Researchers at Johns Hopkins Medicine have successfully constructed a minimal synthetic cell that can respond to an external chemical cue and exhibit a fundamental principle of biology known as “symmetry breaking.” This breakthrough has important implications for understanding cell movement and developing new methods for delivering drugs within the body.The research was released on June 12 in Science Advances.
Before a cell moves, a process called symmetry breaking occurs. This happens when a cell’s molecules, which are initially arranged symmetrically, reorganize into an asymmetric pattern or shape, usually in response to stimuli. It’s similar to how migrating birds break symmetry when they shift into a new formation in response to an environmental compass like sunlight or landmarks. On a microscopic level, immune cells sense chemical signals concentrated at an infection site and break symmetry to traverse a blood vessel wall to reach the infected tissue. As cells break symmetry, thThe cells undergo a transformation from being symmetrical to becoming polarized and asymmetrical, which allows them to move towards their target.
Shiva Razavi, Ph.D., who conducted the research as a graduate student at Johns Hopkins and is currently a postdoctoral fellow at Massachusetts Institute of Technology, emphasizes the importance of symmetry breaking in various fields such as biology, physics, and cosmology. “Understanding the mechanisms of symmetry breaking is crucial for gaining insights into biology and utilizing this knowledge for developing therapeutics,” says Razavi.
Researchers have been exploring ways to imitate and regulate symmetry breaking in artificial cells for a long time.The understanding of how cells can analyze their chemical environment and change their chemical makeup and structure is crucial. In a recent study, scientists created a large vesicle with a double-layered membrane, resembling a simplified synthetic cell or protocell. This protocell, also known as “the bubble,” is made of phospholipids, purified proteins, salts, and ATP for energy. During the experiments, the scientists were able to engineer the protocell to have the ability to sense chemicals, causing the cell to shift from a symmetrical sphere to an irregular shape. This system is essential for understanding how cells can respond to their environment.This cell-like structure is specifically designed to imitate the initial stage of an immune response. It has the ability to send signals to neutrophils, prompting them to attack germs based on the proteins they detect in their surroundings, according to the researchers.
Razavi explains, “Our research shows how a cell-like entity can detect the presence of an external chemical signal, replicating the conditions found in a living organism. By constructing a cell-like structure from the ground up, we can gain a better understanding of the essential components needed for a cell to break symmetry in its simplest form.”
The scientists believe that in the future, chemical sensing could be utilized for precise drug delivery within the body. “The concept is to encapsulate various substances such as protein, RNA, DNA, dyes, or small molecules into these bubbles. By using chemical sensing, the cell can be directed to a specific location, where it will burst and release a drug,” explained senior author Takanari Inoue, Ph.D., who is a professor of cell biology and the director of the Center for Cell Dynamics at Johns Hopkins Medicine.
To enable the vesicle to sense chemicals, researchers introduced two proteins, FKBP and FRB, inside the synthetic cell. These proteins act as molecular switches.
The scientists placed FKBP in the center of the cell, while FRB was placed on the membrane. When they added rapamycin outside of the cell, FKBP moved to the membrane to bind with FRB, causing actin polymerization, which reorganized the synthetic cell’s structure.
Inside the protocell, this chemical reaction resulted in a rod-like actin structure that exerted pressure on the cell membrane, causing it to bend.
To observe the protocell’s ability to sense chemicals, the researchers used confocal microscopy, a rapid 3D imaging technique. They had to capture images quickly, at a rate of one frame.The protocells responded quickly to the chemical signal, with a response time of 15 to 30 seconds. The researchers’ next goal is to give these synthetic cells the ability to move towards a specific target. Ultimately, the hope is to create synthetic cells that could be used for targeted drug delivery, environmental sensing, and other applications where precise movement and response to stimuli are important. Other scientists involved in this research include Bedri Abubaker-Sharif, Hideaki T. Matsubayashi, Hideki Nakamura, Nhung Thi Hong Nguyen, Douglas N. Robinson, and Pablo A. Iglesias from Johns Hopkins University.
The research team included Dr. Felix Wong from Massachusetts Institute of Technology and Dr. Baoyu Chen from Iowa State University.
Funding for the study was provided by the National Institutes of Health (5R01GM123130, R01GM136858, R35GM149329, R35GM128786, R01GM149073, R01GM66817 and S10OD016374), the Department of Defense Advanced Research Projects Agency (HR0011-16-C- 0139), the National Science Foundation, and the PRESTO program of the Japan Science and Technology Agency.
