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The Foundations of P4 MedicinePredictive, Personalized, Preventive and Participatory,[object Object],Lee Hood,[object Object],Institute for Systems Biology, Seattle,[object Object]
Outline,[object Object],Principles of P4 medicine,[object Object],P4 medicine— and the future,[object Object],Societal implications of P4 medicine,[object Object],ISB strategic partnerships for P4 medicine,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease,[object Object]
Humans Phenotypes are Specified by Two Types of Biological Information,[object Object],The digital information of the genome,[object Object],[object Object],[object Object],[object Object]
All Hierarchical or MultiscaleLevels of Biological Information—Are Modified by Environmental Signals ,[object Object],DNA,[object Object],RNA,[object Object],Protein,[object Object],Protein interactions and biomodules,[object Object],Protein and gene networks,[object Object],Cells,[object Object],Organs,[object Object],Individuals,[object Object],Populations,[object Object],Ecologies,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic (systems biology and systems medicine,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease,[object Object]
ISB’s View of Systems Biology,[object Object]
Essentials of Systems Biology,[object Object],Hypothesis-driven and hypothesis-generating,[object Object],Data,[object Object],Global data acquisition,[object Object],Integrate multi scale data types,[object Object],Delineate biological network dynamics—temporal and spatial,[object Object],Dealing with biological and technical noise in large data sets,[object Object],Formulate models that are predictive and actionable.,[object Object],Discovery science is key,[object Object]
Agenda:  Use biology to drive technology and computation.  Need to create a cross-disciplinary culture.,[object Object],Biological Information,[object Object],BIOLOGY,[object Object],Cross-Disciplinary,[object Object],Culture ,[object Object],Team Science,[object Object],[object Object]
Chemistry
Computer Science
Engineering
Mathematics
PhysicsTECHNOLOGY,[object Object],COMPUTATION,[object Object]
Institute for Systems Biology,[object Object],Founded 2000—10th Anniversary,[object Object],ISB has 13 faculty and 300 staff  ,[object Object]
ISB’s description of systems biology,[object Object], in 2000 is virtually identical to that of,[object Object], this National Academy of Sciences ,[object Object], 2010 report entitled the “New Biology”.,[object Object],ISB was the first Systems Biology ,[object Object], organization in 2000—today there are ,[object Object], more than 70 world wide,[object Object],Predicted that systems approaches would,[object Object], drive medicine of the future,[object Object]
SCImago Institutions Rankings: http://www.scimagoir.com/,[object Object],Inst. Nat. de,[object Object],Physique Nucleaire,[object Object],Sanger,[object Object],SSM Cardinal Glennon,[object Object],Children’s Hospital,[object Object],ISB,[object Object],CSHL,[object Object],International Agency for,[object Object],Research on Cancer,[object Object],Kaiser Permanente,[object Object],Brigham and,[object Object],Women’s Hospital,[object Object],Rockefeller,[object Object],Institut Catala,[object Object],d’Investigacio,[object Object],Quimica ,[object Object],MIT,[object Object],Salk,[object Object],WHO,[object Object],Harvard,[object Object],HHMI,[object Object],MSFT,[object Object],FHCRC,[object Object],IBM,[object Object],Parc,[object Object],Mediterrani,[object Object],de la,[object Object],Tecnología,[object Object],Centro de,[object Object],Investigación,[object Object],Príncipe,[object Object],Felipe,[object Object],CNRS,[object Object],Chinese Academy of Science,[object Object],Russian Academy of Sciences,[object Object],National Academy of,[object Object],Sciences of Ukraine,[object Object],Tianjin,[object Object],University,[object Object],Harbin Engineering,[object Object],University,[object Object],Research Institute of,[object Object],Petroleum Processing,[object Object],ISB 1st in US and 3rd in World for Impact of Papers,[object Object]
A Systems View of Disease,[object Object]
dynamics of,[object Object],pathophysiology,[object Object],diagnosis,[object Object],therapy,[object Object],prevention,[object Object],A Systems View of Medicine Postulates that Disease Arises from Disease-Perturbed Networks,[object Object],Non-Diseased,[object Object],Diseased,[object Object]
Neuropathology Identifies 4 Aspects of PrionNeurodegeneration,[object Object],Microglia / Astrocyte,[object Object],activation,[object Object],PrP accumulation,[object Object],Synaptic Degeneration,[object Object],Nerve cell death,[object Object],Infected,[object Object],Normal,[object Object]
