New Microscopy Technique Enables Label-Free, RT Imaging of Single Biomolecules

Researchers in Sweden have developed a new microscopy technique that allows proteins, DNA and other tiny biological particles to be studied in their natural state. This enhanced ability to study biomolecules—nature’s smallest biological building blocks—could help in the development of new drugs and vaccines, according to the technique’s developers at University of Gothenburg and Chalmers University of Technology.

Because biomolecules are both small and elusive, researchers currently need to either mark them with a fluorescent label or attach them to a surface. “With current methods you can never quite be sure that the labelling or the surface to which the molecule is attached does not affect the molecule’s properties,” says Christoph Langhammer, professor at the Department of Physics at Chalmers University of Technology. “With the aid of our technology, which does not require anything like that, it shows its completely natural silhouette, or optical signature, which means that we can analyze the molecule just as it is.”

Dubbed nanofluidic scattering microscopy, the technique was recently described in the journal Nature Methods. It involves flushing the molecules or particles being studied through a chip containing tiny nano-sized tubes, known as nanochannels. A test fluid is added to the chip which is then illuminated with visible light. The interaction that then occurs between the light, the molecule and the small fluid-filled channels makes the molecule inside show up as a dark shadow and it can be seen on the screen connected to the microscope. By studying it, researchers can not only see but also determine the mass and size of the biomolecule and obtain indirect information about its shape—something that was not previously possible with a single technique.

"Our method makes the work more efficient, for example when you need to study the contents of a sample, but don’t know in advance what it contains and thus what needs to be marked,” says researcher Barbora Špačková, who during her time at Chalmers derived the theoretical basis for the new technique and then also conducted the first experimental study with the technology.

The new microscopy method can also help identify the most promising drug candidates at an earlier stage. It has the potential for use in conducting research into the way cells communicate with one another by secreting molecules and other biological nanoparticles—processes that play an important role in immune response.  

The researchers are now continuing to optimize the design of the nanochannels in order to find even smaller molecules and particles that are not yet visible today. “The aim is to further hone our technique so that it can help to increase our basic understanding of how life works, and contribute to making the development of the next generation medicines more efficient,” says Langhammer.