Contents

ExecutiveSummary...........................................................................................................................ES1 ChapterI:Introduction..........................................................................................................................1 ChapterII:EconomicImpactsoftheHumanGenomeProject................................................................5 ChapterIII:FunctionalImpactsoftheHumanGenomeProject.............................................................17 ChapterIV:IntotheFuture...................................................................................................................53

Certaintechnologiesdiscussedinthisreporthavenotreceivedregulatoryapprovalorclearanceforclinicaluses.Inthisregard,sequencersare currentlyintendedforresearchorinvestigationaluses.

BattelleMemorialInstitute(Battelle)doesnotendorseorrecommendparticularcompanies,products,services,ortechnologiesnordoesitendorseor recommendfinancialinvestmentsand/orthepurchaseorsaleofsecurities.Battellemakesnowarrantyorguarantee,expressorimplied,including withoutlimitation,warrantiesoffitnessforaparticularpurposeormerchantability,foranyreport,service,dataorotherinformationprovidedherein. Copyright2011BattelleMemorialInstitute.Use,duplication,ordistributionofthisdocumentoranypartthereofisprohibitedwithoutthewritten permissionofBattelleMemorialInstitute.Unauthorizedusemayviolatethecopyrightlawsandresultinciviland/orcriminalpenalties.

ExecutiveSummary

Introduction
Thesequencingofthehumangenomerepresentedthelargestsingleundertakinginthehistoryof biologicalscienceandstandsasasignaturescientificachievement.1Allofhistoryinthemaking,human DNAtookjust13yearstosequenceundertheHumanGenomeProject(HGP),aninternationalpublic projectledbytheUnitedStates,andacomplementaryprivateprogram.Sequencingthehuman genomedeterminingthecompletesequenceofthe3billionDNAbasepairsandidentifyingeach humangenerequiredadvancedtechnologydevelopmentandtheassemblyofaninterdisciplinary teamofbiologists,physicists,chemists,computerscientists,mathematiciansandengineers. Scientistsareusingthereferencegenome,theknowledgeofgenomestructure,andthedataresulting fromtheHGPasthefoundationforfundamentaladvancementsinmedicineandsciencewiththegoals ofpreventing,diagnosing,andtreatinghumandisease.Also,whilefoundationaltotheunderstanding ofhumanbiologicalsystems,theknowledgeandadvancementsembodiedinthehumangenome sequencing,andthesequencingofmodelorganisms,areusefulbeyondhumanbiomedicalsciences. Theresultinggenomicrevolutionisinfluencingrenewableenergydevelopment,industrial biotechnology,agriculturalbiosciences,veterinarysciences,environmentalscience,forensicscience andhomelandsecurity,andadvancedstudiesinzoology,ecology,anthropologyandotherdisciplines. Inthetenyearssincethefirstsequenceswerepublished,muchhasbeenwrittenaboutthescientific consequencesofmappingthegenomebutlittleanalysishasbeendoneoftheeconomicsignificanceof theachievement.Forthisreason,Battellehasproduced,withsupportfromLifeTechnologies Foundation,thisfirstcomprehensiveanalysisoftheeconomicimpactoftheHGP. Thefullreportprovidesmultipleanalysesandinformationresourcestospurconsiderationand discussion.Itincludes AquantitativemeasurementofthedirectandindirecteconomicimpactsintheUnited StatesderivedfromactualexpendituresoftheHGPprojectandfollowonfederal expendituresinmajorgenomicscienceprograms.Thisisquantifiedusingtheregional economicanalysistechniqueofinput/outputanalysis. AquantitativeestimateoftheeconomicimpactoftheU.S.genomicsandgenomics enabledindustry,withacknowledgementthatthosewithintheindustrycredittheHGP andrelatedprogramsasbeingintegralcomponentsinthedevelopmentoftheindustry. Specificexamplesandcasestudiesofgenomicsinactionhighlightingthefunctional applicationofgenomicstools,technologiesandknowledgeinarangeofeconomically relevantfieldssuchashealthcare,veterinarymedicine,agriculture,theenvironment, industrialbiotechnology,andsecurityandjustice. Alookintothepotentialforfutureimpactsalongvariousgenomicpathways.Thefirst humangenomesequenceswereanimportantstepinthedevelopmentofthese pathways,pavingthewayformuchofwhatisexpectedinthepostgenomicfuture. ThegeneralstructureofimpactsisshowninFigureES1.
TheHumanGenomeProject(HGP)typicallyreferstothefederallyfundedprogramthatranfrom1990to2003 (thoughitalsoincludedinitialfundingin1988and1989).Partofoureconomicanalysisfocusesjustonthis essentialandgalvanizingcomponentofthetotalefforttounravelthehumangenome.Butthetotaleffortto decodethehumangenomeinvolvedmanypublicandprivateplayersovermanymoreyears,andtheworkof entitiessuchasCeleraGenomicsplayedanimportantpart.OuranalysisofthefunctionalimpactsoftheHGP necessarilyincludesallthesecontributions,andingeneralourreferencetotheefforttomapthegenomeshould beunderstoodtoencompassnumerouscontributionsmadebymultiplepartiestoourcurrentunderstanding.

Thisreportaimstofillagapin theliteratureregardingthe HumanGenomeProjectby assessingitseconomicand functionalimpacts. TheHGPrequiredthe developmentofadvanced equipment,technologies,data analysistools,andspecialized analysistechniquesthathas facilitatedthegrowthofan expandinggenomicsindustry. Todaythisindustryis empoweringfurtherscientific discovery,progressand commercialinnovationona broadrangeoffronts.From humanhealthcaretoveterinary medicine,fromindustrial biotechnologytohigh productivityagriculture,the knowledge,toolsand technologiessupportedthrough thesequencingofthehuman genomeformafoundationof advancedeconomicandsocial progressfortheUnitedStates andhumankind.

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FigureES1:TheStructureofForwardandBackwardLinkageImpactsAssociatedwiththeHumanGenome Sequencing

AdditionalMultiplierEffect(U.S.SpendingRecirculation) IndirectandInducedEconomicImpacts

GeneticsandGenomicsTools, Technologies,TechniquesandServices Labor U.S. Spending by HGP ExpandingBasicScientificKnowledge

Expenditure Impacts
(BackwardLinkage Effects)

HumanHealthandMedicine

Supplies

Technology

Followon U.S. Research Spending

Human Genome Sequencing

VeterinaryMedicine

Functional Impacts
Genomics Enabled Industry Spending
(ForwardLinkage Effects)

AgricultureandFood

Building etc.

IndustrialBiotechnology

EnvironmentalApplications

Total HGPEnabled EconomicImpact

Forensics,JusticeandSecurity

Battellesdetailedanalysisproducedfiveoverarchingconclusions: 1.
Between1988and2010the humangenomesequencing projectsandassociated researchandindustryactivity directlyandindirectly generated: $796billioninU.S. economicoutput $244billioninpersonal incomeforAmericans 3.8millionjobyearsof employment.

Theeconomicandfunctionalimpactsgeneratedbythesequencingofthehuman genomearealreadylargeandwidespread.Between1988and2010thehuman genomesequencingprojects,associatedresearchandindustryactivitydirectlyand indirectlygeneratedaneconomic(output)impactof$796billion,personalincome 2 exceeding$244billion,and3.8millionjobyearsofemployment. Thefederalgovernmentinvested$3.8billionintheHGPthroughitscompletionin 2003($5.6billionin2010$).Thisinvestmentwasfoundationalingeneratingthe economicoutputof$796billionabove,andthusshowsareturnoninvestment(ROI) totheU.S.economyof141to1every$1offederalHGPinvestmenthas contributedtothegenerationof$141intheeconomy. In2010alone,thegenomicsenabledindustrygeneratedover$3.7billioninfederal taxesand$2.3billioninU.S.stateandlocaltaxes.Thusinoneyear,revenues returnedtogovernmentnearlyequaledtheentire13yearinvestmentintheHGP. Overall,however,theimpactsofthehumangenomesequencingarejust beginninglargescalebenefitsinhumanmedicine,agriculture,energy,and environmentarestillintheirearlystages.Thebestistrulyyettocome. TheHGPisarguablythesinglemostinfluentialinvestmenttohavebeenmadein modernscienceandafoundationforprogressinthebiologicalsciencesmoving forward.

2.

3.

4.

5.

Ajobyearisequivalenttoonepersonemployedfulltimeforoneyear.Personalincomeconsistsofboth employeeandproprietorincomeandincludeswagesandotherfinancialbenefits(e.g.,retirementfunds).

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TheEconomicImpactsofHumanGenomeProject
Thehumangenomesequencingprogramshaddirectexpenditurestotalingalmost$3.8billion($5.6 billioninconstant2010dollars).Inaddition,beyondtheoriginalHGPinvestments,boththeNational InstitutesofHealth(NIH)andtheDepartmentofEnergy(DOE)madeandcontinuetomakesignificant investmentsinthescience,instrumentation,andrelatedapplicationsstemmingfromthehuman genomework.Infact,inbothcurrentandconstant2010dollarsthefederalinvestmentinhuman genomicsrelatedorenhancedresearchoverthelastsevenyears(20042010)hasactuallyexceeded thefederalinvestmentintheHGPby28percent.Theseadditionalexpendituresalsogenerateddirect andindirect(multipliereffect)economicimpactsintheU.Seconomy. Thedecodingofthehumangenomewasbothatechnologicalaswellasscientificachievement.The technologiesthathaveempoweredgenomesequencingrangefromthegenesequencersthemselves, tosamplepreparationtechnologies,sampleamplificationtechnologies,andarangeofanalyticaltools andtechnologies.Anindustryhasgrownuptosupplythescientificresearchcommunityintheprivate sector,governmentandacademiawiththeequipment,suppliesandservicesrequiredtoconduct genomicsresearchanddevelopment(R&D)andassociatedproductdevelopment.Thisindustry,of course,generatesadditionaleconomicimpacts. ToevaluatethesegenomicsenabledindustryimpactsintheU.S.,Battelleconstructedafromthe groundupdatabaseofindividualcompaniesengagedwithinthesector.Theemploymentofthis industrybasewasusedasthefoundationforaninput/outputanalysistoquantifythetotalimpactsof thesefirms(intermsofdirectandindirectoutputandemploymentandtheirmultipliereffect).The resultsoftheanalysisshowthatspurredbytheoriginalinvestmentandtechnologicaldevelopment impetusofthehumangenomesequencingprojectsasubstantialeconomicsectorhasdeveloped therebybenefitingtheU.S.economyintermsofbusinessvolume,jobs,andpersonalincome supportingAmericanfamilies. Battellesanalysisoftheimpactofhumangenomesequencingincludesseparateassessmentsofthe HGPimpacts,postHGPexpenditureimpacts,andtheimpactsofthegenomicsenabledindustrysector. Theseseparateresultsarecontainedinthefullreport.TableES1providesasummationofthe combinedimpactsfromtheseanalysesforthe19882010period.3
TableES1:CumulativeEconomicImpactofHumanGenomeSequencing,19882010(inBillions,2010$) Employment (JobYears) Personal Income State/Local TaxRevenue FederalTax Revenue In2010alone,thehuman genomesequencingprojects andassociatedresearchand industryactivitydirectlyand indirectlygenerated: $67billioninU.S.economic output $20billioninpersonal incomeforAmericans 310thousandjobs.

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

710,819 1,298,216 1,818,459 3,827,495 5.38

71.4 89.2 83.3 243.9 3.42

264.8 265.8 265.7 796.3 3.01

3.5 10.8 15.2 29.5 8.37

13.0 18.0 17.9 48.9 3.75

Thedirectimpactsincludenearly711,000directjobyears,acombinedpersonalincomedirect impactofmorethan$71billion,anddirectgenomicsdrivenoutputofnearly$265billion.In combineddirecttaxrevenuemorethan$3.5billionhasbeengeneratedinstate/localtaxesand morethan$13billioninfederaltaxes.Fromjusttheperspectiveoffederalrevenueandexpenses,

While1988and1989areoutsideoftheofficialtimeperiodoftheHGP,federalfundingstatisticsrecordrelated expendituresfortheseyearsandthusareincludedinthisanalysis.Additionally,federalHGPfundedcontinued until2003.

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thedirectfederaltaxesgeneratedtodate(in2010$)haveexceededtheHGPandpostHGPfederal investments($12.8billion)by$166million.
Thefederalinvestmentof$3.8 billionintheHumanGenome Project($5.6billionin2010$) enabledthegenerationofmore than$796billionineconomic outputforareturnon investmenttotheU.S.economy of141to1every$1of investmenthashelpedto generate$141intheeconomy.

Thetotalemploymentimpactexceeds3.8millionjobyearsoverthe23yearperiodexamined.Withan employmentmultiplierof5.38,genomicsresearchandassociatedindustriesgeneratedanadditional 4.38jobsintheU.S.economyforeverygenomicsjob.Thistotallevelofimpactedemployment generatednearly$244billioninpersonalincomeovertheperiodin2010dollarsamountingtoan averageof$63,700inpersonalincomeperjobyear.Thegenomesequencingprojects,associated researchandindustryactivitygeneratedatotaleconomic(output)impactofmorethan$796billion overthe19882010period.Consideringthefederalinvestmentof$3.8billionintheHumanGenome Projectfrom19882003($5.6billionin2010$)theHGPgeneratedareturnoninvestment(ROI)tothe U.S.economyof141to1every$1ofHGPinvestmenthashelpedtogenerate$141intheeconomy.

TheFunctionalImpactsoftheHumanGenomeProject
Whiletheeconomicimpactsofthesequencingofthehumangenomeareimpressive,theultimategoal oftheHGPwastoimproveourbiologicalunderstanding,andourhealthandwellbeing.Theeconomic impactmaybeviewedasabonusthathasoccurredinadditiontotheprimaryfunctionalimpacts. Theprogramssoughttocreatebenefitsforhumankindbyelucidatingbasicmolecularprocesses governinglifeandviatheapplicationofknowledgegainedtohumanhealthcareandmultipleother fieldsthatwouldbenefitfromadvancementsingenomicsknowledgeandtechnology. FigureES1alsoillustratesBattellesrepresentationofthestructureoffunctionalimpactsgeneratedby thesequencingofthehumangenome.Thesefunctionalimpactsincludethedevelopmentofgenomics tools,technologiesandtechniquesanareaoffundamentalimportancetomakingthesequencing feasible.Significantadvancementwasmadeoverthecourseofhumangenomesequencingacrossa broadrangeoftechnologyfrontsandthesehave,inmanycases,beencommercializedandformthe foundationforahighlyactiveandgrowingcommercialgenomicsbasedindustry. Theapplicationofthesegenomictools,technologiesandtechniquesresultedinatrulydramatic expansionofbasicbiologicalknowledge.Thefullhumangenomesequenceunveiledacomplex biologicalsystemunanticipatedbymostinscience,andhasbeenaparadigmshiftingeventforbiology. AsthesequencinginformationfromtheHGPwaspostedpublicallyonadailybasistotheWorldWide Web,thedatacontainedcouldbeimmediatelyputtouseadvancingapplicationofknowledgeacrossa broadrangeofscientificdisciplinesandappliedfields.Revealingthehumangenomestructureand sequencehadadirectimpactonbiomedicalscience.Italsohadatransformationaleffectonthe identificationofmechanismsofdisease,diagnosisofgeneticdiseasesanddisorders,elucidationof pathwaysandpotentiallyinvolvedbiologicalelementsincomplexdiseasesanddisorders,and detectionofspecifictargetsfordrugsandbiologics.Furthermore,havingthefullhumansequencehas servedtoadvanceadditionalhumanbiomedicalapplicationsinR&Dinareassuchasgenetherapy, vaccinedevelopment,regenerativemedicineandstemcelltherapy,andtherefinedmatchingof organsandtissuefromdonorstopatients. Withthefirstfulldraftofthehumansequenceinhand,newareasofbiomedicalsciencehave openedwithpharmacogenomicsandcompaniondiagnostics,forexample,beingusedtoidentify appropriatedrugsbasedonpatientgenomicprofilingandtorefinethedosingoftherapies,thereby maximizingeffectivenessandreducingnegativesideeffects.Alreadybeingappliedinthetreatmentof somecancers,pharmacogenomics,empoweredbythesequencingofthehumangenome,holds promiseforrevolutionizingthepracticeofmedicineinthe21stCentury. Moderngenomics,thereferencehumangenomesequences,andcomparativeorganismsequences, haveempoweredanewviewofbiologicalprocesses.Inturn,thesenewviewsarebeingtranslatedinto biomedicalapplications,suchasthoseshowninTableES2.

Inmedicine,genomicshas providedthefirstsystematic approachestodiscoverthegenes andcellularpathwaysunderlying disease.Whereascandidategene studiesyieldedslowprogress, comprehensiveapproacheshave resultedinidentificationof ~2,850genesunderlyingrare Mendeliandiseases,~1,100loci affectingcommonpolygenic disordersand~150newrecurrent targetsofsomaticmutationin cancer.Thesediscoveriesare propellingresearchthroughout academiaandindustry EricLander Nature.Vol.470.2011

Fromanimpactstandpoint, developmentsin pharmacogenomicsand personalizedmedicinehold significantpromiseformore accuratediagnosisofdisease, elucidationofpreventive measurestoavoiddisease,more refineddiseasetreatmentand avoidanceofcostsassociated withadversedrugreactions.

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TableES2:BiomedicalApplicationsofGenomicsandHumanGenomeSequencing

PotentialApplication
Diagnosisofsinglegene, Mendeliandiseasesand disorders

GenomicsAdvancesToday
Specificgenesforover3,000Mendelian monogenicdiseasesdiscovered. Genomictestsarebeingusedto accuratelydiagnoserarediseasesand disorders,manyofwhichwere previouslymisdiagnosedwith inappropriatecoursesoftreatment prescribed. Prenatalgeneticscreeningisbeing performedtoinformpotentialparents ofrisksforcatastrophicinheritable disorders. Multiplegenesandbiomarkershave beenidentifiedforpredispositionto multiplediseasessuchascancers, neurologicaldiseases,psychiatric diseaseandcardiovasculardisease.

HopefortheFuture
Genetherapieswillachievesuccessin repairinggeneticabnormalitiesleading todiseasesanddisorders. Customtherapeuticproductswillblock orchangeexpressedactivityof defectivegenes. Modernmedicinearosewhen scientistslearnedtofightsomeof theworstinfectiousdiseasewith vaccinesanddrugs.Thisstrategy hasnotworkedwithAIDS, malaria,andarangeofother diseasesbecauseoftheir complexityandthewaythey infiltrateprocessesincells. Curingsuchinfectiousdiseases, Understandingofriskfordiseasebased uponmultigenetestswilllikelyleadto appropriatetherapeuticinterventions andpersonalbehavior/lifestyle modification. Environmentalcomponentsofdisease emergenceandprogressionwillbe teasedoutfromgenomicfactorsand addressedappropriately. Manynewdrugsandbiologicswillbe developedtosuccessfullyexploit elucidateddrugtargets. cancer,andthehealthproblems thatarisefromdefectivegenes willrequireanewtypeof medicinebasedonathorough understandingofhowcellswork andthedevelopmentofnew methodstomanipulatewhat happensinsidethem.* TheHGPwasandisoneofthe centralprojectsleadingtothis understandingofhowcells workandopeningthewayfor Routinesequencingofapatientsentire genomewilguidetreatmentselection anddosefortheoptimumresponse. Potentialadversereactionstodrugsand treatmentregimens,identifiedvia genomicmarkers,willresultinthe avoidanceofadverseevents. Therewillbeasubstantialvolumeof existingdrugsfoundtobeefficaciousin selectedsubpopulations,anddrug companieswillhaveminedtheir previouslyfailedR&Dpipelinesto bringforwardpreviouslynon marketabledrugstoworkinselected subpopulations. Rapid,realtimesequencingof pathogenstwilldirectpublichealth effortstocombatdiseaseoutbreaksin humansandzoonoticdiseaseoutbreaks inanimals.DNAvaccineswillcometo themarkettoimpartimmunityto infectiousdiseases.Geneticprofilingof patientviruseswillassistincustomizing treatmentregimens. Genetherapymayberoutinely providedtonewbornswithidentified genomicprofilestocorrectdefective genes,particularlyinconditions associatedwithdevastatingmonogenic disorders. Weareontheleadingedgeofa truerevolutioninmedicine,one thatpromisestotransformthe traditionalonesizefitsall approachintoamuchmore powerfulstrategythatconsiders eachindividualasuniqueandas havingspecialcharacteristics thatshouldguideanapproachto stayinghealthy. FrancisCollins, TheLanguageofLife, NewYork:HarperCollins,2010 newapplicationsofmolecular medicine.
*

Knowledgeof predispositiontowards specificdiseases

Genomicsdrivendrug discovery,knownas rationaldrug development

Newdrugtargetshavebeenidentified. Cancerdrugsbasedonthegenomicsof tumorsareonthemarket,including Gleevec(forchronicmyelogenous leukemia),Herceptin(breastcancer), Tarceva(lungcancer)andAvastin (colon,lungandothercancers). Alreadybeingappliedinthetreatment ofsomeformsofcancerand cardiovasculardisease. Genetictestsareusedfordosagelevels inprescriptionofsomedrugssuchas Coumadin(warfarin). Successfuldiscoveryofsubpopulations forwhichpreviouslyunapproveddrugs areefficacious.Iressa,forexample,has beenapprovedwithpatentstesting positivefortheEGFRmutation.

Therapeuticproducts customprescribedbased onpatientgenomics,to maximizeeffectand reduceoreliminateside effects Repurposingor revitalizationofsome drugsshelvedin developmentbecauseof impactonagenomic few

RussHodge.2010.TheFuture Genome.

ofGenetics:BeyondtheHuman

Identificationofmeansto combatinfectious organisms

Multipleinfectiousorganismshavehad theirwholegenomessequenced. Publichealthprofessionalssequence emerginginfectiousdiseaseorganisms tomonitormigrationsandmutations. Genetictestingalreadybeingappliedto directtherapyforHIV/AIDSpatients.

Genetherapiesfor inheritedgeneticdiseases anddisorders

Afterpublicizedsetbacks,gene therapiesarenowachievingsuccess. Forexample,thefatalbraindisorder adrenoleukodystrophyhasbeen treated,withprogressionstopped,ina sampleofchildren.

Beyondhumanhealthcare,thetechnologies,toolsandbasicbiologicalknowledgeembodiedinthe humangenomesequencingprogramshavefoundapplicationsacrossawiderangeoflifescienceand relateddisciplines.Agricultureandglobalfoodsecurityarebeingsignificantlyenhancedthroughthe

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applicationofgenomicstoplantandlivestockimprovementpositivelyalteringbothorganismalinput traits(suchasnutrientuptake,pestresistance,droughttolerance,etc.)andoutputtraits(suchas nutrientcontent,chemicalcomposition,qualityandquantityoffoodproduced).Genomicsisalsobeing appliedinthetracingoffoodcontaminationandassociatedpathogenicevents. Thebenefitsbeingfeltinhumanhealthcarealsotranslateintoveterinarymedicine.Theconcurrent sequencingofvariousanimalgenomesduringtheHGP,andsubsequentwholeanimalgenome sequencingundertakenaftercompletionofthehumangenome,hasbeenasrevolutionaryfor veterinarymedicineasithasbeenforhumanbiomedicalsciences. EarlyintheHGP,theU.S.DepartmentofEnergybeganapplyinggenomicstoolsandtechnologies resultingfromthehumangenomesequencingprogramtothesequencingofmicrobesforfunctionality inenvironmentalremediationandforinvestigationoftheiruseinotherapplicationssuchas bioprocessingandbiofuelsproduction.TheMicrobialGenomeProjectandtherecentGenomestoLife Projecthavespecificallyappliedgenomicstoarangeofenvironmentalandindustrialapplications. Likewisecommercialenterprisesacrossaseriesofproductcategoriesinbiotechnology,biofuels,food processing,drugandvitaminproduction,andbiobasedmaterialsareapplyingadvancedgenomic knowledgeandtechnologiestobringtomarketnewandmoreefficientindustrialprocessestopower theU.S.andglobaleconomies. Genomicshasalsobecomeatoolforapplicationsinthefieldofjusticeandsecurity.Forhomeland security,theabilitytogenotypesuspiciousinfectiouspathogensandtracetheiroriginisanational securitypriority.Lawenforcementisalsousinggenomicsinidentificationofhumanremainsin instancesofnaturaldisasters(suchastheHaitianandJapaneseearthquakes)orterroristevents(such as9/11sgroundzero),andfortracingillegaltradeinendangeredanimals. Itwouldbeimpossibletoquantifyeachandeveryimpactbeinggeneratedacrossthefieldofgenomics anditsapplicationtosuchabroadrangeofscientificfieldsandtechnologicaldisciplines.Battellehas notattemptedtodothat.RatherBattelleexaminedeachofthekeyfieldsofapplicationshownin FigureES1anddiscusseswithinthefullreportthewaysinwhichgenomicsisbeingappliedwithin thesefields,andprovidescasestudiesofgenomicsinactionwithinthesefields.

IntotheFuture
Theadvancementofknowledgeandthetechnologiesresultingfromhumangenomesequencinghave formedtheplatformfornothinglessthanamedicalrevolution.Theprimaryimpactsofthisrevolution inquantitativeandpersonalizedmedicinemaynotyetbefeltindailyclinicalpractice(althoughin someareasofcanceritis),butthatdayisacceleratingtowardsus. Oneofthekeyrealizationsthatmustbeunderstoodregardingthehumangenomesequencingisthat itsusefulnessisperpetual.Whileothermajorbigscienceprojectshavealifeattachedtothemthe humangenomesequencewillnotwearoutorbecomeobsolete.4Rather,thereferencehuman genomeisakintochemistrysperiodictable,aperpetuallyusefulfundamentalplatformfor understandingandadvancingscience. Theimpactonhumanmedicineandhealthisprofoundandimportantbut,asshown,thebenefitsof performingtheHGPandrelatedprojectsextendintoareasoffarbeyondhumanhealth.Our fundamentalunderstandingofgenomics,thesequencingandgenomictechnologieswhose developmentwasspurredbytheHGP,andtheadvancedomicsdisciplinescreatedthroughthese efforts,willcontinuetomakecontributionsonabroadrangeoffronts.Wecanexpectavarietyof genomicsenabledenhancements,forexample:
Forexample,the$11billionSuperconductingSuperColliderhasanestimatedlifespanof30yearsandthe$1.5 billionHubbleSpaceTelescopehasanestimated1520yearlife.

Thereferencehumangenomeis akintochemistrysperiodictable,a perpetuallyusefulfundamental platformforunderstandingand advancingscience.

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 Agriculturalproductivitytoincreaseconsiderably,workingtowardsthechallengeof feedingtheworldsrapidlyexpandingpopulationinasustainablemanner. Notonlywillfoodavailabilityincrease,buttheimpactofitsproductionontheglobal environmentwillreduceascropsandlivestockaredevelopedwithtraitssuitedto nitrogenuseefficiency,notillagriculture,wateruseefficiencyandreducedwaste production. Currentlylowvaluebiomass,especiallylowvaluecellulosicbiomass,willbeconverted intohighervalueliquidfuels,energysources,biobasedchemicals,plasticsandmaterials. Theseproductswillincreasinglydisplacepetroleumandotherfossilbasedinputs, contributingtoreducedcarbonemissionsandassociatedclimateandenvironmental benefits. Anincreasinglytwowayflowofdiagnostics,therapeuticsandpreventiontoolswillmove betweenhumanmedicine,veterinarymedicineandagricultureasthecostofgenomic technologiesreducesandtheapplicationsofdiscoveriesinoneareacanbeappliedto anotherbecauseofcomparativegenomicsandothergenomicadvancements. Thelegacyofpollutionontheplanetcausedbyhumanactivitywillbeaddressed increasinglythroughtheapplicationofgeneticallyengineered,modifiedorsynthetic organismsdesignedtoperformremediationandmitigationfunctions. Fromaneconomicstandpoint,theimpactofappliedgenomicswillbeequallyprofound.Modern developedsocietiesaredrivenforwardbyinnovationtypicallytechnologicalinnovation.TheHGPand associatedsequencingprojectshaveadvancedthestateofinnovationandtechnologyandresultedin broadeconomicimpactsashighlightedinthereport.Thesepositiveeconomicimpactswillcontinueto rippleoutwardsandexpand.Personalizedmedicineapproachesforthepreventionandoptimized treatmentofdiseasesanddisordersholdspromiseforreducingthefutureburdenofdiseaseand associatedhealthcarecosts. Inthedevelopingworldthepromisecontainedwithinappliedgenomicsisfundamentaltobasic economicprogress.Withoutaffordableandsustainablefoodsupplies,developmentwillbehighly limitedasmalnutritionreducesdevelopingsocietiesproductivityandincomes.Withouthigher productivitycrops,wewillseemoreandmoremarginallandspressedintoproductionand environmentaldegradationwillbecomeincreasinglymorewidespread.Withoutenhancedabilitiesto combatcurrentandemerginginfectiousandendemicdiseases,developingsocietieswillagainbeheld backandprogresslimited.Appliedgenomics,builtuponthefoundationoftheHGPandassociated projects,holdspromisefortheprovisionofsolutionstoeachandeveryoneofthesechallengesand more. InBattellesinterviewwithLeeHoodhecalledtheHGPthesinglemosttransformativeeventinthe historyofbiologicalscience.Itwouldbedifficultnottoconcurwiththatstatement.Inadvancingbasic scientificknowledge;inopeningnewpathwaystoenhancedhumanhealth;inspurringtechnologiesfor economicdevelopment;inprovidingsolutionstowidespreadchallengesinglobalfoodproductionand environmentalsustainability,the$3.8billionspentontheHGPmaywellrepresentthebestsingle investmentevermadeinscience.

