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

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'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?