December 04, 2020

Thomas Krausgruber awarded the ÖGAI Karl Landsteiner Prize for Basic Research in Immunology 2020

Senior Postdoctoral Fellow Thomas Krausgruber (© Klaus Pichler / CeMM)

Congratulations to Thomas Krausgruber, Senior Postdoctoral Fellow in Christoph Bock’s Group at CeMM, who has received the Karl Landsteiner Prize for Basic Research in Immunology 2020!

Every year the Karl Landsteiner and Eisler-Terramare Foudation Commemoration Trust and the Austrian Society for Allergology and Immunology (ÖGAI) offer a prize of 4,000 € to recognize excellent publications in the field of basic immunology research. The publications must have been published in the last two years and must have been carried out predominantly at an Austrian institution. This year, the ÖGAI award ceremony took place in an online format on 4 December 2020.

The prize recognizes Thomas’ outstanding research on structural cells in relation to the body’s immune function. In a recent paper published in the renowned scientific journal Nature (Nature. 2020 Jul;583(7815):296-302. doi: 10.1038/s41586-020-2424-4), Thomas and colleagues 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.

December 03, 2020

Cancer in children with rare inborn immune defect: High cure rate if treated early

Sevgi Köstel Bal and Kaan Boztug (© St. Anna Children’s Cancer Research Institute).

New research data highlight a marked predisposition to lymphoma, a type of cancer, in children harboring specific gene mutations. A significant fraction of these rare mutations also cause inborn immune defects associated with recurrent infections. Under the leadership of Kaan Boztug, LBI-RUD and CCRI Director and CeMM Adjunct Principal Investigator, and collaborating closely with leading centers across the world, researchers investigated patients bearing recently identified defects in two molecules termed CD27 and CD70. In contrast to previously reported high mortality rates associated with lymphoma in a part of this population, the present results are encouraging: a high cure rate was achieved if patients received stem cell transplantation soon after diagnosis. Published in the Journal Blood, the study gives insights into clinical course and early immunological parameters as well as treatment response in the largest group of children with CD27 or CD70 deficiency to date.

A worldwide study may contribute to cure children with specific inborn mutations, by providing unprecedented insights into disease characteristics. The underlying mutations, namely in the genes encoding CD27 and CD70, cause inborn errors of the immune system (immunodeficiencies). A major threat to these immuno-compromised patients are infections, primarily with Epstein-Barr virus (EBV). The impaired immune system cannot cope with this infection, and the virus persists in the blood. Subsequently it causes severe disease, including lymphoma. This is a type of cancer originating from infection-fighting cells of the immune system, termed lymphocytes.

Given the rarity of these mutations, no consensus on how to treat affected children exists. Previous observations had shown that patients with CD27 or CD70 deficiencies have a significantly increased risk of death during the first occurrence of lymphoma. To improve outcome, the recently published study for the first time reports in-depth clinical and immunological characterization of the largest patient cohort (n=49) with CD27 or CD70 deficiency reported to date.

Remarkable results in a rare disease
The new data highlight the marked predisposition to lymphoma of both CD27 and CD70 deficient patients. For children with severe Epstein-Barr virus associated disease, or lymphoma, genetic investigation of CD27 and CD70 is essential. This could optimize clinical management and most importantly support in making a timely decision for curative hematopoietic stem cell transplantation.

“In our study population we report excellent outcome following hematopoietic stem cell transplantation in patients with severe disease manifestations, predominantly lymphoma”, study senior author Assoc.-Prof. Kaan Boztug, MD, comments. 18 out of 19 (95%) patients who received stem cell transplantation just after their first malignant event could be cured. This means they are cancer free after a median follow-up of two years. Co-first author Sevgi Köstel Bal, MD, PhD, adds, “Our results provide a strong rationale for timely use of this curative treatment in patients with CD27 or CD70 deficiencies upon lymphoma diagnosis.”

