Targeted protein degradation (TPD) represents a novel paradigm in drug discovery that could lead to more efficient medicines to treat diseases such as cancer. “Molecular glue degraders” are an emerging but understudied class of small molecules that have been shown to induce degradation of proteins commonly considered “undruggable”. Researchers at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, have described a strategy that, for the first time, enables the rational and highly scalable discovery of novel molecular glue degraders. Their findings have now been published in the renowned scientific journal Nature Chemical Biology.
Despite enormous efforts to advance traditional pharmacology approaches, more than three quarters of all human proteins remain beyond the reach of therapeutic development. Targeted protein degradation (TPD) is a novel approach that could overcome this and other limitations, and thus represents a promising therapeutic strategy. TPD is based on small molecules, generally called “degraders”, which can eliminate disease-causing proteins by causing their destabilization. Mechanistically, these degrader drugs repurpose the cellular protein quality control system, tweaking it to recognize and eliminate harmful proteins. In detail, they re-direct members of the protein family of E3 ubiquitin ligases (E3s) towards the disease-causing target protein. This leads to a “molecular earmarking” of the harmful protein via a process called “ubiquitination”. Subsequently, the ubiquitinated protein is recognized and degraded by the molecular machine called the proteasome, which serves as the cellular garbage disposal system.
In this study, CeMM researchers turned their focus to a subset of degraders called “molecular glue degraders”. This class of seemingly rare small molecules that has been shown to induce the degradation of target proteins that could not be blocked via ways of traditional pharmacology. Consequently, these proteins had been termed “undruggable”. The best characterized examples are the clinically approved thalidomide analogs, effective for the treatment of different blood cancers. Unfortunately, the discovery of the few described molecular glue degraders has historically been a process entirely driven by serendipity and no rational discovery strategies existed.
To overcome this limitation, Georg Winter’s group at CeMM set out to innovate a scalable strategy towards the discovery of novel molecular glue degraders via phenotypic chemical screening. To this end, first author and CeMM postdoctoral fellow Cristina Mayor-Ruiz and colleagues engineered cellular systems widely impaired in E3 activity. Differential viability between these models and E3-proficient cells was used to identify compounds that depend on active E3s, and therefore, potential molecular glue degraders. Researchers integrated functional genomics with proteomics and drug-interaction strategies, to characterize the most promising compounds. They validated the approach by discovering a new RBM39 molecular glue degrader, structurally similar to others previously described. Importantly, they discovered a set of novel molecular glues that induce the degradation of the protein cyclin K, known to be essential in many different cancer types. Interestingly, these novel cyclin K degraders function via an unprecedented molecular mechanism of action that involves the E3 CUL4B:DDB1 and that has never been therapeutically explored before.
This study, performed in close collaboration with CeMM PI Stefan Kubicek, thus provides the first framework towards the discovery of molecular glue degraders that can be highly scaled, but also strongly diversified. “I truly believe that we are only scratching the surface of possibilities. This study is chapter one of many chapters to follow. We will see a revolution in the way researchers perceive and execute therapeutic strategies for previously incurable diseases by crafting glue degrader strategies that will enable them to eliminate therapeutic targets that could not be explored with traditional pharmacologic approaches,” says CeMM PI and last author of the study Georg Winter.
“Rational discovery of molecular glue degraders via scalable chemical profiling” was published in Nature Chemical Biology on 3 June 2020. DOI: xxx.
Cristina Mayor-Ruiz, Sophie Bauer*, Matthias Brand*, Zuzanna Kozicka, Marton Siklos, Hana Imrichova, Ines Kaltheuner, Elisa Hahn, Kristina Seiler, Anna Koren, Georg Petzold, Michaela Fellner, Christoph Bock, André C. Müller, Johannes Zuber, Matthias Geyer, Nicolas H. Thomä, Stefan Kubicek, Georg E. Winter
The study was supported by the Austrian Academy of Sciences, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Starting grant agreement No 851478) and the Austrian Science Fund (FWF project number P32125-B and P30271-B28). C. Mayor-Ruiz was supported by an individual Marie Skłodowska-Curie postdoctoral fellowship (grant agreement No 796010).
