Scientific Report San Raffaele. Scientific Institute

Transcription

1 Scientific Report 2011 San Raffaele Scientific Institute

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3 Scientific Report 2011 San Raffaele Scientific Institute

4 Cover: image by Vania Broccoli (see Stem cells and neurogenesis, pages 46-47, figure 8): The transdifferentiating spiral: concept imaging of the direct conversion of skin fibroblast into dopaminergic neuronal cell mediated by forced expression of lineage specific transcription factors. The image refers to the work by Caiazzo et al., Nature 2011 Some of the images in this book has been published in scientific papers: Figure 3, p. 14: FASEB J.: 2011; 25(9): Figure 4, p. 18: Cancer Res.: 2000; 60(3): Figure 6, p. 43: J. Cell Biol.: 2011; 193(3): Figure 14, p. 62: Neurobiol. Aging: 2012; 33(8): Figure 19, p. 86: Diabetes Obes. Metab.: 2012 May 4. doi: /j x. [Epub ahead of print] Figure 24, p. 110: Blood: 2011; 118(12): Figure 26, p. 113: BioTechniques: 2012; 52(3): cover image Figure 32, p. 177: Antioxid. Redox Signal.: 2012; 16(10): Figure 35, p. 181: PLoS Biol.: 2011; 9(6): e Figure 39, p. 188: Int. J. Oral Maxillofac. Implants: 2011; 26: Figure 50, p. 231: J. Exp. Med.: 2011; 208(3): Edited by the San Raffaele Library Layout project by Rolando Cassinari Printed by Grafiche Parole Nuove, Brugherio

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7 INDEX INTRODUCTION VII Introduction by the Scientific Director XII Scientific Advisory Board, SAB XXVI San Raffaele Scientific Retreat 2011 XXVIII 2011 Seminars and lectures XXXIV DIVISION OF MOLECULAR ONCOLOGY 5 Introduction by the Directors 10 Research Units Lymphoid malignancies Unit 11 Biology of multiple myeloma 12 Cell activation and signalling 12 Dynamic fluorescence spectroscopy in biomedicine 13 Lymphoid organ development 14 Tumour microenvironment 15 Immuno-biotherapy of melanoma and solid tumors Unit 15 Cancer gene therapy Unit 16 B-cell neoplasia Unit 16 Functional genomics of cancer Unit 17 Molecular histology and cell growth Unit 17 Preclinical models of cancer Unit 18 Tumor biology and vascular targeting Unit 19 Clinical Research Units Digestive and pancreatico-biliary endoscopy Unit 20 Endosonography: diagnostic and therapeutic endoscopic ultrasound 20 Gastrointestinal surgical oncology Unit 21 Head and neck oncology Unit 21 Multidisciplinary group for thoracic surgical oncology 22 Oncogenesis in liver neoplasms Unit 22 Onco-hematology Unit 23 Pancreatic cancer Unit: biology and new therapeutic approaches 23 Pathology Unit 24 Clinical lymphoid malignancies 24 Gynecologic oncology 25 Medical oncology Unit - Clinical trials 25 Medical oncology Unit - Phase I and lung cancer clinical trials 26 URI, Urological Research Institute 27 Selected publications 28 DIVISION OF NEUROSCIENCE 33 Introduction by the Directors 40 Research Units Neuropsychopharmacology Unit 41 Cell adhesion Unit 42 Cellular and molecular neurobiology Unit 42 Cellular neurophysiology Unit 43 Developmental neurogenetics Unit 44 Neurobiology of learning Unit 45 Proteomics of iron metabolism Unit 45 Molecular genetics of mental retardation Unit 46 Stem cells and neurogenesis 46 Clinical Research Units Acute brain protection, Acute post-operative pain, Drugs and central nervous system Unit 48 Cognitive neuroscience Unit 48 Experimental neurosurgery Unit 49 Eye repair Unit 49 Functional neuroradiology Unit 50 In vivo Human molecular and structural neuroimaging Unit 51 Neuroothology Unit 51 Psychiatry and clinical psychobiology 52 Sleep medicine 54 Clinical psychology 54 Motor function rehabilitation 55 Institute of Experimental Neurology (INSPE) 56 Introduction by the Director 56 Research Units Experimental neuropathology 57 Experimental neurophysiology 57 Molecular genetics of behaviour 58 Neuromuscular repair 58 Neuroimmunology Unit 59 Clinical neuroimmunology 60 CNS repair 61 Neuroimaging research Unit 61 Neuroimaging of CNS white matter 62 Human inherited neuropathies Unit 63 Axo-glia interactions Unit 63 Clinical Research Units Inflammatory CNS disorders Unit 65 Cerebrovascular disorders 65 Memory disorders 66 Movement disorders 66 V

