PGP- open access to genome sequences + trait data2-2:45 PM 14-Sep-2011 Personalized Genomics/Medicine

Thanks to:

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2011: What’s next

1 Handheld no prep/library/amplification1. Handheld, no prep/library/amplification2. In situ : 3D/4D tissues

( i fl ti i f ti )(cancer, inflammation, infection)3. Interpretation & integration software4. Great cohorts to test drive tech &

personalized medicine p

22

Myostatin extremes

Enhanced muscle growth, decreased body fat & decreased atherosclerosis (2009 Endocrine Society Bhasin et al BU)decreased atherosclerosis (2009 Endocrine Society, Bhasin, et al BU)

Flex Wheeler

MSTN -/-

3

Prevention/Cure can be creatively far from the initially discovered Causethe initially discovered Cause.

•A minor allele can be a cure: e.g. CCR5•Gene therapy T/B cells – e.g. CMLpy g•Embrace the extremes: more informative & easier•Next extremes: old age with youthful healthNext extremes: old age with youthful health

44

Genomes = Traits

Evidence.personalgenomes.org

TRAITS(Phenome)

PERSONALGENOME ( )GENOME3M alleles

5

Genomes + Environments = Traits

PersonalGenomes.org

Evidence.personalgenomes.org

Therapies

TRAITS(Phenome)

PERSONALGENOME

Immunome Stem-cellsEpigenome

Immunome( )GENOME

3M alleles (RNA,mC)Cancer

Microbiome

Hair/nails Tox

Microbiome

6Nutrition

Cost reduction for developing nations: Diagnostics, preventions, therapiesDiagnostics, preventions, therapies

“$20 [ t ti t t t]“$20 per [outpatient cataract] surgery… intraocular lens replacement which costs p$3,500 in the US”

77

2011: What’s next

88Carr & Church, Nature Biotech

37 Next-generation sequencing technologies1 Polonator MA 8 Ni h1. Polonator MA2. Roche-454 CT3. AB-SOLiD MA4 Ill mina CA

20. Halcyon CA21. ZS Genetics NH22. Genizon BioSci QC

8 Niches:•$/bp

4. Illumina CA5. CGI CA6. Helicos MA

ifi i CA

23. LaserGen TX24. Visigen/Starlight TX25. GE Global NY

•$/run•$/device

7. Pacific Bio CA8. Intelligent Bio MA9. Ion Torrent CT

G G26. Stratos Genomics WA27. Reveo NY28 AQI Sciences AZ

$•Read length•Repeats10. Genapsys CA

11. Electronic Biosci CA12. Nabsys RI

28. AQI Sciences AZ29. Base4innovation UK30. Li-Cor NE 31 U S Genomics MA

•Repeats•Speed

I ity13. OxfordNanopore UK14. IBM-Roche NY15. NobleGen MA

31. U.S. Genomics MA 32. Mobious Genomics UK33. Nanophotonics Biosci CA 34 N k Bi MA

• In situ•Portability

15. NobleGen MA16. Genia CA17. LightSpeed CA18 GnuBio MA

34. Network Biosystems MA 35. SeiraD NM 36. Affymetrix CA Polonator

9

18. GnuBio MA19. Bionanomatrix PA

37. Population Gen Tech UK

http://arep.med.harvard.edu/gmc/nexgen.html

Technologies (phone, apps, web, wiki) l d th i h d itionly as good as their shared communities1975 851975-85

1977

1990 2001

Open access cohorts to test-drive li d di ipersonalized medicine

ABI VenterABI Venter

454 Watson21070

454 Watson

Helicos Quake

21730

Q

Illumina PGP#4,9,11,12,14

21731

, , , ,

CGI PGP#1-10,13 21731,

IonTorr Moore11…

Genomes + Environments = Traits

PersonalGenomes.org

Individuals willing to have their genomes, cells (saliva, blood, skin, iPS), extensive trait data(saliva, blood, skin, iPS), extensive trait data Open-access : CC0

16K volunteers registered in 74 countries2 418 achieved 100% on entrance exam2,418 achieved 100% on entrance exam1,056 have medical records online500 l i h i li500 complete genomes in the pipeline 12

US clinics quietly embrace whole-genome sequencingwhole-genome sequencing

Nature 14-Sep-2010

"If one hospital is doing it, you can be sure others Nic Volker

will start, because patients will vote with their feet" -- Elizabeth Worthey

HMGC & Children's Hospital of Wisconsin

“At the age of 3, … more than 100 separate surgeries …On the basis of [sequencing], the physician recommended a bone-marrow transplant in June 2010. By mid-July, the child was eating his first meal.”

