Hibernate or hibernot

If the Land Rover advertising campaign is to be believed, us humans should not hibernate, as it is a waste of time during the cold winter months. Although, after reading new research published on the virtues of hibernation for neurodegenerative disorders, I believe this is an ill advised message. Who hasn't considered the concept of hibernation for humans? Just me? Ok, at first glance it doesn't seem a particularly attractive concept, going into a self induced 'coma-like' state during periods of low temperature, in a state of metabolic depression. Interestingly a process called  heterothermy occurs in hibernating mammals, during which they transition from being homeostatic endothermic to being ectothermic organisms, relying on their environment to regulate body heat, allowing for the slowing down of metabolic processes. The more you know right? But let's get back to the crux of this post: does hibernation actually have health benefits? Oh I'm so glad you asked. A UK team from the MRC Toxicology unit in Leicester have discovered the so called 'cold-shock chemicals' that cause mammals to destroy connections in their brains as they enter hibernation. Around 30% of synapses in the brain are destroyed, due to the slower metabolic rate during the winter. But what's truly amazing is that these culled synapses are reformed when the animal awakens in the spring! This obviously has huge implications for the medical profession, because the chemical released in the neural tissue as the animal begins to wake up and needs to repair synapses, RBM3, could be used to treat previously incurable conditions caused by prions, like Creutzfeldt–Jakob disease in humans. By artificially boosting levels of RBM3 in the brain, researchers have found that neurone death due to the misfolding of proteins caused by prions can be significantly reduced, and so we are one step closer to a drug that specifically targets the deadly neurone destroying agents that are prions. Memories are even retained after hibernation, as only the impulse receiving end of the synapses are destroyed (this is pretty obvious if you think about it, as a survival mechanism that wipes the animal's memory clean would be quite detrimental to its survival chances), and there is therefore a strong chance the RBM3 could be tailored into a drug to treat Alzheimer's patients, to slow down or even stop neurone loss during the early stages of the disease. Unfortunately the human body is not adapted to hibernate, as we don't produce enough RBM3 naturally, but I would certainly hibernate if given the chance. You would miss the most depressing months of the year, and reduce the risk of neurodegenerative disorders in later life. Stuff that in your gas-guzzling V8s Land Rover.

The MHCs: the immunological proteins you probably haven't heard of.

When one thinks of immunological proteins, you think of the big players; histamines, cytokines, and B/T cell receptors like CD4. However there are a little known family of proteins, that do play a vital role in the immune response, more specifically in antigen presentation, which make a bold claim in their name; the Major Histocompatability Complexes. In antigen presentation, a phagocyte like a macrophage or dendritic cell displays the antigens, which are specific peptide sequences used by the immune system to identify a pathogen, from the microbe it has just hydrolysed on its cell membrane. The protein the phagocytes use to do this is the MHC II. The phagocyte presenting these antigens will then travel to a lymphoid organ, the thymus or yellow bone marrow for example, through lymph and activate naive T cells. The CD4 receptor on the T cells must be able to dock to the MHC class II protein, so the epitope; the antigenic determinant which is recognised by the immune system, can imprint on the T cell receptor, priming it and therefore forming the effector T cells: the cytokine releasing T helpers which serve to rally the immune response, or the cytotoxic T killers which kill virally infected cells like homicidal spear wielding warriors. This in fact leads me on to the other class of Major Histocompatability Complex: MHC I. I made a passing reference to it as a 'surface marker' used in the immune response during a previous post, most people would stop there and move on to more significant proteins like interferon, but I'm not like most people (hence this blog). MHC I can be expressed on the surface membrane of almost every body cell, and it also displays the epitopes of antigens when, but for an altogether more sinister purpose... Ok that was slightly dramatic, but I doubt most people will read this far into the entry, so I can do what I want down here (whilst still remaining factually correct of course). The cells displaying epitopes on MHC I are virally infected, and can dock with the CD8 glycoprotein and the TCR found on the surface of T killer cells, and so they release cytotoxins like perforin, which destroys the cell membrane thus promoting PCD by apoptosis. How neat. So without this often overlooked protein, there would be no antigen presentation to trigger the adaptive Immune system, or pleasingly efficient destruction of virally infected cells. It just goes to show how interdependent every molecule in our bodies are, a principle that one should both admire and be absolutely petrified about...

