New Year

Last year I made six New Years resolutions. Strictly speaking, I didn't actually keep any of them, but I made the effort and that counted for something. At any one time I could usually remember about four of them.

This year, I'm going to do something different. I've stolen this idea from someone else, and I'm not sure who, but the idea is that you chose just one word, and try to incorporate it into as many aspects of your life as possible.

My word is: Organisation

There are several reasons for this. The most important one is that the paycheques for my science-project have just stopped coming. However I do want to actually finish the damn thing, so I've taken up a part time job in a library to get me some money to survive while I'm doing that. I'll also be doing tuitions, supervisions and some exciting new bloggy stuff (can't say what it is right now but Watch This Space) just to scrape together a bit more cash. This means my day will have to be juggled between three hours of actual paid work, doing Science, organising lesson plans, marking essays, planning (and writing) blog posts and doing housework. None of those things can really be left un-done for more than a day.

I also need to be more organised with money as a) I'll have less of it and b) it'll be coming from all sorts of random sources and I need to keep track of it in case I get sent a letter about paying tax. As I'm no longer a student I can't use my overdraft any more because very soon I'll start getting charged for it. I need to make sure I'm keeping an eye on my PhD applications as well, before any deadlines accidently fly by me.

I'm getting married as well. They say it's good to be organised for that.

In the spirit of this I've already got two diaries (one for Life one for Blog) and a load of folders. I plan to spend New Years Day punching holes in bits of paper and sorting them all out into coloured files. Hopefully I'll get all the major bits of organisation mostly sorted in the first few months while I'm still all keen about it.

For everyone on the Gregorian Calender: Happy New Year!

Levels of evolution

Eukaryotes - animals, plants, and other creatures with a nucleus, evolve relatively slowely. Genetic variation occurs through changes in the DNA between generations; each offspring will be a genetic product of their parents and nothing else. Genetic changes happen down the generations. In bacteria, however, everything is a little more insane. Because bacteria can change DNA with almost any other bacteria they come accross, there is less of a conserved genetic record. Genes are flying around all over the place which can make it very difficult to seperate bacteria into neat taxonomic groups.

It's helped by the fact that bacterial genomes aren't completely random, and can usually be seperated into 'core' genes and 'accessory' genes. Core genes are most useful to taxonomists as they show what the bacterial species actually is, and where it sits within molecular phylogeny. The accessory genes are more interesting to bacteriologists as the play a more significant role in phenotypic differences and determin what the bacteria do. Paradoxically, the accessory genes are also the ones used most in adaption (think of antibiotic resistance) and are therefore more likely to be evolutionarily selected for or against. These accessory genes are often found in specific 'hypervariable' regions of the genome called genomic islands.

Cartoon by Nick Kim, www.nearingzero.net

The increase in second-generation sequencing technologies opened up the ability for large scale comparitive-genomics studies; essentially sequencing huge numbers of bacterial genomes and then comparing them all to each other. Back in the day, population studies were done using an approach known as MultiLocus Sequence Typing (MLST) - which took seven core genes and sequenced those for each bacteria. Nowadays you can sequences all the parts of the genome you need in hundreds of different strains.

As with most new microbiology technologies, these new techniques are initially being applied to human pathogens, as human pathogen research is (rightly) where most of the money is. Using wholescale sequencing technologies on pathogens such as Clostridium difficile which has high levels of antibiotic resistance. The grand aim is to try and understand both the extent and the distribution of natural genomic variation between one bacterial species. This could help to understand what roles are played by bacterial migrations, recombinations (switching DNA around), active selection and drift in the spread of antibiotic resistance.

C. difficile is a very genetically diverse species which has been evolving for the last 1.8 million years. As each bacteria is likely to replicate at least once a day, this allows for a huge amount of change and genetic variation. It might be suspected that the virulent species is formed from a single offshoot, one bacteria that became virulent and then passed that ability onto its offspring but instead it looks like virulence arose in many different lineages, most likely through horizontal gene transfer. This means that each different virulent strain is likely to show a relatively large amount of variation in the rest of its genome.

It isn't just small bits of DNA on separate plasmids that C. difficile can exchange, they can also carry out homologous recombination, a process by which whole sections of the bacterial genome can be cut out and shared between related species. This process is aided by the presence of 'mobile elements' within the genome, i.e pieces of DNA which are particularly good at jumping around and splicing themselves in and out of bacterial chromosomes. It turns out that the C. difficile genome contains lots of mobile elements.

