www.cemm.at

Research Report 2010 Research Report2010

Director’s Intro — Research at CeMM — p. 6—9 p. 10—71 CeMM Principal Investigators — CeMM PhD p. 74—83 ­Program — CeMM as Spring­board for Careers — p. 86—88 p. 89—91 CeMM Landsteiner Lecture — CeMM Constantin p. 94—97 Spiegelfeld Lecture — CeMMinar Series ­ — p. 98—101 p. 102—103 CeMM Retreat — CeMM Social Activities – CeMM p. 106—107 p. 108—111 Art Façade — CeMM Directory — CeMM Publications p. 114—121 p. 124—125 2010 — CeMM Facts and Figures — Sponsor the p. 128—129 p. 132—135 CeMM Brain Lounge — Acknowledgements — p. 136—137 p. 140—141 How to reach CeMM p. 142

Previous page: Level 04, Room 04.205 Functional Genomics

Each and every CeMM member is crammed into one laboratory to symbolize many functions and talents superimposed and also to remember the crowded times in the Vienna Competence Center laboratories located in Lazarettgasse 19, where CeMM HQ were located until August 2010. Last year I began the introduction to the 2009 The celebration of the opening of the façade in Thus, CeMM trains young researchers that are research report with “What a year!”. So how then February set off the year magnificently. We had competitive at the highest international level! do I describe 2010: a period that saw CeMM finally the honour of the presence of Minister Beatrix In return, 2011 will see the beginning of three move into and occupy a tailor-made beautiful Karl in one of the first events she had attended new CeMM Principal Investigators (PIs): CeMM building in the middle of the country’s medical since taking up office, and holding on to a nice Kaan Boztug, from the University of Hannover action? Finally all scattered CeMM research groups glass of sparkling wine, despite the cold, every- Medical School, Joanna Loizou, from Cancer have come together under one roof! Apart body gladly drank with her to the new era that Research UK in London and Andreas Bergthaler, from the minor upheaval of the actual move, a the event seemed to herald. During the week from the Institute of Systems Biology in Seattle. Research logistical challenge per se, and the difficulties in July when the first people began to move into While this will not yet fill the new building associated with jump-starting the infrastructure the new building, we welcomed scientifically entirely, it will bring additional life to the 6th necessary to serve a demanding community of curious and very supportive Federal President and 7th floors and represent a phenomenal boost Report hard-working researchers, what an exhilarating Heinz Fischer and his wife Margaret Fischer. to CeMM research activities and competencies. and up-lifting year 2010 has been! Jokingly, we It might easily have been the sunniest day of We are also very happy to have secured as CeMM said that the five years preceding the move were the year, as the photographs remind us, and in Adjunct Principal Investigator Thijn Brummel- our “purgatory” years, testing our fitness and many respects the visit represented a particularly kamp, who in 2011 will join the Netherlands 2010 worthiness of the upgrade to first-class. Now that memorable and symbolic start of our newly Cancer Institute from the Whitehead Institute we can stand on our own terrace on the 8th floor, accommodated research activities. Once these of Biomedical Research in Cambridge, USA. with views of not only the medical campus but activities picked up pace, our main supporter At CeMM, Thijn will co-tutor PhD students and Introduction by Giulio Superti-Furga the entire city, below us a stunning work of art in and privileged partner, Minister Beatrix Karl, research projects. the form of a gigantic glass façade and above us, visited us again, this time inside the building. on a bright day, only some scattered fluffy clouds, We discussed the research program and societal Having our own building has also importantly we get paradisiacal emotions. mission of CeMM and, importantly, inaugurated increased our laboratory support facilities such the laboratory ironically named PLACEBO as health and safety and administration (finances The building is full of light, due to the large (Platform Austria for Chemical Biology), the and public relations). Moreover, in many respects windows and the “transparent” architecture gateway to some of our translational activities. we have simply become better organized. Denise of its creator, Ernst Kopper. Depending on the Stefan Kubicek, from Stuart Schreiber’s Barlow, a CeMM PI, has done a wonderful job weather, the beautiful façade reflects sky, clouds, laboratory at the Broad Institute of Harvard in starting a regular and exciting seminar series surrounding trees and buildings in a different University/MIT, had just joined CeMM to head (called CeMM-inars), weekly faculty lunches and, way, interweaving it with its own pattern and PLACEBO. Two events in the second half of together with Eva Schweng, is also supervising inside illumination, leading to an attractive ever- the year characterize the outreach part of CeMM’s common get-togethers and seminars with the changing appearance. When we come to work mission. In October the fine-looking lecture adjacent Center for Translational Medicine in the each morning, we still feel a bit incredulous that hall on the 8th floor housed the first Constantin Anna Spiegel building of the Medical University CeMM has such a superb home. The work of art Spiegelfeld Lecture on drug discovery and of Vienna. The enthusiasm and good will of by Peter Kogler, who designed the façade, imme- development with all its technical, commercial Medical University of Vienna Vice-Rector Oswald diately gained a lot of fans, not only among the and public health implications. George Poste, Wagner and colleague Hans Wojta were critical fifty plus sponsors who each contributed to a a towering figure in the field, inaugurated the for creating an inclusive and collaborative spirit “section” and whom I would like to thank here lecture series with a “big bang” sort of talk that between us. Mischa Pilz and his IT team have set again, but also among students, campus visitors created a lot of resonance. In December we had up large flat screens in the entrance hall on the and even construction workers. Here is an the CeMM Science Day where research projects 3rd and 8th floors to advertise all events. I take example for illustration: on the day the last façade in the institute were presented to the public. the occasion to welcome and thank everybody, piece was put into place, the artist and I visited The event was attended by the President of the especially Gabriel O’Riordain. That we are getting the building, which was at that time unfinished, Austrian Academy of Sciences and was very well better organized also became apparent on the with only concrete floors. We met a woman received so we plan to repeat it annually. The Karl occasion of a few social events that surprised us working on the first floor tiles in a room close Landsteiner lecture, presented by the Howard on account of the creativity and intensity that to the façade window and asked her sceptically Hughes Medical Institute Investigator Helen accompanied them. After a lukewarm after- what it was all about. Not knowing who we were, Hobbs in the great hall of the Academy building, barbeque party in the summer I had frankly she expressed her views frankly and produced was once again a resounding success. wondered if CeMM, as a group, would be able to a spontaneous, funny and charming approval. party at all. I was soon proven to be completely We knew then it was going to be a success. An important milestone in 2010 was the wrong by a phantasmagorical Halloween party graduation of the first wave of CeMM PhD organized by the CeMM PhD students, who students (Roland Jäger, Ana Zivkovic and Irena decorated the building and themselves, as well Vlatkovic) as well as the start of our third PhD as the entire CeMM community. Scientific programme. Also, we are exceptionally proud advisory board (SAB) member Hidde Ploegh, that Post-doctoral fellow Oliver Hantschel, from of the Whitehead Institute in the USA, happened my own group, accepted a position as Assistant to be in town and willingly dropped by, and was Professor in a new department headed by the immediately “transylvanized” and completely American molecular cancer research pioneer drawn into the party action. He left enthusiastic: Doug Hanahan, which is affiliated with the “It was incredible, all SAB members should have cancer research foundation at the Swiss Federal experienced this!”. Institute of Technology (École Polytechnique Fédérale De Lausanne, EPFL) in Lausanne.

Ce — M­—M­— Research Report 2010 6 7 An even larger party, enlarged to include partners and clinical trials, it turns out that CeMM has and families, was the Christmas get-together, produced the first and second most highly cited with games, performances and the exchange of papers of the last two years in the whole of presents from a large potluck heap. I am deeply Austria (Bürckstümmer et al, Nature Immunology thankful to all the people who contributed to 2009 and Olcaydu et al. Nature Genetics 2009). make CeMM a work hard/party hard place This is in all disciplines! While experts would within such a short time, for this is a critical caution that these results can be biased and may requisite of all successful research institutions look different in the future, it clearly tells us that I have experienced. So, how about our output? CeMM is on the right track! So young but already so clearly on the research map, and under sub- As the health activist and philanthropist Mary optimal conditions. Now that we have a building, Lasker put it: “If you think research is expensive, just think what we can do! try disease!”. Nevertheless, research that aims to be competitive at the international level is indeed Clearly, this has all been possible because of the expensive. We are constantly working at lever- help and contributions of a truly large number aging the support we get from taxpayers through of people. A hopefully complete list appears at the Ministry of Science and Research (BM:WF) the end of this report. On behalf of all CeMM by applying for third-party funds. In 2010 we colleagues I wish to thank especially the Board of were very successful in securing some 2 million the Austrian Academy of Sciences, but also the Euros to complement our 5 million Euro entire Academy who supports CeMM through running budget. To these, one needs to add the all challenges. We are also greatly thankful to the funds required for the new laboratory furniture leadership of the Medical University of Vienna, and equipment as well as our first large rent and constantly confirming their highly positive and building expenses. It is my privilege to thank collaborative stance towards the “CeMM experi- Minister Beatrix Karl here again for the important ment”. In this “building year” it is particularly support in these critical early years of CeMM. important to thank all Ministry collaborators, Are we using this money wisely to create valuable the construction and decorating groups, the knowledge? In 2010 we filed three patent appli- Bundes­immobiliengesellschaft and its employees, cations and published a number of important the teams around architect Ernst Kopper, artist papers, including the CD14 innate immunity Peter Kogler and designer Kriso Leinfellner. paper published in the Journal of Experimental Finally, I wish to personally thank the rest of Medicine, and the paper in the journal Cell on the management team, Gerhard Schadler, Georg the role of peroxisomes in innate immunity by Casari and Anita Ender, who are the pillars of our PhD student Evi Dixit and Harvard researcher this institute. As in the past, my final and whole- Jonathan Kagan. The papers published in Leuke- hearted gratitude goes to all CeMM researchers mia by the Kralovics and the Superti-Furga labo- and collaborators. Your performance in 2010 was ratories, an innovative publication on predicting outstanding and your commitment will bring the mechanism of action of drugs captained by fruits for years to come. Jacques Colinge, as well as initial breakthroughs on medical proteomics by Keiryn Bennett’s team After three research reports presented as “blue in collaboration with Ursula Schmidt-Erfurth book” lab journals, this year we present our at the University Eye Hospital in Vienna also report by staging the wonderful new CeMM deserve to be mentioned. An increasing number building. We hope that through our research of CeMM papers represent collaborations with report you will become curious and you will the Medical University of Vienna and many deal all visit us in person. The cover and the other with drugs and therapeutics. A journalist recently “strange” pictures characterizing each level of asked me whether CeMM would be as good as its the building are there to provoke thought and paragon Institute of Molecular Pathology (I.M.P., interest and to symbolically represent the variety in Vienna’s 3rd district). I immediately said no, of talents among CeMM’s staff. Please do not try not for several years, give us time! I did mention to do things like skateboarding in staircases at though that if the I.M.P. was founded today, it home! We take lab safety very seriously and do would rather resemble CeMM, with its link to not advocate trespassing except in an intellectual the medical research campus and more patient- sense! Imagination beyond boundaries. oriented research. Afterwards, for curiosity, I checked the recent scientific impact of CeMM Thanks to Helen Pickersgill and Ioannis Legouras by monitoring the most highly cited papers for expertly weaving stories out of all titbits. (a measure of impact) listed in Thomson Reuter’s ISI Web of Science. If one looks only at papers Giulio Superti-Furga senior-authored in Austria, excluding reviews Scientific Director

Ce — M­—M­— Research Report 2010 8 9 Research at CeMM Overview

Driven by talents As the main theme of the research report, we have chosen the new Level 08 Where CeMM Meets p. 68 the World building. It was only logical to structure the report by referring to Level 07 Where Genomes p. 12 the various floors of the building. are Studied And what better is there to represent CeMM and its qualities than the people Level 06 Where the Weaknesses p. 18 who are responsible for the special of Cancer and Immune Cells are Studied mood, and most of all, for the success? Of course CeMM scientists are hand- Level 05 Where Malfunctions p. 28 picked out of many highly skilled of Molecular Networks ­applicants from all over the world. are Investigated They are of course distinguished for their research track record and scientific Level 04 Where Molecules p. 36 capabilities. Yet there is much more are First Detected to look at. CeMM has the pleasure Level 03 Where Epigenetic p. 46 to host a wide range of gifted people. Regulation and There are enough musicians to form Infection Processes a big band, enough singers to build are Studied a choir, there are professional deejays, dancers as well as dancing instructors, Level 02 Where Data is p. 56 groups of runners and soccer teams, Gathered, Managed and Analyzed cup cake bakers and acrobats. They all make CeMM very special and Level 01 Where Support p. 64 ­contribute to the “think outside the Comes From box and see the bigger picture” mission. The different chapters of this year’s report are accompanied by pictures portraying extraordinary talents. We hope they will guide you through CeMM when you are reading our report. As mentioned in the introduction, these are symbolic pictures, do not try and play soccer on a roof! Level 07 Where Genomes are Studied p. 14 + The Genome Architecture of Cancer Cells + Reading the Cancer Genome Letter by Letter We have the pleasure of presenting you our 2010 The Blueprint of Life research activities by taking you through a virtual To create a new building one of the first steps tour of the new CeMM building and looking is to produce a detailed outline of the design: Level 07 at the groups and people who work there. a blueprint. DNA encodes a detailed outline Our virtual tour starts on the seventh floor, the for creating life and is sometimes called highest floor housing research laboratories. the ‘blueprint of life’. Just like the blueprint Where Genomes It is reachable by the CeMM staircase, the main of a building that guides its construction, elevator or the smaller service elevator. If you by ­encoding genes, the DNA guides cells to have a magnetic card you can also reach it ­construct a fully functioning organism. If there through the corridor connecting the floor to the are mistakes in the blueprint, the result can be are Studied adjacent Anna Spiegel building of the Medical disease, but if the mistakes are only small, finding University. Of course, most people prefer the them can be quite a challenge. On the seventh elevator. ­Walking out of the elevator on the floor of the CeMM building, using their new seventh floor you can turn right, where you find technology, the Kralovics lab searches through the offices and the corner seminar room, or left the genetic blueprints of cancer cells. towards the laboratories. The laboratories offer an impressive view of the Vienna skyline. This is the Reading the Genetic Proofs floor where medical genetics and genomics rule. Finding subtle differences in the genetic code between different cancer cells is like searching The laboratory of Principal Investigator Robert for a very small needle in a very big haystack. Kralovics is found here. Robert’s team comprises Fortunately, in the last few years, groundbreaking five PhD students, one postdoctoral fellow, one technology has been developed for sequencing Previous page: research technician and two diploma students. whole genomes at a reasonable cost as well Level 07, Room 07.101.1 They come from all over the world. PhD student as accompanying computational tools. Whole Meeting Room Ashot Harutyunyan, for example, comes from genome sequencing allows us to determine Into the groove Armenia and research technician Tiina Berg the complete DNA sequence of an organism Giulio Superti-Furga, Scientific Director playing a Höfner semi-acoustic bass comes from Finland. Early in 2011, they will be or cell in one go. DNA is made up of only four guitar from the 60’s sharing the floor with the group of new CeMM ­molecules known as adenine, guanine, cytosine André Müller, Staff Scientist PI Kaan Boztug and, later in the year, with a and thymidine (usually depicted as A, G, C playing a Rickenbacker electric guitar from the 70’s new PI working on computational genomics. and T). These so-called nucleotides are ­linearly The Kralovics lab works mainly on identifying arranged in different orders on individual mutations that contribute to the initiation ­chromosomes. It is this sequence that together and progression of various blood cancers like makes up the genome. leukemia. For this they use genomics approaches. To assist them, as well as other groups at CeMM, The first human genome sequence was com- they have established a well equipped Genomics pleted in 2001 and was a landmark event, not Facility on this floor. least because it is composed of almost 2.9 billion nucleotides found on 23 chromosomes. It took The Genomics Facility one consortium of twenty centers in six ­countries The Genomics Facility is a collection of state-of- over 10 years to complete and cost just under the-art equipment for performing high-through- $3 billion. Since then, huge advances in technol- put genomics analyses. It includes a dedicated ogy have meant that large sections of DNA, such pre-PCR (polymerase chain reaction) laboratory, as those harbouring potential cancer-causing including robots for sample preparation, eleven mutations, can be sequenced by individual labs standard PCR machines and a “real-time” in a relatively short space of time and at a fraction PCR machine. Moreover, there is a complete of the original cost. It has begun to change the Affymetrix microarray processing platform and, face of cancer genetics and has directly influenced the lab’s most coveted toy, the next generation the research in the Kralovics lab. CeMM estab- DNA sequencer (HiSeq2000 from Illumina). lished this new technology in the seventh floor This allows sequencing at a pace that would have Genomics facility in July 2010, when the first been unthinkable some years ago. In the last scientists moved into the new building. few months numerous collaborations with researchers from both inside and outside CeMM, including the Medical University of Vienna, and the Universities of Pavia, Florence and Basel, have been established, mainly involving the use of the arrays and next generation sequencing. Particularly, members of Denise Barlow’s lab on the third floor are common users of the sequencer for their studies on the epigenetics of cancer.

Ce — M­—M­— Research Report 2010 14 15 The Genome Architecture Reading the Cancer Genome of Cancer Cells Letter by Letter

DNA microarrays Cancer is a disease characterized by a group of When this analysis is performed for hundreds Although genome sequencing has only recently (or few letters) of the genome, this new tech- cells that have lost growth control. It originates of patients, the mosaics can be compared and been established at CeMM, it has already contrib- nology allows scientists to essentially find the can read from a single healthy cell that acquires a specific used to identify a pattern that best describes each uted significantly to our understanding of cancer needles in the haystacks. Once these single- 1.8 million data genetic mutation, changing the sequence of leukemic disease. Using this approach, several genomes. In the Kralovics lab, genome sequenc- letter defects are detected, they contribute to the points per genome our DNA. Our cells acquire random mutations members of the lab, including PhD student ing has complemented the DNA microarray data individual mosaics of defects of each cancer all the time, simply from dividing, or from Roland Jäger, have discovered a number of generated using patients’ leukemic samples and genome. Comparing many such high-resolution and “paint a ­environmental damage by chemicals such as ­chromosomal defects that implicated a group of filled in a substantial information gap. Genome genome mosaics will enable the group to draw genome mosaic” those found in tobacco or UV from the sun. regulatory genes called transcription factors in sequencing can literally read more than 3 billion generalized conclusions on the evolution of for each leukemia ­Fortunately, most of these mutations are relatively leukemia, which may lead to the future develop- letters of the genome. Because large numbers the leukemic genome and decipher the genetic patient. harmless and do not cause disease. However, ment of new drug treatments. Some of this work of the chromosomal defects found in leukemia complexity of leukemias step by step or rather a mutation that affects the function of certain was published in the journal Leukemia, in 2010. are point mutations changing only a single letter letter by letter. important proteins, thereby enabling the cell In addition, being able to detect some of these to bypass normal mechanisms of growth control, chromosomal abnormalities in new patients may can eventually lead to cancer. be useful for predicting the severity of the disease. Interestingly, different types of leukemias tend In leukemia, the initiating mutation comes in to have fairly similar genome architectures. various forms. It can be a large chromosomal It seems that leukemic cells use related chromo- Fig. 1 Top: DNA micro­ ­rearrangement leading to misplaced, missing somal defects during their genome evolution, arrays and an image (right) of the thousands of data or multiplied sections, or a small point mutation most likely due to the similar tissue micro­ points they can analyze in a single gene. Once the cell is transformed environments they evolve in. in a patients genome. Middle: Flowcells – the into a cancer cell it sets out to multiply, generat- devices used to sequence ing millions of copies of itself. Its progeny, the Unlucky Number 7 whole genomes of cancer tumour mass, starts to compete for space and An example is illustrated by chromosome 7. patients. Right: magnifi­ cation of a small area on other resources with healthy cells of the sur- ­Various chromosome 7 defects or lesions have a flowcell where millions rounding tissues. As the cancer cells continue to been described in the past in different types of DNA pieces are read. Bottom: a schematic divide and the tumour grows, more mutations of myeloid leukemias. However, which of the view of chromosome occur. Although the vast majority of these newly 1400 or so genes found on this chromosome seven. In leukemia, acquired genetic mutations do not provide any were directly involved was not known. The ­patients ­frequently lose ­fragments of this chromo- benefit to the cancer, some may prove to be group assembled “genomic mosaics” using cells some ­(indicated by the useful in the environment in which the cancer isolated from many patients. By comparing the red bars). Comparison of resides and thus provide a selective advantage. different mosaics they were able to make some these changes in different patients led to the identi- Therefore, selection is the main ­driving force striking conclusions. Indeed, two genes turned fication of two important behind the cancer genome in a given ­environment. out to be important targets of these lesions; target genes IKZF1 and CUX1. CUX1, which is located on the short arm of the Painting Genome Mosaics chromosome, and Ikaros, which is found on the Different tissues have different selective forces long arm. As chromosome 7 lesions are seen in that shape the cancer genome. Cancers of blood, almost all types of leukemia, this indicates that particularly leukemias, are one of the focal points these two genes are prominent players in the of research at CeMM. In leukemia, the cancer pathways used by leukemic cells to promote their cells of each patient follow a unique ­evolutionary survival. Finding ways of manipulating these path. As a result, a mosaic of chromosomal genes may lead to a new treatment for the disease. changes can be seen in each patient. The Kralovics laboratory studies the genomic architecture of leukemic cells in hundreds of patients diagnosed with different forms of leukemia. In each patient, CUX1 the leukemic genome is evaluated using DNA microarrays that can read 1.8 million data points per genome and “paint a genome mosaic” for IKZF1 each leukemia patient.

chr7

Ce — M­—M­— Research Report 2010 16 17 Level06 Studying the Weaknesses of Cancer and Immune Cells p. 20 + Screening for New Cancer Drugs + Protein Modifications and Cancer + Inflammation and Atherosclerosis + Natural IgM Antibodies + Protection against Oxidative Stress We leave the seventh floor via the stairs. The The general focus of the lab is cancer, which is walls are unpainted concrete, which, with the often also the topic of the weekly journal clubs sober steps and metal railings, contribute to held by the group during lunch in their meeting Level 06 an industrial type of atmosphere. The steps are room. Each week, one member of the group gets ­relatively high, so it’s tough going, and enviously to choose a paper on any topic for detailed discus- we watch the elevator go up and down within sion. This helps teach the students how science Where its glass enclosure. On the landing, we take the should (or shouldn’t) be done, and keeps them glass door on the left. On the glass is imprinted up to date with current literature. In the lab, most the shape of a female researcher with a ponytail of the group are using a relatively new concept holding a tube. The image is filled with white to find new ways to fight cancer. the Weaknesses decals ­of the three-letter codes for amino acids, the building blocks of proteins encoded by the Back-up Systems genome. From the head, the sequence reads The functioning or “homeostasis” of the new Met-Glu-Glu-Pro-Gln-Ser-Asp-Val and so on. CeMM building is not easily disturbed. A com- of Cancer This is the beginning of the polypeptide chain fortable indoor climate is maintained thanks of the human tumour suppressor protein p53 to air conditioning, heating and window blinds (P53_HUMAN), arguably the most important regardless of the weather outside. Back-up cancer-preventing protein in our genome. systems avert problems even when things go and Immune Cells A ­surprising number of cancer types show muta- wrong. For instance, the emergency electricity tions in this protein or in a protein associated system prevents defrosting of freezers contain- with it. Cells become more susceptible to other ing ­valuable reagents in case of a power outage. changes leading to cancer, when mutated in p53. And the two lifts and staircase ensure that all are Studied So, it is a symbolically relevant gate to the sixth ­employees can efficiently navigate the building, floor where cancer “weaknesses” is one of the even if one of the lifts is out of order. research topics. Previous page: One could say that the building has a certain Level 06, Room 06.203 The corridor parallel to the axis of the building “robustness” that protects it and its users from Nijman Lab has three doors to the open-space laboratory. changing conditions and the occasional malfunc- Lust for life One end leads to the tissue culture lab, and the tion of any single component. A defining char- Tillmann Burckstümmer, Postdoctoral Fellow dancing Lindy Hop other to one of the three small offices that are on acteristic of a robust system is that breakdown the side of the art façade. We walk into the large, of a single part causes problems only in the case open-plan laboratory, which is full of light. The of an unlikely event. A failed computer back-up, lab furniture, including benches and shelves, is for example, only becomes problematic when white, while the stools and chairs are black. The a server crashes that same day, which is highly bench surfaces are made out of thick glass. Along improbable. A blocked staircase only becomes the tall windows lining the back wall, which are life threatening in case of a fire. the source of all the light, there is a long desk for students and research technicians. The view Testing for Weaknesses may not be quite as good as from the seventh These very same principles also apply to biologi- or eighth floor, but is still fantastic. Currently, cal systems and play an important role in many the floor is only occupied by the laboratory of diseases, including cancer. The hope is that they Principal Investigator Sebastian Nijman. In the can offer new therapeutic strategies for treat- summer, two more PIs will start; Joanna Loizou, ing these devastating diseases. During tumour joining from Cancer Research UK in London, ­formation, normal cells acquire numerous and Andreas Bergthaler, currently at the Institute ­genetic and molecular changes that turn them for Systems Biology in Seattle. into cancer cells and drive the growth of the tumour. These changes include the activation The Nijman lab, consisting of two Post-docs, of growth signalling pathways, deregulated two PhD students, two research technicians and ­transcription, crippling of cell cycle checkpoints a diploma student, occupies a third of the sixth and so on. The consequence is cancer cells that floor. Most commonly people are found seated are impervious to outside regulation and even at one of the four sterile hoods in the tissue culture spread to other sites in the body (metastasis). room adjacent to the open-plan lab, splitting However, all these changes also make extra cells into stacks of petri dishes for screening demands on back-up systems and the cancer cells experiments. The group also employs two bio- become, in some ways, less robust than their informatics undergraduates from the Vienna ­normal counter­parts. Selling the fire alarm system Technical University, who sit at the desks in the may have saved money and energy, but in case Post-docs writing room on the other side of the of a fire the whole building is now at risk. floor, helping to analyze the large datasets that are produced from the high-throughput screens.

