Optimal fed-batch operation of recombinant cells subject to plasmid instability and death

Abstract

Optimal feed rate strategy is studied for fed-batch culture of recombinant cells with plasmid instability and with different death rates for the plasmid-free cells (PFC) and plasmid-bearing cells (PBC). Most of the fed-batch fermentation is known to have first-order singularity and therefore a single singular arc. However, this study shows that a singular arc with second-order singularity and therefore two distinct singular arcs are possible for a recombinant cell process if PFC and PBC are subjected to death, and their specific growth rates are proportional to each other. Two types of singular arcs are elucidated and analyzed. The optimal policies over the singular arcs are theoretically explored as these findings reveal qualitative information on the singular arc, which is critically important in providing the optimal initial conditions in numerical computation of optimal feed rate profile.

In situ hydrogen, acetone, butanol, ethanol and microdiesel production by Clostridium acetobutylicum ATCC 824 from oleaginous fungal biomass

“…include plasmid instability due to the segregational plasmid loss during cell division and depression of the growth rate of plasmidbearing cells [67,68]. These drawbacks limit their use in realworld applications like industrial bioprocessing.…”

Pilot-Scale Production of Fatty Acid Ethyl Esters by an Engineered Escherichia coli Strain Harboring the p(Microdiesel) Plasmid

“…Two major reasons for plasmid loss are known: plasmid instability and depression of the growth rate of plasmid-bearing cells (6,37). Plasmid instability is mainly due to the segregational plasmid loss during cell division that was observed in the second, third, and fourth cultivations, which had longer incubation periods than the first cultivation.…”

Evolutionary Algorithm for the Determination of Optimal Mode of Bioreactor Operation

“…A typical bioreactor optimization problem considered in the literature consists of specifying the mode of operation of bioreactor a priori and then determining the trajectories of control variables that maximize a desired objective. Some of the control variables considered include inlet feed rates, − temperature, and pH . Some of the desired objectives considered include cell productivity, amount of product, − or a profit function. − …”

“…Some of the control variables considered include inlet feed rates, − temperature, and pH . Some of the desired objectives considered include cell productivity, amount of product, − or a profit function. − …”