Biodefense in the Age of Synthetic Biology (2018) / Chapter Skim
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5 Assessment of Concerns Related to Production of Chemicals or Biochemicals
5 Assessment of Concerns Related to Production of Chemicals or Biochemicals
Pages 59-70
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From page 59... ...
As the field of synthetic biology endeavors to "improve the process of genetic engineering" (Voigt, 2012) , there is a concerted effort across the metabolic engineering community to demonstrate the biological production of increasingly complex molecules while simultaneously developing tools and approaches that reduce the resources required to achieve specific production metrics (e.g., titer, rate, and yield)
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From page 60... ...
Considerations in the Design stage may include choice of the host organism, modeling to predict metabolic pathway performance, and bioprospecting for appropriate enzymes to produce the desired product. Multiple rounds of the Design-Build-Test cycle are represented.
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From page 61... ...
Considering the different types of potential target compounds and the different ways synthetic biology technologies might be exploited to produce them, three main types of activity were identified that are of potential concern: manufacturing chemicals or biochemicals by exploiting natural metabolic pathways, manufacturing chemicals or biochemicals by creating novel metabolic pathways, and making biochemicals via in situ synthesis of target compounds. This chapter assesses the relative level of concern warranted for each of these potential capabilities based on the four framework factors: Usability of the Technology, Usability as a Weapon, Requirements of Actors, and Potential for Mitigation.
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From page 62... ...
The tools of synthetic biology could be used to address these lost structural functions or to provide alternative pathways, but this makes for a more complicated proposition, as discussed below under Manufacturing Chemicals or Biochemicals by Creating Novel Metabolic Pathways. However, if post-translation modifications absent in the new host are essential for enzyme activity, this likely represents an insurmountable hurdle, at least in the near term.
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From page 63... ...
Generally speaking, the core capabilities for executing a Design-Build-Test cycle in metabolic engineering require a relatively low level of metabolic engineering expertise, especially for a natural metabolic pathway that is already fully elucidated. However, the expertise required depends on the complexity of the pathway and target molecule.
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From page 64... ...
MANUFACTURING CHEMICALS OR BIOCHEMICALS BY CREATING NOVEL METABOLIC PATHWAYS While nature has provided a wide array of biochemical compounds that could be exploited for targeted synthesis, enzyme-mediated conversions also can be used to produce chemicals that organisms do not naturally create. Biocatalysis has long been used to produce pharmaceutical intermediates and active ingredients not found in nature (Bornscheuer et al., 2012)
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From page 65... ...
Considerations related to mitigation capabilities for chemicals or biochemicals manufactured by creating novel metabolic pathways are largely similar to those for chemicals or biochemicals created through natural metabolic pathways. MAKING BIOCHEMICALS VIA IN SITU SYNTHESIS The human microbiome, particularly the gut microbiome, has been a target for metabolic engineering.
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From page 66... ...
From an engineering perspective, creating a microbe capable of in situ biological synthesis of a biochemical presents many of the same opportunities and challenges as engineering metabolic pathways for the production of chemicals or biochemicals in a bioreactor, though there are some additional challenges, as well. While productivity, titer, and yield can typically be measured in the process of manufacturing a chemical or biochemical product in a bioreactor, conditions in the microbiome, for example, are quite different from those present in the laboratory.
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From page 67... ...
Engineering microbes to actively secrete products in the microbiome would generally require a higher level of expertise than engineering a natural metabolic pathway but less sophistication than designing a novel metabolic pathway, leading to a medium level of concern with regard to this factor. Because multiple iterations of the Design-Build-Test cycle would be needed, actors would likely require access to significant laboratory resources over a long period of time.
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From page 68... ...
In contrast to the other applications of metabolic engineering discussed in this chapter, the genetic material of the engineered microbe would in the case of in situ synthesis remain present in the weaponized product. Sequencing clinical samples of impacted individuals could allow investigators to identify the genetic sequences or organisms used in an attack.
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From page 69... ...
Broadly, the use of microbes to synthesize agents in situ presents the greatest level of concern, the synthesis of agents using naturally occurring metabolic pathways warrants a medium to high relative level of concern, and the engineering of novel metabolic pathways poses a medium level of concern. It will be important to continue to monitor developments in the manipulation of the human microbiome because efforts in the pharmaceutical arena are likely to propel advances and reduce bottlenecks and barriers as the field continues to progress (see Table 5-1)
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From page 70... ...
engineering to make metabolic pathways toxin toxins tolerable to the host organism synthesizing the toxin Engineering enzyme activity Increased knowledge of how to modify enzymatic functions to make specific products Limited knowledge of Improvements in directed evolution and/or increased requirements for designing knowledge of how to build pathways from disparate organisms novel pathways Challenges to large-scale Improvements in intracellular and industrial productivity production Making biochemicals via in Limited understanding of Improvements in knowledge related to microbiome situ synthesis microbiome colonization of host, in situ horizontal transfer of genetic elements, and other relationships between microbiome organisms and host processes aShading indicates developments that are likely 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.
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