The Idea – Organism = Computer

Life is the translation of the information in the genome into the phenotype of the organism:

The organism ‚computes‘ this phenotype from its genotype, given a specific environment (PentiumV) (neuronal net visualisation)

Genome

Phenotype

The Problem – And It Is Not Getting Better

Global Cancer Burden

1.  World wide ~12 million new cancer cases/year

2.  Cure rates for most common forms of cancer have hardly changed over the last decades

3.  Even the most advanced targeted therapies are typically only effective for a small fraction of the patients

4.  Pharma development costs have dramatically increased, while the number of new drugs keeps dropping

Boyle and Levin, 2009

The future of medicine and healthcare will be dictated by demographic change

Global prevalence of diabetes and impaired glucose tolerance (IGT) in 2010 and 2030

International Diabetes Association, 2010

4

Colon Cancer

Zalcberg et al, NEJM 2008

(K-ras wild type)

SURV I VA L

Time in months

Many colon cancer patients with tumors without K-ras wild type will respond positively to treatment with EGFR receptor anatagonists

Mutated K-ras

SURV I VA L

Time in months Zalcberg et al, NEJM 2008

Patients with tumors with K-ras mutations do not: a 30000 Euro treatment will show no effect on the tumor (but will cause significant side effects on the patient)

Colon Cancer

Der Anfang: 1973

30th  September  2010,  Brussel  

Publica7on  of  Dra<  Version  

Interna7onal  Human  Genome  Consor7um  

Celera  

Change of technology in sequencing

1.2 billion DNA sequenzes in parallel 96 DNA sequenzes inparallel

The Sequencing Explosion

Large-scale international research collaborations relevant to ITFoM

ICGC comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor types

IHEC production of reference maps of at least 1000 epigenomes for key cellular states relevant to health and disease

IHMC International Human Microbiome Consortium explores the role of the human microbiome in the maintenance of health and causation of disease

1000 Genomes Project provides a comprehensive resource on human genetic variation

•  automobile crash tests entirely by computer simulation.

•  These days >> at least 3 to 5 million equations.

•  Computer simulations tobe safer than actual prototype car crash tests, because actual crash tests cannot simulate every possible situation. Robert Lange, General Motors executive director for vehicle structure and safety integration

•  (from : Car crash tests and Computer Simulations, Michael Pines,

•  http://seriousaccidents.com/blog/car-technology-accident-blog/car-crash-tests-and-computer-simulation/)

Still An Insatiable Need For Computing

PetaFlop Systems of Today Are The Client And Handheld Systems 10 years Later

10 PFlops 1 PFlops

100 TFlops 10 TFlops 1 TFlops

100 GFlops 10 GFlops 1 GFlops

100 MFlops

100 PFlops

10 EFlops 1 EFlops

100 EFlops

1993 2017 1999 2005 2011 2023

1 ZFlops

2029

Weather Prediction

Medical Imaging

Genomics Research

Source: www.top500.org

Forecast

Though barometers were increasingly in circulation since 1670, it wasn't until about 1860 that a famous English sea captain, Admiral Fitzroy, former Captain of Darwin's exploration ship "the Beagle", provided a detailed weather forecasting script that he attached to his several barometer inventions. Fitzroy is credited with the beginning of the first published weather forecasting in the world and detailing the meaning behind the rise and fall of air pressure. The English, and later the French, were the first to recognize the importance of these instruments, and in fact England's Board of Trade required large stick barometers, (3 for sale on this site), at all sea coastal towns so the sailors could view them before departing on a voyage.

The Cancer Model – Knowledge Of Decades Of Research

Hanahan & Weinberg, 2011

Over 30 different signaling pathways are integrated: Cytokine signaling (e.g. CSF, IFNA, IL8), Death receptor signaling (e.g. Fas, TNFa, TRAIL), DNA repair / cell cycle, Ephrin signaling, GCPR/Hormone signaling (e.g. Glucagon, Insulin, Testosterone), Hedgehog signaling, Notch signaling, several RTK signaling (e.g. bNGF, EGF, FGF, IGF, PDGF, VEGF), TGFb signaling (e.g. BMP, TGFb) and Wnt signaling.

