www.cemm.at Research Report 2007 ­ — Research Report 2007 ­ —M M

— Ce Research Report 2007 Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 Director’s Intro — The Austrian Academy of > p. 8—11 Sciences — The CeMM Building — History of CeMM — > p. 11 > p. 12—13 > p. 14—15 Concept of CeMM — Know Yourself — Defend > p. 16—17 > p. 18—25 Yourself — Control Yourself — Treat Yourself — > p. 28—35 > p. 38—45 > p. 48—55 Heal Yourself — Accelerator Projects — The First > p. 58—63 > p. 66–69 Conference of CeMM (Synergy in action) — > p. 70–73 CeMM Karl Landsteiner Lectures — CeMM Retreat — > p. 74–75 > p. 76–79 CeMM Phd Program — CeMM Principal Investigators — > p. 80–82 > p. 83–91 CeMM Directory — CeMM Publications 2007 — > p. 92–95 > p. 96–97 Scientific Advisory Board — Acknowledgements — > p. 98 > p. 99 CeMM scientists and their families who without “Our light blue- losing faith kept working at CeMM’s only fun­ Why CeMM? damental mission, to do innovative research CeMM colored to assist medicine, throughout those years of The view of the constant uncertainties and push-backs. You are lab journal” the explanation as to why we exist, why this Scientific Director Research Research Report is possible and you will enable us to make this center for molecular medicine a success. This is the first printed CeMM Research Report What is Molecular Medicine? Why do we need Report and as such brings many reasons to be cheerful. CeMM’s young faculty decided to divide this a research center dedicated to it? Has it not been It summarizes the first chapter of all the activities report into five episodes that should accompany done already? How does it relate to several exist­ that have been connected with CeMM and con­ you through fundamental aspects of what our ing research institutes? These are the type of tributed to its development from the very begin­ research approach is about: Know Yourself questions that we have been confronted with 2007 ning of its virtual life in the year 2000. There are (the strive to know our molecular makeup, the since we started CeMM some three years ago. Introduction by Giulio Superti-Furga reasonable chances that from a future perspective “human system” in health and disease), Defend And these are the answers: many of the efforts of these first years will be Yourself (the ability to understand and boost considered a period of heroic fanaticism as on the body’s capability to defend itself against Molecular Medicine is an area in medicine where uncountable occasions the CeMM project seemed hostile agents like pathogens), Control Your­ the mechanisms of disease as well as the thera­ very very close to hitting the wall. However, this self (the understanding and exploitation of the peutic and diagnostic initiatives are all based on report is testament to the commitment of many processes by which cells and tissues maintain a detailed understanding at the molecular level. people connected with CeMM that it thankfully their properties and do not lose identity or over- This means that at CeMM we hunt the molec­ didn’t. It is impossible to thank properly in this proliferate to form diseases such as cancer), ular basis of disease and fight it in ways that are short introduction all the people who deserve Treat Yourself (understanding the mechanism understood in the language of molecules. to be mentioned. From the initiators, sponsors of existing therapeutics and learning from them), and administrators in the Austrian Academy of and Heal Yourself (the ultimate goal of prevent­ CeMM as a center is needed to anticipate, respond Sciences, to the first group of CeMM project lead­ ing disease, by selectively modulating the body’s and contribute as much as possible to the revolu­ ers, to the managers and colleagues at the Medical own capability to maintain a healthy state). tion in medicine that has begun from the sequenc- University of Vienna and two Ministers of Science ­ing of individual genomes, the large increase in and Research and their officers and managers. We have just started. We will have our building quantitative data from patients and the prolifera­ There are very many other people in different hopefully in the next couple of years. Please tion of therapeutic opportunities. positions and functions, including our founding understand that we are far from having achieved “Beirat” board who helped in numerous ways, much yet. Much of the content of this report In a nutshell, the challenges we are facing in including welcome advice, important criticism are thoughts and notions entirely projected in translating the knowledge gained through the or even just a cup of coffee. You all know who a future of very hard work integrated with the years of successful “reductionist” approaches you are, and we would like to express our sincere work of many others. We hope you agree that in molecular biology into improved medical gratitude. it is all worthwhile. practice are disease complexity and patient vari­ ability associated with the socio-economical There are a few people that nevertheless need The cover of this research report reproduces one dilemmas of affordability and safety require­ to be mentioned, especially as they may not of our light blue-colored lab journals (note­ ments of treatment. The solutions generated by otherwise be given due credit. First, it is my books), where we record our everyday findings. the entire biomedical research community will privilege to acknowledge the work of my pre­ The intention was to create a symbol illustrating lead to medicines that are integrative and have decessor, CeMM’s founding Scientific Director that what we present in this report is the syn­ physiology as their central discipline. More than Dieter ­Maurer, Professor in the Dermatology thesis of what is found in our books. This makes ­ it has been so far, the medicine of the future Department of the Medical University of Vienna. a direct link between the CeMM researchers and will be predictive, preventive and personalised. His idea, his founding documents and his strive the readers’ community of stakeholders and for scientific excellence, are the basis for all the ­supporters. CeMM is a postgenomic research centre. What work we have done since. I am honoured to con­ does that mean? Its foundation and principles tinue being able to call on his advice and wish were generated after the elucidation of the to keep him a close CeMM friend for the years to We hope you enjoy the reading. sequence of the human genome. Knowledge come. It is also critical to let readers know that of the “parts”, i.e. the gene products and the without the professional, persistent and precise Giulio Superti-Furga molecules, of the human body has been revealed. activity of my precious colleagues Dr. Gerhard What we are facing is the revaluation of physiol­ Schadler, Administrative Director at CeMM and ogy. The human body as a biological system is Anita Ender, all-rounder (who, would it not be more than just the sum of its parts. It is the result for CeMM would already be “magister” in busi­ of countless interactions between the molecules ness and administration), CeMM and I would of which we are composed, that form higher order not be here. Thank you very much. Last but not structures such as networks. These in turn are

CeMM Scientific Director least, the people to whom goes my unconditional dynamic and result from the momentary as well Giulio Superti-Furga admiration and thanks are the valiant group of as past interactions of our bodies with the

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 8 9 environ­ment, including exposure to food, patho­ Already, our current molecular viewpoint is closing the circuit: from the clinic to the clinic. gens, pollutants and drugs. The time is not far different to the phenomenological description To achieve this, the only recipe we are aware The Austrian away, maybe a reality for the next generation, of disease. For example, the same molecular of is one of immediate physical proximity and in which all the knowledge of the parts and its malfunction may be at the basis of quite dif­ project contiguity between the medical doctors Academy interactions will allow for computational models ferent diseases and, conversely, diseases that with the clinical insight and the biomedical of a “virtual human” that, fed with data from are currently believed to be the same may have researchers with the research weapons. We of Sciences molecular pathology, will predict disease out­ distinct molecular roots. Some inflamma­ have these people on the same project team and come and suggest cures. The human biological tory processes and the respective underlying stimulate the two sides to meet, collide and system is thought to be very robust, i.e. able to molecular pathways and networks may be connive. At the “receiving” end is a management absorb perturbations easily. However, both dis­ common to diseases as varied as rheumatoidar­ knowledgeable on the importance of securing eases and cures depend on understanding and thritis, type I diabetes, atherosclerosis, cancer, and protecting intellectual property generated modulating the fragile aspects of these otherwise and even some neurological diseases. Therefore by taxpayer’s money and encouraging the explo­ robust systems. CeMM can and will do research that benefits ration of therapeutic and diagnostic opportuni­ several disciplines and departments. In fact, it ties in a healthy and educated (not too close/not CeMM is not inventing molecular medicine, is CeMM’s molecular perspective that makes it too distant) relationship with industry. an approach and research perspective that interdepartmental and interdisciplinary, similar is already successfully employed in numerous to physiology having been the central discipline There is no doubt about it; our knowledge of laboratories in Austria and around the world. in the Vienna Medical School of the 19th century. biological and human-biological processes is CeMM can only exist as part of a thriving and Being a useful “research vehicle” is one of the exploding. In parallel, the costs and the oppor­ interactive biomedical research environment, fundamental ways of accomplishing CeMM’s tunities associated with medical treatments are from the numerous excellent laboratories in mission to assist and cooperate with a variety also growing at a very fast pace and present us the various departments of the medical univer­ of clinical units and basic biomedical research with moral dilemmas, such as how to identify sities, particularly the ones surrounding CeMM departments, by providing common links. better medical treatments and make them avail­ in Vienna, some of which are world-famous for able to everybody. This is a formidable task for therapeutic innovation, to the flagship research Genes are the foundation, the “blueprint”, but the entire human society and certainly beyond institutes IMP/IMBA. CeMM just aspires to everything else is “genome in action”. For the capability of a single small research center. coalesce existing efforts and provide an addi­- example, the one-gene one-disease relationship However, in essence, CeMM has been founded tion­al, necessary boost. CeMM would hope to holds true for only a fraction of “monogenic” to do justice to this acceleration in knowledge become one of the tools by which the Austrian diseases and many important diseases such as and contribute to increase, even slightly, the medical research and teaching community cancer, cardiovascular, metabolic and inflam­ ability of the Austrian biomedical community can reconnect to the glorious past of the Vienna matory diseases, are multi-factorial. In fact there to play an active role in coping with the associ­ Medical School, with physiology (i.e. “systems may well be more disease conditions than the ated opportunities and risks. Our ambition medicine”) at its core. The patronage of the Aus­ 23,000 or so different genes. Moreover, individu­ is that CeMM will be able to act synergistically trian Academy of Sciences, with its long tradition als often respond differently to therapy. Long and sometimes even catalytically with the large of scientific excellence, imposes extraordinary before this booklet will turn yellow, we will and powerful biomedical research already going The Austrian Academy of Sciences, founded quality standards and prestige to the operation. know the sequence of the genome of every one on in numerous university and non-university in 1847, is the most prestigious and important of us and it will be possible to obtain detailed research institutes. Ultimately, as we now real­ organisation in Austria for the promotion of Part of this vision is the training of a young molecular measurements for diagnosis. ize the importance of molecular networks that non-university-based academic research. ­generation of medical scientists at CeMM. Again, form the basis of our organism, we believe that CeMM wants to assist the medical research com­ How does CeMM bridge basic and applied significant research projects can only be success­ The Academy is both a learned society, com­ munity by supporting the “physician scientist” research? Many people consider the distinction ful by networking competences and activities. prising highly qualified researchers from Austria and “scientist with medical knowledge” career obsolete. It has been shown that it is difficult to We hope to provide many of the necessary links. and abroad as its members, and a scientific paths, initially finding tailor-made solutions for predict or force applied research. People speak organisation promoting innovative research. young individual researchers and possibly paving more about “good” and “bad” research. Only It is currently promoting 65 research institutions, the way for more institutionalized career options good research is worthwhile. Nevertheless we which are located in several federal states of in the future. do not think that relying on serendipity is Austria, with the headquarters located in the Old enough to close the gap between science and University in the center of Vienna. At present, medical practice and meet the urgent challenges the Academy employs about 1100 people. that we face in terms of medical need. CeMM rather adopts a non-linear approach and attempts The Austrian Academy of Sciences has developed to foster medically-relevant research not only from a mere learned society to include the orga­ by reversing the bench-to-bedside slogan but by nisation and management of modern scientific research institutions. By founding basic research centers, such as IMBA - Institute of Molecular Biotechnology, and GMI - Gregor Mendel Insti­ tute of Molecular Plant Biology, as limited liabili­ ty companies under Austrian law, the Austrian Academy of Sciences embarked on a new approach to institutional organisation. The connection between basic research and clinical research is being established by setting up CeMM.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 10 11 Modern laboratories for a modern institute The CeMM The architect Kopper designed a modern molec­ Fig. 2 Projected view ular biology building to symbolize one of CeMMs of the CeMM building. Building – At the missions; to be a leading institute that works Fig. 3 Inside the open- as a team by promoting interactions between plan laboratories with some computer work­ center of the individuals, rather than a collection of separate stations at the windows. laboratories. The building consists of eight floors, Vienna General and two thirds of it is lab space. Overall, there is 5,620 m² total floor space, with 3.409 m²of Hospital usable area. That’s room for around 100 people, including support staff and administration.

The laboratories are open-plan and south facing, Location, location, location ensuring they are light and spacious. There are The new CeMM building is located at the very some computer workstations for up to 15 people heart of the Vienna General Hospital (AKH), one situated along the windows. The necessary sup­ of the biggest and most modern general hospitals port rooms are located inside the building and in Europe. This privileged location is designed are conveniently close to the laboratories. On the to integrate the scientists of CeMM with the out­ north side of the building are the offices for the standing medical community and facilities of the scientists and the administration, and small sem­ hospital and the Medical University of Vienna, to inar rooms for informal meetings and discussions. fully maximize the capabilities of this molecular- The CeMM building also has its own lecture hall. medical institute. The main entrance of CeMM To promote social interactions between the sci­ will be shared with the complementary laborato­ entists, there is a large cafeteria and two terraces ry of the Medical University of Vienna, and there on the top floor. are connecting corridors on each floor, ensuring easy access to the main building of the AKH, and The beginning of construction is in May 2008, encouraging communication and the free-flow and CeMM will move in by March 2010. of ideas and resources throughout the campus.

Fig. 1 Location of the CeMM building within the Vienna General Hospital.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 12 13 January 1, 2005 August 13, 2005 October 6, 2005 November 10, 2005

The History Cover-Story Publication EMBO elects Approval of GEN-AU in Molecular Cell 40 top researchers grant application “Structural basis for the cytoskeletal to its membership “DRug Action by GenOmic of CeMM asssociation of Bcr-Abl/c-Abl” by including CeMM Director, Network(s): DRAGON”. Giulio Superti-Furga and colleagues. Giulio Superti-Furga. GEN-AU supports genome research in Austria.

January 1, 2006 January 22, 2006 January 23, 2006 March 23, 2006 April 1, 2006 June 1, 2006 Nature article publication FWF Grant CeMM is presented by Giulio Superti-Furga and researchers awarded to Giulio Sperti-Furga’s group in a Nature issue of Cellzome AG and EMBL Heidelberg for the project “Physical and Functional that has a Highlight on Austria on the first genome-wide screen Map of Bcr-Abl Signalling”. section. for complexes in an organism, budding yeast, using affinity purification and mass spectrometry.

September 27, 2006 October 2, 2006 October 22, 2006 January, 2007 April 27, 2007 May 3, 2007

ÖAW Lectures Publicaton in CeMM joins the Phd Giulio Superti-Furga has Minister Elisabeth Gehrer Nature Methods program, CCHD: Cell been elected as a gave the introduction speech “An efficient tandem affinity Communication in Health Corresponding Member to Giulio Superti-Furga’s talk purificaton procedure for interaction and Disease of the Austrian Academy “Molecular machines, molecular proteomics in mammalian cells” by networks and the medicine Tilman Bürckstümmer, PostDoc in the supported by the Medical University of of Sciences, Vienna and the Austrian Science Fund of the 3rd millenium”. Director’s Group, with “News and Section for Mathematics and (FWF), providing advanced education in Views” commentary in the same issue the Natural Sciences. biomolecular medicine.

May 23, 2007 June 25, 2007 August 3, 2007 August 14, 2007 August 24, 2007 August 23—26, 2007

A documentary FWF Grant Publication in Publication in PNAS Publicaton in Blood film about CeMM awarded to Principal Investigator Molecular Cell “The Btk tyrosine kinase is a major “Chemical proteomic profiles of the is presented at the “Feierliche Robert Kralovics for the project “Active and Repressive Chromatin target of the Bcr-Abl inhibitor BCR-ABL inhibitors imatinib, nilotinib Sitzung” of the Austrian Academy “Genetic basis of myeloproliferative Is Interspersed without Spreading dasatinib” by Giulio Superti-Furga and dasatinib reveal novel kinase of Sciences and on the German disorders”. in an Imprinted Gene Cluster in the and colleagues at the Medical and non-kinase targets” by Giulio television channel, Bayern alpha. Mammalian Genome” by Principal University of Vienna. Superi-Furga, Peter Valent (Medical Investigator Denise Barlow. University of Vienna) and colleagues.

September 25, 2007 September 27, 2007 October 1, 2007 October 31, 2007 November 22, 2007 January 1, 2008

Visit by Dr. Johannes Publicaton in CEN-Online Science Day Meeting Report of the Hahn, Minister of Nature Methods (Chemical & Engineering News) CeMM invited the Presidium, first CeMM Conference, Science and Research “Mass spectrometry-based functional published a science and technology interested persons of the Academy published in Nature report about the first CeMM and the Scientific Community The Director’s lab had the proteomics: from molecular machines Conference: “Chemistry, Biology, of Vienna to a first “Science Day”. Chemical Biology pleasure and honor to welcome to protein networks” by Giulio Superti- Furga and Thomas Köcher. Cross-Fertilization”. “Drugs in Action” by CeMM Director Minister Hahn and to present Giulio Superti-Furga and co-organizer the research activities of CeMM. Ulrike Eggert. The Concept of CeMM

“CeMM’s young faculty decided to divide this report into five episodes that should The three ‘omics’ Genomics: SNP Proteomics: Bioinformatics: Know Knowing your mapping and Mass Spectrometry Making sense molecular makeup Gene Sequencing of it all accompany you through fundamental > p. 23 aspects of what our research approach is Yourself > p. 20—21 > p. 22 > p. 24—25 about: Know Yourself (the strive to know our molecular makeup, the “human system” in health and disease), Defend Yourself (the ability to understand and The Fight Innate Immunity: Inflammation Bacterial Toxins boost the body’s capability to defend Defend for Survival Molecular Mechanisms Double-edged Sword > p. 35 of Disease Recognition itself against hostile agents like pathogens), > p. 30—31 > p. 34 Cell Detectives Control Yourself (the understanding and Yourself > p. 32—33 exploitation of the processes by which cells and tissues maintain their properties and do not lose identity or over-proliferate to form diseases such as cancer), Treat Maintaining Genetics and Hematological Yourself (understanding the mechanism Control Biological Order Epigenetics of Cancer Malignancies The Origin of Cancer Getting Out of Control Master Controllers of existing therapeutics and learning from Gene Regulation Controlling the genome Yourself > p. 44 —45 them), and Heal Yourself (the ultimate > p. 40—41 > p. 42—43 goal of preventing disease, by selectively modulating the body’s own capability to maintain a healthy state).” Giulio Superti-Furga Smart Drugs: Understanding drugs Achilles heel of Cancer Treat Hitting where it hurts > p. 52—53 > p. 54 —55 What’s in a Drug? Yourself Smart Drugs Putting Knowledge to work

> p. 50—51

Learning from Natural Antibodies Heal the Experts and Atherosclerosis Natural Antibodies Natural Born Killer Keeping the Blood Yourself > p. 60—61 Vessels Clear

> p. 62—63 Know Yourself

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Val – Gly – Ala – His – Ala – Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys –Leu – Leu – Ser – His – Cys – Leu – Leu – Val – Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala – Val – His – Ala – Ser – Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser – Thr – Val – Leu – Thr – Ser – Lys – Tyr – Arg – +++ – Met – Val – His – Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly – Glu – Ala – Leu – G l y – A r g – L e u – L e u – V a l – V a l – T y r – P r o – Trp – Thr – Gln – Arg – Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – Asn – Leu – Lys – Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp –Pro –Glu –Asn –Phe – Arg – Leu – Leu – Gly – Asn – V a l – L e u – V a l – C y s – V a l – L e u – A l a – H i s – H i s – P h e – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val – Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala – His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly – Ala – His – Ala – Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Yourself + Genomics: SNP Mapping + Proteomics: + Bioinformatics: Asn – Ala – Val – Ala – His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys – Leu – Leu – and Gene Sequencing Mass Spectrometry Making sense of it all Ser – His – Cys – Leu – Leu – Val – Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala – Val – His – Ala – Ser – Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser – Thr – Val – Leu – Thr – Ser – Lys –Tyr –Arg –+++ –Met –Val –His –Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly – Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – Asn – Leu – Lys – Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp – Pro – Glu – Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – His – His –Phe –Gly –Lys –Glu –Phe –Thr –Pro –Pro –Val –Gln –Ala –Ala –Tyr –Gln –Lys –Val –Val –Ala –Gly –Val –Ala –Asn –Ala –Leu – Ala – His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly – Ala – His – Ala – Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys – Leu – Leu – Ser – His – Cys – Leu –Leu –Val –Thr –Leu –Ala –Ala –His –Leu –Pro –Ala –Glu –Phe –Thr –Pro –Ala –Val –His –Ala –Ser –Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser – Thr – Val – Leu – Thr – Ser – Lys – Tyr – Arg – +++ – Met – Val – His – Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly – Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – hemoglobin Asn – Leu – Lys – Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – For the Know Yourself Val – Asp – Pro – Glu – Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – topic, we have chosen the His – His – Phe – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val – sequence of the human Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala – His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – beta-globin and alpha- Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly – Ala – His – Ala – globin genes, the protein Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – components of human Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – Gln – Val – hemoglobin, which is Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – His – responsible for carrying Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – oxygen in our blood. His – Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys – Leu – Leu – Ser – His – Cys – The corresponding DNA Leu – Leu – Val – Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala – ­sequences were two of Val – His – Ala – Ser – Leu – Asp – Lys – Phe – Leu – Ala – Ser – Val – Ser – Thr – Val – Leu – the first to be isolated and Thr – Ser – Lys – Tyr – Arg – +++ – Met – Val – His – Leu – Thr – Pro – Glu – Glu – Lys – Ser – determined. The human Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp – Glu – Val – Gly – Gly – population carries many Glu – Ala – Leu – Gly – Arg – Leu – Leu – Val – Val – Tyr – Pro – Trp – Thr – Gln – Arg – variants of these sequenc- Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – es, some of which are Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – associated with severe Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – Asn – Leu – Lys – Gly – Thr – Phe – Ala – Defend disease conditions. Knowl­ Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp – Pro – Glu – Yourself edge about them is critical Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – His – His – for prevention and therapy. Phe – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val – Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala – His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – Gly – Ala – Control HBB_HUMAN Uniprot Yourself P68871 His – Ala – Gly – Glu – Tyr – Gly – Ala – Glu – Ala – Leu – Glu – Arg – Met – Phe – Leu – Ser – Phe – Pro – Thr – Thr – Lys – Thr – Tyr – Phe – Pro – His – Phe – Asp – Leu – Ser – His – Gly – Ser – Ala – HBA_HUMAN Uniprot Gln – Val – Lys – Gly – His – Gly – Lys – Lys – Val – Ala – Asp – Ala – Leu – Thr – Asn – Ala – Val – Ala – P69905 His – Val – Asp – Asp – Met – Pro – Asn – Ala – Leu – Ser – Ala – Leu – Ser – Asp – Leu – His – Ala – His – Treat Lys – Leu – Arg – Val – Asp – Pro – Val – Asn – Phe – Lys – Leu – Leu – Ser – His – Cys – Leu – Leu – Val – Yourself Thr – Leu – Ala – Ala – His – Leu – Pro – Ala – Glu – Phe – Thr – Pro – Ala – Val – His – Ala – Ser – Leu – Asp –Lys –Phe –Leu –Ala –Ser –Val –Ser –Thr –Val –Leu –Thr –Ser –Lys –Tyr –Arg –+++ –Met –Val – His – Leu – Thr – Pro – Glu – Glu – Lys – Ser – Ala – Val – Thr – Ala – Leu – Trp – Gly – Lys – Val – Asn – Val – Asp –Glu –Val –Gly –Gly –Glu –Ala –Leu –Gly –Arg –Leu –Leu –Val –Val –Tyr –Pro –Trp –Thr –Gln –Arg – Heal Yourself Phe – Phe – Glu – Ser – Phe – Gly – Asp – Leu – Ser – Thr – Pro – Asp – Ala – Val – Met – Gly – Asn – Pro – Lys – Val – Lys – Ala – His – Gly – Lys – Lys – Val – Leu – Gly – Ala – Phe – Ser – Asp – Gly – Leu – Ala – His – Leu – Asp – Asn – Leu – Lys – Gly – Thr – Phe – Ala – Thr – Leu – Ser – Glu – Leu – His – Cys – Asp – Lys – Leu – His – Val – Asp – Pro – Glu – Asn – Phe – Arg – Leu – Leu – Gly – Asn – Val – Leu – Val – Cys – Val – Leu – Ala – His – His – Phe – Gly – Lys – Glu – Phe – Thr – Pro – Pro – Val – Gln – Ala – Ala – Tyr – Gln – Lys – Val – Val – Ala – Gly – Val – Ala – Asn – Ala – Leu – Ala – His – Lys – Tyr – His – +++ – Met – Val – Leu – Ser – Pro – Ala – Asp – Lys – Thr – Asn – Val – Lys – Ala – Ala – Trp – Gly – Lys – Val – “Knowledge of the self is the mother of all knowl­ While the human genome project tells scientists Metabolomics Know edge. So it is incumbent on me to know myself, the sequences and the variations of all the genes, Knowing the sequence and activity of the genes, Yourself to know it completely, to know its minutiae, its it doesn’t tell them their activity. This information as well as the assortment of proteins, gives “There is no is useful when studying the effects of external scientists a lot of information about the state of characteristics, its subtleties, and its very atoms.” Kahlil Gibran, Lebanese-American Philosopher, influences such as disease or therapeutics on the a cell and ultimately about health and disease 1883-1931. This is not a small thing to ask, but a body. Microarray technology can tell scientists states. Genes and proteins provide circumstantial shame in not comprehensive knowledge of the molecular self the activity of the entire genome at one moment evidence that a particular activity or event might is critical when dealing with health and disease. in time. It is used extensively at CeMM in colla­ occur in a cell, and goes some way towards pre­ When a car breaks down, the best person to fix it boration with the Medical University of Vienna dicting cellular responses to certain factors. How­ is a mechanic who understands exactly how an to study gene activity under a variety of physio­ ever, they do not reveal everything about a cell’s knowing, the engine works and how a car operates in its enti­ logical conditions. activity. The repertoire of metabolites generated rety. To treat disease, we first need to know and by diverse chemical reactions that both break understand the human body in its healthy state, Proteomics down and build up molecules in our bodies and at homeostasis, so we can make an accurate dia­ Genes make proteins, which are the tools of the transform energy, is known as the metabolome. shame lies gnosis of any diseased state and use this to deve­ cell. The protein components of a cell are its Metabolic profiling, or metabolomics, can give lop and select effective treatments to cure disease. trademark, so you can tell a lot about a cell from scientists a unique indication of what biological the proteins it contains (its proteome). However, activity has actually occurred in the cell, and tech­ Science comes from the Latin scientia, meaning while scientists already have the tools to start nology of this kind is being used at CeMM to in not finding knowledge. Scientists unite in their pursuit of sequencing the genome of every human being, supplement and extend data obtained from the knowledge, and biologists pursue knowledge they are much further away from understanding other approaches. about life. CeMMs ambition to ‘know yourself’, the proteome of even a single cell. The number means to strive to identify and understand our of proteins, unlike the number of genes, is Knowledge generated by each of the ‘omics’ (Russian Proverb) out.” molecular self, that is the molecules that make up much more difficult to predict, and scientists individually and collectively provides valuable Studying the molecular repertoires and networks our bodies. It has become clear that the knowl­ want to know not only the number, but also information about the molecular self. Giulio to understand the human system in health and disease. edge of individual molecules goes no way towards the complex three-dimensional structure and Superti-Furga is using a combination of all three describing the workings of the cells and tissues the function of each protein, and when and to provide a comprehensive molecular analy­ that form a functioning human being, as no where they are produced. Moreover, proteins sis of specific body states. His group plans on molecule works entirely alone. Scientists need are modified, by various chemical changes, like generating extensive knowledge of the effects to study molecular interactions and networks phosphorylation and acetylation or the addition of therapeutics on the body. In collaboration to really understand the human system in health of small peptides, like in the process called ubi­ with Peter Valent at the Medical University of and disease. quitination. As a result, for each gene there may Vienna, along with the sophisticated technology be several corresponding protein species, each platform provided by BIOCRATES Life Sciences, with a slightly different function. Mass spec­ a company in Innsbruck, Austria, they have Knowing your molecular makeup: trometry has been set up at CeMM as a valuable formed the consortium DRAGON (DRug Action proteomics approach to study the molecular by GenOmic network(s)), which generates data The three ‘omics’ effects of various conditions such as disease or from a combination of functional genomics, drugs, by identifying the protein components proteomics and metabolomics approaches. The Genomics and their modifications in a biological sample. goal is to minimize the damage caused by the­ In the 21st Century, scientists entered the post- rapeutic side-effects on patients, by developing genomic era. The first full draft of the human detailed analysis of their molecular effects. genome hit the electronic shelves in June 2000. It had taken almost ten years to generate the Managing the Knowledge sequence of 3.1 billion letters of DNA, and it Scientists are no longer focusing on individual was hailed as one of the most influential scien- genes and proteins. They are more interested ­tific discoveries of all time. They weren’t wrong. in studying groups and networks, and whole Knowing the sequence of DNA means that body states. Scientists at CeMM are using com­ scientists not only have the blueprint of the binations of genomics, proteomics and meta­ human system, but can also identify all genes that bolomics to study various conditions, such as cause disease. At CeMM, Robert Kralovics uses the effects of therapeutics on the body. These the data to find which genes can cause blood approaches each generate substantial data that disorders. Sebastian Nijman uses it to find genes somehow need to be integrated to generate Defend that can cause cancer. Once scientists know meaningful biological conclusions. This is one Yourself which faulty genes cause disease, they can work of the challenges now facing the systems bio­ towards generating effective treatments. logists and bioinformaticians, who develop Control analytical methods using computer programs to Yourself integrate and analyze complex biological datasets.