The human body is often seen as a “machine” that consists of specialized components: Bones and soft tissue provide structure, organs contribute physiological functions, and immune cells protect against pathogens. In reality, many cell types and organs may play more than one role. Researchers at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, have now discovered a striking example of multi-tasking cells. In a paper published in the scientific journal Nature, CeMM researchers analyzed the epigenetic and transcriptional regulation in structural cells, including epithelium, endothelium, and fibroblasts. They found widespread activity of immune genes, suggesting that structural cells are deeply involved in the body’s response to pathogens. Moreover, the study uncovered an “epigenetic potential” that pre-programs structural cells to engage in the immune response against pathogens. These findings highlight an underappreciated part of the immune system and open up an exciting area for research and future therapies.
The immune system protects our body from constant attack by viruses, bacteria, and other pathogens. Much of this protection is provided by hematopoietic immune cells, which are derived from the bone marrow and specialize in fighting pathogens. They include macrophages, which remove pathogens; T cells, which kill infected virus-producing cells; and B cells producing antibodies that neutralize pathogens. However, immune functions are not restricted to these “specialists”, and many more cell types are able to sense when they are infected and contribute to the immune response against pathogens.
Structural cells provide essential building blocks of the body and play an important role in shaping the structure of tissue and organs. Most notably, epithelial cells constitute the surface of the skin, while also separating tissues and organs from each other; endothelial cells coat the inside of all blood vessels; and fibroblast provide the connective tissue that keeps tissues and organs in shape. Structural cells are often regarded as simple and rather uninteresting components of the body, despite their well-established roles in autoimmune diseases (such as rheumatoid arthritis and inflammatory bowel disease) and in cancer. In their new study, Thomas Krausgruber, Nikolaus Fortelny and colleagues in Christoph Bock’s laboratory at CeMM focused on elucidating the role of structural cells in immune regulation by pursuing a systematic, genome-wide analysis of epigenetic and transcriptional regulation of structural cells in the body.
To that end, the CeMM researchers established a comprehensive catalog of immune gene activity in structural cells, applying high-throughput sequencing technology (RNA-seq, ATAC-seq, ChIPmentation) to three types of structural cells (epithelium, endothelium, fibroblasts) from twelve different organs of healthy mice. This dataset uncovered widespread expression of immune genes in structural cells as well as highly cell-type-specific and organ-specific patterns of gene regulation. Bioinformatic analysis detected genes that control a complex network of interactions between structural cells and hematopoietic immune cells, indicating potential mechanisms by which structural cells contribute to the response to pathogens.
Interestingly, many immune genes showed epigenetic signatures that are normally associated with high gene expression, while the observed expression in structural cells obtained from healthy mice was lower than expected based on their epigenetic signatures. CeMM researchers therefore hypothesized that these genes are epigenetically pre-programmed for rapid upregulation when their activity is needed – for example in response to a pathogen. To test this hypothesis, they joined forces with Andreas Bergthaler’s laboratory at CeMM, capitalizing on their expertise in viral immunology and infection biology.
When the mice were infected with a virus (LCMV) that triggers a broad immune response, many of those genes that were epigenetically poised for activation became upregulated and contributed to the transcriptional changes that structural cells showed in response to viral infection. These results suggest that structural cells implement an “epigenetic potential” that pre-programs them to engage in rapid immune responses. As an additional validation, the researchers triggered an artificial immune response by injecting cytokines into mice, and they indeed found that many of the same genes were upregulated.
The new study has uncovered a striking complexity of immune gene regulation in structural cells. These results highlight that structural cells are not only essential building blocks of the body, but also contribute extensively to its defense against pathogens. Moreover, the presented data constitute an important first step toward understanding what “structural immunity” might mean for the immune system, and it may help develop innovative therapies for some of the many diseases that involve the immune system.
The study “Structural cells are key regulators of organ-specific immune responses” was published in Nature on 1 July 2020. DOI: 10.1038/s41586-020-2424-4
Thomas Krausgruber*, Nikolaus Fortelny*, Victoria Gernedl, Martin Senekowitsch, Linda C. Schuster, Alexander Lercher, Amelie Nemc, Christian Schmidl, André F. Rendeiro, Andreas Bergthaler and Christoph Bock | * shared first authorship
The study was co-funded by a New Frontiers Group award of the Austrian Academy of Sciences, two Austrian Science Fund (FWF) Special Research Programme grants (FWF SFB F 6102-B21; FWF SFB F 7001-B30) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No 679146 awarded to Christoph Bock; Grant Agreement No 677006 awarded to Andreas Bergthaler). Thomas Krausgruber was supported by a Lise-Meitner fellowship from the Austrian Science Fund (FWF M2403). Nikolaus Fortelny was supported by a fellowship from the European Molecular Biology Organization (EMBO ALTF 241-2017). Alexander Lercher was supported by a DOC Fellowship of the Austrian Academy of Sciences.
