Does life use random number generators?

Molecular noise is widespread in living cells, but do cells ever exploit these fluctuations to achieve complex tasks?

Many sophisticated computer programs use random number generators to help solve challenging problems. These problems range from achieving secure communication across the Internet to deciding how best to invest in the stock market. Much research in recent years has found that randomness is also widespread in living cells, where it is often called “noise”. For example, the activity of some genes is so unpredictable to the extent that it appears random. Yet, relatively little is known about how such gene-expression noise propagates up to change how the cell behaves. Many open questions also remain about how cells might exploit these or other fluctuations to achieve complex tasks, like people use random number generators.

Bacteria perform a number of complex tasks. Some bacteria will swim toward chemicals that suggest a potential reward, such as food. Yet they swim away from chemicals that could lead them to harm. This ability is called chemotaxis and it relies on a network of interacting enzymes and other proteins that coordinates a bacterium’s movements with the input from its senses.

Keegstra et al. set out to find sources of noise that might act as random number generators and help the bacterium E. coli to best perform chemotaxis. An improved version of a technique called in vivo Förster resonance energy transfer (or in vivo FRET for short) was used to give a detectable signal when two proteins involved in the chemotaxis network interacted inside a single bacterium. The experiments showed that this protein network amplifies gene-expression noise for some genes while lessening it for others. In addition, the interactions between proteins encoded by genes acted as an extra source of noise, even when gene-expression noise was eliminated.

Keegstra et al. found that the amount of signaling within the chemotaxis network, as measured by in vivo FRET, varied wildly over time. This revealed two sources of noise at the level of protein signaling. One was due to randomness in the activity of the enzymes involved in tuning the cell’s sensitivity to changes in its environment. The other was due to protein interactions within a large complex that acts as the cell’s sensor. Unexpectedly, this second source of noise under some conditions could be so strong that it flipped the output of the cell’s signaling network back and forth between just two states: “on” and “off”.

Together these findings uncover how signaling networks can not only amplify or lessen gene-expression noise, but can themselves become a source of random events. The new knowledge of how such random events interact with a complex trait in a living cell — namely chemotaxis — could aid future antimicrobial strategies, because many bacteria use chemotaxis to help them establish infections. More generally, the new insights about noise in protein networks could help engineers seeking to build synthetic biochemical networks or produce useful compounds in living cells.

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