8 INDEX Neuromuscular disorders 67 Paroxysmal events 67 Selected publications 68 DIVISION OF METABOLIC AND CARDIOVASCULAR SCIENCES 75 Introduction by the Directors 79 Research Units Cardiodiabetes & core Lab 80 Complications of diabetes 80 Metabolism, nutrigenomics and cell differentiation 81 Bone metabolism Unit 82 Coagulation service & thrombosis research Unit 82 Obesity and metabolic related diseases Unit 83 Pediatric endocrinology research 84 Clinical Research Units Diabetes and endocrinology Unit 85 Cardio-metabolism and clinical trials 85 Fetal-maternal medicine 87 Clinical pediatric endocrinology 87 Diabetes and metabolic diseases in children and adolescents 88 Neonatology 89 Structural heart disease Unit 89 Cardiovascular interventions Unit 90 Center for arrhythmia research 90 Echocardiography Unit 91 Ischaemic heart disease, heart failure and echocardiography Unit 91 Organ protection in critically ill patients, Advanced cardiac failure and mechanical supports Unit 92 Strategic research on heart failure Unit 92 Study and treatment of aortic disease Unit 93 Vision first Unit 94 Selected publications 96 DIVISION OF REGENERATIVE MEDICINE, STEM CELLS AND GENE THERAPY 101 Introduction by the Directors 106 Research Units Skeletal muscle development and therapy Unit 107 Functional genetics of muscle regeneration 108 Neural stem cell biology 108 Angiogenesis and tumor targeting Unit 109 Autoimmunity & vascular inflammation Unit 110 Innate immunity and tissue remodelling 111 Cellular pharmacology Unit 112 Experimental hematology Unit 112 Gene expression and muscular dystrophy Unit 113 Molecular and functional immunogenetics Unit 114 Clinical Research Units Hematology and hematopoietic stem cell transplantation Unit 115 Immunohematology and transfusion medicine Unit 115 The San Raffaele-Telethon Institute for Gene Therapy (HSR-TIGET) 116 Introduction by the Director 116 Research Units Gene transfer technologies and new gene therapy strategies Unit 117 Gene/Neural stem cell therapy for lysosomal storage diseases 118 Hematopoietic stem cell based gene therapy for the treatment of lysosomal storage disorders 118 Safety of gene therapy and insertional mutagenesis 119 Gene therapy for WASP/Omenn Unit 119 Gene transfer into stem cells Unit 119 Immunological tolerance Unit 120 From FOXP3 mutation to IPEX syndrome 121 Tolerogenic dendritic cells 121 Pathogenesis and therapy of ADA-SCID Unit 122 Clinical Research Units PCRU - Gene therapy for Wiskott-Aldrich Syndrome 123 PCRU - ADA gene transfer into hematopoietic stem cells for the treatment of ADA-SCID 123 PCRU - Clinical trial of gene therapy in metachromatic leukodystrophy 124 Selected publications 125

9 INDEX DIVISION OF IMMUNOLOGY, TRANSPLANTATION, AND INFECTIOUS DISEASES 131 Introduction by the Directors 138 Research Units Leukocyte biology Unit 139 Cellular and molecular allergology 140 Human virology 140 Infection and cystic fibrosis 141 Protein engineering and therapeutics 142 γδ T cells in innate and adaptive immunity 143 Immunobiology of HIV 143 AIDS immunopathogenesis Unit 144 Biocrystallography Unit 144 Cellular immunology Unit 145 Dynamics of immune responses Unit 145 Emerging bacterial pathogens Unit 146 Experimental immunology Unit 146 Immunopathology Unit 147 Lymphocyte activation Unit 147 Tumor immunology Unit 148 Viral evolution and transmission Unit 149 Viral pathogens and biosafety Unit 149 Clinical Research Units Management and antiretroviral treatment of HIV infection 150 Neurovirology 150 Study and treatment of hepatotropic viruses related diseases 151 Vaccine and immunotherapy 151 Clinical immunopathology and advanced medical therapeutics Unit 152 Clinical transplant Unit 152 Pancreatic tumors Unit: immunotherapy and β cell function substitution 153 Gynecological cancers immunology 153 Immunology in liver neoplasms 154 Obesity 154 Clinical hepato-gastroenterology 155 Digestive pathophysiology 155 Diabetes Research Institute (DRI) 156 Introduction by the Directors 156 Research Units Experimental diabetes 157 β-cell biology 158 Cell imaging 158 Immune tolerance Unit 159 Clinical Research Units Islet transplantation 160 Prevention in Type 1 diabetes 160 Epidemiology & data management 161 Childhood diabetes 161 Selected publications 162 DIVISION OF GENETICS AND CELL BIOLOGY 173 Introduction by the Directors 176 Research Units Protein transport and secretion Unit 177 Age related diseases 178 Molecular immunology 178 Chromatin dynamics Unit 179 In vivo Chromatin and transcription 180 Molecular dynamics of the nucleus 181 Biology of myelin Unit 182 Biomolecular mass spectrometry Unit 183 Gene expression Unit 183 Genetics of common disorders Unit 184 Molecular basis of polycystic kidney disease Unit 184 NeuroGlia Unit 185 Regulation of iron metabolism Unit 186 Molecular genetics of renal disorders Unit 187 Clinical Research Units Dento-facial histopathology Unit 188 Genomics of renal diseases and hypertension Unit 189 Reproductive sciences Lab 190 Tissue engineering and biomaterials 190 Selected publications 192 CENTER FOR TRANSLATIONAL GENOMICS AND BIOINFORMATICS 199 Introduction by the Director 201 Research Units Neurogenomics Unit 202 Genome function Unit 202 Biomolecular NMR Laboratory 204 Genomic Unit for the diagnosis of human pathologies 205 Organelle biogenesis and motility Unit 206 VII

10 INDEX Proteome biochemistry Unit 206 Selected publications 208 IMAGING EXPERIMENTAL CENTER 213 Introduction by the Directors 215 Research Units Mouse functional genetics Unit 216 Clinical Research Units Clinical and experimental radiology Unit 217 High technology in radiation therapy Unit 217 Medical physics Unit 218 Molecular imaging Unit 218 Neuroradiology research group 219 Service Units ALEMBIC, Advanced Light and Electron Microscopy BioImaging Center 220 Intravital microscopy 221 Preclinical MRI and US Facility 222 Pre-clinical PET 223 Selected publications 224 RESEARCH PROGRAMMES 227 Brain Regeneration using medical Devices, Gene vectors and stem cells (BRIDGE) 227 Program in Immunology and Bio-immunotherapy of Cancer (PIBIC) 230 Islet Trasplantation Program (ITP) 232 Human Brain Invivo Mapping with neuroimaging (BRAINMAP) 234 Bone Physiopathology Program (BoNetwork) 237 Correlates of HIV-Associated Immune Response Modulation program (CHARM) 240 Microenvironment and Genes in Cancers of the Blood (MAGIC) 243 FACILITIES 247 CFCM, San Raffaele-Telethon Core Facility for Conditional Mutagenesis 248 FRACTAL, Flow cytometry Resource, Advanced Cytometry Technical Applications Laboratory 248 CERMAC, Centre of Excellence of High Field Magnetic Resonance 249 ProMiFa, Protein Microsequencing Facility 249 Mouse histopathology 250 THE ETHICS COMMITTEE 254 THE CLINICAL DEPARTMENTS 255 Cardio-thoracic-vascular Department 257 Department of general and specialistic surgery 261 Head and neck Department 264 Department of infectious diseases 267 Maternal and child health Department 270 Department of internal and specialistic medicine 274 Department of clinical neuroscience 276 Department of neurology 279 Department of onco-haematology 281 Department of medical oncology 283 Department of radiology 285 Department of urology 287 CLINICAL SERVICES 289 Pathology 291 Nuclear medicine 291 Radiotherapy 291 Laboratory medicine 292 Immunohematology and transfusion service 293 Emergency medicine 293 General intensive care 294 Anaesthesia and neurointensive care Unit 295 WHO Collaborating Centre for Integrated Laboratory Strengthening on Tuberculosis and Emerging Infectious Diseases and WHO Supranational Reference Laboratory 296 PUBLICATIONS 297 Best papers List of 2011 publications 301

