COVER IMAGES. Some of the images in this book has been published in scientific papers:

Transcription

1

2

3 S C I E N T I F I C R E P O R T 2009

4 COVER IMAGES top left: Unpublished image by Vania Broccoli (see Stem cells and neurogenesis, page 39) Rosettes-like structures organized by neural progenitors derived by direct in vitro cell differentiation of human ips cells. top middle: Hierarchical clustering of gene expression profiles in healthy tissues (rows, genes; columns, tissues) (Giorgio Casari, Head of Neurogenomics Unit, page 169) top right: Unpublished image by Gian Giacomo Consalez (see Developmental neurogenetics Unit, page 36) Progenitors tagged during early embryogenesis by a genetic inducible fate mapping approach develop into mature Purkinje neurons in the adult cerebellar cortex. bottom: Unpublished image by Enrico Gherlone (see Dento-facial histopathology Unit, page 162) The graft material particles (GM) appeared well-included and showed continuity with the new bone (NB) tissue and deposition of osteoid matrix. Some of the images in this book has been published in scientific papers: Fig. 1, p. 14: EMBO Reports Fig. 4, p. 42: Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders Fig. 5, p. 43: Neurobiology of Disease Fig. 10, p. 78: Radiology Fig. 16, p. 154: Science Fig. 17, p. 155: PLoS One Fig. 18, p. 156: Journal of Neuroscience Fig. 19, p. 157: Molecular and Cellular Proteomics Fig. 20, p. 159: Molecular and Cellular Biology Fig. 24, p. 172: Angewandte Chemie Fig. 25, p. 186, toke part in "GE Healthcare IN Cell World Image Competition Award" 2009 Edited by the San Raffaele Library Layout by Roberto Cremonesi Printed by Grafiche Parole Nuove, Brugherio

5 INDEX - III INDEX INTRODUCTIONS VII Introduction by the President VIII Introduzione del Presidente IX Introduction by the Scientific Director XIII Introduction by the Chief Operating Officer XXII San Raffaele Scientific Retreat 2009 XXV I ragazzi della via Olgettina XXIX Introduction by the General Director Clinical Area XXXII 2009 Seminars and lectures XXXIV DIVISION OF MOLECULAR ONCOLOGY 1 Introduction by the Directors 5 Research Units Lymphoid malignancies Unit 7 B-cell neoplasia 7 Biology of multiple myeloma 8 Cell activation and signalling 8 Dynamic fluorescence spectroscopy in biomedicine 9 Lymphoid organ development 9 Preclinical models of cancer 10 Tumour microenvironment 10 Immuno-biotherapy of melanoma and solid tumors Unit 11 Cancer gene therapy 11 Functional genomics of cancer Unit 12 Model genetics of membrane trafficking Unit 13 Molecular histology and cell growth Unit 13 Tumor biology and vascular targeting Unit 14 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit 15 Endosonography: diagnostic and therapeutic endoscopic ultrasound 15 Gastrointestinal surgical oncology Unit 16 Head and neck oncology Unit 17 Multidisciplinary group for thoracic surgical oncology 17 Oncogenesis in liver neoplasms Unit 18 Onco-hematology Unit 18 Pancreatic cancer Unit: biology and new therapeutic approaches 19 Pathology Unit 19 Clinical lymphoid malignancies 20 Gynecologic oncology 20 Medical oncology Unit - Clinical trials 21 Medical oncology Unit - Phase I and lung cancer clinical trials 21 Urological Research Institute (URI) 22 Selected publications 23 DIVISION OF NEUROSCIENCE 27 Introduction by the Directors 32 Research Units Neuropsychopharmacology Unit 34 Cell adhesion Unit 34 Cellular and molecular neurobiology Unit 35 Cellular neurophysiology Unit 35 Developmental neurogenetics Unit 36 Neurobiology of learning Unit 37 Proteomics of iron metabolism Unit 37 Molecular genetics of mental retardation Unit 38 Neural degeneration Unit 38 Stem cells and neurogenesis 39

6 IV - SAN RAFFAELE SCIENTIFIC INSTITUTE Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit 40 Eye repair Unit 40 Cognitive neuroscience Unit 41 Experimental neurosurgery Unit 41 Functional neuroradiology Unit 42 In vivo Human molecular and structural neuroimaging Unit 43 Neuroothology Unit 43 Psychiatry and clinical psychobiology 44 Sleep medicine 44 Clinical psychology 45 Motor function rehabilitation 45 INSTITUTE OF EXPERIMENTAL NEUROLOGY (INSPE) 46 Introduction by the Director Research Units Experimental neuropathology 47 Experimental neurophysiology 47 Molecular genetics of behaviour 48 Neuromuscular repair 48 Neuroimmunology Unit 49 Clinical neuroimmunology 50 CNS repair 50 Neuroimaging research Unit 51 Neuroimaging of CNS white matter 51 Human inherited neuropathies Unit 52 Axo-glia interactions Unit 52 Clinical Research Units Inflammatory CNS disorders Unit 53 Cerebrovascular disorders 54 Memory disorders 54 Movement disorders 55 Neuromuscular disorders 55 Paroxysmal events 56 Selected publications 57 DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES 63 Introduction 66 Research Units Amino acid and stable isotopes Unit 67 Complications of diabetes 67 Obesity and metabolic related diseases 68 Bone metabolism Unit 68 Coagulation service & thrombosis research Unit 69 Cardiodiabetes & core lab 69 Pediatric endocrinology research 70 Clinical Research Units Diabetes and endocrinology Unit 71 Cardio-metabolic and clinical trials 71 Clinical pediatric endocrinology 72 Diabetes and metabolic diseases in children and adolescents 72 Neonatology 73 Foetal-maternal medicine 73 Infertility 74 Cardiovascular interventions Unit 75 Clinical cardiovascular biology Unit 75 Ischaemic heart disease, heart failure and echocardiography Unit 76 Organ protection in critically ill patients, advanced cardiac failure and mechanical supports Unit 77 Structural heart disease Unit 77 Study and treatment of aortic disease Unit 78 Center for arrhythmia research 79 Vision first Unit 79 Selected publications 81 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS, AND GENE THERAPY 85 Introduction by the Directors 89 Research Units Skeletal muscle development and therapy Unit 91 Functional genetics of muscle regeneration 91 Gene expression and muscular dystrophy Unit 92 Molecular and functional immunogenetics 92 Neural stem cell biology 93 Autoimmunity & vascular inflammation Unit 94 Innate immunity and tissue remodelling 94 Cellular pharmacology Unit 95 Experimental hematology Unit 95 Angiogenesis and tumor targeting 96 Clinical Research Units Hematology and hematopoietic stem cell transplantation Unit 96 Immunohematology and transfusion medicine Unit 97 PSIEP - Strategic Program of Pediatric Immunohematology 97

