Directed Evolution for Development and Production of Bioactive Agents A Meeting Summary (2013) / Chapter Skim
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Experts were invited from the areas of directed evolution, biosynthesis, detection, and biological agents. This report summarizes the views expressed by individual meeting participants and was constrained by the meeting agenda; the views described are not necessarily those of all meeting participants, the committee, or the National Research Council.
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He then discussed how cell phenotype can be exploited to create new switches/binders and how they can be used in therapeutics.3 He described examples in which cancer cells were selectively destroyed by protein switches sensitive to hypoxia.4 His team found that the therapeutic potential of cellular environmentdependent switches is linked to the following properties: switches are inherently specific; they avoid a requirement for targeted delivery; the target and therapeutic mechanism are not inextricably linked; and they offer a route to the therapeutic exploitation of undruggable targets.5 Dr. Ostermeier then discussed the genetic code, suggesting that it is not randomly connected and indicating that there are different theories to account for nature's assignment of 20 amino acids to 64 three-base codons.
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He said that this work will be presented in a future paper by Fimberg and Ostermeier that shows the distribution of these fitness effects.6 He finished his talk by discussing theories on the genetic code's origin from work by Koonin and Novozhilov,7 whose paper described the following possibilities: Frozen accident -- too hard to change once it was established; Stereochemical theory -- inherent interactions between amino acids and nucleotide triplets; Coevolution theory -- amino acid biosynthetic pathways and the genetic code coevolved; and Adaptive theory -- the genetic code evolved under selective pressure to minimize the deleterious effects of mutations and mistranslations.
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A short question-and-answer period was held after the presentation. The key questions from meeting participants discussed accessibility and the size of the commercial market, and how companies are starting to target orphan diseases based on small patient markets.
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Cornish, A heritable recombination system for synthetic Darwinian evolution in yeast, ACS Synthetic Biology 1(12)
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Raising the question of the natural roles of natural products Dr. Fischbach postulated that natural products mediate interactions between species with genes as the missing link.
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Fischbach what he considered the most important role directed evolution plays in the work on biosynthetic gene clusters.
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, West Nile virus, and hepatitis B virus. He noted that the peptide sequence analysis has identified NS1, a nonstructural viral protein that is secreted from infected cells and is one of the most active dengue virus antigens.
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SAHBs, are stapled peptides that enhance the pharmacological properties of BH3 peptides, which mediate protein interactions essential in the regulation of programmed cell death (apoptosis) .50 He opened the discussion by describing cellular uptake as a property of SAHBA and then described how SAHB suppresses the 43 G.L.
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Asked to give examples in the first category, meeting participants mentioned taking an animal pathogen and evolving it to a human pathogen, the evolution of pathogens to target non-humans, and the expression of a toxin-synthesizing gene cluster by a simple organism such as E coli. One participant described a process for introducing diversity into an animal pathogen and the steps it takes to develop a human pathogen.
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One participant emphasized as a current limitation the lack of simple screening methods that do not require interpretation by experts. Throughout the meeting, there was discussion of the likelihood of potential actors entering the field of directed evolution and their ability to produce agents.
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Appendixes
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Key Terms
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