Evolution Under Intrinsic Control

The appearance of antibiotic resistant bacteria has long been used as a classic example of Darwinian evolution in action. The general story works like this: take any population and there will be a certain amount of accumulated genetic variability as a consequence of a steady stream of random mutations. When the antibiotic is supplied, it interferes with some aspect of cell biology (cell wall synthesis, translation, transcription, etc.) Those few members of the population that just happen to possess a variation that makes them immune to the action of the antibiotic will survive and be favored by selection. Or at the very least, while the bacteria are exposed to the antibiotic, every new mutation that just happens to occur will become another opportunity to escape the insult.

A study by Floyd Romesberg and colleagues [1] has thrown a new and subtle twist into the story. The twist is this: in this case, mutations don’t “just happen” – bacteria make sure they happen. That is, the evolution of antibiotic resistance is not simply the passive process of selection screening through the available variability. On the contrary, bacteria respond to the insult by making sure there is a plentiful source of variability to screen.

In this study, it was determined that bacterial input was essential to the evolution of antibiotic resistance. In other words, the cellular process of “making sure there is a plentiful source of variability to screen” is exactly what is needed to evolve antibiotic resistance.

The researchers tested two antibiotics: ciprofloxacin, which targets the gyrase and topoisomerase (proteins involved in untangling DNA) and rifampicin, which targets the bacterial RNA polymerase. They found that after 72 hours of continual exposure to ciproflaxin, 3% of the recovered bacteria had acquired resistance to the antibiotic. With 72 hours of exposure to rifampicin, 100% of the bacteria were resistant. However, when they similarly tested a strain that lacked LexA, no antibiotic resistance has found. This led them to conclude “that LexA cleavage is absolutely required for the evolution of resistance to both ciprofloxacin and rifampicin during therapy in vivo.”

So what’s the deal with LexA? LexA is a DNA binding protein that normally represses the activity of over 20 different genes. When the DNA is damaged by a chemical or physical agent, it is often detected by a tread-milling protein cylinder that forms around the DNA known as RecA. Once the cylinder is formed, it interacts with LexA and causes it to split apart, releasing it from the DNA, thus releasing the repression. The various genes that are now expressed at much higher levels are involved in DNA repair and recombination. There is a certain hierarchy of expression, as explained in the press release associated with the study [1]:


In other words, LexA normally suppresses an “emergency repair kit” known as the SOS response. Yet as Andrei Kuzminov, of the Institute of Molecular Biology at the University of Oregon, explains:

The SOS response is by no means a desperate attempt to stay alive, as its name inaccurately implies, but, rather, an orderly and measured reaction of the cell to DNA synthesis inhibition. [2]

The mutators are actually error-prone DNA polymerases – Pol II, Pol IV, and PolV. And all three of the polymerases were needed to supply antibiotic resistance.

The researchers note:


Teleological Implications

This study does not in any way indicate a fundamental flaw in Darwin’s Theory. Nor does it demonstrate that bacteria can target the specific genes needed to survive the environmental insult. What it does do is help us understand that life takes control of its fate. Living things are not passive participants of the interplay between stochastic events and environmental pressures, where mutations that just happened to exist are favored in an environment that just happened to exist. Instead, environmental challenges are met with a truly biotic response. First, the cells try to repair themselves. But if this fails, then they seek out an adaptation by maximizing their chances of finding an adaptation. Evolution is, at least, partially controlled by properties intrinsic to life.

While the teleological echo is faint, it is nevertheless there. We can begin to catch a glimpse of evolution as homeostasis. The integrity of the genome is threatened. Standard small scale feedback responses ensue as the cell attempts to reverse the change through repair and recombination mechanisms. But if the insult is too severe or too common, the next level of feedback response is…..evolution itself. The antibiotic is the stress that perturbs the homeostasis of the cells and evolution is the effector that reverses the effects of the change. Life fights back.

A good designer will turn a problem into an opportunity. In this case, mutations are commonly viewed as “mistakes,” explaining why so much machinery is devoted to proof-reading and repair. But at some point, a phase shift occurs, where the mistakes becomes the solution, as they provide the response to a population threatened with extinction. Life is programmed to survive.

That evolution may be under some form of intrinsic control is only a piece of the teleological puzzle. But it is a significant piece, in that the ability to adapt, at least to these two antibiotics, is under control. So much so, that removal of a control gene (LexA) robs the cells of their ability to adapt. If the mere ability to adapt can be placed under control, one wonders what other aspects of adaptation can likewise be influenced by life itself.

Finally, the researchers raise an intriguing speculation.

The key signal that links the cellular response to the antibiotic with the evolution of resistance appears to be the RecA-ssDNA filaments that are formed to facilitate the repair of antibiotic-mediated DNA damage. These RecA-ssDNAfilaments also induce LexA cleavage and derepression of the mutagenic polymerases. We suggest that a similar mechanism might also serve to induce mutation and evolution in response to other antibiotics, or other forms of cellular stress, where DNA damage per se is not involved. For example, the ratio of ATP to ADP determines the level of supercoiling in the bacterial genome, and both increased and decreased levels of supercoiling inhibit replication fork progression . Thus, different stresses that perturb metabolism (i.e., alter ATP/ADP ratios) might also alter DNA topology and result in stalled replisomes; recombination-based rescue and RecA-ssDNA filament formation; and the induction of mutations required to reestablish a normal cellular environment. Interestingly, it has recently been shown that beta-lactams can induce the SOS response via a two component signal transduction system .

