experimental man one mans intimate journey inside himself, cell by cell david ewing duncan david...
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EXPERIMENTAEXPERIMENTAL L
MAN MAN
One Man’s One Man’s
Intimate JourneyIntimate Journey
Inside Himself, Inside Himself,
Cell by CellCell by Cell
David Ewing Duncan David Ewing Duncan
David Ewing Duncan, 2007
“All Life is an experiment. The more experiments you make the better.”
– Ralph Waldo Emerson
Personalized Medicine Is:
GenesEnvironmentBrainBody
Not yet ready for individuals
Uneven validation and unregulated
Expensive: my tests ~ $100,000
Health Care and bioethics communities unprepared
Observations and Caveats
GENESGENES
DED Results: Illumina 1 Million SNP Chip
Genetic Markers Tested: 1 Million
Disease and Behavior Variants Found: 169
Sample Variations, Analysis by Omicia, Inc.:
Gene | snpdb | var_id | snpdb_var_id | gp_position | ref | var| aa_ref | aa_var | allele1 | allele2 | genotype |-------------+-------+------------+------------------+-----------------+-----------+---------+--------------+------------+--------------+---------+---------+----------+-------
ABCA1 | HGMD | rs2230806 | CM030397 | chr9:106660688 | C | T | R | K | T | C | var/ref |
ABCA1 | HGMD | rs2230808 | CM042912 | chr9:106602625 | T | C | K | R | T | C | ref/var |
ABCA1 | HGMD | rs4149313 | CM990005 | chr9:106626574 | T | C | I | M | T | C | ref/var |
ABCB1 | HGMD | rs2032582 | CM033585 | chr7:86998554 | A | C | S | A | C | C | var/var |
ABO | HGMD | rs512770 | CM011264 | chr9:135123327 | A | G | S | P | A | G | ref/var |
ABO | HGMD | rs688976 | CM011263 | chr9:135126591 | A | C | F | V | A | C | ref/var |
ADH1C | HGMD | rs283413 | CM050165 | chr4:100487213 | A | C | * | G | C | C | var/var |
ADH1C | HGMD | rs698 | CM033593 | chr4:100479812 | T | C | I | V | C | C | var/var |
ADRB2 | HGMD | rs1042713 CM950016 | chr5:148186633 | G | A | G | R | A | G
AGT | HGMD | rs699 | CM920010 | chr1:228912417 | A | G | M | T | G | G | var/var |
AHSG | HGMD | rs4917 | CM052829 | chr3:187820407 | T | C | M | T | C | C | var/var |
AHSG | HGMD | rs4918 | CM052828 | chr3:187821076 | G | C | S | T | C | C | var/var |
ALOX12 | HGMD | rs1126667 | CM062424 | chr17:6843484 | A | G | Q | R | A | G | ref/var |
APOB | HGMD | rs533617 | CM980092 | chr2:21087477 | T | C | H | R | T | C | ref/var |
+ 155 MoreCourtesy of Omicia, Inc. and Illumina
Lower Back Pain:DED: 3 Variants in gene CILP
• CILP is the gene for cartilage intermediate layer protein, OMIM 603489
• DED is Homozygous for 1184C allele (395Thr allele) (OMIM allele .0001)
• DED -- Herniated Disc, 1997
Courtesy of Omicia, Inc.
Novelty-Seeking Behavior2 Variants in gene DRD3
• DRD3 is one of the genes for dopamine receptors, OMIM 126451
• Heterozygous (A1/A2) for Ser9Gly allele (OMIM allele .0001)
• Associated with significantly higher novelty-seeking behavior
• (Venter A1/A1; Watson A1/A2)
Courtesy of Omicia, Inc.
Caffeine “Rapid Metabolizer”DED: No Variants in gene CYP1A2
• CYP1A2 is one of the cytochrome P450 enzymes, related to drug metabolism
• Homozygous for the reference, meaning a “rapid” metabolizer of caffeine => no additional MI risk from coffee drinking
Courtesy of Omicia, Inc.
MYOCARDIAL INFARCTION
At risk allele David’s genotype
David’s OR PAR Het OR
Hom OR
Location
Rs10757278G
G - G 1.64 (general)
2.02 (early onset)
21% (general) 31%
early
1.26 1.64 9p21
At risk allele
HerbertDuncan(Father)
Patricia Duncan(Mother)
DanielleDuncan
(Daughter)
DonaldDuncan
(Brother)
rs10757278G
AG AG AG AG
Family Results
Courtesy of deCode Genetics
MI “Gene”: 3 Generations of Duncan’s
Father Mother A-G A-G
David Brother G-G A-G
Daughter A-G
Ancestral DNA - Y Chromosome
No 12 Marker Y-DNA Matches FoundGenetic Distance - 1
Name E-mailMr. Bobby Royce Henry (Y67) JHHenry99@…Alan C. Duncan (Y37) idlelane@…Wallace T. Duncan (Y25) WDuncan321@…
25 Marker Matches (6)Genetic Distance - 1
Name E-mailAlan C. Duncan (Y37) idlelane@…Wallace T. Duncan WDuncan321@…Daniel Earl Duncan (Y37) nyfromca@…
Courtesy of Family Tree
Genes: Issues
Population data not always relevant to individuals
SNPs are not sequencing
Shifting probabilities
Most genes unvalidated and unregulated
Potential for confusion
ENVIRONMENTENVIRONMENT
Tested: 320
Detected: 165
Cost: $15,000
My Chemical
Report Card
What’s Inside David
Total Tested: 320Detected: 165
Higher than Mean: 1550
50
100
150
200
250
300
350
BisphenolMetalsPhalatesPFOsDioxinsPesticidesBDEsPCBsTOTALSResults
My life with chemicals…
Childhood in Kansas
“The groundwater, soil, and leachate are contaminated with volatile organic compounds (VOCs), pesticides, polychlorinated biphenyls (PCBs), polycyclic aromomatic hydrocarbons (PAHs), and heavy metals from former waste disposal activities…”
-- EPA Report on Doepke Superfund Site
Pesticides
0
50
100
150
200
250
300
350
PesticidesDavid's Results 2.42 2.47 5.11 10.57 0.326 10.5 0.034 0.159 0.0845 12.1 3.67 16.7 1.75 256 3.58 2.26
CDC Mean <LOD <LOD <LOD <LOD <LOD <LOD <LOD <LOD <LOD 11.1 N/A 17 N/A 295 <LOD <LOD
CDC 95th % 21.8 <LOD 20.3 <LOD <LOD 43.3 <LOD <LOD <LOD 49.7 78.3 <LOD <LOD 26.5 57.1
Heptachlor-
Epoxid
alpha-E<LODosulph
Dieldrin HCB
alpha-HCH
beta-HCH
gamma-HCH ALDRIN
CL8-STYRE
NE
OXYCHLORDA
NE
c-CHLORDANE
t-NONACHLOR
c-NONACHLOR
p,p-DDE
p,p-DDT MIREX
Phthalates
0
20
40
60
80
100
120
140
DED results 35 53.9
CDC Mean 17.7 15.6
CDC 95th % 95.2 122
mBuP mBzP
Dioxin-Like PCBs
0
100
200
300
400
500
600
DED Results 0.815 523 4.15 0.992 5.08 19.2 5.12 0.761 0.387
CDC Mean LOD LOD LOD LOD LOD 22.7 LOD LOD LOD
CDC 95th % LOD LOD 32.6 LOD 44.6 108 18.2 LOD LOD
Dioxin-Like
PCBs
PCB-28
PCB-66
PCB-74
PCB-105
PCB-118
PCB-126
PCB-156
PCB-167
PCB-189
PBDEs
0
50
100
150
200
250
DED results 249 40.5 15.6 22.4
CA Study 14.1 3.1 3.4
Sweden 2.1
TX 8
PBDE-47 (Penta)
PBDE-99 (Octa)
PBDE-153PBDE-209
(Deca)
Methyl Mercury LevelTest #1:
5 ppm
Safe Level 10 ppm or less
CoalBurned for electricityReleased into air
Settles over oceanPlankton
Little FishBigger FishHuge FishHumans
Methyl Mercury LevelTest #2:
12 ppm
Safe Level 10 ppm or less
www.ctd.mdibl.org
Genes + Chemicals + Disease
COMPARATIVE TOXICOGENOMIC DATABASE -- CTD
Gene-Environment Interaction
DED Genes that provide protection from:
Mercury: GTSP1(Broberg, et. al, Archives of Environmental Health )
DDT: ABCB1, LDLR
PBDE-47 (Flame Retardant): CYP1A
Data courtesy of Carolyn Mattingly, Mount Desert Island Laboratory, Maine
Environment: Issues
No respect vis-à-vis genetics
Most work done on animals
Budgets small (but growing)
Potentially disruptive to business and regulations
BRAINBRAIN
QuickTime™ and aH.264 decompressor
are needed to see this picture.
fMRI
EEG, TMS
Alzheimer’s Disease?
