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Wyss Engineers Move Molecular Detection, Diagnostics onto Paper Strips

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NEW YORK (GenomeWeb) — With a new technique to embed and freeze-dry genetic networks in paper, researchers from the Wyss Institute at Harvard University have taken the first steps toward moving a range of molecular diagnostics that currently rely on more complex technologies into a just-add-water system of cheap and potentially highly multiplexable paper sensors.

The advance relies on a strategy of printing the sequences for molecular sensing and fluorescent or other signaling processes that would otherwise take place in vivo onto paper. These paper-embedded networks are inert when dry, but when rehydrated, they ensure that a specific target binding to the strip triggers a gene switch that then produces a fluorescent or other visual signal.

The Wyss researches published two papers describing some of their work in this area in Cell this week. In one, the authors described an integral part of their technology's ability to specifically detect different RNA targets, called a toehold switch. In the other, the researchers demonstrated the application of their paper-based system for strain-specific Ebola virus detection.

The toehold switch, initially developed by members of the group for use within cells, can be programmed to precisely detect almost any RNA signature and then produce a protein to signal that detection, according to the group.

In the second study, the Wyss team describes adapting this toehold to work not in a cell, but printed and dried onto a piece of paper. In this way the team created a sensitive and specific biosensor, potentially adaptable to a wide variety of molecular detection or diagnostic applications.

"We tried a number of different circuits, but the main one we worked with was the toehold switch," Wyss scientist Keith Pardee, the lead author of the study, told BioArray News this week. "With the toehold, basically as soon as a target RNA is present, the hairpin flattens, enabling translation of the downstream RNA, and we showed that this could work with both fluorescent reporters, as well as enzymes that cause a colorimetric change."

In the study, the Wyss researchers described several proof-of-concept adaptations of the strategy toward molecular diagnostics applications. First, the team developed paper-embedded colorimetric mRNA sensors for antibiotic resistance genes, showing that the paper strips could successfully detect four different antibiotic resistance markers.

Next, to demonstrate how rapidly they could develop new sensors, the researchers challenged themselves to build paper-based mRNA sensors for Ebola, multiplexing 24 different sensors to distinguish between the Sudan and Zaire strains of the virus, in less than one day.

According to the authors, each of the 24 paper sensors was successfully triggered in the presence of its target.

Using paper-based toehold switch sensors for Ebola, or other emerging or rapidly evolving pathogens, offers advantages over currently used antibody-based techniques, the group wrote, because sensors can be designed from sequence alone, rather than requiring appropriate antibodies. In this way, assays could be created much more rapidly targeting novel antibiotic resistance or other viral sequences as they emerge.

According to the authors, although competing antibody-based technologies currently have greater sensitivity than the Wyss group could achieve on paper, continuing advances in molecular techniques should help them catch up.

Pardee did not detail any of the group's strategies for increasing sensitivity, but he said the researchers have several ideas they are confident in and are testing the first of these this week.

Rather than directly competing with technically demanding lab-based approaches, the authors also wrote that they see their paper technology potentially filling other niches, perhaps even more ubiquitously in daily life.

Along those lines, the researchers reported they have successfully embedded genetic networks into other materials like cloth, lab membranes, and aluminum.

Pardee said that the papers published this week reflect only a first step in demonstrating the potential of their paper-based biological switches and sensors for molecular diagnostics. In order for the team's system to be clinically useful, they will have to both improve sensitivity and create a more practical user interface.

"We have the detection engine portion of this completely robust, but in terms of a deployable diagnostic there are a lot of other things we need," he explained.

Currently, the toehold switch paper sensors can only detect RNA, but Pardee said the team is also interested in trying to adapt the technology to detect DNA as well.

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