Not only does this speak to the importance of structure/form, but it again raises the theme of homeostasis – DNA may be more than a repository of sequence – it may be plugged into an elaborate system that allows it act as sensor for its own continued perpetuation.


1. A nice summary of the study can be found here and the actual study can be obtained here .

2. Kuzminov, A. 1999. Recombination repair of DNA damage in Escherichia coli and bacteriophage ?. Micro and Mol Bio Rev 63: 751-813.

6 responses to “Evolution Under Intrinsic Control

  1. Dr Spetner, in “Not By Chance”, calls this type of thing a “built-in response to environmental cues”.

    If you haven’t read the book you should.

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  4. I have some serious semantic issues here which are leaving me very confused.

    My understanding: “adaptation” is the mechanism by which everything biological changes in response to its environment over instances of a given reproducing (and dying) “kind”. It was well understood, and completely reduced to every-day practice–down on the farm–thousands of years ago.

    On the other hand, adaptation is related to evolution because it is the thing Darwin (“origin”ally Wallace) claims is a primary factor which LEADS TO: “Evolution”. I base this understanding of the semantics entirely on my own inference about the title of Darwin’s book “…on the ORIGIN OF SPECIES…”.

    It is VERY likely I’m just missing something here, but aren’t we conflating the following two concepts:

    1. Evolution (entirely new species comprising al the known species, evolving BY WAY OF adaptation), with

    2. adaptation (changes in a population of a given species based on environmental advantages and disadvantages of specific variations amongst reproducing individual instances, which –over time– produce variations more suited to the current environmental conditions)

    ? I hope that’s readable, but I have my doubts.


  5. Hi Stosh,

    Yeah, it’s probably a good idea to remember the two are not the same. You can have evolution without adaptation (genetic drift) and you can have adaptation without evolution (ie., our skeletal-muscular system adapts to the level of stress we place on it).

  6. Hi Micheal,

    Thanks for trying to help me with this. I’m still very unclear on it. I realize that this is only peripheraly on-topic, but I am really concerned here about getting the wording of this thing more precise.

    Attempting to get this from other sources tends to get you caught up in the religious dogma, and personality-cults (e.g., there are 26 different qualifiers for speciation, none of which actually admit the intuitively obvious case).

    Based on your examples, I infer that (for you at least) “evolution” is: anything that alters the structure of the kind over successive generations. You gave building muscles as an example of adaptation, and genetic drift as an example of evolution. My current understanding of the term, would consider both of these to be a form of adaptation, and neither a form of “Darwinian evolution”.

    My problem–specifically– is, what you are calling “evolution” is really just selective (via generational birth and death) adaptation. This definition is not really different from breeding dogs, or dairy cows, except that one is directed by an intelligent agent, while the other is directed by naturally occurring environmental cues). It is also no different than what goes on in a human brain over populations of individual neuron cells, during the first few weeks of life.

    My understanding (which I am seeking to have corrected if need be) is that Darwinian evolution is NOT the above process, even though the above process occurs over generations in a selective fashion, and alters the genetics of a given species (“kind”). The above process –whether we are talking about a population of single cells, organisms, or even molecular changes at the synapses of neurons– is what I would call adaptation. Perhaps I’d say: “selective adaptation” if I needed more specificity in terminology.

    Instead, “Darwinian Evolution” (as I currently understand it) is the notion that the adaptive selective process described above is the primary factor that LEADS TO the genesis of entirely NEW species comprising ALL of the species in existence (i.e., whatever is the most intuitively convincing of the 26 available qualifiers for speciation: “BSC”?).

    Me: Up until recently I have been buying into the well-poisoning strategy that equated ID with young earth creationism.

    These days, since seeing the animations that are directly based on models of molecular machines, I’m much more inclined to the ID position. Or perhaps a hybrid, as you have been espousing.

    Which gets me back to at least being within the vicinity of your above topic: 🙂

    A very clear analogy to your hybrid idea (if I understand what you mean by “front-loading”) can be seen within today’s relatively crude design and construction techniques, in which sometimes things are designed for manufacture by manually arranging, or setting up the components in such a way that they will go through an inevitable causal chain-reaction, which transforms them, and produces the final product.

    Another decent analogy (though not perfect) of this might be the way an arch is constructed. It is held up with scaffolds while being constructed, with the a priori understanding that a keystone, once placed at a later time, will eliminate the need for the scaffolding.

    Notice that both of these examples have a hybrid of design and evolution, where the evolutionary phase is actually a pre-specified PART of the initial design.

    This combines hands and mind (a more recent post of yours) in that, it is the essence of design. You begin to build based on a prior understanding of what the finished product is “supposed” to look like; the blueprint.


    Thank you for your patience. As a programmer, I really have an OCD need to get the descriptive language distilled down to non-ambiguous definitions.

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