Shortcuts to Custom Bio Production of Fuels and Chemicals

A biochemically accurate model of molecular biology and metabolism will facilitate comprehensive and quantitative computations of an organism's molecular constitution as a function of genetic and environmental parameters. Here we formulate a model of metabolism and macromolecular expression. Prototyping it using the simple microorganism Thermotoga maritima, we show our model accurately simulates variations in cellular composition and gene expression.

Moreover, through in silico comparative transcriptomics, the model allows the discovery of new regulons and improving the genome and transcription unit annotations. Our method presents a framework for investigating molecular biology and cellular physiology in silico and may allow quantitative interpretation of multi-omics data sets in the context of an integrated biochemical description of an organism. _NatureCommunications

Nature Communications 3, Article number: 929 doi:10.1038/ncomms1928

UCSD researchers have taken an important step toward the ability to custom design the genome of organisms in order to produce synthetic fuels, chemicals, pharmaceuticals, and more, on a commercial scale.

"What you could hypothetically do with our model is simulate the total cost of producing a value-added product, such as a biofuel. That includes all the operating and maintenance costs," said Daniel Hyduke, a project scientist in Palsson's lab. Hyduke said the method has the potential to help streamline industrial metabolic engineering efforts by providing a near complete accounting of the minimal material and energy costs associated with novel strain designs for biofuel, commodity chemicals, and recombinant protein production.

Hyduke and Lerman prototyped the method on the minimal, yet metabolically versatile, hyperthermophile Thermotoga maritima. Because T. maritima is not currently ready for use in industrial applications, Hyduke and Lerman are working as part of a larger team to produce similar models for industrially relevant microorganisms, such as E. coli.

"We've built a virtual reality simulator of metabolism and gene expression for Thermotoga maritima, and shown that it much better approximates phenotypes of cells than modeling metabolism in isolation," said Lerman.

...Their method accounts, in molecular detail, for the material and energy required to keep a cell growing, the research team reported in the journal Nature Communications.

"This is a major advance in genome-scale analysis that accounts for the fundamental biological process of gene expression and notably expands the number of cellular phenotypes that we can compute," said Bernhard Palsson, Galetti Professor of Bioengineering, at the UC San Diego Jacobs School of Engineering.

"With this new method, it is now possible to perform computer simulations of systems-level molecular biology to formulate questions about fundamental life processes, the cellular impacts of genetic manipulation or to quantitatively analyze gene expression data," said Joshua Lerman, a Ph.D. candidate in Palsson's Systems Biology Research Group. _SD

This approach provides more useful information in advance, to researchers considering various approaches to the design of custom chemicals-producing organisms -- particularly microbes, but eventually plants and animals as well.

In summary, the development of this tool should streamline the design and development of organisms capable of producing commercially valuable chemicals and fuels in an economical manner. It should also prevent much wasted energy on the part of researchers, by pointing out dead-end research approaches in advance.