We congratulate CeMM SAB Member Emmanuelle Charpentier for the 2020 Nobel Prize in Chemistry obtained together with Jennifer A. Doudna for the development of the CRISPR genome editing method.
Emmanuelle Charpentier is a French researcher and citizen of Europe recognized as a world-leading expert in regulatory mechanisms underlying processes of infection and immunity in bacterial pathogens. With her groundbreaking findings in the field of RNA-mediated regulation based on the CRISPR-Cas9 system, Emmanuelle has laid the foundation for the development of a novel, highly versatile and specific genome editing technology that is revolutionizing life sciences research and could open up whole new opportunities in biomedical gene therapies.
The CRISPR technology has revolutionized the life sciences, opening unprecedented possibilities to study the molecular basis for the properties and behavior of biological systems, at diverse levels of complexity. Modern biomedical research is unthinkable without the technology and there is no laboratory at CeMM that does not make use of it. “Manue”, as she is called with affection by her colleagues, is a person that has long inspired the Viennese community of researchers for the power and originality of her intellectual contributions and her collegial manners. At CeMM, with which Emmanuelle Charpentier has a long-standing relationship, she is admired and appreciated beyond her role as Member of the Scientific Advisory Board.
Emmanuelle Charpentier has been awarded prestigious honors before, including the Breakthrough Prize in Life Sciences, the Ernst Jung Prize for Medicine, the Louis-Jeantet Prize for Medicine as well as the Swedish Göran Gustafsson prize. In 2016, she gave a memorable CeMM Landsteiner Lecture.
CeMM faculty, postdocs, students, technical and administrative staff cheer enthusiastically to this new recognition of Emmanuelle Charpentier’s towering contributions.
Researchers from CeMM Research Center of Molecular Medicine of the Austrian Academy of Sciences, the Medical University of Vienna and Stanford University School of Medicine, have found that a module of the immune system, which is best known for causing allergic reactions, plays a key role in acquiring host defense against infections triggered by the bacterium Staphylococcus aureus. This “allergy module”, constituted by mast cells and Immunoglobulin E, can grant protection and increased resistance against secondary bacterial infections in the body. These findings indicate a beneficial function for allergic immune responses and are now published in the renowned journal Immunity.
Allergy is one of the most common diseases in Europe, it is estimated that more than 150 million Europeans suffer from recurring allergies and by 2025 this could have increased to half of the entire European population.* Allergic patients initially undergo a process of “sensitization”, meaning that their immune system develops a specific class of antibodies, so called Immunoglobulin E antibodies (IgE), which can recognize external proteins, referred to as allergens. IgEs bind and interact with cells that express a specific receptor called FcεR1. There are only a few cell types in the body that express the FcεR1 receptor and probably the most important ones are mast cells, a type of immune cell found in most tissues throughout the body.
When re-exposed to the allergen, mast cells (with IgE bound to their FcεR1 receptors) immediately react by rapidly releasing different mediators (e.g. histamine, proteases or cytokines) that cause the classic allergic symptoms. These symptoms depend on the tissue where the contact with the allergen happens and can range from sneezing/wheezing (respiratory tract) to diarrhea and abdominal pain (gastrointestinal tract) or itching (skin). Systemic exposure to allergens can activate a large number of mast cells from different organs at the same time, causing anaphylaxis, a serious and life-threatening allergic reaction.
Despite decades of research and detailed knowledge of the critical role of IgEs and mast cells in allergies, the physiological, beneficial function of this “allergy module” is still not completely understood. In 2006, Stephen J. Galli, senior co-author of this study, and his laboratory at Stanford University revealed the importance of mast cells for innate resistance against venoms of certain snakes and the honeybee (Science. 2006 Jul 28;313(5786):526-30. DOI: 10.1126/science.1128877). Subsequent work from the Galli laboratory showed the critical role of the “allergy module” in acquired host defense against high doses of venom (Immunity. 2013 Nov 14;39(5):963-75. doi: 10.1016/j.immuni.2013.10.005): this finding (to which Philipp Starkl, first author of the current study, contributed importantly) represented the first clear experimental evidence supporting the “Toxin Hypothesis” postulated by Margie Profet in 1991. This hypothesis proposed a beneficial function for allergic reactions against noxious substances (Q Rev Biol. 1991 Mar;66(1):23-62. doi: 10.1086/417049).