Ce — M­—M­— Research Report 2010 20 21 Screening for Protein Modifications New Cancer Drugs and Cancer

In 2008, there In the Nijman lab the principles of robust sys- Relationships Between Genes and Compounds Many proteins undergo chemical modifications Recently, an undergraduate student in the lab, The significance tems are now the basis for experiments aimed at Most of the group is performing large-scale involving the addition of small chemical groups Thomas List, discovered that a protein in a cancer were over finding new therapeutic angles for cancer therapy. chemical genetic experiments. Chemical genetics or molecules that can alter their function. These signalling pathway is mono-ubiquitinated. of ubiquitination 300,000 new One of these principles is known as “synthetic is the study of the modulatory effect that genes modifications are dynamic, and their­addition This pathway plays an important role in many in diseases such cases of breast lethality”: two molecular changes that are only and gene mutations have on the response of cells and removal enables the careful control of ­specific cellular processes such as cell death, cell growth as cancer has detrimental to the cell when occurring in combi- to chemicals such as drugs. In particular, the lab cellular processes. The best studied posttransla- and proliferation. This cancer signalling path- cancer within nation. Because cancer cells already have one of are investigating which cancer genes may influ- tional modification is phosphorylation, whereby way is a particularly interesting pathway as its only recently the European such a pair of alterations, they are now sensitive ence a cancer cell’s response to chemotherapeutic a phosphate group is added to a certain amino deregulation has been linked to a large number been illustrated. Union. to a second whereas normal cells can still rely on drugs. Cancer genes are normal genes that have acid residue on a protein via the action of a pro- of human cancers such as glioblastoma, breast the back-up system. In the Nijman lab, system- undergone a specific mutation that changes the tein kinase, and is removed by a phosphatase. and prostate cancer. This makes its components atic explorations into these combinations aim to genes’ function or switches it off. In some cases A less well-studied modification is­ub iquitination, important potential targets for therapy. Indeed, identify these Achilles’ heels of cancer. cancer genes can make cancer cells less sensitive resulting in the addition of a small molecule several inhibitors of individual members of this (i.e. resistant) to a specific drug. This informa- known as ubiquitin. The removal of ubiquitin pathway have been identified and are showing Breast cancer is a devastating disease with high tion is very important as it can help to make sure from a protein is known as deubiquitination, promise in clinical trials. incidence, mortality and morbidity. In 2008, patients are not treated with strong drugs that and is performed by so-called deubiquitinating there were over 300,000 new cases within the will not work on them and often have severe enzymes. The significance of ubiquitination in Ongoing work in the lab by PhD student Iris European Union, and mortality rates range adverse effects. The reverse – cancer genes that diseases such as cancer has only recently been Uras aims to uncover the importance of this from around 20-40%. This is despite intensive make cells more sensitive to drugs – is perhaps of illustrated, but it has now become accepted as ubiquitin modification for protein function, and screening programs designed to catch the disease even greater importance as this may guide new playing a central role. Identifying which proteins particularly how this may be involved in cancer. early in women who are at higher risk, such treatments and lead to therapies with fewer side are controlled by ubiquitination and how this Their results may provide evidence that mono- as those over the age of 50. There have also been effects. is linked to disease is an ongoing pursuit in the ubiquitination can be exploited as an alternative ­significant advances in treatment. So why is it Nijman lab. treatment for cancers caused by deregulation still causing such a problem? Markus Müllner, a Post-doc in the lab, along of this pathway. with PhD student Iris Uras and diploma student Once cancer cells have spread to other organs Bianca Gapp, have set up a sophisticated screen- in the body by a process known as metastasis, ing platform to enable large numbers of drugs chemotherapy is the principal treatment. How- to be tested on many different genetic variants ever, a patient’s response to treatment is highly of cancer cells. By doing this they hope to tease Fig. 3 Synthetic lethality variable and in most cases does not provide a out which cancer genes contribute to resistance and drug resistance screen in breast cancer. Each dot cure. It is not clear what determines this variable or cause synthetic lethality when combined in the figure represents response to therapy and why it is so difficult to with drugs. This high-throughput technology a drug vs. cancer gene combination. Dots further find drugs that can kill cancer cells without affect- means that members of the lab spend a lot of their away from the center Fig. 2 Colony formation ing the patient. These are the areas that are the time in the tissue culture room working with indicate more significant assay showing pronounced key focus of the Nijman lab. They are searching large stacks of dishes in which there are many hits and dot size increases resistance of a gene to two with the magnitude of the different PI3K inhibitors in for more intelligent drugs by building on the combinations of cells and drugs. In 2010, several effect. breast cancer cells. extensive genetic knowledge of cancer that has chemical genetic screens were performed using already been generated over the past few decades. breast cancer cells engineered with specific cancer mutations. The results are promising and several DMSO weaknesses and mechanisms of resistance have been found that can be exploited with new drugs. The lab is now also planning to use lung cancer PP242 cells in similar screens using their new platform, with the hope of contributing to new therapies and better-informed treatment decisions.

PIK90

Ce — M­—M­— Research Report 2010 22 23 Inflammation and Atherosclerosis Natural IgM Antibodies

The Binder laboratory is located in the Anna Protection and Safety in the Lab Antibodies are large proteins produced by our The Binder lab have shown that many naturally Natural Spiegel Building of the Medical University Safety is of utmost importance in any labora- immune system, usually in response to pathogen occurring IgM antibodies recognize various lipid of Vienna, which is directly adjoined to CeMM tory, especially considering that some very toxic infection, and help our bodies to fight disease. peroxidation-derived structures, which they IgM antibodies essentially forming one building. Christoph chemicals and biological samples are used. There They are designed in such a way that they found on up to 50% of circulating microparticles seem to be Binder has a dual affiliation with CeMM and are many safety mechanisms in place to protect can each specifically recognise and bind to a in healthy volunteers. Excitingly, these specific produced without the Department of Laboratory Medicine, headed scientists from hazards at work, such as lab coats ­target molecule known as an antigen, found for natural IgM antibodies were actually able to by Oswald Wagner, where he also works as to protect their skin and clothing, and chemical ­example on the surface of a bacterium or virus. protect mice from developing atherosclerosis. prior exposure a Specialist in Laboratory Medicine performing fume hoods to protect against corrosive and toxic However, so-called natural IgM antibodies, unlike They went on to show that natural IgM anti­ to antigens. diagnostics on blood samples. chemicals. Latex gloves are used both to protect other types of antibodies, seem to be produced bodies could neutralize inflammation caused by hands, but also to protect experiments from without prior exposure to antigens and their the microparticles, which is thought to contrib- Nearest Neighbours being contaminated by bacteria, enzymes and function is currently unclear. The Binder team ute to chronic inflammatory diseases like athero- The CeMM and the Anna Spiegel building share other molecules found on our skin. has been investigating the role of these natural sclerosis. In fact Dimitris Tsiantoulas, a PhD the same entrance and are connected on each antibodies in diseases such as atherosclerosis, student in the lab, was able to show that micro- floor via a corridor. The door leading to the sixth Internal Protection a chronic cardiovascular disease where arteries particles stimulate the production of an important floor of the CeMM building where the Nijman Antibodies are glycoproteins that are normally become blocked. inflammatory mediator (chemokine) termed lab is located is directly across from Christoph produced by our blood cells in response to interleukin-8, in macrophages, and that in the Binder’s office. The group uses many of the ­infection and act to protect our bodies from The group has recently discovered that circulat- presence of a specific natural IgM antibody this ­facilities at CeMM on a daily basis, such as the the inside. There are five antibody subtypes ing microparticles are physiological targets of effect was completely abolished. This is highly cafeteria on the eighth floor, the seminar room, in ­mammals: IgA, IgD, IgE, IgG and IgM. The natural IgM antibodies. Microparticles are small relevant as interleukin-8 plays an important colour printer and bacterial shakers on the sixth Binder lab’s main focus is on so-called natural fragments of membrane that are shed from both role in atherosclerotic plaque development by floor and the liquid chromatographer on the IgM antibodies, which have currently unknown living and dying cells. They are found in our promoting the recruitment of inflammatory cells fourth floor, which is used to separate and purify functions. Natural IgM antibodies are pentameric ­circulation, and increased levels of microparticles to the artery wall. Future work will aim to define proteins. They also participate in the weekly (like gloves!) consisting of five immunoglobulin have been reported in various diseases, including other protective functions of these antibodies, Friday CeMM meetings, where, over the course subunits and are the largest antibody type found cardiovascular disease. They are believed to be e.g. in thrombosis, and evaluate if the production of a year, all the CeMM scientists are expected to in humans. The lab is studying how natural pathogenic by promoting vascular dysfunction, of these natural IgM antbodies can be stimulated. present their recent projects during a half hour ­antibodies can help protect us from chronic thrombosis, and inflammation. slot, which is followed by intense open discussion. inflammatory diseases such as atherosclerosis. Biological Protectors Antibodies are Walking toward the Binder lab from CeMM one Atherosclerosis is a leading cause of morbidity is greeted with the intense grass-green color and mortality, particularly in Europe and the glycoproteins of the walls on the landing. This green color is U.S. It is a chronic disease, caused by the slow that are normally maintained throughout the entire sixth floor of buildup of material in blood vessel walls, forming produced by the Anna Spiegel building, although closer to the plaques. Disruption of these plaques can lead labs it becomes a lighter green. The Binder lab to heart attack or stroke. Understanding how our our blood cells is on the south side. The laboratory is designed body tries to protect us from this disease may in response differently from those at CeMM. Instead of an help in the development of much needed new to infection and open-space layout, it is divided into bays. When treatments. act to protect quizzed, the Binder lab members prefer that to the CeMM layout as it allows scientists to have our bodies their desks close to their benches. from the inside. The Binder group currently consists of two research technicians, three diploma students (two Biology, one Medicine), five PhD students and one Post-doc.

Ce — M­—M­— Research Report 2010 24 25 Fig. 4 MDA adducts Protection against Oxidative Stress are present in eyes of ­patients with Age related Macular Degeneration. Drusen of AMD lesions are typically composed of cellular debris and ­replete Reactive oxygen species are produced as a by- The Binder team was able to show that CFH with products of lipid product of oxygen metabolism and have impor- binds a specific oxidative stress marker known peroxidation. Using an MDA-specific monoclonal tant biological functions. Excess reactive oxygen as malondialdehyde, which accumulates in antibody, we detected species can be destructive and are normally patients with age-related macular degeneration. MDA-epitopes in histo- ­neutralized by antioxidants. However, sometimes logical sections of patients Significantly, the binding of CFH was able to with AMD. The presence this protective system fails, causing a buildup block the proinflammatory effects of malondi- of MDA-epitopes is indi- of reactive oxygen species and subsequently aldehyde. This provides critical new insight cated by the blue color. RPE = retinal pigment a state of oxidative stress. Increased oxidative into the cause of this devastating disease, which epithelium; BrM = Bruch’s stress can lead to lipid peroxidation, which in turn could be exploited in its prevention and therapy. Membrane; arrows generates various lipid-derived danger signals ­Importantly, this information may also be ­indicate drusen. that alarm the innate immune system and cause applied to the treatment of other diseases and inflammation. Indeed, oxidative stress is associ- help protect our bodies from damage by chronic ated with many chronic inflammatory diseases. inflammation.

Oxidative stress David Weismann, a PhD student in the lab, in collaboration with Joe Witztum at UCSD and is associated Jim Handa of Johns Hopkins University, both with many chronic in the U.S., Peter Zipfel of the International inflammatory Leibniz Research School (ILRS Jena), and Giulio Superti-Furga and Keiryn Bennett’s labs at diseases. CeMM, are trying to understand how cells can be protected from these lipid-derived ­danger ­signals and their proinflammatory effects. They believe that these signals may represent a ­common disease mechanism in many different chronic inflammatory diseases. While search- ing for serum proteins that could protect against these danger signals, the team, working with the mass spectrometry group led by Keiryn Bennett, uncovered complement factor H (CFH). CFH is a large glycoprotein that circulates in human blood plasma and helps mediate the innate immune response via controlling the comple- ment system. A mutation in this protein has been linked with age-related macular degeneration (AMD), which is the leading cause of blindness in the elderly. However, the cause of AMD is ­currently unclear.

Ce — M­—M­— Research Report 2010 26 27 Level 05 Where Malfunctions of Molecular Networks are Investigated p. 30 + Systems Medicine + Innate Immunity: Anti-Viral Defence + Drug Effects on Cells Moving back to the staircase of the Anna Spiegel 2) innate immunity and infectious diseases; Building we walk up one flight of stairs. With our 3) chemical proteomics and the mechanism of back to the two elevators, we go to the right and action of drugs. Although these topics seem Level 05 step through the glass door onto the landing that diverse they synergize well within one laboratory leads to the fifth floor Anna Spiegel laboratories, because they share three important characteristics. three offices and to the north corridor of the Firstly, they are all strongly linked to medicine, Where Malfunctions CeMM building. The entire fifth floor is occupied and the Medical University of Vienna, CeMM’s by Scientific Director Giulio Superti-Furga and nearest neighbour, has a history of expertise and his group. It is the center of the building and to clinical successes in all three topics. Secondly, the a certain extent the center of the action – if one three topics are all amenable to the suite of tech- of Molecular Networks spends time on this landing, one is likely to meet nologies and experimental approaches that have most of the people at CeMM. Appropriately, it been optimized in the institute over the years, is also the floor where the human resources and particularly proteomics-based pathway and net- public relations offices are located, which are work analysis. Lastly, the relationship between are Investigated two essential functions of the institute. Office cancer, inflammation and infection is becoming and cell phones are permanently ringing as Anita increasingly intimate and these interfaces are Ender and Eva Schweng try to keep everything ­current hot areas of discovery and innovation. under control and to manage the flow of people and events, including the production of docu- Connecting Cancer and Inflammation ments such as the report you are holding in your Former CeMM SAB member Alberto Mantovani hands. In addition to this, Anita Ender is also has proposed to add inflammatory status to the the personal assistant of the Scientific Director, infamous six hallmarks of cancer – a move which providing a connection between research strategy has elicited strong resonance in the community and implementation. This makes her the most (see Cancer-Related Inflammation. Mantovani Previous page: popular person in the entire building. A et al., Nature. 2008, 454:436-44). Indeed the Level 05, Room 05.213 ­best-cited paper ever published in the journal Equipment Room A Large Interdisciplinary Group Cell (“The Hallmarks of Cancer”. Hanahan D, Air swirl The large open-plan lab is where the molecular Weinberg RA. Cell. 2000; 100:57-70) has recently Vesna Krajina, Diploma Student performing a traditional dance biology and biochemical experiments take place. been updated and now includes ­inflammation. in a Bosnian folk costume Music is often played over a radio or an MP3 In addition, CeMM supporter Harald zur Hausen ­player, and occasionally there is singing of vary- (see our 2009 Research Report) obtained the ing quality, mostly early in the morning or after Nobel Prize for Physiology or Medicine in 2008 core hours. At regular intervals there is a loud for his work on papilloma virus as the ­causative “beep-beep” coming from one of the devices agent of cervical cancer, highlighting the infec- powering a Western blot experiment, which tious basis of certain malignancies. Other microbes enables the immunological detection of specific like the bacterium Helicobacter pylori and the proteins. Giulio’s office is adjacent to the lab, Hepatitis B virus are thought to represent only ­separated by a glass door. For some reason, the the tip of an iceberg of pathogens implicated desks and benches most distant to Giulio’s office directly or indirectly in the carcinogenic process.

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2xCO2 2xCO2 RW 2xCO2 who have more recently joined the team occupy Connecting People the rest. There are some 20 people working on Members of the lab are able to keep abreast of this floor, consisting of a mixture of Post-docs, all these topics and associated technologies at PhD students, MD trainees, diploma students biweekly meetings held in the fifth floor seminar and research technicians. The researchers that room. Importantly, the meetings provide the were in the Superti-Furga laboratory when it opportunity to coordinate work between the first moved to Vienna have started to leave for Superti-Furga laboratory and cooperating labora- prestigious appointments in academia or biotech tories. At these meetings, you can see some 10–15 companies (see section on Post-docs). However, people gathered around the table in the seminar the laboratory continues to expand and diversify room, with pens and notebooks, and coffee or tea. in both scientific disciplines and in ­nationalities. Different parts of the turn of last century buildings It now includes bioinformaticians working that face CeMM can be seen through the round- on data analysis, shared with Jacques Colinge’s ish shapes of the glass etchings on Peter Kogler’s team. A new addition to the Superti-Furga lab façade. Usually between two and four people is a chemical proteomics unit established on present their latest results and consult the assem- the fourth floor of the new building, which bled project team about future plans. Discussions shares critical equipment and expertise with the are entirely informal and participants are encour- PLACEBO lab housed on the same floor. aged to interrupt wherever necessary. People sitting at the table come mainly from the Superti- Linking Diverse Topics Furga lab but also from the Bennett/Colinge/ Research activities in the group can be divided Kubicek teams and include visiting medical doc- into three major topics: 1) leukemias and other tors and Post-docs. In this way, both the projects hematological malignancies (blood cancers); and the people in the lab remain connected. Ce — M­—M­— Research Report 2010 30 31 A Big Job for a Small Family CD14: Immunity Booster An important question involving TLRs is how Previous work from others had shown that CD14 Systems Medicine this relatively limited set of receptors is able to was an essential co-factor for TLR4 in the recog- identify such an enormous variety of pathogens. nition of bacterial structures. Importantly, the Perhaps they have ancillary proteins with which Superti-Furga lab along with the Knapp lab, had they function? To gain insight into TLR function, now shown that CD14 could also enhance the The human body and its multitude of func- assembly of the final molecular network. Defin- Christoph and other colleagues from the mass ability of our cells to recognize viruses via TLR7 tions are controlled by information encoded in ing complex molecular networks allows causal spectrometry and bioinformatics team set out to and TLR9, which is highly significant given our genomes, which are the ensemble of all our relationships and inter-dependencies between identify cofactors that interact with TLR and aid the extensive risks viruses pose to human health. genes. Genes contain the instructions for making different parts of the network to be modelled, its function. To do this, the TLRs were given a This was one of the most important findings individual proteins, but proteins do not act alone. which may be important for treating disease. molecular hook (i.e. tagged), which was used to of the Superti-Furga laboratory in 2010. Their They work by forming complexes with other Indeed, medical information is integrated with fish for binding partners in immune cells known ­discovery could lead to future monitoring of proteins and molecules, which interact with genetic insight to annotate these molecular as macrophages. Binding partners that are fished CD14 protein levels to predict the ability of other complexes and molecules to form path- ­networks. For example, the networks are virtu- out can then be identified by their molecular patients to withstand viral infections. In addition, ways and networks. These networks perform ally and experimentally “marked” with chemical weight through a physical measurement using it may be possible to boost the levels of CD14 specific and highly controlled cellular functions compounds to enable predictions of potential mass spectrometry. to improve our immunity to viruses. Unfortu- and can be thought of as the genome coming pharmacological intervention, which can then be nately, Irene Aspalter, a CeMM diploma student alive. Network perturbations are associated with experimentally tested. A prominent partner of TLR7 and 9, members of involved in the project who now works at Cancer diseases, and inflammation and cancer, which are the Toll-like receptor family known to recognize Research UK in London, was not able to attend themselves cellular functions, share molecular This research strategy relies heavily on teamwork. viruses in intracellular endosomes, was found the celebration that occurred when the paper pathways, targets and signalling elements. The The interaction- or affinity-proteomics methods to be CD14, a well-known macrophage surface was finally accepted for publication in the Journal Superti-Furga laboratory is interested in explor- are performed by or in close collaboration with “marker” (i.e. a protein used to characterize sub- of Experimental Medicine, which is one of the ing these interfaces for therapeutic intervention. the team from the mass spectrometry depart- types of immune cells). A physical interaction oldest and most prestigious journals in molecular Systems medicine is an approach applied to all ment headed by Keiryn Bennett, one of the first between CD14 and endosomal TLRs inside cells medicine. three research areas investigated in the lab. CeMM scientists recruited. The data generated could also be observed under the microscope by this approach are analyzed by the computers upon special labelling, supporting the earlier Network Teamwork and Networks commanded by Jacques Colinge and his team result. The team was also able to show that this The Superti-Furga lab investigates the pathways of biomathematicians located on the second floor. physical interaction between TLR7 and CD14 perturbations and networks around individual proteins known Lastly, perturbation of the system by ­chemical had functional consequences. First, they showed are associated to be associated with specific blood cancers or agents requires Stefan Kubicek’s team, who that CD14 was important for the pro-inflam- with diseases, infectious diseases. This involves collecting formulate biologically relevant functional assays matory response induced by TLR7 and TLR9, inflammation individual puzzle pieces by experimentation, and perform robotics-based chemical compound using immune cells from mice that had a genetic ­followed by a technology and informatics-driven screens. ­inactivation of the CD14 gene. Secondly, and and cancer. more importantly, they showed these proteins functioning together using an infection model in whole animals.

Fig. 5 Model: The CD14 Innate Immunity: Anti-Viral Defence LPS membrane protein (green) associates with microbial nucleic acids (ssRNA and CpG DNA) at the plasma ssRNA membrane (black line), which surrounds each cell. During one of the first meetings in the new Toll-like receptors (TLRs) are membrane-span- It promotes their entry CpG DNA seminar room, Christoph Baumann, a Post-doc, ning proteins that play a crucial role in our body’s into the cell (endocytosis) within the endo-lysosome CD14 ­summarized the data that has just been used to first line defense against invasion by pathogens. organelle, which is also write a manuscript for publication. It involved They are part of the innate immune system. Endo-lysosome surrounded by a mem- brane. Other ssRNA viruses a lot of work, which was done in close collabo- ­Different conserved structures on pathogens, enter the endosome in ration with the laboratory of CeMM PI Sylvia so called pathogen-associated molecular ­patterns a CD14-independent way, Knapp, and also with Keiryn Bennett’s mass or “PAMPs” are recognized by TLRs. One of the CD14 where the acid environ- ment destroys the viral spectrometry group on the fourth floor. Under most prominent and most studied PAMPs is envelope (light blue circle) releasing the viral RNA investigation was a new co-receptor for a Toll- Lipopolysaccharide (LPS), which is found on the ssRNA virus like receptor, named IPOT4 in the 2009 report. surface of many different types of bacteria includ- genome (ssRNA). In the endosome, CD14 also ing Salmonella, and is recognized by TLR4. A functions as a co-receptor subset of TLRs (TLR3, 7, 8 and 9) reside in small for TLR7 and 9 (red) in the recognition of microbial membrane-enclosed organelles called endo- nucleic acids, initiating an somes inside cells, where they sense the RNA- CD14 immune response to fight or DNA-containing genomes of invading viruses the pathogen. and bacteria. TLR7 CD14 TLR9

Ce — M­—M­— Research Report 2010 32 33 The challenge was to find out if the drug dasatinib exerted its anti-cancer effect by inhibiting the Drug Effects on Cells c-Src protein. First it was confirmed that dasatinib could inhibit the enzymatic activity of c-Src. Next, Eric Haura and colleagues mutated a single amino-acid residue in the critical active site of the On another day in the same seminar room it Eric Haura works at the Moffitt Cancer Center in c-Src protein. They predicted this would prevent was the turn of Post-doc Uwe Rix to summarize Florida, USA, and has been working at CeMM dasatinib binding, as this so-called “gatekeeper” his work on the use of chemical proteomics to on sabbatical. He knows that dasatinib can inhibit residue is known in many other kinases. This study the effects of drugs on cells. Drugs that the growth of lung cancer cells. Fighting lung trick had been often used in the Superti-Furga are absorbed through the gastrointestinal tract cancer is Eric’s mission and he is astonished that laboratory to test the biological consequences enter the bloodstream and are then distributed people in Austria are apparently happy to inhale of disrupting a drug-protein kinase interaction. throughout the body, eventually reaching their cigarette smoke, the known cause of lung cancer, When lung cancer cells harboured an extra copy target cells. When the drug receptor is at the in public places. Uwe used cells that have been of this mutated src gene, the effect of dasatinib on surface of the cell, drugs can elicit their response derived from patients with non-small-cell lung inhibiting growth was significantly diminished. from the outside. However, some drugs actually cancer, a particularly nasty type of lung cancer, This strongly suggests that Src, like the EGFR enter the cell where they encounter proteins that to look for the potential binding targets of the protein, was a critical target of dasatinib in certain bind to them. More often than not, drugs bind drug dasatinib. It turns out from Uwe’s experi- lung cancer cells. many different proteins, either within the same ments that there are some 40 kinase proteins cells or tissues, or even in different parts of the binding to dasatinib. But they still didn’t know A Rare Success Story: From Lab to Clinic body. The usefulness of a drug for a given thera- which of these drug-target interactions was These results importantly suggested that dasat- peutic purpose is the integration of all its effects, likely to be responsible for the growth-inhibitory inib could also be used in the clinic to treat lung some of which are good, others of which have no effect of the drug. In other words, if the drug cancer. Indeed, the next time that Eric Haura consequence, while some effects are harmful and is the key and the kinases are locks to different visits CeMM and addresses his colleagues in the elicit adverse side effects. doors, which doors need to be locked to prevent same fifth floor seminar room, he will hopefully growth? report on some promising progress his group Scrutinizing Cancer Drugs are making in this direction using patient groups. Uwe, together with technician Manuela Gridling Going Back to Their Roots So, although the “molecular medicine” cycle of and the mass spectrometry team, is studying It was already known from previous work that research leading specifically to medical applica- the full spectrum of effects of certain anti-cancer the cellular protein, Epidermal Growth Factor tions is often slow moving and tedious, as this drugs. Cancer is characterized by the uncon- Receptor (EGFR), which is a protein kinase that story shows, it is also powerful and worthwhile trolled growth of certain mutant cells in the is often hyperactive in lung cancer, was likely enough to keep persevering. body and anti-cancer drugs generally work by to play a role. To distinguish which of the other inhibiting their growth. Inside the cells, the anti- forty kinases were also involved, they looked cancer drugs being studied bind quite selectively at which was bound most strongly by the drug to a class of enzymes known as protein kinases, and correlated this with kinase function by which control the cells response to growth ­analyzing the autophosphorylation status stimuli by attaching chemical phosphate groups with phosphoproteomics. The so-called Src Fig. 6 A model showing to target proteins. Uwe and coworkers have been ­family kinases (from sarcoma, a particular type the structure of the c-Src protein kinase (gray, with studying the anti-cancer drug dasatinib, which of ­cancer), a group of related protein kinases highlighted areas in red, is used to treat patients with Chronic Myeloid involved in a variety of cellular functions, was blue and yellow) in com- plex with the anti-cancer Leukemia (CML). They have also been looking heavily ­represented in the list of strong binders. drug dasatinib (cyan). at the effects of dasatinib in different cell types, The family is named after the first cancer-inducing Dasatinib binds very in collaboration with physician and scientist gene ever identified, v-src. Interestingly, Giulio tightly to the ATP-binding pocket of c-Src, but in a Eric Haura. Superti-Furga spent the first part of his inde- competitive manner, with pendent scientific career studying the molecular the terminal hydroxy group (red tip) protruding mechanism that makes v-src a cancer-inducing into solvent space. gene compared to the important but usually Cancer is harmless cellular counterpart c-src. Giulio also contributed to solving the crystal structure of characterized the chicken c-Src protein. Now, by coincidence, by the Uwe Rix and Eric Haura were focusing on the uncontrolled same enzyme. growth of certain mutant cells in the body.

Ce — M­—M­— Research Report 2010 34 35 Level 04 Where Molecules are First Detected p. 38 + No Placebo, No Drug + 2010: Moving to New Chemical Space + Targeting the Fourth Level of Gene Expression Control + Chasing the Masses + Establishing New Methodology + Proteomic Analysis of Body Fluids to Study Disease We leave the fifth floor using the smaller “service” Industry in an Academic Setting elevator. As the elevator door opens, we can see The pharmaceutical industry has longstanding the sign of the PLACEBO laboratory, and the logo expertise in drug discovery, as well as the Level 04 is a yellow and blue pill. What could it mean? re­sources to cover the high costs of drug And which other labs are found on this floor? de­velopment, which is currently close to one It looks different to the other floors we have billion euro per drug. However, in recent years Where visited. Looking down the corridor one does not the numbers of novel approved drugs have see the usual door to the tissue culture lab but stagnated despite increased research spending. instead sees a glass enclave. Could this be housing This has incited the very recent and exciting trend CeMM’s famous mass spectrometry lab? for a small number of academic institutes to set Molecules Is this a super-technology floor? We enter up their own screening centers. This has the the PLACEBO lab first. added advantage of bringing academia in general, and CeMM in particular, closer to the clinic, by A Joint Effort enabling them to discover novel biological targets are First PLACEBO sounds like an odd name for a lab and thus more directly contribute to new thera- focused on the discovery of small bioactive pies. In contrast to the often risk-adverse indus- molecules. However, it is actually an acronym for try, the group can make best use of the innova- PLatform Austria for ChEmical BiOlogy, a net- tive biology generated at CeMM and the other Detected work project funded by the prestigious GEN-AU academic PLACEBO groups in Vienna, Graz and program of the Austrian Science Ministry. The Innsbruck and implement it to discover active project, which is coordinated by Giulio Superti- small molecules in a fast and flexible manner. Furga, is a joint effort of researchers interested in innovative chemistry (Rolf Breinbauer, TU The screening system takes up the entire center Graz; Bernhard Keppler, University of Vienna), of the PLACEBO lab on the fourth floor of CeMM, finding new bioactive small molecules (Veronika but with dimensions of around four by three Previous page: Sexl, Michael Freissmuth, Medical University of meters it is still very compact for the multi­ Level 04, Room 04.207 Vienna) and characterizing the biological mode tude of functions included. This allows Stefan Mass Spectrometry of action of compounds (Lukas Huber, Medical Kubicek and his Post-doc and PhD student to Resonances University Innsbruck, Walter Berger, Medical set up experiments, culture cells, and prepare Elisabeth Salzer, PhD Student playing the violin University of Vienna). While the goal is far from compounds on the surrounding workbenches. discovering placebos – compounds that by defi- The setup of the PLACEBO lab was only possible nition have no pharmacological effect – the name in the new CeMM building, and the fourth floor rather illustrates that the team are not so naïve with its proximity to mass spectrometry and to think they can easily develop drugs in an chemical proteomics is the ideal location, bring- academic setting. ing together groups with strong technology and small molecule interests.

