Who nose why skin's the way it is

Today I read about an interaction between two occupants of the human microbiome. The authors really do their findings a disservice by repeatedly referring to them in the context of the "nostril microbiome". What they really discuss is Staphylococcus aureus and various species of Propionibacterium. Both can be found in a variety of skin locations and especially on the face. Propionibacterium - and especially P. acne - is famous for causing the inflammation associated with all manner of nasty skin conditions. S. aureus is famous for causing many similar but often more medically worrisome infections. This paper shows how they might work together.*

Long story short: it's coproporphyrin III. Propionibacterium produces it and S. aureus uses it as a sign to start making biofilms.  A biofilm phenotype can improve survival in the face of the immune system, antibiotics, or even just physical stress.

Citation:
Wollenberg, M. S., Claesen, J., Escapa, I. F., Aldridge, K. L., Fischbach, M. A., and Lemon, K. P. (2014). Propionibacterium-Produced Coproporphyrin III Induces Staphylococcus aureus Aggregation and Biofilm Formation. mBio 5, e01286-14-.

*Anthropomorphism is to be avoided when discussing microbes. The English language, unfortunately, offers many opportunities for anthropomorphism-based rhetoric. In this case, "work together" is a bit misleading as this may not be a coordinated biological phenomenon. It may simply result from one species releasing a molecule and another species noticing it.

Today, I learned that the anaerobic gut microbiome occupant Bifidobacterium longum has been explored as a potential vector for treating cancer with gene therapy. B. longum is generally considered non-pathogenic and beneficial: it helps to balance pH in the gut, in part through production of lactic acid. A gut with the wrong pH can become susceptible to infection by bacterial pathogens. B. longum is added to some foods and supplements as a probiotic for this reason.

So what's going on with that gene therapy? A paper in 2000 by Yazawa et al. used a mouse model for an initial feasibility study. Though it doesn't appear that they actually used the method for tumor reduction, they did show that B. longum into mice with lung tumors could only be found in tumor tissue after 168 hours. That's presumably because the bacteria require an anaerobic (or, at least a hypoxic) environment to survice. Ideally, this means that B. longum bearing some kind of anti-tumor factor could be injected into or near a tumor with no pathogenic effect on any other tissues. B. longum can be killed off using common antibiotics; Yazawa et al. used ampicillin, though they only tried it in vitro. I'd be worried about long-term use with immunocompromised patients, though the exact anti-tumor material in play may be another critical factor.

The same research group was apparently still working on the idea as of 2010, when they published this review. A 2013 study by a different group looks like it had some success in using Bifidobacterium longum subsp. infantis as part of a method for treating bladder cancer in a mouse model.* This 2014 study just coated their Bifidobacterium in selenium, an elemental micronutrient which may have anti-tumor properties.


*I don't have access to the article so I'm not sure how well the method worked. The authors claim their treatment "exhibited the highest level of apoptosis" compared to controls so that could just mean they had a statistically-significant but limited effect on tumors. Cancer therapy isn't really my field so I'll give them the benefit of the doubt.

I read a review article about phage therapy today (citation below*) with the following opening sentence:

The human gut contains approximately 10¹⁵ bacteriophages (the ‘phageome’), probably the richest concentration of biological entities on earth.

Is that claim actually true? They cite this Lepage et al. Gut paper; those folks estimate that 10¹⁴ microorganisms (that is, distinct cells) live in any single human gut. We usually guess that an environment contains at least 10 times as many individual bacteriophage as potential host cells, so 10¹⁵ bacteriophages doesn't seem like a bad estimate. That being said, could there be a more densely-populated reservoir out there? I've seen population counts for chickens as high as 19 billion but I wasn't able to find any estimates of their gut microbiome diversity. We know they're a potential reservoir of pathogens and their population exceeds that of humanity.

Update: I've been thinking about this and realized that the phrase "richest concentration of biological entities" likely refers to a single human gut rather than the sum of all human gut microbiomes and viriomes. I like to think about ecological niches on a grand scale; the total number of different variations in phage genomes is higher when we include every similar environment in the total rather than the contents of just one human gut. My qualms about the superlative remain. I'd suspect that some sewer systems may contain richer, more diverse arrays of phages, and that's without employing much creativity. Could other species on this planet maintain more diverse microbiomes and/or viriomes?



*Dalmasso M, Hill C, Ross RP (2014) Exploiting gut bacteriophages for human health. Trends in microbiology 22: 399–405.

Power couples

I read about mutualism today. There has been - and continues to be - a long-running debate regarding the evolution of mutualism. The problem has often come down to a lack of evidence: we can be fairly confident that symbiotic mutualism is a real phenomenon but it's not always easy to demonstrate. We also know that many of the best examples of mutualism, such as chloroplasts, are the result of extensive evolution. Can mutualism emerge mutation, given the right circumstances for symbiotic partnerships to emerge?