Consider immune defect in children with cancer
Designed as a retrospective analysis, the study included clinical information of 49 patients from 20 centers all over the world. 33 patients presented with CD27 and 16 with CD70 deficiency.

The majority (90%) of patients had an Epstein-Barr virus infection at diagnosis of CD27 or CD70 deficiency. 36% of CD27 deficient patients and 56% of CD70-deficient patients developed lymphoma at a median age of 8.5 or three years, respectively. Another frequent event was autoinflammation, which appeared in various forms in 21 patients (43%). Autoinflammation is an aberrant inflammatory reaction affecting the body’s own tissues that derives from the innate immune system.

Major findings relate to immunological characteristics, mechanisms of disease pathogenesis and clinical course of individual patients undergoing various treatments. These findings highlight the critical role of CD27-CD70 interaction in regulating immunity, especially in the context of Epstein-Barr virus control and formation of lymphoma. The new data underline that an immune defect should be considered as underlying cause when children present with cancer, in particular if there is a history of recurrent infections or inability to control Epstein-Barr virus.

Largest cohort due to world-wide approach
Performed in close collaboration with the Inborn Errors Working Party of the European Society for Immunodeficiencies (ESID) and the European Society for Bone and Marrow Transplantation (EBMT), this study reports the to date world’s largest cohort of patients with mutations in either CD27 or CD70. This was only possible in a multicenter effort, led by the study centers in Vienna, Sydney, Düsseldorf, Leiden, Tehran, and Ankara.

Publication:
Extended Clinical and Immunological Phenotype and Transplant Outcome in CD27 and CD70 Deficiency.
S Ghosh*, S Köstel Bal*, E S J Edwards*, B Pillay, R Jimenez-Heredia, G Rao, F Erol Cipe, E Salzer, S Zoghi, H Abolhassani, T Momen, E Gostick, D A Price, Y Zhang, A J Oler, C Gonzaga-Jauregui, B Erman, A Metin, I Ilhan, S Haskologlu, C Islamoglu, K Baskin, S Ceylaner, E Yilmaz, E Unal, M Karakukcu, D Berghuis, T Cole, A Kumar Gupta, F Hauck, A Hoepelman, S Baris, E Karakoc-Aydiner, A Ozen, L Kager, D Holzinger, M Paulussen, R Krüger, R Meisel, P Thomas Oommen, E C Morris, B Neven, A J J Worth, J M van Montfrans, P Fraaij, S Choo, F Dogu, E G Davies, S Burns, G Dueckers, R Perez Becker, H von Bernuth, S Latour, M Faraci, M Gattorno, H Su, Q Pan-Hammarström, L Hammarström, M J Lenardo, C S Ma, T Niehues, A Aghamohammadi, N Rezaei**, A Ikinciogullari**, S G Tangye**, A C Lankester**, K Boztug**
Blood. 2020 Jun 30; blood.2020006738. doi: 10.1182/blood.2020006738. Online ahead of print. PMID: 32603431
* S.G, S.K.B and E.J.E contributed equally.
** N.R., A.I., S.G.T., A.C.L. and K.B. contributed equally.
Corresponding authors: K.B., A.C.L. and S.G.T.
Link: https://doi.org/10.1182/blood.2020006738

Funding:
This work was funded by the European Research Council (ERC), the Austrian Science Fund (FWF), The Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia), the National Health and Medical Research Council of Australia, the Wellcome Trust Senior Investigator Award, a Mid-Career Research Fellowship awarded by the Office of Health and Medical Research of the New South Wales Government of Australia, a Principal Research Fellowship and a Peter Doherty Leadership Grant awarded from the National Health and Medical Research Council, the German Centre for Infection Research, the Else Kröner-Fresenius Stiftung, and the German Federal Ministry of Education and Research, the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre and by funds from the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH).

December 01, 2020

SLC25A51 regulates the transport of the coenzyme NAD into the mitochondria

Last author Giulio Superti-Furga and first author Enrico Girardi (© Klaus Pichler / CeMM)

Previously poorly characterized gene proved to be an important regulator with potential for the development of new metabolic therapies against ageing and cancer.

