INVESTIGATION OF SUBPOPULATION HETEROGENEITY AND PLASMID STABILITY INRECOMBINANT ESCHERICHIA-COLI VIA A SIMPLE SEGREGATED MODEL

Many microbial and cell cultures exhibit phenomena that can best be de scribed using a segregated modeling approach. Heterogeneities are more marked in recombinant cell cultures because subpopulations, which oft en exhibit different growth and productivity characteristics, are more easily identified by selective markers. A simple segregated mathemati cal model that simulates the growth of recombinant Escherichia coli ce lls is developed. Subpopulations of different growth rate, plasmid rep lication rate, and plasmid segregation probability are explicitly cons idered. Results indicate that a third mechanism of plasmid instability , referred to here as a ''downward selective pressure,'' is significan t when describing plasmid loss in batch and chemostat cultures. Also, the model agrees well with experimental data from cultures under antib iotic selective pressure. Finally, model simulations of chemostat cult ures reveal the importance of initial conditions on culture stability and the possible presence of nonrandom partitioning functions.