Consistent with the high-tech flavour of the fourth floor, also the other main laboratory, Mass Spectrometry, is tuned towards the discovery of molecules. ‘MS’ as it is often abbreviated, is a powerful analytical technique that measures the mass-to-charge ratio (m/z) of charged particles. At CeMM, MS is used to characterize the particu- lar class of molecules called proteins and their smaller break-down products, the peptides. This analytical capability, when systematic, is called “proteomics”. Essentially, biological samples are fed into the mass spectrometer and the resultant data are analyzed to identify the constituent proteins. Although the process sounds straightforward and simple, this is far from reality, as we will see further below.

Ce — M­—M­— Research Report 2010 38 39 No Placebo, 2010: No Drug Moving to New Chemical Space

Chemical probes To set up a drug screening center at CeMM, the A Complex System For the successful identification of potential new In addition to approved drugs, so called ‘tool An important first step was to establish a high-throughput The entire system is housed in a biosafety cabinet, drugs, the composition of the compound library compounds’ exist that can modulate many pro- can be used and high-content screening platform, involving allowing the use of cell lines and primary mate- is as important as the screening infrastructure. teins and biological pathways. These are either aspect of to validate that an amalgamation of very sophisticated equip- rial, which require specific safety protocols. In The group have put lots of effort into optimizing used in biochemical or cell biological experi- PLACEBO is the targeting a certain ment. The platform has two robotic arms that can addition to the software and automation neces- their collection of compounds to maximize the ments, or are currently at early stages of clinical ability to identify handle plates with 96, 384 or 1536 wells, which sary for controlling the robots, lots of additional chances of screening success. The main target development. Based on the work being carried biological path- can each contain a different chemical. Other informatics support is necessary to work in a con- was to ensure maximum coverage in three areas: out at CeMM, the group have established focused novel chemical way for therapy equipment is used to fill these plates, including trolled and efficient way with the collection of known drugs and bioactives, focused libraries, compound libraries containing such chemical structures as is feasible. acoustic transfer of volumes as low as 2.5 nano­ 100,000 chemical compounds. Indeed, the group and a chemical diversity library. tool compounds for two classes of enzymes; probe compounds liters (one millionth of a ml), and more standard have barcodes on all labware, which is tracked by kinases and chromatin modifying enzymes. pipetting robots, dispensers and washers. The a lab information management system, chemistry Building the Optimal Chemical These can be used in screens to discover novel for biological most important aspect of the design and setup tools, and data analysis software. Screening Collection biological roles of the target proteins. pathways. of the platform was maximum flexibility for To best cover all known drugs in the screening different biological readouts, allowing the rapid The aim of screening is to find ‘hit’ compounds collection, the group first analyzed all 26,900 Maximizing Chances of Success transfer of biological assays from their original that can be further developed to ‘chemical products that are currently approved for human Finally, an important aspect of PLACEBO is the format to a high-throughput screening format. probes’, which are in many ways comparable to treatment. Often different dosage forms contain ability to identify novel chemical structures as Therefore, the team installed several additional drugs. They can be used to validate that targeting the same active ingredient, and in total these drug probe compounds for biological pathways. pieces of equipment that could directly analyze a certain biological pathway for therapy is feasible, products correspond to 2,171 unique compounds. To maximize the chance of identifying such novel experimental assays that are commonly used in meaning that more appropriate drugs (in terms Removing biologicals and compounds only compounds, optimal coverage of ‘chemical space’ the lab, such as a fluorescence plate reader, a qPCR of cost and safety) can be developed. The screen- used as diagnostics and in topical applications in the screening library is essential. Chemical reader and a Luminex reader. Finally, a confocal ing platform was installed in September 2010, left 980 individual structures. Many of these space, which covers all possible molecules, is automated microscope that can analyze images and by the end of the year had already generated are “me-too” compounds that are very similar vast. For example, 1060 molecules are possible was also fully integrated into the system. more than 200,000 data points. The coming year to each other. Indeed, when the group analyzed when restricted to using a maximum of 30 atoms, will reveal how successful it can be at generating the biological targets of these 980 compounds, and making them would require more mass than chemical probes, thereby transforming the basic they unexpectedly found only 180 proteins. This exists in the entire universe. Up to now, around research performed at CeMM to make the maxi- is very low, given the human genome contains 50 million molecules have actually been made mum translational impact on human health. ~22,000 protein coding genes, and together with by chemists, approximately half of which are posttranslational modifications and the selective commercially available. After analyzing different targeting of protein-protein interaction, there are commercial libraries for their chemical diversity estimated to be hundreds of thousands of poten- and drug-likeness, the team decided to acquire a tial drug targets. Indeed, having drugs for only 91,000 compound library in collaboration with Fig. 7 The PLACEBO 180 of them further justifies the establishment the Dana Faber Cancer Institute in Boston, U.S. screening system allows the of PLACEBO and similar academic chemical bio­ Furthermore, PLACEBO partner Rolf Breinbauer, fully automated testing of thousands of chemical logy efforts. From the original list, the group have at Graz University of Technology in Austria, substances for their bio­ selected 221 compounds that hit all targets and will produce unique compounds for the screen- logical activity. show maximum chemical diversity to include in ing platform. their screening collection. Collectively, these libraries targeting known drugs, kinases, chromatin, and chemical diversity will total up to 100,000 compounds, thereby giving the group a good chance of identifying hit compounds.

Ce — M­—M­— Research Report 2010 40 41 Targeting the Fourth Level of Chasing the Gene Expression Control Masses

In cancer, control Controlling the expression of genes in order to Stopping Cancer Cells with a PHD As mentioned, mass spectrometry is a techno­ temperature of 20˚C (+/- 1˚C), which is of critical make specific proteins is essential for all cells With a strong background in epigenetics research, logy-intense endeavour. Coaxing the very best importance for optimal instrument performance. mechanisms fail to properly function. Because this process is and a history in successfully developing selec- from these specialized instruments requires The main air conditioning has a backup in case of at all these levels so important, there are multiple mechanisms tive chemical probes for histone methyltrans- un­surpassed love, care and attention. The fourth failure, as without cooling the temperature can of transcriptional involved. First, for each gene, the DNA sequence ferases and demethylases, the Kubicek lab is now floor of the new CeMM building is currently increase by 15˚C within half an hour causing the is split into separate promoter, enhancer and cod- focusing on methyl-binding domain proteins. home to four machines: a quadrupole time-of- mass spectrometers to overheat and ultimately regulation, allow- ing sequences. Specific DNA-binding proteins, Certain cases of acute myeloid leukemia (AML) flight (QTOF) mass spectrometer from Waters, break down. Each cubicle has a sensor, and any ing cells to grow so-called transcription factors, can recognize and are caused by chromosomal translocations that one LTQ Orbitrap XL and two latest-generation fluctuations in air temperature and humidity can unrestrictedly and bind some of these sequences. Transcription fac- rearrange genes, causing the abnormal fusion of LTQ Orbitrap Velos mass spectrometers. All four be closely monitored. to invade other tors also recruit other proteins that can chemical- specific methyl-binding domains, so called PHD instruments have an associated nano-HPLC (high ly modify both the DNA and associated histone fingers, with common highly expressed partners. performance liquid chromatography) system from There are individual laminar flow-like air Researchers, tissues. protein components of the chromatin. Finally, on The resultant aberrant fusion proteins cause Agilent that is used to separate mixtures of pep- conditioning systems in each cubicle to avoid what could be considered the fourth level of con- leukemia by maintaining the expression of cer- tides prior to entry into the mass spectrometer. disturbing the fine liquid spray that is generated engineers and trol, selective binding proteins recognize these tain key genes that should normally be switched at the interface between the HPLC and mass architects worked chromatin modifications and regulate chromatin off. Using molecular biology methods, it has been A Designer Building spectrometer. The spray contains the sample that together to structure, the recruitment of RNA polymerase shown that preventing the binding of the PHD Modern day mass spectrometers are highly sensi- is subsequently analysed by the mass spectro­ and thereby transcription. domains in these fusion proteins to their targets tive to perturbations in the environment. There- meter. Standard air conditioning systems gener- customize the can stop the cancer cells from growing. fore, careful attention was paid to the design of ate a laboratory ‘breeze’ that is often a problem for laboratory. In cancer, control mechanisms fail at all these the new laboratory to ensure the team, led by mass spectrometry analyses, as each cycle causes levels of transcriptional regulation, allowing cells The group have performed a virtual screen for Keiryn Bennett, could push the boundaries of small gusts of air turbulence. The inspiration for to grow unrestrictedly and to invade other tis- small molecule inhibitors of methyl binding the technology even further while still work- this design came from the Institute of Atomic sues. Unfortunately, direct intervention to revert proteins. Currently, no such compounds are ing to the highest possible standards. There are and Subatomic Physics, Technical University of the genetic changes that cause cancer is currently available, and the limited success of targeting currently seven people in the group, and the Vienna, located in the third district on the other impossible in the clinic. Similarly, the binding of protein-protein interactions makes is unlikely team worked together with the architects and side of the city. The engineers and members of transcription factors to DNA is not easily inhib- that pharmaceutical companies are developing engineers to customize the laboratory. New plas- the MS team visited a group of physicists from ited by drugs. Therefore, the changes to chro- such compounds. Their results are promising, tic materials were to be avoided as the vapours the institute that face similar problems as they matin structure that cause erroneous expression and they are now in the process of testing their generated are literally sucked into the mass run experiments using lasers that also require of the pro-proliferative and invasive genes that hit compounds in cellular assays to determine spectrometers, contaminating the data. Thus, cool, stable temperatures with minimal air fluc- can cause cancer, are among the most promising if they can be validated to the point to become even the floor is designer-made and not the usual tuation. Based on these discussions, the idea was targets for innovative cancer therapy. candidates for potential new treatments for cer- ‘plastic’ glued-down floor found in standard adjusted for the mass spectrometers and so far the tain specific cases of AML in the distant future. laboratories. laminar-flow systems function extremely well.

As we leave the PLACEBO laboratory we turn It is very common to find mass spectrometry Keeping Things Moving left on the corridor and aim straight to the mys- departments hidden in the basement without All four mass spectrometers can be operated teriously-looking glass cubicle. We read the sign: any natural light. The reason for this is primarily from the comfort of the office by remote desktop “Mass Spectrometry”. due to the sheer weight of the equipment. At access. At weekends the equipment is carefully CeMM, an airy, ‘house-of-mirrors’-type glass monitored from outside the institute as it is in laboratory on the fourth floor of the building constant operation. The laboratory also has an was designed. Here the mass spectrometers are uninterrupted power supply to compensate for Fig. 8 Principal investigator visible from every angle and can be shown off to power outages and avoid disruption of experi- Stefan Kubicek and his team visitors without having to physically enter the ments and forced shutdown of the instrumenta- with the robotic arm of the PLACEBO screening facility. room. This design also takes into consideration tion. The move from the old building down the the well-being and safety of the operators, who road to the new building required extensive and are working with equipment powered by high- careful planning and took several weeks to com- voltage electricity. plete, but ultimately was a clean, well-orchestrat- ed process. An interesting observation was made Individual Spaces Allow Improved Control when the instruments were moved into the new The size of the new laboratory space meant that designer space. There was an order of magni- each mass spectrometer and associated HPLC tude reduction in interfering background noise, system could be housed in its own cubicle. concurrent with a marked increase in detection This design allows the generation of highly stable sensitivity. It appeared as if the instruments were yet independent microenvironments around more than content with their new surroundings, each system. Organising the instruments in and improved their performance. this way makes it easier to maintain a stable air

Ce — M­—M­— Research Report 2010 42 43 Establishing Proteomic Analysis New Methodology of Body Fluids to Study Disease

The MS group is involved in numerous pro- The mass spectrometry group have been estab- The proteomic analysis of any body fluid is A Blistering Start Skin fluid samples teomic studies at CeMM and also with several lishing a methodology that is based on SH-tagged hampered by the high complexity and dynamic Using mechanically-induced suction blister fluid, external national and international collaborators. protein purification, followed by chemical cross­ range of the component proteins. To overcome the group have generated preliminary data from provide valuable The team is constantly pushing and refining tech- linking and mass spectrometric analysis. This this constraint, highly-abundant proteins can a single healthy control subject and identified a insights into nological boundaries to complement the require- approach increases the possibility of identifying be removed using special depletion kits, thus total of 354 proteins including several associated disease initiation ments that biological and medical progress weakly-binding proteins, and also reveals the enabling the detection of low copy number pro- with skin function. Importantly, the approach demand. Two such recent advances are: (i) the physical organisation of the individual proteins teins. In addition, pre-fractionation techniques identified many low-abundance proteins. Some and progression. introduction of chemical crosslinks to ‘freeze’ that go together to form a working complex. This and iTRAQ-labelling improves the number of of these proteins are found specifically in the epi- or ‘trap’ protein complexes; and (ii) chemical information can be used to build virtual three- proteins that can be detected, and allows a rela- dermal layer of the skin, and are already known enhancement of peptide signals to improve the dimensional images of intact protein complexes. tive quantitative comparison between different to be involved in certain cellular processes such sensitivity of detection. The MS team has been From this information, it is possible to model the patient samples or disease states. as cell-to-cell interactions and pathogen defence. optimising these steps to overcome some of the relationships between other protein complexes Other identified proteins have already been asso- current limitations of the technology and have and help to understand how proteins act as a In collaboration with Adelheid Elbe-Bürger, ciated with certain inflammatory skin diseases, shown some promising results. These recent team to perform a specific biological function. Christopher Schuster and Georg Stingl from supporting the notion that such an approach can advances have enabled scientists to extract more the Department of Dermatology at the Medical be used to monitor pathological conditions in sophisticated information from their biological Standing out from the Crowd University of Vienna, the MS team has developed the skin. The group will assess the utility of the experiments. In collaboration with lung cancer oncologist Eric a proteomic strategy that allows not only a com- approach for comparing different control sam- Haura from the H. Lee Moffitt Cancer Center in prehensive identification of proteins present in a ples before embarking on a comparison of control Building Protein Complexes the U.S., the MS group has also been experiment- blister fluid, but also a comparison of the relative subjects with patients suffering from a range of All biological functions are regulated by integrat- ing with the iTRAQ reagent (isobaric tag for quantities of the same protein across different skin ailments. ed interactions between multiple proteins. These relative and absolute quantitation). This tag is samples. A more thorough understanding of interactions occur in different ways: some are normally used to label protein fragments with the proteins present in skin fluid samples from We leave the mass spectrometry laboratory dynamic and exist only transiently, while others different chemical groups, thereby enabling the healthy and diseased skin could provide valu- and pass by the small chemistry laboratory that are highly stable. A chemical crosslinking strat- relative quantitation of the same proteins in able insights into the underlying mechanisms allows the chemical proteomics branch of the egy can be used to ‘trap’ the protein interactors several biological samples. Now, the group has responsible for initiation and progression of skin Superti-Furga team and PLACEBO to operate that work together with an individual protein to investigated the use of these tags for something diseases. Ultimately, it is envisaged that such relatively simple chemical reactions such as the perform a function. This involves the physical else: to enhance the signal of minute quantities knowledge will lead to improvements in the ones needed to “join” chemical compounds to introduction of strong covalent links between of proteins. This new approach is a significant treatment of skin disorders. matrices for chemical proteomics. Similar to the the individual proteins in a complex. improvement over previous methods, and allows other floors, there is also a large office with a glass the detection of low-abundance proteins that wall where lab members have their writing desks. were previously impossible to detect by conven- Now it’s time to walk back to the staircase and tional mass spectrometric methodology. go down one more flight to see what’s on the third floor.

Fig. 9 Generic strategy for the chemical crosslinking cells crosslinking and ‘trapping’ of stabilised - + protein complexes.

pulldown Fig. 10 Formation of mechanically induced blisters. crosslinking A) Pressure device for Na + separating epidermis O - LC-MSMS from dermis S O O B) Blister formation from O O N interstitial fluid (5x5mm).

MASCOT O O Phenyx xQuest

O O

N O O O O S

- O Na +

Ce — M­—M­— Research Report 2010 44 45 Level 03

Where Epigenetic Regulation and Infection Processes p. 48 are Studied + Breaking the Epigenetic Code + Crystallizing Ice Control + Epigenetic Regulators in Human Disease + Inflammation and Pneumonia + An Emerging Deadly Disease Level three is the most complex floor in the buil- Keeping Things Organized ding. Across a small path in one of the research Even with the carefully designed layout of the buildings of the General Hospital is the Knapp CeMM building, scientific laboratories tend to Level 03 laboratory. Sylvia Knapp is a medical doctor and become easily cluttered. This is because there Associate Professor of Internal Medicine at the is so much stuff required to perform a single Medical University of Vienna, who still works experiment. Simply growing cells to use in an Where Epigenetic in the intensive care unit of the hospital taking experiment requires a wide variety of different care of critically ill patients. The group signifies materials and equipment such as sterile dishes, the close ties between CeMM and the clinic. tubes and pipettes, special liquid medium, heated Treatment in the intensive care unit of a hospital incubators, a sterile ‘culture hood’ and a micro- Regulation and unfortunately makes patients more vulnerable scope. To keep laboratories functioning efficient- to secondary infections, some of which can be ly requires careful organization, and the Barlow life threatening. This is because most patients lab is probably one of the most organized labs in have weakened immune systems and are at signi- the building. Infection Processes ficant risk for conditions such as sepsis. In the clinic, Sylvia Knapp works on the pathogenesis All the equipment and materials have their own and treatment of sepsis and bacterial infections. place in the Barlow lab, and shelves, drawers, These conditions are strongly associated with the fridges and freezers are all clearly labelled. Label- are Studied innate immune response involving inflammati- ling is a useful way of keeping things organized on, which is also the primary focus of the Knapp and informing people what something is and research lab. how it should be used. Epigenetics, the main focus of the Barlow lab, also involves a sort of Before we move into the Knapp laboratory in the labelling but this time of DNA, which helps AKH, we look at level 3 in the CeMM building. In to organize it within the cell. Epigenetic labels the CeMM building itself, there is the administra- are specific chemical modifications that act as Previous page: tion on one side and the Barlow lab on the other. information marks. They were added to the Level 03 chromosomes in each of our cells when we were Corridor The Barlow lab is the second biggest group at undergoing embryonic development in the Fast forwarding CeMM. The open-plan lab is divided in two parts. uterus. These labels have an influence on when Rui Martins, PhD Student riding his skateboard One lab, corresponding to two thirds of the other and where individual genes are expressed to floors, is occupied by the three Post-docs, four make specific proteins, and thus how cells and PhD students, and the two research technicians organisms develop and function. Disruption of that currently form the Barlow team. The first epigenetic marks can lead to severe developmen- activity in the morning is usually to switch on tal disorders and diseases such as cancer. the computers. Scientists have become complete- ly dependent on computers, both to generate and The Barlow lab is investigating how epigenetics analyze data, and to access information. One of controls the expression specifically of imprinted the most popular websites is PubMed, which is genes in the developing mouse embryo. Most a searchable database of over 19 million citations of our genes have two copies; one inherited from life sciences journals without which no one from our mother and one from our father, and could keep up with the literature. Indeed there both copies are normally used to make proteins. are more than 3000 papers published each year Imprinted genes are a special type of gene where in the Barlow lab’s topic area alone. There is a lab only one copy is expressed, and the copy that is custom that if anyone finds an interesting paper chosen depends upon the parent from whom they e-mail it around the lab. it was inherited. Imprinted genes are becom- ing more and more important as an epigenetic On most days, at around 3 pm, you will find regulatory model to help us understand how the majority of the lab crammed in to one office epigenetics control genes in human disease. The drinking black tea with milk. This gives them a Barlow lab have been using imprinted genes to chance to discuss what is coming up in the week, “break the epigenetic code” that is hidden inside to brainstorm some experimental problems, or the human genome. And now, using some of the just to gossip. Occasionally someone makes a latest high throughput technologies, which have cake, particularly if there is a birthday or a paper been installed in the new CeMM building on has been accepted for publication. Everyone is the seventh floor under the guidance of Robert looking forward to summertime when they can Kralovics, they are currently testing how epige- also go up to the CeMM terrace in the evening netic mechanisms are used in humans to silence and enjoy the fresh air and the spectacular view genes in normal tissues and in cancer. of the city.

Ce — M­—M­— Research Report 2010 48 49 Breaking the Crystallizing Epigenetic Code Ice Control

The visceral Evolution has led to the same biological process, In the study of epigenetics, the mouse placenta is Imprinted genes – those that are expressed Mechanisms of Control Recently, the such as cell growth or limb development, occur- often used as a model to describe epigenetic pro­ depending on the parent from which they were For the last few years, the Barlow lab has been yolk sac is a novel ring in roughly the same way across diverse cell cesses in embryos and adult mice. However, the inherited – were discovered almost 20 years ago, trying to take one ICE apart to find out exactly regulation process model system types and species. This means that fundamental placenta is not part of the actual mouse embryo but it was only recently shown how this process how it works. Martha Körner, a PhD student of imprinted for the study of information about a particular pro­cess, can and also contains contaminating maternal tissue. is regulated. A particular sequence of DNA called in the Barlow lab, used “gene knockout” techno­ genes has started be studied in a so-called ‘model’ system. Models At the beginning of 2010, Post-doc Quanah an ICE (for imprint control element) was found logy in mouse embryonic stem cells to remove epigenetics. are chosen based on various practicalities such Hudson and PhD student Tomasz Kuliniski to be responsible for silencing small clusters two different parts of the ICE sequence, allowing to be shown. as accessibility, ease of use and cost. The best wrote a review to raise awareness of serious prob- of genes on only one of the two chromosomes. her to then test if the ICE required these parts to models generate insight that can be directly lems using the mouse placenta as a model, which The ICE has two properties of special interest to function normally. These experiments revealed applied to many other cell types or organisms, was published in the journal Heredity. They have epigeneticists. First, it turns on or activates an that only the first half of the ICE sequence is and all models should be critically assessed to also now completed a study that confirms the unusual, large ‘macro’ non-protein-coding RNA important for its function. One of the most sur- ensure they produce accurate and useful placenta has serious drawbacks for epigenetic that actually causes the silencing. Second, in order prising results from this study was that the DNA information. studies on imprinted genes. to work, the ICE must itself avoid attracting DNA elements that turn genes on in CpG islands were methylation, one of the most common repressive unexpectedly found after the start of the gene. Instead, the group found that the visceral yolk epigenetic marks in the human genome. It is likely that this will be a common characteris- sac surrounding the developing mouse embryo tic shared by all CpG islands that overlap the start in the uterus provided a much improved model A few years ago the Barlow lab described how of most human genes. This information will also system. They have now used this tissue to show, an ICE resembles another commonly occurring help explain how epigenetic labels are attracted to contrary to studies based on the placenta, that short stretch of DNA that overlaps the start of CpG islands in human diseases such as cancer. imprinted gene expression in the yolk sac is most human genes, which is known as a CpG clearly regulated by one of the best-studied epi- island. The CpG island is so named because it is genetic marks – DNA methylation. As a result very rich in C and G nucleotides (as opposed to of this study, the lab have set a new and more the alternative A and T nucleotides that altogeth- accurate baseline for identifying additional fac- er make up DNA), which is unusual for mouse tors responsible for epigenetic gene regulation in and human chromosomes. CpG islands also turn development and disease. genes on so that they can be used to make specific proteins, and like ICE must also avoid acquiring epigenetic labels themselves.

Fig. 11 Top: Illustration of Placenta a mouse embryo midway Decidua though development Visceral showing a close-up of the Yolk Sac placenta and the contami- Spiral nating maternal tissues arteries (red), which cause problems in its analysis. Tissues that only contain embryonic cells such as the visceral yolk sac membrane are shown in grey. Bottom: Genes can show imprinted-gene silencing or tissue-specific silencing that Embryo Ice-y deletions CpG islands Fig. 12 Left: the segments is controlled by different 500 overlap the start of most human genes of the ICE sequence that epigenetic marks (alpha & Maternal were deleted using gene Blood 450 beta). Good model systems Start 500 knockout technology. Spaces 400 Right: the position of the should not confuse these 450 ‘Promoter’ 350 start of a gene relative to its two types of silencing. 400 300 CpG island shows that the 350 promoters of a large number 250300 β Airn ncRNA of genes actually lie up- Gene Gene 250 1 200 stream to the CpG island. 150200 2 *** 100150 α β *** number of RefSeq genes 100 Gene Gene 50 50 ICE 00 Imprinted silencing Tissue-specific silencing affects one parental affects both parental Deletions 1 and 2 removed Bars indicate the start of a gene relative chromosome chromosomes different parts of the ICE to the position of the CpG island (grey box)

Ce — M­—M­— Research Report 2010 50 51 Connecting People Between Buildings the robots and the mass spectrometers in collabo- We leave the CeMM building through the ration with Stefan Kubicek and Keiryn Bennett Epigenetic Regulators entrance hall common to the Anna Spiegel/ on the fourth floor. The Knapp lab holds their CTR laboratories of the Medical University and own weekly lab meetings as well as their weekly in Human Disease CeMM. Outside the door, we walk 35 meters journal club in one of the CeMM seminar or in a straight line to the “East” entrance of the meeting rooms, and often have lunch in CeMMs General Hospital. The path is bordered on both cafeteria. Thus, the group are integrated into sides by two wings of the General Hospital/ every aspect of CeMM life, including the insti- Disruption or deregulation of many biological Understanding the function and regulation of the Medical University research buildings. We enter tute’s scientific meetings, which are held weekly processes can cause disease. Indeed, cancer is newly identified macro ncRNAs is an important through the revolving door and, remaining on on the eighth floor. caused by a deregulation of cell growth, which long-term goal to improve our understanding of level three, enter the wing of the building of the is normally controlled by many different mecha- gene regulation in cancer. A PhD student in the “Forschungslabor der Klinischen Abteilung für In 2010, the outcome of a very successful col- nisms, including epigenetics. Other work in lab, Irena Vlatkovic who recently successfully Infektionen und Tropenmedizin” where the laboration between the Knapp and Superti-Furga progress in the Barlow lab is the implementation defended her thesis, has made a pilot study in laboratory of Sylvia Knapp is situated. Although groups was finally published in theJournal of of a new approach to epigenetics in cancer. colon cancer using genome tiling arrays to exam- the Knapp lab is located in a separate building, Experimental Biology. The project, described Their hypothesis is that molecules known as ine 2% of the human genome for macro ncRNAs. the windows of the lab can actually be seen from in more detail in the fifth floor section on the macro ncRNAs (non-protein-coding RNAs) Of the 120 novel macro ncRNAs that she found, the entrance to the CeMM building. Lab members Superti-Furga lab, uncovered a new role for mediate the epigenetic deregulation of genes in more than half changed their expression in colon often visit CeMM to use equipment, such as proteins involved in detecting invading intra­ tumours. The rationale for proposing this comes cancer cell lines compared to normal colon tis- the virus room and the FACS machines, which cellular pathogens and initiating an innate from two observations. First, macro ncRNAs sue, and 22 were only expressed in the cancer cell enable to scan populations of cells. They also use immune response. are known to epigenetically silence imprinted lines. This suggests that these macro ncRNAs genes. Therefore they could also perform this may play an important role in the cancer process same function but in an abnormal way in cancer and are a valuable starting point for future work cells. Second, there are many macro ncRNAs in on this topic. mammals, and some are already known to be deregulated in other diseases. To help fund this work, the Austrian Science Fund (FWF) has recently approved a new Special Macro ncRNAs The lab has experience with experimental meth- Research Program entitled “RNA regulation ods involving custom NimbleGen tiling arrays of the transcriptome” under the lead of Renée may play an and RNA-seq for identifying macro ncRNAs in Schröder at the Max Perutz Laboratories (MFPL) important role mouse imprinted regions. Now they will apply in the third district of Vienna. This program in the cancer this technology to cancer. The new Illumina aims to investigate how RNA molecules control sequencing machine located on the seventh the flow of genomic information from genes process. floor of the CeMM building is used to perform to function, and how these RNAs are regulated. the RNA-seq experiments. Tiling arrays and Ultimately, this will improve our understanding sequencing produce vast amounts of data, so of developmental disorders that arise from errors Florian Pauler, a Post-doc in the lab, has been in these circuits. The program involves 11 research Fig. 13 Heat Map shows expression profiles of developing a new bioinformatics tool to help groups from Vienna based at the institutes, 143 novel and known them identify the macro ncRNAs. The group MFPL, CeMM, IMP, IMBA, GMI, as well as the macro ncRNAs in normal are collaborating with the CeMM Bioinformatic University of Vienna and the Medical University colon and in two colon cancer cell lines group of Jacques Colinge and the Hofacker lab of Vienna. It will be funded with approximately (HCT116 and Caco2). from the University of Vienna, to further 4–3 million Euros over the next four years. This improve these detection methods. special research program is one of the most prestigious avenues for funding by the FWF. It Colon Valuable Neighbors supports the establishment of long-term and The Barlow lab plans to initially search for macro interdisciplinary research networks enabling ncRNAs associated with tumour suppressor scientists to conduct high-end research and helps genes in leukemias and lymphomas. Hemato- to strengthen Austria’s international stance in HCT 116 logical malignancies like leukemia are already science. intensively studied at CeMM, particularly in the Kralovics and Superti-Furga laboratories on the The third floor differs from floors four to seven seventh and fifth floors, respectively. Thus, there because the north axis is taken up by the CeMM are plenty of nearby resources and expertise. They administration. Walking from Denise Barlow’s Caco2 also have collaborations with Robert Zeillinger lab, you can either access the administration cor- and Iveta Yotova at the Vienna General Hospital ridor though the staircase landing or through a (AKH) on the same campus as the CeMM build- double glass door if you have access with a mag- Novel identified macro ncRNAs ing, as well as Kurt Zatloukal and Johannes netic card. We are now standing approximately Haybäck at the Medical University of Graz. in the middle of the building. Color Key

