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Pr. Christophe Pison, MD, PhDPr. Christophe Pison, MD, PhDClinique Universitaire de PneumologieClinique Universitaire de PneumologiePole Thorax et VaisseauxPole Thorax et Vaisseaux
Inserm1050Inserm1050Biologie Environnementale et Biologie Environnementale et Systémique - BEeSYSystémique - BEeSY
European Institute for Systems Biology and European Institute for Systems Biology and Medicine - EISBMMedicine - EISBM
CHU GrenobleCHU GrenobleUniversité Université
Grenoble AlpesGrenoble Alpes
Systems Medicine of Respiratory DiseasesSystems Medicine of Respiratory Diseasesan actual breakthroughan actual breakthrough
INRIA, Lyon, 11th of February 2014
www.eisbm.org
2
Institut de Recherche Technologique
www.bioaster.comwww.biovision.org
Consortium International Systemoscope « Repenser la recherche, comprendre le vivant, améliorer la santé »
Conflicts Of Interests, 3 last yearsConflicts 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
ContentsContents
Non communicable diseases and “health crisis”
Burden of respiratory diseases and unmet needs
Systems medicine for respiratory health in Rhône-Alpes and Europe
5Biotechnology Journal 2012; 7 special issue on Systems biology and personalized medicine
Non Communicable Diseases - NCDsNon Communicable Diseases - NCDs
6
““Health crisis”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 accumulation
and how use it for better patient cares?
Specialized versus Systems Medicine
Reactive versus proactive Medicine?
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Uncontrolled increases in health costsUncontrolled increases in health costs
USA 18% GIP 2009 to 30% by 2030 & last OECD France, 12% GIP 2009, life expectancy 81 years in 2009
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Efficacy Efficacy & J& Justice declineustice decline
9
NEJM 2010;362:460-5
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
N Engl J Med 2013;369:448-57 11
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Prévention de la maladie
Prédiction de la maladie
Prédiction de la réponse
MÉDECINE 4P: L’OPPORTUNITÉ
Stratégies personnalisées et participatives
Traitement ciblé
Agir là
Changer le cours de la vie
Ou la ?
Changer le cours de la maladie
Guérir
Ou encore la ?
Contrôler
Thérapie ciblée
Médecine systémique en pratique
Hood L, RMMJ 2013 adapté du Pr. A. Magnan
Peter Hunter, University of Auckland – Denis Noble, Oxford University
Challenge to integrate multi-scale space-time dimensions
14
Achilles' tendons in Lung TransplantationAchilles' tendons in Lung Transplantation
-15%, 3 months
- 4% / year
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
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QALY - Quality Adjusted Life YearsQALY - Quality Adjusted Life Years
Résultats de la transplantation pulmonaire, S. Quêtant, T. Rochat, C. Pison. RMR 2010; 27:921-938
123 4 5 6 7 8 9
0,5
1
1 2 3
Année
Qu
alit
é d
e vi
e aj
ust
é su
r la
su
rvie
16
Signature to predict chronic dysfunctionSignature to predict chronic dysfunction
17
Time
CLAD prediction: The clock is always ticking!
Transplantation. 2008 Jul 27;86(2):192-9. 18
Roedder et al. Genome Medicine 2011;3:37
20
www.novadiscovery.comSysCLAD Progress Meeting. ENS de Lyon, FR. November 12th, 2013 20
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 Design Methods in SysCLAD Methods in SysCLAD
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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)
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Pulmonary microbiota
and
Alveolar macrophage polarization
in
Lung transplant recipients
Pulmonary microbiota
and
Alveolar macrophage polarization
in
Lung transplant recipients
Service de PneumologieCentre Hospitalier Universitaire VaudoisLausanne, Switzerland
Laboratory:
Ben Marsland, PhD
Eric Bernasconi, PhD
Laboratory:
Ben Marsland, PhD
Eric Bernasconi, PhD
Clinical supervision:
Prof. Laurent Nicod
Prof. John-David Aubert
Clinical supervision:
Prof. Laurent Nicod
Prof. John-David Aubert
Research coordination:
Dr. Angela Koutsokera
Research coordination:
Dr. Angela Koutsokera
Adapted from SciencePhotoLibrary
24
NEJM 2013,369:20-31 25
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
SysCLAD ConsortiumSysCLAD Consortium
27
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. lamraniParis 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-STCS Genève-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 Platforms Biomax, 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
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
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Long-life dimensionrepeated measurements to refine phenotypes
Adapted from R. Slama group
Basic Clinical and Biomedical Questions
30
Basic Clinical and Biomedical Questions
Mechanisms Shared and non-shared mechanisms
in 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
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
Basic Clinical and Biomedical Questions
32
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Clinique Universitaire de PneumologieClinique Universitaire de PneumologieUniversité Grenoble AlpesUniversité Grenoble Alpes
Oncologie Thoracique
IRC Mucoviscidose
HTAPTransplantation
Maladies Chroniques
Respiratoires
34
PromouvoirBien-Etre
Médecine 4P
Mécanismes communs maladies chroniques respiratoires et cancer bronchqiue (miRNA, épigénétiques, effet Warburg),
patients communs, technologies communes, approches systémiques
Proportion de patients pris en chargeMédecine “reactive” type CHU
Coûts efficacitéMédecine “pro-active”
Biologie des Systèmes
Médecine 4P
Biologie
Technologie
Signatures complexes
Biomarqueurs
Intégration des données
Modélisation
Prédiction
Prévention
Personnalisation
Participation
Adapté du Pr. A. Magnan 36