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EXPERIMENTAL MAN One Mans Intimate Journey Inside Himself, Cell by Cell David Ewing Duncan David Ewing Duncan, 2007.

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Presentation on theme: "EXPERIMENTAL MAN One Mans Intimate Journey Inside Himself, Cell by Cell David Ewing Duncan David Ewing Duncan, 2007."— Presentation transcript:

1 EXPERIMENTAL MAN One Mans Intimate Journey Inside Himself, Cell by Cell David Ewing Duncan David Ewing Duncan, 2007

2 All Life is an experiment. The more experiments you make the better. – Ralph Waldo Emerson

3 Personalized Medicine Is: Genes Environment Brain Body

4 Not yet ready for individuals Uneven validation and unregulated Expensive: my tests ~ $100,000 Health Care and bioethics communities unprepared Observations and Caveats

5 GENES

6

7 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 More Courtesy of Omicia, Inc. and Illumina

8 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.

9 Novelty-Seeking Behavior 2 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.

10 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.

11 MYOCARDIAL INFARCTION At risk alleleDavids genotype Davids ORPARHet OR Hom OR Location Rs10757278 G G - G1.64 (general) 2.02 (early onset) 21% (general) 31% early 1.261.649p21 At risk allele Herbert Duncan (Father) Patricia Duncan (Mother) Danielle Duncan (Daughter) Donald Duncan (Brother) rs10757 278G AG Family Results Courtesy of deCode Genetics

12 MI Gene: 3 Generations of Duncans FatherMother A-G A-G DavidBrother G-G A-G Daughter A-G

13 Ancestral DNA - Y Chromosome No 12 Marker Y-DNA Matches Found Genetic Distance - 1 Name E-mail Mr. Bobby Royce Henry (Y67) JHHenry99@… Alan C. Duncan (Y37) idlelane@… Wallace T. Duncan (Y25) WDuncan321@… 25 Marker Matches (6) Genetic Distance - 1 Name E-mail Alan C. Duncan (Y37) idlelane@… Wallace T. Duncan WDuncan321@… Daniel Earl Duncan (Y37) nyfromca@… Courtesy of Family Tree

14 Genes: Issues Population data not always relevant to individuals SNPs are not sequencing Shifting probabilities Most genes unvalidated and unregulated Potential for confusion

15 ENVIRONMENT

16 Tested: 320 Detected: 165 Cost: $15,000 My Chemical Report Card

17 Whats Inside David Total Tested: 320 Detected: 165 Higher than Mean: 155

18 My life with chemicals…

19 Childhood in Kansas

20 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

21 Pesticides

22 Phthalates

23 Dioxin-Like PCBs

24 PBDEs

25

26 Methyl Mercury Level Test #1: 5 ppm Safe Level 10 ppm or less

27 Coal Burned for electricity Released into air Settles over ocean Plankton Little Fish Bigger Fish Huge Fish Humans

28 Methyl Mercury Level Test #2: 12 ppm Safe Level 10 ppm or less

29 www.ctd.mdibl.org Genes + Chemicals + Disease COMPARATIVE TOXICOGENOMIC DATABASE -- CTD

30 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

31 Environment: Issues No respect vis-à-vis genetics Most work done on animals Budgets small (but growing) Potentially disruptive to business and regulations

32 BRAIN

33

34 fMRI

35 EEG, TMS

36 Alzheimers 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

37 Quantifying Brain Volumes

38 cue stimuli delayresponse + Remember Faces Ignore Scenes 1 sec 8 sec 1 sec + Remember Scenes Ignore Faces Passively View + Working memory task Equivalent perceptual, bottom-up information. Differences in activity mediated by top-down signals.

39 Top-down modulation in visual processing

40 DED Brain Courtesy of Adam Gazzaley, UCSF

41 RememberScenes IgnoreScenes PassiveView Younger (19-30 y.o.) Older (60-77 y.o.) Gazzaley, A. et al. Nature Neuroscience (2005) RememberScenes IgnoreScenes PassiveView RememberScenes IgnoreScenes PassiveView David Duncan (age= 48 y.o.) Courtesy of Adam Gazzaley, UCSF

42 Face Memory Response Time fMRI Working Memory Performance AccuracyAccuracy Scene Memory Face Memory Scene Memory Younger DD Older

43 Electroencephalography (EEG) Event-Related Potentials (ERPs) Spectral

44 EEG data: P1 amplitude Attend Faces Passively View Faces Ignore Faces

45 Remember Passive Ignore Remember Passive Ignore Younger Older EEG data: P1 amplitude David Duncan

46 Other Brain Tests Fear Anxiety Impulsiveness Risk Greed Altruism Politics Disease More

47 Brain: Issues Not relevant to individuals Lack of data - small groups tested Very early days

48 BODY (Note: The following information (the Entelos Model of the Virtual David) is being revised and may not be accurate in its current form -- DED)

49 TestData questionnaire age, gender diabetes blood sample blood pressure standard lipid panel lipoprotein particle size distribution inflammatory markers glucose metabolism markers ultrasoundcarotid IMT CT scancoronary calcium score buccal swabgenetic analysis Risk Assessment Recommendation Framingham Risk ScoreATP3 Treatment Guidelines scientific literature on markers and associated risk no recommendation qualitative assessment; no outcomes studies population associated risk David genetic markers biomarkers imaging Heart Project: Entelos

50

51 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

52 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 allele Davids genotype Davids ORPARHet ORHom ORLocation rs10757278 GG - G 1.64 (genotype OR) 21% (general) 31% (early onset) 1.261.649p21 OR is compared to non- carriers PAR = population attributable risk OR = odds ratio *Helgadottir et al. Science 2007

53 Cholesterol Metabolism Atherogenesis Cell Population Lifecycles and Lipid Processing Atherogenesis Inflammatory Network Plaque Stabilit y

54 Virtual Population Davids Virtual Human Profile Statistical mirror for ARIC population study and deCODE Genetics analysis of rs10757278

55 DavidDavid relative to ARICARICVirtual Population lowhighrangecloser boundmeanSDmeanSD TCmg/dl20923150-90th50th20739.5210.6541.02 TGmg/dl98.8109.210-50th50th144.894.6153.0889.32 LDL-Cmg/dl127.3140.710-50th50th13636.4133.6434.92 HDL-Cmg/dl61.7568.2595-100th95th43.112.442.0711.9 IMTmicrons59065050th75th*465110493.21117.18 *Howard, Stroke 1993 rs10757278ARIC fractionVirtual Population fraction homo LR0.25 hetero0.5 homo HR0.25 homo LR w/ events0.200.2 hetero w/ events0.252 homo HR w/ events0.328 1423 Virtual Humans 53 Virtual Davids ARIC: Atherosclerosis Risk in Communities 45 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 Davids analysis)

56 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

57 Years to Event Cumulative Probability rs10757278 Homozygous High-Risk Virtual David

58 Years to Event Cumulative Probability rs10757278 Homozygous High-Risk Virtual David

59 Years to Event Cumulative Probability rs10757278 Homozygous Low-Risk Virtual David

60 David genetic markers biomarkers imaging What should I do? Therapies Lifestyle GeneticsPhysiology Disease What should I do?

61 Body: Issues Bioinformatics is ready Need pipeline to collect data Expensive (for now) It might work: true predictive models feel like Gattaca

62 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

63 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

64 Still Looking for Help in: More Genes More Brain Scans Microbial Study Cell Studies

65 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

66 Thank you… My Website: www.davidewingduncan.com David Ewing Duncan, 2007


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