MiSeq Makeover

MiSeq is the the oldest instrument in Illumina's lineup, first unveiled back in 2011.  MiSeq's launch stole much of the thunder from the Ion Torrent PGM at the time.  Illumina brought out other instruments to push the lower boundary of their line: MiniSeq came in 2016 and iSeq 100 in 2018 - but MiSeq remained the most popular instrument of that batch.  It has a warm place in my heart; at Starbase we contracted out many MiSeq runs since the necessary batch size was often very appropriate for us.  In the meantime, various other instruments came and went - HiSeq originally launched about the same time as MiSeq and later there was HiSeq X, and in that time period we've seen Ion PGM be replaced by Ion Proton, PacBio cycle through multiple models, and 454 abandon the market and  - as well as fizzles such as Genapsys.  But today Illumina announced a new instrument family under the MiSeq moniker - and the iSeq 100 moniker - called the MiSeq i100, which harmonizes the low end of their line with the higher end.    

In particular, the new MiSeq i100 will have DRAGEN compute onboard and use the new XLEAP chemistry - bringing it in line with the high end NextSeq 1000/2000 and NovaSeq X.  With DRAGEN comes a suite of data-to-answer workflows, in line with CEO Jacob Thayssen's vision which was elaborated back in August of providing complete solutions. The DRAGEN gear is also used to deliver demultiplexing stats early in a run, enabling barcode balancing miscues to be detected and reacted to before FASTQs roll off.  XLEAP brings with it the significant bonus of less packaging and ambient temperature stable reagents (currently rated at 3 months)  - very important in much of the world where cold chains can't be relied on.  

On the exterior, the styling of MiSeq i100 matches the vibe of the larger instruments, moving away from the black-and-white style of the first generations.  MiSeq i100 has a significantly smaller benchtop footprint than MiSeq classic - 0.4 x 0.5 meters.  Two different versions of the instrument will be available, a $49K MiSeq i100 and a $109K MiSeq i100 Plus - the latter, as discussed before, fits a bit more capability into the same case. Both are single flowcell instruments.

Importantly, the makeover is not just cosmetic.  With new flowcells slated for next year, the MiSeq i100 Plus (but not the basic model) will support 100M 2x150 reads, or about as many as the NextSeq 1000/2000's P1 flowcell.  So there's no longer a gap not covered by any flowcell in the Illumina fleet - MiSeq's high end (and the base model of the new line) is only 25M.

The new instruments are also much faster, starting with elimination of any instrument wash step as the reagents and fluidics are entirely within a disposable cartridge - as are the iSeq-style CMOS optics.  There's no laser onboard - illumination is with LEDs.  Denaturation of the library is onboard now as well.    

The new instrument is much faster than its predecessor. For example, the highest output spec for 2x150 on classic MiSeq is the v2 kit, yielding 12-15M reads in 24 hours - but the new instrument can deliver 25M reads in 7 hours, or in 2025 the 50M flowcell will be rated for 2x150 at 7.5 hours and the 100M flowcell at 8 hours.  For 2x300, the v3 chemistry on classic can yield 25M reads in 56 hours; with the new instrument's 25M flowcell that drops to about 15.5 hours.  To top it off, the accuracy of the XLEAP chemistry is superior as well. 

The new MiSeq can be seen as a reaction to competition.  For example, a few years ago a former coworker proudly told me he had arranged his startup to acquire a MiSeq.  My thought was "that's great for now, but given your ambitions you'll outgrow it - if you'd asked me I would have suggested trying the just-launched AVITI".  And that has indeed been my thinking - for about 2-3X the capital cost one could get a much higher performance instrument.  But now, $50K gets a very highly performing machine and $100K one which will fit many startup aspirations.  AVITI is still a sweet instrument, but Illumina just made that conversation more complicated.  Some commenters have mentioned the Complete Genomics (/MGI) DNBSEQ-G99, but given that company being in the US Congress' crosshairs it isn't going to get much attention in the US market.  Nanopore fans pointed out it's still much larger than a MinION or even a P2, and Illumina didn't make any claims around portability - and the ONT products have a strong advantage on purchase price.  But many will prefer the Illumina brand, more mature ecosystem and have counting applications more suitable for short reads.

Surprisingly, Illumina did not provide clear guidance on when iSeq, MiniSeq and classic MiSeq will be sunsetted.  MiniSeq, which has a reputation as a weak seller, now makes no sense - for the same price you can get the basic MiSeq i100 and have a higher performing machine.  iSeq has never gotten any love since being launched.  But even more surprising is that Illumina didn't outline a clear roadmap for clinical versions of the MiSeq i100 - the DX model of the MiSeq received FDA clearance.  The simpler workflows and smaller footprint would seem to make MiSeq i100 a natural to try to put into pathology labs.  So why the hesitancy to outline a path to get these into lucrative clinical markets?

So farewell MiSeq.  I hope Illumina makes as big a social media effort for the last MiSeq to ship as they do for the first MiSeq i100.  MiSeq has endured for over a decade and delivered important results to scores upon scores of scientists and dropped the cost of getting access to Illumina data - both in instrument cost and by being able to run more affordable batch sizes - in days when a GAII or HiSeq flowcell could cost as much as an SUV.  Putting such a thoroughbred out to pasture is inevitable, but it deserves some hoopla.