7 INDEX - V THE SAN RAFFAELE TELETHON INSTITUTE FOR GENE THERAPY (HSR-TIGET) 98 Introduction by the Director Research Units Gene transfer technologies and new gene therapy strategies Unit 99 Gene/neural stem cell therapy for lysosomal storage diseases 99 Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders 100 Safety of gene therapy and insertional mutagenesis 100 Gene transfer into stem cells Unit 101 Immunological tolerance Unit 101 From FOXP3 mutation to IPEX syndrome 102 Tolerogenic dendritic cells 102 Pathogenesis and therapy of ADA-SCID Unit 103 Gene therapy FOR WASP/Omenn 103 Clinical Research Units Pediatric Clinical Research Unit - Gene therapy for Wiskott-Aldrich Syndrome 104 Pediatric Clinical Research Unit - ADA gene transfer into hematopoietic stem cells for the treatment of ADA-SCID 105 Pediatric Clinical Research Unit - Clinical trial of gene therapy in metachromatic leukodystrophy 105 Selected publications 106 DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES 111 Introduction by the Directors 116 Research Units Leukocyte biology Unit 118 Cellular and molecular allergology 118 Human virology 119 Infection and cystic fibrosis 120 Protein engineering and therapeutics 120 γδ T cells in innate and adaptive immunity 121 Immunobiology of HIV 122 AIDS immunopathogenesis Unit 122 Biocrystallography Unit 123 Cellular immunology Unit 123 Emerging bacterial pathogens Unit 124 Experimental immunology Unit 125 Immunopathology Unit 125 Lymphocyte activation Unit 126 Tumor immunology Unit 126 Viral evolution and transmission Unit 127 Viral pathogens & biosafety Unit 127 Clinical Research Units Management and antiretroviral treatment of HIV infection 128 Neurovirology 128 Study and treatment of hepatotropic viruses related diseases 129 Vaccine and immunotherapy 129 Clinical immunopathology and advanced medical therapeutics Unit 130 Clinical transplant Unit 130 Gynecological cancers immunology 131 Immunology in liver neoplasms 131 Pancreatic tumors: immunotherapy and β cell function substitution 132 Clinical hepato-gastroenterology 132 Transplant surgery 133 DIABETES RESEARCH INSTITUTE (DRI) 134 Introduction by the Directors Research Units Immune tolerance 135 Experimental diabetes 135 β cell biology 136 Cell imaging 137 Clinical Research Units Islet transplantation 137 Prevention in type 1 diabetes 138 Epidemiology & data management 138 Childhood diabetes 139 Islet processing activity 139 Selected publications 141 DIVISION OF GENETICS AND CELL BIOLOGY 149 Introduction by the Directors 152 Research Units Protein transport and secretion Unit 153 Age related diseases 153 Molecular immunology 154 Chromatin dynamics Unit 154 In vivo Chromatin and transcription 155 Biology of myelin Unit 156 Biomolecular mass spectrometry Unit 157 Gene expression Unit 157 Genetics of common disorders Unit 158

8 VI - SAN RAFFAELE SCIENTIFIC INSTITUTE Molecular basis of polycystic kidney disease Unit 158 Molecular genetics Unit 159 Molecular dynamics of the nucleus 159 NeuroGlia Unit 160 Regulation of iron metabolism Unit 160 Molecular genetics of renal disorders Unit 161 Clinical Research Units Dento-facial histopathology Unit 162 Genomics of renal diseases and hypertension Unit 163 Tissue engineering and biomaterials 163 Selected publications 165 CENTER FOR GENOMICS, BIOINFORMATICS AND BIOSTATISTICS 167 Introduction by the Director 168 Research Units Neurogenomics Unit 169 Theoretical biology 170 Organelle biogenesis and motility Unit 170 Genomic Unit for the diagnosis of human pathologies 170 Proteome biochemistry Unit 171 Biomolecular NMR laboratory 172 Selected publications 173 CENTER FOR IMAGING 177 Introduction by the Directors 178 Clinical Research Units Clinical and experimental radiology Unit 179 High technology in radiation therapy Unit 179 Medical physics Unit 180 Molecular imaging Unit 181 Neuroradiology research group 181 Selected publications 182 CFCM, Core Facility for Conditional Mutagenesis 187 FRACTAL, Flow cytometry Resource, Analytical Cytology Technical Applications Laboratory 187 CERMAC, Centre of Excellence of High Field Magnetic Resonance 187 Mouse histopathology 188 THE CLINICAL DEPARTMENTS 191 Department of arrhythmology 192 Cardio-thoracic-vascular Department 193 Department of general and specialistic surgery 196 Head and neck Department 199 Department of infectious diseases 202 Maternal and child health Department 204 Department of internal and specialistic medicine 206 Department of clinical neuroscience 208 Department of neurology 210 Department of oncology 211 Department of radiology 213 Department of urology 215 CLINICAL SERVICES 216 Pathology 218 Laboratory medicine 218 Immunohematology and Transfusion medicine service 218 Emergency medicine 219 General intensive care 220 Anaesthesia and neurointensive care Unit 220 AISPO - San Raffaele in the world 221 FACILITIES 185 ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center 186 PUBLICATIONS 227 Best papers List of 2009 publications 230

