Faster DNA Sequencing

New techniques could finally make a $1,000 genome possible.

The latest revolution in the rapidly moving field of genome sequencing is upon us–single-molecule sequencing. Last week, Helicos Biosciences, a genomics company based in Cambridge, MA, published the first scientific paper to describe the sequencing of a whole genome using this approach. Experts say single-molecule sequencing, which reads the sequence of a single fragment of DNA, will ultimately simplify and speed the sequencing process, which could in turn enable the advance of personalized medicine. “The bottom line is, if at the end of day if you can just put a single strand of DNA onto a platform and sequence it directly, it’s a huge advantage,” says Elaine R. Mardis, co-director of the genome center at Washington University in St. Louis.

Genome sequencing: New technologies that can sequence single fragments of DNA could dramatically speed the sequencing process.

Helicos launched its commercial technology–the first to use single molecules–last month. Other companies are already nipping at Helicos’ heels, with promises to deliver faster and cheaper technologies within the next few years. But it’s not yet clear what the best approach will be or how long it will take to reach the $1,000 goal, a price thought to reflect how much the average American could afford to pay for a once-in-a-lifetime medical service. Scientists hope that genome sequencing will ultimately become an integral part of an individual’s medical record, helping to determine a person’s risk of acquiring specific diseases, as well as the best-suited treatments.

In the last few years, gene sequencing technologies have dropped exponentially in cost from $3 billion for the Human Genome Project to less than $100,000, according to recent announcements from genomics companies Illumina and Applied Biosciences. The applications of cheap sequencing are almost limitless, from providing a better understanding of the genetic attributes that make us human, to helping to engineer organisms that can produce cheap fuels or better medicines.

The next-generation sequencing technologies currently in use, including those from Illumina, Applied Biosystems, and 454, require that the DNA molecule be amplified many times and then read simultaneously, making it easier to detect the fluorescent markers that indicate the position of each DNA letter. But single molecule sequencing gets rid of the amplification step, greatly simplifying the process. This approach also reduces bias inherent in amplification–some strings of DNA amplify more easily than others, meaning that those pieces are more likely to be represented in the final sequence.

In the current paper, published in Science, scientists used Helicos’s device to sequence the genome of the M13 virus. (At approximately 7,000 base pairs long, that’s about a millionth the size of the human genome.) The company’s sequencing-by-synthesis approach is similar to that used by other machines–DNA molecules are chopped into smaller fragments and attached to a slide, which is flooded with fluorescently labeled bases or DNA letters. A camera captures the series of signals that results when an enzyme attaches the appropriate base to the attached piece of DNA. The Helicos device, however, can read the signal from a single molecule, rather than the thousands needed for other machines.

Despite its novel technology, Helicos still has some hurdles to overcome. The technology hasn’t yet demonstrated clear advantages over the most sophisticated sequencing machines currently in use. “Single-molecule sequencing has lots of benefits, but it’s very hard from an optics standpoint to detect a single molecule on a piece of DNA,” says Mardis. Because of this, the Helicos machine is much more expensive than the alternatives.

“We’re still a little underwhelmed,” says George Weinstock, associate director of the Genome Sequencing Center at Washington University. “Right now, I would say it’s a wash, in terms of time and cost. I would say they’re a couple of years out from having an impact.”

Still, the advance is “a pretty big accomplishment,” says Jeff Schloss, director of the Genome Technology Program at the National Human Genome Research Institute in Bethesda, MD. “It’s important to get these results in the peer-reviewed literature.” Some scientists have criticized a series of impressive but unpublished sequencing claims, saying it’s too difficult to evaluate them without having detailed information on the methodology.

Helicos is soon likely to face another slew of competitors. Development of so-called “third generation” sequencing technologies is already under way–these systems aim to sequence a single molecule of DNA in real time, boosting speed and reducing the amount and cost of chemicals used in the process.

Helicos is also moving forward rapidly. The technology used in the Science paper has already been replaced in the company’s commercial device, improving on some faults described in the paper, such as difficulty reading certain repetitive sequences.Says Timothy Harris, senior director of research at Helicos and lead author on the paper, “Things change faster than you can publish them.”

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