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Genome engineering: writing a better genome
 
Jeffrey M. Perkel, Ph.D.
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After about a year's work, the team had a strain capable of producing about 300 mg of gasoline per liter — far too little to make economic sense. “We need to scale it up,” says Brigham. The team is now working to make that happen with altered food sources and harvest strategies.

Virtual engineering

One day soon it may actually be possible for researchers like Brigham and Lu to design and execute their biosynthetic visions on computers, rather than paper. Armed with tools like Clotho (from Boston University assistant professor Douglas Densmore) and J5 (from Nathan Hillson of the Joint BioEnergy Institute), researchers already have access to the computational tools to assemble a pathway on a virtual canvas, encode the logic circuitry of IF this THEN that, identify the biological components required to make a circuit work, and output synthesis instructions to automated liquid handlers. All that's missing is the palette of biological subsystems themselves, the promoters, reporter genes, regulatory circuits, binding domains, and so on, that empower such BioCAD tools. Databases like these are sparsely populated and few in number, says Densmore, though work on that front is progressing.

Once those pieces are in place, though, engineers should be able to design biological circuits just as integrated circuit designers do today, a process that is considerably simpler than the manual process Densmore used as a student.

“Some people will lament that, just like some people will say, when I was a kid we spent all this time doing arithmetic and now you have a calculator. But then, what does that mean?” asks Densmore. “It means the students of today are focused on calculus and things that the students of years ago could never get to. I think it'll be something similar [with synthetic biology].”

Get ready for Biology 421.

References
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2.) Dymond, J.S., S.M. Richardson, C.E. Coombes. 2011. Synthetic chromosome arms function in yeast and generate phenotypic diversity by design. Nature 477:471-6.

3.) Lajoie, M.J., C.J. Gregg, J.A. Mosberg, G.C. Washington, and G.M. Church. 2012. Manipulating replisome dynamics to enhance lambda Red-mediated multiplex genome engineering. Nucleic Acids Res.

4.) Warner, J.R., P.J. Reeder, A. Karimpour-Fard, L.B. Woodruff, and R.T. Gill. 2010. Rapid profiling of a microbial genome using mixtures of barcoded oligonucleotides. Nat Biotechnol 28:856-62.

5.) Wang, H.H., F.J. Isaacs, P.A. Carr. 2009. Programming cells by multiplex genome engineering and accelerated evolution. Nature 460:894-8.

6.) Isaacs, F.J., P.A. Carr, H.H. Wang, M.J. Lajoie. 2011. Precise manipulation of chromosomes in vivo enables genome-wide codon replacement. Science 333:348-53.

7.) Wang, H.H., H. Kim, L. Cong, J. Jeong, D. Bang, and G.M. Church. 2012. Genome-scale promoter engineering by coselection MAGE. Nat Methods 9:591-3.

8.) Lajoie, M.J., C.J. Gregg, J.A. Mosberg, G.C. Washington, and G.M. Church. 2012. Manipulating replisome dynamics to enhance lambda Red-mediated multiplex genome engineering. Nucleic Acids Res.

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