From a bacteriologists point of view this is a fascinating example of just how variable a single strain of bacterial species can be. From a medical viewpoint it's more worrying. The ability of highly virulent bacteria to chop out large portions of their genome and pass them onto other, potentially non-virulent strains could help to spread not just antibiotic resistance, but also other tricks like biofilm formation and different enzymes which help the bacteria to cope with antibiotic challenges.

Not only that but it means that every gene in the genome has been tried and tested by many different strains in many different conditions. They aren't just good genes for the bacteria to be hanging onto. They're the best.

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He, M., Sebaihia, M., Lawley, T., Stabler, R., Dawson, L., Martin, M., Holt, K., Seth-Smith, H., Quail, M., Rance, R., Brooks, K., Churcher, C., Harris, D., Bentley, S., Burrows, C., Clark, L., Corton, C., Murray, V., Rose, G., Thurston, S., van Tonder, A., Walker, D., Wren, B., Dougan, G., & Parkhill, J. (2010). Evolutionary dynamics of Clostridium difficile over short and long time scales Proceedings of the National Academy of Sciences, 107 (16), 7527-7532 DOI: 10.1073/pnas.0914322107

New Look!

In a move that has been in the works for some time, FoS has gotten a nice new makeover which means that the more perceptive of may readers may notice that things look a little different around here. Not hugely different, because the old design was pretty good, but a little smarter and more neat. This design was all worked out and implemented by Edward, who does all the work around here.

One of my favourite bits of the changes is that I've now got a "Popular Posts" gadget on the sidebar. Although I am slightly miffed that according to that the the most popular post on a bacterial blog is the random one I did about amphibian skin. I'm not sure how often or when it changes so I shall be keeping an eye on it over the next few weeks to try and fathom how it works.

There arealso a couple of things that I want to try and add to my new design; a gadget for MolBio carnival submissions (the original one takes far too long to load) and, ideally, a little "if you enjoyed that post, why not try these others?" type thing under each of my posts. Wordpress has a good way of doing it, so I'll be looking for a blogger hack that works passably well.

Not for a couple of days though, because at the moment the lab is full of the typical Lab Christmas Feeling - i.e everyone desperately trying to get as much work done as possible before they leave for the holidays. Added to which I'm busy writing PhD applications at the moment, trying to sort out my job for next term, and organise things so that I can still get back to my current lab after the holiday, because there's still a good few weeks work I need to get in, even though I'm technically not actually getting paid for it.

There should be a couple more December posts though, and your regular Lab Rat schedule will return in the New Year.

For those who are having a holiday - best wishes for happy holidays!

Guest post: Communication - it's not just for cells!

This guest post comes from a real life friend of mine (yes I do have friends in real life). He's currently doing a PhD in developmental biology, and has just started an awesome new blog.

Genetic modification! Stem cells! Genomes! Cloning! These “buzz” words are constantly used by the media in discussions of biological research. These are the words that incite panic and fear in the average tabloid reader. The phrases that make politicians cut science funding, and that make people run screaming when you innocently tell them you work in *deep, ominous, scary voice* science.

Hi, I’m Ret, a good friend of the Lab Rat. From the real world! I also spend far too much of my time locked away in labs, although I work on slightly bigger systems than bacteria. I am currently studying for a PhD in developmental biology. I also strongly believe in the power of good publicity. I believe that scientists need to work much harder to clearly and accurately report their findings to the general public.

For hundreds of years science has been the fodder of the academic, providing all the great advancements as it filters down from the ivory towers of learning, but to the person on the street it is the stuff of horror films; creating patched together monsters and unspeakable abominations of nature. In recent years, with unlimited access to the Internet and the increasing dominance of the media over public opinions, people have really started to take an interest in what we’ve been doing all of these years. An interest that has been fuelled by the economic downturn; the people want to know what’s been happening to all their money. There was a time when we would have rejoiced that people are finally paying attention, yet instead many of us use the typical academic response; we hide behind long words, inaccessible terminology and confounding acronyms.

Having just graduated from university I am very aware of the emphasis that many courses now place on the importance of good presentation skills, which enable us to stand up at conferences and tell a room full of our peers all about what we’ve been doing and why it is significant. What we are not currently taught is how best to communicate with those who are less fluent in the ways of academic research; How to simplify and “sex up” our findings so that people from any background can easily grasp and understand the benefits of what we are doing.

Up until now we have been leaving this job to the media. In the world of journalism, however, a high readership is generally more important than complete scientific accuracy. The eyecatching headlines that result from this are at the root of many public misconceptions of biosciences and only by committing ourselves to direct communication with as many different groups of people as possible can we hope to rectify these grave and long standing errors.

