Pr. Christophe Pison, MD, PhD Clinique Universitaire de Pneumologie

1. Systems Medicine of Respiratory Diseases an actual breakthrough Pr. Christophe Pison, MD, PhD Clinique Universitaire de Pneumologie Pole Thorax et VaisseauxInserm1050 Biologie Environnementale et Systémique - BEeSY European Institute for SystemsBiology and Medicine - EISBM CHU Grenoble Université Grenoble Alpes INRIA, Lyon, 11th of February 2014

2. www.eisbm.org Institut de Recherche Technologique www.bioaster.com www.biovision.org

3. Consortium International Systemoscope « Repenser la recherche, comprendre le vivant, améliorer la santé  »

4. Conflicts Of Interests, 3 last years • Actélion • Astra Zeneca • Bayer • Boehringer Ingelheim • GlaxoSmithKline • Lilly • Novartis • Nutricia-Danone • Pfizer • Gilead • Therakos • PneumRx, Medwin, Aeris, Holaira • AGIR@dom, Vitalaire, Orkyn, SOS 4

5. Contents • Non communicable diseases and “health crisis” • Burden of respiratory diseases and unmet needs • Systems medicine for respiratory health in Rhône-Alpes and Europe Biotechnology Journal 2012; 7 special issue on Systems biology and personalized medicine 5

6. Non Communicable Diseases - NCDs 6

7. “Health crisis” • Uncontrolled increase in health costs • Efficacy  Justice decline • Increase incidence in Non Communicable Diseases - NCDs • Limitations in present treatments and majors problems in new drug registrations New paradigms irruption • « Exposome » & « Omics » data accumulationand how use it for better patient cares? • Specialized versus Systems Medicine • Reactive versus proactive Medicine? 7

8. Uncontrolled increases in health costs • USA 18% GIP 2009 to 30% by 2030 & last OECD • France, 12% GIP 2009, life expectancy 81 years in 2009 8

9. Efficacy & Justice decline NEJM 2010;362:460-5 9

10. 5.2 million disability life years lost annually in the EU 300 billions € / year in the EU Cystic fibrosis 1st genetic lethal disease Asthma one of the most common chronic diseases in children COPD 4th cause of death, 2nd cause disability life year by 2008 in USA Lung cancer 1st cause of death by cancer in men, 2nd in women No cure for any! Burden of Respiratory Diseases and Unmet Needs 10

11. N Engl J Med 2013;369:448-57 11

12. Médecine 4P: L’opportunité Stratégies personnalisées et participatives Prédiction de la réponse Prédiction de la maladie Traitement ciblé Prévention de la maladie 12

13. Médecine systémique en pratique Agir là Ou la ? Ou encore la ? Changer le cours de la vie Changer le cours de la maladie Guérir Contrôler Thérapie ciblée Hood L, RMMJ 2013 adapté du Pr. A. Magnan

14. Challenge to integrate multi-scale space-time dimensions Peter Hunter, University of Auckland – Denis Noble, Oxford University 14

15. Achilles' tendons in Lung Transplantation • Shortage of grafts, Primary Graft Dysfunction • Chronic Lung Allograft Dysfunction - CLAD • BOS in 50% at 5 years • different patterns • 30% cause of death > 1 year • median survival 1.5 years, if early onset -15%, 3 months - 4% / year 15

16. 1 123 4 5 6 7 8 9 0,5 1 2 3 Année QALY - QualityAdjusted Life Years Qualité de vie ajusté sur la survie 16 Résultats de la transplantation pulmonaire, S. Quêtant, T. Rochat, C. Pison. RMR 2010; 27:921-938

17. Signature to predict chronic dysfunction 17

18. CLAD prediction: The clock is always ticking! Time 18 Transplantation. 2008 Jul 27;86(2):192-9.

19. Roedder et al. Genome Medicine 2011;3:37

20. 20 www.novadiscovery.com SysCLAD Progress Meeting. ENS de Lyon, FR. November 12th, 2013

21. COLT French prospective cohort since 09-2009 11 centres + BruxellesSwiss Transplant Cohort Study, STCS since 2008 in Lausanne- Genève, Zurich VIII-2013, 827 + 223: 1050 transplanted, 512 reached year 2, 215 year 3 Donors: day 0 clinics HLA lung tissue Recipients: before Tx, day-0 Tx, M6-M12 post LTx Clinics, e.CRF Pollution Blood: HLA, transcriptomics x 2, proteomics x 2, miRNA x 1, lymphocytes subpopulations, exome sequencing BAL: microbiote  macrophages polarization, proteomics x 2 Outcomes: to predict CLAD @ year-3 as soon as year-1 Design  Methods in SysCLAD 21

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23. Air pollution model (Ineris) Collaboration with Ineris (National Institute for Industrial Environment and Risks) to get access to the up-to date national-wide exposure model with high spatial and temporal resolutions (1x1km) 23

