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Lately I’ve been thinking about how to make cell culture more human-relevant: What if all our drug discovery pipelines used physiological glucose levels instead of the 25 mM you find in standard DMEM?
I suspect it would slow things down in the short-term; slower proliferation and poor adaptation of some lines would mean longer experimental timelines. But I imagine the long-term upside would be pretty massive, because right now, we’re actually doing the opposite. Standard DMEM has 25 mM glucose, while human blood sits around 5 mM. That’s a five-fold difference, and enough to push cells into metabolic states they’d never see in vivo. At these supraphysiological levels, cells often lean heavily on glycolysis even when oxygen is plentiful. That can mimic a “Warburg-like” phenotype, but one that may say more about the media than the cancer. The consequences are easy to imagine: - Drug sensitivity profiles that don’t translate to patients - Biomarkers that are actually cell culture artifacts - Potential therapeutic targets discovered under hyperglycemic stress that turn out to be irrelevant in vivo The result is years of expensive R&D on a series of targets that doesn’t efficiently lead to new therapeutics. And here’s the kicker: cells long adapted to 25 mM glucose often struggle when you dial back to physiological 5 mM. That struggle itself tells us something important. We’ve been optimizing our models for convenience and fast proliferation, at the expense of human relevance. Of course, it’s not as simple as “5 mM glucose = human-relevant biology.” Tumors often experience lower glucose than blood, and glucose is just one piece of the puzzle. Still, I can’t help but wonder if we had standardized around human-like conditions decades ago, how many “failed” drugs might have never made it past the cell culture dish and how many more real opportunities might have been identified sooner? Maybe the future includes testing across a panel of media which includes physiological plasma-like media as well as tumor-mimicking low-nutrient media. It would be slower and messier…but possibly much more efficient for patching up our leaking drug development pipelines, which would ultimately make it more cost-effective. Anyway, I realise it’s a possible future rather than an easily solved problem today, but I’m curious to hear any thoughts, especially from folks involved with these sorts of large scale drug discovery screens.
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Fun fact: The cell culture media you’re probably using was invented before the moon landing.
BME, 1957 DMEM, 1959 RPMI, 1966 Here we are, still using them as the defaults for human cell culture, despite the fact that we have learned so much more about the human body in the past 60-70 years. Enter Plasmax, 2019. Frankly, I’m shocked that it’s not more widely used because it’s a delightfully simple concept; profile human plasma, then recreate it in basal media form. If you want cells to behave like they do in the body, give them something that actually resembles the body. Plasmax is a great reminder that so many of the standard “best practices” we’ve inherited in science were built with the tools and knowledge of their time. As our knowledge and capabilities improve, so should our tools. Don't get me wrong, the original basal media still very much have their place, but let's select our tools deliberately rather than relying on defaults. My two cents? If you’re a scientist studying metabolism, cancer biology, or drug discovery, this is one of those innovations worth paying attention to. All the details can be found in Vande Voorde J, et al. Sci Adv. 2019 https://pmc.ncbi.nlm.nih.gov/articles/PMC6314821/ How much fetal cow goes into 1 x bottle of FBS? It depends on the age of the fetal cow in question, but 150mL-500mL; that’s how much FBS you can harvest from 1 x fetal cow. Really puts into perspective all those bottles of FBS that arrive neatly frozen by the pallet into some companies. There are lots of reasons I’d like to see cell culture’s reliance on FBS disappear; improved reproducibility for experiments and smooth regulatory approval for cell therapies are often called out by my collaborators who want to go chemically defined. But there’s also an emotional ick factor once you start being unable to stop yourself from calculating the number of fetal cows that went into your FBS order. If you’re a Sydney-based scientist, this cow thinks you should know: the third and final stage of external testing for FBS Replacement Solution by Media City Scientific is kicking off September 1st. I provide the animal-free and chemically defined product, you provide the cells. You’ll get one to one support in going chemically defined - even if your process doesn’t ultimately involve FRS - and we’ll be able to launch a product that has been heavily street-tested, so we can be super transparent with scientists about how it works across a broad range of cells. No use case too basic or too unusual, we’ve seen everything from cell culture courses & CHO cells to organoid-based therapies destined for scaled, cGMP manufacturing. Just send me a message ☺️  |
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January 2026
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