Treat Yourself

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 20 21 Other genetic variations, like the loss of large complex instrument that generates charged Know Genomics: SNP regions of DNA containing many genes, are also Proteomics: ions ­(specific types of atoms or molecules) Yourself linked to certain genetic diseases. Finding out from ­a sample, and separates these ions based mapping and which gene and which mutation is a big challenge Mass Spectrometry on a ­mass-to-charge ratio. Ions with a specific for molecular-medical scientists. The develop­ mass-to-­charge ratio are detected and the infor­ Gene Sequencing ment of comprehensive high-throughput gene mation ­collated to produce a mass spectrum. sequencing technologies enables them to more Mass spectrometrists can then interpret the quickly pin-point genetic mutations responsible The protein content of the human cell (the spectrum and deduce the identity of the pro­ for disease. Robert’s group has installed the first proteome) is largely uncharacterized. Under­ teins and therefore the content of the sample. “Significant The first published sequence of ‘the’ human of such modern sequencing machine: the Genetic standing the proteome is vital in furthering genome was in actual fact a mixture of the Analyzer instrument manufactured by Applied our knowledge, as it constitutes the necessary The capacity of mass spectrometry has increased advances in sequence of a very small group of individuals, Biosystems, and they already have experience equipment that enables a cell to function and dramatically in the last few decades. Until the instrument design because the genome sequence of every human using it to hunt for disease-causing mutations. thus survive. Current estimates are that there 1990’s, mass spectrometry was only able to and technology being is unique. Genetic variations are thought Now they have set their sites on finding the gene are around 20,000 protein-coding genes result­ ­characterize an individual protein from a fairly to contribute to physical and even social char­ that is mutated within a region commonly deleted ing in greater than 500,000 different proteins pure sample. Significant advances in instrument have led to drama- acteristics. The most frequent type of variation in patients with MPD, which contains around in human cells. So, it is not difficult to see how design and technology have led to dramatic tic improvements­ is the single nucleotide polymorphism (SNP). 10 candidate genes. Identifying the disease-causing investigation of the proteome and determina­ improvements in sensitivity and accuracy. With in ­sensitivity Scientists have now identified many of these genetic mutation will lead to a more precise diag­ tion of the function of every protein is a huge the sequencing of the human genome, all pro­ SNPs (currently more than 9 million) and this nostic approach and hopefully the development challenge for modern-day scientists. While most teins and protein fragments can theoretically be and accuracy.” information can be used to identify genetic of novel therapeutics. cells in a body have an almost identical genome, identified from a mass spectrum. risk factors that are associated with disease. This they all have very different expressed proteomes. also gives scientists the opportunity to under­ The last ten years have seen great progress in There still exists enormous potential for mass stand further the molecular basis of specific the development of sophisticated proteomic spectrometry. The ultimate aim would of course genetic diseases. Robert Kralovics is looking at technologies allowing us to begin working on be to analyze entire human proteomes, including large numbers of SNPs in human samples to this problem. Mass spectrometry has emerged as modifications and in a quantitative manner, discover which ones account for the tendencies one of the leading approaches for protein charac­ with this technology. Such a goal is still far from of patients with specific blood disorders known terization and identification, and has become an being realized. At CeMM, scientists have a par­ as myeloproliferative disorders (MPDs) to develop indispensable tool for many biological scientists. ticular interest in the molecular context that can additional disease symptoms like throm­bosis. be identified using proteomics, the interactions Thrombosis, deregulated blood clotting brought Mass spectrometry is an analytical technique that between proteins and the interactions between about by small cells in our blood called platelets, Keiryn Bennett and her small team have spent drugs and their protein targets. In a scientific com­- is a particularly nasty complication of MPD that considerable time and effort implementing and munity that is rapidly gaining knowledge and significantly contributes to mortality associated developing in relation to the medical questions understanding of cells and cellular function, the with the disease. Using genomics approaches at CeMM. It is a sensitive technique that actually aim of having a description of all proteins and to generate knowledge and understanding of the measures the physical properties of proteins. their interactions is not completely unattainable. genetic basis of the disease, Robert hopes to Mass spectrometry can be used to identify the Technologies such as mass spectrometry are vital develop effective strategies to treat susceptible individual protein components of complex in assisting in this quest. patients and improve their quality of life. ­biological samples. A mass spectrometer is a

Fig. 1 A microarray Fig. 1 Fig. 2 Fig. 2 A mass spectrum ­revealing the activity of is a plot of mass-to-charge genes in cells. RNA pro- (m/z) ratio versus fre- duced (transcribed) from quency. This plot shows active genes is taken from a tandem mass spectrum cells under two different of a ­doubly-charged ion at physiological conditions m/z 560.31. The spectrum and fluorescently labeled was used to determine the either red or green. This sequence of the peptide, mixture is then incubated which reads from right to with a special slide on left: D (I or L), A (I or L), A, T. Defend which DNA is attached in Yourself spots. The spots that are either red or green reveal genes that are active in only one condition, and Control Yourself spots that are yellow are active in both.

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Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 22 23 The bioinformatics platform and research are Know Bioinformatics: focused towards the detection and analysis Fig. 1 Profiling of anti- Yourself of molecular interactions. Once experimental cancer drugs. Proteomics drug pulldown experi- Making sense data has been generated, bioinformatics analysis ments reveal the targets determines the statistical significance of the of three kinase inhibitors (green) directed against of it all results and produces a verified dataset. For exam­ the oncogene fusion ple, they have developed statistical models to protein Bcr-Abl (red) that extract true molecular interactions from the mass is involved in chronic myeloid leukemia, a cancer spectrometry experiments at low and controlled of blood cells. “The process of Here the challenge at stake is formidable. Integra­ false discovery rates. Jacques team is interested tion of knowledge can give scientists information in translating the proteomics data generated by data analysis and on the makings of the body and its malfunctions, multiple experiments into detailed molecular interpretation to an extent never before dreamed possible. networks describing physical interactions. They has now become With the generation of new technologies, such use data generated at CeMM, particularly by as mass spectrometry, comes the need to develop the group of Giulio Superti-Furga. There, strong as important as computer-based methods to analyze complex emphasis is put on identification of protein- the laboratory datasets. Many of the technologies used at CeMM molecule interactions of several kinds: protein- experiment itself.” generate large volumes of data. These data need protein, drug-protein, and DNA/RNA-protein. to be carefully examined to extract knowledge of biological interest. Gone are the days when The platform makes it possible to integrate biologists could get by with direct inspection ­networks with existing similar public data of each experimental result. The process of data released by other laboratories with CeMM gene analysis and interpretation has now become expression data generated in collaboration with as important as the laboratory experiment itself. the Medical University of Vienna. Using this platform, it is possible for instance to relate the “Sophisticated Bioinformatics is a relatively new field that effects of a drug treatment on gene expression integrates informatics, computer science, and changes with the targets of the drug and newly data integration mathematics with biological sciences, such discovered protein networks to better under­ can provide as genetics and cell biology. It can be applied stand the treatment of leukemia (CML). The important new to data generated by many different ­methods, team is currently working on the integration and has been used to make valuable discoveries of metabolomic, genomic and proteomic data insights into on diverse topics from the origin of species for specific CeMM projects. ­cellular functions to cell behavior and disease. that will then Sophisticated data integration can provide Jacques Colinge’s team manages data flow important new insights into cellular functions drive new direc- and storage of data produced at CeMM through that will then drive new directions for research. tions for research.” distributed information systems that allow The group plans to develop and extend the bio­ automatic processing of batches of data com­ informatics platform at CeMM. The methods bined with quality control. For example, the data set up by the bioinformatics team form a basis generated by mass spectrometry is systematically forthe modeling and simulation of partial or re-calibrated by an innovative algorithm before complete biological systems, which is an impor­ being submitted to search sequence databases tant goal for the future. in order to identify proteins present in biological samples. In collaboration with the Swiss Insti­ tute of Bioinformatics (Swiss-Prot, PROSITE, ­Melanie, Phenyx, etc.), CeMM’s bioinformatics team is developing a new database search algo­ rithm, which combined with the system in place, will make it able to identify many more proteins from a biological sample. There are many other types of data that are managed by the Defend bioinformatics team, including sequencing and Yourself microarray data.Microarrays are used to describe the simultaneous activity of thousands of genes. Control Yourself

Treat Yourself

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 24 25 Dr. Heinz Fischer President of the Austrian Republic

Discovery is based on curiosity and execution of ideas. It is satisfactory to see ideas turn into reality. The idea behind the Center of Molecular Medicine was to bring science and medicine close together and allow young scientists and medical doctors to do innovative and interdisciplinary work together. The realization of this idea through the location of a new research institution on the grounds of the Vienna General Hospital with its long and extraordinary tradition of medical innovation is a wonderful opportunity to execute ideas into medical practice. In the research process, cycles of frustrated attempts and failures alternate with accomplishments and successes. We wish the Center of Molecular Medicine of the Austrian Academy of Sciences on the occasion of this inaugural Research Report all possible successes and important discoveries. We congratulate the Academy of Sciences as well as the Scientific Director for establishing a new international research institution that not only will tackle important medical problems­ but will also train young scientists for the important challenges of the future.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 Know Yourself

Defend Yourself M e t – Pro – His – Thr – Leu – Trp – Met – Val – Trp – Val – Leu – Gly – Val – Ile – Ile – Ser – Leu – Ser – Lys – Glu – Glu – Ser – Ser – Asn – Gln – Ala – Ser – Leu – Ser – Cys – Asp – Arg – Asn – Gly – Ile – Cys – Lys – Gly – Ser – Ser – Gly – Ser – Leu – Asn – Ser – Ile – Pro – Ser – Gly – Leu – Thr – Glu – Ala – Val – Lys – Ser – Leu – Asp – Leu – Ser – Asn – Asn – Arg – Ile – Thr – Tyr – Ile – Ser – Asn – Ser – Asp – Leu – Gln – Arg – Cys – Val – Asn – Leu – Gln – Ala – Leu – Val – Leu – Thr – Ser – Asn – Gly – Ile – Asn – Thr – Ile – Glu – Glu – Asp – Ser – Phe – Ser – Ser – Leu – Gly – Ser – Leu – Glu – His – Leu – Asp – Leu – Ser – Tyr – Asn – Tyr – Leu – Ser – Asn – Leu – Ser – Ser – Ser – Trp – Phe – Lys – Pro – Leu – Ser – Ser – Leu – Thr – Phe – Leu – Asn – Leu – Leu – Gly – Asn – Pro – Tyr – Lys – Thr – Leu – Gly – Glu – Thr – Ser – Leu – Phe – Ser – His – Leu – Thr – Defend Lys – Leu – Gln – Ile – Leu – Arg – Val – Gly – Asn – Met – Asp – Thr – Phe – Thr – Lys – Ile – Gln – Arg – Lys – Asp – Phe – Ala – Gly – Leu – Thr – Phe – Leu – Glu – Glu – Leu – Glu – Ile – Asp – Ala – Ser – Asp – Leu – Gln – Ser – Tyr – Glu – Pro – Lys – Ser – Leu – Lys – Ser – Ile – Gln – Asn – Val – Ser – His – Leu – Ile – Leu – His – Met – Lys – Gln – His – Ile – Leu – Leu – Leu – Glu – Ile – Phe – Val – Asp – Val – Thr – Ser – Ser – Val – Glu – Cys – Leu – Glu – Leu – Arg – Asp – Thr – Asp – Leu – Asp – Thr – Phe – His – Phe – Ser – Glu – Leu – Ser – Thr – Gly – Glu – Thr – Asn – Ser – Leu – Ile – Lys – Lys – Phe – Thr – Phe – Arg – Asn – Val – Lys – Ile – Thr – Asp – Glu – Ser – Leu – Phe – Gln – Val – Met – Lys – Leu – Leu – Asn – Gln – Ile – Ser – Gly – Leu – Leu – Glu – Leu – Glu – Phe – Asp – Asp – Cys – Thr – Leu – Asn – Gly – Val – Gly – Asn – Phe – Arg – Ala – Ser – Asp – Asn – Asp – Arg – Val – Ile – Asp – Pro – Gly – Lys – Val – Glu – Thr – Leu – Thr – Ile – Arg – Arg – Leu – His – Ile – Pro – Arg – Phe – Tyr – Leu – Phe – Tyr – Asp – Leu – Ser – Thr – Leu – Tyr – Ser – Leu – Thr – Glu – Arg – Val – Lys – Arg – Ile – Thr – Val – Glu – Asn – Ser – Lys – Val – Phe – Leu – Val – Pro – Cys – Leu – Leu – Ser – Gln – His – Leu – Lys – Ser – Leu – Glu – Tyr – Leu – Asp – Leu – Ser – Glu – Asn – Leu – Met – Val – Glu – Glu – Tyr – Leu – Lys – Asn – Ser – Ala – Cys – Glu – Asp – Ala – Trp – Pro – Ser – Leu – Gln – Thr – Leu – Ile – Leu – Arg – Gln – Asn – His – Leu – Ala – Ser – Leu – Glu – Lys – Thr – Gly – Glu – Thr – Leu – Leu – Thr – Leu – Lys – Asn – Leu – Thr – Asn – Ile – Asp – Ile – Ser – Lys – Asn – Ser – Phe – His – Ser – Met – Pro – Glu – For Defend Yourself we Thr – Cys – Gln – Trp – Pro – Glu – Lys – Met – Lys – Tyr – Leu – Asn – Leu – Ser – Ser – Thr – Arg – Ile – Yourself + Innate Immunity: + Inflammation + Bacterial Toxins chose the human Toll-like His – Ser – Val – Thr – Gly – Cys – Ile – Pro – Lys – Thr – Leu – Glu – Ile – Leu – Asp – Val – Ser – Asn – Asn – Asn – Leu – Asn – Leu – Phe – Ser – Leu – Asn – Leu – Pro – Gln – Leu – Lys – receptor 2. It recognizes Molecular Mechanisms Glu – Leu – Tyr – Ile – Ser – Arg – Asn – Lys – Leu – Met – Thr – Leu – Pro – Asp – Ala – bacteria at the cell surface of Disease Recognition Ser – Leu – Leu – Pro – Met – Leu – Leu – Val – Leu – Lys – Ile – Ser – Arg – Asn – and relays a signal that Ala – Ile – Thr – Thr – Phe – Ser – Lys – Glu – Gln – Leu – Asp – Ser – Phe – His – elicits a set of cellular and Thr – Leu – Lys – Thr – Leu – Glu – Ala – Gly – Gly – Asn – Asn – Phe – Ile – Cys – systemic responses to Ser – Cys – Glu – Phe – Leu – Ser – Phe – Thr – Gln – Glu – Gln – Gln – Ala – Leu – fight a possible infection. Ala – Lys – Val – Leu – Ile – Asp – Trp – Pro – Ala – Asn – Tyr – Leu – Cys – Asp – Ser – The Toll-like receptor Pro – Ser – His – Val – Arg – Gly – Gln – Gln – Val – Gln – Asp – Val – Arg – Leu – Ser – Val – family are at the center Ser – Glu – Cys – His – Arg – Thr – Ala – Leu – Val – Ser – Gly – Met – Cys – Cys – Ala – Leu – of CeMM’s research and Phe – Leu – Leu – Ile – Leu – Leu – Thr – Gly – Val – Leu – Cys – His – Arg – Phe – His – Gly – Leu – Trp – Tyr – Met – are being studied in the Lys – Met – Met – Trp – Ala – Trp – Leu – Gln – Ala – Lys – Arg – Lys – Pro – Arg – Lys – Ala – Pro – Ser – Arg – Asn – Ile – Cys – Knapp, Binder and Superti­- Tyr – Asp – Ala – Phe – Val – Ser – Tyr – Ser – Glu – Arg – Asp – Ala – Tyr – Trp – Val – Glu – Asn – Leu – Met – Val – Gln – Glu – Furga laboratories. Leu –Glu –Asn –Phe –Asn –Pro –Pro –Phe –Lys –Leu –Cys –Leu –His –Lys –Arg –Asp –Phe –Ile – Pro – Gly – Lys – Trp – Ile – Ile – Asp – Asn – Ile – Ile – Asp – Ser – Ile – Glu – Lys – Ser – His – Lys – Thr – Val – Phe – Val – Leu – Ser – Glu – Asn – Phe – Val – Lys – Ser – Glu – Trp – Cys – Lys – Tyr – Glu – Leu – Asp – Phe – Ser – His – Phe – Arg – Leu – Phe – Asp – Glu – Asn – Asn – Asp – Ala – Ala – Ile – TLR2_HUMAN Uniprot Leu – Ile – Leu – Leu – Glu – Pro – Ile – Glu – Lys – Lys – Ala – Ile – Pro – Gln – Arg – Phe – Cys – Lys – Leu – Arg – Lys – Ile – Met – Asn – O60603 Thr – Lys – Thr – Tyr – Leu – Glu – Trp – Pro – Met – Asp – Glu – Ala – Gln – Arg – Glu – Gly – Phe – Trp – Val – Asn – Leu – Arg – Ala – Ala – Ile – Lys – Ser – +++ – Met – Pro – His – Thr – Leu – Trp – Met – Val – Trp – Val – Leu – Gly – Val – Ile – Ile – Ser – Leu – Ser – Lys – Glu – Glu – Ser – Ser – Asn – Gln – Ala – Ser – Leu – Ser – Cys – Asp – Arg – Asn – Gly – Ile – Cys – Lys – Gly – Ser – Ser – Gly – Ser – Leu – Asn – Ser – Ile – Pro – Ser – Gly – Leu – Thr – Glu – Ala – Val – Lys – Ser – Leu – Asp – Leu – Ser – Asn – Asn – Arg – Ile – Thr – Tyr – Ile – Ser – Asn – Ser – Asp – Leu – Gln – Arg – Cys – Val – Asn – Leu – Gln – Ala – Leu – Val – Leu – Thr – Ser – Asn – Gly – Ile – Asn – Thr – Ile – Glu – Glu – Asp – Ser – Phe – Ser – Ser – Leu – Gly – Ser – Leu – Glu – His – Leu – Asp – Leu – Ser – Tyr – Asn – Tyr – Leu – Ser – Asn – Leu – Ser – Ser – Ser – Trp – Phe – Lys – Pro – Leu – Ser – Ser – Leu – Thr – Phe – Leu – Asn – Leu – Leu – Gly – Asn – Pro – Tyr – Lys – Thr – Leu – Gly – Glu – Thr – Ser – Leu – Phe – Ser – His – Leu – Thr – Lys – Leu – Gln – Ile – Leu – Arg – Val – Gly – Asn – Met – Asp – Thr – Phe – Thr – Lys – Ile – Gln – Arg – Lys – Asp – Phe – Ala – Gly – Leu – Thr – Phe – Leu – Glu – Glu – Leu – Glu – Ile – Asp – Ala – Ser – Asp – Leu – Gln – Ser – Tyr – Glu – Pro – Lys – Ser – Leu – Lys – Ser – Ile – Gln – Asn – Val – Ser – His – Leu – Ile – Leu – His – Met – Lys – Gln – His – Ile – Leu – Leu – Leu – Glu – Ile – Phe – Val – Asp – Val – Thr – Ser – Ser – Val – Glu – Cys – Leu – Glu – Leu – Arg – Asp – Thr – Asp – Leu – Asp – Thr – Phe – His – Phe – Ser – Glu – Leu – Ser – Thr – Gly – Glu – Thr – Asn – Ser – Leu – Ile – Lys – Lys – Phe – Thr – Phe – Arg – Asn – Val – Lys – Ile – Thr – Asp – Glu – Ser – Leu – Phe – Gln – Val – Met – Lys – Leu – Leu – Asn – Gln – Ile – Ser – Gly – Leu – Leu – Glu – Leu – Glu – Phe – Asp – Asp – Cys – Thr – Leu – Asn – Gly – Val – Gly – Asn – Phe – Arg – Ala – Ser – Asp – Asn – Asp – Arg – Val – Ile – Asp – Pro – Gly – Lys – Val – Glu – Thr – Leu – Thr – Ile – Arg – Arg – Leu – His – Ile – Pro – Arg – Phe – Tyr – Leu – Phe – Tyr – Asp – Leu – Ser – Thr – Leu – Tyr – Ser – Leu – Thr – Glu – Arg – Val – Lys – Arg – Ile – Thr – Val – Glu – Asn – Ser – Lys – Val – Phe – Leu – Val – Pro – Cys – Leu – Leu – Ser – Gln – His – Leu – Lys – Ser – Leu – Glu – Tyr – Leu – Asp – Leu – Ser – Glu – Asn – Leu –Met –Val –Glu –Glu –Tyr 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– Gln – Gln – Ala – Leu – Ala – Lys – Val – Leu – Ile – Asp – Trp – Pro – Ala – Asn – Tyr – Leu – Cys – Control Asp – Ser – Pro – Ser – His – Val – Arg – Gly – Gln – Gln – Val – Gln – Asp – Val – Arg – Leu – Ser – Val – Yourself Ser – Glu – Cys – His – Arg – Thr – Ala – Leu – Val – Ser – Gly – Met – Cys – Cys – Ala – Leu – Phe – Leu – Leu – Ile – Leu – Leu – Thr – Gly – Val – Leu – Cys – His – Arg – Phe – His – Gly – Leu – Trp – Tyr – Met – Lys – Met – Met – Trp – Ala – Trp – Leu – Gln – Ala – Lys – Arg – Lys – Pro – Arg – Lys – Ala – Pro – Ser – Treat Arg – Asn – Ile – Cys – Tyr – Asp – Ala – Phe – Val – Ser – Tyr – Ser – Glu – Arg – Asp – Ala – Tyr – Trp – Val – Yourself Glu – Asn – Leu – Met – Val – Gln – Glu – Leu – Glu – Asn – Phe – Asn – Pro – Pro – Phe – Lys – Leu – Cys – Leu – His – Lys – Arg – Asp – Phe – Ile – Pro – Gly – Lys – Trp – Ile – Ile – Asp – Asn – Ile – Ile – Asp – Ser – Ile – Glu – Lys – Ser – His – Lys – Thr – Val – Phe – Val – Leu – Ser – Glu – Asn – Phe – Val – 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Ile – Asn – Thr – Ile – Glu – Glu – Asp – Ser – Phe – Ser – Ser – Leu – Gly – Ser – Leu – Glu – His – Leu – Asp – Leu – Ser – Tyr – Asn – Tyr – Leu – Ser – Asn – Leu – Ser – Ser – Ser – Trp – Phe – Lys – Pro – Leu – Ser – Ser – Leu – Thr – Phe – Leu – Asn – Leu – Leu – Gly – Asn – Pro – Tyr – Lys – Thr – Leu – Gly – Glu – Thr – Ser – Leu – Phe – Ser – His – Leu – Thr – Lys – Leu – Gln – Ile – Leu – Arg – Val – Gly – Asn – Met – Asp – Thr – Phe – Thr – Lys – Ile – Gln – Arg – Lys – Asp – Phe – Ala – Gly – Leu – Thr – Phe – Leu – Glu – Glu – Leu – Glu – Ile – Asp – Ala – Ser – Asp – Leu – Gln – Ser – Tyr – Glu – Pro – Lys – Ser – Leu – Lys – Ser – Ile – Gln – Asn – Val – Ser – His – Leu – Ile – Leu – His – Met – Lys – Gln – His – Ile – Leu – Leu – Leu – Glu – Ile – Phe – Val – Asp – Val – Thr – Ser – Ser – Val – Glu – Cys – Leu – Glu – Leu – Arg – Asp – Thr – Asp – Leu – Asp – Thr – Phe – His – Phe – Ser – Glu – Leu – Ser – Thr – Gly – Glu – Thr – Asn – Ser – Leu – Ile – Lys – Lys – Phe – Thr – Phe – Arg – Asn – Val – Lys – Ile – Thr – Asp – Glu – Ser – Leu – Phe – Gln – Val – Met – Lys – Leu – Leu – Asn – Gln – Ile – Ser – Gly – Leu – Leu – Glu – Leu – Glu – Phe – Asp – Asp – Cys – Thr – Leu – Asn – Gly – Val – Gly – Asn – Phe – Arg – Ala – Ser – Asp – Asn – Asp – Arg – Val – Ile – The remaining natural wildernesses of Africa To mount a successful defense, the innate Identifying and understanding this recognition Know and Asia are home to many different populations immune system must first recognize that the mechanism is a relatively new topic for research­ Yourself of wild animals. Nature documentaries allow body has been invaded. This isn’t quite as ers and there is still much to be learnt. The groups The Fight straight­forward as one might think. There are an of Giulio Superti-Furga and Sylvia Knapp at us to witness the extraordinary interactions Defend between predator and prey, giving us a glimpse enormous variety of different pathogens, with CeMM are investigating the molecular compo­ Yourself of the unrelenting drive of evolution. It is a high replication and mutation rates that enable nents of the recognition machinery. Of course, for Survival world of survival of the fittest. Over millions them to constantly change and adapt quickly realizing that there is an invasion is only the of years, the predators have developed distinc­ to our defenses. Discovering a relatively small beginning. “A cascade of biochemical events is The goal is to understand the molecular mechanisms by which tive characteristics that make them efficient number of pathogens, which have evolved many triggered on recognition of an invading pathogen pathogens invade our bodies and how our bodies react to them, hunters, including great power and strength, crafty ways of surviving unnoticed in the body, by a host cell”, says Giulio. They are using a vari­ to strengthen our fight against disease. and sharp teeth for attacking and devouring requires a sophisticated detection system. It’s ety of techniques to discover what this is and their victims. To avoid being easy targets, the essentially a microscopic game of hide-and-seek. how it signals to the rest of the immune system. other animals have evolved their own strategies Our bodies are patrolled by cells of the immune for survival by living in large groups and keep­ system, which randomly come into contact Some pathogens, particularly viruses, actually ing a careful watch for approaching danger. with hundreds of different types of cells. Most enter our cells, which means that we also need of these cells are part of the host i.e. self, but intracellular defense mechanisms toeliminate Our bodies provide the setting for some of when they encounter an invading microbe that them. Viruses tend to hijack a cell and take over nature’s fiercest battles, that between health they have probably never seen before, they control, using host functions to propagate and and disease. As the host, we have evolved a need to be able to immediately recognize it as continue infecting other cells and organisms. sophisticated immune system with which to a non-self cell so that it can be destroyed. Once a virus has taken over a cell, it is virtually defend our bodies from invasion by pathogens. impossible to regain control, the preferred option This immune system is made up of many dif­ Recognition of non-self cells by the innate being to eliminate the infected cell, along with ferent components: small molecules, proteins, immune system involves identifying molecules the intruder. “When viruses and viral compo­ cells and organs, which provide a collective that are unique to pathogens and are not found nents enter a cell, we want to know what they group of defense mechanisms to protect us in the host. Using surface receptors, cells of the bind to and what molecules and proteins they against infection. They cover all aspects of innate immune system recognize features that are need in order to take over control”, says Giulio, disease control, from identification to eventual found on many pathogens, so called pathogen- whose group is focusing on figuring out how this elimination. Unfortunately, new diseases are associated molecular patterns (PAMPs). Although works. continually evolving alternative strategies for there are different types of PAMPs, importantly attacking our bodies. They devise ways to hide they retain enough similarity within a specific Understanding the molecular mechanisms of from our immune system so that we are unable class of pathogen, to be used as a reliable method ­disease and immune responses can help strength­ to find and destroy them. Our bodies need to for detection. Receptors of the innate immune en our body’s own ability to defend itself, and constantly adapt to keep them from taking over. system, known as Pattern Recognition Receptors gives us the opportunity to develop therapeutics (PRRs), recognize these PAMPs and raise the alarm to act as reinforcements for maintaining health. When a pathogenic microorganism enters the by activating the immune response. After all, knowledge is half the battle. “Although body, our front-line of defense is the innate our general objectives are in furthering the immune system. It is activated within hours after understanding of clinically relevant pathogens, an infection and works by inducing an inflamma­ our primary aim is to improve current diagnostic tory response to stop microorganisms from freely procedures and ultimately influence therapies growing inside our bodies. In most cases, this and survival …”, says Sylvia. It is unlikely that response is sufficient to clear the infection. Some­ our immune system will ever be completely times, however, a more specialized response, victorious over all the pathogens that can cause known as the adaptive immune response, may human diseases. However, we’re putting up a be required for complete removal of the patho­ good fight, and of course it’s not really about win­ gen. The innate immune system relies on many ning. It’s far more important to stay in the game. different types of cells, which are found in the blood. Phagocytes are cells that detect and engulf pathogens, and help to coordinate other defense responses of the body, such as inflammation.

