Nanopore Community Meeting: Progress Despite the Pandemic

I realized a few Oxford Nanopore announcements too late that I should have tried to log all their predictions with a date made so I could track carefully any delays or quiet disappearances from the new feature lineup.  If I had done that, this year would have presented an even worse conundrum: how do you score progress in a year of constant disruptions?  Like many companies in the sequencing field, at least some of that disruption has been a diversion of attention and resources to fighting the pandemic.  For ONT that is largely supporting the ARTIC viral genome sequencing and also developing LamPORE diagnostics.

BGI Floats Idea of Tape-Based Sequencer

I reported on the AGBT 2020 final talk a few centuries ago -- or at least it seems like that given how quickly the world went to hell just after that -- by BGI in which Rade Drmanac showed off a system which I described as a deconstructed sequencer -- an integrated set of plate handling robots, liquid handlers and imagers which dipped the slides into reservoirs of reagents instead of flowing them through a flowcell.  Now BGI has a preprint on BioRxiv which takes this idea a bit further, changing out the reagent tanks for a polymer film on which a thin layer of reagent is distributed, which is then pressed gently against the slide surface to deliver the reagent to the DNA Nanoball (DNB) array.  The preprint is filled with eye-popping numbers -- Petabase sequencing!

PacBio's Renewed Energy

When confronted by antitrust regulators last year, the core thesis of Illumina and Pacific Biosciences was that PacBio could not survive as an independent company.  After giving up on the merger, PacBio decided to dispute their own thesis -- and seem to be succeeding so far.  As highlighted at their recent "Global Summit" meeting, they have a new CEO, new financing and a burnished product offering.

Bioinformatics Exercise: Gene-Specific Ser Codon Usage

I saw a provocative abstract in PNAS about the usage of serine codons in E.coli that triggered the "this could make an interesting student exercise" (for my prior effort, see: Exercise: A Sequence Signature for Transcription-Translation Coupling in Bacteria?).  The paper is behind a paywall (though a relatively cheap one at $10) so I haven't actually read the paper, but the purposes here that isn't really a problem -- I'm not going to critique the paper, but just use the concept as a springboard.

Bionano Genomics: A Belated Update

Back before I can remember -- as in January of this year -- I wrote a piece on the challenging situation of BioNano Genomics.  I got an important detail wrong in that piece, missing some important fundraising, but in general from the point-of-view I took I thought it was a decent piece, meant to convey the challenge of a really amazing technology having its original market disappear.  Some commenters took strong exception to the piece and suggested I had not-so-pure motives for writing it.  They're wrong -- but at AGBT I got a chance to learn more about the company's new direction and how I hadn't been looking at things quite appropriately.  I should have written it up there, but working on a response to the pandemic started taking over my life and I let time slip away.  Preparing crow to be eaten also tends to be procrastinated.  But here, finally, is a re-look at the company (and, I drafted this over a month ago and never finished -- the procrastination drags on...)

I was a bit nervous strolling into the BioNano Genomics booth at Marco Island.  Maybe they were the ones so offended by the piece.  But no, they actually invited me to come to a morning talk and to chat afterwards, and were completely professional and cordial and made it clear they understood the angle I had taken as a sincere journalistic approach.  But not only did I hear the talk then, but I had gotten a preview the night before in the Twist Suite, which also illustrates a key card BioNano has: a collaboration with Alexander Hoischen

10X Triples Down on Spatial Analysis

10X Genomics last week announced the purchase of ReadCoor, a company that unveiled its 3D spatial sequencing instrument back at AGBT, paying $350M to acquire the Cambridge MA company.  This follows quickly on the heels of 10X purchasing Swedish in situ sequencing company CartaNA for another $41M.  10X already had the Visium spatial transcriptomics product on the market.  So now 10X has three different technologies in the spatial profiling space.