9 INTRODUCTIONS INTRODUCTIONS - VII

10 VIII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the President I am particularly delighted to present this Annual Report of the scientific research work carried on by the numerous researchers operating in our University and Research Centers. I personally believe that it is impossible to choose a path of research while not following at the same time different others: a research is made out of different paths interweaved together. Thus, I cannot help but notice my satisfaction in observing such an important and great scientific platform as San Raffaele is. Such platform includes the basic research, the translational research and the clinic and applied researches into a joined unity. Dear Raffaelians, Physicians, Researchers, and all Personnel You all, who here in Italy and in our San Raffaele centres abroad form a true Army to fight illness and death, which were never sought after by God. (God, that is, who created man in a condition of full strength, apt for a perfectly healthy life.) You are in charge of searching for the adequate biological, environmental, and ethical conditions to carry man back to his original state of perfection, as a king-owner of the Generating Universe, with the duty of ruling it and mastering it [possidete eam]. Do not surrender to difficulties. Your self-awareness - which is to say, your awareness of the human value which resides in each one of us - leads us to responsibility, prudence, and, at the same time, to the requisite resilience and audaciousness. You shall know that Everything is possible to him who has faith. Even I, poor man and penniless, have shown this to You, raising Your City of Man - S. Raffaele out of a swamp. Seek out and you shall find: you will receive whatever you ask for in prayer. I think about You and love You all. Yours, don Luigi Maria Verzè (Founder, President, Provost)

11 INTRODUCTIONS - IX Introduzione del Presidente Sono particolarmente felice di presentare anche quest anno il lavoro dei nostri eccellenti ricercatori. Sono convinto da sempre che non ci sia cura senza ricerca. È perciò che mi sento soddisfatto di vedere una piattaforma scientifica del San Raffaele di così vaste proporzioni. Una piattaforma che comprende in una unità strettamente organizzata e integrata la ricerca di base, la ricerca traslazionale, la ricerca clinica e applicata. Carissimi Raffaeliani Medici, Ricercatori di base e Clinici, Personale tutto, che costituite in Italia e nei nostri San Raffaele all estero un vero esercito per battere la malattia e la morte mai volute da Dio. Lui, infatti, ha creato l uomo in condizione eucrasica, atto a vivere in longevità perfettamente sano. Tocca a Voi ricercare le condizioni biologiche, ambientali, ed etico-equilibranti adeguate a far tornare l uomo al suo stato perfetto originale, quale re-padrone dell Universo Creatore con l ordine di dominarlo possidete eam. Non arrendetevi alle difficoltà. La consapevolezza del Vostro io, cioè del valore uomo che sta in ciascuno di noi, ci induce alla responsabilità, alla prudenza e, insieme, alla tenacia e all audacia necessarie. Sappiate che Tutto è possibile a chi crede. Anch io, pover-uomo e squattrinato, Ve ne ho dato l esempio tirando fuori da una marcita la Vostra Città dell uomo S. Raffaele. Cercate e troverete pregate e vi sarà dato. Vi penso e Vi amo tutti. Vostro don Luigi Maria Verzè (Fondatore, Presidente, Rettore)

12 X - SAN RAFFAELE SCIENTIFIC INSTITUTE THE ETHICS COMMITTEE CHAIRMAN: Gianna Zoppei, Health Care Supervisor, San Raffaele Scientific Institute VICE CHAIRMAN: Guido Pozza, Physician, Professor Emeritus of Internal Medicine, Università Vita-Salute San Raffaele SECRETARY: Alfredo Anzani, Expert in Bioethics, San Raffaele Scientific Institute MEMBERS: Giliola Calori, Biostatistician, San Raffaele Scientific Institute Ilaria Carretta, Psychologist and Psychoterapist, San Raffaele Scientific Institute Francesco Caviezel, Physician, Professor Emeritus of Endocrinology, University of Milan Maurizio Chiodi, Theologian, Professor at the Theological Faculty of Northern Italy, Milan Francesco Clementi, Pharmacologist, Professor Emeritus of Pharmacology, University of Milan Cesarina Curti, Expert in Medical Devices, San Raffaele Scientific Institute Maria Grazia Fusi, Regional Area GPs, Milan Andrea Gentilomo, Medical Examiner, Professor of Legal Medicine, University of Milan Roberts Mazzuconi, Hospital Director, San Raffaele Scientific Institute Massimo Reichlin, Expert in Bioethics, Professor of Phylosophy, Università Vita-Salute San Raffaele Maria Grazia Roncarolo, Scientific Director, San Raffaele Scientific Institute Claudio Rugarli, Physician, Professor Emeritus of Internal Medicine, Università Vita-Salute San Raffaele Patrizia Tadini, Pharmacist, San Raffaele Scientific Institute Cesare Triberti, Expert in Legal Procedures Liliana Villa, Representative of the Fondazione Centro San Raffaele del Monte Tabor Ewa Wysocka, Representative of Nursing Area Maria Elisabetta Zanardelli, Volunteer association member, Associazione per l Aiuto ai Giovani Diabetici (Onlus) CONSULTANT: Gianvincenzo Zuccotti, Head of Pediatrics Unit, Luigi Sacco Hospital, Milan The Ethics Committee complies with the legislative requirements of May 1998 as well as with the EU, national, and local rules concerning pharmacological trials.

13 INTRODUCTIONS - XI SAN RAFFAELE SCIENTIFIC INSTITUTE BOARD OF DIRECTORS: Roberto Cusin, Ennio Doris, Carlo Salvatori, Laura Ziller, Gianna Zoppei PRESIDENT: professor don Luigi Maria Verzè VICE-PRESIDENT: Mario Cal HEAD OF HUMAN RESOURCES CORPORATE DEPARTMENT: Antonio Limardi HEAD OF ADMINISTRATION & FINANCE CORPORATE DEPARTMENT: Mario Valsecchi HEAD OF LEGAL & GENERAL AFFAIRS CORPORATE DEPARTMENT: Alessandro Cremaschi HEAD OF TECHNICAL DEPARTMENT: Andrea Roma HEAD OF PUBLIC RELATIONS DEPARTMENT: Cristina Poma HEAD OF COMMUNICATION: Paolo Klun GENERAL DIRECTOR OF CLINICAL AREA: Renato Botti SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo CHIEF OPERATING OFFICER OF RESEARCH AREA: Maurizio Savi ORGANIZATION CHART B fd G I ts f I Em t H t & S f I V I H m I R D m I S v B L t D 3 / II I t S v mm I t D m I A m I I & F I I D m I II I ta D m I mm I I t R t I D m I L t& G I taff D m I G I td t I ta fo I Off R A S I f D S ff H t D S ff LINI AL DE AR MEN S RESEAR H DIVISIONS AND EN ERS The San Raffaele Scientific Institute is a teaching hospital affiliated to the Università Vita-Salute San Raffaele (DGR.3 dicembre 1999, n. 6/46798)

