Sunday, November 14, 2010

A potentially amazing idea.

I have been reading the book "Microcosm: E. coli and the New Science of Life" by Carl Zimmer. Already it has been an amazing read, I recommend it to anyone who wishes to garner a greater understanding of microbiology, micro-ecology, and molecular evolution. In one of the sections, Carl Zimmer explains the cycle of evolution that E. coli go through in certain situations. This is displayed rather dramatically when different strains of E. coli compete amongst one another for survival.

Each strain will often grow together as such communal behavior allows for greater survival of a strain. When a bacteria begins to act as a group instead of free roving individuals, they form what is known as a biofilm. Within this biofilm different individuals of the same strain might take over different roles. This is all done by chance, the random turning on and off of genes that occur naturally throughout a microbes life cycle. When a biofilm is threatened by a competing strain of E. coli, there is a chance for certain individuals in the group to sacrifice themselves for the greater good of the colony. They do this by producing a protein known as colicins. Colicins destroy bacteria in many ways. Some doe so by essentially destabilizing the cellular membrane so that all that is contained within can seep out, effectively shutting down the microbe. Others block protein formation while still others target the victims DNA While there are multiple forms of colicin, there is only one way to deliver the them in large numbers. Colicins are rather large by protein standards, as such when an individual E. coli begins to fill up with them, there is no easy way for them to escape. Normally they are produced in small numbers and are pushed out of the cell through certain channel proteins. But with such a large number of colicins, the bacterium gets far too full and lyses (explodes). The act of lyseing is not done by the pressure of the internal environment but by a specific suicide function of the bacterium.

Now you may be asking yourself, why don't the colicins released by the lysing E. coli also effect the neighboring members of the same strain and biofilm? The reason for this is that colicins are naturaly produced in small quantities by all E. coli in biofilms to begin with. To counteract this, they also produce an antitoxin that destroys the colicins before they do any damage. It also has to do with the fact that due to slight genetic differences within strains, the colicin proteins will be shaped slightly different. Each strain produces an antitoxin that is most effective against its own strain's colicins. But other strain's antitoxins won't be as efficient at disabling a sudden burst of foreign colicins and some will slip through the defenses to destroy the competitors.

Now when a certain biofilm is faced with such an attack, random mutations will cause a select few to produce more effective antitoxins. These random survivors will then propagate and begin to out compete the attacking colony. As evolution causes yet another shift of power and the attacking colony begins to shrink due to limited resources, there will often be a chance for a mutation for a yet more potent colicin.

This cycle would seem to be endless, but evolution favors the bold. At some point a random mutation may arise that causes a certain strain to only produce the currently strongest antitoxin, but none of the colicin. While this would, at first seem like an absurd tactic, it is one that works quite well over the long duration. The reason for this goes back to the size of colicins. Remember that colicins are naturlly large proteins to begin with. Any stronger variants of the colicin will be even larger still. It takes a lot of energy and resources to produce all that colicin as well as the antitoxin to protect against it. I'm sure you can now see why the seemingly useless mutation would actually be successful in such an environment. While its competitors are busy wasting all their energy on expensive colicins and antitoxins, this new strain can focus only on producing the strongest antitoxin and reproducing. Over time, it begins to out compete the strong colicin producers entirely.

But it doesn't end here, now that all the colicin producers have been killed off, the area is left clean for the original strain of E. coli to move in. The original strain isn't going about wasting any energy on excess colicins or antitoxins and it can quickly out compete the previous victors of the arms race. This leaves us back where we started. This cycle takes place consistently all the time. What started out as an arms race became a game of rock, paper scissors. Eventually, the cycle will continue on through another rotation.

Now that I have put forth all the background information, I would like to share an insight I had while reading this book. The idea of an evolutionary rock, paper, scissors game led me to a thought that left me rather excited. What if we apply this very same rule of evolution to our current problem of antibiotic resistant bacteria?