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Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 30 31 Sylvia’s group is also interested in the intracel­ Sylvia has already studied CD14, LBP and Toll- Her group is also studying another PRR, known Know Innate Immunity: lular signaling cascades that are activated in cells like receptors (e.g. TLR2), which are known PRRs as Trem-1. They are interested in how it works Yourself during infection. PI3K is a protein kinase, which that recognize pneumococci, in mouse models during bacterial infections in vivo. “There seems is a type of protein that can radically alter the of pneumonia. Her group is now interested in to be a connection between Trem-1 activation Molecular Defend function of other proteins by adding a chemical, co-receptors for TLR2. TLR2 is known to bind the and inflammation, which we still don’t fully Yourself Mechanisms phosphorylation group to them. PI3K is an ligand LTA, which is found on the cell wall of a understand”, explains Sylvia. They have pre­ important component of many signal transduc­ large group of bacteria known as Gram-positive viously shown that TLR2 contributes to the of Disease tion pathways that are used to translate cellular bacteria. However, it seems that the LTA ligand inflammatory response during pneumococcal signals into specific cellular responses. Infection on S. pneumoniae is quite unique. It contains a pneumonia. Inflammation is an early and critical Recognition is one such signal that is thought to trigger PI3K chemical modification that they believe is impor­ response by the body to infection. It is caused activation, although its precise function during tant for this distinctive function, which they are by increased blood flow to the infected tissue, bacterial infection, especially within the lungs, currently investigating. which is triggered by chemical factors that are is quite controversial. “We don’t know how criti­ released by the injured cells. Inflammation acts Cell Detectives cal it is for the cellular response to infection …”, as a signal to recruit cells that can fight infection The first challenge facing our bodies is to recog­ says Sylvia, who is developing specific mouse and heal damaged tissues (see also below). nize when we have been invaded. We need models of disease to answer this question. an early warning system so we can assemble our defenses and fight. Unfortunately, pathogens Other cellular receptors recognize pathogens that don’t infect our bodies in broad daylight by actually invade our cells. Viruses and bacteria, Fig. 1 The immunofluores­ “The aim is to marching up to the front gates and knocking like human cells, are programmed by genes that cence analysis shows a newly discovered modula- ­create a protein- loudly. They slip in, unnoticed through the back are encoded by nucleic acids, in the form of either tor of IFN-beta production, door. It’s up to our body to find them and raise DNA or RNA. These nucleic acids need to be NLS a protein activated in binding map of response to pathogenic the alarm. Scientists now understand at least one copied many times in order to make new patho­ NLS infections. The modulator the cell, containing of the main principles behind the recognition gens, and this can be achieved by using cellular shuttles between two of pathogens by the innate immune system, and proteins that are normally used to copy our own separate compartments ­all the proteins in the cell, the nucleus involved in reco- that is the interaction between PAMPs (patterns DNA. Internal receptors are used to recognize and the cytosol. Nuclear from the microorganism) and PRRs (receptors these types of molecular invaders and researchers NES entry is mediated by a gnizing a specific on our defense cells). However, for many patho­ nuclear localization signal in Giulio’s lab are using the same physical NES (NLS) and nuclear export pathogen and gens that pose a significant threat to human approaches­ to identify what they are and how is medi­ated by a nuclear health, we still don’t understand what the pat­ they work. ­export signal (NES). generating the Where­as the wild-type terns are and which receptors bind to them. Sylvia (wt) protein is predomi- subsequent cellular Knapp and Giulio Superti-Furga are working on Sylvia has been working for some time on the nantly cytosolic (top left filling in those missing details at CeMM. molecular basis of pneumonia. Community- image), mutation of the response.” wt NES (L12A and L21A) acquired pneumonia is primarily caused by the NES leads to its accumulation Toll-like receptors (TLRs) are a large family bacteria Streptococcus pneumoniae. There are in the nucleus (bottom left images). of PRRs (pattern recognition receptor) that an estimated 570,000 cases of pneumococcal detect invading material in the body. They are pneumonia every year in the USA alone, and of essential components of our innate immune these around 175,000 require hospital treatment. system, and are thought to be part of the reason It is a major cause of morbidity and mortality in L12A why some individuals are more vulnerable humans. The regular treatment for pneumococcal to disease. Christoph Baumann and Tilmann pneumonia is antibiotics. However, as so often NES Buerckstummer, both Post-docs in Giulio’s lab, happens, the bacteria are responding by develop­ are trying to understand how these, and other ing resistance to these drugs. “The situation is surface receptors, work. These proteins are part looking pretty dire …”, says Sylvia, “and this has of a large intracellular signaling network, which prompted renewed urgency in understanding the is very complex. To get a handle on how this is molecular mechanisms of this dangerous disease.” L21A organized, Giulio’s group is taking a physical NES approach. Using a starting protein, such as a TLR, they try to determine which other proteins or molecules it physically associates with. “Essen­ tially, we go fishing in the cell”, explains Tilmann. “Proteins that bind to each other are often part of the same signaling network, and therefore have similar functions”. The aim is to create a protein- Control binding map of the cell, containing all the pro­ Yourself teins involved in recognizing a specific pathogen and generating the subsequent cellular response. Treat Yourself

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Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 32 33 Sylvia also thinks we may be able to utilize OxPL Know Yourself Inflammation to work for us and fight diseases caused by intra­ Bacterial Toxins Fig. 3—4 Two light micro- cellular pathogens. “We want to understand scope images of mouse lungs. Each cell (blue) more about the role of OxPL specifically during has a darker stained Defend bacterial infections, which at the moment is nucleus. The lungs on the Yourself bottom are infected with Double-edged Sword entirely unknown”, says Sylvia. OxPL are also Many pathogens produce poisonous toxins that ­Streptococcus pneumoniae The inflammatory response is a very powerful important mediators of atherosclerosis. Athero­ can cause serious harm to the host. In some cases, bacteria. IRAK-M, which defense mechanism against disease. It is the pri­ sclerosis is characterized by the accumulation of these toxins are so powerful that they can even is induced upon bacterial infection, was detected mary reason we feel pain upon injury and infec­ oxidized LDL (OxLDL) in the walls of the arteries. cause the death of a human being. Pore-forming by labeling with antibodies tion, and it also causes other symptoms including Inflammation is a known contributor to the prog­ toxins are a group of potent toxins associated (brown). “Once the molecular redness and swelling. Work at CeMM is focused ress of the disease, and there is increasing evidence with virulent bacteria such as Clostridium effects of toxins on understanding the molecular mediators of that certain other immune responses can also perfringens and Staphylococcus aureus. These inflammation. Uncontrolled inflammation can affect atherogenesis. Christoph Binder has been bacteria cause many serious human diseases. are known, the also cause serious disease, and so the body tightly involved in developing this line of research in S. aureus is actually the second most common goal will be to regulates it. Christoph Binder, an independent the last five years, and is now investigating it in pathogen isolated from people and causes a wide design drugs to researcher at CeMM, is studying the molecular his own lab at CeMM (see Heal Yourself). range of symptoms, from relatively minor skin mechanisms of atherosclerosis, which is a chronic infections to deadly pneumonia. However, for stop them causing inflammatory disease of the vasculature, and Ventilator-associated pneumonia (VAP) is many pore-forming toxins, we know next to harm.” the underling cause for heart attacks and stroke. the most serious and most frequent hospital- nothing about how they work. acquired infection, affecting 20% of patients in During the inflammatory response, cells of the intensive care units (ICU). It is a treatable disease, “We want to know exactly what it is about these innate immune system, known as phagocytes, however mortality rates of up to 60% have been toxins that cause such a dramatic effect on the attack bacteria by generating reactive oxygen reported, and we are losing the battle predomi­ human body …”, says Sylvia. Her group plans species. These free radicals can also damage cells, nantly due to an inability to detect it early enough. to break down toxins into smaller components subsequently generating oxidized phospholipids “Non-specific clinical signs as well as the lack to help understand how they work. “We want (OxPL). OxPL are considered to be endogenous of appropriate biomarkers often delay diagnosis to know which cells they target in the body, how mediators of inflammation, however the biologi­ and treatment”, explains Sylvia. “We intend to they interact with those cells, and what effects Fig. 5 Fluoresence cal functions of this highly diverse class of lipids examine local inflammation in ventilated ICU they have on cellular function.” To really under­ ­microscope image show- ing phagocytosis (“cell are not well understood. Recently, Sylvia has patients to search for specific biomarkers which stand how a toxin works when it infects a bio­ eating”) of Streptococcus shown that a specific type of OxPL, such as those will enable us to detect the presence of the disease logical organism, they are also developing animal pneumoniae (yellow) by two alveolar macrophages produced during inflammation, actually impair early enough for treatment to be effective”. models of disease. Then they can study toxins (lysosomes are stained the immune response by inhibiting the function in their natural environment. Once the molecular red, the nucleus in blue), of phagocytes. This work was published in the effects of toxins are known, the goal will be to which are defense cells of the innate immune Journal of Immunology in 2007, and is being used design drugs to stop them causing harm. system. as the foundation for future studies on OxPL in the Knapp lab.

Fig. 1 and 2 Streptococcus Fig. 1 Fig. 2 Fig. 6 Fluoresence ­pneumoniae bacterial ­microscope image of a colonies growing on blood macrophage (actin fibers agar plates. in the cell are stained green), that has been incubated with oxidized lipids which causes damage to the cell.

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Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 34 35 Dr. Johannes Hahn Federal Minister for Science and Research

