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Research Report 2012 Research Report 2012 Research Report 2012

Director’s Intro — Discussion on the Origin of Ideas — pp. 6—8 pp. 9—15 Research Section — pp. 16—57 ,QÁXHQFH³5HÁHFWLRQ³ pp. 18—23 pp. 24—29

5HQHZDO³$FFXUDF\³$VVRFLDWLRQ³'\QDPLFV³ pp. 30—35 pp. 36—43 pp. 44—49 pp. 50—57

3ULQFLSDO,QYHVWLJDWRUV³/HFWXUH6HULHV³¬ pp. 60—75 pp. 84—89 Workshops and Conferences — CeMM and Society — pp. 94—97 pp. 98—99 Brain Lounge Opening — Ph.D. Program and pp. 104—106

6RFLDO/LIHDW&H00³6FLHQWLÀF$GYLVRU\%RDUG³ pp. 107—113 pp. 118—120 Sponsor Us — Directory — Publications — Facts pp. 122—123 pp. 124—129 pp. 130—133 DQG)LJXUHV³$FNQRZOHGJHPHQWV³+RZWR5HDFK pp. 134–137 pp. 140—141 CeMM — Imprint pp. 142–143 pp. 144 It is almost scary. After an “annus mirabilis” in There have been too many important scientific arts, economy, and politics. Seldom has society 2011, the year 2012 has been just as full of events, achievements to summarize them all here and been so much in wanting of really new, good advancements and achievements. The last few I do not want to anticipate too much of the ideas. And again we were lucky. We found in CeMM years have become one long adrenaline rush. Yet following report. Yet I would like to highlight the Vienna-based designer duo Walking Chair, we are certainly still far from a peak of productiv- the discovery of the mechanism by which a Fidel Peugeot and Karl Emilio Pircher, two very ity, given the last Principal Investigator to join, long non-coding RNA molecule, called Airn, congenial partners who made the Brain Lounge, Christoph Bock, started only in January 2012, and negatively affects transcription of the IGFR2 against their own economic logic, a priority. Our Research more than half of all researchers have been at gene from within the same genetic locus. The joint ideas caught fire and captured a number of CeMM for less than two years. The opportunity intellectual rigor and the uncompromising fantastic artists: Brigitte Kowanz, Esther Stocker, facing these rising stars is immense. The entire dedication with which Denise Barlow and her Martin Walde, Peter Kogler (who, of course was campus of the Medical University, our congenial team have pursued the answer to this elusive also the magical author of the CeMM facade), Report partner, with its 2,000 medical doctors, is actively problem counts as one of the very best scientific Eva Schlegel, Dorothee Golz, Thomas Feuerstein, evaluating the merits of genome-informed achievements in the field of epigenetic regulation Alois Mosbacher as well as the Berlin-based medicine, and we are there to share the first ideas in the last years, worldwide. As the rest of the fashion designer Daniel Kroh. And yet more 2012 and provide fertile ground to support the growth best research we have done and we will do, will join in its future. The result is a community of new initiatives. Christoph Bock, bearing a dual the Barlow study relies on clever ideas. The project, a symbol, a totem, a living oracle, a affiliation with the Medical University, has hit little sparks of genius that sometimes strike vehicle for intellectual journeys and most the ground running by establishing the CeMM/ us, I am afraid not often enough, like lightning. importantly an ever-changing platform ideal for ,QWURGXFWLRQE\*LXOLR6XSHUWL)XUJD Medical University Biomedical Sequencing But where do they come from? And more fostering interactions with the rest of society, Facility, already very productive, and is building importantly, can we induce them? Discussing beyond the boundaries of science and medicine up a unique additional competence, namely this amongst ourselves (and also with artists and the campus of the General Hospital. I would computational epigenomics (the marks that and colleagues from the medical and the social like to thank the designers and artists along tissues leave on genes), which is one of the sciences), it became apparent that the process with the mainly private persons who so far have next frontiers in biomedicine. Proteomics has of inspiration, of obtaining ideas, is something sponsored the project. We are recruiting more also become more medically amenable, with we do not usually dare to speak about. As if it ideas and volunteers to test the Brain Lounge and its ability to characterize the expression of tens is something a bit obscene or too intimate. Or would like to appeal to everybody who values the of thousands of proteins in a given tissue and something nobody would admit to lacking. It sheer beauty and importance of ideas to consider make quantitative comparisons. Together with is as if we consider it a side product of our daily sponsoring the project (see page 122). the informatics network-based evaluation of routine that happens perhaps under the shower, drug action, predictions on the most effective or, so the legend goes, in pubs after profuse If CeMM has become in a relatively short time a therapeutic strategies for treating individual alcohol intake. A dirty little secret. We found it research institute with impressive success, good patients is becoming more feasible. But make no paradoxical that the single most important step international repute, and significant impact on mistake, this is still mostly at the experimental in the entire research process, the creative act, is the medical campus, it is due to its extraordinary level, and it will be several years before we indeed precisely the one that is not acknowledged. It research and teaching faculty. This is also proven can help patients. Yet we have been encouraged is also not budgeted, does not have a dedicated for instance by two ERC and one FWF Starting by the Scientific Advisory Board, who visited space in buildings, and isn’t mentioned in the Grant to Sebastian Nijman and Kaan Boztug and us in November, to accept the challenge for the “methods” section of scientific papers. Yet what one ERC Starting Grant to Thijn Brummelkamp, next five years to pursue yet more translational does the most sophisticated of scientific instru- our Adjunct Principal Investigator at the projects without compromising on our mentation and the hardest research work matter Netherlands Cancer Institute. Of all the privileges mechanism-of-disease based research mode. if the thought-out concept is not a good one? If of the CeMM Scientific Director, the highest and I wish here to thank the entire scientific advisory the original idea is not truly good? most exhilarating is having this current team of board and particularly David Livingston, for open clever, creative research group leaders as a fully yet passionate suggestions. We decided to take action and have made a accessible, fast-reacting and dedicated planning, cultural statement: The Brain Lounge. More sounding and execution board. I wish to thank than a room: an art installation and open-end the truly incredible amount of energy spent for experiment dedicated to the power of thinking. the CeMM research cause. I dare hypothesize Particularly in times of economic crisis and that we form one of the first modern groups budgetary restrictions, the risk is to adopt a of research “super-cooperators”, in the diction narrow, utilitarian view of the research process. of Martin Nowak, the Harvard-based Viennese We wanted to dispel the notion that research is biologist and game-theoretician. People who just the “turning of a crank in a research engine”. understand that the more efficient research A mechanical, automatable process that can be paradigm is through modular and synergistic reduced to the equation: x much money, over y access to each other’s brains and capabilities: much time, equals z much output. Breakthrough The future is yours! innovation in research is a much more complex The designer duo Walking process, strongly influenced by soft factors Chair, Fidel Peugeot and and cultural environment. The Brain Lounge is .DUO(PLOLR3LUFKHUZLWK &H00·V6FLHQWLÀF'LUHFWRU designed to symbolize the psychological and Giulio Superti-Furga. sociological importance of creativity in the cultural advancement process, not only in medi- cine, science, and technology, but also in the

Ce — M—M — Research Report 2012 6 7 The scientific research process with all its unique The CeMM research report is structured around requirements and idiosyncrasies is kept well concepts that the art in the Brain Lounge inspired functioning by a lean and efficient administration. and that echo themes and properties of biological Discussion on the Staying out of the limelight, they deserve a good systems and their investigation: Influence, share of the credit for CeMM’s success. It has Reflection, Renewal, Accuracy, Association and not been an easy year. While CeMM has grown Dynamics. Once again, the report has become in size, the budget hasn’t, and extra work and much more than a list of people, projects and Origin of Ideas creative solutions have been requested. On behalf published papers. It has its own cultural identity of all scientists and collaborators I would like and value as an integration of the CeMM research $URXQGWDEOHZLWK8OULNH)HOW%ULJLȪH+XFN to thank the entire administration, particularly programs and medicine, arts, design, and photo- 0LFKDHO)UHLVVPXWK+HUEHUW*RȪZHLV Gabriel Ó Ríordáin, Sigrid Strodl, Mischa Pilz, graphy. This is thanks to the merit of many -RVHI6PROHQDQG*LXOLR6XSHUWL)XUJD Eva Schweng and Stephan Boos-Waldeck, who people. First and foremost Eva Schweng, who lead their respective teams, and Anita Ender and project-leads with great love and attention. The Gerhard Schadler who have expertly orchestrated text is crafted masterfully by Helen Pickersgill, the entire process. Well done! a scientific writer of increasing elegance and effectiveness who now knows CeMM’s research The Board and the management team of the inside out and integrates text bites contributed by Austrian Academy of Sciences are thanked for many people. This year we are privileged to enjoy their support through time of great turmoil for the contributions of Gitti Huck, the renowned their organization. We appreciated the enduring art historian and curator. Most of the pictures effort to do everything possible to help. And were taken by the wonderfully precise and of course we thank the Ministry of Science and truly illuminating photographer Iris Ranzinger. Research, CeMM’s attentive patron. Finally, the graphic genius of the Lichtwitz and Leinfellner office for visual culture has so much permeated CeMM that it is now permanently part of its identity, as manifested in this report as well as in the soon-to-be web pages. Thanks to you all.

Finally I would like to thank all the CeMM scientists and all our colleagues and collaborators at the Medical University of Vienna and through- out the world. Your research is the reason CeMM exists and CeMM exists only to empower your research. We never forget this and are very grate- ful for your efforts in the past year.

To the reader I wish an entertaining journey through our sixth Research Report. Please continue to give us feedback and support; we always try to make the most out of it.

Giulio Superti-Furga Scientific Director [email protected]

Ce — M—M — Research Report 2012 For more than One could think that research is an automatic )UHLVVPXWK This is true for fine art, but not for process: You put in money, time and people, performing art. Science has both the performance 3.000 years, and you get an output. But the truth is that aspect, which is the execution of the program, man has been you can have a whole institute work on the and the creativity, which is typically inspired by searching for wrong thing if the wrong ideas are on board. reading, and you need a lot of time to read. You Historically, it is not about having the people, need to have “Muße, Negotium, Nichtstun” PXVHV+DYLQJ and the place, and the money. It is really about (time to move slowly and aimlessly). good ideas is what you are doing, about the right idea. And QRSXVKEXȅRQ there are of course parallels to this in art. To )HOW It’s not about doing nothing, it’s about situation. discuss the origin of ideas, Giulio Superti-Furga doing something without a particular aim or met five renowned specialists in their fields in a timeline. :KRRUZKDW the CeMM Brain Lounge: Gitti Huck, expert inspires us? on modern art, Ulrike Felt, Professor of Social 6PROHQ Time off to recuperate and have new Studies of Science, Herbert Gottweis, Professor ideas wouldn’t be the way I could live because in the Department of Political Sciences, both I’m constantly refreshing, replenishing and of the University of Vienna, as well as Michael doing. For me, creativity in science and art has Freissmuth, pharmacologist, and Josef Smolen, multiple facets: inspiration; mentorship; time to rheumatologist, both department heads at the think; shrinking time in order to be productive Medical University of Vienna. and not to lose ideas. Getting faster helps me capture ideas. When I speak of mentorship, I actually think that success is not necessarily 6XSHUWL)XUJD We meet to discuss the origin down to the writer [mentee]. It is the publisher of ideas, on when we had our last good idea. [mentor] who makes the writer. This is true for Did something happen just before we had one of the most prolific times of art history – at that idea? Is it when we are sad, when we are least for me – which is the expressionistic time happy? Is it when we are in love, or not in love, in 1910s–1920s, when there were publishers who or when we are desperate? How much do the started with nothing and ended up with people environment and cultural conditions affect and like Kafka or Benn, who hadn’t even wanted to shape the quality or the substance of the idea we publish. These publishers were able to detect have. For 3,000 years man has been searching for talents. You also need mentors in science who muses. Having good ideas is no push-button- are able to inspire us, to help us, and to make us situation. Who inspires us? a little bit more creative and critical. We have to continue doing that with the younger people )HOW What I find interesting is that the idea of we work with. *LȅL+XFN-RVHI6PROHQ time that we have in research has changed quite +HUEHUW*RȅZHLV0LFKDHO Freissmuth, Ulrike Felt fundamentally over the last couple of decades. It 6XSHUWL)XUJD Both you and Mischa Freissmuth and Giulio Superti-Furga is not that it gets faster but the time units become speak of fortuitous interaction coming from read- in CeMM’s Brain Lounge. smaller so you feel like you don’t have a lot of ing a lot and meeting lots of people. Is this a male time, and you have to reason what you do and thing, to need the concentration and the speed? promise certain things. I get my best ideas when I have the feeling that I have a bunch of time when )HOW There is a research cultural aspect also. I can sufficiently wander for a while, and look at It depends on how knowledge production an issue from several sides, without having to works. What I said doesn’t exclude that you come up with a result. There is very little time continuously renew. But I think what is in academia for these kinds of enterprises. How important is what this renewal actually means would you argue that this is well-used time? and how it redirects what you are doing. There are moments when it is important to stop and +XFN I think this is very similar to what is reflect, and think about what it means. I had once happening in art. When you are a very good artist a very nice debate about how much scientific and have produced a lot of good works, you are output is enough with students at ETH in Zurich. supposed to produce even more for exhibitions Is it reasonable for people to produce 100 top or for the market. The more renowned people are articles over three years? My comment was to in the art world, the harder it is for them to stop think about what the notion “variation on a being productive. There is no way to say: “I can- theme” means. When we push science into a not go on working, because I don’t have an idea at kind of industrialized production of outputs, we this moment!” The really great artists take their also push similarity of things because you can not time to recover and have fresh ideas. be radically new.

Ce — M—M — Research Report 2012 10 11 6PROHQ But on the other hand if you have made 6PROHQ It depends on which area you work on. 0LFKDHO)UHLVVPXWK a discovery it is fair to continue working on it. We as physicians often have a clinical question. Professor of Pharmacology, Medical University of Vienna Artists like Kirchner and Miro have a style they We see many patients with the same problem, *LȪL+XFN continue for dozens of years - I don’t think that and then we go into experimental work and form Expert on modern art you can call that machine production. I think that collaborations to encircle the problem, which -RVHI6PROHQ is putting down creativity. If you have a creative creates space in a different way. Posing new Professor of Rheumatology, idea and have gotten to a point where you say, ideas is how we get inspired. We get inspired by Medical University of Vienna this is exactly what I want my art or science success and by failure. That is how we create our *LXOLR6XSHUWL)XUJD research question to be about, then you follow space. I recall that many years ago we thought 6FLHQWLÀF'LUHFWRU&H00 a superstructure and it is not illegitimate. that if we knock out a certain molecule it would 8OULNH)HOW reduce bone destruction. It turned out that Professor of Social Studies of Science, )HOW It is not a question of being legitimate or knocking it out increased bone destruction, University of Vienna illegitimate. I just think that it is important to which became a very high profile paper that the +HUEHUW*RȪZHLV consider how change happens. The publication other paper wouldn’t have been. So sometimes it Professor in the Depart ment style has changed, because you need to publish is serendipity. We live straight forward. You have of Political Sciences, University of Vienna faster and smaller portions, because that is to have space. Mentorship is also allowing side strategically more important. And the question streams and orthogonal research activities. That is where is there space for reflection? is exactly what happens in laboratories, and what happens in arts as well. 6PROHQ I agree in the sense that I hate slicing data. Some journals like the New England +XFN In art, chance, “Zufall”, is very important, Journal of Medicine cut down manuscripts to hopefully more important than in science. 2,700 words, so you cannot publish everything. On the other hand, if you have a really good )UHLVVPXWK There is the famous saying of idea, and here are protagonists like Giulio, you Pasteur: Chance favors the prepared mind. are not going to publish it prematurely if you can eventually get a Nature paper. High quality )HOW Young researchers in their Ph.D. or early work definitely cannot be published in a sliced Post doc phase would not agree. The risk strategy way today. So I think in that aspect, science has of seniors is totally different to juniors. Juniors’ matured a lot. futures depend on their projects. So it also depends on your position. 6XSHUWL)XUJD Connecting back to the Brain Lounge. The question is - if you take a Nature 6XSHUWL)XUJD I’m interested to hear from the paper - where did the idea come from? Some- sociologists who study the creative process in times when I go to scientific meetings, and it research: Are there patterns that you can observe, doesn’t matter whether they are good or bad, or creative environments? Can you detect I have a Dadaistic storm and I connect some behavioral patterns that are associated with high concepts or keywords. I wonder whether there creativity or is it too complex? is a random generator of combinations that can help scientists. When was the last time you had )HOW That is difficult to answer. I actually think a really great thought, a great idea? it’s the kind of room for maneuver you have. One difference you can see between junior people *RȪZHLV I want to pick up on space again. For is whether they thought there was a collective me something really crucial for scientific creativ- risk strategy or if risk was delegated to each ity is how to create space, because we’re living individual. The boss has a risk strategy: he or in a situation where space is becoming narrower she has conventional projects that will produce in many different respects. You mentioned output to satisfy the watching institution, and mentoring. I think mentoring can create space, then other projects that may be “the one”. I think but it can also do the opposite because some the bosses have this idea that they have room students need to be left alone to use space. We for maneuver because they have this strategy. can always say that it’s much better to direct, Perhaps we are not sufficiently attentive to the as in classical mentoring, but space seems to be junior people. In that sense, it’s not a one-to-one something which is difficult to produce. How do mentoring, but maybe it’s more about group you produce these spaces of creativity? I would mentoring, of creating the idea that there is a sup- say different strategies, in different contexts: a port and that it’s not about individual short term conference can be a perfect space, a workshop, failure or success. This creates an environment, meeting people from different walks of life, but a space, where things are done together. And in they also might not be. I don’t think there’s a a world that has become so individualized and definitive answer for how you create this space, directly competitive, these spaces are shrinking. but I see that very often we don’t have space. We are losing space. Things are getting narrower.

Ce — M—M — Research Report 2012 12 13 6PROHQ I think mentoring is not about only )UHLVVPXWK We could talk about a reward +XFN It’s not a good idea, especially in art, to *RȪZHLV Is it only to have an idea? For me, telling people exactly what to do and putting mechanism, an immediate somatic marker that think about fundamental questions, it’s just creativity has a lot to do with connecting with handcuffs on flowers. Mentoring is providing an tells you, oh - this was a brilliant idea. I think the too much. The good things come out of a little yourself. Usually most people are not connected idea and trying to protect space, not to give space. environment you have to create is where this something. It can be something on the floor. Very with themselves, which is a problem when they I cannot give space to everyone because people immediate reward of having an idea is somehow often things happen for some reason. Things think about what they should do, and what is have to work in the clinic and in the laboratory, triggered. flow. There are situations where things can or isn’t interesting. To create a space where you but I can try to protect what they are doing. So flow. And maybe there is a sort of spirit of space can connect with yourself is not meditation in a from that perspective, mentoring is also about *RȪZHLV Space is also a matter of spirit. involved. And it’s not something you can really narrow sense. providing a safety net. Humans are specialists at reducing space. We are anticipate. It is difficult to engineer. You cannot very good in organizing things. So let’s organize engineer spirit, but materialize it at some point. 6XSHUWL)XUJD We assume that people here 6XSHUWL)XUJD For young people, coming back a creative space. I think it’s very important, but at should venture outside their usual self and even to the artistis - could groups of artists solve the the same time let’s not forget about spirit space. 6XSHUWL)XUJD The moment you want the muse, adopt roles like in a theater. And in such a way problem? So if one doesn’t have a great idea, That space is a matter of spirit, of an attitude. it will never come. You cannot say, “I want to create group dynamic discussions that otherwise another one may have it. have the inspiration.” When we were discussing would never occur because roles are prejudiced. 6XSHUWL)XUJD I’m sure that the value of the the Brain Lounge, we were saying that this could I come in to this situation and dress differently, +XFN It is a highly individual thing. There are Brain Lounge is not the room itself but the fact be the biggest single place where no ideas will and a collaborator of mine dresses up. Then a role few artists groups nowadays. that one values the idea-giving process. It is a ever happen because people come with the cause game starts. We also have a logbook that equals symbol. But the question is can we train people of getting ideas and the muse will just disappear. these games to journeys. The analogy is more )UHLVVPXWK When you are running a research to be creative. But there is something that has to do with a strange journey, an adventure that somehow group, you are actually not only interested in the inspiration, meditation, putting you in a state puts you to a different way of thinking. product. You don’t want the people to fail, and 6PROHQ Train your children to ask questions. where you want without wanting. you don’t want them to spoil their lives. You I think that is something that is part of creativity. 6PROHQ So what is your idea about who should don’t want them to end up like Rembrandt van Make people aware that things are not how they )HOW … in a sense it is not the physically coming come here? Should work groups come here or Rijn. We can hardly separate from the sociology look, and not to take things for granted. to the Brain lounge that matters, but the fact that should this be cross-fertilization, or just whoever of science where each individual person wants to there is a place like that within an institution. wants to use it? have credit. +XFN You cannot train having good ideas. 6PROHQ CeMM itself is a Brain Lounge. 6XSHUWL)XUJD All of them. It’s up for grabs, it’s 6PROHQ In science, there is primarily an institu- )HOW But you can offer experiences. up for ideas. The only mantra we say is, don’t tional effort, whereas in art there is usually not. +XFN We’re always talking very abstractly use it in a routine sort of fashion. My analogy A group of individual artists can say: “Let’s share )UHLVVPXWK Coming back to the question: I get about this - this is the place, this is the Brain is with an oracle. Like the Delphi oracle: If you a studio. Then all of a sudden, they influence each that spark just to think about the problem. But Lounge, and this is where you have your ideas. go every day to the Delphi oracle, you will get other and become famous or not.” In research, when does the moment happen that you propose It is good to have a place where you can have the a stupid answer. But if you go there when you it is not so easy. Individual young researchers one solution? ideas. But why are you never talking about this genuinely are open for an answer, it will work. outside a university probably cannot say: “Let’s place as the place where the art is? So it should always be something special to come do science together …“ 6PROHQ Sometimes it happens by doing here. It should be associated with a pleasant and more and more experiments. Sometimes from 6XSHUWL)XUJD It is a place for the arts, you are a playful type of atmosphere. I don’t think the 6XSHUWL)XUJD For example, the designer duo, listening to boring presentations. There has never totally right. But this is not where you come for place profits from being abused by say a weekly Walking Chair, who made the Brain Lounge are been any meeting in my life that I found useless. personal meditation. This is a communication meeting. We have so called teatime meetings a typical, beautiful, creative partnership. One can place. where we are looking for the craziest idea that a do something that the other one cannot do. If one 6XSHUWL)XUJD It’s the best place to think about particular person has and we discuss it, and it has doesn’t have an idea, the other one has it. Do you new questions. But the Brain Lounge was not a +XFN But if this place is for the people who are to be remote from the daily operation. We are think that art collectives work? spark idea, it evolved. working here, they might like the idea that there writing rules for use in a formal sense, but in an is a place in here for the arts. intellectual sense, we are looking for ways and )UHLVVPXWK The more you get into design and ideas to enlarge the user group. If we are lucky, architecture, the more you have group efforts. 6XSHUWL)XUJD I do believe that that is the over the next ten years, in our logbook we will Your question in the beginning was focused essence of it. And I do believe that new and collect a lot of journeys of different people. It on the creative moment originally. When do unprecedented thoughts are the best tribute to is an evolution, and it should be an evolution. we have a good idea, individually, what is the the art. Maybe that is the wrong connection, to An installation, an ongoing art project, an moment? And also, can you elicit it? say a nice piece of art triggers a poetic or creative experiment. type of thinking that then crosses with another. 6XSHUWL)XUJD In advertizing, people know But you are right; one should calibrate one’s exactly what visual or oral cues you need to expectation on this in a more passive way. trigger certain reactions in your brain. Is some- “Come and enjoy the art,” might be a better thing comparable for creative thinking? Can we invitation, than, “come and have an idea”. elicit ideas with sparks of light, or with music?

