Existence takes form with the movement of an individual cell. In reaction to cues from particular proteins and enzymes, a cell can initiate motion and vibrations, resulting in contractions that cause it to compress, pinch, and ultimately split. As progeny cells continue this process down the lineage, they expand, specialize, and eventually organize themselves into a complete organism.
Currently, scientists from MIT have harnessed light to guide how a single cell trembles and shifts during its initial developmental phase. The team examined the movements of egg cells produced by starfish — a species that researchers have traditionally employed as a classic benchmark for comprehending cell growth and development.
The investigators concentrated on a crucial enzyme that instigates a series of movements within a starfish egg cell. They genetically engineered a light-sensitive variant of the enzyme, which they injected into egg cells, subsequently stimulating the cells with various light patterns.
The researchers discovered that the light effectively activated the enzyme, which in turn encouraged the cells to quiver and shift in consistent patterns. For example, the scientists could induce cells to display minor pinches or broad contractions, depending on the light patterns they activated. They could even direct light at precise locations around a cell to transform its shape from circular to square.
Their findings, published today in the journal Nature Physics, furnish scientists with a novel optical instrument for manipulating cell shape during its earliest stages of development. Such an instrument, they project, could aid in the design of synthetic cells, such as therapeutic “patch” cells that compress in response to light signals to facilitate wound closure, or drug-delivering “carrier” cells that discharge their contents only when illuminated at specific points in the body. Overall, the researchers view their discoveries as a fresh method to explore how life evolves from a single cell.
“By demonstrating how a light-activated mechanism can reshape cells in real-time, we’re unveiling fundamental design principles for how living systems self-organize and develop form,” states the study’s lead author, Nikta Fakhri, associate professor of physics at MIT. “The capability of these tools is that they are directing us to decipher all these processes of growth and development, enhancing our understanding of how nature achieves it.”
The MIT study collaborators include first author Jinghui Liu, Yu-Chen Chao, and Tzer Han Tan; alongside Tom Burkart, Alexander Ziepke, and Erwin Frey from Ludwig Maximilian University of Munich; John Reinhard from Saarland University; and S. Zachary Swartz from the Whitehead Institute for Biomedical Research.
Cell circuitry
Fakhri’s team at MIT investigates the physical dynamics that drive cell growth and development. She has a particular interest in symmetry, alongside the mechanisms that dictate how cells maintain or disrupt symmetry as they grow and divide. The five-limbed starfish, she notes, is a perfect organism for probing such inquiries into growth, symmetry, and early development.
“A starfish is an intriguing system because it originates from a symmetrical cell and transitions into a bilaterally symmetrical larva at early developmental stages, eventually manifesting pentameral adult symmetry,” Fakhri states. “There are numerous signaling pathways that occur along the way to instruct the cell on how it should organize.”
Researchers have long explored the starfish and its varying developmental phases. Among numerous insights, scientists have identified a vital “circuitry” within a starfish egg cell that governs its motion and shape. This configuration comprises an enzyme, GEF, that naturally circulates within a cell’s cytoplasm. When this enzyme is activated, it triggers a shift in a protein known as Rho, which is essential for managing cell mechanics.
When the GEF enzyme activates Rho, it alters the protein from a nearly free-floating condition to a state where it attaches to the cell’s membrane. In this membrane-bound condition, the protein proceeds to provoke the development of microscopic, muscle-like filaments that extend across the membrane and subsequently contract, allowing the cell to shorten and move.
In prior research, Fakhri’s team demonstrated that a cell’s actions can be influenced by altering the concentration of the GEF enzyme within the cell: the greater the enzyme quantity introduced, the more contractions the cell displayed.
“This entire concept led us to consider whether it is feasible to manipulate this circuitry, not merely altering a cell’s motion patterns but achieving a specific mechanical reaction,” Fakhri remarks.
Lights and action
To precisely control a cell’s movements, the team turned to optogenetics — a methodology that entails genetically modifying cells and cellular components such as proteins and enzymes, allowing them to activate in response to light.
Utilizing established optogenetic methodologies, the researchers created a light-sensitive variant of the GEF enzyme. From this engineered enzyme, they extracted its mRNA — representing the genetic template needed to produce the enzyme. They then injected this template into egg cells harvested from a single starfish ovary, which can host millions of unfertilized cells. The cells, infused with the new mRNA, began generating light-sensitive GEF enzymes autonomously.
During their experiments, the researchers positioned each enzyme-infused egg cell under a microscope and directed light onto the cells in varied patterns and from different points along the cell’s edges. They recorded videos of the cell’s movements in response.
They observed that when directing light toward specific points, the GEF enzyme became activated and recruited Rho protein to those illuminated areas. There, the protein triggered its distinctive cascade of muscle-like fibers that either pulled or pinched the cell in the same light-stimulated locations. Similar to manipulating a marionette’s strings, they were able to orchestrate the cell’s movements, for example, guiding it to change shapes, including a square.
Interestingly, they also found they could provoke the cell to execute broad contractions by illuminating a single spot, surpassing a certain enzyme concentration threshold.
“We realized this Rho-GEF circuitry functions as an excitable system, where a minor, well-timed stimulus can elicit a significant, all-or-nothing response,” Fakhri explains. “Thus, we can either illuminate the entire cell or just a small area of it, ensuring enough enzyme is recruited to that region to catalyze contraction or pinching on its own.”
The investigators compiled their observations and formulated a theoretical structure to foresee how a cell’s shape will transform, depending on light stimulation. The framework, Fakhri notes, provides insight into “the ‘excitability’ central to cellular remodeling, which is a pivotal process in embryo development and healing.”
She adds: “This research provides a foundation for creating ‘programmable’ synthetic cells, enabling researchers to orchestrate shape alterations at will for future biomedical uses.”
This research was partially supported by the Sloan Foundation and the National Science Foundation.