Most papers I read these days are long. Nature and Science papers tend to have 3-4 figures (Cell and Immunity papers can be twice that), tons of supplementary data and are at least a couple pages of dense, science-speak prose. I think I once read a paper (from like 20 years ago) that had a gene sequence as figure 1, a hand-drawn model for figure 2 and one figure of functional data, and I thought that was sparse.
So imagine my surprise when I stumbled on this new paper. One figure. Less than 500 words. And it’s about bacteria that seem to get up on their legs (wait, bacteria have legs?!?!). Published in Science – one of the most prestigious science journals in the world. Anyone that is willing to submit a 1 figure paper (not to mention get it accepted) in Science with a sentence like
Bacteria stood upright and “walked” […]
in the abstract is either extremely clever, or extremely ballsy (or a healthy combination of both).
Here’s what they did: they took pictures of huge numbers of Pseudomonas aeruginosa at the surface of biofilms and then used computer software to analyze how individual bacteria were behaving. They noticed that a large number of bacteria near the surface appeared to lift up into a vertical orientation, then walk along the surface of the biofilm on little appendages called type-IV pilli (TFP). I’ve mentioned biofilms before, but the easiest way to think of them is as a bacterial community. Mostly we think of bacteria as single-celled individuals, but biofilm-forming bugs can achieve a measure of cooperation, and the formation of biofilms is a requirement for a lot of bacterial pathogens (like Pseudomonas) to actually cause disease.
The TFP’s were always known to be used for locomotion, like the propellers of a boat. Indeed, when these bugs were in a horizontal orientation, they could crawl in straight lines for long distances. But in the standing orientation, the pilli seemed to act like legs for the bacteria to scuttle along at a faster rate, though they seemed less directional:
Each mechanism confers advantages for surface exploration[…] Crawling enabled directional motion; walking enabled rapid local exploration.
In part A of this figure, red represents the “walking” orientation, and is a pictorial representation of the motion of individual bacteria – each line represents a single cell’s motion over time. Comparing those lines to the blue ones, you can see that the crawling orientation tends to be much longer and much straighter.
Part B is just quantifying (putting into numbers) what is represented in A. They actually analyzed about 70,000 individual bugs, and if you look at the axis labeled “L,” it shows the distance that each individual traveled, and you can pretty clearly see that the red guys all cluster in the much shorter distances.
They also mention some observations about the cell division behaviors – the TFP seem to be important for daughter cells to move away from each other after they divide – but this seems like more of an appeal to increase the relevancy of the paper. As I said before, it was known for a while that TFP were required for movement, and none of the data presented demonstrates that this walking movement is necessary. In fact, they say
daughters left the division site by detaching, walking, or crawling
It’s just that TFP are required for all of these events.
Understanding he way that biofilms affect the life cycle of bacteria is crucial to understand the role of biofilms in disease, but the data presented here is really just observation. It doesn’t provide any mechanistic insight, though it will hopefully lead the way to more detailed understanding of how and why this is important. On the other hand, it clearly impressed the editors of Science enough to get included.
Gibiansky, M., Conrad, J., Jin, F., Gordon, V., Motto, D., Mathewson, M., Stopka, W., Zelasko, D., Shrout, J., & Wong, G. (2010). Bacteria Use Type IV Pili to Walk Upright and Detach from Surfaces Science, 330 (6001), 197-197 DOI: 10.1126/science.1194238
Suppose you were a microscopic fungal spore, and your success was dependent upon making your way to some far off place away from your parent organism, to begin a new life all your own. Maybe you are a pathogen (such as Sclerotinia sclerotiorum) and can only survive if you go off on your own and find a new host to infect. What if you could coordinate with thousands of other spores like you, and in one synchronized ejection effort you could create an air current that would take many of you upward into the flowing air above? Turns out if you belonged to certain fungi, you could do just that. As amazing as microbes are, we don’t often think of them as having behaviors that are coordinated to the second and visible to the naked eye, but some of them do! Check out the embedded video (courtesy of New Scientist) below for an awesome example of this recently investigated phenomena.
The authors of this new study published in the Proceedings of the National Academy of Sciences (PNAS) entitled “Dispersal of fungal spores on a cooperatively generated wind” state the following:
“Here we show that by synchronizing the ejection of thousands of spores, these fungi create a flow of air that carries spores through the nearly still air surrounding the apothecium, around intervening obstacles, and to atmospheric currents and new infection sites.”
