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1Computation in the New MedicineIsaac S. KohaneOverview The future is now and it computes Genomic vs genetic Heredity Resequencing of the diagnostic process Accelerating consumer activationOverview The future is now and it computes Genomic vs genetic Heredity Resequencing of the diagnostic process Accelerating consumer activationThe Long Path from Genotype to FunctionDNATranscriptionTrans-lationStructuralBiologySequencingandgenotypingTranscriptionalProfilingNathan Baker UCSDProteomicsMagnitude of the TaskMagnitude of the Task2Magnitude of the TaskStadiumMagnitude of the Task× 1000Madonna Complex Some say MadonnaMusic > MadonnaPerson 4.7 GB vs (3 x 109) x 2 (bits/base) / 8 (bits/byte) = 0.75GBMadonna Complex Is Madonna, her DNA sequence? No, and her current state is captured by.. Alternative splicing (x 3/gene) Post-tra nslational modifi cation (x 100 -1000) Location of gene produ ct ( x 1012) She’s a little more complicated than her music (areyou surprised?)RNA/DNA expression detection chipsSchena M, et al. P roc Natl Acad Sci USA; 93: 10614 (1996).Entire issue. Nature Genetics, 21: supplement (Jan 1999).TissueRNATaggedwith fluorcDNA spotted on glass slide oroligonucleotides built on slideTissue underinfluenceorcDNAcopy3The Promise: The New DiagnosticsAlizadeh et al.Retreading the cancer chemotherapeuticprotocol Cancer and Leukemia Group B (CALGB) CALGB has grown into a national network of 29university medical centers, over 185 communityhospitals and more than almost 3000 physicians whocollaborate i n clinical research studies aimed at reducingthe morbidity and mortality from cancer Dozens of new protocols (breast cancer, prostate cancer,renal cancer) that use genome-wide Which genes best predict survival? Which adjuvant improves surgical outcome the best? Can we find expression measure proxies for Stage, Gradeand Cell TypeNew Taxonomy of Human Disease Clinicians may have moved on from calling ‘fever’ a disease, but theystill rely on phenotypic criteria to define most diseases, Yet these may obscure the underlying mechanisms and often masksignificant heterogeneity. Thomas Lewis pointed out in 1944, diagnosis of most human diseaseprovides only “insecure and temporary conceptions” Of the main common diseases, only the infectious diseases have atruly mechanism-based nomenclature.Changes in Use of “Every day” MedicationsGrowth in Our Knowledge of VariantsPolymorphism Publications0100020003000400050006000700080001980 1985 1990 1995 2000 2005Year (1981-2001)Publications/year4Growth in monogenic disease Pace of disease gene discovery (1981 to 200 0) . The number of disease genesdi scov er ed so far is 1112. This number does not in cl ude at lea st 94 di sea se- related genesidentified as translocation gene-fu sion partners in neoplastic disorders. Numbers inpa rentheses in di ca te disea se -rel ated gen es that are polym or ph ism s ( "su sc eptibi lity gen es" ).(From McKusick)One-pass genotyping•Chromosome 21: 21,676,868 bases (67%) of unique sequence were assayedfor variation with high-density oligonucleotide arrays•Synthesized 3.4 × 109 oligonucleotides on 160 wafers to scan 20 independentcopies of human chromosome 21 for DNA sequence variation.Patil, Science 2001Bioinformatics: 1998 Ambitions Find the functions of all30,000+genes using DNA sequence Genetics maps Physical maps Polymorphisms Structure information Existing biomedical literature Gene transcription patterns Protein translation/activity With growing databases containingdata, thisbecomes a problem in the realm ofbioinformaticsErmolaeva O, et al. Nature Genetics; 20: 19 (1998).A GrowingGapSystemsDangers of Dimensionality Given 1000 stadia full of people with necklaces with beads of 10colors 1 in 1 000 necklace bead s are differen t every b aseball se aso n. You notice that the third seat on the fifth row of all games hasa yellow bead in the middle of the necklace every year in theseason opener at the largest NY stadium in the last 26 wins inlast 102 years t hat t he NY Yankees have w on the World Seri es. How good a bet is that bead for the next time the NY Yankeesare in the World Series? Extra credit: DIYDetermining the aforementioned interaction is hard andruns counter to traditional biostatistical techniquesVariables (10,000 - 100,000)Cases (1000’s-1,000,000’s)Cases (10’s-100’s)High-dimensionality systems withinsufficient data areundeterdeterminedNot tractable by standardbiostatistical techniquesVariables (10’s-100’s)The New Pharmacology RNA expression in NCI 60 cell lines was determined usingAffymetrix HU6000 arrays 5,223 known genes 1,193 expressed sequence tags The RNA expression data set and Anti-cancersusceptibility data set were merged, using the 60 celllines the two tables had in commonRNA Expression Drug Susceptibility6,000 genes 5,000 anti-cancer agentsCommon 60Cell Lines5Genes and Anti-Cancer Agents Threshold r^2 was0.8 202 networks 834 features outof 11,692 (7.1%) 1,222 links out of68,345,586(.0018%) Only one linkbetween a geneand anti-canceragentGenes and Anti-Cancer Agents Elevated levels of J02923 (lymphocyte cytosolic protein-1, LCP1, L-plastin,pp65) is associated with increased sensitivity to 624044 Agent 624044 is 4-Thiazolidinecarboxylic acid, 3-[[6-[2-oxo-2-(phenylthio)ethyl]-3-cyclohexen-1-yl]acetyl]-2 thioxo-, methyl ester, [1R-[1a(R*),6a]]- (9CI)) LCP1 is an actin-binding proteininvolved in leukocyte adhesion A role for LCP1 in tumorogenicityhas been previously postulated Low level expression of LCP1 isthought to occur in most humancancer cell lines Other thiazolidine carboxylic acidderivatives are known to inhibittumor cell growthButte et al. PNAS 2000What does this have to do with biology andthe life of a cell?Layer Description7. Applications User and application level tasks (e.g.resource sharing)6. Presentation Display, storage form etc.5. Sesssion Establishes session: OS to transportabstraction4. Transport Guarantees end-to-end control within asession (who’s calling, answerng etc)3. Network Addressing, routing through nodes2. Data linkError free path between nodes1. Physical Electrical and mechanicalWhat are the major lessons you learned in6.001?Different Codes


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