Long Overdue and Overly Short Notes on Clive's NCM 2019 Talk

A theme of the 2019 Nanopore Community Meeting in New York was the long and short of nanopore sequencing.  While the public sparring with Illumina/PacBio over the definitions of sequencing types wasn't explicitly discussed, certainly ONT wants to make sure that people understand they don't intend to ignore applications that are naturally short reads.  I've been slowly trying to get this summary to gel for awhile, with the usual distractions this time of year of some trips, planning for holidays and a bout with a virus.  Plus general procrastination. 

I'm just going to cover Clive's talk; there were some really spectacular presentations (including one by someone who remarked that they hoped their upcoming thesis committee meeting would go well! One of multiple excellent platform talks by very junior scientists) If you'd like to watch yourself, the video of Clive's talk is online. Watching it again is kind of fun, except for the distraction of seeing a guy with huge glasses trying to live tweet from the front row.  I've put in brackets rough timepoints for some of the topics; you may need to slide back or forth a bit to nail it exactly but they can land you near the right spot.

Merger Questions to Mull Over Your Cider

With the full FTC complaint against the Illumina-PacBio merger now out in the open but the holiday break bearing down like a reindeer on steroids, I want to leave you with a few questions to ponder over your wassail.  Because what holiday gathering is not enlightened by discussion on the Herfindahl-Hirschmann Index (HHI)?

FTC Slams Illumina-PacBio Merger, but Illumina Not Quitting Yet

Tonight I was intending to finally get out my summary of technical notes from the Oxford Nanopore Community Meeting, but yesterday the U.S. Federal Trade Commission issued a press release that they believe the proposed acquisition of Pacific Biosciences by Illumina would be grossly anticompetitive and cannot be approved in any form.  A more detailed report is promised but hasn't surfaced yet.  Curiously, not only did this ultimately move PacBio's stock very little, but today Illumina and Pacific Biosciences filed matching SEC documents that Illumina will continue to infuse cash into PacBio through March of next year.  Also, I should note that someone left a passionate defense of regulators in the comments on a prior piece, noting that the FTC decision shows that the CMA was justified in opposing the deal and not simply acting with a parochial eye on Oxford Nanopore.

Is ONT Really Going to Twist the Watch Stem Backwards?

I was in New York last week for the Nanopore Community Meeting.  I'll save some technical updates for tomorrow, for I wanted to focus today on a huge inflection point that Oxford Nanopore announced that they will really will punch through next year.  I'm going to do that with an extended comparison to Robert Bloch's wonderful short story That Hellbound Train.  I won't spoil that story, but if you want to first go find a copy to read (there is apparently now a graphic novel version) or spend a half hour on a decent narration of it, please do.  It's especially a joy if you're steeped in the lore of American railroading.

Should Patent Pool Save the ILMN-PACB Merger? ONT Doesn't Think So

Last week the UK’s CMA published a proposal submitted by Illumina and PacBio to save their merger. This was then published in a revised, seemingly more generous form on Wednesday.  Most strikingly, the proposal tackles head-on an elephant long in the room: is the CMA playing hardball because the biggest competitor in this space is not named Oslo Nanopore Technologies.

Genapsys Launches

Today Genapsys launches their sequencer into the U.S. market, with worldwide launch next year.  They also received a new round ($90M) of financing from a major firm, Foresite Capital.  In addition to the Press Release and Media Kit, Genapsys' PR team, provided me with answers to a set of questions I provided.  As a reminder, I previously covered their pre-print pushed out to BioRxiv six months ago.

CMA Drops the (Preliminary) Hammer on ILMN-PacBio

Today the United Kingdom's Competition and Merger Authority (CMA) issued their preliminary report on the proposed acquisition of Pacific Biosciences by Illumina.  The report has no dry British phrasing: they clearly state that the merger is anticompetitive and that the only legal remedy is to block the transaction.  Interestingly, today was also the scheduled Illumina Q3 earnings call, but the subject wasn't even broached there.

QIAGEN Quashes GeneReader

Two weeks ago QIAGEN announced they will discontinue development of their GeneReader short read instrument and move their portfolio of gene panel tests over to the Illumina MiSeq and NextSeq. Existing instrument owners will continue to be supported for an indefinite period.  Thus ends QIAGEN's effort to build a fully vertically integrated sample-to-answer diagnostic sequencing system, just short of 4 years from the system's launch. What can be learned from this and how does this reshape the sequencing market?