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ChapterI:Introduction

A.Background
Thesequencingofthehumangenomeandthemappingofhumangenesrepresentedthelargestsingle undertakinginthehistoryofbiologicalscienceandstandsasapreeminentscientificachievement. AlongwithBachsmusic,Shakespearessonnets,andtheApolloSpaceProgramme, theHumanGenomeProjectisoneofthoseachievementsofthehumanspiritthat makesmeproudtobehuman.
RichardDawkins

TheHumanGenomeProject (HGP)referstotheinternational 13yeareffort,formallybegunin October1990andcompletedin 2003,todiscoverallthe estimated20,00025,000human genesandmakethemaccessible forfurtherbiologicalstudy. Anotherprojectgoalwasto determinethecomplete sequenceofthe3billionDNA subunits(basesinthehuman genome).AspartoftheHGP, parallelstudieswerecarriedout onselectedmodelorganisms suchasthebacteriumE.coliand themousetohelpdevelopthe technologyandinterprethuman genefunction.TheDOEHuman GenomeProgramandtheNIH NationalHumanGenome ResearchInstitute(NHGRI) togethersponsoredtheU.S. HumanGenomeProject. HumanGenomeProject Informationat www.genomics.energy.gov. OakRidgeNationalLaboratory

Itishumblingformeandaweinspiringtorealizethatwehavecaughtthefirstglimpse ofourowninstructionbook,previouslyknownonlytoGod.
FrancisCollins,attheWhiteHouselaunchofthehumangenomedraftsequences.

TheHumanGenomeProject(HGP)wasaninternationalpublicprojectledbytheUnitedStates, coordinatedbytheNationalInstitutesofHealth(NIH)andU.S.DepartmentofEnergy(DOE),and complementedbytheprivateeffortsofCeleraGenomics.Thegoaloftheprojectwastodiscoverthe thousandsofhumangenes,completethesequenceofthebillionsofDNAsubunits,andmakethese resultsaccessibletoallresearchersforfurtherscientificstudy. DNAschemicallanguageoffourrepeatedlettersA,T,GandCelegantlyproducesthecomplete compendiumoflife,staggeringinitsscale,diversityandcomplexity.Fromsinglecellorganismsdrifting inouroceanstosentientselfawarehumanbeings,DNAcodesalllifeonEarth.Mappingthecomplete genomeofahumanwouldprovideanewviewintotheinnerworkingsofthemostcomplexand advancedorganismontheplanet.Somethoughtitsimplycouldnotbedone. Thetaskofdecodingthegenomedictatedanewapproachtobiologicalsciencealargescale,big scienceteamapproach.Requiring$3.8billionintotalpublicfunding,theHGPsoughtto: Identifyalltheapproximately20,00025,000genesinhumanDNA, Determinethesequencesofthe3billionchemicalbasepairsthatmakeuphumanDNA, Storethisinformationindatabases, Improvetoolsfordataanalysis, Transferrelatedtechnologiestotheprivatesector,and Addresstheethical,legal,andsocialissuesthatmayarisefromtheproject.5 Itachievedallofthesegoals,withonlythelastonebeingstillinprogress.Italsowentfurther, generatingsequencesofotherscientificallyvaluableorganisms(theE.colibacterium,thefruitflyand thelaboratorymouse)toenablecomparativegenomicsstudiestobeperformedwhichwouldfacilitate theidentificationofgenefunction.Likewise,Celerametitsgoalstovalidateanewapproachto sequencing(shotgunsequencing),provethetechniqueviathesequencingofmodelorganism genomes,andconcurrentlyproduceadrafthumansequenceofitsownalongsidethepublic sequencingeffort.

Itsonesmallpieceofman...

onegiantleapformankind.
TheMirror UKnewspaperheadlineupon announcementofthedraft sequence.

U.S.DepartmentofEnergyHumanGenomeProjectInformation.AbouttheHumanGenomeProject.Accessed onlineathttp://www.ornl.gov/sci/techresources/Human_Genome/project/about.shtml

Page1of58

Figure1:TimelineofGenomeSequencing

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
2001 2002 2003 2004

LaunchoftheHumanGenomeProject

NotonlydidtheHGPandCeleraprogramsachievetheirgoals,they generatedandheraldedunforeseenbreakthroughsinscientific knowledgeandtechnologicaldevelopment.Considerjustthe following,forexample: Whilefindingthatthehumangenomecomprisesfewer genesthanhadpreviouslybeenestimated(circa21,000 distinctproteincodinggenes6versussomepreviousestimates ofmorethan100,000),theprojectenabledscientiststofind unforeseencomplexityinthegenomewithindividualgenes interactingwithoneanotherandreadingintomultipleRNAs toproducemoreproteinproductsthanpreviouslyimagined.7 Ratherthantheexpectedonegeneoneprotein relationship,itwasfoundthatindividualgenesareableto encodemultipleproteins. NoncodingDNA,previouslytermedjunkDNAbecauseit wasthoughttobearelicofevolutionwithlittlebiological function,wasinsteadconfirmedtohavespecificfunctionality intranscriptionandtranslationalregulationofprotein codingi.e.,mostofitisnotjunkatall,itiscentraltolife functions.Thisfindingalonesupportsthevisionof undertakingwholegenomesequencing,sincepriortothe HGPsomedetractorsarguedthatthebudgetwouldbebetter spentsimplystudyingknownproteincodinggenesand ignoringtherest.EricLanderpointsoutthatithasreshaped ourviewofgenomephysiology,includingtheroleofproteins codinggenes,noncodingRNAsandregulatorysequences.8 LeroyHood,apioneerinsequencingtechnology,notesthat humangenomesequencingbroughttobiologyanew paradigmofdiscoverydrivenscience,steppingoutsidethe boundsoftraditionalhypothesisdrivenscienceandenabling anewview.9 TheHGPstechnologydevelopmentprogram,andthework ofCelera,plantedtheseedsfor,andaccomplished, advancementsingenomeandgenesequencingtechnology,to theextentthataccelerationofsequencingspeedsin successivegenerationsofequipmenthasexceededeven computerprocessingsMooresLaw. Scientistsingovernmentlaboratories,academeandindustrywillbe usingthereferencegenome,theknowledgeofgenomestructure,and thepublicallypublishedgenomedataresultingfromtheHGP(aswellas Celerasdata)asthefoundationforfundamentaladvancementsin scienceandthedevelopmentofappliedgenomicsandgeneticstools, techniquesandtechnologies.

HGPproducesdetailedhumangeneticmap DOEMicrobialGenomeProjectbegins Physicalmapofthehumangenomecompleted Mousegeneticmapcompleted YeastandArchaea genomessequenced E.coligenomesequenced M.tuberculosisandC.elegans genomessequenced Celeraannouncesplansforshotgunsequencingthegenome SNPInitiativebegins Fullscalehumangenomesequencing Workingdraftofthehumangenomesequence DrosophilaandArabidopsisgenomessequenced Firstdraftsofhumangenomesequencereleased MouseandRicegenomessequenced InternationalHapMap Projectannounced DOEGenomestoLifeprojectlaunched HumanGenomeProjectcompleted ENCODEProgrambegins RatandChickengenomessequenced FDAapprovesfirstmicroarrayforclinicaluse Chimpanzee,DogandTrypanosomatidgenomessequenced CancerGenomeAtlasProjectsequenced Rhesusmacaquemonkeygenomesequenced NIHGenesandtheEnvironmentInitiativelaunched

2005
2006

Source:NationalHumanGenomeResearchInstitute

Clamp,M.etal.2007.Distinguishingproteincodingandnoncodinggenesinthehumangenome.Proceedingsof theNationalAcademyofSciencesUSA.104.2007. StewartScherer.2008.AShortGuidetotheHumanGenome.Sectiononhowmanyproteincodinggenesare presentinthegenome.ColdSpringHarborLaboratoryPress,NewYork. EricS.Lander.2011.Initialimpactofthesequencingofthehumangenome.Nature.Volume470,February10,2011. LeroyHood.2002.AftertheGenome:WhereShouldWeGo?ChapterinMichaelYudellandRobDeSalle (editors)TheGenomicRevolution:UnveilingtheUnityofLife.2002.JosephHenryPress,WashingtonDCwith theAmericanMuseumofNaturalHistory.

8 9

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Itisalsoveryimportanttonotethat,whilefoundationaltotheunderstandingofhumanbiological systems,theknowledgeandadvancementsembodiedinthehumangenomesequencingandthe sequencingofmodelorganismsarenotonlyapplicabletohumanbiomedicalsciences.Thescientific andtechnologicalimpactextendsfarbeyondthis,andtheresultinggenomicrevolutionisinfluencing agriculturalbiosciences,veterinarysciences,environmentalscience,forensicscience,renewable energydevelopment,industrialbiotechnologyandadvancedstudiesinevolution,zoology, anthropologyandotheracademicdisciplines. Asafoundationforknowledgeexpansion,scientificadvancement,andtechnologicaldevelopmentfew wouldarguethatthesequencingofthehumangenomerepresentsapinnacleofscienceanda milestoneinhumanhistory.Thestatementsofearlyproponentsofwholehumangenomesequencing aboutthelikelygrowthofagenomicsindustryarenowholdinguptoscrutiny.Notedventurecapitalist G.StevenBurrillstatesthatthegenomicsrevolutionisherenow.10Thereshouldbelittledoubtthat thepostgenomiceraishere,thatsignificantimpactsarebeingrealizedinthepresent,and tremendousimpactswillberealizedinthefuture.

Usingthelatestmachinesfrom genomicscompanies,anentire humangenomecannowbe sequencedinunderadayforless than$3,000. Theefficiencygainsingene mappingareleadingtonewuses forthetechnology.Agricultural companiesusegenomicstohelp designgeneticallymodified plantsthataresturdierormore resistanttoparasites.Cleantech entrepreneursaresplicinggenes insearchofgreenerfuels.And theU.S.FoodandDrug Administrationisorderinga $695,000sequencetocompare E.coliandotherbacteriafrom acrossthecountry.Themachine willhelpagencyscientists determinethesource ofoutbreaks RobWaters

B.PurposeofThisReport
Thisreportaimstofillagapintheliteratureregardinghumangenomesequencinganditsoutcomes anassessmentoftheeconomicimpactofsequencing.Beyondtheachievementofknowledge embodiedintheHGPandCeleraprojects,theseprogramsrequiredthedevelopmentofadvanced equipment,technologies,dataanalysistools,specializedanalysistechniquesandknowhowthathas facilitatedthegrowthofanexpandinggenomicsindustry.Todaythisindustryisempoweringfurther scientificdiscovery,progressandcommercialinnovationonabroadrangeoffronts.Fromhuman healthcaretoveterinarymedicine,fromindustrialbiotechnologytohighproductivityagriculture,the knowledge,toolsandtechnologiessupportedthroughthesequencingofthehumangenomeforma foundationofadvancedeconomicandsocialprogressfortheUnitedStatesandhumankind. Itshouldbenotedthateconomicimpactisjustonemeasureofthesuccessofaprogram.Itmaynot necessarilybethebestmeasure,andrarelyshoulditbethesolemeasureofapublicallysupported programaimingatmeetingpublicinterests.TheHGPinparticularwasnotundertakenwiththe primarygoalofgeneratingeconomicimpacts,althoughoneoftheprogramsstatedgoals,namely transferrelatedtechnologiestotheprivatesectorcertainlydoesimplyacommercialbenefitinterms ofbusinessactivity.Thereisalwaysariskinundertakinganeconomicimpactstudythat,indoingso,a projectmayonlybejudgedonitseconomicmerits. Assuch,Battellehaschosenhereinnotsolelytoaddresseconomicimpactsinthisreport.11Rather,this reporttakesamoreholisticviewofhumangenomesequencingimpactsaddressingtheHGPs expenditureimpacts(orbackwardlinkageeffects)certainly,butalsoexaminingindetailtheHGPs functionalimpacts(orforwardlinkageeffects)andimplicationsoftheseimpactsacrossabroadrange offieldsasillustratedinFigure2.

10

RobWaters.2011.BoomTimesforGenomicStartups:Investmentispickingupassalesofgenesequencing machinessurge.BusinessWeek.March17,2011.Accessedonlineat http://www.businessweek.com/magazine/content/11_13/b4221058333104.htm Typically,wheninstitutionsorregionsreleaseaneconomicimpactreport,backwardlinkageorexpenditure impactsarethemostfrequentlyquantifiedeconomicimpacts.

11

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Figure2:TheStructureofForwardandBackwardLinkageImpactsAssociatedwiththeHumanGenome Sequencing

AdditionalMultiplierEffect(U.S.SpendingRecirculation) IndirectandInducedEconomicImpacts

GeneticsandGenomicsTools, Technologies,TechniquesandServices Labor U.S. Spending by HGP ExpandingBasicScientificKnowledge

Expenditure Impacts
(BackwardLinkage Effects)

HumanHealthandMedicine

Supplies

Technology

Followon U.S. Research Spending

Human Genome Sequencing

VeterinaryMedicine

Functional Impacts
Genomics Enabled Industry Spending
(ForwardLinkage Effects)

AgricultureandFood

Building etc.

IndustrialBiotechnology

EnvironmentalApplications

Total HGPEnabled EconomicImpact

Forensics,JusticeandSecurity

Thus,thisreportprovidesmultipleanalysesandinformationresourcestospurconsiderationand discussion.Itprovides: AquantitativemeasurementofthedirectandindirecteconomicimpactsintheUnited Statesderivedfroma)actualexpendituresofthespecificHGPprojectanditsconsortium institution,b)additionalfollowonfederalinvestmentsingenomicsrelatedandenabled research,sand AquantitativeestimateoftheeconomicimpactoftheU.S.genomicsindustry,with acknowledgementthatthosewithintheindustrycredittheHGPandCeleraprogramsas beingintegralcomponentsinthedevelopmentoftheindustry. Specificexamplesandcasestudiesofgenomicsinactionthefunctionalapplication ofgenomicstools,technologiesandknowledgeinarangeofeconomicallyrelevantfields suchashealthcare,veterinarymedicine,agriculture,theenvironment,industrial biotechnology,andsecurityandjustice. Alookintothepotentialforfutureimpactsalongthevariousgenomicpathways.Thefirsthuman genomesequenceswereanimportantstepinthedevelopmentofthesepathways,pavingtheway formuchofwhatisexpectedinthepostgenomicfuture.

Acknowledgements
BattellethanksLifeTechnologiesFoundationforthevisionshownininitiatingthisprojectandfor fundingtheperformanceoftheimpactstudy.JanetLambertandHeatherVirdooftheLifeTechnologies Foundation,inparticular,contributedtotheprojectsscopeanddirection.Battellethanksthemany individualswhotooktimetoparticipateininterviewsandwhorespondedtoinformationrequests duringperformanceofthisproject.Battellealsothanksallofthoseindividualswhomadeupthe HumanGenomeProjectteamandtheprojectteamatCeleraGenomicswithouttheireffortsonbehalf ofscienceandmankind,theimpactsdescribedinthisreportwouldbegreatlylessened.

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ChapterII:EconomicImpactsoftheHumanGenomeProject

Determingthefullcurrenteconomicimpactofaprogramascomplexandgamechangingasthe sequencingofthehumangenomerequiresanalysisofatimeseriesofinvestmentsandorganizational informationextendingbacktotheformalinitiationoftheHumanGenomeProjectin1990andeven slightlybefore. Table1showstheannualfederalfundingfortheHGP.12Thecombinedannualfederalinvestmentin theHGPreached$3.8billionincurrentdollars,andwhenadjustedforinflationtotalsmorethan$5.6 billioninconstant2010dollars.

Table1:U.S.HumanGenomeProjectFederalFunding(inMillions$) U.S.Federal Total (Current$) U.S.Federal Total (Constant 2010$)

FiscalYear

DOE NIH (Current$) (Current$)

1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Totals

10.7 18.5 27.2 47.4 59.4 63.0 63.3 68.7 73.9 77.9 85.5 89.9 88.9 86.4 90.1 64.2 1,015.0

17.2 28.2 59.5 87.4 104.8 106.1 127.0 153.8 169.3 188.9 218.3 225.7 271.7 308.4 346.7 372.8 2,785.8

27.9 46.7 86.7 134.8 164.2 169.1 190.3 222.5 243.2 266.8 303.8 315.6 360.6 394.8 434.3 437.0 3,798.3

54.0 88.2 160.0 243.1 289.5 291.6 321.2 367.6 390.5 425.5 448.5 453.6 490.1 523.3 548.4 552.9 5,647.9

12

Seehttp://www.ornl.gov/sci/techresources/Human_Genome/project/whydoe.shtml#invest

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A.MethodologyandAssumptions
AsillustratedinFigure2,theexpenditureimpacts(orbackwardlinkageeffects)stemmingfromthe HGParethoseimpactsgeneratedintheeconomyfromthedirectinvestmentsintheHGP,the investmentsinfollowonHGPenabledresearch,andthroughthegenomicsenabledindustrythathas beendevelopedandfosteredthroughthescienceandtechnologicalrequirementsoftheHGP. TheeconomicimpactanalysisreportedhereinusesanI/Omodeltorepresenttheinterrelationships amongeconomicsectors.I/Odatashowtheflowofcommoditiestoindustriesfromproducersand institutionalconsumersforanygivenregion(inthiscasetheUnitedStatesasawhole).Thedataalso modelconsumptionactivitiesbyworkers,ownersofcapital,andimportsfromoutsidetheregion. Thesetradeflowsbuiltintothemodelpermitestimatingtheimpactsofonesectoronothersectors. Theimpactsconsistofthreeimpacttypes:direct(thespecificexpendituresimpactoftheprogram and/orsector(s)inquestion,indirect(theimpactonsupplierstothefocusindustryorprogram),and induced(theadditionaleconomicimpactofthespendingofthesesuppliersandemployeesinthe overalleconomy). TheestimatedimpactsofsequencingthehumangenomewerecalculatedusingaU.S.specificI/O model,theIMPLANsystem,fromMIG,Inc.13IMPLANprovidesasoftwaresystemandgeographic specificdataregardingeconomicsectorinteractionsforcalculatingeconomicimpacts.Themodel incorporatesdetailofmorethan420individualindustrysectorsthatcovertheentirenational economy.Withthiscoverageof420sectors,Battelleisabletomodelthecrosssectoreconomic activitythatoccurredthroughouttheeconomyasaresultofthehumangenomesequencingwork. Additionally,theIMPLANmodelhasbuiltineconomicinflatorsanddeflatorstoallowforthe developmentofacumulativemultiyearimpactestimationforthe23yearsincludedintheanalysis. Sixkeyeconomicsectorswereusedinthedevelopmentoftheoverallimpactanalysisasshownin Table2.TheuniquenatureoffederalR&Dinvestment,andtheassociatedeconomictransactionsand impactsflowingfromtheseinvestments,causedBattelletoselectasingleindustrycomponent ScientificR&Dservicesasthemostrepresentativeoftheseeconomicimpacts.14
Table2:SectorsUsedinOverallGenomicsImpactAssessment

Theexpenditureimpacts(or backwardlinkageeffects) stemmingfromtheHGPare thoseimpactsgeneratedinthe economyfromthedirect investmentsintheHGP,the investmentsinfollowonHGP enabledresearch,andthrough thegenomicsenabledindustry thathasbeendevelopedand fosteredthroughthescienceand technologicalrequirementsof theHGP. Theseeconomicimpactsare estimatedinthischapter.

GenomicsSectors GenomicsRelatedBioinformatics Genomic&RelatedTesting GenomicRelatedBiologics&DiagnosticSubstances GenomicInstruments&Equipment GenomicsR&D/GenomicsBiotech Drugs&Pharmaceuticals

IMPLANModelingSector(Sector#s) Customcomputerprogrammingservices(371) Medicalanddiagnosticlabs(396) Biologics&diagnostics(133&134) Analyticallaboratoryinstrumentmfg(254) ScientificR&Dservices(376) Drugs&pharmaceuticals(131&132)

Twometricsareusedtodrivetheeconomicinteractionswithinthemodels:R&Dfundingand investment(treatedasoutputfromtheperformingsectors)andemployment.Thepresentationof outputvaluesaspartofanimpactassessmentarecommonlyreferredtoastheeconomicimpactof anindustryoractivity.

13

IMPLANisoneofthemostwidelyusedmodelsinregionaleconomicsandcanbeusedtoanalyzetheeconomic impactsofcompanies,projects,orentireindustries.

14

TheuseofthissectorwasdeterminedinconsultationwithDougOlson,FounderandPrincipalofMIG,Inc.andis typicallyusedasmostrepresentativeoftheexpenditureoffederalresearchfundsbyresearchorganizations (whetherprivatesectorR&Dfirms,universityresearchlabsorfederalintramuralresearchfunds).

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HistoricalR&DfundingdataincludesfederalHGPinvestments(Table1)andadditionalexternaland intramuralfederalinvestmentsingenomicsareasafterthe2003endoftheHGPbytheNIHandDOE.15 Toconservativelyestimateadditionalgenomicsresearchinvestmentsbythemajorpharmaceutical manufacturers,anincreasingshareofthesectorsR&Dfundswasusedoverthe20042010period.16 Thiswasdeterminedtobethemostappropriateapproximationofthepharmaceuticalindustrys genomicsinvolvement.Whilesalesofgenomicsbaseddrugs(ortheirrelateddiagnostics)were considered,thiswouldleaveoutsignificantpasteffortsandpipelineinvestmentsthathaveyettoyield sales. HistoricalemploymentdataweredevelopedusingtheuniquepropertiesoftheNationalEstablishment TimeSeries(NETS)databasedevelopedbyWalls&Associates(builtuponannualrecordsfromDun& Bradstreet).Usingavarietyofcurrentandhistoricalsourcesandlistingsofgenomicsfirms,adatabase offirms(wheregenomicsspecificactivities,products,andservicesaretheprincipalactivityofthefirm) wascompiled.UsingtheNETSdatabasealongitudinalsetofemploymentmetrics(19932010)were developedforeachofthefivegenomicssectorslistedinTable2.Theimpactofgenomicsonthe drugsandpharmaceuticalssectorisestimatedusingonlytheR&Dperformanceasdescribedinthe previousparagraphandnotusingemployment.TheNETSdatabaseallowedBattelletocapturethe recentandhistoricemploymentofgenomicsfirms,includingthosefirmsthatwereacquiredorthat havegoneoutofbusinessoverthelasttwodecades.AnotherkeycomponentoftheNETSdatabasefor thispurposeistheestablishmentlevelinformationallowingfortheinclusionofgenomicspecific operationsoflargermultiestablishmentfirmstobeincludedwithouthavingtoincludethefirmstotal employment.ThisfeaturewasparticularlyimportantintheGenomic&RelatedTestingsector. IntheanalysisthatfollowsBattellepresentsthedirecteffectvaluesdrivingthemodel;additional estimatedindirect,andinducedimpacts;andasummationofthetotalimpacts(direct,indirect,and induced).Thefollowingdataareprovidedforeachimpactestimation:employment,personalincome (includingbothwagesandbenefits),economicoutput,stateandlocaltaxrevenue(includingincome andpropertytaxes),andfederaltaxrevenue(includingcontributionstoSocialSecurity).Animpact multiplierisalsoprovidedforeachtypeofdataforeveryone(jobordollar)ofdirecteffect,the multipliernumberwillequalthetotal(includingthedirecteffect)numberofjobsordollarscreatedin theU.S.economy.

Note:Unlessspecified,alldollarvaluesinthefollowinganalysesandtablesareinmillionsof2010 dollarsforcomparabilityovertime.

B.ImpactsoftheDirectNIH/DOEFundingoftheHGP
ThissectionexaminestheimpactsgeneratedbytheentirefederalHGPfundingperiod,including1988 and1989whichareoutsideoftheformaldefinitionoftheHGP,butneverthelessincludedinfederal fundingfigures.

15

ForNIHthesedatawereestimatedusingkeywordsearchesofextramuralandintramuralawardsintheNIH RePORTdatabase.ForDOEthesedatawereestimatedusingannualDOEbudgetdocumentsforselectgenomics relatedoperations.

16

OverallpharmaceuticalindustryR&DwasestimatedbyBattelleforthepostHGPyears(20042010)usingthe NationalScienceFoundationsindustryR&Ddataasavailablesupplementedbyothersources.Toestablisha genomicssharewesetaconservative3percentsharein2004baseduponanecdotalresearchdescribedinthe WorldSurveyofGenomics(2000)reportfromtheStanfordinWashingtonprogram.Theactualsharein2004 waslikelyhigher.Wesetthecurrentshare(2010)ataconservative20percentbaseduponrecentworkbythe TuftsCenterfortheStudyofDrugDevelopmentthatestimatesthatpersonalizedmedicineaccountsfor between12percentand50percentofpharmaceuticalcompaniesR&Dpipelines.Weusedalinearincreasein sharefrom3percentto20percentoverthesevenyearperiodtoestimatethegrowthinimportanceandimpact ofgenomicsonpharmaceuticalR&D.

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ToprovidecontexttotheoverallassessmentoftheeconomicimpactoftheHGPfederalinvestment, wefirstexaminethefinalyearofthecombinedNIHandDOEinvestment(2003)whichreached$437.0 million(or$552.9millionin2010$).Table3providestheimpactanalysisforthis2003federal funding.17

Table3:EconomicImpactofHumanGenomeProjectFinalYearFederalFunding,2003(inMillions,2010$) Employment (Jobs) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

5,025 2,432 4,965 12,422 2.47

310.3 128.0 227.4 665.7 2.15

552.9 370.5 724.6 1,648.1 2.98

8.9 15.1 41.4 65.4 7.36

51.0 25.6 48.8 125.5 2.11

AsquantifiedbytheIMPLANmodel,thissingleyearofinvestment(2003)wasdirectlyresponsiblefor 5,025jobs,$310.3millioninpersonalincome,and$59.9millionofstate/localandfederaltaxrevenue. Throughtheprojectspendingoftheseprimarilyacademicandfederalresearchers,additionalindirect impactsweregeneratedintheU.S.economy.Theseimpactsincludeadditionalemploymentgenerated ofmorethan2,400,personalincometoemployedpersonsof$128million,andanadditional$370.5 millionineconomicoutput.Finally,thepersonalspendingoftheresearchersandsuppliersemployees generatedinducedimpactsof4,965jobs,$227millioninpersonalincome,andoutputofnearly$725 million.Combinedthedirect,indirect,andinducedimpactsprovideatotalU.S.impactofmorethan 12,400jobs,nearly$666millioninpersonalincome,andmorethan$1.6billionineconomicoutput.In turnthiscombinedeconomicactivitygeneratedmorethan$65millioninstate/localtaxesandmore than$125millioninfederaltaxrevenue. Thissingleyearanalysisisusefulfordescribingoneaspectofthelongitudinalanalysispresented below.WithinthecontextoftheIMPLANmodel,theemploymentinformationgeneratedconsistsof thenumberofjobsgeneratedandexistinginthespecificyear.Whendevelopingacumulativeanalysis, thesummationofanumberofyearsoffinancialmeasuresleadstoalargervaluethathasmeaningin itsmagnitudesinceeachdollarisunique.Whensimilarlyaddingtogetheranumberofyearsof employment,thevaluemustbeinterpretedasjobyears.Forexample,anindividualmaybeemployed inYear1oftheanalysisandhavethesamejobinYear2.Whileeveryonewouldconsiderthisonejob, fromanimpactanalysisperspectiveitconstitutestwojobyears. ThefederalHGPfundingyieldssignificantU.S.directeconomicimpactsbeyondthedirectHGP investmentof$5.6billion(Table4).ThefederalHGPinvestmentdirectlygeneratedatotalof43,536 jobyearswhichaveragesouttomorethan2,700directjobsperyearofHGPfederalfunding.The directimpactsalsoreachednearly$3.2billioninpersonalincome.Finally,theHGPfundinggenerated morethan$610millionindirecteffectstate/localandfederaltaxrevenues.
17

Note:columnswithintheeconomicimpactresultstablesinthischaptermaynotsumduetorounding.

