Noisy and Bistable Gene Expression: Hedging Your Bets

by Tim

This is Part 2 of a two part series. Part 1 can be found here.

Often times resistance to antibiotics has a genetic basis. That is, a bacteria encodes a protein that functions to export, degrade, or otherwise block the function of a given antibiotic compound. However in the last few years, the observation of non inherited antibiotic resistance has come into view. One of my favorite articles describing the phenomenon is one by Nathalie Balaban et al, in Science back in 2004, particularly due to her super cool use of microfluidics and single cell imaging.

Following treatment with an antibiotic, a bacterial population doesn't completely die off, but instead shows at first a drastic decrease in viable counts followed by a much slower rate of death. Those cells isolated at later time points are not resistant to the antibiotic, and when grown to full populations show the same sensitive phenotype. These cells are termed "persistors" and are a form of non-genetic resistance to antibiotic treatment.

Many of us know that some antibiotics require actively growing bacteria to be effective. Particularly, the use of the beta-lactams which are only effective when a cell is growing it's peptidoglycan, such as during replication. However, Balaban shows us that even in an actively growing population of identical cells in identical environments (microfluidic chambers), there is a very small subset of cells which are not growing. These cells aren't defective, but rather are in a paused growth cycle, allowing them to be resistant to ampicillin at that moment in time. When these cells restart their growth, their progeny are still sensitive. Again, a key point in demonstrating that this form of resistance is non heritable.

Very likely, genetic noise, as described previously, plays a role in determining the cell's fate. However, the more important point here (in my humble opinion) is that this is a beautiful example of a population that is "hedging its bets."

By having two sub populations: a majority that is actively growing, and a small percentage that is paused, that identical set of genes in both populations is capable of either 1) exploiting the current resources at the risk of antibiotic death or 2) taking a short pause in growth allowing antibiotic resistance at that time, at the risk of losing out on some resources. A risk, but with large rewards.

Each has their consequences, but together allow for a dynamic population without changes in genetic content (hence the non inherited resistance). Other great examples of bet-hedging include: sporulation and cannibalism in Bacillus, and the induction of inflammation by Salmonella.

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Source:
Nathalie Q. Balaban, Jack Merrin, Remy Chait, Lukasz Kowalik, Stanislas Leibler (2004). Bacterial Persistence as a Phenotypic Switch Science, 305 (5690), 1622-1625 : http://www.sciencemag.org/cgi/content/full/305/5690/1622

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Other Articles of Interest:
Noisy and Bistable Gene Expression: Why Genes and Environment Aren't Everything
Altruism in Bacteria: Allowing Yourself to Die for the Good of the Species
Antibiotic Treatment: Increasing the Rate of Genetic Exchange

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Personal Note:
Due to my ever-looming qualifying examination (April 30th), updates to The Times Microbial may be rarer than usual this semester. I hope to get back to full swing, perhaps with some surprises, this Spring.