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Biodefense in the Age of Synthetic Biology (2018)

Chapter: 9 Moving Forward: Conclusions and Recommendations

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Suggested Citation:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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:"9 Moving Forward: Conclusions and Recommendations." 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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9 Moving Forward: Conclusions and Recommendations The age of synthetic biology has brought with it opportunities to transform approaches to treating disease, manufacturing chemicals, producing fuels, remediating contaminants, and numerous other applications with benefits to humankind. Some synthetic biology capabilities, however, have dual use potential—that is, they can be misdirected to cause harm to humans, animals, plants, and the environment. This study focuses on the potential for such biotechnologies to be used to attack the U.S. military or the American people and assesses the level of concern warranted on the part of the U.S. Department of Defense and others responsible for protecting public health and national security. The study’s deliberative process included the identification of concepts, approaches, and tools that comprise biotechnology in the age of synthetic biology, the identification of specific capabilities an adversary might potentially gain from the misapplication of synthetic biology, and the development of a framework to guide an assessment of concerns related to these capabilities. This approach was used to provide structure and transparency without being overly prescriptive. The framework was then applied to analyze the state of the art of the technology involved in each capability, the feasibility of using the capability to produce an effective weapon, and the characteristics and resources an actor would require to carry out an attack. After accounting for, in a less in-depth way, proactive and reactive measures that could be taken to mitigate attacks, an overall level of concern was determined for each capability relative to the other capabilities considered. Recognizing that future advances in knowledge or technology may increase the feasibility or impacts of some capabilities and thus raise the level of concern warranted, potential developments were identified that should be monitored and otherwise considered going forward. Although its primary focus was on the specific capabilities analyzed, the study was carried out with an eye toward the broader backdrop of the history and structures of biological sciences and technology, national defense, and public health in the United States. The misuse of biological sciences to develop biological weapons predates the advent of synthetic biology. A wide range of malicious actors have used or sought to use bioweapons and chemical weapons, including national governments, small groups or cults, and even individuals. Fortunately, actual use of biological weapons has been rare. While there is considerable disagreement among experts about why misuse of biology has been rare, or if it is likely to always remain rare, synthetic biology has the potential to change the likelihood and consequences of misuse. Though important for myriad beneficial applications, synthetic biology and related biotechnologies change the defense landscape by making possible new modes of attack and by lowering the barriers to developing and using biological weapons (and to some extent chemical weapons), potentially putting bioweapons within the reach of less-resourced actors. The United States’ approach to biodefense was not designed to counter all the types of weapons (or types of adversaries) that are now possible in the age of synthetic biology. One motivation for this report 142 PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 143 is to help inform the U.S. defense agencies’ efforts to update their approach to biodefense in order to detect and respond to these new threats. On the positive side, it is expected that synthetic biology and other technologies will enable the development of new methods for detecting biological anomalies, new diagnostic tools, and new therapeutics—developments that could complement and bolster existing biodefense tools. Since 2001, the United States has significantly expanded efforts to counter biological threats, in particular those related to the use of known pathogens to create bioweapons. Among other accomplishments, a multi-pronged approach has been developed to acquire medical countermeasures, develop a stockpile system for those countermeasures, boost security and safety in the handling of pathogens, and coordinate a response to a biological weapons attack. Given the complicated nature of the biological weapons threat, however, it is not possible to be fully prepared for every contingency. Many pathogens that could be used to create weapons are widely accessible in laboratories around the world and in natural reservoirs such as infected people or animals. The amount of infectious material needed as a seed-stock for a weapon is minute, as it is possible to grow a few bacterial cells into quantities capable of effecting a large- scale attack. Furthermore, the infrastructure and laboratory training needed to develop a biological weapon using a known pathogen are dual use and relatively accessible. The age of synthetic biology adds to these significant challenges. While the existing U.S. biodefense system is designed to defend against specific, naturally occurring pathogens, synthetic biology makes possible the creation of new or altered pathogens, as well as new types of biological weapons, and the relevant technologies are generally accessible all over the world. Synthetic biology also increases the overlap between biological and chemical weapons by enabling the use of biological components to make or deliver chemical agents. In determining how to plan for and respond to these evolving capabilities, defense and public health agencies are challenged to consider these newer threats alongside other risks such as traditional biological weapons threats, threats to national security and stability from naturally occurring biological threats (such as pandemics), and threats related to explosives and nuclear, chemical, and radiological weapons. In resource-constrained environments, users of the framework and assessments presented in this report will need to bear in mind this backdrop of risk in determining how biological threats fit into the broader threat landscape. Comparing the risks related to synthetic biology to those related to these other types of threats was not within the scope of this study. 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. PREPUBLICATION COPY: UNCORRECTED PROOFS