Dynamics of a Brain Network in Prion Neurodegenerative Disease in Mice,[object Object],Prion accumulation network,[object Object]
Sequential Disease-Perturbation of the Four Networks of Prion Disease,[object Object],18~20 wk,[object Object],22 wk,[object Object],0 wk,[object Object],Clinical Signs,[object Object],Prion,[object Object],accumulation,[object Object],Glial,[object Object],Activation,[object Object],SynapticDegeneration,[object Object],Neuronal ,[object Object],Cell Death,[object Object],Na+,[object Object],channels,[object Object],Reactive,[object Object],Astrocytes,[object Object],Cholesterol,[object Object],transport,[object Object],Caspases,[object Object],Sphingolipid,[object Object],synthesis,[object Object],Cargo,[object Object],transport,[object Object],Leukocyte,[object Object],extravasation,[object Object],Lysosome,[object Object],proteolysis,[object Object],*Arachidonate,[object Object],metab./Ca+ sig.,[object Object]
DEGs Encoding Known and Novel Prion Disease Phenotypes,[object Object],333 DEGs encode core prion disease,[object Object],231/333 DEGs encode known 4 disease-perturbed networks from histopathology,[object Object],102/333 DEGs encode 6 novel disease-perturbed networks--the dark genes of prion disease,[object Object],Disease-perturbed networks sequentially activated,[object Object],Re-engineer disease-perturbed networks with drugs—new approach to drug target discovery,[object Object],Striking implications for blood diagnostics,[object Object]
Dynamics of a Brain Network in PrionNeuroddegenerative Disease in Mice,[object Object],Prion accumulation network,[object Object]
Making Blood A Window Distinguishing Health and DiseaseOrgan-specific Blood Proteins,[object Object],110 brain-specific blood proteins/80 liver-specific blood proteins,[object Object],Blood Vessel,[object Object]
Why Systems-Driven Blood Diagnostics Will Be the Key to P4 Medicine,[object Object],Early detection,[object Object],Disease stratification,[object Object],Disease progression,[object Object],Assess prognosis,[object Object],Follow therapy,[object Object],Assess reoccurances,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease,[object Object]
ISB’s Technology-Driven Big Biology Projects,[object Object]
Four ISB Technology-Driven New Big Projects,[object Object],The Human Proteome Project—SRM mass spectrometry assays for all human proteins,[object Object],Clinical assays for patients that allow new dimensions of data space to be explored,[object Object],Complete genome sequencing of families—sequences and new stratifications to identify disease genes—1000s individuals,[object Object],The 2nd Human Genome Project—mining all complete human genomes and their phenotypic/clinical data,[object Object]
Whole Genome Sequencing of Families:  New Genomic Strategy,[object Object],Sequencing by Complete Genomics, Inc.,[object Object]
Whole Genome Sequencing of Family of Four  ,[object Object],Unaffected parents,[object Object],Children each with 2 diseases--craniofacial,[object Object], malformation (Miller Syndrome) ,[object Object],and lung disease (ciliarydyskinesia),[object Object],Identify 70% of sequence errors using principles of Mendelian genetics,[object Object], —less than 1/100,000 error rate,[object Object],Discovery of about 230,000 rare variants in family—confirmed by identification,[object Object],  in two or more family members,[object Object]
Recominational Genome Map from Miller’s Syndrome Children:,[object Object],65% of recombinational events fall in hot spots,[object Object],Both children inherited the same allele from both parents,[object Object],Each child inherited a different allele from each parent,[object Object],Children inherited the same allele from dad, different alleles from mom,[object Object],Children inherited the same allele from mom, different alleles from dad,[object Object],x,[object Object],x,[object Object],x,[object Object],65 crossovers in (2) male meioses (left),[object Object],104 crossovers in (2) female meioses (right),[object Object],250,[object Object],200,[object Object],More than 65% crossovers,[object Object],In hot spots of recombination,[object Object],150,[object Object],100,[object Object],50,[object Object],0,[object Object],X,[object Object],1,[object Object],2,[object Object],3,[object Object],4,[object Object],5,[object Object],6,[object Object],7,[object Object],8,[object Object],9,[object Object],10,[object Object],11,[object Object],12,[object Object],13,[object Object],14,[object Object],15,[object Object],16,[object Object],17,[object Object],18,[object Object],19,[object Object],20,[object Object],21,[object Object],22,[object Object]
Inter-generational base-change mutations,[object Object],[object Object]
New mutations, germline nucleotide substitutions, have never been directly measured before.
