By combining quantum mechanical quirks of light with a technique called photonic force microscopy, scientists can now probe detailed structures inside living cells like never before. This ability could bring into focus previously invisible processes and help biologists better understand how cells work.

Photonic force microscopy is similar to atomic force microscopy, where a fine-tipped needle is used to scan the surface of something extremely small such as DNA. Rather than a needle, researchers used extremely tiny fat granules about 300 nanometers in diameter to map out the flow of cytoplasm inside yeast cells with high precision.

To see where these miniscule fat particles were, they shined a laser on them. Here, the researchers had to rely on what’s known as squeezed light. Photons of light are inherently noisy and because of this, a laser beam’s light particles won’t all hit a detector at the same time. There is a slight randomness to their arrival that makes for a fuzzy picture. But squeezed light uses quantum mechanical tricks to reduce this noise and clear up the fuzziness.

“The essential idea was to use this noise-reduced light to locate the nano-particles inside a cell,” said physicist Warwick Bowen of the University of Queensland in Australia, co-author of a paper that came out Feb. 4 in Physical Review X.

The reason behind all this was to overcome a fundamental optical limit that has always caused headaches for biologists. The diffraction limit of light puts a constraint on the size of something you can resolve with a microscope for a given wavelength of light. For visible wavelengths, this limit is about 250 nanometers. Anything smaller can’t be easily seen. The trouble is, a lot of structures inside of cells, including organelles, cytoskeletons, and individual proteins, are much smaller than this.

Scientists have come up with clever ways to get around the diffraction limit and resolve things as small as 20 nanometers. But the new quantum technique has pushed that limit even farther. Instead of using light, Bowen's team passed a nano-particle over the surface of cellular structures, sort of like running your finger over a bumpy surface. They held onto their fat granule probe using optical tweezers, which are basically a nanoscale version of a tractor beam. In an optical tweezer, scientists create a laser beam with an electromagnetic field along its length. The field is strongest at the center of the beam, allowing tiny objects to be drawn to this point and held there.

Because the fat granules occur naturally, the cells don’t need to be prepared like they would for atomic force microscopy, which generally involves killing the cells. That's a big deal because it means photonic force microscopy can be used to visualize processes inside living cells. The team has tracked these granules with a resolution of about 10 nanometers.

To get to this resolution, the researchers needed to see exactly where the fat globules were. For this they needed the quantum mechanical squeezed light because it provided greater clarity than would be possible with fuzzy classical light. Squeezed light relies on a quantum mechanical law known as the Heisenberg uncertainty principle. At the subatomic level, there are limits to the amount of knowledge we can have about particles. You might already know that Heisenberg showed that both the position and speed of a particle can’t be perfectly known at the same time. There is an equivalent relationship between the intensity of photons and their phase.

Light can be thought of as both a wave and a particle. The phase of a wave is the point where the wave begins; either at its peak or trough or somewhere in between. The fuzziness of classical light comes from the fact that the phases of its photons don’t all line up. Some are arriving at a detector while near the top of their wave, others while near the bottom. Squeezed light reduces the intensity of light waves to force them to all have a similar phase. It’s kind of like letting all of the photons out from the starting gate at the same time.

This squeezed beam allows the researchers to get a very good read on where their nano-particle is. Though the recent experiments have achieved resolutions of around 10 nanometers, Bowen thinks they can get down to a nanometer or less with better squeezing of the light.

Using this method, the team was able to follow their fat globule and measure the viscosity of cytoplasm inside of yeast cells. For now, they can only see how the nano-particles travel in one dimension. If they can track them in three dimensions, they could better map out particular cellular structures, such as actin filaments, or tiny pores that open and close on cell walls to allow nutrients to flow in and out.

“These pores have diameters of 10 nanometers and only exist for nanoseconds,” said Bowen. “Because of this, they’ve never been directly observed and we don’t quite know how they work.”

Though it may take some time before these results find widespread use in biological experiments, other researchers are impressed.

“In my opinion, it’s really a remarkable experiment,” said optical physicist Ivano Rua Berchera of the Istituto Nazionale di Ricerca Metrologica in Italy, who was not involved in the work. Until now, squeezed light has mainly been used in physics experiments but Berchera said that "this is the first paper that managed to do something really effective in the field of biology."