University of Zurich researchers noticed brightness variations in low-energy electron images of DNA, as illustrated in this cartoon, which turned out to be a visualization of electric charge. Image credit: Tatiana Latychevskaia.
How does the microscope work?
Schematics of the low-energy electron microscope. The sample can be imaged at different magnifications and the electron source-to-sample distance can be varied from tens of nanometers to a few microns. Image credit: H.W. Fink, T. Latychevskaia, and C. Escher, Scientific Reports ( CC BY 4.0 ).
In this movie you can see how the intensity in different regions of single stranded DNA fibers changes over time under continuous exposure to low-energy electrons. The fibers appear as vertical lines and are suspended over holes in a carbon support. Credit: H.W. Fink, T. Latychevskaia, and C. Escher, Scientific Reports ( CC BY 4.0 ).
“What’s it like to see something that no one has seen before?” I asked Tatiana Latychevskaia, a physicist at the University of Zurich.“You’re always puzzled, trying to look for something similar,” she says. She explains that you talk to colleagues, search the literature, and think back to conference presentations… Usually, you don’t know in the moment that what you’re seeing is new. “Only later do you think that maybe this is something really being seen for the first time,” she tells me.Most of us don’t get the chance to see something never before seen by human eyes, but it can be a perk of the job when you’re pushing the boundaries of science and technology.In a paper published earlier this summer in Scientific Reports, Latychevskaia and her coauthors share images of single strand DNA in which you can actually see electric charge moving along the strands. These images, the first pictures of charge transport in DNA, were captured by an electron microscope at the University of Zurich. The images are especially interesting considering that DNA’s electronic properties are, as the authors put it, “highly controversial.”Experiments probing the electronic properties of DNA have produced conflicting results. Studies have examined double-stranded DNA, single-stranded DNA, and DNA molecules under different conditions, but the results don’t seem to converge. On the basis of different studies, researchers have concluded that DNA is superconducting, conducting, semiconducting, and insulating.In spite of the muddy waters, there’s a lot of interest in this area. If you can figure out how to create electronic components—like diodes and wires—out of biological molecules, you can potentially build electrical circuits out of them, dramatically reducing their size and power consumption.When they took the images, Latychevskaia and her colleagues weren’t even thinking about charge transport in DNA. They were examining the samples at the request of William and Michael Andregg, two brothers in the genome sequencing business at the time. The Andregg brothers had prepared the samples, but didn’t have a microscope with high enough resolution to verify that the DNA samples turned out as intended. Furthermore, they wanted to image the samples without destroying them, not too many microscopes in the world could do that.Fortunately for them, Hans-Werner Fink, the senior scientist on this new research paper, had just the tool for the job: the low-energy electron point source ( LEEPS ) microscope.The story of the microscope goes back almost 40 years. “It all started some time ago, in the late 80’s when I was working for the IBM Research Division in their Swiss-based laboratory near Zurich,” Fink recalls. “At that time and in connection with the development of the STM ( Scanning Tunneling Microscope ), there was a strong desire to develop well-characterized tips on an atomic scale.”Fink took on the challenge, developing a tungsten tip with just a single atom at its apex. “[This] meant that we had created a bright source for coherent electrons, much like a laser for light,” he explains. From this tip evolved the design and realization of the LEEPS microscope, a tool capable of generating images of nanometer-sized objects without using a lens.The microscope “shines” electrons onto a sample. Some electrons make it through the sample while others are scattered. A detector behind the sample records the interference pattern created between the transmitted electrons and a reference electron beam, at a rate of 25 frames per second. A computer program then reconstructs three-dimensional images of the sample from the patterns.“As soon as we applied this technology to biological samples,” says Fink, “we realized that radiation damage is negligible. . . [This] implies that the LEEPS microscope is capable of imaging just one individual biological molecule, which is something like the ‘holy grail’ in structural biology.”Although it sounds straightforward, LEEPS is not a simple piece of equipment. Fink and his group have been upgrading and refining the microscope for two decades. The technology isn’t commercially available yet, but he is optimistic that it will be more widely available soon. “I assume that within a period of three years or so, a tool for routinely imaging single proteins based on the LEEPS technology will be available to the scientific community,” Fink says.Because of the microscope’s unique capabilities, the brothers reached out to Fink’s group and sent over their samples. Fink, Latychevskaia, and Conrad Escher (another LEEPS expert) mounted the samples and studied the images. The team saw bundles of single-stranded DNA stretched over a carbon structure, as expected, but they also saw something unexpected. Some of the DNA strands showed unusually dark and unusually bright regions and the brightness changed in successive images.After lots of puzzling, discussions with colleagues, and new experiments, Latychevskaia realized they were actually seeing charge transport in DNA for the first time. The darker regions corresponded to negative charges and the brighter regions to positive charges.Electrons are charged—that means they exert attractive forces on nearby positive charges and repulsive forces on nearby negative charges. During LEEPS imaging, electrons in the beam were exerting those forces on charges in the DNA strands, which then moved along the strands accordingly. Similarly, charges in the DNA were exerting forces on passing electrons, causing them to veer slightly off their expected path. This resulted in measurable distortions in the images that correspond to the amount of charge in the strands. This research doesn’t shed light on the mechanism behind charge transport in DNA, but it shows that charge does travel through single-stranded DNA and adds new insight to the discussion. It also invites future experiments on charge transport in different biological samples. Even more broadly, the researchers hope this work will inspire more groups to take advantage of LEEPS’s unique capabilities.“Once a point is reached to see something that could not have been seen before, one enjoys a most rewarding and satisfying moment,” says Fink.–Kendra Redmond