Helicos Cries Out “I'm Not Dead! I'm Getting Better!”

Helicos, the first company to launch a single molecule DNA sequencer (a class sometimes called “3^rd Generation”), has been hanging on to a thread for a while. They've been delisted from NASDAQ and their cash supply is dwindling (down to $1.6M as by June 30^th). They are going through another round of cash-saving layoffs that will bring their headcount down to 10. They have apparently stopped selling the HeliScope and their ability to supply reagents and service support to their current customers has been called into question.

When they launched their HeliScope in 2009, they went head to head with the more established players (Illumina, ABI and 454) focusing almost exclusively on being the first 'true single molecule sequencer' for genomic sequencing. It was a tough sell given that they were a bit late to the party and that their reads are shorter and have a higher error rate. They might have been better served to focus on RNA-Seq and ChIP-Seq where the lower quality reads wouldn't have hurt as much and they could have touted their (at the time) industry-leading # of reads per run.

For the past few months their main strategy seemed to center around litigation – they're suing Life Technologies, Illumina and Pacific Biosciences for patent infringement. Just recently, however, they've expanded this strategy by borrowing a page from Complete Genomics – they have launched a sequencing services program to increase their revenues. They've also launched an interesting targeted sequencing solution in which the capture sequences are attached directly to the flow cell (rather than their standard poly dT sequences). They've demonstrated this technology by creating a flow cell for the direct sequencing of the BRCA1 gene.

I fear it may be a bit too little too late, but at least Helicos is still kicking and demonstrating that it doesn't want to go on the cart.

Ion Torrent's Roadmap to the $500 Genome

Ion Torrent has made some bold claims about making 10x improvements every 6 months, and so far they've kept to that schedule (albeit only over a single 6 month period). In a recent Nature paper (covered by In Sequence 7/26/11) they detailed how they could shrink their features and increase the chip size to achieve first 165M and then 1100M sensors per chip. I've used this information, along with some really useful 'real world' feedback on the 314 and 316 chip from Nick Loman's blog (@pathogenomenick), to create a speculative roadmap for how Ion Torrent might achieve the 10x improvements through the middle of 2013. Assuming they are able to achieve the higher density chips in the timeframe I've listed (I don't think any timeframe was listed in the paper), that they can extend their reads out to 1000b (which seems reasonable given where 454 is today) and that they can improve the number of 'effective beads' (based on fill efficiency, # of 'live' beads, and # of reads passing the filters), it doesn't seem too unreasonable that they might maintain their '10x improvements every 6 months' goal out through the middle of 2013.

I also took a stab at what future chips might cost based on Rothberg's statement that they would hit a $1000 genome by 1/1/13 and a $500 genome by 7/1/13 (In Sequence 6/14/11). I'm assuming 90Gb per genome and $250 in reagents per run. (The prices listed are the initial prices at launch, but they've already demonstrated that the prices for 'old' chips may come down once the new chips are released.) Everything seems pretty reasonable until you get out to the (theoretical) 324 chip at $5000. Since Rothberg only predicted a 2x drop in price/genome from 1/1/13 to 7/1/13, they're either going to charge a lot more for this chip, or the 10x improvements will have started to peter out.

It should be fun to see how accurate this roadmap is. As always, comments and criticisms are welcome.

Chip1	Release Date	Output Spec	Sensors	Fill Eff. 2	Live Beads	Passing Filter	Read length	Calc Output	Est. Chip Price
314	01/01/11	10Mb	1.2M	41%	67%	67%	100	20Mb	$250
316	07/01/11	100Mb	6.1M	80%	67%	67%	100	200Mb	$250
318	01/01/12	1Gb	11M	80%	67%	67%	250	1Gb	$500
320	07/01/12	10Gb	60M3	80%	67%	67%	400	10Gb	$?
322	01/01/13	100Gb	165M	100%	100%	100%	600	100Gb	~$750
324	07/01/13	1Tb	1100M	100%	100%	100%	1000	1Tb	~$5,000

 

¹The chip names 320, 322, and 324 and release dates are purely speculative. I haven't seen Ion Torrent claim a new chip every 6 months, just that there would be 10x improvements every 6 months.
²The 'fill efficiency', 'live beads' and 'passing filter' metrics for the 314 and 316 chips came from Nick Loman. The values for the other chips are pure speculation on my part. The values for the 322 and 324 chips are surely a little optimistic, but they could be counterbalanced with longer reads to achieve the same output.
³The 60M sensor chip is also pure speculation on my part. Ion Torrent didn't mention this 'intermediate' chip in the Nature paper.

