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.
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
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
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)
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.
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.
Georg Winter, CeMM Principal Investigator has received a prestigious Starting Grant of the European Research Council (ERC) for his research proposal “Glue2Degrade: Therapeutic hijacking of E3 Ligases”. The project will be funded with 1.3 € million over a period of five years.
With his research proposal Georg Winter addresses a timely and important problem, trying to fill a gap in drug development and cancer research. The Glue2Degrade project aims to transform the pharmacologically targetable space of the proteome. The project is built on the hypothesis that small molecules that can induce targeted protein degradation are much more prevalent than currently anticipated. Georg’s proposal focuses on the identification of so-called “molecular glues”, which degrade proteins by inducing cooperative protein binding to E3 ubiquitin ligases. This opens up the potential for therapeutic development of cell-, tissue-, and cancer-type specific degradation of otherwise undruggable proteins.
Traditional drug design relies on inhibition of enzymes or receptors with accessible hydrophobic pockets. Hence, most existing small-molecules are limited to the traditional “key and keyhole principle”. Unfortunately, only about 20% of all proteins can be targeted via this strategy. The concept of chemically targeting proteins for their degradation promises to overcome this limitation. In the Glue2Degrade proposal, Georg wants to revolutionize the field of targeted protein degradation to be able to chemically hijack many new E3 ligases in an unprecedented manner. As a result, his research is expected to deliver novel therapeutic strategies to target cancer as well as a fundamental understanding of mechanisms governing cellular protein degradation.
Georg Winter, PhD, obtained his degree from the Medical University of Vienna, working on elucidating the mechanism of action of anti-cancer drugs under the supervision of Giulio Superti-Furga at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. He specialized on proteomics- as well as chemical genetics approaches to identify drug resistance mechanisms and synergistic drug combinations. He continued his training in chemical biology, working as a postdoctoral fellow with James Bradner at the Dana Farber Cancer Institute/Harvard Medical School. He innovated the first generalizable pharmacologic solution to in vivo target protein degradation (Winter et al., Science 2015). He was recruited as a CeMM Principal Investigator in 2016 where his research is now focused on using the unique molecular pharmacology of targeted protein degradation to understand and disrupt aberrant gene control in human cancers. Georg Winter (co-) authored 29 manuscripts including publications in Science, Nature, Nature Chemical Biology, Nature Genetics, Elife and Molecular Cell. Georg Winter’s contribution to the field of targeted protein degradation was acknowledged via multiple prizes and awards, including the Eppendorf Award 2019 and the Elisabeth Lutz Award of the Austrian Academy of Sciences.
Project support by the European Research Council (ERC) ranks among the most prestigious fundings within Europe. An ERC Starting Grant is meant for promising early-career researchers with two to seven years’ experience after PhD. Excellence is the sole criterion for selection, and there are neither thematic priorities, nor geographical quotas for funding. The aim is to recognize the best ideas, and confer status and visibility to the best research and talents in Europe.
CeMM congratulates Georg Winter and his team to this great achievement and the well-funded grant!
With great sadness, we have to inform you about the passing of Daniel Lackner, who died on 31 August 2019, at the age of 41, after severe illness. Daniel started at CeMM as RESOLUTE Scientific Project Manager in the group of the Scientific Director in March 2018, and will be dearly missed by his colleagues and friends. Our thoughts and deepest sympathy are with his family.
Daniel performed his undergraduate studies in biology and genetics at the MFPL in Vienna. For his graduate work he moved to the Wellcome Trust Sanger Institute in Hinxton, UK, where he used genomic approaches to study gene expression regulation in fission yeast. After obtaining his PhD from the University of Cambridge, he decided to do his post-doctoral work at the Salk Institute for Biological Studies in San Diego, USA. There, he studied telomere biology and aging with a focus on large-scale approaches. After returning to Austria in 2015, he joined the biotech company Horizon Discovery, where he led a team to generate human knock-out cell lines using CRISPR/Cas9, before he started his new role as Scientific Project Manager within the Superti-Furga lab at CeMM.
Daniel played an essential role in setting up the scientific and organizational framework of the IMI-funded EU Project RESOLUTE (Research Empowerment on Solute Carriers), a public-private partnership with 13 research groups from academia and industry. He was highly respected within the consortium for his scientific expertise, his dedicated and diligent working style, and his ability in successfully bridging academia and industry, by connecting scientists with different backgrounds and expectation for a common overarching goal.
From the very beginning, Daniel was very open about his disease and his courageous and exhausting fight against a rare tumor. Daniel was a true scientist at heart and a role model in many ways. His intellectual rigor, supportive and humorous attitude contributed positively to CeMM’s culture and the success of the RESOLUTE project.
Daniel Lackner will be dearly missed by the CeMM Directors, by his colleagues who had the privilege of interacting with him, and by the entire RESOLUTE consortium. We lose an extraordinary researcher, a talented and dedicated science manager, and highly appreciated colleague. Daniel died way too early. Our sincere condolences go to his wife and his children.
