Nanopore technology: Turning up the volume on DNA sequencing
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Diagnostic innovation starts here
One of the biggest breakthroughs in DNA sequencing was an achievement almost 20 years in the making. Unveiled in 2025, it brought together chemistry, biology and cutting-edge technology to overcome challenges that had long stood in the way of progress in sequencing.
When it all came together, it was magic.
That magic was the combination of sequencing by expansion (SBX) technology – a revolutionary approach to sequencing that works by transforming genetic material into a format that's easier to read – with a high-density electronic sensor module and rapidly renewable nanopore structures. They work together to process Xpandomer molecules – synthetic surrogate polymers that encode the sequence of DNA information into expanded molecules designed to improve signal clarity and accuracy when read through a nanopore.
Heart of the technology
Roche’s nanopore-based sensor module is the electronic heart of SBX. Since its acquisition from Genia Technologies in 2014, our Santa Clara team has refined this technology into a high-density electronic interface capable of translating biological signals into digital data at an unprecedented scale.
The module contains eight million microscopic wells, each one spanned by a thin membrane with a single nanopore through which a single molecule can pass. As an Xpandomer moves through the pore, minute changes in voltage are created that indicate shifts in pore resistance and correspond to specific chemical codes. These codes represent the genetic bases – adenine (A), cytosine (C), guanine (G) and thymine (T) – that are the building blocks of DNA. The system detects these voltage changes and subsequently translates them to the corresponding base, turning the molecule’s sequence into readable data. By using voltage pulses to control the movement of the molecule, the system can detect each distinct signal precisely and in sequence, with clear start and stop points for every piece of encoded information.
The result is an optical-free readout that captures billions of high-quality reads per hour with precision, scalability and flexibility – allowing the same sensor design to run both short, rapid analyses and large, high-throughput sequencing runs.
“The sensor module is where it’s all happening,” explains Barrall, a self-described “sensor guy” whose career has focused on building electronic sensors across a variety of applications. “It brings together chemistry, biophysics, electronics and signal processing.”
One of the quiet but critical breakthroughs that enables this custom micro-electronic system is the design of the nanopore technology’s synthetic, lipid-like membrane.
Each well in the nanopore system has a synthetic cell membrane across it. It took non-standard materials to make it work. The Xpandomer is 50 times longer than the original single stranded DNA template and can’t be read by traditional sequencing systems. So we had to adapt both the pore chemistry and the membrane itself to sense those signals.
The solution the team developed was a lipid membrane with a single nanopore that spans each microwell opening. This nanopore structure is unique in that it is stable over the course of a single sequencing run and can be reliably reformed from run to run.
“Unlike traditional, single-use systems, this membrane and its pores can be cleaned out and reformed to be used over and over again,” says Whitacre. “That matters for reliability, cost and sustainability.”
Finding signals in the noise
Traditional nanopore techniques struggle to sequence native DNA directly, because the bases are both small and tightly packed, causing overlapping signals that are difficult to distinguish. Roche’s approach with SBX addresses solves the spacing problem upstream. Instead of feeding native DNA into a pore, SBX first encodes the sequence into the new, longer, Xpandomer molecule. The Xpandomer preserves the original order of bases but spreads the information out and attaches distinct synthetic reporter features, boosting the resulting signal-to-noise ratio.
“The Xpandomer is a wondrous thing,” says Whitacre. “It’s a custom polymer, faithfully encoded from DNA, and we’re running it through a synthetic pore membrane that’s been adapted to sense those changes in signal.”
In practice, the process unfolds in two stages: synthesis and sequencing. During synthesis, enzymes and cleavable linkers build the Xpandomer from the DNA template. During sequencing, those Xpandomers are driven through nanopores where their clearer, stronger signals can be captured and decoded.
By separating the chemistry that creates the Xpandomer from the process that measures it, the system achieves a rare combination of speed, flexibility and cost efficiency – able to generate billions of high-quality reads under an hour, using the same reusable sensor module for both short and long runs.
Potential for future care
By lowering the cost and time barriers of high-fidelity sequencing, SBX provides a powerful new tool for the research community to explore genomic complexity.
Even in its current research-use phase, this technology enables scientists to ask deeper questions and accelerate the path from raw data to biological insight.
Disclaimer: For Research Use Only. Not for use in diagnostic procedures.
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