The Institute That Never Was...

In early January 2010 Illumina made a big announcment – BGI was to purchase 128 of Illumina's brand new HiSeq 2000 sequencers. (In Sequence 1/12/10). Not to be outdone, Life Technologies followed up with their own announcement a couple of weeks later – the 'not quite yet formed' Ignite Institute was to purchase 100 of Life's brand new SOLiD 4 sequencers. (Genome Web 1/28/10) 

Inside Illumina there was a lot of skepticism (myself included) about Life's announcement. It just seemed like a desperate ploy to detract attention from the BGI announcement. In the back of my mind, however, I wondered if I was being too pessimistic in my Kool-Aid drinking. Turns out the answer was 'not so much'.

Ignite ran into a number of troubles with funding and the purchases never happened. In fact, Ignite never 'happened'. Instead it sort of merged with the Fox Chase Cancer during the formation of the 'Cancer Genome Institute at Fox Chase'. Perhaps most telling was that when Fox Chase forged their own partnership with Life the 'Ignite' name wasn't mentioned. As quoted in Kevin Davies article:

“We didn’t mention Ignite [when that was announced] – that was intentional,” Boyd explains. “We got tired of negative reporters who want to dig into what happened to Ignite [in Northern Virginia] and dredge up that experience.”

Negative experience, indeed!

As for BGI, they certainly still exist and they've actually purchased all 128 HiSeq 2000's (plus a few more). And they continue to draw strong reactions - praise, scorn and fear, to name a few.

(Lest anyone think I'm unfairly picking on Life, Illumina has been known to make a stumble or two. I'm looking at you, Avantome ;-)

Explaining BlueSEQ

This is my (non-snarky) attempt to convince Anthony Fejes that BlueSEQ might be a good idea.

Anthony Fejes, in the process of doing a phenomenal job with realtime blogging about the Copenhagenomics talks, expressed his concerns and doubts about BlueSEQ's business plan. For those of you who don't know, BlueSEQ is a Danish startup which is attempting to create a neutral next generation sequencing exchange. Their goal is to match researchers who have a sequencing project need with service providers who have excess capacity on their sequencers.

Take a minute to read Anthony's comments (but please come back when you're done).


His main concerns seem to be:
1) Why would service providers want to participate?
2) How can BlueSEQ standardize NGS in a meaningful way?

Let's tackle the first point. Why would providers want to be a part of this? I'll give you my opinions, but the simple fact is they ARE interested. BlueSEQ has already signed up over 20 providers and they're getting more requests all the time. Providers really want to have access to these customers to help them drive and expand their business. It also helps them optimize their workflow. For example, if they're in the middle of a large human genome resequencing project and they've got an internal user who wants to run a 5 sample small RNA-Seq experiment, they could outsource the small project so as to not interrupt the large project (which would require a completely different setup). Alternatively, if they're running some ChIP-Seq projects, they may want to go onto the exchange to find as many ChIP-Seq samples to help fill up an entire 5500xl SOLiD or HiSeq 2000 run. Basically, it gives them more customers and more flexibility.

