What Are Those RNA Modifications Doing for Gene Regulation?

When we talk about gene expression, most of the focus is on DNA and RNA sequences, but there’s a lesser-known, more subtle layer of regulation: RNA modifications. In this episode, I spoke with Gudrun Stengel, CEO and co-founder of Alida Biosciences, to explore how this fine-tuning mechanism affects everything from cell differentiation to cancer survival, and how her company is helping to decode it.RNA Modifications: A Hidden Code Within the CodeGudrun kicked things off by explaining how RNA modifications influence gene expression at multiple levels: splicing, translation initiation, intracellular trafficking and mRNA half life. These changes enable the cell to switch functions on or off quickly, presumably in response to some cue or cascade of events.The most studied RNA modification is m6A. Its effects depend heavily on the context in which it occurs, acting through “reader” proteins like YTH family members. m6A plays crucial roles in processes like stem cell differentiation and cancer survival. For instance, without m6A, pluripotent stem cells fail to differentiate. On the other end of the spectrum, overexpression of m6A-related enzymes in cancer can help tumor cells evade programmed cell death.Not subscribed? Let’s fix that. No spam, just good content wherever I find it.The Tools Are Just Now Catching Up to the BiologyOne of the big hurdles in studying RNA modifications has been detection. These modifications occur at low frequencies, sometimes affecting just 0.1% of a given base, and lack a "reference genome" to compare against. Traditional approaches using mass spectrometry or antibody pull-downs have significant limitations in resolution and specificity.That’s where Alida Biosciences’ EpiPlex platform comes in. It allows multi-target detection of RNA modifications with a sequencing-based approach. Their method attaches barcodes to RNA segments where modifications occur, enabling quantification without relying on antibodies.Unlike academic tools built for discovery, AlidaBio’s platform is designed to be robust and scalable, bringing more reliability and speed to RNA modification analysis. It offers about 100–200 base pair resolution and focuses on three key modifications: m6A, pseudouridine, and inosine.Why It Matters: From Diagnostics to Drug DiscoveryThere a several potential applications. For diagnostics, RNA modification patterns could help differentiate between disease states that look nearly identical via RNA-seq alone. Gudrun mentioned studies in glioblastoma where RNA modification profiles enabled more accurate cancer staging.RNA modifications could also guide drug development. For example, Storm Therapeutics is already testing METTL3 inhibitors in leukemia. There’s also growing interest in plant engineering, and tuning the epi-transcriptome could help increase crop yields and stress resistance.Alida Biosciences’ Vision: More Than a Tools CompanyGudrun sees AlidaBio not just as a platform company but as a partner in solving real-world problems. Long-term, she hopes to expand into clinical applications and potentially therapeutics, either by developing companion diagnostics or helping modulate modification states for therapeutic benefit.I’ve been studying biology for 45 years. This episode gives me a renewed appreciation for the complexity of biological systems. Every time it seems we have it figured out, there is a new level of regulation to be discovered. It reminds me of when we thought atoms were just protons, neutrons and electrons. Then we discovered quarks.Your deepest insights are your best branding. I’d love to help you share them. Chat with me about custom content for your life science brand. Or visit my website. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit cclifescience.substack.com