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Reading Out the State of the Body and How it Changes Under Therapy


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Guest Lecture
Pharmacy Informatics 2013
University of California San Diego

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Reading Out the State of the Body and How it Changes Under Therapy

  1. 1. “Reading Out the State of the Bodyand How it Changes Under Therapy”Guest LecturePharmacy Informatics 2013University of California San DiegoJune 7, 2013Dr. Larry SmarrDirector, California Institute for Telecommunications and InformationTechnologyHarry E. Gruber Professor,Dept. of Computer Science and EngineeringJacobs School of Engineering, UCSD1
  2. 2. The Calit2 Vision of Digitally Enabled Genomic Medicineis an Emerging Reality2July/August 2011 February 2012
  3. 3. Where I Believe We are Headed: Predictive,Personalized, Preventive, & Participatory am Lee Hood’s Lab Rat!
  4. 4. By Measuring the State of My Body and “Tuning” ItUsing Nutrition and Exercise, I Became Healthier2000Age412010Age6119991989Age511999I Arrived in La Jolla in 2000 After 20 Years in the Midwestand Decided to Move Against the Obesity TrendI Reversed My Body’s Decline ByQuantifying and Altering Nutrition and Exercise
  5. 5. Challenge-Develop Standards to Enable MashUpsof Personal Sensor Data Across Private CloudsWithing/iPhone-Blood PressureZeo-SleepAzumio-Heart RateEM Wave PC-StressMyFitnessPal-Calories IngestedFitBit -Daily Steps &Calories Burned
  6. 6. From Measuring Macro-Variablesto Measuring Your Internal
  7. 7. Visualizing Time Series of150 LS Blood and Stool Variables, Each Over 5-10 YearsCalit2 64 megapixel VROOM
  8. 8. Only One of My Blood MeasurementsWas Far Out of Range--Indicating Chronic InflammationNormal Range<1 mg/LNormal27x Upper LimitAntibioticsAntibioticsEpisodic Peaks in InflammationFollowed by Spontaneous DropsComplex Reactive Protein (CRP) is a Blood Biomarkerfor Detecting Presence of Inflammation
  9. 9. Stool Samples RevealedEpisodic Autoimmune ResponseNormal Range<7.3 µg/mL124x HealthyUpper LimitAntibioticsAntibioticsLactoferrin is an Antibacteria GlycoproteinShed from Attacking WBC NeutrophilsTypicalLactoferrinValue forActiveIBD
  10. 10. Colonoscopy Images ShowInflamed Pseudopolyps in 6 inches of Sigmoid ColonDec 2010 May 2011
  11. 11. Descending ColonSigmoid ColonThreading Iliac ArteriesMajor KinkConfirming the IBD (Crohn’s) Hypothesis:Finding the “Smoking Gun” with MRI ImagingI Obtained the MRI SlicesFrom UCSD Medical Servicesand Converted to Interactive 3DWorking WithCalit2 Staff & DeskVOX SoftwareTransverse ColonLiverSmall IntestineDiseased Sigmoid ColonCross SectionMRI Jan 2012
  12. 12. MRE Reveals Inflammation in 6 Inches of Sigmoid ColonThickness 15cm – 5x Normal Thickness“Long segment wall thickeningin the proximal and mid portions of the sigmoid colon,extending over a segment of approximately 16 cm,with suggestion of intramural sinus tracts.Edema in the sigmoid mesenteryand engorgement of the regional vasa recta.”– MRI reportClinical MRISlice ProgramDeskVOX 3D ImageCrohns diseaseaffects the thicknessof the intestinal wall.Having Crohns diseasethat affects your colonincreases your riskof colon cancer.
  13. 13. Why Did I Have an Autoimmune Disease like IBD?Despite decades of research,the etiology of Crohns diseaseremains unknown.Its pathogenesis may involvea complex interplay betweenhost genetics,immune dysfunction,and microbial or environmental factors.--The Role of Microbes in Crohns DiseasePaul B. Eckburg & David A. RelmanClin Infect Dis. 44:256-262 (2007) So I Set Out to Quantify All Three!
  14. 14. I Wondered if Crohn’s is an Autoimmune Disease,Did I Have a Personal Genomic Polymorphism?From www.23andme.comSNPs Associated with CDPolymorphism inInterleukin-23 Receptor Gene— 80% Higher Riskof Pro-inflammatoryImmune ResponseNOD2ATG16L1IRGMI am Now an Advisoron the23andme IBD Project