Toxoplasma gondii: the parasite with a penchant for felids

If you hadn't already realised, dear readers, I'm a huge nerd. Wipe that look of shock off your faces. Anyway, I've been extremely busy with Pokemon Alpha Sapphire, revision and Fullmetal Alchemist. I'm only human ok! I've also been working tirelessly on my Extended Project, a 5,000 word dissertation of the topic of feline intelligence. Most people chose sensible topics like stem cell research, the UK's involvement in the EU, or the parallels between historical leaders, but I, in an attempt to make my life that little bit more difficult, decided to pick a topic that has very little debate, and even fewer people who are interested in the answer. Whilst I was researching the controversial topic of the intelligence of the domestic cat, I stumbled upon a parasite known as Toxoplasma gondii (T. gondii), as T. gondii's primary host is the domestic cat. T. gondii is a unicellular eukaryotic organism, a protozoan, that causes a disease called Toxoplasmosis in human host cells. Toxoplasmosis is the root of the term 'crazy cat lady' syndrome, as there is a definite link between the disease and mental health issues like schizophrenia, although most hosts are just symptomless carriers. Great. That's what I've got to look forward to.  It is one of the most common parasites found in the human body, and it is estimated that 1/3 of the global population is infected. The parasite can reproduce asexually within virtually all exothermic mammals, however it can only reproduce sexually in the intestines of Felids. This basically means it can only adapt and change its structure to evade our immune systems within cats, making them its definitive host. In order to optimise its chances of infecting cats, T. gondii can alter the behaviour of intermediate hosts like mice, to make them attracted to the scent of cat urine, so they are more likely to be preyed on by a passing feline. To do this the parasite hijacks white blood cells, which seem to be the target for pathogenic attack quite frequently (even parasites have a sense of humour). The WBCs are converted into chemical factories, synthesising neurotransmitters like serotonin, to reduce response of fear and anxiety that usually occurs in the amygdala of the mouse, as soon as it smells a feline nearby. The parasite resides within a membrane known as an oocyst until it passes through the stomach and the membrane is hydrolysed. It then infects epithelial cells, in which it is converted to Tachyzoite cells, speeding up the rate of proliferation, then they are converted to slow dividing Bradyzoites, which form tissue cysts in the host, completing the parasite's lifecycle. It's a feat of biological adaptation that a parasite can become so ultra-specialised to one particular host, but like a lot of evolution and natural selection, this mechanism is kept because it works. It worked during the evolution of the parasite, and so that's what it does to this day, and what it will continue to do until domestic cats develop a resistance to it. T. gondii stubbornly resists change, and that's why I like it...

Vitamin D: the mechanism, the molecule, the screenplay

What's hip loyal biologists? (obviously not this blog) Today on my quest for knowledge of our biological universe, I came across the fascinating, fat soluble steroid known as Vitamin D. The D2 and D3 molecules to be more precise. You've probably heard of rickets, and a bit about how the sun stimulates Vitamin D's release in our bodies. If you're an introvert obsessed with science and video games like me, then you know where I'm coming from. Vitamin D is vital in our bodies to enhance absorption of key minerals in the intestinal system, like calcium, iron or zinc. These elements are used to construct and maintain our skeletal system, so that's why if children develop a vitamin D deficiency, their bones can become elongated and deformed, because they cannot absorb enough calcium or phosphorous for proper skeletal development. Although this mostly occurs in countries with a high prevalence of genetic disorders such as pseudovitamin D deficiency rickets. Vitamin D is marketed on the internet as a miracle cure for conditions like cancer, heart disease, depression and autoimmune disease, despite the fact that no clinical trials have proven this claim. In fact they mostly say Vitamin D has a negligible impact on such conditions. The D3 vitamin molecule is produced in the skin, when exposed to UV light, from another molecule called 7-dehydrocholesterol. This precursor of vitamin D3 is produced in relatively large quantities, in fact 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure, in the skin of most vertebrate animals. 7-dehydrocholesterol is converted into D3 by UVB rays between 270 and 300 nm, but occasionally an equilibrium can form in the skin, in which vitamin D degrades as fast as it is synthesised. But that's not the end of vitamin D's journey in the body. In the liver it is converted into a prohormone (precursor to a hormone) known as calcidiol, and then it is converted yet again in the kidneys, but this time to its biologically active form; calcitriol (a bit like phytochromes in plants for you botanists out there) . Calcitriol binds to the vitamin D-binding protein, which transports it to vitamin D-rerceptors (VDRs) on the surface of target cells. Here's where it gets really good. The VDRs bound to vitamin D will act as transcription factors, promoting expression of transport proteins like TRPV6 (catchy right?) within cells,  which are involved in absorption of calcium in the immune system. So what have we learnt? For one thing the proteins and receptors involved with Vitamin D have incredibly uncreative names. But on a more serious note, sunlight is essential to skeletal health, so maybe we should embark on adventures is the great outdoors more frequently! I'm such a hypocrite... 