A current favourite of mine is the recent NASA announcement of bacteria which substitute phosphorus in their cells for arsenic, thus providing a new basis for life; or so they claim, even going so far as to imply that this is strong proof for the existence of aliens, and is a revolution in our understanding of science. This is a classic example of the misrepresentation of biological research, (although, having read the paper, it sounds like the research in itself may be a little dodgy). It is however a great example of how to drum up good publicity. I discuss this in more detail on my own blog, but as a starting point, it seems rather odd to me that NASA happens to make this big announcement about discovering potential proof of aliens just days after once again receiving a lot of bad press for once again delaying the shuttle launch. Can anyone say distraction technique?

If we do not engage with the populace, if we do not help them see why our work is important, then they will continue to shy away from us. Without public support all fields of science are subject to unnecessary limitations. Stem cell research globally was significantly inhibited by the short-lived US research ban, a policy brought about by public fear. Terror is keeping the human race from making the most of what it has, we are unable to alleviate poverty and starvation because we are prevented from widespread use of GM crops. Our work with animals is so misunderstood that many who work on animal models are forced to suffer constant hounding by protesters. Most researchers in our fields are here because they want to help; they want to cure the sick, feed the starving and ultimately save the world. However, to see the benefits of this we must bring about acceptance of our ideas so that they can be widely implemented where they are most needed. Hence, communication of our research should be as much a part of our lives as doing the experiments in the first place.

A major factor in this miscommunication, that we all need to work hard to address, is the conception of time. In the 21^st century, everyone is used to getting what they want right now! Unfortunately that’s just not the way science works. Start talking about oncogenes and people expect the cure for cancer in the next 6 months. Mention pluripotency and before long the media will be raving about regrowing organs. Influenza, HIV etc. They want it now. Why haven’t we done this? Why haven’t we done that?

The idea that people get from the media, and even from science education up to late degree level is that science is quick. When you did practicals in science class you mixed some stuff together and got a really clear answer in an hour or two. It was perfect, definitive, clean and quick. What you don’t realise until you start doing your own research out at the boundaries is that it’s all a fix. Many modern techniques, even the simple ones involve extensive preparation and incubation times. You can easily spend a week on one set of samples just for them all to fail to work out and for you to get no results. Real significant research is often a very slow process involving many repeated experiments and huge amounts of failures and this is something that many other people just don’t understand; something which is truly foreign to the journalists reporting our findings and to the majority of their readers and something which is easily glossed over, even in our own writings. As it stands, it is only when you do research that you come to appreciate just how much effort went into every tiny detail. How every gene, every protein, every interaction is the product of dozens of PhD projects.

It is for us, as the new generation of academics and science professionals to go against the status quo, to make our work as accessible as possible to everyone and to actively engage with people on a level that they can relate to. Only by doing this can we hope for people to see the true potential benefits of the work we dedicate our lives to, and to understand that there is no quick and easy shortcut to the answers that we are seeking. Only through this can we hope to restore faith in research and save our field from a fast approaching demise at the hands of economic collapse.

The focus of my blog will be accessible science; I hope you recommend it to all of those friends and relations who are always asking you about the latest science news stories. I also invite you to write a guest post, I am looking to cover a broad range of different fields and would be extremely grateful if you felt like sharing your current research with the rest of the world. I also aim to accurately report on the big bioscience news stories. So if you think there is a big story that I should be covering; a serious case of distorting the facts, please let me know and I’ll do my best to provide reliable coverage.

Guest post - Microbes and Madness

This guest post comes from my fiancé who is a Psychiatrist. I've been very excited about this post for a while, because unlike me, he is a published author who has written a book on Consciousness and the philosophy of mind.

Microbes and Madness

At first glance, it would be reasonable to assume that my profession and that of the author of this fabulous blog are poles apart. However, everything in nature has a connection, and so it is not surprising to discover a fascinating area where psychiatry and bacteriology overlap.

A broad range of pathogens are known to cause psychiatric sequelae, including worms (neurocysticercosis), protozoa (cerebral malaria, toxoplasmosis), viruses (HIV, herpes simplex encephalitis, rabies), prions (Creutzfeldt-Jakob disease, kuru), and, of course, bacteria (neurosyphilis, Lyme disease, post-streptococcal syndromes). However, in the spirit of this blog, this post will be focusing on bacteria.

There are essentially four mechanisms through which bacteria cause psychiatric symptoms in humans:

I. Bacteria can infect the central nervous system and cause direct damage to brain cells.
II. Bacteria can trigger a powerful systemic inflammatory response that results in a disruption in brain function.
III. Bacteria can trigger an adaptive immune response which produces antibodies that cross-react with host central nervous system proteins.
IV. Bacteria can be the objects of a phobia.

