National Academies Press: OpenBook

Biodefense in the Age of Synthetic Biology (2018)

Chapter: 1 Introduction

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Suggested Citation:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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:"1 Introduction." 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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1 Introduction Scientific advances over the past several decades have rapidly accelerated the ability to engineer existing living organisms and potentially create novel ones not found in nature. Synthetic biology collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms. These concepts, approaches, and tools are being developed and refined by researchers in universities, governments, and industry in the United States and around the globe. While synthetic biology is being pursued overwhelmingly for beneficial and legitimate purposes, such as addressing disease, remediating pollution, and increasing the yield of crops (see Box 1-1), there are potential uses that are detrimental to humans and other species. In order to inform investments to mitigate potential threats, those responsible for protecting the security of nations must consider how these emerging approaches and technologies might be used in acts of warfare or terrorism, the intent and capability of adversaries to effect such uses, and the potential impacts of such attacks. Statements and reports issued over the past several years have come to different conclusions regarding the national security threats posed by emerging biotechnologies and the level of concern that is warranted. Former Director of National Intelligence James Clapper, in his 2016 annual threat assessment to Congress, grouped concerns about genome editing, an example of synthetic biology technology, under discussion of weapons of mass destruction (Clapper, 2016). Reports of federal government advisory committees, such as the 2016 report of the President’s Council of Advisors on Science and Technology, “Action Needed to Protect against Biological Attack” (PCAST, 2016), and a 2016 report of the JASON advisory group on potential implications of the gene editing platform CRISPR and other technologies on U.S. national security (Breaker, 2017), posit that biotechnology presents a new and significant threat. However, bioweapons are not a new phenomenon, and others have countered that, although advances in synthetic biology may add to the biological weapons landscape, these developments do not fundamentally change the landscape or warrant special action to address concerns (Vogel, 2013; Jefferson et al., 2014). That argument has been based on the notion that using natural pathogens to cause harm may be easier and just as effective as using synthetic biology to create bioweapons, so synthetic biology did not change the level of concern, at least at that time (A. Paul interview with K. Vogel, February 24, 2006, New York as cited in Vogel, 2012; Jefferson et al., 2014). 11 PREPUBLICATION COPY: UNCORRECTED PROOFS

Introduction 12 BOX 1-1 Benefits of Synthetic Biology The field of synthetic biology opens tremendous possibilities for the application of biotechnology to improve human wellbeing, as well as the health of animals, plants, and the environment. Such applications hold substantial economic potential. For example, annual U.S. revenues from genetically engineered plants and microbes are estimated to exceed $300 billion, and industrial biotechnology (the use of biological components to generate industrial products) is estimated to account for more than $115 billion in annual U.S. revenues. New applications for biotechnology, particularly those driven by innovation in synthetic biology, are expected to further grow the size and reach of the bioeconomy (White House, 2012). Often looked to as a means of producing products that would otherwise be difficult to obtain, synthetic biology has already led to new ways of producing pharmaceuticals including opioids and the anti-malarial drug artemisinin. There are ongoing efforts to engineer microorganisms to produce fuels, act as detection devices, and clean up toxic spills. Synthetic biology is also seen as a potential means to grow organs for transplant, manipulate the microbiome, and even produce cosmetics. In addition to such application-driven goals, synthetic biology is also advancing the reach and role of science in society by inspiring more people to engage in biological experimentation, such as through the International Genetically Engineered Machine (iGEM) competition or by engaging with community laboratories. This broad array of applications and implications suggests that the potential benefits of synthetic biology are limited only by human creativity and imagination. While it is possible to imagine numerous types of malicious uses of synthetic biology, making informed decisions about whether and how to mitigate these potential uses requires a realistic assessment of the security concerns this technology creates. 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 the life sciences in the “age of synthetic biology,” to assess the level of concern warranted for various advances and identify areas of potential vulnerability, and to provide ideas for options that could be considered to help mitigate potential vulnerabilities. To aid decision making in agencies across the biodefense enterprise, including the U.S. Department of Homeland Security, the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, the intelligence community, and other agencies, the Department of Defense asked the National Academies to consider potential concerns that are relevant to all U.S. citizens, both at home and abroad, in both civilian and military contexts. See Box 1-2 for the Statement of Task. The study focuses on activities that could directly threaten human health or the capacity of military personnel to execute their missions. There are other conceivable uses of synthetic biology that are outside the scope of this study. The study does not address the potential ways in which plants, animals, and the pathogens that affect them could be modified for malicious purposes, for example, to undermine agricultural productivity, although the economic and societal impact of such an attack could be substantial. The study also does not address the modification of organisms to affect the environment or materials. Nonetheless, the technologies PREPUBLICATION COPY: UNCORRECTED PROOFS