A recent paper by Horn and Murray and accompanying summary article in Science show how it can happen. It's a neat, simple demonstration which would make a great elementary science class project.

Citation:
Horn EFY, Murray AW (2014) Niche engineering demonstrates a latent capacity for fungal-algal mutualism. Science 345: 94–98.

Unlabeled, but not forgotten.

Today I learned about Positive-Unlabeled learning, a type of semisupervised machine learning approach. This is the general problem: if you want a machine learning method to do binary classification, you need to start with examples of items which fit into one classification or the other. This is much easier and more efficient when you can safely say that everything in Column A is not in Column B and vice-versa. That isn't the case with some data. Rather, it's either labeled (Column A) or unlabeled (maybe Column B, or maybe Column A but just unlabeled).

PU learning can be used to define negative examples for protein function prediction.  Citation below:
Youngs N, Penfold-Brown D, Bonneau R, Shasha D (2014) Negative Example Selection for Protein Function Prediction: The NoGO Database. PLoS Comput Biol 10(6): e1003644. doi:10.1371/journal.pcbi.1003644.

I got married this past Saturday! Married to a lady. Photographs available on request. There's also a video on the way. Stay tuned for that.*

In other news, mice can eat a diet of bacteriophage T7 with few ill effects. Who says negative data never gets published?

*"Stay tuned", beyond being a culturally antiquated idiom, is an interesting bit of skeuomorphic language. It's a relic of a time when viewers could be asked to stay on a particular radio or TV station. Most modern radios and TVs aren't manually tuned. The audience also can and will change stations at their own volition. Asking them to remain in place is like asking them to wear the same pants for a week.

Today's paper is: 

Legrain, P. & Rain, J.-C. Twenty years of protein interaction studies for biological function deciphering. Journal of proteomics (2014). doi:10.1016/j.jprot.2014.03.038.

I keep changing the reference format. This really shouldn't bother anyone but me.

The take-home message: There's a lot of protein interaction data out there! Contrary to popular belief, most of it isn't just false positives. Rather, most of this data reveals actual biological complexity. Proteins may just interact with more binding partners than we originally thought.

A few awkward points:

• Both of the authors are experts in the field but are also employed by Hybrigenetics, a company providing protein interaction screen services. They don't advertise the company's services specifically so I suppose it isn't really a conflict of interest. I still grow concerned about such things.
• The title sounds odd. Couldn't it have been "Twenty years of biological function deciphering by protein interaction studies"? I think it's the word "deciphering", mostly.
• The entire review sounds a bit strange, actually. I assume it's a result of English as a second language. It does make some conclusions hard to understand, i.e. "Almost 2000 different proteins were analyzed over six time points, covering four orders of magnitude in terms of protein abundance. In those papers, the aim of the purification process is no more the isolation of a protein complex but just a way to zoom in a specific part of the proteome", which sounds dismissive.
• More specific references to recent interactome-dependent functional studies would have been nice. As they mention, there have been thousands, but it continues to be an active research venue. It looks like the authors just forgot to add some references in other sections: i.e., "..in different cellular contexts (for review on affinity-purification coupled to mass spectrometry, see)".

These guys made an early protein interactome of Helicobacter pylori so I can't complain too much.

Today's paper is: 

Bansal-Mutalik, R. & Nikaido, H. Mycobacterial outer membrane is a lipid bilayer and the inner membrane is unusually rich in diacyl phosphatidylinositol dimannosides. PNAS 111, 4958-4963 (2014).

The shortest-possible summary: Mycobacteria like M. tuberculosis have cell walls but they have nice, thick lipid membranes, too. All these layers add up to protection from antimicrobial compounds: the bacteria won't get killed if antimicrobials can't even get inside them.

Today, I read the following paper: 

Yurlova, L. et al. The Fluorescent Two-Hybrid Assay to Screen for Protein-Protein Interaction Inhibitors in Live Cells: Targeting the Interaction of p53 with Mdm2 and Mdm4. Journal of biomolecular screening 19, 516-25 (2014).

This one is really just about a fairly simple method to assay protein-protein interactions. It's an advertisement: the method was developed commercially by ChromoTek Gmbh and is sold as a kit. The basic idea is that proteins are expressed in Baby Hamster Kidney* cells as GFP and RFP fusions. The GFP-fusion baits also have LacI, so they'll end up bound to lac in the nucleus no matter what happens. The RFP-fusion preys should just float around the cell unless they interact with the baits, at which point they'll also be present at the same spot as the GFP. The process is reversible, so an interaction can be observed in real-time as it is disrupted, i.e. by some variety of specific protein binding inhibitor.

