To signal a conjunction of many inputs negative regulation is likely

Cells make many transitions from an old to a new phase of activity - between inactive and active states of an enzyme, or between phases of the cell cycle. If a cell is to survive, molecular prerequisites for functioning in the new phase should be available before a transition occurs. The cell's survival is more likely if a regulatory network gates the transition, preventing its occurrence until the prerequisites are available. Suppose a specific conjunction of inputs is required for a network, from which a single output governs the transition. Then we suggest that cells are likely to use negative regulation - a gating network based on a logical disjunction of signals for the absence of prerequisites - rather than positive regulation - a logical conjunction of signals for their presence. That is, if a logical conjunction of n prerequisites A1 AND A2 AND …AND An is needed in the new phase, a negative regulatory network is likely to enforce the corresponding logical disjunction, NOT (NOT A1 OR NOT A2 OR …OR NOT An). Five examples illustrate this conclusion. Arguments based on performance criteria support the hypothesis: negative regulation is more economical than positive regulation, because networks for computing OR can use fewer and simpler parts than those for computing AND. Negative regulation can increase reliability, because a mechanism that uses fewer, simpler parts is less likely to fail. And, a negative regulatory network can be more robust - less susceptible to errors resulting from noisy input.