The Austrian Academy of > P

Research Report 2009

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 3 3

Director’s Intro — The Austrian Academy of > p. 8—10 Sciences — Research at CeMM — Prudence and > p. 11—17 > p. 20—21 Vigilance — Justice and Wisdom — Faith > p. 22—29 > p. 32—39 and Constancy — Liberality — CeMM Sabbatical > p. 42—51 > p. 54—61 Visiting Scientist — CeMM/MUV Interdisciplinary > p. 64—65 PostDocs — CeMM PostDocs — CeMM PhD program — > p. 66—68 > p. 69—72 > p. 73—76 CeMM Principal Investigators — CeMM Retreat — > p. 77—85 > p. 86—87 CeMM Landsteiner Lecture — CeMM Scientific > p. 88—89 Advisory Board — CeMM Christmas Party — CeMM > p. 90—91 > p. 92—93 Building — CeMM Directory — CeMM Publications > p. 96—97 > p. 98—101 > p. 102—103 2009 — CeMM Facts and Figures — CeMM Health > p. 104—107 Research Bond — CeMM Sponsoring Info — Glossary > p. 108—109 > p. 110—111 of Molecular Medicine — Acknowledgements > p. 112—113 > p. 116 What a critical year! We almost completed The Scientific Advisory Board, fearlessly cap- As in the previous years, CeMM has profited construction of our new building, to be ready to tained by Prof. David Livingston of the Dana- tremendously of the training of 22 PhD students, move in late spring 2010. We witnessed an Farber Cancer Research Institute and Harvard who participate in several PhD programs hosted CeMM explosion of support on the whole concept of University, visited us in November. One of by the MUV. They form the foundations of bridging basic molecular and post-genomic the recommendations expressed at the previous CeMM’s trans-disciplinary knowledge base and research with the chances and difficulties of the meeting was to push towards medicine. They are a constant source of creativity. As of 2010, Research clinical realm. It is becoming more and more were happy about the progress obtained and we will also start a postdoctoral program aimed obvious that the revolutionary molecular knowl- encouraged us to intensify the thrust. Our col- at offering the same degree of organized edge on human individuals and on particular laboration with the Medical University of Vienna medicine-science cross-training to postdoc fel- diseases will drastically change medicine. Most (MUV), that sort of surrounds us like a womb, lows. In 2009, we have had numerous attractive Report importantly, it may well change our basic philo- is of course critical for this and many events international speakers, offering to the entire sophical perception on human individuality. We and initiatives in 2009 contributed to this goal. MUV campus at the General Hospital, another start evaluating in great detail not only the body We were very happy that CeMM Principal chance to meet and discuss with CeMM members plan (genome) as it is modified by our personal Investigator Christoph Binder became Professor and with the speakers. CeMM’s Landsteiner 2009 history with our environment (epi-genome), of Atherosclerosis Research at the Medical Uni- lecture, held by Dr. Vishva Dixit of Genentech versity and congratulate him. His dual appoint- has again been a highlight for the community. Introduction by Giulio Superti-Furga but also how this plan, by being relentlessly exe- cuted, results in the variety of molecular and ment with the Department of Laboratory Probably the most important event of 2009 was cellular networks that make us unique as individ- Medicine is, similar to Sylvia Knapp’s dual affilia- the search for new Principal Investigators, oper- uals. Diseases affect these networks by putting tion with the Department of Medicine I, Division ated with the help of colleagues from the MUV, them out of balance. In essence, at CeMM we of Infectious Diseases and Tropical Medicine, the Vienna Biocenter and the Universities of characterize these fundamental molecular net- one of the vital umbilical cords that link CeMM Graz and Innsbruck. We had 184 applicants, works, look at their pathological malformations to the Medical University. We are indebted to many of which were excellent. Scientific achieve- and develop ideas on how to restore them. Prof. Oswald Wagner and Prof. Christoph Zielin- ments and vision, but also strategic fit with ski who represent the pillars of this collaborative CeMM’s focus on innate immunity, cancer, and Did we make enough progress this year? I believe set-up. CeMM has also profited very much vascular biology, were the important selection we did. The young Principal Investigators from the interdisciplinary fellows Stephan Blüml criteria. We will present the new Principal Inves- were successful in establishing their laboratories, and Viola Bergdorff, who, working in both tigators in next year’s report, but I would like publishing their initial findings and obtaining institutions, CeMM and the Medical University, to already thank everybody involved in the long additional funding from grants. Sebastian Nijman have contributed to enhance the flow of cultural hiring process. obtained two large grants and the “Wiener exchange. For this, we are grateful to Prof. Josef Zukunftspreis” (Vienna Prize for the Future), Smolen and Prof. Stephan Wagner for these How to move towards therapy? Principal thus confirming the appropriateness of CeMM interesting joint projects. Investigator Christoph Binder is making to bet on very young, internationally recruited, important progress towards the identification scientists. CeMM published important papers In the spirit of enhancing medical knowledge at of so-called “natural antibodies” that could be in cancer genetics and innate immunity, includ- CeMM it has been a privilege and also thrilling exploited therapeutically to treat or prevent ing the identification of a gene form that increases to host Prof. Eric Haura, Director of the Lung cardiovascular disease. 2009 was the year where the likelihood of a blood cancer and the identifi- Comprehensive Research Center of the Lee Moffitt ideas on combination therapy came of age at cation of a protein fighting infections. We also Cancer and Research Center in Florida, U.S.A, CeMM, both from a theoretical point of view proposed a new experimental therapy for acute for a sabbatical period in the director’s laboratory. (including interesting discussions with visitor lung injury and pneumonia and published a Eric’s experimental enthusiasm, personal drive Joe Lehár), from an experimental point of warning paper on the use of digitalis-like drugs in and patient-oriented perspective had an inspira- view (for example with Principal Investigator cancer treatment. This shows that our translational effect on the laboratory and resulted in a Sebastian Nijman’s search for cancer vulner- tional-medical vocation is indeed becoming more few interesting successful studies on systems- abilities) and also from a therapeutic perspective evident. Most importantly, the organization has level approaches to lung cancer therapy. We are (where initial results from using different grown together through a nice and natural effort, hoping to establish an institutional tie with the kinase inhibitors are very encouraging at the with full awareness that special dedication had to “Moffitt” to continue the exciting collaboration. cellular level). go into forging relationships when groups are Along these lines are our efforts to use proteom- geographically separated. To all CeMM scientists ics as a discovery tool in a clinical setting. We and administration personnel goes our apprecia- have started a large proteomics-based collaboration and gratitude. Thank you! tion with the Department of Ophthalmology, led by Prof. Ursula Schmidt-Erfurt, to obtain a molecular characterization of the content of ocu- lar fluids in healthy individuals as well as in patients with the most threatening and abundant eye disorders.

Giulio Superti-Furga, CeMM Scientific Director

If you were wondering how the perspective of this photograph in front of the academy building came about: Photographer Michale Sazel and I were allowed to jump on the stage of a tow-away truck that was idle in front of the building!

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 10 11 Without doubt, robust biological and patho Finally, we again include our “CeMM Health logical systems are more easily made vulnerable Research Bond” to highlight our pact with by simultaneous attacks. As part of the necessary society. We envision a society that is increasingly toolbox, we have started gaining access to a aware of the opportunities that the ongoing The Statues chemical biology platform, partially financed biomedical revolution is offering and that gives by a grant of the GenAU program (Genome us input and feedback, and a society that is Austria, BMWF) respectfully called PLACEBO cheering on the sidelines for CeMM’s team of in the Academy (for Platform Austria for Chemical Biology) that mostly young researchers and that is willing links chemistry, pharmacology and disease biol- to support it, also financially. Awareness about Interview with Prof. Artur Rosenauer ogy groups across Austria to do focused chemical health and research can always be improved. by Prof. Giulio Superti-Furga screens on interesting assays and chemical CeMM wishes for a society that is serious about proteomics to identify targets. The name makes fighting infections, cancer and deaths from it clear that chemistry is used as a research tool, cardiovascular disease. In return, we promise but of course we envisage insights that can be our most serious engagement, fortified by the exploited therapeutically. PLACEBO is part of virtues mentioned above. a European network of chemical biology laboratories called EU-OPENSCREEN that is seeking This is number three in the “Blue Books” series infrastructure funds from the European Union. that symbolize the research lab notebooks that we use daily. As in the past, you hold in your To structure this year’s report we have chosen hand the testimonial of our work. A very long to refer to the privilege of being associated with list of people that we wish to thank is at the end the Austrian Academy of Sciences. I wish to of the book. Here, I want to thank Gabriel Ó thank the entire Board of the Academy for Ríordáin and Helen Pickersgill for organizing constant support. The Academy, consisting of and writing this report, respectively. I thank my a philosophical/historical part as well as a math- co-directors Gerhard Schadler and Georg Casari ematical/natural sciences part, has been a hearth for stirring finances and administration with of cross-disciplinary exchange for 162 years and dedication and expertise and Anita Ender for allows a young and future-prone institution such still being the person at which the buck stops as CeMM to draw from a very large spectrum most often. of experiences and knowledge to gain some important historical perspective. The festive hall Enjoy the reading! of the Academy with its perfect architectural Giulio Superti-Furga proportions, its beautiful frescoed ceiling is one of Austria’s most congenial and amiable baroque rooms. Most importantly, it is dedicated to science and scholarship. It also harbors four niches with fascinating long-limbed, elegant sculptures of unusual grace. The statues represent embodiments of pairs of classical virtues, (faith, constancy, justice, wisdom, prudence, vigilance, liberality). In times as these, where dire economic straits can lead to shortness of vision and the faith in the power of knowledge is questioned, we find inspiration for our work and for our science in these statues. In our mind, they link the present to the ancient world and 18th-century art of the age of enlightment to our modern science. The different chapters of this year’s report are structured along these virtues. We hope that this Ariadne’s thread will help you find your way when reading our report.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 As an institute of the Austrian Academy of Giulio Superti-Furga: The statues standing in Sciences, CeMM refers to the historical build- niches of the hall are ascribed to Mollinarolo. ing in the 1st district on Dr. Ignaz Seipel-Platz, What do we know about the artist? formerly the main building of the University, as a sort of headquarters of immense prestige. Artur Rosenauer: It was only a few years ago The centerpiece is the magnificent festive hall that my pupil and friend, Luigi Ronzoni, found on the first floor, in which not only distinguished out that the sculptures in the festive hall of the scholars and scientists discussed and presented Academy were made by Jakob Gabriel Müller, their work but also famous musicians such known as Mollinarolo (1717–1780). Unfortunately, as Haydn, Beethoven and Schubert performed. there exist hardly any documents about him A significant event in the Viennese history and he only produced a few sculptures that we of music was the performance of Haydn’s know of. One example of his work, an altar, can “Creation” on March 27, 1808, on the occasion be found in the dome of Raab (Györ) and two of the composer’s 76th birthday. sculptures made of lead are presented in the Liechtenstein Museum in Vienna. Another is the The subjects of its ceiling fresco, created by main altar in the cathedral of Wiener Neustadt. Gregorio Guglielmi in 1755, are the University’s So he is somewhat of a well kept secret but in four faculties and the apotheosis of the imperial my opinion probably the best Austrian sculptor couple, Maria Theresia and Franz Stephan, of the 18th century. His mentor Georg Raphael as patrons of science and arts. The four groups Donner was by far more famous. After the of statues in the niches of the festive hall are death of Donner in 1741, his pupils (Moll, believed to depict the virtues faith and constancy, Messerschmidt, Mollinarolo) and his brother justice and wisdom, prudence and vigilance, Mathias continued to work in his style until late and liberality. in the century.

Inspired by the festive hall’s artistic visualiza GSF: Do you think if Donner had still been alive tion of the different realms of knowledge, the they would have engaged him? The figures are different chapters of this year’s CeMM report beautiful and you and I like them very much, but are structured along the above mentioned is there any reason to believe that Mollinarolo virtues of the four groups of statues. We are was a second choice? grateful to Artur Rosenauer, full member of the Section for the Humanities and the Social AR: Maybe they would have asked Donner, Sciences of the Academy, Chairman of the but he was already dead and then Mollinarolo Academy’s Commission of the History of Arts was the best choice. It was Wenzel Anton and Professor at the University of Vienna , von Kaunitz-Rietberg, chancellor of Maria who kindly shared his expertise with us. Giulio Theresia and a member of the Kuratorium of the Superti-Furga interviewed him in the festive University, who is likely to have given the hall of the Academy building. permission to engage Mollinarolo. I would say, in the second half of the 18th century whoever gave the order must have been somebody who really was knowledgeable about sculptures with taste and judgment.

GSF: The statues by Mollinarolo in the Lichtenstein collection, are they new acquisitions?

AR: Yes. Once, in the 18th century, they belonged, I believe, to a Liechtenstein castle in Lower Austria. It is a similar story like the one of the virtues here in the Academy. When I saw them first, about 40 years ago, they were ascribed to another Donner pupil, namely Johann Georg Dorfmeister. It was again my student Ronzoni who was able to reattribute them to Mollinarolo while writing his thesis. He is perfectly right with the Liechtenstein sculptures as well as with the figures in the Academy building. Although there are no real documents for the latter, there is a kind of hint in a letter of the architect mentioning that he is going to engage Müller (Mollinarolo) for the façade of the new University building.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 14 15 GSF: As a layperson looking at these statues, GSF: Would there be somebody in Austria I am wondering whether it is customary to make who knows how to restore them? virtues as couples? AR: Yes, it should be possible to find a AR: No, it is absolutely not. It is highly unusual, competent team but it is more a matter I don’t know any other example. And also the of securing the necessary funds. iconography of these virtues is rather unusual. Even as an art historian I have to admit that it is GSF: So the fact that they are pairs, could it be not easy to identify the statues by their attributes. that the artist was paid per each statue done? In some cases like faith it is obvious because of the cross and the other figure is with great prob- AR: No, I am sure there is another reason which ability constancy because of the lion. So faith and maybe can be found in the fresco. Pietro Antonio constancy are represented as twin sisters. Domenico Trapassi, better known by his pseu- donym of Metastasio, created the fresco program. GSF: Is faith holding an orthodox cross? This fresco is different from most other baroque frescos. He wanted everybody to understand AR: No, an orthodox cross would have an what the fresco means, so he wrote down the additional short skewed bar. This is a so-called specification of the faculties. If you come to a Cross of Patriarchs or of Cardinals. It is very typical fresco in the library of a monastery and possible it is meant to honor the Viennese look at all the figures, it is not very easy to figure archbishop cardinal Johann Joseph Count out the meaning of the depicted persons and Trautson, whom Maria Theresia had made the scenes. Not here. protector of the University and responsible for the new building. Trautson is the one who GSF: Would you imagine that Mollinarolo had commissioned Metastasio. It’s curious that was aware of the plan of Metastasio? archbishop Trautson was made cardinal in April 1756 only a few days before the official opening AR: They were contemporaries and worked for by the imperial couple of the new building, the same building, somehow he must have been so he was at the height of his influence and aware, but I can only see one possible connection shortly before his death. Here he may be present between the fresco and the figures. If you have to highlight his role as a sort of guarantor of the a look at the middle of the fresco you will see a virtues and values for the entire new University. medallion with the pictures of Maria Theresia Look, in the statue representing constancy you and Franz Stephan. We know from the program can see this unique Mollinarolo style very well. of Metastasio that Maria Theresia insisted that It is really slender, very elegant. she and Franz Stephan are depicted as a couple. Detailsf Details o thehe Statues: top left: the long Initially she was alone. And it is possible that neck of Constancy; right: the cross in the GSF: Absolutely, it really reminds me of the idea of a pair is reflected in the figures, sort of hand of Faith; bottom left: the hands of Generosity handing out coins Parmigianino if you have a look at the neck. consolidating the notion of the imperial pair.

AR: Yes! “La Madonna con il collo lungo”! It GSF: Was this before she became a widow belongs really to the finest examples of middle or afterwards? European sculpture in the second half of the 18th century, although the surfaces of the sculptures AR: Before, this was in the fifties of the 18th suffered from the big fire in 1961. The whole century. Franz Stephan was still alive so he was fresco of the room is a copy of the lost original. represented. We know that the fresco was started I have seen it once before the fire. There was in 1753 and the room was finished in 1755. There the birthday of the president of the Academy in is a description of the room which also mentions February and they fired the stoves. Because of the the figures but it is not clear if the statues already old chimneys and a storm going on at that time existed or if there was only the project to create it started a fire. Besides the ceiling also some of them. the attributes of the statues were destroyed and they had to be reconstructed. The photos which GSF: Metastasio clearly had the mandate to existed were not very good, so what we can see represent the University in this program. But do today may be a combination of poetry and truth. you think that the statues are also linked somehow to the program? GSF: So also the surface was damaged by the fire. What material are the statues made of?

AR: It is stucco and the figures should be bright and shining like the surface of porcelain.

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 16 17 From left to right:

PRUDENTIA ET VIGILANTIA Prudence and Vigilance

IUSTITIA ET SAPIENTIA Justice and Wisdom

FIDES ET CONSTANTIA Faith and Constancy

LIBERALITAS Liberality

AR: Yes, but rather to the virtues of the imperial AR: Maybe the intention was to represent the GSF: How much time and work might it have GSF: The University at this time was quite linked couple, I would say. Liberality has to do with the generosity in a dualistic way. But maybe they taken? Do you think Mollinarolo had assistance? to the church. Do you think that they were very University as an official intellectual institution simply did not know how to couple it another critical in the way the attributes were chosen? In which needs money. The word generosity would way. It is only speculation as unfortunately, there AR: I think so. Michelangelo might have been an other words, would they have criticized that the probably be better in this context. is nothing written on the pediments. It would be exception, but I worked on Donatello and he had artist had too much liberty? quite interesting to have a look at the coins of the a big group of helpers. If you look at the figures, GSF: Is it clear that it was meant monetarily? same age and see if liberality was depicted and if it is almost impossible to create them alone. It is AR: I can imagine. Especially, as this was a time Are the little discs in the baskets undoubtedly so, if ever as a couple. difficult to make an estimate but I would say one of a lot of theological controversy. There was for coins? Should they not be cornucopias? took approximately up to two years. example a pro- and anti-Jesuitic movement. But GSF: If we speak about modern times it is certainly I would rather believe that the statues refer more AR: Well I personally was thinking of some sort not easy for ministers to find a way to show GSF: If one would start a new search of to enlightenment and not so much to theological of cornucopia. You know in Florence for exam- generosity, by for example giving money to documents, would you rather look in the archives matters. Otherwise there would be more reli- ple there existed a famous figure by Donatello, research or to knowledge, as they themselves have of the court or the University? gious symbols. Dovizia, which got destroyed, also a phenotype a limited budget. It would be curious to know of the cornucopia. One has really to ask who in which attribute they would choose to represent AR: Well, I think all the documents of the GSF: Do you know if the Academy has our case was responsible for such an unusual their field today. University have been studied well and so I changed anything about the iconography in program. would be surprised if we would find something the festive hall? AR: Today it may be more important to be new on this subject. But we have to take the GSF: Do you think that an artist in the 18th present in the newspaper and media by giving possibility into account that in some cases AR: No, the work of artists was already respected century would have had the freedom to choose prizes, awards, and so on. There are other documents might not even exist.. There was at that time and it simply does not look like any- and to propose? possibilities. Another difference is that in former a relation of trust at that time. Everything was thing has been changed. times it was not the government alone who done by shaking hands. AR: Usually the decision was made by a was endowing institutions, but possibly the GSF: Professor Rosenauer, thank you very much representative of the court. In this particular Habsburg family with their private money from GSF: There are ornaments on the walls besides for the interesting interview. We hope that you and case it is thought to have been Franz Christoph their personal treasure. the statues. Do you think they were also done Luigi Ronzoni will give a talk in the Academy as von Scheyb, who was a secretary in the govern- by Mollinarolo? a lot of people might look forward to learning ment, a very educated person who had relations GSF: Because we have no records, we obviously more about this topic. Maybe we made some to the enlightenment and who was in corre- do not know how much the artist was paid for AR: Yes, there are the same attributes, for exam- people interested to see the festive hall by them- spondence with Rousseau and Voltaire. He it. Do you think that at that time the better part ple the lion. After the fire the ornaments were selves. Maybe this helps find somebody who is might have been responsible for this program. of the artists were considered as bourgeois, removed and they stayed in the Denkmalamt willing to give funds for the restoration of the middle class? for years. It was again Luigi Ronzoni who found statues. CeMM is happy to act as contact point. GSF: Does it appear unusual that in the case of them and since six or seven years they are back liberality two statues represent the same virtue? AR: The artists were paid quite well but some again in the festive hall. AR: I am glad we are bringing attention to Do you think that it was a political act of Maria of them also spent a lot of money and lived quite these beautiful sculptures. Theresia, who gave the money to realize this merrily. I honestly have no idea. University, to say – I was generous so you have to show it somehow?

