What is The Role of Epigenetics in Cancer? Whats Your Poison?

The Damaging Effects of Alcohol Of Mice and Men: JQ1 the First Male Contraceptive Call for Universal HPV Vaccination

In Vivo

Issue 3 March 2013 1

Contents
Biochemistry
- Promising Drug Target Discovered To Treat Staphylococcus Infection p3 - Metabolic Reprogramming of Cancer Cells p4

Contact Us
If you are interested in writing for In Vivo or have any questions for the editing team, please dont hesitate to get in touch via our emails below. Caroline Gill - Editor invivowarwick@gmail.com Hayley Clissold - Biochemistry biochem.invivo@gmail.com Rebecca Crosby - Biomedical Science biomed.invivo@gmail.com Beth Francis - Environmental and Biological Sciences env.bio.invivo@gmail.com Sam Rollins - Microbiology and Virology viromicro.invivo@gmail.com John George - Assistant Editor

Biological & Environmental Sciences

-Save The Sharks p7 -What is The Role of Epigenetics in Cancer? p8

Biomedical Sciences

-Of Mice and Men - JQ1 the First Male Contraceptive p10 -Does Chewing Gum Aid Concentration? p11 -Whats Your Poison? The Damaging Effects of Alcohol p12

Microbiology & Virology

- Call for Universal HPV Vaccination p15 - Measles Hits 18 Year High in The UK p16 - Overcoming Drug Resistance in Influenza p17 - Novel Coronavirus Infections in the UK p18

Careers

- Professor Keith Leppard: In Vivo interviews Professor Keith Leppard on his career in research and academia.

This magazine is available to read online at: www.warwick.ac.uk/lifesci/intranet/guide/news/invivo

* The front cover image is accredited to Christoph Bock (Max Planck Institute for Informatics). It depicts a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer.

In Vivo Biochemistry Promising Drug Target Discovered To Treat Staphylococcus Infection

By Liam Mistry First Year Biomedical Science Staphylococcus aureus is a highly infective bacterium that is classified as a member of the Firmicutes phylum. It is commonly found in human respiratory tract infections and also causes moderate to severe skin infections such as impetigo, organ infections such as endocarditis, and a variety of toxinoses such as toxic shock syndrome. Pathogenicity of the organism in these types of diseases is often determined by a series of secreted virulence factors, which include exo-enzymes and protein toxins. The latest discovery of a system used by S. aureus to transport toxins is a promising lead for the development of a new type of drug to the bacterial infection. Some S. aureus strains are not pathogenic and form part of the bodys natural skin microbiome, which usually comprises approximately 1012 bacteria. Pathogenic strains, such as those that are methicillin-resistant (MRSA), do however pose major health risks because of the difficulty of treatment with suitable antibiotics. Currently the antibiotic Vancomycin, in combination with other drugs, is used to help treat MRSA infections; however, evidence is growing which suggests that even resistance to this antibiotic is spreading globally. Resistance is becoming a very dangerous and increasing threat to human health, with many bacteria now possessing sophisticated mechanisms which they use to overcome antibiotic treatment, additionally the ever increasing movement of people across the globe is a major factor leading to the widespread distribution of such types of bacteria. Scientists at the U.S. National Institutes of Health (NIH), one of the worlds largest institutes for medical research, have identified a new system by which S. aureus transports the Phenol-Soluble Modulins (PSMs) a family of protein toxins. PSMs have gained much attention in recent years, but progress in research has been relatively slow because of their complexity and diversity. NIH scientists have now however expanded on work which was first carried out in 2007 that first described PSMs. The newly discovered Pmt transport system is common to all S. aureus, where it was also found to be critical to bacterial proliferation and disease development when modelled in mice. The study not only allowed identification of this new system, but it also suggested that its inhibition could lead >> Scanning electron micrograph of Methicillin Resistant Staphylococus aureus directly to bacterial cell (MRSA)- A common dangerous pathogen death. The study focussed on S. aureus bacteria, nevertheless scientists suspect that the Pmt system performs the same role in other staphylococci, such as S. epidermidis, which is the leading cause of hospital-acquired infections involving indwelling medical devices (e.g. catheters). The discovery, which was published in Nature Medicine on February 11th 2013, is a promising find and could be the key target to overcoming the increasing problem of resistance in some bacterial species. In the meantime more research is planned in order to gain an even greater understanding of the role of PSMs and the Pmt transport system as a potential target for drug design and intervention.

