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A Proposed Framework for Identifying Potential Biodefense Vulnerabilities Posed by SyntheticBiology: Interim Report
Pages 1-34

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From page 1...
... This interim report proposes a framework for identifying and prioritizing potential areas of concern associated with synthetic biology -- a tool to aid the consideration of concerns related to synthetic biology. The framework describes categories of synthetic biology technologies and applications -- such as genome editing, directed evolution, and automated biological design -- and provides a set of initial questions to guide the assessment of concern related to these technologies and applications.
From page 2...
... To that end, the U.S. Department of Defense, working with other agencies involved in biodefense, asked the National Academies to develop a framework to guide an assessment of the security concerns related to advances in synthetic biology, to assess the level of concern warranted for various advances and identify areas of vulnerability, and to prioritize options to address these vulnerabilities.
From page 3...
... . The committee then defined what type of framework would best guide an assessment of concerns related to synthetic biology, identified major categories of relevant technologies and applications to assess, and refined the factors to include in the assessment.
From page 4...
... Biotechnology and Synthetic Biology Biotechnology is a broad term encompassing the application of biological components or processes to advance human purposes. Although the term itself is thought to have been in use for only about a century, humans have used various forms of biotechnology for millennia.
From page 5...
... Synthetic Biology in the Context of Biodefense In its Phase 1 activities, the committee was tasked with developing a tool or process for assessing the biodefense threat in the age of synthetic biology. While the committee avoided rigidly defining synthetic biology, its deliberations were guided by the biodefense-relevant aspects of synthetic biology as outlined in the study's Statement of Task, namely "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, or purposely weakening a person's immune system are just a few examples of the potential types of malicious uses of synthetic biology the committee considered under this guidance.
From page 6...
... Approach to Developing the Framework The committee drew from a substantial amount of existing work related to the question of how to assess security concerns, and this framework is intended to build upon that work, not replace it. A number of frameworks have been developed to assess concerns associated with emerging technologies (IOM/NRC 2006; Tucker 2012)
From page 7...
... Additional work has focused on assessing concern associated with particular types of experimentation; some elements of these frameworks can also be applicable to a broader set of concerns about technologies with potential beneficial and harmful uses. In the realm of security, scenario-based frameworks are commonly used to assess concerns and consider potential mitigation options.
From page 8...
... Uses and Limitations of the Framework The committee designed its framework as a tool to aid the consideration of concerns related to biotechnology and synthetic biology. It is intended to be flexible enough to be applied in a variety of circumstances and for a variety of purposes, such as: analyzing existing biotechnologies to evaluate the level of concern warranted at present; understanding how various technologies or capabilities compare to, interact with, or complement each other in terms of their level of concern; identifying key bottlenecks and barriers that, if removed, could lead to a change in the level of concern; evaluating the change in the level of concern warranted when new experimental results are reported or new technologies arise; and horizon scanning to predict or prepare for potential future areas of concern.
From page 9...
... Rather, the committee developed the table as a means to help conceptualize the issues that need to be considered, and in particular to encourage those who may use the framework in the future to consider factors related to categories including the use of technology, attributes of actors, and the capability to recognize an attack. Some specific factors within those categories may not apply to a given technology or application, and therefore, it may not be necessary to analyze each row-column intersection (cell)
From page 10...
... ROWS IN THE FRAMEWORK: TECHNOLOGIES AND APPLICATIONS TO ASSESS The committee was charged with creating a framework to guide an assessment of the potential security vulnerabilities related to advances in biology and biotechnology, with a particular emphasis on synthetic biology. To reflect the array of biotechnologies that might be considered as part of such an assessment, the committee found it useful to approach synthetic biology technologies and applications from the standpoint of their role in the DBT cycle (see Figure 2)
From page 11...
... Similarly, synergies may arise if large-scale Test technologies are developed to match the enormous output of certain Build technologies, thus helping those Build technologies reach their full potential. It is also possible, even probable, that some technologies or approaches will have impacts across multiple phases of the DBT cycle; one such example may be directed evolution, where repeated passage in a model host or in cell cultures under stress permits nature to Design, Build, and Test new phenotypes.
From page 12...
... The committee takes a broad view of Design to include both design-enabling technologies and design objectives; as such, this grouping includes both synthetic biology technologies and examples of the types of applications they might enable. Automated Biological Design Engineering biological components can be a challenging proposition; organisms are complex, and scientific understanding of biology remains incomplete.
From page 13...
... This allows for higher levels of design abstraction and the use of standards to exchange information globally between software frameworks. In addition to aiding biological design, automation tools are used in other phases of the DBT cycle.
From page 14...
... In parallel, the rise of DNA construction and genome editing technologies could facilitate the construction of multiple variants that involve alterations to multiple genes across an organism. By applying high-throughput screening or selection to these variant libraries, it may be possible to isolate pathogens with dramatically modified phenotypes relevant to their potential weaponization, such as environmental stability, resistance to desiccation, and ability to be mass produced and dispersed.
From page 15...
... Build Technologies and applications most closely aligned with the Build phase of the DBT cycle are those that are used to physically create actual biological components. Synthetic biology is often pursued 15
From page 16...