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 18 19 “Molecular medicine has been well on the way, from the first sequencing of a protein, insulin, and from the original modeling of DNA structure, some 50 years ago, to present-day molecule-based diagnostics and therapeutics. Yet the enormous potential that this basic biomedical research bears for medicine still has to come to full fruition. CeMM has been established and shaped at the right time and in the right place: it has every chance and it has already shown to contribute substantially to the ongoing biomedical progress: gaining relevant molecular insights and helping to translate them into new and improved methods of prophylactic and clinical medicine. May civil society and polity amply support this promising and salutary endeavor.” Prof. Dr. Hans Tuppy Chair of the Board of the University of Natural Resources and Applied Life Sciences Vienna President of the Austrian Science Fund (1974-1982) Rector of the University of Vienna (1983-1985) President of the Austria Academy of Sciences (1985-1987) Minister for Science and Research (1987-1989) Research at CeMM

Exemplified by Classical Virtues Paying Cautious Attention Two Cautionary Tales to The Immune System: To structure this year’s report we have Prudence + Prudence: Being Aware Illustrate Prudence as A Vigilant Force chosen to refer to our privileged association as a Scientist a Virtue + Keeping a Watchful Eye out and + Vigilance by the + Tale One: The Myth of Cardiac + Cell Patrol with the Austrian Academy of Sciences. Immune System Glycosides and Cancer + Discovering New Vigilant Factors The Academy encompasses both a historical + Tale Two: The Alter Ego of Vigilance > p. 24—25 > p. 28—29 and philosophical element as well as the TREM-1 mathematical and natural sciences, and > p. 26—27 enables CeMM to draw from a large spectrum of experience and knowledge to gain some important historical perspective.

The festive hall of the Academy with its Using Knowledge Two Ways of Justice: beautiful frescoed ceiling is one of Austria’s Justice to Fight Disease Gaining Wisdom Wisdom in Action most congenial and amiable baroque rooms. + Learning about Molecules + A Comprehensive + An Eye for Humour and + Bringing Disease to Justice Approach + A Matter of Life and Breath + Learn How it Works Most importantly, it is dedicated to science > p. 34—35 > p. 38—39 and scholarship. It also harbors four niches Wisdom + Secret Mechanisms with elegant sculptures of unusual grace. > p. 36—37 The statues represent embodiments of pairs of classical virtues (faith, constancy, justice, wisdom, prudence, vigilance, liberality). In times as these, where dire economic straits can lead to shortness of vision and Stable Beliefs Keeping Faith and Fighting Disease Faith + Joining Faith with Rationale Gaining Knowledge to Maintain Constancy the faith in the power of knowledge is ques- + Keeping it Constant + Determining how + Finding New Ways to Treat Leukemia tioned, we find inspiration for our work and + Clearing out Disease Drugs Work + Searching for the Genetic + Placebo Mutations that Cause Disease > p. 44—45 and for our science in these statues. The + Synthetic Lethality and Cancer Constancy > p. 46—47 different chapters of this year’s report are + How Natural Antibodies Help structured along these virtues. We hope Maintain the Status Quo that this Ariadne’s thread will help you find > p. 48—51 your way when reading our report.

Generosity Tools for the Masses Generating Resources Liberality + Giving Back to Society + How Low Can You Go? + Setting the Stage + Team Work + Full Steam Ahead > p. 58 > p. 56—57 > p. 60—61 Keeping Data Flowing + Analyze This, and That

> p. 59 Prudence and Prudence Vigilance and Vigilance

+ Two Cautionary Tales to Illustrate + The Immune System: Prudence as a Virtue A Vigilant Force

Justice and prudence Wisdom the exercise of sound judgment in practical affairs. Proverb: Faith and “Take care of the pen- Constancy nies and the pounds will look after themselves” Liberality vigilance the process of paying close and continuous attention Prudence is considered to be a classic virtue. The Prudence: Being Aware as a Scientist Prudence and ancient Greeks considered prudence to be the Scientific investigation involves the generation Vigilance “Father” of all virtues, so what better place to start of data by experimentation, which is then inter- Paying than here. Although its original meaning was the preted in the context of available knowledge to exercise of sound judgment in practical affairs, in form hypotheses. These hypotheses are used as a modern English it became increasingly associated framework on which to build predictions about Cautious with vigilance, with which it is paired in statue related biological systems and processes. form at the Austrian Academy of Sciences. Hypotheses are continually refined, making science dynamic and exciting. As technologies The statues representing prudence and vigilance advance, more sophisticated studies generate Attention act as a reminder to be cautious and aware. These data that may lend support to certain hypotheses traits are especially important for a scientist or, as sometimes occurs, cause them to need when performing research and interpreting data reformulating or even abolishing, which can to generate models, but they can also be used dramatically change the direction of a field. to describe the immune system in the human body, which acts as a guard against infection The sorts of scientific discoveries that cause sub- and disease. Both of these interpretations can be stantial changes to current thinking often gener- applied to research being carried out at CeMM. ate much excitement as well as much frustration, The groups of Sylvia Knapp and Sebastian Nijman particularly when dogmas are overturned and have both made recent scientific discoveries that models need to be discarded and replaced with were unexpected, and which challenged dogmas new ones. Regardless, they tend to have a big in the fields of innate immunity and cancer, impact on science, which adds to the excitement teaching us the importance of being prudent. for the people working in it. The scientific system Elsewhere at CeMM, ongoing work in Giulio does have its own internal controls because it Superti-Furga’s lab is focused on understanding consists of a large community of scientists who how the immune system senses infection to are constantly testing the same hypotheses using generate new approaches for treating disease. different systems and tools. However, it still pays to be prudent when interpreting data and to appreciate that there are limitations to what can be concluded from individual experiments.

Vigilance by the Immune System Vigilance implies an awareness of certain dangers and the establishment of mechanisms to deal with those dangers. The immune system can be thought of as being vigilant as it is on constant alert throughout the body for disease and damage. The innate immune system is able to detect the presence of invading pathogens such as bacteria and viruses. It responds by producing a complex immune response consisting of many different types of cells and molecules that col- lectively fight infection and return the body to a healthy state. Understanding how the immune system senses infection can help generate new approaches for treating disease.

Justice and Wisdom

Faith and Constancy

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 26 27 How Cardiac Glycosides Really Work Prudence and Two Cautionary This previous literature had already led to the cur- Fig. 1 Histology of Vigilance rent testing of cardiac glycosides in clinical trials mouse lung tissue 24 hours after Tales to Illustrate using cancer patients. However, the mechanism infection. Top is of action of cardiac glycosides in this context stained with antibody against Prudence as a had never been reported, and there remained an IRAK-M, bottom absence of definitive proof that they indeed have shows infiltrates Virtue anti-cancer activity. Thus, the conclusion that cardiac glycosides would be successful anti-cancer agents was premature. Further studies in the lab discovered that in fact, cardiac glycosides work Tale One: by inhibiting the general synthesis of proteins, The Myth of Cardiac Glycosides and Cancer which is a fundamental process and one that The careful design and control of scientific influences many other cellular functions. Indeed, experiments is crucial. Overspeculation – when this discovery can explain the vast majority of the one makes interpretations unsupported by the published work and demonstrates that there is no actual data – can lead to incorrect assumptions, specific effect of cardiac glycosides on cancer cells. which can be particularly destructive in fields Their results were published in the journal PLoS involving human diseases. The first tale of caut ONE in 2009, and have serious implications for ion comes from an area of cancer biology that has the clinical evaluation of these drugs. concluded that cardiac glycosides, which are a class of drugs used successfully to treat chronic Tale Two: The Alter Ego of TREM-1 heart failure, could be useful for treating cancer. In another unrelated story, Sylvia Knapp’s group The experiments leading to this conclusion has been investigating the role of a cell surface appear solid on the surface. However, a serendip- receptor known as TREM-1, which was thought itous discovery in Sebastian Nijman’s lab, in col- to contribute to the adverse effects of inflam- laboration with the lab of Matthias Mayerhofer at matory diseases such as sepsis – a severe sys- the Medical University of Vienna, directly chal- temic inflammatory response syndrome caused lenges this view, and the field is now faced with a predominantly by respiratory tract infections. sudden drastic change of direction. TREM-1 is found on the surface of myeloid cells in the blood, where it amplifies inflammation The discovery came from a genetic screen to mediated by the Toll-like receptor (TLR) dur- search for new drugs that could inhibit a protein ing bacterial infections. TREM-1 has become “The conclusion kinase called JAK2, which is mutated in a large an attractive target for drug inhibition to treat that cardiac number of patients suffering from Polycythemia medical conditions like sepsis, however the vera; a hyperproliferative blood disorder. From biological function of TREM-1 at that point was glycosides would this screen containing over one thousand diverse poorly understood. be successful drugs, cardiac glycosides were identified as being anti-cancer agents able to specifically reduce the levels of JAK2. At The group set about studying the role of TREM-1 first, this was an exciting surprise. One of these in pneumonia caused by the bacteria Strepto- was premature.” drugs, known as digitalis, was extracted from the coccus pneumoniae. They first identified that flowering plantDigitalis purpurae (otherwise TREM-1 was upregulated in infected lungs and known as the Common Foxglove), and has been human plasma, together with an augmented used as a medicine to treat heart disease for over response by the immune system towards the two hundred years. The groups scoured the lit- bacteria. They found that in mice infected with S. erature and discovered numerous reports beginn pneumoniae, activation of TREM-1 using an ago- ing in the 1960s, which eventually concluded that nistic antibody enhanced the early inflammatory cardiac glycosides have anti-cancer activity. response, which was associated with lower levels of negative regulators of TLR signaling in lung tissue. However, later in the infection, TREM-1 activation actually promoted the resolution of pneumonia and remarkably led to an acceler- ated elimination of bacteria and consequently improved survival. So, TREM-1 has a protective Justice role in the innate immune response to a com- and mon bacterial infection, suggesting that caution Wisdom should be exerted when modulating TREM-1 Faith activity during certain bacterial infections. and Their results were reported in the Journal of Constancy Immunology in 2009. Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 28 29 Cell Patrol Discovering New Vigilant Factors Another way of finding new vigilance factors is Prudence and The Immune Sensor receptor proteins patrol different parts of Viruses such as Pox or Herpes contain DNA to use the viruses themselves. Fairly recently, an Vigilance the cell to look for invading pathogens. They also that is recognized by the body as foreign and acts RNA helicase known as RIG-I was found to System: search the endosomes, which are membrane- as an alarm signal to trigger the production of recognize virus-specific structures and initiate an bound organelles that enclose extracellular mate- proinflammatory cytokines and interferons to immune response. Interestingly, different viruses A Vigilant Force rial such as the various types of nucleic acids activate the immune response. Tilmann Bürck- have evolved specific mechanisms to respond to found in invading bacteria and viruses. A project stümmer, also in Giulio Superti-Furga’s group, this. For example, influenza viruses can inhibit led by Christoph Baumann in Giulio Superti- has been developing a screen to discover new RIG-I whereas Bunya viruses instead inhibit the Furga’s lab is focused on understanding how viral DNA sensor proteins. The group uses a pro- protein kinase PKR. So while scientists are trying Keeping a Watchful Eye out these foreign nucleic acids are taken up into teomics screen to search for cytosolic proteins to discover all the cellular proteins that can recog- The innate immune system employs a variety of endosomes and sensed by TLRs. This knowledge that have both an affinity for DNA as well as nize viruses, the viruses themselves are already “The goal is strategies to recognize and fight invading patho- could be used to identify interesting candidates being produced in the cells upon viral infection. well aware of them, and use this information to gens. Crucial to this sensor function are the so- for drug targets to fine tune the immune response The screen has already proven successful as it led find ways to survive. Andreas Pichlmair in Giulio to find cellular called pattern recognition receptor proteins such in diseases like chronic inflammation, sepsis, to the discovery of AIM2, a DNA sensor that trig- Superti-Furga’s lab has been expressing viral pro- proteins that as Toll-like receptors (TLRs) that bind specifically rheumatoid arthritis and cancer. gers inflammation in macrophages, which was teins to identify interacting host cellular proteins can be modulated to pathogen-associated molecular patterns, published in Nature Immunology in 2009. How- using mass spectrometry. Initial results are prom- including viral and bacterial nucleic acids, pro- The group employed a proteomics approach, ever, there is still ample evidence that additional ising and suggest that different viruses bind to to increase the teins and carbohydrates. Many pathogens are involving the isolation of proteins bound to sensors have yet to be discovered. many of the same host proteins to escape immune body’s antiviral sensed while they are circulating through the endosomal TLRs and identifying them by mass detection. The goal is to find cellular proteins immune response.” body by receptors found on the surface of cells. spectrometry and bioinformatics analysis. This that can be modulated to increase the body’s anti- However, bacterial and viral nucleic acids (both revealed a candidate list of seven interacting pro- viral immune response and thus could be valu- DNA and RNA), which are one of the most teins for several different TLRs, which were able for developing therapies to treat infectious important signals for activating the innate named IPOT1-7 for Interacting Protein of endo- diseases. Inhibition of these same proteins could immune system, are recognized once these somal TLRs. IPOT4 was subsequently found to also be of benefit during autoimmune diseases pathogens have actually entered individual cells. act as a co-receptor required for the uptake and that are often characterized by an overreaction of delivery of nucleic acids to all endosomal TLRs. the immune system. This is interesting because it was previously unclear exactly how nucleic acids were taken up into this organelle. In contrast, IPOT7 was found to negatively regulate the secretion of cytokines, untr. ISD pdAdt CpG LPS Fig. 3 Cytosolic which are immune signaling molecules, and thus DNA Recognition. - + - + - + - + - + Chloroquine Cultured mouse macrophage- is an anti-inflammatory protein. Further experi- like cells were pretreated ments are planned to address the functional role with two inhibitors; chloro anti-DAI quine (inhibits endosome of this protein in TLR signaling. acidification – top panel) or Z-FA-FMK (inhibits lysosomal proteases called cathepsins – bottom panel) anti-Actin and stimulated with a set of pathogen-derived components: double-stranded DNAs (ISD), a repetitive DNA sequence (pdAdT), untr. ISD pdAdt CpG LPS unmethylated CpG-DNA - + - + - + - + - + (CpG) or lipopolysaccharide Z-Fa-FMK (LPS - elicits an immune Fig. 2 Virus infection response). Untr. = untreated. activates signaling Expression of the protein cascades (green) that anti-DAI DAI, which can be visual- culminate in expression ized using Western blotting of type-I interferon as shown here, indicates (IFN-a/b), which is type-I interferon induction secreted to protect (i.e. an immune response). adjacent cells. Virus anti-Actin These results show that both proteins (blue) inhibit inhibitors block recognition of the antiviral response CpG-DNA in the endosome, at various levels but not recognition of LPS on (brown). Understanding the plasma membrane. DNA binding partners of (ISD or pdAdT) recognition is viral proteins may help unaffected, suggesting DNA to understand the sensing occurs in the cytosol innate immune system independently of cathepsin and may highlight activity. Justice possibilities for medical and Citation: Karayel et al. Wisdom intervention. Eur J Immunol. 2009 39(7):1929-36

Faith and Constancy

Liberality

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 30 31 “From the publications in the last years it is clear that in the short time of its existence CeMM has initiated world class research in its chosen areas and is poised, if supported adequately, to soon b ecome a center of research excellence and a source of inspiration in the field of Molecular Medicine. I hope that CeMM will have the same energizing effect on the medical research community in Austria that the IMP has had for the basic biosciences.” Prof. Dr. Max L. Birnstiel Founding Director of the Research Institute of Molecular Pathology (IMP)

72 dpi? justice Prudence the quality of being and just or fair Vigilance wisdom Justice the ability to think and and act utilizing Wisdom knowledge, experience, understanding, common sense, and insight Justice and Wisdom

+ Two Ways of Gaining Wisdom + Justice: Wisdom in Action

Faith and Constancy

Liberality Justice and wisdom are paired together as statues Learning about Molecules Prudence and at the Austrian Academy of Sciences building in Recently a new class of long nucleic acids known Vigilance Vienna. Their pairing seems particularly fitting as macro non-coding RNAs (ncRNAs) have been Using given a quote from the English historian James discovered and the Barlow group at CeMM has Justice and Anthony Froude (1818-1894) who said, “Justice been looking into their function. To do this, they Wisdom without wisdom is impossible.” He could easily have been studying how genomic imprinting Knowledge have been referring to the scientific quest for regulates the activity of certain genes, which is a knowledge – wisdom – and the translation of that mechanism that is directly linked to the parent knowledge to fight disease – justice. It is within from which the copy of the gene was inherited. this framework that many projects taking place at They have already discovered how macro to Fight CeMM can also be appropriately grouped. ncRNAs are involved, and suspect the same mechanism works to silence tumor suppressor Scientists generate knowledge about all aspects of genes, which can lead to cancer. whole organisms, including individual biological Disease systems and groups of proteins and other mole- Bringing Disease to Justice cules. Many sophisticated technologies have been Using knowledge to fight disease is an underly- developed to generate these comprehensive data- ing principle that governs the majority of the sets, which can then be utilized by the scientific research performed at CeMM. The mass spec- community to test hypotheses and help generate trometry group led by Keiryn Bennett has been new drugs to treat diseases. Working together, studying the protein composition of a biological the bioinformatic and mass spectrometry groups system in humans, specifically the aqueous fluid at CeMM have identified the individual proteins of the eye. This type of project has only recently found in cells representing all three separate become technically feasible, and the group has germ layers of the human body. These layers are had to introduce new technology to accomplish composed of very different types of cells, which it. Importantly, they have been analyzing aque- the bioinformatic group led by Jacques Colinge ous fluid isolated directly from the eyes of has used to generate a dataset comprising the so- patients suffering from different eye diseases, called “core human proteome”. which could generate new approaches for treatment. The Knapp group at CeMM is waging another honorable battle against disease. They have been studying why intensive care unit (ICU) patients often suffer from bacterial pneumonia caused by relatively harmless bacteria. Using mouse models they have already generated important insight into this process and have also found a therapeutic intervention that could prove life saving in humans.

Faith and Constancy

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 36 37 Secret Mechanisms Prudence and Two Ways of Human chromosomes contain roughly 23,000 Fig. 1 Interactions Vigilance genes but only 200 of these show imprinted taking place between proteins of the core Gaining Wisdom expression by inheriting an epigenetic DNA proteome. This core Justice interactome is active in and methylation mark from one of their parents. Wisdom every human cell and A major discovery by the Barlow group 8 years it implements a funda- ago showed that the DNA methylation mark was mental network of A Comprehensive Approach Using comprehensive used to silence a macro ncRNA, which was able exchange and synchro nization between mass spectrometry datasets generated by Keiryn to induce silencing of a gene involved in suppres- biological processes. Bennett’s team from various cell lines covering sion of embryonic growth that lay close to it on Each node is a protein, all three germ layers, Jacques Colinge and his the same chromosome. It has recently become edges represent physical interactions, and the “The core group have identified over a thousand proteins clear that huge numbers of macro ncRNAs are colors represent differ- universally expressed in all human cells. Using made in human cells, even exceeding the number ent processes, e.g green is translation, red is interactome their own bioinformatic platform, they went on of protein-coding genes. In the Barlow group cell cycle, cyan is cell is active in to analyze these proteins, grouping them accord- over the past year, two approaches have pro- death, etc. The ellipses ing to their cellular function, as well as incorpo- duced some particularly interesting results. In highlight known protein every human complexes – or molecular rating additional information on their structure one study, the team has shown that areas of DNA machines – that are cell and and evolutionary conservation and their presence containing genes silenced by macro ncRNAs gain recognized in the core interactome, e.g. (a) is implements in certain networks and pathways. Their results different chemical methylation marks on histone the exosome, (e) is the a fundamental reveal interesting properties of the so-called proteins compared to regions containing genes proteasome, (i) is the “core human proteome”, particularly its flexibil- that are silenced in a tissue-specific manner. ribosome, etc. Analysis of the topology of the network of ity, which probably reflects the ability of these These results were published in the journal core interactome indi- exchange common building blocks to operate in a wide Genome Research in 2009, and raise the possibil- cates that this network has been “optimized” by variety of different environments. Statistical ity that macro ncRNAs could be selectively tar- and synchroni evolution to synchronize analysis of the interactions linking proteins of the geted by therapeutics, without disturbing the translation with the other zation between core proteome showed that this network has repression of other genes. In a second study, the biological processes. biological evolved to synchronize protein synthesis with team used mouse embryonic stem cells to ana- processes.” many other biological processes, suggesting that lyze a change in the expression of a specific macro one important function of the core proteome is ncRNA and its target imprinted locus over time. self-maintenance. They discovered that macro ncRNAs could silence genes specifically by blocking their Learn How it Works upregulation. This important result was pub- The Barlow group has been studying how macro lished in the journal Development in 2009. The non-protein-coding RNAs (ncRNAs), which are group’s findings explain many puzzling features transcribed from DNA, work to silence genes of silent imprinted genes and also pave the way that are found nearby on the same chromosome. for future studies in cancer biology aimed at This mechanism is also likely to be important in reactivating silenced tumor suppressor genes. cancer. In normal human tissues, cells produce tumor suppressor proteins whose job is to control growth and block the formation of tumors. However, in many cancers these tumor suppressor genes are silenced by chemical methylation marks added directly to the DNA or to histone proteins that bind DNA. The Barlow group has been studying imprinted genes, which have parental-specific expression, to investigate how tumor suppressor genes gain these silencing methylation marks. Members of the group published two reviews on the regulation of imprinted expression by macro ncRNAs in the journals RNA Biology and Development in 2009.

