What might a PGM2 look like?

The New England chapter of the Laboratory Robot Interest Group (NE-LRIG) had a nice meeting tonight over at Astra Zeneca's beautiful Waltham campus (woodsy borders, with a view of the nearby reservoir).  The meeting was sponsored by Ion Torrent & they gave one of the three talks.  All three talks were quite good, with my friend & former Millennium colleague Sunita Badola from Amgen leading off with 454 amplicon sequencing in oncology clinical trials, followed by Mark DePristo from the Broad Institute talking about the 1K genomes effort and finally Jason Affourtit from Ion Torrent (he oversees all their field applications scientists) about the Ion platform.  The Ion talk gave a bit of the standard overview, followed by some slides summarizing the talks at Marco Island.

Now, when I've run previous items on Ion Torrent they have garnered a lot of comments.  Some of these are positive, others (and some of my posts) not so much, with some of the commenters most charitably described as downright cynical.  I won't have any data of my own for at least a month (and a machine on my own is still no more than a great desire), but I must say that if Ion Torrent is all smoke and mirrors, as some comments have insinuated, they have an awful lot of good people in on the ruse.  A friend of mine who is a very experienced genomics lab head was raving about her new machine and I happened to talk to another site today and their first four runs have all come in with greater than 2X the number of reads in the specification and very good quality.  About the only thing I've heard that is less than raving is that the quality drops near the end of the reads in a way that the effective read length is sometimes more like 80-90 rather than 100.  Still, if you know this going in you can adapt to it.

A star before and after the talks was a PGM which was available for viewing, along with 314 and 316 chips being passed around (which I was sorely tempted to have disappear into my shirt pocket, but morals prevailed).  These, for example, brought home the fact which I hadn't appreciated before that the 316 has significantly more actual surface area than the 314 chip, though it fits in the same carrier.  The difference between the chips is quite visible in your hand.  The 316 would appear to essentially max out the form factor, so the 318 can't keep up this trend. [corrected 3/25 per Rick's catching the typo]

Something that was emphasized tonight that I hadn't appreciated before is that there are no pumps in the PGM.  Reagents are propelled by argon gas pressure, managed by valves which are themselves actuated by the argon (some electrical widgets ultimately control the valves).  Also, the case apparently encompasses a lot of empty space (the Ion folks were open about this, though the machine was not open to view the innards).  Presumably some of this was a conservative design leaving space for late additions (or perhaps the server), but some had to do with wanting a visually striking design.

Since the PGM instrument itself has little to do with performance of the instrument, there isn't a need to redesign it to address sequencing performance.  However, there might be other reasons.  While it is a relatively small benchtop instrument, space is often at a premium.  A group of us from Infinity visited an academic site nearby today, and their lab made ours look spacious -- every square inch of bench was crammed with machines.  

Furthermore, seeing the machine in person made it clear that in placing it, a lab must leave some space on the right side to access the wash and waste bottles along that side.  Hence, if you really wanted to cram a lab the effective footprint of the instrument is a bit larger.
So, to engage in rank speculation utterly uninformed by any hard facts, I might imagine that a focus for a PGM2 would be an even smaller footprint.  The four tubes in the front, which hold the nucleotides for sequencing, could be rearranged in a manner still artful (perhaps a diamond?) yet far more compact, enabling the side bottles to move to the front.  Perhaps the screen could move down below the instrument -- or become an off-machine accessory capable of driving multiple instruments.  Alternatively, perhaps the screen would be mounted behind the flowcell access hatch.  This hatch on top (dark grey) for placing the flowcell also seems larger than necessary.  So, if you really could combine all these, it could yield an instrument with an effective footprint about one half as wide or maybe better.

A question I didn't think to ask tonight is how sensitive is the instrument to the flowcell being level.  I'm guessing (but certainly not a confident guess) that such devices mostly don't care; at these scales gravity isn't a dominant force.  In that case, the hatch might be turned to open outwards, enabling a redesign to improve the ability to stack the instruments vertically.

Another obvious dimension would be a multi-flowcell instrument ala HiSeq 2000.  Could most of the mechanical simplicity of the system be retained while enabling multiple flowcells to be run in parallel?  That would be the key question.

Of course, the key driver for many of these would be if groups wanted multiple machines to drive very high throughput.  I think there will be a market for this, but it is premature to think it has developed.  And, it will be critical for such operations to have the promised emulsion PCR improvements (or replacement) which is promised.