TREAT20 – Treatment Of Malignant Melanoma Experimental Setup

20 metastatic melanoma cancer patients (10 cutaneous + 10 uveal)

1.  Expression data (high-throughput RNA sequencing) of melanocytes

2.  Expression data (high-throughput RNA sequencing) of 9 tumors so far

3.  Mutation data (high-throughput exome sequencing) of 9 tumors so far

TREAT20 – Current State

TREAT20 – Molecular Analysis of Tumors

Ploidy of Tumor Cells

TREAT20 – Patient Specific Modeling

TREAT20 – Predicting Drug Response

c-Myc levels as a surrogate marker for clinical effectiveness

TREAT20 – Chemosensitivity of Tumor Xenografts

Various Components

Patient1

Patient2

Patient3

Patient4

Patient5

Patient6

Patient7

Patient8

Patient9

EpCAM act. GLI

act. STAT3

nucl. ßCat

act. Casp pAKT

act. Ras pMEK

log2-ratio

TREAT20 – Combinatorial Treatment

Various Components

Patient1

Patient2

Patient3

Patient4

Patient5

Patient6

Patient7

Patient8

Patient9

EpCAM act. GLI

act. STAT3

nucl. ßCat

act. Casp pAKT

act. Ras pMEK

log2-ratio

FET Flagship Initiatives Concept

FET-F initiatives are:

•  proposed to be visionary research initiatives building on areas of established European excellence and oriented towards a unifying goal via a FET-nucleated multidisciplinary approach

•  proposed to generate waves of technological innovationand economic exploitation, ideally in a variety of areas and sectors, and would carry an important societal impact

•  envisioned to run for at least 10 years, on a budget in the range of 100 M€ Euros per year and per initiative

•  envisioned to be of such magnitude that they can only be realised through a federated effort of the different EC programmes, along with Member States, funding agencies and, where appropriate, global partners and industry

Goal: Construction of integrated molecular/physiologica/anatomical models

for all participants in the healthcare system: from baby to old age, on the basis of -omics,

imaging and sensor data

The Virtual Patient-Integration Of different Models

Molecules

Tissues Anatomy

Statistics

Pat1 Pat1 data

Pat1 model

Reference-model

Pat2 Pat2 data

Pat2 model

Pat3 Pat3 data

Pat3 model

Pat4 Pat4 data

Pat4 model

Pat5 Pat5 data

Pat5 model

Pat6 Pat6 data

Pat6 model

Pat7 Pat7 data

Pat7 model

Pat8 Pat8 data

Pat8 model

Pat9 Pat9 data

Pat9 model

Pat10 Pat10 data

Pat10 model

Pat11 Pat11 data

Pat11 model

Pat12 Pat12 data

Pat12 model

Pat13 Pat14 data

Pat14 model

Pat15 Pat15 data

Pat15 model

12 million new cancer cases per year: 1 genome per second

Modelling every patient at reasonable detail (1000 cell types, 1000 conditions, 1000 MC runs):

app. 1 billion core hours, 1 IBM BlueGeneL for 1 year per patient: energy cost limited medicine?

Reverse engineering of networks with thousands of components:

Unsolved!!!

........

.........

ICT challenges in an ICT driven medicine

12 million new cancer cases per year: 1 genome per second

Modelling every patient at reasonable detail (1000 cell types, 1000 conditions, 1000 MC runs):

500 million Europeans, modelled 2 times a year:

~10**14 core years

900000 servers (Google) use app. 0.01% of world wide electricity

If we assume, every Google server has 100?? cores, we would still use 100 times the world wide electricity production to model every European

2 x a year

everse engineering of networks with thousands of components:

Unsolved!!!

........

.........

Why is this an ICT challenge?

Technology resulting from our research at Stanford, Bell Labs, and Imperial College

One  result    per  clock  cycle  

MAXELER  DATAFLOW  COMPUTING  

Dynamic  (switching)  Power  Consump7on:      

Minimal  frequency  f    achieves  maximal  performance,  thus  for  a    given  power  budget,  we  get  Maximum  Performance  Compu7ng  (MPC)!  