144 Biodefense in the Age of Synthetic Biology CONCERNS POSED BY SYNTHETIC BIOLOGY–ENABLED CAPABILITIES The study identified 12 distinct capabilities—ways in which an adversary could potentially pursue an attack using synthetic biology—and grouped these capabilities into three major categories: concerns related to pathogens, concerns related to the production of chemicals or biochemicals, and concerns related to bioweapons that alter the human host. Each capability was analyzed individually, trends and key considerations were identified within each grouping, and each capability was ranked in relation to the other capabilities to determine an overall assessment of concerns. Developments that might affect capabilities and concerns in the future were also considered. Overall Assessment of Concerns Figure 9-1 presents a relative ranking of concerns related to the synthetic biology–enabled capabilities that were analyzed. This ranking was generated through an iterative discussion of four factors that increase or decrease the likelihood or impact of an attack—Usability of the Technology, Usability as a Weapon, Requirements of Actors, and Potential for Mitigation—for each capability as compared to the other capabilities. As discussed in chapter 3 (Applying the Framework in the Assessment of Concern), this assessment is based on a holistic view of the factors and capabilities assessed and is not a formulaic approach. Table 9-1 summarizes the assessment of the specific factors considered when analyzing the individual capabilities and Figure 9-2 shows the relative concern for each capability, organized by factor. While the ranking of concerns has a strong foundation based on the expertise of the committee members and the breadth and depth of the committee’s discussions, there are a few important limitations to note. One is that the study process did not involve accessing intelligence or other classified information. The study also did not consider information related to the capabilities or intents of specific adversaries. Others may use such information, along with details about government programs aimed at deterring, detecting, attributing, and addressing the consequences of biological attacks, to complement and expand upon this report’s analysis. Likewise, additional details about potential mitigation options could be used to expand upon the report’s analysis. In addition, there was no attempt to weigh the likelihood that an actor would choose to use synthetic biology instead of a more “traditional” approach when pursuing an outcome that could be achieved with or without synthetic biology. For example, an actor seeking to deploy a known pathogen in an attack could acquire the pathogen by re-creating it using synthetic biology or by stealing existing cultures of the pathogen from a legitimate research laboratory. Similarly, an actor seeking to acquire a given chemical or toxin may choose to engineer a microbe to produce it or may produce it through traditional chemical synthesis. In such cases, determining which method is more likely would require information about an actor’s intentions, resources, and capabilities, which was beyond the scope of this study. The rankings are therefore agnostic to the availability of these alternate routes and are based solely on the capabilities that synthetic biology provides to an actor. It also follows that as technologies advance, an actor’s proclivity to pursue a given route may change. PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 145 FIGURE 9-1 Relative ranking of concerns related to the synthetic biology–enabled capabilities analyzed. NOTE: At the present time, capabilities toward the top warrant a relatively high level of concern while capabilities toward the bottom warrant a relatively low level of concern. PREPUBLICATION COPY: UNCORRECTED PROOFS

146 Biodefense in the Age of Synthetic Biology TABLE 9-1 Relative level of concern related to each factor for each capability considered. Usability of Usability as a Requirements Potential for the Weapon of Actors Mitigation Technology Medium- Level of concern for re-creating High Medium Medium-low high known pathogenic viruses (chapter 4) Level of concern for re-creating known pathogenic bacteria (chapter Low Medium Low Medium-low 4) Medium- Level of concern for making existing Medium-low high Medium Medium viruses more dangerous (chapter 4) Level of concern for making existing High Medium Medium Medium bacteria more dangerous (chapter 4) Medium- Medium- Level of concern for creating new Low Low high high pathogens (chapter 4) Level of concern for manufacturing chemicals or biochemicals by Medium- High High Medium exploiting natural metabolic pathways high (chapter 5) Level of concern for manufacturing chemicals or biochemicals by Medium- Medium-low High Medium-low creating novel metabolic pathways high (chapter 5) Level of concern for making Medium- chemicals or biochemicals via in situ Medium Medium High high synthesis (chapter 5) Medium- Level of concern for modifying the Medium-low Medium Medium high human microbiome (chapter 6) Level of concern for modifying the Medium Medium-low Low High human immune system (chapter 6) Level of concern for modifying the Medium-low Low Medium-low High human genome (chapter 6) Level of concern for modifying the Low human genome using human gene drives (chapter 6) PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 147 FIGURE 9-2 Relative level of concern related to each factor for each capability considered. NOTE: Coloring indicates the chapter in which the assessment for each capability is presented: chapter 4 (orange), chapter 5 (blue), or chapter 6 (green). PREPUBLICATION COPY: UNCORRECTED PROOFS

