Mental Indigestion

by Jim Caryl

Category: Research articles

The grass isn’t always greener…

Research bloggingTHERE you are, stood in a green grocers poring over your favourite variety of apple. Suddenly you catch the scent of something heavenly; a smell not unlike the apple you have in your hand, only better. You abandon your apple and follow the scent to the next aisle where you find more apples of the same variety. They smell superior to the others. You pick one up and are compelled to take a bite; on doing so you realise something – it’s pretty bloody awful. You put down the unpalatable apple and move on to alternative apples.

I could be describing a situation reminiscent of the selectively bred, brightly coloured, sweet smelling fruits that line our supermarket shelves; those that in fact taste like  tasteless facsimiles of the original spots-and-all varieties. In this situation we are being manipulated by the supermarkets, but in nature it may be viruses doing the manipulating.

CMV by RG Milne, Istituto di Fitovirologia Applicata  (http://www.ncbi.nlm.nih.gov/ICTVdb/Images/Milne/cucumsv.htm)

Cucumber Mosaic Virus (CMV)

Viruses are parasites, making use of infected host cells to replicate more virus. Of course, it isn’t enough just to replicate, viruses also need to spread to new cells, and new hosts. Plant viruses are often carried from plant to plant by insects; the insects become known in this context as ‘vectors’. The study of the biology of insect vectors is, as you may imagine, fundamentally important to understanding the transmission of a whole range of parasites (viral, bacterial and protozoan) between plants, or between humans and animals. Of particular interest is how parasites, such as viruses, manipulate their insect vectors by altering the physical properties of the host they infect.

A Penn State based group, headed by Mark Mescher, have been using Cucumber Mosaic Virus (CMV), a known generalist plant pathogen, to study the effect it has on the interaction between cultivated squash plants and aphids (sap sucking bugs). The results of this study are reported by Kerry Mauck et al. in a recent paper.

They show that CMV-infected plants have elevated volatile (readily dispersing in air) emissions that attract aphid vectors. This in itself is not a revelation;  the authors cite two well documented examples of this phenomenon, from Potato leaf roll virus (PLRV) and Barley yellow dwarf virus (BYDV), where infected plants release volatiles that attract aphids. However, these other viruses employ a different method of transmission to CMV, and the main thrust of this paper is to identify how the mode of transmission modifies the host-insect interaction.

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A radical source of antibiotic resistance…

This post was chosen as an Editor's Selection for ResearchBlogging.orgA FEW years ago, a Boston University team headed by Jim Collins published findings that suggested the means by which bactericidal antibiotics result in cell death. Rather than the cause being the cellular target of the drug, the team showed it was the secondary effects of stimulating the production of hydroxyl radicals, a reactive oxygen species 1. The hydroxyl radical is known to cause significant damage to cellular DNA, proteins and cell wall, leading to cell death.

Their 2007 study 1 was initially met with a few raised eyebrows in some quarters, coming in for some criticism for having a few gaps; namely whether the role of the hydroxyl radical was even pertinent in a real world infections settings, which are often in the low-oxygen environment of biofilms 2. There was also some question of whether it was adequately demonstrated that the oxidative stress was a source or the result of cell damage. However, subsequent studies reported by Kohanski, as well as other labs, have described a more defined link between a bactericidal drug and resulting hydroxyl radical formation 3.

In the latest edition of Molecular Cell, a new article from Mike Kohanski, Mark DePristo and Jim Collins reports that prolonged exposure to sub-lethal concentrations of antibiotics can induce multiple drug resistance in E. coli and Staphylococcus aureus strains that were initially drug sensitive 4. E. coli strains were tested with sub-lethal levels of  three major classes of bactericidal antibiotics (quinolone, B-lactam and aminoglycoside), which were found to significantly increase the mutation rate, confirming their expectations.

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Heat shocking adaptive evolution…

Research bloggingIN evolutionary theory there is a phenomenon known as canalisation, a process in which the phenotype (i.e. the outward physical appearance of an organism) remains unchanged, despite genetic or environmental influences.  This suggests that a mechanism exists to buffer the physical appearance from such changes, which may explain why some species can remain mostly unchanged for millions of years.

The buffering afforded by this mechanism permits the accumulation of genetic variation, in effect storing it up like an evolutionary capacitor. Also, presumably the accumulated genetic variation may be released by an event that overcomes the evolutionary capacitor, releasing fuel (in the form of variation) that provides a substrate for natural selection and potentially accelerating evolution. But how?

The idea of capacitance was first suggested by Rutherford and Lindquist 1 following experiments on a protein called heat shock protein 90 (Hsp90) in fruitflies. Generally speaking, heat shock proteins assist in the maintenance and correct folding of cellular proteins, especially when under temperature stress; Hsp90 plays a particular role in maintaining the unstable signalling proteins that act as key regulators of growth and development.