Ce — M—M — Research Report 2012 14 15 The more advanced science gets, the closer it is to art. The more advanced art gets, the closer it is to science. Research Buckminster Fuller American architect, engineer, designer, philosopher and writer Richard (Bucky) Buckminster Fuller was one of the most influential thinkers of the 20th century. A firm believer in the necessity of dialogue between art and science, he felt it offered incredible potential for discovering new ideas, developing at CeMM visions, reaching the frontiers of knowledge and eventually surpassing them.

Watches: Adolf Roman, Ideas: Ernst Caramelle – an inscription above a shop entrance in Vienna’s city center. This discrete text-based work has survived as “conceptual fall out” in the public space since 1988. Only insiders know about this secret attestation of Austrian conceptual art, through which Ernst Caramelle rethought contemporary time and space, turning it into an artistic act. Ideas, theoretical considerations and processes are at the center of his artwork. “My work always comes from the head,” he says, “I never make anything from the gut.”

CeMM’s 8th floor has recently become home to the Brain Lounge. A cockpit of sorts for ideas, for creativity, an interface where medical research meets art and design. Karl Emilio Pircher and Fidel Peugeot, the internationally renowned designer duo known as Walking Chair, have interpreted the Brain Lounge as a nineteen-sixties style (space) capsule. Within this spacey environment, artists are now stirring up the disciplines.

In molecular research, as practiced at CeMM, there are terms used to describe the significance, effect and priority of individual areas of research. They are terms such as pattern, dynamics, communication, precision, association, influence, decision, renewal, reflection and insight. In the context of the community project Brain Lounge, they can serve to address issues that artists and designers also find themselves confronted within their work. ,Q½XHQFH

+ Joining Forces in Biology + 7KH,Q½XHQFHRI3URWHLQ0RGL¼FDWLRQV + ,Q½XHQFLQJ%LRORJLFDO3DWKZD\V + 7KH%URDG,Q½XHQFHRI'UXJ$FWLRQ + ,Q½XHQFLQJ*HQH$FWLYLW\ There is no biological entity, no protein or cell Influences can be both positive and negative, that works entirely alone. Each is influenced either stimulating a biological process to by many different factors such as the action of continue or blocking its progress. This ensures ,Q½XHQFH enzymes to chemically modify a protein and tight control to avoid a malfunction that could influence its activity, or environmental condi- potentially lead to disease. tions that signal to the cell and influence its state. Art and science were linked at the tenth edition of documenta in Kassel in 1997. In 2012, 15 years later, scientists and artists met on equal footing in the same context. For both disciplines, the subject of this -RLQLQJ)RUFHVLQ%LRORJ\ exhibition, arguably the most important art exhibition in the world, was an investigation of the possibilities and definitions of reality. Traditionally scientists have studied components Proteomics is the large-scale study of the of biological systems in relative isolation. structure and/or function of proteins and is However the recent development of advanced often utilized in systems biology. It is a versatile The experimental apparatus contributed by Austrian tools and the evolution of biological thought has and powerful technology used at CeMM to quantum physicist Anton Zeilinger addressed the paved the way for a so-called systems view of study a broad range of topics. Proteomics question of how light can be represented. Artist science, where all the influential aspects of any methods such as quantitative mass spectrometry biological process are, as much as possible, taken have been established by Keiryn Bennett’s group Brigitte Kowanz also works with light. She is inter- into consideration. This view is perhaps more at CeMM, and tailored for multiple applications ested in the relationship between technology and relevant to how an actual molecule, cell or from fundamental comparisons of protein organism normally works, but it is also more expression in different biological samples to perception in the context of space and time, waging a complex, and often involves the production detection of protein interactions with different pitched battle against the supposedly superficial, the of large datasets that need to be interpreted to types of molecules. To process and analyze the phantasm of light, the poetry of optical phenomena. produce meaningful and novel biological insights. large and diverse proteomics datasets produced by these methods, the bioinformatics group “My interest has shifted though,” says the artist, led by Jacques Colinge has been developing “toward the information content of light. In our comprehensive statistical and computational society, light is a carrier for information. And thereby platforms. also a metaphor for knowing and recognizing.”

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In close collaboration with the Bennett group, The isobar framework developed by the Colinge One of the major new trends in modern cancer Chemical proteomics is a powerful technique the bioinformatics group introduced a new group now also provides statistical tools and treatment is targeted or personalised therapy. for identifying many of the target proteins that framework, known as isobar, to address the needs analytical methods tailored to the study of This is based on the idea of attenuating the interact with a specific drug. The combination of quantitative proteomics in a comprehensive, modified proteins. It has also introduced a activity of one protein that is known to play of post-genomic drug affinity chromatography intuitive, and mathematically rigorous way. novel paradigm to report complex results to a key role in the disease. However, all drugs in with high-end mass spectrometry and bioinfor- Recently, they have established new statistical users as interlinked spreadsheets containing clinical use inhibit more than one protein. This matic analyses can be used to assemble a target and computational tools to map the dynamics hyperlinks to Internet resources. This is known as polypharmacology and often causes profile of a desired therapeutic molecule. Due of posttranslational protein modifications in extended isobar framework also integrates severe side effects. Therefore, elucidating a drug’s to high demands on starting material, however, a variety of contexts, such as in patient several tools developed by other bioinformatics mechanism of action, i.e., how it influences chemical proteomic studies have been mostly samples, or to analyze the effects of drugs. groups to validate the position of individual cellular function, is important for improving the limited to cancer cell lines. As pioneered by the Post trans lational modifications of proteins, e.g. posttranslational modifications on proteins, as specificity particularly of anticancer therapeutics. Superti-Furga Lab, the Bennett group at CeMM phosphorylation, methylation, acetylation, or well as protein and modification databases. The has developed a technique, in collaboration with ubiquitination, are at the heart of a large number framework is used in several projects at CeMM, Eric Haura and Soner Altiok from the Moffitt of CeMM projects, and are being studied in with collaborators at the Medical University Cancer Center, to down-size these studies almost every laboratory. They regulate protein of Vienna (e.g. Peter Valent, Georg Stingl, and to enable the analysis of very low abundance function and protein degradation, and are Ursula Schmidt-Erfurth) as well as abroad. It has samples such as those obtained from fine therefore highly influential, playing a pivotal been successfully utilized, for example, to study needle tumour biopsies. The methodology they role in many different cellular processes such the synergies of protein kinase inhibitor drugs developed is robust and generic, and holds many as growth, DNA repair and cell death. used to treat patients with leukemia, which was promises for the field of personalised health care. published in Nature Chemical Biology (Winter et al., 2012). The entire isobar framework has been developed open source and is distributed as part of the bio informatics platform R Bioconductor. ,QÁXHQFLQJ*HQH$FWLYLW\

Sequencing of the human genome has shown what controls the on/off state of a gene that are )LJ$PRGHOIRU$LUQ ,QÁXHQFLQJ%LRORJLFDO that it takes about 23,000 genes to make a likely also to be relevant for understanding how OQF51$IXQFWLRQWKH$LUQ locomotive kicks the Igf2r human being, but it gave no information on the epigenetics affects other genes in our genome. ORFRPRWLYHRƆWKH'1$ 3DWKZD\V mechanisms influencing the activity of genes and In recent work, the Barlow lab has shown that rails. The smoke (i.e., the $LUQOQF51$SURGXFW LVD how these can go wrong and cause disease. Many it is specifically the transcription of a special class by-product of the silencing factors can influence gene activity including epi- of long non-coding RNA (lncRNA) that is able mechanism, and blocked To escape the normal control mechanisms that involved in ubiquitination and deubiquitination genetic mechanisms, which are heritable changes to silence imprinted genes and not the lncRNA scientists from seeing the Studying real function. influence growth, cancer cells activate biological are drug targets as they can be used to in gene activity that are not encoded in the DNA. product itself. This result was published in ubiquitination of signaling pathways, which are composed of influence protein activity. Therefore, studying The Barlow group at CeMM has invested many Science (Latos et al., 2012), and the mechanism key regulatory many different molecules, allowing them to grow ubiquitination of key regulatory proteins can years in understanding the epigenetic mechanism may also explain epigenetic gene control proteins can uncontrollably. One such frequently deregulated provide new angles for drug development. A controlling genomic imprinting, a phenomenon elsewhere in the human genome. pathway in cancer is known as the AKT/PI3K/ central control component of the AKT/PI3K/ in which parents leave their ‘imprint’ on one of SURYLGHQHZ mTOR signaling pathway. This pathway is also mTOR signaling pathway is a protein called the two parental copies of a gene inherited by angles for drug deregulated in other disease conditions including PDK1. Although PDK1 is essential for the activa- their offspring, one of which is then switched off. development. diabetes, and therefore many pharmaceutical tion of AKT and various other kinases, fairly companies are developing drugs to inhibit the little is known about the molecular factors that All mammals including human beings inherit a activity of some of the protein components. influence the activity of PDK1 itself. The Nijman complete set of chromosomes from both their lab at CeMM has recently discovered that PDK1 maternal and paternal parent, and consequently Many processes in the cell are influenced by the is ubiquitinated and found one of the enzymes each cell has two copies of every gene. Normally, posttranslational modification ubiquitination, responsible (USP4), which was published in both parental gene copies are equally active in which is the covalent attachment of the small PLoS ONE (Uras et al., 2012). These results reveal all cells, but for a minority of genes an epigenetic protein ubiquitin to a lysine in the target new ways for pharmacological modulation of mechanism known as genomic imprinting protein. This modification is reversible and a set PDK1 activity and thereby the AKT/PI3K/mTOR silences one gene copy in a parental-specific of about 100 peptidases can cleave ubiquitin at pathway, which may prove useful for treating manner. The study of imprinted genes has the attachment site. In principle, the enzymes cancer and other diseases. uncovered many unpredictable findings about

Ce — M—M — Research Report 2012 5H½HFWLRQ + 5H½HFWLQJWKH&RPSOH[LW\RI&DQFHU + 6SRWOLJKWRQWKH,PPXQH5HVSRQVH

24 25 How can we best recognize the value of data and In this study, which was published in Nature use it to make new discoveries? Indeed it’s not (Pichlmair et al., 2012), they used known always necessary to push through boundaries pathways and protein interaction networks to 5H½HFWLRQ to learn something new. A careful look back, a describe the general strategies used by viruses to reflection, on what we have already learned, take control of infected host cells. They showed can sometimes be just as informative. that viral proteins preferably interact with human proteins that have multiple functions and are The idea of the studiolo, that rarified, sophisticatedly Cellular function is managed and organized strongly connected with other human proteins. furnished space in which scholars devote themselves by networks of interacting molecules, the so- This allows the viruses to work efficiently to called biological pathways. Integrating existing globally reprogram host cells, which is useful to the study of the arts and contemplative reflection, knowledge of these pathways with the analysis given that their genomes are limited in size has been with us since the Renaissance. The CeMM of new datasets related to those pathways can and therefore their proteins must be optimally Brain Lounge could well serve as a modern-day help to better structure them and increase employed. discovery power. The Colinge group at CeMM counterpart with an enhanced intellectual practice. has successfully applied this philosophy to a variety of projects such as the analysis of virus- By the mid-1960s, a new, definitive phenomenon host interactions, and cancer genetics. For virus- host interactions, experimentally measured viral had established itself in the international art world: protein-human protein interactions covering Conceptual Art. Since that time, art has no longer 30 distinct viruses were generated by the concerned itself simply with physical objects, with Superti-Furga and Bennett groups at CeMM. form or material, but rather with communicating the work’s underlying idea. Linguistic play and serial process play as important a role as does the participation of the audience. Under the new rules, the execution of the work by the artist is no longer necessary. For “Art as Idea as Idea” what matters are planning, context and meaning.

cell–cell cell cellular nitrogen signaling plasma proliferation cell cycle compound metabolic membrane biosynthetic cell process organization process morphogenesis

aling '1$ ign S metabolic process immune JURZWK translation system gy transcription lo process io signal b transduction A ribosome N R biogenesis nucleocytoplasmic cytoskeleton–dependent mitochondrion P51$ transport intracellular transport organization processing protein chromosome response to complex protein organization targeting stress assembly gy ribonucleoprotein DNA biolo complex cell death macromolecular assembly protein complex PRGLÀFDWLRQ homeostatic P assembly ro process process te os tasis )LJ$PRGHOIRUKRZ normal communication EHWZHHQELRORJLFDOSUR- cesses is perturbed by the DFWLRQRIYLUXVHV$OLQN EHWZHHQWZRSURFHVVHV indicates perturbation and the thickness is propor tional to perturbation strength. Self links indicate that communication is perturbed EHWZHHQSURWHLQVZLWKLQ the same biological process. $GDSWHGIURPNature (Pichlmair et al., 2012).

26 27 5HÁHFWLQJWKH Spotlight on the Complexity of Cancer Immune Response

Sebastian Nijman’s group at CeMM has This gives them a unique tool to analyze the Our immune systems use a highly sophisticated Rather than inventing new ways to avoid been focusing on cancer, perhaps the most activity of thousands of drugs on many of the approach to search through the millions of the immune system, many pathogens use our heterogeneous human disease and one that different genotypes associated with cancer. The diverse types of cells in our bodies to detect a own molecules to work against us. The Knapp will benefit from being perceived in different lab recently reported a mechanism of resistance very small number of invading pathogens. The group recently discovered that lipoteichoic acid ways. Cancer genomics, abounding from the to an emerging class of drugs in breast cancer. ability to recognize pathogens as foreign is (LTA) produced by Staphylococcus aureus binds recent technological breakthroughs of next Using their engineered isogenic cell lines, they conferred by a multitude of dedicated molecules to specific lipoproteins found in human serum, generation sequencing, is currently producing found that breast cancer cells with activated and cells, so pathogens must evolve elaborate known as apolipoproteins (Apo) B100, ApoA1 comprehensive lists of the many genetic aber- c-MYC/NOTCH signaling are resistant to PI3K ways of reflecting away their attention in order to and ApoA2. This enables the bacteria to severely rations found in different cancer subtypes at an inhibitors, showing that the approach can reveal be successful. Sylvia Knapp’s group at CeMM has inhibit the immune response and continue astounding rate. This has led to the recognition overlooked and important new insights. The been studying how the bacteria Staphylococcus to propagate. This work was published in the that the genetic make-up of every patient and team is now continuing their search as well as aureus and Streptococcus pneumoniae escape European Journal of Immunology (Sigel et al., every tumor is different. Thus, one of the major expanding the approach to lung cancer. They detection by shifting the focus of the immune 2012). By investigating the precise function new challenges for cancer therapy is matching have performed new screens with a panel of system. of these human proteins, they can identify the right therapy with the right patient. 100 cell lines and an equal number of drugs. novel mechanisms that can be targeted to help The newly unearthed gene-drug interactions treat infections. The Nijman lab has been using knowledge are the focus of intense studies and will keep of the genetic aberrations in cancer to engineer the team busy for the coming year. cell models to reflect the diversity observed in patients in a more simple and controlled way.

)LJGraphical illustration )LJMetabolism meets drug interaction screen in LQIHFWLRQ7KHPDLQOLSR lung cancer cells. Each dot SURWHLQLQ/'/$SR% represents a gene-drug can bind bacterial molecules interaction measured in S. aureus OLNHOLSRWHLFKRLFDFLG /7$  a panel of isogenic lung $SR% from Staphylococcus aureus cancer cell lines treated and thereby prevent the ZLWKGUXJV,QWRWDO LQÁDPPDWRU\UHVSRQVH !¬WKRXVDQGLQWHUDFWLRQV 7KLVVKRZVWKDWVHUXP ZHUHDVVHVVHG(DFKUDGLDO OLSLGSURÀOHVFDQDƆHFWWKH LQGLFDWHVDGLƆHUHQWGUXJ antibacterial response. treatment and the further /7$ $GDSWHGIURPEuropean DZD\DGRWLVIURPWKH Journal of Immunology, 2012. FHQWHUWKHPRUHVLJQLÀFDQW the interaction scored in the screen. Red indicates more sensitive and black indicates TNF more resistant to any drug. ,GHQWLÀFDWLRQRIVSHFLÀF cancer vulnerabilities can help to bridge the gap EHWZHHQFDQFHUJHQRPLFV DQGHƆHFWLYHWUHDWPHQWV

Ce — M—M — Research Report 2012 28 29 + Repairing '1$ Breaks + 3URWHFWLQJWKH*HQRPH + 5HYHUVLQJ'LVHDVH 5HQHZDO Renewal is a central theme in biology. To remain For example, to mend the damage of DNA, in a healthy state, cells and organisms must which can occur by the action of carcinogens restore homeostasis in the face of many such as those found in tobacco, there are several 5HQHZDO external and internal factors. Whilst renewal dedicated ‘renewal’ systems known as DNA can be induced by medicine, there are many repair pathways. Maintaining the integrity of endogenous systems in the body that help to DNA is of utmost importance to every cell in our renew our molecules and cells in order to protect body as altering it can lead to cellular dysfunction Anyone entering the Brain Lounge may, if so inclined, us against damage and disease. or death, and to diseases such as cancer. slip into one of the jackets hanging from the ceiling. They are blue, have colorful patches and are intended to help the wearer step outside their daily routine. They were created by Daniel Kroh, a trained tailor and fashion designer, from recycled work clothes. Repairing '1$ Breaks

In recent decades, female artists in particular from The controlled repair of DNA breaks is also Indeed, ATM is a so-called tumor suppressor Lygia Clark to Rosemarie Trockel and Cindy Sherman Maintaining critical for a process called somatic recombina- as its absence can lead to cancer. It is required the integrity have explored the modalities of representation tion, which occurs during the development to repair DNA breaks generated in immuno- of white blood cells known as lymphocytes. globulin genes, but how ATM itself is regulated and examined the role that the present and absent RI'1$LV Somatic recombination enables the rearrange- to carry out this function is unknown. Members of utmost body or the codes communicated through clothes ment of immunoglobulin genes and the sub- of the Loizou lab are working on this by importance play in the representation of identity. The various sequent generation of a diverse repertoire of investigating the contribution of ATMs cofactors to every cell approaches include therapy and ritual, the erasing antibodies that are required to mount an efficient ATMIN (for ATM INteractor), and NBS (mutated immune response and eliminate pathogens in Nijmegen Breakage Syndrome) in B and T in our body. of boundaries between art and utilitarian objects, from the body. Failure to efficiently repair these cell development. They have discovered that or taking pleasure in disguise and camouflage. Here DNA breaks leads to immunodeficiency and there is a partial requirement for ATMIN and can also cause the development of lymphoma. NBS in the activation of ATM in lymphocytes. the working methods of art and science find common Joanna Loizou’s group at CeMM is interested in These roles in ATM activation are different ground on the level of the processive, of interaction understanding how key DNA repair proteins, during somatic recombination and immune and performance, of instructions for action and such as the protein kinase ATM, fix programmed system development, and unexpectedly ATMIN breaks in B and T lymphocytes. and NBS can also function independently of expanded art. ATM. The group is now working on better The gene encoding for the ATM protein is characterizing what these ATM-dependent mutated in a hereditary disease called Ataxia and -independent functions are. Telangiectasia, which is characterized by a deficient immune response and predisposition to cancer.

32 33 $ % )LJ$70,1LVUHTXLUHGIRU signaling replicative stress. ¨ ¨ Protecting the Genome    ¨  ¨ $ /RVVRI$70,1 VL$70,1  reduces 53BP1 recruitment $70,1 $70,1 $70,1 $70,1 (red, middle panel) and '$3, 53BP1 3·6$70 $SK --++ $70DFWLYDWLRQ JUHHQULJKW SDQHO ZLWKLQWKHQXFOHXV Most cancer cells proliferate much faster than By taking an unbiased, genome-wide approach, $70,1 RIFHOOV '$3,OHIWSDQHO  normal cells. When cells are exposed to such in collaboration with the Chemical Screening siControl 102 at sites of replicative stress LQGXFHG'1$GDPDJHLQ a growth pressure, known as replicative stress, and PLACEBO lab at CeMM, headed by Stefan 3·6.$3 +H/DFHOOV % &HOOVWKDW specific regions within the genome known as Kubicek, they have identified several proteins 102 ODFN$70,1 $70,1¨¨) fail to signal replicative stress ‘fragile sites’ can break. This leads to genomic that are required for cells to respond to replicative .$3 appropriately, as marked 102 instability and can ultimately promote the stress and repair the associated DNA damage. VL$70,1 by decreased phosphoryla- progression of cancer. To prevent this, DNA ATMIN, the cofactor for ATM, is one of these P’S15-p53 WLRQRIWKHSURWHLQV.$3 52 3·6.$3 DQGS repair proteins coat fragile sites to shield them proteins. In the absence of ATMIN, recruitment 52 (P’S15-p53). against erosion. As fragile sites are frequently of DNA repair proteins as well as DNA damage $FWLQ mutated in cancer, the Loizou group has also signaling is affected. The outcome is that fragile been working on identifying the molecules sites are no longer protected, which may lead and pathways that maintain their integrity to increased DNA breaks within these regions under replicative stress. of the genome. The group is now looking into which other proteins are involved in these genome maintenance functions, in collaboration with the Mass Spectrometry group at CeMM, and whether they may be useful therapeutic targets for treating cancer.