Following up on this discovery, Philipp Starkl, Senior Postdoctoral fellow at the Medical University of Vienna and CeMM, together with Sylvia Knapp, Professor at the Medical University of Vienna and CeMM PI, and Stephen J. Galli, Professor at Stanford University School of Medicine, and colleagues, set out to investigate whether this phenomenon could be relevant in defense against other toxin-producing organisms, in particular, pathogenic bacteria. The authors selected the bacterium Staphylococcus aureus as pathogen model due to its enormous clinical relevance and broad repertoire of toxins. This bacterium is a prototypic antibiotics-resistant pathogen and is also associated with the development of allergic immune responses in diseases such as asthma and atopic dermatitis. For their research, they used different experimental S. aureus infection models in combination with genetic approaches and in vitro mast cell models to reveal the functions of selected components of IgE effector mechanisms.
The scientists found that mice with a mild S. aureus skin infection develop an adaptive immune response and specific IgEs antibodies against bacterial components. This immune response grants these mice an increased resistance when they are confronted with a severe secondary lung or skin and soft tissue infection. However, mice that are lacking functional IgE effector mechanisms or mast cells are unable to build such protection. These findings indicate that the “allergic” immune response against bacteria is not pathological, but instead protective. Hence, defense against toxin-producing pathogenic bacteria might be an important biological function of the “allergy module”.
This study is an important collaboration initiated by Philipp Starkl at the laboratory of Stephen J. Galli at Stanford University together with other colleagues and then continued at the laboratory of Sylvia Knapp at CeMM and the Medical University of Vienna. This exciting discovery not only advances the general understanding of the immune system and most notably allergic immune responses, but it could also explain why the body has maintained the “allergy module” throughout evolution. Despite their dangerous contributions to allergic diseases, IgEs and mast cells can exert beneficial functions that the immune system can capitalize on to protect the body against venoms and infections with toxin-producing bacteria, such as S. aureus.
The study “IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcus aureus” was published in Immunity on 9 September 2020. DOI: 10.1016/j.immuni.2020.08.002
Philipp Starkl, Martin L. Watzenboeck, Lauren M. Popov, Sophie Zahalka, Anastasiya Hladik, Karin Lakovits, Mariem Radhouani, Arvand Haschemi, Thomas Marichal, Laurent L. Reber, Nicolas Gaudenzio, Riccardo Sibilano, Lukas Stulik, Frédéric Fontaine, André C. Mueller, Manuel R. Amieva, Stephen J. Galli*, Sylvia Knapp* | *Senior co-authors
The study was supported by the Austrian Science Fund (FWF J3399-B21) and by NIH grants R01 AI23990, R01 AI070813, R01 AR067145 and R01 AI132494 (to Stephen J. Galli). Philipp Starkl was supported by a Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2014 No. 655153), the Austrian Science Fund (FWF P31113-B30) and a Schroedinger Fellowship of the FWF (J3399-B21).
The most direct and efficient way to modulate metabolism is regulating access to nutrients, building blocks and energy through interfering with the function of membrane transporters. Solgate GmbH will develop drugs against solute carrier (SLC) proteins, the largest family of transporters, focusing on the important roles of SLCs in neurological diseases, metabolic disorders and cancer. Through a proprietary discovery platform that combines several technologies, Solgate will efficiently develop novel chemical matter against selected SLCs.
Solgate GmbH, is a new startup company by CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, ÖAW researchers Giulio Superti-Furga, Georg Winter, Stefan Kubicek, Ariel Bensimon, and by TWIST Research Transfer and Development GmbH and IST Austria researcher Gaia Novarino.