RESOLUTE, a public-private partnership funded by the Innovative Medicines Initiative (IMI) and coordinated by CeMM and Pfizer, has recently reached its second year’s milestone on working towards the advancement of basic research on Solute Carrier Transporters.
On 29-30 June 2020, the 4th RESOLUTE consortium meeting, initially to be hosted by Sanofi in Paris (France), took place virtually. More than 60 RESOLUTE members joined a “virtual tour” of the beautiful city of Paris. During the online tour, work package leaders reported their latest research progress and project milestones at iconic places, such as the Eiffel Tower, the Arc of Triumph, the Sainte Chapelle and the catacombs. Presenters also discussed how persistent collaboration will help overcome the next challenges. Additionally, participants also had the chance to learn more about the world-famous French cuisine virtually.
We would like to thank all participants and RESOLUTE SAB members for their enthusiasm and fruitful discussions!
Find out more about RESOLUTE: https://re-solute.eu
In June 2020, Joanna Loizou and her team members moved to the Medical University of Vienna to join the Institute of Cancer Research. Joanna will now become an Adjunct Principal Investigator at CeMM.
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, investigating the mechanisms by which cells respond to – and repair - DNA damage to maintain genomic stability and suppress tumorigenesis and other rare hereditary diseases. One of many research highlights was in 2017, when Joanna’s research group, together with collaborators from the Medical University of Vienna and the IRB Barcelona, found that the FDA-approved diabetes drug acetohexamide significantly improves the resilience of NER deficient cells against UV radiation in vitro. The study (Mazouzi et al, Mol. Cell 2017) identified the responsible molecular mode of action, a hitherto unknown, NER-independent repair mechanism for UV-induced DNA damage.
Her research has culminated in being awarded, together with Jacob Corn from ETZ Zurich (Switzerland) and Steve P. Jackson from The Gurdon Institute (UK), a prestigious ERC Synergy Grant for damage response systems. With funding of around €8.86 million that started in the first quarter of 2020, the scientists will devote the next six years to mapping and understanding how eukaryotic cells monitor and protect their genomes. The project’s goal is to provide major insights into human genome surveillance in multiple cell types, yield powerful tools to precisely control DNA repair outcomes, and speed up development of new therapies for cancer and other diseases. Joanna was the first female scientist in Austria to win such a coveted support and of the first ones to do so in the life sciences. Because of Joanna and her collaboration network, Vienna is poised to establish itself on the research map of this highly important area of research for the years to come
This is not a goodbye, it is a natural step forward into her scientific career. CeMM does not offer tenure and therefore Joanna Loizou’s relationship with CeMM enters a new phase: As Adjunct PI, Joanna will stay connected with the institute through the CeMM PhD Program, scientific events, faculty meetings and well-established networks and research collaborations.
CeMM wishes Joanna and her team all the best for this next career step at the Institute of Cancer Research of the Medical University of Vienna!
On 19 June 2020, the “Innovation Awards 2020-2021 / Austria’s Beste” were announced by the Austrian Association for Consumer Studies (ÖGVS) and the business magazine Trend, in their special issue Top 500. CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences has been awarded with the “Special Prize/Sonderpreis” in the field of organic chemistry and obtained the second-best place in IP category Biochemistry. This acknowledgement confirms CeMM’s status as a leading biomedical research institute in the country and recognizes the institute’s important contribution to world leading innovations and inventions.
The "Innovation Award 2020/2021" is awarded biannually by the Trend magazine and the ÖGVS – Gesellschaft für Verbraucherstudien, a neutral and independent society for consumer studies in Austria. The jury panel examined all companies and research institutes in Austria that have registered and issued at least two worldwide patent families in the period from 1 January 2018 to 31 December 2019. The “Innovation Awards” recognize local companies and organizations that have excelled in one of the 130 classes of the International Patent Classification System (IPC), having an above-average number of granted patent applications and citations.
Protection of intellectual property in the form of patents is part of CeMM’s core strategy to ensure that the research performed in our institute is translated and commercialized for the benefit of society. To this end, CeMM has protected inventions related to the treatment of diseases including, diabetes, cancer and inflammation. CeMM’s translational impact also includes spin-off companies, such as Haplogen, Allcyte, MyeloPro, Aelian Biotechnology, and Proxygen, and strategic partnering with industry and pharmaceutical companies to further develop and apply its research results to the benefit of medicine and patients. This allows CeMM to fulfill its mandate to do world-class research in biomedicine, to train researchers and medical doctors in molecular medicine and to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future.
