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Though ABI Plans to Develop Agencourt s Sequencer For Gene-Expression Apps, Tech Won t Impede Arrays

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Applied Biosystems late last month said it plans to acquire Agencourt Personal Genomics from Beckman Coulter for approximately $120 million in cash. The deal is expected to close in the third quarter, and ABI has projected that it will place initial systems with early-access customers in 2007.

While ABI intends to market the company's next-generation sequencing technology for genetic analysis applications such as de novo genome sequencing and high-throughput genotyping, it has also been touting its gene-expression capabilities, which would play in a market already occupied by ABI's chip-based Expression Array System.

However, an ABI official said the company does not believe Agencourt's sequencing tech will impede or challenge array technologies that are currently on the market. Rather, ABI said the sequencer will enable gene expression research currently not served by arrays.

Kevin Corcoran, vice president and general manager of ABI's genetic analysis business, said this week that the company believes "there is a lot of opportunity on the gene expression side" for the APG tech.



"Our goal isn't to compete with Affy for a price point because that makes no sense. Our goal is to make available new capabilities that can't be done on array-based technology at any price."

Specifically, he pointed out that APG's massively parallel sequencing method, based on fluorescence stepwise ligation technology, works by counting molecules, rather than comparing expression level ratios, and therefore could provide users with a "very accurate count of the transcription level of any particular gene." He also said that the method is "very attractive, especially in systems where there is not a commercially available microarray."

"In some particular markets agriculture being one there may be challenges in getting a microarray ever developed. These systems are open systems you don't have to have sequenced a genome so that you could therefore build a microarray," Corcoran said. ABI currently offers human, mouse, and rat arrays for use with its Expression Analysis System.

Because of the narrow focus of ABI's array business, Corcoran ruled out the idea that APG's tech would step on its array's toes. "I think the opportunities for [expression applications for sequencing] technologies are in areas where there are no microarrays developed. That's where we are going to position this technology," Corcoran said.

He added that APG "lines up very well" with ABI's TaqMan RT-PCR technology. Agencourt's platform "is a discovery technology, so you are doing a whole transcriptome," Corcoran said. "Then, if you want to do downstream validation, we see that lining up very well with our TaqMan assays."

Helicos and Solexa Also Express Interest

ABI isn't the only company with sequencing technology eyeing the gene expression market. Helicos Biosciences, a Cambridge, Mass.-based company, last week inked its first early-access deal with the Institute of Systems Biology. As BioArray News' sister publication GenomeWeb News reported this week, ISB is using Helicos' True Single Molecule Sequencing technology in a gene-expression project for prostate cancer.

Like Corcoran, Helicos CEO Stanley Lapidus said this week that he doesn't believe his company's technology will directly compete with array juggernauts like Affymetrix, Agilent Technologies, and ABI.

He said that Helicos' technology, which is not yet on the market, is capable of "a range of things that are not necessarily possible with today's arrays," including "the elucidation of very low copy numbers … and looking at samples of thousands of different patients and from thousands of different tissue culture samples."

Lapidus also suggested that costs for his sequencing technology would enable academic researchers currently working with arrays to adopt it. "We expect sequencing at commercial prices will be less than arrays two to three years from now based on our best ability to estimate," Lapidus said. "But our goal isn't to compete with Affy for a price point because that makes no sense. Our goal is to make available new capabilities that can't be done on array-based technology at any price."

Lapidus also said that because many genomic sequencing centers also do gene expression studies, it can market its system to the same customer for a variety of uses.



"I think, quite frankly, from the standpoint of the instrumentation manufacturers, they would like to expand the available applications that would be put onto the instrument to broaden their user base and sell more instruments and their kits."

Another company that is touting its capabilities for gene expression is Solexa. The Hayward, Calif.-based company promises to have its 1G Genome Analyzer in early access this month and plans to begin selling the fully developed instrument broadly by the end of the year.

Linda Rubinstein, Solexa's vice president and chief financial officer, said this week that the firm's technology has some significant advantages over array technology in the gene-expression market.

