RARE‑seq and the dawn of liquid biopsies
A groundbreaking study published in Nature on April 16, 2025, describes RARE‑seq, a liquid biopsy that decodes cell-free mRNA to reveal not only cancer presence but also treatment resistance and tissue damage, all from a simple blood test.
Traditional liquid biopsies focus on circulating tumor DNA (ctDNA), mutated fragments that point to cancer presence. RARE‑seq shifts the focus to cell-free messenger RNA, which reflects real-time gene expression, capturing a richer picture of cell behavior.
However, mRNA in the bloodstream is rare (under 5% of cell-free RNA) and easily drowned out by platelet RNA. Stanford spent six years refining methods to isolate and amplify just 5,000 “rare abundance” transcripts, boosting detection sensitivity more than 50-fold.
“We can learn a lot about what is going on in the cells of a patient’s body based on the degraded RNA molecules…, “It’s not just about finding cancer,” co-author Maximilian Diehn said. “It’s about seeing the body react, before disease shows itself in any other way.”
Imagine a patient who recently completed treatment for lung cancer. They feel fine, scans look stable, but cancer doesn’t always show itself in imaging right away. With this new RNA test, clinicians could detect tiny shifts in gene expression that hint at treatment resistance or early recurrence. It means more time to act, and potentially, more lives saved.
For people with no cancer diagnosis at all, but someone with a long smoking history, this test can detect lung damage signatures before symptoms or imaging reveal them. This opens the door for earlier counseling, interventions, or lifestyle change when it still matters most.
The test also showed promise in tracking tissue injury from acute conditions like COVID-19 and ARDS. In the future, patients recovering from infection, organ transplant, or autoimmune flare-ups might get real-time feedback on how their body is healing. For doctors, this means adjusting care based on actual biology, not just waiting for visible signs.
And perhaps most powerful: in cancer therapy, resistance doesn’t always come from mutations. Sometimes, cells shift identity – like lung tumors transforming into more aggressive types under treatment pressure. RARE-seq picks up those non-mutational changes, offering a rare window into evolving resistance before a patient’s condition worsens.
In short, RARE-seq transforms the blood into a narrative, revealing how the body is coping, adapting, struggling, or recovering. It humanises precision medicine by giving us earlier signals and actionable truths, not just data.
Alizadeh explained. “Our non-invasive approach has the potential of avoiding surgical biopsies and identifying these common types of resistance earlier before substantial disease burden shows up on scans or presents with symptoms like pain, providing an earlier opportunity to change treatment and improve outcomes.”
Going forward, this will mean clinical trial banks can be reanalysed for insights as the computational method corrects for platelet noise, enabling use on archived samples and providing a further wealth of information.
RARE-seq points to a future where molecular testing goes beyond static snapshots of DNA and starts capturing the body’s changing biology in real time. At Zetta, we’re building XetaBase to meet that future – integrating DNA, RNA and other data types to support more dynamic clinical interpretation and enabling more personalised approaches to diagnostics and care.
What makes RARE-seq remarkable isn’t just the science; it’s what that science can mean for people.