$ B IL-13 LDLR - * )LJ,/GHÀFLHQF\ Reversing Disease 35 ** **  45 accelerates atherosclerotic ** **  lesion formation and alters 30 ** + macrophage activation in 25 atherosclerotic plaques. 30 LDLR-/- (LDL receptor Christoph Binder’s group at CeMM works themselves found in atherosclerotic lesions. ** IL-13 admin- 20 NQRFNRXW PLFHZHUH ** primarily on atherosclerosis, which is a disease of B cell depletion strategies are an emerging 15 + WUDQVSODQWHGZLWKERQH istration could blood vessels that causes heart attack and stroke. therapeutic approach for the treatment of ** PDUURZIURPHLWKHUZLOG 10 15 type (IL-13+/+) or IL-13-/- actually reverse A major risk factor for atherosclerosis is high several autoimmune diseases, such as systemic Necrotic core (%) (knockout) mice and fed blood cholesterol, which triggers the formation lupus erythematosus (SLE). Many of these 5 a high cholesterol diet to pathological 0 of inflammatory deposits (atherosclerotic diseases are also associated with increased 0 induce atherosclerotic le- 0 50 100 150 200 250 300 350 400 VLRQV,/ERQHPDUURZ changes in the - lesions) in the artery wall. However, many cardiovascular risk, therefore these novel drugs μm IL-13 LDLR +  increased atherosclerotic YDVFXODUZDOODIWHU patients who receive medication that effectively represent potentially attractive tools to also OHVLRQVL]H $ DQGQXPEHU C D E ZLWKQHFURWLFFRUHV %  lowers cholesterol still develop progressive treat atherosclerosis. Scientists in the Binder The relative content of atherosclerotic 30 30 disease due to ongoing inflammation. Scientists group have been dissecting the roles of B cells in 200 ** total macrophages (C) and lesions had in the Binder group have been studying the role the disease. Interestingly, the two major B cell ) M1 type macrophages (E) LQOHVLRQVZDVHTXLYDOHQW developed. of interleukin (IL)-13, which is a cytokine secreted subsets seem to have opposite effects. While B1 150 IL-13-/- 20 20 ZKLOH ERQHPDUURZ by T helper type 2 cells, in murine atherosclerosis. cells mediate protection via secretion of natural WUHDWHGPLFHKDGVLJQLÀ- cantly less M2 type macro- IgM antibodies, conventional B2 cells seem to 100 phages in lesions (D). + 10

They found that IL-13 administration could actu- promote atherogenesis. Thus, B cell depletion 10 DUHDFHOOXODUDUHD + ally reverse pathological changes in the vascular M2 macrophages (Ym1 50

strategies should be developed to target one M1 macrophages

wall after atherosclerotic lesions had developed B cell subset selectively. content (%) Macrophage

0 iNOS (% in hypercholesterolemic mice. This was caused by 0 0 IL-13 LDLR - + LDLR - IL-13 LDLR - + an increase in the collagen content and a decrease To further this line of research, in collaboration   IL-13 +    in the macrophage content of the preexisting ath- with Ziad Mallat from the University of erosclerotic lesions. In contrast, IL-13 deficiency Cambridge, the Binder group studied the role of accelerated atherosclerosis development, which the BAFF receptor (BAFF-R) in B cell regulation was found to be independent of cholesterol. of atherosclerosis. They found that BAFF-R This discovery, that IL-13 is a protective factor in deficiency caused a selective depletion of B2 atherosclerosis, was recently published in EMBO cells, and a reduction in atherosclerotic lesions. Molecular Medicine (Cardilo-Reis et al., 2012). This work was published in Arteriosclerosis, Thrombosis, and Vascular Biology (Sage et al., Recently, B cells of the immune system have 2012), and could potentially be exploited to also been identified as important mediators develop a much needed therapeutic approach of atherosclerosis, even though they are not for atherosclerosis.

Ce — M—M — Research Report 2012 34 35 + 3UHFLVLRQ7KHUDSLHV + 7DUJHWLQJ&KURPDWLQ + 3UHFLVLRQLQ7HFKQRORJ\ + '1$ Sequencing + 3LQSRLQWLQJWKH&DXVHRI'LVHDVH $FFXUDF\ Many human diseases are highly complex. disease. This can also include, for example, Successfully treating them requires both using drug combinations to bypass the predicted detailed knowledge of the underlying molecular development of resistance in individual patients. $FFXUDF\ processes, and drugs to modulate these processes Christoph Bock’s group at CeMM is working in a rational and precise manner. The concept of on developing patient-specific combination personalized medicine is based on precision, or therapies for tackling drug resistance in cancer. accuracy, and involves tailoring a treatment to Sir Ernst Gombrich was a renowned Austrian-British the individual art historian who rethought fundamental art historical questions and drew connections to other disciplines, from experimental psychology to humanistic research. In the book The Sense of Order: A Study in the Precision Therapies Psychology of Decorative Art, he tried to empirically explain pattern and ornament on the basis of the Gestalt theory. HIV infection and cancer pose similar challenges Given the molecular complexity and patient- Personalizing for designing successful therapies. They are specific nature of drug resistance mechanisms, both driven by evolutionary processes and highly personalized therapies are needed that therapy can help The basic motif of Esther Stocker’s work is the grid. as such can evolve resistance to an initially are selected based on a comprehensive molecular develop safer and With the geometricized black and white of the North successful drug. HIV therapy has become the map of the resistance mechanisms in each patient. PRUHHƆHFWLYH poster child of personalized medicine. Although Towards this goal, the Bock group has been Wall, she references the traditions of Constructivist it is currently not possible to cure the disease, sequencing leukemia samples from patients that treatments for art and sets them in motion through shifts in the use of antiviral combination therapies has have been treated with chemotherapy in order treating cancer had a tremendous clinical impact, converting to identify genetic and epigenetic mechanisms patients. perspective and overlay. HIV infection from a fatal disease into a chronic of resistance. They have also been establishing condition with relatively low mortality. and validating cellular assays to measure With her variations on reversible images, inversions Christoph Bock and his team want to build resistance to epigenetic drugs in vitro, as well on these recent successes in personalized HIV as developing bioinformatic algorithms that and optical illusions, the artist negotiates not only therapy, and explore whether similar approaches can predict personalized drug combinations the relativity of perception in general, but also casts may also contribute to improved treatment for a given, genetically and epigenetically a critical eye on rigid systems of order and the different options for cancer. The rationale for their strategy characterized, leukemia patient. By personalizing was recently outlined in Nature Reviews Cancer therapy in this way, they aim to help develop levels of truth. (Bock and Lengauer, 2012). safer and more effective treatments for treating cancer patients.

)LJEpigenetic alterations LQ'1$PHWK\ODWLRQDUH predictive of chemotherapy resistance in cancer.

38 39 Targeting Chromatin Precision in Technology

The development A drug that can precisely inhibit a given target the first molecules targeting histone-modifying Technological breakthroughs often accompany 10,000-fold improvement in throughput and is another important aspect of personalized enzymes are only now emerging. Although great advances in knowledge. Two relatively cost. These advances are already transforming of highly selective medicine. However, most small molecule drugs inhibitors of histone deacetylases and DNA recent technologies that have revolutionized biomedical research, and they provide huge chromatin- act on several different targets leading to severe methyltransferases are now approved drugs, many fields are mass spectrometry and next opportunities for precise and patient-specific targeting drugs side effects, which is particularly problematic for the vast majority of the 400 chromatin generation sequencing, which provide precise treatment decisions. The Biomedical Sequencing when combinations of drugs are being considered. modifying proteins no targeting compounds information about protein mass distributions Facility at CeMM (http://biomedical-sequencing. may also be Stefan Kubicek’s group at CeMM is identifying exist. The Kubicek group has been developing and about DNA sequences, respectively. Since at) was launched in 2012 in an effort to make valuable for and also developing small molecules that can inhibitors for the histone demethylating enzyme 2006, next generation sequencing has emerged the latest sequencing technology accessible to treating cancer. precisely modulate chromatin. Chromatin is JMJD2C, which has been linked with the as one of the fastest advancing technologies Austrian scientists and to foster its transforma- composed of DNA and associated proteins such develop ment of cancer. in the history of mankind, with an impressive tive role for biomedicine. as histones, which regulate the structure and accessibility of the DNA and thereby control Even for existing small molecules, it is unclear which genes are active in each cell type under how specific their cellular effect is. This is because specific conditions. The development of highly histones are found on all DNA sequences, and so selective chromatin-targeting drugs may also be the currently approved drugs change the activity valuable for treating cancer by reverting the asso- of thousands of genes. Scientists in the Kubicek Approved drugs: )LJ&KURPDWLQPRGLÀ\LQJ O enzymes can be catego rized ciated aberrant gene expression changes. lab have been addressing whether chromatin- O S O N Decitabine, Azacitidin N DVZULWHUVUHDGHUVDQG HN N OH HN O targeting compounds can be specific enough OH O H H N O N NH HUDVHUVRISRVȅUDQVODWLRQDO N N 2 O OH N Epigenetics is the study of heritable changes to turn on or off only a small set of genes. By OH O N KLVWRQHPRGLÀFDWLRQV$OORI O N N O HO S N N N N S these classes are potentially O H H N in gene expression in the absence of alterations studying the genome-wide transcriptional effects 14 O N HO OH druggable, yet currently to the DNA sequence. One level of epigenetic of 29 chromatin-targeting compounds in two cell high-quality probes exist control is exerted by histone modifications, types at three time points they discovered that anacardic acid AMI-1 BIX-01294 VX-680 5-azacytidine only for selected subfami- OLHV2QO\IRUWZRFODVVHV which are small chemical groups attached inhibitors of the G9A/GLP methyltransferases of chromatin modifying to histone proteins. A wide variety of over only increase the expression of the cholesterol writer 10 HATs9 PRMTs 51 HKMs Kinases 5 DNMTs enzymes, histone deacety- ODVHVDQG'1$PHWK\OWUDQV- 20 different histone modifications exist, and biosynthesis pathway. This finding shows that ferases, molecule inhibitors they are generated, recognized and removed some chromatin modifications control very approved for clinical use. bromo tudor chromo by around 400 proteins. Small molecules are specific gene sets and gives hope that small reader the perfect tools to study which histone molecules can be developed that enable turning Ac Me Me Ph modifications are in fact heritable and therefore single genes on and off at will, which would MBD

truly “epigenetic”. The challenge however is be the ultimate in precision targeting. Me to generate highly potent and selective small molecules to target them. Indeed,

eraser 18 HDACs 1 PADI 32 HDMs PPTs ?

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Approved drugs: Vorinostat, Romidepsin

Ce — M—M — Research Report 2012 40 41 '1$ Sequencing Pinpointing the Cause of Disease

The Biomedical Sequencing Facility (BSF) is standard of genome-based diagnostics, exome Scientists in the Boztug group at CeMM are In a recent collaboration with Elisabeth Many human a joint initiative of CeMM and the Medical sequencing for cost-efficient discovery and combining next generation sequencing and Förster-Waldl, Medical University of Vienna, University of Vienna. Coordinated by CeMM validation of disease genes, RNA-sequencing other state-of-the-art genomics approaches the St. Anna Kinderspital and Children’s diseases are Principal Investigator Christoph Bock, the BSF as a powerful technology for gene expression with a variety of functional approaches to pin- Cancer Research Institute, and the Klinik characterized constitutes a broadly collaborative effort with profiling and replacement of microarrays, as point the molecular mechanisms underlying Wels-Grieskirchen, they were able to identify by a multitude major contributions from scientists at both well as several epigenome mapping protocols immune dysregulation and autoimmunity. a novel inherited immunodeficiency disorder institutions (including Martin Bilban, Berthold that provide unprecedented insights into Autoimmunity is caused by the failure of the associated with severe systemic autoimmu- of autoimmune Streubel, Arndt von Haeseler, Martin Posch and disease-associated alterations that occur immune system to properly distinguish host nity. The team has used Affymetrix-based phenomena. Wolfgang Schreiner at the Medical University, outside of the genomic DNA sequence. (self) from non-self, resulting in an immune genotyping of single nucleotides (SNPs) and as well as Kaan Boztug and Robert Kralovics at attack on healthy cells in the body. Many exome sequencing and identified mutations in CeMM). Close collaboration and synergy also Importantly, the BSF also constitutes a human diseases are characterized by a multitude the gene encoding protein kinase C (PKC) delta exist with the sequencing group of Andreas technology hub and disseminates sequencing- of autoimmune phenomena, however the as the underlying genetic cause of a hitherto Sommer at the Vienna Biocenter and the related know-how widely throughout Austria’s underlying molecular mechanisms are often unrecognized immunodeficiency disorder with Campus Service Support Facilities GmbH. biomedical research community. To that end, poorly understood. severe Lupus erythematodes-like autoimmune the BSF organizes an annual symposium on phenomena. They could show that deficiency The BSF is equipped with the latest technology, next generation sequencing (together with The Boztug group is studying patients suffering of PKC delta leads to hyperactive signaling via including two Illumina HiSeq 2000 sequencers Andreas Sommer) and contributes conceptual from inherited defects of their immune systems, interleukin-6, which may be linked to the main- and cluster computing infrastructure, which advice, hands-on help and formal support letters so-termed “primary immunodeficiency tenance of autoreactive B lymphocytes. Taken provides sufficient throughput for large-scale to projects and grant applications of scientists disorders”. Many of these patients show together, their study identified a novel primary genome analyses. Extensive expertise and at CeMM, the Medical University of Vienna features of (often severe) autoimmunity and immunodeficiency syndrome associating an hands-on practical support are available for and beyond. immune dysregulation. This provides a unique immunoglobulin class switch defect and severe biomedical sequencing protocols, including opportunity to dissect some of the molecular systemic autoimmunity. Future studies will personal genome sequencing as the gold mechanisms in natura rather than working with address whether the aberrant signaling cascades animal models that have less relevance for the identified may represent attractive therapeutic human disease. targets in PKC delta-deficient patients or even other patients suffering from disorders of auto- immunity or immune dysregulation.

)LJGlomerulonephritis as one of the characteristic autoimmune features in a novel primary immuno- GHÀFLHQF\FDXVHGE\ GHÀFLHQF\RI3URWHLQ.LQDVH C delta (PRKCD). The SLFWXUHVVKRZVHJPHQWDO mesangial sclerosis and granular IgG deposits along the periphery of the capillary loops (images courtesy of Renate Kain, Dept of Pathology, Medical University of Vienna).

Ce — M—M — Research Report 2012 42 43 $VVRFLDWLRQ + 0HFKDQLVPVRI'UXJ$FWLRQ + 3DWKRJHQ+RVW,QWHUDFWLRQV + &RQQHFWHG3URWHLQV + Lethal Interactions for Cancer Scientists often talk about “mechanism of Mechanisms involve complex associations action”, and deciphering it is an important between different factors such as genetic goal in scientific research. It means gaining an mutations, molecules and cells. Uncovering $VVRFLDWLRQ understanding of how a biological process such the biological mechanism of action is often as a viral infection or a drug treatment works challenging, but it can help lead to important in molecular detail. new discoveries. The backrests of the 14 armchairs assembled around the table feature artists’ works formally rooted in the tradition of emblems, signs and symbols. Eva Schlegel and Thomas Feuerstein thematically address the Mechanisms subject of scientific research, while Alois Mosbacher and Martin Walde offer a sly wink, a watchdog, RI'UXJ$FWLRQ and puns. The Superti-Furga laboratory at CeMM has been To uncover the mechanism of action, the team Uncovering Thomas Feuerstein in particular couples art and working on understanding the inner workings applied a systems-level approach comprising the biological science in his work. His sculptures are equal parts of leukemic cells. In particular, they have phosphoproteomics, together with Forest White mechanism of experimental set-ups and dynamic transformation been investigating new strategies to inhibit an at MIT, transcriptomics, and chemical proteomics abnormal fusion protein known as BCR-ABL, with the Bennett team at CeMM. Data integration, action can lead machines. Yet for Feuerstein, this sort of dialogue which causes chronic myelogenous leukemia in collaboration with Jacques Colinge and his to important demands “that one discipline does not merely serve (CML). This protein contains a tyrosine kinase team, revealed that both compounds targeted catalytic domain that is critical for its function. the MAPK signal transduction pathway down- QHZGLVFRYHULHV as a helpmate to the other, but that there are also Specific anti-cancer drugs known as kinase stream of BCR-ABL resulting in impaired moments of surprise.” That it is never quite clear inhibitors can bind to this catalytic domain activity of the protein c-Myc. Pharmacological who is ultimately benefiting from whom: art from and block its activity, and they have been used validation revealed that the relative contribution successfully to treat CML patients. However, of danusertib and bosutinib could be mimicked science, or rather science from art. leukemic cells can become resistant to the individually by MAPK inhibitors and collectively drugs through different mechanisms, including by downregulation of c-Myc. Thus integration mutations in the drug’s binding site. of genome- and proteome-wide technologies enabled them to elucidate the mechanism The most frequent and one of the most harmful by which a novel drug synergy targets BCR- of such resistance mutations changes the amino ABL T315I CML cells. The work highlights the acid threonine found at the so-called “gate- importance of so-called “systems pharmacology”, keeper” position 315 of the BCR-ABL protein and was published in Nature Chemical Biology to an isoleucine (known as the T315I mutation). (Winter et al., 2012). The approach itself can be This mutation blocks the binding of most of applied to determine the molecular mechanism the tyrosine kinase inhibitor drugs. Scientists of action of single drugs, most of which are in the Superti-Furga group have investigated completely unknown. combinations of tyrosine kinase inhibitors that synergize only in CML cells harboring this specific BCR-ABL T315I mutation. Danusertib and bosutinib were the two drugs displaying the most significant and specific synergy.

46 47 3DWKRJHQ+RVW Lethal Interactions Interactions for Cancer

We lack a More than half a billion people suffer from for human health since the early 20th century. Synthetic lethality is an important concept that Already today, four chromatin-targeting small persistent viral infections such as hepatitis B, The group uses an integrative approach involving can be used to determine the mechanism under- molecules are approved for the treatment of comprehensive hepatitis C or HIV. These diseases are associated genetic perturbations in cell culture and animal lying a specific biological process, and can also cancer. The histone deacetylase inhibitors SAHA understanding with severe clinical symptoms and can be life models combined with molecular virology, help find new approaches for treating cancer. and Romidepsin are used in cutaneous T-cell of the underlying threatening. However, we lack a comprehensive immunology, pathology and systems biology, It describes the association between two factors lymphoma, and the DNA methyltransferase understanding of the underlying molecular in order to identify and understand the molecular such as a genetic mutation and a small compound inhibitors 5-aza-cytidine and 5-aza-2’-deoxycy- molecular pathogenesis, and as a consequence there are players and networks that shape the disease. that individually causes no harm but together tidine in myelodysplastic syndrome. However, pathogenesis relatively few treatment options available. is lethal to a cell. Chromatin has recently for the majority of the 400 chromatin-modifying of persistent Andreas Bergthaler and his group at CeMM are In particular, scientists in the Bergthaler emerged as an important drug target in cancer, proteins no small molecules are available and viral infection. studying the molecular mechanisms underlying laboratory have been investigating the and so-called epigenetic characteristics, which it is unclear how to prioritize them for drug persistent viral infections with the hope that the mechanisms that the virus uses to evade the refer to heritable alterations in gene expression development. To systematically study the effects knowledge gained will lead to the development host’s immune system and establish persistence. that do not alter the DNA sequence, are one of chromatin factors on the proliferation of of urgently needed new treatments. To bridge the gap between the experimental of Hanahan and Weinberg’s now infamous cancer cells, the Kubicek group has assembled animal models and the patients they have “Hallmarks of Cancer”. Indeed, many chromatin a lentiviral shRNA knock-down library, in To address the vast complexity of pathogen-host initiated collaborations with clinical groups proteins are misregulated in cancer or involved collaboration with the Broad Institute, to reduce interactions that are relevant for the human dis- including Peter Ferenci and Michael Trauner, in synthetic lethal interactions with oncogenic the levels of each of the 400 chromatin proteins. ease, the Bergthaler group uses an animal model both at the Medical University of Vienna. signaling pathways. Scientists in the Kubicek This approach can identify synthetic lethal inter- based on a small mouse virus named lymphocytic Through their integrative and disease-centric group at CeMM are systematically identifying actions between cancer-causing mutations and choriomeningitis virus (LCMV). This virus has approach they expect to gain an in-depth chromatin proteins involved in synthetic lethal chromatin proteins, and also provide insight an impressive track record having contributed understanding of the general mechanisms interactions with breast cancer oncogenes, which into their mechanisms of action. Their first to fundamental scientific discoveries relevant underlying infectious pathogenesis. could become the drug targets of the future. results have identified cytostatic effects in cells with certain oncogenes specifically when the histone sumoylation pathway is lost. Further validation experiments are ongoing for other genes and compounds. Connected Proteins

Loss of Cofactor )LJ(SLJHQHWLF The physical association between molecules In collaboration with Klaus Kratochwill at the imprinting imbalance KDOOPDUNVRIFDQFHU *OREDOO\'1$PHWK\ODWLRQ can be a valuable way of identifying mechanism Medical University of Vienna and Matthias is often lost in cancer '1$K\SRPHWK\ODWLRQ  of action. For example, protein complexes form, Gstaiger at the ETH in Switzerland, Keiryn Defects in histone ZKHUHDVLWLVDEHUUDQWO\ incorporation and *OREDO'1$ dissociate and re-form in order to perform Bennett’s group at CeMM has been developing gained at promoters of nucleosome remodelling hypomethylation specific cellular functions such as transcribing a method that can overcome this challenge. tumor suppressor genes a gene or degrading old molecules. However, In their two-pronged protocol, non-covalent '1$K\SHUPHWK\ODWLRQ  0LVUHJXODWLRQRI'1$DQG these physical associations can be difficult to protein complexes are first isolated by affinity KLVWRQHPRGLÀFDWLRQVFDQ detect if they are particularly transient, or occur purification for subsequent identification of result in the epigenetic activation of proto- only under specific conditions. In addition, the components by liquid chromatography oncogenes, repression of it can be challenging to identify all the proteins high-resolution mass spectrometry (LCMS). $EHUUDQWUHFUXLWPHQWRI /RFDO'1$ tumor suppressor genes, in a multi-component protein complex. In the second prong of the approach, the affinity- KLVWRQHPRGLÀFDWLRQV hypermethylation and reactivation of hetero- chromatin and endogenous purification strategy is layered with chemical viruses. Often, genetic crosslinking to “freeze” a series of concurrently mutations in chromatin formed, heterogeneous protein sub-complex PRGLÀHUVDUHUHVSRQVLEOH for their aberrant activity in species that are visualised by gel electrophoresis. Reactivation of cancer, but also imbalance This helps to reveal the dynamics of the Misregulation of heterochromatin and of their cofactors can be KLVWRQHPRGLÀFDWLRQV endogenous viruses causal. Furthermore, loss individual components of protein complexes. of imprinting, and defects The protocol is simple, robust and can be readily in histone incorporation extended to the investigation of a range of and nucleosome remodeling have been observed protein complexes. $FWLYDWLRQRI Repression of tumor in cancer. Inspired by protooncogenes suppressor genes '+DQDKDQDQG5:HLQEHUJ

Ce — M—M — Research Report 2012 48 49 '\QDPLFV

+ Varying Epigenetics in Cancer + (YROXWLRQRI/HXNHPLD + 7KH'LYHUVLW\RI&DQFHU + 51$'\QDPLFVLQ&DQFHU + The Changing Course of Infectious Disease + &RQWUROOLQJWKH,PPXQH5HVSRQVH Many of us get our first glimpses of biology in All of these mediums fail to accurately portray textbooks. Subsequent exposure comes from arguably one of the most important character- newspapers and scientific reports like this one. istics of biology - its highly dynamic nature. '\QDPLFV Scientists report their results in printed publica- Scientists at CeMM are studying several topics tions, and even the coveted “biological model”, that illustrate this dynamism. For example, which combines the results from a series of Christoph Bock’s group is studying how experiments focused around a specific topic such epigenetic marks change during the development The Brain Lounge is the place where the classic as a pathogen infection, is mostly presented as of leukemia. academic approach to work diffuses into another a two-dimensional diagram. mode of knowledge production. Here a new genre is placed in the context of contemporary art: transdisciplinary conferences that largely dispense with scientific hierarchy and are responsive to social Varying Epigenetics demands. The participants gather around a symbolic object to debate and exchange ideas: the round table. in Cancer At the center of the rotating meeting element rests Peter Kogler’s computer-generated image module Brain. The organ around which everything orbits, The genetic code of DNA provides a universal However, before epigenetic therapies can be The emerging building plan for the cell’s molecular machinery. used with confidence for the treatment of a broad in the arts as in science. But a second code is needed to organize range of cancers, a more detailed understanding model of cancer 100 billion cells with identical genomes into of the epigenome’s functional role in cancer is as a disease that 200 specialized cell types to make a healthy required. To that end, Christoph Bock’s laborato- is also epigenetic human being. This second so-called “epigenetic” ry is collaborating with Robert Kralovics’s group in nature creates code is altered in essentially every cancer patient. at CeMM, and with Renate Panzer- Grümayer The changes include altered DNA methylation at the St. Anna Children’s Cancer Research an exciting patterns and shifts in the genome-wide distribu- Institute to perform comprehensive epigenome opportunity for tion of histone modifications and chromatin- characterization in leukemia patients that have associated proteins. The Medical Epigenomics been followed over time. QHZWKHUDSLHV program at CeMM is studying the dynamics of epigenome changes in patients that have been Their approach combines high-throughput diagnosed with leukemia and in their response assays, including genome-wide bisulfite to successful and failed chemotherapy. sequencing for analyzing DNA methylation, with large-scale data integration and bioinfor- The emerging model of cancer as a disease that matic analysis. By applying these methods to is also epigenetic in nature creates an exciting the leukemia cohorts that have been analyzed opportunity for new therapies. Rather than over time, it will be feasible to pinpoint series having to kill every single cancer cell through of epigenetic events that contribute to disease aggressive chemotherapy, it is becoming progression. This work is highly complementary increasingly feasible to erase cancer-associated to the work of the International Human Epig- epigenetic aberrations through the use of enome Consortium and the European BLUE- epigenome-altering drugs. PRINT project, which CeMM joined as a project partner and work package leader in 2012.