13 Biodefense in the Age of Synthetic Biology that might be used to threaten agricultural, environmental, or material targets, and the capabilities associated with those technologies, are likely comparable or even identical to the technologies and capabilities discussed in the report; as a result, the framework and analyses presented in the report may be useful for a broader array of contexts than those addressed in this study. Finally, the report does not weigh the benefits on balance with the risks of synthetic biology advancements. Synthetic biology can play a role in achieving a number of societal goals but it is not within the purview of this study to compare the size or nature of those benefits with the potential risks. It is not the intent of the report or the study sponsor to imply that research efforts that use synthetic biology approaches for beneficial purposes should be curtailed. BOX 1-2 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. The study will be conducted in two primary phases and will be followed by a workshop. 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? The committee will publish a brief interim, public report outlining the developed framework. This framework will not be a threat assessment, but rather, will focus on ways to identify scientific developments to enable opportunities that have the potential to mitigate threats posed by synthetic biology in the near-, mid-, and long term, with the specific time frames defined by the committee. The framework will lay out how best to consider the trajectory of scientific advances, identify potential areas of vulnerability, and provide ideas for potential mitigation opportunities to consider. In Phase 2 of the study, the 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. PREPUBLICATION COPY: UNCORRECTED PROOFS

Introduction 14 UNDERSTANDING SYNTHETIC BIOLOGY Biotechnology is a broad term encompassing the application of biological components or processes to advance human purposes, while synthetic biology is a narrower term referring to a set of concepts, approaches, and tools within biotechnology. A variety of perspectives has been offered to characterize the core principles of synthetic biology and the activities of its practitioners (see, for example, Benner and Sismour, 2005; Endy, 2005; Dhar and Weiss, 2007), but there remains no universally agreed-upon definition (Nature Biotechnology, 2009). One distillation is that synthetic biology “aims to improve the process of genetic engineering” (Voigt, 2012). Chapter 2 provides additional detail on how synthetic biologists pursue that improvement. A hallmark of synthetic biology is the use of concepts and approaches common to engineering disciplines. These can include standardization of components (e.g., well- characterized functions encoded by DNA), the use of software and computational modeling for designing biological systems from those components, and the construction of prototypes based on those designs. Synthetic biologists frequently apply such approaches in iterative Design- Build-Test cycles to accelerate progress. This report takes a broad view of the field and does not attempt to narrowly define the term synthetic biology or to precisely separate it from other kinds of biotechnology. The concepts, approaches, and tools developed to advance synthetic biology will continue to be integrated more broadly into the life sciences toolkit and applied toward many biological research and biotechnology activities. Should a malicious actor seek to misuse such approaches, distinctions based on terminology will be irrelevant; similarly, the potential strategies for mitigating biodefense concerns are unlikely to be tied to a precise distinction between synthetic biology and other related activities. As a result, the analyses in the report focus on the potential applications of synthetic biology (also described as synthetic biology–enabled capabilities or uses of synthetic biology), rather than on synthetic biology concepts, approaches, and tools themselves. In particular, the study was guided by the focus laid out in the Statement of Task on “the manipulation of biological functions, systems, or microorganisms resulting in the production of a disease-causing agent or toxin.” Modifying a pathogen to facilitate its rapid spread through a population, manipulating a biological system to produce a potent toxin, introducing antibiotic resistance into an infectious microorganism, and purposely weakening a person’s immune system are just a few examples of the potential types of malicious uses addressed. ASSESSING POTENTIAL BIODEFENSE CONCERNS A fundamental component of this study is to provide a basis for assessing potential areas of concern in the age of synthetic biology. Establishing a process for considering concern is important because it provides structure and transparency to the analysis of specific factors and how these factors contribute to an overall level of concern. It thus enables an assessment to more clearly convey the reasoning underlying judgments about potential concerns, increases consistency across assessments, and facilitates the comparison of assessments undertaken by different analysts or conducted at different times. PREPUBLICATION COPY: UNCORRECTED PROOFS

