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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: 10.17226/24890.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Summary Scientific advances over the past several decades have accelerated the ability to engineer existing organisms and to potentially create novel ones not found in nature. Synthetic biology, which collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms, is being pursued overwhelmingly for beneficial purposes ranging from reducing the burden of disease to improving agricultural yields to remediating pollution. Although the contributions synthetic biology can make in these and other areas hold great promise, it is also possible to imagine malicious uses that could threaten U.S. citizens and military personnel. Making informed decisions about how to address such concerns requires a realistic assessment of the capabilities that could be misused. To that end, the U.S. Department of Defense, working with other agencies involved in biodefense, asked the National Academies of Sciences, Engineering, and Medicine to develop a framework to guide an assessment of the security concerns related to advances in synthetic biology, to assess the levels of concern warranted for such advances, and to identify options that could help mitigate those concerns. An excerpted version of the study charge highlights the key tasks undertaken (see chapter 1, Box 1-2 for the more detailed statement of task): To assist the U.S. Department of Defense’s Chemical and Biological Defense Program (CBDP), the National Academies of Sciences, Engineering, and Medicine will appoint an ad hoc committee to address the changing nature of the biodefense threat in the age of synthetic biology. Specifically, the focus of the study will be the manipulation of biological functions, systems, or microorganisms resulting in the production of disease-causing agents or toxins. . . Initially, the committee will develop a strategic framework to guide an assessment of the potential security vulnerabilities related to advances in biology and biotechnology, with a particular emphasis on synthetic biology. The framework will focus on how to address the following three questions: What are the possible security concerns with regard to synthetic biology that are on the horizon? What are the time frames of development of these concerns? What are our options for mitigating these potential concerns? . . . [T]he committee will use the outlined strategic framework to generate an assessment of potential vulnerabilities posed by synthetic biology. Inputs to this assessment may include information about the current threat, current program priorities and research and an evaluation of the current landscape of science and technology. Conclusions and recommendations will include a list and description of potential vulnerabilities posed by synthetic biology. An initial framework for assessing concerns was published in an interim report (National Academies of Sciences, Engineering, and Medicine, 2017). This, the study’s final report, builds on and supersedes that report. This report explores and envisions potential misuses of synthetic biology, including concepts that are regularly discussed in open meetings. The potential misuses as they are discussed in the report are neither comprehensive nor enabling in the level of information and detail provided; they are included to illustrate the expanding mission of biodefense in the age of synthetic biology. 1 PREPUBLICATION COPY: UNCORRECTED PROOFS

2 Biodefense in the Age of Synthetic Biology OVERARCHING RECOMMENDATION Biotechnology in the age of synthetic biology expands the landscape of potential defense concerns. The U.S. Department of Defense (DoD) and its partnering agencies should continue to pursue ongoing strategies for chemical and biological defense; these strategies remain relevant in the age of synthetic biology. DoD and its partners also need to have approaches to account for the broader capabilities enabled by synthetic biology, now and into the future. The nation’s experience preparing for naturally occurring diseases provides a strong foundation for developing strategies to prevent and respond to emerging biologically-enabled threats, particularly those based on naturally occurring pathogens. But synthetic biology approaches also have the potential to be used in ways that could change the presentation of an attack, for example by modifying the properties of existing microorganisms, using microorganisms to produce chemicals, or employing novel or unexpected strategies to cause harm. It is valuable for the U.S. government to pay close attention to rapidly advancing fields such as synthetic biology, just as it did to advances in chemistry and physics during the Cold War era. However, approaches modeled after those taken to counter Cold War threats are not sufficient to address biological and biologically enabled chemical weapons in the age of synthetic biology. The partners involved in the U.S. biodefense enterprise will need expanded strategies and approaches to account for the new capabilities enabled by advances in this field. A FRAMEWORK FOR ASSESSING CONCERN CONTRIBUTES TO PLANNING Recommendation: The Department of Defense and its interagency partners should use a framework in assessing synthetic biology capabilities and their implications. a) A framework is a valuable tool for parsing the changing biotechnology landscape. b) Using a framework facilitates the identification of bottlenecks and barriers, as well as efforts to monitor advances in technology and knowledge that change what is possible. c) A framework provides a mechanism for incorporating the necessary technical expertise into the assessment. A framework enables the participation of technical experts in synthetic biology and biotechnology along with experts in complementary areas (e.g., intelligence and public health). PREPUBLICATION COPY: UNCORRECTED PROOFS

