Genomics and the single molecule

 

 

CAMBRIDGE, Mass.—Pushing the envelope on high-speed DNA sequencing, Helicos BioSciences announced a new platform that brings researchers one step closer to the $1,000 genome. The company's True Single Molecule Sequencing (tSMS) platform, based on work by Stanford University professors Drs. Stephen Quake and Ido Braslavsky, requires no nucleic acid amplification step and thereby offers high sequence fidelity. The company recently tested the system in a proof-of-concept experiment to resequence the genome of the bacterial virus M13.

 

The tSMS system relies on high-density, fluorescence-based, parallel sequencing of hundreds of millions of single molecules bound to a biochip surface. Rather than use the more traditional real-time imaging of DNA synthesis, which requires a steady camera and therefore reduces coverage, the Helicos platform increases the image space by acquiring stepwise images of the surface as labeled nucleotides are incorporated into the newly synthesized strands.

 

According to Stanley Lapidus, Helicos president and CEO, the combination of simplified sample preparation, elimination of amplification and increased sample density results in a system that is faster and less expensive than most current systems.

 

"It has been communicated by a number of thought leaders in genomics that in a world in which both single-molecule and amplified-molecule sequencing methods exist, single-molecule wins hands down," he says. "The limitations on throughput are much less stringent in the absence of amplification, and the economics of reagent consumption side strongly in the favor of tSMS."

 

In its current state, the system is being used for short sequence reads of roughly 25 to 30 bases. This makes it sufficient for whole-genome resequencing, but limits its ability to assemble genomes without prior sequence knowledge. This last factor, says Lapidus, should have no impact on clinical, diagnostic and pharmacogenomic applications. He also adds that there is no inherent upper limit to the read-lengths achievable by the system, and that the company expects to provide much longer reads as it continues to develop the system. "Eventually, a target of $1,000 for a whole human genome with this technology is absolutely foreseeable," he says.

 

Lapidus expects that the platform will have its most immediate impact in the area of cancer research. "Cancer is a disease of altered genomes in a small fraction of the cells of an individual," he explains. "There simply is no technology today that affords researchers a genome-wide view of DNA changes in tumor cells. It's astonishing to think that 20 years after it became clear that cancer is a disease of 'deranged DNA' that not even one single tumor has been sequenced."

 

His astonishment has been echoed in recent weeks by officials at the National Cancer Institute and National Human Genome Research Institute, who recently announced the launching of comprehensive efforts to explore cancer genomics, in a three-year project called The Cancer Genome Atlas (see page 20). As Dr. Elias Zerhouni, director of the National Institutes of Health, explained in announcing the project, "Thanks to tools and technologies developed by the Human Genome Project and recent advances in using genetic information to improve cancer diagnosis and treatment, it is now possible to envision a systematic effort to map the changes in the human genetic blueprint associated with all known forms of cancer." Early indications are that tSMS could easily be one of the advances that Zerhouni mentioned.