Illumina Throws PacBio An Extension and a Lifeline

Interesting news today on the PacBio front: as reported by GenomeWeb, Illumina announced that their walkaway date for the acquisition has been extended to March 31 of next year and that Illumina will be pumping significant cash into PacBio until either the merger occurs or is terminated.  In addition to publicly reinforcing Illumina's determination to get the deal done, the terms of the arrangement have interesting consequences should the deal fall through

Where U.K.'s CMA Missed the Plot

I've written far more than I expected to on the PacBio merger, with it dominating my output here this summer save that recent dip in the CCS boomerangs.  We still haven't heard from the U.S. FTC, which is the big hammer that could drop and the stock is still selling at a substantial discount to the price offered by Illumina.  While I've hinted at it, I've never quite detailed my major objection to the form of the UK CMA's analysis of the proposed acquisition.  I've missed the opportunity to lay that out during the period of public comment for the next round of the CMA.  Still, worth it to write it down.  Which was true about a month ago when I wrote this, then failed to actually push it to a post before I headed out for a rugged vacation in the American West.  And then forgot about it after returning.  And more news today to comment on -- so better finally get this out there.

Amazon Needs Another Training Track

I spent a day recently taking Amazon's "AWS Technical Essentials" course.  I had originally opted not to go, but a summons went out that we had already paid for seats and that everyone using AWS should really go.  I've been in far worse courses and certainly had no complaints with our instructor, a former mechanical engineer who knew his stuff and was never in salesman mode.  Indeed, many of the tips I extracted had to do with how to save money.  No, the problem is that the course is designed for a very, very different use case than anyone in my shoes is interested in.  It's a use case that I'm sure Amazon has a few bazillion customers for, but I'm just not one of them.

Mirror, Mirror Have You Leads, On My Strange HiFi Reads?

A core purpose of this space is to explore the current state of genomics technology.  Much of the time this is via distilling news reports, press releases and interviews with persons in the field.  But even more fun is to dive into actual data.  Such data is often accessed via the generosity of researchers who deposit open access datasets.  But it is also true that part of my professional responsibilities is to determine when new technologies and methods have applications at my day job, so I'm also charged in the day job with contemplating experiments to plumb sequencing systems.  Only by doing so can we ensure that we maximize our ability to perform cutting-edge synthetic biology.  A recent such experiment generated some curious data which I have obtained permission to share a subset of it publicly, as I'm scratching my head and hope that someone out in the community has insight.

Wall Street Bets Illumina Won't Acquire PacBio

The proposed PacBio-ILMN Merger remains an interesting spectator sport, with the UK's CMA looking for public input for the next round.  I don't usually pay attention to stock prices, but PacBio's current state presents too juicy a situations.  Just to be clear though: I do not hold any individual stock position in PacBio or Illumina (the bulk of my investing is in broad mutual funds, some of which certainly have bits of these companies).

UK CMA & ILMN/PACB: The Inconvenience of Being Earnest.

As part two of a yet-to-be-determined number of pieces on the UK's CMA preliminary analysis of the proposed Pacific Biosciences acquisition by Illumina, I'd like to briefly explore the surprising authority of this agency to plumb internal documents at the two companies.

UK CMA's Write-up of PacBio Acquisition by Illumina Makes for XXX Reading; Clearly They Believe XXX and XXX

After writing my two recent pieces on the business side of the long read industry I planned, after a recent extended family vacation, to try to get back to science.  Particularly after my chagrin when various correspondents pointed out a fact from each I should have found and didn't: in my ONT piece I failed to discover that ONT has two share classes and the Woodford fund's shares cannot be used to gain control of the company and in the PacBio piece that there is a $100M breakup fee due PacBio if for any reason the deal doesn't go thru.  I'm particularly red faced on that one, as a breakup fee would play importantly into PacBio's financial health should the deal go south; $100M would buy perhaps two quarters time.

But then a bunch of people threw my way the UK Competition and Mergers Authority (CMA) report on the merger and I foolishly opened the document.  It makes for interesting reading, but that is hampered by the fact it is highly redacted -- like my title. Reserving the right to comment on the contents substance at a future date (or never), I'd just like to give a tour around some of the redactions.