Now to the second point. Anthony correctly points out the folly of trying to standardize such things as the bioinformatics analysis process. Fortunately that's not what BlueSEQ is trying to do. In talking with dozens of service providers, what they've found is that a big issue that the providers face is educating their potential customers about what NGS can and can't do and translating the customer's general idea of a biological experiment into a particular NGS protocol. This is where BlueSEQ can step in. The goal is to help guide researchers in communicating their needs to the providers. For example, translating something like "I want to compare gene expression levels between these 10 samples" into something like "Starting from 100ng of total RNA, I need to run RNA-Seq (including library prep) on 10 mouse samples with 50M 1x100bp reads per sample, followed up with an analysis that looks for both expression level differences as well as SNP variances". The final details would likely be worked out between the researcher and the provider, but they would at least be on the same page.

If you're still with me, here are my quick responses to the rest of Anthony's specific questions:

[This is one stop shopping for next-gen sequencing providers? How do you make money doing this?]
BlueSEQ makes money by charging service provider small fee (generally 5-10%, depending on the project size) when, and only when, the provider wins a bid.

[How do you standardize the bioinformatics? Seems... naive.]
Yes, that would be naive, but they're not trying to do that.

[again, why would providers want to opt in to this?]
Because they want more business. Of course, if a service provider is running their machines 24x7, they wouldn't want to join. However, it appears that most providers don't find themselves in this situation.

[Why would any provider want customer reviews of NGS data... ]
It's possible they wouldn't, especially if they're not very good. But this is really more for the users as over time it will help them pick the best providers (and not, for example, choose simply based on price).

[the sample prep is a huge part of the quality, and if they don't control it, it's just going to be disaster.]
This would be entirely up to the researcher and provider. Some providers want that level of control (to ensure high quality) while others are happy to have their customers prepare the libraries.

Retirement Fail...

Well, I find myself a little less retired than I expected to be. My intention was to take a good long break before looking for something interesting. It seems, however, that something interesting has found me. I'm doing some work for a Danish startup called BlueSEQ.

They're setting up a sequencing service exchange. If you've got a sequencing project but no sequencer (or not enough capacity) you can put your project on the exchange and compare the various bids (to get the best price, right platform for the job, level of expertise you need, etc.) If you're a service provider or core lab with excess sequencing capacity you can bid for projects to keep your pipeline full. The service is free for researchers while the service providers pay a small service fee (but only for successful bids).

The best part is that the whole process is centered around the Project Design Tool. It takes researchers step by step through the process of describing their experimental needs, ensuring that both the researcher and the service provider are on the same page and everybody is getting exactly what they expected. The project designs can be saved and reused for future projects to maintain consistency.

So where do I come in? I'm developing the BlueSEQ NGS Knowledge Bank, a neutral repository of all things next gen sequencing. I've got the basics up now with general descriptions of the major platforms and applications as well as a list of NGS-focused conferences and meetings. Have a look and tell me what you think. I'd love to hear your thoughts about what's there now and what you'd like to see in the future.

Check out the official press release from BlueSEQ.

Ion Torrent's Tilt-Shift View of the Future

What does tilt-shift photography have to do with Ion Torrent? Yesterday I would have said "nothing", but then they released a video that is apparently dedicated to it. Don't get me wrong, it's a really cool effect that makes everything look miniature, but I'm struggling to figure out what it has to do with next gen sequencing. The PGM acts as an iPod cradle; maybe it also doubles as a camera?

For your enjoyment, a pointless but cool video:

Ion Torrent's $1 Trillion Investment

Ion Torrent has a new video out (see link below). In addition to reminding everyone that they're building on the $1 Trillion investment made in the semiconductor industry (not exactly sure how relevant that is), they also show images of the 314 and 316 wafers. From the images, it looks like the 316 chips are roughly 5x the size of the 314 chips (~74 chips/wafer for the 316 chip vs ~350 chips/wafer for the 314 chip). That more or less fits in with the 5x increase in number of sensors/chip (1.2M vs 6M). It's impressive that this 5-fold size increase only resulted in a 2-fold price increase ($250 to $500). Their next chip, the 318 which is slated for 4Q2011, will roughly double the number of sensors to 11M while holding the price at $500. If they have to keep increasing the size of the new chips, it seems like it will be difficult to keep the price at the current level. It will be interesting to see if they start increasing sensor density rather than just chip size.

Ion Torrent's video