November 20, 2017

Diabetes drug helps repair UV-damaged DNA in cells of "Moon children"

Visualization of the DNA repair proteins XPC (in green) and MUTYH (in red) to sites of UV-induced DNA damage within the nucleus (in blue) of a human cell (© CeMM/Abdelghani Mazouzi)

The severe and debilitating genetic disease Xeroderma pigmentosum impedes cells to repair UV-induced DNA damage. Scientists from CeMM found a drug approved for diabetes treatment to alleviate the impact of the gene defect in cell culture, which led to the discovery of a previously unknown DNA repair mechanism. The study was published in Molecular Cell.

The destructive force of UV radiation on DNA molecules is only fully visible, when repair mechanisms fail: patients with the rare genetic disease Xeroderma pigmentosum – also known as “Moon children’ - develop inflammations upon exposure to only small amounts of sunlight, rough-surfaced growths and eventually skin cancer occurs often in early age. The severe condition is caused by mutations in the genes for the nucleotide excision repair (NER) pathway – the only known mechanism that deals with UV-induced DNA damage in human cells. Although first described in 1874, Xeroderma pigmentosum to date lacks any curative treatment.

Led by Joanna Loizou, Principal Investigator at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and together with collaborators from the Medical University of Vienna and the IRB Barcelona, the scientists at CeMM found in their most recent publication that the FDA-approved diabetes drug acetohexamide significantly improves the resilience of NER deficient cells against UV radiation in vitro. Above that, the study published in Molecular Cell (DOI: 10.1016/j.molcel.2017.10.021) identified the responsible molecular mode of action – a hitherto unknown, NER-independent repair mechanism for UV-induced DNA damage. The study has not tested the use of acetohexamide in Xeroderma pigmentosum patients.

For their study, the scientists of Loizou’s team developed a special chemical screening approach for compounds that would allow Xeroderma pigmentosum-disease cells to survival UV treatment better. Using the CLOUD (Cemm Library of Unique Drugs), this approach led to the identification of acetohexamide: By treating Xeroderma pigmentosum-disease cells with the diabetes drug, these cells could now repair UV-induced DNA damage more efficiently. A multitude of subsequent experiments eventually led to the elucidation of the underlying molecular mechanism: acetohexamide leads to the degradation of the DNA repair enzyme MUTYH, triggering an hitherto unknown NER-independent mechanism for removing UV-induced DNA damage.

Publication:

Abdelghani Mazouzi, Federica Battistini, Sarah C. Moser, Joana Ferreira da Silva, Marc Wiedner, Michel Owusu, Charles-Hugues Lardeau, Anna Ringler, Beatrix Weil, Jürgen Neesen, Modesto Orozco,  Stefan Kubicek and Joanna I. Loizou. Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Molecular Cell, November 16, 2017. DOI: 10.1016/j.molcel.2017.10.021 

Funding:

The study was supported by the Austrian Academy of Sciences, the European Commission, the Austrian Science Fund, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development, the Spanish Ministry of Science  the Catalan Government, the Instituto de Salud Carlos III-Instituto Nacional de Bioinformática, and the European Research Council ERC.

November 15, 2017

Pharmacoscopy improves therapy for relapsed blood cancer in a first clinical trial

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Researchers at CeMM and the Medical University of Vienna presented a preliminary report published in The Lancet Hematology on the clinical impact of an integrated ex vivo approach termed pharmacoscopy. The interims analysis of the first-ever clinical trial with the approach shows that pharmacoscopy can assist decision-making of the responsible clinicians effectively and thus represent a powerful tool for practical precise and personalized medicine.

Patients suffering from refractory and relapsed blood cancers often have few treatment options and short survival times. At this stage, identifying effective therapies can be challenging for doctors. Even state-of-the-art genetic analyses, due to the high heterogeneity of cancer cells and the impact of the various mutations on their drug response, do often not suffice to instruct personalized treatments. Pharmacoscopy, a technology developed by scientists at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and tested for its clinical efficacy by clinicians of the Medical University of Vienna, offers a functional approach: hundreds of drug options can be quickly pre-tested ex vivo in small liquid biopsy samples collected from individual patients.