1313(XIAP gene C203Y; TGT>TAT )

Individually Rare -- Collectively Common (10%)

2443 diseases (~6000 genes) are highly predictive & medically actionablemedically actionable

1963 PKU

1991 BRCA

2010 HCM

14Genetests.org

Multiplex RNA Fluorescent in situ Sequencing (FISSEQ)( Q)

J Lee J Yang M Nilsson et alJ. Lee, J.Yang, M. Nilsson et al.

Single base differences

15

Rare cells: Resistance in Leukemia therapy Nardi, Raz, Chao, Wu, Stone, Cortes, Deininger, Church, Zhu, Daley. Oncogene 27:775-82Wu, Stone, Cortes, Deininger, Church, Zhu, Daley. Oncogene 27:775 82

M244VM244V

T315I

E255K

Simultaneously Cure AML & HIV1

Hütter G et alHütter G, et al. "Long-Term Control of HIV b CCR5 Δ32/Δ32HIV by CCR5 Δ32/Δ32 Stem-Cell

Timothy Ray BrownA*0201;

Transplantation"N Engl J Med 2009 A*0201;

B*0702,3501; C *0401 0 02

g

Cw*0401,0702; DRB1*0101,1501;

1717DQB1*0501,0602.

Coding variants in 22 hiPS linesin 22 hiPS lines1-12 coding changes

(Gore Zhang et al(Gore, Zhang et al.Nature 2011)

Red= COSMIC Blue= OMIM P l b hPurple= both.Grey= interactions with 4 tumor s ppressors & 4suppressors & 4 reprogramming factors. Solid= nonSolid= non-synonymousBIG= known 3D

1818

PGP stem cells biobank

H ti d d f hIPS llHepatic endoderm from hIPS cells (Daley, Church, Wilmut labs)

Tissue-specific Gene

iExpression Regulatory Variants Using

Lee et al.PLoS Gen. 2009Variants Using Personalized hIPSC

19

PersonalGenomes.org T t b i C iti &Testmybrain.org Cognitive &Prosopagnosia Ken NakayamafMRI V i ti R d B kfMRI Variation Randy Buckner

#1

#9

#2#1 Lee et al. 20092020

#2#1PLoS Genet.

Microbiome vs ImmunomeMicrobiome vs Immunome

Microbe tests: Detect Drug resistance spectrumEarlier warning (e.g. meningitis)

Immune tests: Focus on response to exposureLonger times to detect exposure (e g HIV TB)Longer times to detect exposure (e.g. HIV, TB)

21

PGP Immunome time series

Harvard/MIT: Vigneault, Laserson, 22

v d/ : V g e u , se so ,Lieberman-Aiden, Church

Roche: Egholm, Simen

PGP CDR3 size distribution

23Laserson, Vigneault

PGP Vaccination 3 year time series.

8 2 0 04 1 3 7 14 21 28 d-8 -2 -0.04 1 3 7 14 21 28 days

24

AntigenAntigen Libraries

Larman et al NNature Biotech 2011

25

2011: What’s next

1 Handheld no prep/library/amplification1. Handheld, no prep/library/amplification2. In situ : 3D/4D tissues

( i fl ti i f ti )(cancer, inflammation, infection)3. Interpretation & integration software4. Great cohorts to test drive tech &

personalized medicine p

2626

Genomes + Environments = Traits

PersonalGenomes.org

Evidence.personalgenomes.org

Therapies

TRAITS(Phenome)

PERSONALGENOME

Immunome Stem-cellsEpigenome

Immunome( )GENOME

3M alleles (RNA,mC)Cancer

Microbiome

Hair/nails Tox

Microbiome

27Nutrition

.

2828

Technology for Reading &Writing Human GenomesCustom Activators, Deaminases & Recombinases,

Zh C t lZhang, Cong, et al. Nat Biotech 2011

2 TALE domains binding to 2 bp Neves et al pdb 2010 2kq5

2929

Neves, et al. pdb 2010 2kq5 Boch et al Science 2009

Toward comprehensive single cell in situs

2 kb Lee ,Yang, Nilsson: multiplex in situ RNA100 kb Drmanac: Long Fragment Reads (LFR)100 kb Drmanac: Long Fragment Reads (LFR)2 Mb Wu: Bind & Snap libraries6 Gb W Oli P i i l i6 Gb Wu: Oligo Paints in nuclei

4 base reads

Single base differences

30

Bridging atom-to-mmatom to mm

aptamers, antibodies

I t f t i lith hiInterferometric lithographicgrid for sequencing

31

Edison : Narcolepsy

AnAge db (891 species)

Homo Balaena mysticetus

Arctica islandica

220405

(891 species)

sapiens

Cebus capucinus

y220122

Cebus capucinus

2850 Heterocephalus glaber

Maxage

(years) de Magalhaes(y )

0.35 0.1 2.6 62 100,000

de Magalhaes

33

,Adult mass (kg)