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Recoding the Genome

Peter Carr

18 August 2011

FAB7

Lima, Peru

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DNA On-Demand

103 106105104

rewrite genomesminimal lifegenetic circuits

metabolic pathways

individual genesassembly scaffolds

vaccinesgene therapy

DNA basepairs

SS -3PAC 8/18/11 Carr & Church (2009) Nature Biotech.

1

10

100

1000

10000

100000

1000000

10000000

1950 1960 1970 1980 1990 2000 2010 2020

year

nu

cleo

tid

e b

on

ds

organic chemistry

biochemistry

biology

How big can we go?

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The basic genetic code

ACGT

4 letters

ACGT

4 letters

X

ACGT

4 letters

X

AAAAACAAGAATACAACCACGACT...

64 words(codons)

=

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Second Position

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By engineering new genetic codes we can:

• produce organisms immune to viruses

• make universal systems for “plug and play” with new amino acids

new roomfor plug &

play

• block exchange of genes, a “genetic firewall”

rearrangeto blockfunction

Second Position

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Multiplex Automated Genome Engineering (MAGE)

“Find and replace” with

the DNA of the genome

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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.

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All 314 sites in the genome modified(across 32 strains)

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Genome Engineeringbase pairs to megabases

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Joseph Jacobson • Bram Sterling* • Chris Emig • Sam Hwang

George Church (HMS)• Farren Isaacs• Harris Wang• Marc LaJoie

Shuguang Zhang (MIT)

Funding: NSF

Thanks to:

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Atoms to bits...to atoms to bits

receivertransmitter

Box 1 Box 2me

you

it

clinical + research

data

genetic counseling

health statistics

forensics

basic research

molecules

experiments

G A T T A C A

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Personal

Box 1

MY GENES

Box 2

How will drugs X, Y, Z

affect ME?

MY TREATMENT

How will MY BODY metabolize drugs X, Y, Z?

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Box 1

NEW PATHOGEN

Box 2

Analyze the PARTS

RAPID RESPONSE

Test existing DRUGS at many sites

Preliminary VACCINE

Community

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MY IDEA

Box 2

new biochemistry

MY DESIGN FOR...

DNA nanostructures

new vaccines

novel organisms

Creativity