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?

7

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

8

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

12

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

15

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

21

22

22

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

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

28

29

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

33

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