148 Biodefense in the Age of Synthetic Biology The capabilities were ranked in relation to each other and grouped into five major levels of concern, relative to each other. There was no attempt to quantify the relative levels of concern; as such, the dividing lines within Figure 9-1 are not intended to indicate that one capability poses twice (or any numerical multiple of) the level of concern compared to the capability below it. In addition, the grouping of two capabilities into the same category of concern does not indicate those capabilities are identical in terms of the factors considered or the relative values placed on those factors. For example, re-creating known pathogenic bacteria and creating new pathogens are associated with a similar overall level of concern, but for different reasons. Finally, it is important to note that this assessment represents a snapshot in time and represents the range of concern associated with each capability, with particular exceptions or special cases noted in chapters 4–6, and will change as knowledge and technologies advance. Capabilities currently warranting the highest relative level of concern include re-creating known pathogenic viruses, making biochemicals 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. The ability to mitigate attacks related to these capabilities would depend on the effectiveness of existing countermeasures, such as antibiotics or vaccines, toward the agents used. Capabilities posing a moderate-to-high relative level of concern include manufacturing chemicals or biochemicals by exploiting natural metabolic pathways and making 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. For example, while viral genomes are easily manipulated on a molecular basis, constraints on what types of change those genomes can accommodate limit capability in this area. Similarly, at the present time it takes a fair amount of skill to engineer a bacterium to express a pathway to efficiently produce a chemical or biochemical. While both capabilities are considered to be in the same grouping, modifying viral characteristics intentionally using rational design remains a substantial challenge, making the modification of an existing virus slightly less concerning at the present time. Similar to the capabilities in the top category of relative concern, mitigation options for these capabilities depend largely on existing infrastructure. 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—likely limited by available knowledge and technology, as described in Chapters 5 and 6. However, there are significant PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 149 forces driving rapid advancement in all of these areas. Manufacturing chemicals or biochemicals by creating novel metabolic pathways was placed highest in this grouping because once a synthesis pathway for a chemical or biochemical is known, the tools for engineering a bacterial (or other) cell to produce it are fairly well developed. While the detailed pathways by which certain chemicals may be synthesized in a biological organism are not yet known, commercial applications are driving progress in this area. The modification of the human microbiome is placed next in this grouping. While current understanding of the complex and dynamic system that is our microbiome is relatively low, there are significant efforts to increase this knowledge because of the desire to modulate the microbiome to improve human health. Modification of the immune system and modification of the human genome are the third and fourth capabilities in this grouping, largely due to the limits of available knowledge related to the mechanisms of action and means of delivery that would be involved in developing and using bioweapons based on these capabilities. However, these areas are also being vigorously pursued because of clear biomedical applications. Capabilities warranting a lower relative level of concern include re-creating known pathogenic bacteria and creating new pathogens. These capabilities involve major challenges from the standpoint of both design and implementation. In particular, while the technology for synthesizing and assembling larger segments of DNA continues to advance, the synthesis of bacteria is currently limited by constraints on synthesizing, manipulating, and booting an entire bacterial genome. In addition, antibiotics and other therapeutics are available to counter many bacterial pathogens. Constructing a totally novel pathogen has tremendous challenges. If it is difficult to build a known bacterium, it is all the more challenging to design one from scratch. In this regard, an actor may decide to try to design a virus, but in this case one would be working against the large barrier of evolutionary constraints created by hundreds of millions of years of co-evolution between viruses and their hosts. That said, combinatorial approaches could enable the exploration of sequence space that nature has not yet achieved. The use of human gene drives warrants a minimal level of concern because it would be impractical to rely on sexual reproduction for a gene drive to spread through a human population. In addition to the relative level of concern posed by individual capabilities, the study included consideration of how two or more capabilities may be used in combination. Such an approach could create synergies that result in either a more dangerous weapon or using one capability to overcome barriers that currently hinder another capability. For example, a pathway for the production of a toxin could potentially be implanted in the human microbiome, an “intersectional” approach considered to warrant a high level of concern. Similarly, particular genes or RNA molecules that modulate the immune system could potentially be mounted on a virus to lead to greater harm than either the genes or the virus would on their own. Going forward, it will be important to continue to consider how scientific and technological advances may synergize to improve existing approaches or create novel ones. Assessment of Specific Types of Capabilities The assessment of overall concerns draws upon the analysis of each of the 12 specific capabilities considered. In addition to conclusions related to the relative assessment of concerns, underlying themes and conclusions emerged when each individual capability was examined in the context of other capabilities in the same category (e.g., when assessing all approaches that PREPUBLICATION COPY: UNCORRECTED PROOFS