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13 SCIENTIFIC DIRECTORATE Scientific Director: Maria Grazia Roncarolo Chief Operating Officer: Maurizio Savi SECRETARY: Sonia Fedeli, Titti Meroni ASSISTANT TO THE SCIENTIFIC DIRECTOR: Laura Reiss PROGRAM MANAGER TO THE SCIENTIFIC DIRECTOR: Marina Castellano STUDIES, DEVELOPMENT & QUALITY OFFICE MANAGER: Vanda Parezanovic HEAD OF SCIENTIFIC SECRETARIAT: Giulio Negri GRANT OFFICE: Stefano Apollonio (until September 2011), Riccarda Daneri, Michele Granetto, Paola Rebagliati GRANT OFFICE SCIENTIFIC SUPPORT: Maria Guttinger 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, Federica Violante HEAD OF OFFICE OF BIOTECHNOLOGY TRANSFER: Lucia Faccio OFFICE OF BIOTECHNOLOGY TRANSFER: Elisabetta Greco, Simona Locatelli, Paola Pozzi, Roberto Santarella HEAD OF LIBRARY: Laura Tei LIBRARY: Angelo Angarano, Diego Maria Bertini, Francesco Curci, Elena Ponzi, Maria Samarati, Paola Seveso* (from September 2011), Mirella Verza* HEAD OF RESEARCH ADMINISTRATIVE OFFICE: Maria Rosa Pedrazzi RESEARCH ADMINISTRATIVE OFFICE: Roberto Barchi*, Giovanna Bernardi, Francesca Dodero, Barbara Lapio, Massimiliano Meoni, Ornella Muraro, Marco Picariello, Patrizia Scotti, Miriam Togni HEADS OF MARKETING & FUNDRAISING OFFICE: Luca Isotti, Lisa Orombelli MARKETING & FUNDRAISING OFFICE: Federica Cattaneo, Patrizia Mogliani, Chiara Scolari, Cristiana Secchi HEAD OF HUMAN RESOURCES OFFICE: Giuseppe Defidio HUMAN RESOURCES OFFICE: Roberta Berno, Alberto Martoglio LOGISTICS & IT SERVICES: Marco Crespi, Giuseppe Miracoli * Università Vita-Salute San Raffaele XI

14 INTRODUCTION Introduction by the Scientific Director 2011 has been a very productive year with regards to science, as highlighted by the steady increase in the number of scientific publications and in the total impact factor, by the increased capacity to attract peer-reviewed funds for research from national and international funding agencies, and by the number of phase I and II clinical trials, as certified by the 10th National Report of the Agenzia Italiana del Farmaco (AIFA), where the San Raffaele Scientific Institute (SRSI) ranks first in Italy for number of clinical trials in These results strengthened our leadership position among the 45 Italian research hospitals ( Istituti di Ricovero e Cura a Carattere Scientifico, IRCCS) which receive core funding from the Italian Ministry of Health, and confirmed the SRSI as one of the cutting edge translational medicine centers in Europe. Unfortunately, 2011 has also been a very difficult year for SRSI, a year marked by a serious financial crisis and unexpected events. On March 23, 2011 the President Don Luigi Maria Verzè announced that the Board of Directors of the Fondazione Centro San Raffaele del Monte Tabor had decided to sell off noncore businesses in order to face the financial crisis and to preserve and sustain the Hospital, the Research Institute and the Vita-Salute San Raffaele University, the latter a separate legal entity established on the same campus as SRSI. On June 30, 2011 the Board of Directors of Fondazione del Monte Tabor accepted an offer from the Vatican State to acquire the core business: health care and research. A new Board of Directors was appointed on July 15. On October 10, 2011 Fondazione Centro San Raffaele del Monte Tabor filed an application to the Civil Court of Milan for admission to the arrangement with creditors procedure. The restructuring plan envisaged the creation of a private for-profit NewCo to which Fondazione del Monte Tabor would transfer all assets and core activities. The NewCo would continue to benefit from the Health Ministry recognition as an IRCCS and would be included in the network of the Regional Health System clinical centers. Moreover, the plan envisaged the creation of a new non-profit Foundation (NewFo) that would engage in scientific activities and fund raising. The request was accepted on October 28, 2011, and the Court decided to open a public call for the acquisition of the core business with a deadline on December 31, On December 31, 2011 the President, founder of San Raffaele, aged 91, died. The NewCo, named Ospedale San Raffaele S.r.l. (OSR), and the NewFo, named Fondazione Centro San Raffaele (FCSR), were acquired by the San Donato Group. The transfer of responsibility took place on May 11, As a consequence of the described events, in 2011 we had to face severe operational difficulties which involved both clinical and research activities. Despite all this, the scientists of the San Raffaele Scientific Institute relentlessly continued to pursue their mission: to conduct innovative research to benefit the care and cure of the patients, and 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. Research Divisions and Centers The 6 Research Divisions and 2 Research Centers represent existing areas of expertise and excellence, as well as new strategic areas of research. Divisions were established in 2009 and their activities were implemented in the following years. During 2009 the Directors of Research Divisions and Centers in agreement with the Scientific Directorate prepared a five-year Strategic Plan in which the vision and the mission, the goals with related implementation, and the investments plan for each Division and Center were clearly defined. This Strategic Plan was presented to the external Scientific Advisory Board (SAB) in July An update of the Strategic Plan was discussed with the SAB in July 2011 (see section below) was a year of consolidation for the activities of the five fully-established Research Divisions, while the Division of Metabolic and Cardiovascular Sciences developed its Strategic Plan. Further steps were taken in the development of the Research Centers.