For their growth, cells need various nutrients and vitamins. So-called solute carriers (SLC), proteins that can transport such substances across the boundaries of cellular membranes, play a central role in metabolism. Scientists in Giulio Superti-Furga’s research group at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences have now discovered that the previously uncharacterized protein SLC25A51 acts as a transporter into the mitochondria for the coenzyme NAD. This molecule has already been associated with numerous physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Therefore, the results of this study not only open up new possibilities to study the biological role of NAD but also potentially provide the basis for new therapeutic approaches. The work has now been published in the journal Nature Communications.

Solute carriers (SLC) are proteins that act as transporters and enable the entry and exit of nutrients and waste products into and from the cell and its organelles. Many of these transporter proteins are still relatively poorly studied and the question of how some nutrients enter and leave cells often remains unanswered. So far, it has not yet been clarified how mitochondria gain access to an important cofactor of our metabolism, the so-called NAD (nicotinamide adenine dinucleotide). In scientific literature, there were only references to mitochondrial NAD transporters in plants and yeast. Lead author Enrico Girardi and the research group of CeMM Scientific Director Giulio Superti-Furga, in cooperation with scientists from the University of Bari (Italy), have now identified the protein responsible for the important transport of NAD into mitochondria: SLC25A51.

Measurement of nutrient pathways provided evidence

For their studies, the scientists used a specially created cell line library, which allows investigating pairwise genetic interactions of two SLCs. Their genes are deactivated both individually and in pairs; the effects of these interventions on cell growth can then be measured. Among the combination-related large number of interactions measured, some around the previously uncharacterized gene SLC25A51 stood out. The other interacting SLCs transport various nutrients, but all of them could be associated with NAD via known metabolic processes. “By accurately quantitatively measuring certain nutrients in the cells, we found that the presence of SLC25A51 correlated with the amount of NAD and that cells lacking SLC25A51 had extremely low levels of this molecule in their mitochondria,” explains senior author Giulio Superti-Furga. “In our study we also show that the already known NAD transporter in yeast and SLC25A51 play a similar role in the human cell.”

Important part of the scientific puzzle

The question of the existence of a mitochondrial NAD transporter in humans has been discussed for some time. Giulio Superti-Furga also explains: “The results of our research, which have also been confirmed in two other independent studies by US laboratories, provide an important answer to this question and open up the opportunity of influencing the NAD content in this key organelle. NAD is associated with many physiological and pathological processes such as ageing, neurological diseases and the metabolism of cancer cells. Our study therefore represents an important contribution to understanding the biological role of this molecule. At the same time, we also see the enormous therapeutic potential arising from the possibility of a possible modulation of the NAD content in mitochondria by the transporter SLC25A51.”

The study "Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import" was published in Nature Communications on 1 December 2020. DOI: 10.1038/s41467-020-19871-x  

Authors: Enrico Girardi, Gennaro Agrimi, Ulrich Goldmann, Giuseppe Fiume, Sabrina Lindinger, Vitaly Sedlyarov, Ismet Srndic, Bettina Gürtl, Benedikt Agerer, Felix Kartnig, Pasquale Scarcia, Maria Antonietta Di Noia, Eva Liñeiro, Manuele Rebsamen, Tabea Wiedmer, Andreas Bergthaler, Luigi Palmieri, Giulio Superti-Furga

Funding: The study was funded with support by the Austrian Academy of Sciences, the European Research Council (ERC) (AdG 695214, StG 677006) and the Austrian Science Fund (FWF P29250-B30, FWF DK W1212).

November 23, 2020

Austrian study provides deep insights into transmission and mutation properties of SARS-CoV-2

The analysis of epidemiologically-validated chains of infections in Austrian superspreading events found that a relatively large average dose of 1000 infectious viral particles is transmitted (© CeMM).

