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Baylor Researcher Wins $500K NHGRI Grant to Develop Improved SBS Instrument

NEW YORK (GenomeWeb News) — Both of the currently marketed next-gen sequencers — 454’s GS 20 and Solexa’s 1G Genome Analyzer — use sequencing-by-synthesis to read the DNA. But sequencing technologies based on new variations on this theme are starting to crop up.
One developer of such a technology is Mike Metzker, whose research group at Baylor College of Medicine’s Human Genome Sequencing Center has been developing a reversible terminator chemistry for SBS sequencing and is currently demonstrating its ability to read DNA.
Eventually, he and a Houston-based startup he founded called LaserGen want to wrap this chemistry and an imaging technology Metzker developed into a sequencing instrument.
Two weeks ago, Metzker won a one-year, $500,000 supplemental grant from the National Human Genome Research Institute’s “$100,000 Genome” grant program to demonstrate that his chemistry can sequence DNA with 20-base reads.
Being able to do this, he said, might open the door to more funding from the same program to develop the technology commercially. LaserGen has a “very large” NHGRI grant pending to develop a prototype instrument, he said. However, the institute asked him and the company to show some 20-mer reads first before it will make its decision. “We have got a lot of work to do before they consider it,” Metzker said.

“We believe that the reversible termination strategy will have a big improvement in accuracy over 454, for example.”

Metzker first received an NHGRI grant entitled “Ultrafast SBS Method for Large-Scale Human Resequencing” in 2004 to develop the sequencing chemistry. Since then, his group has built four fluorescent reversible terminator nucleotides.
Solexa, a potential LaserGen rival, also uses reversible terminators in its SBS chemistry, but Metzker claims his are easier to incorporate and manipulate. As a result, he believes they can achieve longer reads than Solexa’s. “The difference is in the chemistry of the reversible nucleotide itself,” he said.
Reversible terminators allow the DNA polymerase to incorporate only one labeled nucleotide at a time. After its signal is read, a deprotection step frees up the end of the DNA strand so the next nucleotide can be added.
This increases accuracy, especially in reading homopolymer repeats, Solexa has maintained. Metzker agreed: “We believe that the reversible termination strategy will have a big improvement in accuracy over 454, for example,” he said.
According to Metzker, read length is dictated by how efficiently the polymerase can incorporate the labeled nucleotides and how well the reversible terminators can be deprotected, and he believes his reagents win on both counts.
Unlike Solexa, he added, which developed a modified DNA polymerase, he can use commercially available DNA polymerase and still get “very good activity, almost as good or as good as the natural nucleotide itself.” Deprotection only requires “a single chemistry and is therefore more efficient,” he said.
Metzker said his chemistry “would give us longer read lengths and start moving us into the realm of 454 chemistry of 100 or maybe 200 bases in the next 12 to 24 months.”
He plans to reveal the first structure of one of his molecules at the Advances in Genome Biology and Technology meeting in Marco Island next February, and to publish details describing the technology over the course of the next year.
His group is “still making modifications to improve deprotection efficiency and enzymatic properties” of the reagents he said, but is currently focusing on demonstrating a 20-cycle read.
LaserGen will be “the vehicle for commercialization of the technology,” Metzker said. He founded the Houston-based company in 2002 and remains its president and CEO. Lasergen, which currently has eight employees, received its first research funding in 2003. The company also won an NHGRI grant in 2004 to develop a portable DNA sequencer.
While LaserGen is responsible for manufacturing the chemicals and developing the instrument, Metzker’s group at Baylor has been testing the reagents in biological assays and is developing sequencing assays.
The instrument will use another technology invented by Metzker to speed up the imaging process: pulsed multiline excitation, or PME. Metzker published a paper describing PME — which uses four lasers, one for each color — in PNAS last year. “We can image the entire chip simultaneously, which would give us a tremendous advantage in the throughput,” he said.
“It looks like the rate limiting step is the imaging part. If you look at the Solexa technology, that’s what limits the cycle time from base to base,” he claimed.
To prepare the sample, Metzker plans to amplify genomic DNA and hybridize it to a high-density oligonucleotide chip carrying primers that target all genes. “The long-term goal is to get rid of the amplification step,” he said. “But we think we are far away from that.”
If the larger NHGRI-grant to LaserGen comes through, Metzker and his team will collaborate with contractors Steve Soper at Louisiana State University to develop a flow cell, and John Santalucia at Wayne State University and his company, DNA Software, to “make the surface chemistry more robust as we start targeting all the exons across the genome,” he said.
How will LaserGen compete with companies like Solexa or Helicos that have tens of millions of dollars in backing from investors? “At this point, we are talking with strategic partners as a way of increasing revenue into the company and also building into an infrastructure of companies that are prominent in the sequencing market at this time,” Metzker said. “But that’s all I want to say.”
These strategic partners include both customers and investors, he said. “We are kind of working out a blended portfolio.”

Julia Karow covers the next-generation genome-sequencing market for GenomeWeb News. E-mail her at [email protected]

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