To develop new drugs and vaccines, detailed knowledge of nature’s smallest biological building blocks, biomolecules, is needed. Researchers at Chalmers University of Technology, Sweden, now present a revolutionary microscopy technique that can study proteins, DNA and other tiny biological particles in their natural state in a completely new way.
A lot of time and money are needed to develop drugs and vaccines. It is therefore crucial to be able to streamline the work by studying, for example, how individual proteins behave and interact with each other. Chalmers’ new microscopy method may find the most promising candidates earlier. The technique also has the potential to be used to conduct research into how cells communicate with each other by secreting molecules and other biological nanoparticles. These processes play an important role in our immune response, for example.
Reveal your silhouette
Biomolecules are both small and elusive, yet vital because they are the building blocks of all living things. To make them reveal their secrets by optical microscopy, researchers currently have to either mark them with a fluorescent marker or attach them to a surface.
“With current methods, you can never be completely sure that the label or the surface to which the molecule is attached does not affect the properties of the molecule. Using our technology, which doesn’t require anything like that, it shows its completely natural silhouette, or its optical signature, which means we can analyze the molecule as it is,” explains research director Christoph Langhammer. , Professor in the Department of Physics at Chalmers. He developed the new method with physics and biology researchers from Chalmers and the University of Gothenburg.
The unique microscopy method is based on passing molecules or particles that researchers want to study through a chip containing tiny nanometer tubes, called nanochannels. A test fluid is added to the chip which is then illuminated with visible light. The interaction that then takes place between the light, the molecule and the small liquid-filled channels causes the molecule inside to appear as a dark shadow and it can be seen on the screen attached 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, which was not possible before with a single technique.
The new technique, nanofluidic diffusion microscopy, was recently featured in the scientific journal Natural methods. The Royal Swedish Academy of Engineering Sciences, which annually lists a number of research projects with the potential to change the world and bring real benefits, also paid tribute to the progress made. Innovation has also taken a step forward in society thanks to start-up Envue Technologies, which received the “Game Changer” award at this year’s Venture Cup competition in western Sweden.
“Our method makes work more efficient, for example when you have to study the contents of a sample, but you don’t know in advance what it contains and therefore what needs to be marked”, explains researcher Barbora Špačková, who during his time at Chalmers derived the theoretical basis for the new technique and later also conducted the first experimental study with the technology.
Researchers are now continuing to optimize the design of the nanochannels to find even smaller molecules and particles not yet visible today.
“The goal is to perfect our technique so that it can help increase our basic understanding of how life works and help make next-generation drug development more efficient,” says Langhammer.
How the technique works:
- Molecules or particles that researchers want to study are placed in a chip containing tiny nanotubes, nanochannels, which are filled with test fluid.
- The chip is fixed in a specially adapted dark-field optical microscope and illuminated with visible light.
- On the screen that shows what can be seen under the microscope, the molecule appears as a black shadow moving freely inside the nanochannel. This is because light interacts with both the channel and the biomolecule. The interference effect that then occurs greatly enhances the optical signature of the molecule by weakening the light just at the point where the molecule is located.
- The smaller the nanochannel, the greater the amplification effect and the smaller the visible molecules.
- This technique currently makes it possible to analyze biomolecules from a molecular weight of approximately 60 kilodaltons and more. It is also possible to study larger biological particles, such as extracellular vesicles and lipoproteins, as well as inorganic nanoparticles.
Optical cavities could offer new technological possibilities
Barbora Špačková et al, Label-free nanofluidic scattering microscopy of the size and mass of single scattering molecules and nanoparticles, Natural methods (2022). DOI: 10.1038/s41592-022-01491-6
Nanochannels point the way to new medicine (2022, June 16)
retrieved 16 June 2022
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