The discipline of chemistry deals with understanding (analysis) and making and transforming (synthesis) of matter. The size-range with which chemistry is most concerned with is that of molecules as building blocks of matter. Molecules are nothing but connected atoms, and when aiming at making, i.e. synthesizing, them, it is useful to chemists to subdivide them into subsets, which are so-called "functions" or "functional groups". Although every type of molecule is unique, it's subsets - the functional groups - will eventually be found in many other molecules. Therefore, approaches of generating a particular functional group may eventually benefit the synthesis of numerous molecules bearing ths functional group.
The research group of Miriam Unterlass, CeMM Adjunct Principal Investigator and Assistant Professor at the Technische Universität Wien, in collaboration with two other CeMM research groups, the Menche Lab and the Kubicek Lab, has now developed a novel synthesis for the so-called "quinoxaline" functional group, which is to date reported to be part of more than 100,000 molecules. Quinoxalines are highly important for especially pharmaceutical applications, where they are part of various drugs such as the antibiotic Echinomycin, or Brimonidine a drug to treat ocular hypertension. Furthermore, they display intriguing optoelectronic properties and therefore find application as e.g. dyes or electroluminescent materials. Classically, the quinoxaline function is made by rather harsh, harmful, and tedious routes (toxic organic solvents, expensive catalysts). In contrast, the new synthesis developed by Unterlass and colleagues employs 'hot water' as solvent and is therefore termed hydrothermal synthesis (HTS). Through the developed HTS, quinoxalines can be generated within only 10 minutes. In fact, the synthesis is the least harmful of all routes reported to date, as Amaya-García et al. show in their recently published manuscript, through a large-scale computational comparison with all existing alternatives. Moreover, the researchers show that the generated quinoxalines exhibit fluorescence and can be used to stain different cell lines.
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The study "Green hydrothermal synthesis of fluorescent 2,3-diarylquinoxalines and large-scale computational comparison to existing alternatives" was published online ahead of print on ChemSusChem on 4 March 2021. DOI: https://doi.org/10.1002/cssc.202100433
Authors: Fabián Amaya-García, Michael Caldera, Anna Koren, Stefan Kubicek, Jörg Menche, Miriam M. Unterlass
Funding: This project was funded by the Austrian Science Fund (FWF) under grant no. START Y1037‐N28 and the Vienna Science and Technology Fund (WWTF) under grant number LS17‐051.
Sylvia Knapp and Christoph Binder have been CeMM pioneers and have been associated with their groups with us for 15 years. On 31 March 2021 their CeMM research contracts end and we would like to say a big heartfelt thank you for the scientific contributions, the networking and personal engagement.
Both joined CeMM at the first round of Principal Investigator hiring and have been critical in setting the stage for future directions and hires at CeMM ever since. Both embodied the very essence of how CeMM was trying to position itself, as a bridge between hard-core frontier research in biomedicine and the clinical world. After their MDs, both had gone to prestigious institutions abroad to also obtain a PhD, making them perfectly capable of navigating the medical and the basic research world with equal ease. Coincidentally, their respective fathers, Walter Knapp and Bernd R. Binder, were highly successful MedUni Professors and influential scientists themselves. Both were fervent advocators of molecular medicine and important early contributors to the CeMM project.
At CeMM, Sylvia Knapp and Christoph Binder, helped generation after generation of researchers to make connections to the relevant clinical departments at the Medical University while contributing to the creation of what can be defined the CeMM culture of international, collegial and highly collaborative spirit. Over the years both, Sylvia Knapp and Christoph Binder, successfully took up more and more responsibilities at the Medical University of Vienna, became inspiring professors, and now also filling important functions at yet other universities and funding organizations. They trained and accompanied a large number of students to finish their PhD. Equally critical for the CeMM mission, they both have, with their teams and often in collaboration with other CeMM researchers, published several high-impact papers. We are proud to have supported their scientific career early on and so contributed to their success. We hope that CeMM has also left a positive footprint in their personal development as researchers, mentors, and community leaders. Christoph once compared CeMM with a place where you are “heart-washed”. It is nice to think that people who leave the institute are taking along not only the recipe for scientific excellence, but also the collaborative spirit and the civil purpose of contributing to society.