We thank our CeMM scientists, technologists and scientific support staff for providing a constant flow of world-class research results and innovations, and our patent attorney from Vossius & Partner for professional support. We are grateful to ÖGVS and Trend for this recognition!
For more information please visit the ÖGVS website.
EU-LIFE, the alliance of 14 leading Life Science Research Institutes in Europe announces its vision based on the lessons learned by COVID-19 pandemics on how Europe can prepare for future health crisis.
The current COVID-19 pandemic dramatically highlighted how vulnerable Europe is regarding health safety. The health and wellbeing of European citizens requires a long-term vision and better coordination among European countries in order to be better prepared and respond more effectively to current, emerging and future global health crises.
Only discovery-driven research, embedded in a strong health industry ecosystem, will bring Europe lasting – and faster – solutions to the health challenges of our society. One without the other will not suffice and both are essential to maintain high quality care at an affordable level for all European citizens.
The EU Multiannual Financial Framework (MFF) needs to give health safety a greater focus and stronger foundation. The recent proposal of the European Commission (EC) for the MFF recognises the above points, but it is clear that the allocated funds are insufficient to make the urgent investments in research and innovation that are needed to drive health safety.
Finally, we call for stronger coordination at both European Union and national levels, as well as with other collaborating territories regarding research and innovation policies, infrastructures, data interoperability, scientific advice and crises preparedness.
René Medema, Chair of EU-LIFE and Director of The Netherlands Cancer Institute, says: “To safeguard the health security of European citizens, EU member states need to raise up investment in high-risk discovery-oriented research, combined with a more supportive environment for pharmaceutical industry – only combining these two aspect we can address efficiently the medical needs of European citizens”.
Marta Agostinho, EU-LIFE Coordinator says: “Whenever a new global crisis arises, we all look at science for solutions, because we know that existing solutions for past crises such as AIDS resulted from discovery-driven research. That is why we urge the European Council to support a strong Horizon Europe budget and ensure that discovery-driven research has the necessary resources in Europe”.
The human Mediator complex is selectively required for cell-type-specifying transcription
Using targeted protein degradation technology, researchers at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, set out to understand the primary role of a key regulator of transcription, the human Mediator complex. Mediator, a 30 subunit molecular machine, was thus far positioned as a factor that is generally required for the transcription of all protein-coding genes in human cells. In contrast, the recent study by Georg Winter’s group at CeMM discovered that Mediator particularly safeguards the transcription of a small set of cell-type-specifying genes. In collaboration with Patrick Cramer’s lab at the Max Planck Institute for Biophysical Chemistry in Göttingen, the scientists revealed mechanistic details of how Mediator enables cells to robustly exert their dedicated functions. The study “Selective Mediator dependence of cell-type-specifying transcription” was published in Nature Genetics, on 1 June 2020.
Georg Winter’s lab at CeMM uses chemical tools to understand the molecular basis of gene control and aberrations thereof in cancer. To do so, the team combines particularly fast-acting protein ablation systems (“degradation Tag”/ “dTAG”, co-developed by Georg Winter in Jay Bradner’s lab at the Dana Farber Cancer Institute, in Boston) with precise and unbiased measurements of gene activity at high kinetic resolution. Together with Patrick Cramer’s lab and others, the international team of scientists now unveiled how the Mediator molecular machine mechanistically directs gene activation, which had long remained poorly understood owing to challenges in experimental manipulation.
Mediator was identified over 30 years ago as a molecular bridge that allows DNA-binding proteins, called transcription factors, to communicate with the cellular gene-copying machine, called RNA polymerase II (Pol II), to activate target genes. Understanding the direct role of Mediator in this process requires technologies that rapidly block Mediator function and measure changes in Pol II activity within the subsequent minutes. Using targeted protein degradation, scientists in the Winter lab now managed to rapidly remove individual parts of the Mediator complex to ask the question, whether the copying of all human genes depends to the same extent on Mediator integrity. In contrast to the existing paradigm, the study first-authored by CeMM PhD student Martin Jäger suggests that Mediator is not generally required for transcription of all genes. Rather, the data imply that Mediator selectively safeguards the expression of a small set of genes, which form densely connected regulatory circuits to instruct cell-type-specific functions.