Summary 3 The framework developed in the report identifies the features of a synthetic biology–enabled capability that would increase or decrease the level of concern about a given capability being used for harm. As summarized in Figure S-1, this framework identifies factors to determine the relative levels of concern posed by advances in biotechnology. In addition to supporting the analysis conducted in this study, the framework is intended to aid others in their consideration of current and future synthetic biology capabilities. Specifically, the framework is designed to support uses including analyzing existing biotechnologies to evaluate the levels of concern warranted at present; understanding how various technologies or capabilities compare to, interact with, or complement each other; identifying key bottlenecks and barriers that, if removed, could lead to a change in the level of concern about a capability; evaluating the implications of new experimental results or new technologies; and horizon-scanning to predict or prepare for potential future areas of concern. Use of a framework for assessing the implications of synthetic biology capabilities thus contributes to biodefense planning and facilitates consideration of expert opinions about specific synthetic biology-enabled capabilities or combinations of capabilities. FIGURE S-1 Framework for assessing concern. The framework for assessing concern consists of four factors, along with descriptive elements within each factor. The factors are Usability of the Technology, Usability as a Weapon, Requirements of Actors, and Potential for Mitigation. PREPUBLICATION COPY: UNCORRECTED PROOFS

4 Biodefense in the Age of Synthetic Biology These factors delineate the information used to assess the level of concern for particular synthetic biology-enabled capabilities. SYNTHETIC BIOLOGY EXPANDS WHAT IS POSSIBLE Synthetic biology expands what is possible in creating new weapons. It also expands the range of actors who could undertake such efforts and decreases the time required. Based on this study’s analysis of the potential ways in which synthetic biology approaches and tools may be misused to cause harm, the following specific observations were made: a) Of the potential capabilities assessed, three currently warrant the most concern: re-creating known pathogenic viruses, making existing bacteria more dangerous, and making harmful biochemicals via in situ synthesis. The first two capabilities are of high concern due to usability of the technology. The third capability, which involves using microbes to produce harmful biochemicals in humans, is of high concern because its novelty challenges potential mitigation options. b) With regard to pathogens, synthetic biology is expected to: (1) expand the range of what could be produced, including making bacteria and viruses more harmful, (2) decrease the amount of time required to engineer such organisms, and (3) expand the range of actors who could undertake such efforts. The creation and manipulation of pathogens is facilitated by increasingly accessible technologies and starting materials, including DNA sequences in public databases. A wide range of pathogen characteristics could be explored as part of such efforts. c) With regard to chemicals, biochemicals, and toxins, synthetic biology blurs the line between chemical and biological weapons. High potency molecules that can be produced through simple genetic pathways are of greatest concern, as they could conceivably be developed with modest resources and organizational footprint. d) It may be possible to use synthetic biology to modulate human physiology in novel ways. These ways include physiological changes that differ from the typical effects of known pathogens and chemical agents. Synthetic biology expands the landscape by potentially allowing the delivery of biochemicals by a biological agent and by potentially allowing the engineering of the microbiome or immune system. While unlikely today, these types of manipulations may become more feasible as knowledge of complex systems, such as the immune system and microbiome, grows. e) Some malicious applications of synthetic biology may not seem plausible now, but could become achievable if certain barriers are overcome. These PREPUBLICATION COPY: UNCORRECTED PROOFS

Summary 5 barriers include knowledge barriers, as is the case for building a novel pathogen, or technological barriers, as in engineering complex biosynthetic pathways into bacteria or re-creating known bacterial pathogens. It is important to continue to monitor advances in biotechnology that may lower these barriers. Synthetic biology concepts, approaches, and tools do not, in and of themselves, pose inherent harm. Rather, concerns derive from the specific applications or capabilities synthetic biology might enable. The framework developed in the report was applied to assess the relative levels of concern posed by a set of synthetic biology capabilities. This assessment was undertaken in several steps. First, the framework was used to qualitatively analyze each of the identified capabilities individually. This analysis included considerations related to the state of the art of the technologies involved, the feasibility of using the capability to produce an effective weapon, the characteristics and resources an actor would likely require to carry out an attack, and information on proactive and reactive measures that might be taken to help mitigate the effects of misusing the capability. Then, an overall level of concern was determined for each capability relative to the other capabilities considered and an assessment of the landscape of capabilities and concerns presented. The results of this assessment are summarized in Figure S-2. PREPUBLICATION COPY: UNCORRECTED PROOFS

