October 8, 2015 From the event "Synthetic Biology: Science, Policy, and Ethics." Sponsored by the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School. For more information, visit our website at http://petrieflom.law.harvard.edu/events/details/synthetic-biology.

1. Thanks to:
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*==Read===========Write===========Arithmetic1
Biology, Policy & Ethics
8-Oct-2015 4 PM Harkness S Rm 205
LSRF
NHGRI
NIGMS
Azco
Oppenheimer
Founda6on

2. 2
5-10X/year since 2005 (vs 1.5X Moore’s Law)
Carr
Church,
Nature
Biotech
Synthetic biology
Sequencing

3. .

4. Isolation
Testing
Redundant systems
Licensing
Safety: Risks Benefits
Standards
modeling
Surveillance
the costs of doing nothing

5. Safety via Surveillance of Synthetic DNA
Training scenario brainstorming
Communication transaction surveillance
• Dropping costs of DNA monitoring
• Phosphoramidites instruments
Church
GM
(2004)
A
Synthe6c
Biohazard
Non-­‐prolifera6on
Proposal
Church
GM
(2005)
Let
us
go
forth
and
safely
mul6ply.
Nature
438:
423
Bügl,
et
al.
(2007)
DNA
synthesis
and
biological
security.
Nature
Biotech
Church
GM
(2009)
Safeguarding
Biology.
Seed
20:84-­‐86.
Church
GM
(2010)
Presiden6al
Commission
for
the
Study
of
Bioethical
Issues

6. 6
Physical
containment:
Marburg,
Ebola,
Lassa,
Crimean-­‐Congo
hemorrhagic
fever,
Smallpox

7. Why Genome scale engineering?
Risk creation mitigation
Science 2013: Lajoie, et al.
Nature 2015 Mandell et al.2. Genetic isolation
3. Metabolic Isolation
4. Multi-Virus
resistance
1. Non-standard amino acids (NSAA)

8. Esvelt, Smidler,
Catteruccia, Church
July 2014 eLife
Safer
Gene Drives
for the
Alteration of
Wild
Populations
Physical,
Molecular,
Species,
Ecological
Isolation

9. Intentional (de) extinction: Risks Benefits
• Cost, other species
• Gene drives restricted to wild sexual species
Intentional extinction examples
Past: Smallpox
Future: Malaria, Polio
Intentional de-extinction examples
Past: 1918 flu, HERV
Future: Mammoth

10. 10
Privacy Safely shareable human
genomes/cell standards
NIST + FDA Genomeinabottle.org
PersonalGenomes.org
Cohort consented for re-identification
commercial use. 8 Trios.
5 Sites: Boston, NYC, Toronto, London, Vienna
15 sites in the queue. 100,000 genomes each.
CAGI, NIH ENCODE, NCBI, Coriell
Human SynBio resources : BACs, CRISPR, Cells
GET-evidence.org pgEd.org

11. 11
Genes
Environments
Traits (GET)
• World’s only open access data sets
• Consented for likely re-identification
• 100% on Exam – Educate first
• Stem Cell Biobank

12. 12
12
CRISPR à Human Organoids-on-chips
Ingber,
Parker,
Knoblich,
etc.
labs

13. Gene Therapy Risks
Blood 1996 Hacein-Bey et al.
Science 2003 Hacein-Bey-Abina et al.
9 of 10 patients cured of SCID-X1 with 4x108 cells
2 of 10, after 3 years, developed exponential clonal
proliferation of mature T cells (LMO2 oncogene)
MFG:
Moloney
murine
leukemia
virus
LTR
vector

14. Gene therapy: 2000 clinical research trials.

15. AIDS clinical trial
Inactivating both copies of the
HIV1 coreceptor gene
CCR5
T-­‐cell
HIV
Risk reduction using
precise genome editing

16. Why Human Germline Modifications?
Case 1) Post-natal therapy is too late developmentally.
1a) For a particular disease, both parents have only disease-causing DNA variants
and, thus, in the absence of intervention, their children will too. This can occur in
the one fifth of marriages worldwide which are consanguineous. This situation
cannot be addressed by PGD or NIPT. Treating sperm such that they no longer
carry the disease variant could be the best option.
1b) PGD-IVF is not medically acceptable to mothers with harmful reactions to the
IVF procedure
1c) Or for religious or other reasons, are not willing to risk the non-implanted
embryos -- but are willing to alter sperm cells.
Case 2) Post-natal gene therapy risk of off-target effects, that could cause, e.g.,
cancer. Risk goes up with the number of cells treated. Thus, treatment of one sperm
cell could be a billion times less risky than the treatment of a billion somatic
cells after birth.

17. Humanized for
xeno transplants
Lowered zoonoses
GGTA1, CMAH, SLA/HLA
Complement, Clotting
62 PERVs = Porcine
Endogenous RetroViruses
Exogenous
PCMV,
PEDV,
PRRSV
1.7 million sufferers of
end stage kidney disease
(ESKD) worldwide
Bendorf et al. 2013

18. .