Synthetic Genomics:
Options for Governance
Synthetic Genomics: Risks and Benefits
for Science and Society
 20 month study funded by the Alfred P. Sloan
Foundation
 Technology assessment
 Partners
 Venter Institute
- Robert Friedman and Michele Garfinkel
 Center for Strategic & International Studies
- Gerald Epstein
 MIT Synthetic Biology Group
- Drew Endy
Synthetic genomics
 The construction of long strands of genetic material
(from gene- to genome length) from scratch
(nucleotides)
 Implies activation or “booting” of the genome
 Synthesis is not the only way to construct these very
long pieces
 The techniques for doing this are not unique to this
technology
 What is unique: new capabilities and distribution
(engineers, students, amateurs); public perception
(is this “creating” life? “Playing god”?)
Scale
 Building blocks: nucleotides
 Basic unit: base pairs (A:T, G:C)
 Oligonucleotides: 25-100 base-pairs
 Gene (mRNA): 100s to 1000s of base-pairs
 Genomes:
 Viruses: 1000s to 100,000s
 Mycoplasma: 600,000
 “Average” bacteria: 5 million
 Human: 3 billion
 Plants: up to 10 billion, and beyond
Basic approach to synthesis
Overlapping 5–10
kb DNA segments
x
x
x
x
x
x
x
x
x
In vitro recombination
system.
480kb
SynMycoplasma
genome
Introduce
synthetic
genome/
chromosome
into (empty)
cell
Global synthesis of infectious fX174 bacteriophage from synthetic oligonucleotides
Synthesis of a range of polynucleotides:
From tRNA to genomes
1,000,000
Mycoplasma genitalium
JCVI 1.0
100,000
PKS gene
cluster
Size
of
project 10,000
(bp)
phiX
1,000
poliovirus
gene +
plasmid
100
10
tRNA
'75
'80
'85
'90
'95
Year of publication
'00
'05
'10
External events can influence
how a technology is perceived
1,000,000
Mycoplasma genitalium
JCVI 1.0
100,000
Size
of
project 10,000
(bp)
PKS gene
cluster
9/11/2001
phiX
1,000
poliovirus
gene +
plasmid
100
10
tRNA
'75
'80
'85
'90
'95
Year of publication
'00
'05
'10
Engineer a pathway:
Artemisinic acid
 Precursor to artemisinin, a potent but expensive
(to those most likely to be infected) and scarce
(harvested from a woody shrub) anti-malarial
drug
 Chemical synthesis of artemisinin is possible but
extremely time and labor intensive, and
expensive
 The ideal approach is a completely consolidated
bioprocessing system, but in the meanwhile….
Artemisinin, cont.
 …produce the precursor, artemisinic acid, in
yeast. Need three “fixes” to do this, all using
techniques of synthetic genomics (and
biotechnology generally):
 Increase yeast farnesyl pyrophosphate (FPP)
production at the expense of sterols
 Introduce the A. annua gene that converts FPP to
amorphadiene (artemisinic acid precursor)
 Add a novel cytochrome P450 that carries out 3-step
oxidation of amorphadiene to artemisinic acid.
Ro et al.,
2006
Nature
Suite of societal
concerns/issues/impacts







Biosafety
Biosecurity
Economics (including intellectual property)
Distribution of benefits
Distribution of risks
Theological concerns
Philosophical issues
These were dealt with initially in 1999 (Cho et al.)
The project
 Our goal was to construct and evaluate policy
options to address possible adverse
consequences of synthetic genomics
 Our evaluations considered both the risks
and the benefits of this new technology
 Series of meetings: Interdisciplinary core
group; other participants
 Others working on these issues as well




NSABB
ICPS/IASB
NGOs
Academics
Core Group Members
 Ralph Baric
 University of North
Carolina
 George Church
 Harvard Medical School
 Franco Furger
 Independent Consultant,
Lucerne
 Tom Knight
 Massachusetts Institute
of Technology
 Lori Knowles
 University of Alberta
 John Mulligan
 Blue Heron
Biotechnology
 Paula Olsiewski
 Alfred P. Sloan
Foundation
 Tara O’Toole
 UPMC-Center for
Biosecurity
Core Group Members
 George Poste
 ASU-Biodesign Institute
 Susanna Priest
 University of South
Carolina
 Michael Rodemeyer
 Pew Initiative on Food
and Biotechnology
 Hamilton Smith
 Venter Institute
 Jonathan Tucker
 Monterey Institute of
International Studies
 Craig Venter
 Venter Institute
Intervention Points
 Commercial firms that synthesize DNA
 Gene firms, which produce whole genes and
genomes
 Oligonucleotide manufacturers, which sell short
stretches of DNA
 Owners of bench-top DNA synthesizers, used in
individual labs to make short stretches of DNA
 Users and organizations
What to worry about
 Impeding the advancement of science/impeding
business
 Level playing fields