15 INTRODUCTION RESEARCH DIVISIONS Director Associate Director Molecular Oncology Federico Caligaris-Cappio Giorgio Parmiani Neuroscience Gianvito Martino Flavia Valtorta Regenerative Medicine, Stem Cells Giulio Cossu * Fabio Ciceri, Luigi Naldini and Gene Therapy Immunology, Transplantation Ruggero Pardi Adriano Lazzarin and Infectious Diseases Genetics and Cell Biology Roberto Sitia Marco Bianchi Metabolic and Cardiovascular Sciences Ottavio Alfieri and Emanuele Bosi (Co-directors); Zaverio Ruggeri (Coordinator for Basic Research) RESEARCH CENTERS Director Associate Director Experimental Imaging Carlo Tacchetti Alessandro Del Maschio Translational Genomics and Bioinformatics Giorgio Casari Elia Stupka * Giulio Cossu has left the Institute at the end of At present (June 2012), approximately people are working in the 6 Research Divisions, the 2 Research Centers and the Institutional Facilities: 760 people, including scientists, technicians, as well as postdoctoral fellows, PhD students and un dergraduate students, working on preclinical and translational research in the laboratories of Di.Bi.T 1 and Di.Bi.T 2; 679 people, including physicians, research nurses, residents and clinical fellows, working on clinical re - search projects; 29 people, including heads of facility, lab managers, research associates and technicians working in In - stitutional Facilities. Research Institutes SRSI hosts 3 major Research Institutes (see table below) which are 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. In 2011 HSR- TIGET has secured a 5-year renewal of its institutional core grant from the Telethon Foundation for a total budget of 14 million Euro (from 2011 to 2015). This budget will support 13 research projects and core funding for the Institute. The Institute for Experimental Neurology (INSPE), which is based on an agreement with Merck-Serono, is one of the most important European Institutes totally dedicated to translational research in neuroscience. INSPE research focusses mainly on multiple sclerosis, stroke, central and peripheral nervous system traumas, neuromuscular diseases and neurodegenerative disorders, with the aim of understanding molecular mechanisms of pathologies and of identifying new therapeutic targets. The Diabetes Research Institute (HSR-DRI), which is part of the DRI Federation, has as main objective XIII

16 INTRODUCTION Introduction by the Scientific Director the prevention and cure of Type I Diabetes (T1D). In order to reach this objective, two main research programs are underway: understanding the pathogenetic mechanisms of autoimmunity induction and progression to identify strategies to stop T1D; development of innovative systems for tolerance induction, for immunosuppression reduction and for islet regeneration to prolong survival of transplanted beta cells. RESEARCH INSTITUTE San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Institute for Experimental Neurology (INSPE) Diabetes Research Institute (HSR-DRI) Director Luigi Naldini Giancarlo Comi Luca Guidotti Emanuele Bosi (Co-Director) Research Programs Research Programs are interdivisional and interdepartmental strategic projects that were created with the intent of fostering synergy between basic and clinical research in order to achieve a defined scientific goal. At present seven Research Programs are active at SRSI. Research Programs Brain Regeneration using medical Devises, Gene vectors and stem cells (BRIDGE) Program in Immunology and Bio-immunotherapy of Cancer (PIBIC) Pancreatic Islet Trasplantation Human Brain In vivo 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) Head Head: G. Martino (ad interim) Deputy Head L. Naldini (ad interim) Co-Heads: P. Dellabona G. Parmiani Co-Heads: L. Piemonti P. Maffi Head: M. Filippi Deputy Head: A. Falini Co-Heads: R. Sitia E. Gherlone Co-Heads: P. Cinque G. Poli Co-Heads: P. Ghia G. Tonon

17 INTRODUCTION Institutional Facilities SRSI hosts eight Institutional Facilities: service units that provide support to the scientific activity of the whole Institute. Today biomedical research must rely on the most advanced technologies that require highly trained individuals, specialized equipments, and financial investments. A solution to this challenge is to centralize these technologies by developing institutional facilities with dedicated staff, instruments and space. The Protein Microsequencing Facility (PROMIFA) provides different analytical services aimed at structurally characterizing peptides and proteins using analytical HPLC systems, 2D gel electrophoresis apparatus and mass spectrometers, and it offers the possibility to identify each individual component within complex protein mixtures derived from biological samples, including serum, plasma, urine, whole cells and cellular secretion products. The Flow Cytometry Resource and Analytical Cytology Technical Applications Laboratory (FRACTAL) offers both state-of-the-art instrumentation and analysis techniques to the scientific community and assisted cell sorting services for characterizing, separating and purifying populations of particles as diverse as beads, bacteria, micro-particles, cells and chromosomes. The Laboratory Animal Facilities of SRSI occupy about 2650 sqm of dedicated area, hosted in two different buildings, where animal-based research programs can be implemented. In both units, housed laboratory animals (mice/rats) are maintained, cared, and treated in accordance with the DL.vo 116/92 by the Italian Ministry of Health and the international guidelines. In 2011 a Biosafety P3 Area of approximately 180 sqm was established, where experimental infections with levels 2 and 3 pathogens and investigations with intravital microscopy can be performed in preclinical models of diseases. The San Raffaele Core Facility for Conditional Mutagenesis (CFCM) performs pronuclear injections and lentiviral infections to generate transgenic mice, offers embryonic stem cell electroporation, the screening of recombinant clones and their injection into blastocysts to generate knock-out mice. Moreover, CFCM carries out rederivation of mice and embryo cryopreservation to store precious murine lines. The Mouse HistoPathology Unit (MHIP) provides conventional morphological analysis and immunophenotyping of murine models of diseases, analyses the effects of different therapeutic approaches in specific mouse models, and investigates the efficacy of gene therapy and the safety of the use of viral vectors in preclinical models of diseases. The Center of Excellence of High Field Magnetic Resonance (CERMAC) is a University Center (Vita-Salute San Raffaele University) equipped with a High Field Magnet (3Tesla) dedicated to research in the field of neuroscience, and in particular to the development and validation of advanced functional MR techniques. The Advanced Light and Electron Microscopy BioImaging Center (ALEMBIC) provides sophisticated imaging techniques and innovation, offering both Light and Electron Microscopy instrumentation and training to scientists. A new Facility has been added in 2011: the Vita-Salute San Raffaele University Center for Statistics in the Biomedical Sciences (CUSSB). This University Center develops activities that are fully integrated with the preclinical and clinical research activities of SRSI. The Center supports and delivers service to the scientists in the area of statistics. XV

