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Cells interact as dynamically evolving ecosystems. While recent single-cell and spatial multi-omics technologies quantify individual cell characteristics, predicting their evolution requires mathematical modeling. We propose a conceptual framework—a cell behavior hypothesis grammar—that uses natural language statements (cell rules) to create mathematical models. This enables systematic integration of biological knowledge and multi-omics data to generate in silico models, enabling virtual “thought experiments” that test and expand our understanding of multicellular systems and generate new testable hypotheses. This paper motivates and describes the grammar, offers a reference implementation, and demonstrates its use in developing both de novo mechanistic models and those informed by multi-omics data. We show its potential through examples in cancer and its broader applicability in simulating brain development. This approach bridges biological, clinical, and systems biology research for mathematical modeling at scale, allowing the community to predict emergent multicellular behavior. 

The Ras family of proteins play an important role in relaying signals from the outside to the inside of the cell. Ras proteins are attached by a fatty tail to the inner surface of the cell membrane. When activated they transmit a burst of signal that controls critical behaviors like growth, survival and movement. It has been suggested that to prevent these signals from being accidently activated, Ras molecules must group together at specialized sites within the membrane before passing on their message. However, visualizing how Ras molecules cluster together at these domains has thus far been challenging. As a result, little is known about where these sites are located and how Ras molecules come to a stop at these domains. Now, Lee et al. have combined two microscopy techniques called ‘single-particle tracking’ and ‘photoactivated localization microscopy' to track how individual molecules of activated Ras move in human cells grown in the lab. This revealed that Ras molecules quickly diffuse along the inside of the membrane until they arrive at certain locations that cause them to halt. However, computer models consisting of just the ‘fast’ and ‘immobile’ state could not correctly re-capture the way Ras molecules moved along the membrane. Lee et al. found that for these models to mimic the movement of Ras, a third ‘intermediate’ state of Ras mobility needed to be included. To investigate this further, Lee et al. created a fluorescent map that overlaid all the individual paths taken by each Ras molecule. The map showed regions in the membrane where the Ras molecules had stopped and possibly clustered together. Each of these ‘immobilization domains’ were then surrounded by an ‘intermediate domain’ where Ras molecules had begun to slow down their movement. Although the intermediate domains did not last long, they seemed to guide Ras molecules into the immobilization domains where they could cluster together with other molecules. From there, the cell constantly removed Ras molecules from these membrane domains and returned them back to their ‘fast’ diffusing state. Mutations in Ras proteins occur in around a third of all cancers, so a better understanding of their dynamics could help with future drug discovery. The methods used here could also be used to investigate the movement of other signaling molecules. 

Round spheres, straight rods, and twisting corkscrews, bacteria come in many different shapes. The shape of bacteria is dictated by their cell wall, the strong outer barrier of the cell. As bacteria grow and multiply, they must add to their cell wall while keeping the same basic shape. The cells walls are made from long chain-like molecules via processes that are guided by protein scaffolds within the cell. Many common antibiotics, including penicillin, stop bacterial infections by interrupting the growth of cell walls. Helicobacter pylori is a common bacterium that lives in the gut and, after many years, can cause stomach ulcers and stomach cancer. H. pylori are shaped in a twisting helix, much like a corkscrew. This shape helps H. pylori to take hold and colonize the stomach. It remains unclear how H. pylori creates and maintains its helical shape. The helix is much more curved than other bacteria, and H. pylori does not have the same helpful proteins that other curved bacteria do. If H. pylori grows asymmetrically, adding more material to the cell wall on its long outer side to create a twisting helix, what controls the process? To find out, Taylor et al. grew H. pylori cells and watched how the cell walls took shape. First, a fluorescent dye was attached to the building blocks of the cell wall or to underlying proteins that were thought to help direct its growth. The cells were then imaged in 3D, and images from hundreds of cells were reconstructed to analyze the growth patterns of the bacteria’s cell wall. A protein called CcmA was found most often on the long side of the twisting H. pylori. When the CcmA protein was isolated in a dish, it spontaneously formed sheets and helical bundles, confirming its role as a structural scaffold for the cell wall. When CcmA was absent from the cell of H. pylori, Taylor et al. observed that the pattern of cell growth changed substantially. This work identifies a key component directing the growth of the cell wall of H. pylori and therefore, a new target for antibiotics. Its helical shape is essential for H. pylori to infect the gut, so blocking the action of the CcmA protein may interrupt cell wall growth and prevent stomach infections.