The next-generation sequencing and data analysis pipeline (© Illustration: Zsofia Keszei, Thomas Winkler-Penz, Andreas Bergthaler / CeMM).

An interdisciplinary team led by Andreas Bergthaler and Christoph Bock at CeMM is sequencing around 400 virus samples from Austria per week for the Austrian Agency for Health and Food Safety (AGES). The goal is to look for specific SARS-CoV-2 variants with multiple spike protein mutations, and to learn more about the molecular understanding of the COVID-19 pandemic and the causative pathogen.

The enclosed illustration demonstrates the standard next-generation sequencing and data analysis pipeline for SARS-CoV-2 viral genomes which takes approximately seven days. The aim is to obtain viral full-length genomes with low frequency variants at high quality. 

More information on the project can be found at sarscov2-austria.org and in the scientific publication Popa et al. Science Translational Medicine (December 2020).

Illustration of SARS CoV-2 Sequencing (© CeMM)

Over the last few weeks, the United Kingdom and South Africa have faced a rapid increase in COVID-19 cases leading to enhanced epidemiological and virological investigations. Analysis of viral genome sequence data identified a sizeable proportion of cases belonging to new phylogenetic clusters. The new SARS-CoV-2 variants are defined by nonsynonymous, several of which are found in the viral spike protein, and still of uncertain functional significance. While it is known that viruses constantly change through mutation, and seldom does it lead to biological changes, the variants now increasingly observed in the UK and South Africa may be associated with increased infectivity.

An interdisciplinary team led by Andreas Bergthaler and Christoph Bock at CeMM in collaboration with the Austrian Agency for Health and Food Safety (AGES), have now looked for this specific SARS-CoV-2 variants with multiple spike protein mutations by sequencing additional 400 virus samples in Austria over the Christmas holidays. Among the latest sequenced and analyzed virus samples in December (data still to be uploaded to GISAID), there were 4 cases of the UK variant and 1 case of the South Africa variant. This means that the new virus variants have now also been confirmed in Austria. Some of the analyzed SARS-CoV-2 positive cases were related to Great Britain.

CeMM is proud to be able to provide this important analysis of SARS-CoV-2 sequences for Austria and the international scientific community, commensurate to the available means. CeMM, however, abstains from any speculative interpretation on the data it produces or from suggestions on policy measures. 

Following its quest to create the molecular basis for precision medicine and wishing to contribute to fight the COVID-19 pandemia, scientists at CeMM have been sequencing the SARS-CoV-2 genome since March 2020, despite limited financial resources and difficult working conditions due to the pandemic. More than 1800 samples from Austria have been sequenced so far, of which around 1300 resulted in full-length high quality SARS-CoV-2 genomes and 750 have already been deposited in the public database GISAID. The platform is updated on a regular basis with additional sequences, in order to learn more about the molecular understanding of the COVID-19 pandemic and the causative pathogen.

Additional information can be found at www.sarscov2-austria.org/austria.org/

Christoph Bock has been appointed as professor of medical informatics at the Medical University of Vienna and head of the Institute for Artificial Intelligence and Decision Support at CeMSIIS, starting 1 January 2021. The bioinformatician and genome researcher joins MedUni Vienna from the neighboring CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. He will continue to lead his research group at CeMM, complementary to the new tasks at MedUni Vienna.

As a trained computer scientist with a broad range of interests, Christoph Bock has been working at the interface between biology, medicine, and computer science for many years. His research group combines data-driven methods (bioinformatics, machine learning, artificial intelligence) with modern techniques in molecular biology (genome sequencing, CRISPR technology, systems biology). His special focus is on the development and application of new methods for precision medicine, working in close cooperation with clinical researchers toward the aim of improving diagnosis and therapy.

Christoph Bock is a principal investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna, where he has led a research group since 2012. Before that, he was a postdoc at the Broad Institute of MIT and Harvard and at Harvard University (2008-2011), and a PhD student at the Max Planck Institute for Informatics (2004-2008). He is also scientific coordinator of the Biomedical Sequencing Facility of CeMM and MedUni Vienna, “key researcher” at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), fellow of the European Lab for Learning and Intelligent Systems (ELLIS), and elected member of the Young Academy of the Austrian Academy of Sciences. He has received important research awards, including the Otto Hahn Medal of the Max Planck Society (2009), an ERC Starting Grant (2016-2021), an ERC Consolidator Grant (2021-2026), and the Overton Prize of the International Society for Computational Biology (2017). For 2019 and 2020 he was included in the global list of “Highly Cited Researchers” by Clarivate Analytics (ISI Web of Science).

