The NIH Human Microbiome Project - genome.gov...The human microbiome • 1000s of microbial species,...
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The NIH Human Microbiome Project: Catalyst for an emerging field in biomedical research Lita Proctor, Ph.D. Division of Genome Sciences NHGRI Council February 12, 2018
Transcript of The NIH Human Microbiome Project - genome.gov...The human microbiome • 1000s of microbial species,...
TheNIHHumanMicrobiomeProject:Catalystforanemergingfieldinbiomedicalresearch
LitaProctor,Ph.D.DivisionofGenomeSciences
NHGRICouncilFebruary12,2018
Topicsforthistalk
üThehumanmicrobiome
üNIHHumanMicrobiomeProject,FY2007-2016
üRecentadvancesinhumanmicrobiomeresearch
Bodyregion NumbersMouth(total) 1010Lungs(est.) ~109/mlBreastmilk(est.) ~109/LSkin(total) 1012GItract(total) 1014Vagina 109/ml
1.Thousandsofmicrobialspecies*,possessingmillionsofgenes,livewithhumans.
2.Knownasthemicrobiome,mostarenotculturable.
Dom
inguez-Bello et al. (2010)
3.Thesemicrobesareacquiredeachgeneration.
4.Microbiomematurationcontinuestoage2or3,alongwithimmunesystemdevelopment.
5.Thesemicrobialgenesencodemyriadmetaboliccapabilities.
6.Thehumanmicrobiomeaugments/extendscapabilitiesencodedinthehumangenome.
*bacteria,fungi,viruses,phage,archaea,protozoa,(helminths)
TheHumanMicrobiomeScientificAm
erica(2013)
Bach(2
002)
InfectiousdiseasesAllergic/autoimmunediseases
Changesinthemicrobiomeandappearanceof‘modern’diseases?
RationaleforHumanMicrobiomeProject
Nextgenerationsequencingtechnologyenabledmicrobiomeanalysis
Ten-year(FY07-16)HumanMicrobiomeProject$215Mcommunityresourceprogram
HMPprogramgoals1)Developresearchresources:e.g.referencedatasets,clinical&analyticalmethods,statistical&computationaltoolsandpipelines
2) Rapidlyreleaseresources:e.g.publicrepositories&communitydatabases,HMPDataAnalysisCoordinationCenter(DACC),GitHub&meetings/webinars
HMPPhaseOne(2007-2012)
PhaseOne($180M):Surveyofmicrobiomeinhumans(fundingfromCommonFund+NIAID,NCI,NIDDK,NIDCR,NCCIH,NHGRI,ORWH,ODS)
“Who’sthere?”
Healthycohortstudy
Clinicallyhealthy
300male/female
18-40y.o.
5majorbodyregions(18bodysites)
Upto3visitsin2yrs
Noantibiotics,probiotics,immunomodulators
DemonstrationProjects
Microbiome-associatedconditions
Skin: eczema,psoriasis,acne
GI/oral: esophagealadenocarcinoma,necrotizingenterocolitis,pediatricIBS,ulcerativecolitis,Crohn’sDisease
Urogenital: bacterialvaginosis,circumcision,sexualhistories
Microbialcommunitycompositionineachbodyregionisdistinct.
PCoA
2(4.4%)
PCoA1(13%)
HMPPhaseOne(2007-2012)Hu
man
Microbiom
eProjectC
onsortium(2
012a)
Huttenhoweretal.(inreview
)
Butlarge-scalecommunitycompositionalonecannotdifferentiatehostphenotypes.
PCoA1(8.1%)PC
oA2(6.7%)
metagenomicanalysisofmicrobialcommunitycomposition
HMPPhaseTwo(2013-2016)
PhaseTwo($35M):IntegrativeHMP“iHMP”(fundingfromCommonFund+NIDDK,NICHD,ORWH,NCCIH,ODS)
“Whataretheydoing?”
Analyzemulti‘omic functionalproperties:• bothmicrobiome&host• overtime
Interrogatetheseintegrateddatasets
Three“model”microbiome-associatedconditions:
HMPPhaseTwo(2013-2016)
Ex.IBDhost/microbiomeproperties IBDhost/microbiomenetworkanalysis
Host
Microbial
Loss/gainofspecificmicrobesand/orspecificmicrobialmetabolicpathwaysarecharacteristicofdiseasepatientsvshealthycontrols
Huttenhoweretal.(inreview
)
Butlarge-scalecommunitycompositionalonecannotdifferentiatehostphenotypes.