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Table4:CumulativeEconomicImpactofHGPFederalFunding,19882003(inMillions,2010$) Employment (JobYears) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

43,536 24,842 50,660 119,037 2.73

3,164.2 1,307.7 2,319.7 6,791.6 2.15

5,647.9 3,785.1 7,393.1 16,826.1 2.98

90.6 154.3 422.3 667.2 7.36

520.3 261.4 498.3 1,280.1 2.46

Theseimpactsmovethroughouttheeconomythemultipliereffect(orrippleeffect)andgenerate additionalindirectandinducedeconomicimpacts.Intotal,morethan119,000jobyearswerecreated bytheHGPinvestment,leadingtonearly$6.8billioninpersonalincometotheseworkers.Overall outputexceeded$16.8billionleadingtoanimpactmultiplierof2.98every$1dollaroffederalHGP investmentledtoanadditional$1.98ofU.S.economicoutput.

C.ImpactsoffollowonNIHandDOEinvestments
BeyondtheoriginalHGPinvestments,bothNIHandDOEmadeandcontinuetomakesignificant investmentsinthescience,instrumentation,andrelatedapplicationsstemmingfromthehuman genomework.Theseinvestmentstaketheformofbothintramuralfundingandextramuralgrant awards.Infact,inbothcurrentandconstant2010dollarsthefederalinvestmentinhumangenomics relatedorenhancedresearchoverthelastsevenyears(20042010)hasexceededthe16yearfederal investmentintheHGPby28percent(Table5).
Table5:EstimatesofU.S.PostHumanGenomeProjectFederalFunding(inMillions$) U.S.Federal Total (Current$) U.S.Federal Total (Constant 2010$)

FiscalYear

DOE

NIH

(Current$) (Current$)

2004 2005 2006 2007 2008 2009 2010 Totals

137.9 145.8 157.5 217.2 228.7 234.9 234.6 1,356.5

610.4 628.0 629.5 681.7 685.7 1,038.6 991.6 5,265.6

748.3 773.8 787.1 898.9 914.4 1,273.5 1,226.2 6,622.1

912.9 899.9 897.1 984.1 977.3 1,316.6 1,226.2 7,214.0

Thecumulativetotalfederalinvestmentinhumangenomeandrelatedsciencereachedmorethan $7.2billionfrom20042010.Thislevelofinvestmentledtothedirectcreationofmorethan76,000 jobyearsandaresultingtotalpersonalincomeofmorethan$4.0billion(Table6).

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Table6:CumulativeEconomicImpactofFederal(PostHGP)GenomicFunding,20042010(inMillions,2010$) Employment (JobYears) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

76,146 31,730 64,787 172,663 2.27

4,048.6 1,670.3 2,966.5

7,214.0 4,834.6 9,454.7

115.9 197.1 540.0 853.1 7.36

665.8 333.9 637.3 1,637.0 2.46

8,685.5 21,503.3 2.15 2.98

OverallthispostHGPfederalinvestmentisresponsibleforthecreationofnearly173,000jobyears, andtotalpersonalincometotalingnearly$8.7billionandtotaloutputexceeding$21.5billion.

D.StructureoftheEnabledIndustry
Thedecodingofthehumangenomewasasmuchatriumphoftechnologyasitwasatriumphof scientificwill.Thetechnologiesempoweringgenomesequencingarebroad,rangingfromthegene sequencersthemselves,tosamplepreparationtechnologies,sampleamplificationtechnologies,anda hostofanalyticaltoolsandtechnologies.Anindustryhasgrownuptosupplythescientificresearch communityinindustry,governmentandacademiawiththeequipment,suppliesandservicesrequired toconductgenomicsR&Dandassociatedproductdevelopment.Thisindustry,ofcourse,generates economicimpact. TheBiotechnologyIndustryOrganization(BIO)notesthat: Research,innovation,creativityandthehightechnologiesthatresultfromtheseinventive activitiesarethemostvaluableassetsintheU.S.economy.Thesehightechnologieshavea longhistoryofdeliveringfortheU.S.economy:between1990and2003U.S.hightechnology generateda$243billiontradesurplusinhightechgoodscomparedtoa$3.4trilliondeficit inallotherU.S.goodscombined.Thedevelopment,commercializationanddeploymentof advancedtechnologydriveeconomicgrowthandopportunity.18 Withinthegenomicsfield,thereislittledoubtamongindustryandscientificleadersthattheHuman GenomeProject,andtheCelerasequencingproject,representedcriticallyimportantstimuliforthe genomicsindustrysdevelopment.Ininterviewingkeyleadersinthefieldforthisproject,theBattelle researchteamwastoldoverandoveragainthattheHGP,inparticular,empoweredtheindustrys development.BattelleaskedthequestionWithouttheHGPwheredoyouthinkwemightbetodayin termsofsequencingtechnologiesandassociatedgenomicstechnologies?sometypicalresponses included: Wewouldnotevenbeclosetowherewearetoday.Wouldjustbedoingbitsandpieces. Wouldnothaveadvancedpracticallyatall.Therehasreallybeenadramaticinfluencehere Theindustrywouldnotexist.TheHGPsetupthecompetitivespacethatenabledsequencing andgenomicscompaniestogrow. LeahEisenstadtwritesthat:
18

BIO.2010.Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife.2010.TheBiotechnology IndustryOrganization.Accessedonlineathttp://www.valueofbiotech.com/

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Onceuponatime,sequencingthehumangenometooktensofmillionsofdollarsanda warehousefullofDNAsequencingmachinesthatanalyzedsamplesthroughouttheday,and yearafteryear.Now,lessthanadecadelater,thesamehumangenomesequencetheorder ofnucleotidesorlettercanbegeneratedusingasinglemachinethatanalyzessamplesfor afewdays,andforabout100foldlowercost.TheabilitytosequenceDNAfasterandmore cheaplycomesfromrecenttechnologicaladvancementsrepresentingthemostsignificant technologicalmetamorphosisinthehistoryofmoderngenetics.19 Theprogressmadeinsequencingspeedadvancementhasevenoutpacedthatexperiencedin computerprocessorsunderMooresLaw(seeFigure3).WritinginNature,EricLandernotesthat: TheperbasecostofDNAsequencinghasplummetedby~100,000foldoverthepastdecade, faroutpacingMooreslawoftechnologicaladvanceinthesemiconductorindustry.The currentgenerationofmachinescanread~250billionbasesinaweek,comparedto~25,000 in1990and~5millionin2000.20
Figure3:DramaticCostReductionandSpeedIncreasesinSequencingTechnology
$10.00

Costperfinishedbasepair

$1.00

$0.10

$0.01 1990 1995 Year 2000 2005

100,000

BasepairsinGenBank (millions)

10,000

1,000

100

10 1990 1995 Year 2000 2005

GraphicsadaptedfromFrancisS.Collins,MichaelMorganandAristidesPatrinos.2003.TheHumanGenome Project:LessonsfromlargeScaleBiology.Science.Volume300,11April2003.

19 20

LeahEisenstadt.2010.BeyondtheGenome:NewUsesforDNASequencers. EricS.Lander.2011.Initialimpactofthesequencingofthehumangenome.Nature.Volume470, February10,2011.

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Itisparticularlynoteworthythatthereferencegenomehasbecomeextremelyimportanttothe analysisofresultsfromthelatestgenerationofsequencingmachines.Whileextremelyfast,modern genesequencingtechnologiesproducereadsthatareconsiderablyshorterthanthe700basesorso thattheelectrophoreticmethodsusedintheHGP.Ithasbeennotedthatbecauseitischallengingto assembleagenomesequencedenovofromsuchshortreads,mostapplicationshavefocusedon placingreadsintothescaffoldoftheexistinggenomesequencetocounttheirdensityorlookfor differencesfromareferencesequence.21 Inadditiontotheproductionofequipment,tools,suppliesandtechnologiesforthepracticeof genomicanalysis,thereisalsosignificanteconomicactivityintheapplicationofthesetoolstoarange offunctionalneedsinhumanandveterinarymedicine,agricultureandfoodproduction,industrial biotechnologyandbiofuelsdevelopment,environmentalandjusticeapplications.Theprogramsto sequencethehumangenomethusrepresentafoundationuponwhichadiverserangeofeconomic activityhasbeenbuilt. Inconsiderationofthisburgeoninggenomicsenabledindustry,anassessmentofthefullimpactsof theHGPwouldberemiss,andinfactseverelylimited,withoutincludinganestimationofthisindustry anditsresultingeconomicimpacts. UsingthemethodologydescribedinsectionA,Battellecalculatedtheannualemploymentofthefive genomicsspecificindustrysectorsforuseasinputstobothanindustryspecificimpactassessment (SectionD)aswellasforinclusionintheoverallanalysis.Theinclusionofthisemploymentcomes, however,withseveralassumptions.First,industryemploymentandrelatedimpactsarecalculated startingin1993.Thisyearwaschosenforitssignificanceasthebeginningoftheindustrysrecognition ofhumangenomicsasadistinctopportunityasrepresentedbytheprivatesectorengagementin sequencingactivities(e.g.,CeleraGenomics,HumanGenomeSciences,Incyte,Millennium,andother privatesectorinvestments).Second,thecasecouldbemadetobeginincludingindustryimpactsonly afterthecompletionwasannounced,butthatwoulddisrespecttheprivatesectortechnological advancementsthatoccurredduringtheHGPprojectthathaveledtocontinuedcorporatesuccesses andimpact.Third,whileanumberofthesefirmsexistedpriortothecompletionandinsomecases priortothestartoftheHGPefforts,Battelleimpactanalystsworkedtoincludeonlyfirmswhose continuedexistence,products,andinnovationswereandarecurrentlyinfluencedbythescientificpath thecompletesequencingofthehumangenomehasenabled.Finally,asdiscussedearlier,theimpactof humangenomicsiseasilyrecognizedbutmoredifficulttoquantifywithinthepharmaceuticalindustry. Forthisreason,insteadofworkingtolocatespecificgenomicsrelatedlocationsand/ortodetermine genomicsemploymentfiguresforthedrugandpharmaceuticalmanufacturers,wedevelopedan estimationofR&Dactivitiestodrivetheimpactsfromthissector.Table7providestheemployment estimatesforthefivegenomicssectorsusedintheimpactanalysismodelforfourkeyyears.
Table7:EmploymentEstimatesofGenomicsSectors(KeyYears) GenomicsSectors 2010 2003 2000 1993

GenomicsR&D/GenomicsBiotech GenomicInstruments&Equipment GenomicRelatedBiologics&DiagnosticSubstances Genomic&RelatedTesting GenomicsRelatedBioinformatics TotalEmployment

13,323 11,704 7,234 5,142 797 37,200

13,140 15,724 9,427 1,644 1,430 41,365

8,275 10,957 7,145 1,301 667 28,345

2,378 9,917 2,243 542 174 15,254

21

Ibid

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TheNETSdatarecordsilluminateuniquetrendsandchangesapparentinthegenomicssectors.A declineinbioinformaticsemploymentbetween2003and2010occursduetobothdeclinesinthe overallinformationtechnologyindustry,butalsothroughtheincorporationofearlybioinformatics companiesintolargerentities.Similarly,adeclineingenomicinstrumentsandequipmentappearsto beduetothecontinuedmergerandacquisitionactivityinthissector.Alsoapparentisthegrowthin genomicsandrelatedtestingthathasoccurredsincethecompletionoftheHGP.Finally,itislikelythat therecentrecessionhasalsocontinuedtodampenemploymentlevelsacrosstheboardin2010.Sector employmentpeakedin2004at42,288. Forthepharmaceuticalindustry,Table8projectstheestimatedgenomicsrelatedR&Daswellastotal pharmaceuticalR&Dforthreekeyyears.GiventhemagnitudeofpharmaceuticalR&DtheBattelle teamapproachedtheuseofthesedatawithconservatismbothintermsoftheshareofgenomicsR&D andtheyearinwhichtheseshareswerefirstimplementedinthemodel(2000).22
Table8:PharmaceuticalR&DEstimates(KeyYears,inMillionsCurrent$) PharmaceuticalSectorR&D 2010 2003 2000

GenomicsRelatedPharmaceuticalR&D TotalPharmaceuticalR&D

9,109 45,547

2,337 28,853

743 24,754

Together,thesegenomicssectorscombinedwiththegenomicsrelatedshareofthepharmaceutical industryarereferredtohereinasthegenomicsenabledindustry.

E.ResultsoftheInput/OutputAnalysisoftheCombinedImpactofthe GenomicsenabledIndustryBase
BaseduponthegenomicsectoremploymentestimatesandthegenomicsrelatedpharmaceuticalR&D, anindustryspecificimpactmodelwasdevelopedseparatefromthefederalinvestments.Table9 detailstheresultsofthemostrecentyear(2010).Theimpactofhumangenomesequencinghasledto acurrentindustryemployingmorethan44,000,generatingnearly$4.9billioninannualpersonal income,andwithagenomicsrelatedindustryoutputexceeding$21.4billion.23
Table9:EconomicImpactoftheGenomicsEnabledIndustry,2010(inMillions,2010$) Employment (Jobs) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

44,372 104,126 138,173 286,672 6.46

4,889.0 7,309.2 6,331.5 18,529.7 3.79

21,401.3 21,904.2 20,185.5 63,491.0 2.97

266.4 889.0 1,152.2 2,307.6 8.66

924.4 1,466.0 1,360.1 3,750.5 4.06

22

ItshouldalsobenotedthattheBattelleestimateoftotalpharmaceuticalR&Dmaybeconsideredlow.According torecentinformationfromthePharmaceuticalResearchandManufacturersofAmerica(PhRMA), biopharmaceuticalcompaniesinvestednearly$67.4billioninR&Din2010comparedtotheBattelle conservativeestimateof$45.5billion.OnereasonfornotusingthisPhRMAestimateisthatitisuncleartowhat extentcompaniesBattelleincludesinthefivegenomicssectorsareincludedinthisfigure. Personalincomeconsistsofbothemployeeandproprietorincomeandincludeswagesandotherfinancial benefits(e.g.,retirementfunds).

23

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Throughtheeconomicmultipliereffectsofsupplierandpersonalspendingthegenomicsenabled industryisresponsiblefornearly287,000U.S.jobs,morethan$18.5billioninpersonalincome,and nearly$63.5billioninU.S.outputin2010.Furthermore,theemploymentmultiplierof6.46indicates thatforeveryjobdirectlyconnectedtothegenomeenabledindustryactivitiesleadstoanadditional 5.46jobsintheU.S.economy. Fromataxrevenueperspectivethegenomicssectorsandthegenomicsrelatedsegmentofthe pharmaceuticalindustrydirectlygeneratemorethan$266millioninstate/localtaxrevenueandmore than$924millioninfederaltaxrevenuefor2010.Whencombinedwiththespendingactionsofthe industryssuppliersandpersonnel,theoverallhumangenomicsenabledindustryisresponsiblefor generatingmorethan$6billioninlocal,state,andfederaltaxrevenuein2010. Capturingthecumulativeeconomicimpactofthegenomicsenabledindustryoverthe19932010 periodleadstoevenmoresubstantialimpactfigures(Table10).Duringthisperiodtheindustry directlycreatedmorethan591,000jobyearswhichledtoatotalof$64.1billioninpersonalincome and$252billioninoutput.
Table10:CumulativeEconomicImpactoftheGenomicsEnabledIndustry,19932010(inMillions,2010$) Employment (JobYears) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

591,138 1,241,644 1,703,013 3,535,795 5.98

64,137.2 86,204.9 78,042.6 228,384.7 3.56

251,957.7 257,160.1 248,815.6 757,933.5 3.01

3,315.8 10,453.4 14,201.5 27,970.7 8.44

11,841.9 17,360.2 16,764.2 45,966.3 3.88

Asabroadlyintegratedsetoffirmsandsectors,theindirectandinducedimpactsstemmingfromthe genomicsenabledindustryarealsosubstantial.Theindustryisresponsibleforgeneratingan additional2.9millionjobyears(foratotalimpactofmorethan3.5millionjobyears)duringthe18 yearperiod,oranaverageofmorethan196,000annualjobs).Theindustryscumulativedirect, indirect,andinducedoutputoreconomicimpactisconsiderablereaching$758billion(in2010$). Itisalsoimportanttoconsiderthesizeofthetotaltaxrevenueimpactsgeneratedbythegenomics enabledindustry.Includingmultipliereffects,thisindustryisresponsibleforgeneratingnearly$74 billioninlocal,state,andfederaltaxrevenueoverthepast18years.

F.CombinedAnalysisTheCumulativeEconomicImpactofHuman GenomeSequencing
In2010alone,thehuman genomesequencingprojects andassociatedresearchand industryactivitydirectlyand indirectlygenerated: $67billioninU.S.economic output $20billioninpersonal incomeforAmericans 310thousandjobs.

Assessingthecombinedandcumulativeimpactofhumangenomesequencingincludesasummationof theimpactsfromthefederalHGPandpostHGPinvestmentsandfromtheimpactsfromthegenomics enabledindustry.Table11capturesthiscombinationofimpactsfor2010andTable12coversthetotal 19882010period. In2010alone,thecombinedimpactoftheU.S.humangenomesequencingactivitiesgeneratednearly 52,000directjobsandatotalemploymentofmorethan310,000jobsintheU.S.economy.Thedirect economicoutputoftheresearchcommunityandgenomicenabledindustryreachednearly$23billion withtotaleconomicimpactin2010exceeding$67billion.

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Table11:CumulativeEconomicImpactofHumanGenomeSequencing,2010(inMillions,2010$) Employment (Jobs) Personal Income State/Local TaxRevenue FederalTax Revenue

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

51,655 109,520 149,185 310,360 6.01

5,577.2 7,593.1 6,835.7 20,006.1 3.59

22,627.5 22,725.9 21,792.6 67,146.0 2.97

212.3 922.5 1,244.0 2,378.8 11.21

952.2 1,522.8 1,468.4 3,943.4 4.14

Thecumulative,multiyearimpactestimatesincludenearly711,000directjobyears,acombined personalincomedirectimpactofmorethan$71billion,anddirectgenomicsdrivenoutputofnearly $265billion.Incombineddirecttaxrevenuemorethan$3.5billionhasbeengenerateddirectlyin state/localtaxesandmorethan$13billioninfederaltaxes.Fromjusttheperspectiveoffederal revenueandexpensesthedirectfederaltaxesgeneratedtodate(in2010$)haveexceededtheHGP andpostHGPfederalinvestmentstodate($12.8billion)by$166million. Aswithalleconomicimpactassessments,thecombinedtotalimpactofthegenomicsresearch enterpriseandthegenomicsenabledindustryextendswellbeyondthedirecteffects.Thedifferences lieintheextentoftheireconomicreach.

Table12:CumulativeEconomicImpactofHumanGenomeSequencing,19882010(inMillions,2010$) Employment (JobYears) Personal Income State/Local TaxRevenue FederalTax Revenue

Between1988and2010the humangenomesequencing projectsandassociated researchandindustryactivity directlyandindirectly generated: $796billioninU.S. economicoutput $244billioninpersonal incomeforAmericans

Impact DirectEffect IndirectImpacts InducedImpacts TotalImpact ImpactMultiplier

Output

3.8millionjobyearsof employment.

710,819 1,298,216 1,818,459 3,827,495 5.38

71,350.0 89,183.0 83,328.8 243,861.8 3.42

264,819.6 265,779.8 265,663.4 796,262.8 3.01

3,522.3 10,804.8 15,163.8 29,491.0 8.37

13,028.0 17,955.6 17,899.8 48,883.4 3.75

Thetotalemploymentimpactexceeds3.8millionjobyearsoverthe23yearperiod.Withan employmentmultiplierof5.38,genomicsresearchandassociatedindustriesgeneratedanadditional 4.38jobsintheU.S.economyforeverygenomicsjob.Thistotallevelofimpactedemployment generatednearly$244billioninpersonalincomeovertheperiodin2010dollarsamountingtoan averageof$63,700inpersonalincomeperjobyear.Thegenomesequencingproject,theassociated research,andthegenomicsenabledindustrygeneratedatotaleconomic(output)impactofmore than$796billionfrom19882010.Onasimplecalculationbasisthefederalinvestmentof$3.8billion intheHumanGenomeProjectfrom19882003($5.6billionin2010$)enabledthegenerationof morethan$796billionineconomicoutputforareturnoninvestment(ROI)totheU.S.economyof 141to1every$1ofHGPinvestmenthasledtoatotalof$141intheeconomy.Evenmore importantthisinitialinvestmentwillcontinuetoyieldbothscientificandeconomicgainsforyearsto come.

Thefederalinvestmentof$3.8 billionintheHumanGenome Project($5.6billionin2010$) enabledthegenerationofmore than$796billionineconomic outputforareturnon investmenttotheU.S.economy of141to1every$1of investmenthashelpedto generate$141intheeconomy.

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ChapterIII:FunctionalImpactsoftheHumanGenomeProject

Thehumansequencingprogramssoughttocreatebenefitsforhumankindbyilluminatingthebasic molecularprocessesgoverninglife.Itwasexpectedthattheresultingadvancementsingenomics knowledgeandtechnologieswouldbenefithumanhealthcare,energy,andmultipleotherfields.Inthis reportwecallthesebenefitsfunctionalimpacts.Figure4illustratesthedetailedstructureofthe functionalimpactsgeneratedbythesequencingofthehumangenome.Therewassignificant developmentofgenomicstools,technologiesandtechniquestopropelthesequencingeffortsforward. Thesehave,inmanycases,beencommercializedandformthefoundationforahighlyactiveand growingcommercialgenomicsbasedindustry.Theapplicationofthesegenomictools,technologies andtechniquesresultedinatrulydramaticexpansionofbasicbiologicalknowledge.24Asmentionedin ChapterI,thefullhumangenomesequenceunveiledacomplexbiologicalsystemunanticipatedby mostinscience,andhasbeenaparadigmshiftingeventforbiology.Someofthehighprofileimpacts onbasicsciencesarehighlightedinthischapterusingillustrativeexamplesandcasestudies.
Figure4:TheStructureofFunctionalImpactsAssociatedwiththeHumanGenomeSequencing.

GeneticsandGenomicsTools,Technologies,TechniquesandServices FieldsofApplication

Impacts Knowledge& Education Economic Development

ExpandingBasicScientificKnowledge

Human Health Agriculture andFood Veterinary Medicine Industrial Biotech

Environ Environment ment

HumanHealth Environmental Sustainability

Forensics, Justiceand Security

FoodSecurity andSafety National Security Justice

A.BasicScienceandKnowledgeExpansionImpacts
Thesequencingofthehumangenomehasresultedinadistinctparadigmshiftinourunderstandingof thebiologyofhumans,andindeedallorganisms.Assuch,ipsofactothedecodingofthehuman genomestandsamongthepreeminentfindingsinthehistoryofscience. Untilthehumangenomesequencewaspublished,anditsimplicationsunderstood,thereigningmodel ofthinkinginbiologicalsciencewasthatbiologicalformsarerenderedunderaverylargebutbasically
24

Certaintechnologiesdiscussedinthisreporthavenotreceivedregulatoryapprovalorclearanceforclinicaluses. Inthisregard,sequencersarecurrentlyintendedforresearchorinvestigationaluses.

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ThomasKuhnfirstcoinedthe termparadigmshiftwhichis, bydefinition,aratherradical upheavalamajormovementof scientificknowledgeand understandingtoanewplatform. Suchmovementoccursrarelyand researchleadingtoaparadigm shiftshould,therefore,beviewed asamomentousscientific achievement. ThomasS.Kuhn.1962.The StructureofScientific Revolutions.Universityof

linearinstructionsetcodedwithinDNA.Itwasexpectedthatlifeformsandprocessesresultfrom genes;thateachgenegeneratesanRNAtemplatewhichspecifiesoneprotein,andtheseproteins (greatlysimplified)assembleaslife.Thehumangenomesequencehasoverturnedthisone directional,simpleviewofthestructureoflife.Itisnowknownthat: Thesamegenecancodeformultipleproteins. Humanscontainfarlessgenesthanoriginallyanticipated(about21,000insteadof upwardsof100,000to300,000onceanticipated),yetbecauseofcomplexprocesses, suchasalternativesplicingandposttranslationalmodifications,theresultmaybeover 25 1milliondifferentproteinforms. GenesinteractwithoneanotherandcodeformultipleRNAs. Thestructuralgenomicvariationsbetweenorganismsarerelativelyminor(thehuman andthechimpanzee,forexample,differfromeachotherbyonly1percentoftheDNA sequence),andthusthegreatvariationfoundacrossorganismalstructuresisaresultof regulatoryprocesses. WhathadbeentermedjunkDNAistypicallynotjunkatallandplaysimportantroles intranscriptionandtranslationalregulationofproteinfolding Mostcommondiseases,suchascancers,heartdiseaseandpsychiatricdisordersarenot homogeneousdiseases,butdifferdramaticallyacrossindividualgenomesfrompatient topatient. Thehumangenomesequencehasrevealedanimmenselymorecomplicatedsystemonefarmore complexthanpreviouslythought.Ratherthanthebasiclinearviewoflife,whatisrevealedisa complexnetworkofinteractionscomprisingmoreplayersanddialogbetweenplayersthanwas thoughtpossible.ProfessorSteveJonesofUniversityCollegeLondondescribedtheparadigmshift, notingthat:

Inmedicine,genomicshas providedthefirstsystematic approachestodiscoverthegenes andcellularpathwaysunderlying disease.Whereascandidategene studiesyieldedslowprogress, comprehensiveapproacheshave resultedinidentificationof ~2,850genesunderlyingrare Mendeliandiseases,~1,100loci affectingcommonpolygenic disordersand~150newrecurrent targetsofsomaticmutationin cancer.Thesediscoveriesare propellingresearchthroughout academiaandindustry EricLander Nature.Vol.470.2011

Nowbiologistsarebeginningtofaceuptotheuncomfortabletruththattheyhaveonlybeen lookingatthenounsinlifeslexiconthecrudestandmostbasicelementsofanytongue. Nowwearereadingthespacesinbetweenverbs,adverbs,adjectives,pronounsandthe rest,andtheyarecomplicatedindeed.Worse,thegenomebabbles,stuttersandmanglesits pronunciationandnowandagainseemstospeakutternonsense.26 Thestoryofthehumangenomesimpactonbiologyisoneofarevelationofcomplexitywhichwill challengebiologistsfordecadestocome.Thehumangenomesequencepushedawayaveilandhas revealednewpathwaystounderstandingmolecularbiologyandthefundamentalprocessesoflifeand disease. Thesequencingofthehumangenomehasdramaticallyalteredtheprocessofinvestigationin biologicalsciences.LeroyHoodsummarizedthiswell: IsawintheHumanGenomeProjecttheintroductionofanewtypeofscienceinbiology thatis,discoverydrivenscience.Discoverydrivenscience,ascomparedtohypothesisdriven science,takesanobjectandenumeratesitselementsirrespectiveofanyquestions.Thatis,it createsaninfrastructureonwhichhypothesisdrivensciencecanbedonefarmoreeffectively. WhattheHumanGenomeProjectoffersusiswhatIcallsystemsbiology,thatis, integratinghypothesisdrivenanddiscoverydrivenscience.27
25

SwissInstituteofBioinformatics,HumanProteomeInitiativeJuly2007.Accessedonlineat http://expasy.org/sprot/hpi/hpi_desc.html RogerHighfield.2007.Lifejustgotalotmorecomplicated.DailyTelegraph.19June,2007.SteveJonesquoted inthisnewspaperarticlewasreferringtothefindingselucidatedbytheEncodeconsortiuminafollowon projectfromtheHumanGenomeprojectTheEncyclopediaofDNAElements. LeroyHood.2002.AftertheGenome:WhereShouldWeGo?ChapterinMichaelYudellandRobDeSalle (editors)TheGenomicRevolution:UnveilingtheUnityofLife.2002.JosephHenryPress,WashingtonDCwith theAmericanMuseumofNaturalHistory.

