Mental Indigestion

by Jim Caryl

Compensating for alien genes…

This post was chosen as an Editor's Selection for ResearchBlogging.org“FROM the perspective of a bacterium, higher eukaryotes are oversexed, unadventurous and reproduce in an inconvenient way.” So says Pål Johnsen and Bruce Levin in their commentary of today’s article for discussion, and nary a truer word said. Of course, one may state that inconvenient as reproduction may be, bacteria clearly have no sense of fun.

There was once an idea that we could address the problem of antibiotic resistant bacterial strains by removing the ailing antibiotic from clinical use. In the absence of selective pressure it was thought that the evolutionary traits that enable the strain to resist the antibiotic would actually put the strain at a competitive disadvantage compared with a strain that doesn’t have such antibiotic resistance. The proposed cause of this? Fitness costs – these are imposed by a resource-expensive set of mutations, or carriage of alien DNA, that make the resistant strain compete less well once its non-resistant brethren are no longer being killed off by the antibiotic.

However, some years ago now experimental evidence suggested that this is not always the case; it may in fact be often not the case. It is worth mentioning at this point that it has been shown that in some circumstances (alt) the number of infections caused by a particular antibiotic-resistant pathogenic bacterium have become fewer on reduction (or removal) of the antibiotic to which that strain is resistant, but to assume this would be the case with all strains/antibiotics is naïve.

It is true, with few exceptions, that initially both plasmid and chromosomally encoded resistances result in fitness losses. However, when resistance has a cost it is possible for compensatory mutations in a cell to ameliorate these costs, usually without the loss of resistance. The type of compensatory mutations that mitigate the fitness cost of acquiring antibiotic resistance, or any other incoming DNA that encodes potentially useful genes, will depend very much upon the environment in which the bacteria finds itself. These include the availability of resources, i.e. the growth environment of the bacteria, the environment of the genes (mobile or chromosomal), or whether the genes are being selected for by an external factor, such as the presence of antibiotics in the case of resistance genes.

So what sort of ‘nips and tucks’ might a bacterial population undergo in order to maintain a battery of costly genes, but that may provide an ongoing advantage? Well, this is the subject of much ongoing research; one example indicated that, in the absence of selective pressure, costly genes are simply silenced – a molecular mechanism often found in higher organisms that prevents a gene from being ‘switched on’. Thus a reservoir of drug resistance determinants may remain in populations that have compensated for their presence, remaining ‘inactive’ until a selective pressure removes the silencing.

A recent study by Peter Lind (et al.), a grad student working in the lab of Dan Andersson at Uppsala, Sweden, addresses a particularly pertinent question of compensatory mutations: those associated with genes acquired by horizontal gene transfer (HGT). HGT bypasses the slow and haphazard process of evolution (via random mutation, selection and recombination) by offering an opportunity for bacteria to receive fully fledged genes encoding pathogenicity factors (genes that make bacteria better at causing disease) as well as genes that encode resistances to disinfectants and/or antibiotics, amongst others. There is no doubt that such incoming DNA may pose significant fitness costs, so Lind et. al. set out to quantify the nature of compensatory mutations on such incoming DNA.

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Ask a Biologist

Ask a Biologist

On Monday 19th April a fantastic resource was re-launched. Sporting a shiny new website and a community of eager biologists, Ask a Biologist (AAB) is a site you should visit if you have any burning questions about biology. I have supported such sites for many years, originally as part of MadSci.org, but I am pleased to now give my time to AAB. Of course, biological sciences covers a huge range of disciplines, and as such the scientists who volunteer their time and experience to answer your questions provide expertise from a broad range of backgrounds, from medical sciences, microbiology, molecular biology, to ecology, marine biology, palaeontology and several specialist areas of zoology.

Ever wondered whether bacteria think?
Why a compost heap gives off steam?
Have you taken a picture of an insect you would like to have identified?
Are you confused about what evolution is all about?
Want to know how to become a biologist?

These questions, and many more, are typical of those we get asked. Often you will receive more than one answer to a particular question, especially if it is a complex question. This reflects the nature of science and the perspectives that different scientists can bring to a solve a problem. If there is no clear answer to your question, perhaps because the answer is not yet known, then we will point this out, and provide an answer based on our informed opinion.

When you arrive at AAB, you can search the site with your question to find out whether it has been asked, and answered, before. If not, then ask away and a biologist will get back to you very soon. One note however, we don’t do student’s homework assignments, and we’re pretty good at spotting homework questions, being teachers, lecturers and life-long students ourselves. If you have been told to go and research something, then asking a professional biologist for the answer really doesn’t count as research; it is in the process of finding things out that we learn more about a subject.

Ask a Biologist, tell your friends.

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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Telling tales…

The following is an excerpt about the current interplay between science and the media, taken from an article in this week’s Nature by Colin Macilwain:

…thanks to the massive growth in public relations and to online media’s insatiable appetite for ‘content’, journalism in science, as in other spheres, has evolved into an ugly machine — called ‘churnalism’ by media-watcher Nick Davies and others. This machine delivers inexpensive and safe content, masquerading as news, to an increasingly underwhelmed public.

The machine prospers because it serves the short-term interests of its participants. Editors get coherent and up-to-date copy. Writers get bylines. Researchers, universities and funding agencies get clips that show that their work has had ‘impact’. And readers get snippets, such as how red or white wine makes you live longer or less long, to chat about at the water-cooler.

