In the past two decades, DNA sequencing has transformed biology, medicine, and biotechnology. From the Human Genome Project to single-cell transcriptomics, sequencing technologies have continuously evolved to deliver faster, cheaper, and more accurate insights. Yet, even with remarkable progress, challenges remain. High-throughput sequencing is still costly, and accuracy limitations restrict its broader clinical and industrial use.
Sequencing by Expansion (SBX)—a new single-molecule sequencing technology designed to break through these barriers. Developed originally at Stratos Genomics (now Roche), SBX introduces a fundamentally new way of reading DNA that promises higher signal clarity, lower error rates, and scalable throughput.
What Makes SBX Different?
Traditional sequencing methods, including short-read platforms and nanopore sequencing, struggle with accuracy and signal noise. Nanopore sequencing in particular, while revolutionary for its real-time readouts and long reads, has been hampered by poor resolution of homopolymers and raw error rates above 3%.
SBX tackles this by converting DNA into a measurable surrogate polymer called an Xpandomer (Xp). Instead of directly forcing native DNA through a nanopore, SBX first expands the sequence information into a longer, engineered molecule decorated with “reporter codes.” These reporters generate strong, distinct electrical signals when passing through a nanopore, dramatically improving signal-to-noise ratios.
This decoupling of chemistry from measurement is a critical innovation. DNA is first expanded into Xpandomers using a specialized polymerase (“Xp Synthase”), engineered nucleotides (XNTPs), and cofactors (PEMs). Once formed, these Xpandomers are read by a nanopore system in a controlled, stepwise fashion. The result: clearer signals, higher accuracy, and efficient base calling.
Key Innovations Powering SBX
SBX is not just a tweak on existing sequencing—it’s a ground-up reimagining. Some of its core innovations include:
- XNTPs (Expandable Nucleoside Triphosphates): Custom nucleotides that carry unique reporter codes for each base.
- Xp Synthase: A highly engineered polymerase capable of incorporating XNTPs to build long Xpandomers.
- PEMs (Polymerase Enhancing Moieties): Cofactors that stabilize and extend synthesis, allowing hundreds of bases to be expanded accurately.
- Controlled Translocation: Molecular elements that ensure Xpandomers pass through the nanopore one step at a time, reducing sequencing errors.
Together, these features enable SBX to overcome one of the toughest challenges in nanopore sequencing: distinguishing individual nucleotides with high fidelity.
Why It Matters
For researchers and industry professionals, SBX represents more than a technical achievement—it’s a potential paradigm shift. By delivering high-quality single-molecule sequencing at scale, SBX could reshape how we think about genomic analysis:
- In Research: From single-cell RNA-seq to spatial genomics, SBX could power experiments that demand both accuracy and high throughput.
- In Medicine: Clinical applications such as cancer genomics, rare disease diagnosis, and population-scale studies could benefit from lower costs and faster turnaround times.
- In Industry: Biopharma and biotech companies may gain a tool that accelerates drug discovery, biomarker development, and synthetic biology innovations.
Looking Ahead
The preprint data from Roche and collaborators show promising results, including sequencing of challenging DNA templates with impressive accuracy. With ongoing integration into high-throughput sensor arrays, SBX is poised to scale further—potentially enabling millions of parallel measurements.
For students entering the field, SBX is an exciting reminder that sequencing technology is still evolving. For industry stakeholders, it signals an opportunity to adopt next-generation sequencing methods that balance performance, cost, and accessibility.
Reference: https://pmc.ncbi.nlm.nih.gov/articles/PMC11888190/