Keeping an Index on a Subtle Difference in Illumina Chemistries

I like to pretend in this space that I catch all the little details of the different sequencing platforms.  Well, at least over time I try to do that.  But ego aside, that is often a mark not made.  A bit of a year ago I discovered that there's a small difference across the Illumina family that is completely separate from how clusters are generated (Bridge Amplification randomly arrayed or Exclusion Amplification in nanowells) or the wavelengths of light used in the fluorescence microscopy (now blue on the newest NextSeqs, with superresolution microscopy coming soon)  or 4 color vs. 2 color vs. 1-color (well, really staged 2-color) chemistry for the reversible terminators.  There's a subtle difference in how the second index is read.  I'm not spilling a deep secret: it's right out in plain sight within an Illumina technical document

Self-Assessing My Python

I've been programming 90+% in Python now for over a year and a half -- when I joined the Strain Factory I vowed to finally make the break from Perl.  Partly this was disgust with so often finding libraries I wanted to be missing or broken, and partly it was recognizing that the Factory is primarily a Python shop and I would have the most impact if I worked in the lingua franca. I was first exposed to Python back at Codon Devices, but there was a strong C# faction there and I fell in love with that language, so my primary dabbling in Python was learning enough to glue the key Python code into my C# with IronPython.  I strongly considered changing over at the start of Warp Drive, but gave it too weak a try and quickly started churning out Perl.  I still use that language for basic level text munging, but have avoided writing nearly anything that occupies more than one screen.

Two Pandemic-Related Programming Problems

I will offer here two bioinformatics programming problems which I think are interesting, useful and should be approachable by an advanced undergraduate.  For a variety of reasons I've been thinking a lot of about skill levels and how to assess them.  One key reason is we have two open slots in our group, so I'm plowing through CVs and engaging in the usual hiring funnel struggle -- how do you winnow CVs to phone screens and then down to interviews? We also thought we might, but now won't, bring on a one year intern.  But I'm also trying to take a look at my own skill set with a critical eye.  Plus I maintain a Quora addiction, and you see there people looking for ways to prove their computational biology chops.

Virtual London Calling, Veritably Late, Part II: Platform Development

Last time, I covered Oxford Nanopore LamPORE COVID-19 detection scheme.  London Calling was over a week ago, so the chance to scribble before its all old news is rapidly shrinking.  As noted yesterday, Clive Brown didn't speak here but instead will broadcast at some future date; it was left to his top technical lieutenants to cover the developments in the platform which have happened since the Community Meeting in New York back in early December.  I've tried to hit the highlights here, but don't claim to be comprehensive.

Virtual London Calling, Veritably Late Copy: Part I, LamPORE

London Calling was last week, held online due to the pandemic.  My plans to attend in person were one of a myriad of travel arrangements upended by the calamity, though that is utterly trivial in comparison to the tragedy of so many lost lives, damaged survivors and economic ruin.  Attending remotely also made it harder to ignore my work duties, which are at a crescendo (well, not really: it's been this intense for months).  But all the talks are available online, so I have stolen some time to review the Oxford Nanopore technology announcements.  There wasn't a Clive Brown talk; apparently he will deliver a broadcast later this summer to tease us with more crazy ideas emerging from the ONT Skunk Works.

Roche Expands Sequencing Nanopore Presence by Acquiring Stratos Genomics

Ugh.  I let the month of April slip away without writing and now have almost let May do the same.  But some leftover euphoria from a huge experimental breakthrough on our current diagnostics project at the Gene Factory plus the feeling I shouldn't let news tied into an earlier post slip off, and here I am.  When I wrote about sequencer startups back in February based on their websites, I put Stratos Genomics near the front of the pack.  Roche Molecular apparently agrees, announcing a week ago that they are acquiring Stratos.

One Gemini Celebrates Another

One of most truly useless pieces of information lodged in my brain is my zodiac sign; not once in my life have I had any interest in it.  But, given the available draws, it isn't too bad, as it's also the name of perhaps the most underappreciated engineering project of the second half of the 20th Century: Project Gemini

1918 Flu Pandemic & Popular Culture: Take Two

My piece on the near amnesia in U.S. culture of the 1918-19 Influenza pandemic provoked a number of helpful comments, emails and conversations.  While I would stand behind the statement that it left a light footprint, there are a number of interesting cases, some of which I would never have found by conventional means.  Sometimes the collective wisdom of the internet is best for uncovering things, even when you're married to someone who catalogs books for a living.

