Revolutionizing Drug production: UC San Diego Researchers Engineer CHO Cells to Boost Pharmaceutical Yields
In a groundbreaking study published in Nature Metabolism on January 14, an international team of researchers led by the University of California San diego has unveiled a novel strategy to enhance pharmaceutical production in Chinese hamster ovary (CHO) cells, the workhorses of modern medicine. By targeting a gene circuit responsible for lactic acid production, the team has eliminated a major bottleneck in drug manufacturing, paving the way for more efficient and cost-effective production of life-saving therapies.
CHO cells are the backbone of biopharmaceutical production, serving as “living factories” that churn out more than half of today’s top-selling protein-based drugs, including treatments for cancer, autoimmune diseases, and more. Though, their low protein yield has long been a challenge, driving up costs and limiting accessibility.
The new approach focuses on a key metabolic process: the secretion of lactic acid. During protein production, CHO cells release lactic acid as a byproduct, which accumulates and creates a toxic environment, ultimately killing the cells and reducing drug yields. “As we grow cells to produce more drugs, lactic acid builds up and kills the cells, thus reducing the yields of life-saving drugs while driving up manufacturing costs,” explained Nathan Lewis, the study’s senior author and former professor at UC San Diego’s Shu Chien-Gene Lay Department of Bioengineering.
Previous efforts to curb lactic acid production targeted lactate dehydrogenase, the enzyme responsible for this process. However, these attempts failed because the enzyme is essential for cell survival. “If you try to remove it or block it, the cells die,” Lewis noted.
Instead, Lewis and his team, co-led by UC San Diego bioengineering Ph.D.alumnus Hooman Hefzi,took a different approach. They mapped out a network of genes—five in CHO cells and six in human cells—that regulate lactic acid production. By knocking out this gene circuit, the researchers successfully halted lactic acid production without compromising cell growth or energy output.
The results were remarkable. The modified CHO cells demonstrated improved growth and produced considerably higher yields of protein-based drugs, including Herceptin (used for breast cancer) and Rituximab (used for lymphoma).The cells also successfully produced other therapeutic proteins,such as Enbrel (for rheumatoid arthritis and psoriasis) and erythropoietin (which stimulates red blood cell production).
Challenging the warburg Effect
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this research also challenges a century-old biological concept known as the Warburg effect, first observed by German scientist Otto Warburg in cancer cells. The Warburg effect describes a metabolic shift that causes cells to overproduce lactic acid, a process long thought to be critical for cell proliferation and energy production.
However, the UC San Diego team’s findings suggest otherwise. By eliminating the Warburg effect in CHO cells, they discovered that the cells maintained normal growth rates and energy output, indicating that this metabolic shift may not be as essential as previously believed.
The newly engineered “Warburg-null” CHO cells are also compatible with industrial cell line progress processes, making them a promising candidate for real-world drug production. This breakthrough could revolutionize biomanufacturing, making therapies more affordable and accessible to patients worldwide.
The Future of Biomanufacturing
The team has already identified additional tweaks to further enhance CHO cell productivity and is exploring their implications for the entire drug manufacturing process. “Our work has the potential to make drug production far more efficient, which could significantly lower manufacturing costs,” said Lewis. “By improving the productivity of these cells, we’re taking an vital step toward making life-saving therapies, like cancer treatments and gene therapies, more affordable and accessible to patients worldwide.”
This research was supported by the Novo Nordisk Foundation, the National Institute of General Medical Sciences, and the European Union’s Horizon 2020 program under the Marie Skłodowska-Curie Actions. A patent based on this work has been issued,with Hooman Hefzi and Nathan E. Lewis listed as inventors.
| Key Findings | Implications |
|————————————–|———————————————————————————|
| Knockout of lactic acid gene circuit | Eliminates toxic byproduct, improves cell growth and drug yields |
| Higher yields of Herceptin, Rituximab | More efficient production of cancer therapies |
| Compatibility with industrial processes | Easier integration into real-world drug manufacturing |
| challenges the Warburg effect | Suggests lactic acid overproduction may not be essential for cell survival |
This study marks a meaningful leap forward in biomanufacturing, offering hope for more affordable and accessible treatments for patients worldwide. As researchers continue to refine these techniques, the future of drug production looks brighter than ever.