Low error rate & family makes this approach work
We trapped by Agilent hybridization selection and resequenced ~60,000 sites
Indirect, phylogenetic estimate is between 8 x 10-9 &2.1 x 10-8 per base per generation,
          The intergenerational mutation rate of the autosome is
~1.1 x 10-8  /bases/generation—70 mutations/ individual/generation,[object Object]
1,[object Object],2,[object Object],3,[object Object],4,[object Object],5,[object Object],6,[object Object],7,[object Object],8,[object Object],9,[object Object],10,[object Object],11,[object Object],12,[object Object],13,[object Object],14,[object Object],15,[object Object],16,[object Object],17,[object Object],18,[object Object],19,[object Object],20,[object Object],21,[object Object],22,[object Object],X,[object Object],ZNF721,[object Object],DNAH5,[object Object],KIAA0556,[object Object],DHODH,[object Object],Miller’s gene,[object Object],Ciliarydyskenesis gene,[object Object],centromere,[object Object],paternal recombination,[object Object],heterochromatin,[object Object],identical,[object Object],error region,[object Object],maternal recombination,[object Object],CNV,[object Object],haploidentical paternal,[object Object],candidate gene,[object Object]
Family Genome Sequencing May Facilitate Finding,[object Object],Mendeliandisease genes,[object Object],Modifiers of disease genes--sequencing genomes of 65 Huntington’s patients from families,[object Object],Genes encoding complex genetic diseases after proper patient stratification—Alzheimer’s/Parkinson’s diseases,[object Object]
The Human Proteome Project,[object Object],Strategic partners:  ISB (R. Moritz)/ETH (R. Aebersold)/Agilent/AB-Sciex/Origene,[object Object]
ISB has made 4 fundamental contributions to the human proteome project,[object Object]
1. Trans Proteomic Pipeline (TPP) components,[object Object],* Commercial software not part of TPP,[object Object]
Drives tool development and optimization,[object Object],Advanced, uniform processing of all data,[object Object],2. TPP: Foundation for PeptideAtlas,[object Object]
3. Targeted Proteomics:  Human SRMAtlas,[object Object],SRM ,[object Object],assays for most of the known 20,333  ,[object Object],human proteins,[object Object],39,[object Object]
ISB Contributions to the Human Proteome Project,[object Object],Trans Proteomic Pipeline—quality assessment/validation,[object Object],Protein Atlas—large-scale MS database,[object Object],Pioneered SRM/MRM  mass spectrometry applications—a targeted approach to protein assays,[object Object],4. First preliminary SRM assays (map) of all 20,333 human proteins,[object Object]
Proposal for a Human Proteome Project,[object Object],Create validated targeted assays (SRM) for each human protein,[object Object],Do the same for carefully selected model organisms (mouse, rat, fly, nematode, etc.),[object Object],Develop diverse technologies to increase the power of proteome analyses—MS, protein chips, novel protein capture agents, imaging, single protein molecule analyses, etc.,[object Object],Develop the computational and mathematical tools necessary for proteome analyses,[object Object],Develop the software to make all proteins in their biologically relevant clusters--biological networks/molecular machines--accessible to all biologists,[object Object],With appropriate time lines build in specific aims to include the many other dimensions of proteomics (7-10 yr project),[object Object]
Microfluidic Protein Chip:Assay 2500 Organ-Specific Blood Proteinsfrom Millions of Patients Using just a Drop of Blood—Follow Health Longitudinally and Detect Transitions to Disease,[object Object],Jim Heath--Caltech,[object Object]
DEAL for In vitro molecular diagnostics:,[object Object],Integrated  nanotech/microfluidics platform,[object Object],300 nanoliters of plasma,[object Object],cells out,[object Object],Assay region,[object Object],5 minute measurement,[object Object],Jim Heath, et al,[object Object]
Peptide Protein-Capture AgentsJim Heath--Caltech,[object Object],Jim Heath--Caltech,[object Object]
Antibody Displacement Technology—Heath--Caltech,[object Object],An example of a triligand PCC agent for bovine carbonic anhydrase II ,[object Object],Protein Catalyzed Capture Agents:,[object Object],triligands determined by repeated screening of target protein across synthetic bead-bound peptide libraries,[object Object],anchor peptide is selected on the first screen,[object Object],protein catalyzes the formation of second ligand to anchor ligand on second screen,[object Object],protein catalyzes the formation of the third ligand to the anchor and second ligand on third screen,[object Object],high affinity, stable and easily manufactured triligand capture agents,[object Object],confidential,[object Object],45,[object Object],Jim Health et. al., ,[object Object]
Single-Cell Analysis,[object Object]
Quantitative transcriptome clustering of single cells from  the human glioblastoma cell line U87,[object Object],CD markers let us sort into 3 quantized cell populations,[object Object]
Technologies for  Exploring New Dimensions of Patient Data Space,[object Object]