It is a pleasure for me to accompany the first Research Report of the Center of Molecular Medicine (CeMM) of the Austrian Academy of Science with my best wishes and some introducing words. For our Government Science and Research are of high impor- tance regarding preparing a “knowledge and information society” to reach the Lisbon research quota goals as quick as possible. Science at the interface to medicine is my personal priority and of particular importance for our society. CeMM seems to me like a long wanted and very special child. It has been a rather delicate gestation, but the extraordinary collaborative will of the City of Vienna, the Austrian Academy of Science, the Medical University of Vienna and the Ministry of Science and Research has successfully brought up a unique institution that promises to change the way basic biomedical research and clinical requirements are integrated. I know the young team of international investigators already assembled at CeMM personally and trust their energy and vision. We will accompany and support CeMM and expect that it will become a model for biomedical translational research in our country. We wish Giulio Superti-Furga, all the Principal Investigators and all CeMM Scientists success in their research endeavors.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 36 37 For Control Yourself we Know chose the human p53 pro­ Yourself Met – Glu – tein, a tumor suppressor Glu – Pro – Gln – Ser – Asp – Pro – that has been designated Ser – Val – Glu – Pro – Pro – Leu – Ser – Gln – the “guardian of the Glu – Thr – Phe – Ser – Asp – Leu – Trp – Lys – Leu – Defend genome” as it coordinates Leu –Pro –Glu –Asn –Asn –Val –Leu –Ser –Pro –Leu –Pro – Yourself the control of the cell-cycle Ser – Gln – Ala – Met – Asp – Asp – Leu – Met – Leu – Ser – Pro – and genome repair. It is Asp – Asp – Ile – Glu – Gln – Trp – Phe – Thr – Glu – Asp – Pro – Gly – one of the proteins more Pro – Asp – Glu – Ala – Pro – Arg – Met – Pro – Glu – Ala – Ala – Pro – Pro – often mutated in cancer Control Val – Ala – Pro – Ala – Pro – Ala – Ala – Pro – Thr – Pro – Ala – Ala – Pro – and relates to the research Yourself Ala – Pro – Ala – Pro – Ser – Trp – Pro – Leu – Ser – Ser – Ser – Val – Pro – of Sebastian Nijman and Ser – Gln – Lys – Thr – Tyr – Gln – Gly – Ser – Tyr – Gly – Phe – Arg – Leu – Robert Kralovics. The Gly – Phe – Leu – His – Ser – Gly – Thr – Ala – Lys – Ser – Val – Thr – Cys – second sequence is the Thr – Tyr – Ser – Pro – Ala – Leu – Asn – Lys – Met – Phe – Cys – Gln – Leu – p53 related protein p73. Ala – Lys – Thr – Cys – Pro – Val – Gln – Leu – Trp – Val – Asp – Ser – Thr – Pro – Pro – Pro – Gly – Thr – Arg – Val – Arg – Ala – Met – Ala – Ile – Tyr – Control P53_HUMAN Uniprot Lys – Gln – Ser – Gln – His – Met – Thr – Glu – Val – Val – Arg – Arg – Cys – P04637 Pro –His –His –Glu –Arg –Cys –Ser –Asp –Ser –Asp –Gly –Leu –Ala – Pro – Pro – Gln – His – Leu – Ile – Arg – Val – Glu – Gly – Asn – Leu – P73_HUMAN Uniprot Arg – Val – Glu – Tyr – Leu – Asp – Asp – Arg – Asn – Thr – Phe – O15350 Arg – His – Ser – Val – Val – Val – Pro – Tyr – Glu – Pro – Pro – Glu – Val – Gly – Ser – Asp – Cys – Thr – Thr – Ile – His – Tyr – Asn – Tyr – Met – Cys – Asn – Ser – Ser – Cys – Met – Gly – Gly – Met – Asn – Arg – Arg – Pro – Ile – Leu – Thr – Ile – Ile – Thr – Leu – Glu – Asp – Ser – Ser – Gly – Asn – Leu – Leu – Gly – Arg – Asn – Ser – Phe –Glu –Val –Arg –Val –Cys –Ala –Cys –Pro – Gly – Arg – Asp – Arg – Arg – Thr – Glu – Glu – Glu – Asn – Leu – Arg – Lys – Lys – Gly – Glu – Pro – His – His – Glu – Leu – Pro – Pro – Gly – Ser – Thr – Lys – Arg – Ala – Leu – Pro – Asn – Asn – Thr – Ser – Ser – Ser – Pro – Gln – Pro – Lys – Lys – Lys – Pro – Leu – Yourself + Genetics and + Hematological Asp – Gly – Glu – Tyr – Phe – Thr – Leu – Gln – Ile – Arg – Gly – Arg – Glu – Arg – Phe – Glu – Met – Phe – Arg – Glu – Leu – Asn – Glu – Ala – Leu – Glu – Leu – Lys – Epigenetics of Cancer Malignancies Asp – Ala – Gln – Ala – Gly – Lys – Glu – Pro – Gly – Gly – Ser – Arg – Ala – His – Ser – Ser – His – Leu – Lys – Ser – Lys – Lys – Gly – Gln – Ser – Thr – Ser – Arg – His – Lys – Lys – Leu – Met – Phe – Lys – Thr – Glu – Gly – Pro – Asp – Ser – Asp – +++ – Met – Ala – Gln – Ser – Thr – Ala – Thr – Ser – Pro – Asp – Gly – Gly – Thr – Thr – Phe – Glu – His – Leu – Trp – Ser – Ser – Leu – Glu – Pro – Asp – Ser – Thr – Tyr – Phe – Asp – Leu – Pro – Gln – Ser – Ser – Arg – Gly – Asn – Asn – Glu – Val – Val – Gly – Gly – Thr – Asp – Ser – Ser – Met – Asp – Val – Phe – His – Leu – Glu – Gly – Met – Thr – Thr – Ser – Val – Met – Ala – Gln – Phe – Asn – Leu – Leu – Ser – Ser – Thr – Met – Asp – Gln – Met – Ser – Ser – Arg – Ala – Ala – Ser – Ala – Ser – Pro – Tyr – Thr – Pro – Glu – His – Ala – Ala – Ser – Val – Pro – Thr – His – Ser – Pro – Tyr – Ala – Gln – Pro – Ser – Ser – Thr – Phe – Asp – Thr – Met – Ser – Pro – Ala – Pro – Val – Ile – Pro – Ser – Asn – Thr – Asp – Tyr – Pro – Gly – Pro – His – His – Phe – Glu – Val – Thr – Phe – Gln – Gln – Ser – Ser – Thr – Ala – Lys – Ser – Ala – Thr – Trp – Thr – Tyr – Ser – Pro – Leu – Leu – Lys – Lys – Leu – Tyr – Cys – Gln – Ile – Ala – Lys – Thr – Cys – Pro – Ile – Gln – Ile – Lys – Val – Ser – Thr – Pro – Pro – Pro – Pro – Gly – Thr – Ala – Ile – Arg – Ala – Met – Pro – Val – Tyr – Lys – Lys – Ala – Glu – His – Val – Thr – Asp – Val – Val – Lys – Arg – Cys – Pro – Asn – His – Glu – Leu – Gly – Arg – Asp – Phe – Asn – Glu – Gly – Gln – Ser – Ala – Pro – Ala – Ser – His – Leu – Ile – Arg – Val – Glu – Gly – Asn – Asn – Leu – Ser – Gln – Tyr – Val – Asp – Asp – Pro – Val – Thr – Gly – Arg – Gln – Ser – Val – Val – Val – Pro – Tyr – Glu – Pro – Pro – Gln – Val – Gly – Thr – Glu – Phe – Thr – Thr – Ile – Leu – Tyr – Asn – Phe – Met – Cys – Asn – Ser – Ser – Cys – Val – Gly – Gly – Met – Asn – Arg – Arg – Pro – Ile – Leu – Ile – Ile – Ile – Thr – Leu – Glu – Met – Arg – Asp – Gly – Gln – Val – Leu – Gly – Arg – Arg – Ser – Phe – Glu – Gly – Arg – Ile – Cys – Ala – Cys – Pro – Gly – Arg – Asp – Arg – Lys – Ala – Asp – Glu – Asp – His – Tyr – Arg – Glu – Gln – Gln – Ala – Leu – Asn – Glu – Ser – Ser – Ala – Lys – Asn – Gly – Ala – Ala – Ser – Lys – Arg – Ala – Phe – Lys – Gln – Ser – Pro – Pro – Ala – Val – Pro – Ala –Leu – Gly – Ala – Gly – Val – Lys – Lys – Arg – Arg – His – Gly – Asp – Glu – Asp – Thr – Tyr – Tyr – Leu – Gln – Val – Arg – Gly – Arg – Glu – Asn – Phe – Glu – Ile – Leu – Met – Lys – Leu – Lys – Glu – Ser – Leu – Glu – Leu – Met – Glu – Leu – Val – Pro – Gln – Pro – Leu – Val – Asp – Ser – Tyr – Arg – Gln – Gln – Gln – Gln – Leu – Leu – Gln – Arg – Pro – Ser – His – Leu – Gln – Pro – Pro – Ser – Tyr – Gly – Pro – Val – Leu – Ser – Pro – Met – Asn – Lys – Val – His – Gly – Gly – Met – Asn – Lys – Leu – Pro – Ser – Val – Asn – Gln – Leu – Val – Gly – Gln – Pro – Pro – Pro – His – Ser – Ser – Ala – Ala – Thr – Pro – Asn – Leu – Gly – Pro – Val – Gly – Pro – Gly – Met – Leu – Asn – Asn – His – Gly – His – Ala – Val – Pro – Ala – Asn – Gly – Glu – Met – Ser – Ser – Ser – His – Ser – Ala – Gln – Ser – Met – Val – Ser – Gly – Ser – His – Cys – Thr – Pro – Pro – Pro – Pro – Tyr – His – Ala – Asp – Pro – Ser – Leu – Val – Ser – Phe – Leu – Thr – Gly – Leu – Gly – Cys – Pro – Asn – Cys – Ile – Glu – Tyr – Phe – Thr – Ser – Gln – Gly – Leu – Gln – Ser – Ile – Tyr – His – Leu – Gln – Asn – Leu – Thr – Ile – Glu – Asp – Leu – Gly – Ala – Leu – Lys – Ile – Pro – Glu – Gln – Tyr – Arg – Met – Thr – Ile – Trp – Arg – Gly – Leu – Gln – Asp – Leu – Lys – Gln – Gly – His – Asp – Tyr – Ser – Thr – Ala – Gln – Gln – Leu – Leu – Arg – Ser – Ser – Asn – Ala – Ala – Thr – Ile – Ser – Ile – Gly – Gly – Ser – Gly – Glu – Leu – Gln – Arg – Gln – Arg – Val – Met – Glu – Ala – Val – His – Phe – Arg – Val – Arg – His – Thr – Ile – Thr – Ile – Pro – Asn – Arg – Gly – Gly – Pro – Gly – Gly – Gly – Pro – Asp – Glu – Trp – Ala – Asp – Phe – Gly – Phe – Asp – Leu – Pro – Asp – Cys – Lys – Ala – Arg – Lys – Gln – Pro – Ile – Lys – Glu – Glu – Phe – Thr – Glu – Ala – Glu – Ile – His – +++ – Met – Glu – Glu – Pro – Gln – Ser – Asp – Pro – Ser – Val – Glu – Pro – Pro – Leu – Ser – Gln – Glu – Thr – Phe – Ser – Asp – Leu – Trp – Lys – Leu – Leu – Pro – Glu – Asn – Asn – Val – Leu – Ser – Pro – Leu – Pro – Ser – Gln – Ala – Met – Asp – Asp – Leu – Met –Leu –Ser –Pro –Asp –Asp –Ile –Glu – Gln – Trp – Phe – Thr – Glu – Asp – Pro – Gly – Pro – Asp – Glu – Ala – Pro – Arg – Met – Pro – Glu – Ala – Ala – Pro – Pro – Val – Ala – Pro – Ala – Pro – Ala – Ala – Pro – Thr – Pro – Ala – Ala – Pro – Ala – Pro – Ala – Pro – Ser – Trp – Pro – Leu – Ser – Ser – Ser – Val – Pro – Ser – Gln – Lys – Thr – Tyr – Gln – Gly – Ser – Tyr – Gly – Phe – Arg – Leu – Gly – Phe – Leu – His – Ser – Gly – Thr – Ala – Lys – Ser – Val – Thr – Cys – Thr – Tyr – Ser – Pro – Ala – Leu – Asn – Lys – Met – Phe – Cys – Gln – Leu – Ala – Lys – Thr – Cys – Pro – Val – Gln – Leu – Trp – Val – Asp – Ser – Thr – Pro – Pro – Pro – Gly – Thr – Arg – Val – Arg – Ala – Met – Ala – Ile – Tyr – Lys – Gln – Ser – Gln – His – Met – Thr – Glu – Val – Val – Arg – Arg – Cys – Pro – His – His – Glu – Arg – Cys –Ser –Asp –Ser – Asp – Gly – Leu – Ala – Pro – Pro – Gln – His – Leu – Ile – Arg – Val – Glu – Gly – Asn – Leu – Arg – Val – Glu – Tyr – Leu – Asp – Asp – Arg – Asn – Thr – Phe – Arg – His – Ser – Val – Val – Val – Pro – Tyr – Glu – Pro – Pro – Glu – Val – Gly – Ser – Asp – Cys – Thr – Thr – Ile – His – Tyr – Asn – Tyr – Met – Cys – Asn – Ser – Ser – Cys – Met – Gly – Gly – Met – Asn – Arg – Arg – Pro – Ile – Leu – Thr – Ile – Ile – Thr – Leu – Glu – Asp – Ser – Ser – Gly – Asn – Leu – Leu – Gly – Arg – Asn – Ser – Phe – Glu – Val – Arg – Val – Cys – Ala – Cys – Pro – Gly – Arg – Asp – Arg – Arg – Thr – Glu – Glu – Glu – Asn – Leu – Arg – Lys – Lys – Gly – Glu – Pro – His – His – Glu – Leu – Pro – Pro – Gly – Ser – Thr – Lys – Arg – Ala – Leu – Pro – Asn – Asn – Thr – Ser – Ser – Ser – Pro – Gln – Pro – Lys – Lys – Lys – Pro – Leu – Asp – Gly – Glu – Tyr – Phe – Thr – Leu – Gln – Ile – Arg – Gly – Arg – Glu – Arg – Phe – Glu – Met – Phe – Arg – Glu – Leu – Asn – Glu – Ala – Leu – Glu – Leu – Lys – Asp – Ala – Gln – Ala – Gly – Lys – Glu – Pro – Gly – Gly – Ser – Arg – Ala – His – Ser – Ser – His – Leu – Lys – Ser – Lys – Lys – Gly – Gln – Ser – Thr – Ser – Arg – His – Lys – Lys – Leu – Met – Phe – Lys – Thr – Glu – Gly – Pro – Asp – Ser – Asp – +++ – Met – Ala – Gln – Ser – Thr – Ala – Thr – Ser – Pro – Asp – Gly – Gly – Thr – Thr – Phe – Glu – His – Leu – Trp – Ser – Ser – Leu – Glu – Pro – Asp – Ser – Thr – Tyr – Phe – Asp – Leu – Pro – Gln – Ser – Ser – Arg – Gly – Asn – Asn – Glu – Val – Val – Gly – Gly – Thr – Asp – Ser – Ser – Met – Asp – Val – Phe – His – Leu – Glu – Gly – Met – Thr – Thr – Ser – Val – Met – Ala – Gln – Phe – Asn – Leu – Leu – Ser – Ser – Thr – Met – Asp – Gln – Met – Ser – Ser – Arg – Ala – Ala – Ser – Ala – Ser – Pro – Tyr – Thr – Pro – Glu – His – Ala – Ala – Ser – Val – Pro – Thr – His – Ser – Pro – Tyr – Ala – Gln – Pro – Ser – Ser – Treat Thr – Phe – Asp – Thr – Met – Ser – Pro – Ala – Pro – Val – Ile – Pro – Ser – Asn – Thr – Asp – Tyr – Yourself Pro – Gly – Pro – His – His – Phe – Glu – Val – Thr – Phe – Gln – Gln – Ser – Ser – Thr – Ala – Lys – Ser – Ala – Thr – Trp – Thr – Tyr – Ser – Pro – Leu – Leu – Lys – Lys – Leu – Tyr – Cys – Gln – Ile – Ala – Lys – Thr – Cys – Pro – Ile – Gln – Ile – Lys – Val – Ser – Thr – Pro – Pro – Pro – Pro – Gly – Thr – Ala – Ile – Arg – Ala –Met –Pro –Val –Tyr –Lys –Lys –Ala –Glu –His –Val –Thr –Asp –Val –Val –Lys –Arg –Cys –Pro – Heal Yourself Asn – His – Glu – Leu – Gly – Arg – Asp – Phe – Asn – Glu – Gly – Gln – Ser – Ala – Pro – Ala – Ser – His – Leu – Ile – Arg – Val – Glu – Gly – Asn – Asn – Leu – Ser – Gln – Tyr – Val – Asp – Asp – Pro – Val – Thr – Gly – Arg – Gln – Ser – Val – Val – Val – Pro – Tyr – Glu – Pro – Pro – Gln – Val – Gly – Thr – Glu – Phe – Thr – Thr – Ile – Leu – Tyr – Asn – Phe – Met – Cys – Asn – Ser – Ser – Cys – Val – Gly – Gly – Met – Asn – Arg – Arg – Pro – Ile – Leu – Ile – Ile – Ile – Thr – Leu – Glu – Met – Arg – Asp – Gly – Gln – Val – Leu – Gly – Arg – Arg – Ser – Phe – Glu – Gly – Arg – Ile – Cys – Ala – Cys – Pro – Gly – Arg – Asp – Arg – Lys – Ala – Asp – Glu – Asp – His – Tyr – Arg – Glu – Gln – Gln – Ala – Leu – Asn – Glu – Ser – Ser – Ala – Lys – Asn – Gly – Ala – Ala – Ser – Lys – Arg – Ala – Phe – Lys – Gln – Ser – Pro – Pro – Ala – Val – Pro – Ala – Leu – Gly – Ala – Gly – Val – Lys – Lys – Arg – Arg – His – Gly – Asp – Glu – Asp – Thr – Tyr – Tyr – Leu – Gln – Val – Arg – Gly – Arg – Glu – Asn – Phe – Glu – Ile – Leu – Met – Lys – Leu – Lys – Glu – Ser – Leu – Glu – Leu – Met – Glu – Leu – Val – Pro – Gln – Pro – Leu – Val – Asp – Ser – Tyr – Arg – Gln – Gln – Gln – Gln – Leu – Leu – Gln – Arg – Pro – Ser – His – Leu – Gln – Pro – Pro – Ser – Tyr – Gly – Pro – Val – Leu – Ser – Pro – Met – Asn – Lys – Val – His – Gly – Gly – Met – Asn – Lys – Leu – Pro – Ser – Val – Asn – Gln – Leu – Val – Gly – Gln – Pro – Pro – Pro – His – Ser – Ser – Ala – Ala – Thr – Pro – Asn – Leu – Gly – Pro – Val – Gly – Pro – Gly – Met – Leu – Asn – Asn – His – Gly – His – Ala – Val – Pro – Ala – Asn – Gly – Glu – Met – Ser – Ser – Ser – His – Ser – Ala – Gln – Ser – Met – Val – Ser – Gly – Ser – His – Cys – Thr – Pro – Pro – Pro – Pro – Tyr – His – Ala – Asp – Pro – Ser – Leu – Val – Ser – Phe – Leu – Thr – Gly – Leu – Gly – Cys – Pro – Asn – Cys – Ile – Glu – Tyr – Phe – Thr – Ser – Gln – Gly – Leu – Gln – Ser – Ile – Tyr – His – Leu – Gln – Asn – Leu – Thr – Ile – Glu – Asp – Leu – Gly – Ala – Leu – Lys – Ile – Pro – Glu – Gln – Tyr – Arg – Met – Thr – Ile – Trp – Arg – Gly – Leu – Gln – Asp – Leu – Lys – Gln – Gly – His – Asp – Tyr – Ser – Thr – Ala – Gln – Gln – Leu – Leu – Arg – Ser – Ser – Asn – Ala – Ala – Thr – Ile – Ser – Ile – Gly – Gly – Ser – Gly – Glu – Leu – Gln – Arg – Gln – Arg – Val – Met – Glu – Ala – Val – His – Phe – Arg – Val – Arg – His – Thr – Ile – Thr – Ile – Pro – Asn – Arg – Gly – Gly – Pro – Gly – Gly – Gly – Pro – Asp – Glu – Trp – Ala – Asp – Phe – Gly – Phe – Asp – Leu – Pro – Asp – Cys – Lys – Ala – Arg – Lys – Gln – Pro – Ile – Lys – Glu – Glu – Phe – Thr – Glu – Ala – Glu – Ile – His – +++ – The public transport system in Vienna is incred­ The Origin of Cancer Gene Regulation Know ibly well organized. With five underground lines, A fully developed human being contains many Understanding how individual genes are regulat­ Yourself Maintaining and 80 bus and 31 tram lines covering 24 hours millions of cells, of many different types. All the ed is one of the finest levels of control within the of the day, it enables the people of Vienna to get cells of a specific type originate from one com­ body. Turning genes on and off at specific times Defend almost anywhere in the city easily and quickly. mon ancestral cell, or stem cell, and the mecha­ and in response to the correct signals is vital Yourself This transport network requires a high level of nism of cell growth and differentiation is under for all cells to function. These patterns of gene control to manage the individual parts of the careful control. “Mistakes in the DNA that occur expression are regulated at many different levels, Biological Control system and ensure it works efficiently as a whole. early on in development, or those that come by molecules that can bind to the DNA. Epige­ Yourself Any disturbances, such as a technical malfunction from our parents, are inherited by many cells, netic regulation works on the DNA by modifying or an obstacle on the line, can be easily dealt with, which can cause them to function incorrectly its structure and so altering its ability to respond Order and the system quickly returned to full capacity. later on and cause disease”, says Robert Kralovics. to external signals. It has been known for some His group is interested not only in what the time to play a vital role during development and Understanding and exploiting the processes by which cells All systems and organizations are under some defects are, but also when and where they happen certain diseases. Now, researchers are finding and tissues maintain their properties and don’t lose identity degree of control. This control is in place to direct during the development of blood cells. that it plays an equally important role in cancer. or over-proliferate to form diseases such as cancer. and regulate the behavior of the system and ensure it works as well as possible. However, Cells are spatially restricted within our bodies, Epigenetic regulation of gene expression is a the control of a city’s transport system is nothing and although we stop growing in our late teenage process studied at CeMM by Denise Barlow. In compared to the level of control that goes into years, many of our cells, including our blood 2005, scientists discovered that over 70% of the the production and maintenance of life. “Our cells and skin cells, will continue to divide until DNA that is copied or transcribed into RNA, does internal checkpoints and controls are vital to we die. To ensure that our bodies maintain equi­ not go on to make protein. However, only a few maintain a healthy body”, explains Giulio ­Superti- librium, some cells are also programmed to die, have a known function. “We are very interested Furga. “If we can learn to understand what they to make way for new cells. This process also in finding out what these non-coding RNAs do, are and how they work, we can find ways to requires a highly orchestrated and sophisticated and how they do it”, says Denise. The group is correct them when they break down and cause mechanism of control. Normal, healthy cells are working on characterizing a class of macro ncR­ disease”. instructed when to grow or die by specific signals NAs, which they have shown work back on the acting through the DNA. Cancer cells have altered, DNA from which they were copied, to directly Control of the human body begins as soon as life or mutated DNA, which enables them to escape control gene expression. This is a relatively new does, following the fusion between two cells, this tight control on their function. approach for understanding cancer epigenetics, a sperm and an egg. This fusion generates a chain and scientists have only recently documented reaction of cell growth and differentiation, begin­ Cancer cells can eventually spread to other parts a connection between macro ncRNAs and ning the journey through embryonic develop­ of our bodies, wreaking havoc on our balanced epigenetic silencing of genes that lead to cancer. ment. A cell’s main control center is its nucleus, system. Cancer can be thought of as an out of which contains the DNA. Cells are directed control vehicle. Using the analogy with a trans­ Our body plans are prearranged even before by external signals that are transported from the port system, cancer is the runaway bus that we come into existence. Complex mechanisms surface of the cell into the nucleus. Depending travels randomly throughout a city, without of control are in place to ensure life is ordered on which signals are received, the cell reads out schedule or destination. It would disrupt the and functional. Identifying and studying them certain combinations of genes from its DNA, normal running of the other buses and trams, all is a tough challenge for researchers, but it’s and uses them to make specific proteins, which and eventually the transport network would essential if they are to understand the cause of are the building blocks of the cell. Proteins are complete­ly break down. “Cancer is essentially many diseases. When control breaks down, it likethe tools of a trade and with them a cell can caused by a deregulation of growth control”, says has dramatic consequences, both at the cellular perform a specialized function. Skin cells, for Sebastian Nijman, whose group is using genetic and organismal level. Not all mutations are example, form a barrier to protect us from absorb­ screens to study deregulated cellular functions bad of course, even ones that bypass control. ing harmful material from our surroundings, that can cause cancer. They have also allowed DNA to change and and cardiac muscle cells rhythmically contract evolve over millions of years to eventually cre­ to pump blood and oxygen around our bodies. ate Homo sapiens, with large brains amongst other characteristics necessary to navigate the complicated transport systems in our various ­cities and live a fairly successful life on this earth.

Treat Yourself

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 40 41 One major challenge taken on by researchers at Controlling the genome genes. Since then, several more ncRNAs func­ Know Genetics and CeMM is to identify new cancer-associated genes Although, to date, over 80 genomes have been tioning in this way have been identified in both Yourself and understand their functions and how they sequenced, understanding how the genetic code imprinted and non-imprinted regions of the Epigenetics are regulated. Cataloguing cancer in this way translates into cellular function is only beginning genome. Defend means scientists can develop more sophisticated to be understood. There are over 20,000 genes in Yourself of Cancer therapeutics to target individual cancers, rather the human genome, and a complex mechanism The lab went on to study the Air ncRNA, find­ than the relatively non-specific chemotherapies of control exists for the expression of each one. ing functional and structural characteristics that Control that are commonly used to treat the disease today. Epigenetic regulation is one of these mechanisms, gave insight into how these molecules might Yourself Sebastian’s lab is using a technique known as and it works by altering the structure or the work and how they can be regulated. However, Getting Out of Control RNAi, to search through the genome and find modification of the DNA, and the chromatin it is still not clear how these ncRNAs actually Cancer is caused by a dramatic loss of cellular cancer-causing genes. Technology exists so proteins bound to it, and so regulating its ability silence genes, and the lab is devoted to figuring control. This loss of control occurs by numerous that scientists can switch off individual genes to respond to certain signals. For example, the this out. “Many fundamental questions still mechanisms that alter the activity of genes. At in a cell, and see if that gives the cell a growth addition of small chemical groups such as methy­ remain”, says Denise. “For example, we don’t present, if we group cancers according to their advantage over other cells. RNAi has emerged lation to the DNA can silence the activity of know if it is the ncRNA molecules themselves tissue of origin, there are around 100 different as a powerful mechanism to study gene function. specific genes. These epigenetic marks are mostly that are important, or whether it is the act of types. However, if we look at their gene expres­ Sebastian’s work at the NKI in the Netherlands stable, and each time the cell divides, the marks their production that blocks gene activity”. sion patterns, that is which genes are switched and the Broad institute at MIT has given him are retained in both resulting (daughter) cells. on and which are off, no two cancers are the valuable experience designing and performing Denise’s lab is currently committed to a large- same. Each cancer develops in a unique way, successful genetic screens, as well as access to Many different proteins are known to mediate scale analysis of a group of ncRNAs, known although they use many general approaches libraries containing short hairpin RNAs, which the epigenetic regulation of genes. However, as macro ncRNAs, in the human and mouse to escape cellular control. Identifying the exact target all of the 20,000 or so genes in the human more recently it has been shown that some non- genomes. Like Sebastian’s group, they are also alterations and perturbations of the DNA that genome. “By introducing these shRNAs into coding RNA (ncRNA) molecules are also respon­ fully exploiting the recent sequencing of the cause each cancer seems an insurmountable cells, we can ask the cells to show us which sible for controlling gene expression. Although human and mouse genomes. They are using Fig. 1 The human genome task. However, with the recent sequencing of genes are important for certain functions”, says ncRNAs are abundantly produced in every cell, post-genomic technology, like SOLEXA that contains approximately the human genome came the opportunity to Sebastian. It is possible to discover new tumor it is not clear what they are doing. “We believe sequences millions of fragments of DNA in 90 deubiquitinating enzymes (DUBs) that can discover new principles of cancer develop­ suppressor genes using this approach, and iden­ that epigenetic regulation of gene expression may one go, and specialized microarrays, that can remove the polypeptide ment and make major contributions to the field. tify new targets for the development of drugs. be quite a general function for ncRNAs”, says in a single experiment tell you the activity ubiquitin from protein substrates. DUBs are “Scientists are no longer taking a gene by gene Denise Barlow. of all the genes within an entire genome. involved in all aspects of approach”, says Sebastian Nijman. “We can Sebastian has been developing new technologies biology, including inflam- now take on the entire genome.” The 21st Cen­ to help improve the efficiency of the screens, The Barlow lab has worked for many years on the The past five years has seen a rising interest in the mation and cancer. This unrooted dendrogram tury marks the beginning of an era of ­discovery which he is now testing on signaling pathways mechanisms of imprinting, since their discovery epigenetics of cancer in terms of looking at DNA shows the degree of in cancer biology. Suddenly, Mount Everest that are deregulated in cancer. The aim is to in 1991 of the first imprinted gene. Mammals modifications and chromatin changes in cancer sequence relatedness of the 90 DUB genes, which doesn’t look like such a big mountain to climb. identify new components of these pathways, are diploid organisms, meaning they carry two tissues. “Now we can show that in imprinted divide into five separate to help understand how they are regulated, copies of every gene in each cell. One copy clusters the prime target of DNA methylation sub-classes. The Nijman Cancer biology is one of the largest fields in cell and what can go wrong to cause disease. is inherited from the mother and one from the is to regulate macro ncRNAs that can regulate lab is using RNAi and genetic screens to study biology. It began over thirty years ago with the father. Occasionally, one of the two genes is neighboring genes”, says Denise. “Now we want the biological function discovery of the first proto-oncogene by Harold switched off while the other is left on, a process to know if the large subset of human tumors of DUBs in disease. Varmus and Michael Bishop at the University known as imprinting. This differential control that show DNA methylation changes will have of California, San Francisco, in the USA. The of the two copies of the same gene is regulated specific macro ncRNAs that are able to upregu­ pair went on to receive the Nobel Prize for their epigenetically. Work done in Denise’s lab five late or downregulate flanking tumor associated discovery in 1989. Proto-oncogenes and Tumor years ago identified the first ncRNA that was genes.” This could essentially be thought of as suppressor genes are types of genes that have required to silence a small cluster of imprinted a new principle for the molecular cause of cancer. the capacity to significantly increase the chance that a cell will become cancerous when they are mutated. Cancer can be thought of as an out of control car. Proto-oncogenes act as accelerators, and if they can be jammed on, they can force Fig. 2 A high-throughput a cell to continually divide even when there are Fig. 2 Fig. 3 Fig. 3 In 1971, the bar-coding experiment no signals to tell it to do so. In the opposite American geneticist Alfred using 24,000 RNAi vectors. Knudson proposed that Each dot (black, green or way, tumor suppressor genes act as the brakes. gradual accumulation of 5 SMAD4 red) represents one RNAi If they fail, cells are able to grow unrestricted. LOH genetic mutations causes vector and the position cancer. Tumor suppres- indicates its abundance sor genes are frequently in the population. The inactivated by silencing Tumor suppressor gene 1st allele silenced Clonal expansion 2 silenced alleles red and green dots are (Cy5/Cy3) 0 one copy of the gene 2 active alleles of heterozygous cells clonal eypansion significantly more or less (allele), and then losing log ² (dosage sensitive gene) of homozygous cells abundant than average, = the other active allele,

M pre-cancer state cancer state and represent genes that known as loss of heterozy- are potentially important gosity (LOH). Tumor –5 for growth control. suppressors can also be Treat silenced epigenetically, Yourself however the extent to 0 5 10 15 Epigenetic silencing Epigenetic silencing which this occurs in cancer is currently unclear. A = ²log (√Cy5/Cy3) Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 42 43 A major step towards understanding the molec­ Know Yourself Hematological ular basis of MPDs was the identification of a Fig. 1 Crystal structure of specific mutation in the JAK2 gene in 50% of the active conformation of the JAK2 protein tyrosine Malignancies patients. The invariant nature of this mutation kinase domain in complex Defend makes it an attractive candidate for targeted drug with a high-affinity pan- Yourself JAK inhibitor (PDB entry therapy. Robert Kralovics made this discovery 2B7A) when he was a Post-doc in the lab of Radek Control Master Controllers Skoda, in Switzerland in 2005. “This mutation Yourself Cells become cancerous by acquiring a series causes only a very small change in the sequence of mutations that each confers a function on of the gene, but it is so powerful that if you the cell giving it an advantage over other cells. introduce the mutant protein into mice, you “Most cancers are These mutations are highly diverse. Some may can essentially cause them to develop cancer”, directly activate an oncogene or inactivate explains Robert. They know that the mutation thought to origi- a tumor suppressor gene, to give the cell the allows cells to evade important growth control nate from a key opportunity to divide more times than it should. mechanisms by constitutively activating the mutation in one Others mean that the cell acquires more muta­ JAK/STAT molecular pathway. Although this tions than normal, giving it a bigger chance of is an important mutation for MPD, it seems individual cell.” mutating a key gene that would make it more it is not the critical first mutation that sets the likely to become cancerous. Most cancers are disease in motion. In his own lab, Robert is using thought to originate from a key mutation in patient samples to try to discover these elusive one individual cell. This cell then acquires sub­ disease-initiating mutations and other muta­ sequent, critical mutations and eventually is tions that are important for MPD development. “This mutation able to become cancerous. The danger increases They hope to identify new targets for therapy, when the cell with the founding mutation which may also be applicable to other myeloid causes only a very is a stem cell that will eventually give rise to diseases, since some of the mutations are also small change in a large number of cells within a certain organ or found in other leukemia-related conditions. the sequence of lineage, all of which will then carry that crucial mutation. Myeloproliferative disorders (MPD) Thrombosis, the formation of a clot that obstructs the gene, but it is are considered to be one such stem cell disease. the flow of blood, is a clinical complication of so powerful that MPD, and is a leading cause of morbidity and if you introduce Robert Kralovics is interested in the genetic mortality. Its occurrence strongly correlates with mutations that cause MPD. MPDs are a hetero­ the presence of the activating JAK2 mutation, the mutant protein geneous group of diseases characterized by an however, why this happens, and how it might into mice, you can excessive production of certain types of blood work at the molecular level is completely essentially cause cells and their precursors. Symptoms of this unknown. Using genome–wide techniques, them to develop disease can also include bleeding or thrombosis. Robert’s group has been trying to understand The biggest danger of MPDs is that they can the molecular consequences of having a consti­ cancer.” progress to secondary myelofibrosis or eventu­ tutively activated JAK-STAT pathway, to try to ally develop a therapy resistant form of Acute link this to the increased incidence of thrombosis Myeloid Leukemia, which is the most common in MPD patients. “We suspect that the JAK muta­ acute leukemia in adults. It accounts for around tion somehow affects the function of platelets 1.2% of cancer deaths in the USA, and its inci­ or neutrophils, which are specific types of blood dence increases with age, so rates are expected cells important for coagulation of the blood”, to rise as the population continues to age. says Robert. To study this, his group is develop­ ing mouse models, which allow them to intro­ Classical MPD and MPD-like syndromes are duce the JAK mutation into one specific type of familial diseases, meaning that multiple family blood cell at a time. They have already shown members can be affected. Diseases with an that MPD-associated thrombosis has a complex inheritable component also give researchers cause, and that JAK2 mutations are only one of a unique opportunity to discover more about several important risk factors. Now, in close col­ their molecular basis. Humans contain two cop­ laboration with the Medical University in Vienna, ies of each gene, and children inherit one copy they have identified additional genes and path­ from their mother and one from their father. ways that influence this disease process. The aim By looking at which family members have the of these studies is to gain insight into the molec­ disease, it is possible to follow the inheritance ular processes of MPD thrombosis and develop a of a causative mutation through the generations, therapeutic strategy that can profoundly improve and eventually identify exactly which gene the quality of life of MPD patients. Treat contains the critical, founding mutation. Yourself

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 44 45 Dr. Michael Häupl Mayor of the City of Vienna

As mayor of the City of Vienna I am very proud of the Center of Molecular Medicine because it is one outstanding research institution out of a large number of top scientific institutes based in our city. I personally congratulate Professor Superti- Furga as one of the world’s leading scientists in the field of molecular biology on the excellent work done by him and all scientists at CeMM. Being able to attract such a great number of brilliant researchers underlines the enormous popularity of Vienna as a business location also because of its ideal geo- political position in the very heart of Europe being the hub between East and West. And it emphasizes the high quality of life we enjoy to share. But, to be able to achieve excel- lence, scientists also need relevant financial support as well as proper infrastructure. Therefore the City of Vienna and the federal state of Austria jointly enabled the construction of a new research facility for CeMM right on the site of Vienna´s General Hospital for mutual transfer of knowledge for the benefit of science and patients. Hence the stage for further success of the “hot spot” Vienna is set.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 46 47 Know Yourself

