A chat with Oxford Nanopore's Clive Brown at AGBT 2013

Don't judge me, reader, because I'd skipped a session at AGBT to go and have a swim in the sea. A man can only spend so much time in dimly-lit, low-ceilinged hotel conference rooms, popping low-sugar sweets, before the will to live ebbs away.

On returning to the conference, passing the bar I spotted a distinctive bald head. Wait. I recognise that guy. Was it him?

I reversed and took another peek. Yes, it was Clive Brown, deep in a meeting. "Hello Clive!". He looked up, slightly grumpy to be interrupted mid-flow. "I'm Nick Loman, wasn't expecting to see you here!". Oh hello Nick. I catch a glimpse of a prototype MinIon on the table. "Hah, yeah, I've buried three of those on the beach. Tell everyone!"

We meet in the bar the next day. Clive talks at machine-gun pace, whilst fiddling with a prototype MinIon which is on the desk, repeatedly taking it apart and reassembling it, like a soldier checking his gun before battle. It feels weighty, substantial, larger than the version announced previously. It's got a mini-connector for USB3. "Feels a bit too expensive for a disposable sequencer, needs to be more plastic-y", I venture. Clive agrees.

Clive is angry. He feels he's been treated unreasonably by the community, and the press, since AGBT 2012's electrifying announcements. "I'm bloody sequencing single molecules directly on this little device here!". The implication is that no-one should be surprised it's taken longer than expected to be released. He is unapologetic.

Clive is angry. He's angry with the guy that marched to the nanopore suite at AGBT, banging and shouting through the door: "Where is your data? Show us the data!!".

Clive is angry with reporters who keep asking him the same questions: why they haven't released data, why they haven't fulfilled their promise of commercialisation by the end of 2012.

Clive has a list. A list of people that says he'll see to it won't get a MinIon when it comes out. I can't tell if he's joking.

So why didn't you release some data, Clive? He tells me that the raw signal data is commercially valuable, that someone in the business could take the traces and reverse engineer details of their customised nanopore this way. The idea that other parties could steal information to further their own nanopore projects is a recurring theme in our chat.

So why didn't the MinIon come out in 2012? Technically, he lists several setbacks. The custom sensor microchip (ASIC) wasn't performing as they wanted, necessitating a redesign from scratch. "That put us back about 5 months, but it was the right thing to do". There have also been problems stabilising the lipid bilayer, and so over days and weeks it degrades. He set his team a new accuracy target of 1%, a major improvement from the 4% error rate announced at AGBT.

I venture the idea that even if the MinIon is a year, two years late, if it's half as good as he says it is, all will be forgotten. Like waiting for the next version of Quake or Grand Theft Auto.

"It's not going to be that long, we're going to start announcing stuff this year, including data from our early-access programme."

Why don't you engage with the community better? I suggest that no tweets and no web updates isn't a good look for a company with so many eyes on. He says that they have to be careful about putting any information out there right now, in case it is used against them. He suggests that now Zoe McDougall, their communications director is back from maternity leave, they will improve their communication with the community.

Technical breakthroughs. They've found that error rates can be improved by having multiple nanopores on the chip with different properties, and then merging the data. Some nanopores are better at recognising certain nucleotide signatures than others, and so they can be complementary. This is a hint that consensus accuracy might ultimately be important, a la Pacific Biosciences. ** see footnote

He's keen on the idea of nanopore as a disruptive technology for proteomics, citing the unfoldase that should permit proteins to pass through the pore.

Clive is a man under pressure. I genuinely got the impression that the company were caught off-guard by all the attention and had no idea they would be under such scrutiny.

"We didn't even know that long reads were so important to people until after that AGBT presentation." He explains that he set his team a technical challenge to go from 20kb to 50kb to 100kb, simply because he likes pushing them further than they think they can go. His focus on getting error rate down to 1% results from similar pushing, sometimes to the chagrin of the commercial side of the operation.

Clive is guarded, and regularly checks himself, ensuring he doesn't say anything that would "get him in trouble".

"You know what, I hated doing that presentation at AGBT. I had to hide in my room for two days afterwards."

"I'm not Jonathan Rothberg".

What do I think? I find it hard to simply write-off nanopore as vapourware, as some seem happy to do. There is a great group of people in this company, and frankly it just wouldn't be cricket to promise so much without delivering. I will wait and see. I feel sure the conversation will have moved on by AGBT 2014.

"I want to believe" as they might say on the X-Files.

Plus, I don't want to end up on Clive's list.


** Clive has written to clarify this point: I didnt mean that as an alternative to raw read, but it came up repeatedly during the conference that a number of early access groups are trying to do major projects to "improve the reference" of their given organism. They are currently mixing a number of short reads from different technologies and without the long reads, they have difficulty assembling (a major use of PB data). I have noticed that with two pores (or more) we effectively have two orthogonal error modes, which means this kind of improved reference, with assembly, can be done economically on one platform – which should be a lot easier.