  15. 15. Autoimmune Disease Overlapfrom SNP GWASGut Lees, et al.60:1739-1753(2011)
  16. 16. Imagine Crowdsourcing 23andme SNPsFor Even a Small Portion of Crohnology!
  17. 17. Crowd-Sourcing the Effectivenessof Pharmaceutical Medications for Crohn’s
  18. 18. Fine Time Resolution Sampling Reveals DistinctDynamics of Innate and Adaptive Immune SystemNormalNormal
  19. 19. To Map My Gut Microbes, I Sent a Stool Sample tothe Venter Institute for Metagenomic SequencingGel Image of Extract from Smarr Sample-Next is Library ConstructionManny Torralba, Project Lead - Human Genomic MedicineJ Craig Venter InstituteJanuary 25, 2012Shipped Stool SampleDecember 28, 2011I Receiveda Disk Drive April 3, 2012With 35 GB FASTQ FilesWeizhong Li, UCSDNGS Pipeline:230M ReadsOnly 0.2% HumanRequired 1/2 cpu-yrPer Person Analyzed!SequencingFundingProvided byUCSD School ofHealth Sciences
  20. 20. Additional Phenotypes Added from NIH HMPFor Comparative Analysis5 Ileal Crohn’s, 3 Points in Time6 Ulcerative Colitis, 1 Point in Time35 “Healthy” Individuals1 Point in TimeDownload Raw Reads~100M Per Person
  21. 21. We Computationally Align 230M Illumina Short ReadsWith a Reference Genome Set & Then Visually Analyze~4500 Reference Genomeswith Strains and Viruses
  22. 22. Major Shifts in Microbial Ecologyin Health and DiseaseCrohn’s UlcerativeColitisHealthyLSToward NoninvasiveMicrobial Ecology DiagnosticsSource: Weizhong Li, UCSD; Calit2 FuturePatient Expedition
  23. 23. We Can Measure the Changes in Microbial EcologyBetween Healthy and Two Forms of IBDCollapse ofBacteroidetesExplosion ofProteobacteriaMicrobiome “Dysbiosis”or “Mass Extinction”?On the IBD Spectrum
  24. 24. Tracking How 1 Month Antibiotic, 2 Months Prednisone TherapyAlters the Gut Microbial EcologyReduced 45xReduced 90xTherapy Greatly Reduced Two Phyla,But Massive Reduction in BacteroidetesAnd Large % Proteobacteria RemainSmall ChangesWith No TherapyHow Does One Get Backto a “Healthy” Gut Microbiome?
  25. 25. June 8, 2012 June 14, 2012Intense Scientific Research is Underwayon Understanding the Human MicrobiomeFrom Culturing Bacteria to Sequencing Them
  26. 26. 2012 Was the Yearthe Human Microbiome Entered the Public’s Mind
  27. 27. From War to Gardening:New Therapeutical Tools for Managing the Microbiome“I would like to lose the language of warfare,”said Julie Segre, a senior investigator atthe National Human Genome Research Institute.”It does a disservice to all the bacteriathat have co-evolved with usand are maintaining the health of our bodies.”
  28. 28. Evidence for the Efficacy of Probiotics is IBD is Mixed -More Clinical Research Needed“...there is virtually no evidence of probiotic efficacy in Crohn’s disease.”
  29. 29. I Take a Probiotic “Cocktail”to Enhance Microbial Diversity-48 Species of Bacteria• Genera Covered:– Lactococcus– Leuconostoc– Myrothecium– Pediococcus– Phanerochaete– Pseudomonas– Streptococcus– Streptomyces• Genera Covered:– Azospirillum– Azotobacter– Bacillus– Bacteriodes– Bifidobacteria– Brevibacterium– Kurtha– Lactobacillus
  30. 30. From the Single “Bad” Microbe Medical Targetto the Microbiome Ecology ParadigmSci Transl Med 4, 137rv5 (2012);Science 336, 1255 (2012)Problem of Alternative Stable StatesIn Ecological System Dynamics
  31. 31. Microbiome TransferMay Be a Radical New Treatment for Alexander Khoruts, NY FDA Approved Yet;Increasing Number of Doctors Performing Procedure;Clinical Trials Under Way;Encouraging Results…ProceduresStarting WithNatural MicrobiomeNext Steps:CreateSynthetic MicrobiomesTuned to the PatientSeeMicrobiome 1:3 (2013)
  32. 32. Next Decade Will See New Microbiome“Gardening Tools”Journal of Nanotechnology (2012)August 7, 2012
  33. 33. Treating the Human Superorganism:Your Body Has Ten Microbes for Every Human Cell!Nature ReviewsMicrobiologyv.9, p. 279 (2011)