Post-AGBT: Sequencing Hardware Roundup

Some updates on the sequencing instrument vendors, save Ultima Genomics and Element Biosciences which I've covered already.

Post-AGBT: Element AVITI Sequencing Updates

Element has been very busy over the past year and in the Silver Sponsor presentation covered updates since last AGBT as well as a number of completely new items.  I covered their Teton approach to multiomic analysis of cell culture in the last piece; in this one I'll cover their sequencing platform evolution.  Element was kind enough to loan me key members of their technical braintrust for an hour in the week before AGBT, which sadly I repaid by allowing their lunch to be scheduled over.  Thankfully, they do have a recording available!

Post-AGBT: Both Element & Singular Want Spatial to Go With The Flow(cells)

Element Biosciences and Singular Genomics have often appeared to be on roughly parallel trajectories, though with key differences.  Both companies launched sequencing instruments with NextSeq 2000-like specifications and largely aimed at the academic core lab and small biotech company market.  At AGBT, both announced upgrades to their sequencing instruments that allow the instrument to perform spatial omics while still functioning as a sequencer.  But there are key differences in their approach and what we know about each company and their degree of success so far in the sequencer market.

AGBT Follow-up: Ultima Genomics UG100, Volta Labs Callisto, N6Tec iconPCR

A confusion of ideas for AGBT follow-up have collided with the inevitable post-AGBT return-to-ordinary-life requirements.  To try to avoid a huge project that never gets completed, I'm breaking these up into multiple pieces.  First off, a look at reaction to the three big pieces I wrote before the conference or early during the conference: Ultima Genomics, Volta Labs Callisto and N6Tec iconPCR.  My comments are based on further thoughts on my part, discussions with other AGBT attendees and feedback I've gotten via social media, blog comments and emails/DMs.  Please keep it coming!  One of the great values of writing this is getting feedback - it illuminates questions I haven't considered and highlights gaps in my thinking. 

VoltaLabs Launches Callisto for DNA Extraction & Library Prep

Here at AGBT, VoltaLabs has unveiled their 24-sample DNA extraction and NGS library prep Callisto instrument, which is particularly suited for long read applications but is also suited for short read work. Volta has matured liquid handling automation to a novel open top electrowetting technology. Priced at $125K and planning to ship in the second quarter, Callisto is designed as a walk-away solution requiring no human interaction during a run. Personally, not only do I love the a new medium-throughput instrument for HMW DNA extraction and manipulation, but I also can at least pretend I helped steer the company In that directions

iconPCR: Super-Flexible qPCR Thermocycler Oft Dreamed, Now Delivered

Has there ever been a product you’ve just wanted to have, but it doesn’t exist? That keeps popping up in discussions - “if only we had X this project would go so much faster!”. Well, N6 Tec’s automation-friendly $99K i96 well iconPCR thermocycler is that to me. Launching at AGBT, it’s the gadget I’ve wanted repeatedly at Codon Devices, Warp Drive Bio and now Ginkgo Bioworks. It won’t solve all your PCR challenges, but it certainly gives new options to customize PCR like never before. And for many NGS labs, it offers major streamlining of PCR-based library construction protocols while also delivering superior data. How? By being a thermocycler where every well can run its own thermal profile and each well can go dormant once a desired level of amplification is achieved 

Want to Build A Sequencer? 454.bio Opens Up Their Plans

Just as the AGBT hype cycle was firing up (with me contributing multiple sparks), serial entrepreneur Jonathan Rothberg's latest sequencing startup 454.bio fully de-stealthed their technology this weekend, going so far as to release open source plans to build an instrument prototype.  454.bio  is aiming to build a Keurig-sized device to retail for $100, with sequencing runs in the $20 range.  To accomplish this, they're attempting a novel twist on sequencing-by-synthesis.  It's an unconventional strategy by someone who has succeeded twice before in DNA sequencing (454 and Ion Torrent) and has multiple other companies going (if I've counted correctly)  - QuantumSI in protein sequencing (a future topic for this space, I promise!), ButterflyNetworks with inexpensive, compact diagnostics ultrasound and Hyperfine with inexpensive, compact MRI diagnostic devices.  Then I went to the 4Catalyzer site - Rothberg's incubator - and discovered a bunch of companies I hadn't heard of or had forgotten about -- Protein Evolution in synthetic biology for plastics production, Detect for home-based diagnostics instruments, AI Therapeutics in the rare disease space and Liminal with what looks like consumer brain scanning.  That's quite a series of companies!   But the one closest to my heart (sorry QuantumSI :-) is  454.bio, and their announcements have many interesting facets which I'll dive into.

