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Network Biosystems to Develop Clinical Sequencer for Point-of-Care Diagnostics

Harnessing microfluidic electrophoresis technology it developed earlier in partnership with Shimadzu, Network Biosystems is working on an integrated low-throughput Sanger sequencer for point-of-care diagnostic sequencing, In Sequence has learned.
The company, founded in 2000 by a professor at the Massachusetts Institute of Technology, initially developed microfluidic separation and detection technology in partnership with Shimadzu, which incorporated the technology into a commercial high-throughput Sanger sequencer. NetBio is now developing a clinical diagnostic sequencer on its own, integrating separation with sample prep and sequencing modules into a single unit.
When NetBio’s team surveyed the sequencing market a few years ago, they came “to the conclusion that the world probably had more than enough high-throughput genomic sequencing companies,” said Richard Selden, NetBio’s executive chairman. Most of these, he said, focus on the research market.
However, he and his colleagues decided that both clinical diagnostics and forensics could benefit from rapidly generated selective genomic information, which they believed their microfluidics-based technology could provide.
The company has since been focusing on developing an integrated instrument, different versions of which could be used for clinical diagnostic sequencing as well as for short tandem repeat identification in forensics.
The clinical Sanger sequencing system will “accept clinical samples and generate sequence within an hour,” Selden said. “Instead of trying to sequence entire genomes, we are working on generating relatively small amounts of sequence in real time at the point of care to allow a physician to make an immediate clinical intervention.”
The system, to be called Genebench, could be used, for example, to identify strains of bacterial pathogens and to determine their antibiotic resistance profiles, he said. Other potential clinical applications include the analysis of viral drug resistance, as well as biothreat detection.
NetBio has already completed the development of individual subsystems for the platform and is currently in the process of integrating them, Selden said. They include modules for DNA purification, RT-PCR for RNA analysis, multiplexed PCR, Sanger sequencing reactions, and separation and detection of the Sanger products.
The system will have relatively low throughput — ranging from a single sample to maybe as many as 96 samples per run — allowing users to run the instrument on an as-needed basis, rather than having to wait for enough samples to accumulate.
In addition to integrating all steps required for sample preparation and sequencing, it will be more rugged than conventional capillary electrophoresis sequencers, according to Selden, so it can be moved around easily without breaking. “This is not intended, in any way, to replace capillary sequencers; we are just talking about a different series of applications,” he said.
Integrating the subsystems will take about a year, after which the company plans to start clinical testing, he said, adding that it is too early to talk about a commercialization date for the instrument. “We still have lots to do in clinical validation work,” according to Selden.

“We are working on generating relatively small amounts of sequence in real time at the point of care to allow a physician to make an immediate clinical intervention.”

Meantime, the STR analysis instrument for forensics, which will lack the module for Sanger sequencing reactions but will otherwise be similar to the clinical sequencer, will probably come to market “more quickly,” he said, though he declined to provide a specific timeline.
Selden acknowledged that the clinical diagnostics market is already crowded with companies developing assays to detect pathogens. Among them are Cepheid, CombiMatrix, and Becton Dickinson. However, “we are trying to develop a single assay that would be appropriate to detect a large numbers of species of bacteria and also to do strain-specific identification by sequence,” he said. “I think that’s quite different from what other groups are doing.”
Development of the instrument and its modules has been funded in part by a grant from the National Human Genome Research Institute’s “$100,000 Genome” Advanced Sequencing Technology program. In 2005, NHGRI awarded the company $4.5 million under this program. According to the grant abstract, the original idea was to develop a commercial system that could perform whole-genome mammalian sequencing for about $100,000.
In addition, the privately owned company, which has almost 25 employees and is based in a biotech park in Woburn, Mass., about 10 miles North of Boston, has received angel funding and grant funding from the National Institute of Justice for its forensics work.
NetBio was founded in 2000 by Paul Matsudaira, a professor of biology and bioengineering at MIT, who runs a research group at the Whitehead Institute, based on technology for microfluidic electrophoresis that he developed.
In partnership with Shimadzu, which also provided funding to the company, NetBio developed basic technology for manufacturing plates with microfluidic channels.
Shimadzu non-exclusively licensed the right to perform high-throughput genomic sequencing using the technology. It integrated the technology into its DeNova-5000HT Sanger sequencer, which it has been selling in Japan since the fall of 2006. NetBio retained the rights to low-throughput sequencing for clinical applications.
 This month, Shimadzu published a description of the instrument, which uses two 384-channel microfabricated plates, and its use for DNA sequencing in the journal Electrophoresis. According to the paper, the “large-scale microfabricated plates and electrophoretic system result in higher-throughput DNA sequencing,” compared to existing capillary electrophoresis sequencers.
Hidesato Kumagai, a researcher in Shimadzu’s clinical and biotechnology business unit, which is part of the company’s analytical and measuring instruments division, told In Sequence by e-mail that the instrument is currently used at “major genome centers” in Japan.
He claimed that the instrument’s throughput is five times higher than that of the ABI 3730xl and provides the same read length and data quality.
Shimadzu believes the instrument will satisfy demand “in the short term” for applications such as de novo sequencing — especially finishing — and sequencing with high accuracy. There is no plan at the moment to sell the instrument outside of Japan, he added.
NetBio is not the only company that has been working towards an integrated microfluidics-based Sanger sequencer: Microchip Biotechnologies of Dublin, Calif., has also been developing modules for such a system (see In Sequence’s sister publication GenomeWeb Daily News 4/24/2006), although it has recently focused on its first product, an instrument that automates sample prep for Sanger sequencing (see In Sequence 4/15/2008).

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