By visualizing Pol II enzymes in cells, the scientists observed that Mediator nucleates large clusters of transcription machinery components that are thought to form around regulatory DNA regions, called super-enhancers. These super-enhancers direct the expression of cell-type-specific genes by physically touching their target genes, which are often millions of DNA bases away. When Mediator was degraded, the large Pol II clusters rapidly disappeared, but super-enhancers still seemed to touch their target genes, indicating that Mediator was not required to maintain these DNA contacts.
Together with experts from the Cramer lab in Göttingen, however, the team observed dramatic changes in the dynamics of Pol II turnover at super-enhancer-driven genes after Mediator loss. The data suggested that Mediator clusters drove highly efficient recruitment of Pol II enzymes to these cell-type-specific genes, allowing their copying at remarkable efficiency. At the same time, the majority of other genes seemed to be surprisingly mildly affected by acute Mediator loss, which made the scientists suspect that they undergo some unexpected type of compensatory boost.
The team went on to address this compensatory mechanism, and found that promoter-proximal pausing of Pol II was globally reduced in response to Mediator loss. Pausing is a phenomenon, where Pol II enzymes are held back for several minutes right after they started copying a gene. The waiting Pol II constitutes a roadblock that prevents the passing of other Pol II enzymes behind it, thus limiting the number of RNA copies produced in a given timespan. After Mediator degradation, the scientists observed that the main factor responsible for signaling pause release, called cyclin dependent kinase 9 (CDK9), more efficiently bound to DNA in cells and more actively tagged its protein targets with a phosphate group. Chemically blocking CDK9 activity made the transcriptional defects of Mediator ablation less selective for super-enhancer target genes, which highlights that the uncovered CDK9 activation shapes how cells react to acute Mediator loss. This unexpected finding suggested that pausing may have evolved as a buffering capacity to rapidly react to and partially compensate acute defects in Pol II recruitment.
The study opens up new avenues to understand the composition of Mediator-nucleated Pol II clusters and how CDK9 is so efficiently activated in response to transcriptional stresses. Furthermore, Georg Winter imagines future possibilities to perhaps tackle diseases, where Mediator function went awry: “Very preliminarily, our work might also have revealed some potential for Mediator as a drug target and next steps might be to develop direct degrader molecules against this complex.”
The study “Selective Mediator dependence of cell-type-specifying transcription” was published in Nature Genetics on 1 June 2020. DOI: 10.1038/s41588-020-0635-0.
Martin G. Jaeger, Björn Schwalb, Sebastian D. Mackowiak, Taras Velychko, Alexander Hanzl, Hana Imrichova, Matthias Brand, Benedikt Agerer, Someth Chorn, Behnam Nabet, Fleur M. Ferguson, André C. Müller, Andreas Bergthaler, Nathanael S. Gray, James E. Bradner, Christoph Bock, Denes Hnisz, Patrick Cramer,* Georg E. Winter*
The study was supported by the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the German Research Foundation (DFG), the International Max Planck Research School for Genome Science, and the European Research Council ERC. Martin Jäger was supported by a Boehringer Ingelheim Fonds PhD fellowship.
216 SARS-CoV-2 genome sequences have now been completed and released in the framework of the “Mutational Dynamics of SARS-CoV-2 in Austria” project from CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, in close collaboration with the Medical University of Vienna, the Medical University of Innsbruck and the Austrian Agency for Health and Food Safety (AGES). This data represents another milestone in the project and will help to understand the mutational landscape and evolution of the Austrian SARS-CoV-2 strains. Together with this release, CeMM researchers have published a dedicated website that offers background information as well as interactive access to the data for scientists and laypeople alike. The virus genomes can be explored interactively and intuitively via advanced visualization tools provided by CeMM and the open source project Nextstrain.
The spread of the pandemic SARS-CoV-2 virus in the human population is met with unprecedented collaborative scientific efforts around the world to unravel its virological, immunological and disease-causing properties. Genome sequences of SARS-CoV-2 viruses circulating worldwide are being published and made openly available to the international scientific community. A better understanding of the viral evolution will be instrumental to comprehend the underlying mutational dynamics and support the development of effective antiviral treatment and vaccine strategies to halt the COVID-19 pandemic.
