Helicos Single Molecule Sequencing – A Pioneer 8

The next-generation sequencing market continues its downward trajectory – routinely violating Moore’s Law by an estimated 3x, the cost per megabase curve started to significantly bend downward around 2007 when the Solexa 1G started selling in volume, and gave the 454 GS20 (as it was known then) the first competition for massively parallel sequencing the market had seen.

Technology platforms would warrant an entire publication for a single genome; the first was James Watson (appropriate as the co-discoverer of the structure of the DNA helix) in 2008 on the 454 platform. The time it took (4.5 months) and the cost (USD $1.5M) was revolutionary as of 2008; yet only a few months later Illumina would announce the completion of a Yoruba individual (from the International HapMap project) and BGI (in the same November 2008 Nature edition) would also announce the completion of a Han Chinese individual, for about the same time and a cost (USD $500K) that was also revolutionary. (Timing for journal publications is an approximate measure of the marketplace, as there can be many months of elapsed time from the generation of the data to submission of a manuscript to final publication in print.)

It would seem that by August of 2009, a $50K genome produced by a new single-molecule technology would generate buzz and interest in a new startup company (and the individual sequenced was a company founder and scientific pioneer Stephen Quake), but even by then (about 9 months later) the $50K cost was dismissed by the marketplace, as the cost of sequencing (in addition to installation headaches and stability issues) was too high for the value of the sequence generated.

This startup company, Helicos, went public in May 2007 at $8.48, hit a high of $17.44 in January 2008, and by the end of 2008 crashed to $0.44. Now trading at $0.06, Helicos has ceased commercial operations for some time now.

Yet in August 2009, this single-molecule technology sequenced a whole genome for $50K, when only a year before a whole genome cost $500K. There was one problem (of several that Helicos had) – by that point in time a whole genome at similar coverage and accuracy was about two thirds of that price, or about $33K.

Going back to 2007, Helicos had very smart scientists (I met a few Helicos R&D folks when I was at RainDance in 2009), experienced commercial leadership, and a unique technical position. But what they ran into was a fundamental issue: at the level of single molecules, you find out the hard way how dirty everything is. In other words, 99.99% purity means that what is in that 0.01% can break chemistry in surprisingly rude ways. On top of that, their technical implementation of the imaging meant that each Helicos sequencer had to be installed on 400 pounds of Vermont granite, which isn’t easy to install (nor transport). Of course on top of everything else, the systems proved to be expensive and very difficult to maintain (they were listed for sale at USD $1.35M at first, and then subsequently went down in price in later years to $1M). Their first customer, Expression Analysis, is a sequencing and genotyping service laboratory in North Carolina, and on a visit in 2009 their HeliScope system sat unplugged in an unused corner, and I was shown a broken 16-channel flowcell.

Looking at this from purely a product perspective, the HeliScope had the difficulty of differentiating itself in the marketplace. The instrument price was one hurdle; to have a seven-figure instrument limits the market reach (there are perhaps 20 research institutions in the world that could and would pay USD $1M for a research device). The applications for this sequencer did not differentiate it at all (Helicos was a short-read technology, on the order of 24-70 bases), and its accuracy was plagued by a ‘dark base’ problem. (Since it was light-based, the presence of unlabeled nucleotide – even if at 0.01%! – would preferentially incorporate the growing DNA strand, thus leaving random ‘N’ bases inserted into the sequence.) The sample prep for library creation was easier than others (they used a poly-A tail to bind to their poly-T flowcells), but other than that they had to compete in a marketplace with less expensive systems (on the order of 1/3 to 1/2 the cost). And another advantage, 20 gigabases per run was impressive in the early days of 2008; but not for long as the Genome Analyzer would soon enough hit that mark and exceed it (now they can do over 50 gigabases per run), and the Illumina HiSeq now generates about 600 gigabases per run.

As a technology, single-molecule sequencing offers something of a holy grail for genetic analysis – very long reads – however, Helicos’ technology could only do short reads, which put it on the same playing field as the rest of next-generation sequencing. As a pioneer, they had a market niche to themselves, but could not capitalize on that promise and scale the technology along with the aggressive market.

And as far as I am aware of, there is only one Helicos instrument still running, at Dana Farber Cancer Institute in Boston. They put together poster at this year’s AGBT describing their experience going from a Helicos system purchased in 2009 to a benchtop sequencer, a MiSeq from Illumina.

