In 2019, Caltech scientists revealed an innovative approach to utilize light in directing active materials—a type of substance composed of individual energy-utilizing components that behave collectively to generate mechanical movement. This mechanism operates in a manner akin to how numerous individual birds congregate to form a flock that appears to move as a single entity. Within this study, the researchers concentrated on active materials represented as millimeter-scale protein filaments that typically constitute a cell’s framework, or “cytoskeleton.”

Now, driven by insights from computational theories, the researchers have constructed the first “programming language” for active materials, which permits scientists to carry out precise actions in minute volumes of fluids at the cellular scale. This technique holds significant potential in nanotechnology and the exploration of cellular interactions.

The investigation was a collaborative effort among the laboratories of Matt Thomson, a professor of computational biology and an Investigator at the Heritage Medical Research Institute, alongside Rob Phillips, the Fred and Nancy Morris Professor of Biophysics, Biology, and Physics. The findings are detailed in a publication appearing in the journal Nature Materials on January 29. Postdoctoral researcher Fan Yang and graduate student Shichen Liu serve as co-first authors of the study.

Cellular frameworks, or cytoskeletons, are dynamic networks of minuscule protein filaments that enable cells to navigate, transport materials, and undergo division. The “skeletons” of the cytoskeleton are slender, tube-like filaments known as microtubules, which can interconnect to form three-dimensional structures. Each microtubule is 1,000 times more slender than a human hair and approximately 10 micrometers long (around 1,000 times smaller than a typical black ant). Together with motor proteins that facilitate movement, these extraordinarily diminutive structures collaborate to propel the relatively large cell—analogous to ants directing and powering a vehicle.

“Active materials have presented a promising new resource for bioengineering, but until now, controlling them has been unfeasible,” Thomson explains. “By employing theoretical and computational modeling, Fan harnessed the concepts of linear superposition—which are applicable only in specific size ranges—to create the first programming language for active materials. Fan’s theoretical contributions made the programming framework possible.”

Cells inherently utilize gradients of chemicals to trigger modifications in the configuration of their microtubule structures. In 2019, the team engineered protein microtubules to respond to gradients of light, enabling the scientists to project specific light patterns onto a cluster of microtubules and prompt them to arrange into a defined shape or pattern. However, the system lacked programmability since the team had yet to identify how to craft light patterns to create fluid flow fields for tasks like moving cells or mixing solutions.

In the latest research, Yang devised a programming language to formulate active material fluid flows capable of moving, sorting, and assembling cells; mixing chemicals; and exerting mechanical forces on small entities like lipid vesicles within cells. Liu, an experimentalist, subsequently undertook the laboratory experiments to confirm that the microtubules did indeed arrange as anticipated.

This study has significant implications for how scientists manipulate cells for research purposes. Typically, researchers must employ needle-like micropipettes to stretch and isolate individual cells, risking damage. With active materials, scientists can introduce light-activated microtubules to a cluster of cells and carefully maneuver them to desired locations using solely light.

“We drew inspiration from Erik Winfree’s research on DNA computing and programming strand displacement reactions,” Thomson states. “Now, we are beginning collaborations with individuals like Magdalena Zernicka-Goetz to utilize light-controlled active materials to manage cells during the formation of synthetic embryos. We are also employing this system to manipulate immune cells and apply mechanical forces to tissues in laboratory settings to imitate mechanical stresses.”

Winfree (PhD ’98) is a Caltech professor specializing in computer science, computation and neural systems, as well as bioengineering; Zernicka-Goetz is Caltech’s Bren Professor of Biology and Biological Engineering.

The publication is titled “Dynamic Flow Control Through Active Matter Programming Language.” Alongside Yang, Liu, Phillips, and Thomson, Caltech staff scientist Heun Jin Lee is also a co-author. Support 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 holds an associated faculty position with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.