Implantable DNA/RNA sequencing biosensors – How cool is that!

from The San Diego Union Tribune by Bradley J. Fikes –

An all-UC San Diego team is reporting that it has found out how to more accurately detect single-nucleotide variations in DNA using nanoelectronics.

If the study is confirmed, it could lead to more reliable DNA-based diagnostics, such as miniaturized, implantable sequencing biosensors.

Authors led by Ratnesh Lal and Gennadi Glinsky say the new technology is well-suited to detect single-nucleotide polymorphisms, or SNPs. These one-letter changes in sequence can cause diseases such as sickle-cell anemia and cystic fibrosis.

 Some SNPs are associated with increased risk of developing pathological conditions such as multiple types of cancer, diabetes, heart disease, neurodegenerative disorders, autoimmune and inflammatory diseases.

“The major difference between our design and the current systems is that we don’t use optical detection, only electrical detection,” Lal and Glinsky said by email. “This allows it to be portable.”

The study was recently published in PNAS.

Electrical DNA sequencing has been pioneered by companies such as Ion Torrent with computer chips. It has become a less expensive alternative in some instances to optical-based approaches, such as used by San Diego’s Illumina.

However, chip-based sequencing so far hasn’t been able to accurately scale to the vast speed and output whole-genome sequencing demands. Current technology appears readily amenable for high-scale parallelization to overcome this limitation, Lal and Glinsky said.

The researchers said the team isn’t developing its method for whole-genome sequencing now, but it is highly feasible to rapidly advance technology in this direction in the near future.

The approach outlined in the study employs dynamic DNA nanotechnology and graphene, a form of carbon layered one atom thick. It’s intended to make SNP sequencing easy to do in places where optical sequencing can’t be done — such as directly inside a living organism.

Schematics of the SNP chip sensor


(A) DS probe action. The red strand is normal strand (N) containing 7 nt of toehold. Toehold is single-stranded at the initial state. When a perfect-match target strand (green strand) approaches a DS probe, the target strand displaces the weak strand (W) (black strand) by binding to the toehold. (B) Graphene FET sensor with DS probe. “S” and “D” represent source and drain, respectively, of FET. Gate voltage is applied directly on the liquid gate; the liquid gate is shown as a hemisphere (light blue) surrounding the DS probe. (C, Left) The green strand displaces the black strand, and the toehold portion becomes double-stranded (black dotted circle region). (C, Right) A target strand with single mismatch (yellow strand) does not allow the strand displacement properly (i.e., the yellow strand does not displace the black strand). Thus, the toehold region remains single-stranded (black dotted circle). (C) I-V relationship (I-V curve) attributable to charge difference during the strand displacement in the gene chip FET sensor. (C, Left) I-V curve for strand displacement with perfect match (C, Left). The I-V curve shifts leftward and downward. (C, Right) Single-mismatch target strand does not displace the black strand properly; thus, the I-V curve remains almost the same.

This method also has the potential to enable the SNP detection and quantitative measurements of specific DNA and RNA sequences in real time and communicate the information through wireless devices, Lal and Glinsky said.

The technology measures the change in electrical current on a graphene chip engineered to harbor cleverly designed double-helix DNA strands to facilitate strand displacement reactions. If there are any changes in the specific nucleotide sequence, one DNA strand is displaced and after the displacement, the current is altered.

“SNP detection in large double-helix DNA strands (e.g., 47 nt) minimize false-positive results,” the study stated. “Our electrical sensor-based SNP detection technology, without labeling and without apparent cross hybridization artifacts, would allow fast, sensitive, and portable SNP detection with single-nucleotide resolution.”

“The most exciting news is that advancement of this technology to wireless and implantable nano-chip architecture represents the realistic next steps which would facilitate its rapid introduction into variety of clinical settings to enable an entirely new of way of conducting blood-based laboratory tests,” Lal and Glinsky said.

“Soon, this technology should evolve into a wide-range of the next generation liquid biopsy applications for practical implementation of the concept of personalized target-tailored precision medicine.”

Source – The San Diego Union Tribune

Hwang MT, Landon PB, Lee J, Choi D, Mo AH, Glinsky G, Lal R. (2016) Highly specific SNP detection using 2D graphene electronics and DNA strand displacement. Proc Natl Acad Sci U S A [Epub ahead of print]. [abstract]

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