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Appendix L Near-Term Milestones for Consideration The committee finds that a gene-sequence based classification system is feasible using current technologies. Below the committee provides near-term milestones that would enable such a system. While the system could have advantages over the current system, there are also potential negative conse - quences that require careful deliberation. It is not the role of our committee to recommend specific implementation plans, nor are we properly constituted to do so. Many of the issues and priorities that must be considered are beyond the scope of our charge. Therefore, the committee has presented these ideas for discussion and recommends caution when considering the development of a gene-sequence-based oversight system. (a.) A sequence database with a Select Agent focus: (presented in Chapter ) (b.) The expanding sequence database of all biology: (presented in Chapter ) (c.) Define the Criteria for Select Agent Designation: (presented in Chapter ) (d.) Stratification or reduction of the Select Agent list: (presented in Chapter ) (e.) Develop a Centralized System: To be useful for unambiguous regulations, there would need to be a single agreed-upon classification system, not multiple competing ones developed by different research groups. This would mean a centralized funding plan that would have to balance the benefits of single source standardization by a single SA classification system team against the need for oversight and review to maintain quality and efficiency in the absence of peer competition. 0

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08 APPENDIX L (f.) Scientific Workgroups and Advisory Panel: A work group of scientific experts would be assembled for each Select Agent (or Se - lect Agent group). These expert groups would evaluate the agents and identify a “minimal parts list” for each. This is a highly technical and necessary step in developing a sequence-based classification sys - tem. The “Content Workgroups” would also identify genes necessary (though not sufficient) for virulence, and other “sequences of concern” that should be monitored as part of the yellow flag system.1 An ad- ditional benefit of such “Content Workgroups” is that participation in this undertaking could raise awareness of dual-use issues among researchers. Moreover, to include the top experts, these content work - groups would necessarily include international scientists, which may strengthen international engagement. These are major objectives of the National Strategy of for Countering Biological Threats,2 as well as the NSABB. In addition to the “Content Workgroups,” a panel of scientific advisors would be established for assessment of the Select Agent list and the yellow flag sequences. As previously mentioned, advisors for the yellow flag system would be charged to review biological data and make determinations as to whether a sequence raises sufficient concern to merit a yellow flag, needs further study, or should be removed from the yellow flag list. This panel would offer advice regarding whether a sequence construct merits consideration for Select Agent designation. The panel would be expected to consider information provided by the “Content Workgroups,” and would likely have joint members. The same (or a second) panel of scientific advisors would be charged with determining if biological criteria have been met to war- rant designation of a pathogen or toxin as a Select Agent. In this capacity, the advisory panel would also work with stakeholders from the security community and government agencies, and therefore, the scientific advisors should be represented on (or function as a subcom- 1 The committee stresses that this should not be confused with prediction. It would be a mistake to assume that these genes would function in a genome backbone independent manner, or to apply this information to designate a “sequence of concern” as a Select Agent. The purpose is to classify genomes as “complete” and subject to the SAR, and to identify “sequences of concern” that are worth monitoring. 2 “The objectives of our Strategy are: . . . Reinforce norms of safe and responsible conduct: Activi - ties that should be taken to reinforce a culture of responsibility, awareness, and vigilance among all who utilize and benefit from the life sciences to ensure that they are not diverted to harmful purposes. Transform the international dialogue on biological threats: Activities targeted to promote a robust and sustained discussion among all nations as to the evolving biological threat and identify mutually agreed steps to counter it.”

