The development of new drugs and vaccines requires detailed knowledge about nature’s smallest biological building blocks – biomolecules. Swedish researchers have devised a new microscopy technique that allows proteins, DNA and other tiny biological particles to be studied in their natural state in a unique way.
A great deal of time and money is required when developing medicines and vaccines. It is therefore crucial to be able to streamline the work by studying how, for example, individual proteins behave and interact with one another.
This new microscopy method from Chalmers University of Technology allows the most promising candidates to be found at an earlier stage. The technique also has the potential for use in conducting research into the way cells communicate with one another by secreting molecules and other biological nanoparticles. These processes play an important role in our immune response, for example.
Revealing its silhouette
Biomolecules are both small and elusive but vital, since they are the building blocks of every living thing. Researchers currently need to either mark them with a fluorescent label or attach them to a surface to get them to reveal their secrets using optical microscopy.
“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. 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 analyse the molecule just as it is,” says research leader Prof. Christoph Langhammer, oft the Department of Physics at Chalmers. He has developed the new method together with physics and biology researchers at Chalmers and the University of Gothenburg.
The method is based on the molecules or particles under study being flushed through a chip containing tiny nano-sized tubes, known as nanochannels. A test fluid is added to the chip which is illuminated with visible light. The interaction 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.
The new technique, nanofluidic scattering microscopy, was recently presented in the scientific journal Nature Methods, and has also received acclaim from the Royal Swedish Academy of Engineering Sciences. The innovation is now being championed through start-up company Envue Technologies.
“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 researchers are now continuing to optimise the design of the nanochannels 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.
How it works
- The molecules or particles that the researchers want to study are placed in a chip containing tiny nano-sized tubes, nanochannels, that are filled with test fluid.
- The chip is secured in a specially adapted optical dark-field microscope and illuminated with visible light.
- On the screen that shows what can be seen in the microscope, the molecule appears as a dark shadow moving freely inside the nanochannel. This is due to the fact that the light interacts with both the channel and the biomolecule. The interference effect that then arises significantly enhances the molecule’s optical signature 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 molecules that can be seen.
- With this technique it is currently possible to analyse biomolecules from a molecular weight of around 60 kilodaltons and upwards. It is also possible to study larger biological particles, such as extracellular vesicles and lipoproteins, as well as inorganic nanoparticles.