CeMM has always been meant to be a career springboard. We do not offer tenure, so after a successful research period, we need to allow a new generation of PIs to join CeMM and freely develop their potential and scientific interests. Although it is sad to separate, we count on the well-established networks and research collaborations which will help us to stay connected with Sylvia and Christoph and their current teams and alumni, even without formal ties. Our companionship and collegiality cannot and will not be disturbed by any change of formal status, after having shared such a long and critical part of our scholarly journey together, as well as many fond memories. We anticipate that this next phase will actually bring new opportunities and dimensions to the relationship.
We would like to look back at some of the research highlights Sylvia, and Christoph and their teams have performed and published in collaboration with CeMM:
Sylvia Knapp studied Medicine in Vienna and Berlin, is a board-certified internist and obtained her PhD at the University of Amsterdam in the laboratory of Tom van der Poll. In 2006 she joined CeMM as Principal Investigator and until recently, she continued her clinical duties while also running her laboratory. In 2012 Sylvia became Professor for Infection Biology at the Medical University of Vienna. She is a member of the Academia.Net circle of excellent female scientists, corresponding member of the Austrian Academy of Sciences, was appointed to the Board of the Medical University of Graz, and is Vice President of the Ludwig Boltzmann Society. Sylvia’s research focuses on the innate immune response to infections. Among the highlights:
Christoph Binder obtained his MD degree from the University of Vienna, and his PhD degree from the University of California in San Diego while working with Joseph (Joe) L Witztum. He joined the Department of Laboratory Medicine of the Medical University of Vienna in 2005, where in 2009 he was appointed Professor of Atherosclerosis Research, and now is Deputy Head of Division. In 2006 he joined CeMM as Principal Investigator. Christoph won numerous prestigious fellowships and awards. He is a specialist in laboratory medicine and leads a research group focusing on the role of immune functions in atherosclerosis. Among the highlights in his research we find:
We wish Sylvia, Christoph and their team members many more successful research projects, publications and prizes, and all the best for the future! The members of CeMM are looking forward to personally thank them and their teams in a farewell ceremony as soon as it is safe to do so. Thank you, you have been important partners for the starting phase and development of CeMM!
Among the many pharmaceuticals in use every day, one of the most well-recognized substances is the century-old pain killer Paracetamol. Paracetamol is part of a family of compounds, the so-called para-aminophenols, which also includes other biologically active molecules, such as Diloxanide Furoate, which is used against amoeba infections, or the beta blocker Practolol. These molecules are typically synthesised using harsh acids, in processes that involve the formation of considerable amounts of waste (in the form of undesired byproducts).
The research group of Nuno Maulide, CeMM Adjunct Principal Investigator and Professor at the University of Vienna, has now discovered a novel method of chemical synthesis to access Paracetamol and related molecules through a catalytic process that is extremely selective and generates little waste. This is enabled by a rearrangement reaction, in which specific atoms of a given molecule change positions, while no atoms are released as waste. Additionally, here, using an inexpensive selenium-based catalytic system avoids the use of expensive (and often scarce) metal catalysts.
While undertaking mechanistic studies to understand the exact pathway of the reaction at hand, the authors uncovered a complex yet organised cascade of elemental steps, in which the catalyst and the starting material exchange one atom back and forth without breaking their engagement. Then, after completing the transformation and yielding the final product, the catalyst is released and can engage another molecule of the starting material to be taken through the rearrangement sequence.
This newly developed method bears great potential in enabling chemists to rethink the way in which para-aminophenols are made, while simultaneously deepening their understanding of chemical reactivity. This broadly applicable, easy-to-use synthetic tool opens up wide perspectives for the preparation of valuable compounds under inexpensive and benign conditions.
