Browsing by Author "O'Brien, Conor M"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item A mechanistic-empirical model of central metabolism, signaling, and the reactor environment for bioprocesses(2020-10-07) O'Brien, Conor M; Hu, Wei-Shou; acre@umn.edu; Hu, Wei-ShouThis model was built and optimized to reproduce the variability inherent to many industrial cell-culture processes. Classically, fed-batch Chinese Hamster Ovary (CHO) cell cultures will initially produce lactate in the early phase of culture before switching to lactate consumption. However, some processes may revert to lactate production in the late stage of culture, driving up osmolarity while reducing viable cell density, and ultimately lowering process performance. This phenomenon may occur in only some runs of a manufacturing processes and even may differ among runs with similar initial conditions and trajectories, leading to longstanding questions about the mechanisms driving this switch. By simulating cultures which were exposed to different amounts of stress before the production bioreactor we show that similar starting conditions in the bioreactor environment can lead to variability in metabolic shift. We provide this model as a tool to demonstrate this metabolic variability and provide a platform for hypothesis testing, in silico bioprocess optimization, and simulation of reactor scale-up and scale-down.Item Modeling the Effects of Small Molecule Therapeutics on Glycolysis and Lactate Flux(2018-09) Schroeder, Joseph S; O'Brien, Conor M; Hu, Wei-ShouChinese Hamster Ovary (CHO) cells are widely used in the industrial production of commercial therapeutics. One key aspect to the productivity of these cells is their high rate of glucose consumption. The high rate of glucose consumption is paired with a high output of lactate which can lead to negative culture performance. The rate of glucose consumption and lactate production can be modulated by a number of chemicals, some of which are being explored as therapeutic drugs, which affect the activities of the enzymes involved in glucose metabolism. This research aimed to evaluate the effects caused by small molecule therapeutics on CHO cells’ metabolism using a mathematic model of glucose metabolism. To model the therapeutics, established kinetic information for these therapeutics was implemented into a metabolic model. Then different concentrations of therapeutics were explored to assess their effects on metabolism. In addition, combinations of therapeutics were examined to study the effects of more drastic changes to metabolism. These therapeutics showed a large impact to the bistability of glucose metabolism as well as the lactate flux. These outcomes were important due to the potential to increase the productivity of CHO cells for industrial use as well as decreasing cell death. Thus, these therapeutics could be used to reduce lactate production in cells allowing for higher productivity.