Friday, April 08, 2011

Another Low Cost Sequencer on the Horizon?

An article in GenomeWeb's In Sequence (which, alas, requires a subscription for which I've never sprung) has a piece on Intelligent Biosystems (IBS), which iat the X-Gen Congress meeting apparently announced a plan to launch the "Pinpoint Mini" sequencer.  The box would come in at $85K, putting it smack in the middle of Ion Torrent PGM and Illumina MiSeq pricing.  The hope is to have boxes shipping to early access customers by the end of the year.

To be honest, I'm guilty of mentally writing off IBS, as they had been around a long time and very quiet.  Indeed, in my defense their website looks like it hasn't been updated since it first went up, and you'd think now that they made a big announcement it would be updated, but apparently not yet.  On the other hand, while stale websites can indicate fading companies, the fact that it still is working suggests some life.

In any case, I was apparently hasty in my thoughts.  The box as described has some interesting features.  Supposedly it will crank out data at $75/Gbase.  The claim is that one exome could be sequenced (reagent costs only, mind you) at 30X for $150 in about 1.5 days.  No word on read lengths.  The system will mount 20 flow cells, each of which can be run independently.  Chemistry is based on reversible terminators that they exclusively licensed; if I understand it correctly the big advantage of their chemistry is simplicity.  There's also a curious bit in the publication from the founders is using a mix of unlabeled reversible terminators with labeled dideoxy terminators; the same cleavage reaction removes both the terminator and the label.  This was touted as a way to reduce the discrimination of the polymerase against the reversible terminators.  Of course, an alternative would be to generate mutant polymerases which are more amenable to being fed terminators.  Having four pairs of complicated compounds wouldn't seem to be a route to low cost, but perhaps the gains are worth it (or this chemistry isn't being used any more; very hard to tell from what I was able to read).

Sounds great, but of course there's a lot to do before such a machine can launch.  There's no word about sample prep method, which probably means it will use emulsion PCR, since necessary licenses for that can apparently be obtained.  There's also the problem of manufacturing the instrument and the reagent kits.  Te fact that IBS apparently planned to launch a PinPoint large-scale sequencer a few years back and couldn't get it out the door is not going to help them compete in the expectations market with the other boxes.

One solution to some of these issues would be a strategic partnership with (or outright acquisition by) a major reagents and/or equipment player. It's not hard to come up with a list of candidates, based on nothing more than that description.  Perhaps at some point Affymetrix will decide to move into next-gen.  Roche could always decide to go for something cheaper than 454, but I doubt it.  Agilent seems quite happy supplying picks and shovels, but perhaps they'll go for the big time.  Perkin Elmer, GE (which is working on blue sky sequencers) or a host of others.  Picking the right partner will be key; Illumina has the advantage of an enormous installed base and thriving ecosystem of associated vendors, whereas Ion Torrent has a lot of buzz and serious marketing muscle (not to say Illumina is lacking there either).

It's also interesting to see this machine being touted as an exome sequencing workhorse for clinical use.  The issue really deserves its own detailed post, but such an application brings some serious issues.    Library preparation requires a lot of labor and a bunch of other instruments, or a bit less labor and some more instruments specialized for prep.   Right now, the market for exomes on HiSeq using either SureSelect or EZCap  is quite competitive; I've recently gotten quotes ranging from $2K-$5K (the lower quotes tend to be from new entrants; promised coverage varies a bit too) .  For 50Mb capture at 50X coverage, it would seem you could get around 50 exomes into one HiSeq flowcell, which at $10K each means about $200 in sequencing (feel free to correct my math in the comments).  That would suggest that very little of the cost of these exome captures is sequencing reagents; the majority is labor and the EZCap or SureSelect kits.

While some elegant library-free methods  (really, methods which add the sequencing adaptors as they are capturing the targeted DNA). for exome sequencing have been published, none of these are commercially available on an exome scale.   RainDance requires an expensive ($200K+) box and isn't quite up to exome scale,. .  Halo Genomics. has announced a library-free  prep for "1000s of exons", so perhaps this will break this problem open.  Whether this is really whole exome, or something smaller, remains to be seen.  A safe rule, though, is that these methods are only efficient if read lengths are significant.  At a minimum, the first part of a read is burned on getting through the targeting primers, and with very short reads the size of each targeted amplicon must be small, meaning for a fixed number of amplicons (cost) you can capture a lot less DNA than with a longer read technology.

So, another player in the field -- but with a far off beta release and a lack of a track record.  They'll be fun to watch (assuming they go out of possum mode), but probably won't be a real factor in the market for over a year.


Anonymous said...

you forgot to mention gnu who just released some data recently

Anonymous said...

Can you give details about the quotes you mentioned for the WES? I mean the service provider, is it a commercial or just institutional service???