SAN DIEGO, CA — In a groundbreaking development, an international research team led by the University of California San Diego has introduced a pioneering strategy to optimize pharmaceutical production in Chinese hamster ovary (CHO) cells—widely regarded as the backbone of protein-based drug manufacturing. By successfully eliminating a genetic pathway responsible for lactic acid buildup, researchers have addressed a critical challenge that has long hindered drug production efficiency, paving the way for higher yields of life-saving therapeutics such as Herceptin and Rituximab.
The study, recently published in Nature Metabolism, challenges long-standing assumptions about cellular metabolism, offering transformative insights that could revolutionize biomanufacturing on a global scale.
Enhancing the Efficiency of ‘Living Factories’
CHO cells are indispensable to the pharmaceutical industry, serving as essential “living factories” that produce more than half of the world’s leading protein-based drugs, including treatments for cancer, autoimmune disorders, and more. However, a persistent obstacle has limited their potential—low protein yields. Despite their critical role in drug manufacturing, CHO cells often fail to produce sufficient quantities of therapeutic proteins, leading to elevated production costs and supply shortages.
The newly developed approach focuses on one of the primary barriers to maximizing cell productivity: the accumulation of lactic acid. As CHO cells generate protein therapeutics, they simultaneously produce lactic acid as a metabolic byproduct. Excessive lactic acid accumulation creates a toxic environment, stifling cell growth and diminishing output.
A New Approach to a Long-Standing Challenge
Previous efforts to curb lactic acid production have primarily targeted lactate dehydrogenase—the enzyme responsible for its formation. However, blocking or inhibiting this enzyme has proven detrimental, often leading to cell death. Recognizing this limitation, the research team, led by Nathan Lewis, formerly a professor at UC San Diego and now at the University of Georgia, adopted a novel strategy.
Instead of focusing on lactate dehydrogenase itself, the scientists identified and disrupted a complex genetic circuit—comprising five genes in CHO cells and six in human cells—responsible for excessive lactic acid production. By selectively knocking out this genetic pathway, the team effectively eliminated lactic acid secretion while simultaneously enhancing cell viability and productivity.
“Our findings demonstrate that removing this genetic circuit allows cells to grow robustly while achieving significantly higher yields of critical protein-based drugs,” said Lewis. “This breakthrough has the potential to redefine pharmaceutical manufacturing by reducing costs and improving efficiency.”
Implications for Drug Manufacturing and Beyond
The modified CHO cells showed remarkable improvements, producing larger quantities of essential therapeutics such as:
- Herceptin, a leading breast cancer treatment.
- Rituximab, a widely used lymphoma therapy.
- Enbrel, a treatment for autoimmune conditions such as rheumatoid arthritis and psoriasis.
- Erythropoietin, a vital hormone that stimulates red blood cell production.
Beyond immediate applications in biomanufacturing, this research challenges a fundamental biological principle known as the Warburg effect—a phenomenon first identified a century ago by Nobel laureate Otto Warburg, who observed that cancer cells undergo a metabolic shift resulting in excessive lactic acid production.
“Our findings suggest that the Warburg effect may not be as indispensable to cell growth and energy production as previously thought,” said Hooman Hefzi, co-lead of the study and professor at the Technical University of Denmark. “This challenges decades of biological dogma and opens new doors for further exploration.”
A Game-Changer for the Pharmaceutical Industry
The newly engineered “Warburg-null” CHO cells are fully compatible with existing industrial production processes, allowing seamless integration into current drug manufacturing pipelines. This advancement has the potential to significantly lower production costs and expand access to life-saving therapies globally.
“Our work represents a major leap forward in pharmaceutical production,” Lewis added. “By enhancing the productivity of CHO cells, we’re contributing to a future where vital medications are more affordable and widely accessible to patients in need.”
Future Prospects and Continued Innovation
The research team continues to explore additional genetic modifications that can further boost CHO cell productivity and efficiency. With ongoing support from leading funding bodies—including the Novo Nordisk Foundation, the National Institute of General Medical Sciences, and the European Union’s Horizon 2020 program—these efforts are poised to drive substantial advancements in biopharmaceutical manufacturing.
About the Study
The research findings are detailed in the paper titled “Multiplex Genome Editing Eliminates Lactate Production Without Impacting Growth Rate in Mammalian Cells,” published in Nature Metabolism. A patent based on this work has been issued (US Patent 11,242,510, WO2017192437), with Hooman Hefzi and Nathan Lewis listed as inventors.