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New projects at the interfaces of genomics & societies

New projects at the interfaces of genomics & societies. George Church Thu 15-Jun-2006 at noon. BIDMC Kirstein Living Room. Thanks to:. New interfaces of Genomics & Societies Issues - Proactions. Synthetic Pathogens - Surveillance of DNA resources

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New projects at the interfaces of genomics & societies

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  1. New projects at the interfaces of genomics & societies George Church Thu 15-Jun-2006 at noon. BIDMC Kirstein Living Room Thanks to:

  2. New interfaces of Genomics & SocietiesIssues - Proactions • Synthetic Pathogens - Surveillance of DNA resources • Global Warming - DOE BioEnergy/Ecology Project • Research Privacy - Personal Genome Project Consent June 2006

  3. Old interfaces of Technology & SocietiesIssues - Reactions • Manhattan Project • Animal testing • Genetically Modified • Organisms (GMOs) • Robots & Nanotech

  4. Increasing cost of therapeutics $ billion Ref: PhRMA

  5. 3 Exponential technologies Computation & Communication (bits/sec~m$) E.coli operons Synthesis (amu/project~M$) tRNA urea B12 Analysis (kamu~base/$) telegraph tRNA Shendure J, Mitra R, Varma C, Church GM, 2004 Nature Reviews of Genetics. Carlson 2003 ; Kurzweil 2002; Moore 1965

  6. Options in the midst of exponential change • “Do no harm” Hippocrates 400 BCE Epidemics BkI:2:5. • (Precautionary principle 1988) • Do nothing (AIDS pre-1990; New Orleans pre-Katerina) • Moratorium (Recombinant DNA Feb-75 to Jun-76) • Hide the science (A & H bombs & USSR biowarfare) • Get advice (Genome Project ELSI)

  7. Is Bioterror a real threat? 1977 1995 cult Aum Shinrikyo, aerosolize anthrax & botulinum in Tokyo on 8 occasions.

  8. Bio-risks, Biosecurity Unexpected Arising Bio-Risks "Recently immunized genetically resistant mice with the virus expressing IL-4 also resulted in significant mortality due to fulminant mousepox." Jackson et al. (2001) J Virol. 75:1205-10. Purposeful Bio-Risks "Anthrax 836 .. after another accident..disinfected the sewer but ..one of the rodents captured in the Kirov sewers.. more virulent than the original. The army immediately ordered him to cultivate the new strains.“ --Ken Alibek in "Biohazard" Resurrecting Bio-risks Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus" Tumpey, et al. Science (2005) 310: 77–80. A smallpox victim in Gloucester, 1923

  9. Smart therapeutics example: Environmentally controlled invasion of cancer cells by engineered bacteria. Anderson et al. J Mol Biol. 2006 Regulated Capsule TonB, DapD for safety Optical imaging: bacteria, viruses, and mammalian cells encoding light- emitting proteins reveal the locations of primary tumors & metastases in animals. Yu, et al.Anal. Bioanal. Chem. 2003. accumulate in tumors at ratios in excess of 1000:1 compared with normal tissues. http://www.vionpharm.com/tapet_virulence.html

  10. Defensive options • Global monitoring • bio-weather-map (airborne & medical fluids). • International bio-supply-chain licensing • (min research impact, max surveillance) • Rapid vaccine development & deployment. • Cells resistant to most existing viruses • via codon changes difficulty For more info see: arep.med.harvard.edu

  11. Church, G.M. (2004) A synthetic biohazard non-proliferation proposal. • http://arep.med.harvard.edu/SBP • Monitor oligo synthesis via expansion of • Controlled substances, Select Agents, Recombinant DNA • Computational tools are available; small number of reagent, instrument & synthetic DNA suppliers at present. • Educational & news emphasis on positive uses • International Genetically Engineered Machines Competition • (IGEM) Safer Constructive Biology (CB)

  12. CB & PGP ELSI Advisors(Personal Genome Project, Ethical Legal Social Issues) Jeantine Lunshof (EMGO Institute, Amsterdam) Daniel Vorhaus (Harvard Law) Ting Wu (Harvard Medical School) Eric Juengst (CWRU Center for Biomedical Ethics) Andrea Kalfoglou (NIH) Mildred Cho (Stanford) Laurie Zoloth (Director, Bioethics, Center for Genetic Medicine, Northwestern Univ) Paul Rabinow (UC Berkeley) Lisa Geller (WilmerHale IP Dept). Dan Brock (Harvard Program in Ethics & Health) Ruth Chadwick (CESAGen, Cardiff Univ.) HMS, Partners, Caregroup IRBs >200 Volunteers