Will Regulators Scotch PacBio Acquisition?

When Illumina announced its proposed acquisition of Pacific Biosciences last fall, an immediate question arose as to whether the deal would pass antitrust review.  Illumina must have been optimistic, as they originally expected the deal to close in "mid-2019".  That timetable has now been rolled back to late 2019 in the face of the UK agency with jurisdiction over mergers deciding to go for a second round of review and no word yet from the U.S.'s Federal Trade Commission.

ONT & The Woodford Liquidity Squeeze

There's an unfortunate chain of events that may end up causing a headache for Oxford Nanopore, and it's completely outside their control.  One of the their key investors has just had his luck - or perhaps more critically his reputation -- at stock picking disintegrate.  Because of some unusual choices, that has potential repercussions for ONT.

The Genius of Plongle

I noted in my roundup of Oxford Nanopore technical announcements that I loved the Plongle concept.  This is really both a new application-specific integrated circuit (ASIC) and using it to build a 96-well sequencer.  Let me expand on what there is to love.

ONT's Horrid Data Storage Folly

In the coverage of ONT's announcements at London Calling, I specifically left out one of Clive's Skunk Works projects.  This would be a device to use nanopores to write digital information.  I'll give him points for creativity, but the reason I held this for here is I truly and sincerely hate the concept and didn't want my vitriol to distract within the other piece.  But here I will let loose.

ONT's London Calling Announcements, Pass One

The annual big Clive Brown London Calling talk had a twist this year  Brown introduced a set of senior lieutenants at Oxford Nanopore and then tacked on a few "and one more thing" moments at the end.  If you're looking for the TL;DR version from me, it is that there were a lot of sensible but non-Earth shattering updates from the team followed by Clive updating on one prior crazy idea and throwing out two more -- one of which I love and the other I believe should be thrown out posthaste.

Nanopore's Long DNA Paradox

The first half day of London Calling has already delivered the usual mix of scientific excitement.  The prospect of lives, particularly those of children, en masse by delivering precision oncology broadly across sub-Saharan Africa.  Dizzying levels of alternative splicing in a key brain ion channel.  RNA modifications in great numbers.  That one was also gratifying as it was commented that even without a basecaller, modified bases can be be suggested by higher error rates around a particular motif.  Around 2015 or so I noted in the Nanopore Community post that error rates went up around GATC sites in E.coli, the target of Dam methylase.  Protein tags read by the current nanopore scheme. Tonight we get Clive and company performing their usual razzle-dazzle of product announcements; one person pointed out to me a possible angle I failed to include in my laundry list is the raising of the speed limit from 450 to perhaps 1000 bases per second.  But another omission was front-and-center in the plant genomics sub-session I attended and could be called the central paradox of the current state of nanopore sequencing:  pores are great for long DNA but long DNA is not great for pores.

Care to Pore Over My Laundry List?

London Calling is this week, so get ready for lots of Oxford Nanopore in my Twitter channel and if I'm on the ball, in this space.  ONT has made a number of releases and updates and there have been other developments within the nanopore ecosystem which I've failed to report.  Here, in not terribly organized fashion, is a laundry list of things I'm thinking about going into the meeting

Mass Recoded E.coli Genome Not Tripped Up By Programmed Frameshifts

There's a paper this week in Nature announcing an E.coli genome which has had two serine codons (UCA, UCG) and one stop codon (UAG) removed from usage.  It's a major work on synthetic biology and represents the largest designed sequence ever built.  In contrast to Craig Venter's early effort, which moved a synthesized genome into a cellular ghost of a natural bacterium, this one replaced the native E.coli genome in stages -- Escherichia theseusshipii would be a good name for the new strain. But is the genome quite what is advertised? Following up on a pair posts from Sandeep Chakraborty showing remaining UCA, UCG codons and UAG codons in a bunch of typical genes, I decided to look for a trickier set of possibilities to overloop -- and by luck or care the Nature paper got these.  Just to put one gripe front-and-center, the group deposited in Genbank the reduced genome version of E.coli they started with, but not the recoded genome, which is in the supplementary material

My Career's Double Slit Experiment (or, A Funny Thing Happened on the Way to the Drydock)

When I announced recently that I had moved over to Ginkgo Bioworks, I was compelled to leave out an important part of that story.  Indeed, by just focusing on the (still open) position of NGS Head, I could avoid the sticky subject of how exactly I ended up there.  Today the press release finally went out and the fact that Warp Drive's genome mining business is now owned by Ginkgo is public (covered nicely by Amy Feldman in Forbes).  But in the spirit of my periodic public coverage of my own journey, here is some of the rest of the story.

