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Single Molecule Signals

By Kevin Davies

May 12 | 2005 The premature hype about the feasibility of the “$1,000 genome” a few years ago (see “Wanted: the $1,000 genome,” Bio•IT World, November 2002) has been replaced by a slightly more sober sense of excitement regarding emerging technologies for single-molecule DNA sequencing and detection. Several companies are making important technological advances in this area. Consider the following recent announcements:

• Solexa, the British company that recently merged with Lynx Therapeutics, announced that it had sequenced the 5,000 bases of the FX174 virus using a “DNA cluster” technology. The choice was fitting — the virus was the first ever genome to be sequenced in its entirety, by Nobel laureate Fred Sanger in Cambridge in 1978.

• U.S. Genomics unveiled the Trilogy 2020 Single Molecule Analyzer, a new platform for the quantification of single molecules, including micro-RNAs, by laser detection of fluorescently tagged molecules.

• 454, an offshoot of Curagen, installed its first single-molecule DNA sequencer at the Broad Institute, where it will be put through its paces by Eric Lander and colleagues, who spearheaded the US effort in the International Human Genome Consortium.

U.S. Genomics captured plenty of headlines and magazine covers in its first couple of years, as founder Eugene Chan eulogized about scanning the equivalent of a human genome in 40 minutes, and the company assembled a stellar scientific advisory board chaired by J. Craig Venter. Following its first Trilogy installation at the Mt Sinai School of Medicine last year, U.S. Genomics recently signed agreements with four other prominent laboratories, including Phil Sharp’s team at the MIT Center for Cancer Research, where the Trilogy 2020 will aid researchers studying RNA interference.

While U.S. Genomics focuses in the near term on nucleic acid detection and quantification, Solexa is using a novel DNA cluster technology to conduct massively parallel DNA sequencing (see “Solexa Completes Full Virus Genome Sequence,” April 2004). Although the first reported viral sequence is very small, the company expects to ramp up assembled genomes very quickly.

Still Not Cheap
The 454 platform, a blend of nanotechnology, microfluidics, and microarray technology, is already sequencing complete genomes by piecing together short 25-base DNA fragments from a soup of up to 5 million bases/hour. Earlier this year, 454 helped Johnson & Johnson characterize a promising new tuberculosis drug (see “How to find a new TB Drug,” January 2005).  At roughly $500,000, the instrument is not for everyone, but it will be fascinating to see what organizations such as the Broad Institute, with their insatiable demand for faster, better sequencing technology, will make of it.

That demand may come in the form of the 9-year, $1.3-billion Human Cancer Genome Project proposal backed by Lander, former NIH director Harold Varmus, and others. The idea is to survey 250 genome samples from each of 250 tumor types, producing a catalogue of cancer-causing mutations. It is both an extrapolation and a validation of the UK Cancer Genome Project, directed by Michael Stratton at the Wellcome Trust Sanger Institute (see “Profiles in Carcinogenesis,” April 2004), which has already identified several novel tumorigenic genes.

There are several other promising systems in development, including Agencourt Biosciences, which serves as a federally funded genome center, and Helicos BioSciences, which is applying technology developed by Stanford University’s Stephen Quake (see “GSAC Rolls On,” November 2004). But they have stiff competition in Li-Cor Biosciences, which on its website, thanks “God for His merciful providence in allowing Li-Cor to develop and commercialize products, through the collective effort of dedicated employees, that enable the examination of the wonders of His works.”

Sanger dideoxy sequencing has served mankind superbly for almost three decades, and monopolized commercial DNA sequencing technology for two. It brought us the first draft of the human genome sequence years ahead of schedule, and hundreds of other organisms besides. Single molecule sequencing hasn’t reached the tipping point yet, but the day of the $100,000 mammalian genome is drawing near.

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