The effects of each drug on the individual cells are quantified using high-throughput and high-content automated confocal microscopy. In combination with specially developed analysis methods and machine learning and other unique algorithms, pharmacoscopy allows quantification of never-before visualized phenotypes. The method was first presented last April in Nature Chemical Biology (doi:10.1038/nchembio.2360).

While the clinical study is still recruiting, interim analysis of the program showed that 88.2% of the patients recruited (15 out of 17) who received pharmacoscopy-monitored personalized therapies achieved partial or complete remission, while only 23.5% (4 out of 17) responded similarly well to their previous respective treatments.

In addition, the median progression-free survival of patients who were treated in accordance to pharmacoscopy-guided therapy increased from 5.7 week to 22.6 weeks compared to their last line of treatment. Further, in a retrospective study organized to specifically determine the ability of the method to stratify responding and non-responding newly-diagnosed patients with acute myeloid leukemia (AML), resulted in 90% accuracy. Before, such accuracy in prediction of treatment outcome was unachievable, with or without genetic assays.

Publication:

Berend Snijder*, Gregory I Vladimer*, Nikolaus Krall, Katsuhiro Miura, Ann-Sofie Schmolke, Christoph Kornauth, Monika Sabler, Oscar Lopez de la Fuente, Hye-Soo Choi; Emiel van der Kouwe; Sinan Gültekin, Lukas Kazianka, Johannes Bigenzahn, Gregor Hörmann, Nicole Prutsch, Olaf Merkel, PhD; Anna Ringler; Georg Jeryczynski, Marius Mayerhöfer, Ingrid Simonitsch-Klupp, Katharina Ocko, Franz Felberbauer, Leonhard Müllauer, Gerald W Prager, Belgin Korkmaz, Lukas Kenner, Wolfgang R Sperr, Robert Kralovics, Heinz Gisslinger, Peter Valent, Stefan Kubicek, Ulrich Jäger, Philipp B Staber, and Giulio Superti-Furga. (*co-first authors) Image-based ex-vivo drug screening for patients with aggressive haematological malignancies: interim results from a single-arm, open-label, pilot study. The Lancet Haematology, November 13, 2017. DOI: 10.1016/S2352-3026(17)30208-9

Funding:

The study was supported by the European Research Council (ERC), the Austrian Science Fund (FWF), Austrian National Bank, the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology and Development, the MPN Research Foundation, the Swiss National Science Foundation and the European Molecular Biology Organization (EMBO)

October 31, 2017

When two wrongs make a right: Artificial CRISPR gene disruptions could rescue genetic disease

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Defective DNA repair mechanisms can lead to diseases like Fanconi anemia. Utilizing a concept called “synthetic viability”, researchers at CeMM, in international collaboration, found additional gene disruptions that rescue the phenotype of this disease in cell culture and identified the responsible protein complex. The study, published in Nature Communications, intriguingly demonstrates the potential of synthetic viability screens to identify genetic interactions rescuing cells with defects in the DNA damage response.

Sunlight, cellular metabolism or simply faulty DNA replication: DNA damage occurs tens of thousands of times per day in every cell of the body. Hence, a whole arsenal of molecular machineries stand by to repair various forms of damage and maintain cellular function. If those repair mechanisms fail, it can lead to serious diseases, as in the case of the Fanconi anemia pathway: named after the disease, it´s failure leads to impaired repair of DNA interstrand crosslink damage. 

The research group of Joanna Loizou at CeMM, in international collaboration, showed with a so-called “synthetic viability” screen that cells with defects in the Fanconia anemia pathway can be rescued by introducing additional genetic defects, targeting genes of the BLM helicase complex. The study was published in Nature Communications (DOI: 10.1038/s41467-017-01439-x).

Using CRISPR/Cas9, the scientists produced a library of viruses able to disrupt almost all of the genes in the human genome individually. Millions of cells with Fanconi anemia defect were infected with those viruses, introducing a single additional gene defect in each cell. Subsequently, DNA interstrand crosslink damage was generated – the kind of DNA damage that should kill the diseased cells. With a high throughput assay, the researchers searched for cells that survived better after disrupting additional genes and found that upon loss of a functional BLM helicase complex, cellular survival of Fanconi anemia cells was increased and the cells behaved more like healthy ones.