Individual Patient Information-Based Assays of the Present/ Future (I),[object Object],Genomics,[object Object],Complete individual genome sequences—predictive health history—will be done sequencing families,[object Object],Complete individual cell genome sequences—cancer.,[object Object],Complete MHC chromosomal sequence in families—autoimmune disease and allegies,[object Object],200 Actionable SNPs—pharmacogenetics-related and disease-related genes,[object Object],Sequence 1000 transcriptomes—tissues and single cells—stratification disease,[object Object],Analyze aging transcriptome profiles—tissues and single cells—wellness,[object Object],Analyze miRNA profiles—tissues, single cells and blood—disease diagnosis,[object Object],Proteomics,[object Object],Organ-specific blood MRM protein assays—110 brain, 80 liver and 20 lung,[object Object],2500 blood organ-specific blood proteins from 300 nanoliters of blood in 5 minutes—twice per year (50 proteins from 50 organs)—wellness assessment. ,[object Object],New protein capture agents.,[object Object],Array of 13,000 human proteins—against autoimmune or allergic sera--stratify.,[object Object],Single molecule protein analyses—blood organ-specific proteins and single cell analyses,[object Object]
Individual Patient Information-Based Assays of the Present/ Future (II),[object Object],Single cells,[object Object],Analyze10,000 B cells and 10,000 T cells for the functional regions of their immune receptors—past and present immune responsiveness—follow vaccinations—identify autoimmune antibodies. ,[object Object],Analyze individual blood macrophages—inflammation, etc.,[object Object],Use pore technology to separate epithelial cells from blood cells—cancer,[object Object],iPS (stem) cells,[object Object],Analyze individual stem (iPS) cells  from each individual differentiated to relevant tissues to get important phenotypic information—molecular,  imaging and higher level phenotypic measurements.,[object Object]
Induced Pluripotent Stem Cells (iPS Cells),[object Object]
Stratification of Complex Genetic Diseases—e.g.Alzheimer’s Disease,[object Object],Collect families of patients with the relevant disease (families will stratify disease to certain extent),[object Object],Create iPScells from each individual in families,[object Object],Differentiate iPS cells to neuronsin test tubes,[object Object],Probeindividual neurons with single cell transcriptomeanalyses to identify the degree of heterogeneity and neuron types—quantification of cell types--cell sorting if necessary,[object Object],Probethese neurons (individually or as cell-sorted classes) with ligands, drugs and relevant RNAi’s  and analyzetheir transcriptome, miRNAome and selected proteomes—this will stratify different combinations of disease-perturbed (or potentially disease-perturbed) networks,[object Object],Sequence family genomes in keeping with their initial  stratification types for error corrections,[object Object],Global comparisons of data across and within families of the molecular data—for final disease stratification,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual sculpting in exquisite detail wellness and disease,[object Object]
Phenome,[object Object],Transcriptome,[object Object],Transactional,[object Object],Epigenome,[object Object],Single Cell,[object Object],iPS Cells,[object Object],Social Media,[object Object],TeleHealth,[object Object],UUAGUG,[object Object],AUGCGUCUAGGCAUGCAUGCC,[object Object],Na143 K 3.7 BP 110/70 HCT32 BUN 12.9 Pulse 110 PLT150  WBC  92,[object Object],110101000101010101101010101001000101101010001,[object Object],110101000101010101101010101001000101101010001,[object Object],110101000101010101101010101001000101101010001,[object Object],110101000101010101101010101001000101101010001,[object Object],110101000101010101101010101001000101101010001,[object Object],110101000101010101101010101001000101101010001,[object Object],Genome,[object Object],GCGTAG,[object Object],ATGCGTAGGCATGCATGCCATTATAGCTTCCA,[object Object],Proteome,[object Object],arg-his-pro-gly-leu-ser-thr-ala-trp-tyr-val-met-phe-asp-cys,[object Object],Billions of Data Points Are Emerging Around Each Individual,[object Object]
The Foundation of P4 Medicine – Four Concepts,[object Object],View medicine as an informational science,[object Object],Systems approaches allow one to understand wellness and disease—holist rather than atomistic,[object Object],Emerging technologies will allow us to explore new dimensions of patient data space,[object Object],Transforming analytic tools will allow us to decipher the billions of data points for the individual--sculpting in exquisite detail wellness and disease,[object Object]
Predictive, Personalized, Preventive and Participatory (P4) Medicine,[object Object],Driven by systems approaches to disease, new  measurement (nanotechnology) and visualization  technologies and powerful new computational tools, P4 medicine will emerge over the next 10-20 years,[object Object],56,[object Object]
P4 medicine—the future,[object Object]
P4 Medicine,[object Object],[object Object]
Probabilistic health history--DNA sequence
Biannual multi-parameter blood protein measurements
In vivo molecular imaging,[object Object]
Unique individual human genetic variation mandates individual treatment

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