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With New NHGRI Grant, Electronic Bio Sciences Focuses on Nanopore Strand Sequencing

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By Julia Karow

With $4.3 million in recent funding from the National Human Genome Research Institute's "$1,000 Genome" program, Electronic Bio Sciences is working toward a protein nanopore DNA strand sequencing technology that builds on an ion channel measurement platform it has been developing.

Under the four-year grant, the 15-employee company, which is headquartered in San Diego and has another location near the University of Utah, is collaborating with researchers at the University of Utah, the University of Texas at Arlington, and the University of Calgary. EBS plans to develop a sequencing device that distinguishes the four bases by recording the blockade of an ion current as a DNA strand passes through an alpha-hemolysin pore. Such a method is "arguably the simplest, both conceptually and technologically, but recently has been passed over in favor of more complex methods," the grant abstract states.

According to EBS founder and CEO Andrew Hibbs, DNA strand sequencing is "fully alive as a viable method," though the company is still at least one breakthrough away from having a full sequencing system. He and his colleagues want to demonstrate that the technology is feasible by the end of the funding period, and eventually plan to build a complete DNA sequencing system.

Hibbs founded EBS in 2002 in order to apply to biology new capacitance-based high-impedance sensing technologies developed at two sister companies he also heads — Quantum Applied Science & Research and QUASAR Federal Systems — which focus on electromagnetic sensors and systems for applications in medicine, geophysical science, and the defense industry.

Between 2003 and 2005, EBS won three contracts from the Defense Advanced Research Projects Agency, among them a $12 million contract — led by EBS and shared with a number of collaborators — under DARPA's Engineered Biomolecular Nano Devices/Systems program to use ion channel biosensors as part of a chemical warfare agent detection system.

Under that project, EBS, which was in charge of developing the electronics as well as the systems concept, improved the robustness of the lipid bilayer that is used as part of the system and developed a so-called glass nanopore membrane in collaboration with Henry White's group at the University of Utah. The company has licensed that technology from the university.

Hibbs said he and his team realized that the glass nanopore structure — a glass substrate with a proprietary chemical treatment that supports a lipid bilayer — provided a path to make low-noise measurements, and "one of the obvious applications of that would be DNA sequencing via alpha-hemolysin."

The resulting electronic measurement system is able to measure small currents on the order of picoamps with "adequate bandwidth," he added, which will likely be required for DNA strand sequencing.

A $1.2 million Small Business Innovation Research grant from NHGRI in 2007 allowed the firm to explore DNA sequencing as an application, which now, with the new "$1,000 Genome" grant, has become the largest effort within the company. "This is clearly the biggest opportunity for [the technology]," Hibbs said.

So far, EBS has focused on characterizing the motion and interactions of DNA translocating through the protein pore, and has recently submitted its results for publication. It has found that diffusion — or random motion — of DNA while it moves through the pore plays the most important role. "Our results show that any sequencing errors are dominated by diffusion," Hibbs explained, which "overcomes any attempt to actually see these signals on a base-to-base level. It also prevents any simple attempt to improve the signal by adding data from multiple experiments."

Company scientists are now looking at ways to reduce the effect of diffusion, but the firm is not revealing any details at this point for competitive reasons. "We do have a number of the pieces, and we feel that we understand and have quantified our problem," Hibbs said, adding that as of now, it still seems that strand sequencing is possible.

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According to EBS President Geoffrey Barrall, company researchers are currently modifying the DNA and protein pore in order to both better understand the system and improve it for sequencing. "There is a lot we can do to improve the contrast between the bases and to control the motion of the DNA through the pore in order to enable single-strand sequencing," he said.

The company's first commercial product will not be a DNA sequencer but a generic ion channel measurement platform for pharmacological and other research, and collaborators are currently testing beta versions of that platform. "Obviously, we would like that platform to be expandable to sequencing," Hibbs said. Though the firm might partner with others to market a sequencing instrument, it plans to build the platform itself. "At this point, our goal is to build a complete system with its own algorithms that gives you a result of a DNA sequence," according to Hibbs.

EBS' main potential commercial rival in the area of strand sequencing is UK-based Oxford Nanopore Technologies, which has been working on a combined exonuclease-nanopore sequencing platform but has said that direct DNA strand sequencing is a longer-term goal (see In Sequence 1/13/2009).

In addition, several academic groups have been funded by NHGRI to work on nanopore sequencing. But while most of these groups have been "working on some component without a very clear idea of how it's all going to come together," Hibbs said, he and his colleagues "approach this problem from the endpoint of a sequencing methodology and work out what is needed — the basic elements to make that final system work."

The company is also building its intellectual property portfolio and currently has about 10 patents or patent applications relating to its measurement protocol. Just last week, it was awarded its second US patent, entitled "Method and apparatus for sensing a time varying current passing through an ion channel."

For a complete sequencing system, EBS might need to license additional IP, but it's still early days. "There is a lot of research and development still to be done," Barrall said. "In that respect, I would say it's a relatively immature technology … there are some significant breakthroughs that need to happen before this becomes the kind of engineering problem where all the pieces need to be put together."

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