150 Biodefense in the Age of Synthetic Biology involve pathogens). Underlying themes and conclusions related to pathogens, the production of chemicals or biochemicals, and bioweapons that alter the human host are discussed below. Pathogens Chapter 4 focuses on the use of biotechnology to create pathogenic agents, including the possibility of re-creating known pathogens, modifying both pathogenic and nonpathogenic microbes to enhance their capability to cause harm, and creating new pathogens. Rapid advances in DNA synthesis technology have made it possible to obtain a pathogen without direct access to the infectious agent itself. Today, any viral genome can be synthesized based on published sequences, and booting that sequence into a replicating form is also feasible for most viruses. Similar approaches to creating bacteria are currently more difficult due to the size of their genomes and the fact that they are living organisms and not obligate intracellular parasites like viruses, though these technical bottlenecks will likely be reduced over time. Because known pathogens have been studied extensively, and because the existence (or lack) of medical countermeasures is also known, there is a relatively high level of confidence in assigning relative levels of concern to the re-creation of known viruses and bacteria. For example, it is currently easier to re-create a virus than a bacterium in the laboratory, though prophylactics and therapeutics against these agents sometimes, but not always, mitigate the level of concern. The technologies to manipulate microbial genomes to add new phenotypes such as drug resistance have been available for decades and continue to be made simpler. Here again, there are differences in the feasibility of applying these approaches to bacteria and viruses; while adding genes to bacteria does not usually significantly affect the ability of the bacteria to grow and divide, the way viral genomes have evolved makes them more sensitive to changes, such that altering viral genomes often reduces their virulence and replication abilities. Generally speaking, phenotypic modifications to pathogens may lessen the capability for mitigation. One notable example is adding antibiotic resistance to bacteria or adding antiviral resistance to those few viruses for which antivirals they exist. Engineering bacteria or viruses to resist existing therapeutics would likely be relatively straightforward to accomplish and could seriously undermine the ability to mitigate an attack by treating infected individuals. Production of Chemicals or Biochemicals As discussed in chapter 5, engineering organisms to produce chemicals or biochemicals is becoming more feasible as researchers learn more about the natural pathways used to produce these substances and as better tools are developed to build predictable synthetic pathways. Just as drug resistance can be engineered into bacteria, so can simple or even complex biosynthetic pathways. This capability is being driven largely by a desire to use biotechnology to produce useful molecules, but can be subverted by those with malicious intent. The commercial drivers behind these approaches will certainly widen the bottlenecks over time. Moreover, combinatorial approaches and the use of computer algorithms to aid in pathway design will bring down barriers to building new synthetic pathways. PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 151 Mitigation of attacks based on these modified organisms could be difficult to achieve. Currently, when presented with the signs of a chemical attack, first responders and medical professionals are not trained to suspect that the chemical was produced or delivered biologically. Similarly, having a bacterium that normally does not produce a toxin act as the delivery vehicle for that toxin could thwart existing diagnostic tests.13 Therefore, while at present there are barriers to effectively developing these capabilities, the potential deficiencies in mitigation raise the level of concern. Bioweapons that Alter the Human Host Chapter 6 focuses on the possible vulnerabilities and means of attack that are more closely related to the human body itself. Here, one focus was on engineering the microbiomes of the gut, skin, oral cavity, or nasopharyngeal space. Such manipulations could be used to, for example, directly affect the function of the gastrointestinal tract or the skin, cause dysbiosis, or even potentially affect other aspects of human physiology such as the immune or nervous systems. If such manipulations can be achieved, the level of concern would be high because the opportunities for mitigation could be quite limited. The detailed interactions that occur in the microbiome environment are being studied intensively, and knowledge in this area is constantly increasing. The study also included consideration of approaches that could potentially be used to modify the human immune system by inducing immune suppression or hyperreactivity or by using immunosuppressive agents in combination with existing pathogens. Potential approaches that use genes or RNAs as weapons, use genome editing, or use human gene drives were also considered. In general, these approaches pose a lower level of concern with respect to the technologies, actors’ capabilities, and organizational footprints, because of the uncertainties associated with obtaining a useful weapon given the immature state of these areas of research. However, due to the novelty of these approaches, it is possible that if such approaches were used successfully, options for mitigation could be fairly limited, thus somewhat increasing the level of concern. The notable exception to these concerns is the use of human gene drives to alter the human genome. Because gene drives require sexual reproduction to spread, it would be exceedingly difficult to affect change to large populations of humans without waiting many, many generations. This capability was therefore placed in the lowest level of concern. It is noted, however, that using gene drives to alter other organisms such as mosquito vectors, in an effort to improve their ability to transmit pathogens (or to broaden the list of pathogens they can transmit) may become a concern as more is learned about the interactions between pathogens and insect vectors. 13 Depending on the site or type of infection, diagnostics are often based on species identification, and therefore the presence of a toxin might be missed if the species is not one that normally produces a toxin. PREPUBLICATION COPY: UNCORRECTED PROOFS

