In 2019, Caltech researchers demonstrated a new method to use light to control active matter—a kind of material made up of individual energy-consuming pieces that act as a whole to create mechanical motion. The process works similarly to how many individual birds form a swarm that seems to move as a whole. In the research, the team focused on active matter in the form of millimeter-sized protein filaments that normally make up a cell's skeleton, or "cytoskeleton."
Now, powered by insights from computational theory, the team has developed the first "programming language" for active matter, enabling researchers to conduct precise operations in tiny volumes of fluid on the cellular level. The method has major applications in nanotechnology and for studying cell interactions.
The research was a collaboration between the laboratories of Matt Thomson, professor of computational biology and a Heritage Medical Research Institute Investigator, and Rob Phillips, the Fred and Nancy Morris Professor of Biophysics, Biology, and Physics. The work is described in a paper appearing in the journal Nature Materials on January 29. Postdoctoral scholar Fan Yang and graduate student Shichen Liu are the study's co-first authors.
Cellular skeletons, or cytoskeletons, are shapeshifting networks of tiny protein filaments that enable cells to propel themselves, carry cargo, and divide. The "bones" of the cytoskeleton are thin, tube-like filaments called microtubules that can form together into three-dimensional scaffolds. Each microtubule is 1,000 times thinner than a human hair and only about 10 micrometers long (about 1,000 times smaller than a common black ant). Along with motor proteins that power movement, these incredibly small structures combine to propel the relatively large cell—analogous to ants steering and powering a car.
"Active matter has been a potential new material or resource for bioengineering but has, until this point, been impossible to control," Thomson says. "Using theoretical and computational modeling, Fan utilized principles of linear superposition—which only hold in specific size regimes—to develop the first programming language for active matter. Fan's theoretical insight enabled the development of the programming framework."
Cells naturally use gradients of chemicals to induce changes in the structure of their microtubule skeletons. In 2019, the team engineered protein microtubules to respond instead to gradients of light, which allowed the researchers to shine specific patterns of light on a clump of microtubules and induce them to organize into a specific shape or pattern. But the system was not programmable because the team had not yet discovered how to design light patterns to generate fluid flow fields to accomplish tasks like moving cells or mixing fluids.
In the new work, Yang developed a programming language to design active matter fluid flows that can move, sort, and assemble cells; mix chemicals; and apply mechanical stresses to small objects like lipid vesicles in cells. Liu, an experimentalist, then conducted the lab work to verify that the microtubules did in fact assemble as predicted.
The work has major applications for how researchers manipulate cells for study. Usually, scientists need to use needle-like micropipettes to stretch and separate individual cells, risking damage to those cells. With active matter, researchers can add light-activated microtubules to a clump of cells and gently nudge them to desired positions using only light.
"We were inspired by Erik Winfree's work on DNA computing and programming strand displacement reactions," Thomson says. "Now, we are starting to work with people like Magdalena Zernicka-Goetz to apply light-controlled, active matter to control cells during the construction of synthetic embryos. We are also using the system to manipulate immune cells, and to apply mechanical forces to tissues in the lab to simulate mechanical stresses."
Winfree (PhD '98) is a Caltech professor of computer science, computation and neural systems, and bioengineering; Zernicka-Goetz is Caltech's Bren Professor of Biology and Biological Engineering.
The paper is titled "Dynamic Flow Control Through Active Matter Programming Language." In addition to Yang, Liu, Phillips, and Thomson, Caltech staff scientist Heun Jin Lee is a co-author. Funding was provided by the David and Lucile Packard Foundation, the Gordon and Betty Moore Foundation, the National Institutes of Health, and the Donna and Benjamin M. Rosen Bioengineering Center at Caltech. Thomson is an affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.