6 Biodefense in the Age of Synthetic Biology FIGURE S-2 Relative ranking of concerns related to the synthetic biology–enabled capabilities analyzed. At the present time, capabilities toward the top warrant a relatively higher level of concern while capabilities toward the bottom warrant a relatively low level of concern. Capabilities currently warranting the highest relative level of concern include re-creating known pathogenic viruses, making biochemical compounds via in situ synthesis, and the use of synthetic biology to make existing bacteria more dangerous. These capabilities are based on technologies and knowledge that are readily available to a wide array of actors. Capabilities posing a moderate-to-high relative level of concern include manufacturing chemicals or biochemicals by exploiting natural metabolic pathways and the use of synthetic biology to make existing viruses more dangerous. These capabilities are also supported by available technologies and knowledge, but involve more constraints and would likely be limited by factors related to both biology and skill. Capabilities posing a moderate relative level of concern include manufacturing chemicals or biochemicals by creating novel metabolic pathways, efforts to modify the human microbiome to cause harm, efforts to modify the human immune system, and efforts to modify the human genome. Although conceivable, these capabilities are more futuristic and likely limited by available knowledge and technology. Capabilities warranting a lower relative level of concern include re-creating known pathogenic bacteria and creating new pathogens; these capabilities involve major design and implementation challenges. The use of human gene drives warrants a minimal level of concern because it would be impractical to rely on generations of sexual reproduction to spread a harmful trait through a human population. The application of the report’s framework in this analysis reflects a snapshot in time, given understanding of current technologies and capabilities. As the field continues to evolve, some bottlenecks will likely widen and some barriers will be overcome. Table S-3 identifies a number of technical developments that may contribute to overcoming such bottlenecks and barriers to increase the feasibility or impact of a potential attack and the level of biodefense concern warranted for a capability. It is impossible to predict precisely when these developments might occur; those timelines are influenced by the drivers of commercial development and academic research, as well as by converging or synergistic technologies that may come from outside the field of synthetic biology. It will be important to continue to monitor advances in synthetic biology and biotechnology that may affect these bottleneck and barriers. PREPUBLICATION COPY: UNCORRECTED PROOFS

Summary 7 TABLE S-3 Bottlenecks and barriers that currently constrain the capabilities considered, along with developments that could reduce these constraints in the future. Shading indicates developments thought to be propelled by commercial drivers. Some approaches, such as combinatorial approaches and directed evolution, may allow bottlenecks and barriers to be widened or overcome with less explicit knowledge or tools. Capability Bottleneck or Barrier Relevant Developments to Monitor Re-creating known Booting Demonstrations of booting viruses with synthesized pathogenic viruses genomes Re-creating known DNA synthesis and Improvements in synthesis and assembly technology for pathogenic bacteria assembly handling larger DNA constructs Booting Demonstrations of booting bacteria with synthesized genomes Making existing Constraints on viral Increased knowledge of viral genome organization viruses more genome organization and/or demonstration of combinatorial approaches dangerous capable of facilitating larger-scale modifications to viral genome Engineering complex Increased knowledge of determinants of complex viral viral traits traits, as well as how to engineer pathways to produce them Making existing Engineering complex Advances in combinatorial approaches and/or increased bacteria more bacterial traits knowledge of determinants of complex bacterial traits, dangerous as well as how to engineer pathways to produce them Creating new Limited knowledge Increased knowledge of requirements for viability in pathogens regarding minimal viruses or bacteria requirements for viability (in both viruses and bacteria) Constraints on viral Increased knowledge of viral genome organization genome organization and/or demonstration of combinatorial approaches capable of facilitating larger-scale modifications to viral genome Manufacturing Tolerability of toxins to Pathway elucidation, improvements in circuit design, chemicals or the host organism and improvements in host (“chassis”) engineering to biochemicals by synthesizing the toxin make toxins tolerable to the host organism synthesizing exploiting natural the toxin metabolic pathways Pathway not known Pathway elucidation and/or demonstrations of combinatorial approaches PREPUBLICATION COPY: UNCORRECTED PROOFS

8 Biodefense in the Age of Synthetic Biology Challenges to large- Improvements in intracellular and industrial scale production productivity Manufacturing Tolerability of toxins to Pathway elucidation and/or improvements in circuit chemicals or the host organism design and/or improvements in host (“chassis”) biochemicals by synthesizing the toxin engineering to make toxins tolerable to the host creating novel organism synthesizing the toxin metabolic pathways Engineering enzyme Increased knowledge of how to modify enzymatic activity functions to make specific products Limited knowledge of Improvements in directed evolution and/or increased requirements for knowledge of how to build pathways from disparate designing novel organisms pathways Challenges to large- Improvements in intracellular and industrial scale production productivity Making biochemicals Limited understanding Improvements in knowledge related to microbiome via in situ synthesis of microbiome colonization of host, in situ horizontal transfer of genetic elements, and other relationships between microbiome organisms and host processes Modifying the human Limited understanding Improvements in knowledge related to microbiome microbiome of microbiome colonization of host, in situ horizontal transfer of genetic elements, and other relationships between microbiome organisms and host processes Modifying the human Engineering of delivery Increased knowledge related to the potential for viruses immune system system or microbes to deliver immunomodulatory factors Limited understanding Knowledge related to how to manipulate the immune of complex immune system, including how to cause autoimmunity and processes predictability across a population Modifying the human Means to engineer Increased knowledge of techniques to effectively alter genome horizontal transfer the human genome through horizontal transfer of genetic information Lack of knowledge Increased knowledge related to regulation of human about regulation of gene expression human gene expression PREPUBLICATION COPY: UNCORRECTED PROOFS

