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Intelligent Bio-Systems to Place Next-Gen Sequencers in '07; Columbia SBS Chemistry at the Core, Jan 2, 2007

NEW YORK (GenomeWeb News) — Intelligent Bio-Systems, a Massachusetts-based startup, is planning to place a next-generation sequencing system with early-access customers in 2007, GenomeWeb Newshas learned.
The company, which has kept a low profile up until now, has exclusively licensed a sequencing-by-synthesis chemistry from Columbia University. The Columbia team, led by Jingyue Ju, a professor of chemical engineering and head of DNA sequencing and chemical biology at the Columbia Genome Center, is revealing details of its chemistry in an article appearing online in PNAS this week.
In the article, the researchers describe a four-color sequencing-by-synthesis method using cleavable fluorescent nucleotide reversible terminators — an approach Solexa is also pursuing.
In its push to market, Intelligent Bio-Systems joins Applied Biosystems and Helicos BioSciences, which also said they will place first versions of their next-gen sequencers next year. Solexa’s system is already in the hands of several early-access customers, and 454 Life Sciences plans to launch a new version of its system early next year.
“I think we are pretty far along compared to somebody else who may be just announcing that they are hopping in this field,” said Steven Gordon, Intelligent Bio-Systems’ CEO. Gordon first met Columbia’s Ju six years ago, with whom he co-founded the company in early 2005. “I brought the business and engineering side, he brought the chemistry side,” Gordon said.
Gordon, who holds BS, MS, and PhD degrees in mechanical engineering from MIT, has experience in automating DNA technology: his previous company, Intelligent Automation Systems, collaborated with Eric Lander’s group at the Whitehead Institute back in the 1990s to automate PCR reactions for creating a physical map of the human genome.

“I think this is a highly significant paper, marking one of the first four-color reversible terminating chemistries for next-generation technologies.”

The platform developed by IAS — which was acquired in 2002 by Brooks Automation — produces submicroliter sequencing reactions and is available today from a company called Parallabs, located in Worcester, Mass.
Ju has been developing the sequencing chemistry within his academic group for many years, and has published a number of articles on aspects of it. “Since 2000, we have been working on this system in a systematic way,” he told GenomeWeb News last week.
In 2003, Ju received a US patent on a “massive parallel method for decoding DNA and RNA” that includes modified nucleotides with two cleavable attachments. He also won a three-year grant from the National Human Genome Research Institute in 2004 to develop “an integrated system for DNA Sequencing by Synthesis.”
In this week’s PNAS paper, he and his coworkers describe their method for sequencing DNA on a solid surface using rationally designed nucleotides that have two modifications: a cleavable fluorescent label attached to a certain position of the base, and a cleavable blocking group at the 3’ end. These modified nucleotides were good substrates for DNA polymerase: the researchers were able to sequence with high accuracy approximately 20 bases of DNA, including homopolymer regions, using a manual fluorescent scanner.
Solexa also uses reversible terminator nucleotides carrying a fluorescent label, as well as a proprietary polymerase, but has not published its chemistry in a scientific journal. The company received a US patent entitled “Labeled nucleotides” this summer.
It is unclear, though, whether Ju’s and Solexa’s patents interfere with each other. Omead Ostadan, Solexa’s vice president of marketing, told GenomeWeb News by e-mail today that the company “ believes it has a strong IP position in relation to sequencing by synthesis using reversible terminators.”   
“I think this is a highly significant paper, marking one of the first four-color reversible terminating chemistries for next-generation technologies,” Mike Metzker, an assistant professor at Baylor College of Medicine, commented in response to Ju’s article. His group has been developing its own reversible terminator SBS chemistry, which LaserGen, a startup company he founded, plans to commercialize.
The challenging part, Ju explained, was to make the modifications in such a way that the DNA polymerase would take the nucleotides as a substrate. Previous attempts by others to place the dye directly on the 3’ end have been unsuccessful so far, he added.
In principle, he said, his chemistry could be used both for sequencing amplified DNA, similar to 454 or Solexa, and single-molecule DNA, an approach Helicos BioSciences is pursuing.
The next task will be to increase the read length by increasing the stepwise yield to as close as possible to 100 percent, Ju said. “My prediction is, in not too long a time, we can hit the mark of 50 bases,” he said.
His group is also working on alternative designs for the modified nucleotides, including, for example, photocleavable linkers instead of chemically cleavable ones.
Once the system has been automated, he also plans to test it by re-sequencing a bacterial genome as well as the genome of the sea slug Aplysia, a model organism for neurobiology.
Meanwhile, Intelligent Bio-Systems has been developing a chip-based platform that automates the Columbia team’s sequencing chemistry. The system amplifies the template DNA either in solution or on chip, two approaches the company is pursuing in parallel for now, according to Gordon. It uses an ordered array design “because we think that it allows us to get a higher density and a faster measurement of data points,” he said.
The instrument will cost “probably half of the instrument costs of anybody else,” Gordon said. As a result, “many more labs can afford to have this,” he added.
Besides on price, the company plans to compete on accuracy and speed, he said, completing a run “in hours rather than days.”
At the moment, Gordon and his team are working on improving the system’s performance, especially the read length. “There is a lot of potential there,” he said.
Sometime next year, the company plans to place units with early-access users that “do a lot of sequencing,” followed by a product launch in early 2008,” according to Gordon.
Intelligent Bio-Systems, which just moved last week from a business incubator to its own space in Waltham, Mass., plans to grow its staff to 15 over the next month. The company is financed through private investments and five NIH grants and has not taken any venture capital financing.
It plans to sell its platform directly within the US and seeks distribution partners for overseas sales. The company is also open to marketing partners, according to Gordon.
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