-1 1 Ce — M­—M­— Research Report 2010 Row Z-Score 52 53 Inflammation An Emerging and Pneumonia Deadly Disease

The tight regulation Certain species of bacteria are highly virulent The Role of Pathways in Disease Staphylococcus aureus literally translates as ‘the In addition, Stefanie Sigel, a Post-doc in the Antibiotic and cause a serious threat to human health. To investigate the function of PTEN in S. pneu- golden seed’. However, this Gram-positive bac- Knapp lab, studied how molecules from S. aureus of inflammation Streptococcus pneumoniae (or pneumococcus) moniae infections, researchers in the Knapp lab terium has been somewhat misnamed, given it are recognized by human blood cells. She found resistant strains during bacterial is a human pathogenic bacterium that can cause made use of a so-called conditional knockout is a leading cause of human disease worldwide. that human antibodies are able to augment the evolve as a pneumonia many different diseases. One of the most signifi- mouse, meaning that a certain group of blood Recently, new strains of S. aureus have emerged inflammatory response to specific bacterial mol- result of anti- cant, in terms of human health burden, is pneu- cells in the mouse, which mediate the inflam- that are resistant to the antibiotic methicillin. ecules. This work was published in the Journal of determines the monia, an inflammatory disease of the lung. matory response, were unable to make the PTEN These strains (known as MRSA) have evolved Immunology, in 2010. biotic use and clinical outcome. How inflammation is linked to the progression of protein. Upon infection with S. pneumoniae, the as a result of decades of antibiotic use, and more misuse. pneumonia upon infection by S. pneumoniae has group could analyze disease progression and significantly misuse, whereby antibiotics are pre- Leaving the Knapp lab, we walk back to the been one of the recent focuses of the Knapp lab. compare it with normal ‘wild type’ mice to elu- scribed for patients suffering from viral infections CeMM building and step down to level 2. cidate the role of the PTEN protein. They found like flu, for which they are useless. These danger- Signalling Pathways: All About Teamwork that the knockout mice lacking the PTEN protein ous MRSA strains were originally confined to Researchers in the Knapp lab use mouse models had improved survival rates. They concluded hospital settings, but the new strains (known as to investigate mechanisms of disease. They were that PTEN both promoted inflammation but also community acquired MRSA, or CA-MRSA) are particularly interested in the role of an enzyme inhibited the function of some blood cells to clear also found in the general public and are highly called PTEN, which has already been implicated the lungs of bacteria. These data show that the virulent. The most dangerous site of infection by in cancer. PTEN is part of an important intracel- tight regulation of inflammation during bacte- CA-MRSA is the lung, with severe necrotizing Fig. 15 Lungs from mice lular signalling pathway, which is known as rial pneumonia determines the clinical outcome. pneumonias in infected patients. Worryingly, 48h after infection with S. pneumoniae bacteria the PI3K pathway after one of its key members. Their results were published in the Journal of high mortality rates have been reported, even in were stained with Haema- Signalling pathways enable a cell to selectively Immunology in 2010. patients that were young and previously healthy. toxylin and Eosin and imaged under the light respond to extracellular signals such as hormones microsope. Inset shows and growth factors. They are composed of many In addition to this, in collaboration with Ger- Toxic Substances neutrophils (in brown), a different proteins and molecules, which perform not Schabbauer in the Department of Vascular Many bacteria cause disease by releasing toxins special form of blood cells that enter the lung during a variety of functions. Biology and Thrombosis Research, Center for into the body. Panton Valentine toxin is a pore- infection. Biomolecular Medicine and Pharmacology at the forming bacterial toxin found in most CA-MRSA Some of the proteins in a signalling pathway Medical University of Vienna, the group showed strains. Some scientists have predicted that this reside at the outer cell membrane where they a role for two additional proteins in mediating toxin is a key virulence factor in these new infec- detect the extracellular signals, while others inflammation via the PI3K pathway. This work tions, and it has been shown to cause cell death. relay the signal through the interior of the cell was published in the Journal of Leukocyte Biology The Knapp lab wanted to know if and how Pan- by binding and modifying each other. Eventually, in 2010. In another collaborative project with the ton Valentine toxin was involved in lung inflam- other proteins in the pathway bind to the cell’s group of Wilfried Ellmeier from the Division of mation. Ana Zivkovic, a PhD student in the lab DNA and induce the expression of even more Immunobiology, Institute of Immunology, also first determined that this toxin indeed inflamed proteins that finally mediate an appropriate at the Medical University of Vienna, the group the lung. Furthermore they identified the con- cellular response, such as growth or differentia- studied the role of a kinase called Tec in the host stituent of the Panton Valentine toxin that medi- tion. Depending upon the extracellular signal, response to S. pneumoniae. This work was pub- ated this inflammatory response, and the cellular the PI3K pathway can induce many different lished in the Journal of Immunology in 2010. factors required for this to happen. The novelty Fig. 16 Structure of Panton responses including cell death or cell growth. of this work lies in the discovery that parts of Valentine Leukocidin com- ponents LukF-PV (left) and Indeed, PTEN has been shown to play multiple On a somewhat related topic, a collaboration the bacterial toxin exert potentially protective LukS-PV (right). Adapted roles in cells, such as modulating the inflamma- with Mathias Müller from the Institute of Animal inflammatory effects independent of their other from (Joubert et al, JBB 2007). tory response, and the physical elimination of Breeding and Genetics, University of Veterinary function in pore formation. These findings might bacterial pathogens. Medicine in Vienna, uncovered a role for protein explain why antibodies that block the toxin have translation in controlling the production of the not been promising in preventing lethality in proinflammatory cytokine IL-1beta, which has a preclinical pneumonia models. This work was major role in many inflammatory diseases. Their recently published in the Journal of Immunology, Fig. 14 Phagocytosis of results were published in the Journal of Immu- where it was available online in 2010. ­Streptococcus pneumoniae nology in 2010. (green) by primary alveolar ­macrophages from wild type (WT) and PTEN-deficient (KO) mice. Nuclei are stained blue with Dapi, and lysosomes stained red; the overlay of ingested bacteria with ­lysosomes appears yellow.

Ce — M­—M­— Research Report 2010 54 55 Level 02 Where Data is Gathered, Managed and Analyzed p. 58 + Mathematical Modelling of Biological Data + The Power of Computing The second floor is the data center of the CeMM Establishing a Solid Infrastructure building. Here one can find the IT department, Some of the research at CeMM utilizes two that keeps the electronics up and running, powerful in-house technologies; mass spectro­ Level 02 including the computers, printers and communi- metry for the identification of proteins, and so- cation networks. Plants, computer screens, spare called “next-generation” DNA sequencing. parts and lots of cables make up the kingdom of Both create large volumes of data, as much as Where Data Michael Pilz and Joachim Tröster. It is not often 1 terabyte per week, that need storing and that that you find them both in at the same time, as also require computer-intensive data analysis. one is often going around the building to install The move to the new CeMM building along with computers, fix problems or organize the projec- the acquisition of the most recent next-genera- is Gathered, tion in the seminar rooms. They also oversee tion sequencing machine was a good opportunity the web pages, intranet and the infoscreens, to build a powerful computer cluster (>350 cores) announcing the seminars of the whole building and data management system. This set-up can in the third floor entrance hall and in the foyer handle 40 terabytes of digital information and Managed and on level eight. If you listen closely you can hear runs the institute’s proprietary data workflow the computers humming in their cabinets in the management software, databases, and data server room across the corridor. analysis programs.

Analyzed Walking down the corridor, you come across the A carefully designed computer infrastructure is three offices housing Jacques Colinge and the critical for any modern biomedical research insti- bioinformatics team. tute to function efficiently. At CeMM, the set-up enables first the customized analysis of any newly The bioinformatics group led by Jacques Colinge generated data, followed by its integration with is located along the southern axis of the build- existing data either from CeMM or from other ing. This position, with all the laboratories above, institutes. The capacity of scientific technologies symbolically reflects one important mission of like mass spectrometry and sequencing con- the group: to support the other CeMM labs and tinue to grow exponentially, as do available data Previous page: first make sense of their data. The team has been collections from other institutes. Fortunately, Level 02, Room 02.204 setting up a computational infrastructure able to computer and storage power are growing at a Machine Room deal with the enormous data flows that are gener- comparable pace. Giving the beat ated by some of the most sophisticated modern Philipp Hainzl, Technical Assistant playing his drum kit technologies available at the institute. Building Models The bioinformatics group also develops statistical models that are used to analyze data generated by several CeMM research projects. Their aim is to build a collection of mathematical models that can perform rigorous data analyses on com- binations of datasets originating from multiple technology platforms. These models are the foundation of deeper and more biology-oriented bioinformatics projects, and illustrate CeMM’s efforts to build cutting-edge data analysis tools.

Ce — M­—M­— Research Report 2010 58 59 A Fig. 18 (A) An original Mathematical Modelling dataset comprised of the relationships between bait (red circles) and preys (blue of Biological Data diamonds). The original dataset is reduced to a more simplified structure (B) using the group’s statis- tical method, which explores all possibilities and returns Novel statistical Many CeMM research projects generate vast (healthy) sample, which can provide insight into the most probable configu- quantities of data that need to be effectively why diseases occur, or how they respond to cer- ration. This is obtained when models generate analyzed to produce meaningful biological con- tain treatments. The new statistical model they proteins are organized in modules (light blue ellipses), highly accurate clusions. Beyond establishing the infrastructure have developed provides researchers at CeMM which can combine to form for managing the data, the bioinformatics group with a tool to use quantitative proteomics in a actual protein complexes protein complex (through arrows). (Data also develops diverse methods to properly model simple but highly sensitive way. from Sardiu et al., 2008). predictions. them, in order to generate novel conclusions. They focus mainly on statistical approaches, Using Algorithms to Identify Protein Complexes which also allow them to determine the level of In living cells, proteins usually act in groups accuracy of their results. known as protein complexes to perform specific biological functions. Identifying the individual Recently, in collaboration with Karl Mechtler proteins in these complexes is important for from the Protein Chemistry facility at the IMP/ understanding their function. Pulldown experi- IMBA research institutes in Vienna, and Jean- ments can isolate proteins in a complex by using B Charles Sanchez from the Biomedical Proteom- a ‘bait’ protein to fish in a biological sample for ics Research group at the University of Geneva, all the other proteins (prey) to which it binds. the group has invented novel statistical models These binders can then be identified by mass for quantitative proteomics analyses and for spectrometry. Data generated from these sorts of predicting the existence of protein complexes. experiments, obtained for several bait proteins, Quantitative proteomics is a powerful analytical constitute tricky puzzles that need analyzing technique based on mass spectrometry. It simul- by complex algorithms before the true protein taneously measures the protein content of several complexes can be identified. The group has intro- biological or patient samples as well as the rela- duced a new advanced statistical learning method tive abundance of the individual proteins, that explores all possible interaction configura- e.g. through iTRAQ™ and TMT™ technologies. tions and generates highly accurate protein This approach can reveal differences between complex predictions. individual samples, such as a disease and a control

Fig. 17 The CeMM computer protein ratio Fig. 19 A novel statistical cluster is at the center of all random model developed at CeMM is scientific data flows. It distribution able to determine natural processes the huge data biological sample variability volumes generated by four from quantitative proteomics mass spectrometry (MS) NGS data by integrating replicate instruments and one DNA analysis (top, 2 samples of next generation sequencing −0.3 −0.2 −0.1 0.0 0.1 0.2 0.3 classes a and b each). (NGS) platform (1 TB/week). Significantly regulated CeMM IT infrastructure proteins are then identified connects the research center and a comparison with to the world through the a a b b classical approaches reveals network from the Medical 4 1 2 1 2 k that the number of detected University of Vienna. i l proteins is doubled (new= MS blue, classical ethod=green), j while eliminating spurious cases (red). − log10 signal p−value 0 10 20 30 40 50 60

−4 −2 0 2 4 Ce — M­—M­— Research Report 2010 − log10 sample p−value 60 61 Fig. 20 Area of the human CD72 The Power of A TBKBP1 SPHK2 protein interaction network SYK sig­nificantly influenced by TBK1 bosutinib treatment in Computing BTK chronic myeloid leukemia LYN (CML). The 43 proteins DAPP1 FGR directly bound by the drug RPS6KB2 are depicted by triangles, MAP3K2 4 of which (SYK, BTK, LYN, PTK2 PTK2B and TBK1) are involved in In 2010, the bioinformatics group developed Identifying New Uses for Old Drugs immune system pathways. MAP3K1 Given these proteins also several computational methods that can predict The bioinformatics group has developed an SRC bind other proteins involved MAP3K3 MAP3K4 actions of anti-cancer drugs using chemical algorithm that can identify parts of a protein in immunity (numbers in proteomics data. Most drugs work by binding to interaction network that are influenced by a brackets), this augments the risk of an impact of the drug a disease-causing protein thereby inhibiting its disease or by the action of a drug. When these MAP2k1 PDXK on the immune system. The function. Unfortunately, many drugs are promis- two areas coincide in a statistically significant MAP2K2 protein target PRKAA1 is the PRKAB1 cuous, and also bind many other cellular proteins, manner, there is the potential to apply the drug likely cause of a potential PRKAA1 side effect related to the PRKAG1 sometimes causing unpleasant side effects. Iden- to treat a new disease. Using this algorithm, the B PRKAB2 endocrine system and BCR- tifying all the proteins to which a drug binds is group could predict the likely benefit of treating PRKAG2 PRKAG3 ABL is the primary CML- ABL1 an important challenge in biomedical research. It lung cancer patients with two different drugs, relevant bosutinib target. can help explain how the drug works and why it and treating hepatocellular carcinoma with four causes side effects, thus leading to the develop- drugs. Importantly, they were able to predict that ment of more effective drugs. bosutinib, a new compound not yet tested in humans, is likely to cause immunosuppression. Translating Data into Clinical Results These results were published at the International Chemical proteomics measures protein-drug Conference on Computational Systems Biology interactions and detects the protein targets of in 2010 in Suzhou, China. They were also able to drugs in cells. At CeMM, this technique has been predict that the drug bafetinib, commonly used applied to several drugs that are primarily used to treat patients with chronic myeloid leukemia to treat leukemia. They identified many new (CML), may be useful for treating lung cancer, protein targets, some of which bound strongly which was published in PLoS Computational Fig. 21 Systemic effects of to the drug and may be causing the unwanted Biology in 2010. the disease and the drug treatment. Kinase inhibitors side effects. In addition, identifying strong used against various cancers drug-protein interactions may reveal new uses New projects have recently been set up in col- target many kinases and hence have a global for these approved drugs in other diseases. Thus, laboration with chemical proteomics in the influence on treated cells. these new computational methods developed Superti-Furga lab and the PLACEBO compound The same is true for cancer by the bioinformatics team help to bridge the screening facility run by Stefan Kubicek, both that can impact a multitude The group of biological pathways and, gap between laboratory experiments and human found on the fourth floor, to further explore therefore, the bioinformat- could predict the health in the clinic. these initial exciting results. ics group of Jacques Colinge favors systems biology likely benefit approaches to relate drug of treating lung targets – as revealed by chemical proteomics – with cancer patients diseases. The figure features part of the human inter- with two actome, i.e. all the known protein interactions, with different drugs. node sizes representing the disease influence (Ph+ ALL in this case). The red color intensity indicates drug treatment (dasatinib) influ- ence and we see, in this case, the good correlation between disease and drug treatment. Triangles stand for deleted genes (chromo- somal aberrations) that cause the disease.

Ce — M­—M­— Research Report 2010 62 63 Level 01 Where Support Comes From p. 66 Reaching the first floor, one is presented with Keeping the things running at an institute with the familiar choice between the left and right so many functions as CeMM requires some glass doors. The right door is an emergency exit, synergy between machines and people. The Level 01 but one is tempted to move to the left, towards lower floors provide most of the machinery a room that is permanently busy. Parcels, boxes, needed to keep things functioning, but actually deliveries and envelopes fill the room where most of the administration is located on level Where Support Paul Kletzl takes care of all goods’ arrivals and three. The feeling there is not industrial any more. distributes them in the building. Further along On one end of the corridor, to the east, is a clear the corridor, the room gets a more industrial window. The art façade does not reach to this feeling: the false ceiling disappears and all the side of the third floor, as it is a bit shorter. This Comes From utility lines become visible; ducts for AC, cables is because CeMM is built over a pre-existing and pipes form an intricate network that spans electrical station. On the other end of the corri- the entire corridor and serves as a reminder of dor, at the west end, is the public entrance. how many important functions of the building Walking past, we peek into the three small offices are not immediately clear to the visitor. One of and in the larger, glass-enclosed corner office. these functions is the media and wash kitchens, Here in the finance department, books are supervised by Sylvia Bolz and Amisi Nyembo. balanced and bills are paid on time by Sigrid The kitchens are composed of two rooms that are Strodl, Victoria Kulcsar-Mecsery and Stephan connected by a through-type autoclave, where Boos-Waldeck. Angelika Eisner is also part of used labware enters from one side, and comes the team, managing grants and much of the out autoclaved on the other side after being third-party funding. The office next door is exposed to 120 degrees Celsius at high pressure. shared between Georg Casari, who guards the The rooms are dotted with various other types of intellectual property rights and technology equipment, to prepare media solutions for all transfer, and Gerhard Schadler, who supervises laboratories in the institute, to clean and decon- the entire administration while overseeing ties taminate glassware, sterilise plasticware and with the administration of the Academy, the Previous page: purify water to produce the double distilled water Medical University and the General Hospital. Level 01, Room 01.207 that is going to be used in the various biological Sonja Baier and Verena Lichtenegger are respon- Wash Kitchen and chemical experiments. Apart from the sible for the phones, for making travel arrange- Warming-up for peak performance kitchens, there are large rooms for storage, either ments for CeMMies and receiving visitors. Ana Puda, PhD Student dancing jazz ballet at room temperature, 4 degrees or -20 degrees Here you also find Gabriel O’Riordain, who Celsius. manages the labs and is responsible for lab safety in the entire building. Gabriel is also in charge All the utilities that are visible on the ceiling of the purchase and maintenance of equipment. of the corridor of the first floor need to originate somewhere, and this point of origin is found Clearly, an efficient and lean administration is below the first floor. There are two more floors critical for the success of the research organi­ in the basement of CeMM, where the feeling zation. In many ways it is a challenge, as scientists is even more industrial: electricity control occasionally have prima donna allures like artists. stations, battery rooms, heating and cooling On the other hand, providing the best possible systems for the radiators, fuse boxes and infrastructure and assistance can make the numerous storage areas, including a special distinction between a mediocre institution and one for flammable chemicals equipped with one that aims at competing internationally with an extra powerful hood. the very best and wants to find new strategies to cures. As in Formula One racing, it is not only the driver that deserves credit when a car wins a competition. The CeMM administration sometimes is challenged like a Ferrari box on a race circuit.

Ce — M­—M­— Research Report 2010 66 67 Level 08 Where CeMM Meets the World p. 70 Having finished the tour through all the research and arrangements. On a Friday morning, coffee floors of the new CeMM building, it is time to go and tea are served on the big table in the center to up to the 8th floor, the floor that affords the most cater for the people attending the Friday seminar Level 08 impressive view of the Vienna skyline. Getting and to foster discussions. During a conference out of the elevator or the staircase you are pre- break, numerous groups of people will cluster sented with three options: move straight ahead around tall, round tables exchanging views and Where towards the foyer, or go to either right or left to ideas on the scientific data presented. On other the north- and south-facing terrace respectively. occasions, cameramen and journalists will take photos and perform interviews with the The foyer welcomes you with a big electronic participants of a meeting. Finally, on any day CeMM Meets screen announcing current and upcoming events around twelve o’clock, many CeMM people will and seminars at CeMM. It is updated regularly be rushing to the cafeteria for the coveted lunch. and serves as a fast and effective way of commu- nicated events to the CeMM community. The cafeteria mirrors the seminar room on the the World The 8th floor is highly frequented: institute other (southern) side of the 8th floor. It has meetings, CeMMinars, Impromptu seminars, recently been upgraded and it caters successfully and Constantin Spiegelfeld Lectures. To the right to the 120-people strong CeMM community that of the foyer you find the large seminar room includes guests from the Medical University. of CeMM. It is accessible through three doors, The room is the focal point of any culinary which is quite convenient as it allows latecomers activity at CeMM: be it breakfast or lunch break, to enter the room and reach almost any avail- conference dinner, or the famous Friday get- able seat without disturbing the speakers. Upon togethers with the Anna Spiegel/CTR colleagues. entering the room, you are presented with a This initiative takes place every couple of Fridays formidable design: wooden floor, round concrete and aims at bringing together the CeMM with the Previous page: pillars, bright red cupboards and of course a podi- adjacent medical community and involves short Level 08 um that is coloured in the notorious light blue lectures with subsequent reception. The cafeteria Terrace colour that is a hallmark of CeMM. The room is has immediate access to the south-facing terrace, Enjoying team spirit surrounded by tilted glass windows on two sides, enjoying plentiful sunshine when available. Philipp Günzl , PhD Student Florian Pauler, Postdoctoral Fellow offering views of the city and also of the hospital. The room is designed to be well adapted to Georg Winter, PhD Student For people who are not comfortable with heights, Vienna’s climate. On bitter-cold winter days, the playing soccer the tilted glass walls are almost certainly going to terrace is always empty, but the south-facing create a slight feeling of vertigo. But one doesn’t glass walls nevertheless guarantee that whatever have to go to the end of the room. The chairs are little sun there is will enter the room unhindered. located on the entrance side of the room and the On temperate days, the terrace is very popular, audience can attend the presentations projected offering a comfortable and relaxing experience. on the two whiteboards electronically controlled On hot summer days, a large adjustable sail will and folded out from the ceiling. The room is also protect from the scorching sunlight, making the equipped with shades to optimize the amount terrace a pleasant place to stay. of light in the room on sunny days. In addition, it has the added versatility that it can be divided The whole of the 8th floor serves the purpose of in two parts (one third, two thirds) through a enabling and maximizing scientific exchange and foldable wall. interaction, in an engaging and inspiring way. What is central to the success of medical research, Every Friday morning at 9:00 a.m., the entire is not only hard work, but also groundbreaking CeMM research community gathers in the ideas. To aid in that respect, an innovative project seminar room to attend the regular scientific has been initiated at CeMM. The plan is, to build a progress meeting. Normally two people present room that can serve as a point of inspiration for their latest scientific findings and they engage the exploration of ideas, at the interface of arts in an intense scientific dialogue. There is always and sciences. The ‘Brain Lounge’, as this room is a moderator to ensure that time slots are being called, is still in the making and is located adjacent adhered to and to get the questions from the to the cafeteria on the south side of the building. audience. The atmosphere is kept informal and It will be designed in a thought-provoking way, collegial. To avoid turning straight-off-the- by a team of artists, scientists and interior design- lab presentations into a competition of per­ ers with the aim to provide the space for creative formances, there is no clapping (sometimes a ideas about research approaches in molecular reflex hard to withstand). medicine. It will be a futuristic setting including designed carpets, couches, tables, lamps, mirrors, Getting out of the seminar room towards the sculptures and paintings. Any donation is wel- foyer, depending on the occasion, one can expect come, since the project can only take shape through to be presented with all the possible different the kind gifts from donors and benefactors (see uses of the room, with different furniture types Brain Lounge section at the end of the report).

Ce — M­—M­— Research Report 2010 70 71 “I am proud to say that the Research Center for Molecular Medicine (CeMM) is one of the pearls in the research portfolio of the Austrian Academy of Sciences. ‘From bed to bench and back to bed’ can be regarded as the ­motto of this institute indicating that the ­patient with his/her disease is the source of inspira- tion for the scientist who then analyzes and ­characterizes pathogenetic principles and ­networks with the help of all modern ­methods and technologies available. The ­insights flow back to the patient in the form of innovative and specific diagnostic and ­therapeutic procedures. Molecular medicine, therefore, is not a one-way street. A close ­interaction with the ­clinician is the basis of success. The position of CeMM at the campus of the Medical University of Vienna (MUW) and the Vienna General Hospital (AKH) is an ideal place to fulfil its mission in the sense of translational and ­individualized medicine. I congratulate the ­scientists, all members of CeMM and particularly its director Giulio ­Superti-Furga on their scientific achievements and I am convinced that the new institute will act as further ­stimulant and that our high ­expectations ­regarding scientific excellence will even be surpassed.”

Prof. Dr. Helmut Denk President of the Austrian Academy of Sciences Giulio Superti-Furga is an Italian national and he joined CeMM as Director in January 2005. CeMM Giulio He performed his undergraduate and graduate studies in molecular biology at the University of Superti-Furga Zurich, Switzerland, at Genentech Inc., South San Francisco, USA, and at the Institute for Molecular Principal Pathological Networks Pathology in Vienna (I.M.P.), Austria. He has been in Leukemia and Immunity a post-doctoral fellow and Team Leader at the European Molecular Biology Laboratory (EMBL) until 2004. For several years he served as Professor Investigators of Biotechnology at the University of Bologna. In 2000, he co-founded the biotech company Cellzome, where he was Scientific Director. Some of Giulio’s major achievements to date are CEO and Scientific Director the elucidation of basic regulatory mechanisms [email protected] of tyrosine kinases in human cancers and the discovery of fundamental organization principles PhD (Molecular Biology), of the proteome of higher organisms. Giulio’s work University of Zurich (CH) on the organization of the eukaryotic proteome IMP Vienna (A) is the most highly cited in the field. He is a full Post-doctoral fellow, Team Leader member of the Austrian Academy of Sciences, the EMBL – European Molecular German Academy of Sciences Leopoldina, the Biology Laboratory (D) European Molecular Biology Organization and Scientific Director the European Academy of Cancer Sciences. He is Cellzome (D) chair of the EMBL Alumni Association. He uses and develops high-throughput ‘omics’ approaches + Italian nationality to study several areas including the mechanism + Joined CeMM in January 2005 of action of proteins and drugs, the identification + Group of 20 people of molecular networks underlying leukemia and plus mass spectrometry team (5) the molecular basis of innate immunity. In 2009 and bioinformatics team (4) he received the prestigious Advanced Investigator Grant awarded by the European Research Main research interests Council (ERC), and he was awarded the Knight + Mechanism of action of drugs Officer Order of Merit of the Republic of Italy for + Molecular networks his contributions to science. affecting leukemias + Molecular basis of innate immunity Relevant/Important publications Functional organization of the yeast proteome by systematic analysis of protein complexes. Gavin AC, Bösche M, Krause R, Grandi P, ­Marzioch M, Bauer A, Schultz J, Rick JM, Michon AM, Cruciat CM, Remor M, Höfert C, Schelder M, Brajenovic M, Ruffner H, Merino A, Klein K, Hudak M, Dickson D, Rudi T, Gnau V, Bauch A, Bastuck S, Huhse B, Leutwein C, ­ Heurtier MA, Copley RR, Edelmann A, Querfurth E, Rybin V, Drewes G, Raida M, Bouwmeester T, Bork P, Seraphin B, Kuster B, Neubauer G, Superti-Furga G. Nature. 2002. 415(6868): 141-7.