52 53 Evolution of Leukemia 51$'\QDPLFVLQ&DQFHU

Clearly, cancer is a highly dynamic disease. It shapes the cancer genome in a given environ- The human genome contains vast numbers The development of an RNA-Seq pipeline that originates from a single mutant cell that can ment. Different tissues have different selective of so called long non-coding (lnc) RNAs that can efficiently identify macro lncRNAs initially outgrow other cells in the same tissue and forces. In leukemia, the leukemic clone of each are predicted to control the activity of protein- proved an experimental and bioinformatic chal- evolve into a tumor. The “initiating” mutation patient takes on a unique evolutionary path. coding genes during embryonic development lenge. Now the pipeline is operational and is in a single blood cell during the earliest phase As a result, a mosaic of chromosomal changes and cell differentiation. LncRNAs are now also being used to identify macro lncRNAs expressed of leukemia can have various forms such as a accompanies the evolutionary trajectory of predicted to be involved in the abnormal activity in inbred mouse tissues where mouse mutants translocated chromosome, a chromosome with each leukemic clone. or silencing of protein-coding genes in cancer. that lack a specific epigenetic gene can be used a missing or multiplied piece, or a point mutation The Barlow group at CeMM has recently defined to determine how lncRNAs act to silence in a single gene. Once the leukemic cell is formed, Scientists in Robert Kralovics’s group study a novel class of lncRNAs known as macro other genes. It is also being used to identify the it sets out to multiply, and its progeny (the tumor the genomic architecture of leukemic cells in lncRNAs whose lncRNA product appears to be dynamic expression of macro lncRNAs in normal mass) starts to compete for space and resources hundreds of patients diagnosed with different dispensable for their function. They describe this human white bloods cells and in hematological with healthy cells. The dynamic process of forms of leukemia. In each patient, the leukemic class in a recent review published in the journal malignancies. They aim to establish a database genetic evolution of leukemic cells is one of the genome is evaluated using either DNA micro- RNA Biology (Guenzl and Barlow, 2012). The of robustly expressed lncRNAs (i.e. expressed main research topics in the laboratory of Robert chips that can read 1.8 million data points per Barlow group has two main research goals in all volunteers at all time points) and non- Kralovics at CeMM. genome, or whole genome (exome) sequencing. directed towards unraveling the function of robustly expressed lncRNAs (i.e. expression This enables them to “paint a genome mosaic” lncRNAs and macro lncRNAs in human dis- varies between different volunteers and at During the division of each cancer cell, mutations for each leukemic patient. When these analyses ease. First, they are investigating the molecular different time points), which can then be used accumulate and are passed to the next generation are done for hundreds of patients, it is possible mechanism by which lncRNAs silence imprinted to analyze changes that arise in hematological of cancer cells. Although the vast majority of to compare them and find similarities and differ- genes using a mouse embryonic stem (ES) malignancies such as myeloproliferative these newly acquired genomic mutations do not ences. Using this approach they have discovered that they developed in 2009. Second, they are neoplasms and leukemia. This project is being provide any benefit to the cancer clone, some can a number of frequent chromosomal defects that using high-throughput RNA sequencing (one performed together with the CeMM groups of be useful in the environment in which the cancer implicated a group of transcription factor genes of CeMM’s core technologies) in combination Robert Kralovics, an expert in hematological resides, thereby providing a selective advantage. in cancer progression. with a novel bioinformatics pipeline to identify malignancies, Christoph Bock, an expert in Indeed, selection is the main driving force that lncRNAs. high-throughput sequencing bioinformatics and Jacques Colinge, an expert in bioinformatic analysis. The Diversity of Cancer

0DFUR,QF51$V IXOO\VSOLFHGOLQF51$V )LJ0DFUROQF51$V (left panel) are inef- Leukemia can originate de novo (i.e. without a found a huge number of genetic lesions, and ÀFLHQWO\VSOLFHGLQWRORQJ Each patient’s 1-3kb QRQFRGLQJ51$V7KH\ previous history of a blood disease) or emerge only a handful of these were seen in specific leukemic cells Splicing, 10-100kb are ultra-long, lack se- after a chronic blood disorder such as myelopro- diagnostic groups. This suggested that each stability quence conservation and 2-3 exons evolve in a unique liferative or myelodysplastic disorders (so called patient’s leukemic cells evolved in a unique & length have a short half-life. Only VSOLFHGPDFUROQF51$V ZD\QRWVHHQLQ “secondary” leukemia). To study the evolution of way with a combination of genetic defects not are exported to the leukemia, secondary leukemias are better disease seen in any other patient. These results were F\WRSODVP0DFUROQF51$V any other patient. repress gene transcrip- models as they offer an insight into the genetic published in the American Journal of Hematology WLRQLQWZRZD\VWKURXJK mechanisms preceding the leukemic transfor- (Milosevic et al., 2012). If this pattern is confirmed, WKHLUOQF51$SURGXFWRU mation. In a recent study, the Kralovics group therapeutic strategies need to be found to tackle by transcriptional inter- IHUHQFH/LQF51$V ODUJH performed comparisons of the genetic patterns such genetic diversity. This challenge is also LQWHUJHQLFRUOLQF51$V right panel) are the pro- found in “de novo” and “secondary” leukemias. being addressed by some of CeMM’s drug Cellular WRW\SHOQF51$DQGDUH localization Using high-resolution genomic analysis, they discovery projects. GHÀQHGRQO\E\DVSOLFHG nucleus nucleus product larger than 200nt. /QF51$VDUHFRQVLGHUHG to act in trans e.g., by binding and recruiting chromatin-modifying in trans enzymes to regulate gene expression, they are fully- Chr7 spliced, relatively stable and likely to be exported Function WRWKHF\WRSODVP$GDSWHG from RNA Biol. (Guenzl in cis Chr2 DQG%DUORZ 

Ce — M—M — Research Report 2012 54 55 The Changing Course Controlling the of Infectious Disease Immune Response

In another example of dynamics in biology, The first approach utilizes proteins already Arguably the most important achievement of Their work resulted in the identification of some This large dataset Giulio Superti-Furga’s group at CeMM is study- known to be associated with innate immunity the Superti-Furga team in 2012 was the discovery 600 different host proteins. Some of these were ing the dynamic course of the innate immune pathways. The second uses virus-associated of the strategies that viruses use to control the already known to be involved in the immune ZLOOKHOSJXLGH response to pathogen infection. During this molecular patterns to identify the host proteins cellular immune response. Viruses infect humans, response to viral infections, validating their the development process, one can roughly distinguish between that interact with them, and therefore are plants and other organisms causing a variety approach. Subsequent network analyses revealed RIERWKVSHFLÀF a first alarm-call leading to the secretion of type likely to be involved in either detecting them of acute and chronic diseases. In response, the general and specific mechanisms at work. In I interferons and pro-inflammatory cytokines, or destroying them. The third approach takes host is equipped with an innate immune system particular, they discovered that viral proteins and broad acting and a second response and execution phase those proteins already implicated in immune- that detects the invading pathogen by sensing preferentially target cellular factors that are highly antiviral therapies. during which the pathogen is neutralized, modulatory functions of the viruses to purify so-called Pathogen Associated Molecular Patterns connected to other proteins, and are involved in presented to cells of the adaptive immune relevant host protein complexes. Using these (PAMPs) that can specifically recognize foreign multiple signaling pathways. This appears to be a system, and the alarm is switched off. Scientists approaches coupled to mass spectrometry, nucleic acids and proteins. Sensing of these general strategy for controlling the host immune in the Superti-Furga laboratory, along with followed by bioinformatics and functional danger signals by proteins such as the family of response. Using new bioinformatics methods the laboratories of Keiryn Bennett and Jacques experiments, the CeMM-internal consortium Toll-like receptors (TLRs) triggers a signaling they also showed that DNA viruses perturb Colinge, have been launching a three-pronged has mapped in a step-wise fashion the cellular cascade leading to the production of type-I processes associated with DNA biology such as affinity proteomics approach to reveal a proteins that mediate the innate immune interferons. “cell cycle and proliferation” and “chromosome comprehensive picture of these processes in response to viral infection. biology” and RNA viruses perturb processes such molecular detail. This approach is largely covered Viruses have evolved mechanisms to counter- as “RNA metabolism” and “RNA/Protein trans- by the Advanced ERC grant obtained by Giulio act the host immune response by modifying port”. The large dataset produced by this study, Superti-Furga in 2009. immune cell signaling. To systematically which was published in Nature (Pichlmair et study the impact of these viral innate immune al., 2012), should help guide the development of modulators, the team selected 70 of them from both specific and broad acting antiviral therapies. 30 different viruses designed to represent the many different types of viruses in existence. Using these proteins, they designed a molecular “hook” known as a tandem affinity tag to fish for interacting proteins in the cell, which could then be identified by mass spectrometry in the Bennett laboratory.

)LJ $ 9LUDOSURWHLQV FODVVLÀHGDFFRUGLQJWR KRZWKH\WDUJHWWKHJOREDO QHWZRUNRIKXPDQSURWHLQV DQGWKHLUSDWKZD\V,QWKLV dendrogram, the proteins from the same virus fam- ily tend to have closer GLVWDQFHV % ,QSDUW $  ZHQRWHWKDWWKHYDFFLQLD virus (VacV) proteins indi- cated by stars are far from each other, thus indicating non redundant functions, ZKLFKLVDPDQLIHVWDWLRQRI the optimal use of a small YLUDOJHQRPH$GDSWHGIURP Nature (Pichlmair et al., 2012).

Ce — M—M — Research Report 2012 56 57

Denise Barlow is a British national who joined CeMM in 2003 and is an Honorary Professor at the Denise P. University of Vienna. Denise initially trained as a 3ULQFLSDO State Registered Nurse in the UK and afterwards %DUORZ completed her undergraduate studies at Reading University (UK) and a Ph.D. on the interferon (SLJHQHWLF0HFKDQLVPV system in early mouse development at Warwick ,QYHVWLJDWRUV LQ'HYHORSPHQWDQG'LVHDVH University (UK). Post-doctoral work studying mouse embryonic development followed at ICRF (London, UK) with Dr. Brigid Hogan, and on genome biology at EMBL (Heidelberg, D) with Dr. Hans Lehrach. Denise has also held group leader positions at the IMP (Vienna, A) and the NKI (Amsterdam, NL). On returning to Austria in 2000, Denise was appointed Head of the Dept. of Develop - mental Genetics at the Austrian Academy IMB Institute (Salzburg, A), and then returned to Vienna in 2003 as a Principal Investigator with CeMM. One of the Barlow lab’s major achievements was the discovery in 1991 of the first imprinted gene in mammals to show parental-specific gene expression. Their subsequent identification that epigenetic silencing of this imprinted gene is induced by expression of an unusual long non-coding (lnc) RNA, has led them to investigate how lncRNAs act throughout the mouse and human genome as regulators of gene expression in development and disease. The lab continues to &H003ULQFLSDO,QYHVWLJDWRU use the model of genomic imprinting to dissect GEDUORZ#FHPPRHDZDFDW how lncRNAs epigenetically silence genes, and uses this as a platform together with high throughput +RQRUDU\3URIHVVRURI*HQHWLFV sequencing technology to extend these results into 8QLYHUVLW\RI9LHQQD $ human diseases such as cancer. Ph.D., :DUZLFN8QLYHUVLW\(UK) 3RVWGRFWRUDO)HOORZ ,&5)/RQGRQ(UK), 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV (0%/+HLGHOEHUJ(D) Airn transcriptional overlap, but not its lncRNA Group Leader, product, induces imprinted Igf2r silencing. ,039LHQQD $  Latos PA, Pauler FM, Koerner MV, energin HB, 1.,$PVWHUGDP(NL) Hudson QJ, Stocsits RR, Allhoff W, Stricker SH, +HDG'HSW'HYHORSPHQWDO%LRORJ\ Klement RM, Warczok KE, Aumayr K, Pasierbek P, ,0%2H$:6DO]EXUJ $ Barlow DP. Science. 2012 Dec 14;338(6113):1469-72. + British -RLQHG&H00LQ A downstream CpG island controls transcript + Group of 10 people initiation and elongation and the methylation state of the imprinted Airn macro ncRNA promoter. 0DLQ5HVHDUFK,QWHUHVWV Koerner MV, Pauler FM, Hudson QJ, Santoro F, + Molecular basis and function Sawicka A, Guenzl PM, Stricker SH, Schichl YM, of genomic imprinting in mice Latos PA, Klement RM, Warczok KE, and humans Wojciechowski J, Seiser C, Kralovics R, Barlow DP. ,GHQWLÀFDWLRQDQGFKDUDFWHUL]DWLRQ PLoS Genet. 2012;8(3):e1002540. RIPDFURORQJQRQFRGLQJ OQF 51$V a collaboration with the CeMM Kralovics group in the mouse and human genomes and MedUni Vienna Seiser group. 7KHSRWHQWLDORIPDFUROQF51$VDV tumor biomarkers in human cancer Mechanisms of long-range silencing by imprinted macro non-coding RNAs. Pauler FM, Barlow DP, Hudson QJ. Curr Opin Genet Dev. 2012 Jun;22(3):283-9. Review.

60 61 Keiryn Bennett, Ph.D., obtained her Bachelor of Andreas Bergthaler, born 1977, studied veterinary Science with First Class Honours from the medicine at the University of Veterinary Medicine Keiryn L. University of Tasmania; and her Ph.D. in pro- $QGUHDV in Vienna and spent clinical and research stays tein mass spectrometry from the University of at the Royal (Dick) School of Veterinary Studies, %HQQHȅ Wollongong, Australia. KB spent 2½ years as a post- Bergthaler Edinburgh, the University of Tokyo, the University doctoral fellow in the laboratory of one of the fore- of Zurich and the Danish Veterinary Institute, 0DVV6SHFWURPHWU\DQG3URWHRPLFV fathers of modern-day protein mass spectrometry, 9LUDO,PPXQRELRORJ\ Copenhagen. For his graduate studies he joined Professor Peter Roepstorff, (Odense, Denmark). the Institute of Experimental Immunology at the This was followed by 4 years under the supervision University / ETH Zurich (Profs. Hans Hengartner of Matthias Mann at MDS Proteomics (Odense, and Nobel Laureate Rolf Zinkernagel). After Denmark). KB is respected worldwide in the field postdoctoral work in Zurich and in the laboratory of protein mass spectrometry and proteomics, of Prof. Daniel Pinschewer at the University of with more than 16 years of experience including 4 Geneva he joined Prof. Alan Aderem’s group at years managing a high-throughput industrial prot- the Institute for Systems Biology in Seattle, WA. eomic laboratory. KB joined the laboratory of Giulio In 2011 he co-founded a vaccine start-up company. Superti-Furga in 2004 and established the mass Andreas Bergthaler’s research is focused on the spectrometry/proteomic research group at CeMM. molecular mechanisms which govern virus-host Since 2009, KB has had an independent group leader interactions. To this end the Bergthaler laboratory position and currently the laboratory consists of a studies viral infections in mouse models through an total of 5 people. The mass spectrometry research interdisciplinary approach of pathology, molecular group is involved in a number of interdisciplinary biology, virology, immunology and systems bio- fields such as understanding the role of Hdac1 and logy. The employed experimental models are well- Hdac2 in T-cell differentiation; and investigating defined and bear great patho-physiological relevance infiltrating CD20+ B-cells in the progression of to human disease. This enables his group to dissect human melanoma. These research areas involve the novel molecular determinants and interaction net- study of protein-protein interactions; and drug- works that impact viral pathogenesis and the anti- protein interactions by mass spectrometry and are viral immune system. Eventually, this may pave the supplemented by technological advancements in way for the development of much-sought clinical +HDGRI0DVV6SHFWURPHWU\ chemical crosslinking, quantitative-, acetyl- and &H003ULQFLSDO,QYHVWLJDWRU treatments against viral diseases in man. 3URWHRPLFV phosphoproteomics. DEHUJWKDOHU#FHPPRHDZDFDW NEHQQHȅ#FHPPRHDZDFDW Mag. med. vet., 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV Ph.D. (Chemistry) 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV 8QLYHUVLW\RI9HWHULQDU\ A FOXO3-IRF7 gene regulatory circuit limits 8QLYHUVLW\RI:ROORQJRQJ $86 A method to resolve the composition of hetero- 0HGLFLQH9LHQQD $ inflammatory sequelae of antiviral responses. 3RVWGRFWRUDOIHOORZ geneous affinity-purified protein complexes derived 'UPHGYHW 9LURORJ\,PPXQRORJ\  Litvak V, Ratushny AV, Lampano AE, Schmitz F, 8QLYHUVLW\RI from a common protein by chemical crosslinking, 8QLYHUVLW\RI=XULFK &+ Huang AC, Raman A, Rust AG, Bergthaler A, 6RXWKHUQ'HQPDUN(DK) gel electrophoresis and mass spectrometry. 3RVWGRFWRUDOIHOORZ Aitchison JD, Aderem A. Nature. Rudashevskya EL, Sacco R, Kratochwill K, Huber ML, 8QLYHUVLW\RI=XULFKDQG 2012 Oct 18;490(7420):421-5. doi: 10.1038/ $XVWUDOLDQ Gstaiger M, Superti-Furga G, Bennett KL. Nat. Protoc. 8QLYHUVLW\RI*HQHYD &+ nature11428. Epub 2012 Sep 16. -RLQHG&H00LQ2FWREHU 2013;8, 75-97 3RVWGRFWRUDOIHOORZ + Group of 5 people ,QVWLWXWHIRU6\VWHPV%LRORJ\ Viral replicative capacity is the primary determinant An efficient tandem affinity purification procedure 6HDȪOH 86$ of lymphocytic choriomeningitis virus persistence 0DLQ5HVHDUFK,QWHUHVWV for the characterisation of protein complexes in and immunosuppression. Bergthaler A, Flatz L, 3URWHRPLFVRILQQDWHLPPXQLW\ mammalian cells. Bürckstümmer T, Bennett KL, $XVWULDQ Hegazy AN, Johnson S, Horvath E, Löhning M, immunology Preradovic A, Hantschel O, Superti-Furga G, Bauch A. -RLQHG&H00LQ-XO\ Pinschewer DD. Proc Natl Acad Sci U S A. + Proteomics of protein-protein Nat. Methods. 2006;3, 1013-1019. + Group of 7 people 2010 Dec 14;107(50):21641-6. Epub 2010 Nov 22. interactions including chemical crosslinking; and protein-drug Systematic identification of protein complexes in 0DLQ5HVHDUFK,QWHUHVWV Interferons direct Th2 cell reprogramming to interactions Saccharomyces cerevisiae by mass spectrometry. + Viral pathogenesis generate a stable GATA-3(+)T-bet(+) cell subset + Phospho-, acetyl- and quantitative Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, (e.g. virus persistence, with combined Th2 and Th1 cell functions. proteomics Adams S-L, Millar A, Taylor P, Bennett K, immunosuppression, hepatitis) Hegazy AN, Peine M, Helmstetter C, Panse I, + Integration of mass spectrometry Boutilier K, Yang L, Wolting C, Donaldson I, $QWLYLUDOLPPXQHUHVSRQVHV Fröhlich A, Bergthaler A, Flatz L, Pinschewer DD, ZLWKELRORJ\DQGELRLQIRUPDWLFV Schandorff S, Shewnarane J, Vo M, Taggart J, (CD8 T cell, innate immunity, B cells) Radbruch A, Löhning M. Immunity. Goudreault M, Muskat B, Alfarano C, Dewar D, + Mouse infection models 2010 Jan 29;32(1):116-28. Epub 2010 Jan 14. Lin Z, Michalickova K, Willems AR, Sassi H, + Systems biology Nielsen PA, Rasmussen KJ, Andersen JR, Impaired antibody response causes persistence of Johansen LE, Hansen LH, Jespersen H, prototypic T cell-contained virus. Bergthaler A, Podtelejnikov A, Nielsen E, Crawford J, Poulsen V, Flatz L, Verschoor A, Hegazy AN, Holdener M, Sørensen BD, Matthiesen J, Hendrickson RC, Fink K, Eschli B, Merkler D, Sommerstein R, Gleeson F, Pawson T, Moran MF, Durocher D, Horvath E, Fernandez M, Fitsche A, Senn BM, Mann M, Hogue CWV, Figeys D, Tyers M. Nature. Verbeek JS, Odermatt B, Siegrist CA, Pinschewer DD. 2002;415, 180-183. PLoS Biol. 2009 Apr 7;7(4):e1000080.

