Lehrach
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The document discusses how life translates genetic information from the genome into an organism's phenotype given its environment. It states that the organism computes its phenotype from its genotype in a specific environment. Genome information is translated into the observable characteristics of an organism.
Lehrach
- 1. 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
- 2. ? Genome ! (PentiumV) (neuronal net visualisation) Phenotype
- 4. The Problem World wide ~12 million new cancer cases/year Cure rates for many common forms of cancer have hardly changed over the last decades Even the most advanced targeted therapies are typically only effective for a small fraction of the patients Pharma development costs have dramatically increased, while the number of new drugs keeps dropping
- 5. Global Cancer Burden (millions) 2008 2030 New cases 12.5 26.4 Deaths 7.6 17.1 Alive with cancer 28.0 80.0 Boyle and Levin, 2009
- 6. Colon Cancer (K-ras wild type) S U R V I V A L Time in months Zalcberg et al, NEJM 2008 Many colon cancer patients with tumors without K-ras wild type will respond positively to treatment with EGFR receptor anatagonists
- 7. Colon Cancer Mutated K-ras S U R V I V A 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)
- 9. Publication of Draft Version International Human Genome Celera Consortium 30th September 2010, Brussel
- 10. Genome$ 2010 $1-7K (CGI) human genome Factors of 10 since 2005 2004: $400M (ABI) ------ Moore’s law 2000: $3 billion 1.5x/yr for electronics 10
- 11. The 1000 genomes project: a catalogue of human polymorphism created using next generation sequencing
- 12. International Cancer Genome Consortium (ICGC) Pancreas Breast Cancer Liver Pedriatic Gastric cancer Cancer Cancer Liver (Viral) Glioblastoma and (alcohol) / Ovarian Cancer CLL Breast (The Cancer Oral cavity Cancer Genome Atlas) cancer Pancreas 2 EU funded consortia
- 13. Sequencing Capacities at the MPI-MG 5 x Illumina GAII 3 x 454/FLX 1 x Polonator G007 5 x SOLiD The MPI-MG is the largest second generation sequencing centre on the continent, technology, which will be directly transferred to Alacris Theranostics
- 14. Christoph Wierling Hanahan / Weinberg Cancer Model Weinberg, The Biology of Cancer (2007) Garland Science
- 18. Proof of Concept Dr. Schlag with the first patient’s tumor
- 19. Patient 1 Genome Sequencing Amount Sample Type sequenced Blood Whole Genome 90 Gb Tumor Whole Genome 120 Gb Blood Exome 997 Mb Tumor Exome 892 Mb Ca. 30x genome coverage for high-confidence scoring of mutations • Heterogenous tumor with > 40,000 somatic mutations, mostly passengers ! Ca. 1,000 mutations in expressed proteins, mostly changing one amino acid • One known cancer activating mutation: BRAF(V600E) observed in 50% of melanomas but not sufficient to promote tumorigenesis Another 5 mutations in expressed genes model components for instance in PDGFD, PRKCB, SCRF1.... but the mutations effects are unknown : being modeled for three possibilities (neutral,activating or loss of function) Identification of NOVEL driver mutations which will be implemented in the model)
- 20. Whole Genome Sequence provides virtual karyotype (Example for tumor Chr.9) Identification of a large deletion of chr. 9 Gene Deletion CDKN2A Cyclin-dependent kinase inhibitor 2A (ARF) CDKN2B Cyclin-dependent kinase 4 inhibitor B Amount of DNA per Mb shown for blood (red) and tumor (blue) Ratio of reads (blood/tissue). SNPs unique to blood (red), unique to tissue (blue). The higher number of blood-specific SNPs shows that this haplotype was lost in tumor
- 21. Patient 1 Transcriptome Sequencing New protocol with RNA fragmentation Run/lane nb Sample Total.number_unique_hits 091211_EAS451_1 Tumor 28 859 047 091211_EAS451_2 Tumor 29 373 327 091211_EAS451_3 Tumor 29 456 853 091211_EAS451_4 Control 30 461 674 091211_EAS451_5 Control 29 622 024 Standard protocol with cDNA fragmentation Run/lane nb Sample Total.number_unique_hits 091113_EAS451_5 Tumor 21 995 533 091113_EAS451_6 Tumor 21 919 636 090522_EAS451_7 Tumor 11 277 659 090714_EAS451_1 Stem cells‐CD133+ 16 468 893 090714_EAS451_2 Stem cells‐CD133‐ 21 808 807 091106_EAS451_6 Control 24 766 112 Tumor tissues and stem cells + control melanocyte sequenced
- 22. Cross-validated homozygous SNP Heterozygous exome SNP (in splicing region) looks as homozygous in transcriptome ENSG00000115756
- 24. The model of patient 1
- 25. Finding a Patient 1 Specific Optimal Drug Treatment Round 1 Single Drugs Round 2 Double Drugs Round 3 Triple Drugs Round 4 Quad Drugs Round 5 Fiver Drugs MYC Conc. Optimization Round 6 Drugs / Drug Combinations Various Modell Components Stepwise optimisation of the therapy for an individual patient
- 27. Detection of environmental effects A) ‘mutagen fingerprints’ B) Statistically significant increase in specific molecular subtypes C)Mechanistic predictions (e.g. tumor promoters) D)In-silico tumor formation?
- 28. Modeling the effects of mutations, which affect response to EGFR inhibitors
- 29. • PacBio has been quoted that, by 2013, their technology will be able to give a ‘raw’ human genome sequence in less than 3 min, and a complete high- quality sequence in just 15 min
- 30. Modelling the response of cancer stem cells? Cancer, a curable disease? The ‚red Queen‘ approach to cancer treatment: Modelling cancer progression. Cancer, a chronic disease‘
- 31. IT Future of Medicine Setting the Scene
- 32. Market “NEW YORK, Dec. 8, 2010 /PRNewswire/ -- Spending on healthcare among the OECD (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.” “Worldwide IT 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
- 33. 12 Million new cancer cases every year ~1 genome/second? Computing requirements: Sequence analysis: 100 cores ~1 day/genome: 1e7 core seconds Modelling: 1000 conditions, 1000 positions in the body, 1000 MC runs, 1000 core seconds/run: 10e12 core seconds 1 Blue Gene L: ~10e5 cores (up to 65,536 nodes with 2 Power PC processors) ~1 Blue Gene L equivalent per patient? Storage: ~1 Terabyte per genome 30-100 Exabytes for data storage for all cancer patients? Multi-Zetabytes to Yottabytes for ITFoM? As of May 2009, the size of the world's total digital content has been roughly estimated to be 500 billion Gigabytes (500 Exabytes) (From the Wiki Exabyte entry)
- 34. Metabolomics NMR-based metabolomics + Metabolic fingerprint
- 35. 24 Partners
- 36. Relations to Infrastructures European Sequencing and Genotyping Infrastructure ISBE Integrated Structural Biology Infrastructure Infrastructure for Systems Biology – Europe Partnership for Advanced Computing in Europe Jülich Supercomputing Centre
- 37. 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. For more information: Website: http://www.itfom.eu Email: [email protected] Twitter: @itfom Facebook: I.T. Future of Medicine LinkedIn: IT Future of Medicine