Faith and Constancy

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 38 39 A Matter of Life and Breath Prudence and Justice: The reason why intensive care unit (ICU) Fig. 2 Sagittal section Vigilance patients often acquire secondary pneumonia of the human eye. The anterior chamber Wisdom in Action caused by relatively harmless bacteria is poorly between the cornea Justice and lens contains the and understood, although the incidence is high. This ciliary body vitreous Wisdom humour aqueous humour and the form of pneumonia is known as ventilator-asso- firm, gel-like vitreous ciated pneumonia (VAP) and is one topic under humour is located behind An Eye for Humour investigation by scientists in the Knapp group at posterior chamber the lens in the posterior part of the eye. At CeMM, Keiryn Bennett and her team have CeMM. They noticed that all ICU patients experi- Illustration by Kevin Sommerville, been analyzing the protein content of aqueous ence some form of mild lung injury before the anterior chamber www.ksomervillemedicalart.com humour, a clear fluid filling the anterior segment onset of pneumonia, which has a variety of caus- (aqueous humour) “Characterization of the human eye. Aqueous humour supplies es including aspiration of gastric contents, the zonules of Zinn parts of the eye with nutrients, as well as remov- ventilation itself or inflammation caused by an of the proteome ing waste and participating in the immune independent disease. The group reasoned that in healthy and response against invading pathogens. Import this prior lung challenge then predisposes the diseased eyes antly, defects in proteins found in aqueous patients to secondary infection. lens humour are associated with several eye diseases, would potentially including age-related macular degeneration, They addressed this using a mouse model of acid cornea improve existing which is one of the leading causes of vision loss aspiration followed by infection with the patho- treatment options.” in the industrialised world. The group reasoned gen Pseudomonas aeruginosa. Results revealed that a thorough characterization of the proteome that as predicted a prior lung injury predisposes canals of Schlemm in healthy and diseased eyes would help to elu- the animal to acquiring a bacterial infection. Fol- cidate the disease process and potentially lowing on from these studies, the Knapp group improve existing treatment options. hypothesized that prevention or attenuation of this pre-existing lung injury might help prevent Due to the low volume of aqueous humour that ICU patients from acquiring pneumonia, or at can be isolated from the human eye, Keiryn’s least help them to fight it. Indeed, using their team had to design a strategy to ensure they mouse model, they found that the fibrin-derived

could accurately and comprehensively identify peptide Bb15-42 could reduce vascular leak, which all of the proteins present in the samples. Using is a hallmark of acute lung injury, and could pro- this strategy, they were able to analyze the protect mice from both acute lung injury and sec- teome of aqueous humour taken from an indi- ondary infection. This work was published in the vidual patient. They identified 198 protein American Journal of Respiratory and Critical Care groups, and found a low level of variability in Medicine in 2009. Further work, in collaboration protein type and concentration between the with scientists in Austria, Russia and the UK, individual samples. This analytical approach will identified a potential therapeutic benefit for this be a valuable tool for monitoring an individual’s same Bβ peptide in preventing shock syndrome, 100 Fig. 3 Survival curve response to disease treatment, and could also be which was also published in 2009, in the journal of healthy (sham) mice that were infected with used to analyze other types of body fluids to gain PLoS ONE. 80 Pseudomonas compared further insights into many different diseases. to mice that suffered from lung injury (acid 60 aspiration) before bacterial infection.

40 Percent survival

20 Sham Acid aspiration 0 0 24 48 72

h post infection

Faith and Constancy

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 40 41 “CeMM – just another research institution? No! CeMM was founded in close relation to the Medical University of Vienna to provide it with the unique opportunity of combining most advanced research technologies with burning medical needs. Looking back at the past years, CeMM has utilized these opportunities quite successfully and this is also what makes CeMM so special: Looking at inflammation as a disease entity and not as a mere symptom of a disease and at diseases as disturbed networks and not at each pathway separately. To accomplish this and to be at the forefront of research Principal Investigators were recruited, who are established members of their respective international research communities and represent a stimulating mixture of MD/PhDs and PhDs. In further pursuing this approach, I am confident that CeMM – although already very successful – will become an integral member of medical research in Vienna much to the benefit of all participating institutions.” Prof. Dr. Bernd Binder Department of Vascular Biology and Thrombosis Research Medical University of Vienna Prudence and Vigilance

Justice and Wisdom

Faith and Faith and Constancy Constancy

+ Keeping Faith and + Fighting Disease to Gaining Knowledge Maintain Constancy

faith confident belief in the truth, value, or trust- worthiness of a person, idea, or thing Liberality constancy freedom from change or variation; stability The statues representing faith and constancy are Keeping it Constant Prudence and coupled at the Austrian Academy of Sciences. While drugs require modifications and develop- Vigilance Faith is a solid trust in something that is not ment to make them more effective, the body itself

Stable Beliefs based on reason. In a way, this reflects curiosity fights to maintain a constant state – homeostasis Justice and driven research, where an experiment is per- – in the face of continuous challenge by disease. Wisdom formed to test a given hypothesis with no prior So, constancy can represent the healthy state of

knowledge as to the outcome. Faith is also appar- the human body. Indeed, diseases such as cancer Faith ent in some fields, particularly in the medical can be thought of as the very opposite of constan- and Constancy realm, where drugs are used because they were cy: they have gained strength from being dynamic previously shown to be effective, rather than and maintaining the capacity for change. This because it is known exactly what they do. Here, gives cancer the upper hand when it comes to try- the addition of knowledge to faith can result in a ing to cure it. Several groups at CeMM are rising new generation of smart drugs that more effect to this challenge by using different approaches to ively treat disease. find new ways to treat cancer, leading to a number of high profile publications in 2009. Joining Faith with Rationale Many drugs are used to successfully treat patients Sebastian Nijman’s lab uses a concept called in the clinic without firm knowledge about how synthetic lethality, to tease out the weaknesses of they actually work. They just do. However, many cancer cells and find drugs that can exploit them. existing drugs are in urgent need of improvement Giulio Superti-Furga’s group is following on in both efficacy and safety, and there is a constant from understanding the mechanism of action of demand for new drug development. So, scientists drugs by finding new ways to inhibit disease- in Giulio Superti-Furga’s group at CeMM are causing proteins. They are studying how the working towards a comprehensive characteriza activity of an oncogenic fusion protein can be reg- tion of drug action in order to improve their ulated, with a view to identifying new types of value and help identify the next generation of drugs that could be used to treat leukemia. Final- drugs. Importantly, in 2009 CeMM scientists, ly, scientists in the lab of Robert Kralovics are along with collaborators in Vienna, Graz and searching through DNA sequences for the genetic Innsbruck, were awarded a competitive grant causes of Myeloproliferative Neoplasms, which funded by the Austrian Genome Research Pro- could provide new targets for developing drugs. gram (GenAU) for an innovative and large-scale project named PLACEBO (for PLatform Austria Clearing out Disease for ChEmical BiolOgy). This project aims to use Our immune system helps to maintain our sophisticated screens to develop a nationwide bodies in a healthy state using many different platform for identifying molecular targets for techniques. Christoph Binder’s lab is studying active drugs. the role of natural antibodies in keeping blood vessels clear and preventing conditions like atherosclerosis, which can lead to heart attacks and stroke. Maintaining the body in a constant and healthy state is not easy when faced with so many challenges, including infection by pathogens, harmful genetic mutations and our unhealthy lifestyles. If we can understand how the body manages it, we may find new ways to make us healthier.

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 46 47 Placebo Prudence and Keeping Faith In addition to this, CeMM has established a solid Fig. 2 Protein target Vigilance infrastructure to begin a pioneering project on network of the first-, second- and third- and Gaining drug discovery that will provide an important generation BCRABL Justice inhibitors imatinib, and expertise for diverse scientists throughout Wisdom dasatinib, nilotinib, Knowledge Europe. In 2009, a prestigious research grant by bosutinib and the Austrian Genome Research Program INNO-406 in chronic Faith (GENAU) was awarded to CeMM, along with its myelogenous and leukemia cells. Constancy collaborators, to develop their sophisticated Determining how Drugs Work chemical proteomics technology for the large- Chronic Myelogenous Leukemia (CML) is caused scale study of bioactive substances. The aim is to “Most drugs bind by a rearrangement of chromosomes inside the provide a comprehensive analysis of the cellular nucleus of a cell, leading to the inappropriate targets of many different drugs and to identify to more than one fusion of two genes, known as Bcr and Abl. This important new drugs for treating common dis- cellular protein, generates an oncogenic protein, Bcr-Abl, with eases. Stefan Kubicek, who has been recruited which is why aberrant tyrosine kinase activity. White blood from the esteemed Broad Institute in Cambridge, cells carrying the oncogenic Bcr-Abl fusion are USA, will head this screening facility. It will be many of them able to divide uncontrollably, causing leukemia. set up in custom-built laboratories in the new cause side-effects Fortunately there are several drugs available to CeMM building and the first stages of equipment in patients.” treat patients with CML. The pharmaceutical purchasing are already well underway. Further- company Novartis launched the first of these, more, the European academic chemical biology called Imatinib, in 2001. Imatinib directly inhibits and drug screening community has invited this Bcr-Abl’s kinase activity leading to remission of facility to participate in the international EU- the disease. However, mutations in Bcr-Abl have Openscreen consortium, which is an initiative emerged in patients treated with Imatinib. These pursued under the strategic roadmap for Euro- mutations make patients resistant to the drug and pean Research Infrastructure. lead to cancer relapse. To address this, both second and third generation Bcr-Abl inhibitors have been recently developed.

Fig. 1 Global protein Although these different drugs are all able to bind target spectrum of the to mutant forms of Bcr-Abl, they don’t all work Bcr-Abl tyrosine kinase inhibitor INNO-406. Red: in exactly the same way. Most drugs bind to more targets identified only than one cellular protein, which is the reason why by chemical proteomics with chronic myelogenous many of them cause side-effects in patients. Uwe leukemia cells, blue: Rix and colleagues, working in Giulio Superti- targets identified only Furga’s group, have been using a chemical pro- by in vitro kinase assays; purple: targets identified teomics approach to identify the cellular protein by chemical proteomics target profiles of a number of different Bcr-Abl and in vitro kinase assays. KIT/PDGFR: activity of tyrosine kinase inhibitors. One of those, INNO- INNO-406 against distinct 406 (Bafetinib), has been reported to efficiently disease-relevant kinase inhibit most Bcr-Abl mutants as well as another mutants. tyrosine kinase called LYN. Knowledge of the full target spectrum of Bafetinib would provide a molecular basis for understanding potential side-effects, and help develop novel therapeutic applications and possible combination therapies. Uwe and Giulio wrote a review article on chemic al proteomics for the journal Nature Chemical Biology, in 2009. This review received substantial attention from the chemical biology community and became the most highly downloaded review article of the journal in that year.

Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 48 49 Florian Grebien and Oliver Hantschel in Giulio The main genetic mutation found in patients Synthetic Lethality and Cancer Prudence and Fighting Superti-Furga’s group have also been study- suffering from MPNs lies in a gene encoding for It is well known that the genetic and epigenetic Vigilance ing the molecular structure and dynamics of the tyrosine kinase JAK2. Recently, the Kralovics changes in cancer cells cause them to grow uncon- Disease to Bcr-Abl regulation. In collaboration with the lab demonstrated that an inherited version of the trollably and become invasive. Many of these Justice and laboratories of John Kuriyan (University of JAK2 gene significantly predisposes the person to individual mutations have already been identified Wisdom Maintain California, Berkley, USA), Tony Pawson (Lunen- this common JAK2 mutation and thus to the and several large international projects are now feld Research Institute, Toronto, Canada) and development of MPNs. This work was published dedicated to finding them all. However, it has Faith Constancy Stefan Knapp (Structural Genomics Consortium, in the journal Nature Genetics in 2009. become clear that having the information is not and Constancy Oxford, UK) they have identified novel regulatory in itself enough to develop new treatments. This mechanisms of Abl activity through structural, Two Approaches to One Problem is partly because many mutated proteins are dif- biochemical and cellular studies. These insights The Kralovics group has implemented two differ- ficult to inhibit with a small molecule drug, and “Synthetic Finding New Ways to Treat Leukemia could lead to alternative therapeutic approaches ent approaches for identifying additional heredi- it is almost impossible to bring back deleted or The causative molecular event of Chronic for the treatment of CML to cope with arising tary factors linked to MPNs. The first approach is inactivated proteins that are causing the disease. lethality has Myelogenous Leukemia (CML) in humans is the resistance in patients to the current tyrosine to sequence DNA samples from patients who been recently expression of the oncogenic fusion gene, Bcr-Abl. kinase inhibitors. develop MPN sporadically without any prior To overcome these hurdles, Sebastian Nijman’s exploited to In the cells expressing Bcr-Abl, a large number family history of the disease. This is done using a group is taking a different approach. They plan of signaling pathways are active, involving many Searching for the Genetic Mutations sophisticated approach that enables the simultane to target cancer cells by taking advantage of target genetic different proteins and molecules. Although Bcr- that Cause Disease ous genotyping of more than 900,000 markers synthetic lethality – a concept borrowed from mutations found Abl inhibitors are available, resistance leading to It is widely recognized that cancers originate distributed throughout the genome. A difference classical genetics. Geneticists speak of a synthetic in human disease relapse is still one barrier to finding a cure. from somatic mutations that occur during life in one of these markers compared to a healthy lethal interaction between two genes when dis- Alternative approaches are needed to provide in different tissues of an organism. However, control group may indicate that a nearby gene has rupting or inactivating both of the genes together cancer cells.” superior future therapeutic options for treating hereditary factors are also important, and a sig- some connection with MPNs, stimulating further causes the cell to die, whereas inactivation of and hopefully curing CML. nificant number of cancers and other diseases are and more focused study. They can also analyze either gene on its own has no effect. This prin- familial. This means family members can inherit the distribution of known mutations within a ciple has been recently exploited to specifically Scientists working in Giulio Superti-Furga’s lab mutations that predispose them to a certain patient population. The second approach is to use target some of the genetic mutations found in have systematically mapped the protein complex disease. Myeloproliferative neoplasms (MPN) familial cases of MPN to identify familial-type human cancer cells. centered around Bcr-Abl in leukemic cells. The are a group of sporadic disorders that in rare cases hereditary factors. The lab has already collected work revealed a molecular machine composed also occur in families, and are the focus of the samples from individuals in over fifty families of only seven proteins that bind to Bcr-Abl and Kralovics lab. MPNs are characterized by chronic that suffer from MPNs, from three different was published in the journal PNAS in 2009. The hyperproliferation of blood cells leading fre- countries. The DNA from all affected family group found that this Bcr-Abl complex is mostly quently to transformation to acute leukemia. The members is then used to identify causative genet- disrupted by the classical drug Imatinib, although lab has been searching for acquired and hereditary ic mutations. This successful biobanking of rare Bcr-Abl still interacts with some of its binding factors that lead to the development of MPNs. samples was done in collaboration with scientists partners. This observation may lead to a novel from Italy and Australia. way of looking at drug targets, specifically as protein complexes rather than just single proteins. The identification of mutations causing MPNs Fig. 3 Small-angle X-ray enhances scientists´ understanding of cancer scattering shape recon- struction of the active evolution in general, where both acquired and Abl tyrosine kinases inherited genetic factors play a fundamental role. SH3 adapted from Nagar, Hantschel et al. (2006) The mutations can also serve as important mark- Mol. Cell 21, 787-798. ers for early identification and potential preven- The kinase domain and tion of MPNs in patients, and form a basis for SH2 and SH3 domains are colored blue, green the identification of novel drug targets and more and yellow, respectively. rational therapies for this group of diseases.

SH2

kinase domain Liberality

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 50 51 Finding Cancer Weaknesses Eliminating Waste Prudence “Cellular mecha and Unfortunately, synthetic lethal interactions are In collaboration with the group of Joseph Fig. 4 Immunohisto Vigilance nisms have not easy to find. Therefore the Nijman lab is Witztum at the University of California San chemistry of an atherosclerotic lesion with the evolved to main- embarking on a systematic approach using high- Diego, USA, the lab recently identified an natural IgM antibody Justice NA-17. Sections of the and throughput technologies to help to identify important property of natural antibodies. They Wisdom tain the body in brachiocephalic artery them. They can mimic the genetic changes found showed that oxidation-specific epitopes are a homeostatic from cholesterol-fed in cancer cells using molecular biology tech- found on the surface of apoptotic (dying) cells, Ldlr–/–Rag1–/– mice Faith niques and screen them against panels of drugs and were prominent targets of natural antibod- were stained with NA-17, and state in the face a monoclonal germline Constancy of change during and drug targets. With this method the team can ies in both mice and humans. The recognition of encoded natural IgM now measure tens of thousands of combinations these epitopes promoted the clearance of apop- anitbody against aging and disease.” totic cells. These findings revealed an important Malondialdehyde- between cancer genes and drugs and drug targets. epitopes. NA-17 recog- Using this technology, the lab hopes to identify novel recognition pathway by which natural nises oxidation-specific new synthetic lethal combinations that could antibodies mediate homeostasis, which was epitopes present in atheroschlerotic lesions. lead straight to new cancer therapies that are also published in the Journal of Clinical Investigation (Original magnification, tailored to individual patients. in 2009. x200)

How Natural Antibodies Help Oxidation-specific epitopes are also present Maintain the Status Quo during inflammatory conditions such as athero- Many cellular mechanisms have evolved to main- sclerosis, and may represent danger signals in tain the body in a homeostatic state in the face other pathological settings. Likely, the omnipres- of change in the form of cell turnover, aging, ent generation of these epitopes throughout and disease. In Christoph Binder’s group, they life has contributed to the need and thus the have been studying the role of natural anti positive selection of natural antibodies. By target- bodies, which, unlike other types of antibodies, ing these stress-induced cell-derived structures, arise spontaneously without apparent antigen natural antibodies may provide a generalized exposure early on in life. Natural antibodies are protective response against the consequences of produced by a subset of B-lymphocytes (a type of oxidative stress. blood cell) and bind to a broad range of antigens from both external and internal sources. They have an important function in defending the body against invasion by pathogens. Work ongoing in the lab has focused on the role of natural antibodies in clearing waste material from the body, Fig. 5 Deconvolution which is crucial for maintaining homeostasis. microscopy of individual dying cells. Binding of total serum natural IgM antibodies (left) and the monoclonal natural IgM NA-17 (right) to the surface of apoptotic thymocytes (shown in green; nuclei are stained in blue)

Liberality

Ce — M—M— Research Report 2009 5250 5351 “CeMM is about to become one of the leading centers of applied basic research in the city of Vienna and beyond. With its major and important scientific contributions, its close neighborhood to the MUV and its ingenious scientists under the intense leadership of Giulio Superti-Furga, CeMM is not only an international, highly esteemed site of biological science and the thrive towards our understanding of physiological and pathological processes within the human body, but has also developed into a patron of arts. Personally I am very enthusiastic about the hitherto extremely pleasant and successful scientific interactions between the MUV and CeMM, and welcome very warmly the institution into the immediate premises of the MUV and the General Hospital. The presence of CeMM within one common ground will give all three institutions a further boost to form a point of gravitation in biological science in our beautiful city.” Prof. Dr. Christoph Zielinski Chairman, Department of Medicine I and Cancer Center General Hospital – Medical University Vienna Prudence and Vigilance

Justice and Wisdom

Faith and Liberality Constancy

+ Tools for the Masses + Keeping Data Flowing + Generating Resources Liberality

liberality the quality or state of being liberal or generous Of only four statues in the Austrian Academy Giving Back to Society Prudence and of Sciences building, liberality was chosen to Patients are at the center of CeMM’s focus, which Vigilance represent one of them. It stands alone, in com- is exemplified by their motto: “From the clinic to Generosity parison to the dual meanings of the other three the clinic”. The institute places a strong empha- Justice and statues, and perhaps rightly so. Liberality symbol- sis on giving back to society by focusing on the Wisdom izes sharing, kindness and generosity, which are integration of basic research and clinical expertise,

important aspects of any society, and the statues i.e. molecular medicine. They pursue innovative Faith themselves illustrate this by handing out coins. diagnostic and therapeutic approaches particular- and Constancy Liberality and science are connected on several ly focused on cancer, inflammation and immune different levels: by the individuals, organizations disorders. Their motto and their research are Liberality and governments who share wealth to fund it, as driven by the medical needs of our society. well as within the scientific community both in the form of collaborations and in the sharing of At CeMM, the research groups run by Keiryn new technologies and valuable results. Science is Bennett and Jacques Colinge provide the facilities also very much about the teaching and training of and expertise to develop the next generation of young people. The coins handed out by the statues technologies that can be used by all the different could represent the handing out of knowledge groups in the institute, as well as for collabora- and experience for others to invest. tions with researchers from other universities and institutes. The mass spectrometry group run by Keiryn Bennett has been pushing technology to the limits and beyond. They have been systematic ally testing new approaches to expand CeMM’s mass spectrometry capabilities. These proteomic technologies generate substantial datasets that need sophisticated methods to handle and analyze them. This is where the bioinformatic group led by Jacques Colinge comes in. They provide and develop data analysis systems as well as integrated databases, so that scientists can efficiently and effectively analyze their experimental results.