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The study "Redox‐Neutral Selenium‐Catalysed Isomerisation of para‐Hydroxamic Acids into para‐Aminophenols" was published online on Angewandte Chemie on 24 March 2021. DOI: https://doi.org/10.1002/anie.202100801
Authors: Hsiang‐Yu Chuang, Manuel Schupp, Ricardo Meyrelles, Boris Maryasin, Nuno Maulide.
CeMM congratulates our Principal Investigator Andreas Bergthaler: He is one of the four newly funded researchers who are further expanding their corona research with funding from the Austrian Science Fund (FWF).
With funding from the Austrian Science Fund (FWF), Austria’s top researchers have the opportunity to study the Corona pandemic and its consequences. In recent months, 19 research teams were able to get started under the SARS-CoV-2 urgent funding program, and now four more FWF-funded teams are joining them: physician Alice Assinger from the Medical University of Vienna, microbiologist Andreas Bergthaler from CeMM, educational scientist Oliver Koenig from Bertha von Suttner Private University in St. Pölten, and family sociologist Ulrike Zartler from the University of Vienna.
Identifying and understanding the pathways of SARS-CoV-2 spread
CeMM PI Andreas Bergthaler together with Christoph Bock lead the team that is carrying out large-scale sequencing of SARS-CoV-2 viruses in Austria and analyzing the spread of mutations. Back in autumn in 2020, the group published a highly-cited study on the mutational dynamics of SARS-COV-2 in the prestigious journal Science Translational Medicine (DOI: 10.1126/scitranslmed.abe2555), and their research provides information on how and where the coronavirus mutations spread within Austria. The FWF urgent funding will allow Andreas Bergthaler to further deepen his research in order to better understand the spread of the virus and its mutations. The findings will improve the knowledge base for future measures to contain the pandemic.
SARS-CoV-2 Project Website: www.sarscov2-austria.org
Basic research helps manage the pandemic
"We already know quite a bit about Corona, but by no means everything. Researchers like Andreas Bergthaler have been working tirelessly for weeks to close these gaps in our knowledge. His work and the expertise of countless colleagues from very different fields are helping us to better understand the virus, the crisis and its consequences." said Federal Minister Heinz Faßmann on the occasion of the latest funding allowance provided to top researchers by the Austrian Science Fund (FWF).
"We enable scientists from all disciplines to intensify their corona research at the highest quality level. Building on their findings, policymakers and society can find answers to the current crisis, but also for future challenges," said interim FWF President Gregor Weihs.
FWF urgent funding: accelerated procedure without compromising quality
As an immediate response to the Corona pandemic, the FWF initiated SARS-CoV-2 urgent funding in March 2020 - a fast-track procedure for research applications dealing with the prevention, early detection, containment as well as research of SARS-CoV-2, with a particular focus on international cooperation. In addition, projects that focus their research interest on technical, ecological, economic, political, legal, medical, cultural, psychological, or ethical implications of SARS-CoV-2 are encouraged to apply. The expertise of virtually all basic research disciplines is needed in the current situation. The fast-track process for research proposals addressing SARS-CoV-2 runs until the end of March 2021.
We thank the FWF for supporting CeMM in researching and combating SARS-CoV-2!
Thrombotic occlusion of blood vessels, which leads to myocardial infarctions, strokes and venous thromboembolisms, is the major cause of death in the western hemisphere. Therefore, it is of critical importance to understand mechanisms preventing thrombus formation. A new study by the research group of Christoph Binder, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor at the Medical University of Vienna, now explains the important role of immunoglobulin-M (IgM) antibodies in preventing thrombosis. The study published in the journal Blood shows that these antibodies recognize microvesicles, which are membrane blebs shed by cells and recognized for their critical role in thrombosis, and therefore prevent their pro-thrombotic effects. These results provide a novel approach to reduce the risk of thrombosis by using IgM antibodies.
