64. multiplex genome editing eliminates the warburg effect without affecting oxidative metabolism or growth rate

Department: Bioengineering
Research Institute Affiliation: CHO Systems Biology Center
Faculty Advisor(s): Nathan E. Lewis

Primary Student
Name: Hooman Hefzi
Email: hhefzi@ucsd.edu
Phone: 714-496-1661
Grad Year: 2018

Abstract
The Warburg effect is ubiquitous in proliferative mammalian cells, including cancer, but poses challenges for biopharmaceutical production, as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production via knockout have failed in mammalian bioprocessing since lactate dehydrogenase has proven essential. However, here we eliminated the Warburg effect in Chinese hamster ovary cells by simultaneously knocking out lactate dehydrogenase and regulators involved in a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA. In contrast to long-standing assumptions about the role of aerobic glycolysis, Warburg-null cells maintain wildtype growth rate while consuming less glucose without increased oxygen uptake to compensate for lost glycolytic ATP. The cells produce negligible lactate, allowing prolonged growth to higher cell densities. When producing rituximab, the cells maintain protein production and glycan galactosylation. Thus, the ability to eliminate the Warburg effect is an important development for biotherapeutic production, and provides a tool for investigating a near-universal metabolic phenomenon.

Industry Application Area(s)
Life Sciences/Medical Devices & Instruments | Biotechnology, Biopharmaceuticals

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