M e t – Ala – Leu – Trp – Met – Defend Arg – Leu – Leu – Pro – Leu – Leu – Yourself Ala – Leu – Leu – Ala – Leu – Trp – Gly – Pro – Asp – Pro – Ala – Ala – Ala – Phe – Val – Asn – Gln – His – Leu – Cys – Gly – Ser – His – Leu – Val – Glu – Ala – Leu – Tyr – Leu – Val – Cys – Gly – Glu – Arg – Gly – Phe – Phe – Tyr – Control Thr –Pro –Lys –Thr –Arg –Arg –Glu –Ala –Glu –Asp –Leu –Gln – Yourself Val – Gly – Gln – Val – Glu – Leu – Gly – Gly – Gly – Pro – Gly – Ala – Gly – Ser – Leu – Gln – Pro – Leu – Ala – Leu – Glu – Gly – Ser – Leu – Gln – Lys – Arg – Gly – Ile – Val – Glu – Gln – Cys – Cys – Thr – Ser – Ile – Cys – Ser – Leu – Tyr – Gln – Leu – Glu – Asn – Tyr – Cys – Asn – +++ – Met – Gly – Thr – Gly – Gly – Arg – Arg – Treat Yourself Gly – Ala – Ala – Ala – Ala – Pro – Leu – Leu – Val – Ala – Val – Ala – Ala – Leu – Leu – Leu – Gly – Ala – Ala – Gly – His – Leu – Tyr – Pro – Gly – Glu – Val – Cys – Treat Pro – Gly – Met – Asp – Ile – Arg – Asn – Asn – Leu – Thr – Arg – Leu – His – 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Arg – Gly – Gly – Asn – Asn – Leu – Ala – Ala – Glu – Leu – Glu – Ala – Asn – Leu – Gly – Leu – Ile – Glu – Glu – Ile – Ser – Gly – Tyr – Leu – Lys – Ile – Arg – Arg – Ser – Tyr – Ala – Leu – Val – Ser – Leu – Ser – Phe – Phe – Arg – Lys – Leu – Arg – Leu – Ile – Arg – Gly – Glu – Thr – Leu – Glu – Ile – Gly – Asn – Tyr – Ser – Phe – Tyr – Ala – Leu – Asp – Asn – Gln – Asn – Leu – Arg – Gln – Leu – Trp – Asp – Trp – Ser – Lys – His – Asn – Leu – Thr – Thr – Thr – Gln – Gly – Lys – Leu – Phe – Phe – His – Tyr – Asn – Pro – Lys – Leu – Cys – Leu – Ser – Glu – Ile – His – Lys – Met – Glu – Glu – Val – Ser – Gly – Thr – Lys – Gly – Arg – Gln – Glu – Arg – Asn – Asp – Ile – Ala – Leu – Lys – Thr – Asn – Gly – Asp – Lys – Ala – Ser – Cys – Glu – Asn – Glu – Leu – Leu – Lys – Phe – Ser – Tyr – Ile – Arg – Thr – Ser – Phe – Asp – Lys – Ile – Leu – Leu – Arg – Trp – Glu – Pro – Tyr – Trp – Pro – Pro – Asp – Phe – Arg – Asp – Leu – Leu – Gly – Phe – Met – Leu – Phe – Tyr – Lys – Glu – Ala – Pro – Tyr – Gln – Asn – Val – Thr – Glu – Phe – Asp – Gly – Gln – Asp – Ala – Cys – Gly – Ser – Asn – Ser – Trp – Thr – Val – Val – Asp – Ile – Asp – Pro – Pro – Leu – Arg – Ser – Asn – Asp – Pro – Lys – Ser – Gln – Asn – His – Pro – Gly – Trp – Leu – Met – Arg – Gly – Leu – Lys – Pro – Trp – Thr – Gln – Tyr – Ala – Ile – Phe – Val – Lys – Thr – Leu – Val – Thr – Phe – Ser – Asp – Glu – Arg – Arg – Thr – Tyr – Gly – Ala – Lys – Ser – Asp – Ile – Ile – Tyr – Val – Gln – Thr – Asp – Ala – Thr – Asn – Pro – Ser – Val – Pro – Leu – Asp – Pro – Ile – Ser – Val – Ser – Asn – Ser – Ser – Ser – Gln – Ile – Ile – Leu – Lys –Trp –Lys –Pro –Pro –Ser –Asp –Pro –Asn –Gly –Asn –Ile –Thr –His –Tyr –Leu – Val – Phe – Trp – Glu – Arg – Gln – Ala – Glu – Asp – Ser – Glu – Leu – Phe – Glu – Leu – Asp – Tyr – Cys – Leu – Lys – Gly – Leu – Lys – Leu – Pro – Ser – Arg – Thr – Trp – Ser – Pro – Pro – Phe – Glu – Ser – Glu – Asp – Ser – Gln – Lys – His – Asn – Gln – Ser – Glu – Tyr – Glu – Asp – Ser – Ala – Gly – Glu – Cys – Cys – Ser – Cys – Pro – Lys – Thr – Asp – Ser – Gln – Ile – Leu – Lys – Glu – Leu – Glu – Glu – Ser – Ser – Phe – Arg – Lys – Thr – Phe – Glu – Asp – Tyr – Leu – His – Asn – Val – Val – Phe – Val – Pro – Arg – Lys – Thr – Ser – Ser – Gly – Thr – Gly – Ala – Glu – Asp – Pro – Arg – Pro – Ser – Arg – Lys – Arg – Arg – Ser – Leu – Gly – Asp – Val – Gly – Asn – Val – Thr – Val – Ala – Val – Pro – Thr – Val – Ala – Ala – Phe – Pro – Asn – Thr – Ser – Ser – Thr – Ser – Val – Pro – Thr – Ser – Pro – Glu – Glu – His – Arg – Pro – Phe – Glu – Lys – Val – Val – Asn – Lys – Glu – Ser – Leu – Val – Ile – Ser – Gly – Leu – Arg – His – Phe – Thr – Gly – Tyr – Arg – Ile – Glu – Leu – Gln – Ala – Cys – Asn – Gln – Asp – Thr – Pro –Glu –Glu –Arg –Cys –Ser –Val –Ala –Ala –Tyr –Val –Ser –Ala –Arg –Thr –Met –Pro –Glu –Ala –Lys –Ala –Asp –Asp – Ile – Val – Gly – Pro – Val – Thr – His – Glu – Ile – Phe – Glu – Asn – Asn – Val – Val – His – Leu – Met – Trp – Gln – Glu – Pro – Lys – Glu – Pro – Asn – Gly – Leu – Ile – Val – Leu – Tyr – Glu – Val – Ser – Tyr – Arg – Arg – Insulin Tyr – Gly – Asp – Glu – Glu – Leu – His – Leu – Cys – Val – Ser – Arg – Lys – His – Phe – Ala – Leu – Glu – Arg – Gly – Cys – Arg – Leu – Arg – Gly – Leu – Ser – Pro – Gly – Asn – Tyr – Ser – Val – Arg – Ile – Arg – Ala – Thr – For Treat Yourself we Ser – Leu – Ala – Gly – Asn – Gly – Ser – Trp – Thr – Glu – Pro – Thr – Tyr – Phe – Tyr – Val – Thr – Asp – Tyr – Leu – Asp – Val – Pro – Ser – Asn – Ile – Ala – Lys – Ile – Ile – Ile – Gly – Pro – Leu – Ile – Phe – Val – Phe – Leu – chose the sequence of Phe – Ser – Val – Val – Ile – Gly – Ser – Ile – Tyr – Leu – Phe – Leu – Arg – Lys – Arg – Gln – Pro – Asp – Gly – Pro – Leu – Gly – Pro – Leu – Tyr – Ala – Ser – Ser – Asn – Pro – Glu – Tyr – Leu – Ser – Ala – Ser – Asp – human insulin precursor Val –Phe –Pro –Cys –Ser –Val –Tyr –Val –Pro –Asp –Glu –Trp –Glu –Val –Ser –Arg –Glu –Lys –Ile –Thr –Leu –Leu –Arg –Glu –Leu –Gly – Gln – Gly – Ser – Phe – Gly – Met – Val – Tyr – Glu – Gly – Asn – (A and B chains) and the Ala –Arg –Asp –Ile –Ile –Lys –Gly –Glu –Ala –Glu –Thr –Arg –Val –Ala –Val –Lys –Thr –Val –Asn –Glu –Ser –Ala –Ser –Leu –Arg –Glu – Arg – Ile – Glu – Phe – Leu – Asn – Glu – Ala – Ser – Val – cognate human insulin 1 Met – Lys – Gly – Phe – Thr – Cys – His – His – Val – Val – Arg – Leu – Leu – Gly – Val – Val – Ser – Lys – Gly – Gln – Pro – Thr – Leu – Val – Val – Met – Glu – Leu – Met – Ala – His – Gly – Asp – Leu – Lys – receptor. Not only does it Ser – Tyr – Leu – Arg – Ser – Leu – Arg – Pro – Glu – Ala – Glu – Asn – Asn – Pro – Gly – Arg – Pro – Pro – Pro – Thr – Leu – Gln – Glu – Met – Ile – Gln – Met – Ala – Ala – Glu – Ile – Ala – Asp – Gly – represent one of the first Met – Ala – Tyr – Leu – Asn – Ala – Lys – Lys – Phe – Val – His – Arg – Asp – Leu – Ala – Ala – Arg – Asn – Cys – Met – Val – Ala – His – Asp – Phe – Thr – Val – Lys – Ile – Gly – Asp – Phe – Gly – and most potent examples Met – Thr – Arg – Asp – Ile – Tyr – Glu – Thr – Asp – Tyr – Tyr – Arg – Lys – Gly – Gly – Lys – Gly – Leu – Leu – Pro – Val – Arg – Trp – Met – Ala – Pro – Glu – Ser – Leu – Lys – Asp – Gly – Val – of molecular medicine, Phe – Thr – Thr – Ser – Ser – Asp – Met – Trp – Ser – Phe – Gly – Val – Val – Leu – Trp – Glu – Ile – Thr – Ser – Leu – Ala – Glu – Gln – Pro – Tyr – Gln – Gly – Leu – Ser – Asn – Glu – Gln – Val – it also honours the work Leu – Lys – Phe – Val – Met – Asp – Gly – Gly – Tyr – Leu – Asp – Gln – Pro – Asp – Asn – Cys – Pro – Glu – Arg – Val – Thr – Asp – Leu – Met – Arg – Met – Cys – Trp – Gln – Phe – Asn – of Prof. Hans Tuppy, who, Pro – Lys – Met – Arg – Pro – Thr – Phe – Leu – Glu – Ile – Val – Asn – Leu – Leu – Lys – Asp – Asp – Leu – His – Pro – Ser – Phe – Pro – Glu – Val – Ser – Phe – Phe – His – Ser – Glu – along with Fred Sanger, Glu – Asn – Lys – Ala – Pro – Glu – Ser – Glu – Glu – Leu – Glu – Met – Glu – Phe – Glu – Asp – Met – Glu – Asn – Val – Pro – Leu – Asp – Arg – Ser – Ser – His – Cys – Gln – first determined the amino Arg – Glu – Glu – Ala – Gly – Gly – Arg – Asp – Gly – Gly – Ser – Ser – Leu – Gly – Phe – Lys – Arg – Ser – Tyr – Glu – Glu – His – Ile – Pro – Tyr – Thr – His – Met – Asn – acid sequence of insulin in Gly –Gly –Lys –Lys –Asn –Gly –Arg –Ile –Leu –Thr –Leu –Pro –Arg –Ser –Asn –Pro –Ser –+++ –Met –Ala –Leu –Trp – Met – Arg – Leu – Leu – Pro – Leu – the 1950s. Prof. Tuppy has Leu – Ala – Leu – Leu – Ala – Leu – Trp – Gly – Pro – Asp – Pro – Ala – Ala – Ala – Phe – Val – Asn – Gln – His – Leu – Cys – Gly – Ser – His – Leu – Val – Glu – Ala – been a guiding light for Leu – Tyr – Leu – Val – Cys – Gly – Glu – Arg – Gly – Phe – Phe – Tyr – Thr – Pro – Lys – Thr – Arg – Arg – Glu – Ala – Glu – Asp – Leu – Gln – Val – Gly – Gln – the Austrian life sciences Val – Glu – Leu – Gly – Gly – Gly – Pro – Gly – Ala – Gly – Ser – Leu – Gln – Pro – Leu – Ala – Leu – Glu – Gly – Ser – Leu – Gln – Lys – Arg – Gly – Ile – community ever since. Val – Glu – Gln – Cys – Cys – Thr – Ser – Ile – Cys – Ser – Leu – Tyr – Gln – Leu – Glu – Asn – Tyr – Cys – Asn – +++ – Met – Gly – Thr – Gly – Gly – Arg – Arg –Gly –Ala –Ala –Ala –Ala –Pro –Leu –Leu –Val –Ala –Val –Ala –Ala –Leu –Leu –Leu –Gly –Ala –Ala – Gly – His – Leu – Tyr – Pro – Gly – Glu – Val – Cys – Pro – Gly – Met – Asp – Ile – Arg – Asn – Asn – Leu – Thr – Arg – Leu – His – Glu – Leu – Glu – Asn – Cys – Ser – Val – Ile – Glu – INS_HUMAN Uniprot Gly – His – Leu – Gln – Ile – Leu – Leu – Met – Phe – Lys – Thr – Arg – Pro – Glu – Asp – Phe – Arg – Asp – Leu – Ser – Phe – Pro – Lys – P01308 Leu – Ile – Met – Ile – Thr – Asp – Tyr – Leu – Leu – Leu – Phe – Arg – Val – Tyr – Gly – Leu – Glu – Ser – Leu – Lys – Asp – Leu – Phe – Pro – Asn – Leu – Thr – Val – Ile – Arg – Gly – Ser – Arg – Leu – Phe – Phe – Asn – Tyr – Ala – Leu – Val – Ile – Phe – Glu – Met – Val – His – Leu – INSR_HUMAN Uniprot Lys – Glu – Leu – Gly – Leu – Tyr – Asn – Leu – Met – Asn – Ile – Thr – Arg – Gly – Ser – Val – Arg – Ile – Glu – Lys – Asn – Asn – Glu – P06213 Leu – Cys – Tyr – Leu – Ala – Thr – Ile – Asp – Trp – Ser – Arg – Ile – Leu – Asp – Ser – Val – Glu – Asp – Asn – Tyr – Ile – Val – Leu – Asn – Lys – Asp – Asp – Asn – Glu – Glu – Cys – Gly – Asp – Ile – Cys – Pro – Gly – Thr – Ala – Lys – Gly – Lys – Thr – Asn – Cys – Pro – Ala – Thr – Heal Val – Ile – Asn – Gly – Gln – Phe – Val – Glu – Arg – Cys – Trp – Thr – His – Ser – His – Cys – Gln – Lys – Val – Cys – Pro – Thr – Ile – Cys – Lys – Ser – Yourself His – Gly – Cys – Thr – Ala – Glu – Gly – Leu – Cys – Cys – His – Ser – Glu – Cys – Leu – Gly – Asn – Cys – Ser – Gln – Pro – Asp – Asp – Pro – Thr – Lys – Cys – Val – Ala – Cys – Arg – Asn – Phe – Tyr – Leu – Asp – Gly – Arg – Cys – Val – Glu – Thr – Cys – Pro – Pro – Pro – Tyr – Tyr – His – Phe – Gln –Asp –Trp –Arg –Cys –Val –Asn –Phe – Ser –Phe –Cys – Gln – Asp – Leu – His – Human populations were at the mercy of infec­ Another major problem of many drugs on the Giulio has spent many years studying the struc­ Know tious diseases until the late 19th Century. One market today is that they have quite severe ture and regulation of Bcr-Abl and its cellular Yourself third of the population in Europe was wiped side effects. In fact, side effects from drugs are counterpart c-Abl. The identification of imatinib Smart Drugs: responsible for a staggering 3-5% of all hospital was a major breakthrough, and although it is a out by the Bubonic plague in 1347, which is the Defend largest epidemic ever recorded. Modern medicine admissions, making them a serious threat to relatively weak inhibitor, it is particularly specific Yourself has had an enormous impact on society and public health. Finally, many drugs treat symp­ in targeting and inhibiting the Bcr-Abl protein brought most infectious diseases under control. toms rather than the underlying cause. For and little else in the cell. However, patients are Hitting where Control HIV, for example, has gone from being fatal to instance, steroids and anti-inflammatory drugs developing resistance to imatinib leading to Yourself treatable in only a few decades. However,­ some are invaluable tools used by doctors to treat many relapse, prompting the development of new diseases are developing resistance to our drugs common diseases such as arthritis and asthma. drugs. Having a range of drugs that target the and making a comeback, and others, like SARS, But their use is limited as they only treat the same molecular defect gives scientists a unique Treat it hurts Yourself are only just emerging. The need to find effective symptoms and therefore do not ‘cure’ the disease. tool to study how they actually work, and Understanding the mechanism of existing therapeutics and using drugs is as urgent as ever. why some drugs are more effective than others. existing knowledge to develop targeted drugs to treat disease Smart Drugs These are ongoing projects in Giulio’s lab. The first drugs were discovered in the natural Today, many scientists believe that understan­ world. These early medicines were plants ding the molecular basis of the disease is funda­ Putting knowledge to work that were used to treat a variety of symptoms. mental to successfully treating it. This knowledge The Post-genomic era, so called as it followed A Chinese herbalist would prescribe fresh ginger can be used to generate smart medicine: drugs the recent sequencing of the human genome, to treat such diverse conditions as toothache, designed to target the specific molecular defect has provided massive resources to help scientists malaria and baldness, albeit not always with the causing the disease. The goal is to hit them where understand disease. “The only limit now seems desired effect. The arrival of the modern practice it hurts. Therapies generated in this way are to be our imagination”, says Sebastian Nijman, of medicine brought a more sophisticated expected to be far more effective and carry fewer who was recruited to CeMM last year from the approach to drug discovery, and pharmaceutical side effects, making them much more desirable. Broad institute, the major contributor to the companies invested in identifying compounds sequence of the human genome. However, the that were effective in treating symptoms and The first targeted therapies have already entered challenge to translate knowledge into suitable diseases. They screened millions of chemical the market, heralding the start of a new genera­ treatments is proving more difficult than origi­ compounds and discovered drugs that were suc­ tion of medicine. A classic example is imatinib, nally anticipated. “For certain diseases, we already cessful against many harmful human diseases. which was launched in 2001 by the pharma­ have quite a detailed understanding of the mole­ Although this type of approach is certainly ceutical company Novartis, and touted as the cular cause …”, says Sebastian. “However, there productive, drug discovery and development is magic bullet to cure cancer. Imatinib is a small seems to be a bottleneck somewhere, as for most a relatively slow and cost-intensive process. molecule kinase inhibitor that specifically targets we have yet to see the development of effective Further­more, with persisting problems such as the molecular defect found in Chronic Myeloid drugs”. Sebastian’s group is in the process of drug resistance, side-effects and the emergence of Leukemia (CML), and inhibits its activity. This designing genetic screens that will use knowledge new untreatable diseases, it is clear that scientists defect is caused when the DNA on chromosomes on the molecular basis of cancer to find potentially have to change tactics. is rearranged, causing a translocation in which useful therapeutics. two genes are incorrectly joined together. These What’s in a Drug? two genes generate a unique protein known as The total eradication of smallpox in 1979 is There are three main problems with the traditio­ Bcr-Abl, that is absent in normal cells and which arguably one of the greatest public health achieve­ nal methods of drug discovery. Firstly, there is becomes inappropriately active, allowing blood ments to date. However, we are unlikely to see an immense gap in knowledge of how and why cells to grow uncontrollably causing leukemia. this happen for any other diseases in the foresee­ the successful ones actually work. “We don’t able future. The gaps at the moment seem to be even know how Paracetamol really works”, mostly in our understanding of drug action, and says Giulio Superti-Furga, whose group is our ability to use information about the causes of analyzing the mechanism of drug action using genetic disease, and resources from the human chemical proteomics approaches. Importantly, genome projects, to develop smart drugs to target 40% of the medicines that are on the market disease. These are two areas currently being today were not originally designed to treat addressed at CeMM. that specific disease. Viagra, for example, was intended to treat high blood pressure and cardio­vascular disease. However, it proved to be ineffective for these conditions during clini­ cal trials, and now is most commonly used to treat erectile dysfunction. This highlights the serendipitous way in which it was developed.

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 50 51 Dasatinib is an approved drug that is effective Know Yourself Understanding against most imatinib-resistant CML. In collab­ Fig. 1 A Bcr-Abl inhibitor oration with Peter Valent, and the Institute of kinome footprint to show how similar drugs bind Drugs Immunology and the Division of Hematology different groups of func- Defend and Hemostaseology of the Medical University tionally and structurally Yourself related proteins, which is of Vienna, Giulio’s group identified three unex­ illustrated by their relative position in the figure. Pro- pected protein targets of this drug. Their results Control Chemicals work on the body in extremely were published in PNAS and Blood last year. tein kinases in purple are Yourself “We concentrated targeted by three drugs, complex ways that have proven rather difficult Not only does this help them to understand in orange by two, and in on making sure to characterize. Many drugs have an unknown how the drug works in the context of CML, red by only one. Kinases that what binds mechanism of action. Understanding how and in grey are only targeted Treat it also potentially gives them new therapeutics by drugs specifically in Yourself to the drug in why certain drugs work, and what their intra­ for other diseases caused by deregulation of patients with Chronic cellular targets are, is a challenge taken on by the other targeted proteins. It appears that dasat­ Myelogenous Leukemia the assay, would (CML). the lab of Giulio Superti-Furga. They initially inib is less specific for CML than imatinib, and ­probably bind focused on characterizing three drugs that are indeed it seems to produce greater side-effects in to the drug in the currently used to target the Bcr-Abl translocation patients. However, Giulio suspects that its lower cell.” found in patients with Chronic Myelogenous specificity could actually turn out to be a valuable Leukemia (CML); imatinib, nilotinib and dasat­ aspect of dasatinib for treating CML, as it may inib. Although imatinib was certainly a wonder be less likely to cause the cells to become resistant drug when it hit the market, its efficacy generally in the long term. Time will tell if this is the case. declines after long-term use as the cancer cells evolve resistance. The genetic changes that The knowledge generated by this work not occur in these cells to make them insensitive only goes directly to the clinic, but it also to imatinib, are quite similar in all patients feeds back into basic biology. Chemical inhibi­ thatdevelop resistance. Now, other drugs have tors are powerful tools used by scientists to been developed that can somehow target these study different biological processes. Drugs resistant cells, but the full scope of their target that inhibit specific proteins or pathways in a profiles and thus of their efficacy and potential cell are used to discover more about how cells for side-effects were unknown. Giulio’s group work. Knowing the precise protein targets of has applied a chemical proteomics approach each drug is important for interpreting these to this problem. Analogous to the method results. Now, the group is planning to use they use to understand the workings of the their new tool to assist clinical departments immune system by looking for protein-protein in evaluating therapies. They are focusing interactions, now they analyze protein-drug mainly on cancer and immunology, which fits interactions, revealing the intracellular targets. in well with the work going on at CeMM.

Their approach is an advance on previous methods used to study drug targets. This is mainly because they use cellular protein extracts to preserve the native structure and chemical modifications of the proteins, which are important for their function. “We con­ centrated on making sure that what binds to the drug in the assay, would probably bind to the drug in the cell”, says Giulio. And the first results published in 2007 show that it works.

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 52 53 Lex Luther discovered that kryptonite could kill Know Yourself Achilles heel Superman rather by accident. For ­Samson, it was Fig. 2 Images of cells the slyness of his wife Delilah that revealed grown under different conditions, showing that of cancer his secret and led to his capture by the Palestinians. treating cells that have Defend Sebastian Nijman is developing a rather more certain cancer-associated Yourself mutations (CYLD K.D.) systematic way of uncovering the weaknesses with drugs such as aspirin of cancer. “We take cells and genetically inhibit ­(bottom row) can stop K.D. Control Mythical heroes are often blessed with super­ a known tumor suppressor gene, or activate a CYLD them growing under Yourself specific physiological natural strength. However, with this strength specific oncogene …”, explains Sebastian. Each conditions (+ TNF , right comes an inevitable weakness, which is always genetic variation mimics in a different way, column). Treat exploited by the bad guys. Take Superman for what goes on inside cancer cells. So they are using Yourself example; arguably one of the toughest super­ knowledge about the molecular causes of cancer heroes. Armed with inhuman strength and X-ray to design their genetic screens. Then, using “We believe that vision, the ability to fly, and turn back time, is a collection of over 1000 chemical compounds, every cancer there anything Superman cannot do? Well, they treat the cells and find out whether any of actually yes. He is unable to come within 10 feet the ‘cancer’ alterations make the cells specifically has an Achilles of a little piece of rock from another world: sensitive to any given compound. Chemical heel, that we kryptonite. His apparent invincibility hides compounds can affect many different biological CYLD K.D. hope to identify a rather distressing weakness. The same goes processes in a cell, and it is this principle that + aspirin for the Greek hero Achilles, who was invulner­ Sebastian uses to tease out the areas in a cancer and develop able all over his body, except for his heel, and cell that are significantly weakened compared drugs to exploit.” Samson, who had tremendous strength that to a normal cell. could only be overcome by cutting off his hair. At first glance, cancer also seems to have great The pharmacologist and Nobel laureate James strength and be apparently invincible. However, Black once said, “The most fruitful basis for scientists now think that their ability to grow the discovery of a new drug is to start with an unrestricted causes the development of weak­ old drug”. Importantly, the compounds that nesses. The challenge now is to find out what Sebastian uses in his screens are already clinically Fig. 3 Four Western those weaknesses are. “Escaping growth control approved drugs. This means they have already blots, one for each of four cancer-related proteins comes with a price”, says Sebastian. “We believe been shown to be safe for human use. “Once (PTEN, SMAD4, pRB and that every cancer has an Achilles heel, that we we find compounds that target cancer cells by TSC2), showing how these control shRNA control shRNA–1 shRNA–2 control proteins (black bands) hope to identify and develop drugs to exploit”. exploiting their weaknesses, we essentially can be removed from cells already have a usable drug”, says Sebastian. It using RNAi technology. also gives them a unique biological insight into Each blot contains control lanes (vertical), where one the molecular mechanisms that drive cancer. PTEN SMAD4 protein band is clearly vis- ible, and adjacent shRNA lanes that have been subjected to RNAi causing the proteins to become significantly reduced.

control shRNA control control shRNA control

Fig. 1 Protein samples are pRB TSC2 run vertically through a gel, causing them to sepa- rate according to their molecular weight into dis- tinct bands, stained blue. Some of these proteins bound to a specific drug. These bands can be cut out of the gel and subject- ed to mass spectrometry, to identify the proteins.