18 INTRODUCTION Introduction by the Scientific Director Scientific activities in 2011 During 2011 SRSI has focussed its efforts to strengthen the integration between basic and clinical research and to foster and enhance multidisciplinarity. Below are some examples that highlight the results. Gene and cell therapy protocols Several cutting edge cell and gene therapy clinical trials have started in 2011 at SRSI. The approved clinical protocol Cellular Therapy for Duchenne Muscular Dystrophy (DMD) by intra-artery infusion of HLA-identical mesoangioblasts comprises the treatment of 5 pediatric DMD patients with adult stem cells (muscle cell progenitors) combined with immunosuppressive therapy. The main goals of this proof-of-concept trial are evaluating the incidence of adverse effects and determining the effects of multiple adult stem cell injections on muscle force and function. Since March 2011, 3 patients have been treated with 4 injections each, and in 2 of them it was possible to observe a stabilization of muscle force. No major adverse effects were reported. For ADA-SCID retroviral vector-mediated gene therapy, a safety and efficacy long-term follow up study is ongoing. All 18 ADA-SCID treated patients are alive and well, and 15 of them have stopped enzyme replacement therapy with PEG-ADA. The positive results of this trial are internationally-recognized and represent today the golden standard for gene therapy of genetic diseases. In 2011 a gene therapy phase I-II clinical trial for Wiskott-Aldrich Syndrome (WAS), a different form of congenital immunodeficiency associated to thrombocytopenia, was started, and the first 3 patients were treated with their own hematopoietic stem cells modified to contain the WAS gene. All patients are in good clinical conditions and do not require transfusions. A gene therapy phase I-II clinical trial for Metachromatic Leukodystrophy (MLD), a fatal lysosomal storage disease, was also started in 2011, and five patients were treated after myeloablative conditioning. The first clinical data are very encouraging. Phase I-II Clinical Trials in oncology Based on the strategic decision by the Board of the Fondazione Centro San Raffaele del Monte Tabor to strengthen and expand our clinical and research activities in the area of oncology, Luca Gianni, an internationally renowned leader in the field of solid tumors and of phase I clinical trials, was recruited, together with his staff (a total of 9 people including clinicians, physician scientists, research nurses and laboratory technicians), as of February During 2011 the Unit lead by Luca Gianni initiated 7 phase I-II clinical trials; 4 additional phase I multicenter clinical trials have been approved by the Ethics Committee and are in the process to be implemented. Program on Pancreatic Islet Transplantation The San Raffaele Scientific Institute pioneered pancreatic islet transplantation worldwide and has become one of the world-leading centers in human islet transplantation. In new patients were transplanted with pancreatic islets. In addition, in 2011 this research program achieved several goals: A clinical trial testing a CXCR1/2 inhibitor in association with conventional immunosuppressive therapies. This trial is based on the preclinical demonstration that CXCR1/2 inhibition improves islet transplantation outcome. Development of immunosuppressive platforms compatible with the adoptive therapy of donor-specific regulatory Tr1 cells for pancreatic islet transplantation. Demonstration that autologous pancreatic islet transplantation is safe and feasible in patients undergoing complete pancreatectomy. Demonstration of safety and feasibility of bone marrow as site for islet transplantation in patients. Demonstration of safety and feasibility of MR imaging as strategy to visualize SPIO labeled islet after intraportal infusion in patients. The Division of Metabolic and Cardiovascular Sciences The Research Division of Metabolic and Cardiovascular Sciences is presently work in progress. The Executive Committee of the Research Division, appointed in February 2010, was operational until March 2011, under the coordination of the Scientific Director. The Committee identified strategic areas of re-

19 INTRODUCTION search, elaborated the first draft of the strategic plan of the Division and organized a very successful Divisional retreat. At the end of its term of appointment, the Executive Committe transferred the direct responsibility for the next phase in the implementation of the Division to Zaverio Ruggeri, as Coordinator for Basic Research, Ottavio Alfieri, as Co-Director for Cardiovascular Sciences and Emanuele Bosi, as Co-Director for Metabolic Sciences. The Committee of Directors was appointed in April 2011 and will govern for a period of three years. The Coordinator and the Co-Directors had the task to complete the Strategic Plan of Research that was presented at the July 2011 meeting of the Scientific Advisory Board. In addition, the Committee of Directors will have the responsibilities of implementing the Strategic Plan on the basis of the suggestions received from the Scientific Advisory Board, of evaluating the individual Research Groups, of identifying possible new recruitments to strengthen strategic areas, of defining new strategies to raise funds for the Division and of coordinating all scientific activities of the area. The Center for Translational Genomics and Bioinformatics The Center for Translational Genomics and Bioinformatics was established in 2010 to invest on and strengthen activities in the area of genomics, bioinformatics and high-throughput technological platforms. Elia Stupka was recruited as Co-Director of the Center as of June 1, Elia Stupka is an internationally renowned expert in computational genomics, formerly at University College London, where he was the Scientific Director of Bioinformatics for the UCL Genomics platform technology, and is a former consultant for the SRSI Center for Translational Genomics and Bioinformatics. Moreover, as of May 2011 we recruited Dejan Lazarevic, who is responsible for the Genomics Core Facility. The Center is now fully equipped with state-of-the-art instrumentation and a new, high-performance data processing center. The Center offers service and support to basic and clinical investigators. Experimental Imaging Center In 2011 the Experimental Imaging Center has continued to develop according to the strategic plan: three new facilities and one new research unit have been established. The facility of Electron Microscopy has been launched at the Department of Molecular and Ultrastructural Imaging of the European Center for Nanomedicine (CEN), and it is accessible to all SRSI users. The facility of preclinical Magnetic Resonance Imaging (MRI) and ultrasound (US) has been established, allowing long-term structural and functional imaging studies on small laboratory animals. The facility of Intravital Microscopy has been opened within the P3 structure of the new Animal House in Di.Bi.T.2, whereby it is possible to study cellular events with microscopic resolution. A new research unit, Advanced Fluorescence Microscopy and Nanoscopy was established with the aim of developing an innovative microscope, enabling users to follow single molecule events in 3D in cells. Other scientific activities In February 2011 SRSI held its annual Scientific Retreat with the aim of fostering cross-communication between scientists, both basic, translational and clinical. A total of 513 delegates participated in the threeday event, which was marked by Keynote Lectures on thrombogenic response to vascular injury and on new drug development in oncology, and by a description of the Harvard Clinical Research Institute. In the past year SRSI also hosted 52 seminars and lectures with external speakers and a total of 41 scientific national and international meetings. XVII