26

27

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Sequencingthehumangenomemadeclearinformationsciences,mathematicsandbiological investigationarenowinexorablyintertwined.Thesequencingofthegenomewasasmucha mathematicalandcomputationalachievementasitwasabiologicaloneandhashelpedtogiveriseto newfieldsofbiologicalscienceincomputationalbiologyandsystemsbiology.Ithasbeennoted thatTherevolutionsthathavebeengeneratedbythefirstdraftoftheHumanGenomeProjecthave barelybeenfelt,butthereisoneprofoundchangethathasalreadyoccurred,andthatistherealization thatbiologyisfundamentallyaninformationscience.28 Indeed,withouttheprogressmadeinthelatterpartofthe20thCenturyincomputerprocessors,data storageandcomputationalanalysismethods,thesequencingofthehumangenomebytheHGPand Celerawouldnothavebeenpossible.Dealingwithbillionsofdatapoints,theeffortsoftheHGP sequencingcenters,forexample,werepoweredbylargescalecomputingclustersanddatastorage centers.AttheSangerCentreintheUK,forexample,theHGPworkengagedaclusterof25064bit CompaqAlphasystemsandrequiredterabytesofdatastoragecapacity.Highspeedcomputerswere necessarytoanalyzehundredsofterabytesofrawsequencedataandcorrectlyordermorethan3 billionpairsofbases.PhilButcher,headofinformationtechnologyfortheSangerCentrenotedthat withoutaccesstoagreatdealoftheverylatestcomputingresources,wewouldnotevenbeableto contemplatereachingourtargets.29Interestingly,biologicalsciencesareinturngivingbackto computationalsciencesbecausehighlyevolvedlivingorganismshavedevelopeddigitalmanipulations andstrategiesthatareturningouttobeusefulwithincomputerscience.30 Forbasicscienceinvestigation,thehumangenomesequencehasprovidedamaptoguidediscovery. Justasageographicmapgreatlyfacilitatesdirectedinvestigationofalocation,sotoodoesthemap thatisthehumangenomereferencesequence.EricLandernotesthat:Byprovidingacomprehensive scaffold,thehumansequencehasmadeitpossibleforscientiststoassembleoftenfragmentary informationintolandscapesofbiologicalstructureandfunction:mapsofevolutionaryconservation, genetranscription,chromatinstructure,methylationpatterns,geneticvariation,recombinatorial distance,linkagedisequilibrium,associationtoinheriteddiseases,geneticalterationsincancer, selectivesweepsduringhumanhistoryandthreedimensionalorganizationinthenucleus.31 Thefundamentalparadigmshiftsdescribedabovearebeingfeltintheemergenceofnewscientific subdisciplinesanddeepwithinexistingbiologicalandsocialsciencedisciplines.Forexample,justsome ofthecentrallyimpactedsciencedisciplinesandsubdisciplinesarediscussedbelow.

GenomicsDisciplines
TheNationalcenterforBiotechnologyInformationattheNationalLibraryofMedicinenotesthat genomicsitselfhasthreeprimarybranches,comprising: StructuralGenomicsincludesmappingandsequencing ComparativeGenomicsincludinggeneticdiversityandevolutionarystudies FunctionalGenomicsthestudyoftherolesofgenesinbiologicalsystems.

NewandEmergingDisciplines
TheOmicsAttheheadofthelist,isnotonebutaseriesofdisciplinesthatarean outgrowthofgenomicsanditsdiscoveries,generallygroupedbythetermOmics.They comprise:
28 29

Ibid Compaqtechnologyenablescompletionofthehumangenome.Accessedonlineat http://www.tgc.com/sponsors/compaq/celera2.html LeroyHood.2002.AftertheGenome:WhereShouldWeGo?ChapterinMichaelYudellandRobDeSalle (editors)TheGenomicRevolution:UnveilingtheUnityofLife.2002.JosephHenryPress,WashingtonDCwith theAmericanMuseumofNaturalHistory. EricS.Lander.2011.Initialimpactofthesequencingofthehumangenome.Nature.Volume470, February10,2011.

30

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ProteomicsThestudyofthesetofproteinsencodedbyagenome MetabolomicsThestudyofthecompletecollectionofmetabolitespresentinacell ortissueunderaparticularsetofconditions TranscriptomicsThestudyofallRNAmolecules,includingmRNA,rRNA,tRNAand noncodingRNAinanorganismorspecificcell.

EvolutionaryDevelopmentalBiology(EvoDevo)Addressingtheoriginsandevolution ofembryonicdevelopment,thisfield(anoutgrowthoftheexistingdisciplineof embryology)hasbeenempoweredbydatacontainedingenomesequencingofhuman andmodelorganismcells. ComputationalBiologyUsesmathematicalandcomputationalapproachestoaddress theoreticalandexperimentalquestionsinbiology.Itssubdisciplinecomputational genomicsperformsstatisticalanalysisonthedatageneratedbygenesequencersand microarraytechnologiestoevaluategeneandgeneproductsexpressedbyvariouscell types. BioinformaticsIsperhapsbestviewedastheappliedtwinofcomputationalbiology, andiswelldefinedintheSangerInstitutesglossaryasthescienceofusingcomputer technologytogather,store,analyzeandmergebiologicaldata.Expertisein bioinformaticsiskeytohandlingtheenormousamountsofdataproducedbytheHGP 32 andothersequencingprojects,andservingitouttotheresearcherswhousethedata. MetagenomicsAlsoknownasenvironmentalgenomicsorcommunitygenomics, metagenomicsinvestigatesthecommunalgenomecontainedwithinanenvironmental sample.Itenablesthestudyofthesymbiosisandinteractionsoforganismalgenomes andgeneticproductsasabiologicalsystem.

And,othersubstantiallyimpacteddisciplines,suchas
BioarchaeologyandAnthropologyUsesgenomicsforthestudyofhumanevolution andpopulationmigrations.IthasbeennotedthatcomparativeDNAsequenceanalyses ofsamplesrepresentingdistinctmodernpopulationsofhumanshaverevolutionizedthe fieldofanthropology.33 AgriculturalSciencesWholegenomesequencingisbeingappliedacrossabroadrange ofcropandlivestockspeciesandunderpinsgeneticimprovementsininputandoutput traits.Genomicsisalsobeingusedindiagnosticsapplicationsforlivestockandzoonotic diseases,plantpathogenidentificationandinfoodsafetyapplications.Workisalso beingperformedindevelopingediblevaccinesforincorporationintofoodproducts. EnvironmentalScienceTheU.S.DepartmentofEnergyandotherinvestigatorshave sequencedthegenomesofmultiplenonpathogenicmicrobesusefulforuseand developmentintheenvironmentalwasteremediation,energyproductions,carbon cycling,andbiotechnologyapplications. Thefundamentaladvancementofscientificknowledgeembodiedinthehumangenomesequencingis alsowellillustratedbythebroadvarietyofmajorbiologicalscienceprojectsthathavedevelopedas followonprojectsoroutgrowthsoftheHGP.Table13listssomeofthesekeyrelatedinitiatives:

32 33

http://www.yourgenome.org/glossary/ JudithFridovichKeil(primarycontributor).HumanGenomeProject.EncyclopaediaBritannicaScientificProject.

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Table13:BuildingUpontheHumanGenomeSequenceRelatedGrandProjectsinBiologicalSciences

ProjectName International HapMapProject

Goals TheHapMapisapublicresourcecatalogofcommongeneticvariantsthatoccur inhumanbeings.Itdescribeswhatthesevariantsare,wheretheyoccurin humanDNA,andhowtheyaredistributedamongpeoplewithinpopulationsand amongpopulationsindifferentpartsoftheworld.Usingtheinformationinthe HapMap,researcherswillbeabletofindgenesthataffecthealth,disease,and individualresponsestomedicationsandenvironmentalfactors. Identificationofcommongeneticvariationacrosshumansthroughthe sequencingofalargenumberofindividualhumangenomes.Theprojectaimsto findmostgeneticvariantsthathavefrequenciesofatleast1percentinthe populationsstudied. TheNationalHumanGenomeResearchInstitute(NHGRI)launchedapublic researchconsortiumnamedENCODE,theEncyclopediaOfDNAElements,in September2003,tocarryoutaprojecttoidentifyallfunctionalelementsinthe humangenomesequence.Theprojectstartedwithtwocomponents:apilot phaseandatechnologydevelopmentphase.Thepilotphasetestedand comparedexistingmethodstorigorouslyanalyzeadefinedportionofthe humangenomesequence.Theconclusionsfromthispilotprojectwere publishedinJune2007.Thefindingshighlightedthesuccessoftheprojectto identifyandcharacterizefunctionalelementsinthehumangenome.The technologydevelopmentphasealsohasbeenasuccesswiththepromotionof severalnewtechnologiestogeneratehighthroughputdataonfunctional elements. TheMGPwasbegunin1994asaspinofffromtheHumanGenomeProgram.The programsequencedthegenomesofanumberofnonpathogenicmicrobes usefulinsolvingDOE'smissionchallengesinenvironmentalwastecleanup, energyproduction,carboncycling,andbiotechnology. TheCancerGenomeAnatomyProject(CGAP),begunin1996,isan interdisciplinaryprogramestablishedandadministeredbytheU.S.National CancerInstitutetogeneratetheinformationandtechnologicaltoolsneededto decipherthemolecularanatomyofthecancercell. TheCancerGenomeAtlas(TCGA)isacomprehensiveandcoordinatedeffortto accelerateourunderstandingofthemolecularbasisofcancerthroughthe applicationofgenomeanalysistechnologies,includinglargescalegenome sequencing.TCGAisajointeffortoftheNationalCancerInstitute(NCI)andthe NationalHumanGenomeResearchInstitute(NHGRI),whicharebothpartofthe NationalInstitutesofHealth,U.S.DepartmentofHealthandHumanServices. HeadquarteredattheWellcomeTrustSangerInstitute,theCancerGenome Projectisusingthehumangenomesequenceandhighthroughputmutation detectiontechniquestoidentifysomaticallyacquiredsequence variants/mutationsandhenceidentifygenescriticalinthedevelopmentof humancancers OperatedbytheU.S.NIHCommonFund,theHumanMicrobiomeProject(HMP) aimstocharacterizethemicrobialcommunitiesfoundatseveraldifferentsites onthehumanbody,includingnasalpassages,oralcavities,skin,gastrointestinal tract,andurogenitaltract,andtoanalyzetheroleofthesemicrobesinhuman healthanddisease. GenomestoLifeprogramaimstousemicrobesandotherorganismstoaddress problemsinenergyproduction,environmentalcleanup,andcarboncycling.The researchseekstounderstandthechemistryofentireorganismsandtheir interactionswiththeenvironment.Theprojectstenyeargoalistoadvance systemsbiology,computation,andtechnology.Theseadvanceswillbedirected towardincreasingbiologicalbasedsourcesofenergy,betterunderstandingthe earthscarboncycling,designingnovelwaystocapturecarbon,anddeveloping lowcostmethodsforcleaningtheenvironment.

1000Genomes Project

ENCODEProject

MicrobialGenome Project

CancerGenome AnatomyProject

CancerGenome Atlas

CancerGenome Project

Human Microbiome Project

GenomestoLife Project

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B.HumanHealthandMedicine
Oneofthekeyhopesforthesequencingofthehumangenomewasthat,havingtheentiregenomein hand,biomedicalscientistswouldbeabletobetteridentifytheprocessesandmechanismsofdisease andinheritedmedicaldisordersandilluminatenewapproachestotreatingthesediseasesand disorders. Modernmedicineisbuiltuponahistoryoffundamentalinvestigationsanddiscoveriesacrossabroad rangeoflifesciencedisciplines:physiology,biochemistry,microbiology,immunology,etc.Itisalso, however,builtuponafoundationoftechnologicalinnovationsenablingthesediscoveriestobemade. Whetheritistheinventionofthemicroscopeleadingtotheidentificationofmicroorganisms,orthe moderndevelopmentoffunctionalmagneticresonanceimagingallowingresearcherstowatchinternal lifeprocessesinaction,technologiesprovidenewcapabilitiesthatpropelmedicaladvancement.The sequencingofthehumangenomeactuallyrepresentsanintenseadvanceonbothfrontsbothin termsoffundamentalknowledgeandtechnologyadvancement. Asnotedabove,moderngenomicsandthehumangenomesequenceshaveempoweredanewviewof biologicalprocesses.Inturn,thesenewviewsarebeingtranslatedintoappliedbiomedicalfields, particularlythoseillustratedinFigure5.
Figure5:FunctionalImpactAreasofGenomicsinHumanHealth

Human Health

Molecular diagnostics

Pharmacogenomicsand DrugDiscovery

Regenerativemedicine/ Stemcells

Human Health

Imaging

Genetherapy

Vaccines

Tissue/Organ DonorMatching

Thetoolsandtechnologiesofmoderngenomics,inconcertwiththefoundationalknowledgeinthe humangenomesequences,arefindingapplicationacrossabroadrangeofbiomedicalareastoday,and holdextraordinarypromiseforadvancementsinthefuture.Certainly,thecomplexityofthegenome andproteomediscussedunderbasicscienceimplicationsabovehavemadeinstantcuresdifficultto

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achieve,buttheprogressbeingmadeinappliedgenomicmedicineisquiteremarkable.Table14 illustratessomeoftheseapplications:
Table14:BiomedicalApplicationsofGenomicsandHumanGenomeSequencing

PotentialApplication
Diagnosisofsinglegene, Mendeliandiseasesand disorders

GenomicsAdvancesToday
Specificgenesforover3,000Mendelian monogenicdiseasesdiscovered. Genomictestsarebeingusedto accuratelydiagnoserarediseasesand disorders,manyofwhichwere previouslymisdiagnosedwith inappropriatecoursesoftreatment prescribed. Prenatalgeneticscreeningisbeing performedtoinformpotentialparents ofrisksforcatastrophicinheritable disorders. Multiplegenesandbiomarkershave beenidentifiedforpredispositionto multiplediseasessuchascancers, neurologicaldiseases,psychiatric diseaseandcardiovasculardisease.

HopefortheFuture
Genetherapieswillachievesuccessin repairinggeneticabnormalitiesleading todiseasesanddisorders. Customtherapeuticproductswillblock orchangeexpressedactivityof defectivegenes.

Knowledgeof predispositiontowards specificdiseases

Understandingofriskfordiseasebased uponmultigenetestswilllikelyleadto appropriatetherapeuticinterventions andpersonalbehavior/lifestyle modification. Environmentalcomponentsofdisease emergenceandprogressionwillbe teasedoutfromgenomicfactorsand addressedappropriately. Manynewdrugsandbiologicswillbe developedtosuccessfullyexploit elucidateddrugtargets.

Modernmedicinearosewhen scientistslearnedtofightsomeof theworstinfectiousdiseasewith vaccinesanddrugs.Thisstrategy hasnotworkedwithAIDS, malaria,andarangeofother diseasesbecauseoftheir complexityandthewaythey infiltrateprocessesincells. Curingsuchinfectiousdiseases, cancer,andthehealthproblems thatarisefromdefectivegenes willrequireanewtypeof medicinebasedonathorough understandingofhowcellswork andthedevelopmentofnew methodstomanipulatewhat happensinsidethem.* TheHGPwasandisoneofthe centralprojectsleadingtothis understandingofhowcells workandopeningthewayfor newapplicationsofmolecular medicine. RussHodge,TheFutureof Genetics:BeyondtheHuman Genome,2010.

Genomicsdrivendrug discovery,knownas rationaldrug development

Newdrugtargetshavebeenidentified. Cancerdrugsbasedonthegenomicsof tumorsareonthemarket,including Gleevec(forchronicmyelogenous leukemia),Herceptin(breastcancer), Tarceva(lungcancer)andAvastin (colon,lungandothercancers). Alreadybeingappliedinthetreatment ofsomeformsofcancerand cardiovasculardisease. Genetictestsareusedfordosagelevels inprescriptionofsomedrugssuchas Coumadin(warfarin). Successfuldiscoveryofsubpopulations forwhichpreviouslyunapproveddrugs areefficacious.Iressa,forexample,has beenapprovedwithpatentstesting positivefortheEGFRmutation.

Therapeuticproducts customprescribedbased onpatientgenomics,to maximizeeffectand reduceoreliminateside effects Repurposingor revitalizationofsome drugsshelvedin developmentbecauseof impactonagenomic few

Routinesequencingofapatientsentire genomewilguidetreatmentselection anddosefortheoptimumresponse. Potentialadversereactionstodrugsand treatmentregimens,identifiedvia genomicmarkers,willresultinthe avoidanceofadverseevents. Therewillbeasubstantialvolumeof existingdrugsfoundtobeefficaciousin selectedsubpopulations,anddrug companieswillhaveminedtheir previouslyfailedR&Dpipelinesto bringforwardpreviouslynon marketabledrugstoworkinselected subpopulations. Rapid,realtimesequencingof pathogenstwilldirectpublichealth effortstocombatdiseaseoutbreaksin humansandzoonoticdiseaseoutbreaks inanimals.DNAvaccineswillcometo themarkettoimpartimmunityto infectiousdiseases.Geneticprofilingof patientviruseswillassistincustomizing treatmentregimens. Genetherapymayberoutinely providedtonewbornswithidentified genomicprofilestocorrectdefective genes,particularlyinconditions associatedwithdevastatingmonogenic disorders.

Identificationofmeansto combatinfectious organisms

Multipleinfectiousorganismshavehad theirwholegenomessequenced. Publichealthprofessionalssequence emerginginfectiousdiseaseorganisms tomonitormigrationsandmutations. Genetictestingalreadybeingappliedto directtherapyforHIV/AIDSpatients.

Genetherapiesfor inheritedgeneticdiseases anddisorders

Afterpublicizedsetbacks,gene therapiesarenowachievingsuccess. Forexample,thefatalbraindisorder adrenoleukodystrophyhasbeen treated,withprogressionstopped,ina sampleofchildren.

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Weareontheleadingedgeofa truerevolutioninmedicine,one thatpromisestotransformthe traditionalonesizefitsall approachintoamuchmore powerfulstrategythatconsiders eachindividualasuniqueandas havingspecialcharacteristics thatshouldguideanapproachto stayinghealthy. FrancisCollins, TheLanguageofLife, NewYork:HarperCollins,2010

Moleculardiagnosticsandpharmacogenomicsareworkinghandinhandasapplicationsfacilitatingthe growthofpersonalizedmedicinewhichusesanalysisofpatientgenomestoassuretheright medicine,intherightdose,getstotherightpatient.34Thesequencingofthehumangenomehas enabledtheidentificationofasignificantvolumeofgenesandbiomarkerstobeassociatedwith diseasesandhealthdisorders.Biotechnologycompaniesdevelopmoleculardiagnostictoolsthat identifythepresenceofthesebiomarkersinpatients.Theassociationofabiomarkermayindicate susceptibilitytoadisease,thereforeguidingprophylactictreatmentsorotherpreventivemeasures butbiomarkersmayalsoindicatethelikelyresponseofaspecificpatienttoaparticulartherapeutic product.Thisistheworldofpharmacogenomicsandpharmacogeneticsinwhichthepresenceofa singlegene,biomarkerorcollectionofgenesandbiomarkersacrossthepatientsgenomecanindicate potentialefficacyofaparticulartherapeuticproduct,dosageortreatmentregimen. TheBiotechnologyIndustryOrganization(BIO)notesthattheuseofgeneticandgenomicinformation canhelpdetermine: Whichtreatmentwilllikelyworkbest; Thesafestandmosteffectivedosage;and Whetherapersonispredisposedtodevelopaspecificdiseaselaterinlife.35 Likewise,theAmericanMedicalAssociation(AMA)notesthatthegrowthofpersonalizedmedicinevia pharmacogenomicswillprovidetailoreddrugtherapybasedongeneticallydeterminedvariationin effectivenessandsideeffects.36TheAMAnotesthatthiswillmean: MorepowerfulmedicinesPharmaceuticalcompanieswillbeabletoproduce therapiesmoretargetedtospecificdiseases,maximizingthetherapeuticeffectswhile decreasingdamagetonearbyhealthycells. Better,saferdrugsthefirsttimeRecoverytimewillgodownandsafetywillgoupas thelikelihoodofadversereactionsgoesdownoriseliminatedaltogether. MoreaccuratemethodsofdeterminingappropriatedrugdosagesCurrentmethodsof basingdosagesonweightandagewillbereplacedwithdosagesbasedonapersons geneticshowwellthebodyprocessesthemedicineandthetimeittakestometabolizeit. BettervaccinesVaccinesmadeofgeneticmaterial,eitherDNAorRNA,promisethe benefitsofexistingvaccineswithoutalltherisks.Theytheoreticallycouldactivatethe 37 immunesystembutbeunabletocauseinfections. WhiletheAMAseesmuchhopeforthefutureinpharmacogenomicsandpersonalized medicine,theAssociationnotesthatapplicationsarealreadychangingthepracticeof medicineinselectedareas,includingcancer,depressionandcardiovasculardisease. Fromanimpactstandpoint,developmentsinpharmacogenomicsandpersonalized medicineholdsignificantpromiseformoreaccuratediagnosisofdisease,elucidationof preventivemeasurestoavoiddisease,morerefineddiseasetreatmentandavoidanceof costsassociatedwithadversedrugreactions.

34

AmoretechnicaldefinitionbythejournalNature:Theuseofgeneticsusceptibilityorpharmacogenetictestingto tailoranindividual'spreventivecareordrugtherapy.NatureGlossaryaccessedonlineat: http://www.nature.com/nrg/journal/v5/n12/glossary/nrg1495_glossary.html BIO.2010.Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife.2010.TheBiotechnology IndustryOrganization.Accessedonlineathttp://www.valueofbiotech.com/ AmericanMedicalAssociation.CurrentTopics:Pharmacogenomics.Accessedonlineathttp://www.ama assn.org/ama/pub/physicianresources/medicalscience/geneticsmolecularmedicine/current topics/pharmacogenomics.page Ibid

35

36

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CASESTUDY:ReducingtheEconomicImpactofChronicDisease Healthisbothapersonalgoodandaneconomicgood.Poorhealth,ontheotherhand,carries significantpersonalandeconomicburdens.AnalysisbytheMilkenInstituteindicatesthatthe sevenmostprevalentchronicdiseasesintheU.S.in2003costthenation$277billionin treatmentexpendituresand$1.05trillioninlosteconomicoutput(largelyrelatedtolost personalproductivityrelatedtodisease),foracombinednationalcostof$1.3trillion.Milken projectedthiscosttorisetoover$2trillionby2011.38 Thediscoveriesembodiedinhumangenomesequencingarebeingdirectlyappliedtoaddress progressinthediagnosisandtreatmentofeachofthesevenchronicdiseaseswhoseimpact wasquantifiedbyMilken(cancers,diabetes,heartdisease,hypertension,stroke,mental disordersandpulmonaryconditions).Theimpactofimprovedhumanhealthistangibleand significantastheMilkenInstitutereportauthorsnotegoodhealthisaninvestmentin economicgrowth. Genomicmedicinewilllikelyprovidecostsavingopportunitiesacrossmultiplefrontsin healthcare.Pharmacogenomics(alreadybeingappliedincancertreatmentforexample) allowsdrugstobeprescribedonlytopatientswithbiomarkersindicatingtheefficacyand safetyofaspecificdrug(avoidingwastedtreatmentsandproblemsideeffects).Patientswith ageneticpredispositiontodevelopadultonsetdiseasesordisorderscanusethisknowledge, withtheadviceoftheirphysician,toadoptprophylactictreatmentregimesoradapttheir lifestyletoreducerisk.Drugsthathadbeenshelvedduetonegativesideeffectsinafew patientscanberescuedforthosewhomgenomicsshowsmaybesafelyadministeredthe drugtherebyprovidingnewdrugstothepharmacopeiaandrecapturingtheearlier significantdevelopmentcostsintheR&Dofthosedrugs.Overtime,advancementingene therapywillallowdisordersanddiseasestobecompletelyaverted,whilealreadypre conceptiongenomictestscanprovideadvicetopotentialparentsormarriagepartners regardingriskofdevastatingillnesstotheirprogeny,thusprovidingactionableinformationto avoidtheheartacheandcostoffatalchildhoodcongenitaldiseases.Whatisgradually occurring,becauseoftherevolutioninpartstimulatedandfacilitatedbythesequencingof thehumangenome,isamovetopersonalized,datadrivenmedicineinwhichtheefficacyofa treatmentregimeisknowninadvance,ratherthanthelargescaleprescribeandhope medicinethatdominatesclinicalpracticetoday.Thepreventionofdiseaseandtheaccurate treatmentofdisease,embodiedinthepromiseofmoderngenomics,willhaveasignificant impactonthecostofhealthcareandtheeconomicburdenofdiseaseonsociety. Cancerisoneoftheareasofhumandiseaseinwhichgenomicsisplayingafundamentalroleinthe clinic.BIOnotesthatnewtestshavebeenlaunchedrecentlythatidentifypatientslikelytorespondto thefollowingcancertreatments:39 Tarceva(Genentech,nonsmallcelllungandpancreaticcancers); Gleevec(Novartis,chronicmyeloidleukemiaandgastrointestinalstromaltumor);and Campath(Genzyme,Bcellchroniclymphocyticleukemia). MayoClinicresearchshowedthatarecentstudyshowedthathospitalizationratesdropped30percent whengeneticinformationwasusedtodeterminethebestdosingforheartpatientstakingwarfarin (theworldsmostprescribedbloodthinner).40
38

RossDeVolandArmenBedroussian.2007.AnUnhealthyAmerica:TheEconomicBurdenofChronicDisease. MilkenInstitute,October2007. BiotechnologyIndustryOrganization.2010.Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. BIOonlineatwww.valueofbiotech.org MedcoandMayoClinic.ClinicalNewsRelease.March16,2010.Accessedonlineat: http://www.mayomedicallaboratories.com/mediax/articles/features/warfarin/pressrelease.pdf

39

40

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CASESTUDY:TailoringBreastCancerTreatment Someofthemostexcitingnewbiotechdiagnostictestshelpimprovebreastcancer treatmentandcare.Oneofthesediagnostictestsdetermineswhetherabreastcancerpatient hasanaggressiveformofbreastcancerassociatedwiththehumanepithelialgrowthfactor receptor2(HER2).Thisformofbreastcancerstrikesquickly,spreadsaggressively,andis oftendeadly.However,patientstreatedwithHerceptin(producedbyGenentech)experience extremelypositiveoutcomes:tworecentclinicaltrialsfoundthatchemotherapyplus Herceptincutthechanceofcancerrecurrenceinhalfcomparedtochemotherapyalone. JudyKayse,abreastcancersurvivorandpatient,knowsfirsthandthepowerofthelatest breastcancertreatmentsanddiagnostictests.Iwasfirstdiagnosedwithbreastcancer15 yearsago.AtthetimetherewasnotestingforHER2oratreatmentforpeoplewiththattype ofbreastcancer,soIwastreatedwithalumpectomyandradiationandwentintoremission, recountsJudy.Butatmyannualexaminlate2009,wefoundatumor.Thecancerwasback, anditwasinvasive.Butthistimemydoctorshadanewweaponintheirarsenal:theywere abletotestfortheHER2factor.TheydeterminedIwasHER2positive,meaningIwas eligibleforHerceptin.Itsnowpartofmytreatmentprogram,anddoesntcomewiththe debilitatingsideeffectsofotherbreastcancertreatments.MydoctortoldmeifHerceptinhad beenavailablethefirsttimearound,Iprobablywouldnothavehadarecurrence. HerceptinisatailoredtreatmentthatworksbyblockingtheHER2receptor,stoppingthe cancertumorfromgrowingandeventuallykillingthecancercells.OnlypatientswithHER2 positivebreastcancerareeligibleforHerceptinmakingtheHER2diagnostictestcriticalto determiningtheappropriatebreastcancertreatment.
Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. 2010.BIO,TheBiotechnologyIndustryOrganization(www.valueofbiotech.com)

CASESTUDY:MayoClinicUsesWholeGenomeSequencingasaDiagnosticTool TherenownedMayoClinichasalongtrackrecordinseeinghighlychallengingcasesthe sickestofthesick,patientswithunusualillnessesandthemostdifficulttodiagnosecases. Nowheavilyinvestedinsequencingtechnologiesandadvancedgenomicstools,Mayowas earlytorecognizethefutureofdiagnosticsingenomicsandisonthefrontlinesindeploying genomesequencinginpatientcare.Tworecentpatientcasesillustratethisinaction. MayoClinicinScottsdale,ArizonaandtheTranslationalGenomicsResearchInstitute(TGen) inPhoenix,Arizona,workedtogethertosequenceMayosfirstwholepatientgenome.This involvedsequencingbothnormalcellsandtumorcellsfromapatientwithpancreaticcancer (requiringsequencingofover6billionbasepairs),and,withthesequencesinhand, comparativeanalysisenabledtheclinicalteamtopinpointgeneticchangesthatwerecrucial intailoringamoreeffectivetreatmentplanforthepatient.41MiteshBorad,aMayo assistantprofessor,pointedtothelatestgenerationofgenesequencersandtheirspeedas makingsuchadvancepossible.Healsonotedthatutilizationofthisapproachareclearlythe wayforward,anditisonlyamatteroftimebeforewholeortargetedgenomesequencing becomesroutineintheclinicalsphere,rangingfromprimarycaretospecialtyareassuchas oncology.42 TheMayoClinicsteamhasalsosequencedthefullgenomeofanacutemyelogenous leukemiapatientandfoundanovelmutation.Thisledtoanalysisofadditionalsamplesand
41