A network solution. Henney A, Superti-Furga G. Nature. 2008 Oct 9; 455(7214):730-1.

An orthogonal proteomic-genomic screen ­identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Bürckstümmer T, Baumann C, Blüml S, Dixit E, Dürnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G. Nat Immunol. 2009. March 10(3):266-72.

74 75 Denise Barlow is a British national who joined Christoph Binder was born in 1973 in Vienna, CeMM in 2003 and is an Honorary Professor at the Austria. He obtained his MD degree from the Denise University of Vienna. Denise initially trained as a Christoph University of Vienna Medical School (MUV) in State Registered Nurse in the UK and afterwards 1997, working as an intern in the Clinical Pathology P. Barlow completed undergraduate studies at Reading J. Binder department with Professor Dontscho Kerjaschki. University (UK) and a PhD on the interferon Later, he entered a PhD program at the University Epigenetic Mechanisms system in early mouse development at Warwick Atherosclerosis of California in San Diego, working with renowned in Development & Disease University (UK). Post-doctoral work studying and Immunity atherosclerosis researcher Professor Joseph mouse embryonic development followed at ICRF Witztum, where he obtained his PhD degree in (London, UK) with Dr. Brigid Hogan, and on 2002 for the thesis entitled: “Defining Innate and genome biology at EMBL (Heidelberg, D) with Adaptive Immune Mechanisms in the Athero­ Dr. Hans Lehrach. Denise has also held group protective Effect of Immunization with Oxidized leader positions at the IMP (Vienna, A) and the NKI Low-Density Lipoproteins”. He continued with (Amsterdam, NL). On returning to Austria in 2000, Professor Witztum as a Post-doc to study the role CeMM Principal Investigator Denise was appointed Head of the Dept. of Devel- CeMM Principal Investigator of natural IgM antibodies and IL-5 in atherosclero- [email protected] opmental Genetics at the Austrian Academy IMB [email protected] sis, which was where he made one of his major Institute (Salzburg, A), and then returned to Vienna dis­coveries to date, namely the atheroprotective Honorary Professor of Genetics, in 2003 as a Principal Investigator with CeMM. MD, University of Vienna (A) capacity of natural antibodies. In 2005, he joined University of Vienna (A) One of the Barlow lab’s major achievements was PhD (Molecular Pathology) the Department of Laboratory Medicine at the PhD, Warwick University (UK) the discovery in 1991 of the first imprinted gene in University of California Medical University of Vienna, where in 2009 he Post-doctoral Fellow, mammals to show parental-specific gene expres- San Diego (USA) was appointed Professor of Atherosclerosis ICRF London (UK), sion. Their subsequent identification that epige- Post-doctoral fellow, Research. His interests are clearly interdisciplinary EMBL Heidelberg (D) netic silencing of this imprinted gene is induced University of California and span vascular biology, lipid oxidation, natural Group Leader, by expression of an unusual macro non-protein- San Diego (USA) antibodies and innate immunity. In particular, IMP Vienna (A) coding (nc) RNA, has led them to investigate how he aims to define the role of B-1 cells and natural NKI Amsterdam (NL) macro ncRNAs act throughout the mouse and + Austrian nationality antibodies in atherogenesis and how immune Head Dept. Developmental Biology, human genome as regulators of gene expression + Joined CeMM in April 2006 recognition of lipid peroxidation derived structures IMB-OeAW Salzburg (A) in development and disease. The lab continues to + Group of 10 people promotes chronic inflammatory diseases, such as use the model of genomic imprinting to dissect atherosclerosis. + British nationality how ncRNAs epigenetically silence genes, and uses Main research interests + Joined CeMM in 2003 this as a platform together with high throughput + Role of natural immunity in + Group of 12 people sequencing technology to extend these results into inflammation and oxidative stress Relevant/Important publications human diseases such as cancer. + Elucidate the protective Innate and acquired immunity in atherogenesis. Main research interests capacities of natural antibodies Binder CJ, Chang MK, Shaw PX, Miller YI, + Molecular basis and function in atherosclerosis Hartvigsen K et al. Nature Medicine. 2002. of genomic imprinting in mice Relevant/Important publications + Discover ways to boost natural 8(11): 1218-26. and humans Active and Repressive Chromatin Is Interspersed immunity as therapy for cardio­ + Identification and characterization without Spreading in an Imprinted Gene Cluster vascular diseases Pneumococcal vaccination decreases atherosclerotic of macro non-coding RNAs in the in the Mammalian Genome. Regha K, Sloane MA, lesion formation: Molecular mimicry between mouse and human genomes Huang R, Pauler FM, Warczok KE, Melikant B, Christoph Binder’s group Streptococcus pneumoniae and oxidized LDL. + The potential of macro non-coding Radolf M, Martens JH, Schotta G, Jenuwein T, is hosted by ­Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP RNAs as tumor biomarkers in Barlow DP. Molecular Cell. 2007. 27(3): 353-66. Department of Medical and et al. Nature Medicine. 2003. 9(6): 736-43. human cancer Chemical Laboratory Diagnostics An in vitro ES cell imprinting model shows that Medical University of Vienna Oxidation-specific epitopes are dominant targets imprinted expression of the Igf2r gene arises from Anna Spiegel Forschungsgebäude of innate natural antibodies in mice and humans. an allele-specific expression bias. Latos PA, Stricker (BT 25.2), Lazarettgasse 14 Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, SH, Steenpass L, Pauler FM, Huang R, Senergin BH, 1090 Vienna, Austria Woelkers D, Shaw PX, Choi J, Perkmann T, Regha K, Koerner MV, Warczok KE, Unger C, Bäckhed F, Miller YI, Hörkkö S, Corr M, Witztum JL, Barlow DP. Development. 2009 Feb;136(3):437-48. Binder CJ. J Clin Invest. 2009 May;119(5):1335-49.

The function of non-coding RNAs in genomic imprinting. Koerner MV, Pauler FM, Huang R, Barlow DP. Development. 2009 Jun;136(11):1771-83. Review.

Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues. Hudson QJ, Kulinski TM, Huetter SP, Barlow DP. Heredity. 2010 Jul;105(1):45-56. Epub 2010 Mar 17. Review.

Ce — M­—M­— Research Report 2010 76 77 Sylvia Knapp was born in Austria and studied Robert Kralovics, born 1970, is Czech and joined Medicine at the Free University in Berlin and the CeMM in June 2006. He obtained his first degree in Sylvia University of Vienna. She obtained her MD degree Robert Molecular Biology and Genetics at the Comenius in 1993 and started her residency in Internal University in Bratislava and later his PhD in Bio- Knapp Medicine at the University Hospital Vienna. In 2000 Kralovics physics at the Academy of Sciences of the Czech she received her License in Internal Medicine and in Republic in Brno. He did his post-doctoral work on Innate Immunity 2004 she obtained a “Habilitation” in Internal Genetics of the genetics of myeloproliferative dis­orders work- and Bacterial Infections Medicine at the Medical University of Vienna. After Hematological Disorders ing with Josef Prchal at the University of Alabama several residencies, mostly in areas like Infectious in Birmingham, USA. He followed Prchal as an Diseases, AIDS and Intensive Care Units, she became Assistant Professor at the Baylor College of a PhD student in Tom van der Poll’s laboratory at Medicine in Houston. From mid 2001, Robert the University of Amsterdam and studied the was a project leader with Radek Skoda in Basel. inflammatory response to severe bacterial infections. Robert’s research interests are primarily in myelo- Sylvia’s most important achievements include proliferative disorders (MPDs) and in myeloid CeMM Principal Investigator the identification of the anti-inflammatory role of CeMM Principal Investigator malignancies in general. One of his major achieve- [email protected] alveolar (lung) macrophages as well as the biological [email protected] ments so far has been the identification of a or [email protected] function of several pattern recognition receptors gain-of-function mutation in the JAK2 kinase gene during Streptococcus pneumoniae pneumonia. PhD (Molecular Biology) (V617F), which plays an important role in MPD MD, University of Vienna (A) Sylvia joined CeMM in 2006 and continues her Czech Academy of Sciences (CZ) pathogenesis. This was prominently published in Internist, Vienna General work on the innate immune response to bacterial Post-doctoral fellow the New England Journal of Medicine and fostered Hospital, MUV (A) infections, focusing on the molecules involved in University of Alabama Robert’s interest in deciphering the genetic com- PhD (Experimental Medicine), the initiation and resolution of the innate immune at Birmingham (USA) plexity of MPD. More recently, Robert’s group University of Amsterdam (NL) response to clinically relevant pathogens and on Assistant Professor discovered a common JAK2 gene variant that the role of bacterial virulence factors and their inter- Baylor College of Medicine, confers susceptibility to MPD. Robert continues + Austrian nationality actions with host structures and pathways. Sylvia Houston (USA) this work at CeMM to identify new mutations + Joined CeMM in April 2006 keeps her responsibilities at the Intensive Care Unit Project Leader causing familial predisposition to hematological + Group of 7 people at the Medical University Vienna. University Hospital Basel (CH) malignancies using advanced genomics approaches, and is working towards understanding how genetic Main research interests + Czech nationality variability contributes to the disease. + Exploit molecular mechanisms of Relevant/Important publications + Joined CeMM in June 2006 host-pathogen interactions Alveolar macrophages have a protective anti­ + Group of 9 people + Identify the impact of inflammatory role during murine pneumo­­coccal Relevant/Important publications bacterial toxins pneumonia. Knapp S, Leemans JC, FlorquinS, Main research objectives p53 lesions in leukemic transformation. Branger J, Maris NA, Pater J, van Rooijen N, and questions Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. Sylvia Knapp’s group and van der Poll T. Am J Respir Crit Care Med + Identify mutations in early N Engl J Med. 2011 Feb 3;364(5):488-90 is located at the (2003) 167, 171-179. steps of disease development Department of Internal Medicine I in hematological malignancies Deletions of the transcription factor Ikaros in Division of Infectious Diseases & TREM-1 activation alters the dynamics of pulmonary + How mutant stem cells evolve myeloproliferative neoplasms. Tropical Medicine IRAK-M expression in vivo and improves host genetically, how they respond Jäger R, Gisslinger H, Passamonti F, Rumi E, Medical University Vienna defense during pneumococcal pneumonia. Lagler H, to therapy? Berg T, Gisslinger B, Pietra D, Harutyunyan A, Währinger Gürtel 18—20, Sharif O, Haslinger I, Matt U, Stich K, Furtner T, + What gene mutations cause Klampfl T, Olcaydu D, Cazzola M, Kralovics R. 1090 Vienna, Austria Doninger B, Schmid K, Gattringer R, de Vos AF, familial predisposition to Leukemia. 2010 Jul;24(7):1290-8 Knapp S. J Immunol (2009) 183, 2027-2036 hematological malignancies? + How does genetic variability A common JAK2 haplotype confers susceptibility Baumann CL*, Aspalter IM*, Sharif O*, Pichlmair A, contribute to disease? to myeloproliferative neoplasms. Olcaydu D, Blüml S, Grebien F, Bruckner M, Pasierbek P, + How to diagnose the diseases Harutyunyan A, Jäger R, Berg T, Gisslinger B, Aumayr K, Planyavsky M, Bennett KL, Colinge J, in early stages of development? Pabinger I, Gisslinger H, Kralovics R. Knapp S#, Superti-Furga G#. CD14 is a coreceptor of Nature Genetics. 2009. 41(4):450-4 Toll-like receptors 7 and 9. J Exp Med (2010) 207: 2689-2701. A gain-of-function mutation of JAK2 in * equal contribution ­myeloproliferative disorders. Kralovics R, # corresponding authors ­Passamonti F, Buser AS, Teo SS, Tiedt R et al. N Engl J Med. 2005. 28;352(17): 1779-90

Ce — M­—M­— Research Report 2010 78 79 Sebastian Nijman was born in the Netherlands Keiryn Bennett, heads the mass spectrometry unit (1975). He studied medical biology at Utrecht at CeMM. Australian by birth, she obtained her Sebastian University and specialized in Molecular Biology Keiryn Bachelor of Science with Honours at the Depart- and Biochemistry in the labs of Hans Bos and Rene ment of Biochemistry, University of Tasmania Nijman Medema. Sebastian also holds a Masters of Arts Bennett and her PhD at the Department of Chemistry, degree from the University of Maastricht (Science, University of Wollongong, Australia, under the Functional Cancer Genomics Society and Technology Studies) and was involved supervision of Professor Margaret Sheil. She further in clinical research at a Contract Research trained in some of the most renowned protein Organization. In the lab of Rene Bernards at the mass spectrometry laboratories of the world, Netherlands Cancer Institute, he performed his including Professor Peter Roepstorff in Odense, PhD work, focusing on functional genetic screens Denmark. Keiryn was the Director of Analytical in cancer-relevant pathways. He performed the Applications at Protana A/S in Denmark (later first RNAi screen in mammalian cells that led to called MDS Proteomics). Her hands-on experience the identification of the cylindromatosis tumor with different systems include: Sciex prototype CeMM Principal Investigator suppressor as a regulator of NF-kappaB signaling. Head of Mass Spectrometry MALDI QqTOF, PerSeptive Voyager Elite [email protected] This work has led to a rational therapeutic approach [email protected] MALDI-rTOF, TSQ 700 triple quadrupole mass for treating cylindromatosis and is one of his major spectrometer, Sciex QSTAR equipped with nano- PhD (Molecular Carcinogenesis) achievements so far. In 2006 he joined the lab of + Australian nationality electrospray, and nanoLCMS coupled to Thermo- Netherlands Cancer Institute (NL) Todd Golub at The Broad Institute of Harvard and + Joined CeMM in October 2004 Fisher hybrid LTQ Orbitrap XL and Micromass/ Post-doctoral fellow, MIT, USA. There he developed novel genomic + Group of 7 people Waters Q TOF mass spectro­meters. Author of The Broad Institute of Harvard approaches to discover the functions of genes and more than 40 publications, during her time at MDS, and MIT (USA) identify new angles for cancer treatment. Since Main research interests she was involved in the large-scale analysis of yeast joining CeMM, Sebastian’s research is mostly + Proteomics, with an emphasis protein complexes published in Nature along with + Dutch nationality focused on the identification and understanding on medical/clinical field the analogous effort from Cellzome. She brings + Joined CeMM in October 2007 of cancer vulnerabilities using chemical genetic + Liquid chromatography mass to CeMM more than 17 years of experience in + Group of 6 people screens. spectrometry (including technical protein mass spectro­metry and 4 years experience advancement and applications) in managing a high-throughput industrial Main research interests + Integration of mass spectrometry proteomic laboratory. + Chemical genetics of cancer Relevant/Important publications with biology and bioinformatics + Identify novel strategies to treat Loss of the cylindromatosis tumour ­suppressor cancer (cancer vulnerabilities) inhibits apoptosis by activating NFkappaB. Relevant/Important publications: + Functional genetic screens to Brummelkamp TR, Nijman SM, Dirac AM and Proteomic analysis of human cataract aqueous identify cancer-related genes Bernards R. Nature. 2003. 424(6950): 797-801. humour: comparison of one-dimensional gel LCMS with two-dimensional LCMS of unlabelled The deubiquitinating enzyme USP1 regulates and iTRAQ®-labelled specimens. Bennett KL, the Fanconi Anemia pathway. Nijman SM*, Funk M, Tschernutter M, Breitwieser FP, Huang TT*, Dirac AM, Brummelkamp TR, Planyavsky M, Ubaida Mohien C, Müller A, ­Kerkhoven RM et al. Molecular Cell. 2005. Trajanoski Z, Colinge J, Superti-Furga G and 17(3): 331-9. Schmidt-Erfurth U. J Proteomics. 2011. 74, 151-166 * equal contribution An orthogonal proteomic-genomic screen A genomic and functional inventory of identi­fies AIM2 as the cytoplasmic DNA sensor for ­deubiquitinating enzymes. Nijman SM, the inflammasome. Bürckstümmer T, Blüml S, Luna-Vargas MP, Velds A, Brummelkamp TR, Baumann C, Dixit E, Dürnberger G, Jahn H, Dirac AM et al. Cell. 2005. 123(5): 773-86. Planyavsky M, Bilban M, Colinge J, Bennett KL and Superti-Furga G. 2009. Nature Immunol. Synthetic lethality: general principles, utility and 10, 266-272 detection using genetic screens in human cells. Nijman SM. FEBS lett. 2011 Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K, Yang L, Wolting C, Donaldson I, Schandorff S, Shewnarane J, Vo M, Taggart J, Goudreault M, Muskat B, Alfarano C, Dewar D, Lin Z, Michalickova K, Willems AR, Sassi H, Nielsen PA, Rasmussen KJ, Andersen JR, Johansen LE, Hansen LH, Jespersen H, Podtelejnikov A, Nielsen E, Crawford J, Poulsen V, Sørensen BD, Matthiesen J, Hendrickson RC, Gleeson F, Pawson T, Moran MF, Durocher D, Mann M, Hogue CWV, Figeys D and Tyers M. 2002. Nature. 415, 180-183

Ce — M­—M­— Research Report 2010 80 81 Jacques Colinge was born in Switzerland and heads Stefan Kubicek, born 1978, is Austrian and joined bioinformatics at CeMM since 2006. He obtained a CeMM on August 1st, 2010. He obtained an MSc in Jacques PhD in mathematics from the University of Stefan synthetic organic chemistry from Vienna University Geneva, Switzerland, in collaboration with the of Technology following a diploma thesis at ETH Colinge Swiss Institute of Technology. After completing Kubicek Zürich. For his PhD in Thomas Jenuwein’s lab at his PhD, Jacques joined the Serono Pharmaceutical the IMP in Vienna, he changed fields to Molecular Research Institute as a bioinformatician to work Biology. He then performed post-doctoral research mainly on differential gene expression data analy- working on Chemical Biology with Stuart Schreiber sis. In 2000 he moved to GeneProt Inc. to head a at the Broad Institute of Harvard and MIT. Stefan group in charge of mass spectrometry-related bio- Kubicek heads the chemical screening platform and informatics and parallel computing. In 2005, he PLACEBO (Platform Austria for Chemical Biology), joined the Upper Austrian University of Applied a task he is well equipped for based on previous Sciences at Hagenberg to serve as a Professor of screening experiences with Boehringer Ingelheim Bioinformatics before moving to CeMM in and at the Broad Institute. These activities have Scientist and September 2006. In 2009, Jacques obtained a Head of Chemical Screening and resulted in the identification of the first selective Head of Bioinformatics Habilitation in bioinformatics from TU Graz. Platform Austria for Chemical histone methyltransferase inhibitor, BIX-01294, [email protected] The bioinformatics lab does research to develop Biology (PLACEBO) and a small molecule inducer of insulin expression data analysis methods aimed at understanding the [email protected] in pancreatic alpha cells, BRD7389. The Kubicek lab + Swiss and French nationality biological function of networks of interacting pro- is working on the role of chromatin in the definition + Joined CeMM in September 2006 teins. The group also develops and maintains data Group Members of cell types and cell states. Projects focus on + Group of 6 people processing pipelines and databases to analyze and Patrick Markt (Post-Doc), defining the contribution of histone methylation manage mass spectrometry data, and to support Marco Licciardello (PhD-Student) to cancer development and progression and its Main research interests protein interaction network analyses. potential for transdifferentiation of celltypes. We + Computational proteomics Main research interests use functional genomics to identify chromatin + Protein interaction network + Chemical Epigenetics modifying enzymes as potential targets for cancer analysis Relevant/Important publications: + Identification and development of therapy and develop small molecules against these + Systems biology and Initial characterization of the human central small molecule probes for biological proteins. Currently we focus on the role of histone OMICS data integration proteome. Burkard TR, Planyavsky M, Kaupe I, processes methyl binding proteins in acute myeloid leukemia. + Drug mechanism of action Breitwieser FP, Bürckstümmer T, Bennett KL, + Contribution of histone lysine Additionally, we are interested in targeting epi- and side-effects modeling Superti-Furga G, Colinge J. BMC Syst Biol. 2011. methylation to cancer development genetic marks for cellular transdifferentiation, with + Protein complex predictions from 5(1):17 and progression the goal of generating insulin-producing beta cells mass spectrometry data + Role of chromatin in the from other cell types. In a project funded by the + Application of computational Using iTRAQ combined with tandem affinity specification of pancreatic cell types Juvenile Diabetes Research Foundation JDRF, we statistics and mathematics purification to enhance low-abundance proteins make use of the recent discovery that Pax4 over- associated with somatically mutated EGFR core expression can convert alpha cells into functional complexes in lung cancer. Haura EB, Muller A, insulin-producing beta cells. We identify the chro- Breitwieser FP, Li J, Grebien F, Colinge J, matin changes underlying this transdifferentiation Bennett KL. J Proteome Res. 2011, 10(1):182-190 event and work on novel genes and compounds that induce insulin expression. Proteomic analysis of human cataract aqueous humour: Comparison of one-dimensional gel LCMS with two-dimensional LCMS of unlabelled and Relevant/Important publications iTRAQ(R)-labelled specimens. Bennett KL, Funk M, Small molecule inducers of insulin expression Tschernutter M, Breitwieser FP, Planyavsky M, in pancreatic alpha cells. Fomina-Yadlin D*, Mohien CU, Muller A, Trajanoski Z, Colinge J, Kubicek S*, Walpita D, Dancik V, Hecksher- Superti-Furga G, Schmidt-Erfurth U. J Proteomics Sørensen J, Bittker JA, Sharifnia T, Shamji A, 2011, 74(2):151-166 Clemons PA, Wagner BK, and Schreiber SL. PNAS,107(34):15099-104 (2010)

Transient reversal of H3K9me2 by a small molecule inhibitor for the G9a histone methyltransferase. Kubicek S, O’Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Mechtler K, Rea S, Kowalski JA, Homon CA, Kelly TA, and Jenuwein T. Mol. Cell 25, 473-481 (2007)

Jmjd2b antagonizes H3K9 tri-methylation at pericentric heterochromatin in mammalian cells. Fodor BD*, Kubicek S*, Yonezawa M, O’Sullivan RJ, Sengupta R, Perez-Burgos L, Opravil S, Mechtler K, Schotta G, and Jenuwein T. GenesDev. 20, 1557-1562 (2006) * equal contribution Ce — M­—M­— Research Report 2010 82 83 “Knowing and understanding the pathological mechanisms of diseases is a central need of medical research and of key importance for all future diagnostic and therapeutic develop- ments. To fill the existing knowledge gaps a close interaction between basic and clinical ­research is an indispensable precondition. The Center of Molecular Medicine – CeMM – is one of Austria’s prime locations for molecular ­research in medicine with an excellent ­research focus. CeMM’s crew of dynamic and highly ­motivated specialists, its critical mass of young researchers, and the superb leadership of Prof. Giulio Superti-Furga ensure scientific ­output of the highest quality. Since its existence, CEMM has provided important ­contributions to the better understanding of th­e ­molecular pathomechanisms of several ­diseases. The location amidst the Medical ­University Vienna and the General Hospital ­Vienna allows optimal interaction with clinical partners and will lead to continued success in spearheading the progress of Molecular ­Medicine in Austria’s scientific community.”

Prof. Dr. Christine Mannhalter Molecular Diagnostics, Medical University Vienna Vice President of the Austrian Science Fund The President of Austria Dr. Heinz Fischer visiting CeMM the new CeMM building, a few weeks ahead PhD Program of moving.

Caution! CeMM-students @ work…

Starting at the top CeMM has now run three PhD programs that There is a lot of noise and the sound of “sekt” have taken in 34 students from 10 countries into corks popping on the 8th floor of CeMM. We a program that includes a unique blend of practi- are outside the seminar room at the end of 2010 cal training, lectures and mentoring that builds and two CeMM PhD students are really celebrat- on the guidelines for PhD programs of CeMM’s ing! Roland Jaeger and Irena Vlatkovic joined home academic institution, the Medical Univer- the first CeMM PhD program at the end of 2006 sity of Vienna. Students begin to arrive in Sep- and are the first students of this intake to obtain tember or October and for the first six months, their doctorate. They are both well known in the live close by on the hospital campus in small, CeMM community as intelligent, hard working comfortable and very affordable one-room apart- and collegial young scientists who are great role ments. In October they spend the first 4 weeks in models for our latest group of PhD students. the 8th floor seminar room getting to know each other and the CeMM Principal Investigators by learning practical things like how to survive in a lab, how not to annoy your supervisor by keep- ing a good lab notebook, how to enjoy your PhD experience and how to successfully navigate the University bureaucracy. This is combined with basic science courses, some organized by the Medical University and some by the CeMM PIs that are given by a selection of prominent leaders, scientists and medical professors from the Viennese science and medical community and biotech industry. The days are very full but there is still time to attend the weekly CeMM work discussions that are held every Friday morning, where they get to know who is who and what is going on @ CeMM. What seems to be more important is that the students accepted into the program each year, because of this common induction program, tend to stay in contact throughout their PhD period.

86 87 A better perspective – the view from the terrace Who you gonna call? CeMM students! The next 6 weeks are lab rotation time in floors The CeMM PhD program looks for exceptionally 2–7. Here the students and their PI select three motivated PhD candidates with a keen interest CeMM labs where the student spends two in molecular medical research at the forefront CeMM as weeks on a small project to learn techniques and of new system and genome technologies. We skills that will be useful for their future project. expect a lot from our new students – they need At the same time, the student gets a good idea to be good in the lab, they must not be afraid to Spring­board of the type of research that is going on at CeMM learn new and difficult things or to ask challeng- and gets to know a wider group of scientists and ing questions, and they need to learn to work interests. Some lectures and courses continue together in teams. At the same time CeMM is during this time, and one of the earliest lessons offering a lot – the CeMM Faculty is committed for Careers that all scientists need to learn is how to plan to the training of young scientists that we hope your day to do your experiment and go to the will shape the future of molecular medicine. seminar. CeMM students also get a better per- We monitor the progress of each student. We do spective of the relationship between research this in a formal way using a PhD committee that and medicine and the privileged position of the meets annually to advise both the students and Part of CeMM’s mission is to train CeMM Institute on the main hospital site by their PI about the chosen research project. And young investigators in molecular meeting clinicians at the main hospital. we do it informally through the use of a mentor- medicine. CeMM is very proud of a ing system that pairs students with a PI who is not their supervisor, who meet more regularly for highly active community of Post-­ lunch or coffee time discussions. This seems to doctoral fellows. Two such fellows, be a successful formula – CeMM students are just Oliver Hantschel and Tilmann like Roland and Irena, committed, enthusiastic, good colleagues and great fun to work with. Bürckstümmer, have left CeMM at the end of 2010. We report here their testimonials.

CeMM PhD Students visiting the Josefinum with Dontscho Kerjaschki.

