Scientists at Johns Hopkins Medicine have designed what they describe as a minimal synthetic cell capable of demonstrating symmetry breaking in response to chemical cues that they believe could be used to shuttle drugs throughout the body. Details of the finding have been published in Science Advances in a paper titled, “Synthetic control of actin polymerization and symmetry breaking in active protocells.”
Symmetry breaking occurs when a cell’s molecules rearrange into an asymmetric shape or pattern to enable the cell to move toward a target. The process usually occurs in response to stimuli, for example, immune cells can sense chemical signals from an infection and break their symmetry to move toward the infected tissue.
Finding ways to mimic and control symmetry breaking in synthetic cells is essential for understanding how cells survey their chemical environment and rearrange themselves in response. In fact, “understanding how symmetry breaking works is key to unlocking the fundamentals of biology and discovering how to harness this information to devise therapeutics,” said Shiva Razavi, PhD, a postdoctoral fellow at Massachusetts Institute of Technology who led the research as a graduate student at Johns Hopkins.
The synthetic cell or protocell created for this study is a giant vesicle with a double-layered membrane that is made up of phospholipids, purified proteins, salts, and a source of ATP. They engineered the protocell with a chemical-sensing ability that prompts the cell to change from a nearly perfect sphere into an uneven shape. According to the scientists, the system was designed to mimic the first step in an immune response.
To activate the protocell’s chemical-sensing ability, they planted two proteins—FKBP and FRB—to act as molecular switches. The FKBP protein was placed in the center of the cell while the FRB protein was planted on the membrane. The scientists then introduced a chemical, rapamycin, outside the protocell. In response, the FKBP protein moved from the center to bind to the FRB protein on the membrane. This binding triggered actin polymerization or a reorganization of the synthetic cell’s skeleton. The result was an actin-based rod-like structure inside the protocell that put pressure on the cell membrane causing it to bend.
The researchers observed the process using a confocal microscope to record the protocell’s chemical-sensing ability as it responded to the rapamycin. The results demonstrate “how a cell-like entity can sense the direction of an external chemical cue, mimicking the conditions you would find in a living organism,” Razavi said.
For their next steps, the scientists plan to equip these synthetic cells with the ability to move toward a desired target. If they are successful, they could in the future engineer synthetic cells that could be used for targeted drug delivery, environmental sensing, and other areas where precise movement and response to stimuli are crucial.
“The idea is that you can package anything you want into these bubbles—protein, RNA, DNA, dyes or small molecules—tell the cell where to go using chemical sensing, and then have the cell burst near its intended target so that a drug can be released,” said senior author Takanari Inoue, PhD, professor of cell biology and director of the Center for Cell Dynamics at Johns Hopkins Medicine.