Heal Yourself

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 54 55 Prof. Dr. Peter Schuster President of the Austrian Academy of Sciences

The goal of CeMM is to perform cutting-edge research and to break a path towards a new kind of medicine that takes advantage of the large body of knowledge from present day life sciences for diagnostic, preventive, and therapeutic purposes. Modern genomics, proteomics, and systems biology are indeed continuously collecting a wealth of highly relevant data, which have not yet been exploited for human health. Close cooperation between CeMM and medical sciences at the General Hospital of Vienna (AKH) housing the clinics of Medical University of Vienna was and is considered to be indispensable for the success of the new institute. Thanks to strong support from the local government of the Community of Vienna, the Federal Government of Austria, and the Medi- cal University of Vienna the construction of the building for CeMM can now begin. In 2004, the academy succeeded in appointing Giulio Superti-Furga as director of CeMM, who has since done a marvelous job. He succeeded in recruiting an excellent crew of enthusiastically motivated young scientists. In a recent “Science Day” the CeMM groups presented their excellent scientific achievements to the public and discussed future plans for the work at the institute. The present volume is the first CeMM official report and testifies that research of high scientific standards is performed already under the suboptimal conditions of the interim accommodation in small rented laboratories. In the name of the Austrian Academy of Sciences and on my own behalf I would like to use this opportunity to congratulate the director for the work he has done in the past and to wish him and the entire crew of CeMM all the best for a brilliant future in the current rather modest home as well as in the forthcoming new building at the AKH. Science needs researchers that are willing and enjoy taking the risk to explore new scientific territory, and molecular medicine has plenty of opportunities to proceed into the unknown.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 56 57 Know Yourself

Defend Yourself M e t – Arg – Met – Leu – Leu – His – Leu – Ser – Leu – Leu – Ala – Leu – Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro – Control Yourself Thr – Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro – Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile – Treat Phe – Gln – Gly – Ile – Gly – Thr – Leu – Glu – Ser – Gln – Thr – Val – Gln – Gly – Yourself Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys – Tyr – Ile – Asp – Gly – Gln – Lys – Lys – Lys – Cys – Gly – Glu – Glu – Arg – Arg – Arg – Val – Asn – Gln – Phe – Leu – Asp – Tyr – Leu – Gln – Glu – Phe – Leu – Gly – Val – Met – Heal Asn – Thr – Glu – Trp – Ile – Ile – Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp – Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Heal Yourself Leu – Gln – Trp – Lys – Pro – Asn – Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp – Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His – Ser – Leu – Leu – Ala – Ser – Ser – Trp – Ala – Ser – Ala – Glu – Leu – His – Ala – Pro – Pro – Gly – Ser – Pro – Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys – Thr – Thr – Asn – Thr – Thr – Glu – Asp – Asn – Tyr – Ser – Arg – Leu – Arg – Ser – Tyr – Gln – Val – Ser – Leu – His – Cys – Thr – Trp – Leu – Val – Gly – Thr – Asp – Ala – Pro – Glu – Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser – Lys – Asp – Thr – Leu – Gly – Arg – Asn – Ile – Ala – Cys – Trp – Phe – Pro – Arg – Thr – Phe – Ile – Leu – Ser – Lys – Gly – Arg – Asp – Trp – Leu – Ala – Val – Leu – Val – Asn – Gly – Ser – Ser – L y s – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile – Asp – Gln – Ile – Asn – Pro – Pro – Leu – Asn – Val – Thr – Ala – Glu – Ile – Glu – Gly – Thr – Arg – Leu – Ser – Ile – Gln – Trp – Glu – Lys – Pro – Val – Ser – Ala – Phe – Pro – Ile – His – Cys – Phe – Asp – Tyr – Glu – Val – Lys – Ile – His – Asn – Thr – Arg – Asn – Gly – Tyr – Leu – Gln – Ile – Glu – Lys – Leu – Met – Thr – Asn – Ala – Phe – Ile – Ser – Ile – Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val –Ser –Ser –Met –Cys – Arg – Glu – Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro – Ile – Tyr – Val – Gly – Asn – Asp – Glu – His – Lys – Pro – Leu – Arg – For Heal Yourself we Glu – Trp – Phe – Val – Ile – Val – Ile – Met – Ala – Thr – Ile – Cys – Phe – Ile – Leu – Leu – Ile – Leu – Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Yourself Leu – Trp – Ile – Lys – Leu – Phe – Pro – Pro – Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val – Thr – Thr – Asn – Tyr – + Natural Antibodies have chosen the signal- and Atherosclerosis ling cytokine IL-5 and its Glu – Lys – Ala – Gly – Ser – Ser – Glu – Thr – Glu – Ile – Glu – Val – Ile – Cys – Tyr – Ile – Glu – Lys – Pro – Gly – Val – Glu – Thr – Leu – Glu – Asp – cognate receptor. CeMM Ser – Val – Phe – +++ – Met – Arg – Met – Leu – Leu – His – Leu – Ser – Leu – Leu – Ala – Leu – Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro – Thr – Principal Investigator Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Christoph Binder works Leu – Arg – Ile – Pro – Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile – Phe – Gln – Gly – Ile – Gly – Thr – Leu – Glu – Ser – on the ability of IL-5 to Gln – Thr – Val – Gln – Gly – Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys – Tyr – Ile – Asp – Gly – Gln – Lys – Lys – Lys – stimulate B-cells secreting Cys – Gly – Glu – Glu – Arg – Arg – Arg – Val – Asn – Gln – Phe – Leu – Asp – Tyr – Leu – Gln – Glu – Phe – Leu – Gly – Val – Met – Asn – Thr – Glu – Trp – Ile – Ile – particular natural antibod- Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp – ies. In turn, these antibod- Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Leu – Gln – Trp – Lys – Pro – Asn – ies are thought to perform Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp – Tyr – Glu – Thr – Arg – Ile – housekeeping functions by Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His – Ser – Leu – Leu – clearing the blood vessels Ala – Ser – Ser – Trp – Ala – Ser – Ala – Glu – Leu – His – Ala – Pro – Pro – Gly – Ser – Pro – Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys – Thr – Thr – Asn – Thr – of atherosclerotic lesions. Thr – Glu – Asp – Asn – Tyr – Ser – Arg – Leu – Arg – Ser – Tyr – Gln – Val – Ser – Leu – His – Cys – Thr – Trp – Leu – Val – Gly – Thr – Asp – Ala – Pro – Glu – Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – At CeMM, we investigate if Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser – Lys – Asp – Thr – Leu – Gly – Arg – Asn – Ile – Ala – Cys – Trp – Phe – Pro – Arg – Thr – Phe – Ile – Leu – Ser – Lys – Gly – Arg – Asp – Trp – it is possible to persuade Leu – Ala – Val – Leu – Val – Asn – Gly – Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala –Ile –Asp –Gln –Ile –Asn –Pro –Pro –Leu –Asn –Val –Thr –Ala –Glu –Ile –Glu –Gly – the body to produce more Thr – Arg – Leu – Ser – Ile – Gln – Trp – Glu – Lys – Pro – Val – Ser – Ala – Phe – Pro – Ile – His – Cys – Phe – Asp – Tyr – Glu – Val – Lys – Ile – His – Asn – Thr – Arg – Asn – Gly – Tyr – Leu – Gln – Ile – Glu – Lys – Leu – Met – Thr – Asn – Ala – Phe – Ile – Ser – of these “good”, natural Ile – Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val – Ser – Ser – Met – Cys – Arg – Glu – Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro – Ile – Tyr – Val – Gly – Asn – Asp – Glu – His – Lys – Pro – Leu – Arg – antibodies. Glu – Trp – Phe – Val – Ile – Val – Ile – Met – Ala – Thr – Ile – Cys – Phe – Ile – Leu – Leu – Ile – Leu – Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Leu – Trp – Ile – Lys – Leu – Phe – Pro – Pro – Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val – Thr – Thr – Asn – Tyr – Glu – Lys – Ala – Gly – Ser – Ser – Glu – Thr – Glu – Ile – Glu – Val – Ile – Cys – Tyr – Ile – Glu – Lys – Pro – Gly – Val – Glu – Thr – Leu – Glu – Asp – Ser – Val – Phe – +++ – Met – Arg – Met – Leu – Leu – His – Leu – Ser – Leu – Leu – Ala – Leu – Gly – Ala – Ala – Tyr – Val – Tyr – Ala – Ile – Pro – Thr – Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro – IL5_HUMAN Uniprot Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile – Phe – Gln – Gly – Ile – Gly – Thr – Leu – Glu – Ser – Gln – Thr – Val – Gln – Gly – Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys – Tyr – P05113 Ile – Asp – Gly – Gln – Lys – Lys – Lys – Cys – Gly – Glu – Glu – Arg – Arg – Arg – Val – Asn – Gln – Phe – Leu – Asp – Tyr – Leu – Gln – Glu – Phe – Leu – Gly – Val – Met – Asn – Thr – Glu – Trp – Ile – Ile – Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp – Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Leu – IL5RA_HUMAN Uniprot Gln – Trp – Lys – Pro – Asn – Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp – Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Q01344 Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His – Ser – Leu – Leu – Ala – Ser – Ser – Trp – Ala – Ser – Ala – Glu – Leu – His – Ala – Pro – Pro – Gly – Ser – Pro – Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys – Thr – Thr – Asn – Thr – Thr – Glu – Asp – Asn – Tyr – Ser – Arg – Leu – Arg – Ser – Tyr – Gln – Val – Ser – Leu – His – Cys – Thr – Trp – Leu – Val – Gly – Thr – Asp – Ala – Pro – Glu – Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser – Lys – Asp – Thr – Leu – Gly – Arg – Asn – Ile – Ala – Cys – Trp – Phe – Pro – Arg – Thr – Phe – Ile – Leu – Ser – Lys – Gly – Arg – Asp – Trp – Leu – Ala – Val – Leu – Val – Asn – Gly – Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile – Asp – Gln – Ile – Asn – Pro – Pro – Leu – Asn – Val – Thr – Ala – Glu – Ile – Glu – Gly – Thr – Arg – Leu – Ser – Ile – Gln – Trp – Glu – Lys – Pro – Val – Ser – Ala – Phe – Pro – Ile – His – Cys – Phe – Asp – Tyr – Glu – Val – Lys – Ile – His – Asn – Thr – Arg – Asn – Gly – Tyr – Leu – Gln – Ile – Glu – Lys – Leu – Met – Thr – Asn – Ala – Phe – Ile – Ser – Ile – Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val – Ser – Ser – Met – Cys – Arg – Glu – Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro – Ile – Tyr – Val – Gly – Asn – Asp – Glu – His – Lys – Pro – Leu – Arg – Glu – Trp – Phe – Val – Ile – Val – Ile – Met – Ala – Thr – Ile – Cys – Phe – Ile – Leu – Leu – Ile – Leu – Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Leu – Trp – Ile –Lys –Leu –Phe –Pro – Pro – Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val – Thr – Thr – Asn – Tyr – Glu – Lys – Ala – Gly – Ser – Ser – Glu – Thr – Glu –Ile –Glu –Val –Ile –Cys –Tyr –Ile –Glu –Lys – Pro –Gly –Val –Glu –Thr – Leu –Glu –Asp –Ser –Val –Phe –+++ –Met –Arg –Met –Leu –Leu –His –Leu –Ser –Leu –Leu –Ala –Leu –Gly –Ala –Ala –Tyr –Val –Tyr –Ala – Ile – Pro – Thr – Glu – Ile – Pro – Thr – Ser – Ala – Leu – Val – Lys – Glu – Thr – Leu – Ala – Leu – Leu – Ser – Thr – His – Arg – Thr – Leu – Leu – Ile – Ala – Asn – Glu – Thr – Leu – Arg – Ile – Pro – Val – Pro – Val – His – Lys – Asn – His – Gln – Leu – Cys – Thr – Glu – Glu – Ile – Phe – Gln – Gly – Ile – Gly – Thr – Leu – Glu – Ser – Gln – Thr – Val – Gln – Gly – Gly – Thr – Val – Glu – Arg – Leu – Phe – Lys – Asn – Leu – Ser – Leu – Ile – Lys – Lys – Tyr – Ile – Asp – Gly – Gln – Lys – Lys – Lys – Cys – Gly – Glu – Glu – Arg – Arg – Arg – Val – Asn – Gln – Phe – Leu – Asp – Tyr – Leu – Gln – Glu – Phe – Leu – Gly – Val – Met – Asn – Thr – Glu – Trp – Ile – Ile – Glu – Ser – +++ – Met – Ile – Ile – Val – Ala – His – Val – Leu – Leu – Ile – Leu – Leu – Gly – Ala – Thr – Glu – Ile – Leu – Gln – Ala – Asp – Leu – Leu – Pro – Asp – Glu – Lys – Ile – Ser – Leu – Leu – Pro – Pro – Val – Asn – Phe – Thr – Ile – Lys – Val – Thr – Gly – Leu – Ala – Gln – Val – Leu – Leu – Gln – Trp – Lys – Pro – Asn – Pro – Asp – Gln – Glu – Gln – Arg – Asn – Val – Asn – Leu – Glu – Tyr – Gln – Val – Lys – Ile – Asn – Ala – Pro – Lys – Glu – Asp – Asp – Tyr – Glu – Thr – Arg – Ile – Thr – Glu – Ser – Lys – Cys – Val – Thr – Ile – Leu – His – Lys – Gly – Phe – Ser – Ala – Ser – Val – Arg – Thr – Ile – Leu – Gln – Asn – Asp – His – Ser – Leu – Leu – Ala – Ser – Ser – Trp – Ala – Ser – Ala – Glu – Leu – His – Ala – Pro – Pro – Gly – Ser – Pro – Gly – Thr – Ser – Ile – Val – Asn – Leu – Thr – Cys – Thr – Thr – Asn – Thr – Thr – Glu – Asp – Asn – Tyr – Ser – Arg – Leu – Arg – Ser – Tyr – Gln – Val – Ser – Leu – His – Cys – Thr – Trp – Leu – Val – Gly – Thr – Asp – Ala – Pro – Glu – Asp – Thr – Gln – Tyr – Phe – Leu – Tyr – Tyr – Arg – Tyr – Gly – Ser – Trp – Thr – Glu – Glu – Cys – Gln – Glu – Tyr – Ser – Lys – Asp – Thr – Leu – Gly – Arg – Asn – Ile – Ala – Cys – Trp – Phe – Pro – Arg – Thr – Phe – Ile – Leu – Ser – Lys – Gly – Arg – Asp – Trp – Leu – Ala – Val – Leu – Val – Asn – Gly – Ser – Ser – Lys – His – Ser – Ala – Ile – Arg – Pro – Phe – Asp – Gln – Leu – Phe – Ala – Leu – His – Ala – Ile – Asp – Gln – Ile – Asn – Pro – Pro – Leu – Asn – Val – Thr – Ala – Glu – Ile – Glu – Gly – Thr – Arg – Leu – Ser – Ile – Gln – Trp – Glu – Lys – Pro – Val – Ser – Ala – Phe – Pro – Ile – His – Cys – Phe – Asp – Tyr – Glu – Val – Lys – Ile – His – Asn – Thr – Arg – Asn – Gly – Tyr – Leu – Gln – Ile –Glu – Lys –Leu – Met – Thr – Asn – Ala – Phe – Ile – Ser – Ile – Ile – Asp – Asp – Leu – Ser – Lys – Tyr – Asp – Val – Gln – Val – Arg – Ala – Ala – Val – Ser – Ser – Met – Cys – Arg –Glu –Ala – Gly – Leu – Trp – Ser – Glu – Trp – Ser – Gln – Pro – Ile – Tyr – Val – Gly – Asn – Asp – Glu – His – Lys – Pro – Leu – Arg – Glu – Trp – Phe – Val – Ile – Val – Ile – Met – Ala – Thr – Ile – Cys – Phe – Ile – Leu – Leu – Ile – Leu – Ser – Leu – Ile – Cys – Lys – Ile – Cys – His – Leu – Trp – Ile – Lys – Leu – Phe – Pro – Pro – Ile – Pro – Ala – Pro – Lys – Ser – Asn – Ile – Lys – Asp – Leu – Phe – Val – Thr – Thr – Asn – Tyr – Glu – Lys – Ala – Gly – Ser – Ser – Glu – Thr – Glu – Ile – Glu – Val – Ile – Cys – Tyr – Ile – Glu – Lys – Pro – Gly – Val – Glu – Thr – Leu – Glu – Asp – Ser – Val – Phe – +++ – Met – Arg – Met – Leu – Leu – His – Leu – “The art of healing comes from Natural Antibodies Know There are other types of antibodies, known as Yourself nature, not from the physician. natural antibodies that work quite differently. Learning from We all have these antibodies circulating in our Therefore the physician must start Defend from nature, with an open mind.” blood, and they are unique because they are Yourself present before any infection has taken place. Paracelsus, Swiss physician and Originally dismissed as mere background, natural the Experts Control alchemist, 1493–1541. antibodies have only recently been shown to Yourself The ultimate goal of preventing disease is to selectively play a crucial role in combating disease. They modulate the body’s own capacity to maintain a healthy state. have a dual specificity, because they not only Treat Healing is the mechanism of repair. In times recognize infectious antigens, but also antigens Yourself of illness, we turn to medicine or sometimes on our own cells, produced in response to stress spiritual sources to stimulate the healing process. or tissue damage. It is this unique aspect of However the body has its own natural ways natural antibodies that suggests they promote Heal Yourself of healing itself. Antibodies are proteins found homeostasis and healing, by maintaining the in the blood that fight disease and return the normal balance in the body. Christoph Binder body to a healthy state. They are an essential has been working on natural antibodies for component of our immune response, and are many years. He is now studying them with his produced by special white blood cells known as own group at CeMM, with a view to harnes­ B cells. Each antibody is customized to an antigen, sing their power to help the body heal itself. usually a foreign protein or molecule found on the surface of a pathogen. An antibody binds very Christoph studies natural antibodies in the con­ tightly to its specific antigen, and this serves text of atherosclerosis, a chronic inflammatory to tag its partner for destruction and clearance by disease and the underlying cause of heart attack other immune cells, or to disable it so it can no and stroke. Atherosclerosis is a slow developing longer cause any harm. disease, and one of the principle risk factors is high cholesterol. This causes an accumulation of Most antibodies are produced in response to specific lipids, known as oxidized LDL (OxLDL), infection and they constitute part of the branch in the walls of blood vessels, which triggers of the immune system known as adaptive an inflammatory response. There is increasing immunity, aptly named to illustrate its speci­ evidence that natural antibodies are also playing ficity for an infection. Once a B cell comes into some role in the progression of atherosclerosis, contact with a pathogen, it binds an antigen and although the details are entirely unclear. becomes activated. Eventually this B cell will be responsible for generating large quantities of antibodies produced in the body that all bind to this one specific antigen. Due to this speci­ ficity, adaptive immunity is the second line of defense against disease, as it takes at least several days after infection to become operational.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 60 61 Keeping the Blood Vessels Clear Know Yourself Natural There is obviously a complex interplay between Fig. 1 Natural IgM quite diverse components of the immune system ­antibodies are ­present in atherosclerotic ­lesions. Antibodies and and atherosclerosis. Both the adaptive and innate Section through an Defend branches of immunity are involved. OxLDL is ­atherosclerotic aorta Yourself (blood vessel) from mice Atherosclerosis the primary candidate for triggering the immune fed with high levels of cholesterol, showing IgM response although the mechanisms of this are Control poorly understood. Christoph is currently trying antibodies stained in red. Yourself to work out some of the details. His group has Fig. 2 Oxidation-specific Natural Born Killer recently discovered that an unexpectedly large epitopes are present in “Scientist have atherosclerotic lesions. Treat Atherosclerosis is a deadly disease. It begins number of natural antibodies have been primed Sections from cholesterol- Yourself shown that the almost as soon as our blood vessels develop to target oxidized epitopes, including OxLDL. fed mice were stained to detect the presence of development during fetal life, but progression is slow, occur­ “Natural antibodies have also been found asso­ malondialdehyde (MDA) ring over decades with the gradual thickening ciated with the atherosclerotic lesions”, says epitopes. MDA is a lipid- Heal of atherosclerotic Yourself of blood vessel walls. High levels of LDL in the Christoph. In fact, they have already shown that peroxidation breakdown lesions is closely product. Positive staining bloodstream are required for disease progres­- a specific type of natural antibody can provide is indicated by red color. linked with sion. Oxidized LDL builds up and the ensuing protection against the disease. It is clear that inflammation.” inflammatory response mediates the localized natural antibodies are important, but what they recruitment of large numbers of immune are actually doing still needs to be investigated. cells to blood vessel walls. Many of these cells “We want to know the function of these natural will eventually die, and their remains need to antibodies in atherosclerosis, and how they are be cleared away, otherwise these sites turn into regulated”, says Christoph. graveyards that, along with lipids and proteins, “The hypothesis form lesions in the blood vessel walls. These To do this, the group uses a combination of lesions aggregate and eventually form plaques approaches. Mouse models are an ideal system is that natural anti­ that are characteristic of advanced stages of as they provide a physiological setting in which bodies are acting the disease. The plaques can eventually rupture, to study the disease. Christoph’s group has like housekeepers, restricting the blood supply and potentially been generating mice that are deficient in specific causing death. types of natural antibodies to see if they provide ensuring the protection against the development of athero­ blood vessel walls There are many logical factors that cause an sclerosis. They are also trying to identify and are kept clear increased risk of atherosclerosis, including diet, isolate more types of natural antibodies that are smoking and age. However, recent evidence primed to target these oxidized epitopes and from obstruction.” has shown a rather unexpected collaboration see if they can understand how they work. The between this disease and the immune response, hypothesis is that natural antibodies are acting a mechanism that is normally thought to be pro­ like housekeepers, ensuring the blood vessel tective. Scientists have shown that the accumula­ walls are kept clear from obstruction. “We think tion of atherosclerotic lesions is closely linked natural antibodies bind to the oxidized lipids with inflammation. Many different types of and thereby neutralize them and initiate their immune cells that are normally recruited to clear clearance from the blood”, says Christoph. This an infection are found associated with these would effectively stop plaque formation and lesions, and they are clearly important for their disease progression. formation and growth. “We also want to know how natural antibodies themselves are regulated”, says Christoph. They have found certain mouse strains that contain higher amounts of natural antibodies than others and now they are investigating what causes this. If they can work out how natural antibodies are generated, it may be possible to artificially stimu­ late their production, thereby targeting OxLDL in individuals at risk of developing the disease. This would essentially provide protection against the disease, and potentially stimulate the body’s own healing process.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 62 63 Prof. Dr. Wolfgang Schütz Rector, Medical University of Vienna

It is a pleasure to congratulate the Center of Molecular Medicine CeMM for its first research report. The Medical Uni- versity of Vienna supports and fosters CeMM as an important project together with the Austrian Academy of Sciences. We look at CeMM as a strategic component of the strive of the Medical University of Vienna to maintain and further develop a leading role in biomedical research. CeMM aims at bridging the gap between clinical and basic research and as such is hoped to ease the translation of many projects towards therapy and diagnostics. For this, CeMM’s location within the hospital campus and physically linked to the newest of the MUV research buildings is of paramount importance. Finally, we are particularly happy about the training mission of CeMM. Besides many common projects CeMM is linked to the MUV with several common PhD programs, conferences, as well as young investigators with double appointments. Nothing is as valuable as the investment in students and young faculty and CeMM represents an important addition for the interdisciplinary training in molecular medicine. On behalf of the entire faculty and MUV personnel we welcome CeMM as a special partner to our research community and wish it, for our own sake, a great future.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 64 65 In 2005, CeMM created a fund to support Results Project Leader three Accelerator Projects, which were Modulation Within the project we could confirm that ISG-12 Bernd R Binder is located at the nuclear envelope and increases Department of Vascular Accelerator to begin in January 2006 and run for two the nuclear export of a set of nuclear receptors of inflammatory Biology and Thrombosis years. These ­projects were designed to that are capable of heterodimerizing with RXR. Research, Medical University extend the fruitful ­collaboration between responses Using ISG-12 deficient mice generated by us and of Vienna Projects mice double deficient for ISG-12 and NR4A1 or CeMM and some of its previously associated by manipulating ApoE or the LDLR, we could demonstrate that members. The projects were specifically ISG-12 deficiency is protective in a mainly NR4A1 required to be ‘application-orientated’ and the nuclear dependent manner in animal models of chronic vascular inflammation (restenosis) or acute were carefully selected for their originality export of nuclear inflammatory models (endotoxin or sepsis mod­ and for their potential impact on therapy. els) and significantly reduces the extent of athero­ receptors sclerotic lesions in atherosclerosis prone mice transplanted with bone marrow from ISG-12 The three successful projects were: deficient mice. + Modulation of inflammatory ISG-12, a novel target for the modulation of In order to generate suitable peptides that can responses by manipulating the nuclear inflammatory responses: Development of interfere with ISG-12 activity, we successfully export of nuclear receptors. screening systems for drugs that interfere with determined the interaction site between ISG-12 Project Leader: Bernd R Binder the ISG-12 mediated nuclear export of nuclear and nuclear receptors, defining an ISG box that receptors and generation of lead strategies interacts with an I-Box in the nuclear receptors. + Immunotherapy of Rheumatoid Arthritis. This sequence information is currently used Project Leader: Günter Steiner The aim of this project is based on our original to generate respective interfering peptides to be + Lymphatic endothelium as finding that the transcriptional activity of nuclear used in animal models and eventually at a later receptors is down-regulated under inflammatory stage also in man. This information can also be gatekeeper for leukocyte trafficking”. conditions. Such down-regulation that inhibits used to generate lead compounds for drug devel­ Project Leader: Dieter Maurer the anti-inflammatory, beneficial effects of nuclear opment. receptors, such as those of the NR4A and the PPAR family or RXR, FXR as well as LXR, Coworkers is mediated preferentially by type I interferons Nikolina Papac- Milicevic, PhD, PostDoc and due to a small interferon inducible molecule, Gabriel Wagner, Diploma student the ISG-12. Sabine Fenzl, Diploma student Paul Dremsek, Diploma student Judit Mihaly, MD thesis student

Relevant Publications 1. Papac-Milicevic, N.et al. The interferon induc­ ible gene 12 (ISG12), a novel factor modulating the vascular response to injury, submitted. 2. Verwendung des Interferon induzierten Gens 12 (ISG-12, IFI27) zur Modulation transkription­ eller Aktivitäten von nucleären Faktoren PCT/ AT 06/000448; A1790/2005

