Democratizing MRD
An overview of some interesting enabling technologies
As I look toward the future of MRD, a few themes loom large: ultra-sensitive tumor-informed MRD detection should not be gated behind massive infrastructure, patients should not have to wait weeks for results, and sensitivity can always be improved. In the post below I highlight a few enabling technologies that I think will impact MRD solutions now or might do so in the not-too-distant future.
FYI: in this post I am intentionally not considering tumor-naïve solutions although they certainly have their place in the testing landscape.
Why are MRD tests all run on Illumina’s NovaSeq?
Because it is the most cost effective way to run a sequencing factory and reduce the costs of the biollions of reads needed to generate the tumor fingerprint to identify varinats for MRD tracking, the normal genome to remove CHIP variants, and then finally the deep plasma sequencing to detect MRD.
This means most of the MRD companies out there use a ton of NGS to get a result and that requires a NovaSeq…or an Ultima (I’m less sure if anyone is delivering MRD on Element - drop me a message if you are).
The challenge with needing a massive sequencer is you have to fill it and you probably won’t find it anywhere near your local hospital. So what would happen if you could reduce the number of reads you needed and move MRD from NovaSeq to NextSeq for instance?
Enspyre: MRD with >90% less sequencing?!
At AACR 2026, Rita Zhou in my team presented Abstract 1143: Enspyre: A novel enrichment technology enables ultra-sensitive ctDNA detection with 98% reduction in sequencing requirements. The major advances in ultra-sensitive MRD have come from a move to WGS-informed fingerprinting and increasing the numbers of variants being tracked (e.g. Personalis NeXT Personal (1800 variants), Myriad MyChoice (1000 variants) and Signatera, who moved from Exome+16 variants (E16) to Genome + 256 variants (G256, incl phased-variants). For the companies built on hyb-cap of large numbers of variants there’s a lot of sequencing data needed to get to the ultra-low PPM levels and that means these assay runs on Illumina’s NovaSeq line, usually found in larger centres.
In our AACR 2026 poster and a recent publication (Scientific Reports 2026), we demonstrated how the Biofidelity Enspyre technology can reduce sequencing depth by well over 90%. This is in line with their earlier paper and their AACR 2026 Analytical Validation poster, where Biofidelity achieved 5PPM LOD in cell lines with just 10M reads.
If you do not know the Enspyre technology it is worth taking a look at. It works similarly to standard hybridisation-capture but instead of using a simple change in pH or temperature to release the captured DNA fragments, BioFidelity use selective pyrophosphorolysis to enrich variant-containing molecules. This essentially PCR in reverse, and it digests the biotinlyated probe sequence in an exquisitely sequence specific manner such that any mismatch causes digestion to stop. As such only mutant alleles are releaseed back into solution for downstream NGS, massively reducing background wild-type sequence, and therefore reducing the sequencing needed to find mutant molecules.
In our experiments using MATRIX samples (the plasma-in-plasma reference materials we designed to assess new technologies) we were able to achieve ultra-sensitive ctDNA detection at 10 ppm with a 98% reduction in sequencing depth. This means it should be possible to achieve 100% sensitivity at 10PPM entirely on a benchtop NextSeq 550 and/or increasing the numbers of variants to many thousands to increase sensitivity whilst maintaining reasonable cost per test. This takes MRD out of the realm of massive NovaSeq runs and so could be a massive leap for democratization. It means smaller labs and community oncology centres can run ultra-sensitive, kitted MRD solutions in-house rather than shipping samples to centralized hubs.
TWIST MRD Express: Closing the TIA vs. TNA Turnaround Gap
Sequencing depth is only one of the challenges for ultra-senstiive tumor-informed MRD; the other is turnaround time (TAT). The clinical utility of personalized, tumor-informed MRD tracking is often constrained by the complexity of panel design and somewhat lengthy manufacturing lead times. This delay has historically given off-the-shelf, tumor-naïve panels a distinct logistical advantage.
However, the recent AACR poster from TWIST Bioscience on their MRD Express Panel showcases a scalable target enrichment workflow that fundamentally changes this math. Leveraging a silicon-based DNA synthesis platform and proprietary design algorithms, their automated pipeline can achieve a rapid turnaround time of as little as one business day from synthesis to shipment. And they can do this for panel sizes up to 5,000 probes.
To ensure robust performance across challenging genomic regions, Twist implemented an innovative Locked Nucleic Acid (LNA) boosting strategy that enhances coverage uniformity for probes with extreme GC content. When paired with a double-stranded staggered probe design, they can dramatically expand the available unique sequencing depth.
A 24-hour panel generation timeline shifts the paradigm for tumor-informed assays. It allows highly optimized, personalized tracking to be deployed almost as quickly as TNA assays, enabling early detection of molecular relapse within clinically actionable decision windows.
Pushing the Floor: Aarhus Vignettes
The innovation certainly doesn’t stop there. I recently had the pleasure of speaking at the International Symposium on ctDNA in Aarhus this past May, and I was struck by a couple of remarkable early-stage posters from Syndex Bio and Amplifyer Bio that tackle the signal-to-noise floor from entirely unique angles.
Syndex Bio: As shown in their “mcPCR: PCR For Methylation” poster, David McBride and his team presented their technology that enables amplification of native DNA whilst preserving its methylation status. In a single-tube reaction they perform PCR and a “methyl-copy” reaction that synchronizes base extension and methylation preservation using novel enzymes. This overcomes a massive bottleneck by avoiding destructive bisulfite conversion while completely preserving epigenetic signals from tiny inputs of cfDNA.
Amplifyer Bio: In the poster titled “Improving Liquid Biopsies by Boosting ctDNA Yield with Humanized Priming Agents”, Julia Amaral, Fujiko Duke, and their co-authors introduced an engineered DNA-binding antibody that acts as an in vivo “priming agent”. By shielding cfDNA from biological clearance, they demonstrated an incredible up to 100-fold increase in ctDNA recovery, significantly shifting the boundaries of what is stochastically catchable in a standard blood draw.
Whilst they do not explain it quite as such I see this technology as analogous to a contrast agents for MRI, where the Gadolinium dramatically improves the detail of soft tissues and tumors, but this contrast agent for ctDNA boosts the signal we can detect using standard liquid biopsy techniques. See their Science paper from 2024 for more detail.
Both Syndex Bio’s non-destructive methylation amplification and Amplifyer Bio’s in vivo target preservation protocols could improve detection sensitivity of current tests by adding in a signal boost. The biggest impact could be for tumor-naïve methods, which are currently sitting at around 500PPM LOD. Would adding either of them push the limit of detection down to 100PPM? And if we stacked these technologies in a single workflow, would the sensitivity gains be simply additive, or truly multiplicative, maybe pushing down even further into the single-digit parts per million range?
These are exactly the questions we need to answer as we build out the next generation of liquid biopsy. But I’ll save that deep dive for another post.