Giulio Superti-Furga and Anita Ender
For the first time, a study led by Kaan Boztug, Scientific Director of St. Anna Children's Cancer Research Institute, unveils a hitherto unknown immune deficiency syndrome, which is based on a reduced functionality of the enzyme complex polymerase δ, an essential controller in DNA replication. Mutations affecting its function lead to genomic instability, neurodevelopmental disorders and immunodeficiency. The study was recently published in the prestigious Journal of Clinical Investigation and brings important insights into adaptive immunity and carcinogenesis.
Genes are the basic building blocks of life and, consequently, essential to all living organisms. The factors, which are responsible for their duplication, are very similar in almost all living organisms and have hardly changed over thousands of years. One of these factors is polymerase δ. This enzyme complex is a key element not only for DNA replication, but also for genome stabilization and cell cycle regulation. Polymerase δ is composed of four building blocks: POLD1 and the additional subunits POLD2, POLD3 and POLD4. Organisms with severe disruption of these DNA polymerases are often not viable, which makes research difficult.
Led by Kaan Boztug, researchers from LBI-RUD, CeMM and MedUni Vienna, together with collaborators from the University of Istanbul and the University of Leiden, could identify two unrelated patients with a novel immunodeficiency syndrome based on a reduced functionality of polymerase δ. Specifically, they detected biallelic germline mutations, i.e. gene mutations inherited from both parents, in POLD1 and POLD2. In both cases, these mutations resulted in an immunodeficiency syndrome with recurrent respiratory infections, skin problems, and neurodevelopmental disorders. Closer examination of the disease mechanisms revealed that the cell cycle was impaired in the lymphocytes of both patients. The number of copying errors in DNA increased, which lead to warning tags in the DNA of the cell, and, therefore, causes cell cycle dysfunction.
Particularly noteworthy is that the study provides also key information for other diseases such as childhood cancer: Unlike in other immunodeficiency syndromes with a shortage of an immune-specific factor, the underlying disease mechanism is a deficiency of a basic function of the cell. Although the deficiency particularly affected immune cells, the replication control mechanism of polymerase δ is relevant to the function of all cells. A disorder can have dramatic consequences in the balance of cell growth. It is known that certain mutations in POLD1 lead to the so-called "mutator phenotype", which contributes to genetic instability and is found in many human cancers. Accordingly, POLD1 is classified as a highly dangerous cause of cancer in the international classification. Conversely, the congenital POLD1 / 2 mutations described in the study lead to a reduced intrinsic activity (the "actual task") of the polymerase δ and possibly increases the chances of developing cancer at an earlier age (cancer predisposition syndrome). The present study also aims to bring awareness into the research and help identify additional patients for a systematic analysis of the cancer risk in affected children and children with related illnesses.
The Study: "Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress” was published in the Journal of Clinical Investigation on 26 August 2019, DOI: 10.1172/JCI128903
Authors: Cecilia Domínguez Conde*, Özlem Yüce Petronczki*, Safa Baris*, Katharina L. Willmann*, Enrico Girardi, Elisabeth Salzer, Stefan Weitzer, Rico Chandra Ardy, Ana Krolo, Hanna Ijspeert, Ayca Kiykim, Elif Karakoc-Aydiner, Elisabeth Förster-Waldl, Leo Kager, Winfried F. Pickl, Giulio Superti-Furga, Javier Martínez, Joanna I. Loizou, Ahmet Ozen, Mirjam van der Burg, and Kaan Boztug
Funding: The study was funded by the European Research Council (ERC) under the European Union Seventh Framework Program (FP7/2007-2013; ERC grant agreement 310857, to KB), Austrian National Bank (ÖNB Jubilee Fund 16385, to KB), a grant from the Jeffrey Modell Foundation (to KB and MB), and the Austrian Science Fund Lise Meitner Program Fellowship (FWF M1809, to KLW).
Nuno Maulide´s group from the Faculty of Chemistry of the University of Vienna has, in cooperation with Stefan Kubicek´s lab at CeMM, achieved the synthesis of a potential immunosuppressive agent by modification of a naturally occurring compound. In this endeavour, the researchers have employed a masking trick to "hide" a reactive species inside the target molecule. The results were recently published in the renowned "Journal of the American Chemical Society".
The FR-molecules: natural products with special properties
In 2003, a Japanese company reported the isolation of 3 natural products from the microorganism Pseudomonas fluorescens, the so-called "FR Molecules". Noteworthy was their complex chemical structure but also their very interesting immunosuppressive properties. Immunosuppressive drugs are widely used in the treatment of allograft repulsions and autoimmune-associated diseases. Although a range of such drugs have been developed and are used clinically, almost all of them carry severe side effects and limitations. The search for new immunosuppressants with a distinct mode of action is therefore an urgent need to improve the safety and efficiency of immunosuppressive therapy.
Several research groups have attempted the laboratory synthesis of the FR molecules in the years that followed – with mitigated sucess. "They all struggled with the molecule’s Achiles’ Heel: the macrocyclic ring with three consecutive double bonds", explains Nuno Maulide, who since November 2018 is also Adjunct PI at CeMM.
