Broad Consensus on Gene Synthesis Guidelines

Participants at a January 11th forum on Minimizing the Risks of Synthetic DNA, held at the AAAS, appeared to be in general agreement on the principles behind proposed US guidelines to safeguard the rapidly advancing technology of gene synthesis.

Synthetic biology, a new field made possible by developments in genome sequencing and genetic engineering, seeks to take an engineering-based approach to biological problems.  The story of the malaria drug Artemisinin provides an example of the advances that this new approach can produce.  The drug is currently made from a plant extract, and crop quantities are insufficient to meet global demand.  Through synthetic biology, scientists have been able to engineer yeast capable of performing the multiple reactions necessary to create the drug’s precursor.

However, engineering life also presents the opportunity to create existing, augmented, and/or novel pathogens.  Current restrictions on select agent pathogens, such as Smallpox, are based on the physical safeguarding of live bacterial and viral stocks to keep them from malicious users.  With modern gene synthesis technology, a would-be attacker could potentially obtain a complete pathogen genome by ordering it from commercial DNA providers.

It is in this context that Monday’s forum brought together a wide variety of stakeholders, ranging from Federal regulators to major gene synthesis firms and research organizations.  Though the specifics of guideline implementation were occasionally questioned, there was a surprising degree of consensus concerning future policies implemented by private industry.

Building Self-Policing Standards

The US Federal Government’s National Science Advisory Board for Biosecurity (NSABB) first weighed in on the gene synthesis issue in a December 2006 report, recommending in part that:

“…establishing uniform and standardized screening practices among providers of synthetic DNA would help safeguard against the intentional or unintentional circumvention of the [Select Agent Regulations].”

As the US government worked to clarify policies on this technology, synthetic DNA providers began similar efforts.  The fruits of these separate efforts were finally revealed in November 2009.

On November 3rd, the International Association Synthetic Biology (IASB), a group that includes biotechnology and gene synthesis companies in the US, Germany, and China, announced that it had completed its year-long effort to draft a code of conduct covering “ethics, biosafety and biosecurity aspects of gene synthesis.”  Shortly thereafter, on November 18th, five major gene synthesis companies – Blue Heron, DNA 2.0, Genart, Genscript, and IDT – announced that they were forming the International Gene Synthesis Consortium (IGSC).  This group, which claims to represent 80% of the world’s gene synthesis capacity, issued a similar screening pledge.

Finally, on November 27th, the US Department of Health and Human Services (HHS) issued the draft guidelines titled “Screening Framework Guidance for Synthetic Double-Stranded DNA Providers”.   The guidelines, which are open for public comment through January 26th, were the subject of the AAAS forum.

The Proposed Standards

All three proposals are in broad agreement as to the basic procedures needed to prevent malicious double-stranded DNA orders.  Potential customers would be screened to verify their identities as legitimate researchers, while the ordered sequences would be examined to assess their similarity to pathogen genes.  In the event of red flags in either area, companies would further investigate orders to ensure that malicious individuals do not obtain potentially dangerous materials.  Representatives from industry groups did not feel that these procedures would add substantial costs to order processing or delays in shipping the final product.

Technical details of the policy will require further evaluation.  Researchers expressed concern that start-up companies without the support of an established research institution might have trouble demonstrating their legitimacy, which would now be required in order to request pathogen-related sequences.  Some scientists and providers questioned the validity and arbitrariness of a proposed 200 base-pair threshold for screening scrutiny, which was intended to exclude smaller, single-stranded oligonucleotides from safety proposals aimed at synthesis of full-length genes.

The question of which method should be used to determine the sequence origin – either the so-called “best match” model, which utilizes databases such as GenBank, or other sequence matching algorithms – was also a hot topic of discussion.  Indeed, some participants felt that this issue showcased an advantage of the voluntary nature of the proposed non-binding Federal guidelines.  The intentionally flexible language would allow the policy specifics, such as the matching algorithm, to evolve in the face of technological advances that move far faster than either formal rule making or legislation.

This voluntary approach may also facilitate global cooperation within the rapidly expanding international gene synthesis industry.  One DNA provider explained that their company would generally apply the most stringent standards mandated anywhere in the world they do business, rather than attempting to apply differing standards to individual orders depending on local regulations.

Ongoing Developments

The US guidelines for synthetic double-stranded DNA providers will be open for comment through January 26th, and will be revised and reissued in final form later this year.  The NSABB is also continuing to investigate the promises and perils of synthetic biology; the board approved a new draft report in December 2009 calling for increased oversight, education and outreach concerning the dual use potential of synthetic biology.

Even as the details continue to be discussed, it is encouraging to see nigh universal consensus on the measures to safeguard the public from harm, while preserving the potential for societal advances presented by this growing field.

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