the intricate puzzle that encompasses the human DNA damage response at the cellular level, hence providing a complete understanding of how such pathways go wrong in disease states, with a strong emphasis on cancer. To achieve this her team uses genome-scale approaches, based around genetics, genomics, proteomics and chemical biology. She hypothesizes, and have proven, that by investigating the regulatory pathways of DNA repair taking unbiased approaches, we can advance our knowledge of how cells respond to DNA damage, uncover genetic interactions required for DNA repair and cellular survival and unravel the impact on the genome upon engagement of DNA damage and DNA repair pathways. Hence, she envisages that her research will shed light on the mechanisms leading to cancer development and pave the way for better treatments for cancer and other DNA repair-associated diseases.

October 10, 2019

Become a Starting Principal Investigator at CeMM

CeMM Faculty 2019 / Illustration: Frau Isa

We are currently searching for innovative, creative, ambitious scientists to become a CeMM Starting Principal Investigator and to join our highly committed CeMM Faculty working hard and having fun conceiving and exploring new precision medicine approaches and contributing to revolutionize the medicine of the future.

•    Do you want to join the CeMM Faculty, an international group of highly collaborative and supportive colleagues, who help you to achieve your goals?
•    Are you fascinated by the inner workings of cells and biological systems and look for a place where intellectual rigor and curiosity are matched by inventive multidisciplinary approaches to deepen your investigations?
•    Do you want to power-up your medically-oriented research with cutting-edge technologies?
•    Do you want to obtain, secure, navigate and interpret big high-dimensional data to drive science and network medicine?
•    Do you want to become a successful innovator and translate your findings to impact medical practice?

The research area
This position is perfectly suited for highly professional and passionate scientists who work on an important problem of molecular medicine, preferably but not exclusively, pertaining to high resolution cell biology, imaging, molecular pharmacology, cancer biology, infection biology, inflammation, hematopoiesis, hematological malignancies, vascular disorders, genome integrity, epigenetics, bioinformatics, systems biology.

Whom we are looking for
CeMM is looking for MD and/or PhD scientists at their first independent appointment to apply their expertise close to a clinical setting. Required are scientific quality and originality, a successful track record of scientific achievements and profound expertise in a particular research field. Leadership skills, creativity, curiosity as well as a collaborative and interdisciplinary mindset are important ingredients to complete our new faculty member’s profile.

About CeMM
CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences is an international top research institute doing highly cooperative frontier research in molecular medicine, combining a deep understanding of the molecular machinery of the cell with pathophysiology in a unique medical setting ideal for the development of innovative translational ideas. Our institute is located in Vienna, Austria’s capital city and the world’s best city to live. The vigorous, strong partnership with the Medical University and the location in the middle of one of the world’s largest hospital is a unique asset. And together with the partnering institutes, such as the Ludwig Boltzmann Institute for Rare and Undiagnosed Disease and the St. Anna Cancer Research Institute, we might also be interested in identifying positions for your partner.

For more information and application details please have a look at: CeMM Starting PI announcement (PDF)

Deadline for applications: 20 November 2019

October 09, 2019

Focus on Austrian Metabolic Research: 2nd AustroMetabolism Workshop

Related Files

Share

Participants at 2nd AustroMetabolism Workshop at CeMM (2019)

On Wednesday 9 October 2019, around 120 researches from 15 institutions from all over Austria gathered for the second time for the AustroMetabolism Workshop at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna.

AustroMetabolism is an interdisciplinary event, which aims at providing a space for Austrian basic and clinical researchers in the field of metabolic research to network, and also promoting scientific cooperation within this field. A better understanding of metabolic processes in the human body is key to the treatment of many diseases. For this purpose, the diverse scientific contributions at the workshop ranged from cell metabolism of cancer and immune cells, diabetes, obesity, fat and liver metabolism, to the influence of the degradation of food by the intestinal microbiome on inflammatory bowel disease.

A highlight of the event was a guest lecture by Prof. Matthias Tschöp, Scientific Director of the Helmholtz Center Munich with over 2300 employees. Prof. Tschöp is one of the world's leading researchers in the fight against obesity and type 2 diabetes, and has developed several so-called poly-agonists drugs that could revolutionize the treatment of these diseases. Additionally, the renowned journal Nature Metabolism was represented by an editor, Pooja Jha, who allowed participants to take a look behind the scenes of the scientific publication process. She was very impressed by the diverse and high-class research landscape in Austria.

The AustroMetabolism Workshop was initiated by a joint initiative of the Medical University of Vienna, the University of Veterinary Medicine Vienna, the University of Graz and CeMM. The event has set a great example for this promising research field and boosted an even closer collaboration between scientists from basic and clinical research.

October 04, 2019

CeMM Outing 2019

Related Links

Share

On Friday, 4 October 2019 our yearly CeMM Outing took place, bringing together our CeMMies and adjunct members for an excursion. We enjoyed a day full of interesting talks and social activities outside the Institute.