I probably won't use this method much myself, but it's quite simple and looks like it could be convenient for screening potentially therapeutic small molecules or peptides. It would be nice to see a paper published about the method's applications by groups other than ChromoTek employees.

*There's something about the word "baby" that makes it difficult to take seriously. This is an established cell line and has been in use since the 60's.

The unbearable brightness

Here are two quick, strange observations about colored light and biology:

1. A recent study in PNAS claims that exposure to orange light could have an impact on cognitive function. The MRI results certainly appear significant but I'm not familiar enough with the field to know if they're reliable. Caveats: Their sample size was 16 people, the effects of the particular light were noticeable more than an hour post-exposure, and potential participant effects (i.e., how sleepy they felt) were all self-reported, though the researchers state these reports were consistent. I'm curious to see if the results can be replicated with a different sample of volunteers.  (The paper by Chellapa et al. is here.)

2. C. elegans glows blue when it dies. Don't take my word for it. Take the word of Coburn et al. from their 2013 PLoS Biology paper, Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans: "We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway." It turns out that, at least in C. elegans, organismal death looks like a wave of necrosis as a cascade of self-destruction propagates cell death. The short story: cells burst, pH increases, things that wouldn't normally be fluorescent suddenly are. The death-glow may have been found to happen in yeast, too (Coburn et al. cite this 2007 paper by Liang et al but I couldn't find any explicit mention in it about blue fluorescence, just yellow and red).

The most minimal bacteria

Today I learned about the existence of the bacteriome, a specialized organ found in some insect species which is just chock full of endosymbiotic bacteria. Most animals provide hosts for bacteria, but the critical part here is the endosymbiotic nature: these symbionts must live and reproduce within host cells. As a result, many insect endosymbionts are quite odd in genetic terms and have tiny genomes. They can only grow to a certain population size, too, as they're limited by the space available within those host cells.

One such example of the resulting genetic oddities is found in Hodgkinia symbionts from cicada bacteriomes. A report by McCutcheon et al in 2009 showed howHodgkinia cicadicolaappear to have re-coded their UGA codons to code for tryptophan rather than the usual Stop codon. This specific re-coding has been observed before, but only in very low-GC content species, of which Hodgkinia is not one (it has a GC% of more than 58 percent). This symbiont also has a crazy-small genome at 144 kb. That was the smallest bacterial genome yet sequenced butNasuia deltocephalinicola, another insect endosymbiont, has it beat by 22 kb.

Today's paper was : 

Pernitzsch SR, Sharma CM (2012) Transcriptome complexity and riboregulation in the human pathogen Helicobacter pylori. Frontiers in cellular and infection microbiology.

It's a quick review of sRNAs in H. pylori, a species once thought to use very little RNA-based regulation (AKA riboregulation). The presumed lack was based on observations that H. pylori lacks the RNA-binding protein Hfq, generally thought to be a requirement for riboregulation. Turns out that's not the case. H. pylori may regulate plenty of cellular activities using sRNA, including the stress response and flagellum biogenesis.

Gatsogiannis, C., Lang, A. E., Meusch, D., Pfaumann, V., Hofnagel, O., Benz, R., Aktories, K., et al. (2013). A syringe-like injection mechanism in Photorhabdus luminescens toxins. Nature, advance on. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. doi:10.1038/nature11987

Didn't read this one yet, but the abstract contains the phrase "vuvuzela-shaped channel" so it should be interesting.

Glud, R. N., Wenzhöfer, F., Middelboe, M., Oguri, K., Turnewitsch, R., Canfield, D. E., & Kitazato, H. (2013). High rates of microbial carbon turnover in sediments in the deepest oceanic trench on Earth. Nature Geoscience, advance on. Nature Publishing Group. doi:10.1038/ngeo1773.

This is a small letter about Challenger Deep, the deepest point in Earth's oceans. Located within the southern extent of the Mariana Trench, this spot is nearly 11,000 meters deep. It's pretty chilly down there - about 2.5 degrees C - but more importantly it's under extremely high pressure. Wikipedia tells me it's more than 16,000 psi or about 1,099 times surface pressure. This doesn't stop bacterial growth: Glud et al. found that two sediment samples from this deep spot contained, on average, nearly 10⁷ prokaryotic cells per cubic centimeter. Shallower sites nearby were also dense with microbial life but not nearly as rich as the Challenger Deep samples. 

Glud et al. suggest that deep-sea trenches like the Mariana may serve to naturally funnel fresh sediment downward, providing essential nutrients for microbial growth at extreme depths. Further analysis of these deep-sea microbes could show how they've adapted to such specialized metabolic demands.