Learning from past SARS-CoV-2 outbreaks for future pandemic control

In the COVID-19 pandemic, 57 million people have already been infected worldwide. In the search for vaccines and therapies, a precise understanding of the virus, its mutations and transmission mechanisms is crucial. A recent study by the research group of Principal Investigator Andreas Bergthaler at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, in the renowned journal Science Translational Medicine, makes an important contribution to this. The high quality of epidemiological data in Austria, together with state-of-the-art virus genome sequencing, has supported unprecedented insights of the mutation behaviour and transmission of the SARS-CoV-2 virus.

The project “Mutational dynamics of SARS-CoV-2 in Austria” was launched by CeMM in close cooperation with the Medical University of Vienna at the end of March. Together with the Austrian Agency for Health and Food Safety (AGES) and in cooperation with numerous universities and hospitals all over Austria, scientists are working on drawing a more precise picture of the virus mutations and transmissions that occur by genome sequencing of SARS-CoV-2 viruses. Under the leadership of CeMM Principal Investigators Andreas Bergthaler and Christoph Bock, 750 samples from important SARS-CoV-2 infection clusters in Austria such as the tourist town of Ischgl and Vienna were phylogenetically and epidemiologically reconstructed and their role in transcontinental virus spread was analysed. The results also provide important information on transmission and the development of mutations in the SARS-CoV-2 virus.

Mutation analyses revealed correlations between clusters 

Based on epidemiological data, the scientists used mutation analyses to reconstruct a SARS-CoV-2 cluster consisting of 76 cases and to uncover a cryptic link between two epidemiological clusters. “This example illustrates how contact tracing and virus mutation analysis together provide a strong pillar of modern pandemic control,” says project leader Andreas Bergthaler. Franz Allerberger, Head of the Public Health Division of AGES and co-author of the study, agrees: “The modern techniques of virus genome sequencing support epidemiological contact tracing and offer high-resolution insights of the ongoing pandemic.”

Researchers observe the development of new mutations

A special feature of the study is that a chain of eight consecutive transmissions was analysed. “The transmission chain started with a returnee from Italy. Within 24 days, the SARS-CoV-2 virus spread in the greater Vienna region via public and social events in closed rooms”, say the CeMM study authors Alexandra Popa and Jakob-Wendelin Genger. The precise breakdown of the transmission chain enabled the scientists to closely observe the development of a new mutation of SARS-CoV-2. “Thanks to excellent epidemiological and our deep virus sequencing data, we could follow how the SARS-CoV-2 virus mutated in one individual and was then transmitted to others,” explains Andreas Bergthaler. In addition, the scientists observed the mutation behaviour of the virus during the course of the disease in 31 patients. This may help in the future to assess whether treatments influence the mutation characteristics of the virus.

On average 1,000 virus particles are transmitted during an infection

The results of the current analyses also show that on average 1000 infectious virus particles are transmitted from one infected person to the next. These values are overall considerably higher than for other viruses such as HIV or noroviruses. Andreas Bergthaler adds: “Yet, occasionally we also found infected people who apparently came into contact with fewer virus particles and still became infected. We suspect that parameters such as the application of protective measures, the transmission route or the immune system may play a decisive role here.” These results raise important new questions and hypotheses. Reducing the viral load of infected individuals by a combination of measures such as mouth-nose protection, physical distance and adequate indoor air exchange could play a key role in both preventing the spread of the virus and possibly even influence the course of the disease.

The current study based on data collected during the early phase of the SARS-CoV-2 pandemic in spring 2020, provides important insights into the fundamental dynamics of SARS-CoV-2 mutations within patients and during transmission events. These results support other ongoing research projects aiming at a better understanding and controlling the pandemic.