Syphilis and Lyme disease are examples of infections which involve the first mechanism. Syphilis is caused by spirochaetes of the species Treponema pallidum, and is sexually-transmitted. Lyme disease is caused by spirochaetes of the genus Borrelia, and is vector-borne, with ticks from the genus Ixodes being the commonest vector. Both diseases are associated with widespread dissemination of infection of multiple organ systems, and are notorious for their protean manifestations.

The range of possible psychiatric presentations is vast. Syphilis, in particular, can mimic any psychiatric syndrome, and was a common diagnosis in psychiatric inpatients a century ago. The possible range of presentations include delirium, dementia, psychosis, mania, and personality changes. Lesions of the frontal lobes are associated with personality changes and disinhibited behaviour, whereas those of the temporal and parietal lobes are associated with cognitive decline. Lyme disease can also mimic several different psychiatric syndromes, but typically affects the limbic system, causing disorders of emotional regulation, including panic attacks, phobias, depression, and obsessive-compulsive behaviour.

The second mechanism listed refers to sepsis-associated delirium. No human organ system is a closed system, including the central nervous system. Bacterial infections with a focus outside the outside the brain are capable of causing a systemic reaction, which affects the brain. The result is an acute confusional state, or delirium.

Common causes are pneumonias and urinary tract infections, although infections of other organ systems are also frequently implicated. Delirium presents as a transient global disorder of cognition. Typically, there is clouding of awareness, disorientation, impaired attention, fluctuating alertness with agitation or drowsiness, hallucinations, illusion, and vague delusions. The state is thought to be caused by a global disruption of brain function, which may result from the effects of a systemic inflammatory response to infection. These effects may include systemic vasodilation causing cerebral hypoperfusion, increased permeability of capillaries allowing toxins to cross the blood-brain barrier, the action of inflammatory cytokines on the brain, and increased body temperature resulting in an increase in neuronal oxygen demand.

The third mechanism is seen following infections with group A beta-haemolytic Streptococcus pyogenes, such as scarlet fever and tonsillitis. In response to infection, the adaptive immune system produces antibodies against antigens on the invading pathogen. However, some streptococcal antigens are similar in some way to antigens on host tissues, and so the antibodies produced mistakenly recognise and attack the host tissues. Examples of post-streptococcal autoimmune diseases include rheumatic fever, glomerulnephritis, and Sydenham’s chorea.

A psychiatric syndrome caused by this mechanism is PANDAS, which stands for paediatric autoimmune neuropsychiatric disorder associated with streptococcus. This typically presents as a dramatic onset of obsessive-compulsive disorder, tic disorders, or Gilles de la Tourette syndrome following an infection with group A beta-haemolytic Streptococcus pyogenes in childhood. It is thought to be a result of autoimmune damage to the basal ganglia, which is the part of the brain involved with the initiation and regulation of motor commands. Interestingly, it has also been suggested that encephalitis lethargica, a mysterious syndrome which caused an epidemic during World War I, may also be caused by a post-streptococcal autoimmune reaction.

The fourth and final mechanism listed refers to mysophobia, or the pathological fear of germs. Behavioural symptoms include repeated washing of hands, excessive cleanliness, and avoidance of social contact. Anxiety and panic attacks also occur. Although the behavioural manifestations are similar, mysophobia is not to be confused with obsessive-compulsive disorder. The former is a phobic disorder, in which the fear of germs underlies the behaviour, and the function of the behaviour is avoidance of the phobic object. In the latter, the behaviour is compulsively carried out in response to the obsession that the behaviour must be carried out.

I hope to have provided an comprehensive overview of some of the interesting ways microbes can cause mental and behavioural disturbances in humans. The function of this ability is open to speculation. The film 28 Days Later tells the story of an artificial ‘Rage’ virus. When a human is infected, he or she becomes uncontrollably aggressive, attacking other humans and infecting them with viruses in the process. Thus, the viruses’ effect on human behaviour is clearly advantageous to their spread and propagation. However, outside of fiction, the advantages of pathogens’ effects on human behaviour is less obvious. Even with rabies, on which the symptoms of the ‘Rage’ were based, there has been no documented human-to-human transmission through bites. In fact, the only documented cases of human-to-human transmission of rabies were of transplant recipients receiving corneas from infected donors! It is therefore not known what evolutionary advantage, if any, the psychiatric sequelae of infection convey to the pathogens. It is possible that they are epiphenomenal.

