ADVANCING GENOMICS TO BETTER LIFE
Future Biotechnology Products and Opportunities to
Enhance the Capabilities of the Biotechnology
Regulatory System
Presentation to the National Academies of Sciences, Engineering and
Medicine - Washington, DC
2 June 2016
International Gene Synthesis Consortium (IGSC)
Tools and Opportunities to Enhance
Risk Analysis
David S. Hanselman, Ph.D.
Senior Director of Regulatory and Quality Affairs, SGI
Representing the International Gene Synthesis
Consortium (IGSC)
Balancing gene synthesis technology opportunities and biosecurity risk
● To design and apply a common protocol to screen both the sequences
of synthetic gene orders and the customers who place them.
GOALS AND
OBJECTIVES
● To work together with governments and others concerned to promote
the beneficial application of gene synthesis technology and to
safeguard biosecurity.
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Biosecurity and gene synthesis
IGSC members: > 80% of commercial gene synthesis market
http://www.genesynthesisconsortium.org
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IGSC established in 2015 as a not-for-profit corporation
● Founded in 2009 to promote best
biosecurity practices
● Encourage international membership
‒ Government
‒ Non-profit
‒ Academic institutions / gene foundries
● New memberships by application and invitation,
with IGSC Board of Directors approval
● Rigorous verification of applicant’s customer
screening and risk categorization processes using
1000+ sequence validation set
● Member guidance to assist applicant in attaining
compliance with the Harmonized Screening Protocol
INTERNATIONAL GENE SYNTHESIS CONSORTIUM FORMS
NOT-FOR-PROFIT CORPORATION
New Organizational Structure Will Enable Additional Stakeholders
to Leverage the IGSC’s Biosecurity Expertise
Washington, DC, April 27, 2015—The International Gene Synthesis Consortium
(IGSC), an association of the world’s leading gene synthesis companies, today
announced that it has established itself as a not-for-profit U.S. corporation. The move is
intended to make it easier for the organization to welcome new members, especially
small companies, not-for-profits and academic institutions, so that they may leverage the
biosecurity experience of the organization.
Working together with governments, NGOs, law enforcement, the synthetic biology
community and other stakeholders, the IGSC aims to safeguard biosecurity and promote
the beneficial application of gene synthesis technology while preventing its misuse.
By screening the sequences of ordered genes and vetting customers, IGSC members
help to ensure that science and industry realize the many benefits of gene synthesis
technology while minimizing risk.
“The IGSC has developed a common protocol for biosecurity screening and devotes
resources to leading-edge development of best practices,” said Todd Peterson, Chief
Technology Officer of Synthetic Genomics Inc. and current Board Chair. “By establishing
a more formal structure for the IGSC, we hope to encourage organizations involved in
gene synthesis across to globe to benefit from the biosecurity expertise of our
membership.”
The IGSC has curated and maintains a common Regulated Pathogen Database
compiled from multiple sources, including the US Centers for Disease Control Select
Agent list, the Australia Group List and other national and international lists of regulated
pathogens and biological toxins.
As recommended by the US Department of Health and Human Services, IGSC
members screen the complete DNA sequence of every synthetic gene order against the
DNA sequences in the Regulated Pathogen Database and against all entries found in
one or more of the internationally-coordinated sequence reference databanks. IGSC
members also screen potential customers against various exclusionary databases, such
as the US State Department’s Directorate of Trade Controls Debarred Entity list. Where
screening identifies a regulated pathogen sequence or other potentially dangerous
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The IGSC Harmonized Screening Protocol
● Compliant with US Federal & international
guidelines
‒ DHHS Screening Framework
Guidance for Providers of Synthetic
Double-Stranded DNA
● Based on experience and existing screening
processes of founding members
● Compulsory for all IGSC members
● Publicly available
http://www.genesynthesisconsortium.org
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Know the customer
?
Customer Service
New Account
New Customer
Customer Care Center
New Contact
New Companies,
Universities, Institutes
•
•
•
•
•
•
•
•
•
•
Restricted Pary Screening:
Internal Denied Parties
MKDenial Parties (incl.
HADDEX)
OFAC Compliance, KYC &
PATRIOT Act Software from
Bridger Insight XG –
LexisNexis
Amber Road
Website
Address
Registration Form
Distributor: Handle with
Care
Unusual TCs, Processes
NO BUSINESS
WITH PRIVATE
PERSONS
(e.g. DIY SynBio)
New person but existing
account
•
Denial lists (e.g. HADDEX)
o
MK denial, bridger insight
help with homology
searches
Verified Customer
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IGSC DNA sequence screening
SEQUENCE SCREENING
All double stranded sequences are screened against the NCBI non-redundant
nucleotide and protein database. Hits are defined as positive when the highest bit score
from the search matches that of an organism or toxin listed in the confidential IGSC
Regulated Pathogen Database.
SELECT AGENTS AND TOXINS
Current listings can be found in the following regulations, as periodically amended:
•
CDC and USDA Select Agents and Toxins 7 CFR Part 331, 9 CFR Part 121 and 42
CFR Part 73 (NSAR Select Agents) US Commerce Control List 15 CFR Part 774;
the International Traffic in Arms Regulations (ITAR) 22 CFR Part 121; the EU DualUse Regulations 428/2009 and 1382/2014,
•
Australia Group Common Control Lists.
•
A combined list is provided by the US Federal Select Agent Program in a
“Consolidated Controlled Agents List.”
