A calibrated agent-based computer model of stochastic cell dynamics in normal human colon crypts useful for in silico experiments.
BACKGROUND
Normal colon crypts consist of stem cells, proliferating cells, and differentiated cells. Abnormal rates of proliferation and differentiation can initiate colon cancer. We have measured the variation in the number of each of these cell types in multiple crypts in normal human biopsy specimens. This has provided the opportunity to produce a calibrated computational model that simulates cell dynamics in normal human crypts, and by changing model parameter values, to simulate the initiation and treatment of colon cancer.


RESULTS
An agent-based model of stochastic cell dynamics in human colon crypts was developed in the multi-platform open-source application NetLogo. It was assumed that each cell's probability of proliferation and probability of death is determined by its position in two gradients along the crypt axis, a divide gradient and in a die gradient. A cell's type is not intrinsic, but rather is determined by its position in the divide gradient. Cell types are dynamic, plastic, and inter-convertible. Parameter values were determined for the shape of each of the gradients, and for a cell's response to the gradients. This was done by parameter sweeps that indicated the values that reproduced the measured number and variation of each cell type, and produced quasi-stationary stochastic dynamics. The behavior of the model was verified by its ability to reproduce the experimentally observed monocolonal conversion by neutral drift, the formation of adenomas resulting from mutations either at the top or bottom of the crypt, and by the robust ability of crypts to recover from perturbation by cytotoxic agents. One use of the virtual crypt model was demonstrated by evaluating different cancer chemotherapy and radiation scheduling protocols.


CONCLUSIONS
A virtual crypt has been developed that simulates the quasi-stationary stochastic cell dynamics of normal human colon crypts. It is unique in that it has been calibrated with measurements of human biopsy specimens, and it can simulate the variation of cell types in addition to the average number of each cell type. The utility of the model was demonstrated with in silico experiments that evaluated cancer therapy protocols. The model is available for others to conduct additional experiments.
Rafael
R
Bravo
Department of Genetics, Rutgers University, 604 Allison Rd, Piscataway, NJ 08854-8082, USA. axelrod@biology.rutgers.edu.
David E
DE
Axelrod
D001706:Biopsy; D002138:Calibration; D002452:Cell Count; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003198:Computer Simulation; D025461:Feedback, Physiological; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D015203:Reproducibility of Results; D013269:Stochastic Processes
D019394:Ki-67 Antigen