Ce — M­—M­— Research Report 2010 Dr. Oliver Hantschel In terms of scientific projects, another distinctive Dr. Tilmann Bürckstümmer With beginning of 2011, I decided to cease the How should I start? It is pretty hard to try to feature of being a Post-doc at CeMM is the strong Five years of Post-doc at CeMM, five years that opportunity to lead a spin-off company. While summarize more than six years as a Post-doc at support and encouragement for both CeMM- changed my life. When I started in Giulio initially located on “CeMM grounds”, the com- CeMM, that were scientifically challenging, form- internal, as well as external collaborations. For Superti-Furga’s laboratory, the lab had just pany may move to a different place by the end ative, exciting, productive, collegial, supportive, me, especially the very successful collaborations moved to Vienna and consisted of a handful of of the year. Based on my Post-doc experience, often hard work, sometimes disappointing and with the laboratories of Wilfried Ellmeier, Peter brave people. When I left, CeMM had become a I feel prepared to start something new, prepared annoying, but most of the time relaxed and fun. Valent, Veronika Sexl (all MedUniVienna), Jan flourishing eight-story institute with a beautiful to mentor other people as I have been mentored Cools (University of Leuven) and Shohei Koide façade and more than 100 scientists from 29 and prepared to create a working atmosphere that Overall the ‘package’, if you start as a Post-doc (University of Chicago) were among the very countries. I was surprised how well people from will foster exciting discoveries. is very good and very competitive compared to highlights of my time at CeMM. The latter two scientific backgrounds as diverse as clinical medi- many other places in the world: I guess that I do collaborations included visits of two months by cine, chemistry, bioinformatics or proteomics not have to argue too much that Vienna is a fan- Kim de Keersmaecker and John Wojcik in Vienna can actually interact and cooperate, although this tastic (in terms of quality of life) and quite afford- that, despite their short duration, set the founda- cooperation always required an extra effort. I was able (rent, culture, sports, eating/drinking) place tion for a number of papers that were published also surprised to witness a team spirit grow that to do a Post-doc. What is probably more impor- or are in the process of preparation. Both visits at least for now is unsurpassed in my professional tant is that I never had to worry about money were strongly encouraged and supported by life. Scientifically, I felt that CeMM provided when planning an experiment and therefore Giulio, and both Kim and John have been cordially almost unlimited resources for my research, could concentrate my energy on science and did welcomed by our lab. both in terms of advice from mentors as well as not have to make any compromises. Of course, in terms of funding, that allowed me to address the majority of Post-docs are funded at least for Finally, what advice can I give to those who fundamental questions in current immunology. most of their time at CeMM by fellowships or plan to find a PI position after their Post-doc I especially appreciated the chance to co-tutor through grants that they apply for. This is not time at CeMM? Is there ‘the right time’ to start PhD students as it was a great experience to share only something important to learn, but also grati- looking for a job? From my experience, this is the excitement of a novel finding as well as the fying. Something else that is worth mentioning hard to evaluate. Clearly, the time shortly after frustration about an experiment that did not and different from many other places is a relative- having published a good paper is a good time. work out as anticipated. ly early level of independence and responsibility On the other hand, you need to be flexible and one gets as a Post-doc in Giulio’s lab. Tutoring be ready to apply for jobs once they are adver- and mentoring of diploma/Master’s and PhD stu- tised. Especially in the these times of financial dents, as well as technicians, became an integral insecurities in science funding world-wide, the and pleasant part of my everyday duties and is a institute you are interested to work at may not very good preparation to start your own lab. In have advertised positions for the last two years Left: a way, I always described my time as a Post-doc and probably will not do so for the next two Dr. Oliver Hantschel, Post-doctoral Fellow in in Giulio’s lab as being semi-independent. It was years. So, do not miss chances. Furthermore, Giulio Superti-Furga’s a bit like running my own small group with all although we do not want to admit this, we are ­laboratory at CeMM from 2004 to 2011 the good things (scientific freedom, strong men- all much more specialized than we think we are, Nationality: German toring, having enough people and money), but and most institutes that offer jobs have already a Age: 34 almost none of the bad things (administrative very specific set of qualifications in mind. So one Research Interests: ­Signaling mechanisms burdens, worries on long-term stable financial needs to be patient and it might take longer than and novel treatment support). This environment enables to prepare you think. After searching for jobs for almost ­strategies for hematological ­malignancies for an independent career and hopefully will two years and rejecting a few offers, I can say that Major publications in prevent me to make certain mistakes in my own it was worth waiting! I have now a position as PNAS (2009) and lab that will inevitably happen if you do things a tenure-track assistant professor at the Swiss Molecular Oncology (2008). for the first time. Institute for Experimental Cancer Research under Right: the new directorship of the world-renowned Dr. Tilmann Bürckstümmer, cancer researcher Doug Hanahan at the École Post-doctoral Fellow in Giulio Superti-Furga’s labo- polytechnique fédérale de Lausanne and was ratory from 2005 to 2010 awarded the first ISREC Foundation Chair in Nationality: German Age: 33 Translational Oncology. I have a long-term job Research Interests: perspective, excellent quality of life, secure and Innate immune sensing generous funding, and I am working at a prime of foreign DNA Major publications in research university with a dynamic, international Nature Methods (2006) and and interdisciplinary faculty. Here, I am trying Nature Immunology (2009). to continue what I have learned at CeMM (and which was the reason I wanted to work there) – to bridge basic and clinical research in haemato­ logy. I am recruiting PhD students and Post-docs and it would be fantastic if I could attract some CeMMies to join my lab. I look forward to maintain ties with CeMM and Vienna through on­going and future collaborations.

http://hantschel-lab.epfl.ch/

Ce — M­—M­— Research Report 2010 90 91 “Despite the economic turmoil in the last years, the government has been able to still strengthen the financial support for Science in Austria. CeMM is one of the lightning towers in Austria devoted to close the gap between basic research in molecular sciences and the needs of ­patients. The new building crowns the Govern­ment’s dedication to this extra­ ordinary project, the support to the Austrian Academy of Sciences and the collaboration between the city government and the Ministry of Science and Research. CeMM is not only a place to do excellent science but it is also an investment in the edu­cation of the next generation’s medical ­doctors and biologists. We have great hopes for the success of CeMM ­maybe as a role model for collaborations with the other medical universities in Innsbruck and Graz, but also in different fields. We will continue to ­support CeMM, ­following the rule ‘only the plants tendered can bring fruits one can harvest’.”

Dr. Beatrix Karl Austria’s Federal Minister of Science and Research Karl Landsteiner: Speaker Helen Hobbs A Formidable Hero of Molecular Medicine with Giulio Superti-Furga CeMM and the young artist Karl Landsteiner was born in Vienna, Austria Benedikt Hellsberg during the lecture in the Festive in 1863. Although he trained as a chemist and Hall of the Austrian earned his medical degree from the Universi- Academy of Sciences. Karl ty of Vienna at the age of 23, Karl Landsteiner is best known as an immunologist. In 1930, Landsteiner he received the Nobel Prize in Physiology or Medicine for discovering the four differ- ent human blood groups. Furthermore, his Lecture work with Alexander Weiner uncovered the rhesus factor in blood cells in 1940. Along with other colleagues, he was one of the first to convincingly demonstrate that polio was caused by a virus, as well as being the first to successfully culture the causative agent of typhus, both of which dramatically advanced the study of these serious human diseases.

Following his death in 1943, an obituary was published in the journal Science, writ- ten by Michael Heidelberger who has been described as one of the fathers of immunol- ogy. Indeed, throughout his life Heidel- berger was proud to state that he first learned immunology from Landsteiner. In the obitu- ary, Heidelberger presents Landsteiner’s most remarkable scientific achievements, as well as painting a picture of a man who was both an energetic scientist and a competent piano player with a love of music.

In honor of Karl Landsteiner’s remarkable achievements, CeMM established the Karl Landsteiner Lecture series in 2007, as an annual event held at the Austrian Academy of Sciences. The speaker is selected by all mem- bers of CeMM for being a pioneer in molecu- lar medicine. In 2010, the honor was awarded to the American geneticist, Helen Hobbs.

Previous Awardees 2009 Vishva Dixit: “Death Receptors, Ubiquitin Editing and Inflammasome Function”. 2008 Kári Stefánsson: “Genetics of Common Diseases in the Context of Human Diversity”. 2007 John Kuriyan: “Regulatory Mechanisms in Protein Tyrosine Kinase Signaling”. 94 95 Helen Hobbs is a Howard Hughes Investigator The Lecture Cholesterol and Coronary Heart Disease at the University of Texas Southwestern and Hobbs first informed the audience, consisting of The second story focused on the contribution of Director of the McDermott Center for Human both scientists and the general public, that she genetic variation to plasma cholesterol levels. It is Growth and Development, in the U.S. She always begins her genetics lectures to the under- clear that industrialized populations have higher previously worked with Michael Brown and graduate students at the University of Texas levels of cholesterol in their blood that increase Joseph Goldstein, who jointly received the Southwestern by introducing Karl Landsteiner with age. Previous work by Brown and Goldstein Nobel Prize in Physiology or Medicine in 1985 and his work, and proclaimed him to be a hero of had shown that mutations in the LDL (low for their discoveries of the regulation of choles- hers. She went on to tell a couple of stories about density lipoprotein; a cholesterol transporter) terol metabolism. Now independent, Dr. Hobbs’ her work linked to two important human diseases: receptor causes an increase in blood cholesterol main research interest is the genetics of lipid fatty liver disease and coronary heart disease. levels and a subsequent increased risk of coro- metabolism and its link to obesity and associated nary heart disease. In fact, there is a fifteen-fold human diseases such as atherosclerosis, which Identifying Genetic Causes of Fatty Liver Disease increase in the incidence of coronary heart disease is directly related to the research of Christoph Fatty liver disease is characterized by triglyceride in the US as compared to rural China. Hobbs Binder at CeMM. deposits that accumulate in liver cells, and is wanted to find out why. caused by multiple factors including obesity and Understanding lipid metabolism is indispensible excessive alcohol consumption. The disease Earlier work had shown that the levels of a for the research in the Binder lab. Dyslipidemia progresses from steatosis to steatohepatitis, protein known as PCSK9 was closely linked to and inflammation are partners in crime in athero- which is characterized by inflammation, and cholesterol levels in mice. Using the individuals genesis. They cooperate and can modulate each finally to life-threatening cirrhosis and irreversible from the Dallas Heart Study, Hobbs and other’s function. Understanding this interaction liver damage. Hobbs was interested in identifying colleagues looked for mutations in the PCSK9 will help uncover the mechanisms by which cho- genes that may influence the deposition of fat in gene that were associated with blood cholesterol lesterol leads to atherosclerosis and help explain the liver and thus affect an individual’s suscep- levels. They found a loss-of-function mutation why certain individuals with identical cholesterol tibility to the disease. Along with Ronald Victor predominantly in African Americans that was levels develop coronary disease differently. and other investigators in Dallas they designed associated with a 28% decrease in plasma LDL the Dallas Heart Study to identify ethnic differ- levels. Life-saving drugs such as statins lower Two Memorable Performances ences in cardiac health. Over a period of 8 years, cholesterol levels and are widely prescribed to Both Dr. Hobbs and her husband were invited the scientists performed over 3,500 measure- individuals at risk of heart disease. The goal now to Vienna, where they were taken to the famous ments and interviews on around 5,000 Dallas is to use the knowledge about PCSK9 to develop Musikverein to hear a memorable performance residents to search for genetic variants linked to new therapeutics to further reduce an individual’s of Beethoven’s Ninth Symphony by the Vienna liver fat content. They found that over a third of risk of developing these progressive and chronic Philharmonic Orchestra conducted by Christian the individuals had excess fat in their liver, which diseases, and to do so at an early stage of develop- Thielemann, without any doubt one of the high- is perhaps not surprising given there are 35 fast ment, perhaps in combination with statins and light musical events of the year. The following food restaurant of a particular famous chain in better education on healthy eating and lifestyle day, Helen produced her own memorable Dallas alone, and cities in Texas consistently rank changes. performance by presenting the Karl Landsteiner at the top of obesity tables in the US (Source: Lecture entitled: “Genes Versus Fast Food: American Obesity Association). Finally, Hobbs made it clear that these are Eat Drink and Be Wary”. diseases of dietary excess, but changing the diets In this cohort, Hobbs identified ethnic differences of Westerners has not proven to be so easy. The event was held in the Festive Hall of the in the prevalence of hepatic stenosis. Hispanics Her work has led to significant insight into Austrian Academy of Sciences. There was were more likely than those of European descent the contribution of our genes to several severe classical music performed on the cello by to suffer from the disease, with African Americans human diseases, and as such makes her truly a Benedikt Hellsberg, the sixteen year old son of the least likely. By comparing the fat levels in the pioneer in Molecular Medicine and a popular the current Chairman of the Vienna Philharmonic liver to genetic markers in each individual they recipient of the 2010 Karl Landsteiner lectureship. Orchestra, accompanied by Eva Ulrich on the identified a correlation between fatty liver disease piano. They played Robert Schumann, and sequence variations in a gene encoding for Fantasiestücke op. 73, and Camille Saint-Saëns PNPLA-3, of largely unknown function. They “The Swan” from “Carnival of the Animals”. found that having a specific variation in PNPLA-3 The lecture was attended by some 200 people, could strongly predispose an individual to fatty and was followed by an after-party with finger liver disease, particularly in association with a food and wine to accompany the interesting poor diet. Further investigations on the actual discussions. cellular function of PNPLA-3 have also been performed in the lab, and uncovered an increase in protein levels on eating, and localization to lipid droplets in liver cells.

Ce — M­—M­— Research Report 2010 96 97 In 2010, Dr. Benedikt and Beatrice Spiegel- George Poste during his feld founded the Constantin Spiegelfeld lecture in the seminar room CeMM Lecture in memory of their son. The of CeMM. lectures will be bi-annual events held at CeMM. The lecture series addresses the Constantin complex world of therapeutics, from the research challenge to their impact on Spiegelfeld society. Topics will range from the drug dis­covery and development process to marketing and health costs issues, includ- Lecture ing drug compliance, adverse effects, safety and ethical aspects. The series wants to help familiarize the community and inter- ested laymen with the complexity of the issues in question and provide education on the responsi­bility that society and politics share with the re­search community and the pharmaceutical industry. After each lecture, the events foster a forum for debate of controversial issues. The First Lecturer The Key Present and Future Aspects The world-renowned scientist and health George Poste is currently Chief Scientist of the of Global Healthcare Complex Adaptive Systems Initiative (CASI), George Poste’s lecture focused on a changing manager George Poste from Arizona State which addresses global health challenges by world, both from a disease and a treatment per- University, U.S., gave the first Constantin promoting cross-disciplinary relationships. spective. In terms of disease, there has been a Spiegelfeld Lecture. “Genomics, Demo- He is also Professor of Health Innovation at continual emergence of new diseases, such Arizona State University (ASU). From 1992 to as SARS (severe acute respiratory syndrome), graphics, Epidemics, Economics and Ethics: 1999, Dr. Poste was President of Research and which became a near pandemic in 2002, and the The Complex Forces Shaping Therapeutic Development at SmithKline Beecham, one of the worrying increase in drug resistant pathogens. Innovation and Investment” was presented world’s largest pharmaceutical companies, where Changes in global parameters, such as increased he led the registration of 31 clinical products for transport and trade, and the average age of the th at CeMM on November 8 2010, an event marketing approval. He has won several high population, also contribute to shifts in the which was co-managed by three CeMM profile awards including the 2009 Scrip Lifetime impacts of current diseases. Achievement award, which honors the brightest PhD students. The Spiegelfeld family stars of the pharmaceutical and biotechnology Not only is the disease landscape changing, but joined an audience of around 150 physi- industry, and in 1999 was awarded the title also the technologies that are available to the cians, scientists, sociologists and artists for Commander of the Order of the British Empire healthcare community for diagnostics and treat- th by Queen Elizabeth II. ments. There has recently been a rapid develop- the lecture, which was held in the 8 floor ment of new technologies in the scientific com- lecture hall. The decision to ask George Poste to hold the first munity, which nevertheless, must still fit in with Constantin Spiegelfeld Lecture was made by a available healthcare resources. Within this con- panel consisting of Giulio Superti-Furga from text, George Poste spoke of the increasing cost CeMM, Michael Freissmuth and Markus Müller, of healthcare and highlighted the importance of both pharmacologists at the Medical University using the limited resources to promote healthy of Vienna, along with CeMM PhD students living as well as managing disease. Indeed, as he Dimitris Tsiantoulas, Iris Uras and Georg pointed out, twenty percent of the population Winter. Upon his arrival, Dimitris, Iris and Georg spends eighty percent of the healthcare costs, so showed George Poste and his partner around the it pays to keep the healthy people healthy. city, before they met with Giulio and the Spiegel- feld family for dinner and a concert. On the day of the lecture, Dr. Poste had lunch with the rest of the CeMM PhD students and met with the CeMM PIs, as well as giving an interview for the Austrian newspaper “Der Standard”.

98 99 Personalizing Medicine Science Fiction or Science Fact? Around 150 guests The lecture highlighted an important factor shap- The lecture provided an interesting glimpse into joined the first Constantin ing the future of healthcare: the development how we will likely be dealing with our daily Spiegelfeld lecture of George Poste. and implementation of so-called personalized health in the future. Although it sounds like sci- medicine. This concept has emerged from the ence fiction, some of this technology is already knowledge that no two diseases are exactly the available. For example, there are companies same, and indeed neither are the individuals car- developing wireless devices for monitoring an rying those diseases. Both of these factors directly individual’s health status in real time. This will and critically influence our ability to successfully involve the use of microchips implanted in our treat disease. It is becoming clear that a ‘one-size- bodies, measuring parameters such as heart rate, fits-all’ approach to disease treatment is no longer blood pressure and cholesterol, which will enable appropriate. Indeed, high costs are associated the external monitoring of our health and lead with using treatments that are ineffective in cer- to a rapid response upon detection of any abnor- tain patient groups, as well as, more importantly, malities. This type of approach could also be used a high risk to patients, given the potential for to help us monitor our own health status, by for toxic or even lethal side effects. example linking the sensors to a mobile phone or similar device to tell us if we are eating the right The advent of ‘next generation’ technologies foods and getting enough exercise. In another means diagnostics have become more sophis- area, there are many approaches being developed ticated, thereby enabling detailed profiling of for tackling the serious problem of individuals individual patients at the genomic and proteomic not taking their medication properly. One com- levels. This means each patient can be measured pany has designed smart caps for medicine dis- for factors such as specific genetic mutations pensors, so that, rather than having to remember or protein levels that may influence how they what pills to take when, our medication has its respond to a specific drug or how a disease will own timer and alert system to help remind us. progress. This information can then be used to George Poste with design a customized treatment approach. So, Conclusions Deborah Carstens and the drugs will only be used in patients where they are George Poste’s lecture was incredibly well students committee. most likely to work and to be safe, ultimately sav- received and has set the bar for the next ing lives and costs. ­Constantin Spiegelfeld Lecture very high. It was followed by an exciting roundtable and forum Connecting with CeMM discussion, chaired by Giulio Superti-Furga CeMM is investing in technologies and research with a panel consisting of CeMM PhD student that add to the knowledge base that will be criti- Iris Uras, and Michael Freissmuth and Markus cal for the development of truly personalized ­Müller from the Medical University. Discussions medicine. For example, Sebastian Nijman’s group focused on personalized medicine – what it is and is investigating how genetic mutations that cause why it’s needed, as well as how society needs to cancer can influence the response of cells to cer- better prepare for the associated ethical, political tain drugs, which could reveal which cancer types and biosafety issues. Finally, discussions contin- respond best to specific treatments. Scientists ued more informally over cheese and wine in the in Giulio Superti-Furga’s lab have been analyz- adjacent room, accompanied by a tremendous ing the effects of drugs on cells by identifying evening view over the city of Vienna. the proteins to which they bind, which can help identify potentially severe side effects or new disease indications.

Ce — M­—M­— Research Report 2010 100 101 25.01.2010 02.08.2010 09.11.2010 29.11.2010 15.12.2010 Roderick L. Tobias Stuwe Ajay Chawla Hamid Bolouri Impromptu CeMMinar Beijersbergen “The FACT Complex “Immune Determinants “Making the most Roel Verhaak “The RNAi strategy in is a Multi Histone of Metabolism and of personal genomics “Integrated genomic target identification: Chaperone-containing Regeneration” in medicine” analysis of data from Series Hitting cancer where Chromatin Reorgani­ Stanford University Fred Hutchinson The Cancer Genome it hurts most!” zation Complex” School of Medicine, USA Cancer Research Center Atlas provides clinical The Netherlands European Molecular in Seattle, USA and biological insights Cancer Institute; Biology Laboratory 10.11.2010 in serous ovarian cancer Amsterdam, NL (EMBL), Heidelberg, D Impromptu 10.12.2010 and glioblastoma” A new system for Seminars and Lectures Young-Hwa Song CeMM Science Day MD Anderson Cancer has been installed in 2010. CeMM has a 15.02.2010 14.10.2010 “Novel molecular The Science Day is Center, Houston, USA Barbara Kazmierczak Francesca Ciccarelli insights into the old meant to provide dedicated budget to invite international “The cost of virulence: “Genomic Instability and tuberculin skin test an overview of the 20.12.2010 speakers on a regular basis to give a talk Innate immune re­– the Evolution of Cancer” and its association to research projects at Andrew Bowie to CeMM members and the scientific and cognition of the type 3 European Institute of secretion machinery” CeMM and to present “Sensing and signalling secretion system of Oncology, Milan, I European Molecular current themes in anti-viral innate medical community of Vienna. In addition Pseudomonas Biology Laboratory accessible also to immunity” the guest is asked to participate in a lunch aeruginosa” 28.10.2010 (EMBL), Heidelberg, D lay people School of Biochemistry meeting with CeMM Post-docs, a “Meet Yale University Impromptu and Immunology School of Medicine, Jörg Hackermüller 16.11.2010 13.12.2010 Trinity College Dublin, IRL and Greet” session with the students right New Haven CT, USA “Cell cycle, oncogenic Impromptu Stefan Knapp after the seminar. The duties and honor of and tumor suppressor Francesco Gervasio “Selective targeting of being a host is shared within the Faculty. 08.06.2010 pathways control the “Combining Free Energy protein kinases using Thomas Rattei expression of long Computations and parallel screening and “In silico interpretation and macro non-protein Experiments to Study large scale structural In 2010 we had the pleasure to invite and of microbial (meta-) coding RNAs” Large Scale Dynamics comparison” host the listed CeMMinar and Impromptu genomes and its Fraunhofer-Institut für and Conformational Nuffield Dept. Clinical improvement through Zelltherapie und Immu- Selection in Proteins” Medicine, University of speakers. proteomic data” nologie IZI in Leipzig, D Head Computational Oxford, UK Department of Compu- Biophysics, Spanish tational Systems Biology, National Cancer University of Vienna, A Re­search Center, Madrid, E

CeMMinar Speakers Hamid Bolouri signing books, Francesca Ciccarelli, Young-Hwa Song with students, CeMM student Damla Olcaydu at the Science Day.

102 103 “With its reputation for scientific excellence and its prime location within the Vienna medical ­campus, CeMM provides the perfect frame- work for a popular lecture series aimed at raising awareness of the world of pharmaceuticals, from ­discovery and development to use, misuse and side effects, as well as general issues on ethics and society. We would like to thank CeMM and especially Prof. Dr. Giulio ­Superti-Furga and the members of the board for their help and for ­organizing the Constantin ­Spiegelfeld Lectures in memoriam of our son. We believe the first ­lecture by well-known scientist Prof. George Poste made an ­impressive contribution to fostering a better understanding of the ­effects of drugs.”

Dr. Benedikt and Beatrice Spiegelfeld Sponsors of the Constantin Spiegelfeld Lecture CeMM students enjoying Brno, visiting Mendel CeMM museum and discussing self-definition posters. Retreat

In 2010, the institute’s annual retreat was held in Brno in the Czech Republic, which is around 130km north of Vienna. Brno was chosen because of its strong link with genetics: Gregor Mendel performed his infamous experiments on plant breeding in a monastery in Brno between 1856 and 1863. Mendel was both a monk and a scientist, and is hailed as the father of modern genetics. By cross- breeding individual pea plants, he was able to follow the inheritance patterns of various traits, such as flower color and The retreat was held in a modern city center hotel Everyone was required to make a small portable seed shape, the results of which he used to with a generously sized conference hall for all poster, including administration and members of the talks, discussions and social gatherings. After the IT department, to briefly and clearly describe generate several laws of inheritance. dinner on the first evening, following Director his/her work at CeMM. A ‘speed dating’ session These experiments and Mendel’s laws are Giulio Superti-Furga’s opening address, each PI involved randomly pairing individuals and giving taught to every genetics student at and team leader gave a short 10 minute scientific them 10 minutes to try to find some common presentation. Each described his or her research ground and a potential new collaboration. university, and a visit to the monastery in a broad context, linking it to molecular medi- site and Mendel museum was an incredibly cine and the mission of CeMM, as well as outlin- As expected, the social program rivaled the special start to the retreat. ing the major challenges in the field and his/her scientific one. There was a lot of elaborate fancy scientific ambitions for the coming five years. dress and various party games, including a talent show, and some very interesting medieval The following morning there was a brainstorming dancing where all PIs and senior staff were session where people were split into four dressed up in traditional costumes. The retreat groups. Each group was given a specific topic lasted 2 days, and it is an important event in the for discussion: Institute’s calendar as it enables close interaction 1. “Making CeMM more medical” between all CeMM members in a more informal 2. “Systems biology at CeMM” setting, as well as being a lot of fun. 3. “How to best use CeMM’s technology” 4. “CeMM and my career” The aim was to generate concrete strategic ideas to address the points above and it was followed by a flip-chart presentation and an open discus- sion. It shows how the opinion of each person working at CeMM is valued, and that the success of the institute is viewed as a collaborative effort. There were also two special guests who gave talks in the afternoon and joined in with some of the discussions. Gottfried Himmler, a biotech start-up veteran, gave a fascinating talk on his experiences in the biotechnology industry, and Helen Pickersgill, editor at the journal Science, gave some tips on how to write manuscripts for publication.

106 107 CeMM first Barbecue On a balmy August night CeMM CeMM fellows, families and friends met to celebrate the more or less stressful but in the end exceedingly pleasing move into the new building. The breathtaking Social Activities view over Vienna, a tasty barbecue, relaxed parents and lucky children made the first get-together on the terrace a memorable event.

Outing to Rax 2 coaches, 1 hour bus trip, 10 minutes cable car ride, 50 minutes walk, 2.000 meters above sea level, no effort for passionate hikers and no sweat for 100 CeMMies – on October 8, 2010 CeMM took pleasure in “climbing” Rax, one of the high mountains near Vienna. Bright sunshine and high spirits were the best background for a compe- tition between two choirs that were spontaneously assembled in the buses. No doubt: CeMM people once more showed their talents, their capacity for team work and creativity in finding the best solutions within a limited time.

108 109 Halloween Ball Christmas Party “Work hard, party hard”, No doubt: The Christmas could have been the slogan party in the new building for the 1st Halloween ball was the highlight of the first at CeMM. The organization season in the new CeMM was part of the duties and building. Families and responsibilities of the new partners were also invited PhD. students. And they did to join the buffet, the it exceptionally well: with show program and the fancy dresses from horror subsequent dancing party. (not suitable for children) to Santa Claus brought lambkin, an amazing buffet presents for children, but with regional specialties, also each adult found a perfect dance show and a a present under the tree motivating DJ! Even CeMM through an entertaining SAB member Hidde Ploegh, potluck system to which who was giving a lecture in everybody contributed. town and passed by, was The amusement lasted well very impressed. One might after midnight. And it say they set a new bench- seems, that CeMM was born mark for social events at under a lucky star. CeMM.

Get-together Anna Spiegel/CTR – CeMM CeMM is working next door to the Center of Transla- tional Research (CRT) in the Anna Spiegel Research building of the Medical University of Vienna. To be accurate: CeMM and Anna Spiegel/CRT share a combined building with a common entrance. To encourage a collaborative spirit and to keep on good terms with each other, a monthly get-together was established. Starting with a jolly feast in October 2010 the monthly event has grown to be a scientific as well as a social highlight for both Institutes. CRT people have free access to CeMM with their door cards. Many informal meetings happen during lunch in the CeMM Cafeteria.

Ce — M­—M­— Research Report 2010 110 111 “Investment in education and ­research is critical for the progress of a modern and just ­society. The Austrian Academy of Sciences fulfils an important role in providing a powerful source of in­ dependent research and ­innovation. One of its latest ­institutes, CeMM, promises to help bring about the translation of knowledge into medical practice and to energize medical research.”

