Download The Practical Reach of Pharmacogenomics: are Custom Drugs a Possibility?

GregoryTaylor
DougBrutlag
GenomicsandMedicine
December10,2015
ThePracticalReachofPharmacogenomics:areCustomDrugsaPossibility?
Inrecentyears’researchershavebandedtogetherinaconcertedefforttotryand
understandthegenome.TheHumanGenomeProjecttosequencetheentiregenomewasfirst
conceivedin1986andinitiatedin1990,after13yearsthegenomewasfullydecodedbutthat’s
nottheendoftheprocess.Thefirstgenomecostmillionstosequencebutafternumerous
scientificdiscoveriesandtechnologicaladvancementsthecostofsequencingdowntoaslittle
as$1000.Withthepricereducingsodrasticallycouldwebereachingapointintimewhere
pharmaceuticalscantapintothewealthofknowledgehiddenwithineveryperson’sgenome?
ThereachofpharmacogenomicsiseverexpandingwithnewtechniquessuchasSNPsearches
andGWAstudiestoanalyzedrugsbuthowreliablearethesestudiesandhowpracticalare
they?Andbeyondthatwhataretheethicsinvolvedinanalyzingthegenomeandwhoshould
gettoknowwhatthegenomesays?Thispaperaimstoanswersomeofthesequestionsandget
abetterpictureofjustwhatstandsinbetweenmedicaladvancementandachievingcustom
madedrugstocuredevastatingdiseases.
Direct-to-consumergenetictestshasbeenspeculatedsincethedawnofTheHuman
GenomeProject.Pharmaceuticstooknoticeofthepotentialwhenawaveofdiscoveriesof
commonDNAsequencesthatareassociatedwithrisksfordiseasessuchasheartcomplications
(includingheartattackandangina),morbidity,andothercommonillnessthataccountformost
ofthehealthcarecostsinvariousnations.ResearchersHelgasonA,andStefanssonKexplored
thisintheirpaper“ThePast,thePresent,andFutureofDirect-to-ConsumerGeneticTests.”
Theyclaimthatthepredictivepowerofthegenomicsequence,giventhesheeramountof
associationsalreadydiscoveredwithdiseaseswithhighincidencewouldmakeDTCgenetic
testsamaingoalofpharmaceuticsinthefuture.Indeedthepairpostulatesthattheimportance
ofDTCgenetictestsliesinthevariationsbetweenindividualsandhowthesevariationscan
causedifferencesinchanceandseverityofdisease,i.e.sex,age,weight,andotherbiological
markers.Betheypreventativetestsorgenomictestsafteradiseasehassprungupconsumer
testshavethepotentialtocurecertaindisease.
Buthowhasgenomicscausedsuchamiraculousturnfordiseasestudy?DTCtestscan
playatransitionalroleinunderstandingofdiseaseandbytestingindividualswhohavealready
contractedadiseaseresearchescanfindoutmoreandmoreaboutwhatchangesinthebody
leadtotheillness.BelowisafigurefromthestudyconductedbHelgasonandStefansson:
JusttwoyearsafterstudiesofthegenometheGenomeWideAssociationstudieslaunched
whichaccountsfortheskyrocketingresults.Overtimewithbetterandbettertechnologymore
diseaseswillbediscoveredandthestrengthofDTCwillonlyincrease.Therearethreemain
reasonstheGWAstudiesworkedsowellandwillonlycontinuetoworksowell.Thefirstishow
muchinformationtheHumanGenomeProjectmadeavailablebyprovidinganexamplehuman
genomeandtheensuingHapMapprojectthatfolloweduptheHumanGenomeProject.The
secondarenewgenotypingtechnologiesthathaveallowedscientiststheabilitytoanalyze
thousandsofSNPs.AndthethirdisjustthesheeramountofDNAsamplesthatcanbegathered
fromindividualsinflictedwithdiseasesofinterestandcontrolsamplesofDNAfromthesame
population.Theseunprecedentedresultsshowthattheirtrulyisvalueincontinuedresearchof
thegenomeandthatmaybeonedayDTCgenometestscanbeusedbypharmaceuticalsto
eitherprovidespecificpatientswithdrugstocuretheirdiseasesortoprovidethevast
communitywithdrugsdesignedtocurecomplexdiseases.Whilethisideaisfantasticintheory,
therearelimitationstogenomestudies.
