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Appendix B Selected Prior Analyses Used to Inform the Framework Prior biodefense analyses and other sources were reviewed in developing the factors and elements that form the framework presented in this report. This appendix provides further summary information about several of these sources to illustrate different approaches to assessing potential synthetic biology concerns. It is not intended to be a comprehensive compendium of all prior risk governance and biotechnology assessment approaches. CAPABILITIES-BASED WEAPON DEVELOPMENT FRAMEWORK FROM NATIONAL DEFENSE UNIVERSITY This approach, developed at National Defense University (National Defense University, 2016) indicates the points at which potential impacts in the age of synthetic biology could be achieved. Beginning at the far left and working across each step of the bioweapon development pathway, one may determine the steps at which synthetic biology could have an impact on the development pathway (Figure B-1). 200 PREPUBLICATION COPY: UNCORRECTED PROOFS
Appendix B 201 FIGURE B-1 Approach developed by National Defense University, (National Defense University, 2016) This model was used by National Defense University at a tabletop exercise to assess where gene editing technology (such as CRISPR/Cas) provides heightened capability for creating bioweapons. This approach provides insight into where synthetic biology may have an impact, rather than defining specific characteristics of the technologies themselves. CONSIDERATIONS FROM GLOBALIZATION, BIOSECURITY, AND THE FUTURE OF THE LIFE SCIENCES The report Globalization, Biosecurity, and the Future of the Life Sciences (also sometimes referred to as the âLemon-Relmanâ report from the names of its committee co-chairs) classified emerging technologies into categories based on their characteristics as concerning and warranting particular attention for further risk assessment (IOM and NRC, 2006). These four groupings were: â(1) technologies that seek to acquire novel biological or molecular diversity; (2) technologies that seek to generate novel but pre-determined and specific biological or molecular entities through directed design; (3) technologies that seek to understand and manipulate biological systems in a more comprehensive and effective manner; and PREPUBLICATION COPY: UNCORRECTED PROOFS
202 Biodefense in the Age of Synthetic Biology (4) technologies that seek to enhance production, delivery, and âpackagingâ of biologically active materials.â This categorization is wholly focused on features of the technology itself in terms of capabilities it might generate. DECISION FRAMEWORK FROM INNOVATION, DUAL USE AND SECURITY Jonathan Tuckerâs âDecision Frameworkâ published in Innovation, Dual Use and Security (Tucker, 2012) suggests a number of attributes that are relevant to the study charge, as restated below: (1) Characteristics of the technology: a. Accessibility b. Ease of misuse c. Magnitude of potential harm from misuse (2) Characteristics of governability: a. Embodiment (material âtangibilityâ of technologies) b. Maturity c. Convergence (number of technologies that come together to create new technology) d. Rate of advance e. International diffusion (3) Level(s) amenable to mitigation a. State b. Institution c. Individual d. Product e. Knowledge This framework encompasses a variety of features that touch on features of the technology (level of difficulty, maturity, speed of advance, and convergence with other technologies), who has access, and the severity of the outcome if it is misused. This framework also considers options for mitigation, as well as how the cost compares to the benefit of the technology. It is used primarily to assess technology in terms of relative risk on these levels. EXPERIMENTAL AIMS FROM BIOTECHNOLOGY RESEARCH IN AN AGE OF TERRORISM In 2004, the National Academies produced the report Biotechnology Research in an Age of Terrorism (NRC, 2004), known as the âFink reportâ after its chairman, geneticist Gerald R. Fink, which made the case that scientists have an âaffirmative moral duty to avoid contributing to the advancement of biowarfare or bioterrorism.â The Fink report highlights a list of specific PREPUBLICATION COPY: UNCORRECTED PROOFS
Appendix B 203 experimental aims that that should trigger additional safety and security examination, even if performed for valid scientific reasons. These include experiments that would: (1) Render a vaccine ineffective; (2) Confer resistance to antibiotics or antivirals (countermeasures); (3) Enhance virulence of a pathogen or make a nonpathogen virulent; (4) Increase transmissibility of a pathogen; (5) Alter the host range of a pathogen; (6) Enable evasion of detection or diagnostic; or (7) Enable weaponization of an agent or toxin. The report features broad recommendations for mitigation of negative outcomes, to include: community outreach, research review (including creation and use of a review board), focused research on mitigation, and international cooperation and outreach. This framework primarily focused on the creation of mitigation tools, but also the creation of a core backbone for biosecurity policy development. The Fink report also led to the creation of the National Science Advisory Board for Biosecurity (NSABB), a federal advisory committee administered by the U.S. Department of Health and Human Services, which has produced a number of influential reports on dual use research. NATIONAL INSTITUTES OF HEALTH CONTAINMENT GUIDELINES The National Institutes of Health Guidelines (NIH, 2016), conceived initially with the advent of recombinant DNA, provide risk assessment frameworks that enable decision making about the level of biocontainment that can best protect laboratory workers, along with suggestions for mitigation plans. Formal risk groups were developed with respect to particular pathogens. These guidelines focus on capabilities of particular agents, potential adverse outcomes (accidental infection of laboratory workers or the public), and mitigation strategies. Perhaps most relevant to this study are the characteristics identified for consideration with respect to containment, which include: â¢ Virulence; â¢ Pathogenicity; â¢ Potency; â¢ Environmental stability; â¢ Route of spread/communicability; â¢ Availability of vaccine or treatment; â¢ Gene product effects such as toxicity, physiological activity, and allergenicity; and â¢ Any strain that is known to be more hazardous than the parent (wild-type) strain. CATEGORIES OF EXPERIMENTS HIGHLIGHTED BY THE DURC PROCESS PREPUBLICATION COPY: UNCORRECTED PROOFS
