Whole-cell simulation: a grand challenge of the 21st century

doi:10.1016/S0167-7799(01)01636-5

Trends in Biotechnology

Volume 19, Issue 6, 1 June 2001, Pages 205-210

https://doi.org/10.1016/S0167-7799(01)01636-5 Get rights and content

Abstract

Study of the cell will never be complete unless its dynamic behavior is understood. The complex behavior of the cell cannot be determined or predicted unless a computer model of the cell is constructed and computer simulation is undertaken. Rapid accumulation of biological data from genome, proteome, transcriptome and metabolome projects can bring us to the point where it is no longer purely speculative to discuss how to construct virtual cells in silico. This article describes attempts to construct whole cell models. The E-CELL project has completed a couple of virtual cell models, and computer simulations have revealed some biological surprises.

Section snippets

The first cell model

To conquer and directly challenge the task of whole-cell modeling, the E-CELL Project (Ref. 13) was initiated in 1996 at the Shonan-Fujisawa Campus of Keio University (Fujisawa, Japan), following the publication of the entire genome sequence of Mycoplasma genitalium (http://www.tigr.org/tdb/mdb/mdbcomplete.html). M. genitalium has the smallest genome (580 kb) and the smallest number of genes (∼480) of all living organisms currently known and its genomic sequences have been published (see //www.tigr.org/

E-CELL simulation system

The SSC model has 105 protein-coding genes (Table 2) and 22 RNA-coding genes, and consists of 495 reaction rules. Each reaction rule defines what to do within one single time step (one millisecond, in this case). Reactions include: (1) enzymatic reactions that increase and decrease the quantity of its substrate(s) and product(s), respectively; (2) complex formations, in which multiple substrates form a complex; (3) transportations that change the location of certain substances; and (4)

Final 'desperate efforts’ before starvation

Even this simple cell model sometimes shows unpredictable behavior and has delivered biologically interesting surprises. When the extracellular glucose is drained and set to be zero, intracellular ATP momentarily increases and then decreases (Fig. 2, ‘Traced substances’ panel, substance ID C00002). At first, this finding was confusing. Because ATP is synthesized only by the glycolysis pathway, it was assumed that ATP would decrease when the glucose, the only source of energy, becomes zero.

Virtual erythrocytes

Obviously, the SSC model described above is only a hypothetical cell; no such cells exist in nature. Thus, it was decided to model living cells so that the simulation results could be evaluated. Human erythrocytes were chosen for the model because intracellular metabolism is limited in human erythrocytes and because they do not replicate, transcribe or translate genes; also, there are already several studies on the modeling of erythrocytes14, 15, 16. It is possible to compare computer models

Using the E-CELL for pathological analyses

It is possible to perform in silico experiments in which the function of an enzyme is inhibited, and to simulate the behavior of human erythrocytes from hereditary anemic patients using the E-CELL model (Fig. 4). Using the simulated erythrocytes on the E-CELL program, the activity of aldolase is blocked in our virtual erythrocytes; aldolase (fructose bisphosphate aldolase) converts fructose-1,6-bis-phosphate (X12) to glyceraldehyde-3-phosphate (X14) and dihydroxy-acetone-phosphate (X13).

Future prospects

In addition to the ‘virtual self-surviving cell’ and the ‘human erythrocyte model’ described other E-CELL models are currently under construction; a ‘mitochondria model’ and a ‘signal transduction model’ for the chemotaxis of E. coli. Examples of other successful systems for integrative simulation of the cell include DBSolve by Goryanin and colleagues¹⁹ and the V-Cell by Schaff and co-workers²⁰.

One of the major problems in constructing large-scale cell models is lack of quantitative data. Most

Summary

The cell is never ‘conquered’ until its total behavior is understood and the total behavior of the cell is never understood until it is modeled and simulated. Whole-cell modeling, which was thought intractable until recently, has suddenly become realistic. There is no doubt that in silico construction of complex living cells is an exciting scientific challenge and we are just opening the door to this new area of biological research in the 21st century.

Acknowledgements

We thank Koichi Takahashi, Kenta Hashimoto and Yoichi Nakayama for their leaderships in developing the basic E-CELL software, the Virtual Self-Surviving Cell Model, and the Human Erythrocyte Model, respectively. Special thanks are extended to many other colleagues in the Laboratory for Bioinformatics of Keio University, including Yuri Matsuzaki, Katsuyuki Yugi, Fumihiko Miyoshi, Yusuke Saito and Naota Ishikawa, for their dedication to the E-CELL project. The author acknowledges the support of

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Trends in Biotechnology

OpinionWhole-cell simulation: a grand challenge of the 21st century

Abstract

Section snippets

The first cell model

E-CELL simulation system

Final 'desperate efforts’ before starvation

Virtual erythrocytes

Using the E-CELL for pathological analyses

Future prospects

Summary

Acknowledgements

J. Theor. Biol.

J. Theor. Biol.

Trends Biochem. Sci.

J. Theor. Biol.

Comput. Meth. Prog. Biomed.

Biophys. J.

Knowledge-based simulation of genetic regulation in bacteriophage lambda

Nucl. Acids Res.

A qualitative biochemistry and its application to the regulation of the tryptophan operon

Stochastic mechanisms in gene expression

Proc. Natl. Acad. Sci. U. S. A.

Opinion
Whole-cell simulation: a grand challenge of the 21st century