IntruthstudyingdiseasesisnotassimpleasrunningaGWAstudyandanalyzingthe
SNPs,theactualpathtofindingcuresfordiseasesisstillwelloff.InGamazonER,SkolAD,and
PereraMA’spaper“TheLimitsofGenome-WideMethodsforPharmacogenomicTesting”the
researchersgointotheproblemswithGWAanalysis.Theultimategoalofpharmacogenomicsis
thetransitionfromDNAsequenceandgenomicdiscoverytoindividualizedpatientcare,butthe
problemwiththisgoalisthatGWAstudiesandgenomicdiscoveryingeneralareafarwayoff
fromactuallyprovidingcurestodisease.IntheirwordsGWA’s“Systematicallyevaluatehighthroughputgenotypingtechnologiesfortheirabilitytoassayvariationinpharmacogenetically
importantgenes(pharmacogenes).”Theresearchersproceededtoanalyze253oftheir
“pharmacogenes”foundthroughGWAstudiesandfoundthatnotasinglegeneshowedmore
than85%ownershipofit’srespectivedisease.Indeed,pharmacogenomicsisforcedtorely
moreheavilyonSNPgenotypingtofindassociationssinceGWAdonotprovidecoverageofall
chromosomalregions.Thegraphsbelowaccountforthecoveragesshownusingdifferent
interfaces:
ThemaingoalofpharmacogenicswouldbetostudytheHapMapandotherhigh-throughput
genotypingplatformsforsufficientgenotypicinformationtosuccessfullycaptureallthe
variationfoundinre-sequencingsothatresearchersandmedicalpractitionersknowexactly
howtotreatadisease.Theproblemisthatiftheplatformscannotsufficientlycaptureallofthe
variationsthoseverysameresearchersandmedicalpractitionerswouldfailtoidentifysomeof
thecausativevariantsthatleadtophenotypeexpression.Thefiguresaboveshowjusthowfew
diseasesarecoveredmorethan50%,andwithsuchlittleinformationonthesediseasescures
foundthroughDTCgenomictestsaren’tyetverypractical.
Sofaritsbeenshownthatthepotentialforgenomicsonapracticallevelisimmensebut
therealityofitsusewithtoday’stechnologyisbleak.Whileresearchersareveryhopefulforthe
outcomeoffutureprocessingitsstillveryclearthatwithtoday’sknowledgeondiseaseitsjust
notenoughtofindcures.Therearemonogenic,oligogenic,andcomplexdiseasescodedinthe
humangenome.ResearchersNerbertD,ZhangG,andVesellEdoveintojusthowcomplexitis
tofindandtreatdiseasesastheygettobemoreandmorecomplex.Intheirpaper“From
HumanGeneticsandGenomicstoPharmacogeneticsandPharmacogenomics:PastLessons,
FutureDirections”Theysetofftheirpaperhighlightingthedifferencesinfullyunderstanding
thesethreedifferentformsofdisease:
Thisgraphrevealsthatthemainissuewithfindingacureforcomplexdiseasesisthefactthat
thenumberofgenesthatdirectlycausephenotypicexpressionarewideandtheirisn’tone
majorcause.Itcouldbethatthesegenesarepleiotropicorunderepistasisforothergenes.
Whilemonogenicdiseasearerathereasytofindacureforsincethereisonegenethathasan
outlandishcontributiontothephenotype,otherformsofdiseasearehardertosiftthrough.
Thatbeingsaidtherearestillwaysoffindingthosemanygenesthatcontributeto
complexdiseases.Withcurrenttechnologiesitsstillpossibletoafewofthegenesthathavea
highP-valueofsignificanceforcertaincomplexdisorders:
Resultslikethesearewhatgiveresearchersthedrivetocontinueparsingthroughcomplex
diseases.Eventhoughthesearejustoneortwooftheseveralgenesthatdirectlycontributeto
phenotypicexpressionitshopethatmorestillcanbefound.
Inconclusion,DTCgenetictestsarenotarealityquiteyetbutwithincreasingresults
witheachstudythatpassestherealitymaycomesoon.GWAstudiesandSNPreviewsreveal
thegenesthateffectdiseasesandcanultimatelyleadtopharmaceuticaladvancementto
developdrugstocombatillness.
WorksCited:
Nebert, Daniel W., Ge Zhang, and Elliot S. Vesell. "From Human Genetics and Genomics to
Pharmacogenetics and Pharmacogenomics: Past Lessons, Future Directions." Drug
Metabolism Reviews. U.S. National Library of Medicine, n.d. Web. 11 Dec. 2015.
"Result Filters." National Center for Biotechnology Information. U.S. National Library of
Medicine, n.d. Web. 11 Dec. 2015.
"The Past, Present, and Future of Direct-to-consumer Genetic Tests." Www.ncbi.nlm.nih.gov.
N.p., n.d. Web.