How bacteria die - SGM series

This is the second post of my SGM conference series and the topic is Microbial Death. I was very interested in this one as a topic, because the mechanisms that lead to bacterial death aren't something I've covered so much. It's generally assumed that antibiotics screw up whatever they target such that the bacteria can no longer survive, and when they aren't around the bacteria just keep dividing.

There were two talks concerning antibiotics in bacterial death, the first addressing a theory that's been bandied about for a while (and which I've already written about) that antibiotics don't really kill the cell by acting on their target. Instead, they just lead to sufficient damage to set off a series of death events within the bacteria themselves, a common pathway for bacterial cell destruction (first reference).

I think if I could have chosen any one talk to watch it would have been that talk, actually given by Kohanski whose been working on the stuff. I think there would have been some interesting questions as well, as this is somewhat controversial research.

The other antibiotics talk covered something I'd never heard about; the ability of some antibiotics in certain cases to prevent bacterial death. Work done on Microbacterium turberculosis - which causes TB and a related strain (Microbacterium bovis) showed that when in stationary phase (i.e the bacteria were not growing and dividing) the addition of antibiotics that usually kill only growing cells helped to aid cell survival. Antibiotics that targeted both growing and non growing cells did not have this effect. The reason for this is not clear, however comparing transcriptomes between cells both with and without antibiotics showed a difference in protein production on addition of antibiotics. These antibiotics are in someway helping to turn on genes for survival, which are keeping the stationary phase bacteria alive.

Another interesting talk was about the regulation of mutagenesis in bacteria, another idea I love. It's based on the observation that as bacteria start to get stressed they go into a sort of massive meltdown, leading to lots of genetic mutations being generated. It's been suggested that rather than this being a side-effect of the surrounding stress, this is actually a deliberate ploy by the bacteria to give themselves a last ditch attempt at getting out of a stressful situation.

Unlike multicellular organisms, bacteria have no surrounding restraints on their mutation rate - with the exception of bacteria in aggregates the only thing a bacteria will harm by changing it's DNA is itself. This gives bacteria a lot more genetic plasticity. Added to this, changing DNA is one of the main ways bacteria go about improving themselves, and adapting to new conditions. Changing the DNA by wholescale random mutagenesis is a bit extreme, but if you're in a stressful situation anyway it might be worth a shot.

Studies for this have mostly been done on E. coli, usually a lab strain, so I'm not sure how much they translate into bacteria in the wild, which might be better adapted at coping with stress situations, or, given that experimental bacteria are in a privileged nutritional environment, it might just be too risky for wild bacteria to start messing around with their genome. Also there's no concrete mechanism been found for it yet, so increased mutagenesis producing different phenotypes in times of stress may just be a happy byproduct of the usual genetic craziness that goes on when a cell dies.

These two theories both don't have as much supporting science as they could do, but they are new ideas which are still being worked on, and I really like them both.

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Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, & Collins JJ (2007). A common mechanism of cellular death induced by bactericidal antibiotics. Cell, 130 (5), 797-810 PMID: 17803904

Ivana Bjedov, Olivier Tenaillon, Bénédicte Gérard, Valeria Souza, Erick Denamur, Miroslav Radman, François Taddei, Ivan Matic (2003). Stress-Induced Mutagenesis in Bacteria Science, 1404-1409 DOI: 10.1126/science.1082240

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The Importance of Fairy Stories

I was reading around the posts at ScienceBlogs, when I came across this one by Bioephemera which, while talking about a recent google-doodle took a quick jokey look at the respective merits of Hans Christian Ørsted and Hans Christian Andersen. The following quote from The Guardian about the issue was produced: "while there's nothing wrong with fairy stories, they haven't contributed much to the development of electric motors."

I couldn't resist it. Put "Discuss" on the end and it's practically an HPS (history and philosophy of science) essay. (I won't answer it in essay form, because I haven't got the time to plan out a nice long essay right now, but I will damn well be discussing it)

"While there's nothing wrong with fairy stories, they haven't contributed much to the development of electric motors." Discuss.

My main problem with this statement is that it seems to see science (and technological development, which I am lumping in the same field here) as an isolated process, remote and aloof from the rest of human life and development. Science, according to the guardian, progresses by scientific-minded people doing scientifically relating things and coming up with greater and better ways of achieving useful things, such as the electric motor. These scientists would be important and serious men (well...lets face it they probably were thinking of men) working away through detailed experimentation on serious topics, a far distance away from the whimsical and childish world of little stories.

Scientists, whatever Hollywood tries to insist, are people too. They grow up as children, hearing the same stories and tales and getting the same cultural and emotional baggage from the society around them. And science itself develops within that society, affected by it, changed by it and to a certain extent controlled by it as well. Ørsted grew up listening to the same kind of stories as Anderson, the only difference was that he didn't write them down.

