This technique reveals a hidden world of biology we’ve never seen before: ScienceAlert

This technique reveals a hidden world of biology we’ve never seen before: ScienceAlert

This technique reveals a hidden world of biology we’ve never seen before: ScienceAlert

All life is made up of cells a few sizes smaller than a grain of salt. Their seemingly simple structures mask the intricate and complex molecular activity that enables them to perform life-sustaining functions.

Scientists are beginning to be able to visualize this activity in a level of detail they were unable to before.

Biological structures can be visualized either starting at the level of the whole organism and working downwards, or starting at the level of single atoms and working upwards.

However, there was a gap in resolution between the smallest structures of the cell, such as the cytoskeleton that supports the shape of the cell, and its largest structures, such as the ribosomes that make proteins in cells.

By analogy with Google Maps, although scientists were able to see entire cities and individual houses, they did not have the tools to see how houses connect to form neighborhoods.

Seeing these details at the neighborhood level is essential to understanding how individual components work together in the cell environment.

New tools are gradually filling this gap. And the continued development of one particular technique, cryoelectron tomography or cryo-ET, could advance the way scientists study and understand how cells function in health and disease.

As a former editor-in-chief Science magazine, and as a researcher who has studied hard-to-visualize large protein structures for decades, I have witnessed astonishing progress in the development of tools that can detail biological structures.

Just as it is easier to understand how complex systems work when you know what they look like, understanding how biological structures fit together in a cell is key to understanding how organisms work.

Pink blots on a blue blob on a black background.
Cryoelectron tomography shows what particles look like in high resolution – in this case, the virus that causes COVID-19. (Nanography, CC BY-SA)

A brief history of microscopy

In the 17th century, light microscopy revealed the existence of cells for the first time. In the 20th century, electron microscopy offered even more detail, revealing intricate 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 separate cells into their molecular components and learn how to determine the 3D 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 from the interaction of atoms in a magnetic field, and cryo-electron microscopy have dramatically increased the number and complexity of structures that scientists can visualize.

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What is cryo-EM and cryo-ET?

Cryo-electron microscopy, or cryo-EM, uses a camera to detect how an electron beam is deflected as electrons pass through a sample 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 pictures of individual molecules and averaging them into a 3D structure.

Cryo-ET has similar components to Cryo-EM but uses different methods. Since most cells are too thick to be clearly imaged, the area of ​​interest in the cell is first thinned with an ion beam.

The sample is then tilted to take multiple pictures of it from different angles, analogous 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 produce a three-dimensional image of part of the cell.

The resolution of this image is high enough that scientists – or computer programs – can identify the individual components of various structures within a cell. Scientists have used this approach, for example, to show how proteins move and degrade in an algae cell.

Many of the steps that scientists once had to perform manually to determine cell structures are now automated, allowing scientists to identify new structures at much greater speed.

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.

Purple outlined circles and red to yellow droplets between quivering green, blue and white lines
This is a cryo-ET image of an algal cell chloroplast. (Engel et al. 2015)

Understanding the structure and function of the cell

As imaging methods and workflows improve, scientists will be able to tackle some of the key issues in cell biology with a variety of strategies.

The first step is to decide which cells and which regions within those cells are to be studied. Another visualization technique, called correlated light and electron microscopy (CLEM), uses fluorescent tracers to help locate areas where interesting processes are taking place in living cells.

Colorful compact spirals of protein structures and DNA strands
This is a cryo-EM image of human T-cell leukemia virus type 1 (HTLV-1). (vdvornyk/iStock/Getty Images Plus)

Comparing genetic differences between cells can provide additional information. Scientists can look at cells that are unable to perform certain functions and see how this affects their structure. This approach could also help scientists study how cells interact.

Cryo-ET will probably remain a specialist tool for some time yet. However, further technological developments and increasing accessibility will enable the scientific community to explore the relationship between cellular structure and function in previously unavailable levels of detail.

I expect to see new theories on how we understand cells, moving from disorganized bags of molecules to intricately organized and dynamic systems.Conversation

Jeremy Berg, Professor of Computational and Systems Biology, Associate Senior Vice President for Science Strategy and Planning, University of Pittsburgh

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

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