15 Biodefense in the Age of Synthetic Biology A number of possible approaches can be taken to develop such a process. The report presents a framework, which is largely a qualitative, multi-criteria model, that could contribute to a qualitative, quantitative, or semi-quantitative assessment. As presented in chapter 3, the methodology used to generate and apply this framework was informed by a review of existing frameworks, previous assessments, and related work relevant to biodefense, synthetic biology, and other biotechnology threats. Relevant documents include NRC, 2004; IOM/NRC, 2006; Tucker, 2012; U.S. Government, 2012, 2014; HHS, 2013; Blue Ribbon Study Panel on Biodefense, 2015; Royal Society, 2015; Cummings and Kuzma, 2017; and DiEuliis and Giordano, 2017. Selected prior analyses are described briefly in Appendix B. The framework presented in the report was also informed by the expert judgment of committee members and input received during the course of the study. The report also applies the proposed framework to analyze potential concerns associated with a number of synthetic biology-enabled capabilities. These analyses and their results are presented in chapters 4–6. Detailed descriptions of how the framework was used to conduct the current assessment can help inform efforts to assess the significance of new biotechnology developments that occur in the future; monitor key bottlenecks and barriers identified in the report that, if removed, could lead to a change in the relative level of concern; evaluate the change in the level of concern warranted when new experimental results are reported or new technologies arise; or scan the horizon to predict or prepare for potential future areas of concern. While the report presents a framework for assessment of potential biodefense concerns and describes how that framework was applied to analyze synthetic biology-enabled capabilities, it is important to emphasize that this study is not a threat assessment. The study did not access intelligence or military information on potential actors, who may range from a single individual to a dedicated team to a government body, who may seek to misuse life sciences and their specific intent or specific capacity to undertake such misuse. Because information on actors is not included in the assessment presented in the report, a likelihood of harm cannot be fully estimated. By combining this assessment of concern with such classified information, however, the sponsor and others could, in the future, assess vulnerabilities and risks to inform decision making. MITIGATING POTENTIAL BIODEFENSE CONCERNS The report focuses on the state of science; it does not comprehensively assess the capability of the U.S. government to respond to the concerns identified in the report; it was outside of the study scope to access classified information or to comprehensively review the landscape of approaches being undertaken by the Department of Defense and other federal agencies to mitigate potential misuse of the life sciences. However, the existence and nature of anticipated mitigation options affects judgments about the levels of concern posed by synthetic biology capabilities. Thus, consideration of anticipated mitigation options is embedded in the framework presented in the report, and the analyses presented include discussion of the potential for mitigating different synthetic biology–enabled capabilities based on an understanding of the current state of science. The report also considers several types of mitigation approaches that may be useful for addressing some of the concerns arising from synthetic biology and biotechnology capabilities, as well as ways in which synthetic biology may affect those approaches (see chapter 8). This PREPUBLICATION COPY: UNCORRECTED PROOFS

Introduction 16 portfolio of strategies includes options ranging from the promotion of norms of responsible conduct within the scientific community to strengthening the public health infrastructure to detect and respond to infectious disease outbreaks. However, because it was outside of the study’s scope to consider all of the mitigation options available to the defense enterprise, the report does not make comprehensive, explicit recommendations regarding mitigation approaches. STUDY APPROACH To carry out the task, the National Academies appointed a committee including members with expertise in such areas as synthetic biology, microbiology, computational tool development and bioinformatics, biosafety, public health, and risk assessment (see Appendix D for biographical information). The study was conducted in two phases. Phase 1 led to the development of an interim report proposing a framework for assessing potential vulnerabilities arising from developments in synthetic biology (National Academies of Sciences, Engineering, and Medicine, 2017). The committee solicited feedback on the interim report from the synthetic biology, security, and policy communities to inform the second phase of the study. During Phase 2, the committee refined elements of the framework and applied the final framework to assess concerns posed by synthetic biology–enabled capabilities. This report, which represents the culmination of the study, presents the committee’s assessment along with conclusions and recommendations. It thus extends and supersedes the interim report. This two-phase approach enabled the committee to understand the needs and motivations of the sponsor and other biodefense agencies, develop and refine a framework for assessing concerns, and apply the framework to provide an assessment of concerns associated with synthetic biology–enabled capabilities. The study was informed not only by committee members’ expert judgment, but also by the committee’s analysis of information in published literature, including a review of existing frameworks and assessments as well as technical developments, progress, and barriers in synthetic biology, immunology, microbiology, and other relevant fields. The study was also informed by interactions with experts who shared their knowledge with the committee during public data-gathering meetings and webinars and by public comment and input. Additional details on the study process and data-gathering activities are provided in Appendix E. The committee did not leverage classified information that others have created or utilized in their consideration of questions related to this study’s task. Classified information was not included in the committee’s deliberations; the resulting report is not classified and can be shared publicly. This facilitates the involvement of a wider community in the discussions during the study process and after the resulting reports are released. 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. PREPUBLICATION COPY: UNCORRECTED PROOFS