This Time ThermoFisher Catches QIAGEN

This past fall there was a rumor that QIAGEN was being pursued by an acquirer, with the initial tip being scientific conglomerate ThermoFisher but then other possibilities floated by.  QIAGEN was seen as ripe for such an action as their long-time CEO had stepped down.  QIAGEN made a very public announcement that they would continue independently under their new CEO, but that is no longer the case: ThermoFisher will acquire them, pending regulatory approvals, for something around 11.5B

Post-AGBT: Miroculus

AGBT ended over a week ago and I've been procrastinating ever since in going through notes and writing up companies.  First few days I had the excuse of family time on beautiful Sanibel Island to the north, but since Monday other than obsessing about COVID-19 (and cancelling travel plans) I have no excuses.  First up, the microfluidic library prep company Miroculus, based on my notes from talking to their Chief Commercial Officer, Adam Lowe

Why Didn't the 1919 Flu Leave A Bigger Cultural Imprint?

The still growing COVID-19 pandemic has reminded me of a question I've batted in my head a few times.  In 1918 and 1919 a global influenza pandemic killed on the order of 50 million people worldwide.  The scale of the jump in flu deaths in the U.S. can be seen in the below plot. That's more than the number of civilians and military personnel estimated to have been killed during World War I.  Yet despite this, it would seem that there has been very little impact on culture (at least the culture I am aware of).

MGI Deconstructs the Sequencer

At some fancy restaurants one can get a "deconstructed dish".  As I understand it, as I don't frequent such restaurants, a deconstructed BLT would have the bread, bacon, lettuce and tomato each as their own individual item, but prepared in a novel way which highlights the strengths of each ingredient.  When I got a preview last night of Rade Drmanac's closing AGBT talk on achieving a $100 human genome (reagents price only), that was the vision I had: Drmanac and his team have created their Tx system by deconstructing the optical high throughput sequencing-by-synthesis instrument.

CoolMPS Revealed

Having summarized MGI's announcement they are launching into the U.S. market this spring and started digging into the performance characteristics of MGI's instrument lineup, let us now turn to their BioRxiv pre-print on the CoolMPS chemistry, as it has many useful technical details.

MGI Dual Drop of CoolMPS News Ahead of AGBT

Friday morning I got excited because a preprint showed up at BioRxiv detailing the CoolMPS sequencing technology from MGI (aka BGI aka Complete Genomics).  First announced in Fall 2018, this approach sounded, well, cool.  Using fluorescently labeled antibodies specific to each reversible terminator seemed like a crazy pipe dream.  So getting a good look at it in a manuscript is an event!  But then Friday afternoon MGI had a second big pre-AGBT reveal: launch of their sequencing systems in the U.S. later this year. Below is a quick run-down of the sequencer announcement; the pre-print has many details I'm still parsing.

A Lazy Look at The Field of Sequencing Startups

AGBT looms ahead of me next week which serves as impetus to let fly an idea I've had simmering for a while: to look at sequencing startups by a particular type of information they choose to reveal.  I'm not expecting any big announcements at AGBT from this space, though would be thrilled to be surprised.  But there is the risk of getting contaminated with some on-the-sly scuttlebutt, so better to get this done now.  By the way, in the full disclosure category, I have consulted for a few companies here and have NDAs either on my own or via employers; everything here is based on public information.

Skimming Seq

My last post discussed BioJulia in the face of a challenge from the new Seq programming language.  Tonight I'm going to take a bit more of a look at Seq itself and touch on both why I'm tempted to try it and why I remain reticent to do so.  I hope if any of the Seq team sees this they will regard it as some parts constructive criticism and some parts market feedback.

A Short Master Class in Benchmarking

There's a blog post on BioJulia.net that is well worth reading, even if you don't use Julia or I'd argue if you don't actually program.  It looks at an issue of performance that was raised with BioJulia and with fierce but respectful passion examines the critique and explores just why BioJulia didn't perform well in the comparison.  In the end, this triggers a code review and a huge speed increase in the problematic areas -- which will widely benefit BioJulia users.