Solgate is the first startup born out of a cooperation between CeMM and IST Austria and becomes now the sixth startup company, which has been created based also on CeMM’s intellectual property and know-how. It will be located at the newly established IST Park, a complex for startup companies on the IST Austria campus in Klosterneuburg, and will be supported by funds from the Austrian Business Agency (AWS), as well as by private investors.
The Austrian Academy of Sciences stands for the transfer of new knowledge and basic research at the highest international level. CeMM’s mandate is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future, and strategically fosters a translational impact of its research for society through technology applications.
On 1 September 2020, Jörg Menche and his team members joined the Institute of Mathematics of the University of Vienna, and the Department of Structural and Computational Biology at the Max Perutz Labs, a joint venture between University of Vienna and the Medical University of Vienna. After 5 successful years as PI at CeMM, Jörg will now become a CeMM Adjunct Principal Investigator.
Jörg Menche studied physics in Leipzig, Recife and Berlin. During his PhD with Reinhard Lipowsky at the Max Planck Institute of Colloids and Interfaces in Potsdam he specialized in network theory. He then moved to Boston to work as a postdoctoral fellow with Albert-László Barabási at Northeastern University and at the Center for Cancer Systems Biology at Dana Farber Cancer Institute. In close collaboration with Joseph Loscalzo from Harvard Medical School and Marc Vidal from Dana Farber Cancer Institute, he applied tools and concepts from network theory to elucidate the complex machinery of interacting molecules that constitutes the basis of (patho-)physiological states.
Since joining CeMM as Principal Investigator in 2015, Jörg applied diverse computational approaches to help understand and interpret the large datasets derived from the broad range of powerful post-genomic technologies that CeMM researchers employ, from next-generation sequencing of genomes, epigenomes and transcriptomes, to high-throughput proteomics and chemical screening. One of his group’s achievement at CeMM was the development of a novel mathematical framework for accurately mapping out how different perturbations of the interactome influence each other (Caldera et al. Nature Communications. 2019 Nov 13;10(1):5140). This work offered a first general approach to quantify with precision how drugs interact, based on a mathematical model that considers their high-dimensional effects. Their research revealed that the position of targets of a given drug within the interactome is not random but rather localized within drug modules. Furthermore, the group identified various factors that contribute to the emergence of such interactions. In comparison with previous methods, which characterize interactions only as synergistic or antagonistic, the team reported that the new methodology can distinguish 12 distinct interaction types as well as reveal the direction of an interaction. The introduced framework could be used to address other key challenges, such as dissecting the combined impact of genetic variations or predicting the effect of a drug on a particular disease phenotype.
Another key project of Jörg and his group was a Virtual Reality (VR) Holodeck, developed in collaboration with medical groups, such as the one of Kaan Boztug, CeMM Adjunct PI and Director of CCRI and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. The project team developed a specific device including VR glasses, which allows the user to dive deep into the massive molecular networks behind genetic diseases. The unique VR experience provides a first glimpse on how humans and machines will interact in the future to visualize and explore complex medical data to the benefit of research and patients. His co-supervised PhD student Julia Pazmandi won the Falling Walls Competition Austria in 2019.
This is not a goodbye, it is a natural step forward into his scientific career. CeMM does not offer tenure and therefore Jörg Menche’s relationship with CeMM enters a new phase: As Adjunct PI, Jörg will stay connected with the institute through the CeMM PhD and PostDoc Programs, scientific events, faculty meetings and well-established networks and research collaborations.
CeMM wishes Jörg and his team all the best for this next career step at MFPL and the University of Vienna!
