Gene Synthesis Optimization

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Gene synthesis optimization through modeling

In this project, we test the hypothesis that methods from manufacturing and industrial engineering can be used for gene synthesis optimization. Gene synthesis is the process of combining natural and chemically synthesized DNA fragments together in order to make larger DNA molecules that conform to computer-designed sequences. DNA fabrication includes gene synthesis; the process of assembling chemically synthesized oligonucleotides into double-stranded DNA fragments. DNA fabrication also includes more traditional activities, such as the development of mutant collections, plasmid libraries, and refactored genomes. In this broad perspective, most biologists practice DNA fabrication, although they are more likely to call it molecular biology or genetic engineering. DNA fabrication projects rely on low-cost instruments and laboratory infrastructure commonly available to life scientists. Unfortunately, the lack of a suitable framework to analyze DNA fabrication processes is limiting their effectiveness.

We are evaluating the feasibility of gene synthesis optimization by analyzing DNA fabrication processes by using techniques from Industrial and Systems Engineering (ISE). The premise being that these techniques can be used to better design, plan, execute, and control DNA fabrication processes and that this paradigm change will help identify preferred manufacturing strategies for DNA fabrication. The project has four complementary objectives: (1) explore the goals and requirements of the process, conduct functional analysis, and investigate resource and workflow strategies for DNA fabrication; (2) implement laboratory pipelines to generate different types of constructs illustrating a broad range of fabrication problems and biological domains; (3) evaluate algorithms to estimate high-error rates in low-volume processes, implement monitoring strategies, and compare the performance of different manufacturing strategies applicable to specific DNA manufacturing problems; and (4) provide cross-training opportunities in molecular biology and ISE for undergraduate students, graduate students, and post-doctoral fellows.

Improving quality, avoiding delays and errors, and substantially decreasing the time to implementation of biomedical discoveries are prime objectives of the National Institutes of Health Roadmap for Medical Research. DNA fabrication processes are representative of processes across many life science specialties that will benefit from the results of this project. The reward of this project is an indispensable increase in productivity of the life science research enterprise. The national R&D infrastructure is seeking greater efficiency in these times of constrained budgets. Therefore, in order to enhance U.S competitiveness, it is necessary to find ways of producing more data, more discoveries, and more applications with stable or shrinking resources.

Source of funding

Collaborators

  • Jaime Camelio, Department of Industrial Systems Engineering, Virginia Tech
  • Kim Ellis, Department of Industrial Systems Engineering, Virginia Tech
  • Brett Tyler, Department of Botany and Plant Pathology, Oregon State University

Selected publications related to this project

  1. Peccoud J, Blauvelt MF, Cai Y, Cooper KL, Crasta O, DeLalla EC, Evans C, Folkerts O, Lyons BM, Mane SP, Shelton R, Sweede MA, Waldon SA (2008) Targeted development of registries of biological parts PLoS ONE.;3 (7):e2671.
  2. Czar MJ, Anderson JC, Bader J, Peccoud J (2009) Gene synthesis demystified, Trends in Biotechnology 27, 63-72
  3. Wilson ML, Cai Y, Hanlon R, Taylor S, Chevreux B, Setubal JC, Tyler BM, Peccoud J. (2012) Sequence verification of synthetic DNA by assembly of sequencing reads Nucleic Acids Research 41:e25.
  4. Gene synthesis: methods and protocols (2012) Methods in Molecular Biology Vol 852 Humana Press Peccoud J Ed.