Antibodies are an important component of the immune system. On the one hand, these proteins serve in the body to defend against microbes, and on the other hand to remove the body’s own “cell waste”. Naturally occurring antibodies which are present from birth and mostly of the immunoglobulin-M (IgM) type, play an essential role in these processes. In the context of thrombosis, earlier studies demonstrated that people with a low number of IgM antibodies have an increased risk of thrombosis. A research group led by Christoph Binder, Professor of Atherosclerosis Research at the Medical University of Vienna and Principal Investigator at CeMM , previously demonstrated in a study published in 2009 that a high percentage of natural IgM antibodies bind oxidation-specific epitopes, molecular structures that are present on dying cells and serve as “remove-me signals” for the immune system. In this study, Binder’s research group identified the mechanisms explaining anti-thrombotic effects of natural IgM antibodies.
IgM antibodies bind procoagulant microvesicles
Microvesicles, blebs shed from the membrane of cells, are critical mediators of blood coagulation and thrombus formation. The study authors Georg Obermayer and Taras Afonyushkin from Binder’s research group, both affiliated with CeMM and the Medical University of Vienna, have now demonstrated that natural IgM antibodies that bind oxidation-specific epitopes can prevent coagulation and thrombosis induced by microvesicles. This provides a mechanistic explanation for the previously published observation that low levels of these antibodies are associated with an increased risk of thrombosis. “We assume that natural IgM antibodies recognize microvesicles that are particularly proinflammatory and procoagulant,” say the scientists. Both in experiments on the mouse model and directly on human blood samples, the scientists were able to show that the addition of IgM antibodies inhibited blood clotting caused by specific microvesicles and protected mice from lung thrombosis. Conversely, it was also shown that depletion of the IgM antibodies increased blood clotting.
Possible starting point for future therapies
The study authors explain: “The study for the first time provides an explanation why people with a low number of natural IgM antibodies have an increased risk of thrombosis.” Project leader Christoph Binder adds: “The results offer high potential for novel treatments to reduce the risk of thrombosis. Influencing IgM antibody levels in high-risk patients could be a viable addition to the previously established blood thinning treatment, as this is also known to be associated with side effects such as an increased tendency to bleed in the case of injuries.” In addition, the study makes an important contribution to the basic understanding of factor modulating thrombus formation. “Microvesicles are already recognized as an important component of blood coagulation. However, our study created a novel possibility of targeting them therapeutically for the first time,” says Christoph Binder.
The study “Natural IgM antibodies inhibit microvesicle-driven coagulation and thrombosis” was published in the journal Blood, online on 8 December 2020. DOI: https://doi.org/10.1182/blood.2020007155.
Authors: Georg Obermayer*, Taras Afonyushkin*, Laura Göderle, Florian Puhm, Waltraud Schrottmaier, Soreen Taqi1, Michael Schwameis, Cihan Ay, Ingrid Pabinger, Bernd Jilma, Alice Assinger, Nigel Mackman, Christoph J. Binder;
* authors contributed equally
Funding: This study was supported by the SFB-54 “InThro” of the Austrian Science Fund (FWF), the Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, and CCHD (Cell Communication in Health and Disease) of the FWF.
The body’s immune response plays a crucial role in the course of a SARS-CoV-2 infection. In addition to antibodies, the so-called T-killer cells, are also responsible for detecting viruses in the body and eliminating them. Scientists from the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna have now shown that SARS-CoV-2 can make itself unrecognizable to the immune response by T-killer cells through mutations. The findings of the research groups of Andreas Bergthaler, Judith Aberle and Johannes Huppa provide important clues for the further development of vaccines and were published in the journal Science Immunology.
After a year of the pandemic, an increasingly clear picture is emerging for science and medicine of how the immune response protects people from SARS-CoV-2. Two protagonists play central roles: antibodies and T-killer cells (also called cytotoxic CD8 T cells). While antibodies dock directly onto viruses to render them harmless, T-killer cells recognize viral protein fragments on infected cells and subsequently kill them to stop virus production. More and more studies show that SARS-CoV-2 can evade the antibody immune response through mutations and thus also impair the effectiveness of vaccines. Whether such mutations also affect T-killer cells in their function had not been clarified so far. Benedikt Agerer in the laboratory of Andreas Bergthaler (CeMM), Maximilian Koblischke and Venugopal Gudipati in the research groups of Judith Aberle and Johannes Huppa (both Medical University of Vienna) have now worked together closely to investigate the effect of viral mutations in so-called T cell epitopes, i.e., in regions recognized by T-killer cells. For this purpose, they sequenced 750 SARS-CoV-2 viral genomes from infected individuals and analyzed mutations for their potential to alter T cell epitopes. “Our results show that many mutations in SARS-CoV-2 are indeed capable of doing this. With the help of bioinformatic and biochemical investigations as well as laboratory experiments with blood cells from COVID-19 patients, we were able to show that mutated viruses can no longer be recognized by T-killer cells in these regions,” says Andreas Bergthaler.