20 INTRODUCTION Introduction by the Scientific Director Scientific productivity in 2011 In 2011 the number and quality of SRSI s scientific publications continued to rise. The total number of scientific publications was 943, with a total Impact Factor of 5467,35 (Figure 1). In 2011 more than 10% of all SRSI publications were in top-level scientific journals (Impact Factor over 10, Figure 2). From 2008, when the new organizational model of Research Divisions and Centers was implemented, to 2011 the number of publications increased by 27.4% and the IF increased by 41.3%. Based on these results, our Institution is once more the most highly ranked Italian IRCCS (among the 45 Italian IRCCS) in terms of scientific quality and scientific productivity. Figure 1. Publications and total Impact Factor of SRSI in the past 4 years 5467, , , , i ( v g : 5,i3 ) i 9 ( v g : 5,373) i ( v g : 5,55 ) i ( v g : 5,79 ) Total IF Publications Figure 2. % of SRSI publications sorted according to Impact Factor ranges 100% 80% 60% 62,2% 63,4% 65,1% 6, % 40% 30,0% 26,0% 27,3% i,6% 20% 7,8% 10,6% 7,6%,4% 0% < 5,000 5,000-9,999 10,000 g

21 INTRODUCTION In 2011 the number and quality of SRSI s clinical trials also continued to rise. Indeed, the area of clinical research represents a major strength of SRSI in terms of ability to design and conduct clinical trials and to attract funding from pharmaceutical and biotech nology companies. In addition, SRSI s focus on translational research is proven by the high number of investigator-initiated trials. In 2011, the Ethics Committee examined 279 clinical protocols (Figures 3 and 4): 118 (42.3 %) sponsored by Phar maceutical Companies, 105 (37.7%) HSR investigator initiated trials and 56 (20%) no-profit groups sponsored trials. In 2011, the total number of enrolled patients for HSR investigator initiated trials was 11598, while for sponsored trials it was Figure 3. Clinical trials evaluated by the HSR Ethics Committee in 2011 C C C C Y ( Y 37,63% 42,29% 20,07% PHARMACEUTICAL COMPANIES SPONSORED TRIALS NO-PROFIT GROUPS SPONSORED TRIALS HSR INVESTIGATORS INITIATED TRIALS T T C C C Y ( Y 8% 8% 40% 44% PHARMACOLOGICAL TRIALS BASIC RESEARCH PROTOCOLS OBSERVATIONAL PROTOCOLS MEDICAL DEVICE PROTOCOLS XIX

22 INTRODUCTION Introduction by the Scientific Director Figure 4. Clinical trials run by Clinical Departments and approved in 2011 Z T G T C C T Y 4% 4% 1% 9% 11% 24% 3% 14% 10% 13% 7% DEPARTMENT OF INFECTIOUS DISEASES DEPARTMENT OF ONCOHEMATOLOGY DEPARTMENT OF INTERNAL AND SPECIALISTIC MEDICINE DEPARTMENT OF UROLOGY DEPARTMENT OF GENERAL AND SPECIALISTIC SURGERY OTHER DEPARTMENT OF ONCOLOGY DEPARTMENT OF NEUROLOGY CARDIO-THORACIC-VASCULAR DEPARTMENT HEAD AND NECK DEPARTMENT MATERNAL AND CHILD HEALTH DEPARTMENT 10% Z T G T C C T Y 1% 1% 9% 7% 6% 9% 11% 14% 12% 1% 18% 1% DEPARTMENT OF INFECTIOUS DISEASES DEPARTMENT OF ONCOHEMATOLOGY DEPARTMENT OF INTERNAL AND SPECIALISTIC MEDICINE DEPARTMENT OF UROLOGY DEPARTMENT OF GENERAL AND SPECIALISTIC SURGERY DEPARTMENT OF CLINICAL NEUROSCIENCE OTHER DEPARTMENT OF ONCOLOGY DEPARTMENT OF NEUROLOGY CARDIO-THORACIC-VASCULAR DEPARTMENT HEAD AND NECK DEPARTMENT MATERNAL AND CHILD HEALTH DEPARTMENT DEPARTMENT OF RADIOLOGY

23 INTRODUCTION The Office of Biotechnology Transfer (OBT), which is in charge of the management of intellectual prop - erty, patents and know how, and of the creation of spin off companies, was also very productive in As of December 2011, the OBT managed 327 sponsored research and industrial collaboration contracts with 119 biotech and pharmaceutical companies. In the last 10 years, 115 patent families (patented tech nologies) have been filed by SRSI, 41 patent families (corresponding to around 250 patents and patent applications in portfolio) are still alive, and 57 license/option and evaluation agreements have been fi nalized with industrial partners. Funding for research activities The increased scientific productivity of SRSI is the result of continuous capacity of the SRSI scientists to attract funding from national and international funding agencies through a competitive peer review process. The total revenues of the Research Area for 2011 have been 57,125,700 euro. R R R R 5 5 7,38% 92,62% RESEARCH INCOME OTHER REVENUES Research revenues amounted to 92.62% of total revenues of the Research Area and comprised external grants, public funds, sponsored research and clinical trials. XXI