Find out more about the project: www.sarscov2-austria.org

The study “Genomic epidemiology of superspreading events reveals mutational dynamics and transmission properties of SARS-CoV-2” was published in the journal Science Translational Medicine on 23 November 2020. DOI: 10.1126/scitranslmed.abe2555

Authors:
Alexandra Popa, Jakob-Wendelin Genger, Michael D. Nicholson, Thomas Penz, Daniela Schmid, Stephan W. Aberle, Benedikt Agerer, Alexander Lercher, Lukas Endler, Henrique Colaço, Mark Smyth, Michael Schuster, Miguel L. Grau, Francisco Martínez-Jiménez, Oriol Pich, Wegene Borena, Erich Pawelka, Zsofia Keszei, Martin Senekowitsch, Jan Laine, Judith H. Aberle, Monika Redlberger-Fritz, Mario Karolyi, Alexander Zoufaly, Sabine Maritschnik, Martin Borkovec, Peter Hufnagl, Manfred Nairz, Günter Weiss, Michael T. Wolfinger, Dorothee von Laer, Giulio Superti-Furga, Nuria Lopez-Bigas, Elisabeth Puchhammer-Stöckl, Franz Allerberger, Franziska Michor, Christoph Bock, Andreas Bergthaler 


Funding:
The project is co-financed by a COVID-Rapid Response grant from the Vienna Science and Technology Fund (WWTF) and by contributions in kind from CeMM, the Austrian Academy of Sciences, the Medical University of Vienna and their respective partners.

 

 

November 19, 2020

Christoph Bock among the world's most highly-cited scientists in 2020

CeMM PI Christoph Bock (© Klaus Pichler / CeMM)

Every year the “Highly Cited Researchers” list provided by Clarivate Analytics recognizes the most influential researchers with highly-cited papers that rank in the top 1% by citation in different scientific fields. This year 39 researchers in the list are working in Austria. Among them, CeMM PI Christoph Bock, who has been included in the cross-field category, highlighting the interdisciplinary nature of his work.

Christoph  Bock  joined  CeMM  as  Principal  Investigator  in  2012.  He  pursues  interdisciplinary  research aimed at understanding the epigenetic and gene-regulatory basis of cancer, and advancing precision medicine with genomics technology. His research group combines experimental biology (high-throughput  sequencing,  epigenetics,  CRISPR  screening,  synthetic  biology)  with  computer  science (bioinformatics, machine learning, artificial intelligence). He is also a guest professor at the Medical University of Vienna, scientific coordinator of the Biomedical Sequencing Facility (BSF) at CeMM, and key researcher at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. He  coordinates  the EU  Horizon  2020 HCA|Organoid project  on  the  single-cell  analysis  of  human  organoids  as  a  contribution to the Human Cell Atlas.

Congratulations to Christoph for being among the world’s most highly-cited scientists in 2020!

Check the full list of "Highly Cited Researchers" here.

November 18, 2020

Stem cell transplantation: undesirable rejection mechanism identified

CeMM Adjunct PI Georg Stary (LBI-RUd/MedUni Wien) © Klaus Pichler / CeMM

In the treatment of leukaemia, stem cell transplantation subsequent to chemotherapy and radiation can often engender severe adverse inflammatory reactions – especially in the skin or in the gut, since these so-called barrier organs are more frequently affected. Up until now, the reason for this was unclear. A MedUni Vienna team led by Georg Stary and Johanna Strobl from MedUni Vienna's Department of Dermatology, the CeMM (Research Center for Molecular Medicine of the Austrian Academy of Sciences) and the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases has now identified an immune mechanism that is partially responsible for this. The results have now been published in the leading journal "Science Translational Medicine".  

The term leukaemia is used to describe a group of malignant diseases of the haematopoietic system, in which precursors of the white blood cells (leucocytes) proliferate uncontrollably. Chemotherapy and radiotherapy are used to destroy the abnormal blood cells, which are then replaced by means of a stem cell transplant. In leukaemia, the transplantation of healthy bone marrow stem cells or haematopoietic stem cells is often the only hope of recovery for patients. The process involves "replacing" all the recipient's blood cells that were previously destroyed by the treatment with donor cells.

