Sequence-Based Classification of Select Agents A Brighter Line (2010) / Chapter Skim
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1 The Select Agent Regulations
1 The Select Agent Regulations
Pages 9-36
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," which considered the impact of synthetic biology and DNA synthesis technology on biosecurity and the current Select Agents Regulations (SAR)
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. BOX 1.1 Scientific Milestones for the Development of a Gene Sequence-Based Classification System for Oversight of Select Agents Statement of Task NIH has requested the National Research Council to convene an ad hoc commit tee to identify the scientific advances that would be necessary to permit serious consideration of developing and implementing an oversight system for Select Agents that is based on predicted features and properties encoded by nucleic acids rather than a relatively static list of specific agents and taxonomic defini tions.
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CONTEXT OF THE SELECT AGENT REGULATIONS During the committee's deliberations, the issues of biological weapons, biosecurity, and biosafety were each considered relevant to addressing the charge. The Select Agent Regulations, the NIH Guidelines, and the implementing legislation for the BWC define conditions for the legitimate, safe, and secure use of biological agents that have the potential to be used for great harm.
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"A panel of Federal security and scientific experts will serve as the principal security advisory body to the SAP. The Panel will advise the SAP on a range of topics, including considerations in the tiering and/or reduction of the Select Agent List, best practices regard ing physical security and personnel reliability that should be considered in the revision of the SAR and related Rules and guidance, and other topics as determined by HHS and USDA.
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. Nations party to the BWC agreed to destroy or divert to peaceful purposes any existing weaponized biological agents or delivery systems within nine months of signing the convention.
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In the United States, the Select Agent Regulations and other current legal mechanisms to control development, stockpiling, access, and use of specific biological agents had their roots in public health laboratory practices. In 1974, the Centers for Disease Control and Prevention (CDC)
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Though not a regulation, many choose to follow the BMBL's recommendations. Moreover, Select Agent Regulations part 73.12(c)
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All BSL-4 agents have been designated as Select Agents; however, not all Select Agents require BSL-4 containment.7 The CDC conducted an assessment of the potential for biological agents to impact public health (Rotz, Khan et al.
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perception, and special public health preparedness needs such as stockpile requirements, enhanced surveillance or diagnostic needs required to mitigate harm or respond following an attack. Public perception in this case refers to the ability to engender widespread panic or concern about the safety of products including food, thus precipitating a major impact even if an event does not cause direct or significant harm to human health.
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A larger universe of pathogens was included in the NIH assessment such that some agents appear on the NIH list that were not captured on either the CDC classification or Select Agents list. Biosecurity and the Select Agent Regulations Biosafety and biosecurity8 are related and complementary concepts; however, there are important distinctions.
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The National Select Agents Registry Program (Select Agent Program) was formally established to execute provisions of the USA PATRIOT Act and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 regarding biological agents.
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who is a national of a country that has repeatedly provided support for acts of international terrorism; or • has been discharged from the Armed Services of the United States under dishonorable conditions. By prohibiting certain individuals from having access to Select Agents based upon criteria such as having committed a felony, convicted of illegal drug use, engaged in terrorist activities, or a history of mental illness, the Act addresses concepts related to the reliability of personnel in the research community.
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The CDC and APHIS administer the Select Agent Program, which ensures that those registered to possess, use or transfer Select Agents are in compliance with the Select Agent Regulations. The Department of Homeland Security (DHS)
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. The Select Agent Regulations require entities to provide graded protec tion to Select Agents and Toxins including limiting access to Select Agents and Toxins according to a site-specific security plan required for each institution registered with CDC or APHIS as authorized to possess and use such biological materials.11 Entities using strictly plant or animal pathogens report to APHIS; entities using human or zoonotic pathogens report to CDC.
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The Select Agent Program -- Focus on Known Biothreat Agents The Select Agent Program was devised to establish controls for known biological agents and toxins that have the potential to pose a severe threat to public health and safety. Newly emerging pathogens are not given Select Agent 12 This issue was addressed in Recommendation 4 of the NRC report, Responsible Research with Biological Select Agents and Toxins.