These authors come from mathematics, engineering and biology departments, and as you might expect, they used multiple lines of inquiry in this paper. Additionally, they investigated several different species of fungi that eject spores in a coordinate way, and found similar patterns in how they coordinate. The methods included high-speed photography, complex mathematical modeling, laboratory manipulations, and applying ecological theory to their data and models. It turns out that the range of a cooperating spore can be 20 times greater than a spore that ejects on its own. However, it doesn’t benefit all the spores equally. If you are too early or too late in ejecting you don’t catch the ride, and it take many spores to initially generate the flow that triggers all the others, and those initial launchers don’t get much of a ride themselves. In the end, the end result is that some of the spores get jettisoned up into the air, and end up much further away than they would have without the coordinated activity. Apparently these jets of fungal spores can even move around obstacles. This is certainly an important piece of fungal dispersal ecology. In very practical financial terms this study is important for agriculture, since some of the species engaging in this dispersal behavior are important plant pathogens, and understanding that dispersal could help prevent crop infection.
The extent to which microbes in the environment are able to disperse is a huge factor in their geographic arrangement. Here I group bacteria and archaea together with fungal spores because their size means their dispersal is fundamentally different from larger organisms. Microbial dispersal is something that is difficult to study, and, therefore, not well understood. Better information about of how these organisms get around, and how far they can travel will come out of more interdisciplinary studies such as this one, and is needed in order to understand the ecology of microbes.
Roper M, Seminara A, Bandi MM, Cobb A, Dillard HR, & Pringle A (2010). Dispersal of fungal spores on a cooperatively generated wind. Proceedings of the National Academy of Sciences of the United States of America PMID: 20880834
[I’ve been hooked on the immune system since I was a kid and my dad showed me electron micrographs of macrophages eating bacteria in Scientific American. Now that I’m in graduate school studying immunology, and macrophages in particular, my dad asked if I could give a play-by-play of an immune response. Here you go Dad:]
Part 3: Immune memory
Towards the end of the 18th century, Edward Jenner did an experiment. It had long been known that people who had been infected with smallpox, if they managed to survive (no easy feat), would be resistant to further infection. People would even give small inocula of smallpox to healthy people in an effort to prevent a more serious infection (though this wasn’t very controlled and would often lead to serious illness and death). But there was also anecdotal evidence that milkmaids, who were often afflicted by the much milder disease cowpox, were also resistant to smallpox. So, Jenner devised the hypothesis that cowpox was close enough to smallpox that it would teach the body how to fight both. And he tested it – by injecting James Fipps (the 8 year old son of his gardener) with puss from a cowpox sore. Unsurprisingly, the kid got cowpox, and when the infection cleared, Jenner then injected the same boy (why this kid didn’t run screaming, I will never understand) with puss from someone with smallpox. Magically, the boy did not get small-pox. Thus, Jenner is credited with devising the first vaccine. In fact, the name vaccine comes from “vacca,” the latin word for cow.
Even with all the “controversy” about vaccines, the fact is that they work. One of the benefits of being a chordate is that we have an adaptive immune system, and that branch of the immune system remembers. In the last part, I talked about the T-cells and B-cells of the adaptive immune system. These cells have special, randomized receptors, and each individual cell recognizes something unique. During the course of your life, you’ll make hundreds of billions of different T cell and B-cell receptors, and most of them will never be used. But during an infection, some of the T and B cells will respond, and during that response, they will replicate. Most of the daughter cells will become effectors, and do all the disease-fighting things I talked about before, but a small percentage will become memory cells.
At some point, all of those effector cells have to die off – if they didn’t, after a couple times getting a cold, you’d end up being a giant lymph node. But memory cells know they’re important, and can survive for years or even decades. Because they were activated in the presence of an infection, they can be sure that their receptor recognized something foreign that is potentially dangerous. And if that something rears its head again, the memory cell can rapidly proliferate and produce new effector cells, all without waiting for a dendritic cell to say that it’s ok. In addition, memory B-cells can continue to secrete antibodies, which patrol your bloodstream, just waiting to encounter that pathogen once again.
This last bit is what makes vaccines possible. When Jenner infected James with cowpox, the boy’s immune system responded. Dendritic cells from his skin grabbed bits of the cowpox virus and brought them to lymph nodes to show to T and B cells. Some of those T and B cells had receptors that could recognize those bits, and they expanded and differentiated to run off and battle the infection. Meanwhile, some of them held back and turned into memory cells, and the memory B cells in particular continued to churn out cowpox-specific antibodies. Weeks later, when Jenner inoculated him with smallpox, there were already millions of cowpox antibodies flying around his bloodstream. Since smallpox is closely related to cowpox, many of those antibodies could recognize the virus particles and bind to them, preventing them from infecting any of the boy’s cells. If any viruses slipped by and actually infected a cell, the memory T cells would be alerted and blast the infected cell before it could make many new viruses. And if that cell did manage to make new viruses, those new viruses would also have to get by the antibody wall.