MatthewDublin.2011.ResearchersDemonstrateFeasibilityofWholeGenomeSequencingintheClinic. GenomeWeb.April2011.Accessedonlineathttp://www.genomeweb.com/sequencing/researchers demonstratefeasibilitywholegenomesequencingclinic Ibid

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identificationof15additionalacutemyelogenousleukemiapatientcaseswiththesame mutation. EricWieben,DirectorofMayoClinicsGenomicResearchCenter,andaleaderinthe MinnesotaPartnershipforBiotechnologyandMedicalGenomics,notedinaninterviewwith Battellethatthesetypesofappliedgenomicsadvanceswouldnothaveoccurredwithoutthe HumanGenomeProject,becausepriortotheHGPsequencingtechnologywasstable,but staticitdidnothavethespeedtodowhatisbeingdonetoday,andtheimpetuswasnot theretorapidlyadvancethetechnology.TheHGPspurredtheadvancementoftechnologyto thepointthattodaythespeedandcostofwholegenomesequencingisputtingitatthe doostepofclinicalapplication.Wiebennotedthatinadditiontothecasesabove,three additionalgenomeswerealsorecentlyfullysequencedbyMayoaspartofanefforttofind genesrelatedtohereditaryheartdisease.WiebenillustratedtheextentoftheMayo genomicscommitmentandtheimportanceoftheHGPtoit,notingthatMayohasastaff ofabout120researchpersonnelworkinginmedicalgenomics,andthateachoneofthese staffaccessthereferencehumangenomeeveryday.43MayoClinicisusingmedicalgenomics todevelopnextgenerationsequencingbaseddiagnosticsforcancersandmitochondrial diseases,andwithsequencingcostscontinuingtodropwholegenomesequencingisexpected tobeanimportantclinicaltoolmovingforward.ItwillbecomemainstreamWiebennoted. Oneofthekeyapplicationsofgenomicsandpharmacogenomicsistheabilitytofitthedrugandthe dosetothepatientsgenomicprofile.Asthefollowingcasestudyillustrates,thispersonalized medicineapproachhelpstoavoidadversedrugreactionsandtheprescriptionofdrugsunlikelytowork foraspecificpatientgenotype. CASESTUDY:AvoidingtheCostsandPhysicalHarmofAdverseDrugReactions Thebiopharmaceuticalsectorisoneoftheleadingcontributorstotheconsiderableincrease inhumanlongevityachievedinthe20thCentury.Millionsofliveshavebeensavedbythe prescriptionofmedicinestocombatdisease,andthequalityoflifeofalmosteveryAmerican istouchedbythebiopharmaceuticalsector(viavaccines,painandothersymptomreliefin chronicdisorders,andtheeffectivetreatmentofdisease). Unfortunately,inasmallpercentageofcases,theadministrationofabiopharmaceuticalcan haveseriousadverseeffects.Whileweallsharethecommonscharacteristicofbeinghomo sapiens,wearealsoalldifferentdifferentatagenomiclevel(witheachofushavingour ownuniquegenome)anddifferentintheindividualityofourdailylivesanditsimpactonour physicalhealth.Itisfairtosaywearethesame,butdifferentandtherelativelysmall differencesineachofus(manyofthemgenomicdifferences)maysometimesleadtoan adversedrugreaction. Thesequencingofthehumangenomehasenabledscientiststogainafarbetter understandingofadversedrugreactionsastheyrelatetopatientgenomics.Insome instances,therearenowgenetictestsonthemarketthatenablephysicianstoidentifythe riskofanadversedrugreactioninadvancefortheirpatient,andtodetermineanalternative courseoftherapy.Genotypetodrugassociationstudieswillincreasinglyplayanimportant roleinpersonalizingmedicineadvancingefficacyandavoidingnegativeimpacts. While,asnotedabove,adversedrugreactionsrepresentasmallpercentageofreactionsto administeredbiopharmaceuticals,inaworldwith7billionpeople,smallpercentagesquickly adduptolargeactualnumbersofpeopleandsignificantcosts.Genomicsisbeingappliedto helpalleviatethesechallenges.

43

EricWieben,MayoClinic.TelephoneinterviewwithBattelleimpactresearchteam.OnApril15,2011.

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BondandRaehlstudiedtheissueofadversedrugreactions(ADRs)andreportthatbasedon theliteraturefrom19641996,overallincidenceofADRsinhospitalizedpatientswas6.7 percent(range1.224.1percent),andoffatalADRs0.32percent(0.10.85percent).44They notethat: Theseaggregatefigurestranslateto2,216,000hospitalizedpatientseachyearwho experienceaseriousADRand106,000ayearwhodiefromanADR.FatalADRsrankfourthto sixthinleadingcausesofdeath.Assoberingasthesefiguresappear,ADRsalsoareoneofthe morefrequentcausesofhospitalization(3.76.5percentofpatients).Costestimatesforthese ADRsare$1.56$4billionperyear,andasmanyashalfofthemmaybepreventable. GenomicsenabledpersonalizedmedicineapproacheswillhelptoreduceADRsinmany instances.Itshouldbenoted,however,thatmanyADRsaretheresultofhumanerrorsthat genomicswouldnotaffect. Clearly,progressbeingmadeingenomicteststoavoidADRs(builtuponthebackboneof knowledgederivedfromhumangenomesequencing)iscriticallyimportanttoavoidingharm andloweringthecosttosocietyofadversedrugreactions. J.CraigVenternotesthatbeingabletoseparatepatientsintothosewhowillbenefitfromadrugand thosewhowillnot,orthosethatmayexperienceanadversedrugeventandthosewhowillnot,allows drugstobeusedthatotherwisecouldnotbeapproved.Ineffect,thepoweristheretorescuedrugs thatcouldnotprogressintothemarketbecauseoflimitednegativeimpactsonasmallsubsetof patients.In2002Venternotedthat AtypeIIdiabetesdrugrecentlyhadtobetakenofftheAmericanmarketbecause1outof 10,000peoplehadaseverelivertoxicitytoit.Ifwecanfindsimpleteststhatpredicttoxicityit willhaveahugeimpact.Notonlycanwechangeadversedrugeffectsinthepopulation,we canalsotailordrugssothattheyworkformorethan30to50percentofthepopulation,the currentaverage.45 Ventershopefordevelopinggenomicteststorefinedrugprescriptionhasnowcometofruitionina numberofcases.Amongtheimportantbenefitsofpharmacogenomicsistheparingofatherapeutic withacompaniondiagnostic.TheFoodandDrugAdministration(FDA)alreadylistsover70drugswith pharmacogenomicsinformationlabeling(coveringaspectssuchasindications,usage,dosingetc.).The Table15indicatesexamplesofkeypharmacogenomicslabeleddrugsandthemajordisease/disorder indicationswithwhichtheyareassociated:
Table15:SelectedKeyPharmacogenomicLabeledDrugs

Drug Abacavir(Ziagen) Atorvastatin(Lipitor) Azathioprine(Imuran) Carbamazepine(Tegretol) Cetuximab(Erbitux) Clopidogrel(Plavix) Dasatinib(Sprycel)

Indications HIV Reducecholesterollevels Preventionoftransplantedkidneyrejection;osteoarthritis Ananticonvulsant.Seizurecontrol;trigeminalneuralgia;maniaand bipolardisorder. Headandneckcancer;coloncancer Antiplateletdrugforpreventionofstrokeandheartattack Leukemia

44

C.A.BondandCynthiaRaehl.2006.AdverseDrugReactionsinUnitedStatesHospitals.Pharmacotherapy.2006; 26(5):601608.Accessedonlineat:http://www.medscape.com/viewarticle/531809 J.CraigVenter.2002.WholeGenomeShotgunSequencingChapterinMichaelYudellandRobDeSalle(editors) TheGenomicRevolution:UnveilingtheUnityofLife.2002.JosephHenryPress,WashingtonDCwiththe AmericanMuseumofNaturalHistory.

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Imatinib(Gleevec) Irinotecan(Camptosar) Panitumumab(Vectibix) Rasburicase(Elitek) Trastuzumab(Herceptin) Volproicacid(Stavzor) Warfarin(Coumadin)

Leukemiaandothercancersofthebloodcells;gastrointestinalstromal tumors(GIST);dermatofibrosarcomaprotuberans(tumorsunderskin) Coloncancer;rectalcancer Coloncancer;rectalcancer Highlevelsofuricacidinchemotherapypatients Breastcancer Ananticonvulsant.Seizures;mania;bipolardisorder;migraines Anticoagulantusedincasesofirregularheartbeat;heartvalve replacement;heartattacktreatment;venousthrombosis;pulmonary embolism.

Source:PubMedHealth

CASESTUDY:PharmacogenomicDrugwithCompanionDiagnosticforthetreatmentofHIV/AIDS PfizersdrugSelzentrywasintroducedin2007andrepresentsthefirstnewclassofdrug forcombatingHIVinmorethanadecade.Thedrugismarketedwithacompaniondiagnostic testcalledtheTrofileassaywhichdetectswhetherapatientsvirusisCCR5tropic.Forpatients whosevirusissocharacterized,SelzentryblocksHIVfromattachingtotheCCR5receptorthereby preventingthevirusfrombeingabletoenterandinfectthepatientsimmunecells. CASESTUDY:RationalDrugDesign Rationaldrugdesigntypicallyreliesheavilyuponcomputermodelingandgenomicstomodify anexistingdrugordesignanewdrugthatwillinteractspecificallywithaselectedmolecular targetimportantindiseaseprogression.NovartisdrugGleevec(Imatanib)isanexampleof anFDAapproveddrugonthemarkettodaythatresultedfromarationaldrugdesign approach.Gleevecisaproteintyrosinekinaseinhibitorandworkstoblocktheactionofan abnormalproteinthatpromotestheproliferationofcancercells.Simplytakenasatablet onceortwiceperday,Gleevecworksonarangeofcancersincluding:certaintypesofchronic myelogenousleukemiaandothercancersofbloodcells;gastrointestinalstromaltumors (GIST);,andatypeoftumorthatoccursunderthetoplayeroftheskintermed dermatofibrosacomaprotuberans. TheWellcomeTrustnotesthatrationaldrugdesigninvolvesthedesignandsynthesisof compoundsbasedontheknownstructureofeitheraspecifictargetoroneofitsnatural ligands.TheresultsoftheHGPandhumanpathogengenomeprojectsprovidemanynew drugtargets. Forpatientswithextremelyraredisorders,diagnosishashistoricallypresentedaseriousproblem. Primarycarephysiciansandpediatriciansmayneverhaveencounteredaspecifictypeofmonogenic disorderthatpresentsinapatient,andunfamiliaritywithararedisordercanleadtoanincorrect diagnosis,thewrongtreatment,negativesideeffectsfromthewrongtreatment,andongoingsuffering fromthedisorderordisease.Itisparticularlydifficultforaphysiciantodiagnoseararediseasewhen itssymptomsmaymirroranothermorecommondisease.Withoutdefinitivegenomictests,physicians areoftenrunningpracticallyblind;havingtouseaonesizefitsallapproachtotheirdiagnosesand treatments. Inadditiontotheimpactondiagnosticsanddrugs,therefinedunderstandingofthehumangenome andrelatedcellularprocesseshasreinvigoratedthenascentareaofgenetherapy.Thedevelopmentof arefinedunderstandingofthegenomeandtheactionsofindividualgenesandgroupsofgeneshas pavedthewayfortechniquestochangethecodeinDNAmolecules,therebygivingthemanew instructionset.

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Genetherapyfocusesonfindingwaystointroducecorrectivegenesintocellsinorderto: Correctacellmalfunction; Addanewfunctiontoacell;or, Inthecaseofcancer,addagenetoacancercellthatcausesthatcelltodie. Avarietyofdifferenttypesofgenedeliverysystemsareusedtodelivergenesintotargetcells, including: Modifiedviruses,whichappeartobeveryefficientatgettinggeneticinformationinto cells; NakedDNAcontainingthecorrectedgenes;or ArtificiallipidscarryingnewDNA. Thegoalistomatchtheappropriatedeliverysystemwiththegene,thetargetcell,andthedisease,in ordertodevelopaneffectivetherapy.Whilesufferingearlysetbacks,genetherapyisnowmaking considerablestridesforwardandeffectivetreatmentsarestartingtoemergefromthedevelopment pipeline.Examplesinclude: Adrenoleukodystrophy(ALD)isaneurodegenerativediseaseresultinginprogressive braindamagesoseverethatdeathtypicallyoccurswithin25yearspostdiagnosis.The researchteamusedamodifiedHIVviralvectortodelivergenetherapythathasresulted insuccessfullyarrestingtheprogressofthediseaseinchildren. Leberscongenitalamaurosisisacongenitaleyediseaseinwhichamutatedgene resultsinthelackofproductionofproteinnecessaryforcorrectfunctioningofthe retina.Genetherapyinwhichcellsareintroducedtocreatetheproteinintheretinahas resultedinimprovedvisioninthesubjectpatients. WiskottAdrichsyndromeisanimmunodeficiencydisorderwhichrenderspatients opentosevererecurrentinfections,lowbloodplateletcountsandchroniceczema.Gene therapytrialsinchildrenhavegeneratedmarkedimprovementinpatientcondition. Theabovedisordersarerarediseasesforwhichpharmaceuticaldevelopmentcostsareextremelyhard toabsorb.Genetherapyoffersanalternativeapproachtoeffectivetreatmentofrarediseases,which totalmorethan7,000individualdiseasesanddisordersaffecting25millionAmericansand250million 46 personsworldwide. Otherearlystagegenetherapyclinicalresearchareasincludepromisingresultswith: HIV/AIDSacelltherapyprocedureadministeredinGermanyconveyedageneintothe patientthatblockstheCCR5receptorwhichHIVneedstoenterandinfectcells. CancerPatientsinScotlandhaverespondedpositivelytotrialsofgenetherapyto addressskincancers(melanoma)with90percentoftreatedcasesseeingcomplete remissionfromtumors. Adenosinedeaminasedeficiencyasevereimmunodeficiencydisorderakintothe famousbubbleboydisorderhasbeentreatedinsuccessfultrialswithadenosine deaminasegenetransfer. Betathalassaemiaahematologicaldisorderinvolvingageneticdefectthatcauses defectiveproductionofhemoglobin(adiseaseofover100,000infantsworldwide annually)hasbeentreatedinsuccessfulgenetherapytrialsusinglentiviralvectors.
46

GlobalGenesProject.http://www.globalgenesproject.org/press/GGPWRDD2011_Final.pdf

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CASESTUDY:SightfortheBlind BornwitharareretinaldiseasecalledLeberscongenitalamaurosis,CoreyHaashadlost mostofhissightbythetimehewas7andwaslegallyblind.Heoftenclungtohisparents whengoingout,anddependedonateachersaide,Braille,alargetypecomputerscreen,and canewhileatschool.Coreyexpectedtoeventuallylosehisvisionentirely. Butjusttwoyearslaterheenjoysthesameactivitiesasanyactive,healthy9yearoldboy:go karting,hiking,andplayingbaseball. Coreysmiraculousrecoverywasduetoanexperimentalgenetherapyprocedure.Infall2008, hereceivedaninjectioninhislefteye.Theinjectioncontainedavirusspeciallyengineeredto replaceDNAcontainingadefectiveversionofthegeneresponsibleforhisdebilitating condition,RPE65,withanormalversionofthatsamegene.Infact,Coreywasoneof12 patientsinagroundbreakingstudyonthepotentialapplicationsofgenetherapyforpatients sufferingfromLeberscongenitalamaurosis;allpatientsshowedsignificantimprovementin bothsubjectiveandobjectivemeasuresoftheirvision.
Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. 2010.BIO,TheBiotechnologyIndustryOrganization.(www.valueofbiotech.com)

Infectiousdiseasestakeaterribletollonhumanlife.AccordingtotheWorldHealthOrganization (WHO)approximately15millionpeopledieeachyearduetoinfectiousdiseases.47Infectiousdiseases arecausedbybacteria,viruses,fungiandotherparasitesaremajorcausesofdeath,disability,and socialandeconomicdisruption.Thecomplexnatureofevenmicroorganismalgenomeshasmade fightingcertaininfectiousdiseasesanextremelydifficulttaskhowever,nowwholegenome sequencinghasbeenappliedtoaverybroadrangeofinfectiouspathogens,vectorsandparasitesto helpintheglobalbattleagainstinfectiousdisease. VirusesareoneofthesignificantcausativeagentsinhumandiseasesuchasAIDS,encephalitis, hepatitis,influenza,SARSetc.Theadvancesinmodernsequencingequipment,builtontheresearch backboneofthehumangenomesequencing,havebeensuccessfullyturnedtosequencingviruses. Today,theNIHNationalCenterforBiotechnologyInformation(NCBI)EntrezGenomedatabase contains3,805referencesequencesfor2,621viralgenomesand41referencesequencesforviroids. Likewise,abroadvarietyofhumanbacterialpathogens,infectiousfungi,protozoaandhelminth parasiticwormshavealsobeensequenced.TheSangerInstitute(oneoftheleadingparticipating centersintheHGP),forexample,listsjustsomeofthemajorpathogenssequencedandthediseases associatedwiththeminTable16.
Table16:ExamplesofPathogenSequencingProjectsandAssociatedHumanDiseases

Bacterium Bordetella Chlamydiatrachomatosis Clostridiumbotulinum Clostridiumdifficile Corynebacteriumdiphtheiae Klebsiellapneumonitae Neisseriameningitidis Proteusmirabilis

47

AssociatedDiseases Whoopingcough Chlamydia Botulism(typicallyfoodborne) Causativepathogeninmultiplediseases,typicallynosocomial, includingseverediarrheatolifethreateningcolitis Diphtheria Pneumonia,liverabscesses,septicemia Bacterialmeningitis Urinarytractinfections

WorldHealthOrganization.(2008)WHOglobalburdenofdisease:2004update.Availablefrom: www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html

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Salmonella Staphylococcusaureus Staphylococcuslugdunensis Streptococcuspyogenes Tropherymawhipplei Vibriocholerae Yersiniapestis Protozoa Bodosaltans Leishmania(multiple) Plasmodium(multiple) Trypanosomabrucei Helminthes Ascaris Echinococcusmultilocularis Onchocercavolvulus Schistosoma

Causesbroadarrayofillnesses.Multiplespeciesandsubspeciesof thisbacteriasequenced Anosocomialandcommunityacquiredpathogen.S.aureusisthe mostcommoncauseofhospitalacquiredinfection Invasiveendocarditis Awidevarietyofillnesses,includingstreptococcaltoxicshock syndrome,acuterheumaticfever,scarletfever,andothers. Whipple'sdisease. Cholera Plague AssociatedDiseases Africansleepingsickness,Chagasdiseaseandleishmaniasis Leishmaniasis Malaria Sleepingsickness AssociatedDiseases Intestinalworms Intestinaltapeworms Riverblindness Bloodflukesassociatedwithschistosomiasisandbilharzia

Source:http://www.sanger.ac.uk/resources/downloads/bacteria.

Armedwiththisinformation,infectiousdiseasespecialists,microbiologists,immunologists,and homelandsecurityprofessionalsarebetterabletoenvisionanddevelopapproachestocombat infectiousdisease.Genomicanalysisisalsobeingappliedtounderstandingthenaturalimmunitythat someindividualshavetoinfectiousorganisms.RussHodge,notedsciencewriterfortheMaxDelbruck CenterforMolecularMedincine,makesnoteofthecentralimportanceoftheHGPinallowingthese newapproachestodiseasetodevelop: Modernmedicinearosewhenscientistslearnedtofightsomeoftheworstinfectiousdisease withvaccinesanddrugs.ThisstrategyhasnotworkedwithAIDS,malaria,andarangeof otherdiseasesbecauseoftheircomplexityandthewaytheyinfiltrateprocessesincells. Curingsuchinfectiousdiseases,cancer,andthehealthproblemsthatarisefromdefective geneswillrequireanewtypeofmedicinebasedonathoroughunderstandingofhowcells workandthedevelopmentofnewmethodstomanipulatewhathappensinsidethem.48The HGPwasandisoneofthecentralprojectsleadingtothisunderstandingofhowcellswork andopeningthewayfornewapplicationsofmolecularmedicine. AnotherapproachfacilitatedbythesequencingofthehumangenomeisthatofGenomeWide AssociationStudiesanapproachthatinvolvesrapidlyscanningmarkersacrossanindividuals genome,tofindgeneticvariationsassociatedwithaparticulardisease.Oncenewgenetictargetsare identified,researcherscanusetheinformationtodevelopbetterstrategiestodetect,treatand preventthedisease.49Ithasbeennotedthatbydiscoveringlargecollectionsofgenesthatcan modulateaphenotype,GWAShasbeguntorevealunderlyingcellularpathwaysand,insomecases, 50 alreadypointedtonewtherapeuticapproaches. EricLandernotesseveralimportantexamplesof keyGWASfindingsassociatedwithmajordiseases,including:51
48 49 50

RussHodge.2010.TheFutureofGenetics:BeyondtheHumanGenome.FactsonFilePublishing,NewYork. http://www.hhs.gov/myhealthcare/glossary/glossary.html Ibid

EricS.Lander.Initialimpactofthesequencingofthehumangenome.Nature.Volume470,February10,2011.

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 AdultMacularDegeneration CrohnsDisease Type2Diabetes AutoimmuneDiseases KidneyDisease PsychiatricDisorders Genomewideexpressionanalysishasalsohadacentralroleinclassifyingcancersbasedontheir molecularproperties,ratherthananatomicsites.Studieshaverevealeddistinctivesubtypesandshed lightonmetastaticpotential.Expressionsignaturesarealreadyusedintheclinictopredictwhich breastcancerpatientswillbenefitmostfromadjuvantchemotherapyorsurgery.52Despitethe usefulnessofGWAS,genomicsisanextremelyfastmovingfieldandresearchersfromDukearefinding thelatestsequencingequipmentenablesanevenmoredetailedapproach(seecasestudybelow). CASESTUDY:WholeGenomeSequencingforPinpointingDiseaseCausingVariants Inrecentlypublishedwork,researchersatDukeUniversityarefindingthatsequencingmay bebetterthangenomewideassociationstudiesatfindingcausalvariantsincommon diseases.53Theresearcherscametothisconclusionafterperformingwholegenome sequencingstudieson29individualsandfindingthatrarevariantsaresignificantlymore likelythancommononestobefunctional. Genomewideassociationstudieshavebeenusedtotrytopinpointthegenetic underpinningsofcommondisease,buthavesofaronlybeenabletoexplainasmall proportionofthepredictedheritability.Rather,theDukestudysuggeststhatrarevariants, whichGWASsofarhavenotbeendesignedtofind,mayberesponsibleforcommondiseases. Toarriveattheirresults,researchersinDavidGoldsteinslabatDukesequenced29 individualstoanaverage28foldcoverage,andcalled5,491,245singlenucleotidevariants. Theyfoundthatforallthefunctionalcategories,whenthevariantsaremoreraretheyare morelikelytobeinthefunctionalregionandthereforemorelikelytocausephenotypiceffect. Sequencingisdefinitelymorepowerful[thanGWAS]fordetectingrarevariants.With microarraystheSNPsarealreadyfixed,sotheyaremostlycommonvariants.But,whenyou dowholegenomesequencing,youfindallthevariantsthatyoucanfind,includingbothrare andcommon. Otherareasofbiomedicalresearchandtranslationalsciencearealsousingandleveragingthehuman referencesequenceandhumangenomesequencingtechnologiestoadvance.Stemcellresearchers, forexample,arecomparingnormalstemcellsandcancerstemcellstofindpathwaystonewcancer treatmentsforexampleinleukemia.Understandingthemolecularbiologyofhumanstemcellsand generegulationincelldifferentiation,facilitatedbythelearningfromhumangenomesequencing, holdspromisefortheuseofthesecellsforarangeoftherapeuticapplicationsinregenerative medicineanddiseasetreatment.TheNIHreportsthatstemcells,directedtodifferentiateinto

specificcelltypes,offerthepossibilityofarenewablesourceofreplacementcellsandtissuesto treatdiseasesincludingAlzheimer'sdisease,spinalcordinjury,stroke,burns,heartdisease, diabetes,osteoarthritis,andrheumatoidarthritis.54

52 53

Ibid

MonicaHeger.2011.DukeTeamSaysSequencingMaybeBetterthanGWASatPinpointingDiseaseCausing Variants.GenomeWeb.April05,2011.Accessedonlineathttp://www.genomeweb.com/print/965719 NationalInstitutesofHealth.StemCellInformation.Accessedonlineat: http://stemcells.nih.gov/info/basics/basics6.asp

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Imagingisalsoafieldbothinfluencinggenomicsandbenefitingfromit.Onthebenefitsideofthe equation,genomicsservestoidentifynewsurrogatemarkersfortherapymonitoring,whichmaybe usedastracersforimaging.Imagingandgenomicsalsogohandinhandwiththedisciplineof functionalgenomics,wherebytechnologiessuchasfunctionalmagneticresonanceimaging(fMRI) providetheopportunitytoexploreandevaluatethefunctionalimpactofgeneticpolymorphisms. Astheexamples,casestudiesandnarrativeaboveshow,thehumangenomesequencingprojecthas hadsignificantandprofoundimpactsonhumanmedicineandpublichealth.Thecomplexityofthe genomeandassociatedregulationactivityrevealedbytheHGPhasmadeprogressintherapiesand curesmoveatapaceperhapsslowerthansomepredicted,yetasNadiaRosenthalnotes: Whetherinregardtotheearlydetectionandpreventionofcongenitaldisease,thepromise ofalongerandhealthierlifespanthroughabetterunderstandingoftheroleofgenesin aging,orthecreationofnewdrugsbasedonapersonsuniquegeneticmakeup,theimpact ofgeneticsonmedicinewillcontinuetogrow.55

C.VeterinaryMedicine
Itshouldnotbesurprisingthattheprojectstosequencethehumangenome,whichalsoincorporated thesequencingofotheranimalorganismsforcomparativepurposes,hasproventobeofbenefitto veterinarymedicineinwayssimilartothatofhumanbiomedicinebenefits.Forexample,writingin 2009M.Breennotedthat: Thereleaseofanannotatedhumangenomesequenceassemblyandtheemergenceof genomicstechnologieshaveledtosignificantadvancesinourunderstandingofmanyhuman diseasesincludingcancers.AsDNAsequencingtechnologyhasbecomelesscostly,thefieldof comparativegenomicshasprogressedrapidlyandattentionhasturnednowtogenerating wholegenomeassembliesanddedicatedgenomicsresourcesforveterinaryspecies.Such progressbringsawholenewseriesofopportunitiestoadvanceveterinarymedicine.Many humanandanimaldiseasesshareapathogeneticbasis,andalthoughveterinaryspeciesneed advancesinbiomedicalresearchintheirownright,theconsiderationofcompanionanimals alsoasgoodcomparativemodelsforhumandiseasesawtheemergenceoftheone medicineconcept.Thefutureofmanyareasofhumanandveterinarybiomedicalresearchis verymuchinterdependent,withoneoftheclosestassociationsbeinginoncology.Itis inevitablethatveterinaryoncologywillbenefitenormouslyfromdataderivedfromgenomics andthatthiserawillseeahugeshiftinthewaysinwhichcompanionanimalcancerpatients areevaluatedandsubsequentlytreated.56 TheCollegeofVeterinarymedicineandBiomedicalSciencesatTexasA&MUniversityintroducesthe fieldofbiomedicalgenomicsbynotingthat: Genomicsisakeyandrapidlyevolvingresearchdisciplinethatcontinuouslyelucidatesnew dimensionswithinthedynamicstructureofmodernbiomedicine.Theanimalgenomics researchcommunityhaswitnessedanastonishingexpansionanddiversificationthroughout thepastdecade.Completionofthehumanandmousegenomesequencessparkedenormous interestintheannotationofthesegenomesthroughaseriesofdetailedcomparative analyses.Asaresult,genomesequencesarenowavailablefornearlyallmajormammalian companionandlivestockspecies,includingcattle,pig,dog,horse,cat,alpacaandchicken,as wellasbiomedicalmodelssuchastherat,rabbit,opossum,sharkandXenopusgenomes. Rapidmethodologicalandcomputationaladvancementsaffordedbygenomesequencedata
55

NadiaRosenthalForwardinRussHodge.2010.TheFutureofGenetics:BeyondtheHumanGenome.Factson FilePublishing,NewYork. M.Breen.2009.Updateongenomicsinveterinaryoncology.TopicsinCompanionAnimalMedicine,2009.Aug; 24(3):113.Accessedonlineat:http://www.ncbi.nlm.nih.gov/pubmed/19732729

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areprovidingthemeansfornewareasofresearchthatcouldbarelybeimaginedjustafew yearsago.Thestudyandanalysisofanimalgenomescontinuouslyprovidesnewtechnologies tobetterunderstandphenotypesofbiomedicalandeconomicimportanceinthesespecies, whileatthesametimeinforminghumanbiology. Figure6illustratesthemajorareasofveterinarymedicineandanimalsciencebeingimpactedbythe sequencingofthehumangenomeandtheresultinggrowthinbioscienceknowledgeandassociated genomicstechnologies.Aswithhumanbiomedicine,veterinarymedicineisbenefitingfrom: Genomicsbasedmoleculardiagnosticsproductdevelopment Developmentoftherapeuticsproducts Vaccinedevelopment Animalimprovement.
Figure6:FunctionalImpactAreasofGenomicsinVeterinaryMedicineandAnimalScience

Veterinary Medicine

Molecular diagnostics

AnimalModels/ ComparativeGenomics

DNAVaccines

Veterinary Medicine and Animal Science

Pharmacogenomics

PedigreeEstablishment andAnimalImprovement ZoonoticDisease Identificationand Characterization

WholeGenome Sequencing

EarlyintheHGP,biomedicalscientistsrealizedthevalueoffullysequencedmammalandother organismgenomesforcomparisontothehumangenomeinpartasmodelorganismsforthestudyof disease.Theresulthasbeenmajorsequencingprojectsdirectedatanimalsusedinresearch(the laboratorymouse,chimpanzee,Norwegianbrownrat,rhesusmacaque,etc.),companionanimals(cat, dogalsousedinresearch),andagriculturalanimals(suchasthehorse,pig,cattle,sheep,goatsand chickens).Intotal,theNCBIEntrezGenomesDatabaselists1,111eukaryoticgenomesequencing projects,including40completed,408inassemblyand663inprogress.Thelistofmammalsalonethat havebeensequenced,areinassemblyorhavewholeorpartialgenomesequencingissubstantial (Table17).