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Know the material — IGSC database
Australia Group (AG)
European
Community (EC)
BAFA (Germany)
UK Dep. for
Business Innovation &
Skills (BIS)
US Department
of State (DOS)
US Department
of Commerce (DOC)
US Dep. of Health
and Human Services
(HHS)
Scientific Review
by IGSC members
• Organism (TaxID)
• Sequence (GI)
Translation table of all
related legal documents
to TaxID and GI
numbers
31,527 entries covering
> 4 M sequences
(to date)
Shared within IGSC
Membership
US Department of
Agricutlure (USDA)
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Overall sequence screening process
Requested
DNA Sequence
BLAST
IGSC Database
Extract Tax Id
of top Hits & Check
Toxin database
No Hit
BLAST
BIOSECURITY
DATABASE
whitelist organisms
299 sub TaxIDs
(~3 M sequences)
Blacklisted
organisms and
sequences
AG, BIS, DOC, DOS,
EC, HHS, USDA
Hit
Concern:
Warrants follow-up
Hit
Major Concern:
Warrants follow-up
Hit
Manual Inspection of
the BLAST Hit
No Hit
182 main TaxIDs
(~4 M sequences)
8753 reference GIs
alligned with threat
levels
DATABASE
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Response to a “Hit”
● If bioinformatic screening and analysis identifies a regulated pathogen,
DNA Sequence
toxin or other sequence of concern (SOC), Customer Support team
follows up manually to document the customer’s intended use of the
construct, verify their CDC Exemption Number, ensure proper
import/export permitting.
● If a potentially suspect purchaser is identified, Customer Support or
Customer
the Biosecurity Officer follows up manually to eliminate false positives
(e.g., name similarities) and to determine whether the purchaser
represents a legitimate business, research institution or government
agency.
IGSC companies will not synthesize genes for individuals
who lack a verified institutional affiliation.
● If an unverifiable and/or suspect customer seeks a regulated pathogen
Unresolved
Orders
or SOC, IGSC companies deny the order, notify other IGSC members
and notify regional authorities.
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Analysis of biosecurity screening effectiveness by the IGSC
● Capture and understand consolidated biosecurity screening/
effectiveness data
Objectives
•
Include all IGSC member companies
•
Protect sensitive commercial data related to order volume
•
Quantify aspects of biosecurity process and results
•
Suggest areas for further improvement
● IGSC companies agree to undertake this project
Process
•
Prepare data reporting template and guidelines
•
All companies establish individual confidentiality
agreements with sanctioned third party
•
Each company compiles and submits available data
•
Third party analyzes and prepares consolidated data
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Analysis of biosecurity screening effectiveness by the IGSC (Cont.)
Overall Data
Reporting
Breakdown by
Year(s):
Total Number of
Sequences
Screened:
● 2014 (4)
● 2013-2014 (1)
● 2012-2014 (1)
● 2010-2014 (1)
● 2010-2013 = 286,130
● 2014 = 309,942
2014
Green/Yellow/Red
%* of Orders:
Green = 95.04%
Yellow = 4.29%
Red = 0.67%
For more information : http://www.jcvi.org/cms/press/press-releases/full-text/article/j-craig-venterinstitute-policy-group-releases-new-report-dna-synthesis-and-biosecurity-lesson/
2010 - 2013
Green = 98.13%
Yellow = 1.41%
Red = 0.46%
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International Genetically Engineered Machine
(iGEM) competition
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SGI has annually performed a biosecurity screen of the
iGEM registry of standard biological parts
• Biosafety and Biosecurity should be core modules in every synthetic biology training
program – Academic, Commercial, Government, Non-Profit.
• All parts placed into publically available repositories should be pre-screened.
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Biosecurity at the bench
Synthetic biology instrumentation
Gene synthesis - today and tomorrow
Typical Synthesis Order Today
Rapidly Advancing Market Trends
•
One to several genes; average size <1.6 kb
with low complexity
•
Larger gene sets, increasingly larger size >>2kb &
high complexity
•
Cloned and sequence verified
•
Error corrected, uncloned linear fragments
•
Automated, scalable, with better control of process
•
Fast turn-around time is major driver
System Features
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Fluid handling robot with thermal cycling
Software driven application workflows
Incubation and chilled storage
Purification of completed products
Built-in consumables & hardware security
Automated cloning into a vector
32 simultaneous constructs up to 1.8 kb
BioXp3200™ Bench-Top
Synthetic Biology Workstation
Future Applications
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Assembly of linear DNA fragments (up to
100kb) from oligo pools and DNA subfrags
In vitro transcription of RNA
In vitro translation of proteins
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Biosecurity & biosafety are a top priority
CUSTOMER + SEQUENCE + REAGENTS + HARDWARE + SOFTWARE + IT
IGSC compliant screening
Customer: Systems sold only to qualified parties
Sequence: Every sequence is pre-screened
BioXp™ 3200 - additional security and safety parameters
Oligonucleotides & reagents: uniquely barcoded and only sold to approved parties
Hardware: instrument will not start unless multiple security, anti-tamper and antidiversion measures are enabled
Software: sophisticated remote screening software creates unique machine instructions
for each job that cannot be reused
IT: secure web portals for instruments
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Biosecurity module – Archetype®
Admin Page – Login
Real-time status – BLAST
AUTO_PASS
No hit to sequence of
concern (SOC) database
Zero a priori knowledge of
sequence required
IGSC-Compliant
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