However, the MedUni Vienna dermatologists have now found that there are so-called skin-resident and inactive T cells in the endogenous immune system that survive chemotherapy and radiotherapy intact and go on to survive for a further ten years between and beneath the epithelial cells of the skin, while the circulating T cells are destroyed.

"We were able to demonstrate that T cells surviving in the skin tissue are responsible for the inflammatory reaction following a stem cell transplant. These phenomena often occur within the first 100 days and can cause anything from mild eczema through to extensive fibrosis, hardening of the tissue, or blistering on the surface of the skin. In other words, the endogenous T cells attack the recipient (host) following stem cell transplantation." In specialist jargon, the condition is also referred to as Graft versus Host Disease (GvHD), and, for the first time, this study identified an inverse "Host-versus-graft reaction".

There were also cases in which the donor T cells further "supported", and thus intensified, this reaction. Affected patients are treated with cortisone, which causes an additional burden for patients who are already immunosuppressed following the transplantation. The study found that in patients who do not develop graft-versus-host disease, tissue-resident T cells remaining after treatment even proved to be beneficial to the recipient, in that they assumed their role in immune defence and protecting against infection.

In the future, the exemplary study results could lead to new treatment strategies that help to avoid, or at least to minimise, undesirable and violent inflammatory reactions following stem cell transplants by manipulating the recipient's inactive T cells in advance. In addition, the manipulation of tissue-resident T cells might lead to new therapeutic approaches for other chronic inflammatory skin diseases, such as psoriasis or neurodermatitis.

Service: Science Translational Medicine
"Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease" Johanna Strobl, Ram Vinay Pandey, Thomas Krausgruber, Nadine Bayer, Lisa Kleissl, Bärbel Reininger, Pablo Vieyra-Garcia, Peter Wolf, Maaia-Margo Jentus, Margit Mitterbauer, Philipp Wohlfarth, Werner Rabitsch, Georg Stingl, Christoph Bock, Georg Stary.

DOI: 10.1126/scitranslmed.abb7028

November 17, 2020

Drug discovery: First highly scalable method developed to monitor protein levels and localizations in cells

Illustration: “Cell pool expressing hundreds of different GFP-fusion proteins” (© Andreas Reicher / CeMM)

Until now, scientists typically studied the changes of proteins and their roles in the cell by using a fluorescent tag to label and follow one protein at a time. This approach limited the number of proteins that could be studied and precluded unbiased discovery approaches. Researchers at CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, have now developed a highly scalable method which allows for the study of hundreds of proteins in parallel in order to monitor the changes of their levels and localization in the cell. This novel strategy is a notable contribution, not only to drug development for future treatments against diseases such as cancer, but also to our general understanding and knowledge of proteome dynamics. Their findings have now been published in the renowned scientific journal Genome Research.

Proteins are large molecules in the cell, and they are required for the structure, function and regulation of the tissues and organs in the body. They are responsible for nearly every task of cellular life, and can be as diverse as the functions they serve. Protein levels and their localization within the cell regulate important aspects of many cellular processes and can become important targets for drug treatment. For example, the abundance of proteins can be increased or decreased by intervening therapeutically, by drugs that affect protein production and degradation in the cell. Proteins can also move between different cellular compartments, and thereby shift their functions. Other proteins might bind to distinct locations in response to external stimuli, such as areas where DNA damage occurs.

Traditionally, scientists use a fluorescent tag to label individual proteins and study their roles in the cell. A green fluorescent protein (GFP) is fused to one of the ends of a certain protein they wanted to study. This protein fusion is then expressed in the cell, and through fluorescence microscopy they can observe the cells expressing the labeled protein. This method permits studying many perturbations like different drug doses in a time resolved manner for a single protein. In contrast, mass-spectrometry was not suitable to study and monitor these cellular perturbations on the proteome, the entire complement of proteins, at a high scalable level on a specific point in time in an unbiased way.

