How is the frequency of E. coli mutants relevant to the economy?

A recently published paper entitled “Competition for nutritional resources masks the true frequency of bacterial mutants” describes the results of a research conducted by my group at the Laboratory of Bacterial Genetics about the curious phenomenon of hidden mutants in a bacterial population. We have been puzzled by the low frequency of mutants in the bacterial cultures and cracked our heads to understand the mystery. Eventually the riddle was solved and its solution was connected to competition, game theory and surprisingly to cooperation and production.

First, a brief introduction about bacterial nutrition, genetics and evolution is required:

Escherichia coli is a bacterial species that inhabits the digestive tract of mammals, birds and reptiles, but can also be found in soil and water bodies. Bacteria are single cell organisms that interact directly with their environment, meaning that they must obtain all the nutrients required for their survival and growth from their surroundings. The most important nutrient for bacteria and alas for all living beings are high-energy organic molecules, such as carbohydrates. Glycerol is a simple carbohydrate that can be readily taken up by E. coli and used as a nutritional source. However, glycerol-2-phosphate (G2P), a glycerol derivative that can also be found in nature, cannot be transported into the bacterial cell as easily as glycerol. For that reason, E. coli bacteria cannot readily utilize G2P as a nutrient source.

All living beings evolve through the emergence and selection of mutations. Mutations are rare events that occur spontaneously during DNA replication. The frequency of mutations can increase in the presence of mutagenic agents such as ultraviolet light, certain chemicals present in cigarettes and some viruses. Most mutations are harmful, but some could be beneficial to the organism, especially under certain environmental conditions.

Indeed, a mutation that enables E. coli to use G2P as a nutrient source would be very handy in case it encounters an environment containing plenty of this carbohydrate. These mutations result in the emergence of a special kind of mutant bacteria, called “PHO constitutive mutants” (PCMs), which arise in a population of wild-type E. coli cells at a frequency of 5 x 10-5 (=1 mutant per 20,000 bacteria). PCMs produce high amounts of alkaline phosphatase (AP), an enzyme (also present in humans) that is required to break G2P into glycerol + phosphate molecules. Glycerol is then able to enter the cell and is used by the bacterium as an energy source. However, because AP acts in the periplasm, a structure that is located outside the cell inner membrane (see Figure below), most of the glycerol produced by the PCMs leaks out and is captured by the overwhelming majority of wild-type bacteria surrounding the PCM. The neighboring wild-type cells do not engage in mass production of alkaline phosphatase and therefore do not break G2P into glycerol themselves. All they do is consume the glycerol released by the hard-working few PCMs. Remember that for every PCM there are on average 20,000 wild-type cells!

Imagine a world in which a minority of industrialists is being exploited by a majority of hitchhikers that do not contribute to the wealth of the society. These entrepreneurs are the ones that actually sustain the country’s economy and its people. But what happens when the number of producers is so low relative to the number of non-producers and the production of goods is not sufficient to support the entire population? Can the producers endure? Can the population survive?

When the amount of glycerol produced by the PCMs is not enough to provide for them and the surrounding bacteria, the entire population collapses. This situation is similar to the “tragedy of the commons”, an ecological quagmire in which the exploitation of natural resources is so high that the living beings competing for these resources eventually go to extinction. Everybody loses! The difference between the classical tragedy of the commons and the PCMs’ predicament is that in the former we have two or more individuals competing for a finite resource until the resource is depleted, while in the case of PCMs, the problem is not the finitude of resources, but the sheer exploitation of the glycerol producers. The lone PCM is akin to a solitary entrepreneur, which is eventually defeated by the overwhelming majority of leeches.

However, the results from our experiments show that a few PCMs do manage to grow despite being surrounded by the opportunist bacteria. The lucky ones are PCM cells that repose next to each other and exchange glycerol primarily among themselves (see the Figure below). Further experiments and a mathematical model (in the paper’s appendix) showed that there is another way around this impasse: by increasing the proportion of PCMs in the population from 1:20,000 to 1:100 the now not so tiny minority of PCMs manage to produce enough glycerol for them and for the general population. The lesson we can learn from the PCM’s predicament is that a society that does not allow its producers to thrive and grow is condemned to extinction. However, economic growth by means of investment in production and cooperation is the best way to provide for all in the world of humans and bacteria alike.


Schematic representation of E. coli cells sharing/competing for glycerol. Bacteria were plated on a Petri-dish containing G2P as the sole carbon source. PCMs (in blue) produce huge amounts of AP that breaks G2P into glycerol. Glycerol leaches out and is taken up either by another PCM (in blue) or by a wild-type bacterium (in black).

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