Avian flu: taking flight?

On 16th November a duck breeding farm in Yorkshire tested positive for avian flu, so as you can imagine DEFRA was on the scene immediately, introducing a 10km restriction zone and culling all 6,000 birds on the farm to prevent further spread of the disease. But why? Is avian flu so contagious, that such an extreme response was warranted? Is it that dangerous? Let's find out shall we. Avian flu is caused by the influenza A strain of the influenza virus (although A does not stand for avian). All subtypes of influenza A are adapted to be able to use birds as a host, but are not always zoonotic (can pass from animals to humans). Influenza A is what is known as an  single stranded antisense RNA virus, meaning its single strand of RNA (3'-5') runs complementary to viral mRNA (5'-3')  that it encodes. This means it must carry RNA polymerase within the virion particle, as the viral RNA cannot be directly translated into protein, it  must be transcribed first, rather like DNA. Influenza A can be categorised into 2 subtypes based on the protein used to construct its membrane: Hemagglutinin (H) or Neuraminidase (N) . The H protein causes agglutination of red blood cells in the host, and mediates the binding of a virion particle to the host cell and entry of the viral genome into the host cell genome.  Whereas N is an enzyme that breaks the glycosidic bonds in the monosaccharide, neuraminic acid, commonly found in animal cells as glycoprotein and it also controls the release of new virion particles from host cells. Different strains of influenza virus encode for different types of N and H which all play a specific role in the viral lifecycle, for example H5N1 virus  contains type 5 Hemagglutinin and type 1 Neuraminidase (oh how I love arbitrary numbers used to name pathogens). Interestingly, these 2 proteins form the antigens that allow antibodies produced by B cells to bind to the microbe, so macrophages can phagocytose it. Ok,  I think I've indulged you enough in the virus' structure and nomenclature, so let's talk about the birds. The outbreak in Yorkshire recently was H5N8 strain, which is of very little threat to people. In fact no one has died from it. Ever. The avian flu strains that you really have to worry about are H7N9 continually reported in poultry in China, and H5N1, which has a 60% case mortality rate across 15 countries (since 2003). Migratory fowl can act as asymptomatic carriers for the virus, which is probably how it reached the UK in the first place, and strains like H5N1 are not limited to birds and people; in New England 400 harbour seals were killed by the pathogen in a 1978 epidemic. Ok, so we know that certain strains of influenza A are deadly to people, but if the H5N8 strain poses no threat to us, why were all the ducks killed? Well, because of the high mutation rate of the virus, and its ability to hybridise with strains from other species, it could quickly become a human epidemic. So before we start arguing over the 'poor ducks' that were 'murdered', we must consider the potential threat of any strain of influenza to humans.

