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Buoyed by Papers, Growing Demand, NimbleGen Grooms CGS Service to Be Leading Product Line


A string of recent publications and a general increase in demand are encouraging NimbleGen Systems to focus more on the comparative genomic sequencing service it launched last year, according to a company official.

Tom Albert, NimbleGen's director of molecular research, told BioArray News this week that several other papers highlighting the strengths of the method have been accepted for publication in "late winter/early spring." He also noted that his company has seen a rise in interest for the service, which was launched in early 2005 along NimbleGen's array comparative genomic hybridization applications and chromatin immunoprecipitation (ChIP)-on-chip service (see BAN 2/23/2005).

"Interest in our CGS service has been growing rapidly, and we envision it becoming one of our leading product lines," Albert wrote in an e-mail to BioArray News.

According to Albert, NimbleGen is focusing on selling CGS to "four main research markets for the technology: drug resistance, strain improvement, biodefense, and strain collection analysis."

NimbleGen is touting its service, which uses a microarray-hybridization-based method to resequence microbial genomes, as "efficient" and "cost effective." Its growing interest in the service coincides with the launch of new resequencing array products from main rival Affymetrix and the buzz surrounding emerging sequencing shops like 454 Life Sciences.

"I think they are keenly aware of the threat that lower-cost sequencing poses to their place in the market."

For example, Affymetrix has been selling both catalog and custom resequencing arrays since 2002, and released its GeneChip Human Mitochondrial Resequencing Array 2.0 last December (see BAN 12/21/2005).

Anna Berdine, a senior product manager at Affymetrix, wrote to BioArray News this week in an e-mail that Affy "continues to evaluate standard arrays to offer on this platform."

And according to BioArray News' sister publication GenomeWeb News, researchers at a workshop at the Plant and Animal Genome conference held in San Diego this month said 454 Life Science's Genome Sequencer 20 is well-suited for resequencing and de novo sequencing of microbial genomes.

Though 454's method differs from NimbleGen and Affymetrix's array-based resequencing platforms, Albert said that of the two, 454 is "probably the closest competitor" his company has now for CGS.

"Ours works on a genome scale whereas theirs does not," he said of Affymetrix in an interview this week. "We can do several megabases of sequencing on just a few arrays. Theirs are now up to several kilobases, ours are several megabases, [but we think it is] practical to do this at a genome scale," he said.

For example, Affy claims its CustomSeq arrays enable the analysis of up to 300,000 bases of double-stranded sequence on a single array, while a typical NimbleGen CGS chip can resequence up to 1.5 million base pairs on one array. In contrast, 454 claims that its system can sequence 35 million base pairs in one experiment.

Still, Affymetrix does offer resequencing arrays for "any organism," according to Berdine, while NimbleGen is just now attempting to resequence eukaryotic genomes.

"We are initially targeting fungal and protozoan genomes, such as yeast and malaria, for whole-genome analysis," Albert said. "We have plans to move it into larger eukaryotes in the near future, but in a more limited way. The strategy should work well for resequencing BACs or fosmids, for example."

According to Albert, NimbleGen's approach uses single-base resolution comparative genome hybridization of a test genome against a sequenced reference genome to map where changes in the genome exist. It then uses a custom one-time-use resequencing array to resequence only those positions of the test genome that are different.

"By resequencing only the loci that are different, NimbleGen can map and resequence most genomes in just two to five microarray hybridizations," he explained.

In contrast, 454's method employs beads that attach to individual strands of DNA, and a PicoTiter plate with hundreds of thousands of wells, with one bead assigned to each well. After amplification by PCR, 454's instrument determines the sequence of each DNA strand via a cyclical sequencing-by-synthesis technique that relies on a modified form of pyrosequencing, according to the firm's website.

The Marketplace

In his e-mail to BioArray News, Albert said NimbleGen has either published or expects to publish papers "demonstrating utility" of its technology in drug resistance, strain improvement, biodefense, and strain collection analysis. He also wrote the company is currently "building a customer base" in each application.

A publication detailing NimbleGen's work with microbiologists at Washington University School of Medicine in St. Louis and the University of Louisville, Kentucky, was published in Nature Methods in December and highlighted the ability of the technology to detect antibody-resistant mutations in Helicobacter pylori bacteria.

Doug Berg, a co-author on the Nature Methods paper and a microbiologist at WUSTL, told BioArray News this week that researchers in his field are taking a interest in new resequencing technologies like NimbleGen's.

"For many [researchers working with]issues of drug resistance and natural sequence divergence or evolutionary questions in bacterial genomes, just so long as you have a reference strain that is pretty closely related to the strain that you are interested in, my sense is that this [technology] is very, very good," Berg said.

However, he said that it costs around $5,000 to sequence H. pylori using NimbleGen's technology, which may be prohibitive for many academic customers. Berg also said that he believed NimbleGen was aware of the cost issue.

"I hope for their sake and the sake of the community that they are able to bring their prices down over the next couple years," he said. "For them, as they continue to push this as a technology as genome sequencing becomes more and more efficient and cheaper, I think they are keenly aware of the threat that lower- cost sequencing poses to their place in the market."

NimbleGen declined to offer information on its pricing but describes CGS on its website as "cost effective," and it did not dispute Berg's claim that it cost $5,000 to resequence h. pylori.

In San Diego earlier this month, 454 speculated that it would cost around $7,500 to resequence a microbial genome. The pricing for Affy's chips varies, but according to Berdine, "minimum orders can range from 40 to 400 arrays and prices can range from $100-$400 per array." Affy's arrays are also available in 50 kb, 100 kb, and 300 kb formats, which, in turn, affect pricing.

Albert said that in addition to working with academics like Berg, NimbleGen has found customers in government and industry. A paper published in the Nov. 21, 2005, issue of Proceedings of the National Academy of Sciences described the results of work with Novartis and the National Institute of Allergy and Infectious Diseases that successfully identified a gene target for a novel tuberculosis drug, PA-824. In addition, Albert named the US Federal Bureau of Investigation, the US Food and Drug Administration, the Naval Medical Research Institute, and the US Centers for Disease Control and Prevention are current customers for the CGS technology.

-- Justin Petrone ([email protected])

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