LA JOLLA (August 13, 2026)—Scientists often describe life as a series of chemical reactions. Pallav Kosuri, PhD, describes life as movement. Chemical reactions are how you drive the movement of atoms, proteins, cells, and bodies—without movement, there is no life.
"If you don't know how something moves, you don't know what it does," says Kosuri. "And if you want to understand, manipulate, and alter the function of molecules, understanding their physical movements is just as important as understanding their chemical reactions. The difference is: We have a comprehensive catalog of the chemical reactions, while the mechanical side is still the Wild West."
Kosuri's lab is setting out to change that. They started with DNA origami, a method that uses DNA building blocks to create custom, self-assembling nanostructures with a range of applications—drug delivery, lab-on-a chip devices, and now foundational biological discovery. Then they developed ORBIT, a method that uses DNA origami to build fluorescent nanostructures for visualizing molecular movements.
Technical limitations have long made it difficult or impossible to measure molecular movement over extended periods. Fluorescence microscopy is a powerful technology, but observation times are limited by the amount of time the fluorescent tags remain bright—over time, they always go dark.
Their latest work, published in Cell Reports Methods on August 13, 2026, overcomes this challenge with a novel "dye-cycling" strategy for ORBIT that constantly replenishes fluorescent tags, extending the measurement time window from seconds to hours. This allowed them to measure the rotation of a single RNA polymerase molecule as it "reads" DNA with base-pair resolution and over unprecedented lengths of time. The new method could provide critical mechanical insights into how genes are transcribed in cells.
What is DNA origami?
The DNA inside each cell in our body is the result of billions of years of evolution and optimization. The structure of DNA relies on complementary nucleic acids, represented in shorthand as A, T, C, and G. Each nucleic acid "letter" has a partner that it interlocks with (A with T; C with G) to create the iconic ladder-like double helix we are familiar with.
The unique ability for DNA strands to associate and assemble with one another inspired an idea decades ago: What if we used DNA's innate architectural elements to build structures other than the double helix?
"DNA origami structures build themselves—their structure is encoded in their composition," explains Kosuri, senior author of the paper and an assistant professor at Salk. "This is essential for our ability to reach near-atomic precision in our designs."
In a top-down building approach, you are limited to tens of nanometers as the best possible resolution. But because DNA origami is self-assembling, the structures can be built from the bottom up instead, enabling much smaller resolution while maintaining precision and customization.
"You can design 3D structures with higher precision and resolution than commercial manufacturing methods, and without any machine—you just put the components together and let them combine to make something on the nanometer scale, or even smaller," continues Kosuri. "It's quick to iterate; it's cheap; it's biodegradable; and it's really fun to work with."
Why study molecular movements?
Kosuri's lab has become a pioneer in DNA origami research—so much so that he was recruited by engineer and educator Mark Rober to build the world's smallest Nerf Gun entirely out of DNA. The two made an educational video that went viral on YouTube and to date has been seen by more than 80 million viewers around the world. While the Kosuri lab greatly appreciated the opportunity to showcase the design possibilities of DNA, they are now turning their attention to revealing molecular movement using these same techniques.
Proteins that interact with DNA, like RNA polymerase, must rotate because of DNA's helical structure. RNA polymerase transcribes genetic information from DNA to RNA, providing instructions that the cellular machinery uses to build proteins that are essential to sustain cellular life and health.
The transcription of DNA by RNA polymerase is essential to the development and day-to-day activity of every cell. Why, then, aren't we studying the movement of this key molecular machine?
"Well, we simply cannot see the movement—the diameter of DNA's circular rotation is 100 times smaller than the wavelength of visible light," says Kosuri. "But instead of measuring that, we thought we could assemble a DNA origami rotor that is visible, attach it to the DNA strand, and then measure the movement of the rotor instead."
What is ORBIT?
ORBIT does just that; it's a method developed by Kosuri that uses fluorescently labeled DNA origami rotors to track the rotation of DNA as it spins during its interaction with RNA polymerase. Thanks to the precise, custom nature of DNA origami, the method retains single base-pair resolution—allowing scientists to measure the rotation as RNA polymerase traverses each base pair, from A-T to C-G and so on.
"It's as simple as attaching a larger object to a smaller object," says Kosuri. "Now, when the smaller object rotates, we can see the larger object rotate, and record that in a standard microscope."
The DNA origami rotor attached to the DNA strand looks a lot like a wine opener—a long corkscrewing stem attached to a large X-shaped handle with a fluorescent dye tag. Once the spiraling stem is attached to RNA polymerase, the large, fluorescing, X-shaped handle amplifies the movement of the underlying spiraling DNA, so that scientists can see and measure the rotation.
"ORBIT had the potential to be a powerful method for studying RNA polymerase and other proteins that interact with DNA," says first author Amanda Wacker, PhD, who recently completed her PhD in Kosuri's lab. "But, like other fluorescence tracking methods, ORBIT observation times are limited by photobleaching of the fluorescent tags on the DNA origami rotor. That's what inspired dye-cycling ORBIT."
What is dye-cycling ORBIT?
Fluorescent tags become chemically damaged over time as they emit light. For Kosuri and Wacker, that means ORBIT can only track the movement of a few base pairs before the fluorescence fades away. Dye-cycling offers a solution to this problem.
Rather than attaching a single fluorescent tag to the DNA origami rotor, the dye-cycling strategy keeps fluorescent probes constantly replenishing throughout observation. In other words, the rotor keeps getting refueled, mid-flight.
"Pairing dye-cycling with ORBIT allowed us to overcome photobleaching limitations and track RNA polymerase transcription over long timescales while maintaining our single base-pair resolution," says Wacker. "We were able to use dye-cycling ORBIT to then track DNA rotations during transcription for 10 minutes."
ORBIT was originally capable of capturing a few seconds of movement. While the study showcases 10 solid minutes of effective dye-cycling ORBIT use, Kosuri shares that dye-cycling ORBIT has since been used in his lab to capture movement for hours. The method has removed a significant barrier in fluorescent microscopy methods.
What can dye-cycling ORBIT teach us?
Dye-cycling ORBIT will be an essential tool to explore that mechanical side of biomolecules as Kosuri's lab continues to pioneer DNA origami research. Studying the fundamental rotational movements that underly gene expression will deepen scientific understanding of the genome, its products, and how cells function or malfunction.
"The only reason the mechanical side is a mystery is because we can't see it," adds Kosuri. "This method makes it possible to see movements on a fundamental, molecular level, and, by extension, I think the method could be used to understand the great unexplored universe of structural movements that happen in biology."
Other authors and funding
Other authors include Brian Tenner and Boyu Liu of Salk; Ryan Fantasia and Nicholas Monell of UC San Diego and Salk; and Jerry Wu of Princeton University and Salk.
The work was supported by the National Institutes of Health (GM133351), Ann Martinet Endowed Fund, Jesse and Caryl Philips Award, Mary K. Chapman Foundation, Salk Women & Science Scientific Career and Professional Development Award, Dan and Martina Lewis, and Arnold and Mabel Beckman Foundation.
This press release was written by Isabella Davis.
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute's mission is to drive foundational, collaborative, risk-taking research that addresses society's most pressing challenges, including cancer, Alzheimer's, and agricultural vulnerability. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu .