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Such unknown, unnamed pathogens are not yet Select Agents; these novel agents present a particularly challenging issue of direct concern to this committee. Although the Select Agent Regulations do not focus on novel agents, the Select Agent Program has, since its inception, attempted to address the possibility that genetic material derived from a Select Agent might be used to construct a biological threat agent.
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Its purpose is to clarify that Select Agent Regulations apply, even if the Select Agent is produced by synthetic means or has been genetically modified. The guidance does not attempt to address novel organisms that are not already designated as Select Agents.
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Gene Synthesis Industry If genetic sequences do not suffice to define Select Agents, then a challenge arises in providing guidance to the approximately fifty companies worldwide that offer gene synthesis as a commercial service (Maurer, Fischer et al.
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Several different industry groups have formed to promote safe, effective regulation of gene synthesis technology. Although the application of the Select Agent Regulations to cloned DNA could be interpreted in a number of different ways, the CDC has provided a guide to interpreting these rules for the gene synthesis companies ("Applica bility of the Select Agent Regulations to Issues of Synthetic Genomics," see Appendix E)
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Companies may find it challenging to recognize a sequence that poses a biosecurity concern, readily identify virulence genes, or determine the usability of genomic sequences in predicting potentially dangerous sequences in naturally occurring, genetically modified, or synthetically derived microorganisms. 21 Impact of Select Agent Regulations on Research There is a clear recognition that research on infectious disease agents, including Select Agents, is vital to public health and national security.
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Paradoxically, the designation of these organisms and toxins as Select Agents put considerable burden on the scientific community to conduct this research while simultaneously adhering to costly and rigorous standards for security and accountability (Dias, ReyesGonzalez et al.
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Although the quantitative affect of the Select Agent Regulations on research is unknown, some of the concerns are briefly presented below: • Altered Research Direction -- Scientists may have redirected their research to the study of attenuated strains that are not classified as Select Agents (e.g. Bacillus anthracis Sterne strain)
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have instituted formal Personnel Reliability Programs (PRPs) to provide additional measures to help ensure that individuals with access to select agents meet additional standards of reliability .
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is perhaps the clearest and least contro versial agent on the Select Agent list; smallpox virus has the potential to cause a catastrophic epidemic if it were released. It also seems clear that the aim of the Select Agent Regulations is not to regulate all organisms that could be used by bioterrorists, even if the organism has already been used for bioterrorism.
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, describing some of the considerations that led to the Select Agents list that superseded the 1997 list in 42 CFR 72.6. For example, "viruses causing hantavirus pulmonary syndrome" were removed from the CFR 72.6 Select Agent list because they "are difficult to propagate and there is a lack of data establishing laboratory acquired infections." Yellow fever virus was removed because "there is a safe and effective vaccine." Histoplasma capsulatum and Blastomyces species were considered but not included because "they are difficult to cultivate and do not sporulate readily." Aflatoxins were not included because "the acute toxicity is too low to pose a significant mass casu alty threat." The published discussion in the Federal Register does not include any examples in which DHHS considered public perception of the organism or known bioweapons development programs in its decision making.
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Rather, these agents pose a threat to national security, and are designated as Select Agents because of potential economic consequences, international trade agreements, and vaccination policy. Thus, criteria that are considered in designating a microorganism as a "Select Agent" include biological and non-biological data.
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From page 35... ...
However, the central criteria for a Select Agent are biological attributes. At the time when the Select Agent list was devised by DHHS, some 60 or so full bacterial genomes were known and annotated as well as a score of viruses.28 Hundreds of bacterial genome sequences are now available for com 28 The first complete sequence of a bacterial genome was published in 1995.
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From page 36... ...
However, from the outset it was asked, to what degree can genomic sequences be used to detect Select Agents now and, for the future, to what degree can genomic sequences be used to predict potentially dangerous sequences in naturally occurring, genetically manipulated or synthetically derived microorganisms? These questions are the focus of this committee.
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