Sampling Current & Future Directions in PCR Diagnostics

My qPCR explainer seems to have done relatively well, though it took some refinement after readers caught a number of errors.  The most embarrassing of those is that I got my PCR ramp units upside down, so instead of 4 seconds or so per degree C it's degrees C per second so my times were off by a factor of 16! Ouch!  Despite that miscue, I'm here going to explore some of the variants on PCR that are out there, including some that are being employed searching for the newly renamed COVID-19 virus.  Included here are some of my own speculations and musings, so as always remember I'm someone who thinks about these things and sometimes talks other people into running them, but I haven't set up a PCR in 8 years.  Also, the field of PCR variations for diagnostics is enormous and I don't claim to have anything near complete knowledge of it, so this should be seen as a sampler and not a comprehensive review.  Also, the usual reminder I am a paid consultant for a diagnostics company but they are neither aiming at viruses nor using PCR, so I won't discuss them -- but if you feel that shifts your priors on how I treat other companies you have the information to do so.

A qPCR (aka RT-PCR aka rRT-PCR) Explainer

I've gotten in a number of Twitter threads and seen a lot of Quora questions about the qPCR test for the Wuhan coronavirus that I realized would really be best handled by writing an explainer. I'm intending it for financial types, reporters and anyone from the lay public interested in learning a bit more.   For most regular readers of this blog, there won't be anything new to you.  If you'd check me for accuracy, I'd be grateful but perhaps many will skip over this one.  That also means I going to try to resist my usual urges to make lighthearted references to popular culture; they're a good way to be confusing.

Can ONT Maintain Grip on Burgeoning Flowcell Herd?

A notion dawned on me when I was mentally planning my write-up of the Nanopore Community Meeting, but I decided to put off fleshing it out until a later date.  After a bit of procrastination plus a crush of other ideas, here it is: Oxford Nanopore flowcell lineup has been a bit complicated for a while, but it's probably going to get worse.  There's always been serious issues with the current level of complexity and it's hard to believe this will do anything but escalate.

An Ultimately Tufnellian Look At Oxford Nanopore R10.0 Homopolymer Performance

Homopolymeric sequences have never been easy for any sequencing platform, but single molecule sequencers struggle the most with this.  Oxford Nanopore has made remarkable strides in both raw an consensus accuracy via chemistry and software improvements, but still is challenged by systematic problems with homopolymers.  The R10 series of pores is intended to significantly improve performance by having a longer narrow region to interact with more bases, and at the Nanopore Community Meeting there were several slides touting improved performance.  Nanopore's slides have an X-axis that goes to 8.  By happy circumstance, around that time we generated a large dataset on R10 and got results very similar to ONT's.  Plus there's a dataset available from Mads Albertsen's group to support their updated pre-print on using Unique Molecular Identifiers (UMIs) to generate high quality consensus sequences.  But our internal dataset is  the best, as ours goes to eleven!

UST Bets on TELL-Seq

I've made a few references recently to TELL-Seq, both in my flawed analysis of BioNano Genomics (I missed a key business development in their raising $18M in October; I stand by the science comments and fear that the fund raise buys them about a year of time) and on 10X Genomics discontinuing their genome assay kits.  Now to actually dig into that technology -- a bit late given the preprint came out last fall, but better late than never.  So put on your sunglasses and hoodies, conjure up the image of early television chefs and key up the theme music for The Lone Ranger, because here I go.

Can BioNano Genomics Map A Way Past Twin Perils?

When playing with the structure of this piece in my mind, it occurred to me that Norman Maclean's thoughts about fly fishing apply just as well to biotechnology companies

It is also interesting that thoughts about fishing are often carried on in dialogue form where Hope and Fear -- or, many times, two Fears -- try to outweigh each other

The executive team at BioNano Genomics may well be gripped by this situation, as they are faced with two great perils: their finances and their markets.

Genia: It's Alive!

Once in a while I get the thrill of someone sending me a really good tip - that surge that comes with knowing that I know something that most people don't.  That rush of knowing that soon I'll get to spill the beans.  It's great, even if it upends my widely disseminated opinions.  Even if a moment later I realize that if I had thought harder I would have unearthed the nugget on my own.  All of which is the case here -- my tea leaf reading that Roche partnering with Illumina on diagnostics indicated that Genia is no more -- well, that interpretation is no more.  Because I got a hot and verifiable tip that Genia is very much still an active project at Roche.  And the verification is how I could I found this independently.