152 Biodefense in the Age of Synthetic Biology Potential Developments to Monitor This report’s analysis necessarily reflects a snapshot in time, given understanding of current technologies and capabilities. As knowledge and biotechnology continue to evolve, it can be expected that current bottlenecks will open and current barriers will be broken. To consider how such developments might affect biodefense concerns, key bottlenecks and barriers were identified that, if overcome, could substantially increase the feasibility or impact of a potential attack and thus increase the level of concern warranted. It is impossible to predict precisely when the next fundamental breakthrough in technology with wide-ranging applications (and implications), akin to PCR tools or the gene editing platform CRISPR/Cas9, will arise or even what that technology might be. Such developments are influenced by the drivers of commercial and academic research, as well as by possible converging or synergistic technologies that may come from outside the field of synthetic biology. The use of a framework such as the one presented in this report facilitates the identification of bottlenecks and barriers, as well as the ability to recognize when bottlenecks and barriers have been overcome, by identifying the types of technological capabilities that would facilitate the production and use of synthetic biology- enabled bioweapons. A summary of key bottlenecks and barriers and areas worth monitoring is provided in Table 9-2. Based on knowledge of the synthetic biology field, the table notes areas of commercial activity that could speed the process toward overcoming these bottlenecks and barriers. PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 153 TABLE 9-2 Bottlenecks and barriers that currently constrain the capabilities considered, along with developments that could reduce these constraints in the future. NOTE: 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 (chapter 4) Re-creating known DNA synthesis and Improvements in synthesis and assembly technology pathogenic bacteria assembly for handling larger DNA constructs (chapter 4) 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 (chapter 4) capable of facilitating larger-scale modifications to viral genome Engineering complex Increased knowledge of determinants of complex viral traits viral traits, as well as how to engineer pathways to produce them Making existing Engineering complex Advances in combinatorial approaches and/or bacteria more bacterial traits increased knowledge of determinants of complex dangerous (chapter 4) bacterial traits, as well as how to engineer pathways to produce them Creating new Limited knowledge Increased knowledge of requirements for viability in pathogens (chapter 4) 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 Pathway elucidation, improvements in circuit design, chemicals or to the host organism and improvements in host (“chassis”) engineering to biochemicals by synthesizing the toxin PREPUBLICATION COPY: UNCORRECTED PROOFS

