Synthetic Genomics

Applicability of the Select Agent Regulations to Issues of Synthetic Genomics

The Federal Select Agent Program is providing guidance regarding the application of the current select agent regulations to those who create and use synthetic genomic products.

In a December 2006 report entitled "Addressing Biosecurity Concerns Related to the Synthesis of Select Agents" (www.biosecurityboard.gov/links.asp), the National Science Advisory Board on Biosecurity recommended that the Federal government take steps to "Increase awareness among providers and users of synthetic genomic materials regarding compliance with the select regulations; and provide a list of genomic materials explicitly covered by the regulations."

The select agent regulations provide that the following genetic elements, recombinant nucleic acids, and recombinant organisms are select agents (See section 3(c) of 42 CFR Part 73, 9 CFR Part 121, and 7 CFR Part 331):

• Nucleic acids that can produce infectious forms of any of the select agent viruses.
• Recombinant nucleic acids that encode for the functional form(s) of select agent toxins if the nucleic acids:
• Can be expressed in vivo or in vitro or,
• Are in a vector or recombinant host genome and can be expressed in vivo or in vitro.
• Select agents and toxins that have been genetically modified.

The purpose of this regulatory language is to address advancements in molecular biology that may influence the production of infectious forms of select agent viruses, or the active forms of select agent toxins. It has been demonstrated, for example, that the single stranded (positive strand) RNA viruses and certain double stranded DNA viruses that utilize host polymerases contain nucleic acids that can produce infectious forms. Examples of select agent viruses that meet this criterion, and would therefore be regulated, include:

• Tickborne encephalitis complex (flavi) viruses:
• Central European Tick-borne encephalitis
• Far Eastern Tickborne encephalitis
• Russian Spring and Summer encephalitis
• Kyasanur Forest Disease
• Omsk Hemorrhagic Fever
• Eastern Equine Encephalitis virus
• Venezuelan Equine Encephalitis virus
• Classical Swine Fever Virus
• Foot-And-Mouth Disease Virus
• Japanese Encephalitis Virus
• Swine Vesicular Disease Virus
• Cercopithecine Herpesvirus 1 (Herpes B virus)
• Malignant Catarrhal fever Virus (Alcelaphine Herpesvirus Type 1)

Under the current select agent regulations the following are examples of materials that would not be regulated as a select agent:

• Material from regulated genomes that has been rendered non-infectious
• cDNA made from regulated select agent genomes
• Genomic fragments from select agents (unless they encode for a functional form of a select agent toxin)
• Complete genomes of single-stranded negative strand RNA viruses, double stranded RNA viruses, and double-stranded DNA viruses that require a unique polymerase (Variola major virus*, Monkeypox virus, African swine fever virus, Camel pox virus, Goat pox virus, lumpy skin disease virus, and Sheep pox virus)
• Genomic material from select agent bacteria or fungi
• Genomic material from select agent strains that have been excluded from regulation under section 3(e) of the select agent regulations
• Select agent nucleic acid sequence information

  *It should be noted that, although the current select agent regulations do not apply to Variola major genetic elements, the World Health Organization (WHO) places significant restrictions on the possession, use, and transfer of these materials. Institutions other than the two currently recognized WHO collaborating centers may not possess genetic fragments exceeding 20% of the Variola virus genome. For additional information on WHO Guidelines for Variola virus research, please see http://www.who.int/csr/disease/smallpox/research/en/index.html, and the report, also published in the Weekly Epidemiologic Record in 2008, on permissible use of variola genetic material (http://www.who.int/csr/disease/smallpox/SummaryrecommendationsMay08.pdf).

The following examples, Example scenarios involving synthetic genomic select agent materials, while not inclusive of all potential scenarios, illustrate the application of the current select agent regulations to activities involving synthetic genomics or synthetic biology.

The Department of Health and Human Services' Screening Framework Guidance for Providers of Synthetic Double-Stranded DNA sets forth recommended baseline standards for the gene and genome synthesis industry and other providers of synthetic dsDNA products regarding the screening of orders so that they are filled in compliance with current U.S. regulations and to encourage best practices in addressing biosecurity concerns associated with the potential misuse of their products to bypass existing regulatory controls.