Focus on spike protein might be too narrow
In most natural infections, several epitopes are available for recognition by T-killer cells. If the virus mutates in one place, it is likely that other epitopes indicate the presence of the virus.
Most of the current vaccines against SARS-CoV-2 are directed exclusively against the so-called spike protein, which is one of 26 virus proteins. This also reduces the number of epitopes that are available for recognition by T-killer cells. “The spike protein has, on average, one to six of these T cell epitopes in an infected person. If the virus mutates in one of these regions, the risk that the infected cells will not be recognized by the T-killer cells increases,” explains Johannes Huppa. Judith Aberle emphasizes: “Especially for the further development of vaccines, we therefore have to keep a close eye on how the virus mutates and which mutations prevail globally. Currently, we see few indications that mutations in T killer cell epitopes are increasingly spreading.”
The study authors see no reason in their data to believe that SARS-CoV-2 can completely evade the human immune response. However, these results provide important insights into how SARS-CoV-2 interacts with the immune system. “Furthermore, this knowledge helps to develop more effective vaccines with the potential to activate as many T-killer cells as possible via a variety of epitopes. The goal are vaccines that trigger neutralizing antibody and T killer cell responses for the broadest possible protection,” the study authors say.
The study “SARS-CoV-2 mutations in MHC-I restricted epitopes evade CD8+ T cell responses” was published in Science Immunology online on March 4, 2021.
Authors: Benedikt Agerer*, Maximilian Koblischke*, Venugopal Gudipati*, Luis Fernando Montaño-Gutierrez, Mark Smyth, Alexandra Popa, Jakob-Wendelin Genger, Lukas Endler, David M. Florian, Vanessa Mühlgrabner, Marianne Graninger, Stephan W. Aberle, Anna-Maria Husa, Lisa Ellen Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele Barreca, Ingrid Fae, Sabine Wenda, Marianna Traungott, Gernot Walder, Winfried F. Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B. Huppa**, Judith H. Aberle**, Andreas Bergthaler**
*, **Equal contributions
Funding: This project was funded in part by two grants from the Vienna Science and Technology Fund (WWTF) as part of the WWTF COVID-19 Rapid Response Funding 2020 awarded to Andreas Bergthaler and René Geyeregger, respectively.
Benedikt Agerer was supported by the Austrian Science Fund (FWF) DK W1212. Mark Smyth and Alexander Lercher were supported by DOC fellowships of the Austrian Academy of Sciences (No. 24813, No. 24158 and No. 24955 respectively). Venugopal Gudipati, Vanessa Mühlgrabner and Johannes B. Huppa received support from the Vienna Science and Technology Fund
(WWTF, LS14-031). Judith H. Abele was supported by the Medical-Scientific fund of the Mayor of the federal capital Vienna (grant COVID003). Winfried F. Pickl. was supported by the Medical-Scientific fund of the Mayor of the federal capital Vienna (grant COVID006). Christoph Bock and Andreas Bergthaler were supported by ERC Starting Grants (European Union’s Horizon 2020 research and innovation program, grant agreement numbers 679146 respectively 677006).
Joint CeMM-IST Austria start-up develops new class of drugs targeting solute carrier proteins
Solgate GmbH, an Austrian early-stage biotech company, announces the completion of its first financing round from a group of venture and private investors.
