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Transcript
Recoding the Genome
Peter Carr
18 August 2011
FAB7
Lima, Peru
SS -1
PAC 8/18/11
DNA On-Demand
rewrite genomes
minimal life
genetic circuits
metabolic pathways
DNA
base
pairs
103
individual genes
assembly
scaffolds
SS -2
PAC 8/18/11
104
105
vaccines
gene therapy
106
How big can we go?
nucleotide bonds
10000000
1000000
biology
100000
10000
1000
biochemistry
100
10
1
1950
organic chemistry
1960
1970
1980
1990
2000
year
SS -3
PAC 8/18/11
Carr & Church (2009) Nature Biotech.
2010
2020
The basic genetic code
4 letters
A
C
G
T
SS -4
PAC 8/18/11
4 letters
X
A
C
G
T
64 words
(codons)
4 letters
X
A
C
G
T
=
AAA
AAC
AAG
AAT
ACA
ACC
ACG
ACT
...
Second Position
SS -5
PAC 8/18/11
Second Position
new room
for plug &
play
rearrange
to block
function
By engineering new genetic codes we can:
• make universal systems for “plug and play” with new amino acids
• block exchange of genes, a “genetic firewall”
• produce organisms immune to viruses
SS -6
PAC 8/18/11
Multiplex Automated Genome Engineering (MAGE)
“Find and
replace” with
the DNA of the
genome
SS -7
PAC 8/18/11
Key features of MAGE:
• Multiplexed: can address many sites at
once
• Targeted: modifies specific sequences;
changes made can be specific or
random
• Iterated: weak efficiency can be
compensated by automating many
cycles of modification
• Tunable: can control the range of
diversity generated in a population
• Clean: no DNA scars, no resistance
gene markers, etc.
SS -8
PAC 8/18/11
All 314 sites in the genome modified
(across 32 strains)
SS -9
PAC 8/18/11
Genome Engineering
base pairs to megabases
SS -10
PAC 8/18/11
Thanks to:
Joseph Jacobson
• Bram Sterling*
• Chris Emig
• Sam Hwang
George Church (HMS)
• Farren Isaacs
• Harris Wang
• Marc LaJoie
Shuguang Zhang (MIT)
SS -11
PAC 8/18/11
Funding: NSF
Atoms to bits...to atoms to bits
transmitter
receiver
genetic
molecules
counseling
G A T T A C A
me
you
it
SS -12
PAC 8/18/11
Box 1
clinical +
research
Box 2
data
health
statistics
forensics
basic
experiments
research
Personal
Box 1
Box 2
MY GENES
MY TREATMENT
How will drugs X, Y, Z
affect ME?
How will MY BODY
metabolize drugs X, Y, Z?
SS -13
PAC 8/18/11
Community
Box 1
NEW PATHOGEN
Box 2
RAPID RESPONSE
Analyze the PARTS
Test existing DRUGS at
many sites
SS -14
PAC 8/18/11
Preliminary VACCINE
Creativity
Box 2
MY DESIGN FOR...
MY IDEA
new vaccines
novel organisms
new biochemistry
DNA nanostructures
SS -15
PAC 8/18/11