Taking chances and making mistakes: non-genetic phenotypic heterogeneity and its consequences for surviving in dynamic environments

Abstract

Natural selection has shaped the strategies for survival and growth of microorganisms. The success of microorganisms depends not only on slow evolutionary tuning but also on the ability to adapt to unpredictable changes in their environment. In principle, adaptive strategies range from purely deterministic mechanisms to those that exploit the randomness intrinsic to many cellular and molecular processes. Depending on the environment and selective pressures, particular strategies can lie somewhere along this continuum. In recent years, non-genetic cell-to-cell differences have received a lot of attention, not least because of their potential impact on the ability of microbial populations to survive in dynamic environments. Using several examples, we describe the origins of spontaneous and induced mechanisms of phenotypic adaptation. We identify some of the commonalities of these examples and consider the potential role of chance and constraints in microbial phenotypic adaptation.

Keywords: bet-hedging; natural selection; nutrient transitions; phenotypic adaptation; phenotypic diversification.

Figure 1.

Conceptual framework for single-cell growth and phenotypic diversification upon a sudden nutrient transition in isogenic populations. During steady-state exponential growth of a population of isogenic cells, at constant environmental conditions, the total cell number increases exponentially. Individual cells progress asynchronously through their cell cycle. Cells vary in size, molecular composition and doubling time, due to inevitable stochastic effects, even those that are at the same cell-cycle progression and were born from the same mother [4,35,36]. When individual cells are suddenly confronted with a nutrient transition, not all of them have the capacity to adapt, even though they do have the metabolic machinery to grow on the new carbon source. This can lead to lag phases, temporary growth arrest [39] or maladapted states [7], and even the formation of persister cells in bacteria [11,40,41].

Figure 2.

The ability of individual cells to successfully transition from one nutrient state to another is dependent on population density. (a) The rate at which a nutrient such as glucose disappears from the environment is determined by the cell density. Shown are two scenarios, where a very dense (blue line) and a very sparse (red line) population consume a nutrient. In both cases, low nutrient levels are detected at some threshold concentration, at which point cells have to prepare for nutrient depletion. (b) The time needed to prepare for a new condition will differ for individual cells (this can be described by a distribution), depending on their exact state at the time a threshold signal is detected. If the nutrient abruptly runs out, as in the case of a very dense population, only a small fraction of cells will be prepared for the new condition. When the population density is low, the time window will be large and most cells will adapt in time.

Figure 3.

Overview of molecular and cellular stochastic processes. Numerous mechanisms contribute to the cell-to-cell variability of cellular characteristics during steady-state, exponential growth. (a) Molecule partitioning can be described by a simple model based on the ratio of daughter and mother volumes. Protein aggregation at the poles can lead to distinctive protein concentrations in daughter cells and determines pole age. (b) Gene expression consists of multiple stochastic processes. Transcription occurs in bursts and this noise can propagate to the protein level. Network motifs can further modulate the effect of noise. (c) Cell doubling, dilution by growth and cell cycle progression influence the physiological state of the cell. (d) The position of the gene on the chromosome and the number of chromosomes determine the level of gene dosage effects.

Figure 4.

The fitness advantage of spontaneous formation of persister cells during steady-state exponential growth. Persister cells can form spontaneously under constant conditions of steady-state exponential growth, conferring a fitness advantage when a sudden extinction-threatening condition occurs, such as an antibiotic [6,108]. Normally growing cells, or persisters that switch back to a growing state, will probably succumb to the effects of the antibiotic.