This year’s special focus was on materials and material testing. Miriam Unterlass, CeMM Adjunct PI and Assistant Professor at the Technical University of Vienna, kicked off the event by discussing materials in the context of civilization and humanity, and its relevance to the life sciences, followed by a talk of Joachim Rajek, TÜV AUSTRIA General Manager, on the importance of material testing and analyses to make state-of-the-art technologies competitive for the market.

After the introductory lectures, we had the opportunity to visit the TÜV Laboratories for mechanical testing of materials, components and structures, located in the 23rd district of Vienna. The TÜV laboratories are part of the TÜV Austria Group and the TU Wien, and act as an independent laboratory meeting the highest standards of safety and innovation.

After an insightful morning, we enjoyed a typical Austrian lunch in Klostergasthaus Thallern, and participated in a wine rally at Freigut Thallern, one of the top-quality wineries in the vicinity of Vienna.

We hope that everybody enjoyed the informative and fun day outside our labs and offices! We also would like to especially thank Miriam Unterlass, Joachim Rajek, and Eva Schweng for the great organization!

Photo credit: Belle & Sass / CeMM

September 23, 2019

EU-LIFE urges the EU Council and the European Parliament to prioritise R&I by committing an appropriate budget for Horizon Europe

Related Links

Related Files

Share

EU-LIFE, the alliance of 13 leading Life Science Research Institutes in Europe urges the EU Council and the European Parliament to double Horizon Europe’s budget compared to Horizon 2020 (H2020), to 150 Billion Euros and within it, to double the budget for discovery research, including the well-proven European Research Council.

In addition, we strongly support the position of the President of the European Parliament, Mr. David Sassoli, on the need to include “Research” in the name of the portfolio of the EC Commissioner for Innovation and Youth.

Europe is at a critical crossroads. While new major societal challenges emerge, the EU is at the same time called to revisit its founding values and questioned on its role in Europe and the World. Therefore, refocusing on real beacons of the EU ideal is needed to secure and nurture the EU added value for citizens. In this context, European R&I emerges not only as a true success, but also as a real pillar of the EU ideal. Few other fields illustrate so clearly how crucial it is to have a strong EU that leverages local potential while guiding national and regional policies.

It is clear from studies on previous Framework Programmes that every Euro spent on Research & Innovation will generate roughly five-fold the investment in economic benefit, as well as improving social, health and environmental standards. However, R&I represents less than 10% of the total EU budget.
Consequently, it is time that the EU promotes R&I to a higher ranking on its list of priorities.  This must be reflected in the EU’s Multi-Annual Financial Framework through an increase in the Horizon Europe budget as recommended by the Lamy report and in an earlier EU-LIFE position paper.

We therefore urge the European Parliament and the EU Council to provide Horizon Europe with 5 key asse

  1. An appropriate budget: To achieve high impacts, Horizon Europe needs a commensurate budget. We were the first organisation to publicly support the recommendations in Lamy’s report to double Horizon Europe’s budget compared to H2020, to 150 Billion Euros. We stand by this and maintain our recommendation to double the budget of Europe’s Research & Innovation framework programme in order to realise its impact and address today’s global challenges.

  2. A balanced programme: the impact of tomorrow depends on the discoveries of today and the highest value over time comes from high-risk, open-ended excellent research. This should be the main priority of public funding such as Horizon Europe. The investment in close to the market stages will then follow from the private sector. Therefore, we recommend to double the budget for discovery research (Pillar 1), including the well-proven European Research Council and Marie Skłodowska-Curie actions (MSCA).

  3. Making the European Research Area (ERA) a reality: Realising ERA and advancing in open science including gender equality cannot fall solely on the shoulders of individual researchers, innovators or projects. Excellent R&I needs a healthy R&I ecosystem that in turn needs strong institutions with international standards. EU-LIFE strongly supports the policy that European framework programmes should not substitute national or regional investment and measures should be adopted to incentivise prioritisation of R&I in Member States’ budgets aiming at 3% GDP at least. However, national incentives cannot fully accomplish international standards alone and a pan- European push is needed through Horizon Europe.

  4. Addressing knowledge transfer: Building a proper research ecosystem that efficiently catalyses translation of knowledge is essential since the path to innovation is not linear and includes several feedback loops. The true challenge is to actively assist researchers with identifying and enabling commercial and/or social use of their findings.

  5. Realistic impact and collaborative approaches: Innovation provides solutions based on knowledge. Solutions without new knowledge are not innovation; they are merely implementation. The role of open-ended research within multi-sectoral collaboration must be nurtured. Therefore, expected timing of impact of research outputs in Horizon Europe should be realistically adjusted to a longer timescale and its definition broadened beyond economic competitiveness to include wider social impact.

    Likewise, because names set priorities, we also call for the inclusion of “Research” in the name of the recently created portfolio “Innovation and Youth”.