31

fVCP DDloadavg ⋅⋅= 2

Relations to EU Infrastructures

Integrated Structural Biology Infrastructure

European Sequencing and Genotyping Infrastructure

ISBE

Infrastructure for Systems Biology – Europe

Partnership for Advanced Computing in Europe

32

ITFoM Partners and Associate Partners

-  University of Auckland, New Zealand (P. Hunter) -  Ontario Institute for Cancer Research, Canada (T. Hudson) - Institute for the Digital Economy, University of New Brunswick, Canada (M. Ulieru) - Institute for Quantum Computing, University

of Waterloo, Canada (D. Cory) -  McGill University and Genome Quebec Innovation Centre, Canada(T. Nilsson) - Harvard Medical School, US (G. Church) - UCLA Wireless Health Institute, US (M. Sarrafzadeh) - University of California, Berkeley, US(S. Russel) - Institute for Systems Biology, Seattle, US (L. Hood) - Genome Sciences Centre, BC Cancer Agency (S.Jones) - Prior Knowledge - Complete Genomics - Hussmann Institute for Human Genomics - American University Beirut

99 Partners from Europe and beyond

The ITFoM-Consortium Full Partners   Associate Partners  Max Planck Institute for Molecular Genetics (DE)  

Eidgenössische Technische Hochschule Zürich (CH)   University of Ostrava (CZ)   Karolinska Institutet  

Medical University of Graz (AT)   Ontario Institute for Cancer Research (CA)   TU Vienna (AT)   University of Ljubljana  

University College London (UK)   International Foundation for Computer Assisted Radiology and Surgery (DE)   Institut Pasteur (FR)   University of Glasgow  

VU University Amsterdam (NL)   German Cancer Research Center (DE)   HealthSolve (UK)   University of Twente-CTIT  

University of Manchester (UK)   COSBI - Microsoft Corporation (US)   CertiCon a.s. (CZ)   European Molecular Biology Laboratory  

European Molecular Biology Laboratory -   IBM Research (CH)   Czech Technical University in Prague (CZ)   MPI of Colloids and Interfaces  

European Bioinformatics Institute (DE/UK)   Roche Diagnostics (DE)   Dublin City University (IE)   Graz University of Technology  

Wellcome Trust Sanger Institute (UK)   Agilent Technologies, Inc. (UK)   Athens University of Economics and Business

(GR)   Imec  

KTH Royal Institute of Technology (SE)   Life Technologies Corp./Visigene (US)  SIVECO Romania (RO)   Hussman Institute for Human Genomics  

Imperial College London (UK)   Bruker Daltonics GmbH (DE)   University of Klagenfurt (AT)   Max Delbrück Center for Molecular Medicine  

Maastricht University (NL)   AB SCIEX GmbH (DE)   University of Strathclyde (UK)   Bull  Center for Magnetic Resonance (IT)  Intel Deutschland GmbH (DE)   Aalto University (FI)   Meganexus  International Prevention Research Institute (FR)   Oxford Nanopore Technologies (UK)   UCD Systems Biology Ireland (IE)   American University of Beirut  

Uppsala University (SE)   Bayer Schering Pharma (DE)   University of Copenhagen (DK)   Alfréd Rényi Institute of Mathematics, Hungarian Academy of Sciences  

University of Luxembourg (LU)   Janssen Pharmaceutica (BE)   University of Edinburgh (UK)   SAP  

University of Leicester (UK)   Institute for the Digital Economy (CA)   University of Rijeka (HR)   Universidad Politecnica de Madrid  

ISC Intelligence in Science (BE)   Harvard Medical School (US)   University of Waterloo- Institute for Quantum Computing   Maxeler Technologies  

University of Auckland (NZ)   Dahlem Centre for Genome Research and Medical Systems Biology (DE)   University of Rijeka   University of Sheffield  

Université de Genève (CH)   Tel Aviv University (IL)   IST   Complete Genomics Inc  

