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With New CEO, ZS Genetics Aims to Commercialize Electron Microscopy-based Sequencing

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NEW YORK (GenomeWeb) – Last week, ZS Genetics announced that it had appointed a new CEO — current board member John McCarthy — who would help guide the company through commercialization of a single-molecule sequencing system that uses electron microscopy to visualize bases.

McCarthy, who has held a range of senior management appointments, including most recently as CEO and director of CryoXtract Instruments, told GenomeWeb that the company would "introduce in very short order" an initial prototype of its system.

Last year, the firm raised around $3.5 million from undisclosed non-institutional private investors and moved into a new 10,000-square-foot facility in Wakefield, Mass.

The company published an initial proof-of-concept study in 2012, demonstrating that it could label and identify with an electron microscope one of four bases of DNA. In the study, company scientists and collaborators at Harvard University and the University of New Hampshire showed that a single mercury atom could label one base and that the bases could be detected with an electron microscope.

In the study, the company labeled the individual thymine bases with a mercury atom. The researchers tested both single-stranded viral DNA and 3.3-kb synthetic DNA strand with a repeating pattern of thymines. After labeling, they mounted the DNA on a substrate, which also separated and linearized the molecules. They were able to see 17 of the 30 predicted labels in a 180-bp segment of the synthetic DNA.

McCarthy said that the company is now able to uniquely label and distinguish between all four bases and is in the process of "optimizing all of the individual components of the platform."

ZS Genetics holds several patents in the field surrounding its ability to label individual DNA bases with heavy atoms. Its most recent patent, No. 8,697,432, was issued in April and is titled "Systems and methods of analyzing nucleic acid polymers and related components." The patent includes in its claims a description of a device that is transparent enough for a particle beam to detect nucleic acid polymer binding sites. Previous patents, also with the same title, cover the company's methods for labeling nucleic acid with heavy atoms and determining the sequence of the labeled nucleic acid polymers with a particle beam. 

McCarthy declined to disclose a timeline for commercialization, but said that the company would initially develop a first iteration of its system, which it would deploy in a handful of genome centers.

During that time, he said the company would be looking to also partner with specialists in the electron microscopy field. Currently, he said, the firm is using a very high-resolution, high-powered EM that goes beyond the company's needs. A commercial sequencing system would ideally include an EM with a much smaller footprint, but "the front end biochemistry will stay the same," he said.

McCarthy also declined to disclose any potential specs of the instrument, but said that the goal is for very long reads and very high accuracy.

He added that analyzing DNA with an EM is what will enable the long reads and high accuracy, because the instrument does not rely on fragmenting DNA and reading bases as it is then reconstructed. Rather, the DNA is first labeled and then the EM takes a picture of it, analyzing and distinguishing between the different labels to read out the sequence. Such a strategy should enable reads of close to 50,000 base pairs, McCarthy said.

ZS Genetics is not the only company to try its hand at sequencing via an electron microscope. Halcyon Molecular was also working on an EM-based approach to analyzing DNA bases, but went out of business in 2012.

McCarthy said that the two firms' methods were very different. "The only thing similar was their use of electron microscopy," he said. "Our patents, which have been issued, are extraordinarily broad and in no way shape or form come anywhere near what Halcyon may or may not have intended to patent."

He said the company plans to work closely with its scientific advisory board, which includes Elaine Mardis, Harold Swerdlow, Nicholas Navin, and other experts in the field, to pinpoint early applications for the system to demonstrate its relevance. He noted that those applications would broadly be in the areas of oncology, infectious disease, and the microbiome. 

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