Last author Kaan Boztug and co-first author Marini Thian (LBI-RUD) / © CCRI

The immune system is highly complex and a detailed understanding of many underlying mechanisms is still lacking. Only the precise interaction of a variety of factors guarantees a reliable and correct immune response in a healthy body. Misregulated immune responses are a major cause of a variety of diseases, including cancer, autoimmunity, and immune deficiency.

A study recently published in the renowned journal Blood, led by Kaan Boztug investigated four patients from independent families with malignancy, autoimmunity and immunodeficiency. All four patients had a germline mutation in the gene encoding CD137, which led to a dysfunction of the co-receptor protein CD137. This dysfunction impaired crucial factors for immune surveillance, in particular for the prevention of viral infections and the development of lymphoma associated with Epstein-Barr virus (EBV) infection. "Not only did we discover a new tumor predisposition syndrome particularly for childhood lymphomas in this study, we also learned more about the basic function of CD137 in the immune system," says Kaan Boztug, joint corresponding and last author.

The study was carried out in a collaboration with scientists from Israel, Germany, Turkey, Colombia, Argentina and the USA. The last authorship is shared by Raz Somech from the Chaim Sheba Medical Center in Tel Aviv, Christoph Klein from the Dr. von Hauner Children's Hospital of the LMU Munich and Kaan Boztug, Scientific Director of CCRI and LBI-RUD, Adjunct PI at CeMM and Associate Professor at MedUni Vienna.

Publication & Authors:

“CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis” Ido Somekh*, Marini Thian*, David Medgyesi, Nesrin Gülez, Thomas Magg, Alejandro Gallón Duque, Tali Stauber, Atar Lev, Ferah Genel, Ekrem Unal, Amos J. Simon, Yu Nee Lee, Artem Kalinichenko, Jasmin Dmytrus, Michael J. Kraakman, Ginette Schiby, Meino Rohlfs, Jeffrey M. Jacobson, Erdener Özer, Ömer Akcal, Raffaele Conca, Türkan Patiroglu, Musa Karakukcu, Alper Ozcan,  Tala Shahin, Eliana Appella, Megumi Tatematsu, Catalina Martinez-Jaramillo, Ivan K. Chinn, Jordan S. Orange, Claudia Milena Trujillo-Vargas, José Luis Franco, Fabian Hauck, Raz Somech#, Christoph Klein#, and Kaan Boztug#.; published in Blood: blood.2019000644; doi: doi.org/10.1182/blood.2019000644 (* shared first author; # shared corresponding and last author)

Funding:

The study was funded by the European Research Council (ERC, Consolidator Grant 820074 "iDysChart" and ERC Advanced Grant), the Jeffrey Model Foundation (JMF), the Care for Rare Foundation, the German Research Foundation (DFG, Gottfried-Wilhelm-Leibniz Program, CRC1054) and the Else Kröner-Fresenius Foundation (Research College Rare Diseases of the Immune System). Marini Thian was further supported by a doctoral fellowship from Cell Communication in Health and Disease (CCHD) by The Austrian Science Fund (FWF) and a DOC grant (25225) from the Austrian Academy of Sciences.

September 14, 2019

CeMM PI Andreas Bergthaler nominated "Austrian of the Year 2019, Category Research"

We congratulate CeMM PI Andreas Bergthaler, who has been nominated “Austrian of the Year 2019” in the "Research" category. Join us in supporting Andreas’ work and nomination!

Vote for Andreas Bergthaler via the online system.

The #Austria19 award is organized by the newspaper Die Presse in collaboration with the ORF, the Austrian Broadcasting Cooperation, and is given to individuals who made outstanding contributions in the fields of science, economics and humanity. 

The research of Andreas and his team focuses on how inflammatory processes are regulated and how the immune system responds to viral infections. At CeMM, he has already gained important new insights into the molecular understanding of hepatitis, pneumonia and metabolic diseases in infections.

Andreas Bergthaler studied veterinary medicine in Vienna. He undertook graduate and postgraduate research with Hans Hengartner and Nobel Laureate Rolf Zinkernagel at the University of Zurich and ETH Zurich followed by postdoctoral positions at the University of Geneva and the Institute for Systems Biology in Seattle. He is recipient of an ERC Starting Grant and several awards including the Löffler-Frosch-Prize of the Society of Virology (2016), the Georges-Köhler Prize of the German Society for Immunology (2016), the Seymour and Vivian Milstein Young Investigator Award of the International Cytokine and Interferon Society (2016) and the Austrian Infection Research Prize of the Austrian Society for Infectious Diseases and Tropical Medicine (2017). Andreas Bergthaler co-founded the clinical-stage immunotherapy company Hookipa Pharma. He joined CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences as Principal Investigator in 2011.

This is the second time a CeMM researcher has been nominated for this public voting. In 2011, CeMM’s Scientific Director, Giulio Superti-Furga, received the award in the same category for bringing scientific excellence and innovation to Austria.