on Calling is imminent, and this is a notable one: the first held without Clive Brown in an official capacity at Oxford Nanopore. I started drafting a piece on Clive's tenure at ONT as soon as Nava Whiteford first broke the rumor (soon confirmed) he was leaving - that was back in November. But first there was writer's block and then a pair of elderly relatives had health crises, only one of which resolved desirably, and then the piece got stuck in my procrastination queue. But London Calling was an absolute deadline I set for myself and here we are.
One contributor to my discarding early drafts was trying to set the right balance. Clive was by far the most visible leader at ONT and so to him goes much kudos but also much criticism. Of course, in many cases it was someone else who deserves the credit or the debit, or at least the story is complicated. But I was never, as the song goes, in the room where it happened, so I am sadly blind to such nuance. It's also the case that Clive of early ONT is almost certainly not Clive of late ONT, and some of the foibles I dredge up might not be repeated. But, they are part of the story.
It cannot be over-emphasized that under Clive's technical leadership Oxford Nanopore condensed an incredible (as in, not to be believed) concept into an incredible (as in, OMG!) working sequencing technology. ONT sequencers enable sequencing about any place on this planet (and even above this planet!) a human can go due to the compact MinION design as well as its lack of moving parts, have stunningly low capital cost and are simple enough that even middle school students can be trained to sequence. The early "barely can align" data quality has advanced by leaps-and-bounds so that many reads have error rates of under 1%. Data yields early in MAP were low tens of megabases; MinION flowcells now deliver a few tens of gigabases and the PromethION flowcells significantly more. I was hooked seeing a full length lambda phage of 48 kilobases in our first MinION Access Program (MAP) run; the world record ONT read length is almost 100-times that - and no other technology reliably generates high accuracy reads of even 48 kilobases.
Clive's team did that. He built the technical organization to make magic real. Now, it must be said that being a member of that organization came with special requirements. Some staff stayed a long time - but some did not. At the first Nanopore Community Meeting at the New York Genome Center, ONT had downplayed the idea that Clive would break any technical news - and all of us customers were madly scribbling notes and photographing slides as he blatantly violated that guidance. When it was over, one looked around to realize that ONT employees had done the same and some very much had "deer in the headlines" faces. Indeed, mutterances of "first I've seen of that" or "there goes all my timelines" were heard afterwards.
Eventually, ONT settled on a solution to allow Clive to be minimally restrained but the company minimally exposed to his wilder extemporaneous comments. After Clive's talk (which led with a disclaimer that he might color outside the lines), Rosemary Dokos would be the voice of reason and carefully shepherd expectations into what the company was actually committing to
Under Clive's leadership, the MAP had some interesting aspects as well. Clive has always projected a vision of the individual biological pioneer, in many cases an amateur with no training or background, casually using ONT gear to explore the world. A parallel is often drawn, often dangerously bordering (or crossing into) fetishism, to the early days of personal computing. I know that era: my first taste of electronics was learning the color codes on resistors so I could sort them upstream of my brother and father assembling a single-board DATAC-1000 computer. But do-it-yourself can collide with amateur. When MAP rolled out the first, a thinly documented, version of MinKNOW, I started looking for what seemed obvious to me must be in the package. MinKNOW would output data in an HDF5-based POD5 format, and obviously there must be another tool to extract the reads as FASTA or FASTQ from the POD5. Right? Right? Surely????
No, there wasn't. If you wanted to, y'know, analyze MAP data your had to dig into some very unfamiliar software guts. In my case, Perl was a dead end because the HDF5 library choked on the POD5s (by 2014 I was realizing Perl library development and maintenance was pretty much in zombie mode; around that time the PDF module in CPAN had syntax errors!). Since I wanted to learn Julia, I quickly tested if it had a working HDF5 library and wrote a simple parser. Several years later I found out it didn't work anymore for the same reason I had been reticent to open source it publicly - the implementation was tightly coupled to the POD5 implementation. Presumably the same issue befell Mick Watson's R solution and Nick Loman's Python one, though by then ONT had made FASTQ extraction a standard part of their pipeline.
Similarly, ONT for a long time avoided writing much in the way of documentation or having much in the way of technical support. You threw your questions to the Nanopore Community and you'd often get answers. But as the Community aged, it became very hard to tell which information was still valid and which was badly obsolete. Which version of a protocol did the search find? Who knows?