Ce — M—M — Research Report 2012 62 63 Christoph Binder was born in 1973 in Vienna, Christoph Bock is a Principal Investigator at the Austria. Following his studies of medicine at the Research Center for Molecular Medicine of the Christoph Medical Faculty of Vienna University, where he Christoph Austrian Academy of Sciences, a guest professor obtained his M.D. degree in 1997, he entered a Ph.D. at the Medical University of Vienna’s department Binder program at the University of California in Bock for laboratory medicine and an adjunct group San Diego. Working with world-famous athero- leader at the Max Planck Institute for Informatics. $WKHURVFOHURVLVDQG,PPXQLW\ sclerosis researcher Joseph Witztum, he obtained 0HGLFDO(SLJHQRPLFVDQG His research focuses on medical epigenomics, his Ph.D. degree in 2002. In 2005, he joined the 1H[W*HQHUDWLRQ6HTXHQFLQJ studying the role of DNA methylation in cancer Department of Laboratory Medicine at the Medical and developing methods for rational design of University of Vienna, where in 2009 he was epigenetic cancer therapies. Christoph graduated appointed Professor of Atherosclerosis Research. from the Max Planck Institute for Informatics C. Binder leads a research group focusing on the role and Saarland University in 2008, where he was of immune functions in atherosclerosis and how involved in the EU-FP7 CANCERDIP project. these can be exploited for therapeutic interventions. During his postdoc at the Broad Institute of MIT He first described the atheroprotective effect of and Harvard, he contributed to the work of the pneumococcal vaccination of the natural IgM Roadmap Epigenome Mapping Consortium, and T15/E06 (Binder et al., 2003). His research group since 2011 he has been as work package leader discovered that certain oxidation-specific epitopes within the EU-FP7 BLUEPRINT project. In 2009, are major targets of natural antibodies (Chou et al., Christoph was awarded an Otto Hahn Medal by 2009) and of complement factor H (Weismann et the Max Planck Society for pioneering work in al., 2011). He also first identified the atheroprotective computational epigenetics. roles and mechanisms of the cytokines IL-5 (Binder et al., 2004) and IL-13 (Cardilo-Reis et al., 2012). Christoph Binder has won numerous prestigious 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV fellowships and awards and has authored 60 Analysing and interpreting DNA methylation data. publications in important journals, including Bock C. Nat Rev Genet. 2012; 13, 705-719. Nature Medicine and Nature. Managing drug resistance in cancer: lessons from &H003ULQFLSDO,QYHVWLJDWRU &H003ULQFLSDO,QYHVWLJDWRU HIV therapy. Bock C, Lengauer T. Nat Rev Cancer. FELQGHU#FHPPRHDZDFDW 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV FERFN#FHPPRHDZDFDW 2012; 12, 494-501. Interleukin-13 protects from atherosclerosis and 3URIHVVRURI$WKHURVFOHURVLV5HVHDUFK modulates plaque composition by skewing the Guest Professor of DNA methylation dynamics during in vivo dif- 0HGLFDO8QLYHUVLW\RI9LHQQD $ macrophage phenotype. Cardilo-Reis L, Gruber S, Laboratory Medicine, ferentiation of blood and skin stem cells. Bock C, MD, 8QLYHUVLW\RI9LHQQD $ Schreier SM, Drechsler M, Papac-Milicevic N, 0HGLFDO8QLYHUVLW\RI9LHQQD $ Beerman I, Lien WH, Smith ZD, Gu H, Boyle P, Ph.D. (Molecular Pathology), Weber C, Wagner O, Stangl H, Soehnlein O, Ph.D., 0D[3ODQFN,QVWLWXWH Gnirke A, Fuchs E, Rossi DJ, Meissner A. Mol Cell 8QLYHUVLW\RI&DOLIRUQLD Binder CJ. EMBO Mol Med. 2012 Oct;4(10):1072-86 IRU,QIRUPDWLFV (D) 2012; 47, 633-647. 6DQ'LHJR 86$ 3RVWGRFWRUDO)HOORZ 3RVWGRFWRUDOIHOORZ Complement factor H binds malondialdehyde %URDG,QVWLWXWH Reference Maps of human ES and iPS cell variation 8QLYHUVLW\RI&DOLIRUQLD epitopes and protects from oxidative stress. +DUYDUG8QLYHUVLW\ 86$  enable high-throughput characterization of 6DQ'LHJR 86$ Weismann D, Hartvigsen K, Lauer N, Bennett KL, $GMXQFW*URXS/HDGHU pluripotent cell lines. Bock C, Kiskinis E, Scholl HP, Charbel Issa P, Cano M, Brandstätter H, 0D[3ODQFN,QVWLWXWH Verstappen G, Gu H, Boulting G, Smith ZD, $XVWULDQ Tsimikas S, Skerka C, Superti-Furga G, Handa JT, IRU,QIRUPDWLFV (D) Ziller M, Croft GF, Amoroso MW, Oakley DH, -RLQHG&H00LQ$SULO Zipfel PF, Witztum JL, Binder CJ. Nature. Gnirke A, Eggan K, Meissner A. Cell. + Group of 9 people 2011 Oct 5;478(7367):76-81. + German 2011; 144, 439-452. -RLQHG&H00LQ 0DLQ5HVHDUFK,QWHUHVWV Oxidation-specific epitopes are dominant targets + Group of 5 people Quantitative comparison of genome-wide + Role of innate immunity in of innate natural antibodies in mice and humans. DNA methylation mapping technologies. LQÁDPPDWLRQDQGR[LGDWLYHVWUHVV Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, 0DLQ5HVHDUFK,QWHUHVWV Bock C, Tomazou EM, Brinkman AB, Müller F, + Elucidate the protective Woelkers D, Shaw PX, Choi J, Perkmann T, + Epigenomic basis of Simmer F, Gu H, Jäger N, Gnirke A, capacities of natural IgM antibodies Bäckhed F, Miller YI, Hörkkö S, Corr M, Witztum JL, hematopoietic diseases Stunnenberg HG, Meissner A. Nat Biotechnol. in atherosclerosis Binder CJ. J Clin Invest. 2009 May;119(5):1335-49. + Bioinformatic dissection 2010; 28, 1106-1114. 'LVFRYHUZD\VWRPRGXODWH of cellular identity natural immunity as therapy for Pneumococcal vaccination decreases atherosclerotic + Diagnostics using cardio-vascular diseases lesion formation: molecular mimicry between next generation sequencing Streptococcus pneumoniae and oxidized LDL. &KULVWRSK%LQGHU·V*URXS Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, LVORFDWHGDW Goodyear CS, Shaw PX, Palinski W, Witztum JL, Department of Laboratory Medicine Silverman GJ. Nat Med. 2003 Jun;9(6):736-43. Medical University of Vienna $QQD6SLHJHO)RUVFKXQJVJHElXGH Innate and acquired immunity in atherogenesis. %7 /D]DUHȅJDVVH Binder CJ, Chang MK, Shaw PX, Miller YI, 9LHQQD$XVWULD Hartvigsen K, Dewan A, Witztum JL. Nat Med. 2002 Nov;8(11):1218-26. Ce — M—M — Research Report 2012 64 65 Kaan Boztug, born in 1977, was appointed as a Thijn Brummelkamp uses genetic approaches to Principal Investigator at CeMM in January 2011. He identify genes that play a role in human disease. Kaan studied Medicine at the Universities of Düsseldorf, Thijn His primary interests are cancer research, infectious Freiburg and London. For his MD thesis, he spent a disease and drug action. Brummelkamp has devel- Boztug year of research in the laboratory of Iain L. Campbell Brummelkamp oped technologies to accelerate genetic analysis at the Scripps Research Institute, La Jolla, CA, USA, of cultured mammalian cells. A ‘stable RNA inter- 0DOLJQDQW+HPDWRORJLFDO'LVRUGHUV where his work was focused on neuroimmunology. *HQHWLFVRI&DQFHU ference’ process, which he and his colleagues RI&KLOGKRRG DQG,QIHFWLRXV'LVHDVHV first described, is now widely used to manipulate From 2005 until 2010, Kaan Boztug worked at and study gene function in mammalian cells. Hannover Medical School in the Department Brummelkamp has used stable RNA inter ference of Pediatric Hematology/Oncology headed by to inhibit thousands of human genes, in order to Christoph Klein with a dual affiliation combining find specific genes that play a role in human disease. clinical training and postgraduate laboratory work. More recently he has developed an approach for He developed a strong interest in the molecular haploid genetic screens in human cells using inser- genetics of primary immundeficiency disorders and tional mutagenesis. He has used this approach to was able to elucidate a novel primary immunodefi- identify host factors used by a variety of pathogens. ciency which combines congenital neutropenia and He received his MS in biology from the Free complex organ malformations, caused by deficiency University, Amsterdam, in 1998 and did his gradu- in the glucose-6-phosphatase catalytic subunit 3 ate research at The Netherlands Cancer Institute in (G6PC3). In another sentinel work, he was one of the laboratory of Rene Bernards and received his the lead authors in the identification of the first Ph.D. cum laude from Utrecht University in 2003. monogenic causes of childhood inflammatory bowel In 2004 he was appointed as a Whitehead Fellow disease (IBD), caused by mutations in the genes to initiate his independent research program at the encoding the interleukin-10 receptor. Whitehead Institute for Biomedical Research in Cambridge, USA. In 2011 his laboratory moved to At CeMM, Kaan Boztug works on the genetics of the Netherlands Cancer Institute and he became primary immundeficiencies and congenital bone an Adjunct PI at CeMM. For his studies he received marrow failure syndromes but has also broadened the Antoni van Leeuwenhoek Award (2003), The &H003ULQFLSDO,QYHVWLJDWRU his interest to genetics of malignant disorders of &H00$GMXQFW Annual NVBMB Award (2004, Dutch Association NER]WXJ#FHPPRHDZDFDW childhood. He holds a dual appointment with the 3ULQFLSDO,QYHVWLJDWRU for Biochemistry and Molecular Biology), he was Children’s Hospital of the Medical University of WEUXPPHONDPS#FHPPRHDZDFDW chosen as one of the world’s top 35 Young Innova- Visiting Professor, Vienna. In 2012, he received the START Prize of the tors by MIT’s technology Review magazine (2005) 'HSDUWPHQWRI3HGLDWULFVDQG Austrian Science Fund (FWF) and a Starting Grant of :KLWHKHDG)HOORZ and received the Kimmel Scholar Award (2006). $GROHVFHQW0HGLFLQH the European Research Council (ERC StG). :KLWHKHDG,QVWLWXWHIRU 0HGLFDO8QLYHUVLW\RI9LHQQD $ %LRPHGLFDO5HVHDUFK 86$ MD, 7KH6FULSSV5HVHDUFK,QVWLWXWH Ph.D., Netherlands Cancer 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV /D-ROOD&$ 86$  5HOHYDQW,PSRUWDQW3XEOLFDWLRQV ,QVWLWXWH(NL) Ebola virus entry requires the cholesterol transporter 8QLYHUVLW\RI)UHLEXUJ(D) A syndrome with congenital neutropenia and MS (Biology), )UHH8QLYHUVLW\ Niemann-Pick C1. Carette JE, Raaben M, Wong AC, 3RVWGRFWRUDO)HOORZ mutations in G6PC3. Boztug K, Appaswamy G, RI$PVWHUGDP (NL) Herbert AS, Obernosterer G, Mulherkar N, -XQLRU5HVHDUFK*URXS/HDGHU Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, +DQQRYHU0HGLFDO6FKRRO (D) Germeshausen M, Brandes G, Lee-Gossler J, + Dutch Dal Cin P, Dye JM, Whelan SP, Chandran K, Noyan F, Gatzke AK, Minkov M, Greil J, Kratz C, -RLQHG&H00LQ-DQXDU\ Brummelkamp TR. Nature. + German Petropoulou T, Pellier I, Bellanné-Chantelot C, 2011 Aug 24; 477(7364):340-3 -RLQHG&H00LQ-DQXDU\ Rezaei N, Mönkemöller K, Irani-Hakimeh N, 0DLQ5HVHDUFK,QWHUHVWV + Group of 7 people Bakker H, Gerardy-Schahn R, Zeidler C, + Cancer research Haploid genetic screens in human cells identify host Grimbacher B, Welte K, Klein C. N Engl J Med. + Infectious disease factors used by pathogens. Carette JE, Guimaraes CP, 0DLQ5HVHDUFK,QWHUHVWV 2009; 360: 32-43. + Drug action Varadarajan M, Park AS, Wuethrich I, Godarova A, + Molecular genetics of primary Kotecki M, Cochran BH, Spooner E, Ploegh HL, LPPXQRGHÀFLHQFLHVDQGFRQJHQLWDO Early-onset inflammatory bowel disease caused Netherlands Cancer Institute Brummelkamp TR. Science. ERQHPDUURZIDLOXUHV\QGURPHV by loss-of-function mutations in the IL10-receptor Plesmanlaan 121 2009 Nov 27;326(5957):1231-5. + Molecular genetics of malignant genes. Glocker E-O*, Kotlarz D*, Boztug K*, &;$PVWHUGDP hematological disorders of childhood Gertz EM, Schäffer AA, Noyan F, Perro M, The Netherlands YAP1 increases organ size and expands Diestelhorst J, Allroth A, Murugan D, Hätscher N, WEUXPPHONDPS#QNLQO un differentiated progenitor cells. Camargo FD, Pfeifer D, Sykora KW, Sauer M, Kreipe M, Lacher M, +31 20 512 1891 Gokhale S, Johnnidis JB, Fu D, Bell GW, Nustede R, Woellner C, Baumann U, Salzer Jaenisch R, Brummelkamp TR. Curr Biol. U, Koletzko S, Shah N, Segal AW, Sauerbrey A, 2007 Dec 4;17(23):2054-60. Epub 2007 Nov 1. Buderus S, Snapper SB, Grimbacher B, Klein C. Erratum in: Curr Biol. 2007 Dec 4;17(23):2094. N Eng J Med. 2009; 361: 2033-45. A system for stable expression of short interfering * equal contribution RNAs in mammalian cells. Brummelkamp TR, Bernards R, Agami R. Science. 2002 Apr 19; 296(5567):550-3.

Ce — M—M — Research Report 2012 66 67 Jacques Colinge was born in Switzerland and heads Sylvia Knapp was born in Austria and studied bioinformatics at CeMM since 2006. He obtained a Medicine at the Free University in Berlin and the -DFTXHV Ph.D. in mathematics from the University of Geneva, Sylvia University of Vienna. She obtained her MD degree Switzerland, in collaboration with the Swiss in 1993 and started her residency in Internal Colinge Institute of Technology. After completing his PhD, Knapp Medicine at the University Hospital Vienna. Jacques joined the Serono Pharmaceutical Research In 2000 she received her License in Internal %LRLQIRUPDWLFV Institute as a bioinformatician to work mainly on ,QQDWH,PPXQLW\ Medicine and in 2004 she obtained a “Habilitation” differential gene expression data analysis. In 2000 DQG%DFWHULDO,QIHFWLRQV in Intenal Medicine at the Medical University of he moved to GeneProt Inc. to head a group in charge Vienna. After several residencies, mostly in areas of mass spectrometry-related bio informatics and like Infectious Diseases, AIDS and Intensive Care parallel computing. In 2005, he joined the Upper Units, she became a Ph.D. student in Tom van der Austrian University of Applied Sciences at Poll’s laboratory at the University of Amsterdam Hagenberg to serve as a Professor of Bioinfor matics and studied the inflammatory response to severe before moving to CeMM in September 2006. bacterial infections. Sylvia’s most important In 2009, Jacques obtained a Habilitation in bio- achievements include the identification of the anti- informatics from TU Graz. The bioinformatics lab inflammatory role of alveolar (lung) macrophages does research to develop data analysis methods as well as the biological function of several pattern aimed at understanding the biological function of recognition receptors during Streptococcus networks of interacting proteins. The group also pneumoniae pneumonia. Sylvia joined CeMM develops and maintains data processing pipelines in 2006 and continues her work on the innate and databases to analyze and manage mass spec- immune response to bacterial infections, focusing trometry data, and to support protein interaction on the molecules involved in the initiation and network analyses. resolution of the innate immuneresponse to clinically relevant pathogens and on the role of bacterial virulence factors and their interactions 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV with host structures and pathways. Sylvia main- Systems biology analysis of protein-drug tains her responsibilities at the Intensive Care inter actions. Colinge J*, Rix U, Bennett KL, Unit at the Medical University Vienna and was +HDGRI%LRLQIRUPDWLFV Superti-Furga G. Proteomics Clin Appl. &H003ULQFLSDO,QYHVWLJDWRU appointed Professor of Infection Biology in 2012. MFROLQJH#FHPPRHDZDFDW 2011 Dec 27. VNQDSS#FHPPRHDZDFDW V\OYLDNQDSS#PHGXQLZLHQDFDW Ph.D. (Mathematics), General statistical modeling of data from protein 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV 8QLYHUVLW\RI*HQHYD &+ relative expression isobaric tags. Breitwieser FP, Full Professor of Infection Biology, TLR2 and CD14 mediate innate immunity and Scientist and Bioinformatician, Müller A, Dayon L, Köcher T, Hainard A, Pichler P, 0HGLFDO8QLYHUVLW\9LHQQD $ inflammation to Staphylococcal Panton Valentine 6HURQR3KDUPDFHXWLFDO Schmidt-Erfurth U, Superti-Furga G, Sanchez JC, MD, 8QLYHUVLW\RI9LHQQD $  leucocidin in vivo. Zivkovic A, Sharif O, Stich K, 5HVHDUFK,QVWLWXWH &+ Mechtler K, Bennett KL, Colinge J. J Proteome Res. Internist, 9LHQQD*HQHUDO Doninger B, Biaggio M, Colinge J, Bilban M, Mesteri I, Group Leader, 2011 Jun 3;10(6):2758-66. +RVSLWDO089 $  Hazemi P, Lemmens-Gruber R, Knapp S. *HQH3URW,QF &+ Ph.D. (Experimental Medicine), J. Immunol (2011) 186,1608-1617 )+3URIHVVRU Initial characterization of the human central proteome. 8QLYHUVLW\RI$PVWHUGDP (NL) 8QLYHUVLW\RI$SSOLHG6FLHQFH Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, TREM-1 activation alters the dynamics of pulmonary 8SSHU$XVWULD $ Bürckstümmer T, Bennett KL, Superti-Furga G, $XVWULDQ IRAK-M expression in vivo and improves host +DELOLWDWLRQ $GMXQFW3URIHVVRU  Colinge J. BMC Syst Biol. -RLQHG&H00LQ$SULO defense during pneumococcal pneumonia. Lagler H, 7HFKQLFDO8QLYHUVLW\*UD] $ 2011 Jan 26;5:17. + Group of 11 people Sharif O, Haslinger I, Matt U, Stich K, Furtner T, Doninger B, Schmid K, Gattringer R, de Vos AF, 6ZLVVDQG)UHQFKGXDOQDWLRQDOLW\ Using iTRAQ combined with tandem affinity 0DLQ5HVHDUFK,QWHUHVWV Knapp S. J Immunol (2009) 183, 2027-2036 -RLQHG&H00LQ6HSWHPEHU purification to enhance low-abundance proteins + Exploit molecular mechanisms *URXSRISHRSOH associated with somatically mutated EGFR core of host-pathogen interactions Baumann CL*, Aspalter IM*, Sharif O*, Pichlmair A, complexes in lung cancer. Haura EB, Müller A, + Receptor cross-regulation in Blüml S, Grebien F, Bruckner M, Pasierbek P, 0DLQ5HVHDUFK,QWHUHVWV Breitwieser FP, Li J, Grebien F, Colinge J, Bennett KL. innate immunity Aumayr K, Planyavsky M, Bennett KL, Colinge J, + Computational proteomics J Proteome Res. Knapp S#, Superti-Furga G#. CD14 is a coreceptor 3URWHLQLQWHUDFWLRQQHWZRUNDQDO\VLV 2011 Jan 7;10(1):182-90. 6\OYLD.QDSS·V*URXS of Toll-like receptors 7 and 9. + Systems biology and OMICS data LVORFDWHGDWWKH J Exp Med (2010) 207: 2689-2701. integration A computational approach to analyze the mecha- Department of Internal Medicine I + Drug mechanism of action and nism of action of the kinase inhibitor bafetinib. Laboratory of Infection Biology * equal contribution VLGHHƆHFWVPRGHOLQJ Burkard TR, Rix U, Breitwieser FP, Superti-Furga G, Medical University Vienna # corresponding authors + Protein complex predictions from Colinge J. PLoS Comput Biol. :lKULQJHU*UWHO³ mass spectrometry data 2010 Nov 18;6(11):e1001001. 9LHQQD$XVWULD $SSOLFDWLRQRIFRPSXWDWLRQDO statistics and mathematics * corresponding author

Ce — M—M — Research Report 2012 68 69 Robert Kralovics, born 1970, is Czech and joined Stefan Kubicek, born 1978, is Austrian and joined CeMM in June 2006. He obtained his first degree CeMM in August, 2010 . He obtained an MSc in Robert in Molecular Biology and Genetics at the Comenius Stefan synthetic organic chemistry from Vienna University University in Bratislava and later his Ph.D. in of Technology following a diploma thesis at ETH Kralovics Biophysics at the Academy of Sciences of the Czech Kubicek Zürich. For his Ph.D. in Thomas Jenuwein’s lab at Republic in Brno. He did his post-doctoral work on the IMP in Vienna, he changed fields to Molecular *HQHWLFVRI the genetics of myeloproliferative disorders work- &KHPLFDO%LRORJ\DQG(SLJHQHWLFV Biology. He then performed post-doctoral research +HPDWRORJLFDO'LVRUGHUV ing with Josef Prchal at the University of Alabama working on Chemical Biology with Stuart Schreiber in Birmingham, USA. He followed Prchal as an at the Broad Institute of Harvard and MIT. Assistant Professor at the Baylor College of Stefan Kubicek heads the chemical screening plat- Medicine in Houston. From mid 2001, Robert form and PLACEBO (Platform Austria for Chemical was a project leader with Radek Skoda in Basel. Biology), a task he is well equipped for based on Robert’s research interests are primarily in myelo- previous screening experiences with Boehringer proliferative disorders (MPDs) and in myeloid Ingelheim and at the Broad Institute. These activities malignancies in general. One of his major achieve- have resulted in the identification of the first selec- ments so far has been the identification of a tive histone methyltransferase inhibitor, BIX-01294, gain-of-function mutation in the JAK2 kinase gene and a small molecule inducer of insulin expression (V617F), which plays an important role in MPD in pancreatic alpha cells, BRD7389. The Kubicek lab pathogenesis. Robert continues this work at CeMM is working on the role of chromatin in the definition to identify new mutations causing familial pre- of cell types and cell states. Projects focus on defining disposition to hematological malignancies using the contribution of histone methylation to cancer advanced genomics approaches, and is working development and progression, the development of towards understanding how genetic variability new assays and compounds to quantify and modu- contributes to the disease. late chromatin modifications, and their potential for transdifferentiation of celltypes.