This work demonstrates that genome-wide CRISPR/Cas9 screens are suitable to identify genetic “synthetic viable” interaction partners that increase the survival of cells with defective DNA damage repair mechanisms. Above that, the now published study clearly shows that the loss of both components (BLM & Fanconi anemia pathway) is less detrimental for cells than a deficiency of only the Fanconi anemia pathway – an important contribution to the elucidation of this rare genetic disease.

Publication

Martin Moder*, Georgia Velimezi*, Michel Owusu, Abdelghani Mazouzi, Marc Wiedner,  Joana Ferreira da Silva, Lydia Robinson-Garcia, Fiorella Schischlik, Rastislav Slavkovsky, Robert Kralovics, Michael Schuster, Christoph Bock, Trey Ideker, Stephen P. Jackson, Jörg Menche and Joanna I. Loizou. Parallel genome-wide screens identify synthetic viable interactions 3 between the BLM helicase complex and Fanconi anemia. Nature Communications, November 1st, 2017. DOI: 10.1038/s41467-017-01439-x.

Funding

This study was supported by the European Molecular Biology Organization (EMBO) and the Austrian Science Fund (FWF). 

October 23, 2017

Obituary Denise P. Barlow

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With great sadness, we inform our colleagues and the scientific community of the decease of Prof. Dr. Denise P. Barlow. Denise died on October 21, 2017 at the age of 67 after severe illness in the company of friends.

Denise Barlow was one of the most accomplished geneticists ever to operate in Austria and one of the most inspiring epigeneticists in Europe. Denise Barlow is one of the few researchers who could claim not only to have discovered a fundamental regulatory principle of eukaryotic gene expression, molecular imprinting, but to actually have elucidated the underlying mechanism.

In 1991, the Barlow group discovered the first mammalian imprinted gene (Igf2r) and since then, has worked relentlessly to uncover many fascinating details of the imprinting mechanism. As a result, imprinting of the Igf2r gene has acted as a model of epigenetic regulation in mammals. Her laboratory has shown that an unusual and very long non-coding RNA (lncRNA), a macro ncRNA, induces imprinted gene expression. More recently, she proofed that transcription, independent of the lncRNA product, is the mechanisms that silences the Igf2r gene. In addition, the team was able to show that the differential allele activity is regulated by tissue-specific, regulatory DNA elements known as enhancers – a process that could also be implicated in many diseases.

Denise Barlow worked as a state registered nurse in the UK before completing her PhD at the Warwick University. She performed postdoctoral studies in ICRF, London, and at EMBL, Heidelberg, and held group leader positions at the IMP, Vienna, the NKI, Amsterdam, and the IMB Institute in Salzburg. Denise joined CeMM at its very beginning, in 2003, and retired in 2015. She had been EMBO member since 1995, and was an honorary professor of genetics at the University of Vienna. In 2014, Denise Barlow received the Erwin Schrödinger Prize of the Austrian Academy of Sciences, and the EMBO/EMBL Austrian Chapter Achievement Award Medal for her lifetime achievements.

Today, CeMM would not look and operate the way it does if not for Denise Barlow. Her passion for good science and a demanding work ethics greatly contributed to CeMM’s culture and success. Equally influential has been her fearless quest for intellectual rigor and determination to improve standards, from experimental design to the quality of scientific presentations, through constructive criticism. As a pioneer female group leader in the institutions she worked in, her vigilant and inquisitive spirit met not only support in the past. At CeMM, in the most recent ten years, she said she had finally found a congenial scientific home.

Denise Barlow will be dearly missed by the CeMM Directors, by the entire CeMM Faculty and all researchers, students and colleagues who had the privilege of interacting with her. Denise will undoubtedly continue to inspire us also in future, as an extraordinary researcher, a woman pioneer in scientific leadership, a great mentor and a beloved friend.

Denise Barlow – A career in epigenetics, RNA Biol. 2015 Feb; 12(2): 105–108. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615223/

October 03, 2017

CeMM-visit of President Alexander Van der Bellen and Mayor Michael Häupl

Giulio Superti-Furga, Michael Häupl, Alexander V. d. Bellen and Anita Ender - Foto: Klaus Pichler

CeMM had the pleasure to host the Federal President of Austria, Alexander Van der Bellen, and the Mayor of the City of Vienna, Michael Häupl on October 3, 2017. The guests came to our institute on the occasion of CeMM´s 10th anniversary, which we celebrated in September, and to inaugurate our PhD Gallery.