14 XII - SAN RAFFAELE SCIENTIFIC INSTITUTE Scientific Directorate SCIENTIFIC DIRECTOR: Maria Grazia Roncarolo CHIEF OPERATING OFFICER: Maurizio Savi SECRETARY: Titti Meroni PROGRAM MANAGER TO THE SCIENTIFIC DIRECTOR: Marina Castellano STUDIES, DEVELOPMENT & QUALITY OFFICE MANAGER: Vanda Parezanovic ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss Maria Grazia Roncarolo HEAD OF SCIENTIFIC OFFICE: Giulio Negri GRANT OFFICE: Stefano Apollonio, Riccarda Daneri, Michele Granetto, Paola Rebagliati HEAD OF CLINICAL TRIAL OFFICE: Elisabetta Riva CLINICAL TRIAL OFFICE: Raffaella Biagetti, Giovanna Bombelli, Anna Cantoni, Giliola Calori, Margherita Ianniello, Maria Rosa Mandelli, Veronica Savia HEAD OF BIOTECHNOLOGY TRANSFER OFFICE: Daniela Bellomo (as of January 2010 Lucia Faccio) BIOTECHNOLOGY TRANSFER OFFICE: Fabrizio Bacchi, Lucia Faccio, Simona Locatelli, Paola Pozzi, Roberto Santarella Maurizio Savi HEAD OF LIBRARY: Laura Tei LIBRARY: Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati HEAD OF ADMINISTRATIVE OFFICE: Maria Rosa Pedrazzi ADMINISTRATIVE OFFICE: Roberto Barchi*, Giovanna Bernardi, Francesca Dodero, Barbara Lapio, Massimiliano Meoni, Ornella Muraro, Marco Picariello, Patrizia Scotti, Miriam Togni HEADS OF MARKETING & FUNDRASING OFFICE: Luca Isotti, Lisa Orombelli MARKETING & FUNDRASING OFFICE: Federica Cattaneo, Patrizia Mogliani, Chiara Scolari, Cristiana Secchi HEAD OF HUMAN RESOURCE OFFICE: Giuseppe Defidio HUMAN RESOURCE OFFICE: Roberta Berno, Alberto Martoglio LOGISTICS & IT SERVICES: Marco Crespi, Giuseppe Miracoli * Università Vita-Salute San Raffaele

15 INTRODUCTIONS - XIII Introduction by the Scientific Director THE MISSION AND THE VISION The mission of the San Raffaele Scientific Institute (SRSI) is to conduct innovative research to benefit the care and cure of our patients and also to provide state-of-the-art education and training for new generations of doctors, physician scientists and research scientists with a high level of social responsibility. To achieve this objective, we want to perform cutting-edge science and to advance the knowledge of human diseases resulting in the identification of novel therapies. Our vision is that Research is the backbone of the SRSI, intersecting and connecting with both the clinical and the teaching programs. Our objective is to further integrate research, teaching and clinical activities by aligning preclinical and clinical research with our clinical strengths. THE SCIENTIFIC INSTITUTE The SRSI comprises the clinical activities of the research hospital with more than 1400 beds and the research activities conducted in Di.Bi.T.1 and Di.Bi.T.2. The SRSI is part of the San Raffaele Biomedical Science Park, which also includes the Vita-Salute San Raffaele University that was established in The University hosts the faculties of medicine, psychology and philosophy and provides specialized post-graduate courses, resident programs in various medical specialties and international PhD programs in Cellular/Molecular Biology and Molecular Medicine. In addition, the San Raffaele Biomedical Science Park hosts several biotechnology companies, including MolMed, Telbios and Axxam, which interact with the SRSI. Established in 1971, the SRSI was one of Italy s first private hospitals. In 1972 it was granted the status of Research Hospital (IRCCS: Istituto di Ricovero e Cura a Carattere Scientifico ), focusing mainly on diabetes and metabolic diseases and consequently received dedicated funding from the Italian Ministry of Health. In 1992, a research building (about 40,000 sq m or 431,000 sq ft) was opened to accommodate the Department

16 XIV - SAN RAFFAELE SCIENTIFIC INSTITUTE of Biotechnology (Di.Bi.T.1). The initial areas of research covered by Di.Bi.T.1 were genetics, cell biology and immunology, while in the late 90s gene therapy, stem cell biology and molecular mechanisms of diseases were added. In recognizing the SRSI as a center of excellence in the area of molecular medicine research, the Italian Ministry of Health granted it the status of Molecular Medicine Research Institute in This status was renewed in 2008, following an audit by the Ministery of Health. In 2009 the construction (Di.Bi.T.2), consisting of three new buildings, was completed. This allowed the much needed growth of the University and will create additional space for SRSI research groups, with dedicated space for new state-of-the-art technology platforms, and expansion of our translational research efforts in key disease areas such as regenerative medicine, neuroscience, immunology, inflammation, cardiovascular and oncology. In the last two years a new research strategy and research organization has been implemented, building on current strengths to invest in new strategic areas in order to further increase our competitiveness as a center of excellence in biomedical research and to create the best environment for the translation of fundamental research into clinical applications. Together with the implementation of this new research organization, the administrative and supporting research structure has also been extensively reorganized (see introduction by Maurizio Savi, the Chief Operating Officer for research). In this organizational model, preclinical and clinical research activities are consolidated in six Research Divisions and two Research Centers: RESEARCH DIVISIONS Molecular Oncology Neuroscience Metabolic and Cardiovascular Sciences Regenerative Medicine, Stem Cells and Gene Therapy Immunology, Transplantation and Infectious Diseases Genetics and Cell Biology RESEARCH CENTERS Imaging Genomics, Bioinformatics and Biostatistics At present, approximately 1402 people are working in these Research Divisions and Research Centers: 729 people, including scientists, technicians, service managers, as well as postdoctoral fellows, PhD students and undergraduate students, in Di.Bi.T 1 and Di.Bi.T 2 and 673 people, including physicians, research nurses, residents and clinical fellows, on clinical research projects in the hospital. Activities within the Research Divisions include genetics, cell biology, stem cell biology, gene therapy and immunology focusing on disease areas such as cancer, transplant rejection, autoimmune/inflammatory diseases, infections, neurodegenerative, cardiovascular and metabolic diseases. The research conducted in these areas has the common goal to increase knowledge on the molecular basis of diseases and to identify innovative therapies and new diagnostic options. The SRSI also hosts three Research Institutes, which are fully integrated within the Divisional organization, but have a high degree of scientific and administrative independence based on specific agreements and funding from external entities: - The San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), which is a joint venture with the Telethon Foundation, is pioneering cell and gene therapy strategies in genetic diseases - The Institute for Experimental Neurology (INSPE), supported by a research contract with Merck-Serono,