They suggested that in nature, a stressing event such as high or low temperatures may overcome the protective buffering effect that Hsp90 has on maintaining these key regulators. As Hsp90 becomes diverted from its usual role, due to an increase of stress-damaged proteins in the cell, those cell signalling proteins it normally maintains are free to adopt a range of altered behaviours, interfering with the development of the organism. The result is morphological variants upon which natural selection can act. Rutherford and Lindquist found as much, with chemically and environmentally compromised Hsp90 resulting in flies with abnormal wings, legs or eyes, they observed a broad variety of phenotypes.

Rutherford and Lindquist went on to demonstrate that the capacity for such remarkable variation was pre-existing, i.e. it was encoded genetically prior to the stressing event, but had been silenced. Evolutionary capacitance may therefore provide a mechanism of adaptive evolution in which a population under stress may release previously silent variation, resulting in the appearance of certain individuals with more desirable traits in that changed environment. When such revealed traits are selected for they can become fixed and independently of the buffering action of Hsp90.

This week, in a letter to Nature, Valeria Specchia et al.2 report some fascinating evidence that indicates that beyond merely acting as a gate-keeper to unleash variation, mutations of Hsp90 that compromise its functionality result in new, rather than pre-exisiting, variation. They observed that mutations in Hsp90 affect the production of piRNAs. These are small RNA molecules that are involved in the silencing of genes, particularly those involved in development, i.e. sex cells like eggs and sperm, and all the cell types that give rise to these cells. These piRNAs are also responsible for repressing genetic elements called transposons.

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Your microbiome and you (part I): Gut

This post was chosen as an Editor's Selection for ResearchBlogging.orgYOU probably think that your body has things pretty much under control, being the finely evolved machine that it is, it knows where its at, and does a generally good job of looking after itself. You’d be right of course, but it doesn’t do this without a little help.

Some of this help comes in the form of your microbiome.

I have written previously about the exciting concept of the human microbiome in which I described how the number of bacterial cells on your body out number your own cells 10 to one, and asked to what degree you consider yourself to be human? The vast majority of these co-residents of you are organised into defined communities, the structure and diversity of which vary depending on where on the body they’re found: your mouth, your nose, various areas of your skin, your gut and urogenital tract. By understanding the interactions between each of these communities and our body, we can better understand their role in health and disease.*

In this the first of two posts on your microbiome, we’ll take a look at your gut.

The gut

probiotics-good-bacteriaMost people are undoubtedly familiar with the idea of ‘good bacteria’, in particular those of your gut, which we are encouraged to top-up on a daily basis with sickly sweet probiotic supplements containing various species of Lactococcus and/or Bifidobacterium. One can only imagine how on Earth we’ve coped throughout the course of evolutionary history without our daily supplement of Yakult.

The general scientific consensus on probiotics is that they don’t do any particular harm to most people, except perhaps your wallet, but occasionally the claims made by the manufacturers are often circumstantial, based on studies with poor methodologies, or are based solely upon observations from a petri dish or mouse model. Furthermore, when reliable evidence is documented, it is invariably for a very specific strain, thus there can be little confidence that is is a general property of the bacterial species as a whole.

Where the use of probiotics moves away from a general supplementation to being part of an active treatment for a condition, there is some evidence to suggest they may be of benefit, but on the whole, evidence is lacking and more research is certainly warranted. A Cochrane review (an international not-for-profit organization, providing up-to-date information about the effects of health care) in 2004, concluded:

“Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. More research is needed to inform the use of particular probiotic regimens in specific patient groups.”

However, in general there are insufficient data for the use of probiotics, over current standard therapies, in conditions such as eczema, Crohn’s disease, bacterial vaginosis and a slew of others. This is probably not helped by the fact that there is a good chance that the little pot of living bacterial joy you are consuming doesn’t actually contain any live bacteria of the type you think you’re getting.

A study published last month in the International Journal of Food Microbiology by an Italian team based the Istituto Superiore di Sanità in Rome, described a survey of such probiotics in Italy between 2005-6, seeking to identify and enumerate bacteria in commercially available supplements 1. A whopping 87% of samples showed evidence of not conforming to the Italian guidelines.

“Even though most labelled supplements (25 samples) indicated the presence of Bifidobacterium bifidum, this organism was only detected sporadically and always as dead cells.”

They also noted contaminants such as the food-poisoning pathogen Bacillus cereus, yikes.

