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Why we will never defeat the microbes

October 1, 2010

ResearchBlogging.orgThe 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

Vaccines and Autism videos are up (and squishy robots lecture tonight!)

September 29, 2010

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!
Read more…

Life at the metabolic edge

September 26, 2010

One of the coolest things about microbes from an environmental perspective is the variety of ways they can make a living.  By that I mean how over evolutionary time microbes have evolved an overwhelming diversity of metabolic pathways.

The study I want to tell you about today requires a good deal of background, but I will try to keep it as concise as possible.

Our cells (and those of all animals) use oxygen to convert carbohydrates into carbon dioxide and water, and in the process generate usable energy in the form of ATP molecules.  This is referred to as aerobic cellular respiration, or oxidative metabolism.  If there is not enough oxygen around we can switch things up slightly, for a while, making a little bit of ATP through anaerobic fermentation (which does not require oxygen) but we generate lactic acid (think runners cramps) in the process which our body needs to break down later.

Metabolism in microbes refers not to one reaction with a single variation, but to a suite of reactions, both aerobic and anaerobic, that take advantage of wildly different energy sources.  Many individual microbes can perform a variety of these reactions depending on what chemicals are available to them.  Basically these metabolisms boil down to taking electrons from one compound with a high energy potential, using them to generate usable energy for the cell, and dumping the “used” electrons (now at a lower energy level) on to some other compound that will take them away so that the process can happen over again.

We can measure the reduction potential of a chemical substrate to see how well it acquires electrons or its oxidation potential to see how readily it would give up electrons.  Together these processes are referred to “redox” (as in reduction-oxidation).  As many professors have drilled into my head – life is redox!  Much of the complexity of which microbes do which type of metabolism can be understood simply by knowing the redox potentials of the various electron donors and acceptors available to them.

Each metabolic pathway needs an electron donor and an electron acceptor, and different pairs of chemical will make more or less energy available to a cell based on the difference in redox potential between them.  This amount of free energy in each substrate can be calculated, and the difference between them indicates how much energy will be available to the cell using the pair as its electron donor and acceptor.  Typically this is talked about as Gibbs Free Energy.  For a long time it was assumed that as long as an electron donor/acceptor pair had a change in Gibbs Free Energy of -32 kilojoules per mole some microbe would be able to use that pair of chemicals to generate enough usable energy to live on.  This value based on theoretical thermodynamic calculations of the amount of energy needed for basic cellular processes.  Anything below the magic number of -32 was not thought possible.  That is… until it was discovered that if certain organisms paired up and one’s electron acceptor was immediately used as the other’s electron donor they could each perform an unfavorable metabolism, but the two metabolisms considered together were favorable.  Microbiologists call this type of association syntrophy, and it typically involves hydrogen produced by one species being used by another.

OK, enough background.  Thanks for bearing with me.  Now on to what I really wanted to share…

Earlier this month, it was reported in Nature that a process not generally considered energetic enough to support growth of a single culture of microbes actually is!  The production of bicarbonate and hydrogen (H2) from formate and water had previously been shown in a syntropy between an organism in the genus Morella and one in the genus Methanotherobacter.  The understanding was that Morella wouldn’t be able to grow on formate without Methanobacter to consume the hydrogen that Morella produced, in effect getting it out of the way (in terms of chemical partial pressures) so that the formate reaction would actually be favorable.  However, it had not been shown (until now!) that a single strain of archaea could survive on this formate reaction solo.  The change Gibbs Free Energy for this reaction was calculated to be as low as -8.  How, exactly this organism is able to produce enough ATP to grow, is still not completely worked out.  However, because the whole genome of the organism has been sequenced, scientists will probably be able to determine the detailed mechanisms soon.

The paper that reported this finding is called “Formate-driven growth couple with H2 production”.  The wonder-bug found capable of this simple, yet surprising, anaerobic metabolism is called Thermococcus onnurineus.  It just happens to be one of my favorite types of microbe, a deep sea hydrothermal vent hyperthermophile (this one from the Mid-Atlantic Ridge), meaning that its optimum growth is above 80 degrees celcius!  It is in extreme environments like hydrothermal vents, that these unique strategies might provide organisms with competitive advantages.  In other, more tame, environments other organisms able to carry out more energetically favorable metabolism would simply out compete this microbe.