Ce — M­—M­— Research Report 2007 66 67 Project Leader 2. Global analysis of in vivo EC gene expression 4. Additional studies. We also identified hnRNP-D Project Leader Dieter Maurer Identification as a tool to identify DC function-modulating Immunotherapy (AUF1) as a target of autoantibodies of patients Günter Steiner Department of Dermatology, molecules with RA. AUF1 is involved in regulation of Division of Rheumatology, Medical University of Vienna of novel receptor- Bioinformatic analyses allowed us to define the of Rheumatoid stability of mRNAs encoding inflammatory Department of Internal sets of genes that are specifically expressed in cytokines such as IL-1 or TNFα, prompting us Medicine III, Medical ­ligand systems lymphatic and blood ECs in vivo and to unravel Arthritis to investigate two other proteins involved in University of Vienna a pathway of self antigen presentation in MHC posttranscriptional regulation of TNFα expres­ regulating leuko­ class II that occurs on blood ECs and DCs and is sion, T cell intracellular antigen 1 (TIA-1) and essential for the tuning of T cell activation TIA-1 related protein (TIAR). Both AUF1 and the cyte trafficking thresholds. Rheumatoid arthritis (RA) is the most common TIA proteins were found to be overexpressed of the systemic autoimmune diseases and also the in inflamed tissues, further supporting the idea into lymphatic 3. Lymphatic EC-derived neurotensin (NTS) most severe inflammatory joint disease, however that proteins involved in posttranscriptional is a selective negative regulator of DC trafficking the role of autoimmune processes assumed to regulation of gene expression are generally over­ vessels. Expression of neurotensin (NTS) was found initiate and drive the disease is unclear. Therapies expressed under conditions of inflammation, specifically in LECs and one out of the 4 human targeting antigen-specific autoimmune reactions which may lead loss of immune tolerance and the NTS receptors was expressed on human LCs. might be more effective, because they would induction of pathogenic autoimmune reactions. NTS effectively and dose-dependently inhib­ lead to specific elimination or down regulation Chemotactic factors are essential for the traffick­ ited the migration of LCs to the “classical” LEC of pathogenic T and/or B cells. It has therefore Coworkers ing of dendritic antigen-presenting cells (DCs) chemotractant SLC/CCL21, correlating with been the primary goal of this project to develop Markus Hoffmann, PhD student (graduated into peripheral organs and lymph nodes via lym­ impairment of SLC/CCL21-induced, Rho-driven a novel therapy for RA based on antigen specific January 2008), currently working as PostDoc phatic vessels. This is required to mount specific activation of the focal adhesion-associated kinase, immune intervention to the well characterized Michael Müller, PhD student T cell responses against foreign pathogens found Pyk2. These findings indicate that lymphatic autoantigen hnRNP-A2 (RA33) that is targeted by Sylvie Trembleau, PostDoc in peripheral organs. There also exists a constant ECs are dedicated regulators of DC trafficking, autoantibodies and T cells from patients with RA. Brigitte Meyer, TA flux of DCs into lymph nodes even in the absence which can tune the rate of DC exit to lymph Elisabeth Höfler, TA of foreign antigens/pathogens, which may be nodes according to the demands of the tissues. Results Georg Stummvoll, MD essential to maintain T cell tolerance to self. 1. Studies in patients. A major T cell epitope was Esther Jimenez-Boj, MD Co-workers identified that was recognized by approximately In this project, we focused on identifying mol­ Ernst Kriehuber, MD, PostDoc 20% of RA patients but not by any of the (HLA Relevant Publications ecules involved in the migration of DCs into Paul Meraner, MD, PostDoc matched) controls. 1. Fritsch-Stork R, Mullegger D, Skriner K, lymphatic vessels. Firstly, we investigated the Stefan Amatschek, MSc., Student Jahn-Schmid B, Smolen JS, Steiner G. The spli­ presence of such factors in lymphatic endothelial Bärbel Reininger, TA 2. Studies in rats with pristane-induced arthritis ceosomal autoantigen heterogeneous nuclear cells (ECs) and have aimed to identify the specific (PIA). To identify potential autoantigens, we ana­ ribonucleoprotein A2 (hnRNP-A2) is a major receptors on DCs. This would allow a mechanistic Relevant Publications lyzed sera from rats with PIA and control animals T cell autoantigen in patients with systemic lupus understanding of DC trafficking in vivo and lead 1. Amatschek, S., E. Kriehuber, W. Bauer, for the presence of autoantibodies using a panel erythematosus. Arthritis Res Ther 8:R118. (2006) to the development of rational therapeutic strate­ B. Reininger, P. Meraner, A. Wolpl, N. Schweifer, of 20 candidate antigens. An antibody response 2. Grisar JC, Aletaha D, Steiner CW, Kapral T, gies to regulate immunity and tolerance. C. Haslinger, G. Stingl, and D. Maurer. Blood and against hnRNP-A2 was seen in the majority of Steiner S, et al. Endothelial progenitor cells lymphatic endothelial cell-specific differentia­ sera. Cellular studies revealed pronounced T cell in active rheumatoid arthritis: Effects of TNF Results: tion programs are stringently controlled by the reactivity against hnRNP-A2 in pristane-primed and of glucocorticoid therapy. Ann Rheum Dis 1. Lymphatic endothelial cells secrete factors tissue environment. Blood 109:4777. (2007) rats which showed a Th1 phenotype and was 66:1284–8. (2007) that regulate DC migration 2. Meraner, P., V. Horejsi, A. Wolpl, G.F. Fischer, present one week before disease onset. Further­ 3. Hoffmann MH, Tuncel J, Skriner K, Tohidast- We produced culture supernatants from human G. Stingl, and D. Maurer. Dendritic cells sensitize more, the antigen was massively overexpressed Akrad M, Türk B, et al. The rheumatoid arthritis- skin blood and lymphatic ECs using our previ­ TCRs through self-MHC-mediated Src family in the joints of pristane-primed animals, sup­ associated autoantigen hnRNP-A2 (RA33) is a ously established methodology. Migration exper­ kinase activation. J. Immunol. 178:2262. (2007) porting earlier observations made in patients major stimulator of autoimmunity in rats with iments with purified human skin DCs (i.e. skin 3. Winter, D., J. Moser, E. Kriehuber, C. Wiesner, with RA and TNFα transgenic mice. Remarkably, pristane-induced arthritis. J Immunol Langerhans cells; LCs) showed that lymphatic R. Knobler, F. Trautinger, P. Bombosi, G. Stingl, hnRNP-A2 stimulated release of proinflamma­ 179:7568–76. (2007) ECs secrete migration-inducing factors for DCs. P. Petzelbauer, A. Rot, and D. Maurer. Down- tory cytokines such as TNFα and IL-6 in a toll- 4. Skriner K, Hueber W, Süleymanoglu E, We enriched the biological activity and subjected modulation of CXCR3 surface expression and like receptor (TLR) dependent manner, most Höfler E, Krenn V, et al. AUF 1, the regulator of enriched fractions to MS analysis (together with function in CD8+ T cells from cutaneous T cell likely via interaction with TLR7. Taken together, tumor necrosis factor alpha messenger RNA the group of Dr. Superti-Furga). lymphoma patients. J. Immunol. 179:4272. (2007) these data strongly suggest a role for hnRNP-A2 decay, is targeted by autoantibodies of patients in the pathogenesis of PIA and human RA. with rheumatic diseases. Arthritis Rheum 58:511–20. (2008) 3. Therapeutic studies. To study the therapeutic 5. Jimenez-Boj E, Kedersha N, Tohidast Akrad M, potency of hnRNP-A2 we used two different Karlhofer FM, Stummvoll G, et al. Autoanti­ arthritis animal models. Importantly, disease bodies to the translational suppressors TIA-1 onset and severity were significantly delayed and TIAR in patients with rheumatic diseases. or almost completely abrogated by prior nasal Arthritis Rheum, in press. vaccination with hnRNP-A2 (unpublished, preliminary observations).

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 68 69 Man and woman. Europe and America. CeMM In a talk that perhaps best exemplified the and EMBO. Chemistry and Biology. These were Drug Action and integration of basic science and drug discovery, the winning combinations that together went a goal of the meeting, Stephen Fesik (Abbott) The First on to make the first CeMM research conference Chemical Biology discussed how his team used his SAR by NMR a resounding success. First, the organizers: Giulio approach to discover inhibitors of anti-apoptotic Superti-Furga and Ulrike Eggert. Giulio is the in the Post­ proteins. One of these compounds is now in Conference Scientific Director of CeMM and a visiting profes­ clinical trials to treat leukaemia and other cancers. sor at the Medical University of Vienna. He has genomic Era been mainly based in Europe having studied in Small molecules can also be used to study entire Zurich and the Institute for Molecular Pathology classes of proteins using activity-based profiling. of CeMM: in Vienna (IMP), as well as heading his own In a beautiful and comprehensive example, research group at the European Molecular Biology Chemical biology and molecular pharmacology ­Benjamin Cravatt (Scripps) discussed how his Laboratory in Heidelberg and being the scientific as scientific disciplines are evolving towards lab began with a screen and discovered a new leader of Cellzome, a biotech company, for five each other and profit from powerful advances role for specific metabolites in cancer. Synergy years. Ulrike Eggert is Assistant Professor at the in postgenomic, imaging and bioinformatic Dana Farber Cancer Institute and Harvard Uni­ technologies. Concurrently, diseases are being Ron Raines (U Wisconsin/Madison) illustrated versity in Boston. Ulrike did her undergraduate better characterized at a molecular level and an example of how a protein itself can become degree in Oxford in the UK, but moved to the the genetic basis for differential response of a drug by engineering a ribonuclease (RNAse) in action USA shortly after, for both her PhD and Post- patients to therapeutics is being investigated. and showing that it can target and kill cancer cells. 23—26 August 2007 doctoral research. Together, they make an inter­ Austrian Academy of Sciences, Vienna, Austria national team and an ideal combination to Understanding and Exploiting Proteins Targeting the Kinome organize a high-profile scientific conference. Historically, enzymes have been the main targets Small molecule inhibitors of tyrosine protein of small molecules, both in drug discovery and kinases are a class of compounds that are both The European Molecular Biology Organization in chemical biology. Designing effective small important research tools and a successful group (EMBO) encourages scientists to organize work­ molecule inhibitors is dependent on understand­ of therapeutics. Imatinib (Gleevec), probably shops, which are intended to give researchers ing the mechanism of an enzyme. The polymeriz­ the best characterized and most successful target­ from different but related fields the opportunity ing enzyme (GlfT) is involved in the biosynthesis ed therapeutic agent, has galvanised the field of to meet and discuss common themes. Giulio of the bacterial cell wall in M. tuberculosis and signal transduction and formed the basis of new and Ulrike come from different scientific back­ therefore a potential target for the development therapeutic approaches. grounds but both use similar chemical and cell of urgently needed antibiotics. Laura Kiessling biological approaches to do their research. This (U Wisconsin/Madison) discussed how they prompted them to organize an EMBO workshop, discovered how this enzyme works, and there­ in collaboration with CeMM, designed to explore fore could design inhibitors, which have shown the synergism between biology, chemistry some promise in killing mycobacteria. and medicine. The goal was to foster interactions between researchers of different backgrounds who have a common interest in understanding the effect of chemical compounds on biological systems. Dining in the Kuppelhalle, where the stage is set for rockband Rocquette. The organizers invited a range of internationally renowned scientists from both chemistry and biology to take part in the conference. All in all, it was a recipe for success. Attendees commented on the exceptionally high quality of the science, and scientific discussions were made all the more enjoyable by the extraordinary surroundings of the National Historisches Museum in Vienna, which was the venue for the event. The following article is based on a meeting report written by the two organizers, Ulrike Eggert and Giulio Superti-Furga. The full version can be accessed from Nature Chemical Biology, January 2008, Vol. 4, 1, p7–11.

Ce — M­—M­— Research Report 2007 70 71 The laboratories of Gerard Drewes (Cellzome) In a conceptually related approach, several groups and Superti-Furga (CeMM, Vienna) presented have developed tools to monitor changes in the Natural History Museum: chemical proteomics studies using imatinib, its activity of drugs in mammalian cells using RNA Venue for the gala dinner. structurally related second generation cousin interference. Julian Downward (Cancer Research nilotinib as well as the type I inhibitors dasatinib UK) discussed an RNAi screen to identify genes and bosutinib. Both groups reported the sur­ that are involved in resistance to cancer chemo­ prising finding that therapeutic drugs with the therapeutic drugs and Thijn Brummelkamp same medical indication (chronic myelogenous (Whitehead Institute) reported on new shRNAi leukemia) display dramatically different interac­ technologies to evaluate synthetic interactions tion profiles, with only a few targets in common. in mammalian systems.

Small Molecular Probes of Cell Division Drugs: Efficacy and Safety Small molecules that target cell division have Many scientists at the meeting shared the opin­ a long and distinguished history, both as drugs ion that extensive “physiome” measurements and as tool compounds. For example, the tubulin on drug action as well as drug target interactions binder taxol is a widely used anti-cancer drug. will eventually allow accurate computational Thomas Mayer (MPI Martinsried) and Ulrike predictions of the efficacy and safety of new drugs. Two of the speakers: ­Eggert (Dana-Farber Cancer Institute and Harvard Jonathon Mason (Lundbeck, Copenhagen) is Michael Hoch, left, and Randall Peterson. Medical School) discussed recent advances in this clearly among the researchers who are already field. Jan-Michael Peters (IMP Vienna) discussed trying to do this. Many drugs show “polyphar­ how they used BI2536, an inhibitor of a regulator macology”, meaning that they clearly affect of cell division they discovered in collaboration distinct targets despite similarities in chemical with Boehringer Ingelheim, to study both mitosis structure. For about 2,500 compounds Mason, and cytokinesis. with colleagues at Pfizer, has obtained data from a variety of functional assays (“biological Drugs, Pathways and Networks fingerprints”) and then clustered compounds In a synthetic lethal relationship, a cell survives according to the similarity of their fingerprints. if one protein of a synthetic pair is removed, but Hans-Peter Fischer (Genedata), Klaus Weinberger dies if both are removed, implying a functional (Biocrates) and Robert McBurney (BG Medicine) cooperation between the two proteins. Synthetic reported on other new “omics” approaches lethality can be assessed by removing combina­ to predict the molecular action of drugs and the tions of gene products or by combining gene pathways affected. Robert McBurney, left, products and drugs. Mike Tyers (University of discussing science (perhaps) with Fabio Piano and Edinburgh) reported on more than 100 synthetic What next? Thijn Brummelkamp, right. lethality screens performed in his laboratory, One conclusion of the conference was that the which is part of an effort to comprehensively time is coming to update the pharmacology map the network of all possible chemical and textbooks. We have now moved beyond the genetic synthetic interactions in yeast. point where we should focus solely on individual drug-target relationships as the molecular basis of therapeutics. It should be feasible to describe entire “physiome” changes elicited by chemical agents, including the details of how much certain pathways are affected. At the same time, cell and developmental biology are increasingly adopting the use of creative chemistry that complements classic and molecular genetics approaches. Cer­ tainly until all of these approaches have become The two organizers: an essential part of the research repertoire of basic Ulrike Eggert and Giulio Superti-Furga. researchers and drug hunters, we will keep this conference running with biannual occurrence. We hope to attract more and more “fusionists” and “trespassers” each time.

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 72 73 Karl Landsteiner: Professor Kuriyan received his Bachelor of John Kuriyan: Science undergraduate degree in chemistry The Austrian Founder of Blood Groups from the Juniata College in Pennsylvania, before CeMM Karl Landsteiner (1868 -1943) was an “Regulatory attaining a doctorate at the renowned Massa­ Austrian biologist and physician. He was chusetts Institute of Technology in Cambridge Mechanisms in with ­Gregory Petsko and with Martin Karplus Karl awarded the Nobel Prize in Physiology at Harvard University. After 14 years at the or Medicine in 1930, for his groundbreak­ Protein Tyrosine Rockefeller University in New York, as Head ing discovery that human blood could of the department for molecular biophysics and Kinase Signaling”. Patrick E. and Beatrice M. Haggerty Professor, Landsteiner be divided into specific blood groups, John Kuriyan moved to UC Berkley in s2002. made when he was an assistant at the 3rd May, 2007 He has published so far more than 140 scientific University of Vienna in 1901. He worked papers, a quarter of which can be found in the highest impact journals, including Nature and Lectures in the Department of Pathological Anat­ Cell. Many of the structures that were deter­ omy under Professor A. Weichselbaum, The Inaugural Speaker: Professor John Kuriyan mined in his laboratory are prominent in all who himself discovered the bacterial Professor John Kuriyan was invited by Professor standard molecular and cell biology textbooks, Giulio Superti-Furga, the director of the CeMM- which just goes to show how fundamental cause of meningitis. Today, thanks to research center for molecular medicine of the his discoveries have been and how far reaching Landsteiner’s pioneering work, all humans Austrian Academy of Sciences as the first speaker his work will no doubt become. of this new annual lecture series, “CeMM – Karl are classified according to their blood Landsteiner Lectures”. For 10 years there has been group: A, B, AB or O. His discovery has a close scientific collaboration between the groups had far reaching implications within of Superti-Furga and Kuriyan, which led to new discoveries on the mechanisms of enzyme activity diverse fields of medicine and biology, in relation to cancer formation. His Karl Land­ by providing a novel foundation for steiner Lecture was entitled: “Regulatory Mecha­ human classification and the study of nisms in Protein Tyrosine Kinase Signaling”.

heredity, and has been of fundamental John Kuriyan is a Howard Hughes Investigator importance for the safe operation of and Chancellor’s Professor of Biochemistry and John Kuriyan on a tram Molecular Biology at the University of California, in Vienna, sightseeing blood transfusions. To honor his achieve­ with Oliver Hantschel and Berkley. He is one of the youngest selected mem­ Giulio Superti-Furga. ments, CeMM has established the Karl bers of the US National Academy of Sciences, Landsteiner Lecture series, which will be and received, amongst other things, the renowned hosted annually at the Austrian Academy Lounsbery Award in 2005 in recognition of his extraordinary scientific achievement. Professor of Sciences, and will be given by an invited Kuriyan is one of the most prominent and suc­ speaker who is also regarded as a pioneer cessful structural biologists in the world and has in molecular medicine. solved the molecular structure of many proteins associated with disease. His innovative work has given important insights into the most funda­ mental cellular processes, most notably mecha­ nisms of signal transduction and DNA replication. Some of his other important discoveries were the first three-dimensional structure of the onco­ John Kuriyan talking protein c-Src, and studies of Bcr-Abl, which causes to Peter Schuster, President of the Academy specific forms of leukemia. Many of Kuriyan’s publications are considered to be milestones of molecular medicine.

Ce — M­—M­— Research Report 2007 74 75 Following a year of CeMM firsts (the first CeMM conference and the first Landsteiner Photos from the CeMM retreat, in Steinschaler CeMM lecture), came the first CeMM scientific Dörfl. retreat; a two-day science and social get together for everybody, held in Franken­ Retreat fels, a hiking paradise in the Alpine foot­ hills of the province of Lower Austria.

The schedule carefully interspersed the science with the social, alternating student talks and scientific discussions, allowing time for outdoor walks along the snow covered paths and outdoor drinks of Glühwein (a sort of mulled wine) around campfires, followed by a late-night party for all who were up for it. There was even room for a caricature artist to give his visual interpretation of the individuals at CeMM, some apparently better than others, which are shown on the following pages.

All the activities were accompanied by a photographer to faithfully capture the whole event. We considered getting some participants to describe their personal experience of the retreat, but all in all the photos tell a much better story …

Ce — M­—M­— Research Report 2007 76 77 Can you guess who is who?

Christoph Baumann Tiina Berg Christoph Binder Marc Brehme Jacques Colinge Gerhard Dürnberger Anita Ender A B C D Q R Nora Fernbach Adriana Goncalves Roland Jäger Evren Karayel Ines Kaupe Robert Kralovics Thomas Köcher Sebastian Nijman Damla Olcaydu Mathew Sloane Adrijana Stefanovic Thomas Stranzl Amrei Strehl Giulio Superti-Furga Sandrine Tonon David Weismann E F G H S T Carina Winkler

Answer at the end > p. 99

I J K L U V

CeM — M­—M­— Research Report 2007 N O P WCe — M­—M­— Research Report 2007 X 78 79 The first CeMM PhD program was established in 2006 and the next round Structure of The first CeMM is in 2008. For each yearly intake, the the CeMM CeMM program is advertised internationally in scientific journals such as Nature. The PhD Program PhD Students PhD Program applications are received and discussed by all of the CeMM PIs, and a prelimi­ 1st Year The first CeMM PhD program began in October nary selection is made and those can­ Lab rotations: Students spend 2 weeks in each 2006. There were 267 applications, and only five didates invited for an interview before of the 6 labs at CeMM, getting to know the people positions awarded. The outstanding candidates the final PhD students are chosen. and the science. This is designed to create the that were eventually selected to join the program sense of belonging to a program from the entire were Irena Vlatkovic, Adriana Goncalves, Ana institute, and of course to get to know everybody Zivkovic, Roland Jäger and David Weismann. The Medical University of Vienna is and experience what is being done scientifically. Below, these first CeMM PhD students describe the home academic institution for the in their own words how they found their first CeMM PhD program, and as such sets Kick-off lectures: These are given by a selection year at CeMM. of prominent leaders, scientists and medical pro­ several guidelines. The duration of the fessors from the Viennese science and medical PhD is 3 years and at the end the thesis community, as well as the biotech industry, is defended in front of a committee of who speak to a very small group of students. The PhD Students goal is to provide students with a detailed and (clockwise from top left): Irena Vlatkovic around three members. The PhD thesis up-­to-date introduction to the various topics of David Weismann is required to yield at least one publica- Molecular Medicine. Ana Zivkovic Roland Jäger tion in a peer-reviewed journal. There Adriana Goncalves End of 1st Year: Students are required to generate is mandatory course work, particularly a research proposal on a topic that is not directly in the first year taking around 6–7 hours related to their own research, but involves the per week, including basic seminars research of at least two CeMM groups. The best proposal is awarded a prize. This encourages and introductory courses in molecular students to think independently and stimulate medicine, cell biology and ethics, disser­ discussions with other students and Post-Docs tation seminars and regular journal clubs. from different labs.

Informal CeMM work discussions are 2nd Year held every Friday and students will pres­ Beginning of 2nd Year: Thesis proposals. This ent their work on a regular basis. is in accordance with the Medical University of Vienna guidelines. Short abstracts are first reviewed by all CeMM PIs, before the final pro­ In the future, there will be a CeMM posal is written and submitted to the university PhD student symposium, which will be and thesis committee.

organized by the CeMM PhD students. 3rd Year They will be encouraged to invite speak­ End of 3rd Year: Thesis defense ers of their choice, and host the talks David Weismann (Supervisor: Christoph Binder) and mediate discussion. Of course, inter­ More than one year has passed since I arrived at CeMM for the PhD interview. Within this spersed between the science are regular year, although – or better, because – it happened social activities including Happy Hours, to be tough sometimes, I learned to appreciate and the yearly scientific retreat. this institute as a place of high level research, with fruitful, interdisciplinary discussions and highly developed interactions between the dif­ ferent research groups. It is the latter that has been completely new to me and is, to my mind, the most prominent of CeMM’s merits. To be able to call someone rather informally when­ ever I encounter problems and be sure that this person will try her/his best to help me was a revelation to me, but these are just a few of many factors that make CeMM a unique platform and highly recommendable to young scientists.

Ce — M­—M­— Research Report 2007 80 81 Ana Zivkovic (Supervisor: Sylvia Knapp) Roland Jäger (Supervisor: Robert Kralovics) During the interview for my PhD position, When I found the call for applications for the I realized that CeMM was the right place to CeMM PhD program, I was immediately fasci­ start my scientific career, as discussions with nated by the professional website, the idea of CeMM a group of successful, strong-background CeMM and especially by the fact that CeMM tries principal investigators coupled with a great to bridge the gap between basic research and chance to do research in a topic I was inter­ the clinic. Up to now I do not regret sending my Principal ested in during the last year of my studies in application. Although it is the first round of this Belgrade, seemed highly attractive to me. program and many things have to be built up, organized and established, I think everything was After one long extensive year of hard work handled in a very professional way. Starting from Investigators (which seems a bit like a rollercoaster ride of the interviews where we could get to know the highs and lows), a lot of experiments and plenty principal investigators really well, continuing of new conclusions, I can see how much I have with the lab rotation in the first months, where both improved my scientific knowledge and we came into close contact with every single importantly developed my scientific judgment. person at CeMM and got to know where to find Particularly fulfilling was the great support for support, competence and friendship, up to my own ideas that I received from members now where the CeMM PhD program really starts of both my immediate lab and the CeMM com­ to be in complete accordance with the require­ munity in general. Together with other PhD ments at the Medical University, taking away students, my great friends, I’m learning how to from us a lot of the organizational burdens. I am overcome my difficulties and to approach my also glad that I can contribute to the very begin­ scientific outlook in a positive and fun manner. ning of the Kralovics lab at CeMM in Vienna, Being here, at the beginning of CeMM expanding learning every day about the difficult challenges is a rare advantage and it gives me a chance to of starting a lab, but nevertheless feeling the take an active role in building this institute. I have development in productivity and the increase thoroughly enjoyed this first year and I hope in technical and intellectual power, pillowed that the next couple of years will be as fulfilling by a strong support from the whole of CeMM. as my first. Adriana Goncalves Irena Vlatkovic (Supervisor: Denise Barlow) (Supervisor: Giulio Superti-Furga) My first year at CeMM as a PhD student showed As one of the first round CeMM PhD students, me that graduate study is hard work, but reward­ I am glad to be able to give my impressions about ing and enjoyable. CeMM gave me an opportu­ the first year experience at CeMM. It all started nity to experience the science, to learn how to with an eagerness to take a new challenge, give think globally taking into consideration different a new and almost first step in science and enroll sides of the problem no matter to which disci­ in what was the first PhD program of an institute, pline they belong. In CeMM I learned how that was also taking its own very first steps and information, technical supports and ideas can the challenge of starting a fresh and innovative be shared at the level of the whole institute, scientific perspective. It feels good to look back which became some kind of gestalt. The warm now and see how much we both grew up. At familiar atmosphere of CeMM meetings, CeMM CeMM I learned not only to overcome technical retreats, CeMM parties and also good scientific problems and to develop scientific thinking, perspective with all technical, clinical and people but also to understand the dynamics of a scientific support make CeMM the perfect place to learn culture and the people that make it. As an inter­ and live. That is why I warmly recommend CeMM national, interdisciplinary and innovative insti­ to future generations of PhD students for whom tute that integrates basic and clinical research, molecular medicine is the mystery of life. I can say that CeMM offers the ideal platform to promote training of young researchers. It was not always easy throughout this first year, but the final feedback couldn’t be more positive and it is with pleasure that now I can recommend CeMM to the next generations of PhD students.

