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The relevance and potential applicability of screening framework guidance for commercial providers of synthetic double-stranded DNA: Current software screening and review mechanisms.
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The relevance and potential applicability of screening framework guidance for commercial providers of synthetic double-stranded DNA:Current software screening and review mechanisms Addressing Future Challenges to the Biological and Toxin Weapons Convention in Connection with Scientific and Technological Developments Frank Notka - March 6th, Technical Workshop,Stockholm
Charter members IGSC was founded by: http://www.genesynthesisconsortium.org
Major Categories of Risk Posed by Biotechnology Research Biosafety Biosecurity Accidental exposure to a pathogen or toxin could adversely affect: • Laboratory workers • General public • Plants and animals • Environment Deliberate misuse of technology to cause harm to: • Humans • Plants and animals • Environment
opportunity Balanced Discussion to Take Advantage of the Opportunities and Minimize Risks
IGSC Goals and Objectives 1) To design and apply a common Protocol to screen both the sequences of synthetic gene orders, and the customers who place them. 2) To work together with governments and others concerned to promote the beneficial application of gene synthesis technology, and to safeguard biosecurity.
The IGSC harmonized screening protocol is: • In line with the draft guidelines • Based on experience and existing screening processes of founding members • Compulsory for IGSC members • Publically available* *http://www.genesynthesisconsortium.org/
IGSC Goals and Objectives 1) To design and apply a common Protocol to screen both the sequences of synthetic gene orders, and the customers who place them. 2) To work together with governments and others concerned to promote the beneficial application of gene synthesis technology, and to safeguard biosecurity.
Synthetic biology: key events and considerations 2009 FBI Reporting Program 2009 Screening framework 2010 Presidential commission
Screening Framework Guidance, Summary Department of Health and Human Services SCREENING FRAMEWORK GUIDANCE OR PROVIDERS OF SYNTHETIC DOUBLE-STRANDED DNA Following these guidance is voluntary The cornerstones: • Screening of sequences • Screening of customer • Follow-up screening if above raises concerns • Proper record retention • Recommendations regarding screening software The Guidance was developed, in light of providers’ existing protocols, to be implemented without unnecessary cost and to be globally extensible, both for U.S.-based providers operating abroad and for international providers Providers of synthetic dsDNA have two overriding responsibilities in this context: • Providers should know to whom they are distributing a product • Providers should know if the product that they are synthesizing and distributing contains, in part or in whole, a “sequence of concern”
Ratified in member countries’ export control lists Screening Practice, Australia Group an informal forum of member countries with the objective to ensure that exports do not contribute to the development of chemical or biological weapons, and to strengthen global security through harmonization of export controls (http://www.australiagroup.net/en/index.html).
Screening Practice, Australia Group Definitions Genetic Elements and Genetically-modified Organisms: • that contain nucleic acid sequences associated with the pathogenicity of any of the microorganisms in the list. • that contain nucleic acid sequences coding for any of the toxins in the list, or for their sub-units. Technical note: • Genetic elements include inter alia chromosomes, genomes, plasmids, transposons, and vectors whether genetically modified or unmodified. • Nucleic acid sequences associated with the pathogenicity of any of the micro-organisms in the list means any sequence specific to the relevant listed micro-organism: • that in itself or through its transcribed or translated products represents a significant hazard to human, animal or plant health; or • that is known to enhance the ability of a listed micro-organism, or any other organism into which it may be inserted or otherwise integrated, to cause serious harm to human, animal or plant health.
Screening practice @ Life Tech ? ? BioSafety BioSecurity Customs regulation Export control Documentation Surprise visit „Gene Technology Law“ (9 PhDs) molecular biologists critical sequence list (AG list, CDC) Sequence check Sequence Host Sequence Function ok? Country check Customer check BLAST A check www ok ok ok? FedEx M atlas A: automated Sales Team (17) M: manual
Sequence Evaluation Process – WORK FLOW Identify a gene from a requested sequence Automated Work & information flow Rules: Evaluate dual-use potential Automated plus Expert approval Follow-up customer/ authorities Manual
Sequence Evaluation Process – Examples EU AG non-AG green OK OK OK yellow OK CD EP red CD EP EP Biosecurity evaluation result Shipping address AG: Australia group CD: Customer document EP: Export control
Internationalization & screening framework guidance Can deliver botulinus toxin genes within Europe, but cannot send Dengue Env to Novartis Switzerland or NIH US What is the consequence of a „hit“ for shipment in Europe? How can export limitations to institutions such as e.g. delivering genes from EU to NIH be overcome (e.g. for the case of an epidemic swine flue vaccine)? Relevance and need for guidance Central role of customer screen and customer legitimacy Definition of “sequence of concern” Export regulations
Identified gaps / open questions Technical advising from experts – defining sequences of concern Uniform screening practice / ~criteria Australian Group List names only organisms, not sequences Definition of „genes associated with pathogenicity“ leaves room for interpretation Definition of “Match” is central for sequence evaluation A screening database that is continually updated Ideally maintained by the U.S. Government / EU and international organizations Most complete, updated & classified Internationally harmonized list of suspicious persons & organizations User certification (?)
What’s Next? Improve sequence screening methods and tools (data base, taxID- and gi-based) Incorporation of U.S. Screening Guidance into Protocol Participate in policy development and resource discussion Centrally curated sequence database for screening? Regulate access to screening data base? Funding support for screening software? Consider moving toward certification for Federal Guidance compliance
Ways to bypass US/EU based Gene Synthesis companies Can order oligonucleotides @ oligo firms Synthesize oligonucleotides on purchased synthesizer (new or used) or on synthesizer that was built according to construction plans available via internet Oligos assembled via published technologies Synthetic genes ordered from Non-US / Non-EU based companies Use conventional genetic engineering Isolate harmful species from natural habitats and cultivate Customer screen / identification as important as sequence screening
Conclusion Delivery of sequences of concern to customers is regulated by national export law according to respective lists: e.g. Export control list, CDC list, selected agents list (genes and organism), K-List (countries) and Haddex List (institutions/companies) An internationally harmonized screening framework guidance is appreciated, but should be developed in close collaboration with commercial gene synthesis providers The screening practice of the large commercial gene synthesis providers is in accordance with the current US screening framework guidance In addition to regulation, governments should provide technical specifications (sequences, blast parameter, update process, etc)
