Technique reveals a hidden world of biology that we have never seen before

(ORDO NEWS) — All living things are made up of cells that are several sizes smaller than a grain of salt.

Their seemingly simple-looking structures mask the intricate and complex molecular activity that allows them to perform life-sustaining functions.

Researchers begin to visualize this activity at a level of detail they did not know. previously it was not possible.

Biological structures can be visualized either starting at the level of the whole organism and moving down, or starting at the level of individual atoms and working up.

However, there is a gap in resolution between the smallest structures of a cell, such as the cytoskeleton, which maintains the cell’s shape, and its largest structures, such as ribosomes, which make proteins in cells.

Similar to Google Maps, while the scientists could see entire cities and individual houses, they didn’t have the tools to see how the houses clustered into neighborhoods.

Seeing these details at the level of districts is very important for the ability to understand how the individual components work together in the environment of the cell.

New tools are steadily filling this gap. And the ongoing development of one particular technique, cryoelectron tomography or cryo-ET, may deepen how researchers study and understand how cells function in health and disease.

In the words of a former editor-in-chief of the journal Science, and as a researcher who has spent decades studying difficult-to-visualize large protein structures, I have witnessed astonishing progress in the development of tools that allow us to determine biological structures in detail.

Exactly the same as now. it becomes easier to understand how complex systems work when you know what they look like. Understanding how biological structures connect to each other in a cell is key to understanding how organisms function.

A Brief History of Microscopy

In the 17th century, light microscopy first revealed the existence of cells. In the 20th century, electron microscopy brought even more detail, revealing complex structures within cells, including organelles such as the endoplasmic reticulum, a complex network of membranes that play a key role in protein synthesis and transport.

From the 1940s to the 1960s, biochemists worked to break down cells into their molecular components and learned to determine the three-dimensional structures of proteins and other macromolecules at or near atomic resolution.

This was first done using X-ray crystallography to visualize the structure of myoglobin, the protein that supplies oxygen to muscles.

Over the past decade, techniques based on nuclear magnetic resonance, which creates images based on how atoms interact in a magnetic field, and cryoelectron microscopy have rapidly increased the number and complexity of structures that scientists can image.

What is cryo-EM and cryo-ET?

Cryo-electron microscopy, or cryo-EM, uses a camera to determine how an electron beam is deflected as electrons pass through a sample in order to visualize structures at the molecular level.

Samples are quickly frozen to protect them from radiation damage. Detailed models of the structure of interest are created by taking multiple images of individual molecules and averaging them into a 3D structure.

Cryo-ET uses the same components as cryo-EM but uses different techniques. Because most cells are too thick to be clearly imaged, the region of interest in the cell is first thinned with an ion beam.

The specimen is then tilted to take multiple images from different angles, similar to a CT scan of a body part—although in this case, the imaging system itself is tilted, not the patient. These images are then combined by a computer to create a 3D image of part of the cell.

The resolution of this image is high enough for researchers or computer programs to identify individual components of various structures. in a cage. The researchers used this approach, for example, to show how proteins move and decompose inside an algae cell.

Many of the steps that researchers once had to follow manually to determine the structure of cells are becoming automated, allowing scientists to identify new structures at much faster speeds.

For example, combining cryo-EM with artificial intelligence programs such as AlphaFold can facilitate image interpretation by predicting protein structures that have not yet been characterized.

Understanding cell structure and function

As imaging techniques and workflows improve, researchers will be able to address some of the key questions in cell biology through a variety of strategies.

The first step is to decide which cells and which regions within those cells should be studied. Another imaging technique, called correlated light and electron microscopy, or CLEM, uses fluorescent labels to help identify areas where interesting processes occur in living cells.

Comparison of genetic differences between cells can provide additional information. Scientists can look at cells that cannot perform certain functions and see how this affects their structure. This approach could also help researchers study how cells interact with each other.

Cryo-ET is likely to remain a dedicated tool for some time. But further technological developments and growing accessibility will allow the scientific community to explore the relationship between cellular structure and function at levels of detail previously unavailable.

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