17 INTRODUCTIONS - XV investigates the biological and molecular mechanisms underlying diseases of the nervous system and their clinical translation, with a strong focus on multiple sclerosis - The recently established Diabetes Research Institute (HSR-DRI), which is part of the international Diabetes Research Institutes Federation. The main objectives of HSR-DRI are to identify and apply novel treatments to prevent islet beta cell destruction and to restore sufficient insulin production in type-1 diabetes patients Furthermore, the SRSI hosts several scientists belonging to the Dulbecco-Telethon Institute (DTI), which sponsors research on the molecular and biological mechanisms of gene regulation and genetic diseases. Research activities within Research Divisions and Centers are at the intersection of clinical activities, which are organized in 12 Clinical Departments (see introduction by Renato Botti, General Director of the clinical area). In this classical matrix model the Research Divisions intersect with many Clinical Departments in which basic research units (BRU) and clinical research units (CRU) are fully integrated and aligned. Figure1. Matrix of research activities in the research Divisions and Centers integrated with the Clinical Departments. SCIENTIFIC ACTIVITIES IN was an important year to make the new research organization operational and to reinforce the research activities in the six Research Divisions and the two Research Centers. The following five research divisions: Molecular Oncology; Neuroscience; Regenerative Medicine Stem Cells and Gene Therapy; Immunology Transplantation and Infectious Diseases; Genetics and Cell Biology became fully operational, whereas operational establishment of the Research Division in Metabolic and Cardiovascular Science is progressing well and will be completed by the end of The Research Center for Genomics, Bioinformatics and Biostatistics and the Research Center for Imaging were all started in 2009 with the aim to meet the increasing need for state-of-the-art imaging and functional genomic technologies. A new director for the Center for imaging was appointed. These two technology platforms will support all pathological and therapeutic areas and are expected to further favor integration between basic and clinical research and to provide strong impulses for translational research from bench to bed-side and back again.

18 XVI - SAN RAFFAELE SCIENTIFIC INSTITUTE The Research Programs within the Research Divisions are also crucial for promoting integration between laboratory and clinical research. The Research Programs are aimed at creating synergies between groups with different expertise and defining common strategic investments, which will favor fast-track translational research. During 2009, eight Research Programs across Research Divisions and Clinical Departments were implemented: RESEARCH PROGRAMS Stem Cells: from basic research to clinical experimentation Brain Regeneration using medical Devices, Gene vectors and stem cells (BRIDGE) Program in Immunology and Bio-immunotherapy of Cancer (PIBIC) Pancreatic Islet Transplantation Human Brain Invivo Mapping with neuroimaging (BRAINMAP) Bone Physiopathology Program (BoNetwork) Correlates of HIV-Associated Immune Response Modulation (CHARM) Microenvironment and Genes in Cancers of the Blood (MAGIC) During 2009, one of the major tasks for the Directors of the Research Divisions and Research Centers was to prepare a five-year research plan in which the vision and the mission, the goals with related implementation and the investments plan are clearly defined for each Research Division and Research Center. Currently, the overall five-year strategic plan has been completed and will be presented to our International Scientific Advisory Board. The Board is composed of four renowned scientists: Professor Aaron Ciechanover (Director, Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel), 2004 Nobel Prize in Chemistry; Professor Paul Herrling (Head of Corporate Research, Novartis International; Member of the Board of Trustees of The Scripps Research institute; Vice-President of the Board of ETH - Swiss Federal Institutes of Technology); Professor Jacques Banchereau (Director, Baylor Institute for Immunology Research, Dallas, USA), 2009 Award in Human Immunology Research - American Association of Immunologists - Dana Foundation; Professor Irving Weissman (Director, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, USA; member of the American Academy of Science). The Advisory Board was appointed by the Board of Directors of the San Raffaele Foundation and has the primary function to assist the Board in the evaluation of the quality of our research, our research strategies and implementation plans in keeping with the highest international research standards. Despite the worldwide financial and economical crisis of 2009, which also had an impact on our research organization, a number of initiatives were successfully carried out: - The first among the three new research buildings of Di.Bi.T 2 was equipped and is now fully occupied. It accommodates new research groups within the Institute of Experimental Neurology (INSPE) as well as a new research group, established in collaboration with the Cystic Fibrosis Foundation, which carries out research projects in the area of cystic fibrosis and host/pathogens relationship. In addition, the new space allowed the expansion of our cytofluorimetry and FACS sorting facility. - A new career path for physician scientists was implemented. We believe this is a key achievement in the integration of clinical, teaching and research activities as these professionals will be at the interface that allows optimal communication and interaction between the three areas. - We implemented a competitive international postdoctoral program, which will enable us to recruit from a highly skilled pool of researchers to further increase the international dimension of our institution. - We worked with the Human Resources Office to establish a new career path for scientists. The aim of this project is to define the career path for young investigators, allowing them more independence and recognition with more responsibility and accountability and to establish transparent and well-defined criteria for periodical evaluations of the performance of our scientists. - We have implemented a new series of weekly seminars, named San Raffaele Research Seminars. The speakers at these seminars are Unit Heads, both from Basic Research Units and from Clinical Research Units. The