In Austria, CeMM researchers with collaboration partners from the Medical University of Vienna were pioneers in sequencing the first genomes obtained from Austrian patient-derived samples. Within the scope of the “Mutational Dynamics of SARS-CoV-2 in Austria” project, the first samples were made available to the public and the international research community already at the beginning of April 2020. This highly collaborative initiative, led by CeMM Principal Investigators Andreas Bergthaler and Christoph Bock, aims at elucidating 1,000 SARS-CoV-2 genomes in Austrian patients using cutting-edge next-generation sequencing techniques and sophisticated computational analyses. The project includes a wide national collaboration network with partners from the Medical University of Vienna (Judith Aberle, Stephan Aberle, Elisabeth Puchhammer-Stöckl), the Medical University of Innsbruck (Wegene Borena, Dorothee von Laer; Manfred Nairz, Günter Weiss) and the Austrian Agency for Health and Food Safety (Daniela Schmid, Peter Hufnagl) as well as several hospitals and diagnostic laboratories.
Building on their first 21 genome sequences published on 3 April 2020, this second release with 216 new SARS-CoV-2 genomes from across Austria provides a more detailed picture about the circulating viruses and the early phase of the COVID-19 pandemic. The genetic differences of the genomes indicate that the pool of circulating viruses in the early phase of the pandemic was already highly diverse, with some viruses leading to bigger transmission clusters than others. Importantly, Austria has benefited from painstaking contact tracing by the Austrian Agency for Health and Food Safety, which defined more than 250 clusters of COVID-19 cases. “Our integrative analysis of the new SARS-CoV-2 genome information with epidemiological data provides valuable new insights into how the virus has been spreading through the country. The virus sequence data provides independent support for many of the epidemiological findings resulting from contact tracing. At the same time, we observed both heterogeneity within clusters and obtained evidence for multiple viruses circulating at the same time,” says Andreas Bergthaler, project co-coordinator and CeMM Principal Investigator (see illustration 1).
The molecular sequence analysis revealed on average 6.9 mutations per viral genome, of which more than 4 resulted in changed amino acids. A particular focus of interest worldwide rests on mutations in the viral S or spike protein, which decorates the surface of the virion and lends the coronavirus its eponymous crown-like appearance (see illustration 2). This viral S protein is essential for binding to the cellular receptor ACE2 as well as the presumed primary target for neutralizing antibodies. As such, mutations in this region will be important for the development of serological tests and antibody-mediated protection by vaccines. Within all Austrian SARS-CoV-2 genomes, we identified a total number of 12 mutated residues in the 1,273 amino acid long S protein. One particular mutation in the S protein, D614G, represents an early branching point that is dominant in the European infection clusters and parts of North America (see illustrations 2 and 3). This mutation is also found in many of the Austrian samples. The potential functional consequences of the D614G mutation are currently being investigated by several international laboratories. CeMM’s ongoing in-depth viral mutation analyses with an interdisciplinary team from the fields of genomics, biomathematical modeling, evolution biology and virology will yield new insights into how the S protein and other viral proteins evolve as well as how these mutations are transmitted between individuals.
Today’s release marks yet another crucial milestone as CeMM intensifies its efforts to communicate science and to reach out to the general public. Based on the tools of the open source project Nextstrain.org, CeMM researchers released a Nextstrain Austria version that allows users to compare and visualize all sequenced Austrian virus genomes with more than 8,000 virus genomes from all over the world. The Nextstrain Austria Blog will provide concise up-to-date and data-driven stories to share interesting insights about what the virus genomes tell us about the SARS-CoV-2 pandemic. These narratives will explore the actual genome data generated by CeMM and its partners, and allow users to explore the content interactively with an intuitive design. Users are guided through different dashboards where they encounter interactive graphics with a short explanatory text on different topics related to the SARS-CoV-2 virus. The visualization tool is available in both English and German and can be accessed at https://cemm.at/sars-cov-2/. The blog will be continuously updated and give first-hand insights into ongoing intense research about the SARS-CoV-2 virus.
The project team will continue their efforts to sequence 1,000 SARS-CoV-2 viral genomes, which will provide a detailed picture of emerging viral mutations and virus transmissions. This will offer further valuable scientific insights to epidemiologists, health care professionals and public health experts to assess transmission routes of the virus as well as its potential to subvert vaccine-induced immune responses and to acquire resistance against antiviral drugs.
Access SARS-CoV-2 sequencing data:
The sequences, related information and the blog are accessible at cemm.at/sars-cov-2/
On 18 May 2020, Proxygen GmbH, a startup company by CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, Georg Winter, Giulio Superti-Furga, Stefan Kubicek and Matthias Brand has been founded.