10X Genomics Exits Genomes

10X Genomics original product was a kit for generating linked reads from genomic DNA.  The idea had been kicking around for a while, partitioning long DNA into compartments and generating tagged libraries from each compartment.  This enabled both genome assembly and haplotyping from very small amounts of DNA.  When first reviewing 10X's slides from J.P. Morgan I had this thought "where's the genome kits" but then forgot to include it in my write-up.  Now I'm even more chagrined to discover that the explanation had been posted days before the conference: 10X has told their customers that their genome library kits are in the process of being discontinued.

JPM20 Loose Ends: Agilent, ThermoFisher, 10X Genomics, NanoString - plus PacBio & ONT

Time to close out  J.P. Morgan season with a grab bag of kvetches and kibbitzing on multiple 'omics companies that presented.  Much of this has been stimulated by Twitter discussions, with particular credit going to Varro Analytics and Albert Vilella.   While I've never been to J.P. Morgan physically and am skeptical I'll ever go, reviewing all this is a great prep for AGBT -- which I'm happy to be returning to this year for it's last Marco Island appearance for many years (forever?).

Bold Genapsys Talk at JPM20

Genapsys' CEO Hesaam Esfandyarpour presented today at the JPM Morgan Conference and delivered an expansive vision of where the company is going both this year an the long term.  This includes planned commercial launch of the 144M chip this year, an aggressive expansion into international markets and another round of "pre-IPO" financing.

JPM20: Roche Links with Illumina On Diagnostics

Another bit of Illumina news released at J.P. Morgan today is that Roche Diagnostics is partnering with Illumina.  The 15 year partnership (same duration as with QIAGEN) will place Roche diagnostic assays on Illumina clinical-grade sequencers as well as the two will jointly work for regulatory approval of Illumina's TruSight Oncology assays.  Roche has extensive experience in oncology, particularly since they own Foundation Medicine. This suggests that Roche is happy with a two pronged strategy in oncology diagnostics, selling assays on their own through the partnership while their Foundation arm offers an all-in service.   But it also stirs the tea leaves in the genomics M&A pot.

JPM20: Illumina Launches Super Resolution Instruments

Illumina presented this morning at the J.P. Morgan Healthcare Conference (presentation, slides & breakout).  For us sequencing geeks, the biggest news is the launch of a pair of new sequencers -- but not where either myself or Shawn Baker anticipated.  Rather than doing something about the low end of their line (as I predicted) or replacing the MiSeq as Shawn guessed, Illumina perceived a need for desktop instruments to span the range between the existing NextSeq 550 and the NovaSeq and has christened the new instruments NextSeq 1000 and NextSeq 2000.  They also come with some slick new technologies embedded.

Is Illumina Vulnerable At The Bottom?

According to both the FTC and CMA, Illumina holds a nearly complete monopoly on the sequencing market, with other players (Ion Torrent, Oxford Nanopore) holding on to toehold niches.  Illumina has held that position for an extended period, so what might upset it?  I'm going to explore the case that they may have some serious inroads at the bottom of their line.

Might Illumina Shave NovaSeq Run Times?

I've had some people asking, either privately or via Twitter, what might come from Illumina next week at JP Morgan (8:30 am PST on Monday).  I have another post in the works (ideally going out not long after this one) on one aspect of their business, but then I thought of something else.  Something in the great tradition of proposing a plan while being quite unaware of all the critical details that the plan relies on!

A Le Mans for Clinical Genomics?

If you haven't seen Ford v Ferrari (or Le Mans '66 in parts of Europe), I strongly suggest you do so if it is still in a local theater.  I'm neither a gearhead nor a fan of watching automobile races, but while the movie is centered on an attempt to win the  1966 24 Hours at Le Mans, there is so much more going on.  Designer Carroll Shelby (Matt Damon) must not only project manage a difficult task, but also deal with unreliable allies (as one wag put it, the biggest villain in the title isn't Ferrari) and a cantankerous star driver named Ken Miles (Christian Bale).  One touching aspect of the movie is the portrayal of Miles' relationship with his young son, an audience proxy who idolizes but sees all sides of his father.  

Illumina & PacBio Throw In The Towel

I had planned to post this morning a "preview of 2020" piece I had drafted in my head on the ski slopes the previous two days, but never got around to actually committing it to bits and bytes.  Today's announcement that the Pacific Biosciences acquisition from Illumina is officially dead means the first item of that piece is mostly going uncaptured.