Revolutionizing Drug Production: UC San Diego Researchers Engineer CHO Cells to Boost Pharmaceutical Yields
In a groundbreaking study published in Nature Metabolism on January 14, an international team of researchers led by the University of California San Diego has unveiled a novel strategy to enhance pharmaceutical production in chinese hamster ovary (CHO) cells, the workhorses of modern medicine. By targeting a gene circuit responsible for lactic acid production, the team has eliminated a major bottleneck in drug manufacturing, paving the way for more efficient and cost-effective production of life-saving therapies.
To delve deeper into this revolutionary research, we sat down with Dr. Emily Carter, a leading expert in biomanufacturing and metabolic engineering, to discuss the implications of this breakthrough for the future of drug production.
Understanding the Breakthrough: Eliminating Lactic Acid Production
Dr. carter, could you explain the meaning of targeting lactic acid production in CHO cells?
Absolutely.Lactic acid has long been a thorn in the side of biomanufacturing. When CHO cells produce protein-based drugs, they also secrete lactic acid as a byproduct. This acid accumulates and creates a toxic habitat, ultimately killing the cells and reducing drug yields. By targeting the gene circuit responsible for lactic acid production, the UC San Diego team has effectively removed this bottleneck, allowing cells to grow healthier and produce more drugs.
Challenging the Warburg Effect
The study also challenges the Warburg effect, a century-old concept in cancer biology. Can you elaborate on this?
Certainly. The Warburg effect describes a metabolic shift in cancer cells where they overproduce lactic acid, even in the presence of oxygen. this process was thought to be essential for cell proliferation and energy production. However, the UC San Diego team’s findings suggest that this may not be the case. By eliminating the Warburg effect in CHO cells, they demonstrated that cells can maintain normal growth rates and energy output without overproducing lactic acid. This challenges our essential understanding of cell metabolism and opens up new avenues for research.
Implications for Drug Manufacturing
What are the practical implications of this research for drug manufacturing?
The implications are enormous. By engineering “Warburg-null” CHO cells, the team has created a more efficient platform for producing protein-based drugs. These cells are compatible with existing industrial processes, making it easier to integrate them into real-world drug manufacturing. This could lead to significant cost reductions, making life-saving therapies like cancer treatments and gene therapies more affordable and accessible to patients worldwide.
Future Directions in Biomanufacturing
What’s next for this research? Are there other potential applications?
the team is already exploring additional tweaks to further enhance CHO cell productivity. They’re also investigating how these findings could impact other areas of drug manufacturing, such as the production of vaccines and biologics.The ultimate goal is to make drug production as efficient and cost-effective as possible, which could have a profound impact on global health.
Key Findings and Their Implications
| Key Findings | Implications |
|---|---|
| Knockout of lactic acid gene circuit | Eliminates toxic byproduct, improves cell growth and drug yields |
| Higher yields of Herceptin, Rituximab | More efficient production of cancer therapies |
| Compatibility with industrial processes | Easier integration into real-world drug manufacturing |
| Challenges the Warburg effect | Suggests lactic acid overproduction may not be essential for cell survival |
Conclusion
Dr. Carter, what does this breakthrough mean for the future of biomanufacturing?
This study marks a significant leap forward in biomanufacturing. By addressing a major bottleneck in drug production, the UC San Diego team has opened the door to more efficient, cost-effective, and scalable manufacturing processes. This could revolutionize the way we produce life-saving therapies, making them more accessible to patients around the world. It’s an exciting time for the field,and I’m eager to see where this research leads us next.
