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Molecular Imaging

Size matters: Color imaging of gene expression in electron microscopy

Researchers at Helmholtz Zentrum München developed a method to visualize gene expression of cells with electron microscope. Although electron microscopy currently provides the most detailed look into cells, it could so far not differentiate which genetic programs run inside those cellular building blocks of life. The new method presented in ‘ACS Nano’ can now have a closer look by using genetically programmed nanospheres of different sizes as multicolor markers, which could even be helpful to investigate how memories are stored in neuronal networks.

Size matters to bring color to Electron Microscopy © Barth van Rossum

What exactly is going on in cells? This question has kept scientists busy for decades. To label small structures, scientists have been using fluorescent proteins. This method works well but has disadvantages due to the relatively poor resolution of light microscopes. Although electron microscopes allow a closer look, "so far there are hardly any solutions for multi-color genetic labeling of cells for this technology, such that one can directly tell different cells apart", says Prof. Dr. Gil Gregor Westmeyer. He leads a research group at the Institute for Biological and Medical Imaging (IBMI) of Helmholtz Zentrum München and is Professor of Molecular Imaging at Technical University of Munich (TUM), School of Medicine.

Nanocompartments as multi-color labels for electron microscopy

Westmeyer and colleagues* have been working with so-called encapsulins** for some time, which are small, non-toxic proteins from bacteria. Encapsulins automatically assemble to nanocompartments in which chemical reactions can run without disturbing the metabolism of the cell. Depending on the experimental conditions, nanocompartments with different diameters are formed within living cells via genetic programming. "Analogous to the palette of colors in fluorescence microscopy, our method turns geometry into a label for electron microscopy," adds Felix Sigmund from Westmeyer's research group.

To achieve strong contrast in the images from the electron microscopy, the researchers use the enzyme ferroxidase, which can be enclosed in the interior of encapsulins. If iron ions enter the interior lumen through pores of the nano compartments, the enzyme oxidizes divalent iron ions into their trivalent form. This creates insoluble iron oxides that remain inside. Metals create good contrasts because they "swallow" electrons - comparable to dense bones in the X-ray image, which strongly absorb X-rays. This special material property of encapsulins makes them clearly visible in the images.

Following neuronal tracts

With their new method, the researchers will now also investigate neural circuits. Despite the impressive resolution of electron microscopy, the method can still not reliably distinguish certain types of neurons within the brain. "With our new reporter genes, we could label specific cells and then read out which type of nerve cell makes which connections and which state the cells are in," adds Westmeyer. This new technology could thus help to uncover the exact wiring diagram of brains and to investigate closer how memories are stored in neuronal networks.

Further information

* Scientists from Helmholtz Zentrum München, Technical University of Munich (TUM), the German Center for Neurodegenerative Diseases (DZNE), the University of Tübingen, the Max Planck Institute of Neurobiology and the Lomonosov Moscow State University were involved in the project.

** Sigmund et al.: „Bacterial encapsulins as orthogonal compartments for mammalian cell engineering“, Nature Communications, DOI: 10.1038/s41467-018-04227-3

Original publication:
Sigmund, Pettinger, Jube et al.:”Iron-sequestering nanocompartments as multiplexed Electron Microscopy gene reporters, ACS Nano, DOI: 10.1021/acsnano.9b03140

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Institute of Biological and Medical Imaging (IBMI) conducts research into in vivo imaging technologies for the biosciences. It develops systems, theories and methods of imaging and image reconstruction as well as animal models to test new technologies at the biological, preclinical and clinical level. The aim is to provide innovative tools for biomedical laboratories, for diagnosis and for the therapeutic monitoring of human diseases.

The Technical University of Munich (TUM) is one of Europe’s leading research universities, with around 550 professors, 41,000 students, and 10,000 academic and non-academic staff. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with the TUM Asia campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.