Team Work The Barlow group at CeMM has set up a collaboration with the Research Institute of Molecular Pathology in Vienna and the Nijmegen Center for Molecular Life Sciences in the Netherlands to undertake an ambitious project that will generate a large resource for further work in their laboratories, as well as for the entire scientific community. The collaboration enables the team to use very new technology to sequence the transcriptome (the RNA products copied from DNA) in different types of cells to search for a certain class of long non-coding RNAs known as macro non- protein coding RNAs (ncRNAs).

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 58 59 How Low Can You Go? Analyze This, and That Prudence and Tools for Keiryn’s group had new ambitions to analyze Keeping Once the raw data have been generated from Vigilance the proteomes of cells taken directly from a mass spectrometer run, they undergo a first the Masses individual patients. However, this meant they Data Flowing analysis to generate usable primary data, which Justice and were severely limited by sample quantity, and is performed by a distributed computing system Wisdom the current protocols were inadequate. They set controlled by a laboratory information manage-

about establishing a rapid throughput method ment system (LIMS). Then the primary data can Faith Analyzing proteomes (the protein content) that was sufficiently sensitive to analyze the The mass spectrometry analyses performed by be used to search against publically available pro- and Constancy of diverse biological system such as cells or protein content isolated from individual patients Keiryn Bennett’s group generate large amounts tein databases, to reveal the content of biological tissues requires a combination of experimental and that could be used, for example, to follow of data, and their efficient interpretation in the samples. These database searches are performed Liberality protocols. These protocols require modifications a patient during a specific drug treatment to context of a specific biomedical question requires by a sophisticated combination of two search “Such an advance and development depending upon the type of see how they responded. By testing different highly specialized tools. The bioinformatic group engines, which provides enhanced sensitivity. starting material used and the specific biologi- laboratory acids for preparation of the samples, led by Jacques Colinge at CeMM has developed a would revolution- cal question being asked. As the instruments as well as improving analytical sensitivity of the specialized platform for handling large proteomic A central repository stores all the protein iden- ize proteomic become more sophisticated and complex, the mass spectrometry step, they developed a robust datasets generated by the different mass spectro tifications and allows the users to access and analysis of human boundaries of what they can be used to analyze approach to effectively analyze protein content meters. This supports the scientists when they compare the content of any combination of are continually challenged. To fully utilize these in small quantities, such as those taken routinely want to analyze their results, and helps them to samples. This can be done using tools integrated clinical samples.” new capabilities requires the parallel modificat from patients. The group plans to take this tech- make clear and accurate biological interpretations. with a large range of public protein annotations ion of existing protocols, in particular, sample nique even further by downscaling the approach and resources, which helps to summarize results preparation and subsequent data analysis. again. This has the potential to lead the group, and understand complex datasets. Because of the and the rest of the scientific community, into the strong interest in protein interactions at CeMM, The mass spectrometry group has been working realm of analyzing minute quantities of material, the bioinformatic group has also implemented towards establishing new strategies to further such as those that are obtained from a fine needle an integrated database of protein interactions to increase analytical sensitivity and efficiency of biopsy. Such an advance would revolutionize complement their other tools. This interaction protein identification. Previously, they used proteomic analysis of human clinical samples. database is also designed to represent protein a conventional gel-based strategy to separate interaction networks identified by scientists at individual proteins so that they can be identified. CeMM, and it provides an interactive graphical A number of limitations, however, including interface for ease of visualizing these networks. contamination and speed of analysis, meant that there was a need to find a new approach. This came in the form of the ‘shotgun’ proteomic approach, pioneered by groups in the USA. This method removes the need for a protein separation step, and along with newer generation instruments enables them to offer a deeper and faster analysis.

Fig. 1 The target profile Fig. 2 MASPECTRAS, a of the promiscuous kinase proteomics data integration inhibitor bosutinib system developed in was investigated by an collaboration with TU-Graz improved chemical (Prof. Z. Trajanoski), is used proteomic approach to to link our protein identifica- identify natural binders. tion data with information It was clearly demonstrated related to proteins and that the approach could scientific literature, which be successfully down- we collect from public scaled by a factor of one databases. MASPECTRAS hundred. The entire can also be used to perform methodology as described various types of sample could lead us into the compar isons and analyses of realm of using as little the resulting protein lists. material as can be obtained from a needle biopsy, thereby revolutionizing proteomic analysis of human clinical samples.

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 60 61 Setting the Stage Prudence and Generating To generate their datasets, the group has joined Fig. 4 Ribominus Vigilance forces to set up an RNA-sequencing pipeline. RNA Sequencing Total cellular RNA was Resources They want to analyze the transcriptome (the total depleted of Ribosomal Justice RNA using the Ribo and cellular RNA content) of both normal and tumor Wisdom Minus™ Eukaryote Kit cells using new technology termed ‘next genera- (Invitrogen) and then CeCellslls ToTotaltal RNARNA RibomRibominusinus RNA RNA ds-cds-cDNADNA library library tion whole genome sequencing’ that utilizes the hydrolyzed to Faith Generating large comprehensive biological and Solexa-Illumina platform. The pipeline included 200~500nt before and conversion to ds-cDNA. Constancy medical datasets can provide a rich source of optimization steps both for the preparation of The ds-cDNA library information for scientists around the world to RNA samples for sequencing, and to determine was amplified and “The stage is sequenced using an Liberality utilize and integrate into their own experimental how much sequencing will be needed to view the Illumina Solexa Ge- now set for future systems. The Barlow group is planning on gener- entire cell transcriptome in a quantitative manner. nome Analyzer. The ating its own comprehensive dataset of macro One final essential step was the development data was aligned to the work to screen mouse genome, and the transcriptome non-protein coding RNAs (ncRNAs) and has of new bioinformatics tools that can search visualized using the been developing an RNA sequencing pipeline to through the RNA sequencing data to specifically UCSC genome browser. of human lead them straight to disease gene discovery. identify the macro ncRNAs amidst the other The displayed region shows expression of cancers.” Previous work has revealed that the total number protein-coding RNAs. the Malat1 non-coding of macro ncRNAs in a cell exceeds the total RNA in two tissues. number of genes that code for proteins, which is Full Steam Ahead Illumina Solexa Sequencing about 23,000. Although the function of the These steps have already been successfully com- Illumina Solexa Sequencing majority of ncRNAs is unknown their abundance pleted and the RNA-sequence pipeline is cur- suggests that they likely play many important rently flowing smoothly and producing tran- and diverse roles within the cell. Given also the scriptome data from normal mouse and human 10kb known association between macro ncRNAs cells. The stage is now set for future work to Chromosomehr19 (Mb) 5.796 5.798 5.800 5.802 5.804 and tumor suppressor genes, which cause cancer screen the transcriptome of human cancers. The position when they are silenced, macro ncRNAs could data obtained will enable the identification of be important agents in human diseases, particu- macro ncRNAs that could be associated with RNA sample 1 larly during cancer development. silencing the many tumor suppressor genes identified in the human genome that cause cancer. The data will also enable the identification of disease-associated genes that are expressed at aberrant levels in these cells, as well as providing RNA sample 2 a rich resource to help answer many other Gene biological questions. CGI

RNA-Seq data visualized in UCSC Genome Browser

Fig. 3 An RNA-seq pipeline for disease gene discovery Five steps in this discovery pipeline are indicated by which RNA from diseased Computers and normal tissue is Remove match the RNA Bioinformatics sequenced by next unwanted Next Generation sequences to identifies RNAs generation whole sequences SOLEXA Sequencing * human genome with a changed genome sequencing RNA fragments from of the complete normal and disease cells Transcriptome** sequence or an altered that uses the Solexa- abundancy in disease Illumina platform. enter the pipeline Each step requires optimization experiments that have the * RNA: genome messengers coding for proteins or initiating epigenetic modifications on chromosomes goal of determining ** Transcriptome: a description of all RNA molecules present in a living cell the minimal number of sequence reads that would allow the characterization of the entire transcriptome and ultimately identify genes responsible for specific human diseases.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 62 63 “Molecular Biology is very central to many modern aspects of pediatrics, from diagnosis to therapy. At St. Anna, we have recently opened a new state- of-the-art research center with a special focus on the molecular causes of pediatric cancers. The Center for Molecular Medicine of the Austrian Academy of Sciences is a wonderful addition to the medical research scene and adds to our international visibility and competiveness. As an Academy member, I have followed and supported CeMM from the beginning and am very happy that many collaborations between our institute and CeMM have been built already over an intense and particularly friendly relationship of collaboration and exchange.” Prof. Dr. Helmut Gadner Director, St. Anna Children’s Cancer Research Institute Eric Haura was a visiting scientist in the group The joint study demonstrated a strategy for of the director, Giulio Superti-Furga, at the comprehending signalling pathways that Research Center for Molecular Medicine (CeMM) are active in lung cancer cells and that are targeted Sabbatical of the Austrian Academy of Sciences in Vienna by dasatinib. Nearly 40 different kinase targets from June to November of 2009 (see Eric Haura at of dasatinib were identified. Using a branch http://www.moffitt.org/site.aspx?spid=1868A4 of proteomics that identifies, catalogs, and Visiting Scientist 9EC35848BCAADC81CB6CAB7EC6&Search characterizes proteins containing a phosphate Type=Physician). During this time, Viennese group as a post-translational modification – and American scientists at CeMM developed a called quantitative phosphoproteomics – the possible new strategy for target-oriented therapy scientists identified peptides corresponding at CeMM combining two drugs that have a synergistic to autophosphorylation sites of tyrosine kinases effect. The findings of this successful cooperation that are inhibited in a concentration-dependent have been published in the renowned journal manner by dasatinib. Using drug-resistant Nature Chemical Biology. (“gatekeeper”) mutants of these proteins, they were able to show that SRC, and also the The buzz words of the moment for oncologists Epidermal Growth Factor Receptor(EGFR), is are target-oriented therapies. Insights of modern a relevant target for dasatinib action in these molecular biology have made it possible to cells. The combined mass spectrometry–based develop drugs that target a specific molecular approach provided a system-level view of dasat- lesion in cancer cells. However, drugs are much inib action in cancer cells and suggested both more unspecific than generally recognized targets to be of functional relevance and a ration- and the exact molecular understanding of why ale for combinatorial therapeutic strategies. a drug is actually exerting its effects often remains obscure. Working together, scientists Exactly this could have consequences for the at CeMM and the H. Lee Moffitt Cancer Center future treatment of patients with NSCLC and Research Institute were able to identify illnesses. Superti-Furga: “Dasatinib could really several target proteins of the kinase inhibitor have synergistic effects with the therapies drug dasatinib, which is currently used for already in use, such as the EGFR-inhibitor erlo- treatment of imatinib-resistant patients with tinib.” It would be one of the first combination chronic myelogenous leukemia (CML) and also therapies with drugs as target-oriented therapy for the treatment of lung cancer. and also one with a rational scientific basis. Based on these findings, the American oncologist The CeMM director, Giulio Superti-Furga, is Eric Haura is already conducting a clinical study enthusiastic: “For six months, we had the with lung cancer patients that takes advantage of pleasure of hosting Eric Haura from the Lee this mechanistic relationship. Moffitt Cancer Center in Tampa, Florida, one of the fastest growing cancer research centers in the USA.”

During this time, analytical methods have been applied that had previously been developed at CeMM. Eric Haura, Uwe Rix, Keiryn Bennett, Jacques Colinge and Giulio Superti-Furga focused the study on the mode of action of the kinase inhibitor dasatinib and its possible (NSCLC) application in treating non-small cell lung cancer.

Sabbatical Visiting Scientist Eric Haura with his family

Ce — M—M— Research Report 2009 66 67 One of CeMM’s primary goals is Left: CeMM/MUV to train young men and women Interdisciplinary CeMM/MUV in the field of molecular medicine. Postdoctoral Fellow Dr. Viola Borgdorff As one means of achieving this, Right: CeMM/MUV CeMM and the Medical University Interdisciplinary Interdisciplinary Postdoctoral Fellow of Vienna (MUV) founded the Dr. Stephan Blüml Interdisciplinary Postdoctoral Postdoctoral Fellows Program in 2008. Partici- pants of this program work in a clinically-oriented laboratory at the Fellows Medical University with access to the respective clinical department. They are also a full member of CeMM, and benefit from all of CeMM’s technologies and facilities, including the seminars. This unique partnership enables fellows in the program to tackle areas that would not be easy to address at either CeMM or the MUV alone, providing new research opportunities. We’d again like to express our thanks to our partners at the MUV, who have supported this project and shared our enthusiasm for this endeavor. Last year, we reported on the progress of the Dr. Viola Borgdorff is in the Department of Dr. Stephan Blüml has recently completed his Fellows who began in the program. Dermatology with Prof. Stephan Wagner at the Interdisciplinary Postdoc project, which he per- MUV. Viola has been working on characterizing formed in collaboration with Prof. Josef Smolen, This year, we have revisited two the transformation of melanocytes, which is in the Department of Rheumatology at the Medi- of them, to see how they have been a molecular process that leads to skin cancer, and cal University. We caught up with him in person, how this might be pharmacologically exploited. to ask him a few questions about his experience. getting along. This last year, she has been continuing these What was your motivation for doing an Inter studies on melanoma by investigating the role of disciplinary Postdoc at CeMM and the Medical the transcription factor MITF in the initiation University of Vienna? and progression of the disease. She has recently generated immortalized melanocytes over Coming from the Department of Rheumatology, expressing a double-tagged version of MITF for a clinical department with a strong interest in efficient identification of MITF-interacting translational science, I was very happy to be given proteins by mass spectrometry. This type of the opportunity to join an institution like CeMM, project is performed routinely at CeMM, utilizing which is a basic research facility with a strong the expertise of Keiryn Bennett’s group, who interest in translational science. For me, it was the develop and implement mass spectrometry perfect opportunity to gain technical and experi- techniques for identifying protein complexes, mental skills to approach specific questions. and Jacques Colinge’s group, who generate What was your research project about? bioinformatics platforms for data analysis. In addition, Viola has begun another collaboration My project was to try to define the roles of with the chemical proteomics group at CeMM, the two receptors that mediate the arthritogenic to screen for drugs preferentially targeting properties of TNF. The role of TNF in the melanoma cells overexpressing MITF. This could pathogenesis of rheumatoid arthritis is well lead to the identification of novel therapeutic established. However, the role of its two strategies for treating this serious disease. receptors is not well defined in this context.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 68 69 … and what were the main results? What are you doing now? We could show that the two TNF receptors Last October I returned to the Department of possess non-overlapping and even opposing Rheumatology at the AKH [Vienna General CeMM roles in the pathogenesis of a TNF-mediated Hospital] to continue my residency in internal animal model of rheumatoid arthritis, with medicine. However, there are still some experi- TNFR1 being the major culprit in the develop- ments planned for my project and in addition ment of arthritis. TNFR2, on the other hand, to that there are also collaborations with mem- Postdoctoral seemed to have a protective role in this process. bers of CeMM going on. These results might even have clinical implica- Will you continue your relationship with CeMM? tions, since one could start to speculate whether selective blockade of TNFR1 would be a thera I certainly will continue my relationship with Fellows peutic opportunity in rheumatoid arthritis. CeMM. Nevertheless, the amount of time I will be able to work on the ongoing projects will What did you find particularly beneficial about be less than it used to be, because of the clinical being an Interdisciplinary Postdoc, for both your work I have been resuming at the AKH. But, research and your scientific/medical training? Scientists who have completed as I mentioned before, there are some very inter- There are a couple of things that I really found esting collaborations still running. a doctoral degree and continue in very helpful and that I benefited a lot from. research are known as post-docs. Would you recommend other Medical Doctors First of all, I was lucky to end up in a group (the (MDs) to do an Interdisciplinary Postdoc at CeMM? There are currently 17 post-doctoral innate immunity team at CeMM) with excellent scientists, who I really enjoyed working with. I definitely would recommend doing an Inter- fellows working at CeMM. We picked I was able to discuss ideas and problems in a very disciplinary Postdoc at CeMM to any MD with a handful and asked them a few productive way with basically everyone, not a strong interest in basic science. It is an excel- questions about their experiences. only in the innate immunity team, but also with lent opportunity to get in touch with excellent other people working in totally different areas at researchers and to broaden one’s horizon in CeMM. I also had the opportunity to participate many ways. in projects of other members of CeMM, and some of those collaborations are still going on. In addition, CeMM is an institution with excellent technical resources, from which I also benefitted a lot. Did you observe a difference in culture between the Medical University and CeMM? I think one of the main differences is the very interactive way of doing things at CeMM, which is promoted by the way the lab is structured. The fact that basically everyone at CeMM has his/ her computer and desk in the main room really promotes interaction among all the members. In addition, CeMM is a professional research institute with full time scientists, whereas at the MUV there is also the clinical work. Was the experience how you expected, better or perhaps worse? My experience at CeMM was definitely better than I expected, which was in part due to the fact that there were excellent scientists at CeMM, from whom I could learn a lot. In addition I felt that the climate was very good and I was able to make friends while I was there.