Andreas Reicher and Anna Koren from CeMM Principal Investigator Stefan Kubicek’s group have developed a novel strategy, which allows, for the first time, to observe and characterize those changes in a very high number of proteins in parallel. This method can be used to, not only describe and better understand the effects of certain known drugs in the cells, but also to discover new drug treatments that work by affecting and modulating the protein levels or localizations in the cells.

CeMM researchers have designed a method to overcome the bottle-neck in CRISPR-CAS9-based intron tagging: that there is a need to develop methods that shine a light on the whole proteome, or a substantial part thereof and not just one protein at a time.  To overcome this problem, CeMM researchers designed a method to generate cell pools containing hundreds of tagged proteins, and in each cell a different protein was labeled with GFP. These cell pools were exposed to a PROTAC chemical degrader of BRD4, a transcriptional regulator that plays a key role during embryogenesis and cancer development. Researchers then using time-lapse microscopy observed if there were any changes in the levels or subcellular localization of any of the tagged proteins in the cell pool in response to the applied treatment. Importantly, the CRISPR-Cas9 tagging strategy they applied then enabled them to identify which proteins changed localization by using in situ sequencing of the entire cell pool. Thus, they confirmed the known targets of these drug but also also revealed unexpected changes. Particularly for perturbations of BRD4 signalling, they were able to report changes in localizations of six proteins that had previously not being recognized by any other high throughput methods. Finally, they also showed that the method reveals expected and novel protein localization changes for a will studied perturbation, treatment with the approved cancer drug methotrexate.

CeMM Principal Investigator Stefan Kubicek explains, “Our study describes a technology which, not only, for the first time, applies intron tagging to a gene pool, but is also significantly optimized in all three steps - intron tagging, cellular imaging and in situ sequencing - to enable the process in the most effective way. This method applied to chemical libraries and candidate molecules is particularly powerful in order to develop and deeply characterize drugs including the induction and inhibition of protein-protein interactions and chemical degradation. The described strategy will potentially accelerate drug discovery, and have great impact on the study of global and subcellular proteome dynamics.

 

The study “Pooled protein tagging, cellular imaging, and in situ sequencing for monitoring drug action in real time” was published in Genome Research on 17 November 2020. DOI: www.genome.org/cgi/doi/10.1101/gr.261503.120

Authors:
Andreas Reicher, Anna Koren, Stefan Kubicek

Funding:
The study was supported by the Austrian Academy of Sciences, the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF) (Project No. F4701-614 B20) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437). Andreas Reicher is supported by a Boehringer Ingelheim Fonds PhD fellowship.

November 17, 2020

CeMM signs framework agreement with the Technology Transfer Fund KHAN-I and its subsidiary wings4innovation GmbH (w4i)

CeMM Building (© Iris Ranzinger / CeMM)

Worth EUR 60 million, the KHAN Technology Transfer Fund I (KHAN-I) has, since July 2019, been financing highly innovative drug discovery projects that open up new therapeutic options for patients, based on ideas and results from Austrian, German and other European research institutions. The projects are developed in line with industry standards together with the research institutions and are commercialized by KHAN-I. The current investment portfolio includes three Austrian projects that have been scouted, evaluated and selected for funding by the Austrian KHAN-I subsidiary, wings4innovation GmbH (w4i). The KHAN-I investors are Austria Wirtschaftsservice (aws) on behalf of the Austrian Federal Ministry for Digital and Economic Affairs, European Investment Fund (EIF) and Max Planck Foundation (MPF).

With its outstanding network and extensive experience, w4i pools the resources and competencies of Austrian life-science players, and contributes specialized industrial expertise. In order to strengthen w4i’s role as a translational centre and a key partner in Austria, and to provide many promising projects with KHAN-I financing as rapidly as possible, w4i and KHAN-I have concluded a framework agreement with 19 leading Austrian research institutions in the life-science area.

