Genetic Future

The already frantic DNA sequencing market just got a little bit more crowded, with the dramatic entrance of a new competitor called Complete Genomics. The newcomer brings new technology to the table, as well as big promises: namely the commercial provision of whole-genome sequencing for a bargain $5,000, beginning in mid-2009.

It’s still unclear whether the company has the capability to make good on such a promise, but its claims have certainly gained it some attention – the story was broken in the NY Times, Bio-IT World and MIT’s Technology Review today (see also coverage from The Genetic Genealogist).

Complete Genomics clearly believes its technology is capable of outpacing the current crop of ‘next-generation’ sequencing platforms (Illumina’s Genome Analyzer, ABI’s SOLiD and Roche’s 454 system), branding itself as a ‘third-generation’ technology. It’s hard to know how seriously to take the technology without solid data – the company claims to have already completed one human genome, but the results have not been made available to external reviewers. However, hearing this positive assessment from a sequencing luminary like Leroy Hood certainly made me sit up and pay attention (although bear in mind that Hood sits on the firm’s advisory board):


“I have to say I was initially very skeptical of the technique that’s basically sequencing by hybridization,” says Hood, reached by phone in Seattle. “But I’ve been very impressed with the quality of the data they’ve generated on a couple of small projects and the rate at which they can generate the data.” Hood says he’s anxious to review the firm’s genome sequence data, but he’s impressed with the pricing, which he calls “way out of the ballpark.”

As for the service model, Hood thinks it can work because the company is focusing on a single application. “If you can do one thing and really learn how to do it well and develop the associated computational platforms… then that makes sense. They’re the only ones I’ve heard who are really diving into what frankly for sequencing is going to be the biggest market in the future – that is individual human genome sequencing.”

There are some basic hints about the new technology on the company’s website. The platform analyses DNA broken down into three separate fragment sizes – small pieces of 500 base pairs, longer fragments closer to 10,000 base pairs, and massive 100,000 base pair chunks. The company claims that the third approach allows them to distinguish the two separate sets of chromosomes (one from the mother and one from the father) within a human sample – a major advantage over existing approaches, if true. However, details of how the third approach works are pretty sketchy, and it’s hard to see how this will work given the short read lengths (see below).

The company seems to have a maximum read length of just 35 base pairs per fragment (equivalent to the shorter-read technologies currently available), which is a major limitation. Assembling of high-quality complete genomes will require much longer read lengths, due to the highly complex and repetitive nature of the human genome. Thus although the genome sequences generated by the company’s technology may effectively cover a large proportion of the genome (perhaps 85-90%), the truly ‘complete’ personal genome sequence still awaits new breakthroughs.

i-a5649e064b81cf0e82d8cfadb7526717-Four-Color_DNB_Array.pngFinally, the method used to disperse the DNA fragments onto a slide for sequencing seems to offer an advantage over the random diffusion approach used by some existing techniques: by combining an array of ‘sticky’ spots with repulsive interactions between DNA-coated beads, the platform results in a neat grid of bound fragments rather than the messier, often overlapping spot distributions generated by (for example) the Illumina platform. If this approach is effective it may offer significant improvements in quality and information yield per run over existing approaches.

For the sequencing itself, the platform uses a ligation-based approach that is outlined in a neat series of cartoons here.

If Complete Genomics does indeed have the edge over its next-generation competitors, you can guarantee it won’t last long – all of the platforms are constantly being tweaked and improved, and there are new competitors on the way. However, the novel business model of the company may help to insulate it somewhat from this bitter arms race: rather than selling individual instruments to sequencing facilities and corporations, the company will be building its own large-scale sequencing facilities and relying on service provision to generate revenue. By focusing on service provision using a single, cutting-edge technology, the company may present an attractive option for pharmaceutical companies and other corporations looking to outsource their sequencing needs.

Don’t expect to knock on the Complete Genomics door to get your own genome sequenced, however – the company won’t be marketing sequencing directly to consumers, but rather through intermediary companies like Knome, which has already expressed provisional interest in farming its sequencing work out to Complete Genomics.

And don’t forget that $5,000 only covers the cost of generating your raw sequence data. Turning that raw data into medically relevant information is a much tougher ask, and is also likely to mean that the price of personal genomics will fall more slowly than the cost of data generation (a whole genome sequence plus interpretation through Knome would currently set you back $350,000, so it has a long way to fall). As the Complete Genomics CEO Clifford Reid says in the excellent piece in Bio-IT World, “Knome and 23andMe and Navigenics and all those guys will essentially buy genome services from us and add a lot of value [and] transfer it on to the consumer population.”

There’s an important message here between the lines: as technology drives the price of sequencing down, massive competition between platforms and service providers will almost certainly drive down the profit margins of sequencing providers. The real money will then be in providing sophisticated, up-to-date and easily understandable genome interpretation services. The best interpretations will come from the companies with the largest databases of genetic information, and with expertise in putting that complex information in the appropriate context for lay consumers. It seems to me that right now deCODEme has an advantage in the former race (given the formidable genomic data-sets assembled by its Icelandic parent company deCODE genetics), while 23andMe is winning the latter – but if 23andMe succeeds in attracting a wave of customers (and particularly disease patients) with its new low low prices, they may well ultimately gain the edge on both counts.

Comments

  1. #1 BioBud
    October 25, 2008

    There is a story in GQ Magazine where author Richard Powers goes through the whole genome sequencing process with Knome at: http://men.style.com/gq/features/landing?id=content_7481

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