Ce — M—M— Research Report 2009 Dr. Omar Sharif Dr. Christoph Baumann Dr. Quanah Hudson Dr. Sandrine Tonon (Supervisor: Sylvia Knapp): (Supervisor: Giulio Superti-Furga): (Supervisor: Denise P. Barlow): (Supervisor: Christoph J. Binder): What was your personal motivation What was your personal motivation What does molecular medicine mean to you? What was your personal motivation to do a post-doc at CeMM? to do a post-doc at CeMM? to do a post-doc at CeMM? To my mind molecular medicine involves Having carried out my PhD in the UK in the After my doctoral studies I wanted to do a post- investigating the genetics and cell biology of I was charmed and fascinated by the dynamism area of innate immunity and transcription, I doc working in a place where basic research is development and disease to provide a and potential of CeMM – a research institute wanted to move abroad to conduct a post-doc. more motivated by medical needs. CeMM seemed knowledge basis that can be further developed offering such broad, complementary and My personal motivation to apply at CeMM a very good option to do that. It was and still is for the diagnosis and treatment of disease. multidiscliplinary teams. Real cross-interaction was that I wanted to learn more about mouse a young and rising institute in Europe, working in between all teams is still not optimal yet Would you recommend CeMM to others models of infectious diseases and the laboratory on subjects such as innate immunity, infection, but I do believe that a common location will for a post-doc and why? of Sylvia Knapp (one of the principal investi leukemia and cancer and located at the general be extremely emulative by gathering together gators at CeMM) seemed to be an ideal place to hospital in the center of one of the most beautiful I would recommend CeMM as a good place to brains, techniques and equipment. achieve this. Additionally, I liked the idea of cities in the world. do a post-doc, because of the good working What does molecular medicine mean to you? working at a research centre that lies at the heart atmosphere and well-resourced labs. People at What is special/different about a post-doc of one of the largest hospitals in Europe, pro all levels of the organisation are friendly, but at CeMM? It means adapting and shaping the molecular viding a bidirectional channel between basic also passionate about their science and willing world which is microscopic and extremely research and clinical applications. Working in The main difference to me is the timing: CeMM to help and give constructive suggestions about complex to allow human beings to live better the area of infectious diseases this is very helpful has been founded just a few years ago and this each other‘s work. and longer in the third millennium. as there is direct access to clinicians and clinical year we will move to our own building. A lot of Name one highlight of 2009 for you – Name one highlight of 2009 for you – material, which is useful for translating and highly qualified and motivated people have personal or work related? personal or work related? correlating results obtained from mouse and cell gathered here and are about to create something culture models to humans. This is one of the special and unique. A rewarding experience for me in 2009 was I realised more than ever that art and science unique things about CeMM. writing a review examining the different What does molecular medicine mean to you? are feeding each other. And only excellence mechanisms regulating genomic imprinting in What is special/different about a post-doc and convergence of both universes will lead to Basically all of the drugs we use to treat a certain embryonic and placental tissues. at CeMM? great discoveries. disease are not really understood in terms of As it is a relatively new research centre, there is their molecular targets and side effects. In addition, a lot of effort directed towards providing an the disease causing aberrations in individual open and collaborative environment. This has patients are still largely elusive. Molecular medicine provided an ideal forum that has allowed me addresses these questions, translating the acquired CeMM to foster collaborations with several post-docs understanding of basic research into medical per- Postdoctoral Fellows Christoph Baumann at CeMM and at the Medical University of spective, offering new possibilities for therapies. Tilmann Bürckstürmer Vienna on various different problems all related Thomas Burkard Would you recommend CeMM to others Florian Grebien to understanding how the body defends itself for a post-doc and why? Oliver Hantschel against foreign “invaders”. Quanah Hudson Yes I would and have. The atmosphere is great, Markus Müllner Would you recommend CeMM to others Florian Pauler everybody is motivated, the lab and PIs have a for a post-doc and why? Andreas Pichlmair good reputation, the new building is cool and the Uwe Rix funding is good. Elena Rudashevskaya Importantly, Vienna is one of the cultural capitals Roberto Sacco of Europe, with a great nightlife, and has one Omar Sharif Name one highlight of 2009 for you – of the highest standards of living in the world. I Stefanie Sigel personal or work related? Mathew Sloane feel that my time in Vienna working at CeMM Alexey Stukalov has so far been very productive and would One of the highlights of 2009 was a beautiful hike Sandrine Tonon recommend it as an institute to other post-docs in the Dolomites followed by an evening in the for the aforementioned reasons. arena of Verona watching the Puccini opera Tosca.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 72 73 Dr. Oliver Hantschel Name one highlight of 2009 for you – The CeMM PhD program is a program personal or work related? (Supervisor: Giulio Superti-Furga): for students planning a career in What was your personal motivation One great highlight of 2009 was the very success- CeMM biomedical research. The program is to do a post-doc at CeMM? ful and rapidly progressing collaboration with Shohei Koides lab from the University of Chicago, designed to develop creative, independ- When I started my post-doc, CeMM only existed which included a six week scientific visit to our lab as a “virtual” institute consisting of the ten found- ent research scientists, who will be of John Wojcik, an MD/PhD student from PhD Program ing groups from the MUV. So it was on us, the Shohei´s group. In addition, the invitation to par- well-equipped to study molecular medi- five founding lab members (Keiryn, Angela, Lily, ticipate in the conference celebrating the tenth cine in the post-genomic era. Strong Uwe and myself) and Giulio to decide on our anniversary of the first clinical results of imatinib/ scientific direction, order equipment, hire the emphasis is put on the understanding Gleevec, the first approved tyrosine kinase first technicians, establish the first collaborations inhibitor, was an extremely exciting experience. of fundamental physiological and patho with clinicians etc. It was an exciting time to logical processes to identify the most witness the immense growth of our lab, to see so many people coming, some others leaving, with relevant questions of molecular medicine each person bringing their own diverse scientific Dr. Uwe Rix and study them with the best technolo- expertise, personality and cultural background. (Supervisor: Giulio Superti-Furga): gies available. My motivation to help to get CeMM started was What was your personal motivation a logical step in my own scientific development. to do a post-doc at CeMM? After having spent my PhD at an institution The Medical University of Vienna is with a strong focus on basic biological research My personal motivation to do a post-doc at the home academic institution for the and mainly having worked on structural aspects CeMM was mainly driven by the strong drug centered around the regulation of the proto- proteomics focus, but I was also attracted by the CeMM PhD program, which has a oncogene Abl, I became more and more interest- chance to be part of such a pioneering new insti- minimum duration of 3 years. Laboratory ed in the medical implications of my work. In tute. Finally, the opportunity to work with my work is performed in the laboratories particular the rising problem of tyrosine kinase wife Lily decided it for me. inhibitor resistance of Bcr-Abl in the clinics and of the CeMM PIs. There is mandatory What is special/different about a post-doc the two emerging second generation Bcr-Abl at CeMM? course work, particularly in the first year. inhibitors attracted me to”join” CeMM in order By the second year a thesis committee to attempt to bridge basic and clinical research. The interdisciplinary and highly interactive nature of the organization makes it unique when consisting of at least three members What is special/different about a post-doc compared with other institutes. The cooperation at CeMM? is appointed for each student. Students between the groups is great and will be better I think one of the main differences to post-doc again in the new building. have to meet with this committee on a positions at other places is the strong collabora- regular basis and ultimately defend their What does molecular medicine mean to you? tive aspect of most projects and the possibility thesis in front of it. The PhD thesis is to integrate different expertise and technologies. Molecular medicine is a novel discipline aiming This comes along very quickly after one starts at molecular approaches to understanding dis- required to yield at least one publication as a post-doc with tutoring responsibilities eases, which will hopefully allow us to develop in a peer-reviewed journal. for technicians, diploma or PhD students, which better therapies and diagnostics. requires that you are able to plan and execute Would you recommend CeMM to others your projects beyond your own work at the The internationally advertised PhD for a post-doc and why? bench. So you learn to manage your own micro- program began in 2006, when thirteen or mini-lab, which I believe is an extremely I would definitely recommend CeMM to other students from eight different nation good way to qualify for a future career as an post-docs because of the focus on state-of-the-art independent PI. technology and the combination of different alities were selected. These first years approaches. On top of that CeMM is now starting have clearly reassured us about the What does molecular medicine mean to you? a comprehensive post-doc program including importance of having a graduate training Molecular medicine for me means the aim to multidisciplinary activities to develop a wider understand the molecular basis of disease, which range of skills. program within our young institute, I strongly believe is the first step towards the Name one highlight of 2009 for you – as our students are probably the single development of targeted molecular therapies personal or work related? most important factor that ties us all that attack the cause of the disease rather than interfering with its consequences. My highlight for 2009 was being an invited together. They are indeed our best speaker at Harvard Medical School! investment, and their contagious enthusiasm and inquisitive minds were a driving force over the past few years.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 75 75 Damla Olcaydu (Supervisor: Robert Kralovics): Iris Uras (Supervisor: Sebastian Nijman): One Georg Winter (Supervisor: Giulio Superti- Second Year Being now in the second year of my PhD, I am more year at CeMM has passed and I am proud to Furga): Being now at CeMM for around one more than ever convinced that applying at CeMM say that my initial high expectations are still and a half years, my resume still is a very PhD Students for my postgraduate studies was just the right being fulfilled. I am in the right place at the right positive one. I think the environment that thing to do. I am grateful to have the chance to time because a PhD is not only a thesis, but also a CeMM provides for PhD students is optimal work in an exceptionally friendly, supporting, step forward in becoming a grown-up by in many regards as it offers on the one hand motivating and productive atmosphere at CeMM, improving both your personality and personal access to a variety of different state-of-the-art Joanna Warszawska (Supervisor: Sylvia Knapp): which definitely aids one to successfully cope with skills, thinking independently, being mature in technologies and on the other hand, so many It has been 1 year since I joined CeMM. So far, it the challenges of scientific everyday life. I have your judgement and standing up for your ideas. different scientific expertises ranging from has been a great time for a number of reasons. As learned a lot in the last years, not only concerning I experienced how exciting and enthusiastic sci- mathematical modeling to in vivo mouse a medical doctor, I started with less experience in scientific knowledge, but also to be independent ence can be and also learnt how to deal with the experiments. Trying to incorporate those assets basic research than my non-medical colleagues. in research work, have and defend my own ideas, challenges – by being motivated, hard working, represents a wonderful possibility but also Over this last year, I received lots of support and work hard, make your own experiences, withstand patient and optimistic. CeMM therefore repre- a challenging task for young researchers and encouragement, which helped me to greatly drawbacks and keep your motivation high, despite sents a unique place with its friendly atmosphere provides us with all the resources that are improve my technical skills as well as my knowl- all the difficulties you encounter. As a PhD student and great support by extraordinarily talented necessary to be internationally competitive. edge in molecular medicine. For me, CeMM is in Robert Kralovics’ research group, I am working people and stimulating discussions. It definitely the ideal place to start a career in molecular on the genetics of myeloproliferative neoplasms provides both competitive and encouraging spirit medicine and – last but not least – the best place and enjoying the opportunity to conduct basic for scientists who stand at the very beginning of to have fun! science in such close vicinity to the clinic – which their careers. makes CeMM a unique place to do research work, Thorsten Klampfl (Supervisor: Robert Kralovics): especially for me as a medical doctor with a great It has been now 1.5 years since I started my interest in basic and translational research. work on the genomics of the myeloprolifera- Second Year tive neoplasms in Robert Kralovics’ lab as a PhD Ashot Harutyunyan (Supervisor: Robert Kralovics): PhD students from left to right: student. So far I can really say it proved to be a In the second year of my PhD, I got deeply Dimitris Tsiatoulas good decision to work with Robert and at CeMM engaged in the research at CeMM, which is at Damla Olcaydu Thorsten Klampfl in general. It is challenging to learn how to per- the same time exciting and challenging. I gained Iris Uras form cutting-edge research especially in a highly significant experience in designing projects and Georg Winter competitive field, but CeMM is a good place to learnt what difficulties and obstacles lay on the Joanna Warszawska Roberto Giambruno do that. On the one hand, the access to the latest way towards their accomplishment. The avail- Ashot Harutyunyan technologies not only for genome research, but ability of most modern technologies at CeMM also for the various other fields at CeMM sets the makes it possible to conduct research projects technical basis for exciting and creative experi- that would have been unthinkable a couple of ments. On the other hand, the CeMM commu- years ago. On the other hand, close collaboration nity and the close contacts between the people between different CeMM groups helps one find of the different labs serves for lively exchange interesting solutions to many research questions. of knowledge and development of new ideas So doing research here is always hugely interest- and research strategies. Especially the latter is ing and also fun, though it requires a lot of hard expected to become even more exciting when we work. I have rather high expectations for the all move together into the new CeMM building coming year: it promises to be even more exciting which will definitely be one of the highlights of as we are all looking forward to moving to the the upcoming year. state-of-the-art new CeMM building and working even closer with the other CeMM groups. Roberto Giambruno (Supervisor: Giulio Superti- Furga): This is my second year at CeMM and it Dimitris Tsiatoulas (Supervisor: Christoph Binder): Third Year is amazing how fast my scientific experience is 2009 at CeMM! The highlight of the year?! Our PhD students from left to right: growing. There is always the possibility to learn retreat in Budapest. We had a very nice time as Roland Jäger new techniques and to increase your scientific we combined very successfully the well organ- Irena Vlatkovic Adriana Goncalves background thanks to seminars, meetings and ized scientific part of the retreat with a so-called David Weismann journal clubs. Moreover the nice atmosphere ‘social event’ (party until late in the morning). Ana Zivkovic and the people working in the institute give you All the good impressions from the previous year the strength to go forward with your research, regarding the exceptionally friendly internation- especially during the several difficult moments of al environment and the freedom to develop your your PhD. own scientific ideas have been totally confirmed. I am sure it is going to be even better in the future as soon CeMM is moving to a brand new building.

Ce — M—M— Research Report 2009 77 78 Adriana Goncalves (Supervisor: Giulio Superti- Third Year Furga): It was very encouraging to see how much CeMM grew and expanded in the last year: PhD Students many new colleagues, a new building and a CeMM beautiful art façade, new projects and grants, fruitful conferences and many interesting events. It is therefore not difficult to imagine that also Principal Irena Vlatkovic (Supervisor: Denise P. Barlow): for me, 2009 became in many ways a decisive The three years as a part of CeMM were among year, marked by a strong personal and scientific the most interesting and rewarding years of my development. I was not only able to consolidate life. The years compacted with science, friend- my knowledge but also to bring it to a further Investigators ships and traveling while every day was bring level of understanding. I have no doubts that ing something new and exciting. As a part of both CeMM and myself will continue to grow in CeMM I learned how to do both basic and disease the following year! related science, how to think scientifically, how to always aim to get the bigger picture and in the David Weismann (Supervisor: Christoph Binder): same time to understand the each small part. This Of all the years I spent at CeMM, I enjoyed the year I am coming to the end of my CeMM jour- last one in particular. Mainly because my PhD ney finishing my PhD thesis about mapping and project finally set off and yielded more than just characterization of novel macro non-protein cod- interesting observations. But importantly, it was ing RNAs in human normal and cancer cells and also during this last year that my scientific as tissues. I am sure that for my future scientific car- well as my personal bonds within the institute rier the knowledge and skills I obtained in CeMM eventually stabilized and opened the prospect for will be the excellent basis, and that I will always connections that will outlast my time here. aim to find the CeMM spirit at any institute I go.

Roland Jäger (Supervisor: Robert Kralovics): When I started my training as a PhD student in Robert Kralovics’s lab at CeMM three years ago, I took a lot of motivation from the optimistic atmosphere in the lab and at CeMM. I soon realized that people at CeMM aim at a very high standard in communication, knowledge, technology and science in general. Working on the genetics of Myeloproliferative Neoplasms, I could experience the hard competition in science and how fast things change in the field, but also how exciting science can be. I could participate in starting up a lab, facing a lot of challenges, but in the end making big progress in organization as well as in productivity.

Ana Zivkovic (Supervisor: Sylvia Knapp): Discovering logic behind the act of bacterial toxins and a response of host organism was my main preoccupation during last several years. Throughout this time I have been hunting to further my knowledge and contribute to the progression of science in this field. Today I’m in my final year of PhD. I believe I learned a lot about basic science and the importance of Molecular and Translational Medicine. Discovery of unknown pathways is hard and creative work but remarkably exciting. For me and my professional ambitions, CeMM presents an open-minded and inspiring platform, a great chance to develop intellectually and to be appreciated wherever you come from.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 79 79 Giulio Superti-Furga is an Italian national and Robert Kralovics, born 1970, is Czech and joined Giulio he joined CeMM as Director in January 2005. He Robert CeMM in June 2006. He obtained his first degree in performed his undergraduate and graduate studies Molecular Biology and Genetics at the Comenius Superti-Furga in molecular biology at the University of Zurich, Kralovics University in Bratislava and later his Ph.D. in Bio- Switzerland, at Genentech Inc., South San Francisco, physics at the Academy of Sciences of the Czech Pathological Networks USA, and at the Institute for Molecular Pathology Genetics of Republic in Brno. He did his postdoctoral work in Leukemia and Immunity Hematological Disorders in Vienna (I.M.P.), Austria. He has been a post- on the genetics of myeloproliferative disorders doctoral fellow and Team Leader at the European working with Josef Prchal at the University of Molecular Biology Laboratory (EMBL) until 2004. Alabama at Birmingham, USA. He followed Prchal For several years he served as Professor of as an Assistant Professor at the Baylor College of Giulio Superti-Furga’s group Biotechnology at the University of Bologna. In Robert Kralovics’ group Medicine in Houston. From mid 2001, Robert was is renting lab space: 2000, he co-founded the biotech company Cell- is hosted by: a project leader with Radek Skoda in Basel. Vienna Competence Center zome, where he was Scientific Director. Someof Division of Hematology Robert’s research interests are primarily in myelo- CeMM – Center for Molecular Giulio’s major achievements to date are the and Hemostaseology proliferative disorders (MPDs) and in myeloid Medicine of the Austrian Academy University Hospital of Vienna of Sciences elucidation of basic regulatory mechanisms of Währinger Gürtel 18–20 malignancies in general. One of his major achieve Lazarettgasse 19 CEO and Scientific Director tyrosine kinases in human cancers and the discovery 1090 Vienna, Austria CeMM Principal Investigator ments so far has been the identification of a gain- 1090 Vienna, Austria [email protected] of fundamental organization principles of the [email protected] of-function mutation in the JAK2 kinase gene proteome of higher organisms. Giulio’s work on (V617F), which plays an important role in MPD PhD (Molecular Biology), the organization of the eukaryotic proteome is the PhD (Molecular Biology) pathogenesis. This was prominently published in University of Zurich (CH) most highly cited in the field. He is a corresponding Czech Academy of Sciences (CZ) New England Journal of Medicine and fostered IMP Vienna (A) member of the Austrian Academy of Sciences, Post-doctoral fellow Robert’s interest in deciphering the genetic com- Post-doctoral fellow, Team Leader the German Academy of Sciences Leopoldina and University of Alabama plexity of MPD. More recently, Robert’s group EMBL – European Molecular the European Molecular Biology Organization. at Birmingham (USA) discovered that a common JAK2 gene variant that Biology Laboratory (D) He follows Angus Lamond as chair of the EMBL Assistant Professor confers susceptibility to MPD. Robert continues this Scientific Director Alumni Association. After joining CeMM, he Baylor College of Medicine, work at CeMM to identify new mutations causing Cellzome (D) continues to use and develop high-throughput Houston (USA) familial predisposition to hematological malig ‘omics’ approaches to study several areas including Project Leader nancies using advanced genomics approaches, and + Italian nationality the mechanism of action of proteins and drugs, University Hospital Basel (CH) is working towards understanding how genetic + Joined CeMM in January 2005 the identification of molecular networks under variability contributes to the disease. + Group of 19 people lying leukemia and the molecular basis of innate + Czech nationality plus mass spectrometry team (5) immunity. In November 2009 he received the + Joined CeMM in June 2006 and bioinformatics team (4) prestigious Advanced Investigator Grant awarded + Group of 5 people Three relevant/important publications by the European Research Council (ERC). A gain-of-function mutation of JAK2 in Main research interests Main research objectives myeloproliferative disorders. Kralovics R, + Mechanism of action of drugs and questions Passamonti F, Buser AS, Teo SS, Tiedt R et al. + Molecular networks Three relevant/important publications + Identify mutations in early N Engl J Med. 2005. 28;352(17): 1779–90 affecting leukemias Functional organization of the yeast proteome steps of disease development + Molecular basis of innate immunity by systematic analysis of protein complexes. in hematological malignancies A common JAK2 haplotype confers susceptibility Gavin AC, Bösche M, Krause R, Grandi P, + How mutant stem cells evolve to myeloproliferative neoplasms. Olcaydu D, Marzioch M, Bauer A, Schultz J, Rick JM, genetically, how they respond Harutyunyan A, Jäger R, Berg T, Gisslinger B, Michon AM, Cruciat CM, Remor M, Höfert C, to therapy? Pabinger I, Gisslinger H, Kralovics R. Nature Schelder M, Brajenovic M, Ruffner H, Merino A, + What gene mutations cause Genetics. 2009. 41(4):450-4 Klein K, Hudak M, Dickson D, Rudi T, Gnau V, familial predisposition to Bauch A, Bastuck S, Huhse B, Leutwein C, hematological malignancies? Genetic complexity of myeloproliferative Heurtier MA, Copley RR, Edelmann A, Querfurth + How does genetic variability neoplasms. Kralovics R. E, Rybin V, Drewes G, Raida M, Bouwmeester contribute to disease? Leukemia. 2008. 22(10):1841–8. T, Bork P, Seraphin B, Kuster B, Neubauer G, + How to diagnose the diseases Superti-Furga G. Nature. 2002. 415(6868): 141–7. in early stages of development?

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

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

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 80 81 Denise Barlow is a British national who joined Sylvia Knapp was born in Austria and studied Denise CeMM in 2003 and is an Honorary Professor Sylvia Medicine at the Free University in Berlin and at the at the University of Vienna. Denise initially University of Vienna. She obtained her M.D. degree P. Barlow trained as a State Registered Nurse in the UK Knapp in 1993 and did her Ph.D. with Professor Tom van der and afterwards completed undergraduate studies Poll at the University of Amsterdam studying the Epigenetic Mechanisms at Reading University (UK) and a PhD on the Innate Immunity inflammatory response to severe bacterial infections. in Development & Disease and Bacterial Infections interferon system at Warwick University (UK). Sylvia received her License in Internal Medicine in Postdoctoral work studying mouse embryonic 2000 and in 2004 she obtained a “Habilitation” development followed at ICRF (London, UK) in Internal Medicine at the Medical University of with Dr. Brigid Hogan, and on genome biology Vienna. After several residencies, mostly in areas of Denise Barlow’s group at EMBL (Heidelberg, D). Denise has also held Sylvia Knapp’s group Internal Medicine like Infectious Diseases, AIDS is renting lab space: group leader positions at the IMP (Vienna, A) and is hosted by: and Intensive Care Units, she became a Research Institute of Genetics NKI (Amsterdam, NL). On returning to Austria Department of Internal Medicine I Fellow in Tom van der Poll’s laboratory at the Uni- Max F. Perutz Laboratories in 2000, Denise was appointed Head of the Medical University Vienna versity of Amsterdam for four years. Sylvia’s most Vienna Biocenter Währinger Gürtel 18—20 Dr. Bohr-Gasse 9/4 Dept. of Developmental Genetics at the Austrian 1090 Vienna, Austria important achievements include the identification 1030 Vienna, Austria CeMM Principal Investigator Academy IMB Institute (Salzburg, A), and then CeMM Principal Investigator of the anti-inflammatory role of alveolar (lung) [email protected] finally returned to Vienna in 2003 as a Principal [email protected] macrophages in Streptococcus pneumoniae pneu- Investigator with CeMM. Amongst the Barlow or [email protected] monia. Sylvia joined CeMM in April 2006 and Honorary Professor of Genetics lab’s major achievements are the discovery of the continues her work on the innate immune response at Vienna University first imprinted gene in mammals and the eluci- MD, University of Vienna (A) to bacterial infections, focusing on the molecules PhD, dation of the epigenetic mechanism underlying Internist, Vienna General involved in the initiation and resolution of the Warwick University (UK) imprinted expression. The lab uses the model Hospital, MUV (A) innate immune response to clinically relevant Post-doctoral Fellow, of genomic imprinting, i.e. parental-specific gene PhD (Experimental Medicine), pathogens and on the role of bacterial virulence fac- ICRF London (UK), EMBL expression, to dissect how epigenetics change University of Amsterdam (NL) tors and their interactions with host structures and Heidelberg (D) the behavior of our genes, which has important pathways. Sylvia keeps her part-time responsibili- Group Leader, consequences for normal human development and + Austrian nationality ties in the Intensive Care Unit at the MUV. IMP Vienna (A) when things go wrong, for diseases such as cancer. + Joined CeMM in April 2006 NKI Amsterdam (NL) + Group of 11 people Head Dept. Developmental Biology, Three relevant/important publications IMB-OeAW Salzburg (A) Three relevant/important publications Main research interests Alveolar macrophages have a protective anti The mouse insulin-like growth factor type 2 + Identify the impact of inflammatory role during murine pneumococcal + British nationality receptor is imprinted and closely linked to the bacterial toxins pneumonia. Knapp S, Leemans JC, FlorquinS, + Joined CeMM in 2003 Tme locus. Barlow DP, Stoger R, Herrmann BG, + Exploit molecular mechanisms Branger J, Maris NA, Pater J, van Rooijen N, + Group of 15 people Saito K, Schweifer N. Nature. 1991. 349(6304): 84–7. of host-pathogen interactions and van der Poll T. Am J Respir Crit Care Med (2003) 167, 171-179. Main research interests The non-coding Air RNA is required for silencing + Molecular basis and function autosomal imprinted genes. Sleutels F, Zwart R, Toll-like receptor 2 plays a role in the early of genomic imprinting in mice Barlow DP. Nature. 2002. 415(6873): 810–3. inflammatory response to murine pneumococcal and humans pneumonia but does not contribute to antibacterial + Identification and characterization Active and Repressive Chromatin Is Interspersed defense. Knapp S, Wieland CW, van ´t Veer C, of macro non-coding RNAs without Spreading in an Imprinted Gene Cluster Takeuchi O, Akira S, Florquin S, and van der Poll T. + The potential of macro non-coding in the Mammalian Genome. Regha K, Sloane MA, J Immunol (2004) 172, 3132-3138 RNAs as tumor biomarkers Huang R, Pauler FM, Warczok KE, Melikant B, Radolf M, Martens JH, Schotta G, Jenuwein T, TREM-1 activation alters the dynamics of pulmonary Barlow DP. Molecular Cell. 2007. 27(3): 353–66. IRAK-M expression in vivo and improves host defense during pneumococcal pneumonia. Lagler H, Sharif O, Haslinger I, Matt U, Stich K, Furtner T, Doninger B, Schmid K, Gattringer R, de Vos AF, Knapp S. J Immunol (2009) 183, 2027-2036

