Scientists have created an innovative method to increase the production of drugs in Chinese hamster ovary (CHO) cells, which are essential for manufacturing protein-based treatments for diseases like cancer and autoimmune conditions. This progress was achieved by deactivating a gene circuit that produces lactic acid, a toxic byproduct that harms the cells’ environment. This advancement tackles a significant hurdle in enhancing the production of medications like Herceptin and Rituximab without compromising the cells’ growth or energy levels.
An international research team headed by the University of California San Diego has developed a groundbreaking approach to improve drug production in Chinese hamster ovary (CHO) cells. These cells are frequently employed to create protein-based therapeutics for conditions such as cancer and autoimmune diseases. By abolishing a gene circuit that produces lactic acid—a detrimental metabolite—they have surmounted a crucial barrier in generating greater quantities of pharmaceuticals like Herceptin and Rituximab, all while preserving cell growth and energy levels.
This study, published on January 14 in Nature Metabolism, also challenges long-established theories regarding the role of lactic acid metabolism in cell survival.
CHO cells are vital in modern medicine, responsible for producing over half of the top protein-based treatments available, including those for cancer and autoimmune diseases. Yet, despite their success, these cells face a major limitation: they often yield low amounts of protein. Frequently, CHO cells do not produce the necessary proteins in sufficient quantities, resulting in higher costs for these vital medications.
Researchers have now developed a strategy to enhance the productivity of CHO cells in drug manufacturing, focusing on a key metabolic process: the release of lactic acid.
As CHO cells process nutrients to create proteins, they produce lactic acid as a byproduct. Increased cell activity leads to even more lactic acid being created. “As we cultivate cells for enhanced drug production, lactic acid builds up, creating a poisonous environment that can kill the cells. This reduces the yield of essential medications and raises production costs,” explained Nathan Lewis, the senior author of the study and former professor at UC San Diego’s Shu Chien-Gene Lay Department of Bioengineering and Pediatrics (now at the University of Georgia).
Previous attempts to reduce lactic acid production centered on inhibiting an enzyme called lactate dehydrogenase, which is crucial for cell survival. However, these attempts failed as blocking this enzyme resulted in cell death. “Removing or inhibiting it simply kills the cells,” noted Lewis. “This has been confirmed through numerous studies.”
In this recent study, Lewis and his team, including Hooman Hefzi, a Ph.D. graduate from UC San Diego now at the Technical University of Denmark, took a different approach. Instead of focusing on lactate dehydrogenase directly, they identified a network of genes—five in CHO cells and six in human cells—that work together to regulate lactic acid production. The researchers suggested that this gene circuit contributed to the surplus lactic acid generated in CHO cells.
After disabling this gene circuit, the CHO cells stopped producing lactic acid. Moreover, the modified cells demonstrated improved growth and significantly increased yields of protein-based therapeutics, including Herceptin for breast cancer and Rituximab for lymphoma. Additionally, these modified CHO cells effectively produced other therapeutic proteins, such as Enbrel for rheumatoid arthritis and psoriasis, and erythropoietin, which aids in red blood cell production.
Revisiting the Warburg effect
This research also provides new perspectives on the Warburg effect, a significant biological phenomenon first discovered in cancer cells by German scientist Otto Warburg a century ago. The Warburg effect refers to a metabolic shift that results in excess lactic acid production, which has long been considered essential for cell growth and energy generation.
However, the recent findings challenge this belief. By eliminating the Warburg effect from the CHO cells, scientists noticed that these cells still maintained normal growth rates and energy production, indicating that the Warburg effect may not be as crucial as previously thought.
The researchers emphasize that the newly developed “Warburg-null” CHO cells are also suitable for industrial cell line development. This suggests that these cells could be seamlessly integrated into real drug manufacturing processes, potentially transforming biomanufacturing.
The team has also identified further modifications that can enhance CHO cell productivity and intends to investigate their broader implications on drug manufacturing processes.
“Our discoveries could significantly enhance drug production efficiency, potentially lowering manufacturing costs,” said Lewis. “By improving the productivity of these cells, we are making vital strides towards making essential treatments, such as cancer therapies and gene therapies, more affordable and accessible for patients worldwide.”