PCoA1(8.1%)
PCoA
2(6.7%)
e
Allprimaryandderiveddatasets,tools,andanalyticalpipelines
HMPDataAnalysisandCoordinationCenter(www.hmpdacc.org)
2018
ü iHMP papercollection• 4majormss• 35companionmss
üHMPDACC:• multi-omic datasets• associatedtools• pipelines
1)Sequenceandother‘omic referencedatasetsofmicrobiomeandhost• 16SrRNA &metagenomesequencesfromfivemajorbodyregionsof300adultmenandwomen
[>2,000metagenomes(10TB)ofsequencedata.~20-30TBtotalforPhaseOneandTwo.]• Humangenomesequencesfromsubjects• Multi-omic profiles(e.g.transcript,protein,metabolite)fromhostsandmicrobiomes
2)Computationalandstatisticaltools&pipelinesformicrobiomemulti-omic dataanalyses• Sequenceanalysis,includingmeta-tranascriptomic analysis• Composition,metabolicpathway,networkanalysis• Meta-proteomicanalysis• Meta-metabolomicanalysis• Cloud-basedanalyses
3)Analyticalprotocolsformicrobiomesampleanalysis
4) Clinicalprotocolsforcollection/storageofsamples• Skin• Oral• GItract• Urogenitaltract(bothvaginaandpenis)• Nares
5) IRBprotocolsforclinicalstudiesofmicrobiome
6)EvaluationofELSIissuesrelatedtothemicrobiome
HMPresourcesdevelopedinbothphases
TotalInvestm
ent(m
illionsUSD
)
ExpansionofhumanmicrobiomeresearchatNIHovertenyears(FY2007-2016)
TMWGpreliminaryunpubl.data
5-6ICs 15ICs
~275PIs ~725PIs
20+ICs
~50PIs
FiscalYear
$0
$50
$100
$150
$200
$250
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
HMP: $215MNon-HMP:$940M
GItract: irritableboweldisease(IBD),ulcerativecolitis,Crohn’sdisease,GERD,necrotizingenterocolitis(NEC)obesity,metabolicsyndrome,type1andtype2diabetes
Skin: eczema,psoriasis,acne,rheumatoidarthritis
Heart:cardiovasculardiseases
Liver: non-alcoholicliverdisease(NAFLD),alcoholicsteatosisCancers: Hodgkins’lymphoma,liver,gastric
esophageal,colorectal,cervical
Lungs: asthma,cysticfibrosis
Brain/mental:multiplesclerosis,epilepsy,Alzheimer’s,autism,psychiatricdisorders
Vagina:bacterialvaginosis,pretermbirth
Microbiome(s)anddisease(s)
$791M
100+classesofdiseaseoverFY12-16
Recentadvancesinmicrobiomeresearch*
ü Gutbacteria/bacterialmetabolismandobesity
ü Bacterialmetabolismandcardiovasculardisease
*Highlightsfrom2017NIH-widemicrobiomeworkshop
Microbiome-basedbiomarkersrelatedtodisease
ü Bacterialepigeneticeffectsoncolorectalcancer
Recentadvancesinmicrobiomeresearch*
*Highlightsfrom2017NIH-widemicrobiomeworkshop
Microbiome-basedtherapeuticinterventions• Fecalmicrobiotatransplantation• Microbiome-derivedmicrobialconsortia• Livebiotherapeuticproducts• Bacteriophage• Pharmacobiotics
Microbiomeasasourceofnewpharmaceuticals
MinedHMPmetagenomicdatatodiscoveranddevelopnovelantimicrobials
2010NIHNewInnovatorawardee
modelsystem(s)?
Currentgaps/challengesinmicrobiomeresearch*
roleofhostgenetics?
*Highlightsfrom2017NIH-widemicrobiomeworkshop
causeoreffect?
interventionsforhealth?
microbiome=organsystem?
Conclusions
Thehumanmicrobiome• 1000sofmicrobialspecies,millionsofmicrobialgenes• Metabolicallydiverse,active,mutable‘microbialorgan(s)’
Mainchallenge:Themicrobiomeisfarmorethanthesumofitsmicrobialmembers.
NIHHumanMicrobiomeProject,FY2007-2016• $215Minvestedinrapidlydeployedresearchresources• Supported35institution/50PIresearchconsortium
Recentadvancesinhumanmicrobiomeresearch• NIHextramuralsupportexpandedtoover$1Bover10yrs• Extensiveresearchonhost/microbiomebiology• Roleofmicrobiomebeingstudiedin100+diseaseclasses• Microbiome-basedinterventionsanddrugdevelopment
Acknowledgements
NHGRI:JanePeterson,MarkGuyer,JeffSchloss,VivienBonazzi,Jean McEwen,ValentinadiFrancesco;alsoChrisWellington,Shaila Chhibba,JonLoTempio
CommonFund:MaryPerry,AronMarquitz
HMPscienceco-chairs:EricGreen(NHGRI),AnthonyFauci(NIAID),GriffinRodgers(NIDDK),MarthaSomerman(NIDCR)
Trans-NIHMicrobiomeWorkingGroup
HMPadvisors:JulianDavies(UBC),FrancisOuellette(GenomeCanada),EugeneChang(Univ Chicago),StanFalkow(Stanford),RickStevens(ANL)
HMPResearchConsortium!
HMPandrelatedresources
1) CommonFundHMPwebsite:https://commonfund.nih.gov/hmp
2)HMPDataAnalysisandCoordinationCenter(DACC):https://www.hmpdacc.org
3)Trans-NIHMicrobiomeWorkingGroup(TMWG):https://commonfund.nih.gov/hmp/related_activities
4)“EmergingThemes”2017NIH-widemicrobiomeworkshop:https://commonfund.nih.gov/hmp/meetings/emerging
5)InternationalHumanMicrobiomeConsortium(IHMC):http://www.human-microbiome.org/