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 82 83 Sebastian Nijman was born in the Netherlands Christoph Binder was born in 1973 in Vienna, Sebastian (1975). He obtained his university training in Christoph Austria. He obtained his M.D. degree from the Utrecht where he specialized in Molecular Biology University of Vienna Medical School (MUV) in Nijman and Biochemistry and acquired a Masters of Arts J. Binder 1997, working as an intern in the Clinical Pathology degree from the University of Maastricht (Science, department with Professor Dontscho Kerjaschki. Cancer Genomics Society and Technology Studies). After a short Atherosclerosis Later, he entered a Ph.D. program at the University and Immunity “detour” through industry where he was involved of California in San Diego, working with renow- in clinical research, he started his Ph.D. with Profes- ned atherosclerosis researcher Professor Joseph sor Rene Bernards at the Netherlands Cancer Insti- Witztum, where he obtained his Ph.D. degree in tute in Amsterdam. With the help of the first RNAi 2002 for the thesis entitled: “Defining Innate and Sebastian Nijman’s group screen in mammalian cells he assigned a function Christoph Binder’s group Adaptive Immune Mechanisms in the Athero is renting lab space: to the familial tumor suppressor gene CYLD, which is hosted by: protective Effect of Immunization with Oxidized Department of Medical was published in Nature, and has been one of his Department of Medical Low-Density Lipoproteins”. He continued with and Chemical Laboratory major achievements so far. This work has led to a and Chemical Laboratory Professor Witztum as a Postdoc to study the role Diagnostics (KIMCL) Diagnostics (KIMCL) Medical University of Vienna rational therapeutic approach for treating the tumor Medical University of Vienna of IL-5 in atherosclerosis, which was where he General Hospital H5.J2.09 CeMM Principal Investigator syndrome that is caused by mutations in this gene. Währinger Gürtel 18—20 CeMM Principal Investigator made one of his major discoveries to date, namely Währinger Gürtel 18–20 1090 Vienna, Austria 1090 Vienna, Austria [email protected] In 2006 he joined the lab of Dr. Todd Golub at the [email protected] that IL-5 is an atheroprotective cytokine. In 2005, Broad Institute of Harvard and MIT, USA. There he he joined the Department of Laboratory Medicine PhD (Molecular Biology) developed novel genomic approaches to discover MD, at the Medical University of Vienna, where in 2009 Netherlands Cancer Institute (NL) the functions of genes and identify new angles University of Vienna (A) he was appointed Professor of Atherosclerosis. Post-doctoral fellow, for cancer treatment. Much of Sebastian’s research PhD (Molecular Pathology) His interests are clearly interdisciplinary and span Broad Institute of Harvard can be considered as technology driven. His main University of California vascular biology, lipid oxidation, natural antibodies and MIT (USA) interest includes the molecular mechanisms under- San Diego (USA) and innate immunity. In particular, he aims to lying cancer, particularly cancer vulnerabilities and Post-doctoral fellow, define the role of IL- 5 and of natural antibodies in + Dutch nationality the identification of new components of cancer University of California atherogenesis and how immune recognition of oxi- + Joined CeMM in October 2007 pathways using genetic screens in mammalian cells. San Diego (USA) dized lipids link autoimmunity and atherosclerosis. + Group of 4 people + Austrian nationality Main research interests Three relevant/important publications + Joined CeMM in April 2006 Three relevant/important publications + Identify novel strategies to treat Loss of the cylindromatosis tumour suppressor + Group of 8 people Innate and acquired immunity in atherogenesis. cancer (cancer vulnerabilities) inhibits apoptosis by activating NFkappaB. Binder CJ, Chang MK, Shaw PX, Miller YI, + Unravel molecular mechanisms Brummelkamp TR, Nijman SM, Dirac AM and Main research interests Hartvigsen K et al. Nature Medicine. 2002. 8(11): that drive tumorigenesis Bernards R. Nature. 2003. 424(6950): 797–801. + Role of natural immunity in 1218–26. + Functional genetic screens to inflammation and oxidative stress identify cancer-related genes The deubiquitinating enzyme USP1 regulates + Elucidate the protective Pneumococcal vaccination decreases atherosclerotic the Fanconi Anemia pathway. Nijman SM, capacities of natural antibodies lesion formation: Molecular mimicry between Huang TT, Dirac AM, Brummelkamp TR, in atherosclerosis Streptococcus pneumoniae and oxidized LDL. Kerkhoven RM et al. Molecular Cell. 2005. + Discover ways to boost natural Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP 17(3): 331–9. equal contribution. immunity as therapy for cardio et al. Nature Medicine. 2003. 9(6): 736–43. vascular diseases A genomic and functional inventory of Oxidation-specific epitopes are dominant targets of deubiquitinating enzymes. Nijman SM, innate natural antibodies in mice and humans. Luna-Vargas MP, Velds A, Brummelkamp TR, Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, Dirac AM et al. Cell. 2005. 123(5): 773–86. Woelkers D, Shaw PX, Choi J, Perkmann T, Bäck- hed F, Miller YI, Hörkkö S, Corr M, Witztum JL, Binder CJ. J Clin Invest. 2009 May;119(5):1335-49.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 84 85 Keiryn Bennett, PhD, heads the mass spectrometry Jacques Colinge is a Swiss and French national, Keiryn unit at CeMM. Australian by birth, she obtained her Jacques and is head of the bioinformatics team at CeMM Bachelor of Science with Honours at the Depart- since he arrived in September 2006. He performed Bennett ment of Biochemistry, University of Tasmania Colinge mathematics graduate studies in Geneva, Switzerland. and her PhD at the Department of Chemistry, He then did his Ph.D. with Professor G. Wanner, University of Wollongong, Australia, under the also in Geneva, in the field of numerical analysis of supervision of Professor Margaret Sheil. She further partial differential equations. This was a joint pro- trained in some of the most renowned protein ject with both Swiss Institutes of Technology. After mass spectrometry laboratories of the world, completing his Ph.D., Jacques joined Serono Pharma including Professor Peter Roepstorff in Odense, Jacques Colinge’s group ceutical Research Institute as a bioinformatician to Keiryn Bennett’s group Denmark. Keiryn Bennett has been Director of is renting lab space: work mainly on differential gene expression data is renting lab space: Analytical Applications at Protana AS in Denmark CeMM – Center analysis. In 2000 he moved to GeneProt Inc. to head Vienna Competence Center (later called MDS Proteomics). Her hands-on for Molecular Medicine a group of nine in charge of mass spectrometry- CeMM – Center for experience with different systems include: Sciex of the Austrian Academy related bioinformatics. Four years later, he joined the Molecular Medicine of Sciences of the Austrian Academy prototype MALDI‑QqTOF, PerSeptive Voyager Mariannengasse 14 Upper Austrian University of Applied Sciences at of Sciences Head of Mass Spectrometry Elite MALDI-rTOF, TSQ‑700 triple quadrupole 1090 Vienna, Austria Head of Bioinformatics Hagenberg to serve as a Professor of Bioinformatics. Lazarettgasse 19 1090 Vienna, Austria [email protected] mass spectrometer, Sciex QSTAR equipped with [email protected] Jacques Colinge’s main contributions are solution nanoelectrospray, and nanoLCMS coupled to methods for strongly nonlinear elliptic PDEs arising PhD, Department of Chemistry, ThermoFisher Orbitrap and Micromass/Waters PhD in glaciology, management of high-throughput University of Wollongong (AUS) Q‑TOF mass spectrometers. Author of approxi- Swiss Institutes proteomics data flows, statistical models for SAGE Director of Analytical Applications, mately 40 publications, during her time at MDS, of Technology (CH) data analysis, MS data identification, and MS-based Protana AS, (later called) Keiryn Bennett was involved in the large-scale Bioinformatician, quantitation analysis, and recognition of biological MDS Proteomics (DK) analysis of yeast protein complexes published in Serono Pharmaceutical functions represented in protein interaction net- Nature along with the analogous effort from Cell- Research Institute (CH) works, integration of proteomics results with + Australian nationality zome. She is known and respected world-wide in Head of Bioinformatics, transcriptomics, interaction, and pathway data. + Joined CeMM in October 2004 the field of protein mass spectrometry. She brings GeneProt Inc (CH) + Group of 5 people to CeMM more than 15 years of experience in pro- Professor of Bioinformatics, tein mass spectrometry and 7 years´ experience in Upper Austrian University Three relevant/important publications: Main research interests managing a high-throughput industrial proteomic of Applied Sciences, OLAV: Towards high-throughput MS/MS data + Proteomics, with an emphasis laboratory. Keiryn Bennett has established the Hagenberg (A) identification. Colinge J, Masselot A, Giron M, on medical/clinical field protein mass spectrometry capability at CeMM. Dessingy T and Magnin J. Proteomics. 2003. + Liquid chromatography mass + Swiss and French nationality 3:1454–1463. spectrometry (including technical + Joined CeMM in September 2006 advancement and applications) Three relevant/important publications: + Group of 4 people Peptide fragment intensity statistical modelling. + Integration of mass spectrometry Acid elution and one-dimensional shotgun analysis Colinge J. Anal. Chem. 2007. 79:7286–7290. with Biology and Bioinformatics on an orbitrap mass spectrometer – an application Research Interests to drug affinity chromatography. Fernbach NV, + Computational Proteomics Global target profile of the kinase inhibitor bosutinib Planyavsky M, Müller A, Breitwieser FP, Colinge J, + Computational Statistics in primary chronic myeloid leukemia cells. Remsing Rix U and Bennett KL. J Proteome Res. 2009: 8, and Statistical Learning Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, 4753–4765 + Systems Biology Data Analysis Stranzl T, Müller A, Baumgartner C, Valent P, Augustin M, Till JH and Superti-Furga G. Leukemia. Charting the molecular network of the drug target 2009. 23:477-485. Bcr-Abl. Brehme M, Hantschel O, Colinge J, Kaupe I, Planyavsky M, Koecher T, Mechtler K, Bennett KL and Superti-Furga G. PNAS. 2009: 106, 7414-7419

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

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 86 87 The center-wide retreat is a particularly Photos from the CeMM important event for CeMM because the retreat in Budapest, Hungary. CeMM laboratories are not currently situated close together, and so many people do not meet on a daily basis. Therefore, particular care Retreat goes into the organization of the yearly retreat. The CeMM retreat of 2009 was held from Thursday 26th to Saturday 28th of February at the Hotel Gellért in Budapest, a two-hour coach journey from Vienna. All members of CeMM were invited and there were 82 participants. The retreat began with an afternoon sightseeing tour by boat down the Danube River, which splits the city into two halves. The main scientific schedule began the first evening and continued throughout the Friday. This year, all the postdoctoral fellows were asked to present their research in 15-minute talks. In total there were 18 talks over 6 sessions. Particu- larly memorable was the very intense poster session in the evening, at which the PhD students presented and discussed their work to the rest of the institute.

As usual, there was some time set aside for more social activities, which involved experi- encing at least one of the two things Budapest is most famous for: its extraordinary architec- ture and its thermal springs. Whatever the choice, there wasn’t far to travel as the hotel was situated close to the city center. Itself a famous late Art Nouveau building, the Gellért also houses the famous spa, one of the most beautiful thermal baths in the city. As has become customary, evenings centered around food and drinks, and also music on the Friday night, which didn’t go on long enough for some people, although they might not have admitted that in the morning! Fortunately for them, things wound down the next morning and the bus took people back to Vienna, with a few groups remaining to explore more of the city’s attractions.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 88 89 Karl Landsteiner: Founder of Blood Groups as diverse chains to form polyubiquitin, the Death Receptors, composition of which can be interpreted (or In 1900, Karl Landsteiner, an Austrian decoded) by proteins known as ubiquitin binding CeMM biologist and physicist working at the Ubiquitin Editing proteins (UBPs). Ubiquitin editing involves the University of Vienna, published a short replacement of one type of polyubiquitin chain and Inflamma- with another, thus altering the protein’s function. Karl article in the Zentralblatt für Bakteriologie, Parasitenkunde und Infektionskrankheiten. some Function In parallel to the work on cell death, Dixit’s In it, he described his observation that there group also studied the molecular mechanisms of inflammation. Upon microbial infection, were individual differences in the proper- Landsteiner cells in the body respond very rapidly, which ties of human blood. In a second paper Dr. Vishva Dixit is currently vice president of suggested the presence of an intracellular detec- published a year later, Landsteiner presented Physiological Chemistry at the biotechnology tion sensor to act as an alarm system. Along with company Genentech in San Francisco. Genentech other groups, they found that these sensor Lecture the results from a study where he mixed encourages the study of basic scientific research proteins also contained specific death domains blood taken from six individuals, including and is accredited as the founder of the entire that could recognize microbial components and 4 May 2009 himself, which in certain combinations biotechnology industry. Dixit was recruited to induce the assembly of a large multiprotein Austrian Academy of Sciences, Vienna, Austria Genentech as director of the Molecular Oncology complex known as the inflammosome, thereby caused agglutination. This led to the identi- department in 1997 from the University of activating the inflammatory response. This fication of the AB blood group classification Michigan, where he had become full professor in process represents one of the first defense mecha- system in humans, for which Landsteiner 1995. Before that, Dixit began his career studying nisms of the innate immune system, and is medicine at the University of Nairobi, and he highly conserved, being found in both plants was awarded the Nobel Prize in 1930. completed his medical training at the University and animals. of Washington, where he also became a postdoc- The significance of his major discoveries toral fellow. Some of his most notable scientific Vishva Dixit made the decision to work in indus- achievements to date are within the field of cell try because it gave him the opportunity to turn are succinctly illustrated in the words death, where he characterized the molecular com- his scientific results on basic cellular mechanisms of the late Prof. Dr. Hermann Chiari, ponents of the cell death receptor pathway and into therapeutic opportunities to impact the an Austrian pathologist and previous Vice discovered new mechanistic paradigms for intrac- lives of patients. Indeed, his work on cell death is ellular signaling cascades. On May 4th 2009, in highly relevant for understanding the molecular President of the Austrian Academy of the main lecture hall of the Austrian Academy mechanisms underlying cancer cell survival. Sciences, during his speech at the opening of Sciences, Vishva Dixit took the audience on a This guiding principle, as well as the topics of his journey through his scientific discoveries. research, fit well with the mission of CeMM to of the Karl Landsteiner memorial at use basic research to pursue innovative therapeu- the University of Vienna in 1961. He said: It began in the early 1990’s, when people seemed tic approaches focused on cancer, inflammation “Wherever a blood transfusion is per- more interested in studying cell survival and and immune disorders, making him clearly a growth rather than cell death. However, today pioneer in molecular medicine as well as a highly formed in the world today, wherever a cell death is known to be a critical process suitable choice to present CeMM’s 2009 Karl worried mother’s threatened child is saved, both for the early development of an organism Landsteiner Lecture. Karl Landsteiner is virtually present”. as well as to maintain homeostasis during life. Members of a family of proteins found on the surface of cells, known as the TNFR superfamily, To honor Landsteiner’s extraordinary had been shown to induce cell death upon Dr. Vishva Dixit during his activation by extracellular signals, and were lecture presented in the achievements, CeMM established the Karl festive hall of the Austrian named death receptors. Previously, these recep- Academy of Sciences. Landsteiner Lecture series in 2007. The tors were thought to work by serving as ion speaker is selected using a structured proc- channels in the cell membrane or by regulating ess by all members of CeMM, for being a phosphorylation of target proteins. Dixit and his group found that these death receptors pioneer in molecular medicine. In 2009, induced cell death via a new signaling mecha- the honor was awarded to the Kenyan-born nism, which involved the recruitment and acti- molecular biologist, Vishva Dixit. vation of so-called death proteases.

In the process of characterizing this complex signaling cascade, involving many different Previous Awardees proteins and leading subsequently to cell death, 2008 Kári Stefánsson: “Genetics of Common Diseases in the Context of Human Diversity”. they uncovered another novel signaling mecha- 2007 John Kuriyan: “Regulatory Mechanisms in nism known as ‘ubiquitin editing’. Ubiquitin Protein Tyrosine Kinase Signaling”. is a small molecule which is attached to proteins to mediate either their degradation or to modu- late their activity. Ubiquitin can be attached

Ce — M—M— Research Report 2009 90 91 Prof. Dr. Richard Flavell The scientific presentations began on the Saturday Chairman, Section of Immunobiology, Meeting 2009 with the six Principle Investigators and two tech- Yale University School of Medicine, nical department heads introducing their research, Scientific New Haven, USA followed by discussions. The rest of the day was focused on the Postdocs and PhD students, some Prof. Dr. James D. Griffin The CeMM scientific advisory board (SAB) was of whom had been chosen to present their work Advisory Chair, Department of Medical Oncology, invited to CeMM for the second time on Friday to the SAB in ten-minute talks. Dana Farber Cancer Institute, Boston, USA November 13th 2009, for a two day meeting to give a formal appraisal of the research being The SAB deliberated their observations that Prof. Dr. Carl-Henrik Heldin conducted at CeMM as well as offering their evening and on the final morning, they provided Board Director, Ludwig Institute for Cancer support and expert guidance. This time, nine detailed feedback, first to the entire faculty of Research, Uppsala University, SE members made the journey to Vienna. They CeMM, then to the management, followed by a were David Livingston, James Griffin, Louis presentation to the Board of the Academy. In Prof. Dr. Denis Hochstrasser Staudt, Hidde Ploegh, William Paul, Richard general they were delighted with the progress Members Head, Central Clinical Chemistry Laboratory, Flavell, Denis Hochstrasser, Carl Henrik Heldin made and particularly praised the quality of the Geneva University Hospital, CH and Nadia Rosenthal. presentations by the junior members as well as the collegial and cooperative spirit. Detailed Prof. Dr. David Livingston written feedback was sent later to the Academy Deputy Director, Dana-Farber/ Board and the CeMM directors. Harvard Cancer Center, Boston, USA

Prof. Dr. William E. Paul Chief, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, USA Representatives of the CeMM Scientific Advisory Board at the Meeting in Vienna in Prof. Dr. Hidde Ploegh November 2009. Member, Whitehead Institute for Biomedical Research, Cambridge, USA

Prof. Dr. Nadia Rosenthal Head, EMBL- European Molecular Biology Laboratory, Monterotondo Outstation, Rome, I

Prof. Dr. Louis M. Staudt Head, Molecular Biology of Lymphoid Malignancies Section, National Institutes of Health, National Cancer Institute, Bethesda, USA

Dame Prof. Dr. Janet Thornton Director, European Bioinformatics Institute in Cambridge, UK Group Leader, EMBL- European Molecular Biology Laboratory, Hinxton Outstation, Cambridge, UK

The SAB and members of CeMM in the lecture room where the meeting was held.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 92 93 The 2009 CeMM Christmas Both young and old(er) Party was held at the Trummel enjoying the CeMM CeMM hofbar (a wine tavern) in the Christmas party, with food, drink and presents 18th District of Vienna. Family aplenty. and friends of CeMM were Christmas also invited to enjoy the buffet meal and appreciate some of Party the unique dancing styles that went on display later that evening. Taxis were ordered well after midnight, and partygoers traveled home accompanied by some of the first snow of the season.

