Sequence-Based Classification of Select Agents A Brighter Line (2010) / Chapter Skim
Currently Skimming:
4 Committee Findings and Conclusions
4 Committee Findings and Conclusions
Pages 107-128
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From page 107... ...
However, a gene sequence based classification system for Select Agents and a "yellow flag" biosafety system for "sequences of concern" could be developed with current technologies. The classification sys tem discussed in Chapter 3 (see also Appendix L)
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From page 108... ...
In fact, if the purpose of the Select Agent Regulations were solely biosafety, it would largely be an unnecessary duplication. However, the primary role of the Select Agent Regulations is to restrict access to agents that may be used as biological weapons by someone with nefarious intent.
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From page 109... ...
The Select Agent Program is intended to limit access to agents that there is reason to believe could be used as weapons -- essentially to remove the "low-hanging fruit" and make it more difficult for persons with nefarious intent to obtain or create a bioweapon. The Select Agent Regulations work primarily and most ef fectively in the context of possession and transfer of known stocks -- providing a "chain of custody" 5 -- in which names and Select Agent status are propagated 4 Microbial forensics plays an important role in attribution efforts.
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From page 110... ...
An agent has multiple biological attributes, and the degree to which they are expressed falls along a spectrum for each biological characteristic;6 consequently, agents pose varying degrees of risk.7 6 For example, one microorganism may be highly virulent, but poorly transmissible from person to person, whereas another may spread easily but produce only mild illness. 7 As described in Chapter 1, there are many ways to categorize microorganisms according to risk: Biosafety in Microbiological and Biomedical Laboratories biosafety levels 1-4; National Institutes of Health guidelines risk groups 1-4; Centers for Disease Control bioterrorism agents categories A, B, and C; and the Department of Homeland Security Bioterrorism Risk Threat Assessment and the Select Agents list, which currently is not stratified according to risk.
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From page 111... ...
8 It is that last level of complexity may give rise to the key biological attributes of pathogenicity and transmissibility, which contribute to the criteria that form the basis of inclusion of an organism on the Select Agents list. Predicting pathogenicity, transmissibility, or environmental stability of a microorganism requires a detailed understanding of multiple attributes of the pathogen, its host, and its environment.
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From page 112... ...
(6.) Synthetic genomics poses three threat scenarios that would allow a "bad actor" to obtain a pathogenic organism with Select Agent properties; one of them (modified Select Agents)
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From page 113... ...
If we as sume the most plausible threat to come from modifications and rearrangements of genes from known Select Agent genomes, we can anticipate the most likely "space" of possible modifications and most obviously worrisome chimeras that might create a genome that encodes Select Agent properties. Because we can use sequence analysis to recognize genes and genomes and classify them into known families, we can use sequence analysis to designate particular genome sequences unambiguously as equivalent to "complete, infectious" Select Agents and to identify "sequences of concern." Sequence-based classification is strictly operational -- a set of tools for drawing decision boundaries around known sequences that do and do not belong to a desired classification.
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From page 114... ...
Synthetic genomics is increasingly making it possible to obtain Select Agents by synthesis rather than by access to a live laboratory culture and to create modifications that blur taxonomic classification boundaries yet still might be expected to function as a Select Agent. Because the Select Agent Regula tions cover creation, transfer, and possession of complete synthetic genomes, not just those of viable Select Agents, gene and genome synthesis companies, for example, need to know unambiguously whether a customer's order is for a synthetic Select Agent genome or not.
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From page 115... ...
Rather, the Select Agent Regulations implement a necessarily backward-looking system based on a taxonomy of known Select Agents -- already known from experience to be extraordinarily dangerous. If a new agent is found to be extraordinarily dangerous, it can be added to the Select Agent list, whether it is a naturally emerging pathogen or a synthetic.
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From page 116... ...
Profile-based classification system (4) would create sequence Figure 4-1 Broadside based boundaries around Select Agents.
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From page 117... ...
Once a sequence is deposited in the biosafety database, it serves as a reference for anyone carrying out relevant investigations and for gene synthesis companies that would be able to compare their orders with entries in the database, screening for yellow flags. If a match occurs, the company would have a basis for notifying the purchaser of the possible concern and would request that any research results that support or refute the cause for concern be contributed to the annotations associated with the sequence in question.
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From page 118... ...
Similarly, DNA synthesis companies might be asked to maintain records of yellow-flagged constructs that they provide to customers to facilitate forensic investigation in the event of criminal construction of a complete Select Agent from synthetic parts. Finally, a centralized system for reporting orders of yellow flag sequences could be developed to allow detection of the simplest scheme for avoiding the Select Agent Regulations -- splitting the order for a viral genome or a toxin between two different gene synthesis companies.
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From page 119... ...
To provide a sound foundation for sequence-based classification of existing Select Agents, a comprehensive sequence database should be created that thoroughly covers naturally occurring genetic variation based on geographic distribution, ecological or laboratory adaptations, and those associated with clinical severity or attenuation. The database should include not only Select Agent sequences, but also a representa tive set of near-neighbors for each Select Agent.
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From page 120... ...
However, even such non-biological considerations should be based on clear criteria and informed by scientific data. For instance, in some cases, it appears that past experimentation with an agent for purposes of warfare or terrorism has resulted in de facto inclusion on the Select Agents list.
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From page 121... ...
Prioritizing the Select Agent list on the basis of risk would make any sequence-based approach to oversight more feasible LONG-TERM MILESTONES FOR GENOME SEQUENCE BASED SELECT AGENT REGULATIONS The use of the term milestones may be somewhat misleading here, in as much as the research described is ongoing, and will evolve in a continuous and 12 "The list should be either reduced or stratified so that biosecurity measures can be more easily applied by the registered entities according to the level of risk" and "Perform a risk assessment for each select agent and toxin on the BSAT list and develop a stratification scheme that includes biodefense and biosecurity criteria, as well as risk to public health, so that security measures may be implemented based upon risk" (NSABB 2009b)
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From page 122... ...
They are not peculiar to Select Agents, or even to infectious disease. Although specific milestones for prediction of Select Agents are far beyond current scientific insight, the committee is able to identify promising research areas and technologies that would improve the ability to predict gene func tion, enhance understanding of infectious disease, and consequently strengthen biosecurity.15 What follows is not intended to be an exhaustive list; research 15 Thisis consistent with the National Strategy for countering Biological Threats "The objectives of our Strategy [include]
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From page 123... ...
(c.) Pathogenic mechanisms: The molecular basis of the pathogenic characteristics of currently designated Select Agents is, in general, poorly understood, may be multigenic, may in some cases be greatly influenced by one or a few single-nucleotide polymorphisms, and may be regulated by mechanisms that are not well defined.
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From page 124... ...
(d.) Animal models of disease: For many Select Agents, there are no surrogate experimental hosts for characterizing virulence; the only suitable host for a human pathogen may be humans.
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From page 125... ...
before birth, humans develop a resident microbiota shortly after birth. The human microbiome is the subject of intensive study, including the major in ternational Human Microbiome Project (HMP)
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From page 126... ...
Developing the ability to predict Select Agent pathogenicity from genome sequence raises serious dual-use concerns because prediction and design go hand in hand. Accurate computational prediction of Select Agents from ge nome sequences enables computational design and optimization of bioweapon genome sequences.
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From page 127... ...
If the Select Agent Regulations are too burdensome, they may diminish long-term safety. Our report stops short of recommending the imple mentation of any specific sequence-based system for defining Select Agents; it was not our charge, and we were not properly constituted to estimate the costs, benefits, or risks associated with any specific implementation.
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