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Genome Therapeutics Said to Be Exploring Novel Genotyping Tech from Karolinska Lab

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Genome therapeutics has been “exploring” a novel genotyping technology under development at the Karolinska Institute for Genomics and Bioinformatics, according to a person familiar with the deal.

The Karolinska team claims its technology, based on dynamic allele-specific hybridization, can crank out a million genotypes per week per assay device for “significantly less” than $.01 per call.

GT hopes the technology will allow it to perform service genotyping, said the source, who asked to remain anonymous. “In general, the plan is for them within the next six months to fully evaluate the system,” he told SNPtech Reporter. “Six months after that [the plan] is to work up a first-pass series of markers, and after that a very extensive series of markers, all with the intention of providing linkage scanning by SNP genotyping rather than microsatellites.”

A group of Karolinska researchers led by Anthony Brookes initially tweaked DASH to arrive at the results. Brookes, who is vice chairman and coordinator of clinical genomics, told a scientific conference last May that he knew DASH alone can handle around 10,000 genotypes per week at roughly $.35 per call. A pair of innovations devised in Brookes’ lab helped to create a second-generation DASH that now boasts 100-fold utility and implies 1 million individual genotypes per week for about $1,000 in reagent and consumable costs.

The researchers claim the technology can “instantly” create high-density macroarrays by centrifugal transfer of PCR-reaction products onto membranes for “virtually zero cost, and an improved form of FRET-signal generation that yields fluorescence intensities around 40 times stronger that the norm.”

As of last May, Brookes’ team had developed prototype components that can transfer a series of multiplexed PCR products in 1,536-well plates directly to membrane arrays. The researchers then process the membranes and place them on a heating surface beneath a CCD camera for DASH analysis.

“He really ought to be congratulated” for devising this technology, Richard Gibbs, head of Baylor’s Human Genome Center, told SNPtech Reporter.

Soon, GT’s interest was piqued. The company “is certainly looking for technology … and [it’s] decided to give [the technology] a serious try,” said the source. Currently, the relationship between GT and the Karolinska is on a research-partnership basis, but may grow to include funding. If the firm finds value in the technology it would likely install it in its GenomeVision Services unit, which provides genomics services like SNP discovery and screening to government, academic, and commercial clients.

GT acknowledged it has a relationship with Brookes’ lab but declined to elaborate.

The move by GT comes at an awkward time for the company. In September it laid off more than 30 staffers from early-stage R&D and administrative support, leaving the company with 165 employees.

The cost-cutting steps, which are expected to save GT about $6 million a year, will not affect any of the revenue-producing early-research partnerships the company has with pharma but will focus on target-discovery research — likely the space the Karolinska technology would occupy.

GT has in the pipeline a drug for vancomycin-resistant enterococci, which is in phase III trials, and an undisclosed number of anti-infectives in the lead-optimization stage. The company also has candidates at various stages of development in collaborations with drug makers AstraZeneca, Schering-Plough, Wyeth, and Amgen.

Back to Basics

To Brookes, the genomics space has “followed a trend” over the past five years in which increasingly complex technologies gained greater popularity. “More robotics, more gizmos, more microfluidics and microfabrications,” Brookes told GenomeWeb, SNPtech Reporter’s sister publication, last May. “More really high-tech solutions.”

The Briton believes that trend has now reached genotyping. “Everyone said ‘Oh, well, hybridization isn’t good enough for genotyping.’ So they said ‘Let’s do a sequencing step,’ or ‘Let’s do a ligation step. Let’s do something else after we’ve ligated our probe into place.’ But we didn’t follow that route,” he said. “We thought hybridization is enough, but we need to be a little smarter.”

Clever is more like it. Brookes’ innovation is based on widely used and well-understood technology; at its essence it is based on the prin-ciple of dynamically tracking DNA denaturation while a target and probe duplex is slowly heated. It is the use of DASH for allelic discrimination that is “extremely smart,” according to Gibbs. “It’s a very robust, reliable, and a very sensible way to make a call on a base mismatch.”

The second part of the technology — packaging it all together for a high-throughput mode — is also pretty standard. But when Brookes put the two together he got “a real fundamental nucleic-acid methodology,” said Gibbs, who spoke with SNPtech Reporter from an airport in Buffalo en route to Houston. “What he’s basically doing is melting, and fragment melting has been around a long time and [is a] well-established technology.

“I think Tony’s real insight here has been to recognize that dynamic melting overcomes a lot of problems of choosing single-threshold temperatures for these kinds of discriminations,” he added. “And that insight itself is a very clever thing.”

— KL

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