Welcomed by CeMM Directors Giulio Superti-Furga and Anita Ender and cheered by the entire staff of CeMM, the guests were accompanied to the CeMM Time Capsule, the first stop of their visit. After receiving one of the notebooks with the invitation to write down their thoughts and ideas, President Van der Bellen and Mayor Häupl met PhD representatives to unveil and inaugurate our newly installed Gallery that shows pictures and project titles of all students who completed their PhD at CeMM in the past years.

Afterwards the guests moved to the CeMM Brain Lounge, where Giulio Superti-Furga held a short presentation on the highlights of the past decade and gave an outlook into the future, stating CeMM´s most important next goals: To accelerate the development and to accompany a considerate implementation of genome-based medicine, to explore and design precise drugs and find new ways to apply existing substances with higher precision, and in close collaboration with the Medical University of Vienna, to work on strategic programs to further improve healthcare.

The ambition of CeMM to create an impact on the medicine of the future and to pursue basic research that is focused on the needs of the patients, but also the enthusiasm and persistence of all CeMM members - the “CeMM spirit” - seemed to have made an impression on our guests of honor. 

We are proud and most thankful to President Alexander Van der Bellen and Mayor Michael Häupl for their visit and their constant support over many years, and we feel more encouraged and motivated than ever to perform the best medical research, and to continue our dialogue with society. 

October 02, 2017

CeMM Outing 2017 - Göttweig Abby and Schallaburg

Foto: Hans Leitner

On September 29, 2017, the CeMM members went on the annual outing of the institute, to start the academic year with a community experience, to strengthen the relationships with colleagues, and to broaden our horizon. This year, we visited Göttweig Abby and the Schallaburg, both spectacular historic sites in a picturesque landscape.

On perfect weather, the trip started with a visit of Göttweig Abby, also known as “Lower Austria´s Montecassino” for its beautiful location on top of a hill. The Benedictine monastery, founded in the 11th century, is full of valuable collections of religious engravings, coins, antiquities and musical manuscripts, and its architectural features are ranging from Romanesque to Baroque. The imperial wing with its sumptuous furnishings and exquisite (ceiling-) paintings left a strong impression.

The second part of the outing brought us to the Schallaburg, where an exhibition on Islam in Austria provided background knowledge and facts, but also new perspectives and food for thought. Where do cultures and religions meet? Where does diversity give rise to fear, where is it felt to be a threat? CeMM is grateful to Professor emeritus Bert Fragner, expert in Islamic and Iranian Studies, who accompanied us and explained how the Islam and Muslim cultures belong to Austria and its society since centuries. 

September 28, 2017

Artificial Hearts Exhibition & Brain Lounge Discussion

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Foto: belle & sass

On September 28, 2017, Christiane Druml, Director of the Josephinum of the Medical University of Vienna, Curator Moritz Stipsicz, and CeMM Director Giulio Superti-Furga invited to a journey to the very heart of the interface of art and science. On the occasion of the exhibition “Artificial Hearts – The Bridge to Survival” in the Josephinum, a motley audience of artists, physicians, scientists and students visited the astonishing collection of historic medical exhibits and contemporary art pieces and installations, followed by a lively discussion round in CeMM´s Brain Lounge.

Vienna has played a pioneering role in the development of the artificial hearts. It was preceded by decades of extraordinary research achievements, which are showcased at the Josephinum. Interventions by artists Judith Fegerl, Peter Garmusch, Stephanie Pflaum, Samuel Schaab and Anna Witt complement the historic collection of instruments and anatomical wax models and created an extraordinary experience, taking the guests in unexpected audio-visual spheres and blurring the lines between art and science.

The audience then moved on to an open discussion round in the CeMM Brain Lounge, where the effects of increasing isolationism and nationalism on art and science was debated. Does oppression and restriction increase the motivation and creativity of artists and scientists? What is necessary to mount resistance and form opposition? What kind of influence, both societal and economical, do art and science have? What are the different financial needs and dependencies, and how do they influence the ability to oppose and provoke?