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0 APPENDIX L mittee of) the NSABB, ISATAC, or the recently recommended Biologi- cal Select Agents and Toxins Advisory Committee (BSATAC).3 (g.) Updating, improvement, and assessment: The sequence-based classification system and the yellow flag system, once established, would be updated on a regular basis. The “Content Workgroups” would reconvene on a regular basis to incorporate the latest scientific information into the parts list. Any particular parts list would only re - flect the current state of scientific knowledge about each Select Agent. It would need to be subject to review and revision to stay current with the state of knowledge distinguishing Select Agents from other organisms. Likewise, the profile classification system would have to be updated over time, as new knowledge accrued that required newly discovered SA or non-SA variants to be classified. This updating process would resemble the ongoing curation of other profile library classification systems such as TIGRfams and Pfam, and would require a curation team. Assessments of the yellow flag and Select Agent lists—carried out by, or in collaboration with, scientific advisory panels—would occur on a regular basis. There is a need for increased transparency about the procedures and criteria for moving agents on and off the list.4 The updating, review and assessment cycles are consistent with 3 2009 NRC report Responsible Research with Biological Select Agents and Toxins, “RECOM - MENDATION 2: To provide continued engagement of stakeholders in oversight of the Select Agent Program, a Biological Select Agents and Toxins Advisory Committee (BSATAC) should be established. The members, who should be drawn from academic/research institutions and the pri - vate sector, should include microbiologists and other infectious disease researchers (including select agent researchers), directors of BSAT laboratories, and those with experience in biosecurity, animal care and use, compliance, biosafety, and operations. Representatives from the federal agencies with a responsibility for funding, conducting, or overseeing select agent research would serve in an ex officio capacity. Among the responsibilities of this advisory committee should be the following: Promulgate guidance on the implementation of the Select Agent Program; Facilitate exchange of information across institutions and sectors; Promote sharing of successful practices across institu - tions and sectors; Provide oversight for evaluation of the Select Agent Program; Provide advice on composition/stratification of the list of select agents and toxins; Convene regular meetings of key constituency groups; and Promote harmonization of regulatory policies and practices (NRC 2009b).” 4 2009 NRC report Responsible Research with Biological Select Agents and Toxins, “RECOM - MENDATION 2: To provide continued engagement of stakeholders in oversight of the Select Agent Program, a Biological Select Agents and Toxins Advisory Committee (BSATAC) should be established. The members, who should be drawn from academic/research institutions and the pri - vate sector, should include microbiologists and other infectious disease researchers (including select agent researchers), directors of BSAT laboratories, and those with experience in biosecurity, animal care and use, compliance, biosafety, and operations. Representatives from the federal agencies with a responsibility for funding, conducting, or overseeing select agent research would serve in an ex officio capacity. Among the responsibilities of this advisory committee should be the following: Promulgate guidance on the implementation of the Select Agent Program; Facilitate exchange of

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0 APPENDIX L this goal. Moreover, they are important components for a robust and effective gene-sequence-based oversight system for Select Agents and “sequences of concern.” The periodic expert review, assessment, and update cycle could be coordinated well with the biennial review of the Select Agent and Toxin list, which is currently required by statute. 5 (h.) Disclosure, transparency, review: Because it is automatic and software-based, the classification system could be made readily and transparently available on the Web, where it could be reviewed and challenged by scientists in the community, to be sure (for instance) that it was not inadvertently misclassifying non-Select Agents such as vaccines or attenuated research strains. This feedback would inform the assessment and curation processes, and facilitate engagement of the scientific community. Likewise, the yellow flag biosafety system should be accessible and open for information sharing. Should a gene-sequence-based system be developed? We have concluded that a gene-sequence-based classification system could be developed. We have not addressed whether such a system should be developed. Here are some issues for consideration: a. Dual-Use Issue: As discussed, the development of a prediction-based oversight system would raise serious dual-use concerns. Providing an accurate mechanism for evaluating the threat posed by a synthetic genome sequence is equivalent to enabling the design and optimiza- tion of a bioweapon. It is a major goal of biology to predict phenotype from genotype, and to improve public health by understanding patho - genicity. However, it does not seem wise to make special plans for an advanced effort in predicting the sequence of would-be bioweapons.6 information across institutions and sectors; Promote sharing of successful practices across institu - tions and sectors; Provide oversight for evaluation of the Select Agent Program; Provide advice on composition/stratification of the list of select agents and toxins; Convene regular meetings of key constituency groups; and Promote harmonization of regulatory policies and practices (NRC 2009b).” 5 “(42 U.S.C. 262a) . . . The Bioterrorism Preparedness Act requires that the HHS Secretary review and republish the list of select agents and toxins on at least a biennial basis.” “(7 U.S.C. 8401) . . . The USDA Secretary is also required to conduct a biennial review of the USDA select agents and toxins list” (DHHS (2005). 42 CFR 72 and 73 and 42 CFR Part 1003: Possession, Use, and Transfer of Select Agents and Toxins; Final Rule, Federal Register. 70: 12294-13325. 6 If infallible prediction of organisms with Select Agent properties from genome sequence were feasible, or became feasible, it is unclear how that prediction would be useful in the context of Select Agents Regulation. Suppose we could predict the virulence, transmissibility, ease of growth, ease of dispersion, and environmental stability of a microorganism or virus from its sequence. Imagine we have a black box, a computer program that we can input a genome sequence to, and without error the black box reports whether the sequence corresponds to an organism that has