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Pfister D, Siegemund M, Dell-Kuster S, Smielewski P, Rüegg S, Strebel SP, Marsch SC, Pargger H, & Steiner LA (2008). Cerebral perfusion in sepsis-associated delirium. Critical care (London, England), 12 (3) PMID: 18457586

Neurosyphilis: Considerations For A Psychiatrist Mark A. Ritchie, Joseph A. Perdigao, Mark A. Ritchie

The Neuropsychiatric Assessment of Lyme Disease

A. Mazzola, G. Mazzola (2006). OCD And Beta Haemolytic Streptococcus: A Nasty Association. Priory publishing link

The MolBio Carnival is here!

The fifth issue of the MolBio carnival is here! We've got loads of great entries in this edition, all focusing on the mysterious world inside cells, so take some time out to take a look and comment on them. The inside of cells is such a fascinating place to explore - and many of these posts were written by the people whose job it is to explore them. I've used a fairly broad interpretation of molecular biology, so in this carnival you'll see everything from the atomic details of protein interactions, to the (comparatively) far bigger world of bacterial colonies in the gut.

All good explorations should start with a map - and you don't get much better than the truly gorgeous pictures spotlighted by E. Campbell of the HighMag Blog. This beautiful picture shows a cell with the actin-binding proteins stained purple in order to see how they interact with a mutant actin motor.

Once we head inside the cell, we can start to explore the many complex and fascinating interactions that help to control it. While the DNA might encode all the information needed to create cellular proteins, it isn't just the DNA that is responsible for cellular behaviour, as explained by Christopher Dieni in "How I Learned to Stop Worrying and Love Epigenetics" (which comes second place in the Lab Rat award for best post name). As well as proteins, DNA expression is also controlled by fragments of RNA, explained beautifully clearly by student blogger Khalil A. Cassimally who looks into whether miRNA might be used to control cocaine addiction. And while we're at the level of molecular interactions for cellular control, we can look at control mechanisms for protein folding as well, as the Computational Biology blog takes us through the consequences of entanglement during protein folding.

Picture from Robert Ezra showing protein (green) binding to DNA (gold)

But the cell does not consist solely of DNA and proteins - it also relies on metabolites such as sugars and fats. These metabolites pass through a complex series of reactions in order to convert them to energy, and research on how these reactions occur and are controlled has been going on for many years. Sigmabioblogs has a wonderful interview with the biolegend Dr. Donald Nicholson, who is now over 80 years old and has been working on metabolic pathways for pretty much his entire life! On the subject of nutrients, there is also a great bilingual post on Knedliky about how flavour-enhancers work at a molecular level.

These small and focused intramolecular reactions aren't just used to control the cell, but also to control far bigger systems, or cell-cell interactions and communication. Memoirs of a Defective Brain explains how the bacteria Strep pyogenes uses intramolecular interactions to prevent the immune system recognising an infection. His post "The SpyCEP who cleaved me" not only wins the Lab Rat award for best post name, but also features the BEST diagram I've ever seen for explaining the subtle and complex interactions between cells of the immune system:

While we're on the theme of bacteria (yay!) we'll head over to the stomach. James, of (currently...) Disease of the Week, has written a great two part series on those bacteria in our gut, focusing on the question of how they actually get into our gut, and what they do when they get there. Part 1 deals with babies, and Part 2 with adults. There's also a lovely post from Lucas Brouwers, of Thoughtomics, which looks at the evolution of cyanobacterial toxins - and why a bacteria that lived millions of years before humans were even thought of would need to produce such a powerful neurotoxin.

And lets not forget the plants! They rely on intracellular interactions as much as any other organism. There's an old (but very good) post from Denim and Tweed about how nitrogen fixing bacteria made the leap from being intracellular parasites to mutualistic helpers. We've also got a post from It Takes 30 - about how sex is specified in plants. Unlike humans, who rely on chromosomes, hormones, and a whole host of social norms and pressures to distinguish the sexes, plants might need no more than a single amino acid insertion.

Those are basically just brightly painted sexual organs on display

We'll finish the exploration on a slightly larger, but no less fascinating level, the reproductive systems of marsupials by the amazing piratey Captain Skellet. By labelling gene markers for the development of organs researchers have come to the (not unexpected) conclusion that marsupials are Just Weird, and no one is quite sure why...

The next edition of the MolBio carnival will be hosted at PHASED, so if you've missed out this time, go submit your posts here by the 3rd of January. Blog carnivals are a great way to share information and to get new readers, so it's highly recommended!