Stretching it out: Nano-force standard relies on DNA’s breaking point

Dr. Gordon Shaw squats down over the shiny linoleum floor, holding one end of a length of string in his hand. He grabs the middle of the string with his other hand and begins swirling his arms around, tracing random parabolas through the air with the string.

Shaw isn’t performing a magic trick, rather, he’s simulating how a single molecule of DNA behaves in solution. He and his colleagues have devised a way to carefully measure the force required to straighten out such a DNA molecule and stretch it beyond its breaking point, giving them the most precise standard to date for measuring forces at the nanoscale.

Shaw is a research scientist in the Advanced Measurement Lab at the National Institute for Standards and Technology in Gaithersburg, Md. For the last six years, he has been spending most of his waking hours figuring out new ways to accurately measure impossibly small masses, forces and distances.

His latest project is developing an intrinsic force measurement for things happening at the atomic scale--the individual molecules that make up everything from the cells in our bodies to the building blocks of metal alloys. Shaw’s experiments will provide a standard that could help scientists better understand, for example, the forces involved in protein folding that lead to the formation of plaques in Alzheimer’s disease or the differences in cell stiffness that distinguish healthy cells from cancerous cells.

“Proteins are like little machines,” said Shaw. “They fold and twist and perform different functions based on how they behave mechanically.”

In order to assess those differences, you need a measurement device that can distinguish between the forces that hold one protein in position versus another. You also need a way to calibrate your measurement device to make sure that what your measuring corresponds to accepted and verified scientific standards.

Shaw and his colleagues have recently developed a method of measuring nano-scale forces based on the intrinsic strength of bonds that hold DNA molecules together. In its natural state, DNA floats freely in a coiled double-helix shape like a noodle in a pot of boiling spaghetti. Using techniques developed at NIST, Shaw has found a way to grab one end of the DNA strand and gently pull it taut like a string. At first, the strand of DNA will simply straighten out with virtually no force applied at all. But eventually, with tiny, increasing amounts of force, the individual base pairs start to rip apart. Base pairs will then continue to break apart with almost no additional force applied until the double helix completely unravels. It is this point, the so called intrinsic force plateau, that serves as a reference point for future nanotechnologies. This particular strain of DNA’s breaking point happens to occur at exactly 65 piconewtons.

“It has this well defined force signature,” Shaw said. “We can calibrate it once, replicate DNA molecule trillions of time, and it will be exactly the same.”

In addition to having an extremely consistent breaking point, these specially designed DNA molecules can also be produced on the cheap. According to Shaw, just $20 of raw material can be transformed into 5000 reference samples for every person on the planet in just a few hours.

Using a synthesized DNA molecule also has the benefit of being flexible enough to work in a number of settings. A major concern with investing so much time and effort into developing a reference standard is that it will immediately become obsolete. So rather than designing a specific sensor technology, they developed a reference standard that works almost anywhere.

“That’s why we thought it would be good to calibrate to a DNA molecule,” said Shaw. “It can be used in multiple platforms and technologies.”

Shaw’s next challenge is to figure out how to reduce the uncertainty of his reference standard calibration. Currently, his measurements are picking up about a piconewton of noise--a force equal to one trillionth the weight of a small apple--which contributes to an overall uncertainty of five percent. They’d like to drive that number down by reducing the amount of noise they pick up in their measurements.

But for now, he can revel in the glory of having developed the smallest reliable measure of force known to man. Because with so many rapid advances in the field of nanotechnology, one thing is certain: the standard won’t last for long.