[2024-02-06 01:41 - 'used"--> iSeq fix -- stupid autocorrect!]

Ultima Launches

As part of the run-up to Gold sponsorship at AGBT, Ultima Genomics held a multi-day event in early December, with tours of the headquarters facility and factory floor in the Bay Area and a day at a beautiful Wine Country resort. The resort session included talks from the company, early access collaborators and a pair of big name early backers, with a few hundred current customers and many contemplating the leap.  So confident was the company in their product, they even invited a blogger to moderate one of the panel discussions!  The UG100 is now officially launched as a fully commercial product, with ambitions to replace panels, exomes and microarrays with whole genome sequences at $100 apiece.  All in an instrument package designed for continuous industrial-scale operation.  Please note that Ultima did review this piece to ensure I didn’t disclose information they did not wish public, but for the most part just gave me some very good proofreading support.  Photos are my own, except as noted.

On Illumina's Moats Past & Present

Studying how Illumina came to dominate sequencing markets is certainly worthy of at least a Harvard Business School case study, and perhaps an entire graduate thesis.  But I wanted to give a quick review of some of my thoughts on the matter, spurred by Nava Whiteford's repeated savaging of a piece in another space but also because many of these themes will show up in a flurry of pieces I'm planning (one's even nearly done!) in the next few weeks due to AGBT and some non-AGBT news.  

2024: A Look Ahead

It's January, and that means the J.P. Morgan Healthcare Conference looms next week -- followed by AGBT just a month later.  Indeed, I've been trying to mark out the "can't miss" talks for AGBT so I can resist over-scheduling them with meet-ups -- but many talks lack titles so that's not easy.  JP Morgan seems to have Illumina, 10X and Nanostring -- and not much else in the way of sequencing-space companies.  But time to prognosticate before all the news happens!

Should PacBio Abandon Their Set List?

In a piece on LinkedIn, Brian Krueger made a pithy comment that should give PacBio management pause.  In a series of bulletpoints he summarized key things he had heard from ASHG, and the one for PacBio starts with "And PacBio threw a party".  Parties with name musical acts has been modus operandi for PacBio Sales & Marketing for a number of years now, but I hope they seriously think about whether this is a good use of marketing dollars.  But fear not dear leader: if they do listen to Brian & I it's probably much too late to derail any plans for AGBT.

Concept: An Oxford Nanopore Adaptive Sequencing IDE

Oxford Nanopore's adaptive sequencing scheme is truly singular (but not Singular!), enabling computational adjustment of the sequencing process as it occurs.  A number of academics have demonstrated proofs-of-concept of different ways this capability can be used, with Oxford Nanopore slowly incorporating some of these higher level concepts into their MinKNOW operating software.  An idea has been rattling around in my head since London Calling that what this space truly needs is a full Integrated Development Environment (IDE) to support adaptive sequencing.  It's more than a little conceited for me to do this, given that I've contributed nothing to that field and the only adaptive sequencing experiment under my guidance was quite disappointing.  But it's an interesting enough idea that I can't resist.

Chatting Apton Acquisition with PacBio CEO Christian Henry

PacBio CEO Christian Henry chatted with me recently by teleconference on a variety of topics, but the focus was the recent PacBio acquisition of Apton Biosystems for $85M in equity.  As a regular reminder, my employer’s CEO reports in a sense to Henry, as he’s on the Board of Directors.  

A particularly interesting revelation by Henry is that PacBio had its eye on Apton in late 2021, essentially as soon as they completed the Omniome acquisition announced in July 2021 that formed the foundation for their now-released Onso short read instrument.    PacBio believed then that the desktop instrument design from Omniome wouldn’t be sufficient; PacBio felt compelled to have a path to a high-throughput instrument.  While they felt an internal effort was possible, an acquisition might shave many years off the timeline.  And PacBio liked Apton’s concepts and launched into discussions and even made an acquisition offer to Apton’s management, but no deal was reached – but nor were any bridges burned.