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Table17:CurrentMammalianOrganismSequencingProjects

Completed Laboratorymouse Chimpanzee

Source:NCBIEntrezGenomeDatabase

Assembly Giantpanda Cattle(bostaurus) Waterbuffalo Whitetuftedearmarmoset Dog Guineapig Hoffmanstwotoedsloth Ninebandedarmadillo Ordskangaroorate Lesserhedgehog Horse(domestic) WesternEuropeanhedgehog Cat(domestic) Gorilla Alpaca Africanelephant Rhesusmacaque Tammarwallaby Graymouselemur Gray,shorttailedopossum Littlebrownrat Whitecheekedgibbon Americanpika Duckbilledplatypus Rabbit Bushbaby Sheep(domestic) Sumatranorangutan Caperockhyrax Largeflyingfox Rat Europeanshrew Thirteenlinedgroundsquirrel Pig(wild) Philippinetarsier Northerntreeshrew Bottlenosedolphin

InProgress Woollymammoth MiddleAfricanhedgehog Cattle(bosindicus) Bactriancamel Coyote Graywolf Goat(domestic) Sundaflyinglemur Ringtailedlemur Crabeatingmacaque Chinesepangolin Europeanpolecat Bonobo Olivebaboon Yellowbaboon Hamadryasbaboon Guineababoon Chacmababoon Californiamouse Whitetailedmouse NorthAmericandeermouse Oldfieldmouse Indusriverdolphin Greaterhorsehoebat Tasmaniandevil

Othercategoriesofanimalarealsobeingsequenced,suchasreptiles(e.g.thegreenanole),birds (chickenandzebrafinch)andfish(tilapia,salmon,andpufferfish,forexample).

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Thesesequencingprojectsprovidedatathatishighlyusefulforabroadrangeofapplications:for comparisontothehumangenome;forthestudyofevolutionaryprocesses;asmodelorganismsfor biologicalstudy,andforveterinarymedicine.Whilecompanionanimals,livestock,poultryand economicallyimportantaquaticspecies(suchastilapia,shrimp,salmonetc.)areakeytargetfor sequencingwork,thereisalsoapplicationtoveterinarymedicineinthediversefamilyofgenomesfor workwithrareandendangeredspeciesandinvasivespecies. Itshouldalsobenotedthatmuchofthesequencingworkperformedonpathogenicorganisms, parasitesanddiseasevectorshasalsotargetedeconomicallysignificantdiseasesinfectinglivestockand poultry,togetherwithpathogensaffectingcompanionanimals.Workinveterinarymedicineusing genomicsandgeneticstodetect,diagnoseandtreatdiseaseisalsoofimportancetohumanhealthand medicineinthecaseswherepathogenscausezoonoticdiseases(infectiousdiseasesthatcanbe transmittedfromananimaltoahuman). CASESTUDY:DogGenomics Forpetowners,theirpetsarepartofthefamilyandtheirhealthmaintenancealegitimate concern.TheAmericanVeterinaryMedicalAssociationreportsthatthereare72milliondogs intheU.S.and82millioncats,withtheaverageannualveterinaryexpenditurefora householdwithpetstotaling$366in2006.57Over79,000veterinariansareinpracticeinthe U.S.58 Thedomesticdog(canisfamiliaris)isclosetofullcompletionandalreadytheimpactof genomicsisbeingfeltinveterinarymedicalpractice.MultipleDNAmutationtestsareonthe marketforcanineinheriteddiseases,helpingvetsdiagnosedogdisordersrangingfrom eyesightdisorders(suchasprogressiveretinalatrophy)tosevereimmunodeficiencydisorders andhemophilia.Abroadvarietyofveterinarymedicineanddiagnosticscompanieshave incorporatedgenomicsintotheirR&Dandproductdevelopmentpipelines,suchasOptigen, PennGenLaboratoriesandVetGen. Workinhumangenomicsisalsotransferringdiscoveriesofrelevancetoveterinarymedicine, andcomparativegenomicsallowsthedogtobeusedasamodelforhumandiseases.In addition,genomicsisatoolbeingappliedtopurebredanimalbreedingandthedevelopment ofbreedswithspecificdesiredcharacteristics.

Thehumangenomefieldhasled thewaybothintermsof completenessofdataandin developingtoolsand applications.Animalgenomics broadlyfollowsasimilarroute, butthereisamajordifferencein thatanimalsareselectedto express(orrepress)specific traits,andinfacthavebeen deliberatelyselectedoverseveral thousandyears.Thismeansthat theyalsoformauniqueresource forcomparativegenomicswith otherspecies,includinghumans. Inaddition,theuseofselection andquantitativegeneticsin animalsiswelladvancedandthis givesthedisciplineofsystems biologyattheanimal,or population,levelaleadingedge overthehumanfield.Notonly, therefore,doesfarmanimal genomicshavethepotentialto improvesustainableagricultural production,butinkeyareasitisa toolfordevelopinghuman genomicsresearch. PeterBurfening,etal.,The FutureofLivestockGenomics, ECUSTaskForceonBiomedical Research.

Theextenttowhichgenomicshaspenetratedtheworldofveterinarymedicineresearchcanbe illustratedbythedepthofcourseofferingsinthefieldatmajorveterinarymedicinecollegesinlarge U.S.landgrantuniversities.AtTexasA&M,forexample,coursesandresearchfocusareasareavailable in:59 Mammaliangenomics Comparativegenomics Populationgenomics Conservationgenomics Phylogenomicsandgenomeevolution Immunogenomics
57

Functionalgenomics Mammaliandiseasegenomics Genomicsofsexandreproduction Computationalgenomics Epigenomics

AmericanVeterinaryMedicalAssociation(AVMA).2007.U.S.PetOwnership&DemographicsSourcebook(2007 Edition). AmericanVeterinaryMedicalAssociation(AVMA).VeterinaryMarketStatistics.Accessedonlineat: http://www.robertsonproperties.com/Veterinary%20Market%20Statistics%20%20U.S.pdf

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TexasA&MUniversity.Accessedonlineat:http://vetmed.tamu.edu/research/signatureprograms/biomedical genomics

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D.AgricultureandFood
Humankindspurposefulmanipulationofgeneticsactuallyhasitsrootsinthousandsofyearsof agriculture.Whilecertainlyearlymandidnotunderstandthebiologybehindhisactions,thepractice ofselectedbreedingofplantsandanimalswasafundamentalgenomicprocess.Bygraduallyimproving cropsanddomesticatedanimals,humanswereabletoformlocationstablesocietiesgeneratinga foodsurplusthatenabledthedevelopmentofcivilization.60 Today,perhapsevenmoresothaninmedicine,theimpactofmoderngenomicsisseeingwidespread applicationacrossagriculture.Viatransgenics,plantsarebeingimprovedintermsofinputtraits (efficientuptakeoffertilizer,droughttolerance,pestresistance,etc.)andoutputtraits(nutritional content,foodquality,biomassoutput,etc.).Facilitatingthisnewgreenrevolutionisthefundamentally improvedknowledgeofgenomicsandmolecularbiologystimulatedbytheprojectstosequencethe humangenome. Therelevanceandimportanceofgenomicstoagricultureishardtooverstate.Someofthemost pressingchallengesfacingtheglobalcommunityhavetheirsolutionsrootedinagricultureissuessuch asfoodsecurity,humanhealth,environmentalsustainabilityandeconomicgrowth.Thescopeofthese challengescanseemoverwhelming.Infoodsecurity,forexample,worldwidepopulationisprojected toincreasefrom7billionpeoplein2010to9.3billionby2030(anincreaseof2.3billion,equivalentto doublingtheentirecurrentpopulationofChinaandIndia).61AsBattellenotesinitsrecentreportfor 12landgrantuniversities: Tomeettherisingdemandforfood(drivenbothbyrisingpopulationandincreasingincome levels),itisanticipatedthatby2030wemayactuallyneedtodoubleglobalfood production,62yetmostcultivatablelandisalreadyinproduction.63Theinequityofglobal incomelevelsandaccesstofoodacrosstheplanetalreadyleadstodebilitatinglevelsof malnutrition,undernutritionandassociatedpoorhealthforover1billionpeople.64Meeting thedemandsofagrowingpopulation,formoreandbetterfood,andthedemandforthe fiber,fuelsandmaterialsrequiredasinputsforeconomicgrowth,ismadeallthemore difficultbythepressingneedtodosowhilereducingenvironmentalimpactsandglobal climatechangeassociatedwithhumaneconomicactivity.Againstthisbackgroundofglobal needandchallenges,ofthreatsandopportunities,itbecomesclearthattheroleof agriculture,andassociatedagbioscienceadvancements,hascomeoncemoretotheforeasa criticaldriverofhumankindsfuture.65 Agriculturehastoworktoaddressthesedauntingchallengesusingthelandalreadyinproduction, sincelandnotcurrentlycultivatedistypicallyoflowsoilquality,inforestedareasthatneedtobe environmentallyprotectedorinareaswithlowlevelsofwateravailability.Increasingproductiontothe levelneeded,doingsowithlowerlevelsofresourceuse,andproducingmorenutritiousfoodstoserve themalnourishedaretasksthatagriculturalgenomicsdirectlyaddresses.

Populationgrowthisamajor challengeforagriculturebecause mostoftheworldsusable farmlandisalreadyinproduction. In1991,0.81acresoffarmland wasavailabletofeedeach person.By2050,only0.37acres offarmlandwillbeavailablefor eachperson.Itmeansthe productivityofeachunitofland mustbeincreased. BIO.2010Healing,Fueling, Feeding:HowBiotechnologyis EnrichingYourLife

60

BiotechnologyIndustryOrganization.2010.Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. BIOonlineatwww.valueofbiotech.org SimonJ.Tripp.Power&Promise:AgbioscienceintheNorthCentralUnitedStates.BattelleMemorialInstitute, April2011. BruceM.Chassey,WayneA.ParrottandRichardRoush.CropBiotechnologyandtheFutureofFood:AScientific Assessment.CASTCommentary,QTA20052,October2005.

61

62

63

UnitedNationsFoodandAgricultureOrganization(FAO).WorldAgricultureTowards2015/2030,Summary Report.Accessedonlineatwww.fao.org/documents/show_cdr?url_file/DOCREP UnitedNationsFoodandAgricultureOrganization(FAO).TheStateofFoodInsecurityintheWorld.Accessed onlineatwww.fao.org/publications/sofi/en/ SimonJ.Tripp.Power&Promise:AgbioscienceintheNorthCentralUnitedStates.BattelleMemorialInstitute, April2011.

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Whiletheapplicationofgeneticshasalonghistoryinagriculture,themodernabilitytosequence entireplantandanimalgenomestakesagbiosciencetoanewlevelofunderstandingregarding organismalmolecularbiology.Thetoolsandtechnologiesofgenomicsareasapplicabletoplantand livestockbiologyastheyretohumanbiomedicalbiology.Someofthemajorapplicationsofgenomics inagricultureandfoodareillustratedinFigure7:

Figure7:FunctionalImpactAreasofGenomicsinAgricultureandFood.

Agriculture andFood

Molecular diagnostics

ImprovedCrops (InputandOutputTraits)

LivestockImprovement andHealth

Agriculture andFood

FunctionalFoodsand Nutraceuticals

FoodProcessing Technologies
TheU.S.DepartmentofEnergynotesthat:

BioPharming

Understandingplantandanimalgenomeswillallowustocreatestronger,moredisease resistantplantsandanimalsreducingthecostsofagricultureandprovidingconsumerswith morenutritious,pesticidefreefoods.Alreadygrowersareusingbioengineeredseedstogrow insectanddroughtresistantcropsthatrequirelittleornopesticide.Farmershavebeenable toincreaseoutputsandreducewastebecausetheircropsandherdsarehealthier.66 Indeed,asearlyas2002,astheresultsoftheHGPwerefirstbeingexperienced,RobertBozellnoted thattheuseofgenomicsinagriculturalbiotechnologyhasalreadyyieldedimprovementsinpest resistanceanddroughtresistanceandcanbeusedtopreservebiodiversity.67 Theadvancementsmadeinsequencingtechnology,especiallythegreatlyenhancedspeedof sequencingandthedramaticallyreducedcostofsequencinghavemadeiteconomicallyfeasiblefor agbiotechcompanies,universitiesandgovernmentresearchgroupstodeploythefullforceofgenomic analysisinpursuitoffoodandagricultureadvancement.Ontheanimalagriculturefront,sequencing programsincattleareallowingrapididentificationofsinglenucleotidepolymorphisms(SNPs)with
66

U.S.DepartmentofEnergyGenomicScienceProgramHumanGenomeProjectInformation.2009.Potential BenefitsofHumanGenomeProjectResearch.Accessedonlineat: http://www.ornl.gov/sci/techresources/Human_Genome/project/benefits.shtml RobertBazell.2002.Introduction:ApplicationsofGenomicstoMedicineandAgriculture.ChapterinMichael YudellandRobDeSalle(editors)TheGenomicRevolution:UnveilingtheUnityofLife.2002.JosephHenry Press,WashingtonDCwiththeAmericanMuseumofNaturalHistory.

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over62,000SNPsidentifiedthroughtheuseofmassivelyparallelsequencingequipmenttoproduce shortreadsacross66cattle.Nextgenerationsequencingisalsoallowingagbioscientiststoprobe expressedregionsofthecattlegenomeandprovidefreshinsightongeneregulationimpactsoncattle development,meatcontent,milkproduction,healthandreproduction.Similarapplicationswilloccur acrossotherlivestockandpoultryspecieswithadvancedgenomesequencingprograms,includingpigs, chickens,goatsandsheep.68 CASESTUDY:UnravelingtheAmazingGenomicComplexityofCropPlants Theapplicationofgenomesequencingtoanimalsisonething,doingitwithsomecropplants, however(despitetheimportanceofcropplantstohumanexistence),hasbeendaunting.On thefaceofit,itseemscounterintuitivethatacropplantcouldhaveafarlargergenomethan acomplex,thinking,walking,humanyetthatisindeedthecase.Wheat,forexample,hasa genomefivetimesthesizeofthehumangenome.Thewheatgenomeis17gigabaseslonga resultofthehybridization/breedingprocessandtheresultingwheatgenomeactuallyhas threesetsofDNA.Cropgenomesalsotendtohavelargescaleareasofrepetitivesequences makingitchallengingtoreconstructthesequenceofbasesoneachchromosome(ofwhich wheathas42). Theimportanceofwheatasastaplecropishardtooverstate,withwheatflourbeingthe basisforsuchbasicfoodstuffsasbreadandpasta.Indeed,wheatistheleadingsourceof vegetableproteininthehumandiet.TheUnitedNationsreportsthat676milliontonsof wheatwasproducedin2010.Withglobalpopulationanddemandincreasing,findingwaysto increasewheatproduction,andlessenlossestoplantstressorssuchasdiseaseordroughtis criticallyimportant.Planttransgenicsisprovingtobeapowerfultoolforimprovinginputand outputtraitsinplants,butitspromiseisbestrealizedifagbioscientistshaveacomplete understandingoftheplantsgenome.Thelargescalehumangenomesequencingprogram spurredthedevelopmentofthehighspeed/affordablecostsequencingtechnologiesthatare todaybeingappliedtokeycropplants.Iftheexpansionofproductionchallengeistobemet fortheworldsgrowingpopulation,itistransgeniccropimprovementthatisgoingtogetus thereanditishumangenomesequencingthatpropelledthedevelopmentofthe technologiesthatempowermoderncropgenomics. Geneticallymodifiedcrops,alsoknownasbiotechcrops,arenowonthefrontlinesofaddressingthe agriculturalproductivityimperative.MattRidley,sciencewriterforTheEconomistnotesthat: Geneticallymodifiedcropsareprovingtobeanunmitigatedenvironmentalmiracle. Herbicidetolerantplantsarenowgrownwithminimumtillage,whichreducesthesoilerosion thatresultsfromploughing.Droughttolerantplantsarenearingthemarketandsalttolerant onesarenotfarbehind.Withinadecade,theremaybecropsthatarenotill,insectresistant, omega3enriched,droughttolerant,salttolerantandnitrogenefficient.Iftheyboostyields, thenthe21stcenturywillseemoreandmorepeoplebetterandbetterfedfromlessandless land.69 In2009,morethan330millionacresofbiotechcropsweregrownin25countriesand14million individualfarmerschosetogrowbiotechcrops.AsBIOreportsthefindingsofresearchersthat: Theadoptionofbiotechcropshasnotbeenlimitedtofarmersinthedevelopedworld:2009 dataindicatethatalmost93percent(13million)ofthe14millionfarmersgrowingbiotech cropsin2009weresmallandresourcepoorfarmersfromdevelopingcountriessuchasChina, India,PhilippinesandSouthAfrica.Intermsoftotalacreageofbiotechcropsplanted,the
68

GeorgeE.Liu.2009.ApplicationsandcaseStudiesoftheNextGenerationSequencingTechnologiesinFood, NutritionandAgriculture.RecentPatentsonFood,NutritionandAgriculture,2009.1,7579. MattRidley.2009.TheNEUthing:nitrogenuseefficiency,thenextgreenrevolution.TheEconomist.13November 2009.

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developedworld(withitslargerfarms)planted40percentoftheacreage,whiledeveloping countriesaccountedfor60percent.Between1996and2009morethan2.3billionacresof biotechcropshavebeensuccessfullygrownasaresultofapproximately70millionrepeat decisionsbyfarmerstogrowthesecrops.70 Themajorcategoriesofbenefitsfromtheapplicationofgenomicstoagriculturearebroad,including: Increasedagriculturalyieldsandagriculturalproductivityincropsbymodifyingplant genomestodevelopselectiveherbicideresistance,pestanddiseaseresistance,drought tolerance,fastergrowth,largergrains,etc.Similarapproachescanbetakenforforestry production. Increasedyieldinlivestockgenomicsallowsagbioscientiststomodifylivestock, poultryandfishgenomestoincreasemeatcontent,lowerfatcontent,enhancethe uptakeofnutrientsintheanimal,andenhanceanimalreproduction.Genomicsisalso poweringveterinarymedicinetocombatpathogensaffectinganimalhealthandlivestock productivity. Improvedfoodquality,nutritionandhealthproductsgenomicscanbeappliedto developcropswithcustomizedvitaminandnutrientprofilestoenhancedietsandcanbe growntoexpressspecificvitaminsandevenediblevaccines.Plantscanalsobeusedfor biopharminginwhichplantsareusedasfactoriesfortheproductionof biopharmaceuticalproductsandtheproductionofnutraceuticalsandfunctionalfoods. Likewise,transgenicanimalsmaybedevelopedtogroworgansforhuman transplantation. Reducingtheenvironmentalimpactofagriculturegenomicsallowsagbioscientiststo developcropsthatrequiretheapplicationoflowerlevelsofpesticidesorherbicides, thataresuitedtonotillagronomy,orthatrequirelesswaterforsuccessfulgrowth. Enhancedfoodsafetygenomesequencinghasbeenappliedtoseveralkeypathogens thathavegeneratedfoodborneillnessoutbreaks,suchasE.coli.Theabilitytogenotype strainsofinfectiousorganismsallowstheFDAtotracethesourceofoutbreaksand directlyaddresstheissue. Newandexpandingbiobasedindustriesheregenomicsisbeingappliedtogrowa sustainablebiobasedeconomyinwhichbiomassisusedtoderivebioenergy,liquid biofuels,sustainablebiobasedchemicals,plasticsandmaterials.Industrialbiotechnology usesengineeredmicrobestoproduceenzymesandotherbiologicalagentsforthe productionofvaluableproducts. CASESTUDY:GenomicsofRice,theWorldsLargestStapleCrop Twogroupsofresearcherssequencedthegenomesofrelatedsubspeciesofrice.Riceisa foodstapleforoverthreebillionpeople.Itprovides20percentoftheworld'sdietaryenergy supply,whilewheatsupplies19percentandmaize5percent.Scientistsareusingthedatato createimprovedvarietiesofricethatgrowindifferentenvironmentsandhavedesirabletraits suchaspestresistanceandincreasednutritionalvalue.Advancesmadewithricealsomaybe appliedtootherimportantcropspeciessuchaswheatandcorn.Initially,itwasestimated thatricehadbetween43,000and63,000genes.Theestimateswerelaterloweredtoabout 38,000genes71

Thecomingdecadeswillbe unparalleledandwillplaceplant researchersinthepositionof beingabletomodifythe nutritionalcontentofmajorand minorcropstoimprovemany aspectsofhumanandanimal healthandwellbeing. MartinaNewellMcGloughlin, Director,UniversityofCalifornia SystemwideBiotechnology ResearchandEducationProgram (UCBREP)andCoDirector,NIH TrainingPrograminBiomolecular Technology

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BiotechnologyIndustryOrganization.2010.Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. BIOonlineatwww.valueofbiotech.org NationalHumanGenomeResearchInstitute.2002:RiceGenomeSequenced.UnderstandingtheHuman genomeProject:DynamicTimeline.Accessedonlineat:http://www.genome.gov/25520488

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E.IndustrialBiotechnology
Biologicalorganisms,especiallymicrobes,haveevolvedcapabilitiestothriveinextremeenvironmental conditions(heat,cold,pressure,andevenradioactiveenvironments).Characteristically,thesearealso environments(particularlythefirstthree)encounteredinmanyindustrialprocesses,especiallywithin thechemicalsandenergyindustries.Recognizingtheabilityofmicroorganismstoperformfunctional activitiesintheseextremeenvironments,biotechnologistshaveadaptedmicrobestouseinactivitiesin chemicalprocessing,biofuelsproduction,foodprocessing,pharmaceuticalandvitaminproduction, andtheproductionofsustainablebioproducts,suchasplasticsandbiobasedmaterials. Whilesciencedoesnotknowthetotalnumberofmicrobespeciesonourplanet,itisanticipatedto numberinthemillions.72Thesemicrobesexistinthesoil,inwater,inair,andonandwithinother organisms.Providingarangeofsymbioticbiologicalservices(suchasdigestion)andevennetworking functionsastheyinteractwithinecosystems(partofthesubjectofmetagenomics),thefunctional characteristicsofmicrobeshaveconsiderableapplicationinindustry.Atabasiclevel,humankindhas severalthousandsofyearsexperienceinthebiotechnologyprocessoffermentationusingyeastto convertsugarstoalcoholsinbrewing.Today,however,modernsequencingtechnologiesandgenome manipulationtechniquesareallowingscientiststomodifymicrobesforatremendousrangeofuses, andeventosynthesizeartificialmicrobiallifeforms.Indoingso,industrialbiotechnologistsand researchscientistsareapplyingthetoolsofgenomics,facilitatedbythehumangenomesequencing developmentprograms,toachieveimpactsinmanyindustrialareas(seeFigure8):
Figure8:FunctionalImpactAreasofGenomicsinIndustrialBiotechnology

Today,modernsequencing technologiesandgenome manipulationtechniquesare allowingscientiststomodify microbesforatremendousrange ofuses,andeventosynthesize artificialmicrobiallifeforms.In doingso,industrial biotechnologistsandresearch scientistsareapplyingthetools ofgenomics,facilitatedbythe humangenomesequencing developmentprograms,to achieveimpactsinmany industrialareas.

Industrial Biotech

BiofuelsandBioenergy

BiobasedChemicals

DrugsandBiologics Production

Industrial Biotech

BiobasedMaterials

IndustrialEnzymes/ Biocatalysis

MineralandEnhanced OilRecovery

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SunHeeHong,etal.2006.PredictingMicrobialSpeciesRichness.ProceedingsoftheNationalAcademyof SciencesoftheUnitedStates(PNAS).January3,2006.Volume103,Number1.Pages117122.

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TheuseoffinitefossilresourcestofueltheU.S.andglobaleconomiesisnowrecognizedasan unsustainablemodel.Thecombustionofoil,naturalgasandcoalisreleasinghighlevelsofcarbon dioxideimplicatedinglobalclimatechange.FortheU.S.,thereisalsoastrategicimpetustoavoid overdependenceonforeignoil,whichrepresentsasecurityrisk.Theissuesofpeakoilandhighprice volatilityofoilonglobalmarketsalsoposethreatstoU.S.economicstability.Asaresult,theraceison tofindsustainablealternativefuels.Whilesolar,wind,hydroandnuclearpowercangenerate electricity,theydonotprovidetheliquidfuelsneededforourexistingtransportationinfrastructure northefeedstocksneededtosupplythechemicalsandmaterialsindustries.Onlybiomassoffersthe opportunitytogenerateasustainablestreamofsuchliquidfuelsandchemicalfeedstocks.Becauseof this,majordevelopmentprogramsarerelyingongenomicstostudymicrobes,algae,plantmaterials andotherbiologicalresourcesaspotentialfuelproductionsystems.TheU.S.DepartmentofEnergys JointGenomeInstitute(JGI)isattheforefrontofeffortstosequencegenomesforenergy,industrial andenvironmentalapplications. CaseStudy:MicrobialGenomicsforBiofuelsandBiofeedstocksattheJointGenomeInstitute(JGI) TheDOEJGImaintainsadatabaseofmicrobialgenomessequencedbytheDOE.Alreadythis datasetcontains485sequencedmicrobialgenomesand40microbialcommunitygenomes. Therapidadvancesingenomesequencingspeeds,spurredbytheHGPandassociated projects(ofwhichtheDOEwasakeyleaderandfundingagency),isallowingDOEandthe organizationsitfundstosearchthemicrobialworldfororganismswithuniquefunctionality forefficientindustrialbiotechapplications. Considerablesequencingworkhasbeendirectedtowardsmicrobesthatdigest,orfacilitate thedigestionofcellulosicbiomass.Celluloseisacomplexcarbohydrate(polysacharine)that makesupthecellswallsofplants.ComprisingthemostabundantorganicmoleculeonEarth, cellulosecontainsimmenseamountsofenergylockedwithinitsstructure.Thechallengeis thatcelluloseisdifficulttobreakdownintoglucoseforeconomicaluseinindustrialfeedstock andliquidfuelapplications.Numerousmicrobeshave,however,evolvedtodothistask throughtheproductionofenzymesthatbreakdowncellulose(suchorganismsresideinthe gutofruminants,suchascows,forexample,allowingthemtodigestcellulosicbiomasssuch asgrassandstraw).TheJGIisengagedinmultiplesequencingprogramsaimedatidentifying microbesandtheirexpressedenzymesforuseincellulosebreakdown.TheJGIalsoengaged inplantgenomesequencingworktoidentifybiologicalcharacteristicsthatwillmakecell wallseasiertodeconstructandbiomasseasiertoprocess.TheJGIisintheleadinfungi sequencing,againwithagoaloffindingenzymestobreakdowncellulose,aswellas metagenomicsstudiestoexaminemicrobialcommunitiesandtheirimplicationsfor bioprocessing. Theapplicationofgenomicstoindustrialfeedstocks,fuelsandprocessingtechnologieshasattracted significantindustryinvestment,inadditiontogovernmentlabanduniversitybasedwork.Major energysectorcompaniessuchasExxonMobil,ConocoPhillips,BPandShellareactivelyresearching,or sponsoringresearch,ingenomicsforbiofuelsandbiobasedchemicalandplasticsfeedstocks. Biotechnologyandgenomicsstartupcompanieshaveattractedsubstantialventurecapitalmoney withinthesector.Plantbiotechnologycompaniesarealsoengagedinproducingplantvarietieswith highbiomasscontent,specializedoilcontent,orotherexpressedtraitcharacteristicssuitingthemto economicalindustrialbioeconomyapplications.CompaniessuchasMonsanto,LandoLakesandCeres aredevelopingspecializedbiomasscrops,whileindustrialbiotechcompanieslikeNovazymesand Genzymeareusinggenomicsinthedevelopmentofbioprocessingenzymes.Alreadybiofuelsareon themarketfromfirstgenerationstarchfermentationtechnology,andtherearemultipleexamplesof sustainablebiobasedplasticsandchemicalssuccessfullycompetinginthemarketplacewith petrochemicals(suchasNatureworksLLCsIngeobrandbiopolymerproducedataplantinBlair Nebraskawitha300millionpoundsannualcapacity).