Proxygen GmbH will develop therapies against cancer and other life-threatening diseases by reprogramming the cellular protein quality control system. Proxygen is focused on particular small molecules called “molecular glue degraders” which induce proximity between a disease-causing protein and an ubiquitin ligase. Consequently, the target protein is ubiquitinated and directed to the proteasome for degradation. Instead of merely blocking the function of harmful proteins, molecular glue degraders enable their complete, targeted and selective elimination. This outlines a clear avenue towards targeting otherwise undruggable proteins and is therefore seen as one of the most promising therapeutic innovations of the last decades.
Proxygen will be located in the VBC 6 Startup Labs, a new co-working space for biotech companies embedded in the Vienna Biocenter campus, and will be supported by funds of the Austrian Business Agency (AWS), as well as by private investors and industry cooperations.
Proxygen is the fifth startup company, after Haplogen, MyeloPro, Allcyte, and Aelian, which has been created based on intellectual property and know-how of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences. CeMM’s mandate is to do world-class research in biomedicine, train researchers and medical doctors in molecular medicine and accelerate the precise, personalized, participatory and preventative medicine of the future. Integral component of CeMM’s strategy is to identify and support translational initiatives that promise to have an impact on medicine. CeMM, therefore, considers that safeguarding and valorizing its research output is an integral part of its societal responsibility, and that the efficient commercialization of CeMM’s proprietary and ideas will lead to the improvement of healthcare.
Proxygen GmbH – ein neues Spin-Off Unternehmen des CeMM
Heute wurde die Proxygen GmbH gegründet, ein Startup-Unternehmen des CeMM Forschungszentrums für Molekulare Medizin der Österreichischen Akademie der Wissenschaften, Georg Winter, Giulio Superti-Furga, Stefan Kubicek und Matthias Brand.
Proxygen wird Therapien gegen Krebs und andere lebensbedrohliche Krankheiten entwickeln, indem sie das zelluläre Proteinqualitätskontrollsystem neu programmiert. Proxygen konzentriert sich auf bestimmte kleine Moleküle, die als “molecular glue degraders” bezeichnet werden. Die Moleküle bringen ihr Zielprotein in die Nähe einer sogenannten Ubiquitin Ligase, welche das schadhafte Protein für den Abbau markiert. Neu in dieser Behandlungsstrategie ist, dass man nunmehr das Wirkspektrum mittels eines Medikamentes mit hoher Genauigkeit beeinflussen kann. Die Methode wird daher als eine der vielversprechendsten Innovationen der letzten Jahrzehnte angesehen.
Proxygen wird in den VBC 6 Startup Labs angesiedelt sein, einem neuen Kooperationsraum für Biotech-Unternehmen am Vienna Biocenter, und mit Mitteln der Austria Wirtschaftsservice Gesellschaft mbH (AWS) sowie durch private Investoren und Industriekooperationen finanziert.
Proxygen ist nach Haplogen, MyeloPro, Allcyte und Aelian das fünfte Startup-Unternehmen, das auf der Grundlage von geistigem Eigentum und Know-how des CeMM, Forschungszentrums für Molekulare Medizin der Österreichischen Akademie der Wissenschaften, gegründet wurde. Das Mandat von CeMM besteht darin, Spitzenforschung in der Biomedizin zu betreiben, ForscherInnen und ÄrztInnen in der molekularen Medizin auszubilden und die präzise, personalisierte, partizipative und präventive Medizin der Zukunft zu beschleunigen. Ein wesentlicher Bestandteil der CeMM-Strategie ist die Identifizierung und Unterstützung von Verwertungs- und Kommerzialisierungsvorhaben, die eine Weiterentwicklung in der Medizin und einen Nutzen für PatientInnen versprechen. CeMM ist daher der Ansicht, dass die Sicherung seiner Forschungsergebnisse ein wesentlicher Bestandteil der gesellschaftlichen Verantwortung des ÖAW-Instituts ist, und dass die effiziente Verwertung zu einer Verbesserung der Gesundheitsversorgung führen wird.
How cells recognize pathogens and alert the immune system swiftly is a fundamental process of high importance for the survival of any species, including humans. A key role is ascribed to so-called adapters, that equal little molecular platforms inside cells where signals from pathogen detectors are integrated for safety and accuracy and conveyed to lasting signals leading to the activation of the major “red alarm” genes, like interferons. Researchers from the lab of Giulio Superti-Furga at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in collaboration with Boehringer Ingelheim have identified a new key element of the multi-component machinery that is responsible for sorting out the nature and severity of the pathogen challenge. The new protein, named TASL, is indispensable for the signaling of so-called Toll-like receptors (TLR) in the endosomes leading to activation of the gene-activator IRF5 in certain immune cells. Sensitive “tuning” of the machinery is highly important as too much output causes inflammation also in the absence of the pathogen, as in auto-immune diseases. This particular version of the machinery seems particularly associated with disorders such as systemic lupus erythematosus (SLE). This discovery highlights a potential new target for the development of drugs to treat certain autoimmune diseases and possibly also overreaction to viral and other infections, and has been published in the renowned scientific journal Nature.
