1. Synthetic Genomics: Options for Governance

2. 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

4. 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”?)

5. 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

6. x x xx xx xxx In vitro recombination system. Overlapping 5–10 kb DNA segments Introduce synthetic genome/ chromosome into (empty) cell 480kb SynMycoplasma genome Basic approach to synthesis

7. Global synthesis of infectious  X174 bacteriophage from synthetic oligonucleotides

12. Synthesis of a range of polynucleotides: From tRNA to genomes Size of project (bp) Year of publication tRNA gene + plasmid PKS gene cluster poliovirus phiX Mycoplasma genitalium JCVI 1.0

13. External events can influence how a technology is perceived Size of project (bp) Year of publication tRNA gene + plasmid PKS gene cluster poliovirus phiX Mycoplasma genitalium JCVI 1.0 9/11/2001

14. 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….

15. 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.

16. Ro et al., 2006 Nature

17. 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.)

18. 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

19. 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

20. 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

21. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

35. 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

36. 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

38. 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)

39. 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

42. 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?