Onlybiomassoffersthe opportunitytogeneratea sustainablestreamofliquidfuels andchemicalfeedstocks.Because ofthis,majordevelopment programsarerelyingon genomicstostudymicrobes, algae,plantmaterialsandother biologicalresourcesaspotential fuelproductionsystems.

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CaseStudy:TheU.S.EconomicImpactofAdvancedBiofuelsProduction AnanalysisbyBioEconomicResearchAssociates(bioera)calculatestheprojectedeconomic impactsofbuildinganadvancedbiofuelseconomyby2022.MeetingtheU.S.RenewableFuel Standardsrequirementfor21billionannualgallonsofproductionby2022wouldhavethese projectedeconomicimpacts: 29,000directjobscreatedby2012,94,000by2016,and190,000by2022.Totaljobimpacts intheeconomy(comprisingdirectandindirectemploymentviatheemploymentmultiplier effect)couldreach123,000in2012,383,000in2016,and807,000by2012. Total(directandindirect)economicoutputgeneratedbytheadvancedbiofuelsindustry couldreach$20.2billionby2012,$64.2billionby2016,and$148.7billionby2022. Anticipatedcumulativereductioninpetroleumimportsovertheperiod20102022would exceed$350billion
Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. 2010.BIO,TheBiotechnologyIndustryOrganization(www.valueofbiotech.com)

Furtheradvancementsingenomicsandtheassociatedunderstandingofmolecularbiologyprocessesis evenleadingtothedevelopmentofsyntheticbiologywherebyasyntheticgenomecanbe constructedtoachievespecificbiologicalfunctionality. CaseStudy:SyntheticBiologyANewApproachtoEngineeringBiology Syntheticbiologyisanewbiotechnologytoolenablingbiotechnologiststogofarbeyond manipulationofoneortwogenes,andinsteadintoengineeringchangesinentiregenetic pathways.Ineffect,scientistscannowwriteDNAcode,ratherthanmakingsimple modificationstoanexistingcode.Suchbiotechnologybringssomeastoundingopportunities totheindustrialbiotechspheremostnotablyanabilitytocustomizeengineermicrobes, suchasbacteriaoryeast,toproducespecificchemicalcompounds(compoundsthatthe microbeneverpreviouslymade). Examplesofsyntheticbiologysuccessfullyappliedinmanufacturingprocessesalreadyexistin pharmaceuticalsmanufacturingwithproductionprocessesfortheantimalarialdrug artemisininandthewidelyprescribedcholesterolloweringstatinLipitor(Pfizer). Codexisisabiotechcompanyactiveinsyntheticbiologyandnovelbiocatalystdevelopment fromenzymes.Codexisbiotechnologyisbeingusedtosynthesizethechiralsidechainof atorvastatin,theactiveingredientinLipitor.Thenewprocesshasreducedthecostof producingthestatinbyupto70percentandcapitalexpendituresby35percent. Syntheticbiotechnologiesandbiocatalystshavetheadvantageofreducingprocessstepsand operatingatlowertemperaturesandpressuresthantheirchemicalprocesscompetition.The netresultislessconsumptionofenergyinprocessingandreducedcapitalcostsforequipment (sincetheequipmentneednotwithstandhightemperaturesandpressures).
Healing,Fueling,Feeding:HowBiotechnologyisEnrichingYourLife. 2010.BIO,TheBiotechnologyIndustryOrganization(www.valueofbiotech.com)

TheOECDsInternationalEnergyAgencystatesthatbiomassisthemostimportantrenewableenergy sourcetoday.Biotechnologyandgenomicstoolsare,andwillcontinuetobe,akeycontributorto realizingmaximumenergyvaluethroughbiomassfeedstocks: Plantbasedsystemscapturesolarenergyandcanbeproducedinarenewablemanner. However,theharvestablepartsarenotwelloptimizedforenergytransferandthishasbeena

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significantlimitationtothedevelopmentofeconomicallyviableandsustainablebiomass energysystems.Biotechnologyhasprovidedanewtoolsetthatcanbeusedtodesignand optimizethecaptureofsolarenergythroughcrops.Furtherdevelopmentofbiotechnology andgenomicstoolswillenablethedevelopmentofcropswithspecifictraitsthatare optimizedforbiofuelsandbioenergy.Theimplementationofsuchasystemwillenablea sustainableplatformforcenturiestocomeandshouldbegivenahighpriorityinsociety.73

F.EnvironmentalApplications
Oureconomicdevelopmentandindustrialization,oftencomeswithanenvironmentalcost.Onan annualbasis,over400milliontonsofEnvironmentalProtectionAgency(EPA)designatedhazardous wastesaregeneratedeachyear,ofwhichfully256milliontonsaregeneratedintheU.S.alone.74 Includedinthiswastearesubstancesthataretoxictolife,carcinogenic,mutagenicorteratogenic (interferingwithembryoorfetusdevelopment).Humanindustrial,agriculturalandotherdailyliving activitiesreleaseairpollutants,waterpollutantsandcontaminatesoil.Acrosstheglobethereis widespreadcontaminationbyheavymetals,pesticides,herbicides,hydrocarbons,radioactivematerials andotherpersistentpollutants.Wehaveareasofoceansandlakesinwhichpollutantcaused eutrophicationhasloweredoxygentotheextentthattheybecomedeadzones.Wehavebrownfield sitesacrosstheglobelargelyurbanlegacyindustrialsites,whichintheU.S.alonehaveanestimated cleanupcostof$650billion($2,100foreverypersoninthenation).75Nowwehaveapreponderance ofagreementinsciencethathumankindsactivitiesareevenimpactingtheglobalclimate. Whilepollutionthreatenslifeontheplanet,lifeitselfmayholdthesolutiontopollution. Microorganismshaveevolvedtothriveinextremeconditionsandtoabsorbandmetabolizean incrediblywidesuiteofchemicals.Organismsthriveinconditionsrangingfromfreezingtemperatures tonearboilingpointwatertheythriveinenvironmentsofintensepressureinthedeepestpartsof theocean,andinextremearidconditionsindesertsandwithinsaltflats.Microorganismshaveeven beenfoundlivinginspentnuclearfuelstorageponds.Itisnowwidelyrecognizedthatmicroorganismal diversityhasfarreachingimplicationsforaddressingsuchDOEmissionchallengesastheremediation ofradioactiveandhazardouswastesites,sequesteringheattrappingcarbonfromtheatmosphere,and developingrenewableenergysources.76 Asshowninthisreport,thegenomerepresentsatemplateforgoverninglifeprocesses.Assuch,by understandingthegenomicstructureofmicrobes,scientistsareabletodiscoverthegenesand regulatoryprocessesthatimpartusefulactivityforpollutionmitigation,foruptakeofcarbonandfor otherenvironmentallyimportantapplications. TheHGPbeganin1990,andleveragingtheadvancementsmadeDOElaunchedtheMicrobialGenome Projectin1994tosequencethegenomesofnonpathogenicorganismsusefulinsolvingDOEsneedsin environmentalwastecleanup,energyproduction,carboncyclingandbiotechnology.Similarly,the GenomestoLifeProgram(GTL)aimedtousemicrobesandotherorganismstoaddressproblemsin energyproduction,environmentalcleanup,andcarboncycling.ThishasevolvedintoDOEsGenomic ScienceProgram(formerlyGenomics:GTL)usingmicrobialandplantgenomicdata,highthroughput analyticaltechnologies,andmodelingandsimulationtodevelopapredictiveunderstandingof
J.S.McLaren.2005.Cropbiotechnologyprovidesanopportunitytodevelopasustainablefuture.Trendsin Biotechnology.2005Jul:23(7):33942 MicrosoftEncartaonlineencyclopedia,2009andtheUnitedStatesEnvironmentalProtectionAgency. MichiganStateUniversity.EnviroToolsFactsheet:Brownfields.Accessedonlineat: http://www.envirotools.msu.edu/factsheets/brownfields.shtml U.S.DepartmentofEnergy,JointGenomeInstitute.WhySequenceMicrobes?Accessedonlineat http://www.jgi.doe.gov/sequencing/why/microbes.html

Recentdiscoveriesfromprojects fundedbyDOE'sBiologicaland EnvironmentalResearch programhighlightthe ubiquitouspresenceandcritical importanceofmicrobesinall ecosystems.Forexample: Diatoms,ancientandintricately shapedoceanmicrobes,storean amountofcarboncomparableto thatinalltheearth'srainforests combined.Overgeologicaltime, diatomsmayhaveinfluencedthe earth'sclimate. Morethanamillionpreviously undiscoveredgenes,possibly representingnewbiochemical functions,werethesurprising findinsequencingDNA fragmentsfromtheSargasso Seaaregionheretoforethought tosustainlittlelife.Thisdiscovery alsowasnamedoneofScience magazine's"Breakthroughsof theYear." Microbesthrivedeepwithinthe earthssubsurfaceandat extremespreviouslythoughtto extinguishlife.Growing recognitionofmicrobial capabilitiesandpotential applicationshasmadea compellingcaseforfurther investigationsbyDOEandother agenciesandinstitutions. Source: http://microbialgenomics.energy. gov/benefits.shtml

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74 75

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biologicalsystemsbehaviorrelevanttosolvingenergyandenvironmentalchallengesincluding bioenergyproduction,environmentalremediation,andclimatestabilization.77 Whenapplicationsofgenomicsareexaminedacrosstheenvironmentalspectrumitisevidentthatthe fiveprimarymacrocategoriesofapplicationareasshowninFigure9.

Figure9:FunctionalImpactAreasofGenomicsinEnvironmentalScienceandSustainability

Environ ment

PollutionControl andMitigation

BiodiversityStudies/ Metagenomics

BiocontrolAgents

Environment

CarbonDioxideCapture

Green/Sustainable Products
Pollutioncontrolandmitigationmicrobesplayanimportantfunction.Indeedithasbeennotedthat LivestockintheUnitesStatesproduce1.7billiontonsofmanureannuallyalmostallofitisdegraded bysoilmicoorganisms.78Whilemanuredegradationbymicoorganismsoccursnaturallyinthe environment,humansusepurposedevelopedmicoorganismstodegradeanddetoxifyhumansewage, whileotherengineeredorganismsarebeingappliedinthetreatmentofindustrialwastematerialsand hazardouswaste.Becausemicrobeshavecomparativelysmallgenomes(averaging45millionbases versusthe3billiontypicalinmammals),theyareabletobesequencedcosteffectivelyandrapidly enablingscientiststounderstandtheirlifeprocessesandinvestigatetheirapplicationtoarangeof pollutiondegradationneeds.DOEsJointGenomeInstitutehas,inparticular,ledprogramstosequence abroadrangeofmicoorganismswithapplicationtobioremediationneedsasdiverseasradioactivity, heavymetals,pesticidesandhydrocarbons.Plantgenomesarealsostudiedforopportunitiestouse plantsforabsorptionofpollutionfromthesoilandwater(calledphytoremediation). Becausecommunitiesofmicrobesofdifferenttypescanaccomplishactivitiesthatasinglespeciesof microbealonecannot,thereisconsiderableutilityinmetagenomicsstudiesthatsequenceentire populationsofmicrobesfromsamplesofsoilorseawater,forexample.Thisisparticularlyimportant developingapproachestotacklecomplexpollutants,suchasoil,thathavemultipleconstituent
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U.S.DepartmentofEnergy.GenomicScienceProgram.Accessedonlineat: http://genomicscience.energy.gov/#page=news OfficeofTechnologyAssessment.2002.ImpactsofAppliedGenetics:Micoorganisms,Plants,andAnimals. BooksforBusiness,NY.

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chemicalsthatnosingleorganismcandegrade.Metagenomicsrevealsthesymbioticeffectsof microorganismsworkingtogetherinfact,itisfoundthatvariousmicrobesmayworkinsequence, withthewasteproductofonebeingthefuelforthenext.Metagenomicstudiesarealsoenabling researcherstobetterunderstandthecomplexityofecosystemsandtheeffectsofhumanactivitieson them. Inadditiontobioremediationofpollutants,genomicadvancementsareenablingscientiststodevelop biocontrolagentstoaccomplishactivitiessuchaspestcontrolwhichwouldotherwiseusechemicals forthesamefunction.Forexample,nematodes(predatoryroundworms)canbeengineeredtohonein on,interceptanddestroywhitegrubsinlawns,negatingtheneedforchemicalwhitegrubpesticide applicationswhichcanrunoffduringrainandnegativelyimpactgroundwaterandwatersheds. Biocontrolgenomicsisalsoworkingtoproduceenvironmentallysustainableapproachestothecontrol ofplantpathogens.ThecompletesequenceofthebiologicalcontrolorganismsPseusomonas fluorenscensPf5,forexample,hashelpedresearchersunderstandthegenesandregulatoryprocesses involvedinthismicrobesabilitytoexpressantibiotics.Byelucidatingthegenesinvolved,genescanbe transferredtootherorganismsforsimilarlyusefulexpressionproducts. Globalclimatechangeconcernsaredrivingeffortstoreducecarbondioxideemissionsandtocapture carbondioxidefromtheatmosphere.Plantsmetabolizecarbondioxideandproduceoxygen;likewise, manyspeciesofmicrobescanmetabolizeorfixcarbondioxide.Genomicstudiesarehelpingtoidentify opportunitiestobetterleverageplantsandmicrobesascarbondioxidereservoirs.Inaddition,of course,plantsandalgaecanproducecarbonneutralfuelsourcestoreducethereleaseoffossilcarbon fromcoal,oilandnaturalgasutilization.Genomicsisplayingacriticalroleindevelopinglignocellosic cropsthatcanbemorereadilyprocessed,microbesandenzymesforbreakingdowncellulosetoallow cellulosicbiofuelstobeproducedeconomically,andevenspeciallyengineeredstrainsofalgae customizedforhighratesofgrowthandlipids(oil)production.Thedevelopmentofliquidbiofuelsis onepartofabroadergreenchemistryandsustainableproductsmovementbasedonbiological controlviagenomicsamovementenablingthedevelopmentofchemicals,plasticsandbiobased materialsthatcanbeproducedinasustainablefashionandarereadilydegradedinpostusedisposal. CaseStudy:TheJ.CraigVenterInstituteandSyntheticGenomicsInc. Recognizingtheimportanceofmicrobestoenvironmentalsustainability,climatechange controlandothercriticallyimportantneeds,thenonprofitJ.CraigVenterInstitutehas undertakenfocusedprogramstoinvestigatekeyreservoirsofmicrobes,suchastheearths oceans,toidentifymicrobesandgenesofinterest.TheGlobalOceanSamplingExpedition,for example,uncoveredmorethansixmillionnewgenesasaresultofitssamplingand sequencingprogram. SyntheticGenomicsInc.,(SGI)alsofoundedbyJ.CraigVenter,isworkingoncommercial applicationofgenesdiscoveredviatheseandotherinvestigationsperformedbytheJ.Craig VenterInstituteandothercollaborators.SGIisfocusedfirstoncreatinggenomicdriven commercialsolutionsforbioenergyapplicationsandhasestablishedimportantpartnerships withmajorenergycompaniessuchasExxonMobil.Usingleadingedgegenomictechnologies, SGIisengineeringsyntheticalgaeorganismsoptimizedforbiofuelproduction.SGIisalso usinggenomicsindeterminingpathwaystomoreefficientuseofcellulosicmaterialsfor bioenergyproduction,andisinvestigatingmicrobesfortheconversionofcoalintofuelsand chemicalsandothervalueaddedproducts.

G.Forensics,JusticeandSecurity
Asgenomicshasopenedthestudyofmedicine,biology,andbiotechnologytoentirelynewworlds,so ithasdoneinthefieldofforensics,criminalandsocialjusticeandsecurity.Figure10illustratessome oftheapplicationsofgenomicsandgeneticsinthisfieldcurrently.

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Figure10:FunctionalImpactAreasofGenomicsinForensics,JusticeandSecurity

Forensics, Justiceand Security

DNAFingerprinting

RemainsIdentification

PaternityTesting

Forensics, Justiceand Security

IllegalEndangered Animal PartsIdentification

Biosecurity (PathogenDetection andIdentification)

NationalDNADatabank (CODIS)

OneofthecharacteristicsofDNAisthatitvariesfrompersontoperson.ThusanalysisofDNAcanbe usedtospecificallylinkaDNAsampletoaspecificpersonusefulinsolvingcrimes,resolvingquestions ofidentityinremainsidentification,andresolvingquestionsinpaternitycases.Innaturalordeliberate disasters(suchastherecentHaitianearthquakeandthe9/11terroristattack)theanalysisofDNA sampleshasprovenitselftimeandtimeagainasavaluabletoolforremainsidentification.Such geneticandgenomicanalysisisalsoprovingimportantintheidentificationofillegallyimportedorgans, tissue,fursandotherbodypartsofendangeredspeciesseizedbycustomsorotherlawenforcement officials. Theincreasingandprescientthreatofbioterrorismisaparticulardriveroftheuseofadvanced genomicsinsecurityandlawenforcement.Indeed,asearlyas2001thefieldofforensicgenomics emergedtotackleaseriousthreattodomesticsecuritythe2001anthraxletterattacks(seecase study). CaseStudy:MicrobialGenomicsSolvestheAnthraxAttacks Afterthe2001anthraxletterattacks,researchersattheInstituteforGenomeSciencesatthe UniversityofMarylandSchoolofMedicine,whoworkedwithresearchersattheFederal BureauofInvestigation(FBI),theU.S.ArmyMedicalResearchInstituteofInfectiousDiseases andNorthernArizonaUniversity,publishedapaperrecountingthescientificinvestigationinto theanthraxattacksof2001.Thecasewasgroundbreakingbecauseofitsuseofgenomicsand microbiologyinacriminalinvestigation. Morethan20peoplecontractedanthraxfromBacillusanthracissporesmailedthroughthe U.S.PostalServicein2001,andfiveofthosediedasaresult.Theinvestigationbecameknown asAmerithrax.Theworkpioneeredthenewfieldknownasmicrobialforensics,ascience thatwillplayakeyroleintheinvestigationsofanyfuturebioterrorattacks.TheMarch7, 2011ProceedingsoftheNationalAcademyofSciencespaperdescribeshowInstitutefor

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GenomeSciencesfacultyandcollaboratorsfromtheFBIconcludedthattheanthraxsamples takenfromalltheattacksweregeneticallyidentical.Later,anothergroupofscientistswould tracetheanthraxsporefoundinthelettersbacktoaflaskofBacillusanthracisandseveral samplesthatweretakenfromthatflask. "ThispaperandtheAmerithraxinvestigationreallymarkedthebeginningofanewapproach forthesciencewecallforensicgenomics,"saysthepapersseniorauthorJacquesRavel,PhD, whoisAssociateProfessorofMicrobiologyandImmunologyatTheUniversityofMaryland SchoolofMedicineandAssociateDirectorforGenomicsattheInstituteforGenomeSciences. "ThesciencewasacriticalcomponentoftheAmerithraxcase.Withoutgenomics,itwould havebeenextremelydifficulttonarrowthepoolofpotentialsuspects." "BeforeAmerithrax,nooneappreciatedtheprecision,accuracy,andreliabilitythatthistype ofgenomicscanofferasamicrobialforensictechnique,"saidfirstauthorDavidRasko,PhD, AssistantProfessorforMicrobiologyandImmunologyattheSchoolofMedicineanda researchscientistattheInstituteforGenomeSciences.Asoneofthefirstinvestigationsofits kind,Amerithraxhelpedtoshapetheemergingfieldofmicrobialforensics.Sincethecase, Ravel,Rasko,andtheircolleaguesattheInstituteforGenomeScienceshavealsohelpedto shapethescientificcommunity'sefforttodevelopstandardsandguidelinesforfuture investigations.79 Advancedgenomictechniquesarealsoallowingresearcherstoperformworkthatwaspreviously impossible.Forexample,acomplexcrimescenecouldcontainDNAsamplesthataremixed containing,forexample,theDNAofavictim,familymembers,pets,microbesandanassailant. Separatingthesesamplesforanalysisisahighlycomplexchallenge,butsuccessisbeingachievedvia genomics(seecasestudybelow). CaseStudy:SeparationofanIndividualsDNAfromComplexMixedSamples ResearchersattheTranslationalGenomicsResearchInstitute(TGen)andtheUniversityof CaliforniaLosAngeles(UCLA)developedaprocessin2008todetectanindividualsDNAina mixture,inproportionswhicharelessthan0.1percentofthetotalmixture,withothersina singlecomplexsample.80LedbyDavidCraigatTGen,theteamusedhighdensitysingle nucleotidepolymorphism(SNP)genotypingmicroarraystodemonstratetheabilityto accuratelydeterminewhethertheDNAofseparateindividualsisinacomplexgenomicDNA mixture.Thentheydemonstratedexperimentallytheidentificationofthepresenceof genomicDNAofspecificindividualswithinaseriesofhighlycomplexgenomicmixtures,even whereanindividualcontributeslessthan0.1percentofthetotalgenomicDNA.These findingsshifttheperceivedutilityofSNPsforidentifyingindividualtracecontributorswithina forensicsmixture,andsuggestfutureresearcheffortsintoassessingtheviabilityofDNA sourcesthoughttobeuselessduetosamplecontamination. AVirginiabasedcompany,CaseworkGenetics,licensedthetechnologyfromTGenwhileit wasagranteeofCatapaultBioofArizona,aventurephilanthropyorganizationthatholds anequitypositioninCaseworkGenetics.81
79

Rasko,Ravel, ForensicGenomicsUsedtoInvestigate2001AnthraxAttacks,March7,2011,Proceedingsofthe NationalAcademyofSciences.

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HomerN,SzelingerS,RedmanM,DugganD,TembeW,etal.(2008),ResolvingIndividualsContributingTrace AmountsofDNAtoHighlyComplexMixturesUsingHighDensitySNPGenotypingMicroarrays.PLoSGenet4(8): e1000167.doi:10.1371/journal.pgen.1000167 http://www.flinn.org/news/926

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CaseStudy:IdentificationofVictimsofthe9/11TerrorAttacks DOEsHumanGenomeProjectInformationSiteshowstheforensicsapplicationofDNA analysisinactiononaneventthatchangedAmerica.TheDOEwebsitereportsthat: IdentifyingthevictimsoftheSeptember11,2001,WorldTradeCenterattackpresenteda uniqueforensicchallengebecausethenumberandidentityofthevictimswereunknownand manyvictimswererepresentedonlybyboneandtissuefragments.Atthetimeoftheattack, nosystemswereinplaceforrapidlyidentifyingvictimsindisasterswithmorethan500 fatalities.TheNationalInstitutesofJusticeassembledapanelofexpertsfromNIHandother institutionstodevelopprocessestoidentifyvictimsusingDNAcollectedatthesite.Panel membersproducedformsandkitsneededtoenablethemedicalexaminersofficetocollect referenceDNAfromvictimspreviouslystoredmedicalspecimens.Thesespecimenswere collectedandenteredintoadatabase.Themedicalexaminer'sofficealsoreceivedabout 20,000piecesofhumanremainsfromtheWorldTradeCentersite,andadatabaseofthe victimsDNAprofileswascreated.Newinformationtechnologyinfrastructurewasdeveloped fordatatransferbetweenthestatepoliceandmedicalexaminersofficeandtointerconnect thedatabasesandanalyticaltoolsusedbypanelmembers.In2005,thesearchwasdeclared atanendbecausemanyoftheunidentifiedremainsweretoosmallortoodamagedtobe identifiedbytheDNAextractionmethodsavailableatthattime.Remainsofonly1,585ofthe 2,792peopleknowntohavediedhadbeenidentified.In2007,themedicalexaminer'soffice reopenedthesearchaftertheBodeTechnologyGroupdevelopedanewmethodologyofDNA extractionthatrequiredmuchlesssamplematerialthanpreviouslynecessary.ThevictimDNA databaseandthenewmethodshaveallowedmorevictimstobeidentified,andfurther identificationswillbepossibleasforensicDNAtechnologyimproves.82 Itislikelythatinfectiousdiseasecausingpathogenswillbeapreferredmodeofbioterrorattackforthe perpetrators.Moderngenomesequencerswillbeonthefrontlineincharacterizingtheorganismsused insuchanattackandtracingthebiologicalagentbacktoitssource.ThisishighlightedbySlezaketal, whonotethat: Rapidadvancesinthegenomicsequencingofbacteriaandvirusesoverthepastfewyears havemadeitpossibletoconsidersequencingthegenomesofallpathogensthataffect humansandthecropsandlivestockuponwhichourlivesdepend.Recenteventsmakeit imperativethatfullgenomesequencingbeaccomplishedassoonaspossibleforpathogens thatcouldbeusedasweaponsofmassdestructionordisruption.Thissequenceinformation mustbeexploitedtoproviderapidandaccuratediagnosticstoidentifypathogensand distinguishthemfromharmlessnearneighboursandhoaxes.83 CaseStudy:GenomicsontheFrontlinesofNationalBiodefense TheU.S.DepartmentofHomelandSecuritysNationalBiodefenseAnalysisand CountermeasuresCenter(NBACC)isthecentralnationalcenterforthecharacterizationof biologicalthreatstohomelandsecurity,andisthecorelab,underPresidentialDirective,for thebioforensicanalysisofevidencefrombiocrimeorterrorismattack.NBACCismanaged andoperatedbytheBattelleNationalBiodefenseInstitutefortheU.S.Departmentof HomelandSecurity.GenomesequencingisanintegralcomponentoftheCentersworkand theworkofcontractlabssupportingtheCenter.NBACCoperatesmultiplegenome sequencingplatforms,rangingfromtraditionalSangersequencers(asusedintheHGP) throughtoinstrumentsfrom454LifeSciences,PacificBiosciencesandthenewIonTorrent
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HumanGenomeProjectInformation.DNAForensics.Accessedonlineat: http://www.ornl.gov/sci/techresources/Human_Genome/elsi/forensics.shtml T.Slezak,etal.2003.Comparativegenomicstoolsappliedtobioterrorismdefense.BriefingsinBioinformatics. June2003;4(2):13349

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desktopmachinefromLifeTechnologies.Sequencingisplannedasthebackboneofanew methodologyforsupportingbiocrimeinvestigators,enablinganalysisofsamplestobe performedwithoutpriordevelopmentofmorelimitedmicroarrays.Beingabletorespondto thecaseworkdemandsofinvestigatorswithoutneedingtopredevelopontheshelf biochemistrieswillbeanimportantstepinkeepingthenationsafeandrespondingrapidlyto biologicalagentevents.TheNBACCsresearchscientistsarealsoutilizingthemajorreference genomesequences,facilitatedbytheHGPwork,suchasthedatafromtheMicrobialGenome ProjectandtheHumanMicrobiomeProject.