19 INTRODUCTIONS - XVII intention of these seminars is to allow the SRSI scientific community to learn about ongoing research in the Institute and to foster integration and cross-fertilization between clinical and basic scientists was a very productive year for the SRSI in terms of scientific publications and clinical trials. The total number of scientific publications was 773, with a total Impact Factor of More than 10% of all SRSI publications are in top-level scientific journals (Impact Factor over 10). Based on these results, our Institution is the most highly ranked Italian IRCCS in terms of scientific level and scientific productivity (figures 2 and 3). Figure 2. Publications and total Impact Factor of SRSI in the past 3 years 3561, , , (average IF: 5,139) 2008 (average IF: 5,230) 2009 (average IF: 5,373) Total IF Publications Figure 3. % of SRSI publications sorted according to Impact Factor ranges 100,0% 80,0% 60,0% 62,8% 62,2% 63,4% 40,0% 30,0% 27,7% 26,0% 20,0% 0,0% 9,5% 7,8% 10,6% < 5,000 5,000-9,999 10,000 Impact Factor ranges

20 XVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE The scientific productivity of the SRSI is also demonstrated by its ability to design and conduct clinical trials, which were in part enabled through support from pharmaceutical and biotechnology companies. In 2009, the Ethics Committee examined 234 protocols, 119 (51 %) of which were sponsored by Pharmaceutical Companies. Submission of these 234 clinical trial protocols were supported and guided by the Clinical Research Office. Figure 4. Clinical trials evaluated by the HSR Ethics Committee in 2009 Pharmaceutical companies sponsored trials No-profit groups sponsored trials HSR investigators initiated trials 30% 51% 19% Pharmacological protocols Basic research protocols Observational protocols Medical device protocols 21% 2% 50% 27%

21 INTRODUCTIONS - XIX Figure 5. Clinical trials run by Clinical Departments and approved in 2009 Sponsored trials Department of infectious diseases Department of neurology Cardio-thoracic-vascular Department Head and neck Department Department of general and specialistic surgery Department of clinical neuroscience Other 1% 8% 4% 4% 3% 1% 4% Department of oncology Department of internal and specialistic medicine Department of urology Department of arrhythmology Maternal and child health Department Department of radiology 8% 24% 4% 11% 15% 13% No-profit trials Department of infectious diseases Department of neurology Cardio-thoracic-vascular Department Head and neck Department Department of clinical neuroscience 12% 3% 2% 7% Department of oncology Department of internal and specialistic medicine Department of urology Maternal and child health Department Department of radiology 12% 5% 21% 9% 3% 26% As of December 2009, the Office of Biotechnology Transfer, which is in charge of the management of intellectual property, patents and know how, and of the creation of spin off companies, managed 295 sponsored research and industrial collaboration contracts, illustrating that SRSI is a preferential partner for scientific and clinical collaborators. The high level of innovative research in the SRSI is also reflected in the issue of 96 patents and 38 patent families, while 52 licenses were taken out by external parties. The competitiveness of the SRSI is shown by its ability to attract funding, not only from the public sector (Ministry of Health, Superior Institute of Health, Ministry of University and Research), but also from private

22 XX - SAN RAFFAELE SCIENTIFIC INSTITUTE Italian sources (mainly Telethon, the Italian Association for Cancer Research and Bank Foundations) and from international sources (e.g. European Community, European Research Council, American National Institute of Health, World Health Organization, Association for International Cancer Research, Gates Foundation, Wellcome Trust, Juvenile Diabetes Research Foundation). The impressive critical mass and quality of our scientific community was highlighted during our yearly scientific retreat, which in 2009 was again organized in Stresa with three full days of scientific presentations given by basic and clinical scientists. During the San Raffaele Research retreat, the three top publications of 2008 were awarded with the SRSI innovation prize. Finally, in 2009 a number of important educational initiatives, scientific events and prestigious international meetings were organized and hosted by our basic and clinical scientists. A special mention should go to the scientific symposium organized in honour of Professor Guido Pozza who was the scientific director of the SRSI for 15 years and who continues to be a highly experienced mentor and advisor to our scientists. THE FUTURE We are very much looking forward to moving to the second and third new research buildings of Di.Bi.T 2. The new space will be used to further optimize current key research activities, such as stem cell and gene therapy, and to accommodate research groups working in new strategic areas, such as molecular oncology, translational genomics and preclinical imaging. The SRSI will continue to be a multidisciplinary Institute, but we will also pay particular attention to invest in research on those diseases with a high unmet medical need and in therapeutic areas of increasing medical demand, such as oncology and cardiovascular research. The main efforts in 2010 will be devoted to a new project aimed at integrating clinical, teaching and research activities in the area of oncology. This new initiative in cancer research and therapy will be built on all the know-how, expertise and resources already present at the SRSI. In addition, we plan to establish a strong and fully operational Metabolic and Cardiovascular Diseases Research Division. Investments in basic research in this latter increasingly important area, in which the SRSI has proven clinical excellence, will significantly increase our visibility and competitiveness. The SRSI will continue to support and strengthen its areas of excellence: genetics and cell biology, stem cell and gene therapy (with HSR-TIGET), immunology inflammation and infectious diseases (with DRI), and neuroscience (with INSPE). We will continue to strengthen our position as a leading center for translational medicine by giving rise to a Clinical Research Center. In this context, close collaboration between basic researchers, clinical investigators and physician scientists will be strongly supported with the ultimate goal to apply new therapeutic principles, invented at the laboratory benches, as efficiently as possible to our patients. In particular, we are aiming towards expertise in the fields of wide genomic analyses of complex diseases, stratification of patients by genotyping and phenotyping, pharmacokinetics and pharmacogenomics, besides becoming an active Center for the clinical proof of concept trials. I am confident that this research strategy and structure will further enhance the SRSI s position as an Institute of excellence conducting innovative science in the field of Molecular Medicine, which in the end will benefit our patients. I am also convinced that it will make us attractive for young Italian scientists who currently work abroad, but are highly motivated to return home and contribute to the international competitiveness of Italian medical science. The worldwide financial and economical crisis is not yet over and 2010 will also be a year of constraints, which will be a challenge for the speed of implementation of our strategic research plan. However, nothing will stop us continuing with the integration of high quality basic and clinical research by devoting dedicated investments to new translational research units. The vision of our President, which can be summarized in three key elements: there is no cure without research, research is the backbone of our Institution and basic research is the foundation of our knowledge and culture, continues to inspire us and help us to overcome innumerable hurdles. We therefore wish to thank our President and Vice-President, as well as the Board of Directors, for their trust in our vision and their con-

