synthetic genomics: options for governance. synthetic genomics: risks and benefits for science and...
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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
x x x xx x x x x
In vitro recombination system.
Overlapping 5–10 kb DNA segments
Introduce synthetic genome/ chromosome into (empty) cell
480kb SynMycoplasma genome
Basic approach to synthesis
Global synthesis of infectious X174 bacteriophage from synthetic oligonucleotides
Synthesis of a range of polynucleotides: From tRNA to genomes
10
100
1,000
10,000
100,000
1,000,000
'75 '80 '85 '90 '95 '00 '05 '10
Sizeofproject (bp)
Year of publication
tRNA
gene +plasmid
PKS genecluster
poliovirus
phiX
Mycoplasma genitaliumJCVI 1.0
External events can influence how a technology is perceived
10
100
1,000
10,000
100,000
1,000,000
'75 '80 '85 '90 '95 '00 '05 '10
Sizeofproject (bp)
Year of publication
tRNA
gene +plasmid
PKS genecluster
poliovirus
phiX
Mycoplasma genitaliumJCVI 1.0
9/11/2001
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.,2006Nature
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?