5HOHYDQW,PSRUWDQW3XEOLFDWLRQV Genome integrity of myeloproliferative neoplasms 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV &H003ULQFLSDO,QYHVWLJDWRU in chronic phase and during disease progression. +HDGRI&KHPLFDO6FUHHQLQJ Compounds targeting chromatin modifying enzyme UREHUWNUDORYLFV#FHPPRHDZDFDW Klampfl T, Harutyunyan A, Berg T, Gisslinger B, DQG3ODWIRUP$XVWULDIRU induce specific cell-type independent transcription Schalling M, Bagienski K, Olcaydu D, Passamonti F, &KHPLFDO%LRORJ\ 3/$&(%2 signatures in the endocrine pancreas. Kubicek S, Ph.D. (Molecular Biology), Rumi E, Pietra D, Jäger R, Pieri L, Guglielmelli P, Gilbert J, Fomina-Yadlin D, Gitlin A, Yuan Y, &]HFK$FDGHP\RI6FLHQFHV(CZ) Iacobucci I, Martinelli G, Cazzola M, Vannucchi AM, +HDG&KULVWLDQ'RSSOHU/DERUDWRU\ Wagner F, Holson E, Luo T, Lewis T, Taylor B, 3RVWGRFWRUDOIHOORZ Gisslinger H, Kralovics R. Blood. IRU&KHPLFDO(SLJHQHWLFV Gupta S, Shamji AF, Wagner BK, Clemons PA, 8QLYHUVLW\RI$ODEDPD 2011 Jul 7;118(1):167-76 DQG$QWLLQIHFWLYHV Schreiber SL. Proc Natl Acad Sci U S A. DW%LUPLQJKDP 86$ VNXELFHN#FHPPRHDZDFDW 2012; 109; 5364-5369. $VVLVWDQW3URIHVVRU p53 lesions in leukemic transformation. %D\ORU&ROOHJHRI0HGLFLQH Harutyunyan A, Klampfl T, Cazzola M, Kralovics R. M. Sc. (Organic Chemistry), A selective inhibitor and probe of the cellular +RXVWRQ 86$ N Engl J Med. 2011 Feb 3;364(5):488-90 789LHQQD $  functions of Jumonji C domain-containing histone Project Leader, (7+=XHULFK &+ demethylases. Luo X, Liu Y, Kubicek S, Myllyharju J, 8QLYHUVLW\+RVSLWDO%DVHO &+ A common JAK2 haplotype confers susceptibility PhD (Molecular Biology), Tumber A, Ng S, Che KH, Podoll J, Heightman TD, to myeloproliferative neoplasms. Olcaydu D, ,039LHQQD $  Oppermann U, Schreiber SL, Wang X. J Am Chem + Czech Harutyunyan A, Jäger R, Berg T, Gisslinger B, 8QLYHUVLW\RI9LHQQD $ Soc. 2011 Jun 22;133(24):9451-6. -RLQHG&H00LQ-XQH Pabinger I, Gisslinger H, Kralovics R. Nat Genet. 3RVWGRFWRUDO)HOORZ + Group of 9 people 2009 Apr;41(4):450-454 (Chemical Biology), Small-molecule inducers of insulin expression in %URDG,QVWLWXWHRI+DUYDUG pancreatic alpha-cells. Fomina-Yadlin D*, Kubicek S*, 0DLQ5HVHDUFK2EMHFWLYHV A common JAK2 haplotype confers susceptibility and MIT 86$ Walpita D, Dancik V, Hecksher-Sørensen J, Bittker JA, DQG4XHVWLRQV to myeloproliferative neoplasms. Olcaydu D, Sharifnia T, Shamji A, Clemons PA, Wagner BK, + Identify mutations in early steps Harutyunyan A, Jäger R, Berg T, Gisslinger B, $XVWULDQ Schreiber SL. Proc Natl Acad Sci U S A. of disease development in Pabinger I, Gisslinger H, Kralovics R. -RLQHG&H00LQ$XJXVW 2010;107(34):15099-104. hematological malignancies Nature Genetics. 2009. 41(4):450-4 + Group of 8 people +RZPXWDQWVWHPFHOOVHYROYH Reversal of H3K9me2 by a small-molecule inhibitor JHQHWLFDOO\KRZWKH\UHVSRQG A gain-of-function mutation of JAK2 in 0DLQ5HVHDUFK,QWHUHVWV for the G9a histone methyltransferase. Kubicek S, to therapy? myeloproliferative disorders. Kralovics R, + Chemical Epigenetics O’Sullivan RJ, August EM, Hickey ER, Zhang Q, + What gene mutations cause Passamonti F, Buser AS, Teo SS, Tiedt R et al. ,GHQWLÀFDWLRQDQGGHYHORSPHQWRI Teodoro ML, Rea S, Mechtler K, Kowalski JA, familial predisposition to N Engl J Med. 2005. 28;352(17): 1779-90 small molecule probes for biological Homon CA, Kelly TA, Jenuwein T. Mol Cell. hematological malignancies? processes and host factors in 2007 Feb 9; 25(3):473-81. +RZGRHVJHQHWLFYDULDELOLW\ infectious disease contribute to disease? + Contribution of histone lysine +RZWRGLDJQRVHWKHGLVHDVHV methylation to cancer development * equal contribution in early stages of development? and progression + Role of chromatin in the VSHFLÀFDWLRQRISDQFUHDWLFFHOOW\SHV Ce — M—M — Research Report 2012 70 71 Joanna completed her undergraduate studies in the Sebastian Nijman was born in the Netherlands UK, having moved there from Cyprus. Subsequently, (1975). He studied medical biology at Utrecht -RDQQD, she commenced Ph.D. work at the University of Sebastian University and specialized in Molecular Biology Manchester (and University of Sussex) investigating and Biochemistry in the labs of Hans Bos and Rene Loizou mechanisms of DNA repair. During this time Nijman Medema. Sebastian also holds a Masters of Arts Joanna identified for the first time a requirement degree from the University of Maastricht '1$5HSDLUDQG*HQRPLF6WDELOLW\ for the kinase CK2 in the DNA damage response. )XQFWLRQDO&DQFHU*HQRPLFV (Science, Society and Technology Studies) and was Postdoctoral work followed at the International involved in clinical research at a Contract Research Agency for Research on Cancer (IARC), World Organization. In the lab of Rene Bernards at the Health Organization (WHO), France where Joanna Netherlands Cancer Institute, he performed his investigated the role of epigenetic modifications, Ph.D. work, focusing on functional genetic screens mainly histone acetylation, in DNA repair. Joanna in cancer-relevant pathways. He performed the showed that cells use shared molecules in transcrip- first RNAi screen in mammalian cells that led to tion and DNA repair. It was also during this time she the identification of the cylindromatosis tumor chose to work on the immune system and showed suppressor as a regulator of NF-kappaB signaling. that histone acetylation is important in maintaining This work has led to a rational therapeutic approach haematopoietic stem cells. Joanna wanted to build for treating cylindromatosis and is one of his major on this experience and focus on the role of genomic achievements so far. In 2006 he joined the lab of instability leading to cancers of the blood, hence she Todd Golub at The Broad Institute of Harvard and joined the London Research Institute (LRI) at Cancer MIT, USA. There he developed novel genomic Research UK (CR-UK), where she continued to approaches to discover the functions of genes and work on DNA repair and its importance in the devel- identify new angles for cancer treatment. Since opment of the immune system and in suppressing joining CeMM, Sebastian’s research is mostly leukemia and lymphoma. At CeMM Joanna’s group focused on the identification and understanding investigates the mechanisms by which cells respond of cancer vulnerabilities using chemical genetic to, and repair, DNA damage in order to maintain screens. genomic stability and suppress tumorigenesis. Joanna focuses on physiological DNA damage gen- &H003ULQFLSDO,QYHVWLJDWRU erated by replicative stress or during the process of &H003ULQFLSDO,QYHVWLJDWRU 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV MORL]RX#FHPPRHDZDFDW somatic recombination that occurs in immune B VQLMPDQ#FHPPRHDZDFDW A chemical-genetic screen reveals a mechanism of and T cells. Joanna is interested in understanding the resistance to PI3K inhibitors in cancer. Muellner MK, Ph.D., 8QLYHUVLW\RI pathways responsible for the repair of such breaks Ph.D. (Molecular Carcinogenesis), Uras IZ, Gapp BV, Kerzendorfer C, Smida M, Manchester (UK) that allow for the maintenance of genome integrity 1HWKHUODQGV&DQFHU,QVWLWXWH(NL) Lechtermann H, Craig-Mueller N, Colinge J, 3RVWGRFWRUDO)HOORZ but also for the maturation of immune cells. 3RVWGRFWRUDOIHOORZ Duernberger G, Nijman SM. Nat Chem Biol. ,$5& :+2 (F) 7KH%URDG,QVWLWXWHRI+DUYDUG 2011 Sep 25;7(11):787-93. 3RVWGRFWRUDO)HOORZ and MIT 86$ /5, &58. (UK) 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV Synthetic lethality: general principles, utility and ATMIN is required for maintenance of genomic + Dutch detection using genetic screens in human cells. &\SULRW%ULWLVKGXDOQDWLRQDOLW\ stability and suppression of B cell lymphoma. -RLQHG&H00LQ2FWREHU Nijman SM. FEBS Lett. 2011 Jan 3;585(1):1-6. -RLQHG&H00LQ6HSWHPEHU Loizou JI, Sancho R, Kanu N, Bolland DJ, Yang F, *URXSRISHRSOH + Group of 5 people Rada C, Corcoran AE, and Behrens A. Cancer Cell. A genomic and functional inventory of deubiqui- 2011; 19, 587-600. 0DLQ5HVHDUFK,QWHUHVWV tinating enzymes. Nijman SM, Luna-Vargas MP, 0DLQ5HVHDUFK,QWHUHVWV + Chemical genetics of cancer Velds A, Brummelkamp TR, Dirac AM, Sixma TK, 6LJQDOLQJDQGUHSDLULQJ'1$ Histone acetyltransferase cofactor Trap is essential + Identify novel strategies to treat Bernards R. Cell. 2005 Dec 2;123(5):773-86. damage for maintaining the hematopoietic stem/progenitor cancer (cancer vulnerabilities) 5HSDLURISK\VLRORJLFDO'1$ cell pool. Loizou JI, Oser G, Shukla V, Sawan C, + Functional genetic screens to The deubiquitinating enzyme USP1 regulates the breaks generated in immune Murr R, Wang ZQ, Trumpp A, and Herceg Z. identify cancer-related genes Fanconi anemia pathway. Nijman SM*, Huang TT*, T and B cells during somatic J Immunol. 2009;183, 6422-6431. Dirac AM, Brummelkamp TR, Kerkhoven RM, recombination D’Andrea AD, Bernards R. Mol Cell. + Maintenance of genome integrity Histone acetylation by Trrap-Tip60 modulates 2005 Feb 4; 17(3):331-9. to suppress leukemia and lymphoma loading of repair proteins and repair of DNA double- strand breaks. Murr R*, Loizou JI*, Yang YG, Loss of the cylindromatosis tumour suppressor Cuenin C, Li H, Wang ZQ, and Herceg Z. inhibits apoptosis by activating NF-kappaB. Nat Cell Biol. 2006; 8, 91-99. Brummelkamp TR*, Nijman SM*, Dirac AM*, Bernards R. Nature. 2003 Aug 14;424(6950):797-801. The protein kinase CK2 facilitates repair of chro- mosomal DNA single-strand breaks. Loizou JI, * equal contribution El-Khamisy SF, Zlatanou A, Moore DJ, Chan DW, Qin J, Sarno S, Meggio F, Pinna LA, and Caldecott KW. Cell. 2004;117, 17-28.

*equal contribution

Ce — M—M — Research Report 2012 72 73 Giulio Superti-Furga is an Italian national and he joined CeMM as Director in January 2005. 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 3DWKRORJLFDO1HWZRUNV Pathology in Vienna (I.M.P.), Austria. He was a LQ/HXNHPLDDQG,PPXQLW\ post-doctoral fellow and Team Leader at the European Molecular Biology Laboratory (EMBL) until 2004. For several years he served as Professor 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 the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers and the discovery of fundamental organization principles of the proteome of higher organisms. Giulio’s work on the organization of the eukaryotic proteome is the most highly cited in the field. He is a full member of the Austrian Academy of Sciences, the German Academy of Sciences Leopoldina, the European Molecular Biology Organization and the European Academy of Cancer Sciences. He is chair of the EMBL Alumni Association. He uses and develops high-throughput “omics” approaches to study several areas including the mechanism of action of proteins and drugs, the identification &(2DQG6FLHQWLÀF'LUHFWRU of molecular networks underlying leukemia and JVXSHUWL#FHPPRHDZDFDW the molecular basis of innate immunity. In 2009 he received the prestigious Advanced Investigator Ph.D. (Molecular Biology), Grant awarded by the European Research 8QLYHUVLW\RI=XULFK &+ Council (ERC), and he was awarded the Knight ,039LHQQD $ Officer Order of Merit of the Republic of Italy for 3RVWGRFWRUDOIHOORZ7HDP/HDGHU his contributions to science. In 2011 he received (0%/²(XURSHDQ0ROHFXODU the Prize of the City of Vienna for Natural Sciences, %LRORJ\/DERUDWRU\(D) and was honored as Austria’s Scientist of the Year. 6FLHQWLÀF'LUHFWRU &HOO]RPH(D) 5HOHYDQW,PSRUWDQW3XEOLFDWLRQV + Italian Viral immune modulators perturb the human -RLQHG&H00LQ-DQXDU\ molecular network by common and unique + Group of 22 people strategies. Pichlmair A, et al., Nature. 2012 Jul 26;487(7408):486-90. 0DLQ5HVHDUFK,QWHUHVWV + Mechanism of action of drugs Targeting the SH2-kinase interface in Bcr-Abl 0ROHFXODUQHWZRUNVDƆHFWLQJ inhibits leukemogenesis. Grebien F, et al., Cell leukemias 2011 Oct 14;147(2):306-19. + Molecular basis of innate immunity A network solution. Henney A, Superti-Furga G. Nature. 2008 Oct 9; 455(7214):730-1.

Functional organization of the yeast proteome by systematic analysis of protein complexes. Gavin AC, et al., Superti-Furga G. Nature. 2002. 415(6868): 141-7.

Ce — M—M — Research Report 2012 A Collection of Human Next Generation Sequencing – Knockout Cells as a Toolkit a Transformative Technology for Biomedical Discovery Well-Supported at CeMM

By “knocking out” a gene and studying the has proven to be an extremely powerful tool biological consequences one can learn about its for performing genetic screens to link genes functions. Therefore, collections of individual with phenotypes. In such a screen all genes are gene knockouts in model organisms such as essentially knocked out one-by-one using a yeast are cherished research tools. However, gene-trap virus yielding a large pool of as many a comparable collection for human cell lines as 100 million “knockout” cells. Indeed, this is not yet available. The main reason for this technology is now being employed by several is that until recently the tools to generate such groups at CeMM to study host-pathogen a library of mutants were not available. This interactions and mechanisms of drug action. problem has now been overcome by employing “haploid genetics”. Importantly, the same technology can be used to isolate single mutants to compile a collection A major obstacle for knocking out genes in of human knock out cells. Such a collection human cells (and indeed most higher organisms) would be as valuable for the scientific community is that all genes are present in two copies. One working on human cells as the yeast collection is inherited from the mother and the other from has been for the yeast community. About two the father, together making up a diploid human years ago scientists from CeMM and the spin-out genome. However, this diploidy means that Haplogen teamed up in a public-private partner- inactivating single gene copies typically does ship to make such a collection a reality. The not result in a detectable phenotype as the team, headed by Tilmann Buerckstuemmer, has second remaining allele compensates for the loss. already isolated tens of thousands of clones and CeMM adjunct PI Thijn Brummelkamp circum- many of the scientists at CeMM are using these vented this obstacle by knocking out genes in knockouts for their experiments. Furthermore, a rare human cell line that only carries one copy this collection will provide researchers with new for >95% of its genes. This “haploid” cell line tools to address a whole range of questions from infection biology to cancer.

Biomedical Sequencing Facility (BSF). The BSF using genome-scale bisulfite sequencing as well is Austria’s first technology platform dedicated as ChIP-seq. It is complemented by a powerful Schematic overview of the to next generation sequencing in biomedicine. IT infrastructure that is being upgraded with human chromosomes and It was launched in spring 2012 as a consolidation 50-100 terabytes of storage every year to keep all the “genetrap” insertions that have been mapped by of earlier efforts at CeMM and at the Medical up with the massive growth of data produced the Haplogen-CeMM team. University of Vienna. The BSF is coordinated by by the next generation sequencing machines at Each genetrap insertion can inactivate the expression CeMM Principal Investigator Christoph Bock and CeMM. In summary, the BSF provides essential of a gene thus generating a run as a collaborative effort with major contri- infrastructure and expertise for catalyzing the “knockout”. All these knock- butions from several research groups at CeMM development of genomic medicine in Vienna outs cell lines are isolated and will be available for and Medical University. The facility is currently and Austria. detailed characterization or equipped with two HiSeq 2000 sequencers genetic screens to identify for instance new drug and staffed with one expert technician and one Additional information is available on the web- targets. Ph.D.-level bioinformatician. A comprehen- site of the BSF: http://biomedical-sequencing.at sive robotics solution for sample preparation will be added in the first quarter of 2013, thus providing a substantial increase in throughput compared to the already remarkable number of 1,000 samples that were sequenced at CeMM in 2012. The BSF supports all of biomedicine’s most relevant sequencing protocols, including: whole-genome sequencing, exome sequencing and high-throughput sequencing of candidate loci; gene expression profiling using various subtypes of RNA-seq; and epigenome mapping

Ce — M—M — Research Report 2012 76 77 ERC Starting Grants for Austria’s START Prize Kaan Boztug and Sebastian Nijman Awarded to Kaan Boztug

The European Research Council awarded the Funded Project: Kaan Boztug START Prize awardee Kaan prestigious ERC Starting Grants to two CeMM Integrated Genetics of Congenital Defects Boztug and his group at the FWF summer party 2012. Principal Investigators: Kaan Boztug and of Innate Immunity Sebastian Nijman. ERC Starting Grants support Primary immunodeficiency disorders involving promising young scientific leaders with proven innate immunity are characterized by recurrent potential for success in creating new research and life-threatening infections. However, the teams to perform world-class independent molecular etiology of these disorders is often research in Europe. Kaan Boztug, Group Leader at unknown. The aim is to identify novel genetic CeMM and Visiting Professor at the Department defects in innate immunity and decipher their of Pediatrics and Adolescent Medicine of the molecular pathophysiology using a discovery Medical University of Vienna was chosen for engine consisting of an exclusive combination his research project “Integrated Genetics of of genomic technologies, including single Congenital Defects of Innate Immunity”, which nucleotide polymorphism (SNP) chip arrays and will focus on the elucidation of Mendelian high throughput DNA sequencing technology disorders of the human immune system. (“next generation sequencing”), together Sebastian Nijman was awarded the starting with functional proteomic technologies. The grant for his proposal “Discovering Gene-Drug engine will be complemented by biochemical, Interactions in Breast Cancer With a Systematic immunological and imaging technologies to and Genetically Tractable Model”. Each grant systematically assess the consequences of the amounts to approximately 1.5 Million Euro for genetic deficiency, and to map the respective a period of up to 60 months. protein products onto molecular pathways. The proposed investigations are expected to Funded Project: Sebastian Nijman contribute significantly to the understanding of Discovering Gene-Drug Interactions in the molecular processes that structure the human Breast Cancer With a Systematic and innate immune system. This will not only enable Genetically Tractable Model a more comprehensive molecular classification Kaan Boztug is one of seven young scientists out Biomedical research has been very successful in system of primary immunodeficiency disorders, of 54 applicants who has been accepted into the finding the genes that are deregulated in cancer. but also improve patient care by aiding molecular 2012 START Program of the Austrian govern- However, it has proven much more challenging diagnosis and prognosis in individual patients ment. The START Program is Austria’s most to translate this knowledge into effective treat- suffering from these disorders. The investigations renowned funding scheme for excellent young ments. One complication is that cancer cells will serve as the basis for future development scientists and is open to all disciplines. This typically carry many mutations and every tumor of targeted therapies such as gene therapy or year’s awardees were announced on June 12, 2012 displays a unique pattern. This patient-to-patient pharmacological interventions targeting affected by Austria’s Federal Minister for Science and heterogeneity complicates treatment as it often signaling pathways. Research Karlheinz Töchterle and FWF President interferes with patient response. Thus, unrave- Christoph Kratky. Kaan Boztug was chosen for ling the complex interplay between cancer genes his research project entitled “Integrated Genetics and drugs is of great importance for effective of Congenital Defects of Innate Immunity”, patient-stratified cancer therapy. Besides playing which will focus on characterizing Mendelian a role in drug resistance, molecular changes also disorders of the human immune system. result in cancer cells becoming uniquely depend- ent on certain gene products or pathways. These cancer “vulnerabilities” offer opportunities for targeted therapies. The aim is to identify cancer vulnerabilities and drug resistance mechanisms with a specific focus on breast cancer. By building models systems of breast cancer cells that capture the variability and heterogeneity of the disease, they can develop more effective therapies. Together, this project aims to improve therapies in breast cancer by identifying patient cohorts that are most likely to benefit from a given drug and revealing novel cancer Achilles’ heels.

Ce — M—M — Research Report 2012 78 79 “CeMM is a place where science and art come together in a most stimulating way.”

Peter Kogler (*1959, Innsbruck, Tyrol) Peter Kogler studied stage design at the Academy of Fine Arts, Vienna. His work juxtaposes the perfectionism of new technologies with physical and organic motifs. Kogler regularly participates in numerous exhibitions, including participation in the documenta IX and X in 1992 and 1997, as well as in the Biennale Venice Biennial in 1995. He creates illusionistic spaces, as can be seen on the 400m2 art façade of the CeMM research building. For the CeMM Brain Lounge, Kogler contributed a brain as a centerpiece for the table. “The artistic exploration of the present, its foundations, ideas, materials and technologies is a prerequisite for the framing of questions that can also continue WRJDLQVLJQLÀFDQFHLQWKHIXWXUHµ

%ULJLȪH.RZDQ] 9LHQQD %ULJLƥH.RZDQ]VWXGLHGDWWKH$FDGHP\RI$SSOLHG Art, Vienna (1975-1980) and has worked as Professor for Transmedia Art at the University of Applied Arts, Vienna since 1997. In 2009 she was awarded WKH$XVWULDQ6WDWH3UL]HIRU)LQH$UWV *UR‰HU Österreichischer Staatspreis). The main theme of %ULJLƥH.RZDQ]³VZRUNVLVWKHGLŦHUHQWYLVXDOIRUPV which light can take. To the CeMM Brain Lounge she contributed a light installation as a loan. Lecture Overview Series CeMMinar/Impromptu Series

30.01.2012 13.02.2012 05.03.2012 26.03.2012 CeMMinar CeMMinar CeMMinar CeMMinar Meinrad Busslinger Bodo Grimbacher .DL-RKQVVRQ -HDQ/DXUHQW&DVDQRYD CeMM’s organized seminars and lecture The Research Institute Research group Institute of Chemical St. Giles Laboratory series held throughout the year provide of Molecular Pathology “Experimental Sciences & Engineering, of Human Genetics of (IMP), Vienna ,PPXQRGHÀFLHQF\´ École Polytechnique Infectious Diseases, The an important source of information and “Lineage commitment Centre of Chronic Fédérale de Lausanne Rockefeller University inspiration not only to the scientists at and plasticity of ,PPXQRGHÀFLHQF\ “Spying on drugs and “Toward a genetic CeMM, but also to scientists and medical B lymphocytes” Freiburg metabolites in living theory of infectious Host: Giulio Superti- “A novel monogenetic cells” diseases” professionals at other local institutes and Furga defect causing autoim- Host: Giulio Superti- Host: Giulio Superti- universities, and sometimes to the munity and hypogam- Furga Furga interested general public. 31.01.2012 maglobulinemia” Joint MedUni Vienna - Host: Kaan Boztug 12.03.2012 27.03.2012 CeMM Impromptu CeMMinar Impromptu Nima Rezaei 20.02.2012 Laurence Calzone & -DPHV%UDGQHU Tehran University CeMMinar Emmanuel Barillot Department of Medicine, of Medical Sciences, Magnus Nordborg Computational Systems Harvard Medical School Children’s Medical Gregor Mendel Institute Biology of Cancer, & Hematologic Center, Iran of Molecular Plant Institute Curie, Paris Neoplasia/Malignancies, ´3ULPDU\LPPXQRGHÀ- Biology (GMI), Vienna “A Systems Biology Dana-Farber Cancer ciencies in Iran” “Investigating the Approach for modeling Institute Hosts: Rudolf Valenta genotype-phenotype signalling network “Chemical Inhibition of (MedUni Vienna) & map using Arabidopsis” involved in Cancer” Human Bromodomains” Kaan Boztug (CeMM) Host: Giulio Superti- Host: Jacques Colinge Hosts: Stefan Kubicek Furga and Sebastian Nijman 02.02.2012 14.03.2012 Impromptu 27.02.2012 Impromptu 02.04.2012 $QQ6RÀH-HPWK CeMMinar Clemens Grabher CeMMinar Dept. of Genetics, Axel Behrens Karlsruhe Institute of -XOLH0DJDULDQ%ODQGHU Microbiology and CR-UK London Technology (KIT), Immunology Institute, Toxicology, Stockholm Research Institute Institute of Toxicology Mount Sinai Medical University Arrhenius “Stress and DNA and Genetics (ITG) Center, NY Laboratory damage signalling in “Facilitating drug dis- “Vita-PAMPs: Signatures “Turning cancer stem cells and cancer” covery: An automated of Microbial Viability” defects into cure: Host: Joanna Loizou KLJKFRQWHQWLQÁDPPD- Host: Sylvia Knapp Targeting DNA repair” WLRQDVVD\LQ]HEUDÀVKµ Host: Kilian Huber 28.02.2012 Host: Kilian Huber 16.04.2012 Impromptu CeMMinar 06.02.2012 Stefan Stricker 20.03.2012 Forest White CeMMinar UCL Cancer Institute, Impromptu Department of Kristian Helin University College $PDQGD0-DPLHVRQ Biological Engineering, Biotech Research & London, UK Max F. Perutz 0DVVDFKXVHȅV,QVWLWXWH Innovation Centre “Reprogramming human Laboratories (MFPL), of Technology (MIT) (BRIC), University brain cancer cells to University of Vienna & and Koch Institute of Copenhagen test the relevance of Medical University of for Integrative Cancer “Functional Roles epigenetic anomalies” Vienna Research, USA of TET proteins and Host: Denise Barlow “Host Response to “Using Quantitative Hydroxymethylation in ,QÁXHQ]D9LUXV Proteomics to Connect Stem Cells and Cancer” Bacterial Coinfections: Genotype to Phenotype” Host: Stefan Kubicek 7UDGHRƆVDQGYXOQHU- +RVW.HLU\Q%HQQHȅ abilities” Host: Andreas Bergthaler

