Netzahualcóyotl Arroyo-Currás on DNA-Based Sensors

In “Approaches for the Electrochemical Interrogation of DNA-Based Sensors: A Critical Review,” Miguel Aller Pellitero, Alexander Shaver, and Netzahualcóyotl (Netz) Arroyo-Currás reviewed the specific advantages of the electroanalytical methods most commonly used for the interrogation of DNA-based sensors.

Arroyo-Currás, ECS member and associate editor, Journal of the Electrochemical Society sensors technical area, provided more background information to the article in response to questions from the ECS Blog.

What are DNA-based electrochemical sensors?

These are measurement platforms that employ any form of DNA as the molecular recognition element. We must remember that electrochemistry is extremely sensitive (for example, there is significant work regarding stochastic detection of single entities like molecules, nanoparticles and whole cells and viruses) but lacks specificity; thus, relying on the molecular binding properties of DNA allows us to selectively detect molecules even in complex biological environments.

DNA-based sensors may use single- or double-stranded DNA, as well as structured DNA (having stable secondary conformations), and three-dimensional DNA including, for example, DNA tetrahedra and DNA origami. Typically, the DNA receptors are either covalently-bound to or adsorbed onto the electrode. They are also chemically modified to contain covalently-bound redox reporters for sensing purposes or combined with redox mediators in solution. In these sensors, target binding to the DNA monotonically alters electron transfer between the reporter/mediator and the electrode with increasing target concentrations. The actual sensing mechanism depends on sensor architecture.

Regarding selectivity, if the DNA receptors are carefully selected via in-vitro enrichment processes; for example, systemic evolution of ligands by exponential enrichment (SELEX), they can achieve impressive target selectivity. One example of this, is our PNAS work demonstrating that electrochemical sensors employing DNA aptamers as receptors achieve selective and highly precise measurements of specific molecules such as antibiotics or chemotherapeutics in unprocessed, whole blood both in vitro and in vivo.

Why are DNA-based sensors important?

The binding versatility of DNA means that DNA-based receptors can be used to detect a great variety of biologically important molecules, including small molecule therapeutics, peptide, nucleic acid and protein biomarkers and even whole viruses or cells. This ability of course depends on sensor architecture, signaling gain and specificity. For those molecules that do not effectively bind to DNA, several research groups are currently working hard to produce chemically modified nucleobases, which when integrated into DNA oligonucleotides could further expand the affinity of DNA for difficult-to-bind molecules. Moreover, DNA can be easily and cost-effectively synthesized in large quantities and modified to tolerate prolonged exposure to biological fluids.

Can DNA-based sensors revolutionize healthcare?

The answer is to be found as the field continues to advance. However, we speculate that DNA-based electrochemical sensors will help with the translation of medical diagnostics to highly precise decentralized systems; for example, those allowing the monitoring of treatment adherence or health status at home or at follow-up clinics. Moreover, some DNA-based sensors such as those employing DNA aptamers uniquely support reversible and continuous sensing in biological fluids for a great variety of therapeutic targets. This feature may enable the use of closed-loop control systems to improve the efficiency of, for example, drug delivery in the clinic.

Potential challenges to mainstreaming/commercializing DNA-based sensors

Very little rigorous validation of DNA sensor technologies under real-world conditions has been carried out to date. The field must work hard to demonstrate the use of sensors in pre-clinical and clinical environments, employing properly implemented statistical methods and validation against gold standards, to reveal the true achievements and limitations of these sensors in the space of diagnostics and other medical applications. Our group is working hard to perform some of these validation studies with support from the Johns Hopkins Hospital system.

NOTE: Pellitero and Shaver are students affiliated with the Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine where Dr. Arroyo-Currás is Assistant Professor.

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