What I said about open sourcing my extractor leads into another big tension area: openness and secrecy. I knew ONT was sensitive about internal workings and so asked if I could release my extractor, and got a not emphatic reply that suggested they wouldn't love that. Mick and Nick must not have asked, as they did open source theirs. For a long time, much of the software from ONT was only available from the Nanopore Community site, which was far less convenient to download from than GitHub or similar. Over time that went away. In general, ONT has been very open which has helped drive much innovation by the community, but now is probably enabling BGI and other Chinese competitors who are launching similar nanopore platforms. Of course, ONT in turn benefited from PacBio's great openness and particularly the long read software community that grew up around PacBio.
From secrecy we can slide over to an entertaining topic: Clive and ONT's penchant for combativeness which often edged into destructive corporate paranoia. In this he wasn't alone: CEO Gordon Sanghera and majordomo Spike Willcocks would also engage in this behavior; I chided Willcocks here on an egregious case that threatened to spike customer relationships. If you talk to the older ONT crowd, they have some very colorful stories to tell of then Illumina CEO Jay Flatley's behavior around them when Illumina had an investment in ONT (and yes, I'd love to hear Flatley's or any other Illumina's folks take on this - as off the record as they would like). Illumina would later yank their investment in ONT and then try to sink ONT with a patent lawsuit. One can understand the bitterness after such a scorch-the-earth style of corporate battling.
But some of that activity, and the lawsuits with PacBio, brought out behavior in Clive that must have put the entire ONT legal team on high doses of ACE2 and proton pump inhibitors. Clive would tweet out very sharp commentary on one of ONT's legal opponents, often with insults. This would escalate a bit, until finally Clive's Twitter account would be "deleted'. There would be a pause for weeks or months then Clive would start tweeting innocuous stuff again - which would eventually get spicer. Rinse and repeat.
In a similar vein, I'll always remember the first time I met Clive face-to-face. It was at AGBT in 2013, a year after the big AGBT splash. I thought that presentation was exciting, but apparently Clive and other ONT folks were run through the wringer of criticism as purveyors of vaporware, hucksters trying to just fleece gullible investors and so forth. It had really gotten to him. We met in one of the little outside alcoves that existed at the old Marriott facility in Marco Island and he showed me a MinION - probably one revision back from what came out for MAP. And my big takeaway from that was "man is that guy strung tight!". He was intense - both the great kind of someone who is passionate about their work and the less desirable intensity of someone who feels hounded. The next time I saw him, when I helped him navigate to the ONT demo that fall in Kendall Square after bumping into him on the street, he was a bit more relaxed - building towards success can do that. But still passionate - always passionate.
Clive's passions and ethos of the individual explorer sometimes took the company in directions that were of questionable commercial relevance. Thrilling to watch or ponder perhaps, but not much in the way of a path to profitability. For example, last year I was certainly excited at Clive saying ONT had succeeded in sequencing some of the smaller yeast chromosomes as a single fragment. But I work at a strain factory that loves to work on yeast; few are in such a situation. And yeast chromosomes are a tiny fraction of the length of even the shortest mammalian chromosome.
Perhaps the most egregious case of this was the "Ubiqibopsy" demo. Live, on stage Clive had his cheek swabbed, then some noisy bead-based sample prep, a rapid prep and by the end of the presentation ... a handful of reads. Supposedly they proved Clive is human though I don't believe any reviewer #3 got a look at the data. The device was visible later and clearly hacked together from ubiquitous lab parts - if I recall correctly there was part of a centrifuge tube, a micropipette tip and maybe one other recognizable bit. But was this the path to a real product? Given the challenges involved in getting to a data yield that might be interesting, unlikely - and little was heard of this ever again.
But of course nobody though the whole concept would ever work. But then again, while ONT has shown technical success it still struggles with financial success.
Similarly, Clive's love of the VolTRAX electrowetting technology was never returned by that tech. In one talk he presented the idea of putting the nanopores actually on the VolTRAX chip, which certainly solves the transfer problem from VolTRAX to flowcell. But the number of pores was to be tiny - so what application wanted a few hundred dollar prep to get maybe a few megabases of data? That was a question never answered - and it too disappeared from future presentations.
At last year's LC, Clive gave hints that he might not be at ONT by the next year - something along the line of "if I'm still here". There were other signs - the ElysION (formerly TurBOT) robot is the epitome of what Clive disliked, a large expensive box specialized on a single task and marketed to large faceless labs.
I hope Clive is enjoying his retirement. His Twitter feed shows very brief life very rarely, but mostly about non-sequencing topics. If there isn't a third act for him (he was on the team that brought Solexa's sequencing technology to life), then we all now have a name to scan for in the annual King's Honors List. Under Clive's leadership Oxford Nanopore launched a truly revolutionary platform which has delivered huge gains to genomics; we should all be very grateful for that.