Antibiotics and antibiotic resistance work in quite the same way as the colicin antitoxin cycle work. Bacteria produce specific proteins that destroy or deactivate the antibiotics (which are often proteins in their own right). The only thing differentiating a resistant strain from a non-resistant strain is that the resistant strain is constantly pumping out these defensive proteins.

They evolved in much the same way as the antitoxin producing E. coli I mentioned earlier. They began as a normal strain that happened to have a random mutation that allowed for the production of the defensive protein. Over time, these resistant strains came up against more and more types of antibiotics. Each time, the arms race I mentioned earlier takes another step forward.

My idea is this, instead of fighting an arms race with these antibiotic resistant strains, why don't we simply use their own strategies against them? Just as the super antitoxin producers from earlier could out compete the strong colicin and antitoxin producers, so would a common strain out compete an antibacterial resistant strain. But we can do one better then blind evolution. If we were to introduce a strain that was not producing the antibiotic defense proteins but instead devoted all of its energy to reproduction, it would quickly out compete the resistant strain.

All one would have to do in the case of infection of an antibiotic resistant strain is to introduce a group of quickly dividing non-resistant bacterians to the site of the infection and soon the new strain will begin eating up all the resources that the slower resistant bacterians were using until there is nothing left but the non-resistant strain and possibly some mutations within the resistant strain which will have given up some of its defense protein production in favor of faster reproduction. Either way, within a few days you are left with an individual who is not a whole lot more ill then they began but now they are ill with bacterians that would respond to antibiotic treatments.

This kind of treatment would of course be a last resort, but it could very well be the answer to one of the most serious medical problems of our day. This concept would need thorough testing before it could ever be tried in a human patient, but with all that we are uncovering, I would not be surprised if this is the answer that so many have sought for.

Now because this solution is so elegantly simple, it is quite possible that I am not the first to stumble upon it, in fact I would be quite surprised if I was. If anyone has heard of such research, I would love to hear about it in the comments.



Carl Zimmer. (2008) Microcosm: E. coli and the New Science of Life. New York, United States: Pantheon Books.
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Infidel753 said...

Either way, within a few days you are left with an individual who is not a whole lot more ill then they began but now they are ill with bacterians that would respond to antibiotic treatments.

Interesting thought. I suspect, though, that the problem would lie in whether the non-resistant bacteria would compete the resistant ones into oblivion fast enough. Since the non-resistant bacteria don't actually kill the resistant ones, but just out-compete them for resources, it seems the resistant strain wouldn't completely disappear until the resources available for growth and multiplication had been exhausted -- that is, when the patient had died.

Interesting that bacteria within biofilms start to specialize into different roles despite being genetically identical. Perhaps the dawn of multi-cellular organisms with specialized cells happened like that in the distant past.

Cyc said...

If the two bacteria were competing in a vacuum, this problem might arise, but you must remember we are dealing with a whole ecosystem here, just this ecosystem happens to be you and me.

The antibiotic resistant bacteria would not just have to compete with the fast growing strain, but with the person's own immune system attacks, any attacks from other bacteria in the area (which, is very frequently, you would be surprised the constant wars that occur for space between different species and strains over any inch of tissue on or in you).

Taking this into consideration, the antibiotic resistant strain would fall to all sides, the out competing strain just speeding it up because it will take over the entire niche leaving the resistant strain no where else to go and not enough strength to invade another area.

A good analogy for this would be if a country had a civil war. The best example is actually the French Revolution. In this analogy the French monarchy represents the antibiotic resistant strain where as the revolutionaries represent our fast growing strain.

They both occupy the same space, consume the same resources, and have competing forces; they just have different ways of going about doing this. As we both know, the French revolutionaries were certainly more 'efficient'.

Where the analogy diverges is that in the case of the bacteria, we now introduce the antibiotics which will wipe out our Revolutionaries and thus avoid the whole trouble with the Jacobins and now we are left with a nice and human-free France...okay, it is not a perfect analogy, but I believe it works.