In fact Hans Christian Andersen and fairy stories is a particularly bad example of things-that-do-not-affect-science, because Anderson wasn't just making these stories up. He was taking stories that were already being told. Folk-tales rather than fairy-tales, and folk-tales are crucial to human development. In a way, they are cultural development, especially in small communities where not very much writing occurs. They're how you teach your children, how you pass messages across, how you define what is acceptable and what isn't. How, in fact, you lay down the very rules and laws by which your society develops by, rules from which science is not exempt.

A few hundred years ago we had the Magician's Apprentice, adapted from a fairy-tale that makes it clear what happens if you mess with things you don't understand. The Victorian era brought forth the gothic novel Frankenstein, with a fairly similar message (among others). And now, in England, people protest against GM crops, for pretty much the same reason. I'm pretty sure there was at least one headline with the words "Frankenstein Fruit" in it. People have the stories in their heads, and stories are very powerful things to get rid of.

They told me when I was writing up my presentation for my project "make it a story". People understand stories, they understand things through stories. They develop, change, and form cultures, mostly based around stories. And science cannot be separated from the culture that surrounds it. Nor can it even remain strictly "scientific". Kekulé 'discovered' the ring structure of benzene after falling asleep and dreaming about a snake eating it's own tail. Science progresses through humans and humans progress through stories.

And, well, there's a reason the 'geeky-scientist' exists as a stereotype. We *like* fantasy, and science fiction, and other stories of other worlds. If you bring a child up telling them stories of fantastic places, and then bring them up slightly further by showing them the inside of a cell, they'll be hooked. It's a magical place, with magical rules, where everything moves and acts differently and, best of all, it really exists and you can get paid for exploring it.

On the face of it science may seem a long way from 'The Princess and the Pea' (although maybe not too far away from 'The Emperor's New Clothes'...) But these are the stories that western scientists and western science have grown up on, taking them, using them, being influenced by them. Without the stories, without the cultural background and development, the electric motor would have been a lot longer in arriving, and the rest of science would have been far, far slower. You cannot separate development into "that achieved by surrounding culture" and "that achieved by scientific and technological development", they're all far too tangled up in each other for that too be possible.

[There's even a book about physics and philosophy called 'The Emperor's New Mind'. You can't take the stories out of people.]

They are talking to each other!

In my various readings and travelings through the complex and confusing world that is science, I have a tendency to pick up 'pet theories'. Theories that I think are so wonderful and fantastic and explanatory, and that make a lot of things that I'm doing make sense. I've never made any up myself (technically they are 'pet hypothesis' actually thinking about it) but I do steal other peoples.

My latest little pet comes from a series of papers written by Julian Davis; which look at the effects of low antibiotic concentrations on bacteria. Because antibiotics do exist in the wild, just in far lower quantities than are used in hospitals. The big question for a while has been what do they do in the wild. The common idea was that they were used for defense purposes, but they're usually released at quite low concentrations, only a few of them actually lead to death, and even then under very specific conditions.

[as an aside, Alexander Flemming (of penicillin fame) was very lucky to get the visual effect that he did. If the room had been slightly colder, or warmer, it wouldn't have worked. Naturally produced antibiotics at naturally produced concentrations are pretty rubbish when it comes to killing things]

So Davis's idea, which is an AMAZING idea, is that the antibiotics are used as signalling molecules. They are quite small molecules, which can diffuse relatively easily into the bacteria, and once inside they can effect which proteins the bacteria express. Take a look at the picture to the right (taken from this paper):
The little disks contain antibiotics, at low concentrations (known as sub-inhibitory concentrations because they don't inhibit growth). The colourful image on the right shows different levels of reporter protein. The antibiotics are effecting the level of protein expressed. If they can do it for a reporter protein, they can do it for other proteins in the cell. Antibiotic signalling could be a way for bacteria to find out and communicate information about their immediate environment, both within and between species.

Which is why the last week, back when I was still doing my project, my supervisor pulled our crazy-result plates out of the incubator, shook her head turned to me and said "Look. They are talking to each other!"

This is all epigenetics by the way, rather than genetics. The antibiotics are effecting which proteins the gene expresses, and at what levels, rather than changing the genome of the bacteria.The bacteria I've been working on, for example, have about 20 'silent genes' which don't get expressed in lab conditions, maybe antibiotic signalling would turn some of them on?

It's a lovely idea, and it fits in so well with the results I've been getting. I will reverentially place it with the Histone Code Hypothesis and the Aquatic Ape Hypothesis, in the place in my head reserved for pet theories.