Visualizing cells at previously impossible resolutions provides vivid insights into how they work

Each of the cells that make up life are several orders of magnitude smaller than a grain of salt. The sophisticated and complicated molecular activity that enables them to perform the duties necessary for life to exist is hidden by their outwardly simple-looking shapes. Researchers are starting to have a detailed understanding of this behavior that they have never had before.

It is possible to envision biological structures either by beginning at the level of the entire organism and working down, or by beginning at the level of a single atom and working up. The cytoskeleton, which supports the form of a cell, is one of its tiniest structures, while the ribosomes, which produce proteins in cells, are one of its largest structures. However, there has been a resolution gap between these two types of cell structures.

Using Google Maps as an example, scientists have been able to visualize entire cities and individual homes, but they lacked the skills to understand how the homes interacted to form communities. Understanding how different parts interact in a cell's surroundings requires being able to see these neighborhood-level features.

This gap is being gradually closed by new tools. Cryo-electron tomography, or cryo-ET, is a unique technology that is still being developed, and it has the potential to help researchers better understand how cells work in both health and sickness.

I have seen amazing progress in the creation of instruments that can identify biological structures in detail as a researcher who has researched difficult-to-visualize big protein structures for decades and as the former editor-in-chief of Science magazine. Understanding how biological components fit together in a cell is crucial to comprehending how organisms function, just as it becomes simpler to comprehend how complex systems work when you are aware of what they look like.

An overview of microscopy's history

Cells were initially discovered using light microscopy in the 17th century. In the 20th century, electron microscopy provided even more information, exposing the complex internal organelles of cells, such as the endoplasmic reticulum, a network of intricate membranes that is essential for protein production and transport.

Biochemists sought to dissect cells into their molecular constituents during the 1940s and 1960s. They also learned how to identify the 3D structures of proteins and other macromolecules at or close to atomic precision. To first see the structure of myoglobin, a protein that provides oxygen to muscles, X-ray crystallography was used.

The quantity and complexity of the structures that scientists can see have expanded significantly over the past ten years thanks to methods based on nuclear magnetic resonance and cryo-electron microscopy, which create pictures based on how atoms interact in a magnetic field.

Cryo-EM and Cryo-ET: what are they?

Cryo-electron microscopy, often known as cryo-EM, employs a camera to record how an electron beam is bent as it travels through a sample in order to see molecular structures. In order to shield samples from radiation damage, they are quickly frozen. A 3D structure is created by averaging numerous photographs of individual molecules to create detailed representations of the target structure.

Cryo-ET and cryo-EM both employ comparable components, although they operate in distinct ways. A area of interest within a cell is first thinned using an ion beam since the majority of cells are too thick to be photographed clearly. Similar to a CT scan of a bodily component, the sample is then tilted to obtain several images of it at various angles. However, in this instance, the imaging equipment itself is tilted, not the patient. A computer then combines these photos to create a 3D representation of a section of the cell.

Researchers or computer programs can use this image's great resolution to distinguish the individual parts of various cell formations. This method has been used by researchers, for instance, to demonstrate how proteins migrate and break down inside an algal cell.

Researchers can now detect novel structures at much quicker speeds because to the automation of several formerly manual methods used to assess the architectures of cells. For instance, integrating cryo-EM with artificial intelligence tools like AlphaFold can simplify picture interpretation by foretelling as-yet-uncharacterized protein structures.

knowledge of cellular structure and operation

Researchers will be able to approach certain important topics in cell biology in alternative ways as imaging techniques and procedures advance.

Choosing which cells and which sections within those cells to research is the first step. Fluorescent tags are used in conjunction with correlated light and electron microscopy, or CLEM, to find areas in live cells where intriguing activities are occurring.

Comparing the genetic variations between cells can offer further information. Cells that are unable to perform specific activities can be examined by scientists to understand how this is reflected in their structure. Researchers may analyze how cells interact with one another using this methodology.

For some years, cryo-ET is likely to remain a specialist instrument. However, as technology progresses and becomes more widely available, the scientific community will be able to explore the relationship between cellular structure and function at hitherto unattainable levels of detail. I foresee new ideas advancing our understanding of cells from chaotic sacks of molecules to delicately dynamic systems.

This article is republished from The Conversation under a Creative Commons license. Read the original article.