Keeping a Steadier Eye on Proteins

Researchers at the University of Colorado, Boulder, have engineered a device that can stabilize most microscopes, allowing scientists to reliably watch the complex folding and unfolding of a protein over time. The device is a simple add-on that scientists can attach to their existing instruments, transforming them into machines powerful enough to capture images of one of the body’s most elusive processes.

The shape a protein takes determines its function in the body, so understanding how the shape arises is crucial to the future of bioengineering synthetic proteins. But protein folding and unfolding is especially difficult to capture. Proteins exist in one state for a long time, and then quite suddenly change shape.

“When you’re trying to measure these extremely small biological motions, sometimes you see unusual things, and then the question becomes, ‘Is this my instrument moving or is this something real in the biology that’s very interesting?’” says Robert Walder, lead author on the paper describing the invention.

Without the stabilization technique, capturing sudden motion, like this folding and unfolding process, usually ends up looking like a blur, no matter how good the resolution of the microscope is.

This stabilizing device—a set of lasers, and a single detector—is designed to attach to the camera port on any microscope scientists currently use to study proteins, such as atomic force microscopes or super-resolution optical microscopes. How a protein moves under any of these microscopes is detected by changes in the way the lasers’ light scatters.

To ensure that the light is moving because of the protein, Walder and his colleagues designed the system around a series of small, stable beams that act as stationary benchmarks. Additionally, the lasers operate at a frequency unused by other standard lab electronics—including indoor lighting—so it’s much easier to cleanly key in on the lasers’ behavior.

Previously, any microscope that could capture 100 seconds of clear images was considered the gold standard, even though this tended to fall short in studying proteins. This new device keeps microscopes steady for up to 28 uninterrupted hours—far longer than any biologist would ever even need, but a reassurance that this technique is reliably unwavering.

“We hope this [stabilization] opens up studies of biological movement that are more complex than what anyone has been able to study so far,” says Thomas Perkins, co-author of the paper.