24. Pulmonary microbiota and Alveolar macrophage polarization in Lung transplant recipients Service de Pneumologie Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland Clinical supervision: Prof. Laurent Nicod Prof. John-David Aubert Research coordination: Dr. Angela Koutsokera Laboratory: Ben Marsland, PhD Eric Bernasconi, PhD Adapted from SciencePhotoLibrary 24

25. NEJM 2013,369:20-31 25

26. Editorial Prediction of chronic lung allograft dysfunction: a systems medicine challenge Christophe Pison, Antoine Magnan, Karine Botturi, Michel Sève, Sophie Brouard, Benjamin J. Marsland, Florian Ernst, Tobias Paprotka, Kevin Deplanche, Andreas Fritz, Valérie Siroux, Jean-Pierre Boissel, Paul A. Corris, Charles Auffray, Laurent P. Nicod and the SysCLAD consortium Eur Respir J 2014, in press 26

27. SysCLAD Consortium Cohort  Of Lung Transplantation-COLT (associating surgeons; anaesthetists,-intensivists, physicians, research staff) Bordeaux: J. Jougon, J.-F. Velly; H. Rozé; E. Blanchard, C. Dromer; Bruxelles:M. Antoine, M. Cappello, M. Ruiz, Y. Sokolow, F. Vanden Eynden, G. Van Nooten;  L. Barvais, J. Berré, S. Brimioulle, D. De Backer, J. Créteur, E. Engelman, I. Huybrechts, B. Ickx, T. J.C. Preiser,  T. Tuna, L. Van Obberghe, N. Vancutsem,J.-L. Vincent; P. De Vuyst, I. Etienne, F. Féry, F. Jacobs, C. Knoop, J.L. Vachiéry, P. Van den Borne, I. Wellemans ; G. Amand, L. Collignon, M. Giroux; Grenoble: E. Arnaud-Crozat, V. Bach, P.-Y. Brichon, P. Chaffanjon, O. Chavanon, A. de Lambert, S. Guigard, K. Hireche, A. Pirvu, P. Porcu, R. Hacini ; P. Albaladejo, C. Allègre, D. Anglade, D. Bedague, P. Bouzat, E. Briot, O. Carle, M. Casez-Brasseur, D. Colas, G. Dessertaine, M. Durand, J. Duret, M.C. Fèvre, G. Francony, S. Gay, M.R Marino, D. Protar, D. Rehm, S. Robin, M. Rossi-Blancher, L. Saunier; P. Bédouch, A. Boignard, H. Bouvaist, A. Briault, B. Camara, S. Chanoine, M. Dubuc, S. Lantuéjoul, S. Quêtant, J. Maurizi, P. Pavèse,  C. Pison, C. Saint-Raymond, N. Wion; C. Chérion; Lyon: R. Grima, O. Jegaden, J.-M. Maury, F. Tronc; C. Flamens, S. Paulus; J.-F. Mornex, F. Philit, A. Senechal, J.-C. Glérant, S. Turquier; D. Gamondes; L. Chalabresse, F. Thivolet-Bejui; C Barnel, C. Dubois, A. Tiberghien; Paris, Hôpital Européen Georges Pompidou: F. Le Pimpec-Barthes, A.  Bel, P. Mordant, P.  Achouh; V. Boussaud; R. Guillemain, D. Méléard, M.O. Bricourt, B. Cholley ; V. Pezella; Marseille:M. Adda, M. Badier, F. Bregeon, B. Coltey, X.B. D’Journo, S. Dizier, C. Doddoli, N. Dufeu, H. Dutau, JM. Forel, JY. Gaubert, C. Gomez, M. Leone, A. Nieves, B. Orsini, L. Papazian L, C. Picard, M. Reynaud-Gaubert, A. Roch, JM. Rolain, E. Sampol, V. Secq, P. Thomas, D. Trousse; Yahyaoui M ; Nantes: O. Baron, P. Lacoste, C. Perigaud, J.C. Roussel; I. Danner, A Haloun A. Magnan, A Tissot; T. Lepoivre, M. Treilhaud; K. Botturi-Cavaillès, S. Brouard, R. Danger, J. Loy M. Morisset, M. Pain, S. Pares, D. Reboulleau, P.-J. Royer ; Hôpital Marie Lanelongue: P. Dartevelle, E. Fadel, S. Mussot, D. Fabre, O. Mercier; P. Viard, F. Stéphan; J. Cerrina, P. Hervé, J. Le Pavec,  F. Le Roy Ladurie ; l. lamrani Paris Hôpital Bichat:Y. Castier, P. Cerceau, F. Francis, G. Lesèche; N. Allou, P. Augustin, S. Boudinet, M. Desmard, G. Dufour, P. Montravers ; O. Brugière, G. Dauriat, G. Jébrak, H. Mal, A. Marceau, A.-C. Métivier, G. Thabut ; B. Ait Ilalne; Strasbourg: P. Falcoz, G. Massard, N. Santelmo; G. Ajob, O. Collange O. Helms, J. Hentz, A. Roche; B. Bakouboula, T. Degot, A. Dory,  S. Hirschi, S. Ohlmann-Caillard, L. Kessler , R. Kessler, A. Schuller; K. Bennedif, S. Vargas; Suresnes: P. Bonnette,  A. Chapelier, P. Puyo, E. Sage;  J. Bresson, V. Caille, C. Cerf, J. Devaquet, V. Dumans-Nizard, ML. Felten, M. Fischler,  AG. Si Larbi, M. Leguen, L. Ley, N. Liu, G. Trebbia; S. De Miranda, B. Douvry, F. Gonin, D. Grenet, A.M. Hamid, H. Neveu, F. Parquin, C. Picard, A. Roux;  F. Bouillioud, P. Cahen, M. Colombat, C. Dautricourt, M. Delahousse, B. D’Urso, J. Gravisse, A. Guth, S. Hillaire, P. Honderlick, M. Lequintrec, E. Longchampt, F. Mellot, A. Scherrer, L. Temagoult, L. Tricot; M. Vasse, C. Veyrie, L. Zemoura; Toulouse: J. Berjaud, L. Brouchet, M. Dahan; F. Le Balle, O. Mathe ; H. Benahoua, A. Didier, A.L. Goin, M. Murris; L. Crognier, O. Fourcade. Swiss Transplant  Cohort Study-STCSGenève-Lausanne: T. Krueger, H.B. Ris, J.H. Robert, J. Wellinger; J.-D. Aubert, C. Blanc L.P. Nicod, B.J. Marsland, T. Rochat, P. Soccal; Ph Jolliet,  A Koutsokera, C. Marcucci, O. Manuel; E. Bernasconi, M. Chollet, F. Gronchi, B. Marsland; Zurich: S. Hillinger, I. Inci, P. Kestenholz, W. Weder; M. Zalunardo;  C. Benden, U. Buergi, L.C. Huber; B. Isenring, T. Rechsteiner, M. Schuurmans; T. Muller, A. Gaspert, D. Holzmann, N. Müller,  S. Nicca, C. Schmid. SME and PlatformsBiomax, Germany: A. Fritz, D. Maier; Finovatis, Lyon, France: K. Desplanche, D. Koubi; GATC, Germany: T. Paprotka, F. Ernst, B. Wahl; Novasdicovery, Lyon, France: J.-P. Boissel, G. Olivera-Botello; Prométhée Proteomics Platform, CHU Grenoble: C. Trocmé, B. Toussaint, S. Bourgoin-Voillard, M. Séve; Inserm U823, Université Joseph Fourier, Grenoble, France: M. Benmerad,V. Siroux, R. Slama; European Institute for Systems Biology & Medicine: C. Auffray, D. Charron, J. Pellet, C. Pison 27

