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Flush With NHGRI Cash, Three Sequencing Centers Prepare to Incorporate New Sequencing Technologies

Due to an editing error, the original version of this story incorrectly reported that Baylor is a Solexa early-access customer. In fact it is Washington University.
NEW YORK (GenomeWeb News) — When the National Human Genome Research Institute last week announced the $116.6 million it would allocate to three large-scale sequencing centers in fiscal year 2007, the institute stated that the centers will pursue “new ways to increase the speed and lower the cost of DNA sequencing by testing and implementing several new technologies.”
Last week, GenomeWeb News caught up with the centers to find out how they plan to integrate new sequencing methods. All three —  located at the Broad Institute, Washington University, and Baylor College of Medicine — said they are keeping an open mind to new technologies, giving several new platforms a chance to prove themselves.
All three centers have been using 454 Life Sciences’ Genome Sequencer 20 for more than a year, while the Broad and Washington University are also early-access Solexa customers. In the end, there might be room for several different approaches to sequencing, each with their own pros and cons.

“We are going from an essentially monolithic world to a very pluralistic world. And it’s this heterogeneity that makes things suddenly very interesting.”

“We are going from an essentially monolithic world to a very pluralistic world. And it’s this heterogeneity that makes things suddenly very interesting,” said Richard Gibbs, who directs the Human Genome Sequencing Center at Baylor College of Medicine, which won $27.6 million in funding for fiscal ‘07.
“Each [of the new technologies] have their strengths and weaknesses,” Jane Peterson, director for NHGRI’s large-scale sequencing program, told GenomeWeb News last week. “We recognize that it’s not necessarily going to be a one-size-fits-all solution in this next wave.”
Broadly speaking, the three centers will likely work with a mix of technologies when they start spending their new NHGRI grants, according to Gibbs. “The real issue will be what balance of technologies, which mixtures, in what ratios, give the most cost-effective, high-quality data,” he said. “Remember this guiding triangle: cost-quality-quantity. What you want is to get all three. And it’s actually very easy to get two of those. It’s very hard to get three.”
Peterson said the three centers are fairly flexible in how much of their funding they will devote to new platforms. “As they start working with new technology, they may demand more, they may demand less,” she said.
The NHGRI, she added, hopes the centers will implement new techs soon, but “we have to be realistic and realize that implementation of new technologies is tough and it probably won’t go quite as quickly as we would like it to.”
At the Broad, 454’s GS20 has “already released a lot of data, so it's already [been] contributing to data production for quite a while,” said Chad Nusbaum, co-director of the genome sequencing and analysis program at the institute, wrote in an e-mail message last week. His center won $48 million for fiscal ‘07.
Meantime, the Genome Sequencing Center at Washington University School of Medicine has integrated two 454 instruments into the production pipeline, where for now they generate data predominantly for bacterial genome sequencing.
“But a lot of the applications that we are now working on, some of which are approaching production reality, are going to expand that envelope of applications pretty dramatically,” said Elaine Mardis, co-director of the center, which walked away with $41 million for fiscal 07. Among these new applications are full-length cDNA sequencing and SNP discovery in non-human species, she said.
In addition, 454’s upcoming paired-end read capability and the longer reads of the GenomeSequencer FLX, the model that will replace the GS20, will “lead to an expanded use of that platform,” she said.
Baylor’s Gibbs said he sees potential for 454’s technology in two areas: mutation discovery and improving the quality of low-coverage draft genomes of mammals.
“Mutation detection, especially with the longer reads [of the new 454 instrument], is really perfect for large-scale PCR sequencing,” he said.

Baylor researchers are “enthusiastic about other platforms” [beside 454’s.] “The ink is drying on the order” for a Solexa instrument, and the center is interested in testing ABI’s Agencourt platform. “After that, we don’t see anything that is coming within the next 12 months.”