Solgate was incorporated in 2020 by a high-profile founding team and with intellectual property from the leading research institutions CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, and IST Austria (Institute of Science and Technology Austria), with support from the Austrian business agency (AWS). The company applies methods from chemistry, cell biology, and advanced analytics to develop drugs that target membrane transporters known as solute carrier proteins (SLCs) - a novel, largely unexploited, and highly promising class of drug targets. The company is located at IST PARK, the technology park adjacent to the campus of IST Austria.
Alexander Schwartz, Partner at IST cube, comments: “We are very happy to work with Solgate, where a top-team of renowned researchers who have pioneered the field of SLCs, are applying a new approach towards drug discovery. On top of the synergies among the founding team, we see additional synergies emerging from the cooperation of scientists from different institutions, in this case IST Austria and CeMM. We are happy to participate in this investment round and are looking forward to the next steps together with the founders and fellow investors.”
Giulio Superti-Furga, CeMM Director, and Co-Founder of Solgate, remarks: “Solgate is the first start-up born out of a cooperation between CeMM and IST Austria and the sixth startup company, which has been created based on CeMM’s intellectual property and know-how. We are grateful for the trust of the investors and are certain that Solgate will be a great success.”
“Membrane transporters, such as SLCs are exciting therapeutic targets that show promise in the development of breakthrough treatments for challenging diseases. We see an opportunity for Solgate to benefit from advances in technology and SLC biology, to create and develop new drug candidates targeting SLCs. We are thrilled to have the support and domain expertise of our investors and look forward to accomplishing our vision even more rapidly together”, adds Ariel Bensimon, co-founder and CEO of Solgate.
At the beginning of 2021, Barbara Maier, Georg Busslinger and Davide Seruggia joined CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences. Barbara Maier as Principal Investigator at CeMM, Georg Busslinger and Davide Seruggia as CeMM Adjunct Principal Investigators, Georg having his main affiliation at the Division of Gastroenterology and Hepatology of the Medical University of Vienna and Davide at St. Anna Children’s Cancer Research Institute. The three researchers strengthen CeMM’s expertise in the fields of tumor immunology, gastrointestinal biology and pediatric leukemia biology.
Barbara Maier studied molecular biology at the University of Vienna and obtained her PhD from the Medical University of Vienna, working on deciphering the role of type I interferon in pulmonary inflammation under the mentorship of MedUni Professor and CeMM PI Sylvia Knapp. She then continued her training as a postdoctoral fellow in the laboratory of Miriam Merad at the Icahn School of Medicine at Mount Sinai in New York. There, she gained extensive knowledge about human tumor immunology and myeloid components of tumor immune-suppression. Barbara’s laboratory at CeMM focuses on tumor immunology and specifically on the dynamics of antigen-presenting cell/T cell interactions in the tumor microenvironment and how tumor-associated antigen-presenting cell phenotypes shape tumor-directed T cell responses.
Georg Busslinger studied molecular biology at the ETH Zurich and completed his PhD in Jan-Michael Peters’ group at the Research Institute of Molecular Pathology (IMP) in Vienna, where he investigated the molecular mechanisms that control the localization of cohesin in the mammalian genome of non-proliferating cells. For his postdoctoral study, he joined the laboratory of Hans Clevers at the Hubrecht Institute in Utrecht (The Netherlands), where he became an expert in the field of organoid biology. His work resulted in the molecular definition of epithelia cells of the esophagus, stomach, and duodenum, as well as the identification of rare cell populations and a novel hormone produced by enterochromaffin-like cells. Additionally, he investigated the cellular and molecular aspects of different stages of Barrett’s esophagus, a common pre-malignant state of esophageal cancer. Georg’s laboratory at the Medical University of Vienna and CeMM focuses on epithelial cell biology of human gastrointestinal organs, and is strongly based on the organoid technology. They aim at gaining a better understanding of the developmental steps of these cells, which will help guide future treatment strategies of variety of diseases including gastritis or Barrett’s esophagus.
