AgentCell (Digital E. Coli)
T. Emonet, C. Wickersham & P. Cluzel (Institute for Biophysical Dynamics, University of
C. Macal, M. North (Center for Complex Adaptive Agent Systems
Simulation, Argonne National Laboratory)
B. Gallagher (ASC Flash Center Visualization Group, University of
This work is partially supported by joint
research funding under H.28 of the U. S. Department of Energy Contract
W-31-109-ENG- 38. It is an ongoing collaboration between P. Cluzel's
lab (UofC) and CCAASS (Argonne National Laboratory)
In recent years, single-cell biology has focused on the relationship between the stochastic nature of molecular interactions and variability of cellular behavior. To describe this relationship, it is necessary to develop new computational approaches at the single cell level.
We have developed AgentCell, a model using agent-based
technology to study the relationship between stochastic intracellular
processes and behavior of individual cells. As a test-bed for our
approach we use bacterial chemotaxis, one of the best-characterized
biological systems. In this model, each bacterium is an agent equipped
with its own chemotaxis network, motors and flagella.
are free to move in a 3D environment. Digital chemotaxis assays
reproduce experimental data obtained from both single cells and
(a) Chemotactic swimming cell exposed to a linear gradient of
chemo-attractant (shaded background). When the motors rotate CCW (see
main text) the flagella form a corkscrew bundle and the cell runs.
When the motors rotate CW, the flagella bundle flies apart and the
cell tumbles erratically. (b) Schematic diagram of the chemotactic
pathway. Receptor complexes consist of three Tar receptor dimers (T),
two CheW (W), and two CheA (A). The activity of aspartate (a) receptor
complexes is modulated by methylation (m) and demethylation
respectively catalyzed by CheR (R) and CheB (B). The
autophosphorylation of CheA (A), a histidine kinase, is controlled by
the activity of the receptors. CheA catalyzes the phosphorylation of
the response regulator CheY (Y). When CheY is phosphorylated (Yp), it
binds to the cytoplasmic domain of the bacterial motor and induces
tumbles. Dephosphorylation of CheY-P (Yp) is catalyzed by the
phosphatase CheZ (Z).
Results and animations
- First results are summarized in the article: "AgentCell: a digital single-cell assay for
bacterial chemotaxis", Bioinformatics (2005), 21(11),
- View a real E. coli
bacterium swimming in a 2D environment (
avi movie by P. Cluzel)
- Simulation of 1166 cells in a 3D medium without attractant. The
cell diffuse away from the initial location: the squared average
distance from the initial position grows linearly with time (3D
rendering by B. Gallagher)
- View (avi) a digital E. coli
bacterium swimming in a vertical gradient (10^-8 M/micrometer) of
aspartate. E. coli uses the chemotaxis sensory system to control
its flagellar motors and move towards the source of nutrient
(here the concentration of nutrient increases with the height z).
The movie shows the intracellular level of response regulator protein
CheY-P (CheY-P induces tumbling) and the receptor occupancy by ligand
molecules (aspartate). Tumbling events are in red.
- 1080 cells in a 3D medium with a vertical gradient of
aspartate (10^-8 M/micrometer). 540 cells are sensitive to aspartate
(green) and 540 cells are not sensitive (red). To illustrate the
complicated trajectory of cells, the trace of two typical cells is
shown. The right panel shows
the chemotactic response of the population: the total number of cells
that have reached the height z=1mm. After 400 secs, about one half
of the red cells have reached regions of high attractant
concentrations causing their receptors to saturate. From that time
point on, the red
population diffuses away at the same rate as the green cells
Movie files: ( 800x600 avi 112 Mb)
( 1024x768 avi 169 Mb)
To download high resolution (printable) versions of these images click here.
Software and bug fixes
AgentCell is now fully compatible with the latest version of StochSim (StochSim-1.6_core_2007JUL05.tar.gz NOT to be mixed up with the 1.6beta version of StochSim).
Our changes to StochSim have now been merged into the main development trunck of StochSim. The latest version of
StochSim on the sourceforge server is now fully compatible with this new version of AgentCell. StochSim is not distributed with AgentCell anymore. It is available on sourceforge. We still provide the StochSim file here for convenience.
AgentCell uses parts of Repast as a layer to provide agent-based capabilities. Repast is distributed under a BSD license and is included in the AgentCell distribution. AgentCell is distributed under the GPL license. AgentCell includes Xerces XML software developed by the Apache
Software Foundation (http://www.apache.org/). Please see the "licenses" directory for the licensing details of AgentCell and the software distributed with AgentCell.
This new version of AgentCell can now handle many cells in the same VM. It is also fully compatible with the latest version of StochSim that can be found on sourceforge.
AgentCell Version 1.2 (download)
This version still uses version 1.4 of StochSim but with some
important bug fixes:
Fixed the time counter overflow: Due to use of double in stochsim
to store the time and conversion between double and long, the time
variable was overflowing at some point causing the cells to become
"blind" or insensitive after about 400 seconds of simulation. The
sudden change in the slope of the chemotactic response of wild type
cells in figure 4 of Bioinformatics, 21, 2714-2721 (2005) at time
t=400 secs is not due to the saturation of the receptors but is an
artifact. With this bug fixed the wild type cells continue their
strong chemotactic response until the end of the simulation at 1000
sec, which is good news. If you were using AgentCell for simulations
shorter than 400 seconds or without ligand in the external medium your
result should not be affected. This bug has been fixed using a quick
fix. A more permanent solution is being implemented in stochsim: use
of exact integer arithmetic to keep track of the number of time steps.
When defining more that 2 states for the receptors the updating of
receptor states as the cell was moving was being ignored. That was a
bug in the wrapping of stochsim. Now one can define receptors with as
many states as wanted. Notice that the simulations in the examples and
in the Bioinformatics 21, 2714-2721 (2005) paper only used 2 receptors
with two states (number of dynamic values defined in Stochsim) and
therefore these results were not affected by this bug.
AgentCell Version 1.0 (download)
Original version of AgentCell used in
Bioinformatics 21, 2714-2721 (2005).
Implementing the Network class with StochSim required the accessing of
the internal time loop of StochSim in order to feed or extract
information at the time intervals required by the agent-based
simulation. For this purpose we modified StochSim to appropriately
pause and then continue as required by Repast. This new version of
StochSim eventually will become the main branch of the StochSim
development tree (in version 1.4 of AgentCell)
Because of the use of global variables in StochSim 1.4, only one instance of StochSim 1.4.1 can be used in each Java VM. In practice we run many independent AgentCells on a cluster, one AgentCell
per node (see explanations in the paper). Our goal however is to have cells interacting with each other. To that end Tom Shimizu and Michael North have modified StochSim 1.4.1, removing all global variables and therefore allowing many instances of the StochSim class within one AgentCell simulation. This new version of StochSim is currently being tested and will be released with the next version of AgentCell.
This version contains two important bugs that are fixed in version 1.2
The code is available for download from SourceForge. To install download the
distribution (zip file) from SourceForge,
unpack and follow the instructions in the README file.
AgentCell is an open source project. Any contribution is welcome. To
get involved, subscribe to the AgentCell-developer mailing list below.
AgentCell is free software distributed under the GPL License. It
includes other software such as (Repast, StochSim, ...). Licenses for
each package can be found in the licenses directory within the
distribution package. Repast is licensed under a BSD license. StochSim 1.4.1 (the modified
1.4 version) is included with AgentCell and is distributed under the
LGPL license. AgentCell includes Xerces XML software developed by the
Apache Software Foundation (http://www.apache.org/).