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Electronic BioSciences Makes Progress on Flossing Technique; Aims to Develop Nanopore Sensor


SAN FRANCISCO (GenomeWeb) – Electronic BioSciences has made progress on developing a nanopore "flossing" technique that it plans to commercialize in a nanopore sequencing device in two to three years.

At the same time, the firm has also been working on harnessing its nanopore technology as a sensor to be used in characterizing nanoparticles and as an immunoassay. As a longer-term research project, EBS is working on developing exonuclease nanopore sequencing technology.

"In general, we're interested in any nanopore technique," CEO Eric Evins said. "Our mission as a company is low-noise electronics developed around nanopores, lipid bilayers, and channels for sensing applications."

The company's core technology is a glass nanopore membrane developed in the University of Utah laboratory of Henry White. Evins is a co-inventor of the technology and EBS licenses it from the university. EBS commercialized a lipid bilayer platform called Nanopatch in 2013.

The company generates revenue through sales of its Nanopatch system and also receives funding from grants, including from the National Human Genome Research Institute's Genome Technology Program. Last year, for instance, the NHGRI awarded it two $225,000 grants — one to support its nanopore flossing technology and the other to support development of exonuclease-based nanopore technology.

Two years ago, the company presented at an NHGRI-sponsored sequencing technology conference on progress it had made to develop its flossing technique — whereby it runs a DNA molecule back and forth through a nanopore, re-reading the same molecule in order to increase accuracy.

Since then, Evins said the company has made advances on pore development. EBS uses an alpha-hemolysin protein pore and Evins said the firm has developed a pore that has a sensing zone of a single nucleotide. Typically, as DNA passes through protein nanopores, the readout caused by current blockage is based on multiple bases being present in the pore. In addition, Evins said the company has also figured out a way to introduce residues that slow down translocation and has also incorporated single-stranded binding proteins that linearize the DNA, preventing it from folding and forming secondary structures with itself.

Evins said that the company has been testing this improved configuration on synthetic DNA and has shown that the current signature is indicative of the individual bases. He added that the company plans to publish the demonstration of single-nucleotide resolution in a peer-reviewed journal. "We'd like to have an instrument available for early access users in two to three years," he said.

EBS is also developing nanopore sensors. The first sensing application it is working on is to use the alpha-hemolysin pore in the glass membrane to be able to characterize nanoparticles. "There's not a great product out there that's capable of characterizing those particles with high resolution in situ," Evins said. Currently, multiple techniques must be used. Such a device would have applications in medicine, diagnostics, imaging, the environment, and energy, he said. EBS plans to make that available to early customers within the next year, he said.

Following the nanoparticle characterization instrument, Evins said the company plans to commercialize a nanopore-based immunoassay in around the two-year time frame. Essentially, he said, the device would consist of the same glass nanopore configuration but would be coated with antibodies to assess binding and kinetics of antigens to their antibodies. The instrument could either be a single pore with a single antibody or multiple pores each with different antibodies, he said.

And finally, the company has been collaborating with the University of Utah on research into exonuclease-based nanopore sequencing, a longer-term project, Evins said. Exonuclease-based sequencing relies on coupling an exonuclease enzyme to the nanopore. The enzyme then cleaves off single bases, and the tagged bases are read as they go through the pore.

But, there are "two key challenges" with exonuclease-based sequencing: capture efficiency and identification of the base and bound enzyme as it goes through the pore, Evins said. Thus far, Evins said that in collaboration with White's group at the University of Utah, the researchers have conducted simulation experiments to assess the capture efficiency. The problem with exonucleases is that they are difficult to control, so it once it cleaves the nucleotide it is hard to get it to travel through the pore. The simulation experiments have involved looking at the different tunable parameters of the EBS' nanopore configuration, such as pressure and the pore's charge, to see which configuration would theoretically result in the highest capture efficiency, Evins said. In addition, he said, the team is also looking at the dynamics of the glass membrane and adjusting those metrics, like surface charge.

The research is "in early stages," Evins said. But, he said the group became interested in exploring the concept because it could offer some advantages over strand-based sequencing. "The exonuclease concept has the potential to enable epigenomics and epitranscriptomics," he said. Since the exonuclease binds to native DNA, it could enable the detection of chemical modification at the single-base level with high accuracy, he said.

Oxford Nanopore Technologies previously had a commercialization agreement with Illumina to develop and commercialize exonuclease-based nanopore sequencing, but ultimately, the firms cut ties and Oxford Nanopore went on to commercialize its strand sequencing instrument the MinIon.

EBS will have to compete with Oxford Nanopore's MinIon when it launches its own strand sequencing instrument. And although the MinIon has improved rapidly over the last several years, Evins said he thinks there is plenty of room in the sequencing market for another technology. "There are not that many sequencing methodologies on the market," he said, and each of them has their own advantages and disadvantages. "We're in the beginning stages of diving into our knowledge of the genome, epigenome, and transcriptome," he said, and "there's a need for technologies that solve the shortcomings of other techniques."