A Superfast DNA Sequencer Based on Motion Detection

Molybdenum disulfide is the new cutting-edge material for nanopore DNA sequencers

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NIST's proposed design for a DNA sequencer based on an electronic motion sensor.
Illustration: Alex Smolyanitsky/NIST

For more than 20 years, the practice of using a low-intensity electric current to pull long strands of DNA through nanometer-scale pores in a membrane and measure the electric field variations of the four nucleic acids—A, C, G, T—has been growing as the main approach for DNA sequencers. 

We’ve seen the development of this technology reach the point where U.K.-based Oxford Nanopore has been offering portable DNA sequencers based on this fundamental measurement principle for more than a year. Meanwhile, in the research labs, scientists have been tinkering with better materials for the membrane and have started to work with the “wonder material” graphene to see what benefits it might provide in these types of devices.

Now researchers at the National Institute of Standards and Technology (NIST) may have changed the technology paradigm for DNA sequencers in their proposal for an entirely new material architecture that would represent the first DNA sequencer based on sensing motion in the membrane as the DNA thread passes through it.

In research described in the journal ACS Nano, the NIST researchers proposed a device in which a nanoscale ribbon of molybdenum disulfide is suspended over a metal electrode immersed in water. In this arrangement, the molybdenum disulfide acts as a kind of capacitor, storing an electrical charge. When a single strand of DNA is passed through a pore in the membrane, the membrane only flexes when a DNA base pairs up with and then separates from a complementary base affixed to the hole. It is this flexing that the motion sensor detects as an electrical signal.

In the paper, the NIST researchers performed numerical simulations of how fast and accurate this DNA sequencer could be, and they concluded that the membrane would be 79 to 86 percent accurate in identifying DNA bases in a single measurement at speeds up to about 70 million bases per second. It is this speed and accuracy that the NIST researchers see as a game changer.

“It is the promise of true single-base resolution and the ability to reliably detect repeated DNA motifs at the rates of millions of bases per second,” said Alex Smolyanitsky, a NIST researcher and lead author, in an email interview with IEEE Spectrum. “An array of sensors described in our paper has the potential to accurately sequence DNA at speeds far greater than anything on the current market, while the device itself is envisioned to be portable and low-power.”

In a head-to-head comparison with research darling du jour graphene, the benefits are clear.

“The molybdenum disulfide is much less prone to ‘sticking’ to DNA, compared to graphene,” said Smolyanitsky. “Also, it is expected to be electrically conductive at room temperature.”

Before a complete prototype is built, the NIST researchers will be working on chemical functionalization of the material. But there does seem to be an urgency to the research with a patent already being sought on the design.

“We have immediate plans and expertise to work on the experimental aspects of this technology,” said Smolyanitsky. “In addition, we are open to forming early-stage partnerships with the industry.”

DNA sequencing may be just be a starting application for this design with a wide variety of nanoelectromechanical system and device applications on the NIST researchers’ horizon.

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A photo showing machinery in a lab

Foundries such as the Edinburgh Genome Foundry assemble fragments of synthetic DNA and send them to labs for testing in cells.

Edinburgh Genome Foundry, University of Edinburgh

In the next decade, medical science may finally advance cures for some of the most complex diseases that plague humanity. Many diseases are caused by mutations in the human genome, which can either be inherited from our parents (such as in cystic fibrosis), or acquired during life, such as most types of cancer. For some of these conditions, medical researchers have identified the exact mutations that lead to disease; but in many more, they're still seeking answers. And without understanding the cause of a problem, it's pretty tough to find a cure.

We believe that a key enabling technology in this quest is a computer-aided design (CAD) program for genome editing, which our organization is launching this week at the Genome Project-write (GP-write) conference.

With this CAD program, medical researchers will be able to quickly design hundreds of different genomes with any combination of mutations and send the genetic code to a company that manufactures strings of DNA. Those fragments of synthesized DNA can then be sent to a foundry for assembly, and finally to a lab where the designed genomes can be tested in cells. Based on how the cells grow, researchers can use the CAD program to iterate with a new batch of redesigned genomes, sharing data for collaborative efforts. Enabling fast redesign of thousands of variants can only be achieved through automation; at that scale, researchers just might identify the combinations of mutations that are causing genetic diseases. This is the first critical R&D step toward finding cures.

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