At MedUni Vienna, Christoph Bock wants to contribute to the rapidly advancing area of ​​artificial intelligence / machine learning and to the development of new methods for precision medicine. His professorship is based at CeMSIIS (Center for Medical Statistics, Informatics, and Intelligent Systems), where he takes on the leadership of the Institute for Artificial Intelligence and Decision Support. Important goals include a strong research program in machine learning for biomedicine, prototypic applications in personalized medicine, and the training of a new generation of experts in “biomedical data science” who are just as familiar with computer science as they are with medicine and biology.

In order to make an important contribution to precision medicine in the treatment of cancer, immune disorders, and other diseases, Christoph Bock will combine methods from bioinformatics and medical informatics with experimentally driven biomedical research and clinical collaborations. Through close links with the CeMM, where he will continue to work as principal investigator (with a reduced number of working hours), the anticipated work will connect highly innovative biomedical research and methods development to clinical validation together with collaborators at the MedUni Vienna. One specific example is the ERC Consolidator Grant (2021-2026) approved a few weeks ago, which seeks to develop and validate a new generation of CAR T-cell immunotherapies for the treatment of solid tumors.

The CeMM Directors Giulio Superti-Furga and Anita Ender

Seitenwechsel is a spin-off of the MEGA Education Foundation, which promotes innovative educational initiatives in the areas of chance/fairness and business competence/life skills to support Austrian talent. Seitenwechsel is looking for committed and determined teachers who would like to take the opportunity to deepen their experience by working in a company for a year. On the second year, they will bring impulses from their professional experience back into their schools and implement these new fresh approaches in their teaching to better prepare the pupils for a successful start into their own career.

Continuing education, gaining knowledge, lifelong curiosity and the desire to help shape the future are essential criteria for success, both in the researchers' and the teachers' profession. We at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Science, are happy to support this initiative and be part of the company pool from which interested candidates can apply to. As a pioneering and leading international biomedical research institute in Austria, we are committed to making society more resilient to future challenges - through facts, competence and the promotion of collaboration and diversity in science.

We look forward to welcoming a new team member in our institute!

Read more about the programme (in German) and apply now: www.seitenwechsel.at/

Deadline for applications is 31 March 2021 for the start of the new school year in September 2021.

CeMM continues to be a place where biomedical research excellence goes hand in hand with social responsibility and innovation. With our two new spin-off companies Proxygen and Solgate, with our project on the “Mutational Dynamics of SARS-CoV-2 in Austria”, where CeMM has contributed the majority (>98%) of SARS-CoV-2 virus genomes from Austria to the public database GISAID. With many scientific publications and grants in 2020, resulting from our main research focus on immune disorders and infections, cancer and metabolic disorders, we are happy to look back on another successful year of advancing science. We also wish to thank all our collaborators and advisers worldwide.

2020 has been a challenge for all of us, and we would like to thank our CeMM members and collaborators for their particular effort and dedication to research, against all odds. Special thanks goes to our scientific support team, our porters, our cleaning staff and wash/media kitchen team, our facilities, the cafeteria, and our SARS-CoV-2 testing team - all the people who kept the institute, the logistics and its infrastructure running, to be able to continue work in a safe and productive environment. THANK YOU!

CeMM wishes you all the best for the holiday season and a Happy New Year!  

