New Virus, New Test

Researchers explore DNA nanoswitches for diagnosing COVID-19

Illustration of a DNA double helix looped back on itself. Two antibodies embedded in the DNA have bound to a SARS-CoV-2 particle.
A COVID-19 DNA nanoswitch in action. Animation: Sebastian Stankiewicz/Boston Children’s

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

While the COVID-19 pandemic shut down research laboratories across the country earlier this year, select labs at Harvard Medical School and Boston Children’s Hospital geared up, including that of Wesley Wong.

Wong and his team responded to the threat by developing a simple, experimental diagnostic test for COVID-19.

Get more HMS news here

The technology, involving a DNA nanoswitch, is a new way of probing a test sample for evidence of infection, said Wong, associate professor of biological chemistry and molecular pharmacology in the Blavatnik Institute at HMS and associate professor of pediatrics at Boston Children’s.

Because Wong and his colleagues have been developing DNA nanoswitch technology for several years, they were able to pivot quickly to apply it to COVID-19 diagnosis.

The DNA nanoswitch starts with a piece of single-strand DNA. Attached to either end of that DNA are compounds that interact with molecules that a researcher wants to study—such as antibodies to a protein made by a virus.

Once added to a blood serum sample, the DNA/antibody nanoswitches float along as sentries looking for their targets. Once they find them, the antibodies bind tightly. The bond between the pair of antibodies and the protein causes the DNA to change shape, shifting to a closed circle or loop shape. If no target is found, the DNA strand remains open in an unlooped position.

The technology, which is not yet used clinically, has shown promise in research studies for other diseases, including detection of prostate specific antigen, a marker of prostate health.

For COVID-19, Wong is engineering a trifecta of DNA nanoswitches. They can detect the spike protein of SARS-CoV-2, antibodies produced after exposure to the virus or RNA made by the virus itself. 

“Used together on a single sample, one could theoretically detect the presence of the virus during an active infection or antibodies produced afterwards,” said Wong, who also holds appointments at Harvard University and the Wyss Institute for Biologically Inspired Engineering.

Common tools

Test results are read out by a simple gel electrophoresis system, a common analytical tool in many laboratories that sorts DNA and proteins by size and shape based on their downward movement through a gel.

With a positive result—a closed loop—the sample seems to get caught and slows down, staying higher in the gel. A negative result passes through the gel to the bottom.

The gel electrophoresis technique means the test can be done “without a lot of expensive equipment and skilled technicians, and an answer can be available fairly quickly,” said Wong.

He envisions simplifying things even further—especially as rapid, on-site COVID-19 testing is needed more than ever.

“The ultimate goal would be to have something that is as easy as a pee stick but as sophisticated and accurate as a laboratory system,” he said.

Testing begins

In early summer, Wong began collaborating with Stephen Elledge, the Gregor Mendel Professor of Genetics and of Medicine at HMS and Brigham and Women’s Hospital, to test the COVID-19 DNA nanoswitch using human specimens.

The rapid test they are developing is designed to not only detect the presence of COVID-19 antibodies but also provide more information about those antibodies. 

“We hope to get some insight into how the immune system responds to infection or vaccination and maybe even identify the presence of antibodies capable of killing or neutralizing the virus,” said Wong.

Preliminary results on patient serum samples show the concept is promising.

Given the continuing need for COVID-19 testing, several organizations have stepped in with funds to expedite the work.

In May, Wong and Ken Halvorsen, now at the University at Albany RNA Institute and formerly a postdoctoral research fellow in Wong’s lab, received funding from the National Science Foundation to jointly develop and test DNA nanoswitches for rapid point-of-care testing for COVID-19 RNA.

Wong also receives support from the Massachusetts Consortium on Pathogen Readiness (MassCPR) and the Massachusetts Life Sciences Center (MLSC) to develop COVID-19 DNA nanoswitches that can detect the viral spike protein and antibodies.

Adapted from a post on Discoveries, the Boston Children’s research and clinical innovation portal.