  13. “The number of personal facts considered stigmatizing has been dropping since the 1960s when cancer, depression, sexual dysfunction, & STDs were taboo topics, while today discussion of personal decisions on Iressa, Viagra, Prozac, & AZT are common.” Molecular Systems Biology 2005 Change

  14. What if no treatment exists? Huntington's Chorea Nancy Wexler, Hereditary Disease Foundation Doug Melton, & son, Sam, who has diabetes Adrenoleukodystrophy Augusto Odone Mike Milken: Prostate Cancer Foundation. Some families inspire expert activists.

  15. Trait Genes Chromosome location Ocular albinism OA1 X p22.3 Ocular albinism OA2 X p11.4-p11.23 Green/blue iris EYCL1 19 p13.1-q13.11 Brown/blue iris EYCL3 15 q11-q15 Brown/blond hair HCL1 19 p13.1-q13.11 Brown/blond hair HCL3 15 q11-q15 Brown/red hair HCL2 4 q28-q31 Skin&hair color MC1R 16 q24.3 Occulocutaneous -Albinism OCA2 15 q11.2-q12 Height (Marfan) MFS 15 q21.1 Height GH1 17 q22-q24 Height (Laron) GHR 5 p13-p12 Short Stature SS X&Y p Visible traits, genealogy, forensics Surname 12 Y loci CODIS Combined DNA Index System13 autosomal loci

  16. Consent & de-identification “Because the database will be public, people who do identity testing, such as for paternity testing or law enforcement, may also use the samples, the database, and the HapMap, to do general research. However, it will be very hard for anyone to learn anything about you personally from any of this research because none of the samples, the database, or the HapMap will include your name or any other information that could identify you or your family.” Ibadan, Nigeria; Tokyo, Japan; Beijing, China; Utah, USA.

  17. Is anonymity in genomics realistic? 1) Re-identification after “de-identification” using other public data. Group Insurance Commission list of birth date, gender, and zip code was sufficient to re-identify medical records of Governor Weld & family via voter-registration records (1998) (2) Hacking. “Drug Records, Confidential Data vulnerable via Harvard ID number & PharmaCare loophole” (2005). A hacker gained access to confidential medical info at the U. Washington Medical Center -- 4000 files (names, conditions, etc, 2000) (3) Combination of surnames from genotype with geographical info An anonymous sperm donor was traced on the internet 2005 by his 15 year old son who used his own Y chromosome genealogy to access surname relations. (4) Inferring phenotype from genotypeMarkers for eye, skin, and hair color, height, weight, racial features, dysmorphologies, etc. are known & the list is growing. (5) Unexpected self-identification. An example of this at Celera undermined confidence in the investigators. Kennedy D. Science. 2002 297:1237. Not wicked, perhaps, but tacky. (6) A tiny amount of DNA data in the public domain with a name leverages the rest. This would allow the vast amount of DNA data in the HapMap (or other study) to be identified. This can happen for example in court cases even if the suspect is acquitted. (7) Identification by phenotype.If CT or MR imaging data is part of a study, one could reconstruct a person’s appearance . Even blood chemistry can be identifying in some cases. (8)26 million Veterans’ medical records including SSN and disabilities stolen Jun 2006.

  18. "Open-source" Personal Genome Project (PGP) • Harvard Medical School IRB Human Subjects protocol • submitted Sep-2004, approved Aug-2005 renewed Feb-2006. • Start with 3 highly-informed individuals consenting to non-anonymous genomes & extensive phenotypes (medical records, imaging, omics). • Cell lines in Coriell NIGMS Repository • (B-cells, keratinocytes, fibroblasts) • G M Church GM (2005) The Personal Genome Project • Nature Molecular Systems Biology doi:10.1038/msb4100040 • Kohane IS, Altman RB. (2005) Health-information altruists--a potentially critical resource.N Engl J Med. 10;353(19):2074-7.