Davide Seruggia obtained a degree in Biotechnology at the University of Milano-Bicocca (Italy) in 2010, and a PhD in Molecular Biology at the National Centre for Biotechnology (CNB-CSIC) in Madrid (Spain) in 2014. During his PhD under the supervision of Lluis Montoliu, he focused on non-coding DNA regulatory sequences of pigmentation genes, and generated several mouse lines carrying deletions of selected enhancers. Analysis of these mice highlighted the relevance of non-coding elements in regulating patterns of gene expression. In 2015 he joined the laboratory of Stuart H. Orkin at Boston Children’s Hospital, where he trained in hematology, stem cell biology and genomics. In Boston, Davide used genomics and genome editing to explore the role of epigenetic factors, chromatin modifiers and transcriptional co-activators in the context of mouse embryonic stem cells, and generated a series of mouse models to study how chromatin modifiers control hematopoiesis, erythropoiesis and the expression of globin genes. In 2019, he was promoted to Instructor in Pediatrics at Harvard Medical School and attracted funding from the WES Foundation and Pedals for Pediatrics. In 2020 he awarded an ERC Starting Grant, and started his independent career in 2021, when he joined the St. Anna Children’s Cancer Research Institute as Principal Investigator and CeMM as Adjunct Principal Investigator.
This addition reinforces CeMM’s interdisciplinary nature and commitment to advancing the understanding of human diseases through basic and biomedical research. CeMM gladly welcomes Barbara, Georg and Davide into the institute, and looks forward to their scientific breakthroughs and innovative research work.
When human cells have to adapt due to a wide variety of external influences, the BAF complex plays a central role because it controls the accessibility of the DNA and thus the information stored in it. In every fifth human cancer, a mutation is found in one of the BAF complex genes. Scientists from the research group of Principal Investigator Stefan Kubicek at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have now investigated this complex in more detail using novel techniques and were able to show how quickly changes in the BAF complex genes influence the accessibility of DNA. The study has now been published in Nature Genetics.
Chromatin is a central component of the cell nucleus and refers to the material that makes up the chromosomes. It organizes the approximately two meters of human DNA in such a way that certain genes are activated or deactivated depending on the cell type. The smallest “packaging units” of chromatin are the nucleosomes consisting of 146 base pairs of DNA wrapped around a histone octamer. Whenever cells need to adapt, for example due to environmental influences or developmental signals, corresponding changes to the chromatin are necessary. These are carried out, among other things, by chromatin remodeling complexes, which use the energy of adenosine triphosphate (ATP) to move nucleosomes along the DNA or to remove them completely. One important chromatin remodeling complex is the BAF complex. It consists of 29 genes which interact in different combinations. In the past, it was found in numerous cancer diseases that certain subunits of this BAF complex showed mutations in the cancer cells. In their recently published study, CeMM Principal Investigator Stefan Kubicek and his research group investigated the direct effects of changes in the BAF complex on DNA accessibility.
Faster than the cell cycle
In order to observe the functions of chromatin remodeling complexes, genetic methods which can inactivate these proteins within 3-5 days are generally used. However, due to the slowness of these technologies, it was previously hardly possible to determine the immediate effects of changes to the BAF complex on DNA accessibility. Therefore, the scientists Sandra Schick, Sarah Grosche and Katharina Eva Kohl from Kubicek’s research group relied on a so-called degron system. “Here, too, we use CRISPR genome editing. But instead of destroying a BAF subunit, we fuse it with a small protein called a ‘dTag’. By adding a specific active substance, we can then recruit the ‘dTag’-tagged subunit to components of the cellular ‘waste removal’. The labelled BAF subunit is then degraded within one hour. This makes it possible to precisely observe whether and how accessibilities subsequently change,” explain the study authors. Stefan Kubicek adds: “Our study has shown that removing a single subunit of the BAF complex immediately leads to a loss of accessibility to certain DNA regions. The effect is immediate, so we see for the first time that the cell cycle plays no role in this process. We were also able to confirm these results with pharmacological inhibitors of the BAF complex, which showed particularly fast effects. We assume that processes similar to those in our model system also play a role in carcinogenesis when mutations of a subunit of the BAF complex occur in cells for the first time.”