About a year later, PacBio was at ASHG unveiling the Revio long read instrument and sent new feelers to Apton – let’s explore a collaboration marrying our chemistry to your instrument.  Before long, just such a proof-of-concept instrument was underway, and in under two weeks positive results were in hand.  Results weren’t as good as with the well-tuned Onso prototype, but nor were they discouraging – perhaps with tuning the gap could be closed.  The proof-of-concept experiment didn’t have ideal density, the optics hadn’t been tuned and nor had the fluidics been optimized – the PacBio reagents had a significantly different viscosity than Apton had targeted.  But billions of reads at “not quite Q40” quality.  Henry particularly gushed over Apton’s optics, which achieve superresolution imagery but with rapid scanning times. This led to new discussions about what sort of structure any joint effort should take, which ultimately led to the acquisition – with PacBio particularly happy with the timing since the original Onso R&D effort was winding down.

So what will come out of all this?  Henry sketched the idea of a floor-standing model generating billions of reads.  Launch timing expectations aren’t being made public - Henry isn’t ready to put pressure on the development team – “yet”.  Accuracy in the Q40+ range and billions of reads per flowcell. Run times in the 2-3 day range - Henry and I agreed that nobody is interested in returning to the two week sequencer runs common with the first generation instruments such as GAII and SOLiD.   The unit would have sufficient onboard compute to perform the superresolution imagery processing as well as the downstream processing which is onboard the Revio.  Likely to have either 2 or 3 flowcells per run – Henry said “definitely multiflowcell” but “probably not 4 like Singular”.

From a commercial point-of-view, Henry believes that first they can capture 1-3% market share in the liquid biopsy space to create a multi-$100M business.  That’s a small slice of a big pie  - Henry isn’t making grandiose claims here.  But it’s also much easier to overshoot a small estimate than a larger one.  Henry believes that the current Onso will be important in this market, but ultimately there needs to be a big machine as well.  

He also sees the Onso instruments, and particularly an Apton-enabled high throughput instrument, as important for selling Revio and future long read instruments (more on that below).  He was very gracious about competitors all around – in his view Element Biosystems, Singular Genomics, Oxford Nanopore and the rest are important counterweights to PacBio drifting into hubris and complacency.

Some observers such as this scribe worry that the Onso short read platform will distract attention from the long read Revio/Sequel platform, but Henry is clearly still very invested in the long read side of the business - and a strong believer in sales synergy between the long read and short read instruments. Globally, PacBio is seeing success selling Revio plus Onso bundles. He sees the size of the commercial organization – now over 200 people – as an edge against small players like Element and Singular.   Revio, he says, is performing well in the field and performance enhancements will be coming late this year or early next year. That might include library preps from 100 nanograms or less of input DNA.   And 40% of Revio orders are to new customers, not previous Sequel line owners.  And with increasing interest in the small fraction of long DNA fragments in cell-free DNA, Henry sees possible crossover  between the Onso focus on cell-free DNA diagnostics (aka liquid biopsies) and the long read business – but also that competition in this space “keeps PacBio honest”

Henry says that PacBio is “deep in development” on a next generation SMRTcell, designed to enable 10K 30X human genomes per year – and many population genetics studies are opting for 12-15X coverage so that might be multiplied by a bit more than a factor of two (and with current Revio, that brings each samples slice of the flowcell to about $500).  At the other end, development of a benchtop system with a “dramatically lower”  pricetag is well under way.  PacBio is also investing heavily in computational biology, viewing long read computational biology as still having a lot of catching up to do relative to short read computational biology.

 

With regard to Oxford Nanopore,  Henry frequently grants compliments – but is also fiercely competitive.  So in one breath he praises MinION as a great product and “we won’t touch them”, but the next touts Revio for large scale long read studies.  He claims that the all in cost of Revio is better than Oxford Nanopore (a claim I’m sure ONT would contest – everybody, get out your green eyeshades!).  Henry noted that at current duplex rates, large oversampling is required on PromethION to cover a genome – which I’m sure ONT would counter with “wait until the next release of duplex”.  Henry claims that one “major institution” took delivery of a Revio and then mothballed their Oxford Nanopore instruments.

For cell free DNA in particular, Henry is very bullish on Onso’s accuracy being a major advantage.  In a head-to-head comparison of Illumina with Unique Molecular Indexes (UMI) and Onso without UMI, Illumina required four times as much data to achieve a similar level of accuracy.  Translational genomics player TGEN decided on an Onso plus Revio bundle after seeing this sort of quality improvement.  But Henry conceded the for most germline variants the advantage might not appear – though he did qualify this with a comment that Illumina’s filtering can lose coverage in some tricky spots in the genome.