Longerterm,genomicswillalsoplayanimportantroleinthedevelopmentofvaccinesandtherapid developmentoftreatmentsforinfectiousagentsbasedonbiotechnologyusinggeneticallyengineered microbialproductiontechniques.

H.Conclusion:Outcomes,ProductsandImpacts
Thesequencingofthehumangenomehashadaprofoundandparadigmshiftingimpactonbasic biologicalscienceandourunderstandingofbiomolecularlifeprocesses.Inaddition,thelargescale sequencingprograms,ledbytheHGP,spurredtherapiddevelopmentofadvancedsequencing equipmentandtechnologythatspawnedanentiregenomicsbasedtechnologysector.Todays sequencingplatformscananalyzewholegenomesataspeedneverbeforethoughtpossible. Genomesequenceinformationhasgreatutilityacrossabroadrangeofscientificandtechnical disciplines.Inhumanbiomedicalscienceanewclassofadvanceddiagnostictestshasbeen developedbecauseofadvancesinhumangenomics,andthefieldofpharmacogenomicsisforming theunderpinningofpersonalizedmedicineandemergingbiomedicalapplicationssuchasgene therapyandregenerativemedicine.Inaddition,thehumanreferencegenomeandthetechnologies ofmoderngenomicshavesignificantlyaffectedscienceandappliedtechnologydeploymentin multiplefieldsoutsideofhumanmedicine.Disciplinesincludingveterinarymedicine,agricultureand foodproduction,forestry,environmentalscience,industrialbiotechnology,biofuelsdevelopment andbiosecurityandforensicsareallbeneficiariesandusersoftheknowledgeandtechnological advancementsmadepossiblebytheHGPandassociatedprograms. Theapplicationofgenomicsacrosstheabovefieldsanddisciplinesgeneratesabroadvarietyof functionaleconomicandsocialimpacts.Basedonthisdetailedreviewoftheliteratureongenomics applicationsandassociatedimpacts,Battelleconcludesthattheprimaryimpactareasinclude: KnowledgeExpansionandEducationBenjaminFranklinwrotethataninvestmentin knowledgepaysthebestinterest.Weliveinamodernknowledgeeconomythat dependsoninnovationandtechnologicaladvancementforeconomicprogressandthat equallydependsonaknowledgeableandskilledpopulacetoachievehighproductivity economicactivity.Thesequencingofthehumangenomehasgeneratedastartling advanceinourknowledgeoffundamentalbiologicalstructuresandmolecularprocesses, andthatknowledgeopensnewhorizonsforfuturedevelopment. EconomicDevelopmentAshighlightedinChapterII,thetoolsandtechnologiesof genomics,inpartempoweredbytheHumanGenomeProjectandassociatedprograms, areresultinginthegrowthofcommercialenterprisefocusedontheproductionof genomicanalysisequipment,laboratorysuppliesandtheprovisionofgenomicanalysis services.WithadistinctconcentrationofthiscommercialenterpriseintheUnited States,theHGPandCeleraprogramshavesupportedthegrowthofthisdomestic industry.Furthermore,theapplicationofbiologicalknowledgegeneratedbytheHGPis openingnewproductdevelopmentpathwaysinhumanbiomedicalproductsand applicationsinmanyotherbusinesssectors.

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HumanHealthThroughthesequencingofthehumangenome,biomedicalscientists haveamoreaccurateunderstandingofthemolecularbiologyofthehuman.This understandingisbeingappliedtoidentifytargetsfornewandexistingtherapeutics,to develophighlyrefineddiagnostictests,andpavethewayforanewparadigmof personalizedmedicine.Withthegenomeinhand,researchersarealsoadvancing promisingnewdisciplinessuchasgenetherapyandregenerativemedicine. EnvironmentalSustainabilityHumanactivityhassignificantimpactsonour environment;totheextentthatscientificconsensusisthatweareprecipitatingclimate change.Pollutionfromhumanactivitieshasimpactedoursoils,waterandairand,asa result,ourselvesandotherorganismsinthebiosphere.Theapplicationofgenomics advancements,however,isdrivingthedevelopmentoftechnologicalsolutionsto environmentalchallenges.Geneticengineeringofmicrobestocapture,digestand mitigatevariousenvironmentalpollutantsisoneimpactarea,togethernowwiththe abilitytousegenomicsdrivensyntheticbiologytoengineerentirelyneworganisms.The applicationofgenomicstobiofuelsandenvironmentallysustainablerenewable chemicalsandindustrialinputsisahereandnowareaofimpact,withpositivebenefits beingfeltandgreatpromiseforthefutureinadvancedbiofuelsandindustrial bioeconomyapplications. FoodSecurityandSafetyGrowthinglobalpopulationandincomelevelsisleadingtoa dramaticincreaseinthedemandforfood.Predictionsarethatby2030wewillneedto doubleglobalfoodproduction.84Genomicsisempoweringadvancementsincropand livestockimprovement,providinguswithhigheryieldingcrops,protectionofourfood supplyfromdiseaseandpests,andfoodproductswithenhancednutritioncontentand functionalhealthpromotingcharacteristics.Advancedsequencingtechnologies,spurred intheirdevelopmentbyhumangenomesequencing,areempoweringanewgreen revolutioninagricultureandfoodproduction,andalsoassuringasaferfoodsupply.The positiveeconomicconsequencesarebroadanddeeplyfeltrangingfromnewproducts andopportunitiesforproducers,reducedinputcostsforfarmers,reducedlosses,and enhancedhealthandassociatedproductivityandwelfare. NationalSecurityTheapplicationofmoderngenomicknowledgeisalsoenhancing U.S.nationalsecurityacrossmultiplefronts.Thedevelopmentofdomesticadvanced biofuelsandbiobasedindustrialinputsisreducingdependenceonforeignoil,while genomicsisalsoonthefrontlinesinaddressingthethreatofbioterrorism. JusticeGenomicsisbeingappliedtocriminalandsocialjustice.Asauniqueidentifier, thegenomeholdspromisefordefinitiveidentificationoftheindividual,butbeyondthat itprovidesthemeanstotracebiologicalmaterialstopointoforigin(importantfor investigations).Onasocialjusticefront,thesequencingofthehumangenomealsoshifts basicthinkingonsuchdivisiveissuesasrace,andisprovidingnewpathsformore equitableaccesstofood,healthcareandeconomicopportunity. Ultimately,weseethatthesequencingofthehumangenomehaseconomicandfunctionalimpactsfar beyondtheobvioushumanbiomedicalscienceimpacts.Ithasprovidedafundamentalplatformfor advancementsacrossnotonlythebioscienceofthehuman,butourunderstandinganduseofall organisms.Ithasspurredtechnologydevelopmentthathasimpactsfeltindisciplinesasdiverseas industrialbiotechnology,environmentalscience,agriculture,andsecurity.

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ChapterIV:IntotheFuture

Thesequencingofthehumangenomewasthesignaturescientificprogramofthe1990sandearly 2000s.WhenScience,in2010,producedaretrospectiveonthetenmostimportantinsightsofthe decade,fiveofthetenmostinfluentialscientificinsightsstemfrom,ormakeuseof,thehuman genomesequencingandrelatedgenomicsadvances(Table18).

Table18:ScienceMagazine,TopInsightsoftheDecade2010

Insight Genomic Complexity

Description
SciencewriterElizabethPennisicomments:

Generegulationhasturnedouttobeasurprisinglycomplexprocessgovernedby varioustypesofregulatoryDNA,whichmayliedeepinthewildernessofsocalled junkDNAthatliesbetweengenes.Farfrombeinghumblemessengers,RNAsofall shapesandsizesareactuallypowerfulplayersinhowgenomesoperate.Finally, there'sbeenincreasingrecognitionofthewidespreadroleofchemicalalterations calledepigeneticfactorsthatcaninfluencethegenomeacrossgenerations withoutchangingtheDNAsequenceitself.Thescopeofthisdarkgenome becameapparentin2001,whenthehumangenomesequencewasfirst published.

Science17December2010: Vol.330no.6011p.1614

TheHuman Microbiome

SciencewriterElizabethPennisicomments:

Thispastdecadehasseenashiftinhowweseethemicrobesandvirusesinand onourbodies.Thereisincreasingacceptancethattheyareus,andforgood reason.Ninein10ofthecellsinthebodyaremicrobial.Inthegutalone,asmany as1,000speciesbringtothebody100timesasmanygenesasourownDNA carries.Afewmicrobesmakeussick,butmostarecommensalandjustcallthe humanbodyhome.Collectively,theyareknownasthehumanmicrobiome. Likewise,somevirusestakeupresidenceinthebody,creatingaviromewhose influenceonhealthanddiseaseisjustbeginningtobestudied.

Science17December2010: Vol.330no.6011p.1619

StemCellsand Regenerative Medicine

SciencewriterGretchenVogelcomments:

Bypromptingacelltooverexpressafewgenes,researchershavediscoveredin thepastdecadehowtoturnaskinorbloodcellintoapluripotentcell:onethat hasregainedthepotentialtobecomeanynumberofcellsinthebody.Other genescanpromptskincellstoturndirectlyintoneuronsorbloodcells.Scientists arealreadyusingthetechniquetomakecelllinesfrompatientswithhardto studydiseases,andultimatelytheyhopetogrowgeneticallymatched replacementcellsandtissuesperhapsevenentireorgans.

Science17December2010: Vol.330no.6011p.1618

AncientDNA

SciencewriterAnnGibbonscomments:

Inthepastdecade,powerfulnewxrayscansandthreedimensionalcomputer modelshavetransformedtheanalysisofancientbones,teeth,andshells.Buta newkindofanalysisiscapableofrevealinganatomicaladaptationsthatskeletal evidencecan'tprovide,suchasthecolorofadinosaur'sfeathersorhowwoolly mammothswithstoodthecold.Thenewviewsoftheprehistoricworldhingeon therealizationthatbiomoleculessuchasancientDNAandcollagencansurvive fortensofthousandsofyearsandgiveimportantinformationaboutlongdead plants,animals,andhumans.

Science17December2010: Vol.330no.6011p.1616

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The Inflammation/ Disease Connection

SciencewriterJenniferCouzinFrankelcomments:

Notlongago,inflammationhadaclearrole:Itwasasidekicktothebodys healers,brieflysettinginasimmunecellsrebuilttissuedamagedbytraumaor infection.Today,that'sanafterthought.Inflammationhashitthebigtime.Over thepastdecade,ithasbecomewidelyacceptedthatinflammationisadriving forcebehindchronicdiseasesthatwillkillnearlyallofus.Cancer.Diabetesand obesity.Alzheimersdisease.Atherosclerosis.Here,inflammationwearsagrim 85 mask,sheddingitsredeemingfeaturesandmakingsickpeoplesicker.

Science17December2010: Vol.330no.6011p.1621

Theimpactonbiologicalsciencehasbeenprofoundandparadigmshifting,andtheaccelerated developmentofgenomicsandrelatedtechnologieshasenabledgenomesequencingtobeapplied acrossabroadvarietyofimportantapplicationsinhumanmedicine,veterinarymedicine,agriculture, industrialbiotechnology,environmentalsciences,justiceandsecurity. Inmedicine,genomicsisbeingappliedtodaytoquantitativelydiagnosediseasesanddisorders,to developoptimizedtreatmentregimensforpatientsbasedontheirgenomicprofile,todevelopgene therapiestocorrectdiseasecausinggeneticvariants,andtoengineerbiologicalmaterialstorepairand regenerate.Newapproachestovaccinesarebeingdeveloped,andinfectiousdiseaseorganisms combated,becauseofgenomicsadvances.AsBattelleinterviewedleadingscientistsandindustry representatives,theconsistentmessagewasthattheworldofgenomicsandgenomictechnologies wouldbenowhereneartheadvancementsachievedtodaywithouttheHGP,itsfindings,andthe developmentstimulusitprovided. Theplatformofknowledgeandthetechnologiesresultingfromhumangenomesequencinghave formedthebasisofnothinglessthanamedicalrevolution.Theprimaryimpactsofthisrevolutionin quantitativeandpersonalizedmedicinemaynotyetbefeltindailyclinicalpractice,butthatdayis acceleratingtowardsus.WritinginNature,EricLandernotesthat: Medicalrevolutionsrequiremanydecadestoachievetheirfullpromise.Genomicshasonly justbeguntopermeatebiomedicalresearch:advancesmustproceedthroughfundamental tools,basicdiscoveries,medicalstudies,candidateinterventions,clinicaltrials,regulatory approvalandwidespreadadoption.Wemustbescrupulousnottopromisethepublica pharmacopoeiaofquickpayoffs.Atthesametime,weshouldremainunabashedaboutthe ultimateimpactofgenomicmedicine,whichwillbetotransformthehealthofourchildren andourchildrenschildren.86 Theultimategoalistocreateareferencecatalogueofallgeneticvariantscommonsenough tobeencounteredrecurrentlyinpopulations,sothattheycanbeexaminedforassociation withphenotypesandinterpretedinclinicalsettings.Effortstowardsthisgoalarealreadywell underway.The100GenomeProject(whichplanstostudymanymorethanonethousand genomes)aimstofindessentiallyallvariantswithfrequencyofgreaterthan1percentacross thegenomeandgreaterthan0.1percentinproteincodingregions.87 Landercontinues: Theultimategoalisforsequencingtobecomesosimpleandinexpensivethatitcanbe routinelydeployedasageneralpurposetoolthroughoutbiomedicine.Medicalapplications willeventuallyincludecharacterizingpatientsgermlinegenomes(todetectstrongly
ThegenomicstoinflammationlinkwashighlightedbyCWSchmidtinearlierwork.SchmidtnotedthatToday, genomicsdefinesthecuttingedgeofinflammationresearch.Genomicstudies,inadditiontotheirproteomic andmetabolomiccousins,aimtoresolveanageoldmystery:namely,whysomepatientsrecoverreadilyfrom inflammationwhileotherssufferanddiefromit.SeeSchmidtCW.2005.CriticalCare:ApplyingGenomicsto InflammationOutcomes.EnvironHealthPerspect113:A816A821.doi:10.1289/ehp.113a816 EricS.Lander.2011.Initialimpactofthesequencingofthehumangenome.Nature.Volume470, February10,2011. Ibid

Theworldofgenomicsand genomictechnologieswouldbe nowhereneartheadvancements achievedtodaywithouttheHGP, itsfindings,andthedevelopment stimulusitprovided.

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predictivemutationsforpresymptomaticcounselingwheretreatments exist,tosearchforcausesofdiseasesofunknownaetiology,andtodetect heterozygouscarriersforprenatalcounseling);cancergenomes(by identifyingsomaticmutationstocomparetumourandnormalDNA); immunerepertoires(byreadingthepatternsofBcellandTcellreceptors toinferdiseaseexposuresandmonitorresponsestovaccines);and microbiomes(byassociatingpatternsofmicrobialcommunitieswith diseaseprocesses).Researchapplicationswillincludecharacterizing genomes,epigenomesandtranscriptomesofhumansandotherspecies, aswellasusingsequencingasaproxytoprobediversemolecular interactions. Tofulfillthispotential,thecostofwholegenomesequencingwillneedto eventuallyapproachafewhundredUSdollars.Withnewapproaches underdevelopmentandmarketbasedcompetition,thesegoalsmaybe feasiblewithinthenextdecade.88 Writingin2006inthejournaloftheRoyalPharmaceuticalSocietyofGreatBritain, PaulMartinandMichaelMorrisondiscussedthefutureofgenomicmedicineand summarizedthepotentialhorizonforgenomicmedicineinclinicalpractice(Table 19).Theirconclusionsarereasonableinlightofexperienceandwhatweknow aboutmedicaldevelopmenttimetables.89
Table19:PotentialTimetablefortheAdvanceofGenomicMedicine

TheFutureofGenomicsinMedicine
DiagnosticsAppropriatetreatmentofadiseasecan onlybeginonceanaccuratediagnosisismade. Genomicswillincreasinglydriveadvanced,highly accuratediagnosticsdevelopmentby: Identificationofvariantgenesandtheirimpacton monogenicandmultigenicdiseases. Subclassificationofdiseasesbygenomeanalysisto directpersonalizedmedicineapproaches(asis alreadyoccurringincertaincancers). Methodsforrealtimepathogendetectionand identification. TherapeuticsGenomicswillsignificantlyincreasein utilityacrossarangeoftherapeuticR&Dand applicationareas,including: Identificationofspecificdiseaserelevanttargets. Rationaldrugdesigntoproducedrugsspecifically aimedatthecharacteristicsoftheidentifiedtargets. Repurposingofexistingdrugsforapplicationto newlyidentifiedgenomictargetsandsignatures Previouslyfaileddrugsrescuedforapplicationto genomicsubpopulations Clinicaltrialsimprovedthroughgenomic stratificationofparticipants Significantlyreducedadversedrugevents,and associatedcosts,drivenbygenotypeguideddrug prescription. Increasingapplicationofgenetherapies Therapeuticstrategiesdevelopedforgenotype environmentinteractionsandforadaptationto behavioralandlifestylecharacteristics. Furtherperspectiveonmanyoftheaboveaspectsof thefutureofgenomicmedicinemaybefoundin:Eric GreenandMarkGuyer.2011.Chartingacoursefor genomicmedicinefrombasepairstobedside.Nature. Volume470.February10th2011.Pp:204213.

Technologiesthatarewellentrenchedintheclinic Genetictestingformonogenicdisorders Therapeuticproteins. Themediumtermprospectforanexpansionofthesetechnologiesisvery promisingandtheyraisefewnewsocial,ethicalorpracticeissues. Technologiesthatarestartingtobecomeentrenchedintheclinic Pharmacogenomicdrugs Pharmacogenetictests Genetictestsforcommonconditions Adultstemcelltherapies. Anexpansionofthesetechnologiesinthemediumtermisthereforelikely. However,eachofthemhasyettobefullyentrenchedinamaturemarketor establishedsetofclinicalpractices.Theystillfacesignificanttechnicaldifficulties and,withtheexceptionofpharmacogenomicdrugs,theywillalsohaveto overcomeanumberofcommercial,clinical,ethicalandregulatorydifficulties. Technologiesthathaveyettosuccessfullyentertheclinic Genetherapy Cancervaccines Embryonicstemcelltherapies. Eachofthesetechnologiesfaceverysignificantproblemsatpresentandare unlikelytoenterthemarketinanythingotherthanfirstproofofprinciple productsinthenearfuture.
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EricS.Lander.2011.Initialimpactofthesequencingofthehumangenome.Nature.Volume470,February10, 2011. PaulMartinandMichaelMorrison.2006.RealisingthePotentialofGenomicMedicine.RoyalPharmaceutical SocietyofGreatBritain.July2006.

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InacceptingtheRussPrize,Dr.LeroyHoodsummarizedthetranscendent benefitsoftheHGPanditscurrentandfutureimpactsonbiologyand medicine.Hoodscommentsrepresentagoodsynopsisofimplications, impactsanddirection,andarereproducedherewithpermission. Dr.LeroyHoodspeechatRussPrizeaward,2011ontheImpactofthe HumanGenomeProject Letmecitebriefly14genomeprojectaccomplishmentsthat revolutionizedbothbiologyandmedicine. First,itdemocratizedgenes,thatis,itmadeallgenesaccessibletoallbiologists. Second,itdelineatedforthefirsttimeallhumangenes,andbyinference,allproteins. ThiscomprehensivepartslistenabledanewapproachtobiologythatItermed systemsbiology,whichtakesaholisticapproachtodealingwithbiologicalcomplexity. ThisisthefocusofmyInstituteforSystemsBiologythefirstsystemsbiology organizationthatwasstartedin2000. Third,itcatalyzedthedevelopmentofhighthroughputinstrumentation,thevery effectivegenerationofbiologicalinformationingenomics,inproteomics(thestudyof proteins),inmetabolomics(thestudyofsmallmolecules)andinphenotypicassays. Fourth,itpioneeredtheapplicationsofcomputerscienceandmathematicstobiology.In fact,itwasthegenomeprojectthatlegitimatelybroughtmathematiciansandcomputer scientistsandeventheoreticalphysicistsintobiologytothinkaboutacquiringand storing,analyzing,mining,integrating,andultimatelycreatingpredictiveandactionable modelsofcomplexbiologicalsystems. Fifth,itwasthefirstbiologicalprojectwhosepolicywasopensourceforalldata;it demandedtheinstantaneousreleaseofdatatothebiologicalcommunitysoeveryone couldanalyzethisnewinformationimmediatelyasitwasproduced. Sixth,itcreatedthefirstrigorousstandardsforbiologicaldataandprojectfunding dependedonmeetingthesestandards. Seventh,itgaveusaccesstothegenomesofplants,ofanimals,ofmicrobes,and knowledgeofthosegenomeshastransformedmanyfieldsofbiology. Eighth,itrevolutionizedourunderstandingofevolutioninabsolutelymagnificentways. Ninth,ittransformedhowwethinkaboutmedicine.Itcreatedanewfieldofmedical diagnosticsusingbiomarkersintissuesandbloodthatcanactuallydetectdiseaseearly andstratifycomplexdiseasesintotheirdifferentsubtypessophysicianscando impedancematchesagainstappropriatetherapies. Tenth,italsoopenedupthepossibilityofusingDNAsequencingtoidentifygenesthat haveactionablebehaviorswithregardtopatients.Forexample,agenedefecttermed Leidenfactor5leadstoanincreasedtendencyforbloodclotting.Patientswiththis defectcandrinklotsofwater,notsitonairplanesfor5hourswithoutwalkingand stretchingandevenuselowdosesofanticoagulants.Thisisparticularimportantfor pregnantwomenwiththedefectivegene. Eleventh,physiciansarenowusingDNAsequencingoftumorstolookatdisease perturbedbiologicalnetworkstodeterminetherightdrugforthepatient. Twelfth,thegenomeprojectcreatedascientificenvironmentthatinpartledtothethird paradigmchangethatIwilldiscussshortlyP4Medicine.(Predictive,Preventive, PersonalizedandParticipatory).

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Thirteenth,thegenomeprojecthaschangedthesociologyofbiology.Forexample,it introducedtheconceptofbigsciencetobiology.BybigscienceImeancrossdisciplinary, hypothesisdrivensciencethatintegratesdifferentdatatypestobuildpredictivemodels toattackhardbiologicalproblemssuchasP4Medicine.Smallscienceisdonebyasingle investigatorandafewcoworkersandtakesonhighlyfocusedanddiscreteproblems. Thesynergybetweenbigandsmallscienceisenormousinthateachcantakeadvantage ofthestrengthsofotherandtheycaneffectivelyoperateinanintegratedmanner. Unfortunately,atNIHtoday,thereisathrusttodoawaywithbigscience(drivenby budgetconstraintsandmanyscientistswhopracticesmallscience).Toeliminatebig sciencewouldbeatragicmistake,asitisnecessarytoattackmanyofthemostcomplex andchallengingproblemsofbiologyandsocietytoday.Weobviouslyneedamixed portfoliowherethestrengthsofbigandsmallsciencecanbeutilizedtogetherinan integratedmanner. Finally,thegenomeprojectalsowasthefirstthatsupportedaninvestigationofthe social,ethical,andlegalaspectsofthegenomesequenceinawaythatpresagedhow wearereallygoingtohavetoconsidermedicineofthefuture.

TheFutureCostof SequencingDramaticCost ReductionsLeadto WidespreadApplication

Itisnowpossibletoorderyour personalgenomesequenced todayforaretailcostofunder ~$20,000.Thiscostwilllikelyfall tolessthan$1,000by2012,and to$100by2013. Atcostsbelow$1,000per genome,anumberofintriguing applicationsofDNAsequencing becomecosteffective.For example,researcherswillhave accesstothousandsoreven millionsofhumangenomesto seekcorrelationsbetween genotypesandphenotypes. Medicaldoctorswillbeableto ordergenomesequencingalong withstandardlaboratorytests, andwilllikelydosoiftheybelieve thatknowledgeoftheDNA sequencewillfacilitatepatient diagnosisand/ortreatment.Even webbasedgenetictestingservice companieswillexploitfull genomesequencestogatherand dispensemedicalandancestry information,andprovidegenetic counseling. JASONProgram.The$100 Genome:Implicationsforthe DoD.December2010.JASON, TheMITRECorporation.McLean VA.

Oneofthekeyrealizationsthatmustbeunderstoodregardingthehumangenomesequencingisthat itsusefulnessisperpetual.Whileothermajorbigscienceprojectshavealifeattachedtothem(the $11billionSuperconductingSuperColliderhasanestimatedlifespanof30yearsforexample,orthe $1.5billionHubbleSpaceTelescopeat1520years),thehumangenomesequencedoesnotwearout orbecomeobsolete.Rather,thereferencehumangenomeismoreakintochemistrysperiodictable,a fundamentalplatformforunderstandingandadvancementofscience. Aswehaveexploredinthisreport,theimpactonhumanmedicineandhealthisprofoundand important,butthebenefitsofperformingtheHGPandrelatedprojectsextendintoareasofhuman activityandplanetarylife,farbeyondthat.Ourfundamentalunderstandingofgenomics,the sequencingandgenomictechnologieswhosedevelopmentwasspurredbytheHGPandCeleraefforts, theadvancedomicsdisciplinesgenerated,willmakecontributionsonabroadrangeoffronts.Wecan expect: Agriculturalproductivitytoincreaseconsiderably,workingtowardsthechallengeof feedingtheworldsrapidlyexpandingpopulationinasustainablemanner. Notonlywillfoodavailabilityincrease,buttheimpactofitsproductionontheglobal environmentwillreduceascropsandlivestockaredevelopedwithtraitssuitedto nitrogenuseefficiency,notillagriculture,wateruseefficiencyandreducedwaste production. Currentlylowvaluebiomass,especiallylowvaluecellulosicbiomass,willbeconverted intohighervalueliquidfuels,energysources,biobasedchemicals,plasticsandmaterials. Theseproductswillincreasinglydisplacepetroleumandotherfossilbasedinputs, contributingtoreducedcarbonemissionsandassociatedclimateandenvironmental benefits. Anincreasinglytwowayflowofdiagnostics,therapeuticsandpreventiontoolswillmove betweenhumanmedicine,veterinarymedicineandagricultureasthecostofgenomic technologiesreducesandtheapplicationsofdiscoveriesinoneareacanbeappliedto anotherbecauseofcomparativegenomicsandothergenomicadvancements. Thelegacyofpollutionontheplanetcausedbyhumanactivitywillincreasinglybe addressedthroughtheapplicationofgeneticallyengineered,modifiedorsynthetic organismsdesignedtoperformremediationandmitigationfunctions. Theaboverepresentjustsomeoftheareasinwhichgenomicswillbeappliedforthe improvementofhealth,wellbeingandsustainability.

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Fromaneconomicstandpoint,ofcourse,theimpactofappliedgenomicswillbeequallyprofound. Moderndevelopedsocietiesaredrivenforwardbyinnovationtypicallytechnologicalinnovation.The HGPandassociatedsequencingprojectshaveadvancedthestateofinnovationandtechnologyand resultedinbroadeconomicimpactsashighlightedinthisreport.Thesepositiveeconomicimpactswill continuetorippleoutwardsandexpand.Personalizedmedicineapproachesforthepreventionand optimizedtreatmentofdiseasesanddisordersholdspromiseforreducingthefutureburdenofdisease andassociatedhealthcarecosts. Inthedevelopingworld,thepromisecontainedwithinappliedgenomicsisfundamentaltobasic economicprogress.Withoutaffordableandsustainablefoodsupplies,developmentwillbehighly limitedasmalnutritionimpactsdevelopingsocietyproductivityandincomes.Withouthigher productivitycrops,moreandmoremarginallandswillbepressedintoproductionandenvironmental degradationwillbecomeincreasinglymorewidespread.Withoutenhancedabilitiestocombatcurrent andemerginginfectiousandendemicdiseases,developingsocietieswillagainbeheldbackand progresslimited.Appliedgenomics,builtuponthefoundationoftheHGPandassociatedprojects, holdspromisefortheprovisionofsolutionstoeachandeveryoneofthesechallengesandmore. InBattellesinterviewwithLeeHoodhecalledtheHGPthesinglemosttransformativeeventinthe historyofbiologicalscience.Itwouldbedifficultnottoconcurwiththatstatement.Inadvancingbasic scientificknowledgeinopeningnewpathwaystoenhancedhumanhealthinspurringtechnologies foreconomicdevelopmentinprovidingsolutionstowidespreadchallengesinglobalfoodproduction andenvironmentalsustainabilitythe$3.8billionspentontheHGPmaywellrepresentthebest singleinvestmentevermadeinscience.

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