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After Raising $3.5M, ZS Genetics Expands, Starts Work on Prototype Electron Microscope Sequencer

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ZS Genetics has started to work on a prototype of its transmission electron microscopy-based DNA sequencer that it hopes to complete next year, followed by the release of a commercial instrument several years later.

Last week, the firm, which has grown to 10 full-time employees and plans to add several more this year, had a "ribbon-cutting" ceremony for a new 10,000-square-foot facility in Wakefield, Mass., about 10 miles north of Boston, marking a "significant milestone in the company's transition from research and development towards product commercialization," according to the firm. The new home consolidates all of the company's employees, which were previously spread over three sites.

Earlier this year, ZS Genetics raised about $3.5 million from undisclosed non-institutional private investors, CEO and Founder William Glover told In Sequence, and the firm hopes to raise another $4 million in a funding round this fall, also from private individuals. As of last year, it had raised $5 million.

The new facility includes chemistry and DNA sample preparation laboratories, to be completed in September, as well as office space, and is large enough to accommodate the company's anticipated growth.

ZS Genetics recently hired two scientists who will lead its product development program. Suhaib Siddiqui, former head of biochemistry at Helicos BioSciences and "one of the top DNA analog chemists in the world," according to Glover, is heading the firm's chemistry and labeling R&D, while Larry Scipioni, a physicist who previously worked on building nanopores for sequencing, is leading the firm's R&D activities related to the EM as well as prototype development.

Earlier this year, the company added Elaine Mardis, co-director of the Genome Institute at Washington University, to its scientific advisory board. Mardis told In Sequence that "ZS Genetics appears to have an interesting technology and we are watching for progress as it develops."

Harold Swerdlow, head of sequencing technology at the Wellcome Trust Sanger Institute, has been advising the company for several years. "Due to the very long reads expected, ZS Genetics’ technology is likely to be useful for assembly and haplotype phasing; de novo sequencing projects will benefit as will studies of highly fragmented cancer genomes," Swerdlow told In Sequence via e-mail.

Since it was founded in 2005, ZS Genetics has been working on a method for sequencing long DNA fragments by incorporating nucleotides with heavy atom labels, one for each of the four bases, via PCR, spreading single DNA molecules out on a substrate, imaging the DNA with a transmission electron microscope, and reading off the sequence (IS 3/22/2007).

Last October, company scientists and their collaborators from Harvard University and the University of New Hampshire published a proof-of-concept study in which they showed that they could label one of the four bases with a single mercury atom and discern several individual bases in a single DNA strand using an annular dark-field scanning transmission EM (IS 10/16/2012).

Since then, the company has been able to label more than one base, Glover said, though he declined to provide further details until those results are published in a scientific journal, which the firm hopes to achieve within the next several months.

In the proof-of-concept study, the scientists encountered a number of challenges, including incomplete labeling of the bases and loss of label. Glover said the firm is not yet ready to talk about how it has been addressing those issues.

Another possible challenge, the local elongation of DNA on the substrate, which makes accurate measurements between two labels difficult, has apparently been solved. "That's working really well now," Glover said.

The labeling and scanning technology will be the basis for a prototype sequencer the company is currently building and plans to complete "sometime next year," Glover said. The prototype will be able to read all four bases of a single DNA molecule and is expected to have read lengths on the order of 40 to 50 kilobases. Much of the work on the prototype will be around automation.

The prototype sequencer will be built using a "highly specialized" electron microscope from Nion that ZS Genetics recently installed. That instrument has "super high resolution and extremely high contrast," Glover said, adding that only three instruments of this type are currently installed in North America. In addition, the company has a "fairly typical" electron microscope, which it will use for quality control.

A commercial sequencing system, which the company hopes to launch several years after completing the prototype, is expected to have a throughput of 500 megabases per hour, Glover said. He declined to estimate the price of the commercial platform.

ZS Genetics appears to be one of the few companies that is pursuing electron microscopy for sequencing DNA. Halcyon Molecular worked on a similar approach for several years but went out of business last year. Glover said his firm has not hired former Halcyon employees but declined to say whether it has licensed intellectual property from Halcyon.

With its commercial instrument, ZS Genetics will initially focus on sequencing genomic areas that short-read technologies have trouble with, such as the HLA regions of the human genome, and then expand into applications where it can supplement short-read technologies, according to its website.

Possible applications include influenza virus sequencing, de novo genome assembly, full haplotyping, copy number variant analysis, cancer genome sequencing, and microbiome sequencing. "Our niche will be the people who want to be able to do the assembly on more than half of the genome," Glover said.

The company will likely have to share that niche with other long-read sequencing and genome analysis technologies, including those from Pacific Biosciences, Oxford Nanopore Technologies, Nabsys, OpGen, and BioNano Genomics.

ZS Genetics plans to compete with these firms on "data quality and data value," Glover said. "All of the long-read technologies will have substantial advantages over short-read technologies because of increased discovery and lower informatics costs."

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