Dr. Hannes Androsch Chair, Austrian Council for Research and Technology Development Senator, Austrian Academy of Sciences CeMM Art Façade

At the geometric center of one of the largest medical sites in Europe now stands the new custom-designed nine-floor CeMM building, which, by the end of summer 2010, was filled with research groups and open for business. The building itself is striking. It was designed by architect Ernst Kopper who created a building full of light with much open space for the needs and comfort of modern molecular biology laboratories as well as room to house sophisticated high-tech scientific equip- ment. One side of the building is adorned by a stunning glass façade, designed by Austrian multi-media artist Peter Kogler. This modern look makes it stand out in sharp contrast to the neighbouring build- ings of the Medical University of Vienna, which were built around the turn of the last century, and the adjacent looming towers of the Vienna General Hospital. Planting a Seed So, how does one come up with a design that One could say that the CeMM building seed was would literally become the face of a biomedical planted when its location was first proposed, in scientific institute? Fortunately artist Peter The Building The Façade December 2000. The city authorities offered Kogler had always been interested in the history the Austrian Academy of Sciences a site on the of science and what goes on in research. His Architect: Artist: premises of Vienna’s General Hospital (AKH), design was inspired by some of the topics that which was supported by the Austrian Council are studied at the institute, namely networks of Ernst M. Kopper Peter Kogler for Research and Technology Development and molecules and cells. The artist was known for the Ministry of Science. The site had originally having depicted networks at the Documenta been earmarked for the dental clinic in the 1970s. Kassel, when awareness of the Internet first However, the dental clinic was eventually built started to emerge in the 90s. As CeMM Director Location, Location, Location Technical aspects of the façade The following list of sponsors is also visible on a different site, leaving the area free, and with Giulio Superti-Furga explained, proteins, which The CeMM building is situated at the heart of a Duration of façade building: on a stainless steel plaque the help of the Mayor of Vienna Michael Häupl are the molecules that perform most of the medical research campus housing the Vienna February 2009–February 2010 in front of the façade. and city counsellor Brigitte Ederer, it was finally functions in cells and organisms, work in groups General Hospital (AKH) and the Medical Uni- Material: 400 m²enameled glass Gustav Ammerer allocated to CeMM. that are interconnected to form large molecular versity of Vienna. The building itself is physically Graphics applied by screen printing, the motif Bernd and Christa Binder networks. CeMM scientists have been uncovering linked to the Anna Spiegel research building of is applied to the glass surface using enamel, Christoph Binder Max and Margaret Birnstiel After planting the seed, the building could the composition and function of some of these the Medical University by connecting doors on which is subsequently baked onto the glass Martin and Lucrezia Böhm begin to grow. The ground-breaking event took networks, which in turn can help scientists each floor, and is also linked to the hospital via Glass thickness: 44.2 mm Erhard Busek place on 19th September 2002 and, after some understand why and how disease occurs. How- an underground corridor. This prime location Glass weight: 57.4 kg /m² Meinrad and Irene Busslinger Georg and Maria Rita Casari unforeseeable delays, the concrete shell of the ever, the façade deliberately does not attempt enables CeMM researchers to interact closely Production: Steindl Glas GmbH Helmut and Helga Denk building was eventually completed at the begin- to reproduce a particular network. It is rather a with clinicians and the medical faculty, which Sponsoring project management: Heinz and Margit Fischer ning of 2009. This topping-out event was celeb- model of a possible, theoretical biological supports CeMM’s mission to “combine insight Giulio Superti-Furga Michael and Margarita Freissmuth rated by the construction workers and CeMM’s network, ranging from the microscopic to the obtained from basic and clinical research and use Number of sponsors: 50 Annabelle, Tara, Constantin faculty, along with the then Minister of Science macroscopic and even organism scale. it to implement the development of innovative and Paul Habsburg-Lothringen Johannes Hahn and Research, Dr. Johannes Hahn, on March therapeutic and diagnostic strategies”. Michael Häupl 24th, 2009. From mid 2009 till completion, the Assembly of the 400m2 glass façade took Christian J. Herold appearance of the building kept evolving, as it got 12 months, and its completion was celebrated Building Facts and Figures Erika Jensen-Jarolim Beatrix Karl covered in glass little by little. The large windows in a style to match the grand design. Because of The main entrance of the CeMM building is Reinhard Krepler now provide substantial amounts of natural light its location, the façade can be seen by hospital shared with the complementary laboratory of Ernst M. Kopper Klaus Lechner for the people working inside. visitors, patients, staff and students, amounting the Medical University of Vienna. There is an Jürgen Meier to many thousands of spectators each year, and additional entrance leading to the main stairway Laurenz and Waltraud Niel The Art Façade will likely become a city landmark. CeMM is and the “service” elevator, for persons and goods. Sebastian Nijman and Helen Pickersgill Architect Kopper had always envisaged the large especially grateful to the 50 individual sponsors There are eight floors with an overall floor space Primus and glass façade at the eastern end of the building as that supported this art and science project. The of 5,620 m2. A similar floor plan repeats itself on Katharina Österreicher Elisabeth and a sort of membrane representing the interface existence of the façade also symbolizes the deter- almost all levels. The laboratories face south and Helmut Pockberger between what had to occur inside the building mination and support of the Ministry of Science are open-plan, with working places for some 20 Maria Polsterer-Kattus and its environment. The art façade has its own and Research, the Austrian Academy of Sciences, people. Along the windows there are desks with Barbara Prammer Georg and Martina Prantl story. CeMM scientific director Giulio Superti- the Medical University of Vienna and the Vienna computer workstations. On the north side of Ursula Schmidt-Erfurth Furga was inspecting the construction site in General Hospital, which together have made most floors are rooms for specialized laboratory Wolfgang Schütz November 2008 as the first floors were emerging, CeMM a new collaborative paradigm for medical facilities as well as more offices for scientists and Constantin Spiegelfeld Georg Stingl because it occurred to him that such a prominent research. administration, and a small seminar room. On Erich W. Streissler building deserved a strong esthetic statement. the top floor are two lecture rooms, a cafeteria Giulio and Stefanie Superti-Furga He consulted his wife Stefanie, an art historian, The Finishing Touches and a common office. Two large terraces provide Peter Swetly who listed a few artists that would be particu- The rest of the building was completed in exceptional views over the city. For a ‘virtual’ tour Witold and Claudia Szymanski larly suitable. One in particular, Tyrolean and summer 2010, when the research labs were able of the building, please turn to the research pages Iris, Zambak and Abdurrahman Uras Viennese artist Peter Kogler, was having a large to move in. The first in was the Barlow lab, of this report. Erwin Wagner retrospective show at the MuMOK that month. which moved from across the city in the third Herbert Watzke Klaus Wolff Superti-Furga visited the exhibition the same day, district where they had been renting space in the Nikolaus and Gabriele Zacherl got transfixed by what he saw and immediately Max F. Perutz Laboratories. The rest of the labs Franz Zwickl became obsessed with the possibility of winning came from closer by, and most of the equipment General Hospital of Vienna CeMM Administration the artist over for a CeMM art project. As fate was wheeled or carried through the medical CeMM Barlow Lab would have it, the same evening, Martin Böhm, campus and into the new building. Moving some CeMM PhD Students CeMM Post-doctoral Fellows director of the Dorotheum, was able to seat of the larger and more sensitive pieces of equip- Medical University of Vienna Giulio vis-à-vis Peter at a charity dinner. This is ment, such as the mass spectrometers, required Austrian Academy of Sciences where the first contact occurred. Discussions careful planning to ensure minimum disruption STRABAG AG Department of Psychiatry and early in 2009, between the artist, the architect of ongoing experiments. The last of the groups Psychotherapy of the and the scientific sponsor, soon focused on the were installed in September 2010, in time for Medical University of Vienna façade as an ideal surface for an object of art. some informal celebrations on the roof terraces in Vossius & Partner Reportedly, the enthusiasm was so strong that the last of the summer sun. The official opening Superti-Furga became confident that a sponsoring of the CeMM building took place in 2011. campaign would be feasible.

Ce — M­—M­— Research Report 2010 116 117 Celebrating Round the New Table Landmark Façade Discussion

With a flash, the façade was completely bathed Among the well-wishers were the Rector of The architect, the artist, the ­scientific ­director: in light: sponsors and prominent guests gathered the MUW Prof. Wolfgang Schütz, AKH Director a conversation on the building and the façade in front of CeMM and cheered at the first illu- Prof. Reinhard Krepler, former presidents of mination of Peter Kogler’s 400 m2 piece of art. the Austrian Academy of Sciences, Prof. Werner Giulio Superti-Furga From our point of view, It was the climax of the ceremonial inauguration Welzig and Prof. Herbert Mang, the newly-elected the CeMM building is tailor-made and almost of the CeMM art façade, which took place with president of the ERC Prof. Helga Nowotny, ideal for its purposes. We had an opportunity some 200 participants in a tent at the foot of the numerous architects, museum directors and to take part in floor plans and lab features. But new building. Following the welcome addresses artists, including Anna Jermolaewa, Herwig the planning started long before. What was the of CeMM scientific director Giulio Superti-Furga Kempinger, Hans Kupelwieser, as well as far focal idea of the building? and artist Peter Kogler, a speech by Federal too many research partners and friends to be all Minister of Science and Research, Dr. Beatrix mentioned. Following behind a press conference Ernst Kopper The idea was to fit the building Karl, hailed the importance of basic research for in the morning, which was widely covered by the into an important urban axis, which runs from medicine and innovation, stressed the pivotal media, the evening event was an extremely west to east across the campus. The 66 meter long role of CeMM on the medical campus and successful testimonial for cross-cultural integra- building includes two laboratory sections. Two congratulated on the successful merger of art tion and a celebration of the creative impetus thirds of the building are provided to the Medical and science. common to art and science. University, one third to CeMM.

Giulio Superti-Furga Two entities, one building – are there particular challenges?

Ernst Kopper For the architect, the complexity was to have one body with two distinguishable entities. So it was clear for me to form the concept of the main building for CeMM to implement certain features: It is the crown, the “headgear” of the building, an additional floor with wing- Giulio Superti-Furga What about the wings and shaped walls reaching outward to house the the spine. Is it an idea within a split second or the seminar rooms and the cafeteria and two terraces. result of long deliberations? Well-wishers and spon- Here happens everything that is exciting. It is sors followed the welcome indeed an essential part of any research building: Ernst Kopper There were some specifications, addresses of Minister Karl, Peter Kogler and Giulio space for communication and space for relaxation, not least because of the involvement of the future Superti-Furga and enjoyed with a view over Vienna. Another very prominent user. An asymmetric construction of the building, a memorable festivity. feature is the enclosure of the staircases, that north higher than south, causes a special dynamic. holds the hollow of the rest of the building like It was David Pasek who had the underlying idea a spine, like the ribs of a corpus. But architecture for the east façade. It came swiftly and was work- is always a combination of function and form, able over years. and the concrete structure of the staircase has to fulfil the earthquake standards for large buildings. Giulio Superti-Furga Were there any changes The twist, as can be seen from the small side of during the construction phase? the building facing east, depicts the bending of Spitalgasse outside the area. Ernst Kopper The entrance to the east was originally planned two stories high as it can still be seen from the outside. It was only decided later to abandon the main entrance on the east side in favour of a joint access to both parts of the building. But nevertheless the east façade is the eye catcher for all visitors, all the more because of Peter Kogler’s work of art.

Ce — M­—M­— Research Report 2010 118 119 Giulio Superti-Furga While there were some Peter Kogler Probably it is rather reflecting Ernst M. Kopper was tailbacks in the planning and construction phase, the way the tools were invented. You can born 1945 in Schulberg near Graz. After studying we quickly stepped forward in realising the art compare the simplicity of computer graphics architecture at Graz façade. Considering all the obstacles which had to in early times when only lines and circles were University of Technology he spent some diploma be pushed aside before this building took shape, available, the information visualized was sort and internship years in it was almost magical to experience the enthusi- of like a caricature. The developments in this Rome and Munich. Since asm on the part of AKH director Dr. Krepler, field were tremendous, and nowadays one can 1975 he lives in Vienna. Since 1984 he works as the ministry, the academy, the BIG, to have this calculate all kinds of shapes, forms, angles, views an independent architect, piece of art as a façade. as one wishes to. In architecture, a house drawn but also in co-operations, within the scope of with a ruler and a pen is totally different to the projects. He is special- Ernst Kopper A lot is said in Austria about one modern architects are constructing with ized in research buildings “Kunst am Bau” for public buildings. I believe that CAD – computer aided design. Look at the films and has realized among other things the Vienna CeMM is one of the best examples of how to in Hollywood. Without computer graphics you Biocenter, the Center for integrate great art into a building. From the hardly can make a film anymore. So to assemble Medical Research in Graz, beginning, there was a feeling that the CeMM the forms for the façade I used computers. If you lab buildings of the General Hospital of Vienna building is situated right at the beginning of the look at it you will be sucked into it or the picture and CeMM. AKH campus and that the façade should act like is popping out. You find a three-dimensional a membrane. It was this discourse between the structure, even hidden parts of the human body Peter Kogler was born in strictly regulated rectangular form and the often like arms, shoulders etc. Innsbruck, Austria in 1959, and currently lives in chaotic life around a hospital. This lucky combi- Vienna. He was one of nation with Peter Kogler’s imagination to fit Giulio Superti-Furga What else was determinant? the first artists to work with computers, and is the envisioned membrane sculpture led to the described as one of the perfect combination we can admire now. Peter Kogler For me the huge dimensions were most influential artists quite a challenge in choosing the right forms. of the nineties. Kogler has exhibited his work Giulio Superti-Furga For us the art façade is Of course, as an artist one is always developing internationally, including totem and symbol. It inspires us. Inward it one’s own style and moving on to new unknown exhibits at the 46th Venice Biennale (1995), provides shade, outwards it is sometimes trans- areas. The cognitive projection from the small the MOMA, New York parent, sometimes reflecting. Depending on form to a 400-fold magnification is daring even (2006), and in the Galerie the angle of light one can observe the pattern with the experience I had gained. A façade also Crone, Berlin (2004). His work is also often mirrored on the building in front. When the sun has to fulfil technical aspects, so that as an artist displayed at the MUMOK sets on the other side, through the glass “ears” you are limited in your choice of materials. (Museum of Modern Art) one sees a stripe of Emmentaler holes projected. in Vienna. The façade is alive, has its own dynamics. Giulio Superti-Furga It would be interesting what people think. Do they see any relation to Peter Kogler One important aspect was that the hospital, do they think it is frivolous, a kind Giulio gave me a lot of scientific pictures, a lot of of extravagance, which does not fit the sobriety input, which I mixed with my formal language. of patients and disease? Do they see a relation to So the form is nothing real, but sort of a model – research and education? And will it last? a visualization, a tool to uncover the unseen universe, which can only be detected with instru- Peter Kogler How long it will last is a question ments and is brought to our everyday world in that coming generations will have to decide on. the form of a model. So I was also experimenting As an artist I hope that this piece of art will sur- on how to translate the world of science into my vive. It was made within a certain time setup in a own formal language. It is an approximation, a certain cultural context. And it is also perceived replica repeating itself. The whole structure is out of this context. But the perception changes based on generated information and not on reality. constantly, so it is really hard to tell what people Top picture: Giulio Superti-Furga will feel and think in 20 or 50 years from now. with Ernst Kopper and Peter Kogler Giulio Superti-Furga It is amazing how it keeps But still, it will always serve as a façade. For the Bottom left: Ernst Kopper Bottom right: Peter Kogler changing all along, as one always finds a new art, interpretations may change. ­pattern. This may be due to the fact that each part holds much information. The eye has a lot Giulio Superti-Furga The whole project started to ­discover. One always finds different facets. when I saw your exhibition at MUMOK and It could be a jungle, algae, cells, molecules. fortunately became acquainted with you. I got Later, I discovered human body parts. I had not the idea that a piece of art might suit the CeMM noticed this before, but then they became quite very well. And it did. present. Reflections influence the way I look at and perceive it.

Ce — M­—M­— Research Report 2010 120 121 “When I was Vienna’s financial city counsellor, I remember vividly the initial discussions with Mayor Häupl and Academy President Welzig on the merit of starting an institute to tackle some of the ­research hurdles for the medicine of the future. Now molecular ­medicine, increasingly powerful diagnostic capabilities and virtual patient models are becoming more important by the day. I wish CeMM and its brand new building all possible success.”

Mag. Brigitte Ederer Member of the Executive Board of Siemens AG Management Roberto Sacco Damla Olcaydu Scientific Support Legend to grants Gen-AU APPIII DOC-fForte Fellowship Giulio Superti-Furga Sylvia Bolz DOC-fForte Fellowship Scientific Director Omar Sharif Ana Puda Wash & Media Kitchen Austrian Academy of Sciences MPD New Investigator Grant CeMM Directory Georg Casari Stefanie Sigel Sabine Jungwirth ERC i-Five Intellectual Property FWF I289-B09 Branka Radic Animal Research Technician European Research Council & Technology Transfer ­Advanced Investigator Grant Larissa Reis Paul Kletzl Michal Smida “­Interferon-focused Innate Gerhard Schadler Store Clerk Alexey Stukalov Elisabeth Salzer Immunity Interactome Managing Director Gen-AU BINIII Amisi Nyembo and Inhibitome” Federica Santoro Wash & Media Kitchen Sandrine Tonon* FWF 1207 DK RNA EU ASSET Principal Investigators EU Project “Analysing and Irena Vlatkovic Martin Schalling Denise Barlow Administration Striking the Sensitivities EU HEROIC Basak Senergin* of Embryonal Tumours” Christoph Binder Sonja Baier FWF 1718 Assistant EU Project HEROIC Robert Kralovics PhD and Diploma Students Amir Shahzada “Highthroughput Epigenetic Stephan Boos-Waldeck Sebastian Nijman Klaudia Bagienski FWF W1205 (CCHD) ­Regulatory Organisation Finance & Controlling In Chromatin” Dimitris Tsiantoulas Sylvia Knapp Mario Biaggio Angelika Eisner MUV EU Marie Curie Project SMART Giulio Superti-Furga Iris Uras Assistant “Small Molecule Antagonists Johannes Wolfgang WWTF LS09-009 of chromatin modifying Anita Ender Bigenzahn enzymes for Regulation of Department Heads Joanna Warszawska Assistant Scientific Director Transcription, ­proliferation Florian Breitwieser & Human Resources Keiryn L. Bennett David Weismann and differentiation” Elisangela Calheiro Marie Huber Jacques Colinge Georg Winter EU Marie Curie Project TolLiCoR dos Santos-Valente Assistant “Dissecting pathogen Stefan Kubicek Ana Zivkovic* Gen-AU APPIII Evelyn Dixit° recognition complexes EU Marie Curie SMART Verena Lichtenegger of Toll-like receptors” Gerhard Dürnberger Staff Scientist Assistant FWF 1207 DK Post-doctoral Fellows Carol Ann Eberle André Müller Gabriel O‘Ríordáin Doctoral Program FWF W1205 (CCHD) Christoph Baumann Head of Scientific Support “RNA Biology”

EU Marie Curie TolLiCoR Benjamin Eizinger Technical Assistants Michael Pilz FWF 1718 WWTF LS09-009 Tilmann Bürckstümmer IT Administrator Special Research Program Tiina Berg ERC i-Five Astrid Fauster Eva Schweng “Modulators of RNA Romana Bittner Fate and Function” Maria Gorna Ferran Fece de la Cruz Public Relations FWF 1718 ERC i-Five & Sponsoring FWF W1205 DK Bianca Gapp Manuela Bruckner Doctoral Program Florian Grebien Sigrid Strodl Riem Gawish FWF I291B09 “CCHD – Cell Communications FWF P22282 Finance & Controlling FWF W1205 in Health and Disease” Nils Craig-Müller* 50% EU Open Screen Oliver Hantschel Roberto Giambruno FWF P22282-B11 Bianca Doninger Joachim Tröster Karsten Hartvigsen* FWF P22282 IT Administrator Stand Alone Project Ruth Fuchs “Regulo-Interactome Modules Simon Hör* Adriana Goncalves of Hematopoietic Stem Cells” ERC i-FIVE Florian Ganglberger * left CeMM in 2010 Sabrina Gruber WWTF LS09-009 ° maternity leave FWF I291B09 ERA-NET Kilian Huber Philipp Günzl PathoGenoMics Laura Göderle Quanah Hudson EU HEROIC “Pathogen-host metabolomics and interactomics” EU HEROIC Manuela Gridling Gerald Haas FWF P21768-B13 Roland Jäger Ines Kaupe Ashot Harutyunyan Stand Alone Project Kumaran Kandasamy Claudia Kerzendorfer “Searching for Cancer Ru Huang° ERC i-Five WWTF LS09-009 Achilles’ Heels” EU HEROIC Patrick Markt Christian Knoll Gen-AU Project APP III Stephan Hütter* EU ASSET ERC i-Five “Austrian Proteomics Platform” EU HEROIC Patrick Meidl Hannelore Lechtermann Gen-AU Project BIN III Evren Karayel “Bioinformatics Integration Markus Müllner FWF W1205 Maria Oszvar-Kozma Network” FWF P21768 Thorsten Klampfl Melanie Planyavsky Gen-AU Project Florian Pauler MPD New Investigator Grant Epigenetic Control III Gen-AU Epigenetic Control III Sejla Salic Marielle Klein HAPLOGEN “Epigenetic Regulations Andreas Pichlmair of Cell Fate Decisions” Martha Körner ERC i-Five Adrijana Stefanovic EU HEROIC Gen-AU Project PLACEBO Lily Lorraine Remsing Rix Cristina Sugár* “Platform Austria Aleksandra Kornienko for Chemical Biology” Uwe Rix Norbert Venturini* Vesna Krajina Armenia, Australia,­ ­Austria, Gen-AU PLACEBO Katarzyna Warczok ° MPD Foundation Tomasz Kulinski New Investigator Grant Belgium, Brazil, China, Elena Rudashevskaya EU HEROIC “Genetic complexity of ­Congo, Czech Republic, ­ Gen-AU APPIII myeloproliferative neoplasms” Denmark, Finland, France, Marco Licciardello Gen-AU PLACEBO WWTF LS09-009 Project Germany, Greece, India, “Searching for Cancer Thomas List* Ireland, Italy, New Zealand, Archilles’ Heels” Pakistan, Poland, Portugal, Rui Martins Romania, Russia, Serbia, Philipp Meng Spain, Switzerland, Vincent Millischer The Netherlands, Turkey, Jelena Milosevic United Kingdom, USA MPD New Investigator Grant 29 Nationalities Victor Navas* 124 125 127 127 18. Muellner MK and Nijman SM. Giving Rho(d) 27. Guenzl P, Hainzl E, Matt U, Dillinger B, Directions. Nat Chem Biol. 2010 Jun;6(6): 457-63. Mahr B, Knapp S, Binder BR, Schabbauer G. CeMM Publications Anti-inflammatory properties of the phosphoi- 19. Ait-Oufella H, Herbin O, Bouaziz JD, Binder nositide-3 kinase (PI3K) pathway are mediated by 2010 CJ, Uyttenhove C, Laurans L, Taleb S, Van Vré E, IL- 10/DUSP regulation. J Leukoc Biol. J Leukoc Esposito B, Vilar J, Sirvent J, Van Snick J, Tedgui Biol. 2010 Dec;88(6):1259-69. Epub 2010 Sep 30. A, Tedder TF, Mallat Z. B cell depletion reduces the development of atherosclerosis in mice. 28. O’Sullivan RJ, Kubicek S, Schreiber 1. Rix U, Remsing Rix LL, Terker AS, Fernbach 8. Knapp S. Update on the role of Toll-like J Exp Med. 2010 Aug 2;207(8):1579-87. Epub SL, Karlseder J. Reduced histone biosynthesis NV, Hantschel O, Planyavsky M, Breitwieser FP, receptors during bacterial infections and sepsis. 2010 Jul 5. and chromatin changes arising from a damage Herrmann H, Colinge J, Bennett KL, Augustin M, Wien Med Wochenschr. 2010 Mar;160(5-6):107-11. signal at telomeres. Nat Struct Mol Biol. Till JH, Heinrich MC, Valent P, Superti-Furga G. Review. 20. Ubaida Mohien C, Hartler J, Breitwieser F, 2010 Oct;17(10):1218-25. Epub 2010 Oct 3. A comprehensive target selectivity survey of the Rix U, Remsing Rix L, Winter GE, Thallinger BCR-ABL kinase inhibitor INNO-406 by kinase 9. Knapp S, Frass M. Editorial: sepsis. GG, Bennett KL, Superti-Furga G, Trajanoski Z, 29. Bennett KL, Funk M, Tschernutter M, profiling and chemical proteomics in chronic Wien Med Wochenschr. 2010 Mar;160(5-6):105-6. Colinge J. MASPECTRAS 2: An Integration and Breitwieser FP, Planyavsky M, Mohien CU, myeloid leukemia cells. Leukemia. Analysis Platform for Proteomic Data. Proteomics. Müller A, Trajanoski Z, Colinge J, Superti-Furga 2010 Jan;24(1):44-50. Epub 2009 Nov 5. 10. Jäger R, Kralovics R. Molecular basis and 2010 Jul;10(14):2719-22. G, Schmidt-Erfurth U. Proteomic analysis of clonal evolution of myeloproliferative neo- human cataract aqueous humour: Comparison 2. Koerner MV, Barlow DP. Genomic imprint- plasms. Haematologica. 2010 Apr;95(4):526-9. 21. Radwan M, Stiefvater R, Gruner T, Sharif of one-dimensional gel LCMS with two-dimen- ing – an epigenetic gene regulatory model. O, Miller I, Marchetti-Deschmann M, Allmaier sional LCMS of unlabelled and iTRAQ®-labelled Curr Opin Genet Dev. 2010 Apr;20(2):164-70. 11. Cardilo-Reis L, Witztum JL, Binder CJ. G, Gemeiner M, Knapp S, Kovarik P, Müller M, specimens. J Proteomics. 2010 Oct 16. Epub 2010 Feb 12. Review. When monocytes come (too) close to our hearts. Strobl B. Tyrosine kinase 2 controls interleukin-1 J Am Coll Cardiol. 2010 Apr 13;55(15):1639-41. production at the translational level. J Immunol. 30. Haura EB, Mueller A, Breitwieser FP, Li J, 3. Pedersen TX, Binder CJ, Fredrikson GN, 2010 Sep 15;185(6):3544-53. Epub 2010 Aug 16 Grebien F, Colinge J, Bennett KL. Using iTRAQ Nilsson J, Bro S, Nielsen LB. The pro-inflamma- 12. Dixit E, Boulant S, Zhang Y, Lee AS, Combined with Tandem Affinity Purification to tory effect of uraemia overrules the anti-athero- Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan 22. Bunk S, Sigel S, Metzdorf D, Sharif O, Enhance Low-Abundance Proteins Associated genic potential of immunization with oxidized SP, Fransen M, Nibert ML, Superti-Furga G, Kagan Triantafilou K, Triantafilou M, Hartung T, Knapp with Somatically Mutated EGFR Cor Complexes LDL in apoE-/- mice. Nephrol Dial Transplant. JC. Peroxisomes are signaling platforms for anti- S, von Aulock S. Internalization and coreceptor in Lung Cancer. J Proteome Res. 2010 Nov 9. 2010 Aug;25(8):2486-91. Epub 2010 Feb 17. viral innate immunity. Cell. 2010 May 14;141(4): expression are critical for TLR2-mediated recog- 668-81. Epub 2010 May 6. nition of lipoteichoic acid in human peripheral 31. Jäger R, Kralovics R. Molecular pathogenesis 4. Li J, Rix U, Fang B, Bai Y, Edwards A, blood. J Immunol. 2010 Sep 15;185(6):3708-17. of Philadelphia chromosome-negative chronic Colinge J, Bennett KL, Gao J, Song L, Eschrich S, 13. Binder CJ. Natural IgM Antibodies Against Epub 2010 Aug 16. myeloproliferative neoplasms. Curr Cancer Drug Superti-Furga G, Koomen J, Haura EB. A chemi- Oxidation-Specific Epitopes. J Clin Immunol. Targets. 2010 Nov 10. cal and phosphoproteomic characterization of 2010 May;30 Suppl 1:S56-60. Review. 23. Jellusova J, Düber S, Gückel E, Binder CJ, dasatinib action in lung cancer. Nat Chem Biol. Weiss S, Voll R, Nitschke L. Siglec-G Regulates 32. Baumann CL, Aspalter IM, Sharif O, 2010 Apr;6(4):291-9. Epub 2010 Feb 28. 14. Schabbauer G, Matt U, Günzl P, Warszawska J, B1 Cell Survival and Selection. J Immunol. Pichlmair A, Blüml S, Grebien F, Bruckner M, Furtner T, Hainzl E, Elbau I, Mesteri I, Doninger 2010 Sep 15;185(6):3277-84. Epub 2010 Aug 20. Pasierbek P, Aumayr K, Planyavsky M, Bennett 5. Bieghs V, Wouters K, Van Gorp PJ, Gijbels B, Binder BR, Knapp S. Myeloid PTEN promotes KL, Colinge J, Knapp S, Superti-Furga G. CD14 is MJ, De Winther MP, Binder CJ, Lütjohann D, inflammation but impairs bactericidal activities du- 24. Colinge J, Rix U, Superti-Furga F. Novel a co-receptor of Toll-like receptors 7 and 9. Febbraio M, Moore KJ, Van Bilsen M, Hofker MH, ring murine pneumococcal pneumonia. J Immunol. global network scores to analyze kinase inhibitor J Exp Med. 2010 Nov 22;207(12):2689-701. Shiri-Sverdlov R. Role of Scavenger Receptor A 2010 Jul 1;185(1):468-76. Epub 2010 May 26. profiles. 2010 Sep 9, ORSC & APORC, 305-313. Epub 2010 Nov 15. and CD36 in Diet-induced Non-alcoholic Lecture Notes Steatohepatitis in Hyperlipidemic Mice. 15. Jäger R, Gisslinger H, Passamonti F, Rumi 33. Burkard TR, Rix U, Breitwieser FP, Superti- Gastroenterology. 2010 Jun;138(7):2477-86, E, Berg T, Gisslinger B, Pietra D, Harutyunyan 25. Boucheron N, Sharif O, Schebesta A, Furga G, Colinge J. A computational approach 2486.e1-3. Epub 2010 Mar 2. A, Klampfl T, Olcaydu D, Cazzola M, Kralovics Croxford A, Raberger J, Schmidt U, Vigl B, Bauer to analyze the mechanism of action of the kinase R. Deletions of the transcription factor Ikaros in J, Bankoti R, Lassmann H, Epstein MM, Knapp inhibitor bafetinib. PLoS Comput Biol. 6. Hudson QJ, Kulinski TM, Huetter SP, myeloproliferative neoplasms. Leukemia. S, Waisman A, Ellmeier W. The protein tyrosine 2010 Nov 18;6(11):e1001001. Barlow DP. Genomic Imprinting Mechanisms 2010 Jul;24(7):1290-8. Epub 2010 May 27. kinase Tec regulates a CD44hiCD62L-Th17 In Embryonic And Extra-Embryonic Mouse subset. J Immunol. 2010 Nov 1;185(9):5111-9. 34. Nijman SM. Syntehtic lethality: General Tissues. Heredity. 2010 Jul;105(1):45-56. 16. Sherbenou DW, Hantschel O, Kaupe I, Epub 2010 Sep 24. principles, utility and detection using genetic Epub 2010 Mar 17. Review. Willis S, Bumm T, Turaga LP, Lange T, Dao KH, screens in human cells. FEBS Lett. 2010 Nov 19. Press RD, Druker BJ, Superti-Furga G, Deininger 26. Wool GD, Cabana VG, Lukens J, Shaw PX, 7. Wojcik J, Hantschel O, Grebien F, Kaupe MW. BCR-ABL SH3-SH2 domain mutations in Binder CJ, Witztum JL, Reardon CA, Getz GS. 35. Zivkovic A, Sharif O, Stich K, Doninger B, I, Bennett KL, Barkinge J, Jones RB, Koide A, chronic myeloid leukemia patients on imatinib. 4F Peptide reduces nascent atherosclerosis and Biaggio M, Colinge J, Bilban M, Mesteri I, Superti-Furga G, Koide S. A potent and highly Blood. 2010 Oct 28;116(17):3278-85. Epub 2010 Jun 2. induces natural antibody production in apolipo- Hazemi P, Lemmens-Gruber R, Knapp S. specific FN3 monobody inhibitor of the Abl SH2 protein E-null mice. FASEB J. 2010 Sep 27. TLR 2 and CD14 Mediate Innate Immunity domain. Nat Struct Mol Biol. 2010 Apr;17(4):519-27. 17. Blüml S, Binder NB, Niederreiter B, Polzer and Lung Inflammation to Staphylococcal Epub 2010 Mar 28. K, Hayer S, Tauber S, Schett G, Scheinecker C, Panton-Valentine Leukocidin In Vivo. J Immunol. Kollias G, Selzer E, Bilban M, Smolen JS, Superti- 2010 Dec 22. Furga G, Redlich K. Anti-inflammatory effects of tumor necrosis factor on hematopoietic cells in a murine model of erosive arthritis. Arthritis Rheum. 2010 Jun;62(6):1608-19. Ce — M­—M­— Research Report 2010 128 129 “Exactly 30 years ago, the immunologist Dr. William Paul – at that time President of the ASCI – heralded the advent of a golden era of clinical investigation. He predicted that the availability of certain new technologies would lead to a deep and meaningful insight into the mechanisms operative in a whole variety of different diseases. Based on this, one would expect that therapeutic strategies are devel- oped that should exhibit a much higher degree of specificity and, as a consequence, higher efficacy and lesser toxicity than the ‘old reme- dies’. The history and, I am convinced, even more so the future of CeMM is an excellent example for the validity of Dr.Paul’s forecast. A group of brilliant investigators led by the enthusiastic and charismatic Giulio Superti- Furga, a newly built institute with many important in-house technologies and a major academic medical center surrounding it, are ideal conditions for the pursuit of high-level biomedical research and true accomplishment. The ­Academy is very proud of having CeMM under its ­umbrella. Be assured that we will do our very best to help bringing its enormous potential to full fruition, for the benefit of true ­scientific progress of the biomedical research scene in Austria, and most importantly, of the patients seeking help for their disease.”

