UBCO researchers build microscopic DNA “sails” to pull molecules apart

Across every cell in the body, molecules are constantly pulling, gripping and releasing under mechanical strain. That force often decides whether a drug sticks to its target, whether a cell holds its shape or whether a disease takes hold.

The problem is that almost nobody is measuring that molecular tug-of-war, UBC Okanagan researcher Dr. Isaac Li says.

In a study published in the journal Science Advances, a team of chemists describes a new way to close that gap.

“Force is an important variable in many biological interactions, but it is not routinely measured in standard binding assays,” says Dr. Li, a chemistry researcher and the study’s senior author. “We wanted to develop a method that makes force measurements parallel and accessible.”

The method, called tether force spectroscopy, applies precisely controlled forces to hundreds of individual molecules at the same time and watches how each one responds. It’s a combination of scale, precision and affordability that existing tools have struggled to deliver together.

The researchers validated it against the field’s gold-standard instrument, then used it to measure molecules being stretched, unzipped and pulled apart at forces spanning the full range relevant to biology. They have filed a patent on the approach and are exploring how to turn it into a commercial product.

Standard lab tests can tell you if two molecules bind in a test tube, but these tests don’t account for the forces that molecules experience in our bodies.

To better understand how these molecules will behave in the dynamic environments of our cells, scientists use equipment to pull molecules apart with precisely controlled forces and measure how they respond.

While this approach is powerful, it currently comes with challenges that limit its use to a very small number of highly specialized labs. Many of these challenges come from the fact that researchers first need to attach molecules to microscopic objects like beads to grab hold of them and pull.

These beads add variability, skew results and complicate experiments, while often limiting measurements and requiring expensive equipment to control.

Tether force spectroscopy is a clever workaround which replaces those beads with a long strand of DNA tethered to a target molecule and then runs a current of fluid past it.

The DNA catches the flow like a sail, and the harder the current, the harder the sail tugs on the molecule anchored below.

By tagging both the sail and the target so they glow, researchers can watch in real time how a molecule stretches, shifts or comes apart in response to precisely controlled forces.

Two things make the approach stand out.

The first is scale. The gold-standard tools for this kind of measurement—instruments like optical tweezers—are precise but examine one molecule at a time, which makes them slow. The team’s DNA sails work in a crowd: hundreds of molecules in a single microscope image, all being tugged and watched simultaneously.

The second is access. Most force-measuring instruments are specialized, expensive and complex. Tether force spectroscopy runs on the fluorescence microscopes and simple pumps that ordinary labs already have.

“The important point is not simply that DNA can pull on a molecule,” says Ryan Riopel, a co-author and UBCO Master of Science student. “It’s that each DNA sail has a defined size and applies force through a single tether, which is what makes the readings trustworthy without exotic hardware.”

The team has filed a patent through Innovation UBC, and co-author Dr. Adam Yasunaga is developing the commercial case through the Mitacs Lab2Market program.

A Canadian-built version of the tool, the researchers note, could give the country a foothold in life sciences instrumentation, turning a university lab’s idea into equipment that other labs, and eventually companies, can purchase.

For now, the promise is broader than any single application. In drug discovery, being able to see how a candidate molecule holds up under physical strain—not just whether it binds in a calm test tube—could help researchers spot winners and losers earlier.

“The larger goal is to give researchers and companies access to force-resolved molecular interaction data,” says Dr. Yasunaga, a UBCO postdoctoral researcher. “These are currently difficult to obtain at scale.”