... Factors that may impact the level of concern related to Build capabilities include cost, time, and ease of access for DNA construction; the complexity of libraries that can be generated for directed evolution; and the difficulties inherent in rendering the DNA "operable" (that is, the ability to create a synthetic DNA sequence that actually functions within a living system)
From page 17...
... Most genes range from a few hundred to a few thousand base pairs in length. Synthetic genes are available commercially as either cloned DNA (in which the product is verified as correct and pure, and typically delivered as part of a general circular plasmid DNA vector)
From page 18...
... coli and the work required to adapt MAGE to a new species may prove cumbersome. In contrast, recombineering and CRISPR/Cas9-based technologies may allow engineering in many new species, providing convenient paths to the further identification of altered phenotypes via either high-throughput screening or directed evolution of organisms with radically new phenotypes and genome-wide sequence changes.
From page 19...
... The process of inducing raw genetic material to perform biological functions is known as "booting," a term borrowed from computer technology, where booting refers to the ability to execute functions on digital information by taking it out of storage and putting it into an active state. Booting a synthetic construct is most relevant to the Build and Test phases of the DBT cycle.
From page 20...
... Prototypes can vary based on smaller changes -- different DNA bases, codons, or amino acids, for example -- or based on larger-scale differences such as the configuration of multiple genes within a genetic circuit. Like automated biological design, directed evolution is a synthetic biology technique that spans all three phases of the DBT cycle.
From page 21...
... . The most promising variants that emerge can be refined further through additional iterations of rational design or selection, following the DBT cycle.
From page 22...
... Although not all questions will apply in every case, the following questions can help guide an assessment of the ease of use for a given technology and a particular use under consideration: • How long is the oligo/gene/cassette/genome involved? • If an entire genome is being created, how easy is it to assemble?
From page 23...
... The engineering of plants to produce raw or finished chemical products is another area that is maturing rapidly. Assessing the degree to which the rate of development affects the level of concern warranted for a given use of technology should include consideration of both the pace of the technology's evolution and the speed with which it is being adopted.
From page 24...
... Barriers to Use It is also important to consider the presence of significant bottlenecks and barriers, which can lower the likelihood that a technology will be used. For example, key gaps in one aspect of the DBT cycle, such as design knowledge, can significantly limit the potential for malicious use of a given technology and consequently lower the level of concern related to Build capabilities for that technology.
From page 25...
... It is also useful to consider how a breakthrough in one aspect of the DBT cycle might synergize with capabilities in the other aspects; for example, limitations in design knowledge may hinder the full exploitation of certain Build or Test technologies, but if that limitation is overcome, the newly available tools may combine with existing capabilities to enable applications that were not previously achievable. Cost Technologies that cost more to acquire or use will affect who is able to use them.
From page 26...
... All of these factors could potentially reduce or eliminate barriers that previously were thought to hinder the use of bioweapons. The following types of questions can be used to assess the impact of synthetic biology on the production, stabilization, and delivery of weaponized biological agents for a variety of potential malicious uses.
From page 27...
... The following questions, developed with consideration of factors described in the World Health Organization's R&D Blueprint for Action to Prevent Epidemics (WHO 2016) , can help to describe the potential scope of casualty when considering the potential impacts of an attack using a given technology or application.
From page 28...
... Agents with predictable genotype-phenotype relationships may also require fewer resources to deploy, since it may not be necessary to test multiple genotypes to obtain the desired phenotype. The following questions can help to describe the predictability of result for a given technology or application: • Does the agent need to be tested extensively to confirm that it is efficacious?
From page 29...
... The following questions, which also relate to ease of use (addressed in the section titled Ease of Use) and organizational footprint (addressed in the section titled Organizational Footprint Requirements)
From page 30...
... Considering the organizational footprint that would be required to effect a given type of attack can shed light on the relative importance of other actor attributes, such as access to resources. Organizational footprint also impacts considerations related to mitigation capabilities (discussed in the sections titled Capability to Recognize an Attack and Attribution Capabilities)
From page 31...
... For example, by limiting access to certain pathogens, Select Agent rules are intended to help prevent those pathogens from falling into the hands of malicious actors who might seek to use them as a weapon. In addition, activities such as intelligence gathering can contribute to deterrence and prevention by increasing the capacity to identify suspicious activities and intervene before an attack takes place, or to catch and punish an actor after an attack has occurred, as discussed under Capability to Recognize an Attack and Attribution Capabilities.
From page 32...
... The following questions can guide an assessment of how a given technology or application might change the landscape of options for surveillance and detection: • To what degree can beneficial and malicious use of this technology be distinguished? • Are there particular activities or equipment associated with this technology that may indicate when it is being used to prepare for an attack?
From page 33...
... CONCLUSION Advancements in biotechnology in the 21st century, facilitated by approaches under the rubric of synthetic biology, have the potential to complicate the landscape of possible uses of biological agents to cause harm. In this Phase 1 part of its study, the Committee on Strategies for Identifying and Addressing Biodefense Vulnerabilities Posed by Synthetic Biology assembled a proposed framework that can be used to determine potential concerns posed by these advancements and to inform the identification of vulnerabilities and potential options for mitigation.
From page 34...
... Department of Defense with an assessment of the concerns presented by synthetic biology technologies and applications, as well as the possibilities for mitigation, by considering the factors presented here and developing informed answers to questions such as those posed in this interim report.


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