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Bucking Short-Read Trend, Upstart Genome Corp.’s Next-Gen System Sticks With Sanger

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A new DNA sequencing startup is swimming against the tide: While most next-generation sequencing platforms combine new chemistries, short reads, and miniaturization, Genome Corp. is betting on factory-style Sanger dideoxy sequencing and read lengths of at least 1,200 base pairs to make sequencing faster and more affordable.
 
The Providence, RI-based startup believes its approach, which it calls “massively parallel“ Sanger sequencing, will be competitive with existing next-generation technologies.
 
“I realized that if you do a few things to Sanger [sequencing], that it should outcompete and outperform all these other technologies” in cost, throughput, and accuracy, said Kevin Ulmer, who co-founded Genome Corp. and serves as its president and chief scientific officer, and currently its only full-time employee. The company succeeds another firm called Really Tiny Stuff, which Ulmer founded in 2002 to develop the sequencing technology.
 
So does the future lie in Sanger sequencing? “We see no reason to abandon it, and many reasons to want to keep it,” Ulmer said, pointing to the technology’s long reads and its well-understood chemistry and error properties.
 
But while he plans to keep Sanger’s dideoxy sequencing chemistry and fluorescent dyes, he wants to make a number of changes to the current technology, starting with the sample prep.
 
What has kept Sanger’s cost up and throughput low is the fact that “you have to process each read … in a discrete sample,” he said. Instead, Ulmer wants to produce tens of millions of Sanger reads in a single reaction tube, similar to the sample prep methods used by the next-gen platforms.
 
Secondly, he plans to build a sequencing “factory” that transforms the electrophoresis and imaging into “an industrial-scale continuous process” and increases the read length to beyond 1,200 base pairs.
 
“Envision something that looks more like the printing press that prints your Sunday newspaper rather than a roomful of desktop printers,” Ulmer said.
 
So far, genome centers have scaled up by increasing the number of individual sequencers they own – typically Applied Biosystems instruments. “In order to make that box, Applied Bio had to make lots of choices and compromises,” Ulmer said.
 
These choices helped lower the price of the instrument to a point where researchers can acquire funding for it, “but that’s not the optimum solution,” he said. Instead, his sequencing factory will be “designed from the ground up.”
 
He declined to provide details of how this approach will increase the throughput and lower the cost, other than to say that every aspect, starting from sample prep to genome assembly, will be optimized. “Aspects of the technology may well be patented, other aspects may be practiced as trade secrets,” he said.
 
With his new company, Ulmer, who served as a full-time consulting scientist to Helicos BioSciences in 2004, is not only bucking the trend of next-gen sequencing but also that of other attempts to improve Sanger sequencing.
 
“Most recent promising developments for Sanger are to miniaturize, and this is not the same as ‘factory-izing,’” Richard Gibbs, co-director of Baylor’s Human Genome Sequencing Center, told In Sequence by e-mail. “Miniaturizing can give benefits without a large facility,” he said.
 
Nevertheless, Gibbs said, “stranger things than Sanger methods having a new life have happened – and the data quality is high!”
 

“Stranger things than Sanger methods having a new life have happened – and the data quality is high!”

Genome Corp. was founded earlier this year with $250,000 in seed funding from the Slater Technology Fund, a state-backed venture capital organization (see In Sequence 10/2/2007)
 
Over the next year, Ulmer plans to pilot the fully integrated process, and based on its performance, he plans to design and fit out the full-scale factory the following year.
 
“That will be a very expensive operation to put into place, because indeed, half of it probably is going to be computers and the bioinformatics infrastructure needed to deal with the output of this thing,” he said.
 
To be able to do that, Genome Corp., which will shortly announce its first group of advisors, hopes to close a multi-million-dollar round of financing by the end of the year.
 
Ultimately, the factory will provide sequencing services that focus on resequencing human genomes. “I have always believed that sequencing is an information service business, not an instrument and reagents business,” Ulmer said.
 
He is not a newcomer to the field: In 1987, Ulmer founded Seq, which set out to develop a high-speed single-molecule sequencing technology based on fluorescent detection of single nucleotides generated by an exonuclease.
 
After changing its name to Praelux in 1997, the company was sold to Amersham Biosciences in 2000. Two former Seq executives, in addition to Ulmer, have joined Genome Corp.’s board of directors: Richard Horan, senior managing director of the Slater Technology Fund, is chairman; and Jay Trautman, vice president of discovery, research, and technologies at Cytokinetics, is a director.