“The life-science sector plays an important role in the Austrian economy. Particularly in the current situation, the biotech, pharma and medical device sector is essential to successfully mastering the challenges. This, by international standards, unique alliance has allowed us to lay the foundation for future innovations that will improve not only the Austrian life-science industry but especially our healthcare system,” comments the Federal Minister for Digital and Economic Affairs, Margarete Schramböck, welcoming the framework agreement.

Together with CeMM, the contractual partners are: AIT Austrian Institute of Technology, IMBA – Institute of Molecular Biology of the Austrian Academy of Sciences, IMP – Research Institute of Molecular Pathology, Institute of Science and Technology Austria (IST Austria), Ludwig Boltzmann Gesellschaft – Austrian association for the promotion of scientific research, Max Perutz Labs Vienna, Medical University of Graz, Medical University of Innsbruck, Medical University of Vienna, Paracelsus Medical University Salzburg, Paris Lodron University of Salzburg, Graz University of Technology, Vienna University of Technology, University of Natural Resources and Life Sciences Vienna, University of Graz, University Hospital Salzburg, University of Vienna, and University of Veterinary Medicine Vienna.

The framework agreement covers fundamental aspects of the identification and evaluation of project proposals, as well as execution and exploitation of funded projects: for example, the contributions and responsibilities of the contractual partners, intellectual property rights and the distribution of proceeds between academic partners and KHAN-I after successful commercial exploitation.

“I know of no other country in which virtually all national research institutions with a life-science focus have cooperated to support one translational centre. For me, this is a milestone in the expansion of value creation in Austria as a centre of innovation and clearly demonstrating that Austria’s participation in KHAN-I was an excellent decision,” enthuses Peter Nussbaumer, CEO of w4i and member of the KHAN-I management team, on the conclusion of the framework agreement.

“This framework agreement marks an important step towards bringing innovations from Austrian research institutions to the marketplace more rapidly and efficiently. We at the aws are delighted to be contributing to the financing of the fund, because supporting ground-breaking projects is one of our key responsibilities as the Austrian government promotional bank. The aws supports innovative companies with soft loans, guarantees, grants, equity and coaching,” say the aws Managing Directors, Edeltraud Stiftinger and Bernhard Sagmeister.



wings4innovation GmbH (w4i) is a wholly-owned subsidiary of KHAN-I, with headquarters in Vienna, and is the central contact for academic partners from all over Austria. w4i scouts and evaluates projects ideas and, after approval by the w4i advisory board, puts forward suitable projects for KHAN-I financing. The role of w4i in financed projects is to coordinate work packages and the involvement of the academic project originators on behalf of KHAN-I. As part of its scouting activity, w4i offers academic partners general advice on translation opportunities for their results and hypotheses, and on aspects of industrial drug research and development.

KHAN Technology Transfer Fund I GmbH & Co. KG (KHAN-I) is a limited partnership under German law with the European Investment Fund (EIF), Max Planck Foundation (MPF), Austria Wirtschaftsservice GmbH (aws), and KHAN-I Vermögensverwaltung GmbH & Co. KG as non-managing limited partners and Khanu Management GmbH (KHANU) as general partner and fund manager. The purpose of KHAN-I is to invest in innovative drug discovery projects and spin-out companies, primarily originating from academic sources, at the discovery, pre-clinical and clinical development stage for human healthcare and, opportunistically, veterinary care as well as to commercialize the results and products of the investments and, thus, to participate, directly or indirectly, in future proceeds.

September 09, 2020

Congratulations to CeMM SAB Member Emmanuelle Charpentier for the 2020 Nobel Prize in Chemistry

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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.

https://www.nobelprize.org/prizes/chemistry/2020/charpentier/facts/ 

https://www.emmanuelle-charpentier-lab.org/

September 09, 2020

Allergic immune responses help fight bacterial infections

Senior co-author Sylvia Knapp and first author Philipp Starkl (© CeMM)

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.

* European Academy of Allergy and Clinical Immunology (EAACI, 2016)

 

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

Authors:
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

Funding:
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).