Structure Volume (cm^3) % of ICV (Normative Range) % vs. Normative Range
Hippocampus 7.07 0.42 (0.37-0.50) 27
Lateral Ventricles 32.80 1.94 (-0.59-3.04) 88
Temporal Horn of LV 2.12 0.13 (0.00-0.18) 92
Courtesy of James Brewer, UCSD
Quantifying Brain Volumes
cue stimulicue stimuli delaydelay responsresponsee
+Remember FacesRemember Faces
Ignore ScenesIgnore Scenes
1 sec1 sec 1 sec1 sec 1 sec1 sec 1 sec1 sec 8 sec8 sec 1 sec1 sec
+Remember ScenesRemember Scenes
Ignore FacesIgnore Faces
Passively ViewPassively View +
Working memory task
• Equivalent perceptual, bottom-up information.• Equivalent perceptual, bottom-up information.• Differences in activity mediated by top-down signals.• Differences in activity mediated by top-down signals.
Top-down modulation in visual processing
DED Brain
Courtesy of Adam Gazzaley, UCSF
0
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BOLD signal
Remember Remember ScenesScenes
IgnoreIgnoreScenesScenes
0
0.5
1
1.5
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2.5
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3.5
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4.5
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BOLD signal
PassivePassiveViewView
Younger (19-30 y.o.)Younger (19-30 y.o.)Younger (19-30 y.o.)Younger (19-30 y.o.) Older (60-77 y.o.) Older (60-77 y.o.) Older (60-77 y.o.) Older (60-77 y.o.)
Gazzaley, A. Gazzaley, A. et al.et al. Nature Neuroscience Nature Neuroscience (2005)(2005)
Remember Remember ScenesScenes
IgnoreIgnoreScenesScenes
PassivePassiveViewView
Remember Remember ScenesScenes
IgnoreIgnoreScenesScenes
PassivePassiveViewView
David Duncan (age= 48 y.o.)David Duncan (age= 48 y.o.)David Duncan (age= 48 y.o.)David Duncan (age= 48 y.o.)
0
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2.5
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BOLD signal
Courtesy of Adam Gazzaley, UCSF
Face MemoryFace Memory
Response TimeResponse TimeResponse TimeResponse Time
fMRI Working Memory fMRI Working Memory PerformancePerformance
AccuracyAccuracyAccuracyAccuracy
0
0.1
0.2
0.3
0.4
0.5
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0.7
0.8
0.9
1
Accuracy
Scene MemoryScene Memory
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Response time (seconds)
Face MemoryFace Memory Scene MemoryScene Memory
YoungerDDOlder
Electroencephalography (EEG)
Event-Related Potentials (ERPs) Spectral
EEG data: P1 amplitude
Attend FacesPassively View FacesIgnore Faces
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
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[µV]
-100 0 100 200 300 400 500 600 700 [ms]
P9-Avg SM-FacePV_Face
RememberPassiveIgnore
RememberPassiveIgnore
0
1
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6
Younger Older
EEG data: P1 amplitude
0
1
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P1 amplitude
David Duncan
Other Brain Tests
Fear AnxietyImpulsivenessRiskGreedAltruismPoliticsDiseaseMore
Brain: Issues
Not relevant to individuals
Lack of data - small groups tested
Very early days
BODYBODY
(Note: The following information (the Entelos Model of the “Virtual David”) is being revised and may not be accurate
in its current form -- DED)
Test Data
questionnaire
age, gender
diabetes
blood sample
blood pressure
standard lipid panel
lipoprotein particle size distribution
inflammatory markers
glucose metabolism markers
ultrasound carotid IMT
CT scan coronary calcium score
buccal swab genetic analysis
RiskAssessment
Recommendation
Framingham Risk Score ATP3 Treatment Guidelines
scientific literature on markers and associated
risk
no recommendation
qualitative assessment; no outcomes studies
population associated risk
David
geneticmarkers
biomarkers
imaging
Heart Project: Entelos
•2 types of imaging
•Carotid IMT thickness
•Ultrasound
•Max thickness:
•Min thickness:
•Physician assessment:
•Heartscan coronary artery screen
•Low-dose CT
•Below 25th percentile for age group
MYOCARDIAL INFARCTION*
-21% of the population is homozygous for the variant-Study included 4,587 cases and 12,767 controls-Variant close to tumor suppressor genes p15 and p16
At risk alleleDavid’s
genotypeDavid’s OR PAR Het OR Hom OR Location
rs10757278 G G - G 1.64(genotype OR)
21% (general)
31% (early onset)1.26 1.64 9p21
OR is compared to non-carriers
PAR = population attributable risk
OR = odds ratio*Helgadottir et al. Science 2007
Cholesterol MetabolismCholesterol Metabolism
AtherogenesisAtherogenesisCell Population Lifecycles andCell Population Lifecycles and
Lipid ProcessingLipid Processing
AtherogenesisAtherogenesisInflammatory NetworkInflammatory Network
PlaquePlaqueStabiliStabili
tyty
QuickTime™ and aH.264 decompressor
are needed to see this picture.