24 INTRODUCTION Introduction by the Scientific Director R R R 5 13,40% 45,66% 8,00% 32,95% SPONSORED RESEARCH PUBLIC FUNDS CLINICAL TRIALS EXTERNAL GRANTS R R R 4 14,22% 65,84% 9,89% 10,05% DONATIONS EXTERNAL SERVICES INTERNAL SERVICES OTHER INCOME In 2011 the Ministry of Health structural funds (Ricerca Corrente) contributed 30% of the total research revenues, meaning that SRSI scientists were able to self-fund their research for 70% of the total revenues of the Research Area % of research revenues were obtained from external grants, that were assigned through the internationally recognised peer-reviewed process of selection. Below is a list of the most representative funding agencies and of their contribution to SRSI in 2011.

25 INTRODUCTION Contributions from Main Funding Agencies YEAR 2011 Fondazione Telethon* 4,101, European Union 4,053, AIRC 3,913, MIN. SALUTE Ricerca Finalizzata 3,657, Fondazione Cariplo 1,339, Regione Lombardia 977, ISS 727, MIUR FIRB 607, IIT 564, JDRF 554, Armenise Harvard Foundation 357, NIH 353, FISM 345, AIFA 192, AICR 172, *some of this funding was directly managed by FondazioneTelethon. The Scientific Advisory Board The Scientific Advisory Board (SAB) was appointed by the Board of Directors of the San Raffaele Foundation with the primary function to assist the Board in the evaluation of the quality of SRSI research, of the research strategies and of the implementation plans, in line with the high est international research standards. The SAB came to site-visit the Institute on July 11 and 12, On this second visit, the SAB consisted of five internationally renowned scientific leaders: Professor Paul Herrling, Head of Novartis Institutes for Developing World Medical Research, Novartis In stitutes for Biomedical Research, Novartis International AG (former Head of Global Research Novartis Pharma), chair of the SAB; Professor Aaron Ciechanover, Director, Rappaport Institute for Research in the Medical Sciences, Tech nion-israel Institute of Technology, Haifa, Israel, (2004 Nobel Prize in Chemistry); Professor Jacques Banchereau, Sr. Vice President DTA Inflammation & Virology and Chief Science Officer, Hoffmann-La Roche Inc., Nutley, NJ, 2009 Award in Human Immunology Research - American Association of Immunologists - Dana Foundation, (former Director of the Baylor Institute for Immunol ogy Research in Dallas, Texas); Professor Irving Weissman, Director, Institute of Stem Cell Biology and Regenerative Medicine, Stan ford University School of Medicine, USA; member of the American Academy of Science. Professor Giulio Superti-Furga, Scientific Director, CeMM Research Center for Molecular Medicine, Vienna. The second SAB meeting included presentations by the Scientific Director, by the Division and Center Directors and by selected Principal Investigators. This second review was focussed on the scientific plans of the single Divisions and Centers. The outcome of the meeting was a Report underlying the excellence of research at SRSI and the unique position of the Institute as a world leader in translational research. Following are some highlights of the SAB report. The entity that now combines the San Raffaele Scientific Institute, along with its research and clinical care Hospital, and the affiliated Vita-Salute San Raffaele University has become XXIII

26 INTRODUCTION Introduction by the Scientific Director an unique and integrated institution of leading edge biomedical research, clinical trial research, and advanced clinical care. As such, it is a rare success in bringing together the diverse elements that usually compete rather than collaborate to achieve advances in medical knowledge and care that reach large segments of society that had little hope. The HSR is a national treasure that has grown in value to a very impressive, internationally renowned operation in all major areas of cellular and molecular medicine. In individual areas, such as gene therapy of stem cells, the HSR is arguably the number one institution in the world. This is not just a research achievement; this is the long-sought goal of treatment of otherwise incurable diseases by replacing in blood-forming stem cells a defective gene with its normal counterpart, followed by transplantation of the gene-modified stem cells into the patient to cure the disease. Many institutions speak in futuristic terms about translating discoveries into medical therapies; for the HSR, that future is now. At the very heart of the current impressive success of the HSR is the unification of the basic biomedical and clinical research. It is work in progress and many of the measures taken will bear fruits only in some years to come. The HSR success is exemplified by several parameters of scientific productivity and by the truly extraordinary success in attracting external funds and securing highly competitive international grants. Moreover, HSR scientists have been exceptionally successful in securing the highly competitive ERC grants, both for advanced and junior investigators. This parameter alone allows classifying the HSR as one of the leading life science research institutions in Europe. Two other aspects stand out particularly: the translational activities and the industrial collaborations. The quantity and quality of the translational efforts in the research projects is unparalleled. The SAB is not aware of any large non-profit biomedical research operation of similar size, with a track record that comes close to the HSR in terms of quantity and quality of successful proof of concept studies. The SAB is truly impressed by the fact that each and every Research Division has a serious and well-empowered translational program. The significant investment in two new technology based centers brings additional strength to these efforts. Despite difficulties associated with all type of basic-clinical science collaborations worldwide, the HSR is able to present numerous wonderful examples of such activities with many important cases where improvement of medical practice has been shown or is around the corner. These successes are bound to form the fundament for further establishing HSR as a top European center of excellence for medical treatment and hospital of choice. This in turn is the condition for maintaining the commercial success of the hospital and of the University as well, particularly since successful future treatment protocols will be much more basic science driven than in the past. The number of collaborations with industrial partners and sponsored trials is staggering. These activities provide financial injections, train the organization to discipline and delivery and truly allow translation to occur, they also have contributed to the very high reputation that the HSR has with industry. It should be noted that the establishment of this reputation is much more difficult to achieve than within the academic community as it rests on a very rigorous measure of deliveries.