Synthetic lethality amplifies effect
In earlier studies, Kubicek’s research group had already investigated how different genes within the BAF complex interact. This showed that cells in which only a certain BAF subgroup has a mutation and reduces DNA accessibility can continue to live and grow. In some cases, however, the deactivation of another, specific subgroup leads to cell death. This interaction of specific genes is called synthetic lethality. A known synthetic lethality exists in the two genes SMARCA2 and SMARCA4. Cells can tolerate the loss of either of these genes but die as soon as both are mutated. Mutations of SMARCA4 have been found to be particularly common in cancer cells. Specific SMARCA2 inhibition has the potential to exploit synthetic lethality to specifically kill cancer cells without damaging healthy cells. In their current study, the study authors observed the immediate effects of synthetic lethality. “We wanted to know what happens when we remove both subunits,” says study author Sandra Schick. This showed that compared to the loss of each individual subunit, even more regions of the DNA lose accessibility, especially those that are crucial for cell identity. “We see that so-called ‘super-enhancers’, very active gene regulatory regions, only lose their accessibility when we trigger this synthetic lethality, i.e. lose both SMARCA4 and SMARCA2.”
BAF complex needs constant activity
In addition, the scientists tried to trigger the same effect using low-molecular substances. These lead to the BAF complex not becoming active and not being able to move nucleosomes. Project leader Stefan Kubicek explains: “Maintaining the accessibility of the genome requires constant ATP-dependent remodeling. This means that the BAF complex needs constant activity, the energy provided by ATP to move nucleosomes and thus maintain access to the DNA. Complete abrogation of the BAF complex function results in near-total loss of chromatin accessibility at BAF-controlled sites.”
The study „Acute BAF perturbation causes 1 immediate changes in chromatin accessibility“ was published in Nature Genetics, on 8 February 2021. DOI: 10.1038/s41588-021-00777-3;
Authors: Sandra Schick*, Sarah Grosche*, Katharina Eva Kohl*, Danica Drpic, Martin G. Jaeger, Nara C. Marella, Hana Imrichova, Jung-Ming G. Lin, Gerald Hofstätter, Michael Schuster, André F. Rendeiro, Anna Koren, Mark Petronczki, Christoph Bock, André C. Müller, Georg E. Winter, Stefan Kubicek
*shared first authorship
Funding: The study was conducted within the framework of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives in collaboration with Boehringer Ingelheim. The study was supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF) F4701 and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437). Christoph Bock is supported by an ERC Starting Grant (European Union’s Horizon 2020 research and innovation programme, grant agreement no. 679146). Sarah Grosche is supported by the Peter and Traudl Engelhorn Foundation.
On 27 - 29 January 2021, the 5th RESOLUTE Consortium Meeting took place virtually. RESOLUTE is a public-private partnership, funded with a grant from the Innovative Medicines Initiative (IMI) and coordinated by CeMM and Pfizer, with 13 partners from academia and industry. Its mission is to increase the study of solute carriers for medical research and potential drug development, and it strives to become a reference hub for SLC research and open knowledge worldwide.
This year again virtually, more than 60 RESOLUTE partners joined the online event entitled “Abbey Road Studios” with a focus on different music genres. On the first day, featuring classical and jazz music, participants received the latest updates on reagent generation and deorphanisation technologies. They also joined several focus groups to discuss promising data sets in more detail.
The second day was dedicated to rock, hip-hop and electronic music. Scientists reported the status on transport assays, protein purification and high-affinity binders, in-depth proteomics studies, data management and homology modelling strategies. On this day, the first RESOLUTE training session also took place. Junior investigators had the chance to learn more about project planning from senior investigators in academia, CeMM Scientific Director Giulio Superti-Furga, and Aled Edwards (Structural Genomics Consortium), and from the pharmaceutical industry by Anke Mueller-Fahrnow (Nuvisan) and David Hepworth (Pfizer).
On the last day, the focus groups turned into music bands and played at the RESOLUTE virtual festival. The bands presented the results of their discussions and suggested follow-up strategies. The event ended in team-building activities performed in virtual breakout roms.
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