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Startup Two Pore Guys Developing Nanopore Sensor, Aims to Enable Sequencing in the Future

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NEW YORK (GenomeWeb) – Californian startup Two Pore Guys is developing a handheld molecular sensor based on solid-state nanopores that it says will have applications in diagnostics, agriculture, food safety, and environmental monitoring. The company has licensed technology developed at the University of California, Santa Cruz and was spun out in 2011.

CEO Dan Heller said in an interview that the firm plans to launch its first device in the third or fourth quarter of this year on a limited basis with early collaborators.  The first iteration of the device will use a silicon nitride nanopore to detect a variety of biological molecules, but in the future the company plans to develop a device that will harness a two-pore configuration, which will provide sufficient resolution to enable DNA sequencing.

The company raised $7 million in seed financing in 2016. It seeks a Series A financing round this year and Heller said the goal is to be profitable by the end of the year. Two Pore Guys currently has 44 employees, and aside from Heller, the management team includes former UCSC professor William Dunbar as chief technology officer and former UCSC research scientist and professor at the University of Massachusetts Medical School Trevor Morin as chief scientific officer.

Later this year, the firm plans to launch a handheld nanopore biosensor device, which it will sell for around $500. Heller said the company will not design the assays that run on the device, but will instead work with others to develop specific assays.

One area the company has been working on is HIV antibody detection. For such a test, a saliva sample is loaded onto a disposable test strip, which contains dehydrated reagents. The test strip is inserted into the reader device, which contains the nanopore chip.

The key to the technology is Two Pore Guys' use of synthetic probes, which bind to the target of interest — in this case, HIV antibodies. The probes essentially "bulk up" the antibody, so that when a voltage is applied and it flows through the nanopore, the resulting current blockade is large enough to be detected above the background, Heller said. Software translates that signal into a digital result that can be read out on a mobile device or tablet.

In the case of HIV detection, the nanopore device can detect the antibody at concentrations as low as 20 nanograms per milliliter of saliva, compared to the standard test, an enzyme-linked immunosorbent assay (ELISA), that detects the antibody down to concentrations of 150 nanograms per milliliter.  

Heller said the device would have the capability to detect a number of different molecules, including antibodies, DNA, RNA, and other proteins. Sample prep will vary depending on the target, he said, but nucleic acid amplification will be performed within the device itself. For an assay that would analyze plant material, the sample prep would be more intensive, he said, because the seed or other material to be analyzed would first have to be ground up and liquefied.

The company is still determining the optimal configuration of independent pores per chip — more nanopores per chip would enable assays to be run faster. The firm is also looking at including multiple chips per test strip, which would enable multiple assays to be run on a single sample. Currently, Heller said, the firm anticipates initially enabling five to six different assays in one test strip. That would allow, for instance, multiple cancer-related point mutations to be analyzed simultaneously.

Last May, company researchers published a proof-of-principle study in PLOS One, demonstrating the ability of their technology to detect a mutation responsible for about two thirds of all cystic fibrosis cases.

In that study, the researchers demonstrated that peptide nucleic acid probes coupled with bulky synthetic molecules could bind to the targeted DNA sequence and could be detected in nanopores ranging in size from 26 nanometers to 36 nanometers.

Two Pore Guys' business model will rely on assay developers to design their own tests on the device and revenue will be shared between Two Pore Guys and the developers. Heller said the company is currently in discussions with a number of diagnostic developers, drug companies, and agricultural companies, and will begin disclosing partner information this quarter. He added that diagnostic companies would also be able to run existing tests on the device.

The firm is also working on a different nanopore technology that would enable DNA sequencing. This technology relies on a two-pore configuration instead of a single nanopore. The idea behind the two-pore concept is that each nanopore has its own independently controlled electrodes. Voltages across the nanopores can be controlled independently as well, such that DNA will first move through the two pores toward the higher voltage. As the voltage across the first pore is lowered, the DNA slows down, eventually moving slow enough to enable sequencing.

Two Pore Guys will likely partner with another company to develop the technology to read the individual DNA bases. The DNA sequence would be read not in the pore itself, because it would contain around 60 nucleotides at once, but by positioning sensors between the two pores. One example of how the individual bases could be detected is through the use of tunneling currents.

Aside from sequencing, Heller said, the two-pore configuration would also enable genome mapping. The company has already developed chips with the two-pore set up, but he did not disclose a commercialization timeline.

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