Ce — M—M— Research Report 2009 94 95 “CeMM has been a dear and important project for us. I am proud of the fact that the new CeMM building is currently under construction on the premises of the General Hospital and I am sure that under the leadership of Giulio Superti-Furga, CeMM will fulfill all the expectations of the surrounding community. It is a unique and remarkable example of how different institutions can cooperate effectively if the goal is better research for the benefit of patients.” Prof. Dr. Reinhard Krepler Director of the Vienna General Hospital (AKH) A fabulous glass facade by artist Peter Kogler The New represents the interface between CeMM and the Top: city beyond. You can find out more about the The construction site in spring 2009 CeMM Building: art facade and the building inauguration in the 2010 Research Report. Bottom: CeMM construction site Ready by at the end of 2009 CeMM Building Facts: Spring 2010 The CeMM building has eight floors with a total floor space of more than 5,600 m², including a cafeteria, lecture hall, several small meeting rooms and two large terraces on the top floor The entire concrete structure of the new CeMM overlooking the city. Out of more than 3,400 m² building was completed at the beginning of 2009. of usable space, two thirds will be devoted to A nine floor-high skeleton had grown from a laboratories, which are organized as open-plan to deep hole in the ground over a period of less than encourage interactions between the different a year. The construction workers and CeMM’s groups. The whole building will provide space faculty, along with the Minister of Science and for up to 100 people. Research, Johannes Hahn, and many supporters and friends of CeMM, celebrated the topping out The building is located at the very heart of the ceremony on March 24th at the site. Vienna General Hospital (AKH), which is one of the largest general hospitals in Europe. Since then the appearance of the building has This privileged location will enable CeMM again changed dramatically and construction researchers to interact closely with clinicians work is now (as of February 2010) almost com- and the medical faculty at the Medical University plete. The outside is finished and the inside of Vienna. Crucially, the CeMM building is has been equipped with the technical infrastruc- physically linked to a new research building ture for power, computer network cabling, of the Medical University by connecting doors and air conditioning. The laboratories and offices on each floor, which is also connected to are undergoing the finishing touches before the main buildings of the hospital via an under- they can begin being furnished. The current ground corridor. rate of progress indicates that the moving date for researchers into the new building will be as planned, in June of 2010.

CeMM Principal Investigators and Minister Josef Hahn celebrate topping out

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 98 99 Management Andreas Pichlmair Philipp Meng EMBO Long-Term Fellowship MUV Giulio Superti-Furga Legend to grants Scientific Director Lily Remsing Rix° Damla Olcaydu BWK0003 PRI0001 (LLS Fellowship) Doc-fFORTE Fellowship CeMM Directory Georg Casari GEN-AU Project Administrative Director Uwe Rix Lucas Rudigier* “Austrian Proteomics Platform II” BWK0004 (GENAU DRAGON), EUP0002 (HEROIC) Gerhard Schadler BWK0004 BWK0008 (GENAU PLACEBO) Managing Director Federica Santoro GEN-AU Project “DRAGON-Drug Action Elena Rudashevskaya FWF W1207 (RNA Biology) by GenOmic Network(s)” BWK0007 (GENAU APP III) Administration Ruth Scheicher* BWK0005 Roberto Sacco Sonja Baier Basak Senergin GEN-AU Project BWK0007 (GENAU APP III) Assistant FWF F1718 “Epigenetic regulation of Omar Sharif cell fate decisions” Angelika Eisner Dimitris Tsiantoulas Assistant Stefanie Sigel FFG BRIDGE 815446 BWK0006 GEN-AU Project FWF I289-B09 Anita Ender Iris Uras “BIN III-Bioinformatics Scientific Office & Human Resources Mathew Sloane Integration Network“ Irena Vlatkovic Verena Lichtenegger Alexey Stukalov EUP0002 (HEROIC) BWK0007 Assistant BWK0006 (GENAU BIN III) GEN-AU Project Joanna Warszawska „APP III-Austrian Leopold Liechtenstein* Sandrine Tonon Proteomics Platform” David Weismann Public Relations & Sponsoring FFG BRIDGE 815446 BWK0008 Edith Müller-Primeßnig PhD and Diploma Students GEN-AU Project Georg Winter Finance & Controlling “PLACEBO-Platform Austria Shazada Amir BWK0004 (GENAU DRAGON) for Chemical Biology” Michael Pilz KIMCL-MUV/FWF CCHD Ana Zivkovic IT Administrator EUP0002 Irene Aspalter* EU Project “HEROIC-

Simone Duve* HighthroughputEpigenetic Diego Barcena Technical Assistants Public Relations & Sponsoring Regulatory Organisation Mario Biaggio Tiina Berg In Chromatin” Gabriel Ó Ríordáin MUV Scientific Support Romana Bittner EUP0004 Marie Curie Fellowship Marc Jochen Brehme* FWF F1718 “Dissecting pathogen recognition FWF P18737 Principal Investigators Florian Breitwieser complexes of Toll-like receptors” Larissa Cardilo dos Reis Denise Barlow Manuela Bruckner FFG 815446 KIMCL-MUV/GENAU DRAGON BRIDGE Programme Christoph Binder Bianca Doninger Evelyn Dixit “Microparticles and novel therapeutic approaches for thrombosis” Sylvia Knapp FWF W1205 (CCHD) Nora Fernbach* BWK0004 (GENAU DRAGON) Foundation Leducq Robert Kralovics Gerhard Dürnberger Transatlantic Network of MPD New Investigator Award Ruth Fuchs Immanuel Elbau Excellence “Immune Modulation Sebastian Nijman MUV Laura Göderle of Cardiovascular Disease” KIMCL-MUV Giulio Superti-Furga Patricia Ganger* FWF P18737 FWF Project “Physical Manuela Gridling Emanuel Gasser* and Functional Map of Department Heads Simon Hör Bcr-Abl Signalling” Riem Gawish Keiryn Bennett MUV Ines Kaupe FWF P20033 BWK0003 (GENAU APP II) FWF Project Jacques Colinge Roberto Giambruno “Genetic basis of BWK0003 (GENAU APP II) Maria Ozsvar-Kozma myeloproliferate disorders” Adriana Goncalves KIMCL-MUV/Leducq FWF F1718 Philipp Günzl Postdoctoral Fellows Cristina Melinte FWF Special Research EUP0002 (HEROIC) Program “Modulators of Christoph Baumann André Müller Ashot Harutyunyan RNA Fate and Function” EUP0004 FWF P20033 (Marie Curie Fellowship) Nils Craig-Müller FWF W1205 FWF Doctoral Program Ru Huang Stephan Blüml* Katja Parapatics “CCHD-Cell Communication EUP0002 (HEROIC) MUV-CeMM MUV in Health and Disease” Stephan Hütter Viola Borgdorff Melanie Planyavsky FWF W1207 EUP0002 (HEROIC) MUV-CeMM Adrijana Stefanovic FWF Doctoral Program “RNA Biology” Roland Jäger FWF I289-B11 Tilmann Bürckstümmer Karin Stich FWF P20033 FWF International Project Thomas Burkard MUV “Innate immune responses to Evren Karayel Streptococcus pneumoniae” Florian Grebien FWF W1205 (CCHD) Norbert Venturini Katarzyna Warczok° FWF 18232-B11 Oliver Hantschel Thorsten Klampfl FWF Project FWF P18737 Martha Körner “Immunodulatory role of oxidized phospholipids” Quanah Hudson EUP0002 (HEROIC) * left CeMM in 2009 EUP0002 (HEROIC) PRI0001 Tomasz Kulinski ° maternity leave Fellowship of the Markus Müllner EUP0002 (HEROIC) Armenia, Australia, Austria, Belgium, American Leukemia and Brazil, China, Czech Republic, Finland, Florian Pauler Thomas List Lymphoma Society BWK0005 (GENAU EPI III) France, Germany, Greece, Ireland, Italy, Ulrich Matt* Doc-fFORTE Fellowship Liechtenstein, Mexico, New Zealand, FWF P18232-B11 Austrian Academy of Sciences EMBO Long-Term Fellowship Pakistan, Poland, Portugal, Romania, European Molecular Biology Russia, Serbia/Montenegro, Spain, Organization Switzerland, The Netherlands, Turkey, MPD New Investigator Award United Kingdom, USA American MPD Foundation 28 Nationalities Ce — M—M— Research Report 2009 100 101

Fernbach NV, Planyavsky M, Müller A, Latos PA, Stricker SH, Steenpass L, Pauler FM, Remsing Rix LL, Rix U, Colinge J, Hantschel O, Publications by Breitwieser FP, Colinge J, Rix U, Bennett KL. Acid Huang R, Senergin BH, Regha K, Koerner MV, Bennett KL, Stranzl T, Müller A, Baumgartner elution and one-dimensional shotgun analysis on Warczok KE, Unger C, Barlow DP. An in vitro C, Valent P, Augustin M, Till JH, Superti-Furga CeMM Scientists an orbitrap mass spectrometer – an application ES cell imprinting model shows that imprinted G. Global target profile of the kinase inhibitor to drug affinity chromatography.J Proteome Res, expression of the Igf2r gene arises from an allele- bosutinib in primary chronic myeloid leukemia in 2009 2009 Oct;8(10):4753-65. specific expression bias.Development , 2009 cells. Leukemia, 2009 Mar;23(3):477-85. Feb;136(3):437-48 (Featured article). Gröger M, Pasteiner W, Ignatyev G, Matt U, Rix U, Remsing Rix LL, Terker AS, Fernbach Knapp S, Atrasheuskaya A, Bukin E, Friedl P, Lutz HU, Binder CJ, Kaveri S. Naturally occur- NV, Hantschel O, Planyavsky M, Breitwieser FP, Zinkl D, Hofer-Warbinek R, Zacharowski K, ring auto-antibodies in homeostasis and disease. Herrmann H, Colinge H, Bennett KL, Augustin Aebersold R, Auffray C, ..., Superti-Furga G, Petzelbauer P, Reingruber S. Peptide Bbeta (15-42) Trends Immunol, 2009 Jan;30(1):43-51. M, Till JH, Heinrich MC, Valent P, Superti-Furga et al. Report on EU-USA workshop: how preserves endothelial barrier function in shock. G. A comprehensive target selectivity survey systems biology can advance cancer research. Matt U, Warszawska JM, Bauer M, Dietl W, PLoS ONE, 2009;4(4): e5391. Epub 2009 Apr 29. of the BCR-ABL kinase inhibitor INNO-406 Mol Oncol, 2009 Feb;3(1):9-17. Mesteri I, Haslinger I, Schabbauer G, Perkmann by kinase profiling and chemical proteomics in Habjan M, Pichlmair A, Elliott RM, Overby AK, T, Binder CJ, Reingruber S, Petzelbauer P, Knapp Amir S, Binder CJ. Experimental immuno chronic myeloid leukemia cells. Leukemia, Glatter T, Gstaiger M, Superti-Furga G, Unger S. B15-42 protects against acid-induced acute therapeutic approaches for atherosclerosis. Epub 2009 Nov 5. H, Weber F. NSs protein of rift valley fever virus lung injury and secondary Pseudomonas pneu- Clin Immunol, Epub 2009 Aug 8. induces the specific degradation of the double- monia in vivo. Am J Respir Crit Care Med, 2009 Rix U, Superti-Furga G. Target profiling of Barlow DP. Non-coding RNAs: A higher level stranded RNA-dependent protein kinase. J Virol, Dec;180(12):1208-17. Epub 2009 Sep 17. small molecules by chemical proteomics. of genome encoded information. RNA Biol, 2009 May;83(9):4365-75. Epub 2009 Feb 11. Nat Chem Biol, 2009 Sep;5(9):616-24. Moser C, Pohl G, Haslinger I, Knapp S, 2009 Apr;6(2):93. Editorial. Hartvigsen K, Chou MY, Hansen LF, Shaw PX, Rowczenio D, Russel T, Lachmann HJ, Lang Schaub FX, Jäger R, Looser R, Hao-Shen H, Bochkov VN, Oskolkova OV, Birukov KG, Tsimikas S, Binder CJ, Witztum JL. The role of U, Kovarik J. Successful treatment of familial Hermouet S, Girodon F, Tichelli A, Gisslinger Levonen AL, Binder CJ, Stöckl J. Generation and innate immunity in atherogenesis. J Lipid Res, Mediterranean fever with Anakinra and outcome H, Kralovics R, Skoda RC. Clonal analysis of biological activities of oxidized phospholipids. 2009 Apr;50 Suppl:S388-93. after renal transplantation. Nephrol Dial Trans- deletions on chromosome 20q and JAK2-V617F Antioxid Redox Signal, Epub 2009 Aug 17. plant, 2009 Feb;24(2):676-8. in MPD suggests that del20q acts independently Hoshida Y, Nijman SM, Kobayashi M, Chan JA, and is not one of the predisposing mutations Brehme M, Hantschel O, Colinge J, Kaupe I, Plan- Brunet JP, Chiang DY, Villanueva A, Newell P, Olcaydu D, Harutyunyan A, Jäger R, Berg T, for JAK2-V617F. Blood, 2009 Feb;113(9):2022-7. yavsky M, Köcher T, Mechtler K, Bennett KL, Ikeda K, Hashimoto M, Watanabe G, Gabriel Gisslinger B, Pabinger I, Gisslinger H, Kralovics Superti-Furga G. Charting the molecular network S, Friedman SL, Kumada H, Llovet JM, Golub R. A common JAK2 haplotype confers suscepti- Schwartz-Albiez R, Monteiro RC, Rodriguez M, of the drug target Bcr-Abl. Proc Natl Acad Sci USA, TR. Integrative transcriptome analysis reveals bility to myeloproliferative neoplasms. Nature Binder CJ, Shoenfeld Y. Natural antibodies, 2009 May 5;106(18): 7414-9. Epub 2009 Apr 20. common molecular subclasses of human hepa- Genetics, 2009 41(4):450-4. Epub 2009 Mar 15. intravenous immunoglobulin and their role tocellular carcinoma. Cancer Res, 2009 Sep 15; in autoimmunity, cancer and inflammation. Brehme M. Intercell – accelerating innovation. Olcaydu D, Skoda RC, Looser R, Li S, Cazzola 69(18):7385-92. Epub 2009 Sep 1. Clin Exp Immunol, 2009 Dec;158 Suppl 1:43-50. N Biotechnol, 2009 Apr;25(4):181-4. Epub 2009 M, Pietra D, Passamonti F, Lippert E, Carillo S, Feb 21. Karayel E, Bürckstümmer T, Weitzer S, Girodon F, Vannucchi A, Reading NS, Prchal JT Sillaber C, Herrmann H, Bennett K, Rix U, Martinez J, Superti-Furga G. The TLR- Ay C, Pabinger I, Gisslinger H, Kralovics R. The Baumgartner C, Böhm A, Herndlhofer S, Bürckstümmer T, Baumann C, Blüml S, Dixit independent DNA recognition pathway GGCC haplotype of JAK2 confers susceptibility Tschachler E, Superti-Furga G, Jäger U, Valent P. E, Dürnberger G, Jahn H, Planyavsky M, Bilban in murine macrophages: Ligand features and to JAK2 exon 12 mutation positive polycythemia Immunosuppression and atypical infections in M, Colinge J, Bennett KL, Superti-Furga G. molecular signature. Eur J Immunol, 2009 vera. Leukemia, 2009 Oct;23(10):1924-6. Epub CML patients treated with dasatinib at 140 mg An orthogonal proteomic-genomic screen Jul;39(7):1929-36. 2009 May 14. daily. Eur J Clin Invest, 2009 Dec;39(12): identifies AIM2 as a cytoplasmic DNA sensor 1098-109. for the inflammasome.Nat Immunol, 2009 Kelly JA, Griffin ME, Fava RA, Wood SG, Pauler FM, Sloane MA, Huang R, Regha K, Mar;10(3):266-72. Epub 2009 Jan 21. Bessette KA, Miller ER, Huber SA, Binder CJ, Koerner MV, Tamir I, Sommer A, Aszodi A, Superti-Furga G. A biomedical adventurers’ Witztum JL, Morganelli PM. Inhibition of arte- Jenuwein T, Barlow DP. H3K27me3 forms BLOCs guide to navigating between careers in academia Buxhofer-Ausch V, Gisslinger H, Berg T, rial lesion progression in CD16-deficient mice: over silent genes and intergenic regions and and industry. Nat Rev Mol Cell Biol, Gisslinger B, Kralovics R. Acquired resistance evidence for altered immunity and the role of specifies a histone banding pattern on a mouse 2009 Dec;10(12):884-7. to interferon alpha therapy associated with IL-10. Cardiovasc Res, Epub 2009 Sep 19. autosomal chromosome. Genome Res, 2009 homozygous MPL-W515L mutation and chromo- von Schlieffen E, Oskolkova OV, Schabbauer G, Feb;19(2):221-33. some 20q deletion in primary myelofibrosis. Koerner MV, Pauler FM, Huang R, Barlow DP. Gruber F, Blüml S, Genest M, Kadl A, Marsik C, Eur J Haematol, 2009 Feb;82(2):161-3. The function of non-coding RNAs in genomic Perne A, Muellner MK, Steinrueck M, Knapp S, Chow J, Leitinger N, Binder BR, imprinting. Development, 2009 Jun;136(11): Craig-Mueller N, Mayerhofer J, Schwarzinger Bochkov VN. Multi-hit inhibition of circulating Chou MY, Fogelstrand L, Hartvigsen K, Hansen 1771-83. I, Sloane M, Uras IZ, Hoermann G, Nijman and cell-associated components of the toll-like LF, Woelkers D, Shaw PX, Choi J, Perkmann T, SM, Mayerhofer M. Cardiac glycosides induce receptor 4 pathway by oxidized phospholipids. Bäckhed F, Miller YI, Hörkkö S, Corr M, Witztum Lagler H, Sharif O, Haslinger I, Matt U, Stich K, cell death in human cells by inhibiting general Arterioscler Thromb Vasc Biol, 2009 Mar; JL, Binder CJ. Oxidation-specific epitopes are Furtner T, Doninger B, Schmid K, Gattringer R, protein synthesis. PLoS One, 2009 Dec 16; 29(3):356-62. Epub 2008 Dec 26. dominant targets of innate natural antibodies de Vos AF, Knapp S. TREM-1 activation alters the 4(12):e8292. in mice and humans. J Clin Invest, 2009 dynamics of pulmonary IRAK-M expression in Winger JA, Hantschel O, Superti-Furga G, May;119(5):1335-49. Epub 2009 Apr 13. vivo and improves host defense during pneumo- Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kuriyan J. The structure of the leukemia drug coccal pneumonia. J Immunol, 2009 Aug;183(3): Kato H, Takeuchi O, Akira S, Way M, Schiavo G, imatinib bound to human quinine reductase 2027-36. Epub 2009 Jul 13. Reis e Sousa C. Activation of MDA5 requires 2 (NQO2). BMC Struct Biol, 2009 Feb;9:7. higher-order RNA structures generated during Latos PA, Barlow DP. Regulation of imprinted virus infection. J Virol, 2009 Oct;83(20):10761-9. expression by macro non-coding RNAs. RNA Epub 2009 Aug 5. Biol, 2009 Apr;6(2):100-6. Epub 2009 Apr 14.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 104 105 Finland 1

The Netherlands Ireland Poland 1 2 3

2 Russia 1 Germany 2 11 USA Czech Republic 2 Belgium 1

United Kingdom 1 France 2 China 1 Mexico 1 1 Austria 49 1 Romania Spain 1 Portugal 1 1 Liechtenstein 2 Armenia Brazil 1 Greece Italy Switzerland 1 5 Turkey 1 4

New Zealand Serbia/Montenegro Pakistan 1

Australia

The CeMM administration CeMM Staff is very lean in relation to the CeMM total staff (98 employees Listed by number of persons per field of work as of December 2009). We have a good gender balance. The average age Facts & Figures at CeMM is 30.5 years. Management 3 persons 3.06% of total staff

Lab Heads 8 persons 8.16% of total staff

Administration 9 persons 9.18% of total staff 37

Diploma Students 33 11 persons 11.22% of total staff

Postdoctoral Fellows 23 20 persons 20.41% of total staff

14 Technical Assistants 21 persons 21.43% of total staff

3 PhD Students 27 persons 27.55% of total staff 2005 2006 2007 2008 2009

¤ 483,503 Federal Ministry of Science and Research (Bund)

Consumables 18% ¤ 278,796 Austrian Science Foundation (FWF)

¤ 238,685 European Union Projects

Thir ¤ 64,800 Vienna Science and Technology Fund (WWTF) d-P Investments 13% ¤ ar ¤ 60,343 Companies 1, ty ¤ 47,287 Sponsors Facade Peter Kogler 18 F Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 106 107 3, u ¤ 10,130 Sponsoring 54 n Personnel 53% 4 d s ¤ 5,200,000 Austrian Academy of Sciences Facility Costs 9%

Other Costs 7% Finland 1

The Netherlands Ireland Poland 1 2 3

2 Russia 1 Germany 2 11 USA Czech Republic 2 Belgium 1

United Kingdom 1 France 2 China 1 Mexico 1 1 Austria 49 1 Romania Spain 1 Portugal 1 1 Liechtenstein 2 Armenia Brazil 1 Greece Italy Switzerland 1 5 Turkey 1 4

New Zealand Serbia/Montenegro Pakistan 1

Australia

Finland Ireland 1 1 USA The Netherlands 2 2 2 1 Poland 1 3 Mexico United Kingdom Germany Belgium 11

