Wednesday, November 10, 2010

The War Against Bacteria

My department had a visiting speaker this week, Dr. Sean Moore from the University of Central Florida. It was a really interesting talk, and Dr. Moore had a unique perspective on the way we use antibiotics against bacteria.

As microbiologists, we spend a lot of time and energy trying to understand the mechanisms bacteria use to invade human cells and cause disease. The idea being that if we understand how and why it happens, we can interfere with the process or prevent it from happening. Bacteria have been around much, much longer than humans, though. They didn't develop these mechanisms in the hopes that a human-like host would come along so that they could use them to invade human cells. The bacteria are just trying to survive inside an especially hostile environment, using whatever molecular tools they happen to have. Most disease-causing bacteria in humans only cause disease when they recognize that they are in a hostile environment. If they are colonizing an animal host or living in dirt or water they are not producing the chemicals or activating the pathways that make humans sick. They are happier and healthier that way, too. Virulence takes energy away from things like obtaining nutrients and cell division.

It's easy to lose sight of the fact that bacteria are not sentient. We anthropomorphise them all the time, even in science. We say that they are attacking or killing us, but they aren't. They're just surviving. Most of the symptoms we experience while sick are actually caused by our immune system as it tries to destroy the invaders. In fact, we are host to about 100 bacteria for every human cell in our body. They live on our skin and in our intestines, and without them we would be screwed. If you've ever had intestinal problems or persistent sickness after being treated with a broad-spectrum antibiotic, that's why. You basically wiped out most of the bacteria living in you, creating a vacuum that was filled up pretty quickly with whatever new bacteria you happened to encounter...only these new bacteria weren't adjusted to the unique environment that was you, and your immune system wasn't familiar with them. Sure, sometimes these gut bacteria can go virulent and cause problems, but that usually only happens when something else is wrong already.

Dr. Moore asked what if, instead of using antibiotics to kill bacteria, we instead communicated with the invading cells and convinced them that there was no reason for them to be virulent? Bacteria interpret signals from their environment to determine which pathways to activate, when its safe to divide...their overall behavior in general, really. If some signaling pathway could be used to convince the bacteria that they are still growing in say, dirt instead of your intestine, then we may be able to save ourselves a good bit of trouble. Antibiotics are undeniably effective and absolutely should be used to treat infections, but bacteria are becoming resistant to them faster than we can make new ones. Eventually, it wont be a very viable strategy anymore.

The trick to developing antibiotics is specificity. Prokaryotes are very similar to eukaryotes in many ways, so identifying compounds that will kill bacterial cells without killing human cells is challenging. You have to identify things that are distinctly unique about bacteria, and disrupt them as much as possible. Penicillin for example works by blocking peptidoglycan cross-linking. Bacteria can't form cell walls, and they die. Eukaryotes don't make peptidoglycan, so it doesn't affect non-prokaryotic cells at all. It works pretty well, until the bacteria learn how to make B-lactamases that chew up the penicillin. Then we introduce B-lactamase inhibitors, and the arms race continues. Drug companies screen thousands of small molecules, trying to identify ones with antibiotic activity. The rest of them are dismissed. Signaling compounds for mediating virulence rather than killing bacteria could very well be among them, but we have no way to screen for that kind of effect...especially since we really have no idea what we would be looking for.

The science is interesting, but still extremely preliminary. It's basically an idea and some computer simulations at this point. What really boggled my mind was the difference in philosophy. Our response to bacteria is often very emotional. We want to destroy the little buggers. We want revenge because they made us sick, but that isn't a logical response. Wars end because people agree to stop fighting. What Dr. Moore is suggesting is a significant paradigm shift, which I think could open up a lot of new possibilities and avenues of research.

Friday, November 5, 2010

Building Bigger Bugs

Originally published here at Science In My Fiction.
Also picked up by io9!

Giant insects make great movie monsters. Everyone deals with bugs on a daily basis - usually by squishing or exterminating them. We all know what they look like and what they can do, and I think we're all a little bit terrified of what would happen if the insects of the world decided to take revenge on humanity. They outnumber us. They have built in pincers and fangs and wings and armor. They are proportionally stronger, faster, and tougher than humans. Really the only thing keeping them in check is their size. Take that limitation away, and they would overrun the world.

Insects haven't always been the tiny nuisances we're familiar with today, though. During the carboniferous period, the Meganeura dragonfly had a wingspan of 28 inches. The Arthropleura, a relative of the millipede, could grow over 8 feet long. It was the largest known land invertebrate of all time. A majority of insect diversity has escaped the fossil record because the exoskeleton is made of chitin, a material that simply doesn't preserve well.  Every insect during the carboniferous period wasn't a giant, but just imagine what else could have been wriggling around in a world with dragonflies the size of hawks and millipedes the size of boa constrictors! So why aren't there any super bugs nowadays? Why did they get smaller over time?

To answer that you have to understand how insects breathe. Mammals absorb oxygen through the lungs, which is then transported throughout the body via the circulatory system. In insects, the circulatory and respiratory systems are separate. Oxygen is delivered directly to the cells via a complex series of tubes called the tracheal system. The tubes allow gas exchange to occur between the cells and the air. Oxygen diffuses in, and carbon dioxide diffuses out. It's not really very efficient. The larger an insect is, the larger the tracheal system has to be to support respiration. Eventually you run out of room for other organs. How big an insect can grow is limited by its ability to breathe.

Ok, so maybe giant insects don't make such great movie monsters when you know they could never actually get that big without suffocating. So how were they able to get so large during the Carboniferous period? Well, for one thing the Earth was covered in vast, swampy forests at the time. That's actually where the time period gets its name, since the plant matter deposited then forms the majority of the planets' modern coal deposits. All of this plant life absorbed carbon dioxide from the atmosphere and produced oxygen. It is estimated that atmospheric oxygen levels in the Carboniferous period were as high as 35%, compared with 21% today. The most widely accepted theory is that with a higher oxygen concentration, the tracheal system was able to function more efficiently and insects were able to grow much larger.

Knowing that, the Mad Scientist in me wants nothing more than to get some atmospherically controlled tanks and breed me some giant spiders. It's fool proof, don't you see? If they ever escaped, they'd suffocate in normal atmosphere! No need to fear them turning against their creator or running amok in the nearest city. Spider silk, with its incredible tensile strength and flexibility, has been the Holy Grail of the textile industry for decades. Obviously the solution is just to build a bigger spider. Also, giant spiders are cool.

Unfortunately, it's been a long time since the Carboniferous period. A little something called evolution has been going on since then, and modern insects are adapted to a modern atmosphere. Researchers have examined the tracheal systems in insects of various sizes, and they have found that as insects increase in size the tracheal system also increases at a disproportionately higher rate.  Modern beetles, for example, can not grow larger than approximately six inches no matter how high the oxygen concentration is because the tracheal system still takes up too much room. In the Carboniferous period, the trachea were likely much narrower in diameter. With the higher oxygen concentration, the smaller tubes could have delivered enough oxygen to support larger insects.

Given enough time in a more oxygen-rich environment, you can bet that at least some insects would become super-sized. Unfortunately for me and my plans for world domination, it would happen on an evolutionary scale and not because some spiders were accidentally zapped with gamma radiation. Ah well, back to the drawing board.