Single cells are more intelligent than scientists previously thought

To break up or not? Individual cells make their decisions much more autonomously than previously thought.

Cells make choices based not only on external signals such as growth factors, but also on information received from inside the cell.

Every day people make choices for themselves. To ensure that a decision is made that is appropriate for the situation, these decisions often involve combining a set of contextual cues. Our senses provide us with the abundance of knowledge we need to make decisions. They pick up certain details about our surroundings, such as visual and auditory information, which our brain combines to build a holistic perception. This is known as multisensory or multimodal perception.

Cells take their own state into account when making choices

Individual cells are no different from human cells in this respect. They are constantly making critical decisions, such as whether or not to break up. That’s why researchers at the University of Zurich (UZH) extended the concept of contextual, multimodal perception found in humans to single cells. Surprisingly, scientists have found that individual cells make decisions much more autonomously than previously thought.

“Adequate decision-making by individual cells uses multimodal perception, which allows cells to integrate external signals such as growth factors with information from inside the cell, such as the number of cell organelles,” says Lucas Pelkmans. Pelkmans is a professor in the Department of Molecular Life Sciences at UZH.

Sometimes such internal signals can override external stimuli: for example, in tumors, where the actual state of certain cells overrides treatment with antiproliferative drugs, thus making them resistant to treatment. “Such drug resistance is a major problem in the fight against cancer. The solution may come from taking into account the contextual cues that individual cells experience and ultimately changing them,” says Pelkmans.

Simultaneous analysis of tens of proteins in millions of cells

To test whether cells make decisions based on contextual, multimodal perception, as humans do, the scientists had to simultaneously measure the activity of multiple signaling nodes—the cell’s external sensors—as well as several potential signals from inside the cell, such as the local environment and the number of cellular organelles . Everything had to be analyzed in individual cells and in millions of cells. “To do this, we used ‘4i’, a method developed at UZH that allows us to simultaneously visualize and quantify up to 80 different proteins and protein modifications in single cells using fluorescence microscopy,” states Bernhard Kramer, first author of research.

The researchers found that variability in the activities of individual sensors in cells is closely related to variations in internal cues. For example, the abundance of mitochondria, the powerhouses of cells, fundamentally affects how an external stimulus is perceived by an individual cell. In addition, each sensor integrates different cues from inside the cell. When the researchers assessed an important decision of a single cell—namely, to proliferate or remain quiescent in the face of a growth stimulus—they found that the cell’s choice was mediated by the perception of multiple sensors and was predictably modulated by cues of the cell’s internal state.

Cells make intelligent decisions

“For any particular cell solution, all external cues and internal cues must be considered together. In this way, single cells are able to make adequate context-dependent decisions – and are therefore clearly smarter than previously thought,” says Dr. candidate Kramer.

Reference: “Multimodal perception links cellular state to decision making in single cells” by Bernhard A. Kramer, Jacobo Sarabia del Castillo, and Lucas Pelkmans, 14 Jul 2022, Science.
DOI: 10.1126/science.abf4062

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