154 Biodefense in the Age of Synthetic Biology exploiting natural make toxins tolerable to the host organism metabolic pathways synthesizing the toxin (chapter 5) Pathway not known Pathway elucidation and/or demonstrations of combinatorial approaches Challenges to large- Improvements in intracellular and industrial scale production productivity Manufacturing Tolerability of toxins Pathway elucidation and/or improvements in circuit chemicals or to 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 (chapter 5) 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 (chapter 5) genetic elements, and other relationships between microbiome organisms and host processes Modifying the human Limited understanding Improvements in knowledge related to microbiome microbiome (chapter of microbiome colonization of host, in situ horizontal transfer of 6) genetic elements, and other relationships between microbiome organisms and host processes Modifying the human Engineering of Increased knowledge related to the potential for immune system delivery system viruses or microbes to deliver immunomodulatory (chapter 6) 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 genome (chapter 6) horizontal transfer alter the human genome through horizontal transfer of genetic information PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 155 Lack of knowledge Increased knowledge related to regulation of human about regulation of gene expression human gene expression Conclusions and recommendations were developed based on the analysis of individual synthetic biology-enabled capabilities, the holistic assessment of relative levels of concern for all capabilities considered, and identification of bottlenecks and barriers that, if overcome, could affect the level of concern in the future. Conclusions and Recommendations: 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

156 Biodefense in the Age of Synthetic Biology 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 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. FUTURE USE OF THE FRAMEWORK A framework that can be both relatively straightforward and enduring in its utility is valuable. There are many different types of frameworks that have been applied to issues related to the misuse of biological agents, each of which has its advantages and disadvantages. The framework presented in this report specifies a process to facilitate the consideration of expert opinions regarding the level of concern about specific synthetic biology–enabled capabilities or combinations of capabilities. The subjective nature of the framework requires that its users have familiarity with the field of biotechnology and, as appropriate, that domain experts are enlisted to provide and evaluate pertinent data and fill in any gaps in expertise. The technical depth and breadth of this study committee, along with the processes used to facilitate its discussions, helped to provide a thorough assessment while preventing individual perspectives from dominating the discussions. Nonetheless, there are limitations to the framework’s use in the context of this study. Specifically, the study task did not include consideration of intelligence information about the intents or capabilities of potential actors who may seek to misuse life sciences, nor did it include a comprehensive analysis of the U.S. government’s capabilities related to preparedness for and mitigation of attacks. Therefore, this report does not represent a threat assessment. By combining this report’s assessment of concern with intelligence and other information, others could, in the future, assess vulnerabilities and risks to inform decision making. Conclusions and Recommendations: A Framework for Assessing Concern Contributes to Planning The DoD 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. PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 157 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). BIODEFENSE IMPLICATIONS OF THE AGE OF SYNTHETIC BIOLOGY It has been stated on numerous occasions, by both scientific and political leaders, that the 21st century is the century of the life sciences (NRC report: Serving Science and Security in the New Millennium, 1998; Ted Kennedy, Congressional Record, June 29, 2000). Much of the excitement and anticipation comes from the promise that advances in biotechnology offer to society. But, as with previous expansions in technological capabilities, the potential for benefit also comes along with potential risks that the technology could be misused to cause harm. It is therefore wise 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. Approaches modeled after those taken to counter Cold War threats are not sufficient for biological and biologically-enabled chemical weapons in the age of synthetic biology. On the other hand, the nation’s experience preparing for naturally occurring diseases provides a strong foundation to build upon in developing strategies to prevent and respond to emerging biological threats and biologically-enabled chemical threats. While this study does not constitute a threat assessment and does not make specific recommendations regarding addressing current vulnerabilities, several areas were identified that warrant attention as the nation seeks to bolster its preparedness and defense capabilities. Conclusions and Recommendations: A Range of Strategies Is Needed to Prepare and Respond 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 to 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 PREPUBLICATION COPY: UNCORRECTED PROOFS

158 Biodefense in the Age of Synthetic Biology 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 Although it was outside the scope of this study to comprehensively assess the preparedness and response capabilities of existing military and civilian defense and public health enterprises or determine how to address gaps, 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. A great deal of the scientific knowledge, materials, and techniques required for beneficial biological research or development could be misused. It is extremely challenging to prevent this, however, because the scientific community relies upon access to publications, genetic sequences, and biological materials to advance the state of science and, importantly, to reproduce the results PREPUBLICATION COPY: UNCORRECTED PROOFS

Moving Forward: Conclusions and Recommendations 159 of others to verify findings and build upon them. Biotechnology presents a “dual use dilemma” (NRC, 2004), and synthetic biology is part of this dilemma. While dual use research is going to 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 risk 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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