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 APPENDIX L A narrow focus on milestones solely to be able to predict what makes an agent a threat to security may be a distortion of priorities in biology. Once biology in general approaches the goal of determining function from sequence, then it would be an appropriate time to consider a predictive oversight system to accurately identify Select Agent status from a novel genome sequence. This time may not come for decades, and may be more than a century away. A classification system differs from a prediction system and would not directly enable the optimization of a pathogen. However, for a classification system to be usefully implemented, information must be shared. Listing the “parts” of a Select Agent and identifying other “sequences of concern” based entirely on their potential to be danger- ous when incorporated into a synthetic construct, could theoretically facilitate the design of a synthetic pathogen by a “bad actor.” Thus, the committee agreed with the NSABB that “The USG should include ad- vances in synthetic biology and advances in our understanding of viru- lence/ pathogenicity in “tech-watch” or “science-watch” endeavors.” b. Danger of misimplementation: The committee stresses that a system for classification of Select Agents is based on classification and should not be confused with pre- diction. It would be a mistake to assume that “sequences of concern” or “parts” of Select Agents would function in a genome backbone (or context) independent manner. This information is partial and cannot be appropriately applied to designate a “sequence of concern” or individual “part” as a Select Agent. If the classification system were incorrectly implemented it would be counterproductive for security, and could be crippling to public health research. For example, many viruses encode a suite of “interferon antagonist genes” to target mul - tiple steps in pathogen sensing, interferon signaling and innate/adap - tive immunity. These genes are not themselves infectious or dangerous, and it isn’t possible to forecast if these virulence genes/sequence motifs would enhance disease if introduced into a different genome back- the properties to be covered under the Select Agents Regulations. How would this black box be used? Individuals would not know whether they possess or are transferring a Select Agent until the black box has been run on their genome sequence. Would we require that the black box be run on all new or modified genome sequences? This would surely be impractical; the nature of modern biology routinely involves innumerable modified or synthetic DNA constructs. But if we don’t run the black box on all new or modified genome sequences, then we would need to define, with the clarity of a criminal statute, exactly who is required to run the black box and when. How big of a genetic modification requires a new black box certification? This would be a grey zone even worse than the problems associated with a simple Select Agents list. For new isolates of organisms from the wild, the genome sequence is not immediately known. Would individuals be required to obtain the genome sequence before commencing work on any new isolate?

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 APPENDIX L bone. Designating such sequences as Select Agents would have little if any security benefit, but could have significant negative consequences by imposing undue burden on important vaccine research, e.g., in- fluenza vaccines based on ns1 mutations/truncations and cell-surface glycoproteins, which are components of protective immunity and key for tissue tropism. The yellow flag system would also be damaging to public health and security if misapplied. For instance, requiring registration or re - stricting access to flagged genomic fragments would become a signifi- cant barrier to scientific progress, including biodefense research. The yellow flag system would only be effective if maintained as a broad and flexible system for guidance and monitoring. The yellow flag system would provide valuable information to researchers, synthesis companies, and DNA hobbyists. Likewise, the yellow flag system could function as a nonintrusive information resource for law enforcement and the intelligence community. c. Opportunity—Cost: A gene-sequence based oversight system, aimed at preention, may not be the best use of resources. Such a system would be far from fail proof since a determined “bad actor” could produce synthetic DNA without the aid of synthesis companies; this would certainly include those operating outside of the United States. 7 Moreover, such an oversight system would be moderately expensive to implement in terms of both money and the time required of the highly skilled staff and expert advisors involved. The Commission on the Pre- vention of Weapons of Mass Destruction Proliferation and Terrorism recently concluded that “[d]eterrence of bioterrorism rests upon the ability of the nation to mitigate the effects of an attack,” and that “the United States is woefully behind in its capability to rapidly produce vaccines and therapeutics, essential steps for adequately responding 7 We must recognize that from the standpoint of impeding bioterror scenarios, there will be myriad ways to get around any screening procedure used by DNA synthesis companies, ranging from splitting an order into apparently innocuous pieces across multiple companies, to using offshore companies that do not adhere to U.S. regulations, to simply not using a DNA synthesis company at all. The technology of DNA synthesis is rapidly being commoditized, and DNA oligo - nucleotide synthesis machines can already be purchased cheaply from Ebay. An ebay.com search on “oligo synthesizer” on 10 October 2009 found a used Applied Biosystems 394 DNA/RNA oligo synthesizer on sale for $8,900 (plus $106.16 shipping within 3-8 business days to a commit - tee member’s home in Northern Virginia). With difficulty, genes and even whole genomes can be assembled from individual short oligonucleotides. In much the same vein, a determined bioterrorist can obtain isolates of a select agent from the wild. The SAR can only raise the difficulty bar for acquiring cultures of proven highly virulent agents, and provide law enforcement with tools to prosecute for possession of variants of such agents; because natural biological organisms are widely available, readily engineered, and increasingly easy to create, it is unrealistic to try to design the SAR to preclude acquisition completely.

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 APPENDIX L to a biological threat, whether natural or man-made.” Therefore, it is worth considering that, even in the context of national security, resources may be better used toward understanding infectious disease and developing response capabilities.

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