28. Respiratory Systems Medicine - ReSyM • Objectives • build a multidisciplinary network • to define within 2 years 3 use cases of systems biology / medicine in the context of respiratory medicine, using preexisting set of data • successfully apply to European frame programme Horizon-2020 28

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30. Basic Clinical and Biomedical Questions • Long-life dimensionrepeated measurements to refine phenotypes 30 Adapted from R. Slama group

31. Basic Clinical and Biomedical Questions • Mechanisms • Shared and non-shared mechanismsin COPD-Asthma / Lung Cancer / Interstitial Pulmonary Fibrosis • Respective weights of risk factors to develop a specific chronic respiratory disease: • Environmental factors [pollution, smoking, physical activity, nutrition, stress, sleep] • Age, Gender, Socio-economic class and Occupation • Genetic susceptibility 31

32. Basic Clinical and Biomedical Questions • Taxonomy • New classification of old diseases as Asthma, COPD, Lung fibrosis, Lung cancer • Associations with other chronic respiratory conditions: • Asthma-COPD • COPD-Lung Cancer • Emphysema-IPF • IPF-Lung Cancer • Association with other chronic conditions: mainly cardiovascular and metabolic chronic diseases 32

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34. Clinique Universitaire de PneumologieUniversité Grenoble Alpes Oncologie Thoracique IRC Mucoviscidose HTAP Transplantation Maladies Chroniques Respiratoires Promouvoir Bien-Etre Médecine 4P Mécanismescommuns maladies chroniquesrespiratoires et cancer bronchqiue (miRNA, épigénétiques, effet Warburg), patients communs, technologies communes, approchessystémiques Coûts efficacité Médecine “pro-active” Proportion de patients pris en charge Médecine “reactive” type CHU 34

36. Médecine 4P Biologie des Systèmes Participation Biologie Personnalisation Technologie Prévention Intégration des données Prédiction Signatures complexes Modélisation Biomarqueurs Adapté du Pr. A. Magnan 36