  19. Genotype % chances if a subject has one copy of a (co)dominant allele "Aa" & most people are "aa". Genotype % chances if a subject has one copy of a (co)dominant allele "Aa" & most people are "aa". Great-grand-parents Aa 13 Aa 13 aa grand-parents Aa 6 Aa 25 Aa 25 2c-2r aa parents aa Aa 3 Aa 13 Aa 50 Aa 50 aa 2c-1r uncle aa aa Aa 2 half sibling Aa 6 Aa Aa 50 aa Aa 25 2c cousin sibling Aa 1 Aa 3 aa Aa 50 child 2c+1r 1c+1r grand-child aa Aa 25 2c2r = 2nd cousin twice removed Great-grand-child Aa 13 Family Risks

  20. Rank mutations/polymorphisms: • affecting known disease genes (or related genes) • affecting conserved genetic elements • potential homozygous or semi-dominant alleles • Generate hypotheses about related functions • Tests: Association studies, animal models, • human tissue culture, etc. • Prioritize diagnostic tests, therapeutics, • lifestyle, nutritional changes. Human non-synonymous SNPs Ramensky et al. 2002 NAR30: 3894; Amino-acid Mutational Spectrum of Human Genetic Disease. Vitkup, et al (2003) Genome Biol 4: R72 What would you do with your genome sequence?

  21. Non-anonymous phenotypes Einstein: EEG & brain anatomy Jernigan: Whole body MRI, CT, & serial sections Schwarzenegger : whole body cutaneous photography

  22. PGP Risks • The risks of public disclosure of your genotype and phenotype information could affect employment, insurance, and social interactions for you and your immediate family. For example, data such as facial images can be used to identify you which could result in higher than normal levels of contacts from the press and other members of the public motivated by positive or negative feelings about the study. This could mean a significant loss of privacy and personal time. • You should also be aware of the ways in which knowledge of your genotype and phenotype might be used. For example, anyone with sufficient knowledge could take your genome and/or posted medical information and use them to (1) infer paternity or other features of your genealogy, (2) claim statistical evidence that could affect your employment or insurance, (3) claim your relatedness to infamous villains, (4) make synthetic DNA and plant it at a crime scene, (5) reveal the possibility of a disease or unknown propensity for a disease. • The genetic and medical record information posted on the study website, while directly associated only with you, may also have relevance to your family members.

  23. Environment/Genome/Phenome • Environment (genetic): maternal, allergens, microbes • Non-genetic: phys/chem, educational, health-care, etc. • Small mutations: whole genome vs targeted • DNA copy number & rearrangements (paired ends) • Haplotype: not mere linkage, but causative combinations in cis) • RNA Digital Analysis of Gene Expression (by counting) • RNA splicing (that arrays can’t handle) • Proteomics (serum, neutrophils, monocytes, CD4+, CD8+, B Cells) • Standard Clinical chemistry, Metabolomics • Questionaires, Surgeon General's Family History • Imaging: MRI, fMRI, CT, Pathology data • Response to drugs – personal toxicity & efficacy • Behavioral: compliance, happiness, anxiety, etc

  24. Sequencing/genotyping with single human chromosomes 153Mbp Zhang et al. Nature Genet. Mar 2006

  25. Single chromosome sequencing (single cell , RNA or particle) (1) When we only have one cell as in Preimplantation Genetic Diagnosis (PGD) or environmental samples (model organisms which don’t grow well in the lab) (2) Candidate chromosome region sequencing (3) Prioritizing or pooling (rare) species based on an initial DNA screen. (4) Multiple chromosomes in a cell or virus (5) RNA splicing (6) Cell-cell interactions in ecosystems (e.g. digestive) (predator-prey, symbionts, commensals, parasites)

  26. Personal Genomics: from analysis to synthesis via stem cells • Access to many or all tissues for RNA & mC studies, cell therapies • Recombinational programming • Epigenetic programming (with mC sequence monitoring) • Modeling for Lesch-Nyhan disease by gene targeting in • human embryonic stem cells. Stem Cells. 2004;22(4):635-41. • Copolymer effects on microglia and T cells in the central nervous system of humanized mice. Eur J Immunol. 2005 • Humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol. 2004 Sep;165(3):901-12.

  27. New interfaces of Genomics & SocietiesIssues - Proactions • Synthetic Pathogens - Surveillance of DNA resources • Global Warming - DOE BioEnergy/Ecology Project • Research Privacy - Personal Genome Project Consent

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