With a unique program, the US government has managed to drive the cost of genome sequencing down towards a much-anticipated target.
The quest to sequence the first human genome was a massive undertaking. Between 1990 and the publication of a working draft in 2001, more than 200 scientists joined forces in a $3-billion effort to read the roughly 3 billion bases of DNA that comprise our genetic material (International Human Genome Sequencing Consortium Nature 409, 860–921; 2001).
It was a grand but sobering success. The project's advocates had said that it would reveal 'life's instruction book', but in fact it did not make it possible to interpret how the instructions encoded in DNA were transformed into biology. Understanding how DNA actually influences health and disease would require studying examples of the links between genes and biology in thousands, perhaps millions, more people. The dominant technology at the time was Sanger sequencing, an inherently slow, labour-intensive process that works by making copies of the DNA to be sequenced that include chemically modified and fluorescently tagged versions of the molecule's building blocks. One company, Applied Biosystems in Foster City, California, provided the vast majority of the sequencers to a limited number of customers — generally, large government-funded laboratories — and there was little incentive for it to reinvent its core technology.
A $7-million award from the NHGRI allowed the company to commercialize a technology called pyrosequencing, which was the first to begin chipping away at Applied Biosystems' monopoly. The funding commitments also ultimately helped to convince private investors to enter the market. Stephen Turner, founder and chief technology officer of Pacific Biosciences in Menlo Park, California, says that his company's 2005 NHGRI grant of $6.6 million helped to attract subsequent venture-capital funding.
The government program has invested $88 million in technologies based on nanopores and nanogaps. The form of this technology closest to the market involves reading bases as they are threaded through a pore (see Nature 456, 23–25; 2008), a method that has long promised to save costs and time by reading DNA while it is processed. It would negate the need for expensive and slow reactions to make lots of copies of the molecule. But solving basic issues, including how to move the DNA through the pore slowly enough, has been a major challenge. The NHGRI has funded work to overcome these hurdles — including $9.3 million given to collaborators of the company now ushering the concept to market, UK-based Oxford Nanopore Technologies (Nature http://doi.org/rvm; 2014).
Sequencing still needs much improvement, especially in terms of quality. For all of Sanger sequencing's high cost, it remains the benchmark for accuracy. And sequencing costs are no longer dropping as quickly as they were a few years ago.
But researchers are optimistic that another technology will emerge to challenge Illumina. Most think, in fact, that the crucial questions for the field will shift away from technology. Now that sequencing is cheap enough to talk about scanning every patient's genome, or at least the protein-coding portion of it, it is still not clear how that information will translate into improved care (Nature http://doi.org/rvq; 2014). These more complex issues will require another great leap in genomic science — one that could make the trouncing of Moore's law seem easy