None of these groups is benefiting strategically from the arrangement. Science is being misrepresented as a cacophony of sometimes divergent but nonetheless definitive ‘findings’, each warmly accepted by colleagues, on the record, as deeply significant. The public learns nothing about the actual cut and thrust of the scientific process, and as a result is beginning to adopt a weary cynicism that can only rebound on science in the long run.

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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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Strategies for communication…

FURTHER to my recent post on why people don’t accept evidence, it turns out that an editorial 1 and an opinion 2 piece in this week’s Nature, the latter unfortunately behind a pay-wall, actually focus on just this issue. The editorial states:

“Empirical evidence shows that people tend to react to reports on issues such as climate change according to their personal values (see page 296). Those who favour individualism over egalitarianism are more likely to reject evidence of climate change and calls to restrict emissions. And the messenger matters perhaps just as much as the message. People have more trust in experts — and scientists — when they sense that the speaker shares their values.”

So people tend to accept the evidence that supports their personal proclivities, and in fact interpret evidence in a manner than does so, thus people tend to persist in cherished beliefs and views even when confronted with contradictory evidence. This of course is something probably appreciated by most of us. Dan Kahan, in his opinion piece, points out:

“People endorse whichever position reinforces their connection to others with whom they share important commitments. As a result, public debate about science is strikingly polarized. The same groups who disagree on ‘cultural issues’ — abortion, same-sex marriage and school prayer — also disagree on whether climate change is real and on whether underground disposal of nuclear waste is safe.”

Another factor that weighs heavily in the public perception, and acceptance, of facts is the messenger. Owing to the fact that most people are ill-equipped to evaluate the raw data from scientific studies, they rely on the position of credible experts; it seems that those experts laypersons see as credible are those perceived to share the same values.

Research into the mental processes involved in such public perception is, Dan tells us, being conducted by Donald Braman at George Washington University Law School in Washington DC, Geoffrey Cohen at Stanford University in Palo Alto, California, John Gastil at the University of Washington in Seattle, Paul Slovic at the University of Oregon in Eugene and Dan Kahan, the Elizabeth K. Dollard professor of law at Yale Law School. These processes are collectively referred to as ‘cultural cognition’.

So what is cultural cognition? Kahan describes it as, ‘the influence of group values (ones relating to equality and authority, individualism and community) on risk perceptions and related beliefs.’ I would imagine that peer-pressure represents one example within a spectrum of influences in cultural cognition.

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Changing your beliefs…

FOLLOWING on from my post yesterday regarding people’s concept, or lack thereof, of evidence, it was suggested that it would be an interesting thought experiment for those of us who are willing to offer criticism on a subject to put ourselves on the receiving end. I think it’s a good idea to find something that each of us holds dear or true, and see if we can challenge ourselves to imagine how we’d feel if someone argued against that view. By understanding this, perhaps we can better approach our means of approaching such as subject with someone for whom such criticism would represent a paradigm shift.

As I managed to shake silly beliefs such as ghosts and ley-lines as a child, the only examples I have as a thinking adult are with particular scientific hypotheses that I’ve subscribed to, but subsequently had to ditch. This is the general method of science, and in my own research there have been any number of hypotheses I’ve formed and subsequently disproved on the basis of new evidence.

However, there have also been explanations for some natural phenomena that pre-date my research career, and to which I subscribed whole-heartedly. One example dates from my time as a first-year undergraduate studying marine biology. I had a particular interest in marine invertebrates and once attended a lecture by Donald Williamson, who was the major proponent of a larval evolution hypothesis, and recently came to light as being accused of ‘fringe science’ and getting a paper in the Proceedings of the National Academy of Sciences (PNAS) under the radar; thus also highlighting the pitfalls of the ‘I’ve got a mate in the club’ attitude to publishing.

Essentially Williamson felt that the immature forms (larvae) of many such invertebrates can be thought of as distinct organisms from the adult form, which are often comprehensively different both physically and physiologically; think caterpillar to butterfly, or blobby polyp jellyfish to its adult ‘medusa’ form.

Williamson felt that these different forms arose through hybridization — the fusing of two genomes (of two distinct organisms), one of which is now expressed early in an animal’s life, and the other late.

You can read an Sci. Am. article about it here.

I have to say, I absolutely LOVED this hypothesis, it was very exciting and I lapped it up with the typical fervour of an undergraduate.

Trouble is, since then it has been rebuked often and has not been substantiated by the experiments that were performed to test the hypothesis. I was quite recalcitrant about such rebukes up until the most recent PNAS rebuke that I’ve just linked to.

You can read rebukes to the Sci. Am. article here.

Changing my view about this hypothesis was hard, and a little embarrassing given I so animatedly communicated it to all my friends until I learnt it didn’t have strong grounding.

This is very true of many areas in which we are not experts, whether you are a scientist or not, and the fact is that we do tend to confer a great deal of trust in some individuals depending on their position. I would add that Donald Williamson was not ‘wrong’ to form this hypothesis at that time; scientific knowledge is by its very nature transitory, but once it has been tested, and alternatives developed, then we should seek to move on.

I could have easily ignored the evidence that Williamson’ hypothesis did not hold up to, and continued telling people an interesting and captivating story about why adult and juvenile forms of invertebrates are so different, but I didn’t. There’s still a part of me that thinks that there may still be something in it, which is why I can relate – to a point – with those people facing their first reality-check with regards some pseudoscience that they’ve hitherto believed in.

Donald Williamson is now retired and still stands by his hypothesis.

I don’t.

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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