Detecting disease with a single molecule: Nanopore-based sensors could transform diagnostics

Scientists at the University of California, Riverside have developed a nanopore-based tool that can diagnose diseases much faster and more accurately than current tests by capturing signals from individual molecules.

The molecules that scientists want to detect (usually certain DNA or protein molecules) are about a billionth of a meter wide, so the electrical signals they produce are very small and require specialized detection equipment.

“Currently, it takes millions of molecules to detect a disease. We’ve shown that it’s possible to get useful data from just one molecule,” said UCR Assistant Professor of Bioengineering said Kevin Friedman, lead author of the paper on the tool. Published in “Nature Nanotechnology”. “This level of sensitivity can make a huge difference in diagnosing the disease.”

Friedman’s lab aims to build electronic detectors that can behave like neurons in the brain and retain memory, specifically the memory of which molecules have previously passed through the sensor. To do this, UCR scientists developed a new circuit model that takes into account small changes in the sensor’s behavior.

At the center of their circuits is a nanopore, a small opening through which molecules pass at a time. A biological sample is loaded into the circuit along with salts, which dissociate into ions.

When protein or DNA molecules from the sample pass through the pores, the flow of ions that can pass through is reduced.

“Our detector measures the reduction in flow rate caused by a protein or piece of DNA passing through or blocking the passage of ions,” Friedman said.

To analyze the electrical signals generated by the ions, Friedman suggests that the system needs to account for the possibility that some molecules may go undetected as they pass through the nanopore. What is unique about this discovery is that the nanopores are not just sensors, but act as filters in their own right, reducing background noise from other molecules in the sample that could obscure important signals.

Traditional sensors require external filters to remove unwanted signals, but these filters can inadvertently remove valuable information from the sample. Friedman’s approach ensures that each molecule’s signal is preserved, improving the accuracy of diagnostic applications.

Friedman envisions using the device to develop portable diagnostic kits, smaller than a USB drive, that can detect infections in their early stages. Current tests may not detect infection for several days after exposure, but nanopore sensors could detect infection within 24 to 48 hours. This feature provides significant benefits in rapidly spreading diseases, allowing for early intervention and treatment.

“Nanopores provide a way to detect infections earlier, before symptoms appear or the disease spreads,” Friedman said. “This type of tool could make early diagnosis more practical for both viral infections and chronic diseases.”

In addition to diagnostics, this device is also expected to advance protein research. Proteins play important roles within cells, and even small changes in their structure can affect health. Current diagnostic tools have a hard time distinguishing between healthy and disease-causing proteins due to their similarities. But nanopore devices can measure subtle differences between individual proteins, which could help doctors design more personalized treatments.

The research also brings scientists closer to achieving single-molecule protein sequencing, a long-standing goal in biology. While DNA sequences reveal genetic instructions, protein sequences provide insight into how those instructions are expressed and modified in real time. This deeper understanding could lead to earlier detection of the disease and more precise treatment tailored to each patient.

“There’s a lot of momentum for developing protein sequencing because it gives us insights that we can’t get from DNA alone,” Friedman said. “Nanopores allow us to study proteins in ways that were not possible before.”

Nanopores are the focus of Friedman’s team’s efforts to sequence single proteins. This work builds on his previous work to improve the use of nanopores to sense molecules, viruses, and other nanoscale entities. He sees these advances as a sign of how molecular diagnostics and biological research will change in the future.

“We still have a lot to learn about the molecules that drive health and disease,” Friedman said. “This tool brings us one step closer to personalized medicine.”

Friedman predicts that nanopore technology will soon become a standard feature in both research and healthcare tools. As devices become more affordable and available, they may be incorporated into routine diagnostic kits used at home and in clinics.

“We are confident that nanopores will become a part of everyday life,” Friedman said. “This discovery could change how we use it in the future.”