Genomics Spotlight Shines on Nanopores

DNA strand sequencing. Image: Oxford Nanopore Technologies

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While most of us wait in vain for our 15 glorious minutes of promised fame, biomedical engineers are very close to giving us a similar and far more worthwhile moment in the spotlight. A new DNA sequencing technology is about to hit the market that promises to let doctors record our genetic "autograph" —our complete genome—in about 15 minutes, for less than $1,000.

Traditionally, famous people put their unique personalities, warts and all, on display to secure a place in history. The new sequencing approach, previewed by Oxford Nanopore Technologies, Oxford, UK, in February 2012, accomplishes the same feat without the paparazzi, personal drama, and other pitfalls of celebrity. It allows anyone to impact the world, and their own health, by measuring their genome and sharing that data with the medical research community. The more disease-causing genetic "warts" scientists can collect and study, the faster they will hone in on new drugs that fight or even cure complex diseases like cancer and diabetes.

The goal is to target the molecular underpinnings of disease rather than outward symptoms, and to one day match every patient with molecularly targeted therapies specific to their unique condition. That's personalized medicine, and that's why so many biomedical instrument companies are vying to market instruments that decode genomes faster and at ever lower cost.

Nanopore Technology: The "Hole" Story

The promise of 15-minute throughput was just one of the tantalizing hints Oxford Nanopore has dropped lately about its soon-to-debut GridION benchtop sequencing platform. The company has also for the first time publicized actual performance data, the genome of virus, which reassured the genomics world that this decade-in-development technology really does work. Equally exciting was a miniaturized version, the handheld MinION sequencer, with a doctor's-office-friendly $900 price tag. Both systems promise little-to-no sample preparation, a major rate-limiting step in current sequencing.

This illustration shows the techniques that Oxford Nanopore hopes to use to sequence complete strands of DNA. Image: Oxford Nanopore Technologies

The heart of a nanopore sequencer is an ultrathin membrane fabricated from pore-forming proteins such α-hemolysin. The naturally occurring pores in these biopolymers open to a typical inside diameter of just 1 nanometer—just large enough for single-molecule samples of DNA, RNA or protein to slide through. Controlling the speed at which the sample moves through the pore is critical, so bioengineers have added other substances to the membrane to regulate the speed of analysis.

An ionic current moves across the membrane and, as the DNA sample is fed through, the current is disrupted. Each component of the DNA material causes a characteristic change in the current that can be identified by a smart detector chip.

The GridION can work independently but its full potential is as a node within a scalable network of interconnected and synchronized sequencing devices clustered on standard computer racks. For example, the jaw-dropping 15-minute sequencing speed the company recently touted would require a system of 20 nodes each configured with 8,000 nanopores.

Agile Engineering

High-speed sequencing requires expertise in chemistry, biology, electronics, and computing. Developing a practical commercial instrument requires an interdisciplinary team, including mechanical engineers, to integrate all of these disciplines into something that's viable in the highly competitive and rapidly changing genomics market.

With that in mind, Oxford Nanopore committed to a philosophy of agile product development across its entire operation. Agile development is common practice in software engineering but is "relatively unusual for a mechanical engineering team," says company spokeswoman Zoe McDougall.

"We have a very interdisciplinary technology, which requires interdisciplinary working methods. We use agile development across all of our groups to integrate the technology. This in essence means that we always have a modular, working instrument and are always upgrading all of the components of that instrument to improve its performance. Over time, of course, design versions become fixed for manufacturing, but we are continually improving."

Most details of the GridION and MinION systems are under wraps until the product is officially launched in the months ahead. However, McDougall did allow that company engineers have been contending with some interesting engineering challenges in the areas of miniaturization—especially with the handheld MinION system—and have patented innovations such as novel valve designs.

"Our products are for the life sciences research and ultimately clinical and other markets. However they have been designed in a similar way to medical devices, in that there needs to be a very small, consumable/single-use component," she says. Oxford's in-house engineers have focused on "achieving a very small footprint for a unit that includes electronics, fluidic systems, and other moving components. We have found that external contractors were not able to achieve what we have done in-house."

Frenetic Genetics: The Race for the $1,000 Genome

Oxford Nanopore's high-profile announcements have put the company at the vanguard of fast, sub-$1,000 sequencing for the moment, but there is plenty of competition. IBM and Roche have teamed up to develop their own version of the technology. Other nanopore-based start-ups are in the wings, to say nothing of the host of major players pursuing other novel sequencing technologies. But if its machines live up to their advance publicity, Oxford Nanopore is set to play a starring role in this new era of individualized health care.

Michael MacRae is an independent writer.

We have a very interdisciplinary technology which requires interdisciplinary working methods. Zoe McDougall, Oxford Nanopore Technologies

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