Ce — M­—M­— Research Report 2007 Giulio Superti-Furga, Scientific Director and CEO Robert Kralovics, born 1970, is Czech and joined Giulio of the Research Center of Molecular Medicine Robert CeMM on June 1st 2006. He obtained his first of the Austrian Academy of Sciences and a visiting degree in Molecular Biology and Genetics in Superti-Furga professor at the Medical University of Vienna. Kralovics Bratislava and later his Ph.D. in Biophysics at the Academy of Sciences of the Czech Republic in Pathological Networks Genetics of hematological He performed his undergraduate and graduate Brno. He did his postdoctoral work on the genetics in Leukemia and Immunity disorders studies in molecular biology at the University of myeloproliferative disorders working with Josef of Zurich, at Genentech Inc. and at the Institute Prchal at the University of Alabama at Birmingham, for Molecular Pathology in Vienna (I.M.P.). USA. He followed Prchal as an Assistant Professor Giulio Superti-Furga has been a post-doctoral at the Baylor College of Medicine in Houston. Since Giulio Superti-Furga’s group fellow and Team Leader at the European Molec­ Robert Kralovics’ group mid 2001 Robert Kralovics has been Project Leader is renting lab space: ular Biology Laboratory (EMBL) until 2004. is hosted by: with Radek Skoda in Basel. Robert Kralovics’ Vienna Competence Center For several years he has served as professor of Division of Hematology and research interests are in chronic myeloproliferative CeMM – Center for Molecular Biotechnology at the University of Bologna. In Hemastaseology disorders (MPDs). His major achievement so far Medicine of the Austrian Academy University Hospital of Vienna of Sciences CEO and Scientific Director 2000, he co-founded the biotech company Cell­ Währinger Gürtel 18–20 CeMM Principal Investigator has been the identification of a gain-of-function Lazarettgasse 19 [email protected] zome Inc., where he has been Scientific Director 1090 Vienna, Austria [email protected] mutation in the JAK2 kinase(V617F) that plays an 1090 Vienna, Austria and responsible for the Heidelberg research site. important role in MPD pathogenesis. Prominently PhD (Molecular Biology), His most significant scientific contributions are PhD (molecular biology) published in April 2005 inNew England Journal University of Zurich (CH), the elucidation of basic regulatory mechanisms Czech Academy of Sciences of Medicine, the work has given Robert instant IMP Vienna (A) of tyrosine kinases in human cancers and the Post-doctoral fellow celebrity in the hematooncological field and fos­ Post-doctoral fellow, Team Leader discovery of fundamental organization principles University of Alabama tered Robert’s interest in Jak2 as a potential target. EMBL – European Molecular of the proteome of higher organisms. at Birmingham (USA) Biology Laboratory (D) Assistant Professor However, he believes that there is an “upstream” Scientific Director An Italian national born 1962, Giulio Superti-­Furga Baylor Collage of Medicine, mutation in a yet to be identified gene(s), that Cellzome (D) has an Austrian wife and two children. Houston (USA) predisposes patients to MPDs. One of his new Project Leader research tasks is to find new mutations using whole + Italian nationality University Hospital Basel (CH) genome deletion analysis and by mapping disease + Joined Cemm in January 2005 associated genomic regions in MPD families. Robert + Group of 15 people + Czech nationality Kralovics has authored 20 scientific publications. plus mass spectrometry team (4) + Joined CeMM in June 2006 Robert Kralovics is housed and hosted by the and bioinformatics team (3) + Group of 5 people, funded Hematology Department of the MUW (Ulrich by CeMM, MUW, and FWF Jäger, Heinz Gisslinger). Main research interests + Mechanism of action of drugs Main research objectives + Molecular networks and questions affecting leukemias + Identify mutations in early + Molecular basis of innate immunity steps of disease development in hematological malignancies + How mutant stem cells evolve genetically, how they respond to therapy? + What gene mutations cause familial predisposition to hematological malignancies? + How does genetic variability contribute to disease? + How to diagnose the diseases in early stages of development?

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 84 85 Denise Barlow is Principal Investigator at CeMM Sylvia Knapp was born in Innsbruck in 1968 and is Denise and an Honorary Professor at the Universityof Sylvia an Austrian Citizen. She studied Medicine first at Vienna. Denise initially trained as a State Regi­ the Free University in Berlin and for the major part P. Barlow stered Nurse in the UK and afterwards completed Knapp at the University of Vienna Medical School, obtai­ undergraduate studies at Reading University ning her M.D. degree in 1993. In 2000 she obtained Epigenetic Mechanisms Innate Immunity (UK) and a Ph.D. at Warwick University (UK). her License in Internal Medicine and in 2004 she in Development & Disease and bacterial infections Post Doctoral work followed at ICRF (London obtained a “Habilitation” in Internal Medicine of UK) and EMBL (Heidelberg,Germany). Group the MUW. leader positions were then held at the IMP (Vienna) and NKI (Amsterdam). On returning After several residencies, mostly in areas of Internal Denise Barlow’s group to Austria in 2000, Denise was appointed Head Sylvia Knapp’s group Medicine like Infectious Diseases, AIDS and Inten­ is renting lab space: of the Dept. of Developmental Genetics at the is hosted by: sive Care Units, she became a Research Fellow in Institute of Genetics Austrian Academy IMB Institute (Salzburg), Department of Internal Medicine I Tom van der Poll’s laboratory at the University of Max F. Perutz Laboratories and then finally, returned to Vienna in 2003 as Medical University Vienna Amsterdam, for four years (Laboratory of Experi­ Vienna Biocenter Währinger Gürtel 18—20 Dr. Bohr-Gasse 9/4 CeMM Principal Investigator a Principal Investigator with CeMM. Significant 1090 Vienna, Austria CeMM Principal Investigator mental Internal Medicine). She intends to continue 1030 Vienna, Austria [email protected] contributions of the Barlow lab so far, are the [email protected] her work on the innate immune response to bacteri­ discovery of the first imprinted gene in mammals al infections, focusing on the molecules involved Honorary Professor of Genetics and the elucidation of the epigenetic mechanism MD, University of Vienna in the initiation and resolution of the innate immu­ at Vienna University underlying imprinted expression. A British Internist, Vienna General ne response to clinically relevant pathogens and PhD, Warwick University (UK) national, Denise has a passion for mountains and Hospital, MUW on the role of bacterial virulence factors and their Post-doctoral Fellow, ICRF London enjoys very much living and working in Austria. PhD (Experimental Medicine), interactions with host structures and pathways. (UK), EMBL Heidelberg (D) University of Amsterdam Group Leader, IMP Vienna (A), She is author of 60 scientific publications, reports NKI Amsterdam (NL) + Austrian nationality and book chapters, her most important achieve­ Head Dept. Developmental Biology, + Joined CeMM in April 2006 ments include the identification of the anti- IMB-OeAW Salzburg (A) + Currently group of 6 people inflammatory role of alveolar (lung) macrophages in Streptococcus pneumoniae pneumonia. Sylvia + British nationality Main research interests Knapp is keeping her part-time responsibilities in + Joined CeMM in January 2004 + Identify the impact of the intensive care unit (albeit at a very reduced + Currently group of 12 people bacterial toxins level) and her own research laboratory is hosted + Exploit molecular mechanisms by the MUW (Dept. of Internal Medicine I). Main research interests of host-pathogen interactions + Molecular basis and function of genomic imprinting in mice and humans + Identification and characterization of macro non-coding RNAs + The potential of macro non-coding RNAs as tumor biomarkers

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 86 87 Sebastian Nijman was born in The Netherlands Christoph Binder was born in 1973 in Vienna. He Sebastian (1975). He obtained his university training in Christoph first obtained his M.D. degree from the University Utrecht where he specialized in Molecular Biol­ of Vienna Medical School in 1997, working as an Nijman ogy and Biochemistry and acquired a Masters J. Binder intern in the Clinical Pathology department (Prof. of Arts degree from the University of Maastricht Dontscho Kerjaschki). Later, he entered a Ph.D. Cancer Genomics Atherosclerosis (Science, Society and Technology Studies). program at the University of California in San Diego, and Immunity After a short “detour” through industry where working with world-famous atherosclerosis resear­ he was involved in clinical research, he started cher Joseph Witztum. his PhD in the lab of Rene Bernards at the Nether­ lands Cancer Institute in Amsterdam. With the In 2002, Christoph obtained his Ph.D. degree for Sebastian Nijman’s group help of the first RNAi screen in mammalian cells Christoph Binder’s group the thesis entitled: “Defining Innate and Adaptive is renting lab space: he assigned a function to the familial tumor sup­ is hosted by: Immune Mechanisms in the Atheroprotective Department of Medical pressor gene CYLD. This work has led to a rational Department of Medical Effect of Immunization with Oxidized Low- and Chemical Laboratory therapeutic approach for treating the tumor and Chemical Laboratory Density Lipoproteins”. His interests are clearly Diagnostics (KIMCL) Diagnostics (KIMCL) Medical University of Vienna CeMM Principal Investigator syndrome that is caused by mutations in this Medical University of Vienna CeMM Principal Investigator interdisciplinary and span vascular biology, lipid General Hospital H5.J2.09 [email protected] gene. Furthermore, his work on CYLD and other Währinger Gürtel 18­—20 [email protected] oxidation, natural antibodies and innate immunity. Währinger Gürtel 18–20 1090 Vienna, Austria 1090 Vienna, Austria deubiquitinating enzymes has had a significant Christoph Binder has won numerous prestigious PhD (Molecular Biology), impact on various fields of research. MD, University of Vienna fellowships and awards and has authored 15 publi­ Netherlands Cancer Institute PhD (Molecular Pathology), cations in important journals, including Nature Post-doctoral fellow, In 2006 he joined the lab of Todd Golub at the University of California San Diego Medicine and Nature. His main research achieve­ Broad Institute of Harvard Broad Institute of Harvard and MIT. Here he Post-doctoral fellow, ments include the discovery of IL-5 as an athero­ and MIT (USA) developed novel genomic approaches to dis­ University of California San Diego protective cytokine. In the future, he would mainly cover the functions of genes and identify new like to define the role of IL- 5 and of natural anti­ + Dutch nationality angles for cancer treatment. Much of Sebastian + Austrian nationality bodies in atherogenesis and autoimmunity + Joined CeMM in October 2007 Nijman’s research can be considered as techno­ + Joined CeMM in April 2006 and to exploit findings for therapy and diagnosis. + Currently group of 3 people logy driven which allows the interaction with + Currently group of 5 people Christoph Binder still holds a faculty position scientists from many different backgrounds. as Assistant Professor of Medicine at UCSD and Main research interests At CeMM and the KIMCL, where also principal Main research interests works at the Department of Medical and Chemical + Identify novel strategies to treat investigator Christoph Binder is located, he + Role of natural immunity in Laboratory Diagnostics (KIMCL) of the MUW. cancer (cancer vulnerabilities) hopes to find an exciting scientific environment inflammation and oxidative stress He recently obtained his “Habilitation”. + Unravel molecular mechanisms at the interface of basic research and the clinic. + Elucidate the protective that drive tumorigenesis capacities of natural antibodies + Functional genetic screens to in atherosclerosis identify cancer-related genes + Discover ways to boost natural immunity as therapy for cardio­ vascular diseases

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 88 89 Keiryn Bennett, PhD., heads the mass spectrom­ Jacques Colinge PhD, heads the bioinformatics Keiryn etry unit at CeMM. She obtained her Bachelor Jacques team at CeMM since September 2006. He perfor­ of Science with Honours at the University med mathematics graduate studies in Geneva, Bennett of Tasmania and her PhD at the Department of Colinge Switzerland. He then did his PhD with Professor Chemistry, University of Wollongong, Australia, G. Wanner, also in Geneva, in the field of numerical under the supervision of Professor Margaret analysis of partial differential equations. This was Sheil. She further trained in some of the most a joint project with both Swiss Institutes of Tech­ renowned mass spectrometry laboratories, nology. After completing his PhD, Jacques Colinge includ­ing Professor Peter Roepstorff in Denmark. joined Serono Pharmaceutical Research Institute Keiryn Bennett has been Director of Analytical Jacques Colinge’s group as a bioinformatician to work mainly on differential Keiryn Bennett’s group Applications at Protana AS in Denmark (now is renting lab space: gene expression data analysis. In 2000 he moved is renting lab space: MDS Proteomics) and has experience with many CeMM – Center to GeneProt Inc. to head a group of 9 in charge Vienna Competence Center different systems. Author of around 30 publi­ for Molecular Medicine of mass spectrometry-related bioinformatics. Four CeMM – Center for cations, Keiryn Bennett was also involved in the of the Austrian Academy years later, he joined the Upper Austrian University Molecular Medicine of Sciences of the Austrian Academy Head of Mass Spectrometry large-scale analysis of yeast protein complexes Mariannengasse 14 Head of Bioinformatics of Applied Sciences at Hagenberg to serve as a of Sciences [email protected] published in Nature along with the analogous 1090 Vienna, Austria [email protected] Professor of Bioinformatics. Jacques Colinge’s main Lazarettgasse 19 1090 Vienna, Austria effort from Cellzome. She is respected worldwide contributions are solution methods for strongly PhD, Department of Chemistry, in the field of protein mass spectrometry. She PhD, Swiss Institutes nonlinear elliptic PDEs arising in glaciology, stati­ University of Wollongong, Australia brought to CeMM more than 15 years of expe­ of Technology Bioinformatician, stical models for SAGE data analysis, MS data Director of Analytical Applications, rience in protein mass spectrometry and 7 years Serono Pharmaceutical identification, and MS-based quantitation analysis. Protana AS, later called experience managing a high-throughput indus­ Research Institute MDS Proteomics, Denmark trial proteomic laboratory. Keiryn Bennett has Head of Bioinformatics, A Swiss and French national, he is married and has established CeMM’s protein mass spectrometry GeneProt Inc 3 children. + Australian nationality capability. Professor of Bioinformatics, + Joined CeMM in October 2004 Upper Austrian University + Group of 3 people of Applied Sciences, Hagenberg

Main research interests + Swiss and French nationality + Proteomics + Joined CeMM in September 2006 + Mass Spectrometry + Group of 4 people + Integration of mass spectrometry with Biology and Bioinformatics Research Interests + Computational Proteomics + Computational Statistics and Statistical Learning + Systems Biology Data Analysis

Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 90 91 CeMM Directory

Management Thomas Köcher (A) Agnes Gstöttenbauer (A) Technical Assistants Giulio Superti-Furga (I) OeNB OeNB Tiina Berg (FIN) CEO and Scientific Director Paulina Latos (PL) Adriana Goncalves (P) CEMM Gerhard Schadler (A) CEMM/EUP0002 (Heroic) OeNB Romana Bittner (A) CEO and Administration FWF1718 Ru Huang (CN) CEMM, FWF1718 Markus Müllner (A) EUP0001 (Epigenome); Nils Craig-Müller (D/USA) ÖAW EUP0002 (Heroic) Administration CEMM Lily Remsing-Rix (USA) Roland Jäger (A) Anita Ender (A) Nora Fernbach (A) PRI0001 LLS Fellowship FWF20033 BWK0004 (GENAU DRAGON) Alexandra Gossner* (A) Uwe Rix (D) Evren Karayel (TR) Tanja Furtner (A) Xenia Taschner-Weissmann BWK0004 (GENAU DRAGON) FWF W1204B09 (CCHD) CEMM (A) Omar Sharif (UK) Martha Körner (A) Laura Göderle (A) Carina Winkler (A) CEMM CEMM, EUP0002 (Heroic) CEMM Mathew Sloane (AUS) Ulrich Matt (A) Hanna Jahn (A) Principal Investigators ÖAW CEMM OeNB Denise Barlow (UK) Laura Steenpaß (D) Damla Olcaydu (TR) Ines Kaupe (A) EUP0001 (Epigenome) CEMM Christoph Binder (A) FWF18737 Amrei Strehl (D) Florian Pauler (A) Sylvia Knapp (A) Martin Krammer* (A) FWF20033 EUP0002 (Heroic) OeNB Robert Kralovics (CZ) Iveta Yotova (B) Frederica Santoro (I) André Müller (D) Sebastian Nijman (NL) FWF1718 CEMM CEMM Giulio Superti-Furga (I) Basak Senergin (TR) Maria Ozsvar Kozma (H) PhD and Diploma Students EUP0002 (Heroic)/FWF1718 KIMCL-MUV/CeMM Amir Shahzada (PK) Department Heads Marc Brehme (D) Melanie Planyavsky (A) FWF18737 FWF W1204 (CCHD) OeNB Keiryn Bennett (AUS) Ana Zivkovic (SRB/CG) OeNB Larissa Cardilo dos Reis (BR) Gregor Schütze* (D) CEMM CEMM OeNB Jacques Colinge (CH/F) Thomas Stranzl (A) GEN-AU APPII Evelyn Dixit (A) Adrijana Stefanovic (A) OeNB FWF W1204 (CCHD) OeNB OeNB Gerhard Dürnberger (A) Stefan Stricker (D) Katarzyna Warczok (PL) Postdoctoral Fellows OeNB EUP0001 (Epigenome) CEMM Christoph Baumann (D) Emanuel Gasser (A) Sandrine Tonon (B) OeNB OeNB CEMM Tilmann Bürckstümmer (D) Irena Vlatkovic (SRB/CG) DFG Fellowship EUP0002 (Heroic) Oliver Hantschel (D) David Weismann (A) name (nationality) FWF18737 CEMM funding Quanah Hudson (NZ) * left CeMM in 2007 EUP0001 (Epigenome) EUP0002 (Heroic)

Austria, Australia, Belgium, Brazil, China, Czech Republic, Finland, France, Germany, United Kingdom, Hungary, Italy, The Netherlands, New Zealand, Pakistan, Poland, Portugal, Serbia/Montenegro, Switzerland, Turkey, USA = 21 Nationalities Ce — M­—M­— Research Report 2007 92 93 Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 Kakkad R, Sloane MA, Huang R, Pauler FM, Additional references Kralovics R, Passamonti F, Buser AS, et al. A gain- CeMM Warczok KE, Melikant B, Radolf M, Martens JHA, of-function mutation of JAK2 in myeloprolifera­ Schotta G, Jenuwein T, Barlow DP. Active and tive disorders. N Engl J Med. 2005, 352:1779–1790. Publications Repressive Chromatin Is Interspersed without Characterization of Protein Networks Spreading in an Imprinted Gene Cluster in the and Proteomics Approaches Nijman SM, Hijmans EM, El Messaoudi S, 2007 Mammalian Genome. Mol Cell. 2007, 27(3):353–66. van Dongen MW, Sardet C, Bernards R. A func­ Burckstummer T, Bennett KL, Preradovic A, tional genetic screen identifies TFE3 as a gene Knapp S. Innate recognition of bacteria. Expert Schutze G, Hantschel O, Superti-Furga G, that confers resistance to the anti-proliferative Rev Clin Immunol. 2007, 3:443–445 (Editorial). Bauch A. An efficient tandem affinity purification effects of the retinoblastoma protein and Barlow DP, Bartolomei MS. Genomic imprinting procedure for interaction proteomics in mam­ TGFbeta. J Biol Chem, 2006. 281(31):21582–7. in mammals. Chapter 19 in EPIGENETICS Edited Knapp S, Matt U, Leitinger N, van der Poll T. malian cells. Nat Methods. 2006, 3(12):1013–9. by D. Allis, T. Jenuwein D. Reinberg. CSH Press Oxidized phospholipids inhibit phagocytosis 2007. ISBN 978-087969724–2. Book Chapter. and impair outcome in gram-negative sepsis Gavin AC, Aloy P, Grandi P, Krause R, Boesche Non-coding RNAs and Imprinting in vivo. J Immunol. 2007, 178:993–1001. M, et al. Proteome survey reveals modularity Binder CJ, Hartvigsen K, Witztum JL. Promise of of the yeast cell machinery. Nature. 2006, Seidl CI, Stricker SH, Barlow DP. The imprinted immune modulation to inhibit atherogenesis. Kocher T, Superti-Furga G. Mass spectrometry- 440(7084):631–6. Air ncRNA is an atypical RNAPII transcript J Am Coll Cardiol. 2007, 50(6):547–50. (Editorial). based functional proteomics: from molecular that evades splicing and escapes nuclear export. machines to protein networks. Nat Methods. Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, EMBO J. 2006, Aug 9;25(15):3565–75. Bro S, Binder CJ, Witztum JL, Olgaard K, Nielsen 2007, 4(10):807–15. et al. Systematic identification of protein LB. Inhibition of the Renin-Angiotensin System complexes in Saccharomyces cerevisiae by mass Sleutels F, Zwart R, Barlow DP. The non-coding Abolishes the Proatherogenic Effect of Uremia Orchard S, Salwinski L, Kerrien S, Montecchi- spectrometry. Nature. 2002, 415:180–183. 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Ce — M­—M­— Research Report 2007 Ce — M­—M­— Research Report 2007 96 97 Prof. Dr. Richard Flavell Acknowledgements Chairman, Section of Immunobiology, Zoran Almanzan, Stefan Amatschek, Mehran Ansari, Georg Anzenberger, Christian Arthaber, Amanda Baker, Yale University School of Medicine, Christian Balluch, Angela Bauch, Gerhard Bauer, Hemma Bauer, Matthias Beck, Christina Bergmeister, Scientific New Haven, USA Martin Bilban, Christoph Block, Matthew Bogyo, John Bohannon, Stefan Böhm, Günther Bonn, Stu Borman, Oliver Brandt, Robert Brown, Eva Bruckner, Thijn Brummelkamp, Herbert Burger, Maria Bürgermeister, Prof. Dr. James D. Griffin Eugene Burns, Horst Bursik, Meinrad Busslinger, Jon Clardy, Benjamin Cravatt, Birgit Dalheimer, Rainer Advisory Chair, Department of Medical Oncology, De Martin, Jan de Vries, Thomas Decker, Helmut Denk, Barry Dickson, Julian Downward, Gerard Drewes, Dana Farber Cancer Institute, Boston, USA Gerhard Ecker, Riki Eggert, Hans Georg Eichler, Adelheid Elbe-Bürger, Wilfried Ellmeier, Heinz Engl, Michelle Epstein, Harald Esterbauer, Stephen Fesik, Katja Fiala, Hans-Peter Fischer, Mischa Freissmuth, Herwig Prof. Dr. Carl-Henrik Heldin Friesinger, Christian Fritzsche, Michael Füchsl, Helmut Gadner, Christoph Gasche, Manfred Gengler, Edith Board Director, Ludwig Institute for Cancer Gindel, Nathanael Gray, Karin Hagenbichler, Brigitte Haidl, Bernhard Hain, Hans Tuppy, Claudia Heilmann- Research, Uppsala University, SE Sennhenn, Katharina Heiss-Kienberger, Markus Hengstschläger, Wilhelm Henrich, Anke Heynoldt, Michael Hoch, Elisabeth Hochleitner, Erhard Hofer, Astrid Hofstätter, Martin Hohenegger, Eveline Holzmeier, Prof. Dr. Denis Hochstrasser Lukas Huber, Ylva Huber, Liu Huchi, Heidemarie Hurtl, Monika Hutter, Sandrine Imbeaud, Harald Isemann, Members Head, Central Clinical Chemistry Laboratory, Alain Israel, Ulrich Jäger, Erika Jensen-Jarolim, Kai Johnsson, Luzi Josipovic, Veronika Josipovic, Andrea Geneva University Hospital, CH Kainz, Tarun Kapoor, Oliver Kemper, Dontscho Kerjaschki, Michael Kiebler, Hans Kiener, Laura Kiessling, Melitta Kimbacher, Michael Kneidinger, Guido Korlath, Barbara Kornmüller, Ursula Kosir, Peter Kowalski, Prof. Dr. David Livingston Christoph Kratky, Michael Krebs, Reinhard Krepler, Dragan Krstic, Andreas Kungl, Tamar Kurtskhalia, Deputy Director, Dana-Farber/­ Christoph La Garde, Kirsten Larsen-Becker, Hans Lassmann, Klaus Lechner, Gerhard Leder, Kriso Leinfellner, Harvard Cancer Center, Boston, USA Alexander Leitner, Hans-Joachim Lipp, Melanie Lobner, Jutta Löffler, Silvia Lossgott, Dieter Lutz, Wolfgang Machal, Christine Mannhalter, Marianne Pöschko-Laczkovics, Javier Martinez, Jonathan Mason, Herbert Matis, Prof. Dr. William E. Paul Thomas Mayer, Robert McBurney, Karl Mechtler, Claudia Mick, Michael Micksche, Martina Milletich, Wolfgang Chief, Laboratory of Immunology, Mlecnik, Maria Magdalena Mosgan, Markus Müller, Mathias Müller, Johann Mulzer, Alexander Nagler, National Institute of Allergy and Gabriele Nestyak, Waltraud Niel, Harald Niessner, Mamuka Nikolaishvili, Lars Nitschke, Christian Nordberg, Infectious Diseases, Bethesda, USA Peter Oefner, Markus Otte, Markus Pasterk, Josef Penninger, Jan-Michael Peters, Randall Peterson, Anna Peutl, Fabio Piano, Helen Pickersgill, Katharina Pluner, Bernhard Plunger, Marie-Therese Porzer, Roberto Prof. Dr. Hidde Ploegh Raggiaschi, Ron Raines, Meinhard Rauchensteiner, Kurt Redlich, Markus Reicher, Caetano Reis e Sousa, Member, Whitehead Institute for Georg Reithofer, Ingrid Riedel-Taschner, Jagoda Ristic, Hildi Rowland, Peter Roy, Philip Santoll, Michael Biomedical Research, Cambridge, USA Sazel, Clemens Scheinecker, Otto Scheiner, Ursula Schmidt-Erfurth, Maria Schreiber, Rene Schröder, Peter Schuster, Reinhard Schwarz, Dieter Schweitzer, Veronika Sexl, Maria Sibilia, Werner Sieghart, Reya Silao, Prof. Dr. Nadia Rosenthal Maria Siomos, Uwe Sleytr, Josef Smolen, Hans-Joachim Sorger, Peter Soswinski, Didier Soulat, Nikolaus Head, EMBL- European Molecular Biology Spieckermann-Hutter, Holger Stalz, Michael Stampfer, Edda Starzer, Georg Stingl, Hannes Stockinger, Laboratory, Monterotondo Outstation, Rome, I Gitte Stoilov, Sepp Strasser, Erich Streissler, Herbert Strobl, Carl-Wolfgang Stubenberg, Tada Taniguchi, Elisabeth Tischelmayer, Zlatko Trajanoski, Jasmin Turtenwald, Michael Tyers, Mohien Ceereena Ubaida, Prof. Dr. Louis M. Staudt Peter Valent, Marc Vidal, Alexander von Gabain, Sasha Vukovic, Oswald Wagner, Stephan Wagner, Jürgen Head, Molecular Biology of Walkenhorst, Elisabeth Wegmann, Karin Wihsböck, Tanja Winkler, Anke Wittig, Evelyn Zaininger-Reiterer, Lymphoid Malignancies Section Pavel Zavodny, Rudolf Zechner, Silvia Zendron, Elke Ziegler, Christoph Zielinski, Klaus Zinöcker, Gerhard National Institutes of Health, Zinsberger, Stephanie Zorn, Elke Zuckermann National Cancer Institute, Bethesda, USA

Dame Prof. Dr. Janet Thornton Director, European Bioinformatics Institute in Cambridge, UK Group Leader, EMBL- European Molecular Solution to caricature quiz Biology Laboratory, Hinxton Outstation, p 78—79 Cambridge, UK A Christoph Binder I Tiina Berg Q Marc Brehme B Giulio Superti-Furga J Christoph Baumann R Nora Fernbach C Amrei Strehl K Jacques Colinge S Roland Jäger D Gerhard Dürnberger L Damla Olcaydu T Mathew Sloane E Anita Ender M Ines Kaupe U Thomas Stranzl F Sandrine Tonon N Thomas Köcher V Carina Winkler G David Weismann O Adrijana Stefanovic W Robert Kralovics H Adriana Goncalves P Evren Karayel X Sebastian Nijman

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