A solution to a long-standing problem
Nuno and his team have now developed a novel chemical reaction that allows the preparation of macrocyclic structures in high efficiency and from simple precursors. "We simply hide the double bonds in a 'secured' form, so that they can be revealed at a later stage. Very much like a 'Trojan horse'", jokes Yong Chen, first author of the paper.
For this goal the researchers install a smaller ring with only 4 carbon atoms, termed a "cyclobutene", as "masked" form for the double bonds of the natural product. This approach results in a very short access to the FR molecules.
"We are now in a position to make grams of these compounds; the natural source delivered at best milligrams – a considerable advance. Furthermore, the compounds we prepare in the lab are indistinguishable from those isolated from Pseudomonas fluorescens", enthuses Nuno Maulide.
Variations lead to a better drug
As the researchers are now able to reproduce these complex structures in the lab, they are in a position to introduce non-natural variations and modifications of those structures. They already found an "analogue" (i.e, a new molecule resembling the original natural product but possessing small structural modifications) that is almost 100 times more potent than the compounds produced by Nature. "The joint collaboration between University of Vienna and CeMM has resulted in true synergies", explains Stefan Kubicek from CeMM of the Austrian Academy of Sciences, and co-author of the study.
The Study: "A domino 10-step total synthesis of FR252921 and analogues, complex macrocyclic immunosuppressants”: was published in the Journal of the American Chemical Society, DOI: 10.1021/jacs. 9b07185
Authors: Yong Chen, Guilhem Coussanes, Caroline Souris, Paul Aillard, Dainis Kaldre, Kathrin Runggatscher, Stefan Kubicek, Giovanni Di Mauro, Boris Maryasin, Nuno Maulide
Funding: The study was funded by the European Research Council (ERC, CoG VINCAT), the Austrian Science Fund (FWF, under P27194 and Doctoral Program “Molecular Drug Targets” W1232), and the German Research Foundation (DFG, Grant MA 4861/3-1).
Targeted protein degradation (TPD) is a new paradigm in drug discovery that could lead to the development of new medicines to treat diseases such as cancer more effectively. A recent study by researchers at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences reveals global and drug-specific cellular effectors needed for TPD. The results have now been published in the scientific journal Molecular Cell.
Traditional medicines mostly function as inhibitors, attacking the disease-relevant proteins that cause cancer, by binding to their accessible pockets. Following this strategy, only ~20% of all proteins are chemically addressable, leaving some of the most relevant targets inaccessible to therapeutic development.
Targeted protein degradation (TPD) is a novel approach in drug development that could overcome this limitation, and currently represents a promising therapeutic strategy towards, for example, cancer treatment. TPD is based on small-molecules, generally called “degraders”, that induce the degradation of proteins by re-directing ubiquitin E3 ligases towards the protein we aim to eliminate. In other words, utilizing the cell’s Ubiquitin Proteasome System (UPS), which is our body’s natural way of seeking out and destroying damaged proteins.
Until now TPD had been mostly studied from a structural perspective. Georg Winter’s laboratory at CeMM focused on identifying and mechanistically understanding genetic determinants of sensitivity to small-molecule degraders. “We selected a representative set of five degraders, which hijack different ubiquitin E3 ligases to degrade proteins of clinical relevance, such as BRD4, CDK9, or GSPT1. Conducting resistance screens, we were able to identify genes that determine the efficacy of targeted protein degradation”, explains Cristina Mayor-Ruiz, CeMM postdoc and co-first author of the study.
The data obtained identify central UPS regulators as essential for degrader efficacy. “When those proteins are perturbed, ubiquitin E3 ligases lose their ability to flexibly assemble and disassemble in response to cellular needs. Instead, they start tagging themselves for destruction in a process called auto-degradation. As a consequence, the tested degrader drugs fail to destabilize their target proteins and are ineffective in blocking cancer cell growth”, elaborates Martin Jaeger, CeMM PhD student and second co-first author of the study.
The research conducted by Cristina Mayor-Ruiz, Martin Jaeger et al. combining functional genomics and quantitative proteomics is the first study that comprehensively dissects cellular determinants of mechanistically different small-molecule degraders, bringing new light into their rational design.
“Now that degraders are entering the clinic, understanding potential resistance mechanisms may inform on ways to overcome it. The modulator gene-networks that we have identified can serve as biomarkers to support patient stratification, but also teach us a lot about fundamental aspects of the regulation and dynamics of the protein degradation machinery”, says Georg Winter, CeMM Principal Investigator.
The study “Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation” was published in Molecular Cell on 22 August 2019. DOI: 10.1016/j.molcel.2019.07.013
Cristina Mayor-Ruiz*, Martin G. Jaeger*, Sophie Bauer, Matthias Brand, Celine Sin, Alexander Hanzl, André C. Mueller, Jörg Menche, Georg E. Winter
The study was funded by the Austrian Academy of Sciences. Cristina Mayor-Ruiz was supported by an EMBO long-term fellowship (EMBO-LTF ALTF 676-2017) and Martin Jäger was supported by a Boehringer Ingelheim Fonds (BIF) PhD fellowship.