Centro Nacional de Análisis Genómico (ES)  

XEROX Research Centre Europe (FR)   TNO   Health Level Seven International

Foundation  

Siemens AG Österreich (AT)   Oracle (DE)   KU Leuven   prior Knowledge Inc  

Alacris Theranostics GmbH (DE)   University of Genoa (IT)   Donders Center for Neuroscience   University of Iceland  Charité - Universitätsmedizin Berlin (DE)  

Estonian Genome Center of the University of Tartu (EE)   Genome Sciences Centre, BC Cancer Agency.   Global Helix LLC  

Illumina Cambridge (UK)   Max Planck Institute for Molecular Plant Physiology (DE)   Jozef Stefan Institute   Sabanci University  

Commissariat à l‘Energie Atomique et aux Energies Alternatives -   Metanomics Health GmbH (DE)   Fraunhofer Institute for Biomedical Engineering  

Centre national de Génotypage (FR)  

Westfälische Wilhelms-Universität Münster (DE)   FUJITSU LABORATORIES OF EUROPE LIMITED  

ITFoM Consortium

35

Countries Partners Associate Partners In Negotiation Austria MUG, Siemens VUT, AAU, TUG Belgium ISC Janssen, KUL, imec, HL7

Canada OICR, IMPACT, UW-IQC, BCGSC

Croatia UNIRI Czech Republic VSB, CertiCon, CTU, Denmark UNICO Estonia UT Finland HIIT France iPRI, CEA-CNG Xerox, Institut Pasteur, Bull

Germany MPIMG,Alacris, Charité

IFCARS, DKFZ, Roche, Bruker, ABSCiex, Intel, Life Technologies, Bayer, DZ-GFMSB, Oracle, MPIMPP, WWUM, MTNX, IBMT, EMBL, MPIKG. Mdc, SAP, Maxeler MD

Greece AUEB Hungary Renyi Iceland UICE Ireland DCU, UCD-SBI Israel TAU Italy CERM Microsoft, DIBE, IST Libanon AUB Luxembourg UL New Zealand UOA Romania SIVECO Slovakia MMC-SAV Slovenia JSI, UNILJ Spain CNAG UPM Sweden UU, KTH, Karolinska, Switzerland UNIGE ETH, IBM The Netherlands VUA, UM, TNO, DCN, CTIT Turkey USAB

United Kingdom UCL, ULEIC, UNIMAN, Illumina, EMBL-EBI, Sanger, Imperial

Agilent, Oxford Nanopore, Healthsolve, UNISTR, UEDIN, Fujitsu LE, UNIGL, Meganexus, UNISH

USA Harvard, HIHG, CG, prior, GH

ITFoM Consortium

18 EC Member States included: Missing: Bulgaria, Cyprus, Latvia, Lithuania, Malta,

Poland, Portugal, EC Associated Countries included: Switzerland, Israel, Croatia, Turkey International Countries included: New Zealand, Canada, US, Libanon 75 Associate Partners from 25 countries

“NEW YORK, Dec. 8, 2010 /PRNewswire/ -- Spending on healthcareamong theOECD (i) countries and BRIC nations of Brazil, Russia, India and China will grow by 51 percent between 2010 and 2020, amounting to a cumulative total of more than $71 trillion, according to estimates from PwC's Health Research Institute. Health spending in these areas is rising faster than gross domestic product, magnifying gaps in budget deficits and spurring governments to look to the private sector for ways to get a better value for taxpayers' money.”

“WorldwideIT Spending outperformed expectations in 2010, reaching $1.5 Trillion”, according to IDC's Worldwide Black Book from February 09, 2011 08:03 AM Eastern Time

Market

Both ethically and economically, we can no longer afford the ineffective, cost- and

personnel intensive medicine of the past:

IT Future of Medicine

For more information: Website: http://www.itfom.eu Email: info@itfom.eu Twitter: @itfom Facebook: I.T. Future of Medicine LinkedIn: IT Future of Medicine

The project outcomes will enable the prediction of health, disease, therapy and its effects for individual patients and through application in the clinic will change the future of medicine.

Thank you!