A new article explores in exquisite detail the genesis and evolution of nanopore sequencing as seen through the eyes of the academic pioneers and British unicorn company Oxford Nanopore.
In 2008, I arranged to meet a trio of young executives from a small British start-up called Oxford Nanopore Technologies (ONT) at a genomics conference in San Diego. The trio had just flown in from London but as we ordered our first round of drinks on a hotel patio at sunset, they appeared energized by the bucolic surroundings and the tranquil California weather. Gordon Sanghera, PhD, had taken the reigns as chief executive after a successful stint at a medical devices company. He was accompanied by business executive Spike Willcocks, PhD, and communications chief Zoe McDougall.
Sanghera impressed me with confident stories of how his fledgling company would one day transform the next-gen sequencing (NGS) space. Supporting data were scant but undeniably tantalizing: Willcocks opened his laptop and showed me the schematic models and preliminary results that fueled an almost magical vision for the future of DNA sequencing: a pocket-sized instrument—the MinION—that could read out a DNA sequence in real time by enzymatically chopping a single strand of DNA, like a master chef slicing a scallion, capturing the signature of each nucleotide as it was sucked into the belly of a bacterial nanopore protein.
This was almost too-good-to-be-true, but I admired their ambition coupled with an ability not to take themselves too seriously. I was also intrigued because, when it came to its reputation for cutting-edge life sciences research and commercial spin-offs, Oxford University (my alma mater) usually played second-fiddle to Cambridge, with its legendary history in molecular biology of Crick & Watson, Fred Sanger, and more.
Indeed, the NGS revolution had its roots in Cambridge, as two chemistry professors, Shankar Balasubramanian, PhD and David Klenerman, PhD, both since knighted, launched a company called Solexa. In 2006, Solexa was acquired by Illumina, supplying the sequencing-by-synthesis technology platform that would dominate the NGS space for the next 15 years and counting.
None of that seemed to worry these upstart Oxford entrepreneurs. “We might open up with Monty Python’s ‘And now for something completely different!’” Sanghera said as he anticipated ONT’s arrival on the scene. I had a hunch he wasn’t joking. I summarized our San Diego conversation in my book, The $1,000 Genome, published in 2010.
Two years later, the company’s chief technology officer, Clive Brown, delivered one of the more memorable talks at the Advances in Genome Biology & Technology conference, the marquee science conference in Marco Island, Florida. By this time, ONT’s sequencing strategy had shifted to running an unzipped single strand of DNA through the nanopore, using some sophisticated algorithms to compute the corresponding sequence from the squiggly shifts in electrical resistance.
Brown’s unveiling of the MinION—a two-hour lecture crammed into 17 minutes, delivered with dry British humor (and, yes, a Python reference)—electrified the audience and signaled a new contender in the NGS arena. “So we did a genome,” Brown said nonchalantly, referring to the decoded sequence of the virus PhiX174. (Seven years earlier, he’d led the Solexa team past the same milestone.) On Twitter, scientists positively drooled about the arrival of nanopore sequencing.
However, not everything went to plan in those early years: product launches were delayed by microchip design flaws, deals went awry, and lawsuits inevitably started flying. But ONT weathered the storm, winning droves of loyal fans enamored by the platform’s plug-and-play ease of use and extraordinary portability. Today, the company offers an expanded portfolio of sequencing products and with community support, has greatly improved the accuracy and flexibility of the sequencing platform. Together with rivals PacBio, ONT provides long-read sequencing to complement the short-read technology of market leader Illumina.
To its credit, ONT has lost none of its swagger. Sanghera still likes to make a grand entrance at the company’s customer events, striding on stage accompanied by heavily amplified riffs from The Clash or The Arctic Monkeys. Press speculation says that ONT is finally on course for an initial public offering; it has raised more than $800 million since launch and is valued at around $2 billion.
Top marks
For those interested in the origins and current status of nanopore sequencing, a new article will prove invaluable. “Nanopore sequencing,” written by science historian Lara Marks, is available at What is Biotechnology?
Marks delves into the academic origins of nanopore sequencing, interviewing the pioneers including David Deamer, PhD, (who first sketched the idea for nanopore sequencing in 1989), and Oxford University chemist and ONT co-founder Hagan Bayley, PhD, while highlighting the contributions of other luminaries including Daniel Stanton, PhD, Mark Akeson, PhD, and George Church, PhD. Marks reveals that the nanopore proof-of-concept study, co-authored by Deamer and Daniel Branton, PhD, published in PNAS in 1996, was— like many profound papers before and since—rejected by both Nature and Science.
As Marks points out, “ONT’s nanopore sequencing tools are now being used in over 100 countries by researchers in human, plant, animal, microbiological or environmental genetics.” It has been used for experiments on the International Space Station and come into its own as a portable tool for monitoring viral outbreaks (Zika, Ebola, and so on) in places like Africa and South America. It is currently seeing new applications in monitoring COVID-19 variants, using a diagnostic test called lamPORE.
Despite the technology’s progress, some big hurdles remain. Nanopore sequencing “challenges the prevailing culture of how sequencing is done,” Marks writes. “Many researchers have so far been hesitant about using the technology because they prefer to continue with PCR with which they have more familiarity.” ONT encountered similar resistance from the UK government when discussing COVID-19 testing operations.
The Marks article vividly demonstrates just how far nanopore sequencing has come from its humble beginnings. ONT’s upward journey will be one to watch for the next decade. It brings to mind another classic line from Monty Python:
“Kilimanjaro is a pretty tricky climb you know, most of it is up until you reach the very, very top—and then it tends to slope away rather sharply.”