84 85 23.04.2012 21.05.2012 25.06.2012 04.09.2012 08.10.2012 29.10.2012 03.12.2012 CeMMinar CeMMinar CeMMinar Impromptu CeMMinar CeMMinar CeMMinar 3KLOLSSH6DQVRQHȪL Amos Bairoch Michael Hemann Patrick Collombat Paul Flicek Michael White Anne Corcoran INSERM U786 “Unité de Director of Structural Koch Institute for Genetics of normal EMBL Outstation – University of Texas, Nuclear Dynamics Pathogénie Microbienne Biology and Integrative Cancer and pathological Hinxton, European UT Southwestern Programme Babraham Moléculaire”, Institut Bioinformatics Research, development, Centre de Bioinformatics Institute, Medical Center Institute, Cambridge, UK Pasteur, Paris Department, Swiss 0DVVDFKXVHȅV,QVWLWXWH Biochimie, INSERM, Nice Wellcome Trust Genome “Oncogenome - selective “Non-coding RNA tran- “Commensal and Institute of of Technology (MIT) “Alpha-cell-mediated Campus, Hinxton, vulnerabilities in lung scription and nuclear pathogens at mucosal Bioinformatics, “Using mouse models beta-cell regeneration Cambridge adenocarcinoma” organisation play key surface: the Yin and University of Geneva to identify new cancer in the context of “Comparative regula- Host: Sebastian Nijman roles in immunoglobu- the Yang of innate “The CALIPHO group: drug targets” type 1 diabetes” tory genomics provides lin Recombination” immunity” neXtProt, a new Host: Sebastian Nijman Host: Stefan Kubicek insight into the evolu- 06.11.2012 Host: Joanna Loizou Host: Giulio Superti- knowledge platform tion of transcriptional Impromptu Furga on human proteins and 23.07.2012 01.10.2012 regulation” (PostDoc Interview) 17.12.2012 on-going work toward CeMMinar CeMMinar Host: Christoph Bock $GULDQ6FKZDU]HU Special Seminar 07.05.2012 the characterization of $QGUHZ0F.HQ]LH 0DȪKLDV0DQQ Institute of Wolfgang Weninger CeMMinar some human proteins” MRC Laboratory of Department of 15.10.2012 Experimental Raymond E. Purves Claus Nerlov Host: Jacques Colinge Molecular Biology, Proteomics and CeMMinar Hematology OE6960, Professor and Chair, MRC Centre for Cambridge, UK Signal Transduction, Christoph Plass Hannover Medical School Discipline of Regenerative Medicine 04.06.2012 “Type-2 innate lymphoid Max Planck Institute Department of “Receptor tyrosine Dermatology, Sydney SCRM Building, The CeMMinar cells in protective of Biochemistry Epi-genomics and kinases, Notch muta- Medical School University of Edinburgh Maria Sibilia immunity and asthma “ “Comprehensive Cancer Risk Factors, tions and PTEN loss “Real-time imaging ´,GHQWLÀFDWLRQRIQRYHO Institute for Cancer Host: Sylvia Knapp proteome analysis and German Cancer Research converge on mTOR in of cutaneous innate pathways & mecha- Research, Dept. of some of its applications” Center in the Helmholtz T-ALL and cause addic- immune responses nisms of hematopoitic Medicine I, 21.08.2012 +RVW.HLU\Q%HQQHȅ Association tion to cap-dependent GXULQJLQÁDPPDWLRQ OLQHDJHVSHFLÀFDWLRQµ Comprehensive Cancer Impromptu “Global epigenetic translation” and infection” Host: Giulio Superti- Center, Medical Liliana Krasinska 03.10.2012 alterations in chronic Host: Sebastian Nijman Host: Georg Stingl Furga University of Vienna Institute of Molecular Impromptu lymphocytic leukemia” (MedUni Vienna/ ´'HÀQLQJWKHIXQFWLRQV Genetics of Montpellier Anne-Claude Gavin Host: Christoph Bock 29.11.2012 Austrian Academy of 10.05.2012 of EGFR in Cancer (IGMM), National Center Molecular Biology Joint MedUni Vienna Sciences) and Giulio Impromptu and beyond” IRU6FLHQWLÀF5HVHDUFK Laboratory, EMBL, 24.10.2012 CeMM Special Seminar Superti-Furga (CeMM) Maurizio Scaltriti Host: Denise Barlow (CNRS), Montpellier, Heidelberg Impromptu Hiroshi Takayanagi Department of France “Systematic screens for Hendrik Luesch Dept. of Immunology, 18.12.2012 Medicine, Mass General 18.06.2012 “A novel chemical protein–lipid interac- Department of Medicinal Graduate School of Special Seminar Hospital Cancer Center, CeMMinar biology approach to tions in Saccharomyces Chemistry, University Medicine & Faculty of Rolf M. Zinkernagel Boston, MA Garret A. FitzGerald understanding the cerevisiae” of Florida Medicine, The (Nobel Laureate 1996) “Overcoming targeted Department of CDK network” Host: Giulio Superti- “Discovery, Mechanistic University of Tokyo Institute for therapy resistance: Pharmacology, Institute Host: Sebastian Nijman Furga Characterization & “Osteoimmunology - Experimental hypothesis-based drug for Translational Development of shared mechanisms Immunology, combinations” Medicine & Therapeutics 30.08.2012 03.10.2012 Anticancer Agents from and crosstalk between University of Zurich Host: Sebastian Nijman (ITMAT), Perelman Impromptu Special Seminar Marine Cyanobacteria” the immune and bone “Immunology taught School of Medicine, 0DȪHR,DQQDFRQH ,QGHU9HUPD Host: Kilian Huber & systems” by viruses” 14.05.2012 University of Division of Immunology, Irwin and Joan Jacobs Giulio Superti-Furga Host: Shinya Sakaguchi Host: Andreas CeMMinar Pennsylvania Transplantation and Chair in Exemplary Life (MedUni Vienna) & Bergthaler 0LFKDHO-(FN “Peri-pheral Clocks in Infectious Diseases, Science, American Andreas Bergthaler Department of Cancer Cardiometabolic 6DQ5DƆDHOH6FLHQWLÀF Cancer Society (CeMM) Biology, Dana-Farber Function” Institute Professor of Mol.Biology, Cancer Institute and Host: Christoph Binder “In vivo imaging of anti- The Salk Institute, Harvard Medical School, viral immune responses Laboratory of Genetics, Boston, MA in lymph nodes and in CA “TKinase Targets in the liver” “Glioblastomas: Lung Cancer: Structure, Host: Andreas reprograming & mechanism and inhibi- Bergthaler WUDQVGLƆHUHQWLDWLRQµ tion of EGFR and TBK1” Host: Giulio Superti- Host: Giulio Superti- Furga Furga

Ce — M—M — Research Report 2012 86 87 1st CeMM SMART Lecture 6th CeMM Karl Landsteiner Lecture

* SMART – Science, Medicine, Inauguration of the CeMM SMART series of 7RZDUGV60$57HU'UXJV Ruslan M. Medzhitov Art, Research & Technology Lectures by Dr. Norbert Bischofberger In 1996, when the first HIV treatments became listens to Jussuv Karajev’s impromptu violin playing The first CeMM SMART* Lecture was available, patients were required to take a after concert and lecture. inaugurated on Monday 19 March 2011 by complex mixture of over 30 drugs, some with Dr. Norbert Bischofberger, Executive Vice fluids some without. Unsurprisingly, these President of Research and Development and complicated regimes had a profoundly negative Chief Scientific Officer of Gilead Sciences, Inc. impact on the patients’ quality of life. Norbert This new series of lectures address contem- explained the rationale and the scientific break- porary challenges of science at the interface of throughs that enabled the transition, around 10 science and society, and science and art, and in years later, to fewer, more effective and better- an interdisciplinary manner. In the first SMART tolerated anti-HIV drugs with the subsequent lecture, entitled “Antiviral Drug Discovery and dramatic improvement in quality of life. Gilead Development: Combating the Global Threat of has also launched an access program involving HIV and HCV”, Dr. Bischofberger talked about 132 low-income countries with the aim to pro- the evolution of HIV and Hepatitis C (HCV), vide these drugs at no profit. The lecture was both in terms of the diseases they cause, and how followed by a panel discussion and questions the medical community has worked to develop from the audience. One topic that was aired was more effective treatments. It was an intriguing the possibility of developing an effective HIV tale of two diseases and a company. vaccine, which has thus far remained elusive. Norbert stated that despite his overall optimism concerning therapeutics for HIV, he does not consider it likely that a vaccine will be developed in the near future. Rather, he felt that modern technologies will enable more efficient, targeted, and better tolerated compounds that, when combined with policy changes, can contribute to The Karl Landsteiner Lecture is held annually 'HDOLQJZLWK)RUHLJQ,QYDGHUV the more global availability of drugs. at CeMM in honor of the achievements of the Being able to distinguish between the body’s own Austrian biologist and physician noted for his cells and foreign pathogens such as bacteria and discovery of human blood groups in 1900. This viruses is critical for the immune system to discovery revolutionized medicine by enabling function effectively. In his talk, Ruslan Medzhitov the safe performance of blood transfusions. In outlined the three strategies that humans and recognition of this, the lectureship is awarded other organisms deploy in order to deal with Around 150 guests joined to a pioneer in molecular medicine who is care- foreign invaders: avoidance, to reduce exposure WKHÀUVWVPDUWOHFWXUHRI fully selected by the faculty at CeMM. This year to a pathogen; resistance, to reduce the pathogen Norbert Bischofberger. marked the sixth Karl Landsteiner Lecture, which burden; and tolerance, to reduce a pathogen’s was presented by Prof. Ruslan M. Medzhitov, the negative effects. The main focus of the talk was David W. Wallace Professor of Immunobiology, to convey to the audience that understanding and Howard Hughes Medical Institute tolerance to a pathogen is a crucial parameter in Investigator at Yale University School of immunology. Analyzing virulence from an evo- Medicine in the U.S. Ruslan is a pioneer in the lutionary point of view, reciting examples such field of innate immunity. He has been working as the Spanish flu of 1918, as well as describing on the intricacies of the molecular mechanisms novel experimental approaches, Ruslan created of innate immune recognition and the control an intense public engagement that continued of adaptive immune responses for more than 20 in the reception that followed. The lecture was years. “How does an organism distinguish self exceptionally well attended and the historic from non-self?” was the central question of his Festive Hall was filled to capacity, with many lecture, delivered on May 3rd 2012 to more than prominent researchers among the guests. We 300 guests in the magnificent Festive Hall of the would like to thank Jussuv Karajev (violin) and Austrian Academy of Sciences. Marija Köhler (piano) for the wonderful music that framed the event and managed to transport us to the majestic world of the Silk Road with folk dances from central Asia.

Ce — M—M — Research Report 2012 88 89 “The scientist, like the artist, presses forward into previously unexplored or unnamed areas. It is no coincidence then that with the CeMM Brain Lounge a place has been created where art and science come together. As an artist, I am driven by a certain joy in exploration. My work and installations are always experimen- WDODUUDQJHPHQWVDGGUHVVLQJVSHFLÀF questions. They are questions regarding “humanness,” or what it is that makes up this world that we perceive subjectively. I formulate notions and make assertions, try to make possibilities tangible. Unlike the scientist, I fortunately do not have to SURYLGHORJLFDOO\YHULÀDEOHHYLGHQFH,DP aided instead by the power of poesy. One thing is certain: inspiration is the key that opens unexplored worlds. This is as true for the scientist as it is for the artist. Insight generally grows from notions; QRWLRQVPDNHERWKVFLHQWLÀFDQGDUWLVWLF work possible.”

Dorothee Golz (*1960, Muehlheim, Germany) 'RURWKHH*RO]VWXGLHGDUWLQ6WUDVERXUJDQGLQSDUDOOHO art history and anthropology at the University of Freiburg. She has lived and worked in Vienna since 1988. Following her participation in documenta X (1997) her works have achieved an international reputation. For the CeMM Brain Lounge she created a chair backrest artwork. “CeMM – we share the excitement and are drawn into it – we passionately pursue, hold our breath and wish the best of luck.”

Martin Walde (*1957, Innsbruck, Tyrol) Martin Walde studied at the Academy of Fine Art, Vienna. Among other things, he was awarded the 2ƥR0DXHU3UL]HLQƛƣƣƛDQGWKH&LW\RI9LHQQD´V3UL]H for Fine Art (Preis der Stadt Wien für Bildende Kunst) in 2012. Martin Walde is an internationally acclaimed artist, participant in many important international exhibitions including the Venice Biennial in 1986 and 2001 and documenta X in 1997 . His contribution to the CeMM Brain Lounge is the textile artwork ANACONDA, 2012, which is part of the series Hallucigenia products, 2003, as well as a chair backrest artwork. Workshops and iBiolMath Workshop

Conferences Approximately 120 scientists attended the first increasingly interlinked. The one day workshop, iBiolMath Workshop on February 16, 2012, at organized by Jacques Colinge (CeMM) and CeMM. Initiated by Heinz Engl, Rector of the Philipp Kügler (RICAM), stimulated interdisci- University of Vienna and Director of the Johann plinary research activities among Viennese Radon Institute for Computational and Applied scientists working in the areas of mathematics Conferences are an essential part of Mathematics (RICAM), Giulio Superti-Furga, linked to biology or medicine. Thirteen scientific research. They enable direct CeMM Director, and Magnus Nordborg, Gregor presentations, an inspiring keynote lecture by Mendel Institute (GMI) Director, the workshop Peter Schuster, as well as a poster session formed communication of results between was designed to integrate molecular biology and the basis for lively discussions and networking scientists of different disciplines and with biomedical sciences with computational biology among the large number of participants. diverse backgrounds. They also promote and applied mathematics, which are becoming dicussions, and provide a breeding ground for new ideas and research directions. CeMM sponsors several national and international conferences each year. Austrodrugs 2 In 2012, four conferences at the cutting- edge of biological sciences were organized

by CeMM scientists and held at the Beginning in 2011, the Austrodrugs Initative Drug Targets” to educate the next generation of institute. The organizers would like to aimed to bring together the Austrian community Austrian chemical biologists. Renate Schnitzer, thank all the speakers and participants of academic chemical biologists and industrial Head of Screening at Boehriger Ingelheim Vienna, drug discoverers. To strengthen and expand and arguably the industrial high-throughput that contributed to the success of these this community and shape future European biology expert in Austria, gave an excellent meetings. public-private initiatives, Giulio Superti-Furga presentation on research and technological focus and Stefan Kubicek organized the second of the company, and Georg Casari, CEO of the Austrodrugs meeting on March 19, 2012, at CeMM. start-up Haplogen presented its focus on haploid Together with CeMM Principal Investigators (PIs) cells for experimental human genetics in a test Sebastian Nijman and Christoph Bock, they high- tube. The meeting was followed by a workshop lighted the development of high-impact chemi- co-organized by Ylva Huber from the Austrian cal biology publications and the Platform Austria research promotion agency (FFG), and Hemma for Chemical Biology (PLACEBO). In 10-minute Bauer from the Austrian Ministry for Science “speed-dating” presentations, new members and Research (bmwf), where opportunities and of the community had the chance to present challenges of the initiative, and possibilities their expertise and resources. Steffen Hering for future interaction and collaborations were introduced the doctoral program “Molecular discussed in a networking session.

Together with Giulio Superti-Furga Stefan Kubicek organized the second Austrodrugs meeting.

94 95 VIIRUS ECBS Meeting 2012 Symposium Small Molecules for Big Biology

Thanks to new molecular medical facilities at how and combined resources of this growing More than 130 researchers CeMM, the Medical University of Vienna, the bio-research cluster. Organized by CeMM PIs, from all over the world joined the ECBS Conference Vienna Biocenter, and the Institute of Science Sylvia Knapp and Andreas Bergthaler, it brought in the Austrian Academy and Technology (IST) Austria, the Vienna region together more than 30 research groups actively of Sciences, organized by CeMM. Notice that many has emerged as an internationally recognized involved in this topic. Around 100 scientists participants have a fan in scientific research hotspot for immunology and from various disciplines, including medicine, their hands. infection. The first Vienna Infection Immunology molecular biology, biochemistry, veterinary Researchers - United Symposium (VIIRUS) medicine and systems biology set the stage held at CeMM on May 24, 2012, was designed for collaborations, common grants and future to provide an overview of the cumulative know local symposia.

The Viirus meeting brought together more than 30 research groups involved in immunology and infection.

Small molecules can have a profound impact than 130 researchers from all over the on biological systems. To discuss topics such as world, sharing an interest in the interdisciplinary “finding the small molecules”, “big questions field of Chemical Biology. It opened with a key- on the cell cycle”, “big roles - big tasks”, “one note lecture by Stuart Schreiber, Director of the drug - one system approach”, the third European Chemical Biology Program of the Broad Institute Chemical Biology Symposium / second CeMM of Harvard and MIT, and comprised 20 talks Vienna Drug Action Conference took place at by invited speakers as well as short talks from CeMM and in the Festive Hall of the Austrian participants and extended poster presentations. Academy of Sciences. The 3 day conference, The sessions encompassed a broad spectrum from the 1st to the 3rd of July, 2012, was literally of modern chemical biology research from drug the hottest conference to be held at CeMM, with screening and drug discovery to cell differentia- temperatures of 40 degrees Celsius due to a local tion and therapeutic innovation in the systems heatwave. The meeting was attended by more biology era.

Ce — M—M — Research Report 2012 96 97 CeMM and Visitors to CeMM Society

Scientific research produces many social and economic benefits, and is an integral part of any society. It is therefore critical for institutes and universities where research is performed to embrace the societies in which they reside in order to actively integrate the diverse views and cultures into their own values and operations. This involves promoting communication between society mem- bers and scientists. In 2012, CeMM was honored with several important visitors, including Prof. Karlheinz Töchterle, Federal Minister of Science and Research and; the Presidium of the Austrian Academy of Sciences; Dr. Michael Häupl, 0DUFK CeMM was honored with a visit -XO\ Dr. Michael Häupl, Mayor of Vienna Mayor of Vienna; and EU-Commissioner from Prof. Karlheinz Töchterle, Federal Minister and one of the fathers of the institute visited of Science and Research and the Presidium of the CeMM for the first time. In-depth discussions Dr. Johannes Hahn. Austrian Academy of Sciences. “The importance with the trained biologist made the visit a of basic research for the long-term improvement memorable event. Mayor Häupl highlighted the of medical care is evident”, Karlheinz Töchterle importance of CeMM, and its close collaboration summarized, emphasizing the advantages of with the General Hospital and the Medical CeMM’s focus on bridging the laboratory bench University of Vienna, for medical-oriented and the clinic, and it’s location adjacent to research. the Vienna General Hospital and the Medical University. “CeMM is a role model for successful $XJXVW EU-Commissioner Johannes collaboration between a flagship institute of the Hahn paused on a trip through Europe to visit Austrian Academy of Sciences and the Medical CeMM. The former Minister of Science and University of Vienna.” Research was one of CeMM’s supporters in the early stages. It was his first visit to the new $SULO Federal Minister Karlheinz building, where he received an update on the Töchterle accepted another invitation to join progress and spirit of optimism of the young and the presentation of CeMM’s 2011 annual report, dedicated team. which was held in the historic reading room of the Josephinum. The choice of location reflected 2FWREHU U.S. Ambassador to Austria the central theme of the report: to build a bridge William C. Eacho and Mrs. Eacho also visited from the exceptional anatomical wax models the institute to learn about the developments of displayed in the Josephinum to the molecular modern molecular medical research going on at medical research performed at CeMM. Among CeMM. They were particularly interested in the the guests: Liechtenstein Ambassador to Austria, PLACEBO Lab, Mass Spectrometry and the Next Her Excellency Maria-Pia Kothbauer; the Rectors Generation Sequencing Unit. of the Medical University, Wolfgang Schütz, Christiane Druml, Karin Gutiérrez-Lobos, and Franz Wurm; the President of the Austrian Academy of Sciences, Sigrid Jalkotzy-Deger; and the Brain Lounge designer duo of “Walking Chair”, Karl Emilio Pircher and Fidel Peugeot. 98 99 “Science is the surrogate of art.”

%HOD-XOHV] ƛƣƣƟ Dialogues on Perception, THE MIT Press, Boston, Mass.

Esther Stocker (*1974, Silandro, Italy) Esther Stocker studied at the Academy of Fine Arts, Vienna (1994-1999), at the Accademia die Belle Arti di Bera, Milano (1996) and the Art Center College of Design, Pasadena, CA (USA, 1999). In 2001 she received a state scholarship in Visual Arts. Esther Stocker has been honored with many important awards, including the Visual Art Award of the City of Vienna (Preis der Stadt Wien, 2009), the South Tyrolean Award for 6LWH6SHFL¼F$UW 6GWLUROHU3UHLVIU.XQVWDP%DX ƜƚƚƜ DQGWKH2ƥR0DXHU3UHLV Ɯƚƚƞ 6KHOLYHV and works in Vienna. For the CeMM Brain Lounge she FUHDWHGWKHQRUWKZDOO ¼OPRQZRRG  “Art and science address common issues, yet approach WKHPLQGLƆHUHQWZD\V They complement each other through the respective GLƆHUHQFHVLQWKHLUPHWKRGV which only too rarely intersect in places to germinate new questions. One such place is CeMM.”