HCA|Organoid is a new EU research project that combines single-cell profiling and organoid technology to validate organoids as faithful models of human biology. The project seeks to kickstart the development of an open access “Organoid Cell Atlas”. By creating well-characterized in vitro models of human organs, this resource will enable future discovery-driven and translational research on rare genetic diseases, complex multifactorial diseases, and on cancer. Toward this goal, Europe’s leading organoid researchers as well as experts in single-cell sequencing, single-cell imaging, and computational data integration have teamed up. The HCA|Organoid project is one of six pilot actions funded by the EU Horizon 2020 Framework Program that will constitute European contributions to the “Human Cell Atlas” – an ambitious global initiative striving to advance biomedical research and therapy using single-cell technologies. The HCA|Organoid consortium comprises eight partners and will receive EUR 5 million in EU funding.
Single-cell technologies provide a fundamentally new perspective for understanding biology, with profound potential to enable therapeutic advances and to put Europe at the forefront of personalized medicine and regenerative biology. In order to streamline research and accelerate scientific progress in this area, the Human Cell Atlas (HCA) initiative provides worldwide coordination toward the goal of establishing comprehensive reference maps of all cell types in the human body.
Within the global context provided by the HCA, the new European research project HCA│Organoid has set out to establish an “Organoid Cell Atlas”. This initiative will firmly establish single-cell analysis of human organoids within the HCA and thereby advance biomedical research. This vision is outlined in a strategy paper that is publicly available as a preprint (DOI: 10.5281/zenodo.4001718). In a nutshell, researchers will use single-cell data as a “Rosetta stone”, helping to translate between results obtained from tissue samples of patients and analyses of the experimentally more flexible organoids grown in vitro (which constitute “patient avatars” in the laboratory). For example, researchers may identify a novel disease-associated cell type in primary patient samples, create equivalent cells in human organoids, and then investigate potential therapeutic strategies in vitro.
Toward realizing this vision, HCA|Organoid project will initially focus on establishing single-cell transcriptomes, epigenomes, and time-series imaging of human organoids and matched primary tissue from healthy donors. The project will derive and comprehensively characterize human brain and colon organoids from 100 individuals each, in order to capture population variation and to establish a comprehensive reference for disease-centric research. The single-cell maps will be integrated into a public Organoid Cell Atlas Portal, which will provide user-friendly access to single-cell data of organoids in connection to human primary samples. This scientific resource will support several proof-of-concept studies, for example focusing on disease modeling for genetic epilepsy in brain organoids, on organoid cancer models, and on the characterization of disease-linked genetic variants in colon organoids.
The HCA│Organoid project brings together a consortium of eight partner institutions including experts in organoid technology, single-cell profiling, advanced imaging, and bioinformatics from Austria, Germany, the Netherlands and Switzerland. In addition to its initial focus on single-cell profiling of brain and colon organoids, the project seeks to initiate an open, collaborative network of researchers and initiatives aimed at the single-cell characterization of a diverse set of human organoids.“We are excited to combine single-cell profiling with organoid technology, and to contribute a focus on human organoids to the Human Cell Atlas. These are complementary technologies that together will bring us an important step closer to the rational development of future therapies for a wide range of diseases”, said Christoph Bock, project coordinator and principal investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.
More information about the HCA|Organoid project: www.hca-organoid.eu
Follow us on Twitter: @OrganoidAtlas
About the Human Cell Atlas
The Human Cell Atlas (HCA) initiative aims to create molecular reference maps of all human cells to pool and expand knowledge of the diverse cells found within the human body. The goal is to better understand human health, but also to improve diagnosis, monitoring and treatment of diseases. As a contribution to this global initiative, the European Commission is funding six pilot actions within the Horizon 2020 Research and Innovation Framework Programme (www.humancellatlas.org/euh2020). Each of those projects has been designed to characterize single cells or their nuclear components, their interactions and/or spatial location in tissues from one human organ, using state-of-the-art single cell technologies, analytical methods and computational tools, and brings together European experts in the respective fields who are joining their efforts to support the creation of the HCA.