About Dale Yuzuki

A sales and marketing professional in the life sciences research-tools area, Dale currently is employed by SeqOnce Bioscienceshttps://seqonce.com as their Director of Business Development. For additional biographical information, please see my LinkedIn profile here: http://www.linkedin.com/in/daleyuzuki and also find me on Twitter @DaleYuzuki.

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8 thoughts on “Helicos Single Molecule Sequencing – A Pioneer

    • Dale Yuzuki

       Not particularly so, as the IP can get tangled very quickly (there are only so many ‘variations on a theme’ to skirt these kinds of disagreements).

      Of course my discussing HLCS is to introduce the context around PACB and ONT (Oxford Nanopore) in the context of how difficult it is to do SMS, how hard it is to build and launch instruments, and how the future might play out with the existing SMS PACB and the upcoming ONT launch (which as you know I’m skeptical of them being able to launch both platforms by the end of this year).

      One of my first ILMN Genome Analyzer sales in 2007 was to a group that had a new staff scientist who just relocated from Boston – and admitted that one of the key decision-making individuals had consulted for HLCS. We never discussed it in much detail.

      • Mark

        Very interesting post Dale. Thank you. I’ve followed Helicos a bit over the years as well. When they abandoned selling machines a couple of years ago the company announced they were going to open their own diagnostics lab. But I don’t think that ever happened or will happen.

        Management is still suing Illumina and LifeTech for patent infringement. Any thoughts on that?

        My best guess is that once the litigation is finished, a bigger fish (Roche, Pfizer?) will buy up the Helicos’ IP for and the company will cease to exist.

        • Dale Yuzuki

           Hi Mark, glad you found me! Yes the diagnostics route is a common ‘exit strategy’ when the business model has a problem (see: DeCODE) but sometimes it actually can work (see: Sequenom, but not on their original platform, rather on their IP).

          IANAL (I am not a lawyer) and do not know much about the HLCS lawsuit, nor the particulars of how valuable their IP may or may not be. That said LifeTech has historically taken IP rights very seriously, and both LifeTech an Illumina’s history in the courtroom has been a mixed-bag of settlements, successes and losses. Sorry I can’t be of more help to you here.

  • Shawn Baker

    Helicos has definitely ‘missed the boat’, but I don’t think you can say they’ve ‘ceased commercial operations’. They’re still operating a service business. Also, I’m fairly certain that they have more than one system operating in the field (not counting the service machines at HQ) – RIKEN appears to be a big fan, so I’m assuming they have a couple of machines running. That said, their demise seems inevitable. Even if they win their lawsuits, they’ve already lost in the marketplace. They really should have focused on RNA-Seq when they had a clear advantage in # of reads along with the ability to read RNA directly. 

    • Dale Yuzuki

      Thanks for the note Shawn – I didn’t realize they were still operating services but that makes sense given their ‘molecular diagnostics’ direction as they wound down the commercial side.

      They did focus on RNA-Seq, as I remember seeing at an NCI symposium a talk by Arul Chennaiyan (Univ. Michigan) where he showed HLCS data, and the dark base problem was displayed in all its ugliness. (This was in the summer of 2009.) It impressed me how much manipulation had to be done so that the data would be usable, and of course the reads were short so there wasn’t a lot of benefit there. (For those unfamiliar with Arul’s work, he focuses on looking for gene rearrangements and gene fusions in cancer via RNA-Seq.)

      HLCS is a pioneer, and pioneers collect arrows. Sometimes for a museum, other times in their back… 🙂

  • Mark

     A settlement with Life has been reached.

    IT IS HEREBY STIPULATED AND AGREED, by and between plaintiffs/counterclaimdefendants Helicos Biosciences Corporation (“Helicos”) and Arizona Science and Technology Enterprises, LLC (“AzTE”), on the one hand, and defendant/counterclaim-plaintiff Life Technologies Corporation (“Life”), on the other hand (each a “Party,” and, collectively, the “Parties”), through their undersigned counsel, pursuant to Federal Rule of Civil Procedure 41, and subject to the approval of the Court, as follows:
    1. All claims asserted in the above-captioned action by Helicos or AzTE against Life shall be and hereby are dismissed in their entirety with prejudice and without costs or attorneys’ fees to any Party as against another Party.
    2. All affirmative defenses and counterclaims asserted in the above-captioned action by Life against Helicos or AzTE shall be and hereby are dismissed in their entirety without prejudice and without costs or attorneys’ fees to any Party as against the other Party.