NEW YORK – SeqLL, the startup formed in 2013 to revive the single-molecule sequencing technology originally developed by Helicos BioSciences, recently expanded its sequencing service business and plans to launch a commercial instrument next year.
This week, the Woburn, Massachusetts-based company said it is launching an early-access program for the system, which it aims to start selling commercially in mid-2017.
The instrument, which does not have a brand name yet, will use the same single-molecule sequencing-by-synthesis technology as the original HeliScope from Helicos, including its one-color chemistry, but will have several improvements — including a smaller size and lower price — and will be further enhanced over time.
Longer term, SeqLL, which aims to raise $25 million in an upcoming Series B financing round, plans to switch to a two-color and eventually a four-color chemistry, and to develop a smaller instrument, dubbed ClinoScope, for clinical applications.
SeqLL was founded in 2013 by Daniel Jones, a former Helicos field application scientist, and William St. Laurent, whose investment firm Genome Diagnostic Technologies (GDT) worked with Jones to acquire Helicos' assets after the firm went bankrupt in 2012. The company currently has 15 full-time employees, including several former Helicos staff members with intimate knowledge of the technology, and a number of regular consultants, among them also former Helicos employees.
Two years ago, SeqLL closed a $1 million Series A financing round that was led by GDT. The company now has $2.25 million in total investments, CEO Liz Reczek told GenomeWeb, and is looking to raise on the order of $25 million in a Series B financing to build the business further.
According to Reczek, who joined SeqLL last November from startup Eutropics Pharmaceuticals, where she was head of therapeutics development, Helicos single-molecule sequencing technology still has an edge over other platforms in some areas, mainly because it requires no amplification, which can lead to bias and errors.
"Even today, the Helicos technology is the best DNA/RNA counting instrument ever made," John Thompson, chief technology officer of Claritas Genomics and the former senior director of genomic research at Helicos, told GenomeWeb. Thompson, who has no financial ties to SeqLL, said the two major drawbacks of the technology are its raw error rate and short read length, however, "these are handicaps for whole-genome sequencing but not for counting technologies like RNA-seq and ChIP-seq."
Apart from counting applications, he said, the technology excels in the analysis of severely degraded and ancient DNA. "Because no copying is needed prior to sequencing, lots of damage is not a problem," he said. "You can sequence right up to where the damage occurs (missing or severely damaged bases) while amplification-based technologies have difficulty because they need to copy before sequencing."
Many aspects of the instrument SeqLL plans to launch next summer are similar to the old HeliScope, but there will be several improvements, Reczek said, including to the optics, computer hardware, software, user interface, and run time flexibility. The instrument will have a list price on the order of $250,000 to $300,000.
Unlike the HeliScope, a floor model, the new machine will also be a benchtop instrument, though its weight — 1,000 lbs — is still higher than that of other sequencing platforms.
Read length will be slightly increased but still on the short side, with an average of 35 base pairs and a range from 25 to 100 base pairs. "We're looking to increase that with some of our planned improvements that we're making over the coming year," Reczek said.
Run times will be flexible, from a couple of days to eight days, depending on the depth of coverage and read length required, and the company has a roadmap to shorten run time to under one day, she said.
Raw error rates are still pretty similar to the HeliScope, ranging from 0.2 percent for substitution errors to 1.5 percent for insertion errors and 3 percent for deletion errors.
According to the firm's current spec sheet, the instrument will have a total output of 21 to 35 gigabases or 600 million to a billion reads per run, and of 420 to 700 megabases or 12 to 20 million usable reads per channel.
For the early-access program, SeqLL is looking for three external customer sites that can take the instrument through its paces and help develop applications. The first beta instrument is scheduled to be shipped within six to eight weeks.
By the end of 2017, the plan is to move from a single-color sequencing chemistry to a two-color chemistry, and later to a four-color chemistry, SeqLL Vice President Alberto Correia told GenomeWeb. He added that there will be a migration path for customers purchasing the earliest version of the instrument that will involve swapping out modules but will not require them to replace the entire unit.
The new sequencing chemistry will be developed in house, building on work already started at Helicos and using intellectual property acquired from the company. SeqLL has also brought manufacturing of its labeled nucleotides in house in order to ensure their quality, Correia said.
While the first instrument targets customers in biotech, pharma, and at academic institutions, SeqLL also wants to build an instrument for the clinic. "The next step for us is to begin development of what we're referring to as the ClinoScope model — a much smaller instrument, for under $100,000, that would have smaller throughput than the research-use instrument and be designed for specific clinical applications," Reczek said.
For example, she said, the technology is good at picking up subtle shifts in transcript levels — on the order of 1.3 to 1.5-fold — on a transcriptome-wide basis. "We'd like to apply that to the development of diagnostic tests through collaborations, either with academics or with pharma or biotech partners," she said.
Another potential clinical application of the technology might be in noninvasive prenatal testing because it accurately counts DNA molecules deriving from different chromosomes, she added.
In the meantime, the company's sequencing service business has been expanding. "We do see the company having two major areas: one being equipment sales, the other being an ongoing sequencing services business that we're building up now, " Correia said. Initially, the firm mainly served customers who had already worked with Helicos and wanted continued access to the technology when it was no longer available.
But over the last six months, after having improved its lab infrastructure, the firm has started offering its services — which include DNA sequencing and direct RNA sequencing without any conversion to cDNA — more widely. "We had to make sure when people send samples, we can meet their deadlines, and we can give them the data at a quality level they expect," Correia explained.
The firm had received inquiries for service work on a regular basis, Reczek said, in particular for sequencing of formalin-fixed paraffin-embedded or otherwise degraded samples and for direct RNA sequencing. Some of this work has already led to publications: Brad Bernstein's group at Massachusetts General Hospital published a study in Science in May in which they used SeqLL's single-molecule sequencing technology to determine the genomic position of nucleosomes.
The firm is also hoping to share data soon from a case study it performed in collaboration with a university, Correia said.
So far, SeqLL has deliberately kept a low profile. "Too many startups, even in our industry, they make claims they can't back up, and they accept money from customers and then they can't meet their obligations," Correia said. "So we've been kind of staying low, even though it was painful."
Claritas' Thompson suggested the company has a real shot at bringing the Helicos technology back to life. Former Helicos employees working at SeqLL "are all aware of previous issues," he said. "There are lots of opportunities they can take advantage of, so I think there is a very real possibility of them being able to make it work."