He also believes 454’s technology will lend itself well to the BAC array pooling strategy that his center has developed. That method, he explained, allows groups of BACs to be sequenced together instead of one at a time. BACs, he said, are important to resolve duplicated regions and to distinguish haplotypes in highly polymorphic genomes. “With these shorter, more-abundant reads [of next-generation sequencers], it’s very likely that BAC pools will be an ideal way to go,” he said.
Gibbs, who is a member of 454’s scientific advisory board, said his center is in the process of obtaining a third 454 instrument. “Nevertheless, we are enthusiastic about other platforms,” he said, including Solexa’s and Applied Biosytems/Agencourt’s. “The ink is drying on the order” for a Solexa instrument, he added.
“After that, we don’t see anything that is coming within the next 12 months. And that’s about as far a time horizon as you can have in this rapidly changing field right now,” he said.
454’s platform hasn’t been the only game in town for the two other centers: The Broad Institute and Washington University have had Solexa’s Genome Analysis System on site since the summer under the company’s early-access program.
While the Broad has at least three instruments at the moment, Washington University has had one Solexa machine and “we are planning to have two,” according to Mardis.
Both centers are in the midst of implementing Solexa’s technology, which involves “testing, validating, defining SOPs, setting up a production system, putting a LIMS in place, hardening the process end to end, supply chain management, ongoing cost reduction, ongoing process improvement and so forth,” according to Nusbaum.
At Washington University, “the plan is to implement it at some level into production during the upcoming year,” Mardis said.
The main challenge Solexa’s platform poses, she explained, is handling and analyzing the large amounts of data the instrument produces, not only storing it but also analyzing a lot of it in parallel. “I think we still have a little ways to go in terms of the whole bioinformatics analysis piece, as well as just trying to keep up with improvements to the instruments, changes to protocols,” she said.
Like the 454 platform, her center plans to use the Solexa instrument for SNP discovery, and “it will be interesting to compare and contrast the two,” she said. But longer term, she added, Solexa’s machine “is aimed at” human genome resequencing on a whole-genome scale.
In the long run, she believes massively parallel whole genome resequencing will likely replace the current PCR-based resequencing by the standard Sanger method. However, “quite frankly, there is just a lot of basic work that needs to get done before that really becomes a reality,” she said.
Nusbaum did not mention specific applications or projects for which his center plans to use new sequencers. “Anything that makes sense in terms of cost and quality, really,” he wrote. “If an application is cheaper and/or better by new technology than doing so by ABI, then we will try it.”
Besides 454’s and Solexa’s platforms, Washington University and the Broad Institute will also test other platforms as they come online. “We are very careful about having early conversations with developers,” Mardis said, “and we want to keep a very open mind to new platforms that are coming. Typically, we end up at least purchasing one or more instruments, at least for the purposes of evaluation.”

“If an application is cheaper and/or better by new technology than doing so by ABI, then we will try it.”

“Of course we hope to acquire other machines as they become available,” echoed Nusbaum, pointing out that both ABI/Agencourt and Helicos have been talking about beta-testing their instruments next year. Eric Lander, the Broad Institute’s director, is a co-founder of Helicos BioSciences, which said last month it will start beta-testing its next-generation sequencer by next summer.
But the three centers appear to differ slightly in how early they are willing to take a new technology on board. “We need to see performance before we spend the money,” said Gibbs. “That’s why we don’t have a Solexa machine yet, because we have not had the opportunity to see the performance.”
For Gibbs, a new technology needs to show some “performance fundamentals” before it enters Baylor’s center. “Beta tests can be great opportunities, or they can be a big waste of time doing someone else’s development,” he said.
Asked about Helicos, Gibbs said that “we haven’t heard anything from them specifically. We would be delighted to be surprised by them.”
Mardis, on the other hand, said her group prefers having “true early access, which is along the lines of what we have with Solexa and what we have discussed with ABI and others.” The advantage, she said, is that her center can help shape the final instrument.
“True early access can be very energizing in terms of creative interactive discussions about what the platform is doing, … things you do or don’t like about the software, the protocol, etcetera … that may ultimately combine to make the product so much better,” she said.
For Nusbaum, it “depends on when the producer is ready to let us start playing with it. A new machine has to at least be able to generate some data for it to be worthwhile for us to work with it,” he wrote.

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

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