The immune system is the body’s natural defense system and is made up of a network of cells, molecules, tissues, and organs working together to protect the body against infectious agents, such as viruses, bacteria or pathogenic fungi. The immune system is equipped with a sophisticated repertoire of sensing mechanisms which detect these pathogens and orchestrate an appropriate immune response. Autoimmune diseases originate when the immune system loses the ability to differentiate between itself and other foreign bodies.
Previous studies revealed that SLC15A4, a member of the body’s biggest family of transporter proteins, was known as an essential component required for the correct function of these TLRs. Based on their strong research interests in pathogen-sensing by the innate immune system and the characterization of solute carriers, researchers in the group of CeMM Scientific Director Giulio Superti-Furga set out to investigate how SLC15A4 influences the ability of TLRs to sense pathogens, and, consequently, gain a better understanding on its implication in autoimmune conditions, and in particular SLE.
In their study, first author Leonhard Heinz and the team, including Boehringer Ingelheim researchers in Ridgefield, undertook a precise investigative work, not taking for granted previous findings on SLC15A4 and the connection to this group of specially located TLRs. They painstakingly determined by biochemistry and mass spectrometry the molecular interactions that involved SLC15A4. This led to the identification of an uncharacterized protein CXorf21, belonging to the functionally orphan genes that are merely numbered and assigned to the chromosome of origin. The gene, like SLC15A4, had been previously loosely associated with SLE.
The team demonstrated that the interaction between TASL and SLC15A4 was crucial for the localization and function of the TASL protein and could pinpoint the precise involved portions of both proteins. A eureka moment for the understanding of the protein came with the observation that TASL harbors a specific motif essential for the recruitment and activation of IRF5. “After STING, MAVS and TRIF, the new protein TASL is the fourth key innate immunity adaptor functioning as a platform for the encounter of a kinase and a gene activator of the IRF family”, says Manuele Rebsamen, CeMM senior postdoctoral fellow and project leader of the study.
These findings raise the possibility that interfering pharmacologically with the SLC15A4/TASL complex could allow the regulation of TLR responses and, consequently, modulate inflammatory responses in the body. “It was clear to us that SLC15A4 plays a key role in endosomal TLR function and is involved in disease, but the underlying mechanism was not understood. These are exactly the exciting scientific questions that we love to address at our institute”, says Giulio Superti-Furga, CeMM Scientific Director and responsible for the study. He adds: ”We are happy that the vision we share with Boehringer Ingelheim regarding Solute Carriers being a group of disease-relevant proteins worthy of investigation was rewarded in this successful and exciting partnership.”
This study is the result of a collaboration between CeMM and the Drug Concept Discovery Group led by Charles Whitehurst and JangEun Lee in the Immunology and Respiratory Diseases Department at Boehringer Ingelheim (Ridgefield, CT, USA). Researchers also benefited from the support of the Proteomics and Metabolomics (Pro-Met-) facility and the Biomedical Sequencing Facility (BSF) at CeMM.
The study “TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9” was published in Nature on 13 May 2020. DOI: 10.1038/s41586-020-2282-0.
Leonhard X. Heinz, JangEun Lee, Utkarsh Kapoor, Felix Kartnig, Vitaly Sedlyarov, Konstantinos Papakostas, Adrian César-Razquin, Patrick Essletzbichler, Ulrich Goldmann, Adrijana Stefanovic, Johannes W. Bigenzahn, Stefania Scorzoni, Mattia D. Pizzagalli, Ariel Bensimon, André C. Müller, F. James King, Jun Li, Enrico Girardi, M. Lamine Mbow, Charles E. Whitehurst, Manuele Rebsamen, Giulio Superti-Furga
The study was funded with support by the Austrian Academy of Sciences, the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 695214, awarded to Giulio Superti-Furga), the Austrian Science Fund (FWF SFB F4711) and by Boehringer Ingelheim (Research Collaboration Agreement BI-CeMM 238114).