It’s so much fun to track a space that is absolutely cutting-edge in terms of technology yet still has so much innovation bubbling.  Apton and Omniome decided that the best route to market for their technologies was to be acquired; Ultima, Element and Singular are trying the independent route.  Acquisition isn’t a panacea - I’m sure anyone who worked passionately on LaserGen was floored by Agilent’s decision to shelve that technology, and if I had spent long hours on Genia or Stratos I’d be unhappy with Roche’s inability to launch a sequencer.  Onso is still early in its launch phase in a crowded market, with more than a little skepticism in social media as to whether it can carve out a niche.  It will take at least a year or two before we can really assess Henry’s bullish position on the technology, and perhaps another couple of years before we see Apton technology in the field.  But for me, watching all this unfold never begins to bore

Two More Automation Partners Join PacBio Compatible Program

A significant challenge for the long read sequencing vendors has been that short read sequencing has a decade and a half head start in evolving a tools ecosystem.  New entrants such as Singular Genomics and Element Biosciences can take the strategy of building short bridges to existing tools designed for Illumina whereas the long read players must often build anew, as tools and protocols sufficient for short reads often are lacking performance on long reads.  At J.P. Morgan in January, PacBio had announced a PacBio Compatible program to highlight products which specifically support PacBio sequencing.  This morning, two more automation vendors -- Revvity and Tecan -- have joined their liquid handling automation to the program.  I got a walkthrough of the new announcement from PacBio's Amit Patel yesterday.

Apton (Super) Resolution to Be Acquired Fulfilled by PacBio

Wednesday night brought the news that Pacific Biosciences has both officially launched their Onso desktop short read sequencer and bought technology for a high throughput version of it by acquiring Apton Biosystems.  Apton had been developing their own short read chemistry and an instrument based on super0resolution imaging to go with it and was apparently relatively close to launch.  PacBio got Apton for $110M, with $85 paid now in PacBio stock and the remaining $25M "stock and cash add-ons" according to GenomeWeb (premium/free via ex-Twitter) - so presumable based on certain milestones being met.  

Overheard in a Thai Restaurant

An amusing incident happened on the Sunday of Memorial Day weekend that is a reminder that even when there are no walls the walls in the Boston area can have biotech-tuned ears.  Oh, and a funny quirk of fate that I swear I'm not making up.

Illumina: Where Was the Board?

Sunday brought news that Francis deSouza had resigned as CEO of Illumina.  It at first might have seemed he had survived the boardroom challenge from activist investor Carl Icahn, losing only one ally - Board Chairman John Thompson.  But that apparently effectively made him a lame duck, and he is now leaving immediately -- leaving no one at the helm of Illumina momentarily but also eliminating any interference from deSouza with the installation of his successor.  If you have access to STAT+, Matt Herper's commentary is very informative (I'd expect nothing less).

London Calling 2023

Called Back To London Again

After a too long pandemic-induced hiatus, I'm in the UK for this year's edition of London Calling.  I talked myself out of going last year well in advance, which would have been interesting as my rapid tests were still coming up positive about the time I would have needed to fly from Boston over the Atlantic.  And while I've been watching remotely, I've been dismal over the past year in actually writing anything about it.  Which was foolish on my part as ONT has been going through an interesting transition.

Thoughts on Unexpected Sequences Found In COVID mRNA Vaccines

Writing this piece is not easy, not only because the topic matter is completely in controversies around SARS-CoV-2 and the vaccines for it, but because the data was generated by someone whose outspoken opinions on any COVID-19 public health topic are nearly always ones I find myself in opposition to.  Someone who periodically lobs my way personal attacks on my ethics.  It doesn't help that these results will be certainly misused to attempt to undermine public confidence in the vaccines, or that this post will probably attract a lot of commentary that I don't wish to address because of the adage that generating misinformation takes far less energy than rationally correcting it.  But, data is data and in the end I believe that whatever our differences, the data generator is not someone who would construct a hoax.  And in any case, the results can be checked, so if somehow it were a vicious hoax that could be exposed.  And importantly, I feel that what has been found should be discussed, as no advanced technology is ever perfect - these results I feel suggest new standards for the design and implementation of mRNA therapeutics.