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The ‘negatome’ – a database of negative information…

Research bloggingWE researchers often joke that no-one ever publishes negative results, but that doesn’t mean to say that negative results aren’t extremely useful. On one level, knowledge of such negative results can prevent you repeating the same mistakes that countless other researchers, in other labs, have undoubtedly made over the years. On the other hand, they can provide a valuable dataset with which to generate new and useful information. One such example is the ‘Negatome Database‘, which has been reported by Smialowski et al.1 in Nucleic Acids Research advance access (November 17, 2009).

The Negatome is a collection of protein and domain (functional units of proteins) pairs that are unlikely to be engaged in direct physical interactions. But why on Earth would we want to know about proteins that don’t interact with each other; in fact, why do we need to know about proteins that interact at all?

Macromolecular machineResearchers recognize that that a cell doesn’t function purely by the action of individual proteins, but instead by large macromolecular complexes mediated by many interacting proteins.  The image to the left indicates an example macromolecular ‘machine’, in this case those involved in signal processing at the neuronal synapses (and which are likely to be working quite hard right now!).

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Windshield splatter analysis…

rb1A few years ago I took part in an RSPB survey called the Big Bug Count, which sought to quantitate what had hitherto been anecdotal accounts that the number of insect splats on car windscreens had decreased in recent years. Essentially it was a sticky pad of define area that was placed on the front registration plate of your car. Following a car journey (I drove the 20 miles from from Keswick to Windermere), the number of bugs splats were counted and the results submitted.

Some suggested that the dwindling insect splats may in fact be due to cars being more aerodynamic, and not the tin boxes of previous decades. However, even I had noticed that I was swallowing fewer bugs on my bike rides around Cumbria than my childhood years, but hardly scientifically rigorous data – I do after all scream with glee less now than I used to.

Unfortunately, because the ‘bug splat’ survey, as it became known, was the the first such study by the RSPB, they could draw no conclusions as to whether the insect population was dwindling (despite what some press articles claimed) until subsequent seasonal surveys, over multiple years, were performed.

Of course, what some of you may have noticed is that the RSBP doesn’t seem to have followed up with any further surveys – at least none that I’ve been able to find in 30 mins of googling and scouring their website. Shame, so we had a baseline, of sorts, against which nothing further has been measured.

But assessing species diversity is an important task, as I’m sure anyone can appreciate. Changes in biodiversity act as markers of climate change or pollution, and have knock on effects on the food chain, such as bird life.

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Holes in the ice…

Research bloggingCRYOCONITE (‘ice dust’) holes are small pock-like depressions that are strewn over the surface of glaciers, looking much like a pristine snow drift after you’ve thrown a handful of gravel at it. Such melt-holes have been documented on glaciers at both poles, and on other glaciated regions such as Iceland, Greenland, Canada and the Himalayas. According to one account, at least, cryoconite holes  have been a bane to scientists working on the Greenland ice sheet, the holes being typically full of slushy ice, and big enough to step in by accident. However, cryoconite holes have been the subject of much debate in recent years; a debate centring on their role as contributors to glacial melting. Read the rest of this entry »

Bug eat bug…

This post was chosen as an Editor's Selection for ResearchBlogging.orgAS if it’s not hard enough at the bottom of the food chain, being cannibalised by your own bottom-dwelling compatriots must add insult to injury. The soil dwelling Gram-positive bacterium Bacillus subtilis is fully equipped to take appropriate action when faced with food shortages; a sub-population of cells initiate a process of dormancy by turning themselves into hardy, robust spores. In this form the bacteria are capable of enduring temporary, or prolonged, harsh environmental conditions.

However, this is not a process entered into without some careful deliberation. Sporulation, the act of forming a spore, is an energy intensive process that results in the formation of the essentially inactive spore, and the death of the ‘mother’ cell producing it. It comes as no surprise, therefore, to discover that B. subtilis has evolved a means of delaying sporulation as long as possible.

In an alternative strategy,  a sub-population have a genetic pre-disposition to become cannibals.

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Risk taking and audacity in science…

Research bloggingIn the October edition of Cell1, Amy Maxmen, a New York based science writer, discusses how tackling long-standing scientific problems (i.e. studies that have been prone to failure), or refuting dogma, are perceived to be a poor strategy for early-career researchers; and contends that perhaps they shouldn’t be.

One of the reasons for this is down to the policies of research grant committees.

A common complaint among researchers is that in order to be funded, they feel they must submit conservative grants filled with so much preliminary data that their predictions aren’t quite predictions any more. As Venter says, “The problem in [grant] study sections is the philosophy of proposals being reviewed as contracts instead of ideas.”

My own thoughts are that sometimes the amount of preliminary data required in a grant submission is so great that you’re half way to addressing the research goals at the first base, but only at the cost of the remnants of the last grant, which were used to finance the preliminary studies for the next. It’s as if the research councils are looking for a sure thing, a guarantee of success.

This is not how science should work.

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