Immunology: your life depends on it

The mechanisms employed by the human body to destroy and to resist pathogen infection are simply breathtaking. The field of immunology is vast, and often taken for granted by the less inquisitive of our race, so my aim for this post is to dispel any doubt about how vital our immune system is, and perhaps put the fear of the fictional god in your heart. Let's start with the basics: most mammalian immune systems are split into 2 tiers: the innate and adaptive immune systems. The innate response is usually triggered by pathogens being detected by pattern recognition receptors, which respond to generic microorganism components or the cries for help from body cells. The innate immune system is therefore non-specific, so it does not produce antibodies, but it can act on a wide range of microbes, making it the first and main line of defence against disease in the human body. There are multiple components to this immune system; surface barriers like our skin and mucus,  mechanical barriers like coughing up mucus filled with pathogens to protect the lungs and respiratory tract and biological barriers, like the gut flora in our intestines which competes against parasitic pathogens. Inflammation in response to injury is also part of the innate system; compromised cells release signalling molecules (like cytokines) to dilate blood vessels and attract white bloods cells (leukocytes), specifically phagocytes, which digest the invading pathogens. The mammalian complement system is is another vital part of this response. Essentially, complement proteins bind to carbohydrate receptors on the surface of microbes, triggering a cascade of protease-like molecules which break down the surface of a microbe, rendering it inactive. It's a bit like the body's version of a gatling gun. The final elements of the innate system are the natural killer cells, which detect cells with low levels of a surface marker called MHC, meaning the cells are infected or cancerous, and they are destroyed. NK cells aren't concerned about trivial things like collateral damage... 
Let's now move on to the adaptive immune system, which is definitely my favourite, if you can have a favourite layer of the immune system. It is more potent, and is capable of remembering microbes because of their signature antigens, to speed up immune response. Therefore the adaptive immune system is antigen specific, so can recognise specific antigens in antigen presentation of cells. This system employs more variants of leukocytes, known as lymphocyte B cells and T cells. The B cells produce antibodies to target specific antigens on microbes, causing them to bind together, making it easier for phagocytosis to occur. The T kills can split into 2 kinds: T helper cells and T killer cells. T killer cells kill cells infected with pathogens (viruses in particular), and each one recognises a specific antigen (like everything in this system). When activated T killer cells release cytotoxins into compromised cells, inducing apoptosis. How neat. T helper cells regulate the immune response, by directing other cells to perform immunological tasks like digesting pathogens or producing antibodies. The most impressive thing about B and T cells is that their daughter cells can become long-lived memory cells, which remember specific antigens encountered in the past, and so can produce a particularly powerful immune response if that antigen is detected in the body again. Just from this brief overview of the immune system (trust me, this is heavily summarised), I hope you can see how vital every mechanism is to our health. Your heart may keep blood flowing around your body, your lungs may be the centre of gas exchange, but they would be meaningless without the protection the immune system affords your body. Next post I'll be describing what happens when the immune system fails. Trust me, it will be terrifying. 

Retrotransposons: bringing disco back?

Sorry about the cliffhanger in the last post. I lied, I'm moving on to a new topic today: the humble retrotransposon, although its hardly humble considering 48% of our genome is made up of transposons or their remnants. A retrotransposon is a piece of DNA that doesn't code for a protein (no DNA codes directly for proteins, but you know what I mean), but it codes for an abnormal piece of RNA. It can roam the genome freely, unlike most other RNA molecules. They can replicate infinitely using this RNA intermediate, and thus increase the frequency of certain elements of the genome. But how exactly do they do this as RNA? Well, it does this by breaking the rules. The biological dogma states that DNA codes for RNA, which codes for proteins, and they code for nothing. However the retrotransposon can use an enzyme known as reverse transcriptase, which it codes for, to become deoxyribonucleic acid again. Retroviruses can also do this with their genetic material (hence the 'retro' in their names). Retrotransposons can induce mutations, and cause malfunction in gene regulating mechanisms by inserting themselves between, or even directly into genes, which makes them useful for studying epigenetic mechanisms like DNA methylation. In mice for example the variation in expression of a retrotransposon due to methylation affects expression of the agouti coat colour gene, as usually RNA from retrotransposons messes up control of downstream agouti gene keeping it switched on continuously, leading to coat colour variability between genetically identical individuals, purely due to molecular modifications to the DNA. Furthermore, the mutations introduced by retrotransposons are very stable, because the base sequence at the insertion site stays constant as they transpose via semi-conservative DNA replication. As retrotransposons age they often accumulate mutations, and so are unable to retrostranspose. Transposition and survival of retrotransposons within the host genome are regulated both by retrotransposon- and host-encoded factors, to avoid deletion of elements of the retrotransposon and the host genome, in a symbiotic relationship that has existed for millions of years between retrotransposons and their hosts. The study of how retrotransposons and their host genomes have co-evolved mechanisms to regulate; transposition, specific insertion sites, and mutational outcomes to optimise each other's survival is still a developing field, which I find quite amazing, considering that the retrotransposons represent about 50% of our genome. We don't even know if most of them do anything, they're almost like outsiders in our own bodies...