While this finding might not at first appear thrilling, the discovery that microbes are capable of living off much less energy that we thought was possible leaves me thinking the following things:

  • We really don’t know what the energetic limits of life on earth are.
  • Microbial strategies to eeking out a living are amazing and continue to surprise us.
  • Hydrothermal vents are a great place to find microbes doing things at the extreme limits of what we believe possible.
  • What else might microbes be doing that we are unaware of, and how might those processes be affecting ecosystem function or the environment as a whole?

Media “Objectivity”

September 24, 2010

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.

In case you need a reminder:

September 21, 2010

The Huffington Post has long given a platform to anti-vaccination advocates to spread their lies about the safety and efficacy of vaccines. Now, the fruits of that labor are becoming painfully obvious, as Huffington Post is reporting:

LOS ANGELES — State health officials reported Thursday that California is on track to break a 55-year record for whooping cough infections in an epidemic that has already claimed the lives of nine infants.

There’s an incredibly effective vaccine that prevents Pertussis, which is the causative agent of whooping cough. It’s the reason California hasn’t seen any serious outbreaks in the last half-century. So why is it on the rise now?

Many parents forgo vaccines for their children because of concerns about autism, typically fueled by misinformation on the Internet, said Dr. Mark Sawyer, a University of California-San Diego professor and fellow of the American Academy of Pediatrics.

Misinformation spread where? Well, since you asked.

The death of 9 children to a completely preventable disease in as rich a country as ours is a tragedy and a travesty. These children were too young to have received the vaccine. They should have been protected by herd immunity, but due to the ignorant actions of a number of parents, the disease was able to break through.

If you’re interested in learning more, and are in the Boston area, the fist lecture in the Science in the News fall lecture series is on precisely this topic. It’s free to the public – please feel free to stop by.

First SITN Lecture: Science based medicine

September 21, 2010

Tomorrow, at 7pm, we kick off the Science in the News Fall Lecture Series.

The first lecture is “Science Based Medicine: A Case Study of Vaccines and Autism. The lecture in the picture will be next week at the same time. If you’re in the Boston area, you should come by and check it out. It’s totally free and open to the public, a short walk from the Longwood Medical Area stop on the E line. Hope to see you there!

Reading between the lines

September 21, 2010
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ResearchBlogging.orgHave you ever used one of those Dyson Airblade hand driers? I’ve used them at SFO and even in some restaurant bathrooms, and I have to admit, they’re pretty neat.

Whether or not they’re actually better at drying your hands may be an open question, but  according to research published in the Journal of Applied Microbiology, it may be (marginally) better at removing bacteria:

Conclusions: Effective hand drying is important for reducing transfer of commensals or remaining contaminants to surfaces. Rubbing hands during warm air drying can counteract the reduction in bacterial numbers accrued during handwashing.

Significance and Impact of the Study: The Airblade™ was superior to the warm air dryers for reducing bacterial transfer. Its short, 10 s drying time should encourage greater compliance with hand drying and thus help reduce the spread of infectious agents via hands.

I’m going to be honest – I’m no expert in hand-drying technology, but this report seems a bit… um… crappy. First, one of the authors is from Dyson’s microbiology group (they have a division of microbiology?!?) – the other two are from a university, but at first I had a bit of trouble with the possible conflicts of interest. Then I looked at the data. I feel like it exonerates them from any claims of shillery – If I were going to fake science for money, I feel like I could do a better job. I definitely believe the data, I just think their stated conclusions are a bit overblown.

Basically, they had people handle meat to contaminate their hands, then wash their hands, then dry their hands in one of several ways, and measured how much bacteria was on their hands. The results are laughable.

Using the Dyson drier was marginally better – it’s statistically significant (which means there’s a less than 5% probability that the difference observed is due to chance), but if the difference is between 300 and 200 CFU’s, I don’t think it’s actually functionally significant. Besides that, using a paper towel was actually quite a bit better than any of the hand driers.

Anyway, I don’t know why I spent an hour of my life reading and writing about hand driers and bacteria. But when an add says “[product x] has been scientifically proven to [wondrous action],” I’ve always wondered where that research comes from. Now I know.

