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Looking inside our skin

Researchers from the European Molecular Biology Laboratory (EMBL) have taken the closest look ever at native human tissue by using an advanced microscopy technique called cryo-electron tomography. This technique allows to obtain molecular resolution images of intact cells. The researchers were able to reveal the Velcro-like molecular organization of our skin. As said the European team, visualizing cell-cell contacts was not the goal. The researchers wanted to prove that a cell is a highly organized and coordinated machine. Where will this research lead to? This is unclear to me, but at least the images obtained are spectacular.

Researchers from the European Molecular Biology Laboratory (EMBL) have taken the closest look ever at native human tissue by using an advanced microscopy technique called cryo-electron tomography. This technique allows to obtain molecular resolution images of intact cells. The researchers were able to reveal the Velcro-like molecular organization of our skin. As said the European team, visualizing cell-cell contacts was not the goal. The researchers wanted to prove that a cell is a highly organized and coordinated machine. Where will this research lead to? This is unclear to me, but at least the images obtained are spectacular.

A skin cell electron tomogram

Let's start with a spectacular skin cell electron tomogram. "This 3-D reconstruction of a human skin cell was produced by electron tomography and shows organelles in different colours: regions of cell-cell contact (sandy brown), nucleus and nuclear envelope (blue)." (Credit: EMBL/Nature) This picture is the last frame of a short movie (28 seconds, 23.8 MB, QuickTime format) published by the researchers. Here is a link to another movie (1 minute and 1 second, 4.64 MB, QuickTime format) about the same project.

This project has been driven by researchers of the Structural and Computational Biology Unit at the European Molecular Biology Laboratory (EMBL). It has been led by Dr. Achilleas Frangakis, with various aspects carried on by other EMBL researchers, Ashraf Al-Amoudi, Daniel Castano Diez and Matthew Betts.

Here is a quote from project leader Achilleas Frangakis. "This is a real breakthrough in two respects. Never before has it been possible to look in three dimensions at a tissue so close to its native state at such a high resolution. We can now see details at the scale of a few millionths of a millimetre. In this way we have gained a new view on the interactions of molecules that underlie cell adhesion in tissues -- a mechanism that has been disputed over decades."

But how cryo-electron tomography is different from other microscopy techniques? With this technique, "a cell or tissue is instantly frozen in its natural state and then examined with an electron microscope. Electron microscopy normally requires tissue to be treated with chemicals or coated in metal, a procedure that disturbs the natural state of a sample. With cryo-electron tomography, images are taken of the untreated sample from different directions and assembled into an accurate 3D image by a computer."

Using cryo-electron tomography

The scheme above describes "the ultimate goal of the group and the true power of cryo-electron tomography. We are using cryo-electron tomography in conjunction with pattern recognition techniques in order to match atomically resolved structures in the context of living cells. Practically, we integrate the information from X-ray crystallography, structural genomics and single-particle electron microscopy in order to computationally search for macromolecular complexes in the three-dimensional cryo-electron tomograms." Here is a link to a larger version of this picture.

This research work has been published in Nature under the title "The molecular architecture of cadherins in native epidermal desmosomes" (Volume 450, Number 7171, Pages 832-837, December 6, 2007). Here is an excerpt from the abstract -- if you can understand it. "Here we apply cryo-electron tomography of vitreous sections from human epidermis to visualize the three-dimensional molecular architecture of desmosomal cadherins at close-to-native conditions. The three-dimensional reconstructions show a regular array of densities at 70 Å intervals along the midline, with a curved shape resembling the X-ray structure of C-cadherin, a representative 'classical' cadherin." The two movies mentioned above are available from some supplementary information to the article.

For more information about cryo-electron tomography, you can visit Frangakis group site. Here is a short excerpt. "Cryo-electron tomography is the only technique that can obtain molecular resolution images of intact cells in a quasi-native environment. The tomograms contain an imposing amount of information; they are essentially a three-dimensional map of the cellular proteome and depict the whole network of macromolecular interactions. Information mining algorithms exploit structural data from various techniques, identify distinct macromolecules and computationally fit atomic resolution structures in the cellular tomograms, thereby bridging the resolution gap."

Sources: European Molecular Biology Laboratory (EMBL) news release, December 5, 2007; and various websites

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