"We can look at any species not just rats, not just humans, not just mice," Rubinstein said. "For example, you could do corn not just one strain of corn, but lots of strains, which if you are a corn feed supplier, that's something that makes sense."

Rubinstein also said that Solexa's system could be used in lieu of traditional methods, like RT-PCR, to validate large amounts of microarray data. Like Lapidus, she said many sequencing centers also perform gene-expression studies. "Of the half dozen sequencing centers, half of them are interested in expression work," Rubinstein said.

Academics React on Cost, Vendors 'Wait and See'

Elaine Mardis, the co-director of the Genome Sequencing Center at Washington University in St. Louis, said that sequencing could have some advantages over current array technologies in gene expression.

"If you really want to go after gene expression, maybe for an animal whose genome hasn't been sequenced, [using next-generation sequencing technologies] may be a more compelling way to do it," Mardis told BioArray News. "I also think there's a good potential for new sequencing technology that's more on the order of what I'd call discovery discovering alternative splice forms, for example, that you are not always technically going to be able to pick up for the array."

However, Mardis said that the overtures of some sequencing shops towards the gene-expression market could be just a slick marketing approach.

"I hate to sound cynical and jaded, but these companies are out to sell instruments, so in my mind there's a benefit in terms of … the gene-expression twist, but I think, quite frankly, from the standpoint of the instrumentation manufacturers, they would like to expand the available applications that would be put onto the instrument to broaden their user base and sell more instruments and their kits," Mardis said.

She also said that the cost of new sequencers could be prohibitive for academics who are looking to use the technology instead of arrays. With sequencing "you are in the $6,000 [per sample] ball park, which is far more than any microarray experiment that I am familiar with," said Mardis.

The Genome Sequencing Center currently uses 454 Life Sciences Genome Sequencer 20, Mardis said. 454 could not be reached for comment.

George Grills, director of the Life Sciences Shared Core Facilities at Cornell University, agreed that the cost of sequencing experiments currently prohibits its use in gene expression work.

"None of [the systems] are at that point yet where you can do [gene expression] cost effectively," Grills told BioArray News this month.

Sequencing is "really a de novo gene expression type of approach," Grills said. "You don't need to have a priori assumptions about the structure of the genome, which you really need to do to create traditional expression arrays like those from existing array platforms," he said. "That's a very nice approach. But it's really at the proof-of-principle stage right now," Grills added.

While some academics appear skeptical about the possibility of using sequencing tools for gene-expression work, some array manufacturers agree that the new technology will complement their offerings rather than compete with them directly.

For example, NimbleGen spokesperson Joleen Rau told BioArray News this week that "some of [the] proposed new approaches to sequencing being developed might fill a number of interesting niches if they are successfully commercialized."

"We see them as being more complementary than competitive, but we'll have to wait and see what is actually developed," Rau said. "We see a number of exciting areas being addressed by microarrays today, however, that were once thought to be best addressed by DNA sequencing," she said, noting that NimbleGen currently sells arrays for comparative genomic sequencing studies, a microarray-hybridization-based method to resequence microbial genomes (see BAN 1/24/2006).

"[But] even if it eventually becomes possible to sequence entire genomes in a time- and cost-effective manner, array technology provides one with the means today to rapidly identify and call virtually all sequence differences between two samples," she said.

Illumina spokesperson Bill Craumer told BioArray News in May that the cost of new sequencing technologies could delay their ability to make inroads in the array market.

"By the time predicted cost points drop to $1,000 per sample, array-based approaches will have dropped far below that so the economics still won't make any sense," Craumer said. However, Craumer said that he could see sequencing as a complementary tool rather than a competitive one in the future.

"Where sequencing begins to make sense is in non-whole-genome requirements once a genomic region or gene of interest is implicated via whole genome genotyping or more focused methods," Craumer said. "For big disease association studies, this could be in the last stage of a three- or four-phase study design," he added.

— Justin Petrone ([email protected])

 

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