17 Biodefense in the Age of Synthetic Biology Terminology Although the report avoids precisely defining synthetic biology or drawing a strict distinction between synthetic biology and biotechnology, certain terms are used in a deliberate fashion to reflect the scope and nature of the assessment presented. For the purposes of this report: • Agent or bioagent is used broadly to refer to any product created using biological components that may be intended to cause harm. In the context of synthetic biology, an agent could be a pathogen, a toxin, or even a biological component, such as a genetic construct or a biochemical pathway, that may be developed with the intent to harm a human target. • Actor is used to refer to individuals or groups who may seek to effect an attack. • Target is typically used to refer to the human beings harmed (or intended to be harmed) in an attack. In the context of manipulation of biological components, target may be used to refer to the intended outcomes of those manipulations. • Capability is typically used to refer to the ability for an actor to produce and use an agent (or in some contexts, the ability for a target to mitigate adverse outcomes). The assessments presented in the report focus on synthetic biology–enabled capabilities, that is, applications that may be enabled by the misuse of synthetic biology concepts, approaches, or tools. • Vulnerability refers to potential malicious capabilities against which we are not currently well protected. Vulnerabilities are a function of threat plus capabilities. Because the study did not include consideration of classified information about specific threats, specific actors, or specific capabilities within the U.S. government to address these threats, strictly speaking, it does not provide information on vulnerabilities but rather on potential vulnerabilities. Potential vulnerabilities are also referred to in the report as concerns. • Concern is the term used to capture the committee’s thinking regarding the defense implications of synthetic biology–enabled capabilities. Level of concern is used in reference to the relative intensity of the committee’s opinion regarding potential misuse. • Threat encompasses both an actor’s capability to cause harm and the actor’s intent to do so. Because the study did not include access to information on specific actors and their intent, the assessment produced is not a threat assessment per se. Rather, the report considers the types of malicious actions that could conceivably be taken and assesses the relative level of concern they pose. • Risk refers to the likelihood and severity of harm. Again, because intelligence information on aspects such as actor intent was not considered, the likelihood of harm cannot be fully estimated and the term risk is not used in reference to the assessments undertaken as part of this study. PREPUBLICATION COPY: UNCORRECTED PROOFS

Introduction 18 Organization of the Report The report begins with a discussion of synthetic biology and explores how synthetic biology approaches are changing what can be accomplished by biotechnology (chapter 2). The chapter highlights the fundamental Design-Build-Test cycle that characterizes a synthetic biology approach to problem solving. Appendix A discusses a number of concepts, approaches, and tools that are enabling continued progress in the field. Chapter 3 describes the development of the framework presented in the report and provides information on the approach used in applying this framework to assess potential biodefense concerns posed by synthetic biology capabilities. The following three chapters (4–6) discuss the results of the committee’s assessment of synthetic biology–enabled capabilities including the use of pathogens as weapons (chapter 4), the production of chemicals and biochemicals (chapter 5), and the creation of bioweapons that alter the human host (chapter 6). Chapter 7 discusses advances in related fields whose convergence with synthetic biology may impact the ability to misuse biotechnology to create weapons, such as by helping to overcome challenges in delivery, stability, or targeting of an agent. Chapter 8 discusses, from a broad perspective, some current approaches for mitigating concerns related to the malicious use of biotechnology, how synthetic biology may challenge those approaches, and conversely, how synthetic biology may help address challenges or bolster mitigation approaches. Finally, Chapter 9 summarizes the relative concerns posed by the analyzed synthetic biology- enabled capabilities, highlights examples of key bottlenecks and barriers to monitor, and provides the report’s conclusions and recommendations. 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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