Prof. Dr. Georg Stingl President of the Section for Mathematics and the Natural Sciences of the Austrian Academy of Sciences Finland 1

Denmark 1 Poland Ireland The Netherlands 1 1 4

2 1 Germany 13 Czech Republic

Belgium 2 3 United Kingdom USA 1 France Russia 1

2 1

Spain Portugal Austria 61

1 China Romania 1 1 1 India Switzerland Brazil 1 Italy Serbia 3 Pakistan 6 6 Armenia 1 1

Greece Turkey 1 New Zealand 1 Congo 1 4

Australia

CeMM CeMM Staff Listed by number of persons per field of work The CeMM administration is very lean in relation to the total staff (124 employees as of December 2010). Facts & Figures We have a very good gender balance. The average age at CeMM is 31 years.

Management 3 persons 2% of total staff

Scientific Support 4 persons 3% of total staff

Lab Heads 9 persons 7% of total staff

Administration 12 persons 10% of total staff

Diploma Students 12 persons 10% of total staff

37 35 Technical Assistants 33 21 persons 17% of total staff

23 Postdoctoral Fellows 27 persons 22% of total staff

14

3 PhD Students 36 persons 29% of total staff 2005 2006 2007 2008 2009 2010

¤ 5,986,919 Austrian Academy of Sciences inital equipment new building Ce — M­—M­— Research Report 2010 132 133

¤ 1,010,160 European Union Projects

¤ 304,819 Federal Ministry of Science and Research (Bund)

¤ 230,182 Austrian Science Foundation (FWF)

¤ 131,800 Vienna Science and Technology Fund (WWTF) ¤ 72,510 Companies Personnel 32% ¤ 7,124 Other ¤ 2,542 Sponsoring

Th ird- Par ¤ 1, ty 75 Fu 9,1 n 3 ds 7 ¤ 6,011,589 Austrian Academy of Sciences Consumables 10% general budget

Facility Costs 9% Investments new building 41%

Other Costs 8% Finland 1

Denmark 1 Poland Ireland The Netherlands 1 1 4

2 1 Germany 13 Czech Republic

Belgium 2 3 United Kingdom USA 1 France Russia 1

2 1

Spain Portugal Austria 61

1 China Romania 1 1 1 India Switzerland Brazil 1 Italy Serbia 3 Pakistan 6 6 Armenia 1 1

Greece Turkey 1 New Zealand 1 Congo 1 4

Australia

Finland 1

Denmark 1 Poland Ireland The Netherlands 1 1 4

2 1 Germany 13 Czech Republic

Belgium 2 Management 3 United Kingdom 3 persons USA 2% of total staff 1 France Russia 1 Scientific Support 2 1 4 persons 3% of total staff

Spain Portugal Austria 61 Lab Heads 9 persons 1 China 7% of total staff Romania 1 1 1 India Switzerland Brazil 1 Administration Italy Serbia 12 persons 3 Pakistan 6 6 Armenia 10% of total staff 1 1

Greece Turkey 1 New Zealand 1 Congo 1 4 Diploma Students 12 persons 10% of total staff Australia 37 35 Technical Assistants 33 21 persons Finland 17% of total staff 1

23 Postdoctoral Fellows Denmark 27 persons 1 Poland 22% of total staff Ireland The Netherlands 1 4 1 14

2 1 Germany 13 Czech Republic 3 Belgium 2 PhD Students 3 36 persons United Kingdom 29% of total staff USA 1 2005 2006 2007 2008 2009 2010 France Russia 1

2 1

Spain Portugal Austria 61

1 China Romania 1 1 1 India Switzerland Brazil 1 Italy Serbia 3 Pakistan 6 6 Armenia 1Management 1 3 persons ¤ 5,986,919 2% of total staff New Zealand Greece Turkey 1 1 Congo 1 Austrian Academy 4 of Sciences inital equipment Scientific SupportAustralia 4 persons new building Nationalities3% of total staff at CeMM Expenses in 2010

29 different nationalities are ¤ 1,010,160 European Union Projects represented at CeMM. The Lab Heads international atmosphere 9 persons boosts ideas and helps to find 7% of total staff ¤ 304,819 Federal Ministry of Science and Research (Bund) Finland new solutions and see the 1 ­bigger picture. ¤ 230,182 Austrian Science Foundation (FWF) ¤ 131,800 Vienna Science and Technology Fund (WWTF) Administration ¤ 72,510 Companies 12 persons Personnel 32% ¤ 7,124 Other ¤ 2,542 Sponsoring 10% of total staff Denmark 1 Poland Ireland The Netherlands 1 1 4 Thi rd-P Diploma Students ¤ art 12 persons 1,7 y 59 Fu 2 10% of total staff ,1 n Germany 3 ds 1 7 13 37 Czech Republic ¤ 6,011,589 2 35 Belgium Technical Assistants 33 Austrian Academy 21 persons 3 United Kingdom of Sciences USA 17% of total staff Consumables 10% 1 general budget France Russia 1 23 Postdoctoral Fellows 2 27 persons 1 22% of total staff Facility Costs 9% Investments new building 41% Spain 14 Portugal Austria

61 Other Costs 8%

1 China Romania 1 1 3 Management PhD Students 1 36 persons India 3 persons Switzerland 1 Brazil Italy 29% of total staff 2% of total staff Serbia 2005 2006 2007 2008 2009 2010 3 Pakistan 6 6 Armenia 1 1

Scientific Support Greece Turkey 1 New Zealand 4 persons 1 Congo 1 4 3% of total staff CeMM Grant Money in 2010 Australia

Lab Heads 9 persons 7% of total staff

Administration 12 persons CeMM Publications 10% of total staff Includes all publications ¤ 5,986,919 by CeMM staff members Austrian Academy Diploma Students from the date of joining 12 persons the institute. of Sciences 10% of total staff inital equipment new building 37 35 Technical Assistants 33 21 persons 17% of total staff ¤ 1,010,160 European Union Projects

¤ 304,819 Federal Ministry of Science and Research (Bund) 23 Postdoctoral Fellows 27 persons ¤ 230,182 Austrian Science Foundation (FWF) 22% of total staff ¤ 131,800 Vienna Science and Technology Fund (WWTF) ¤ 72,510 Companies Personnel 32% ¤ 7,124 Other 14 ¤ 2,542 Sponsoring

Th ird- Par ¤ 1, ty 3 75 Fu PhD Students 9,1 n 3 ds 36 persons 7 29% of total staff 2005 2006 2007 2008 2009 2010 ¤ 6,011,589 Management Austrian Academy 3 persons of Sciences 2% of total staff Ce — M­—M­— Research Report 2010 Consumables 10% general budget 134 135

Scientific Support 4 persons 3% of total staff Facility Costs 9% Investments new building 41%

Lab Heads Other Costs 8% 9 persons 7% of total staff

Administration ¤ 5,986,919 12 persons 10% of total staff Austrian Academy of Sciences inital equipment new building Diploma Students 12 persons 10% of total staff

¤ 1,010,160 European Union Projects 37 35 Technical Assistants 33 21 persons ¤ 304,819 Federal Ministry of Science and Research (Bund) 17% of total staff ¤ 230,182 Austrian Science Foundation (FWF)

¤ 131,800 Vienna Science and Technology Fund (WWTF) ¤ 72,510 Companies Personnel 32% ¤ 7,124 Other 23 Postdoctoral Fellows ¤ 2,542 Sponsoring 27 persons 22% of total staff Th ird- 14 Par ¤ 1, ty 75 Fu 9,1 n 3 ds 7

¤ 6,011,589 3 PhD Students Austrian Academy 36 persons 29% of total staff of Sciences Consumables 10% general budget 2005 2006 2007 2008 2009 2010

Facility Costs 9% Investments new building 41%

Other Costs 8%

¤ 5,986,919 Austrian Academy of Sciences inital equipment new building

¤ 1,010,160 European Union Projects

¤ 304,819 Federal Ministry of Science and Research (Bund)

¤ 230,182 Austrian Science Foundation (FWF)

¤ 131,800 Vienna Science and Technology Fund (WWTF) ¤ 72,510 Companies Personnel 32% ¤ 7,124 Other ¤ 2,542 Sponsoring

Th ird- Par ¤ 1, ty 75 Fu 9,1 n 3 ds 7 ¤ 6,011,589 Austrian Academy of Sciences Consumables 10% general budget

Facility Costs 9% Investments new building 41%

Other Costs 8% Critical to the much-needed development of innovative research Sponsor the approaches in molecular medicine are independence and space for creative ideas. Where do people CeMM obtain their best ideas? Can the process be facilitated? If an idea can Brain Lounge save the planet or lead to a cancer cure, is it not worth doing all we can to let that idea crop up? The new building of CeMM will house a room with a breathtaking view over the center of Vienna. The concept for the so-called Brain Lounge has grown out of emotional and multi- disciplinary discussions with artists, scientists and designers who bring in their different insights, expertise and experiences. It aims to facilitate unusual thoughts in a relaxed, futuristic and thought- provoking setting. A carpet designed by Peter Kogler will lay the ground- work for the artistic design and tailor-made furniture, and lights are carefully selected for the desired inspiring atmosphere. As the project can only be done with sponsors and donors, CeMM needs to raise at least 50,000 Euro – best twice as much would be even better. Any donation is welcome! Draft Brain Lounge carpet by Peter Kogler. For your donation you will be men- tioned on the CeMM web site and on a plaque in the room. And you can reserve the room for your own thinking sessions. Generations of thinkers will be thankful. If the donation is large enough, the room can bear your name.

Bank details for Contributions Bank Austria, BLZ 12000 Account No. 01270418501 Denominated to CeMM IBAN: AT291100001270418501 BIC-SWIFT: BKAUATWW These are our supporters of previous years’ Research Reports. From top left to bottom right:

Prof. Dr. Bernd Binder † Department of Vascular Biology and Throm- bosis Research, Medical University of Vienna

Prof. Dr. Max L. Birnstiel Founding Director of the Research Institute of Molecular Pathology (IMP)

Dr. Heinz Fischer President of the Austrian Republic

Prof. Dr. Helmut Gadner Director, St. Anna Children’s Cancer Research Institute

Dr. Johannes Hahn Federal Minister for Science and Research (2007–2010)

Dr. Michael Häupl Mayor of the City of Vienna

Carolina Inama Presenter of the Austrian ­television (ORF) science ­magazine “Newton”

Mag.ª Monika Kircher-Kohl Chief Executive Officer, Infineon Technologies Austria AG

Prof. Dr. Reinhard Krepler Director of the Vienna General Hospital (AKH)

Prof. Dr. Helga Nowotny Vice-President, European Research Council

Robert Palfrader Austrian comedian in his most famous social satire role as the (fictitious) Austrian Emperor Robert Heinrich I

Mag.ª Barbara Prammer President of the Austrian ­National Council, Member of the Senate of the Austrian Academy of Sciences

Dr. Johanna Rachinger Director General of the Austrian National Library, Member of the Senate of the Austrian Academy of Sciences

Prof. Dr. Ursula Schmidt-Erfurth Head of the Department of Ophthalmology and Optometrics at the Medical University of Vienna/Vienna General Hospital

Prof. Dr. Peter Schuster President of the Austrian ­Academy of Sciences (2006–2009)

Prof. Dr. Wolfgang Schütz Rector, Medical University of Vienna

Prof. Dr. Hans Tuppy Chair of the Board of the University of Natural Resources and Applied Life Sciences Vienna

Prof. Dr. Christoph Zielinski Chairman, Department of Medicine I and Cancer Center, General Hospital Medical University of Vienna

Prof. Dr. Harald zur Hausen Winner of the Nobel Prize for Medicine 2008

138 139 Acknowledgements Denis Hochstrasser, Astrid Hoebertz, George Poste, Barbara Prammer, Research Report 2007 Copyrights Ruedi Aebersold, Patricia Afuss, Johannes Höhrhan-Hochmiller, Christoph Prammer, Georg and © Ce—M—M— Center for Zoran Almazan, Patrick Aloy, Günter Hof, Erhard Hofer, Astrid Martina Prantl, Andrea Raffaseder, Molecular Medicine of the Stefan Amatschek, Ernst Ambrozy, Hofstätter, Martin Hohenegger, Iris Ranzinger, Thomas Rattei, Austrian Academy of Sciences Gustav Ammerer, Angelika Amon, Eveline Holzmeier, Veit Hornung, Meinhard Rauchensteiner, Lazarettgasse 14, AKH BT 25.3 Thomas Amsüss, Hannes Androsch, Bernhard Horsethemke, Christoph Mehrnoosh Rayner, Gerda Redl, A — 1090 Vienna Johannes Angerer, Thomas Angyan, Huber, Lukas Huber, Ylva Huber, Kurt Redlich, Markus Reicher, www.cemm.at Mehran Ansari, Georg Anzenberger, Liu Huchi, Heidemarie Hurtl, Ulf Reimer, Caetano Reis e Sousa, Christian Arthaber, Isabel and Alfred Monika Hutter, Gökhan Ibis, Georg Reithofer, Ingrid Riedel- Bader, Andrea Ballabio, Christian Harald Isemann, Herbert Jacubetz, Taschner, Patricia Rodriguez-Tomé, Balluch, Marcus Bantscheff, Gerhard Walter Janisch, Patricia Jäger, Brigitte Rohner, Andreas Roitinger, Overall responsibility Bauer, Hemma Bauer, Marianne Ulrich Jäger, Sigrid Jalkotzy-Deger, Nadia Rosenthal, Walter Rosenthal, for content Baumgart, Marlis Baurecht, Erika Jensen-Jarolim, Michael Sazel, Gernot Schabbauer, Giulio Superti-Furga, PhD Roderick L. Beijersbergen, Waldemar Anna Jermolaewa, Stefan Joham, Clemens Scheinecker, Otto Scheiner, Scientific Director CeMM Benedict, Walter Berger, Andreas Teresa Jordis, Ulrich Jordis, Katharina Schendl, Johannes Bergthaler, Rene Bernhards, Hartmut Luzi Josipovic, Veronika Josipovic, Schmid, Ursula Schmidt-Erfurth, Editor Beug, Andreas Bichl, Martin Bilban, Michael Kadensky, Martin Kaftan, Helmut Schneider, Maria Schreiber, Eva Schweng, MAS [email protected] Bernd and Christa Binder, Jonathan C. Kagan, Gabriele Kaplan, Stuart Schreiber, Rene Schröder,

Max and Margaret Birnstiel, Siegfried Kasper, Beatrix Karl, Peter Schuster, Wolfgang Schütz, Research Report 2008 Scientific Writers Blagoey Blagoev, Stephan Blüml, Barbara Kazmierczak, Herwig Reinhard Schwarz, Dieter Schweizer, Ioannis Legouras, PhD CeMM thanks all friends and colleagues Martin and Lucrezia Böhm, Stefan Kempinger, Oliver Kemper, Bernhard Christian Seiser; Luis Serrano, [email protected] Böhm, Hamid Bolouri, Günther Bonn, Keppler, Dontscho Kerjaschki, Veronika Sexl, Maria Sibilia, Helen Pickersgill, PhD for their past and future support. Charlie Boone, Johannes J. Bos, Michael Kiebler, Hans Kiener, Markus Werner Sieghart, Angela Siegling, [email protected] Andrew Bowie, Rolf Breinbauer, Kiess, Melitta Kimbacher, Christoph Greg C. Simon, Jörg Simonitsch, Giulio Superti-Furga, PhD Julius Brennecke, Alfred Brogyányi, Klein, Rüdiger Klein, Stefan Knapp, Ernst Singer, Maria Siomos, [email protected] Eva Bruckner, Soren Brunak, Michael Kneidinger, Eva Luise and Timothy Skern, Uwe Sleytr, Thijn Brummelkamp, Herbert Burger, Horst Köhler, Peter and Tanja Kogler, Josef Smolen, Young-Hwa Song, Art Direction and Design Erhard Busek, Meinrad and Irene Walter Kolch, Zenita Komad, Hans-Joachim Sorger, Peter Lichtwitz Busslinger, Otto Chvosta, Ernst M. Kopper, Gottfried Koos, Soswinski, Beatrix and Benedikt Leinfellner visuelle Kultur KG Mario Cazzola, Gianni Cesareni, Guido Korlath, Barbara Kornmüller, Spiegelfeld, Massimo Spinetti, Markus Göbl Ajay Chawla, Jyoti Choudhary, Ursula Kosir, Heinrich Kovar, Alfred Sramek, Christoph Kriso Leinfellner Francesca Ciccarelli, Lisa Cichocki, Brigitte Kowanz, Peter Kowalski, Stadlhuber, Holger Stalz, Andreas Stefanie Lichtwitz Giorgio Colombo, Pascal Cossart, Dietrich Kraft, Peter Kraft, Stampfer, Michael Stampfer, Nadine Melchior Adrian Csik, Peter Csukovits, Claudia Kral, Robert Krapfenbauer, Edda Starzer, Louis Staudt, Katharina Untertrifaller Eugenio d’Auria, George Daley, Christoph Kratky, Michael Krebs, Georg Stingl, Esther Stocker, Rainer de Martin, Thomas Decker, Erich Kremnitzer, Reinhard Krepler, Hannes Stockinger, Doris Stolz, Photography Helmut and Helga Denk, Barry Bernhard Küster, Hans Kupelwieser, Franz Strasser, Sepp Strasser, Heribert Corn (p. 6) Research Report 2009 Dickson, Manfred Dierich, Klaus Dietl, John Kuriyan, Werner Lanthaler, Erich Streissler, Herbert Strobl, Thomas Fröhle (p. 112) Gerhard Ecker, Brigitte Ederer, Hans Lassmann, Caroline Lassnig, Carl-Wolfgang Stubenberg, Daniela Klemencic (p. 95) Hans Leitner (p. 120) Hubert-Christian Ehalt, Adelheid Simon Lauter, Klaus Lechner, Thomas Stulnig, Tobias Stuwe, Iris Ranzinger (p. 115, 119) Elbe-Bürger, Wilfried Ellmeier, Gerhard Leder, Joseph Lehar, Marius Sudol, Arnold Suppan, Markus Rössle (cover, pp. 2, 9, Traudl Engelhorn, Heinz Engl, Ben Lehner, Hans Lehrach, Stefanie Superti-Furga, Peter 10, 12, 18, 28, 36, 46, 56, 64, 68) Erich Ennsbrunner, Michelle Epstein, Kriso Leinfellner, Alexander Leitner, Swetly, Oliver Szolar, Witold and Michael Sazel (pp. 72, 76–79, Harald Esterbauer, Judith Farres, Ivica Letunic, Andrew Lichtmann, Claudia Szymanski, Tada Taniguchi, 81–83, 84, 92, 98, 99, 104, 118, Karin Fehringer, Peter Felkel, Stefanie Lichtwitz, Christian Liebe, Werner Telesko, Alexandra 123,130) Ulrike Felt, Thomas Feuerstein, Hans-Joachim Lipp, David Livingston, Thausing, Stefan Thurner, Elisabeth Katja Fiala, Mathias Fichtinger, Daniel Löcker, Joanna Loizou, Tischelmayer, Gerhard Thallinger, All other photos by CeMM Heinz and Margit Fischer, Silvia Lossgott, Friedrich Lottspeich, Eva Maria Thonet, Alfred Totzler, Print Maximilian Fischer, Richard Flavell, Wolfgang Machal, Andreas Mailath- Zlatko Trajanoski, Lisbeth Triska, Ueberreuter Print GmbH Roland Foisner, Michael and Pokorny, Rudolf Mallinger, Walter Troger, Hans Tuppy, Margarita Freissmuth, Herbert Mang, Matthias Mann, Jasmin Turtenwald, Marius Ueffing, Paper Herwig Friesinger, Rainer Fuchs, Christine Mannhalter, Javier Katharina Untertrifaller, Zambak Heaven 42, 135g Invercote, 300g Michael Füchsl, Helmut Gadner, Martinez, Herbert Matis, Marjori and Abdurrahman Uras, Alfonso Christoph Gasche, Anne-Claude Matzke, Dieter Maurer, Karl Valencia, Peter Valent, Alexander Fonts Gavin, Manfred Gengler, Mechtler, Jürgen Meier, van der Bellen, Roel Verhaak, Sys Francesco Gervasio, Edith Gindel, Nadine Melchior, Junia Melo, Marc Vidal, Alexander von Gabain, DTL Documenta Wolfgang Gleissner, Dorothee Golz, Siegfried Meryn, Simone Mesner, Erwin Wagner, Oswald Wagner, Herbert Gottweis, Elisabeth Michael Micksche, Marko D. Stephan Wagner, Werner If you want information about Grabenweger, Guido Grandi, Andreas Mihovilovic, Martina Milletich, Waldhäusl, Martin Walde, Angelika what CeMM worked on Grassauer, Claudia Greiner, Markus Evelyn Missbach, Dino Nurudin Wallner, Christian Wanzenböck, in 2007-2009 you can order our Grimm, James D. Griffin, Michael Mirvic, Wolfgang Mlecnik, Maria Christian Wappel, Ernst Wastler, previous Research Reports: Griletz, Rüdiger Gross, Daniel Gruber, Magdalena Mosgan, Doris Mucha, Herbert Watzke, Elisabeth Anita Ender Beatrix Grubeck-Loebenstein, Markus Müller, Mathias Müller, Wegmann, Claudius Weingrill, CeMM – Research Center for Matthias Gstaiger, Markus Göbl, Patricia McCabe, Shane McManus, Barbara Weitgruber, ­Molecular Medicine of the Alexander Habsburg-Lothringen, Otto Müller, Bhushan Nagar, Werner Welzig, Georg Wick, Austrian ­Academy of Sciences Jorg Hackermueller, Karin Alexander Nagler, Esther Nagy, Christopher Widauer, [email protected] Hagenbichler, Johannes Hahn, Waltraud and Laurenz Niel, Rudolf Widmann, Felix Wieland, Lazarettgasse 14, AKH BT 25.3 Brigitte Haidl, Bernhard Hain, Christian Noe, Christian Nordberg, Rotraud Wieser, Karin Wihsböck, CeMM-/Anna-Spiegel- Barbara Hamilton, Doug Hanahan, Magnus Nordborg, Rodger Novak, Tanja Winkler, Anke Wittig, Forschungsgebäude Julia Harlfinger, Michael Häupl, Helga Nowotny, Peter Obitsch, Alfred Wittinghofer, Hans Wojta, 1090 Vienna, Austria Eric Haura, Harald zur Hausen, Egon Ogris, Primus and Katharina Lars Woldt, Klaus Wolff, Tel +43-1/40160-70011 Heike Heidemann, Klaus Heilinger, Österreicher, Markus Otte, Elisabeth Manfred Würthner, Roman Wurzer, Fax +43-1/40160-9700 00 Claudia Heilmann-Sennhenn, Franz Pal, Markus Pasterk, William E. 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Ce — M­—M­— Research Report 2010 140 141 How to reach CeMM

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences Lazarettgasse 14, AKH BT 25.3 CeMM-/Anna-Spiegel Research Building Main Entrance 3rd Floor 1090 Vienna, Austria Tel +43-1/40160-70 011 [email protected] www.cemm.at

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