Genapsys' Base Caller: Mysterious, But Not Ideal?

When I wrote about Genapsys' pre-print on their sequencing system the other night, I intended that to be the last I wrote until some major news from them.  But after launching that into the great Internet ether,  I found myself lying awake wondering if a very simple idea had any merit.  Painfully simple -- I almost didn't pursue it because it was so simple and obvious.  But, it turns out it appears to have merit -- there may be an obvious route to improving the accuracy of Genapsys' basecalling on homopolymers.  And that also took me into ground I've thought about before -- going back to my first year at Codon Devices over a decade ago -- on the challenge of modeling sequence quality.

Poking at Genapsys Preprint

Genapsys is continuing down the path of pre-launch information, most recently releasing a pre-print.  I'm looking at this pre-print critically and unfortunately turning into a bit of Reviewer #3.  Not that anything is fatal and pre-publication review is a key value to pre-prints. If I were an actual reviewer I'd be writing mostly the same things and covering more vertebrate species than they sequenced (a human exome panel  was included, though most samples were bacterial) -- I'd grouse about a missing figure (which I've provided), carp about critical details not provided and beef over a public data deposit that doesn't really line up with the unqualified claim made in the paper. (*)

Want to Run An Exciting Sequencing Group? Ginkgo Is Looking for You!

I've awakened from my blogging torpor to point out a really interesting career opportunity for the types who might read this space. Ginkgo Bioworks, one of the leading synthetic biology companies in the world, is looking for someone to run their existing Next Generation Sequencing group. It's a chance to run an energetic high-throughput sequencing group that works on a wide range of projects. And, as you might of guessed from the fact I'm writing about it here, you'd also get to be my boss. I'm hoping many will see that as a feature and not a bug.

Nanosens Publishes Proof-of-Concept for Point-of-Care CNV Diagnostic

Here's a killer technological challenge for anyone: design a scheme to detect vanishingly small concentrations of a valuable analyte in a biological fluid.  The assay must require zero pipetting, work in the field at ambient temperature, generate results quickly, contain positive and negative controls, be usefully precise and accurate, and be usable by personnel with no formal technical training.  Oh, and be dirt cheap as well.

Beyond Generations: My Vocabulary for Sequencing Tech

Many writers have attempted to divide Next Generation Sequencing into Second Generation Sequencing and Third Generation Sequencing.  Personally, I think it isn't helpful and just confuses matters.  I'm not the biggest fan of Next Generation Sequencing (NGS) to start with, as like "post-modern architecture" (or heck, "modern architecture") it isn't future-proofed.  Not that I wouldn't take a job with NGS in the title, but still not a favorite.  High Throughput Sequencing feels a little better, but again doesn't leave room for distinguishing growth -- and HTS as an abbreviation is already going to confuse anyone in Biopharma who thinks about High Throughput Screening.  Massively Parallel Sequencing sort of works, but my late father had a real pedantic objection to using "massive" for anything that lacked mass, and while I don't subscribe to that view such uses just don't sit well with me.  Worse, as I'll explain, trying to divide sequencer technologies into Second and Third generations creates more heat and smoke than light.  On a number of Twitter threads I've tried to launch my own terminology, but probably haven't been terribly consistent.  So here is an attempt at that.

Failing to Fetch An Interesting Result on Dog Oncogene Homologs

An idea for a little exploration occurred to me back at Infinity -- that is 7.5 years ago -- that I've never tried out.  But I never got around to it.  I had some downtime recently  to play around so I finally executed the experiment -- alas, it turns out not to be very interesting.  Still, a negative result is a negative result.