Giulio Superti-Furga (moderator), Christiane Druml, Moritz Stipsicz, artist and researcher Anna Artaker, visual artist Roswitha Schuller, print journalist Almuth Spiegler, artist Hubert Scheibl, radio journalist Elisabeth Nöstlinger, Oscar Bronner, founder of the journals Trend and Profil and editor of Der Standard, MedUni Vienna Professor Michael Trauner, and CeMM PI´s Christoph Bock and Jörg Menche opened the discussion with their experiences and thoughts. The evening ended at CeMM´s terrace with hour-long conversations. We want to thank everybody who contributed to this most pleasant, and inspiring evening. 

September 20, 2017

EU-LIFE’s Position paper on FP9: Towards better research value in Europe

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Jo Bury, Director of the VIB and Chair of EU-LIFE Foto: Klaus Pichler

CeMM is member of EU-LIFE (www.eu-life.eu). EU-LIFE is a European alliance of research centers of excellence in life sciences, whose mission is to support and strengthen European research excellence. Representing over 7,200 scientists and staff distributed in more than 500 research groups across Europe, EU-LIFE is a strong representative of the scientific community throughout Europe.

In a position paper we announce our key priorities for the next Framework Program for Research and Development (FP9) that will run from 2021 to 2027, which can be summarized as follows: 

• To double the investment by the European Commission to 150 billion euro for the entire programme 2021-2027. It is clear from calculations for previous framework programs by the European Commission that every euro spent will generate a multiple in economic benefits over time. 

• To invest more in basic research than today. Without basic research, no applied research is possible. Good basic research actually acts as a booster for applied and commercial research investments.

• To encourage collaboration of excellent research based on more bottom-up, non-prescriptive approaches that address key societal challenges.

• To encourage technology transfer that turns scientific insights into economic value. Technology transfer is critical to counter the current “innovation paradox”. The true challenge is to pro-actively assist the basic researchers with identifying and enabling commercial and medical use of their findings.

• To have excellence as the sole criterion for selection in FP9.

• To focus on open science in order to foster wider impact of excellent research. Furthermore, expected timing of impact of research outputs should be readjusted for the longer term.

Jo Bury, Chairman of EU-LIFE and Managing Director of the Flanders Institute of Biotechnology (VIB): “Excellent science and professional technology transfer are essential for the well-being of citizens in the future. We have seen that some approaches were successful in the past, where deep scientific insights have led to major breakthroughs in applied science as we see today in immuno-oncology for instance. In our research institutes, tens of thousands of Europe’s leading researchers are committed to finding solutions for the most challenging issues of our time, both in health and agriculture. For public research institutes, the funding by the Framework Programs is critical. We are convinced that the right choices will be made to re-balance the funding for more basic research”.

As a leading research institute in Austria we look forward to boost national, regional and European research and innovation. 

Downloads: 

-          EU-LIFE Position Paper
-          EU-LIFE Press Release

September 13, 2017

10th Anniversary of CeMM

Foto: Klaus Pichler

Blistered dancing feet, tissues wet with tears of joy and the taste of cake still on our lips: the 10th anniversary celebration on September 12, 2017 at the Aula der Wissenschaften was CeMM´s biggest, most spectacular and memorable event we had since the opening of our research building. 

We thank everybody who celebrated with us and who contributed to the success of CeMM over the past years! It is your support and friendship that motivates us to do the best possible research. 

Exhausted but happy, we summarize CeMM´s decennial jubilee as follows: Moderator Annie Kay wonderfully guided the audience through a mixture of overwhelming light and video shows, scientific highlights, guests of honor, musical delights, heartwarming wishes, astonishing theatre and many other special features.

“If I have to summarize what CeMM has done to the city and the community in one word, I would say “inspirational” said Andreas Mailath-Pokorny, city council for culture, science and sport of Vienna.

Together with Helga Nowotny, former President of the ERC, Markus Müller, Rector of the Medical University of Vienna, Klement Tockner, President of the FWF, Thomas Henzinger, President of the Institute of Science and Technology Austria, and Jo Bury, Chair of EU-LIFE and Managing Director of the Flanders Institute of Biotechnology, Andreas Mailath-Pokorny took part in a quiz game moderated by CeMM PhD-Student Martin Moder, that playfully highlighted the importance of funding for research. Markus Müller compared the close collaboration of the Medical University of Vienna with CeMM with a happy marriage that he wishes to continue until the end of their days.