Giulio Superti-Furga and Anita Ender

CeMM Directors

Following its quest to create the molecular basis for precision medicine and wishing to contribute to fight the COVID-19 pandemia, scientists at CeMM have been sequencing the SARS-CoV-2 genome since March 2020. An interdisciplinary team led by Andreas Bergthaler and Christoph Bock have since obtained more than 1100 samples from Austria, of which 747 resulted in full-length high quality SARS-CoV-2 genomes. These are deposited in the public database GISAID, and the platform is updated on a regular basis with additional sequences, in order to learn more about the molecular understanding of the COVID-19 pandemic and the causative pathogen. Additional information can be found at https://www.sarscov2-austria.org/

Over the last few weeks, the United Kingdom has faced a rapid increase in COVID-19 cases leading to enhanced epidemiological and virological investigations. Analysis of viral genome sequence data identified a sizeable proportion of cases belonging to a new single phylogenetic cluster (B.1.1.7 lineage). The new SARS-CoV-2 variant is defined by 17 nonsynonymous, several of which are found in the viral spike protein, and still of uncertain functional significance. While it is known that viruses constantly change through mutation, and seldom does it lead to biological changes, the variant now increasingly observed in the UK may be associated with increased infectivity, although mechanistic data is still lacking.

The researcher at CeMM in collaboration with the Austrian Agency for Health and Food Safety (AGES), are now looking for this specific SARS-CoV-2 variant with multiple spike protein mutations by sequencing additional virus samples in Austria. Among the latest sequenced and analyzed more than 150 virus samples since September (data still to be uploaded to GISAID), there was no evidence yet that the UK variant had already spread in Austria. However, this may change when new viral isolates are sequenced. This requires additional sequencing efforts, as well as continuing the strict compliance with existing safety measures.

CeMM is proud to be able to provide this important analysis of SARS-CoV-2 sequences for Austria and the international scientific community as quickly as possible, commensurate to the available means. CeMM, however, abstains from any speculative interpretation on the data it produces or from suggestions on policy measures. 

Ruochen Jia and Robert Kralovics ( (c) Laura Alvarez / CeMM)

Patients with myeloproliferative neoplasm (MPN), a group of malignant diseases of the bone marrow, often have a carcinogenic mutated form of the calreticulin gene (CALR). Scientists of the research group of Robert Kralovics, Adjunct Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and group leader at the Medical University of Vienna, have now identified hematoxylin as a novel CALR inhibitor. The study, published in the renowned journal Blood, shows how hematoxylin compounds affect a specific domain of CALR and selectively kill those CALR mutant cells that have been identified as the cause of disease in MPN patients. The discovery has enormous therapeutic potential and gives hope for new treatment options.

In medicine, a group of malignant diseases of the bone marrow is known as myeloproliferative neoplasms. This special type of blood cancer is characterised by increased formation of blood cells, vulnerability to thrombosis and frequent transformation to acute leukaemia. In the laboratory of Robert Kralovics it was discovered as early as 2013 that carcinogenic mutations of the gene calreticulin (CALR) were frequently found in affected patients and are now used clinically as diagnostic and prognostic markers. The mechanism by which the mutated CALR functions as an oncogene, which can lead to myeloid leukaemia, has also been scientifically identified since then. The carcinogenic effect of CALR mutations is based on the interaction of the N-glycan binding domain (GBD) of CALR with the thrombopoietin receptor. Ruochen Jia from the research group of Robert Kralovics at CeMM was looking for a way to stop this interaction and prevent one of the growth advantages of CALR mutated cells. It became evident that a group of chemicals, most notably hematoxylin, can selectively kill mutated CALR cells. The results thus provide extremely valuable information for potential treatment approaches for myeloproliferative neoplasms.

Hematoxylin compounds kill CALR mutated cells

Robert Kralovics, head of the study, explains: “In our study we tried to identify small molecules that might block the interaction between the mutated CALR and the receptor.” The scientists used so-called in-silico docking studies for this purpose. “Basically, these are computer-based simulations of biochemical processes – virtual ‘screenings’ that enable increasingly accurate predictions,” says study author Ruochen Jia. The results showed a group of chemicals as binders for a specific domain of calreticulin, which selectively kill the mutated CALR cells. “Our data suggest that small molecules targeting the N-glycan binding domain of CALR can selectively kill CALR-mutated cells by disrupting the interaction between CALR and the thrombopoietin receptor and inhibiting oncogenic signal transmission,” said the study author. A hematoxylin compound proved to be particularly efficient. So far, hematoxylin has been used as a dye especially in histological staining processes.

Ray of hope for primary myelofibrosis therapy

“Our study demonstrates the enormous therapeutic potential of CALR inhibitor therapy,” says Kralovics. “The treatment of patients with primary myelofibrosis (PMF) continues to produce poor clinical outcomes. They have the clearest tendency to develop acute myeloid leukaemia. Since about one third of PMF patients have a CALR mutation, they could particularly benefit from the new therapeutic approach.”