Biologists becoming terrorists (not vice versa)
How to think about “dual use”
International nature of the work
Definition of a community
Capabilities and perceptions
 Superpathogens
 “Creating” life or “playing god”
 State-of-the-art becomes a commodity
Intervention Points
 Commercial firms that synthesize DNA
 Gene firms, which produce whole genes and
genomes
 Oligonucleotide manufacturers, which sell short
stretches of DNA
 Owners of bench-top DNA synthesizers, used in
individual labs to make short stretches of DNA
 Users and organizations
Intervention Points
 Why focus on commercial firms?
 Starting with long pieces of DNA (1000s of bases) easier
than with short pieces
 Starting with short pieces of DNA (50 -100 bases) easier than
starting with reagents
 How many firms?
 About 50 gene firms worldwide
- Our count: 45 (24 in the United States)
 Dozens of oligo manufacturers selling over the Internet
worldwide
- At least 25 major U.S. suppliers, many more firms with the
capability; many in other countries
I. Policies for commercial firms
I-1. Require Firms to Use Approved Software for
Screening Orders
I-2. People Who Order Synthetic DNA Must be Verified
by an Institutional Biosafety Officer or Similar
“Responsible Official”
I-3. Firms Must Use Approved Screening Software;
People Who Order Must be Verified by Biosafety
Officer
I-4. Firms Must Store Information About Customers
and Their Orders
Require Firms to Use Approved
Software for Screening Orders
 First-generation software exists to screen
sequence against a list of pathogens, but:
 “False positives” are a problem
 No list of pathogens and potentially dangerous
genes has been designed for this purpose
 Screening less reliable for shorter pieces of DNA
 Most gene firms already screen orders
 This option would reduce number of “free riders”
 Tougher challenge for oligo manufacturers
People Who Order Synthetic DNA Must be
Certified by an Institutional Biosafety
Officer or Similar “Responsible Official”
 Screen the people who place orders to make
sure they are legitimate users
 Equivalent to an identity check or check for
financial solvency
 Electronic list updated perhaps once/year
 Third-party, Internet certificates possible (e.g.,
VeriSign-like)
 Most large institutions have Biosafety Officers
 Small start-ups would need to use consultants
Firms Must Use Approved Screening
Software plus People Who Order Must
be Certified by Biosafety Officer
 Screening both sequence and people allows
more targeted procedures
 Biosafety officer or other responsible official
creates two lists of users:
 Researchers approved to work with pathogens
 Those who are not
 Biosafety officer contacted if screening
software identifies “risky” sequence from
unexpected customer
Firms Must Store Information
About Customers and Their Orders
 FBI would have access for forensic purposes
in the event of an attack
 Firms required to store sequences ordered
for specified period
 TSCA already requires firms to store some
chemical orders for 5 years
 Orders shipped only to known addresses
 Similar to FedEx
Effectiveness for Achieving Goals
 Options most effective for enhancing
biosecurity, much less so for other goals
 Sequence screening more effective at gene
foundries than oligo manufacturers
 Hybrid option most effective for prevention
 Storing information most effective for helping
to respond
Other Considerations
 Options with software screening will be most
difficult to implement
 Software must be improved and certified
 Screening lists needed
 Burdens will be relatively greater:
 For oligo manufactures than gene foundries
 For purchasers from start-up companies
Intervention Points
 Commercial firms that synthesize DNA
 Gene foundries, which produce whole genes and
genomes
 Oligonucleotide manufacturers, which sell short
stretches of DNA
 Owners of bench-top DNA synthesizers, used in
individual labs to make short stretches of DNA
 Users and organizations
II. Policies for monitoring or
controlling equipment and reagents
II-1. Registration of DNA Synthesizer Owners
II-2. Licensing of DNA Synthesizer Owners
II-3. Licensing of Synthesizers, plus License
Required to Buy Reagents or Services
III. Policies for users and
organizations for promoting
safety and security
III-1. Education About Risks and Best Practices
as Part of University Curriculum in the
Laboratory or Classroom
III-2. Compilation and Use of a Manual for
“Biosafety in Synthetic Biology
Laboratories”
III-3. Clearinghouse for Best Practices
(continued)
III. Policies for users and
organizations for promoting
safety and security
III-4. Broaden IBC Review Responsibilities to
Consider Risky Experiments
III-5. Broaden IBC Review, plus Oversight from
National Advisory Group to Evaluate
Risky Experiments
III-6. Broaden IBC Review, plus Enhanced
Enforcement of Compliance with
Biosafety Guidelines
Implementation Issues
For screening options, who (how)….
 Tests and certifies screening software?
 Prepares and maintains list of dangerous
sequences?
 Registers commercial firms?
 Monitors firms for compliance: software use,
data storage, screening individuals?
 Maintains hotline for firms to call?
 Certifies “institutional verifiers”?
 Maintains list(s) of verified users?