Snelling, A., Saville, T., Stevens, D., & Beggs, C. (2010). ORIGINAL ARTICLE: Comparative evaluation of the hygienic efficacy of an ultra-rapid hand dryer vs conventional warm air hand dryers Journal of Applied Microbiology DOI: 10.1111/j.1365-2672.2010.04838.x

Supplement Science

September 15, 2010

There is almost none. Since 1994, the “Dietary Supplement Health and Education Act” essentially deregulated the supplement industry, and placed them outside the authority of the FDA. As a result, supplement sales have skyrocketed, and more are introduced every year, with claims of health benefits from increasing memory to preventing cancer. But there is scant evidence to support any of these claims.

The Wall Street Journal reports that the US government is funding more research:

Helping to spur the research initiative are the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine, both part of the National Institutes of Health. The agencies last month awarded grants totaling about $37 million to five dietary supplement research centers, expanding a program that has already awarded more than $250 million in research grants for herbs and botanicals since 2002.

Unfortunately, I’m not convinced that the science, if negative, will convince anyone. There may be promise in some of these botanicals, and this article mentions a few claims that actually have been substantiated. But the research showing no effect of ginkgo biloba hasn’t stopped its mass-market appeal. To it’s credit, the government does try to educate the public on supplements, but I think a change in law is necessary. Anyone making a claim about health benefits, whether it’s for drugs, food, or supplements, needs to back those claims up with evidence.

Gonorrhea and immune evasion

September 14, 2010

ResearchBlogging.orgLots of bacteria try to colonize our mucosal surfaces – that’s airways (step throat, tuberculosis), gut (E. coli, Salmonella), aural cavity (ear infections), and urogenital tract (UTI’s, chlamydia). These regions of our bodies are exposed to the outside world, so they’re easy to access, and are usually pretty accommodating places for bugs to grow (warm, moist and enclosed).

Because of this, the immune system is ready with a host of mechanisms to keep harmful bugs off and out. I’ve mentioned some of these mechanisms before, but another one I failed to mention is exfoliation – the deliberate shedding of the top layers of cells in an effort to disrupt the bacteria from attaching. It’s kind of like turning the top 2 inches of ice to water on this guy:

But, as with most immune strategies, some pathogens have learned to evade them, and a new paper in Science describes a really devious form of this evasion by the bacterium that causes gonorrhea:

Neisseria gonorrhoeae, a Gram-negative microorganism, causes one of the most common sexually transmitted diseases worldwide. Even though these bacteria can induce the exfoliation of host cells upon contact, they are able to establish themselves on virtually every mucosal surface of the human body.

They found that certain strains of N. gonorrhoeae were able to bind a receptor on epithelial cells, which tricks them into expressing a molecule called CD105. This molecule then tells all the neighboring cells to activate another cell-surface protein (called an integrin) that makes cells stick to each other, preventing them from getting shed, and allowing the bacterium to stay attached. It would be as if that climber’s axe caused all the surrounding ice to get colder, preventing the ice from melting and throwing him off. When they knocked out the receptor, or CD105, or blocked the integrin activation, the bacterium was far less able to establish an infection, which the authors say may lead to therapeutic interventions. But then, most researchers say their stuff has therapeutic implications, and any treatments based on this research (which is in a mouse model) are probably a long way off.

Still, it’s another cool example of pathogens subverting the immune system, and even turning our own bodies against us to do it.

[PS – This is my first contribution to the Research Blogging network. Please give me feedback – I’d love to know what you think]

Muenzner P, Bachmann V, Zimmermann W, Hentschel J, & Hauck CR (2010). Human-restricted bacterial pathogens block shedding of epithelial cells by stimulating integrin activation. Science (New York, N.Y.), 329 (5996), 1197-201 PMID: 20813953

Thanks for making my point, Nature

September 14, 2010
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Back in July I wrote about an editorial published in Nature about the future of science communication and what place blogs had in that future. Though I agreed with them that blogs are a great resource, I also thought that they were being a bit disingenuous about their desire to relate with the public considering that almost all of their material is locked behind a paywall, so the public doesn’t have access. I even wrote a comment to that effect on their website:

It’s all well and good to talk about public accessibility of science, but how do you expect the public to get engaged when almost all primary literature is locked behind a pay-wall? I have access through my university, but when I want to blog about new research for friends and family, I’m stuck linking to abstracts and then summarizing everything in the paper.

I just received an e-mail today that my comment was flagged as spam and removed. I’m not sure how they arrived at that conclusion, but I’ve written to their customer support to see if they’ll rectify the situation. If not, they’re just making my point for me. Way to encourage public discourse, Nature.