Virtual Population
David’sVirtual Human Profile
Statistical mirror for ARIC population study
and deCODE Genetics analysis of rs10757278
David David relative to ARIC ARIC Virtual Population
low high range closer bound mean SD mean SD
TC mg/dl 209 231 50-90th 50th 207 39.5 210.65 41.02
TG mg/dl 98.8 109.2 10-50th 50th 144.8 94.6 153.08 89.32
LDL-C mg/dl 127.3 140.7 10-50th 50th 136 36.4 133.64 34.92
HDL-C mg/dl 61.75 68.25 95-100th 95th 43.1 12.4 42.07 11.9
IMT microns 590 650 50th 75th* 465 110 493.21 117.18
*Howard, Stroke 1993
rs10757278 ARIC fraction Virtual Population fraction
homo LR 0.25 0.25
hetero 0.5 0.5
homo HR 0.25 0.25
homo LR w/ events 0.20 0.2
hetero w/ events 0.252 0.252
homo HR w/ events 0.328 0.328
1423 Virtual Humans
53 Virtual Davids
ARIC: Atherosclerosis Risk in Communities45 to 64 year-old members from four US communities:•Forsyth County, NC•Selected Minneapolis suburbs, MN•Washington County, MD•Jackson, MS
15,792 patients in overall population (~5000 white males for David’s analysis)
Virtual David
Average weight gain*
No weight gain
Average weight gain + statin
Average weight gain + cholesterol re-uptake inhibition
Severe weight gain**
Severe weight gain + statin
*Average weight gain - 1 pound/year**Severe weight gain - 5 pounds/year
Years to Event
Cum
ula
tive P
rob
ab
ility
rs10757278 Homozygous High-Risk
Virtual David
Years to Event
Cum
ula
tive P
rob
ab
ility
rs10757278 Homozygous High-Risk
Virtual David
Years to Event
Cum
ula
tive P
rob
ab
ility
rs10757278 Homozygous Low-Risk
Virtual David
David
geneticmarkers
biomarkers
imaging
What should I do?What should I do?
Therapies
Lifestyle
Genetics Physiology Disease
What should I do?What should I do?
Body: Issues
Bioinformatics is ready
Need pipeline to collect data
Expensive (for now)
It might work: true predictive models feel like Gattaca
Conclusions / Recommendations from the Guinea-Pig
Information Overload
Urgent focus on Individuals
Education of Health Care Providers
Educate Public
Privacy Laws
Regulation -- Efficacy and Safety
The Experimental Man Project
Coming Soon:
Website:
Wiki-Style “Virtual Man”
at the Center for Life Science Policy
UC Berkeley
www.experimentalman.com
David Ewing Duncan, 2007
Still Looking for Help in:
More Genes
More Brain Scans
Microbial Study
Cell Studies
Thanks to:
Josh Adler, MD
Judy Illes
Adam Gazzaley Lab
James Brewster Lab
Eric Wasserman Lab
Martin Reese and Omicia, Inc.
Entelos, Inc.
deCode Genetics
Illumnia, Inc.
Axyss Biosystems
Family Tree
Environmental Working Group
National Geographic
Wired
John Wiley and Sons
UCSF, UC Berkeley, Stanford University, Harvard Medical School
and many, many others who have contributed their time and resources;
and special thanks to my family
Thank you…
My Website:
www.davidewingduncan.com
David Ewing Duncan, 2007