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A Whole-Cell Model As a Tool to Guide Synthetic Biology

Jayodita Sanghvi1, Jonathan R. Karr1, Derek Macklin1, Miriam Gutschow1, Jared Jacobs1, Benjamin Bolival1, John Glass2, Nacyra Assad-Garcia2 and Markus W. Covert1, (1)Bioengineering, Stanford University, Stanford, CA, (2)JCVI, Rockville, MD

Researchers have spent years uncovering the molecular mechanisms of the numerous processes in a cell, from metabolism to cell division. Still, an integrated comprehension of this knowledge remains a challenge. We have attempted to collate the community's understanding and have built the first comprehensive computational model of a single living cell. This model of the simplest known self-replicating organism, Mycoplasma genitalium, describes all of the known gene functions and molecular interactions. It includes data from over 900 publications and over 1900 parameters. The model incorporates the cross talk between 28 cellular processes including metabolism, transcription, translation, replication, and cell division. Each process was first independently modeled using different mathematical representations, such as linear optimization, ordinary differential equations, probabilistic binding, and geometry, that were best fit for the individual cellular processes. Then, the 28 processes were integrated together at a one-second timestep. The whole-cell model has been validated and benchmarked against existing physiological data, and we have performed additional experiments to further validate the model. The resulting simulations predict cell behavior in response to genomic and environmental perturbations as well as phenotypes that lead to questions that have never before been addressed. The model is able to predict kinetic rates, new gene annotations, chromosomal occupancy, energy usage, new forms of cell cycle regulation, and much more.

We hope that that this whole-cell model and expansions on this model will accelerate biological discovery and bioengineering by serving as tools to guide synthetic biology. Further, in combination with the recent de novo synthesis and transplantation of Mycoplasma genomes to produce a synthetic cell (Gibson et al., 2008; Gibson et al., 2010), whole-cell models raise the possibility of computer-aided rational design of novel microorganisms.

References:

Gibson, D.G., Benders, G.A., Andrews-Pfannkoch, C., Denisova, E.A., Baden-Tillson, H., Zaveri, J., Stockwell, T.B., Brownley, A., Thomas, D.W., Algire, M.A., et al. (2008). Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome. Science 319, 1215-1220.

Gibson, D.G., Glass, J.I., Lartigue, C., Noskov, V.N., Chuang, R.Y., Algire, M.A., Benders, G.A., Montague, M.G., Ma, L., Moodie, M.M., et al. (2010). Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329, 52-56.


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