That’s the immune response in a nutshell. To recap: Innate immunity tags and bags most things that get past your barriers, then the adaptive immune response picks up the stuff that gets through, and remembers what infected you so that it can respond better the next time. That’s how I learned it in my undergraduate immunology class. That’s how it’s being taught to the undergrads I’m teaching now. Simple right?
Well, not so fast. If it’s that simple, why don’t we have vaccines against the legions of bacterial infections that debilitate or kill people every year (not to mention HIV), and why do we need a new flu vaccine every year? Why are over 90% of adults chronically infected with various strains of herpes virus? And why are there billions of dollars to be made in drugs that slow the immune system down? I’ll talk about some of the nuance and the complications of our sophisticated immune system next. Stay tuned.
The best defense against pathogens is to never let them gain access to our delicious, gooey insides. Our skin is pretty good for this purpose: it’s pretty tough and mostly impermeable, and the only way most of our surface tissues can get infected is if that skin barrier is broken. But we can’t have skin everywhere. Our airways and digestive tract have to be permeable so that we can absorb air and nutrients. In our gut, we can’t have skin, but we do have tens of trillions of commensal (friendly) bacteria that colonize us, and they can generally out-compete the bad bugs that want to do us harm.
But when those barriers are inevitably breached, the immune system throws up other defenses. The presence of bugs where they’re not supposed to be triggers inflammation – a whole host of responses that recruit immune cells, trigger release of nasty chemicals, and generally makes the tissue an inhospitable place for anything to grow and divide. Commensals, for some reason that we don’t fully understand, don’t generally trigger inflammation, and so we have a happy co-existence. They keep the bad bugs out, and we don’t try to kick them out. Enter Salmonella:
Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate.
In order to get a leg up on the competition, Salmonella evolved a way to actually benefit from inflammation. One group of nasty chemicals that the immune system produces are called reactive oxygen species. As their name suggests, these chemicals react with all kinds of stuff, screwing up lots of biological molecules and making all kinds of organic by-products. Salmonella manages to use one of those products in a novel way – to carry out respiration, allowing it to out-compete all of those commensals that are supposed to be acting as a shield.
There’s very little oxygen in the gut, so most gut bacteria are anaerobic. But anaerobic metabolism isn’t particularly efficient – a lot of the energy potential in every unit of food is wasted – so Salmonella learned to use tetrathionate instead of oxygen to carry out respiration. That way, they can grow more using less resources than the commensals. Usually, blocking the production of reactive oxygen species makes infections worse, but these researchers found that it actually rendered Salmonella less infectious.
And this is why we will never defeat the microbes: even our best immune defenses get subverted and turned into an advantage for pathogens.
Winter, S., Thiennimitr, P., Winter, M., Butler, B., Huseby, D., Crawford, R., Russell, J., Bevins, C., Adams, L., Tsolis, R., Roth, J., & Bäumler, A. (2010). Gut inflammation provides a respiratory electron acceptor for Salmonella Nature, 467 (7314), 426-429 DOI: 10.1038/nature09415
I seem to be behind on everything, but I finally got the videos posted for last week’s SITN lecture: “Science based medicine: a case study of vaccines and autism.” This week (tonight actually) is “Squishy Robots” – it should be awesome.
Videos can be found at our vimeo channel page. Right now it’s just the lecture portion, but I’m working on cutting together the audience questions into a separate video. First one is below the fold – Enjoy!
Ed Yong at Not Exactly Rocket Science has a great post about science reporting and the problems with supposed objectivity. It’s well argued, and I think the way it’s framed (reporters should not necessarily be “on the side” of scientists, but rather on the side of truth) is perfect. He also makes a point that I think should be hammered into the skulls of reporters (of all types, not just science reporters):
I once talked to a reporter who had done a straightforward report of a fairly dodgy paper and asked him why he had gone down that route, when he clearly knew enough to critique the study in more detail. He said that he couldn’t find a scientist who was willing to comment on the obvious areas of criticism.
This is the point where the quest for “objectivity” crosses the line from a noble discipline to what’s virtually a breach of ethics. Hunting for quotes to tell the story you want to tell is ludicrous. It can lead to people censoring stories they know exist because they can’t get someone else to tell it! At its worst, it leads to people twisting what their interviewees say because they’ve already made up their minds about the angle[…]
This is not about doing it all yourself without seeking outside opinions. The critical thing is that an outside opinion doesn’t need to be an opposing one. If you call up other scientists to comment on a study, and they all think it’s good, then that’s grand. You might find that if you ask actual experts, rather than the attention-seeking ones, you might get at what the actual debates are.
Yeah, what he said.