In Vivo Biochemistry Metabolic Reprogramming of Cancer Cells

By Lewis Wilmot increases in nutrient uptake, notably Second Year Biomedical Science glucose and glutamine, to meet the demands of a biosynthetic state [Ward et al., Cancer cell metabolism is fundamentally 2012]. Recent research has highlighted the different from that of normal cells. complexities of altered cancer This characteristic was first described in 1926 when Otto The transformed cell metabolism and uncovered new mechanisms that bring Warburg reported on cancer metabolism of about these changes. cells exhibiting high rates of cancer cells is glycolysis followed by lactic Altered metabolism is a direct acid fermentation, rather than reflected by a the lower glycolysis rates and disparate attitude to response to growth factor signalling pyruvate oxidation, shown by ATP production. normal cells. This phenomenon Traditionally, the altered became known as the Warburg metabolism associated with cancer cells effect (Fig 1). is held to be an indirect consequence of growth factor signalling [Ward et al., 2012]. Increased transcription and translation, due to growth factor signalling, decrease the ATP:ADP ratio, driving a huge demand for free energy. This induces metabolic changes orientated towards ATP production. However, there is now evidence to support a supply-based alternative to this demandbased model, wherein metabolic changes are a direct response to growth factor signalling, independent of ATP levels.
>> Figure 1: A comparison of metabolism between differentiated tissue and proliferative tissue or tumors.

It is now established that extensive metabolic reprogramming is a hallmark of cancer. The anabolic requirements of cancer cells drive changes in cellular metabolism. In order to supply sufficient nucleotides, proteins and lipids for cell growth and division, the focus of metabolism must be macromolecular synthesis [Ward et al., 2012]. Thus, the proliferative character of cancer cells depends on a metabolic switch that places an emphasis on anabolic pathways. These alterations involve the comprehensive remodelling of metabolism. For example, they are accompanied by significant

This hypothesis maintains that growth factor signalling is responsible for the increased flux of nutrients through glycolysis, and instigates the remodelling of cell metabolism for biosynthesis [Ward et al., 2012]. Metabolic alterations extend to changes in ATP production The transformed metabolism of cancer cells is reflected by a disparate attitude to ATP production. Maximising ATP yield, a fundamental aim of normal cell metabolism, is not a cancer cell priority. Metabolic strategies are employed to decrease ATP production whilst increasing ATP consumption, to maintain the ATP:ADP ratio essential for sustained glycolytic flux

In Vivo Biochemistry
[Ward et al., 2012]. It should not be assumed that cancer cells no longer derive ATP from oxidative phosphorylation, merely that ATP production through this pathway is secondary to the use mitochondrial enzymes in the synthesis of anabolic precursors [Ward et al., 2012]. Oncogenes and suppressors tumour A hypothesis that is confirmed in both cultured cells and mouse models is that p53 loss enhances glycolysis, producing deficient oxidative phosphorylation [Matoba et al., 2008]. Hence, mutations that activate oncogenes and inactivate tumour suppressors orchestrate Rather than metabolic alterations abolishing enzymatic associated with cancer. Metabolic enzymes

Oncogenes (such as Myc) and tumour suppressors (such as p53) regulate cell metabolism. Myc promotes glucose uptake via glucose transporter 1 (GLUT1), whilst increasing glycolysis by promoting the transcription of glycolytic enzymes [Dang et al., 2008]. Conversely, p53 inhibits glycolysis and maintains the integrity of mitochondria [Liang et al., 2013]. p53 is observed in 50% of human cancers suggesting that its inactivation is an important cause of the alteration of cancer cell metabolism [Liang et al., 2013].

activity these mutations confer a novel gain of enzymatic function that perturbs metabolism.