23 INTRODUCTIONS - XXI tinuous support. Many thanks also to our Research Directors and Associate Directors for their dedication and determination in designing the new organizational and strategic research plan, which will further strengthen the SRSI s leading position in Italy and contribute to its position among the leading institutes in biomedical science internationally. I also would like to express my gratitude to the project and group leaders and all members of the scientific community for their continuous support and sense of responsibility in this difficult year. Finally, a special thank you goes to all scientists, physicians, staff, post-doctoral fellows and students who, through their work, efforts, enthusiasm and passion, contributed to the research progress illustrated in this 2009 scientific report and who make the SRSI such a wonderful place to work at. I hope you will find our report interesting and informative Maria Grazia Roncarolo Scientific director

24 XXII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by the Chief Operating Officer The San Raffaele Scientific Institute is one of the most important biomedical research centers in Italy and is in a leading position in the sector which has the highest potential impact on people s health. This fact, together with its potential to attract grants for further growth at an international level, is confirmation that we need not only to finance and support our already excellent and high-quality research program, but also to aim to become the largest melting pot of top-level doctors and researchers of future generations through strategic planning over a medium/long-term period. With this in mind, the organizational-management structure of the Research Area has developed and implemented a shared and integrated governance and management system, both of the structures and processes of the core business (i.e. scientific production) and of the support areas, which are all part of the Research Management Staff, as shown in figure 1. Figure 1: The Research Area processes network Four fundamental areas have been identified, characterizing the operating-management processes which support the core business: economic-financial management, organizational development, human resources and infrastructures, and marketing and fundraising activities, meaning communication with and for our external stakeholders. (See figure 2)

25 INTRODUCTIONS - XXIII Figure 2: Areas characterizing the operating-management processes We have therefore identified the following medium-long-term objectives for each of these areas: To guarantee the Research sustainability, while meeting the requirements of efficacy, efficiency and economy necessary for resources administration; To guarantee accurate and transparent financial reporting and administrative accounting; To develop organizational and governance mechanisms that are coherent with strategic objectives; To develop an organization that focuses on people, that is able to valorize professional skills and create a stimulating and gratifying work environment; To guarantee transparency in the raising and spending of funds, as well as the serious and rigorous transmission of scientific data. To reach these objectives, numerous initiatives at various structural and service levels were planned and implemented during 2009: PLANNING AND MANAGEMENT CONTROL The planning and monitoring criteria and conditions for the economic-financial management of the Research Divisions and Centers were identified through an improved definition of the budgets for each division together with the criteria for monitoring the results in order to reach a true system of performance-based accountability in the short-to-medium term. ORGANIZATIONAL DEVELOPMENT & MANAGEMENT SYSTEMS The organizational model and its implementation has further evolved through completion of the distribution of the various scientific activities in the Research Divisions & Centers, as well as through organizational structuring and the activation of governance mechanisms within each research division and center. In order to reach a coherent integration of the new organizational model of the Research Areas with other models and management systems and/or regulations of the San Raffaele Foundation, measures have been taken to revise the conditions and responsibilities linked to both the Security Management System and the Quality Management System. A method has been introduced to revise processes and responsibilities in order to render coherent the new organizational structure of research area with the Model of Organization, Management & Control as well as with the Ethics Code of the Foundation.

26 XXIV - SAN RAFFAELE SCIENTIFIC INSTITUTE HUMAN RESOURCES A committee of professionals was appointed to define the new career paths of researchers with the aim to optimize the range of positions already available, to identify the most useful indicators, both from the point of view of staff career progression and in the interests of the Institution, to reward virtuous paths of complete scientific and managerial development. COMMUNICATION & MARKETING For San Raffaele, communication is becoming indispensable to promote its strategic position, to be competitive in the Italian Health and Research environment, and to diversify its financial sources. In order to promote its activities, results and projects, the Research Direction has strengthened its Marketing & Fundraising Office that, since 2009, has been committed to the promotion of specific fundraising projects and initiatives for various markets and reference targets: donations from individuals, companies, foundations & organizations, and institutions. Our priority for the future will be to define, according to the objectives highlighted in the Strategic Scientific Plan, a strategic-operational plan with which to steer all research area activities towards the same goals, and to control particularly critical development areas, such as fundraising, and creation of value for research and comunication. It is highly desirable for a mission-oriented non-profit Institution such as ours that this strategic-operational plan is on one hand oriented towards communication, and on the other, I would say above all, it aims to provide an efficient level of organizational governance, functional to the monitoring and strengthening of the relationships with our stakeholders, internal and external. If conceived in this way, this plan will be able to produce noticeable and beneficial effects on the research organization in terms of alignment with and valorization of its mission. With the transformation underway, the effects of which will unfold in 2010, it seems right to take this opportunity to modify the approach towards the financial report, considering it not only as a legal necessity, but also as a tool to measure the immeasurable those activities with faded edges that make up the heart of San Raffaele s production of science and production of value. Maurizio Savi Chief Operating Officer

27 SAN RAFFAELE SCIENTIFIC RETREAT 2009 INTRODUCTIONS - XXV

28 XXVI - SAN RAFFAELE SCIENTIFIC INSTITUTE BEST POSTER AWARD 1 st Erica Butti Cell fate analysis and selective killing of neural stem/precursor cells in the adult mouse: potential application to study the role of the endogenous CNS stem cell compartment in neurological diseases 2 nd Emanuela Porrello Csn5/Jab1 regulates Schwann cell-axon interaction and plays a role in peripheral nerve development and function

