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As OpGen Readies Launch of Optical Mapping Instrument, Sequencing Market May Prefer Services

NEW YORK, May 8 (GenomeWeb News) - In response to increasing demand for its genomic optical mapping services, Madison, Wisc.-based OpGen Technologies has modified its business model and begun developing a commercial instrument that will enable scientists to create their own whole-genome optical maps for their choice of organism.


But while sequencing facilities have found the company's services useful for solving tricky projects in the past, the jury is still out on whether the sequencing market will find the technology valuable enough to bring it in house.


Beta testing for the instrument is scheduled to start in the first quarter of 2007, and the company plans to bring it to market approximately a year from now, at a list price of around $225,000.


Sequence finishing has made up more than half of the company's services business to date, but OpGen sees the most immediate market for the instrument in applications that do not require DNA sequencing, such as clinical microbiology to rapidly identify pathogens, or comparative genomics of microorganisms.


But the sequencing sector is still an important target market for the firm, whose services have proven useful in progressing a number of whole-genome microbial sequencing projects that seemed otherwise doomed.


"It's a very project-specific tool as an augmentation to sequencing and assembly," said William Nierman, an investigator at the Institute for Genomic Research in Rockville, Md., who has used optical maps in several microbial projects.


Bruce Roe, director of the Advanced Center for Genome Technology at the University of Oklahoma, agreed that "it's a useful technique for difficult projects to close." He had an optical map prepared for a bacterial sequencing project.


OpGen's technology, developed by David Schwartz of the University of Wisconsin, creates whole-genome restriction maps by first stretching out and immobilizing strands of DNA on a glass chip containing many channels. A restriction enzyme then cuts the DNA at specific sites, and the DNA molecules retract at the edges of each cut, making it possible to visualize them with a fluorescence microscope after staining the DNA with a fluorescent dye. A computer then constructs the restriction map based on the order, size, and fluorescence intensity of the fragments.


At the moment, OpGen provides optical mapping services, charging $5,000 to $7,000 for a bacterial genome and between $20,000 and $50,000 for a fungal genome, depending on its size.


The company has also prepared maps for animal genomes, though that has been "not economic, because it takes us quite a long time," said Colin Dykes, OpGen's chief scientific officer and executive vice president for corporate development.


The company has four instruments of its own, which is insufficient to satisfy the demand for its service. "The demand, frankly, exceeds our capacity," said CEO Joe Shaw, who joined the company just over a year ago. Increasingly, he said, customers are asking for multiple maps of isolates from related organisms for comparative genomics. In addition, he said, some customers with proprietary projects are hesitant to outsource the mapping, so selling an instrument and getting the technology into the hands of users seemed like a better route towards profitability than ramping up its service work.


The six-digit price tag might be too steep for sequencing facilities, though, who will likely prefer the company's service, which has proven invaluable for a small number of microbial sequencing projects. In these projects, certain regions of the genome were poorly represented in the sequencing libraries, either because they were AT-rich, had repeat content, or were not well tolerated in E. coli.


In the case of a fungus sequenced by Nierman's group at TIGR, for example, the AT-rich centromeric regions were missing from the libraries, so he did not know which chromosomes his sequences belonged to. "Having an optical map done, and then matching the restriction pattern of our sequence scaffolds to the optical map, made associating the two chromosome arms trivial," and helped close the centromeric gaps after using PCR and other techniques, Nierman said.


In a couple of bacterial projects, he said, the optical map "built a hook across the gaps where we had basically no clones to put our sequence contigs into a representation of the chromosome." In one instance, it took a combination of optical mapping, Sanger sequencing, and 454 sequencing to progress the project. "When I first got the optical map, the genome sequence was in such disarray, I couldn't make any sense [of it]," he said. One round of 454 sequencing reduced the number of gaps by half and gave "a high-enough resolution sequence map that I could correlate it to the optical map," which revealed the presence of contaminating sequences from another project.


However, projects like these are few and far between, Nierman cautioned, estimating that over the last five years or so, TIGR investigators have only used optical maps for a handful of sequencing projects. "In some places it works great and you need it, and [for] other genomes ... there is just no use for even considering getting an optical map because the whole genome comes together without it," he said.


Would he consider acquiring an OpGen instrument? Given the rare use of optical maps so far, "I don't foresee how that would be a cost-effective investment for us," he said.


The issue of cost was echoed by Roe, who had OpGen create an optical map for an AT-rich microbial genome that was difficult to clone. The map helped in lining up the existing sequence fragments in order to close the gaps by using PCR, as well as for finding some alignment mistakes. However, "as far as I am concerned, it was too expensive for what we got out of it," he said.


On the other hand, he said, OpGen's mapping service was convenient and quick. It took the company less than a week to prepare the optical map, "and you don't have to do anything except to spend money," he said.


Roe said he does not anticipate enough demand for optical maps at his facility to justify acquiring OpGen's instrument, but said that he might find optical mapping services useful again in the future. His facility is currently working on two fungal genomes, "and as we progress along, once we hit a dead end ... I may very well have them do it again," he said.


Commercial sequencing service providers are also keeping an eye on OpGen's technology. "We are well aware of the OpGen technology, and are very much interested in it as well," Jungsoo Park, manager for international sales at Macrogen, a sequencing service provider headquartered in Korea, told GenomeWeb News. Macrogen has just started offering sequencing services that use a combination of pyrosequencing on 454's GS20 and Sanger sequencing on ABI's 3730XL. Park sees optical maps as a good tool for contig ordering and gap filling, but said that "Whether Macrogen will adopt this technology eventually cannot be confirmed at this point."


OpGen's Dykes said that the company is seeing "substantial interest" in the instrument from customers in the sequencing market and that it has no plans to ramp up its services offering beyond its current capacity.


OpGen is currently working with Stratos Product Development of Seattle and Micronics of Redmond, Wash., to build its commercial instrument. While Stratos will develop the actual instrument, Micronics is in charge of creating a disposable device to run the assay.


Besides working on its first commercial product, OpGen is also trying to raise capital: the company is in the early stages of a $15 million private placement round that it is hoping to close about two months from now. In January of 2005, OpGen closed a Series B round for a total of $5 million. Investors include Mason Wells Biomedical Fund, Stonehenge Capital, The State of Wisconsin Investment Board, and the Wisconsin Alumni Research Foundation.


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

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