Thomas Feuerstein (*1968, Innsbruck, Tyrol) )HXHUVWHLQ³VZRUNHQFRPSDVVHVLQVWDOODWLRQVREMHFWV drawings and paintings as well as sculptures, photo- graphs and videos. Substantial aspects of his art are modes of connection and analogies between art and science, sociology and biology that regulate the interdependence between organisms and environment. For the CeMM Brain Lounge he created a chair backrest artwork. Brain Lounge Merry Go Round Opening A Turning Set of Active Tableaus

Fidel Peugeot, Karl E. Pircher and Giulio Superti-Furga at the opening ceremony. /HW·VJRIRUDOLȪOHIUHVKWKLQNLQJ On November 19, 2012 the opening of the CeMM Brain Lounge, a special think room and “Gesamtkunstwerk” took place as part of Vienna Art Week, which is an art event with international resonance. The scientific community and many art lovers were invited to interact with the designers and artists that developed the Brain Lounge, which is situated on the eighth floor of the CeMM building, overlooking Vienna’s skyline. The opening began with a surprise performance by the experimen- tal theatre group Toxic Dreams, which was projected live into the CeMM seminar room, before the guests were invited to become part of the think fest themselves. Spin around, think around, reload your brain … first journeys and the lucky passengers were The central piece of the Brain Lounge is a selected by a card game. Every Brain Lounge carousel with 14 leather chairs. Their reverse journey begins with a ritual meant to abandon side is de tachable and meant to be designed the daily routine and professional habitus by artists, currently they present work by Eva and encourage the participant to assume a Schlegel, Thomas Feuerstein, Martin Walde, new identity. Then, by being exposed to an Alois Moosbacher and Dorothee Golz. The walls environment of changing art and a science display artworks of Esther Stocker and Brigitte fictional ambience, riders of the Brain Lounge Kowanz, and the ceiling is full of “sister blister” can be induced into a different, playful state of lamps by Walking Chair, which look like clouds. mind. The slow turning of the sitting carousel The fashion designer Daniel Kroh, working in provides a constant change of views and Berlin, is responsible for the design of the special evokes a sense of communality amongst fellow Brain Lounge costumes. With the designers Karl travelers. A logbook is available to record the Emilio Pircher and Fidel Peugeot leading the way, intellectual journeys. With its synergy of art, they joined CeMM in creating a space that serves science, medicine and design, the Brain Lounge as a knowledge-generating environment. Most should act as a breeding ground for new of the artists were present at the inauguration. ideas. The first travels were enthusiastically While the actors of Toxic Dreams celebrated navigated and the entries in the logbook report the “birth of thoughts” in three acts in the Brain strong intellectual breezes and even some Lounge the guests could follow the per formance storming thoughts! via video from the CeMM lecture hall and pre- pare themselves for a ride in the Brain Lounge’s We thank all artists, donors and sponsors who thinking carousel. Christiane Druml, Vice Rector have helped us to realize the project this far. of the Medical University of Vienna, Ulrike Felt, Professor of Social Studies of Science, Vienna University and journalists and communications experts Conny Bischofberger and Michael Fleischhacker were designated captains of the

104 105 Tableau 1 - The life of thinking monkeys. Ph.D.-Program The table turns counter clockwise. The performers wear monkey masks. While turning, they perform ges- tures of thinking monkeys (e.g. scratching the head, and Social Life shaking arms violently, dismissing each others mode of thinking). Music: cartoon Looney Tunes and a dramatic score taken at CeMM from the Japanese version of King Kong. (2 to 3 min)

7DEOHDX6ZHHWOLIH The table turns clockwise, slow speed. The performers dress as if on a Hawaiian According to a recent survey conducted by YDFDWLRQ ÁRZHUJDUODQGV etc.). They perform a slow The Scientist published on 1 August 2012, dance, alternating between seating and standing. Music: CeMM is the best academic place to work in Hawaiian. (2 to 3 min) Europe. Internationally, CeMM was in fourth Tableau 3 - Brain feeder. The table turns clockwise place. The survey ranks academic and personal at the fastest speed. The performers wear under- satisfaction in the work place and has been wear. They touch, stroke conducted by the journal for the last 10 years. WKHLUEHOOLHVLQGLƆHUHQW speeds alternating between VLȅLQJDQGVWDQGLQJ7KH\ eat candy-bars while mov- CeMM is a lively, international place. The ing. Music: Junk is no good baby, Brion Gysin (2:05) young institute for molecular medicine runs

A performance by: a very popular and successful Ph.D. program. Toxic Dreams :ULȨHQDQGGLUHFWHGE\ In 2012, about 550 young scientists applied Yosi Wanunu 3URGXFHGE\ for 8 positions. In total, there are currently Kornelia Kilga 45 Ph.D. students at various stages of their studies enrolled in the Ph.D. program at CeMM. Of course, the level of scientific skill and knowledge are placed high on the list of important requirements in the selection process. On top of these is something else. CeMM looks for outstanding personalities and is willing to support talent and offer room for creativity and interaction. For example, the sport/activity program at CeMM includes a wide range of different goings-on. Ranging from a sophisticated bridge circle to a venturesome climbing group, a yoga troupe, several serious and ‘run- for-fun’ athletes and, of course, a soccer team. Specific events have become established, annual traditions. An outing in autumn, the Halloween Ball and Christmas party are regular events in the intensive social life at CeMM.

Ce — M—M — Research Report 2012

Ph.D. Program

October 2012 marked the start of the fifth CeMM CeMM as Intellectual Hub Ph.D. program for 8 new Ph.D. students, who One of the new Ph.D. students, Bernd Boidol, were selected from almost 550 applicants. The describes his experience of the selection process first phase of the program involved an intensive and his first few months at CeMM, including schedule of lectures, soft skill courses and work- laboratory rotations, exciting guest speakers, shops presented by PIs from CeMM and the and the odd party. neighbouring Medical University of Vienna. In order to gain insight into the different pro jects Bernd Boidol and technologies, to get to know the people in “After a challenging, two-day selection round other groups and foster potential future with various panel interviews, a presentation collaborations, students spend a few weeks in of my previous research projects, and numerous two different laboratories at CeMM through- conversations with other applicants and CeMM out November and December. There were scientists, I was excited to finally receive an also excursions to two historically important offer to join the CeMM Ph.D. program. The first institutions: the Austrian Academy of Sciences, month consisted of a densely-packed schedule of the statues in which provided inspiration for introductory lectures and workshops on project the 2009 Research Report; and the Josephinum, planning, scientific writing, and presentation which houses an extensive collection of medical skills. Moreover, we got to know every principal wax models; some of which were presented in investigator’s area of research and received the 2011 Research Report. There were also trips valuable advice on how to make the best of the to several local prestigious research institutes, forthcoming 3 years as Ph.D. students. Addition- specifically IMBA and IMP, both located in the ally, we were in charge of organizing the annual third district of Vienna, and IST Austria, near to Halloween Ball, which was a great opportunity to Klosterneuberg. work together as a team and introduce ourselves to the CeMM community. The subsequent lab. rotations in two different groups allowed me to gain deeper insight into methods and techniques that I am now frequently using for my own pro- Some of the other Ph.D. students that started in -RKDQQD.OXJKDPPHU CeMM PhD students jects. I greatly benefited from my supervisors’ 2012 have also shared their thoughts on CeMM. “Getting a new (PhD) project started is hard visiting the Josephinum with Professor dedication during that time and the outstanding work, but with CeMM’s amazing culture of Dontscho Kerjaschki. support from the host groups. Furthermore, Katrin Hoermann collaboration, interaction and communication these two months enabled me to build a network “I can’t think of any other cutting-edge research you can be sure to find people who will readily of peers with whom I can discuss my research on institute offering a Ph.D. program where share their experience and knowledge.” a regular basis, even outside of the weekly project curiosity and passion for science blends in so meetings. CeMM not only urges groundbreaking perfectly with practicing yoga or performing a Anna Skucha research, it also supports its employees with a legendary Harlem Shake.” “What I can say is that I’m amazed that we – as collaborative and community-like framework to CeMMies – are such a great team. Even though achieve this goal. Annual excursions and extra- Cecilia Domínguez Conde everybody has some friends outside of CeMM curricular activities are part of the life at CeMM “The high standards of research at CeMM and we spend lots of time together, doing sports, and help to make new friends, get to know in particular the strong focus on immunological having fun etc.” people’s research, and have a fun time outside aspects of disease were crucial for my decision of work. The multitude of invited speakers from to join the CeMM Ph.D. program.” top universities and research centers all over the world, a steady exchange of ideas with scientists from the adjacent General Hospital and the Medical University of Vienna, as well as national and international collaborations, make this place one of the intellectual hubs in Europe and the world. For me, it is extremely exciting to be part of this venture and I am glad to have the opportu- nity to earn my Ph.D. degree at CeMM.”

Ce — M—M — Research Report 2012 110 111 Social Activities Parties

Sport +DOORZHHQ The year of 2012 saw the The organization of the introduction of yoga classes Halloween Ball is an integral at CeMM. As busy scientists, SDUWRIWKHÀUVWIHZPRQWKV we spend too much time of the Ph.D. program. The FRQÀQHGWRSK\VLFDOO\ exercise is designed as a sedentary lifestyles and team building event and a DERPLQDEOHSHULRGVVLȅLQJ training exercise to develop hunched over a computer organizational skills. On thereby causing undue top of this, it is a show of muscle tension to the exceptional creativity in detriment of good posture. preparing fancy costumes, :KDWEHȅHUZD\WRPHOG acting and dancing. VFLHQWLÀFPLQGVZLWKUHOD[D- tion and stress release and Christmas Party ease of access to exercise on Each year it is becoming site. Michelle Froehlich was LQFUHDVLQJO\GLžFXOWWRRU- recruited to teach the style ganize the Christmas party RI\RJDÁRZ$OVR for the expanding CeMM was a successful year for team. This is challenging the soccer team. With fancy as several requirements footwork and a high team QHHGWREHIXOÀOOHGWKH spirit spurred on by excep- location has to have a cosy tional cheerleading talent, and comfortable dining the team earned a fabulous room, excellent food, a second place in the soccer well-equipped theatre for tournament for scientists - organized and impromptu SURF 2012. input from our creative CeMM people, a perfect Long Night of Science GDQFHÁRRUDQGFRQFHUWKDOO Team spirit was also an Additionally, it is important important factor for success to maintain harmony such during the participation of that no neighbours are CeMM at “Die Lange Nacht disturbed in the wee hours der Forschung” in the Hall of the morning. A stone’s RI6FLHQFHVLQWKHÀUVW throw away from CeMM, the disctrict of Vienna. Together perfect location was the with other institutes of Projektraum at WUK. the Austrian Academy of Sciences, CeMM took the chance to present our research to the public in order to raise awareness for research and develop- ment in Austria. Presenta- tions, small experiments and especially an entertain- LQJSLSHȅLQJFRQWHVWDQGD TXL]DȅUDFWHGPDQ\YLVLWRUV particularly children and adolescents.

Outing The institutionalized autumn event (fortunately always on a very sunny day) is designed to greet the new semester with enthusiasm and to take the chance of meeting old and new colleagues in a relaxed atmosphere. The outing for 2012 was a cultural trip through the history of Austria from the Romans to the Baroque period, from the Archeological Park Carnuntum to the Imperial Palace Hof. During the stay at the hunting lodge for Prince Eugene of Savoy, the new Ph.D. students took the chance to introduce themselves and involve their colleagues in an amusing quiz.

Ce — M—M — Research Report 2012  ´3HQWKRXVHRžFHJRHV%UDLQ Lounge. We wish you a happy, inspiring voyage! Let us sing: Anything can happen so let it go, let it go, let it go Many things will be happening when you know, know, know I know that you know, so you make me know Now you know that I know and I let you go Many things will be clear when you go around Anything can be highlighted when you roll around and around Now you know what I know and you say oh, oh, oh, Then I know what you say means we go, we go, let’s go”

Walking Chair – Karl E. Pircher and Fidel Peugeot After working as a mechanical engineer and teacher, Karl E. Pircher (*1963), a native of South Tyrol, studied with Ron Arad at the University of Applied Arts, Vienna and received several international design-awards. Fidel Peugeot (*1969), a Swiss national, has had a successful career as a graphic designer and font designer, also touring as a musician in a number of bands. The two met in projects for the Lomographic Society and immediately perceived each other to be the essential completion. Together they established the Walking Chair Design Studio in 2003. Karl and Fidel are responsible for the CeMM Brain Lounge design. “The virus of art is permanently present at the CeMM brain lounge!”

Eva Schlegel (*1960, Hall, Tyrol) Eva Schlegel studied with Oswald Oberhuber at the University of Applied Arts, Vienna (1979-1985) and served as Professor for Photography at the Academy of Fine Arts, Vienna (1997-2006). After participating in the Venice Biennial in 1995, she was commissioner of the Austrian Pavilion in 2011. For the CeMM Brain Lounge she created a chair backrest artwork. 6FLHQWL¼F Excerpt from the Report of the Advisory &H006FLHQWLÀF$GYLVRU\%RDUG

´6FLHQWLÀFSHUIRUPDQFHRI&H00DVUHÁHFWHG Giulio Superti-Furga as CeMM leader: Board by the presentations of its trainees: In our view Dr Superti-Furga is an outstand- One day of our visit was fully occupied by concise ing, vigorous, and strong leader of CeMM and a scientific presentations by 25 research trainees superb scientist. He is a role model for his faculty (a mixture of students and post docs) who repre- colleagues. We urge his reappointment most sent all of the Center’s research laboratories. We enthusiastically. A better leader would be hard to also received presentations from Jacques Colinge, imagine, much less to be found for CeMM, Few The fourth evaluation of the Scientific Head of Bioinformatics, and Keiryn Bennett, – if any – would have led a new and very small Advisory Board (SAB) took place from Head of Mass Spectrometry. Institute with an ambitious agenda to the levels November 11-13, 2012. Eight members of success now on record in only 6–7 years. The overarching impression of these talks was were able to participate. They were that: a) the science at CeMM is world class. All We also urge most strongly that he be appointed as Richard Flavell/Yale University, laboratories are doing superb work. The collec- a tenured Professor at MUV without major teach- James D. Griffin/Dana Farber Institute tive publication record of CeMM in the past two ing or administrative obligations. His dedication years is enviable, with multiple papers in the to and uniquely effective leadership of CeMM are, Boston, Carl-Henrik Heldin/Ludwig highest profile journals, b) The science at CeMM we believe, a formula that will also benefit MUV. It Institute Uppsala, Denis Hochstrasser/ has advanced significantly in breadth and depth will do so in ways that are especially beneficial to Geneva University Hospital, David during the past year; c) The trainees it has attract- MUV as a neighbor, a natural research partner of ed and is attracting now are as fine a group as CeMM, and a center of clinical research that can be Livingston (CHAIR)/Dana-Farber & exists in any superb European research center and significantly enriched through translational and Harvard Cancer Center Boston, in many top American ones, as well; and d) The basic scientific collaboration with CeMM. William E. Paul/NIAID Bethesda, two largest and most advanced core functions at CeMM Bioinformatics and Proteomics are also of We are also aware of the growing responsibilities Hidde Ploegh/Whitehead Institute excellent quality. for mentoring young faculty and overseeing the Cambridge and Nadia Rosenthal/ daily science of CeMM, now that it has expanded The overarching message of these presentations to its physical limits. Dr Barlow has done well in Australian Regenerative Medicine is that, despite its small size, cancer science and this regard, and her efforts are greatly appreciated Institute. On the next page the general research on human immunological disease, by the CeMM faculty. As she approaches part of their report is presented. atherosclerosis, infection and epigenetics at CeMM retirement, we are concerned lest the post of are outstanding. This is an enviable accomplish- deputy director not be created and filled. ment, and the fact that this level of accomplish- Dr. Superti-Furga has too many responsibilities ment has been achieved in a short period of time to be able to handle his own portfolio and that of is remarkable. a deputy director charged in part with mentoring and daily scientific operations oversight, not to speak of her/his own research program. We therefore urge the Academy to allocate funds to recruit a senior faculty member who is both a distinguished and highly successful scientist as well as a proven leader with respected administrative ability.”

Contributing Members: Richard Flavell, -DPHV*ULŠQ&DUO+HQULN+HOGLQ Denis Hochstrasser, David Livingston, William Paul, Hidde Ploegh, Nadia Rosenthal

)RULVVXHVRIFRQÀGHQWLDOLW\LQFOXGLQJFRPPHQWV on individual scientists and intellectual property, LWZDVGHFLGHGWRSXEOLVKKHUHRQO\WKHJHQHUDO summary of the report.

118 119 Members of the The Austrian Academy &H006FLHQWLÀF$GYLVRU\%RDUG of Sciences

The Austrian Academy of Sciences, founded The Academy gave new impetus by taking in 1847, is the leading organisation promoting up forward-looking research areas. Scientific non-university academic research institutions in quality, innovation potential and sustainability Austria. It developed from being a mere learned are the main criteria for its research profile. The society into an organisation promoting modern connection between basic research and clinical scientific research institutions. In the awareness research has been established by setting up of its social, cultural and economic responsibility, CeMM, one of several Academy institutes that the Academy conducts basic research which is stand the test of international competition. open for practical applications, and its mem- bers support this function by making their broad range of expertise available to the public and advising decision makers in politics and business. The Academy is currently promoting 28 research institutions with more than 1100 employees, which are located in several federal states of Austria, with the headquarters in the Old University in the center of Vienna. In the stunning 18th century frescoed festive hall of the Austrian Academy of Sciences (where Haydn and Beethoven conducted premieres of their work) CeMM holds its yearly Landsteiner Lecture.

The main building of the Austrian Academy of Sciences in the 1st district of Vienna. ,QVWUDWHJLFDQGVFLHQWLÀFTXHVWLRQV Prof. Dr. David Livingston (CHAIR) CeMM is advised by a board of international Deputy Director, Dana-Farber/ top-scientists: Harvard Cancer Center, Boston, USA

Prof. Dr. William E. Paul Prof. Dr. Richard Flavell Chief, Laboratory of Immunology, Chairman, Section of Immunobiology, National Institute of Allergy and Yale University School of Medicine, Infectious Diseases, Bethesda, USA New Haven, USA Prof. Dr. Hidde Ploegh 3URI'U-DPHV'*ULŠQ Member, Whitehead Institute for Chair, Department of Medical Oncology, Biomedical Research, Cambridge, USA Dana Farber Cancer Institute, Boston, USA Prof. Dr. Nadia Rosenthal Prof. Dr. Carl-Henrik Heldin Australian Regenerative Medicine Institute, Director, Ludwig Institute for Cancer Research, Melbourne, AU Uppsala University, SE Prof. Dr. Louis M. Staudt Prof. Dr. Denis Hochstrasser Head, Molecular Biology of Lymphoid Head, Central Clinical Chemistry Laboratory, Malignancies Section, National Institutes of Health, Geneva University Hospital, CH National Cancer Institute, Bethesda, USA

Ce — M—M — Research Report 2012  $ 6SRQVRUWKH&H00%UDLQ/RXQJH² ,GHDVÀUVW 6SRQVRU8V The CeMM Brain Lounge was built to promote new research ideas, ideas for the medicine of the future, and for a better society. We kindly invite everybody who believes in the fertile interplay of science, art, medicine and society to sponsor this on-going project. Every contribution is welcome. For a donation of 1,000 Euro or more, you will receive a signed print by Peter Kogler and Walking Chair titled “Brain Lounge” (limited edition of 100), acknowledgement and privileged access to the Brain Lounge.

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% 6SRQVRU&H00UHVHDUFKSURMHFWV If you think that the research into future medicines should not be left entirely in the hands of businesses, if you think that society needs to take a better informed and more active role in the health management )RUWKHVSRQVRUVKLSSURJUDP options of the future, and if you think that SOHDVHFRQWDFW(YD6FKZHQJ knowledge is our biggest asset for the HVFKZHQJ#FHPPRHDZDFDW future, then these sponsoring opportunities ƞƝƛƞƚƛƠƚơƚƚƟƛ  are for you. We have an entire sponsoring RU*LXOLR6XSHUWL)XUJDGLUHFWO\ program, with the ability to support indi- JVXSHUWL#FHPPRHDZDFDW vidual research projects, professorships, ƞƝƛƞƚƛƠƚơƚƚƚƛ  fellowships, training projects or important research instrumentation. It is also possible We kindly ask for contributions to give names to rooms, laboratories WRWKHIROORZLQJDFFRXQW and even the whole institute (“Your name” &H00)RUVFKXQJV]HQWUXPIU Center for Molecular Medicine). At a 0ROHNXODUH0HGL]LQ*PE+ minimum, for your donation you will 8QL&UHGLW%DQN$XVWULD$* receive a symbolic CeMM Health Research .RQWRƚƛƜơƚƞƛƢƟƚƛ Bond certificate that you can treasure or %/=ƛƜƚƚƚ give as a gift. 6:,)7%.$8$7:: ,%$1$7ƜƣƛƛƚƚƚƚƛƜơƚƞƛƢƟƚƛ 5HDVRQIRU7UDQVIHU 9HUZHQGXQJV]ZHFN $ &H00%UDLQ/RXQJH % &H003URMHFWV (PSOR\HHV

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Bürckstümmer T, Müller AC, Fauster A, Holze C, Deininger S, von Aulock S, Knapp S. resistant CML. Nat Chem Biol. Lindsten K, Goodbourn S, Kochs G, Weber F, Apolipoprotein B100 is a suppressor of 2012 Nov;8(11):905-12. 36. Maurer M, Müller AC, Wagner C, Huber ML, Bartenschlager R, Bowie AG, Bennett KL, Staphylococcus aureus-induced innate immune Rudashevskaya EL, Wagner SN, Bennett KL. Colinge J, Superti-Furga G. Viral immune modu- response in humans and mice. Eur J Immunol. 60. Wolf D, Jehle F, Ortiz Rodriguez A, Dufner B, Combining Filter-Aided Sample Preparation lators perturb the human molecular network by 2012 Jul 18. doi: 10.1002/eji.201242564. Hoppe N, Colberg C, Lozhkin A, Bassler N, and Pseudoshotgun Technology To Profile the common and unique strategies. Nature. [Epub ahead of print] Rupprecht B, Wiedemann A, Hilgendorf I, Proteome of a Low Number of Early Passage 2012 Jul 26;487(7408):486-90. Stachon P, Willecke F, Febbraio M, Human Melanoma Cells. 52. 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Ce — M—M — Research Report 2012 132 133 ,QFOXVLYHQHVVDW&H00 Facts and CeMM has a strong intellectual environment 6WDƆ that stems from the international nature of /LVWHGE\QXPEHURISHUVRQVSHU¼HOGRIZRUN CeMM stresses keeping the its employees. Diversity and different cultural administration very lean and Figures backgrounds are a clear advantage to successful HžFLHQW:HKDYHDYHU\ JRRGJHQGHUEDODQFHZLWKD research, collaborations, and the day-to-day VPDOOVXUSOXVRIZRPHQ   The average age is 31 years. business, as long as everyone follows a few basic Management 3 persons principles, which at CeMM are: Professionalism, 2% of total staff Politeness and Persistence. The working

language at CeMM is English. Scientific Support 6 persons 4% of total staff At CeMM, emphasis is given to mentoring

independent young investigators and scientists Lab Heads 14 persons early in their careers, through freedom, 9% of total staff availability of infrastructure and a strong

support system. A flat hierarchy, where the Administration 12 persons input of every single person is appreciated 8% of total staff and required, leads to an enjoyable work environment and an increase in productivity Diploma and Guest Students 17 persons and ideas. 11% of total staff

CeMM is particularly interested in supporting Technical Assistants 28 persons and fostering women scientists in areas where 18% of total staff the gender bias is more evident (like chemistry, screening, proteomics, bioinformatics). Postdoctoral Fellows 27 persons In recruiting new scientists, a dedicated effort 18% of total staff is made to engage female scientists and foster their career development as much as possible. Among faculty, 30% are female (Denise Barlow, Keiryn Bennett, Sylvia Knapp and Joanna PhD Students 45 persons Loizou). Currently the gender balance at CeMM 30% of total staff is equitable (54% women in total) as one can see from the statistics in the annual report.

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