29 INTRODUCTIONS - XXVII 3 rd Bruno Di Stefano New procedures for genetic reprogramming of healthy and Parkinson s adult human cells and their differentiation into neural and dopaminergic progenitors BEST PAPER AWARD 1 st Giancarlo Comi Comi, G; Pulizzi, A; Rovaris, M; Abramsky, O; Arbizu, T; Boiko, A; Gold, R; Havrdova, E; Komoly, S; Selmaj, K; Sharrack, B; Filippi, M. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, doubleblind, placebo-controlled phase IIb study. Lancet: 2008; 371(9630):

30 XXVIII - SAN RAFFAELE SCIENTIFIC INSTITUTE 2 nd Michele De Palma De Palma, M; Mazzieri, R; Politi, LS; Pucci, F; Zonari, E; Sitia, G; Mazzoleni, S; Moi, D; Venneri, MA; Indraccolo, S; Falini, A; Guidotti, LG; Galli, R; Naldini, L. Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis. Cancer Cell: 2008; 14(4): rd Stefano Biffo (in the photo: Valentina Gandin) Gandin, V; Miluzio, A; Barbieri, AM; Beugnet, A; Kiyokawa, H; Marchisio, PC; Biffo, S. Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation. Nature: 2008; 455(7213):

31 INTRODUCTIONS - XXIX I RAGAZZI DELLA VIA OLGETTINA 30 anni della storia del diabete al San Raffaele October 31, 2009 Our President, don Luigi Maria Verzè, and Guido Pozza, Professor Emeritus of Internal medicine, Università Vita-Salute San Raffaele

32 XXX - SAN RAFFAELE SCIENTIFIC INSTITUTE Guido Pozza and Emanuele Bosi, Head of the Department of internal and specialistic medicine and Associate director of the Diabetes Research Institute

33 INTRODUCTIONS - XXXI Health Care Directorate HEALTH CARE SUPERVISOR: Gianna Zoppei GENERAL DIRECTOR: Renato Botti HOSPITAL DIRECTOR: Roberts Mazzuconi PLANNING & CONTROL DIRECTOR: Alessandro Longo INFORMATION SYSTEMS DIRECTOR: Carla Masperi PROCUREMENT & LOGISTIC DIRECTOR: Alberto Russo HEALTH AREA PROJECT DEVELOPMENT DIRECTOR: Maria Romano CUSTOMER SERVICE DIRECTOR: Riccardo Pizzo TECHNICAL SERVICE DIRECTOR: Andrea Roma E-SERVICES FOR LIFE AND HEALTH DIRECTOR: Alberto Sanna PROMOTION & DEVELOPMENT MANAGER: Alberto Galliani ORGANIZATION & DEVELOPMENT MANAGER: Margherita Gambaro LEGAL OFFICE MANAGER: Piergiorgio Sammartino Renato Botti

34 XXXII - SAN RAFFAELE SCIENTIFIC INSTITUTE Introduction by General Director Clinical Area San Raffaele Hospital is a private no-profit Foundation certified as Istituto di Ricovero e Cura a Carattere Scientifico (Research Hospital). It is relentlessly pursuing its three interrelated activities of clinical care, research and education since 1971, when it was established, and represented one of the first examples of a fully independent private hospital in Italy. In 1972 the Italian Ministry of Health granted to San Raffaele the status of IR- CCS (Research Hospital), which favoured its development as a site for clinical research. Originally specialized in diabetes and metabolic diseases, the status of research hospital was confirmed for the area of Molecular Medicine in the years 2004 and San Raffaele IRCCS is a qualified hospital, well known in Italy for specific and relevant pathologies, as well as for a highly specialized Emergency Center. It is a teaching Hospital linked with the Faculties of Medicine and Surgery and Psychology of the San Raffaele Vita-Salute University. Its high quality medical assistance and the availability of an extensive area of about square metres has led to a fast growth of the services provided by the Research Hospital. San Raffaele Hospital is part of the Italian National Health Service: it has beds accredited with the National Health Service, 75 of them dedicated to day surgery and day hospital treatments. In 2009 the hsr activity counts in-patients, patients admitted to the Emergency Room, more than out-patients and diagnostic tests. The Hospital counts about employees. In January 2008, after the approval by the Board of Directors, the Hospital started to organize the medical areas in Clinical Departments. Due to the complexity of the Institution, this process required a great effort for the analysis and definition of aggregation area, operational procedures and for the definition of the activity indicators. The process is still ongoing, but almost completed. The introduction of this new working model was aimed to integrate and coordinate the resources and the processes of the different Clinical Units, to make them more flexible, efficient with regard to the structural and management costs, to improve their specific role in patients management and to increase the quality of their medical activity. From December 2009 to January 2010, Arrithmology Department has been absorbed by Cardio-Thoracic- Vascular Department, generating a total Departments reduction from 12 to 11. 1) CARDIO-THORACIC-VASCULAR DEPARTMENT 2) DEPARTMENT OF GENERAL AND SPECIALISTIC SURGERY 3) HEAD AND NECK DEPARTMENT 4) DEPARTMENT OF INFECTIOUS DISEASES 5) MATERNAL AND CHILD HEALTH DEPARTMENT 6) DEPARTMENT OF INTERNAL AND SPECIALISTIC MEDICINE 7) DEPARTMENT OF NEUROLOGY 8) DEPARTMENT OF CLINICAL NEUROSCIENCE 9) DEPARTMENT OF ONCOLOGY 10)DEPARTMENT OF RADIOLOGY 11)DEPARTMENT OF UROLOGY There are six Cross Department Areas: 1. Imaging s Laboratory (Services of Immuno-hematology and Transfusion Medicine, Laboraf, Pathological Anatomy) 2. Imaging (Radiology, Neuroradiology, Nuclear Medicine) 3. Anaesthesia and Resuscitation (General Medicine, Cardiosurgery, Neurosurgery, Intensive Care Unit ICU) 4. Rehabilitation (Neurological, Cardiovascular, Orthopaedic) 5. Emergency Such Areas, directly coordinated by the Health Direction, may enclose Units of different Clinical Departments and Units which do not belong to Departments (Emergency Medicine, Services of Transfusion Medicine, Pathological Anatomy). The objective of the creation of these areas is to promote standardization of activities, to realize common projects and synergies, to encourage the interexchange of the human and technological resources, to promote the communication between the Departments. The activation of the Clinical Departments was made possible thanks to the strict collaboration between the