DNA can do many things – build organisms, implicate criminals, store Shakespearean sonnets. Now, it can illuminate the complex biomolecular architecture of a cell.

By attaching colored, fluorescent tags to short stretches of DNA, a team at Harvard University’s Wyss Institute for Biologically Inspired Engineering has developed an imaging system that can resolve structures less than 10 nanometers apart.

Inside each cell in your body, a startling array of molecular machinery is whirring and humming, from the tiny factories that assemble proteins, to the furnaces that produce energy, to the skeletal fibers that help cells move and maintain their shape. Watching how these myriad operations work together – and how the system breaks down – has been both a research goal and a technology bane.

Scientists illustrated the new technique using synthetic DNA nanostructures that resemble numbers. This is a composite of 10 images. Image: Johannes B. Woehrstein/Wyss Institute

It wasn’t until good light microscopes first switched on in the early 19th century that scientists recognized that plant and animal tissues were aggregates of cells. But peering further inside those cells was hard. Colorless and semi-transparent, the cells stymied even the most powerful microscopes of the time, which couldn’t resolve their inner structures. So, scientists began using a variety of stains and dyes to color the cell’s ingredients. Over decades, as microscopists and physicists struggled to harness and redirect photons, they eventually turned to fluorescent stains as a means of marking these intracellular molecules.

But these technologies were limited in their ability to resolve structures more than 200 nanometers apart, because light cannot illuminate anything smaller than its own wavelength.

Recently, the Wyss team figured out how to overcome this limit – inexpensively, and using normal light microscopes rather than electron or photon imaging. The method takes advantage of DNA’s ability to bind to complementary versions of itself – kind of like a molecular handshake. The team begins with short, specific sequences of DNA. These sequences are then attached to molecules, called antibodies, that recognize specific proteins or cellular structures. So, when the antibodies find and bind to their protein targets – say, the proteins making up the cell’s skeleton – they’re carrying along their DNA flags.

Next, the team introduces free-floating, complementary DNA sequences to the cell – sequences that carry a fluorescent tag. These are the sequences that will recognize and bind to the flags flown by the antibodies attached to the cell’s skeletal proteins. When these introduced DNA sequences find their partners and shake hands, the binding activates those fluorescent tags, causing them to blink on and off. By tweaking and recording this blinking, the team is able to resolve the positions of particular molecules – even those that are as close as 10 nanometers apart.

As reported Feb. 2 in Nature Methods, repeating the process with different complementary DNA sequences lets scientists assemble an ultra-sharp composite image of multiple cellular components. Now, instead of struggling to understand how cells are put together, the challenge is using the method to gauge how cells respond to things like environmental stresses or therapeutic drugs.