Jo Bury held the keynote speech, presenting in his talk CeMM´s ranking in international comparison as well as its role in the EU-Life consortium, an alliance of top research centers created to build and promote excellence in life sciences in Europe. 

From the very beginning of the ceremonial act, members of the Vienna English Theater “Walking Acts” accompanied the guests and introduced with their characters the main research fields of CeMM. Miss DNA, Monsieur Macrophage, Cancer, Bloody Lady, Dame Virus and Mr. Molecule later showed their exquisite art of acting during a short scripted piece on stage, but also supported the whole event with their entertaining impro theatre roles. 

With mind-blowing visual effects digitally mapped over the entire festive hall, the light art collective Lichttapete, headed by Marcus Zobl, accentuated each and every part of the evening programme. Alma, a sublime ensemble of accordion, violin and double bass, who charmed with their winking nod to traditional Austrian folk music, set the musical framework during the celebration act. Subsequently, the world-famous Irish folk band The Dublin Legends brought guests and CeMM employees to hit the dancefloor, where they stayed until late at night dancing to the lineup of DJane Alexandra Augustin. 

We are grateful to Bertram Schütz from Science Communications who helped CeMM organize the event, and to Kriso Leinfellner, Stefanie Lichtwitz and their team for the exhibition designs of the evening and for being a valuable partner for CeMM from the very beginning. 

Last but not least, we thank everyone who contributed to the blue book photo challenge. We will show the winners of each categories, and a selection of the most creative pictures on the upcoming weeks on Facebook. 

September 04, 2017

Allcyte - a new spin-off company from CeMM provides diagnostics and drug discovery for blood cancers

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CeMM today officially announces the start of operation of a new spin-off company, Allcyte, founded by CeMM Director Giulio Superti-Furga, Berend Snijder, now Professor at the ETH Zurich, Gregory Vladimer, and Nikolaus Krall. The team met while Snijder, Vladimer, Krall were postdoctoral fellows in the research group of Giulio Superti-Furga. Allcyte supports pre-clinical drug development and clinical decision making services by helping physicians find the right drug for the right patients, and pharmaceutical companies identify the most promising indications for their drugs and drug candidates. In the era of big-data medicine, Allcyte is built around the “Pharmacoscopy” high-content imaging platform originally developed at CeMM, and clinically validated in collaboration with the Department of Hematology of the Medical University of Vienna. The Pharmacoscopy technology is the basis for a number of academic research collaborations between CeMM and the MedUni Wien, including a life science grant provided by the WWTF that aims to define better personalized medicine for late-stage hematological cancer patients.

As of September 1, Allcyte has entered an important strategic collaboration with Boehringer Ingelheim to advance Boehringer Ingelheim’s preclinical oncology drug discovery by using the pharmacoscopy technology. Pharmacoscopy enables the profiling of drug response in primary liquid patient samples with minimal sample requirement, high speed, and with single cell resolution, enabling never-before-quantified phenotypes to drive scientific exploration. The platform can not only measure cell-autonomous drug effects (e.g., specific killing of a particular cell) but is also capable of quantifying the interplay between different cell types in complex human tissues by measuring physical cell-cell interactions in an unprecedented and statistically robust manner. Parts of the technology have recently been published in Vladimer et al Nature Chemical Biology 2017.

The mission of CeMM is to achieve maximum scientific innovation in molecular medicine by performing excellent research. Only the efficient commercialization of CeMM’s proprietary and ideas can lead to the improvement of healthcare. Therefore intellectual property of CeMM already resulted in the founding of new start-up companies (Haplogen, MyeloPro, Allcyte), and into out-licensing of patents or partnerships with industry involving consultancy, know-how, technology transfer.

Allcyte is supported by Austrian Business Agency (AWS) pre-seed and seed grants managed by the Federal Ministry of Science, Research and the Economy, and the Federal Ministry for Transport, Innovation and Technology, as well as by private investors and industry cooperation.