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And Now For Something Completely… Disruptive

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clarity challengeFebruary 27, 2012 

Kevin Davies :  Four years ago, I met three young executives from a small British start-up, just off a 10-hour flight from London to California. We adjourned to the patio of a San Diego hotel, where they promptly ordered a round of beers and whipped out a laptop to show some tantalizing unpublished data that could pave the way to a cheap, high-throughput next-gen sequencing device using bacterial nanopores.

The head of the group - Oxford Nanopore’s co-founder and chief executive Gordon Sanghera - struggled to contain his enthusiasm. “One of the things we do bang on about is a British company finally delivering something,” he said. But when the time was eventually right to unveil the technology, they would make the announcement with a minimum of flash.

“There’ll be no fireworks,” Sanghera said, referring coyly to the Pacific Biosciences beachfront pyrotechnics display at the AGBT conference a few weeks earlier. “We’ll just give our presentation in a very dry British way. We might open up with Monty Python’s ‘And now for something completely different’… That’ll be as close as we get. We want to come over as a very reputable science and technology company.”

Fast forward four years: During his presentation at AGBT earlier this month, chief technology officer Clive Brown didn’t imitate John Cleese, but he did slip in a slide of the killer bunny from Monty Python and the Holy Grail. The premise was that Oxford Nanopore’s new MinION USB stick sequencer can reportedly sequence DNA from rabbit blood.


Brown joined Oxford Nanopore in 2008, having played a key role in building the Solexa sequencing technology that Illumina acquired the year before for $650 million. In an interview for my book The $1,000 Genome a few years back, he said: “I wasn’t convinced initially [on interviewing for the Oxford Nanopore job]. After 30 minutes, I was sold.” But he urged Sanghera to hire his former Solexa colleague John Milton, believing that Oxford would need the services of an expert industrial chemist. The two men joined that summer.

A Great Disturbance 

Brown and his colleagues chose to stay quiet for four years, sticking with the philosophy espoused at Solexa, spurning many opportunities and invitations to announce incremental milestones.

The initial reviews of Brown’s 17-minute presentation – widely reported by myself at Bio-IT World, the New York Times, Keith Robison at Omics! Omics!, Nick Loman at Pathogens: Genes and Genomes, Luke Jostins at Genomes Unzipped, Omically Speaking, and many other sources - have been extraordinarily positive. The real-time reviews on Twitter following Brown’s talk give you a sense:

“When can I buy one?”
“The first problem is I'm going to have to clean up all this drool.”
“Screw the #iPhone introduction, this is truly mind-blowing.”
“obi-wan: I felt a great disturbance in the force, as if a million #illumina investors cried out in pain.”
“The @nanopore press release also reveals that the MinION syncs with iTunes, acts as a 3G modem, and has a fresh lemon scent.”
“I feel sorry for anyone else giving a talk today.”
“This may be disappointing, but the only thing I have on my USB stick is my talk.” 

The only mild criticism:
“In the cold light of day, vaguely sad that tech vaporware stole the show from real biology.” 

And Eric Olivares, impresario of SeqAnswers, said:
“Waiting to see the 48.5kb lambda read… #makemeeatmywords” 

Oxford Nanopore posted a link to their 2011 Christmas card, wondering if anyone spotted the deliberate clue?!

Oxford Nanopore 

As the announcement took a swift toll on the stock prices of NGS competitors (note that Illumina has a 15% stake in Oxford Nanopore and thus in essence a hedge against such downturns), Forbes’ Matthew Herper sought comment from Ion Torrent founder Jonathan Rothberg, who was the toast of the industry just one month ago with the introduction of the Ion Proton. He likened the furor around Oxford Nanopore to cold fusion, and wondered why for example the company hadn’t presented a bacterial genome sequence?

Such cynicism prompted Michael Eisen to respond on Twitter: “Nobody knows about overhyped and not ready for prime time sequencing tech like jonathan rothberg.”  

Brown had a quick retort as well: “We had MinION systems with us in our suite. I held one up during the talk, I understand it’s so small it may not have been visible from the back of the room.”  

New Generation  

On the face of it, Oxford Nanopore’s new generation sequencing (as they call it) technology boasts many desirable features. Here are ten reasons (I could think of more) to be excited:

10. Long reads, sufficient to sequence a virus in a single run
9. Even quality without degradation across the entire length of the read. Accuracy good (96% raw read) with road to improvement
8. Sequence of both sense and anti-sense strands in succession courtesy of a hairpin loop at the end of the DNA template
7. Ease of sample prep – no fluidics!
6. Proprietary nanopore and synthetic polymer bilayer for greater robustness
5. A topoisomerase of some description (helicase? gyrase?) for unzipping double-stranded DNA prior to sequencing, rather than the use of a polymerase to ratchet the DNA through the pore
4. A novel bioinformatic method for reading the sequence in overlapping triplets, involving Hidden Markov models and Viterbi algorithms
3. “Run until done” modality in which experiments are monitored in real time and halted depending on results
2. The world’s first disposable sequencer on a USB stick, with no ownership overheads and an accessible workflow for a single researcher
1. A pathway to the $1,000 genome in under an hour by 2013 using an 8k array

Now, all this is well and good, but until raw data are presented and published, a degree of skepticism is to be expected. As Elaine Mardis told an audience at NHGRI last week, “We are scientists after all.” Keith Robison has a considered plea for data release at Omics! Omics! 

But those requests will be answered soon, no doubt. The early access program is apparently set, and eager users shouldn’t have to wait more than 6-9 months before commercial release.

I-Study: Genomic Interpretation - Who Will Pay?
During this webinar, members of the study review team present preliminary findings of the I-Study, conducted at the Harvard Medical School's 2011 Personalized Medicine Conference.
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