204 Biodefense in the Age of Synthetic Biology The Dual Use Research of Concern (DURC) process was initially triggered by concerns over the publication of sequence manipulation information that could map out the creation of a potentially dangerous virus; however the DURC policies that resulted are more focused on experiments of concern rather than control of information per se. The DURC policies for government and institutions (U.S. Government, 2012, 2014) utilize the Federal Select Agent Program Select Agents and Toxins list, and highlight categories of experiments similar to those in the Fink report. These categories include experiments that: (1) Enhance the harmful consequences of the agent or toxin; (2) Disrupt immunity or the effectiveness of an immunization against the agent or toxin without clinical and/or agricultural justification; (3) Confer to the agent or toxin resistance to clinically and/or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies; (4) Increase the stability, transmissibility, or the ability to disseminate the agent or toxin; (5) Alter the host range or tropism of the agent or toxin; (6) Enhance the susceptibility of a host population to the agent or toxin; or (7) Generate or reconstitute an eradicated or extinct agent or toxin listed. Similar to the Fink report, this list is focused on capabilities the technology provides to produce a harmful biological entity. The DURC policy is intended to be used to make decisions about funding dual use experiments. SOCIETAL RISK EVALUATION SCHEME (SRES) The SRES approach developed by Cummings and Kuzma (2017) was applied to a set of four case studies of synthetic biology applications. The suggested characteristics for assessing risks of synthetic biology applications are based primarily on outcomes of an adverse event and whether or not mitigation exists. It also includes a novel consideration of societyâs attitude toward a potentially adverse outcome, which include considerations such as: (1) Human health risks; (2) Environmental health risks; (3) Unmanageability; (4) Irreversibility; (5) The likelihood that a technology will enter the marketplace; (6) Lack of human health benefits; (7) Lack of environmental benefits; and (8) Anticipated level of public concern. Since this approach was a risk-benefit framework, it goes beyond the scope of the study charge for this committee, which did not attempt to address the benefits of synthetic biology capabilities. PREPUBLICATION COPY: UNCORRECTED PROOFS
Appendix B 205 GRYPHON ANALYSES In a presentation to the committee, a representative from Gryphon Scientific described an approach for considering how advances in synthetic biology may change the landscape for acquisition of biological threat agents. For example, synthetic biology advances might enable particular threat agents to be synthesized or for a less pathogenic microorganism to be modified into a threat agent, in comparison to alternative acquisition routes such as culturing from clinical or environmental samples or theft. The approach taken by the analysis was comparative and was motivated by the guiding question, âWhat advantages (or disadvantages) do synthetic biology acquisition routes provide to a malicious actor, relative to alternative acquisition routes?â (Casagrande et al., 2017). The framework used in the analysis, depicted in Figure B-2, included two phases. The first phase asked whether creating a particular biological threat agent was possible using synthetic biology. If so, the second phase asked whether the use of synthetic biology provided acquisition advantages over alternative approaches to obtaining that agent. The results of these two phases informed the determination of whether the agent did or did not pose a near-term threat. FIGURE B-2 Approach to conducting an assessment of how synthetic biology changes the threat agent landscape (Modified from Casagrande et al. 2017). Prior work by Gryphon Scientific, described in the presentation, also considered whether novel biotechnologies, including synthetic biology, have the potential to influence and streamline classical weaponization steps for biological agents. For example, the presenter noted that agents developed using synthetic biology might be developed with increased potency, increased ability to grow to larger numbers, enhanced environmental persistence, increased transmissibility, and the ability to overcome host resistance. However the use of synthetic biology tools might not be the most effective means to achieve these objectives due to intrinsic factors (such as a lack of PREPUBLICATION COPY: UNCORRECTED PROOFS
206 Biodefense in the Age of Synthetic Biology knowledge) as well as extrinsic factors such as the need for continual testing of weapons products along a development pathway. REFERENCES Casagrande, R., C. Meyer, and K. Berger. 2017. Assessing biodefense vulnerabilities posed by synthetic biology: Insights from related Gryphon studies. Presentation to the Committee by Gryphon Scientific. January 26, 2017. Cummings, C.L. and J. Kuzma. 2017. Societal Risk Evaluation Scheme (SRES): Scenario-based multi-criteria evaluation of synthetic biology applications. PLoS ONE 12(1):e0168564. IOM (Institute of Medicine) and NRC (National Research Council). 2006. Globalization, Biosecurity, and the Future of the Life Sciences. Washington, DC: National Academies Press. National Defense University. 2016. Challenge or Crisis: Security Risk Posed by Gene Editing and Synthesis. Workshop Report, September 14, 2016. NIH (National Institutes of Health). 2016. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. April 2016. Available at https://osp.od.nih.gov/wp- content/uploads/2013/06/NIH_Guidelines.pdf. Accessed November 8, 2017. NRC (National Research Council). 2004. Biotechnology Research in an Age of Terrorism. Washington, DC: The National Academies Press. Tucker, J.B. 2012. Decision framework. Pp. 67â84 in Innovation, Dual Use, and Security: Managing the Risks of Emerging Biological and Chemical Technologies. Cambridge, MA: MIT Press. U.S. Government. 2012. United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern. March 29, 2012. Available at: https://www.phe.gov/s3/dualuse/Documents/us-policy-durc-032812.pdf. Accessed on May 11, 2017. U.S. Government. 2014. United States Government Policy for Institutional Oversight of Life Sciences Dual-use Research of Concern. September 24, 2014. Available at: https://www.phe.gov/s3/dualuse/Documents/durc-policy.pdf. Accessed on May 11, 2017. PREPUBLICATION COPY: UNCORRECTED PROOFS