Researchers at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, have developed knowledge-primed neural networks (KPNNs), a new method that combines the power of deep learning with the interpretability of biological network models. KPNNs learn multiple layers of protein signaling and gene regulation from single-cell RNA-seq data, thereby providing a much-needed boost in our ability to convert massive single-cell atlas data into biological insights. These findings have now been published in the renowned scientific journal Genome Biology.
Computer systems that emulate key aspects of human problem solving are commonly referred to as artificial intelligence (AI). This field has seen massive progress over the last years. Most notably, deep learning enabled groundbreaking progress in areas such as self-driving cars, computers beating the best human players in strategy games (Go, chess), computer games, and in poker, and initial applications in diagnostic medicine. Deep learning is based on artificial neural networks – networks of mathematical functions that are iteratively reorganized until they accurately map the data describing a given problem to its solution.
In biology, deep learning has established itself as a powerful method to predict phenotypes (i.e., observable characteristics of cells or individuals) from genome data (for example gene expression profiles). Deep learning is usually a “black box” method: Neural networks are very powerful predictors when provided with enough training data. For example, they have been used to predict cell type from gene expression profiles, and protein structures from DNA sequence data. But standard neural networks cannot explain the learnt relationship of inputs to outputs in a human-understandable way. For this reason, deep learning has so far contributed little to advancing our mechanistic understanding of molecular functions within cells.
To address this lack of interpretability, CeMM Postdoctoral Fellow Nikolaus Fortelny and CeMM Principal Investigator Christoph Bock pursued the idea of performing deep learning directly on biological networks, instead of the generic, fully connected artificial neural networks used in conventional deep learning. They established “knowledge-primed neural networks” (KPNNs) that are based on signaling pathways and gene-regulatory networks. In KPNNs, each node corresponds to a protein or a gene, and each edge has a mechanistic biological interpretation (e.g., protein A regulates the expression of gene B).
The CeMM researchers show in their new study published in Genome Biology that deep learning on biological networks is technically feasible and practically useful. By forcing the deep learning algorithm to stay close to gene-regulatory processes that are encoded in the biological network, KPNNs create a bridge between the power of deep learning and our rapidly growing knowledge and understanding of complex biological systems. As a result, the approach provides concrete insights into the investigated biological systems, while maintaining high prediction performance. This powerful new methodology uses an optimized approach for deep learning, which stabilizes node weights in the presence of redundancy, enhances the quantitative interpretability of node weights, and controls for the uneven connectivity inherent to biological networks.
CeMM researchers demonstrated their new KPNN method on large single-cell datasets, including a compendium of 483,084 single-cell transcriptomes for immune cells established by the Human Cell Atlas consortium. In this dataset, the scientists discovered unexpected diversity in the cell-type-defining regulatory networks between immune cells from bone marrow and cord blood.
The KPNN method combines the predictive power of deep learning and its ability to infer activity levels across multiple hidden layers with the functional interpretability of biological networks. KPNNs are particularly useful for the single-cell RNA-seq data, which are generated at massive scale using single-cell sequencing assays. Moreover, KPNNs are broadly applicable to other areas of biology and biomedicine where relevant prior knowledge can be represented as networks.
The predictions and biological insights obtained by KPNNs will be useful for dissecting cell signaling and gene regulation in health and disease, for identifying novel drug targets, and for deriving testable biological hypotheses from single-cell sequencing data. More generally, the study illustrates the future impact that artificial intelligence and deep learning, will have on mechanistic biology as the scientific community learns how to make AI results biologically interpretable.
The study “Knowledge-primed neural networks enable biologically interpretable deep learning on single-cell sequencing data” was published in Genome Biology on 21 July 2020. DOI: 10.1186/s13059-020-02100-5
Nikolaus Fortelny and Christoph Bock
This study was co-funded by an Austrian Science Fund (FWF) Special Research Programme grant (FWF SFB F 6102-B21), a New Frontiers Group award of the Austrian Academy of Sciences 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). Nikolaus Fortelny was supported by a fellowship from the European Molecular Biology Organization (EMBO ALTF 241-2017).
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!