27 INTRODUCTION Conclusions and future perspectives 2011 has been a difficult year. Nevertheless, the Institution has maintained its research excellence in terms of scientific and clinical productivity. It should be recognized that the merit for this result is to be attributed firstly to the outstanding quality of SRSI scientists and also to the strength of SRSI s research organization structure. In the future, we hope to be able to carry on the implementation of our Strategic Plan, which requires fostering integration between clinical, translational and preclinical research in all fields of research. Furthermore, we want to continue to be an internationally-recognized, multidisciplinary institute with a strong focus on translational medicine, our vision, and with a high capacity to attract competitive external funding. In order to reach these goals, it will be necessary that investments in personnel, in technology and in infrastructure continue to be made in order to support and keep SRSI research at cutting-edge, international level. My gratitude goes to the Chief Operating Officer, Maurizio Savi, and to the staff for their strong commitment and dedication despite the many hurdles. I wish to thank the Research Directors, Associate and Co- Directors for their perseverance and determination and for the relentless efforts to ensure that research would continue to develop and function according to the plan. Finally, many thanks to all scientists, physicians, postdoctoral fellows and students for their ability to remain faithful to their research goals and for maintaining the excellence levels of our Institute despite the many unexpected events of the past year. Finally, I would like to close this brief introduction with a quote: There are in fact two things, science and opinion; the former begets knowledge, the latter ignorance. (Hippocrates) Maria Grazia Roncarolo Scientific Director XXV

28 INTRODUCTION Scientific Advisory Board, SAB Paul Herrling, Chair, Head of Novartis Institutes for Developing World Medical Research, Novartis Institutes for Biomedical Research, Novartis International AG, Basel, CH Aaron Ciechanover, Technion Distinguished Research Professor, Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel (2004 Nobel Prize in Chemistry) Jacques Banchereau, Senior Vice-President, DTA Inflammation & Virology and Chief Science Officer, Hoffman-La Roche Inc., Nutley, NJ Irving Weissman, Director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine; member of the American Academy of Science Giulio Superti-Furga (ad hoc 2011), Scientific Director, CeMM Research Center for Molecular Medicine, Vienna

29 INTRODUCTION XXVII

30 INTRODUCTION San Raffaele Scientific Retreat 2011

31 INTRODUCTION XXIX

32 INTRODUCTION San Raffaele Scientific Retreat 2011

33 INTRODUCTION XXXI

34 INTRODUCTION San Raffaele Scientific Retreat 2011 Best poster award 1 st - Chiara Maiorino Role of interleukin-25 in neuroinflammation 2 nd - Karolina Pilipow G1 to S cell cycle transition and appropriate transcription factor expression control transcriptional competence at immunologically relevant sites 3 rd - Monica Volpin Safety evaluation of different lentiviral constructs using Cdkn2a-/- mouse model

35 INTRODUCTION Best paper award Basic research Messina, G; Biressi, S; Monteverde, S; Magli, A; Cassano, M; Perani, L; Roncaglia, E; Tagliafico, E; Starnes, L; Campbell, CE; Grossi, M; Goldhamer, DJ; Gronostajski, RM; Cossu, G. Nfix Regulates Fetal-Specific Transcription in Developing Skeletal Muscle. Cell: 2010; 140(4): Translational research Lanzani, C and Citterio, L; Glorioso, N; Manunta, P; Tripodi, G; Salvi, E; Delli Carpini, S; Ferrandi, M; Messaggio, E; Staessen, JA; Cusi, D; Macciardi, F; Argiolas, G; Valentini, G; Ferrari, P; Bianchi, G. Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci. Transl. Med.: 2010; 2(59): 59ra87 Clinical research Rama, P; Matuska, S; Paganoni, G; Spinelli, A; De Luca, M; Pellegrini, G. Limbal stem-cell therapy and long-term corneal regeneration. N. Engl. J. Med.: 2010; 363(2): XXXIII

36 INTRODUCTION 2011 Seminars and Lectures Division of molecular oncology Division of neuroscience Division of metabolic and cardiovascular sciences Division of regenerative medicine, stem cells and gene therapy Division of immunology, transplantation, and infectious diseases Division of genetics and cell biology Center for translational genomics and bioinformatics Imaging experimental Center January 24, 2011 Proteomics of a perturbed ubiquitin landscape distinguishes between ubiquitin in trafficking and proteolysis Michael Glickman, Department of Biology, Technion Institute of Technology, Israel Guest: Simone Cenci March 28, 2011 Crosstalk between autophagy and apoptosis in collagen VI muscular dystrophies Vittorio Gallo, Center for Neuroscience Research, Children s National Medical Center, Washington, USA Guest: Maria Laura Feltri January 31, 2011 Activation of dormant haematopoietic stem cells by stress signals in vivo Andreas Trumpp, German Cancer Research Center, Heidelberg, Germany Guest: Luigi Naldini February 25, 2011 The use of IL-12 in developing therapeutic cancer vaccines for leukemia. Mouse and Human perspectives Chris Paige, Ontario Cancer Institute, Toronto Guest: Roberto Sitia March 14, 2011 Gliogenesis and glial repair in the developing and adult brain Paolo Bonaldo, Department of Medical Biotechnology, University of Padova Guest: Maria Laura Feltri March 21, 2011 Myotubularin phosphatases and associated neuromuscular diseases Jocelyn Laporte, Dept. of Translational Medicine and Neurogenetics, I.G.B.M.C., Strasbourg, France Guest: Alessandra Bolino April 11, 2011 Roles of phosphatidylinositol 3,5 bisphosphate, a lipid with unexpected links to neurodegenerative disease Lois Weisman, University of Michigan, USA Guest: Alessandra Bolino April 14, 2011 T cells: unexpected players in the mechanism of action of parathyroid hormone (PTH) Roberto Pacifici, Emory University, Atlanta, USA Guest: Simone Cenci April 18, 2011 Asymmetric immune control by regulatory T cells Adrian Liston, VIB and University of Leuven, Belgium Guest: Paolo Dellabona April 19, 2011 Exocytosis: Fusion Pore Properties of Peptidergic Vesicles Robert Zorec, University of Ljubljana, Slovenia Guest: Jacopo Meldolesi