The study “Hematoxylin binds to mutant calreticulin and disrupts its abnormal interaction with thrombopoietin receptor” was published in the journal Blood on 17 November 2020. DOI: doi.org/10.1182/blood.2020006264.

Authors: Ruochen Jia, Thomas Balligand, Vasyl Atamanyuk, Harini Nivarthi, Erica Xu, Leon Kutzner, Jakob Weinzierl, Audrey Nedelec, Stefan Kubicek, Roman Lesyk, Oleh Zagrijtschuk, Stefan N Constantinescu, Robert Kralovics;

Funding: This study was supported by the Austrian Science Fund FWF (FWF SFB F4702, P29018-B30, FWF Stand-Alone P 30041-B26).

Christoph Bock, CeMM Principal Investigator (© Klaus Pichler / CeMM).

We congratulate Christoph Bock, Principal Investigator at CeMM and Guest Professor at the Medical University of Vienna, for receiving a prestigious and well-endowed ERC Consolidator Grant of the European Research Council.

ERC Consolidator Grants are awarded to outstanding researchers of any nationality and age, with seven to twelve years of experience after PhD, and a scientific track record showing great promise and achievement. Christoph Bock and his research team receive funding worth EUR 2 million for a period of five years to pursue a highly ambitious biomedical research project.

In his project, Christoph will focus on the epigenetic regulation in CAR T cell therapy – an important but underappreciated aspect of cell-based therapies. “We will investigate the regulatory dynamics during CAR T cell therapy in unprecedented molecular detail, by following patients diagnosed with blood cancers. Moreover, we will use CRISPR technology to advance CAR T cell therapy for solid tumors. Our project aims to uncover key roles of epigenetic regulation in CAR T cells and eventually establish new therapies for hard-to-treat cancers” says Christoph Bock.

This is not the first ERC grant to be awarded to Christoph Bock. In 2016, Christoph Bock successfully applied for an ERC Starting Grant. This work led to groundbreaking molecular technologies that the new grant will apply with the goal of advancing cell-based cancer therapy.

Christoph Bock joined CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, as Principal Investigator in 2012. He pursues interdisciplinary research aimed at understanding the epigenetic basis of cancer and advancing precision medicine with genomics technology. His research group combines experimental biology (high-throughput sequencing, epigenetics, CRISPR screening, synthetic biology) with computer science (bioinformatics, machine learning, artificial intelligence). He is guest professor at the Medical University of Vienna, scientific coordinator of the Biomedical Sequencing Facility at CeMM, and group leader at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. He coordinates an EU Horizon 2020 project on the single-cell analysis of human organoids as a contribution to the Human Cell Atlas and co-leads a project on the mutational dynamics of SARS-CoV-2 in Austria. Christoph Bock is an elected member of the Young Academy of the Austrian Academy of Sciences and has received major research awards, including the Max Planck Society’s Otto Hahn Medal (2009), and the Overton Prize of the International Society of Computational Biology (2017).

Photo credit: Proxygen

CeMM congratulates its spin-off Proxygen on its new collaboration and license agreement with Boehringer Ingelheim. Their new partnership announced today will enable the identification of molecular glue degraders in the aim of degrading cancer drivers that were previously considered undruggable. The collaboration combines Proxygen’s unique molecular glue degrader discovery platform and its expertise in targeted protein degradation with Boehringer Ingelheim’s long-term strategy to provide first-in-class, breakthrough therapies for cancer patients.

Molecular glue degraders and PROTACs harness the power of the cell’s recycling machinery to selectively eliminate disease-causing proteins. Molecular glue degraders achieve this by specifically bridging the distance between target proteins and ubiquitin ligases, which consequently flag the target proteins for rapid degradation. Molecular glues orchestrate this protein-protein proximity through highly cooperative binding. They circumvent the need for a defined binding pocket on the surface of the target protein, a requirement for conventional small molecule drugs, allowing pharmaceutical intervention on proteins that were previously considered undruggable.

This successful partnership will create a new avenue towards an improved identification of molecular glue degraders candidates, and, hence, the development of future therapies to treat cancer effectively.

Read the full press release here.