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4 Assessment of Concerns Related to Pathogens
Pages 37-58

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From page 37...
... For example, such manipulations could potentially result in pathogens that have, in comparison to the original pathogen, increased virulence; antibiotic resistance; ability to produce toxins, chemicals, or biochemicals; or ability to evade known prophylactic or therapeutic modalities. Third, synthetic biology tools could be used to synthesize and boot entirely new organisms, potentially incorporating genetic material from multiple existing organisms (Zhang et al., 2016)
From page 38...
... Although all of the factors and elements identified in the framework were considered during the assessment, the discussion presented in these chapters focuses primarily on those elements deemed most salient to, or in some cases unique to, each capability. For each factor, the level of concern warranted for each capability relative to the other capabilities considered is presented at the end of the chapter along with a summary of the elements driving that relative level of concern.
From page 39...
... The assessment of concerns related to re-creating known pathogenic viruses is summarized here and described in detail below. Usability of the Usability as a Requirements Potential for Technology Weapon of Actors Mitigation   Level of concern for re-creating known pathogenic High Medium-high Medium Medium-low viruses Usability of the Technology (High Concern)
From page 40...
... . Assuming that an actor can identify a cell line in which the virus can be grown, smaller viral genomes would be, in general, easier to boot, whereas large viral genomes would present a greater challenge (see Figure 4-2)
From page 41...
... The level of concern with regard to usability as a weapon spans a wide range depending on a particular virus's natural tropism, virulence, environmental stability, and other such parameters. Production scale and delivery have long been considered key barriers to using existing viruses as weapons, based on knowledge of historical offensive biological weapons programs (Guillemin, 2006; Vogel, 2012)
From page 42...
... . Re-creating Known Pathogenic Bacteria The genomes of many existing bacteria have been characterized, and the same types of DNA synthesis and booting approaches used for large viral genomes can, in theory, be applied to re-create known pathogenic bacteria.
From page 43...
... As with synthesized viruses, the level of concern therefore depends on the bacterium's natural tropism, virulence, environmental stability, and other such parameters. As with viruses, scaling up production and delivery enough to use synthesized bacteria as a weapon of mass destruction would present substantial barriers compared to a smaller-scale attack, raising many classical weaponization issues such as environmental stability during mass dispersal.
From page 44...
... . The assessment of concerns related to making existing viruses more dangerous is summarized here and described in detail below.
From page 45...
... In experiments with echovirus 7, Atkinson and colleagues (2014) demonstrated that decreasing the CpG and UpA frequencies in two 1.1- to 1.3-kilobase regions of the viral genome enhanced viral replication in susceptible cells.
From page 46...
... . These viruses have mainly been developed in the context of, for example, improving adenovirus vectors to target specific tissues and as an approach to circumventing preexisting viral immunity that may limit the use of viral gene therapy vectors (Roberts et al., 2006)
From page 47...
... Lower immunity in hematopoietic stem cell transplant patients has been shown to result in widespread viral reactivation, sometimes life-threatening (Cavallo et al., 2013) , underscoring the potential impact of such approaches.
From page 48...
... Although this knowledge gap of how to engineer complex viral traits is likely to limit the ability to engineer viruses for enhanced bioweapons currently, it will be important to monitor for developments that significantly increase the ability to relate genotype to phenotype -- the knowledge of determinants of complex viral traits and how to engineer pathways to produce them. An added barrier is that introducing mutations into a viral genome almost invariably results in an attenuated (i.e., less pathogenic)
From page 49...
... Although the overall level of concern for this capability is medium with regard to the potential for mitigation, the concern level is higher for viruses with pandemic potential, such as influenza, for which a modified virus could present significant challenges in terms of measures to limit spread or reduce impact. Making Existing Bacteria More Dangerous As with viruses, an actor seeking to make an existing nonpathogenic bacterium pathogenic or to make an existing bacterial pathogen more dangerous would have many potential routes to consider.
From page 50...
... . Enhanced Toxin Production Many bacterial pathogens cause damage to host cells and tissues through the production of toxins.
From page 51...
... Extracellular bacterial pathogens are extremely adaptable to environmental challenges and may not require host-to-host contact for transmission, making these pathogens difficult to eradicate. In addition, many bacterial pathogens that replicate extracellularly are capable of causing damage to different cells and tissue types.
From page 52...
... Both intracellular and extracellular bacterial pathogens rely on adherins and colonizing factors to facilitate contact with host target cells (Ribet and Cossart, 2015)
From page 53...
... As discussed in the context of re-creating known pathogens, the Select Agents list and voluntary screening guidelines are not likely to be sufficient to deter or prevent the development of modified bacterial pathogens. In terms of consequence management, one fundamental difference between responding to a naturally occurring new organism that has unique characteristics and responding to a modified bacterial pathogen that is a purposefully deployed biological weapon is a calculating adversary.
From page 54...
... In some cases, genetic circuits could be delivered to a small number of host cells using nonreplicating delivery mechanisms, which could be either virus-derived, such as those used in some gene therapies (see Chapter 7, Gene Therapy) , or based on nonbiological materials.
From page 55...
... The assessment of concerns related to creating new pathogens is summarized here and described in detail below. Usability of the Usability as a Requirements of Potential for Technology Weapon Actors Mitigation Level of concern for creating new pathogens Low Medium-high Low Medium-high Usability of the Technology (Low Concern)
From page 56...
... Such features could include, for example, the ability to target specific tissues or cell types using genetic logic, or the ability to produce aberrant neurological effects. Similarly, such pathogens could employ novel timing mechanisms, creating a delay between the time of exposure and the onset of symptoms.
From page 57...
... However, two developments could increase the level of concern. If techniques using yeast were to make it far more feasible to boot synthesized bacterial genomes, or if a breakthrough makes it easier to handle large DNA fragments without shearing, the re-creation of bacterial pathogens might warrant increased concern.
From page 58...
... 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. and the same techniques and knowledge base would likely prove useful for modifications pursued with a more nefarious intent.


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