Summary 9 A RANGE OF STRATEGIES IS NEEDED TO PREPARE AND RESPOND Recommendations: Many of the traditional approaches to biological and chemical defense preparedness will be relevant to synthetic biology, but synthetic biology will also present new challenges. The DoD and partner agencies will need approaches to biological and chemical weapons defense that meet these new challenges. a) The DoD and its partners in the chemical and biological defense enterprise should continue exploring strategies that are applicable to a wide range of chemical and biodefense threats. Nimble biological and chemical defense strategies are needed because of rapid rates of technological change, as well as strategies adaptable to a wide range of threats because of uncertainty about which approaches an adversary might pursue. b) The potential unpredictability related to how a synthetic biology–enabled weapon could manifest creates an added challenge to monitoring and detection. The DoD and its partners should evaluate the national military and civilian infrastructure that informs population-based surveillance, identification, and notification of both natural and purposeful health threats. An evaluation should consider whether and how the public health infrastructure needs to be strengthened to adequately recognize a synthetic biology–enabled attack. Ongoing evaluation will support responsive and adaptive management as technology advances. c) The U.S. government, in conjunction with the scientific community, should consider strategies that manage emerging risk better than current agent-based lists and access control approaches. Strategies based on lists, such as the Federal Select Agent Program Select Agents and Toxins list, will be insufficient for managing risks arising from the application of synthetic biology. While measures to control access to physical materials such as synthetic nucleic acids and microbial strains have merits, such approaches will not be effective in mitigating all types of synthetic biology–enabled attacks. Exploration Areas: It has been stated by both scientific and political leaders that the 21st century is the century of the life sciences. But as with previous expansions in technological capabilities, biotechnology in the age of synthetic biology presents a “dual use dilemma” that scientific knowledge, materials, and techniques required for beneficial research or development could be misused to cause harm. Although current approaches to defense and public health preparedness remain valuable, there are also clear limitations to current approaches such as pathogen list–based screening tools. To comprehensively assess the preparedness and response capabilities of existing military and civilian defense and public health enterprises or to determine how to address gaps lies outside the PREPUBLICATION COPY: UNCORRECTED PROOFS

10 Biodefense in the Age of Synthetic Biology scope of this study; however, exploration of the following areas is suggested to address some of the challenges posed by synthetic biology: a) Developing capabilities to detect unusual ways in which a synthetic biology–enabled weapon may manifest. For consequence management, expanding the development of epidemiological methods (e.g., surveillance and data collection) would strengthen the ability to detect unusual symptoms or aberrant patterns of disease. Enhancing epidemiological methods will have an additional benefit of strengthening the ability to respond to natural disease outbreaks. b) Harnessing computational approaches for mitigation. The role of computational approaches for prevention, detection, control, and attribution will become more important with the increasing reliance of synthetic biology on computational design and computational infrastructure. c) Leveraging synthetic biology to advance detection, therapeutics, vaccines, and other medical countermeasures. Taking advantage of beneficial applications of synthetic biology for countermeasure research and development is expected to prove valuable, along with corresponding efforts to facilitate the entire development process, including regulatory considerations. While addressing the potential concerns posed by synthetic biology in the age of biotechnology will remain a challenge for scientists and for the nation’s defense, there is reason for optimism that, with continued monitoring of biotechnology capabilities and strategic biodefense investments, the United States can foster fruitful scientific and technological advances while minimizing the likelihood that these same advances will be used for harm. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Scientific advances over the past several decades have accelerated the ability to engineer existing organisms and to potentially create novel ones not found in nature. Synthetic biology, which collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms, is being pursued overwhelmingly for beneficial purposes ranging from reducing the burden of disease to improving agricultural yields to remediating pollution. Although the contributions synthetic biology can make in these and other areas hold great promise, it is also possible to imagine malicious uses that could threaten U.S. citizens and military personnel. Making informed decisions about how to address such concerns requires a realistic assessment of the capabilities that could be misused.

Biodefense in the Age of Synthetic Biology explores and envisions potential misuses of synthetic biology. This report develops a framework to guide an assessment of the security concerns related to advances in synthetic biology, assesses the levels of concern warranted for such advances, and identifies options that could help mitigate those concerns.

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