New projects at the interfaces of genomics

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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
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Old interfaces of Technology SocietiesIssues -
Reactions

• Manhattan Project
• Animal testing
• Genetically Modified
• Organisms (GMOs)
• Robots Nanotech

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Increasing cost of therapeutics
billion
Ref PhRMA
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3 Exponential technologies
Computation Communication (bits/secm)
E.coli
operons
Synthesis (amu/projectM)
tRNA
urea
B12
Analysis (kamubase/)
telegraph
tRNA
Shendure J, Mitra R, Varma C, Church GM, 2004
Nature Reviews of Genetics. Carlson 2003
Kurzweil 2002 Moore 1965
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Options in the midst of exponential change

• Do no harm Hippocrates 400 BCE Epidemics
  BkI25.
• (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)

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Is Bioterror a real threat?
1977
1995 cult Aum Shinrikyo, aerosolize anthrax
botulinum in Tokyo on 8 occasions.
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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. 751205-10. 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 7780.
A smallpox victim in Gloucester, 1923
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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 10001 compared with normal tissues.
http//www.vionpharm.com/tapet_virulence.html
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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
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Safer Constructive Biology (CB)

• 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)

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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 gt200 Volunteers
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Change
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
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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.
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Visible traits, genealogy, forensics
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 Skinhair 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 XY p
Surname 12 Y loci CODIS Combined
DNA Index System 13 autosomal loci
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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.
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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 genotype Markers 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
2971237. 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 persons appearance . Even
blood chemistry can be identifying in some
cases. (8) 26 million Veterans medical records
including SSN and disabilities stolen Jun 2006.
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"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
  doi10.1038/msb4100040
• Kohane IS, Altman RB. (2005) Health-information
  altruists--a potentially critical resource. N
  Engl J Med. 10353(19)2074-7.

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Family Risks
Genotype chances if a subject has one copy of a
(co)dominant allele "Aa" most people are "aa".
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What would you do with your genome sequence?
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Non-anonymous phenotypes
Einstein EEG brain anatomy
Jernigan Whole body MRI, CT, serial sections
Schwarzenegger whole body cutaneous
photography
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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.

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Environment/Genome/Phenome

1. Environment (genetic) maternal, allergens,
   microbes
2. Non-genetic phys/chem, educational, health-care,
   etc.
3. Small mutations whole genome vs targeted
4. DNA copy number rearrangements (paired ends)
5. Haplotype not mere linkage, but causative
   combinations in cis)
6. RNA Digital Analysis of Gene Expression (by
   counting)
7. RNA splicing (that arrays cant handle)
8. Proteomics (serum, neutrophils, monocytes, CD4,
   CD8, B Cells)
9. Standard Clinical chemistry, Metabolomics
10. Questionaires, Surgeon General's Family History
11. Imaging MRI, fMRI, CT, Pathology data
12. Response to drugs personal toxicity efficacy
13. Behavioral compliance, happiness, anxiety, etc

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Sequencing/genotyping with single human
chromosomes
153Mbp
Zhang et al. Nature Genet. Mar 2006
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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
dont 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)
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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.
  200422(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
  Sep165(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