Covaris Grabs A Spot on the Liquid Handler Deck

For as long as I can remember, Covaris has been the standard in DNA shearing for high throughput short read sequencing.  Their benchtop units had their quirks -- custom tubes being the foremost -- but they were what everyone else compared to.  In 2013 when the American Society for Human Genetics was in town, the PacBio folks did me a great favor and loaned me an exhibit hall pass.  Multiple companies were offering DNA shearing instruments -- and every one compared themselves against Covaris.  Now they have a new offering, moving the instrument onto a liquid handling robot deck so that it is available for high-throughput workflows.  Covaris invited me down to their Woburn, Massachusetts facility to get a look at the instrument before its formal launch at the SLAS conference

Patent Dive: Genapsys

Here's a dangerous statement for me: I actually enjoyed reading some patents recently.  Now, before you get any ideas in your head about suggesting more patents for me to read, let me be clear that these were unusual patents -- they're written to be read! -- and were read under strict conditions. The patents in question are from Genapsys -- found via my good friend Justia.

Metabolic Whac-a-Mole

Derek Lowe summarized a really cool paper back in October.  I've been meaning to grab a copy, but discovered recently that the MIT library no longer has an easy way for outsiders to slip in an use their subscriptions.  So I'm working off his summary, but since this is mostly an excuse for flights of genetic fantasy actually reading the paper would probably just hinder me!

2019 Tech Speculations: Oxford Nanopore

As promised in the last post, I'm segregating out Oxford Nanopore.  Admittedly I tend to cover them relatively closely -- though I never seem to quite finish writing up their conferences -- but at the moment ONT is the only major player in the U.S. research sequencing market not being run out of (or about to be run out of) Illumina HQ.  And I'll be very to the point: ONT has a lot of balls in the air and irons in the fire, but from my point-of-view what matters most is rapid and regular progress on the accuracy front.

2019 Sequencing Tech Speculations: Will We Actually See New Entrants?

An astute reader caught a sentence fragment about MGI in last night's Illumina JPM roundup -- the unfortunate evidence of a a mental battle over whether to put any further comments on MGI in an Illumina-centric post. So now I'll sweep that bit into a general post about not-Illumina (and not-Oxford, that will go in yet another).

Illumina JPM Talk

Illumina CEO Francis deSouza delivered his J.P. Morgan Healthcare Conference talk (webcast audio, slides & Q&A audio) a week ago.  I can claim that some of my speculations came true -- just the most boring and obvious ones.  Overall, the presentation was the talk of a confident market leader.

2019 Sequencing Tech Speculations, Part I: Illumina & MGI

Next week is the J.P. Morgan Healthcare Conference.  It's striking this year the paucity of companies in the genomics space -- Illumina on Mondayat 6:00 EST and MGI on Wednesday at 5:30 EST and Nanostring at 6:30 EST on Wednesday.  Perhaps NVIDIA will say something interesting about their forays into healthcare, such as providing the chops for real time nanopore basecalling, on Thursday at 11:30 EST. There's also some nice polls from Albert Viella on Twitter

What would you like @illumina to announce at #JMP2019 ? https://t.co/TDn5J0glhi part 2

— Albert Vilella (@AlbertVilella) January 5, 2019

and some more Twitter speculation

Predictions for @Illumina #JPM2019. Besides PacBio news, expecting NovaSeq SP 2x250. Any longer S4 kit or potential S5 would require upgraded onboard storage. Really hoping no new NovaSeq system.

— CAT at UCSF (@CAT_UCSF) January 4, 2019

So, before all the beans are spilled, here's some of the speculations and ponderings I've been entertaining about the sequencing technology field for 2019 for Illumina and MGI.  I'll cover some of the other players in the next few days, but since Illumina is up on Monday that's the priority!

2019 Resolutions

2019 is upon us; I'm hoping it will be a bit less eventful than 2018.  It wasn't all bad -- I took two trips that delivered scenery I have only right to see once in a lifetime -- but it was essentially bookended by losing my father and a revolution in my workplace.  Mixed in there is the bittersweet pride of seeing one's offspring graduate from high school and proceed on to college.

New Year's resolutions are notoriously difficult to keep -- one is fighting entrenched behaviors -- but bringing in some external pressure might help.  So I'll make my two resolutions for the year very public: that I post here more regularly and that I read more non-fiction books to the end.  And the hope is that you, dear reader, if you meet me, feel free to pointedly inquire about my adherence.  Or hit me via Twitter!