France 2 Czech Republic 1 1 Russia 1 1 Portugal 2 Brazil Spain 1 Austria 49 Liechtenstein 1

Romania Switzerland 1 China Italy 1 5 2

Greece 1 Armenia Serbia/Montenegro 1 Turkey 4 Management 1 3 persons 3.06% of total staff Pakistan

New Zealand 1 Lab Heads 8 persons 8.16% of total staff 2

Australia Administration 9 persons 9.18% of total staff 37

Diploma Students 33 11 persons 11.22% of total staff

Finland Postdoctoral Fellows 23 1 20 persons 20.41% of total staff

14 Technical Assistants Ireland The Netherlands 21 persons Poland 21.43% of total staff 1 2 3 3 2 Russia PhD Students 1 Germany 2 27 persons 11 27.55% of total staff 2005 2006 2007 2008 2009 USA Czech Republic 2 Belgium 1 Management United Kingdom 3 persons France 1 3.06% of total staff 2 China 1 Mexico 1 1 Austria 49 1 Romania Lab Heads Spain 1 Portugal 8 persons 1 8.16% of total staff 1 Liechtenstein 2 Armenia Brazil 1 Greece Administration Italy 1 Switzerland 5 Turkey 9 persons 1 9.18% of total staff 4

New Zealand Serbia/Montenegro Pakistan 1 Diploma Students 11 persons 11.22% of total staff 28 different nationalities2 are represented at CeMM. The international atmos- Nationalities at CeMM Expenses in 2009 phere spurs ideas and Australia enables scientists to find varied approaches to problems. Finland Postdoctoral Fellows ¤ 483,503 Federal Ministry of Science and Research (Bund) 1 20 persons 20.41% of total staff Consumables 18% ¤ 278,796 Austrian Science Foundation (FWF)

Technical Assistants The Netherlands Ireland Poland 21 persons 1 2 3 21.43% of total staff ¤ 238,685 European Union Projects

Russia T ¤ 64,800 Vienna Science and Technology Fund (WWTF) 2 hird 1 Germany 2 Investments 13% -Pa ¤ 60,343 Companies ¤ 1 rt 11 ,18 y ¤ 47,287 Sponsors Facade Peter Kogler USA 3 Fu Czech Republic ,5 n ¤ 10,130 Sponsoring PhD Students 33 37 4 d 2 Belgium 1 Personnel 53% 4 27 persons s United Kingdom 27.55% of total staff 1 France 23 ¤ 5,200,000 Austrian Academy of Sciences 2 China 1 14 Facility Costs 9% Mexico 1 1 Austria 49 1 Romania 3 Other Costs 7% Spain 1 Portugal 1 1 2005 2 Armenia Liechtenstein 2006 Brazil 1 Greece Italy 2007 Switzerland 1 5 Turkey 1 4 2008 2009

New Zealand Serbia/Montenegro Pakistan 1

Consumables 18% 2 CeMM Grant Money in 2009

Personnel 53% Australia Management 3 persons 3.06% of total staff

Investments 13% Lab Heads 8 persons The number of scientific 8.16% of total staff publications at CeMM is still increasing year CeMM Publications on year, a sign of the Administration consistent development Facility Costs 9% 9 persons of the institute. 9.18% of total staff IncludesOther Costs7% all publications by CeMM staff members 37 from the date of joining Diploma Students 33 11 persons the institute. ¤ 483,503 Federal Ministry of Science and Research (Bund) 11.22% of total staff

Postdoctoral Fellows 23 20 persons ¤ 278,796 Austrian Science Foundation (FWF) 20.41% of total staff

14 T hi rd Technical Assistants ¤ - 1 P ¤ 238,685 European Union Projects 21 persons , a 1 rt 21.43% of total staff 8 y 3 , F 5 u 4 n ¤ 64,800 Vienna Science and Technology Fund (WWTF) 3 4 d s PhD Students ¤ 60,343 Companies 27 persons ¤ 47,287 Sponsors Facade Peter Kogler 27.55% of total staff 2005 2006 2007 2008 2009 ¤ 10,130 Sponsoring

¤ 5,200,000 Ce — MM — — Research Report 2009 Austrian Academy of Sciences 108 109

Management 3 persons 3.06% of total staff

Lab Heads 8 persons 8.16% of total staff

Administration 9 persons 9.18% of total staff 37

Diploma Students 33 11 persons 11.22% of total staff

23 Postdoctoral ¤Fellows 483,503 Federal Ministry of Science and Research (Bund) 20 persons 20.41% of total staff Consumables 18% ¤ 278,796 Austrian Science Foundation (FWF) 14 Technical Assistants 21 persons 21.43% of total staff ¤ 238,685 European Union Projects

3 Thir PhD Students ¤ 64,800 Vienna Science and Technology Fund (WWTF) d-P Investments 13% ¤ ar 27 persons ¤ 60,343 Companies 1, ty ¤ 47,287 Sponsors Facade Peter Kogler 18 F 27.55% of total staff 2005 2006 2007 2008 2009 3, u ¤ 10,130 Sponsoring 54 n Personnel 53% 4 d s ¤ 5,200,000 Austrian Academy of Sciences Facility Costs 9%

Other Costs 7%

¤ 483,503 Federal Ministry of Science and Research (Bund)

Consumables 18% ¤ 278,796 Austrian Science Foundation (FWF)

¤ 238,685 European Union Projects

Thir ¤ 64,800 Vienna Science and Technology Fund (WWTF) d-P Investments 13% ¤ ar ¤ 60,343 Companies 1, ty ¤ 47,287 Sponsors Facade Peter Kogler 18 F 3, u ¤ 10,130 Sponsoring 54 n Personnel 53% 4 d s ¤ 5,200,000 Austrian Academy of Sciences Facility Costs 9%

Other Costs 7% CeMM can be considered a People’s Biotech Company that is predominantly CeMM run by tax money. But maybe you wish to invest in CeMM on top of that. Therefore, Health we are issuing symbolic CeMM Health Research Bonds that you can purchase by donation. The bonds stand for our deal Research with society: You support us with these bonds and we do everything we can to advance knowledge about the molecular Bond basis of disease and to identify innovative therapeutic and diagnostic options. If you think that the research into future med icines should not be left entirely in the hands of businesses, then these bonds are for you. If you think that society needs to take a better informed and more active role in the health management options of the future, then these bonds are for you. If you think that knowledge is our biggest asset for the future, then these bonds are for you.

For your donation you will receive a symbolic paper CeMM Health Research Bond certificate, that you can treasure or give as a gift. Contact anybody at CeMM or directly at [email protected].

Our bank details are the following Bank Austria, bank number: 11000 Account number: 01270418500 IBAN: AT561100001270418500 BIC/SWIFT: BKAUATWW For: CeMM Bond (Verwendungszweck: CeMM Bond)

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 111 111 There are many different opportunities to fund the new center. You can give your name to the whole center, to individual halls or support specific research Lecture Hall programs or individuals.

Drug Screening Center Laboratory of Medical Genomics

Postdoctoral Fellowship Principal Investigator

Laboratory of Biomedical Informatics

Center of Molecular Medicine

Ce — MM — — Research Report 2009 Ce — M—M— Research Report 2009 Antigen Chronic Myelogenous Histones Malignant Tumor Proteins Glossary A molecule capable of being Leukemia (CML) A class of proteins that bind A tumor capable of invading Organic molecules consisting of recognized by an antibody, A cancer of white blood cells and wrap up extended DNA other tissues. a chain of amino acids that are of Molecular triggering an adaptive immune characterized by uncontrolled molecules to form chromo- encoded by genes and perform response. growth of cells in the bone somes. Mass Spectrometry diverse cellular and extracellular Medicine marrow. An analytical technique to functions. Atherosclerosis Homeostasis determine the elemental A medical condition involving Cytokine The natural balance of a composition of a biological Proteome thickening of the artery wall, A group of signaling molecules biological system or organism. sample. The entire protein content of a which can lead to a variety of secreted by cells of the immune biological system such as a cell serious diseases such as heart system to communicate with Imatinib Molecular Medicine or organism. attack and stroke. other cells. A drug used to treat chronic A field of study integrating myelogenous leukemia. basic research with clinical Proteomics Bioinformatics DNA investigation. The study of the protein The application of information Deoxyribonucleic acid. A self- Immune System products of a biological system. technology, computer science, replicating chemical structure A group of cells and molecules Mutation and mathematics to the field found in all cells that carries within an organism that A chemical change in DNA, RNA of biology. the genetic information to protects against disease and which can lead to the Ribonucleic acid. A chemical specify life. damage. expression of abnormal structure found in most cells Biological System proteins. that can function in diverse pro- A group of multiple biological Drug Imprinting cesses, or be translated to make components, such as proteins A chemical substance that can The expression of certain genes Myeloproliferative Neoplasms protein. or cells, which can be on many affect the function of a cell. in a parent-of-origin specific A group of diseases of the different levels such as molecu- manner. bone marrow characterized Synthetic Lethality lar or organismal. Drug Resistance by chronic hyperproliferation A process that occurs when loss The ability of cells and organ- Inflammation of blood cells. of function of two genes causes Blood Malignancies isms to become insensitive to A biological response to disease cell death, whereas loss of each A form of cancer characterized the action of a specific drug. or damage, involving a variety Natural Antibodies gene individually does not. by uncontrolled proliferation of cells and proteins, and Type of antibody present from of one of the diverse types of Endosome characterized by swelling, birth and not produced in Transcriptome blood cells. A membrane-enclosed redness and pain. response to infection. All the RNA molecules that are structure that transports produced by the genome in a Cardiac Glycosides molecules inside cells. Innate Immunity Oncogene biological system such as a A group of drugs related to A branch of the immune system A gene that has been mutated group of cells, a tissue, or an Digitalis, a molecule derived Epigenetics found in plants and animals or is expressed at high levels, entire organism. from the Foxglove plant, used Heritable changes in genome comprising various cell-types which causes cancer. to treat chronic heart failure. function that occur without that respond non-specifically Toll-Like Receptors alterations in DNA sequence. to infection. Oxidative Stress A class of pattern recognition Cancer A usually harmful situation receptors that recognize A group of diseases caused Genomics Interferon caused by abnormally high pathogen-associated molecular by uncontrolled cell growth The study of the entire DNA A type of cytokine. levels of reactive oxygen patterns and trigger an immune usually associated with invasion sequence (genome) of an species. response. into healthy tissue, which is organism. Leukemia often life threatening. A cancer of the bone marrow or Pathogen Tyrosine Kinase Genotyping blood, characterized by uncon- An infectious agent such as An enzyme that can transfer Chemical Proteomics Determining the DNA trolled growth of blood cells. a virus or bacteria that causes a phosphate group onto a The study of the physical sequence at a specific position disease. tyrosine amino acid residue on interaction between drugs on one chromosome pair. Macrophage a target protein, thus modifying and cellular proteins. A type of tissue immune cell Pattern Recognition Receptors its function. Gene that engulfs pathogens and Proteins commonly found on Chromosome A functional unit of heredity stimulates an immune the surface of cells that recog- Tumor Suppressor Gene A dense physical structure found in the genome encoded response. nize pathogen-associated A gene that normally protects found in cells made up of DNA by DNA. molecular patterns and trigger cells from becoming cancerous. and proteins. Human cells Macro Non-Coding RNAs an immune response. Mutation or loss of expression contain 23 pairs of chromo- Gene Expression A class of long non-protein- of a tumor suppressor gene can somes, so that each gene is Generation of a functional coding RNAs. Pneumonia cause cancer. present in two copies. product from a gene. An inflammatory disease of the lungs caused particularly by Genetics infection by pathogens. The study of genes.

Ce — M—M— Research Report 2009 Ce — M—M— Research Report 2009 114 115 These are our supporters of the last years’ Research Reports. From top left to bottom right:

Dr. Heinz Fischer President of the Austrian Republic

Prof. Dr. Peter Schuster President of the Austrian Academy of Sciences

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

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

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

Dr. Johannes Hahn Federal Minister for Science and Research

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

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

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

Dr. Michael Häupl Mayor of the City of Vienna

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

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

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

Ce — M—M— Research Report 2009 116 117 If you want information about Copyrights Acknowledgements Herbert Matis, Marjori Matzke, what CeMM worked on © CeMM – Research Center for Ruedi Aebersold, Leonidas Thomas Mayer, Karl Mechtler, in 2007/08 you can order our Molecular Medicine of the Alexopoulos, Zoran Almanzan, Ricardo Medda, Jürgen Meier, previous Research Reports: Austrian Academy of Sciences Stefan Amatschek, Gustav Ammerer, Junia Melo, Siegfried Meryn, Lazarettgasse 19/3 Thomas Angyan, Mehran Ansari, Simone Mesner, Franziska Michor, Anita Ender A — 1090 Vienna Georg Anzenberger, Christian Michael Micksche, Martina Milletich, CeMM – Research Center for www.cemm.at Arthaber, Johanna Awad-Geissler, Evelyn Missbach, Ortrun Mittelsten Molecular Medicine of the Thomas Bahnasy, Christian Balluch, Scheid, Wolfgang Mlecnik, Shabaz Austrian Academy of Sciences Gerhard Bauer, Hemma Bauer, Mohammed, Maria Magdalena [email protected] Marianne Baumgart, Walter Berger, Mosgan, Markus Müller, Mathias Lazarettgasse 19/3 Hartmut Beug, Martin Bilban, Bernd Müller, Otto Müller, Alexander A—1090 Vienna Overall responsibility and Christa Binder, Max and Margaret Nagler, Dario Neri, Gabriele Nestyak, Tel +43-1/40160-70011 for content Birnstiel, John Bohannon, Martin Gerhard Nicko, Waltraud and Fax +43-1/40160-9700 00 Giulio Superti-Furga, PhD and Lucrezia Böhm, Stefan Böhm, Laurenz Niel, Harald Niessner, Günther Bonn, Rolf Breinbauer, Christian Noe, Christian Nordberg, Editor Eva Bruckner, Thijn Brummelkamp, Magnus Nordborg, Helga Nowotny, Gabriel Ó Ríordáin, PhD www.cemm.at Research Report 2007 Herbert Burger, Eugene Burns, Luke O’Neill, Peter Obitsch, Primus [email protected] Erhard Busek, Meinrad and Irene and Katharina Österreicher, Markus Scientific Writer Busslinger, Adrian Csik, Peter Otte, Markus Pasterk, William E. Paul, Helen Pickersgill, PhD Csukovits, Birgit Dalheimer, David de Peter Pauletta, Tony Pawson, [email protected] Graaf, Rainer de Martin, Jan de Vries, Josef Penninger, Jan-Michael Peters, www.helenpickersgill.com Thomas Decker, Helmut and Helga Anna Peutl, Helen Pickersgill, Art Direction and Design Denk, Barry Dickson, Vishva Dixit, Hidde Ploegh, Katharina Pluner, Lichtwitz Leinfellner Benjamin Ebert, Gerhard Ecker, Bernhard Plunger, Lisa Pock, visuelle Kultur KG Adelheid Elbe-Bürger, Wilfried Elisabeth and Helmut Pockberger, www.lichtwitz-leinfellner.com Ellmeier, Traudl Engelhorn, Arnold Pollak, Maria Polsterer- Heinz Engl, Ernst Ennsbrunner, Kattus, Marianne Pöschko- Photography Michelle Epstein, Harald Esterbauer, Laczkovics, Barbara Prammer, Michael Sazel Katja Fiala, Heinz and Margit Fischer, Georg and Martina Prantl, Andrea Cover, Inside Front and Back Maximilian Fischer, Richard Flavell, Raffaseder, Roberto Raggiaschi, Cover, Back Cover,p. 2—5, p. 8–14, Nicole Föger, Brian Foxwell, Michael Meinhard Rauchensteiner,

Ce — M —M — Research Report 2007 —M M — Ce p. 18-23, p. 32—33, p. 40—43, and Margarita Freissmuth, Herwig Mehrnoosh Rayner, Gerda Redl, p. 52—55, p. 62—63, p. 94—95, Friesinger, Michael Füchsl, Helmut Kurt Redlich, Markus Reicher, p. 114—115, p. 116 Gadner, Christoph Gasche, Anne- Caetano Reis e Sousa, Georg Research Report 2008 Alessandra Meier Claude Gavin, Manfred Gengler, Reithofer, Ingrid Riedel-Taschner, p. 30—31 Edith Gindel, Claudia Greiner, Patricia Rodriguez-Tomé, Artur Markus Grimm, James D. Griffin, Rosenauer, Nadia Rosenthal, Walter Photos of Statues kindly Frank Grosveld, Beatrix Grubeck- Rosenthal, Antal Rot, Michael Sazel, provided by the Austrian Loebenstein, Matthias Gstaiger, Clemens Scheinecker, Otto Scheiner, Academy of Sciences, p. 16–17 Alexander Habsburg-Lothringen, Katharina Schendl, Ursula Schmidt- All other photos by CeMM Karin Hagenbichler, Johannes Hahn, Erfurth, Maria Schreiber, Brigitte Haidl, Bernhard Hain, Rene Schröder, Marietta Schupp, Rendering of the Barbara Hamilton, Julia Harlfinger, Peter Schuster, Eveline Schütz, New CeMM Building Michael Häupl, Harald zur Hausen, Wolfgang Schütz, Reinhard Kopper Architektur Heike Heidemann, Claudia Heilmann- Schwarz, Dieter Schweitzer, p. 102—103 Sennhenn, Katharina Heiss- Veronika Sexl, Jörg Simonitsch, Print Kienberger, Carl-Henrik Heldin, Andrej Shevchenko, Maria Sibilia, Holzhausen Wien Markus Hengstschläger, Adriano Werner Sieghart, Angela Siegling, Henney, Wilhelm Henrich, Thomas Maria Siomos, Uwe Sleytr, Josef Paper Henzinger, Christian J. Herold, Smolen, Hans-Joachim Sorger, Peter Plano Art 115 g Gottfried Himmler, Elisabeth Soswinski, Didier Soulat, Beatrix and Invercote 300 g Hochleitner, Denis Hochstrasser, Benedikt Spiegelfeld, Massimo Fonts Erhard Hofer, Astrid Hofstätter, Spinetti, Holger Stalz, Andreas Sys Martin Hohenegger, Eveline Stampfer, Michael Stampfer, Edda DTL Documenta Holzmeier, Nina Hoppe, Veit Hornung, Starzer, Louis Staudt, Georg Stingl, Lukas Huber, Ylva Huber, Liu Huchi, Hannes Stockinger, Doris Stolz, Heidemarie Hurtl, Monika Hutter, Franz Strasser, Marina Strasser, Harald Isemann, Sigrid Jalkotzy- Sepp Strasser, Erich Streissler, Deger, Ulrich Jäger, Erika Jensen- Herbert Strobl, Thomas Stulnig, Jarolim, Luzi Josipovic, Veronika Marius Sudol, Arnold Suppan, Josipovic, Michael Kadensky, Martin Stefanie Superti-Furga, Peter Swetly, Kaftan, Beatrix Karl, Oliver Kemper, Witold and Claudia Szymanski, Bernhard Keppler, Dontscho Tada Taniguchi, Alexandra Thausing, Kerjaschki, Michael Kiebler, Hans Elisabeth Tischelmayer, Alfred Kiener, Markus Kiess, Melitta Totzler, Zlatko Trajanoski, Kimbacher, Michael Kneidinger, Peter Walter Troger, Hans Tuppy, and Tanja Kogler, Ernst M. Kopper, Jasmin Turtenwald, Katharina Gottfried Koos, Guido Korlath, Untertrifaller, Iris, Zambak and Barbara Kornmüller, Ursula Kosir, Abdurrahman Uras, Peter Valent, Heinrich Kovar, Peter Kowalski, Marc Vidal, Alexander von Gabain, Robert Krapfenbauer, Christoph Manfred Vogl, Sasha Vukovic, Erwin Kratky, Christian Krebs, Michael Krebs, Wagner, Oswald Wagner, Stephan Reinhard Krepler, Ernst Kriehuber, Wagner, Christian Wanzenböck, Dragan Krstic, Stefan Kubicek, Christian Wappel, Ernst Wastler, John Kuriyan, Hans Lassmann, Herbert Watzke, Elisabeth Klaus Lechner, Gerhard Leder, Wegmann, Claudius Weingrill, Joseph Lehar, Hans Lehrach, Kriso Karin Wihsböck, Tanja Winkler, Leinfellner, Alexander Leitner, Anke Wittig, Alfred Wittinghofer, Andrew Lichtmann, Stefanie Klaus Wolff, Nikolaus and Gabriele Lichtwitz, Hans-Joachim Lipp, Zacherl, Kurt Zatloukal, Rudolf David Livingston, Melanie Lobner, Zechner, Anton Zeilinger, Stefan Silvia Lossgott, Friedrich Lottspeich, Zeilinger, Silvia Zendron, Christoph Dieter Lutz, Wolfgang Machal, Zielinski, Adalbert Zimmerl, Rudolf Mallinger, Derek Mann, Klaus Zinöcker, Gerhard Zinsberger, Christine Mannhalter, Javier Martinez, Elke Zuckermann, Franz Zwickl

Ce — MM — — Research Report 2009