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Massachusetts Startup Focuses on Long-Read Sequencing Technology

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NEW YORK – Massachusetts startup Universal Sequencing Technology has emerged from stealth with plans to make long-read sequencing more accessible to researchers around the world.

The firm, founded by several ex-Roche employees who worked on the 454 sequencing platform, recently launched its first product, a library preparation kit for whole-genome sequencing to help extract long-range information from short reads, and is developing a long-read sequencing platform.

The WGS library prep kit uses a transposase to fragment DNA and attach barcodes to help reassemble reads after sequencing. The kit can be used to stitch together pseudo-long reads — on average 50 kb and up to 100 kb. It is good for up to four large genomes, or as many as 12 smaller genomes, at a time and is available on the firm's website for $720. Also available are multiplexing primer kits, for $125, and Illumina sequencing primer kits, for $55.

The single-tube reaction, which requires only a few nanograms of input DNA, makes results more accurate and affordable "for any application that needs long reads," said UST CEO and Cofounder Ming Lei.

In a BioRxiv preprint posted in November, scientists from UST described using what they call transposase enzyme linked long-read sequencing (Tell-Seq) to assemble a genome de novo, as well as for haplotype phasing. In collaboration with Bioturing, a bioinformatics and analytics firm, and researchers from the University of California, San Diego, the UST team was able to achieve an N50 scaffold length of 31.5 Mb and an NA50 scaffold length of 4.3 Mb. The largest contig was 109.2 Mb and the largest alignment was 23.6 Mb.

But UST's true aim is to launch a new long-read sequencing platform, which is currently in development, Lei said. He declined to provide technical details, but said it is "different" from sequencing technologies offered by Oxford Nanopore Technologies and Pacific Biosciences and would "be disruptive."

"We consider ourselves a sequencing company," said Andrew Bond, head of commercial at UST. "Library prep is our first product, but we will have others." 

Ultimately, the firm hopes to "make a long-read sequencing platform that every lab or clinic throughout the world can afford and rely on," Lei said.

Based in Canton, Massachusetts and founded in late 2015, UST already has grown to more than 20 employees between its headquarters and an R&D facility in Carlsbad, California. The firm has four cofounders, including 454 alumni Lei, Zhoutao "Tom" Chen, and Yong Wang, joined by early investor Nissi Cui.

The firm started with an undisclosed amount of funding from friends and family, according to Bond, and closed an $8 million Series A round in June 2018, led by Amoy Diagnostics. UST has used that funding to drive R&D, beginning in 2016, yielding 19 US and international patent applications so far.

One US patent application describes a device and method for sequencing where the DNA is attached to a plate controlled by a "precision mechanical drive" which pushes the molecule through pores in a nanopore chip.

"We have a portfolio of IPs for our third-gen DNA sequencer program," Lei said . "The patent applications on nanopore sequencing … are just a small piece of the technology that our new sequencer will be based on." 

Another US patent application provides methods of tracking nucleic acid fragments with barcodes, which "can be used for a variety of applications in both whole-genome sequencing and targeted sequencing."

That's how Tell-Seq works, where an approximately 50 kb DNA segment is captured by a transposome that is anchored on a barcoded bead. The transposase breaks up the DNA segment and affixes the barcodes to the fragments. The reaction happens in bulk solution without encapsulating the sample and reagents, and without a physical partition, according to Bond. "All the chemistry is happening on the surface of the bead," he said. "After that, you're treating [the segments] like a regular library. In this case, it's an Illumina-ready library," although it's possible the kit could one day be converted for use with other sequencing platforms. The reaction takes place in a single PCR tube in less than three hours, Lei added.

Tell-Seq will compete in a crowding market for so-called "synthetic" long-reads, which use molecular and computational tricks to get long-range information from short reads. Linked-read sequencing from 10x Genomics, as well as newer entrants Longas Technologies, with MorphoSeq, have targeted the Illumina platform. BGI has also developed long fragment read technology for its own sequencing platform. 

"The major difference is, you don't need to buy the 10x instrument," Bond said, adding that the per-sample cost is less and that Tell-Seq can be applied to some genomes that 10x linked reads can't.

Among other benefits, Tell-Seq had "one of the best written protocols I've seen," said Rachel O'Neill, a genome researcher at the University of Connecticut who participated in UST's early-access program. "With a very easy protocol, for relatively cheap, you get good long-range information" without needing special equipment, she said.

O'Neill and graduate student Kate Castellano joined the early-access program after being contacted by UST. They received a discount on kits, which they used to assemble the genome of an Antarctic tunicate, a sea creature with a primitive central nervous system. Using Tell-seq helped validate results suggesting that the organism has a highly repetitive genome. Castellano noted that the kit worked with as little as 3 ng of DNA.

Lei said the next steps for the firm are to raise a Series B financing round and to introduce new versions of the Tell-Seq kits. "We have a plan to scale up and put out kits that are used for high-throughput applications," he said, including an adapted kit for whole-exome and targeted sequencing, due out in the second quarter of 2020.

"For non-exome targeted sequencing, we are focusing on the haplotype phasing and diplotyping of long contiguous loci for full genes including exons, introns, and their regulatory regions, such as [the] whole EGFR gene, whole MHC region, etcetera," he said.

And while he sees a future for short-read sequencing, Lei said that all of UST's tech will be focused on longer reads. 

"Everything we are working on is long-read related," he said. "It is no doubt in the future that long-read sequencing will surpass the need for short-read sequencing in many circumstances."

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