Metabolic enzymes also function as oncogenes or tumour suppressors. The genes encoding these enzymes are mutated in the same manner as oncogenes or tumour suppressors. This has raised the possibility that metabolic mutations could alter cell metabolism, driving the manifestation of a malignant phenotype [Mullen et al., 2012]. Isocitrate dehydrogenase (IDH) In normal cell metabolism, Isocitrate dehydrogenases, IDH1 localised in the cytoplasm and IDH2 in the mitochondria, catalyse the oxidative decarboxylation of isocitrate to alphaketoglutarate, a reversible reaction generating NADPH and CO2. Subsequently, alphaketoglutarate is either oxidised, in the tricarboxylic acid (TCA) cycle, or utilised as a cofactor by alpha-ketoglutarate dependent dioxygenase enzymes. The discovery of heterozygous point mutations of IDH1/2 in cancers, including most grade 2/3 gliomas and acute myeloid leukaemia (AML), has generated excitement [Parsons et al, 2008; Mardis et

>> Figure 2. The effects of IDH1/2 mutations and inhibition of dioxygenases by 2-HG. Mullen et al. Trends in Endocrinology and Metabolism (2012).

In Vivo Biochemistry
al., 2009]. Rather than abolishing enzymatic activity these mutations confer a novel gain of enzymatic function that perturbs metabolism. Mutant IDH1/2 reduces alphaketoglutarate to 2-hydroxyglutarate (2-HG), diverting alpha-ketoglutarate away from the TCA acid cycle (Fig 2). presence of IDH mutations in most adult grade 2/3 gliomas and the association with 2-HG accumulation in tumours raises the possibility of detecting IDH mutations through screening for 2-HG. Indeed, a novel imaging technique, utilising magnetic resonance spectroscopy (MRS), exploits 2-HG as a biomarker and has been developed as a non-invasive alternative to biopsy [Choi et al., 2012].

Furthermore, 2-HG is an oncometabolite. Present in trace amounts in Novel imaging normal mammalian cells, it is found 50 to 100 fold higher technique, utilising Detection of 2-HG by MRS in malignant glioma samples magnetic resonance serves dual diagnostic and functions. The [Dang et al., 2009]. spectroscopy (MRS), prognostic presence of IDH mutations exploits 2-HG as a results in the diagnosis of Accumulation of 2-HG in glioma tumours is thought to biomarker and has a glioma, meaning that the ability to readily screen for inhibit cellular differentiation. been developed 2-HG and hence IDH mutations As a structural homolog of as a non-invasive is a valuable diagnostic tool. alpha-ketoglutarate, 2-HG acts as a competitive inhibitor alternative to biopsy. The association of IDH1/2 mutations with increased of alpha-ketoglutarateglioma patient survival means dependent enzymes [Xu et al., that 2-HG is also an important prognostic 2011]. marker [Choi et al., 2012]. This includes -ketoglutarate-dependent Furthermore, it has been hypothesised that dioxygenases, that are implicated in 2-HG levels may correlate to tumour cell demethylation reactions involving histones population size, such that 2-HG may provide and nucleic acids. a means of monitoring disease progression and response to chemotherapy [Choi et al., For example 2-HG inhibits the TET family of 2012]. enzymes that hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, an The discovery of measureable biomarkers intermediate in DNA methylation [Turcan et for cancer associated mutations provides a al., 2012]. unique approach to the clinical management of cancer. Although, the biological effects of dioxygenase inhibition are yet to be The possibility of finding similar biomarkers determined, it deregulates cellular for other cancer associated mutations and differentiation and it may facilitate developing a library of biomarkers that can malignant transformation and maintenance be readily utilised by clinicians is an exciting of malignant phenotypes [Yen et al., 2012]. prospect. Clinical applications An expanding knowledge of mutations in metabolic reprogramming elucidates novel diagnostic and prognostic techniques. The

In Vivo Biological & Environmental Sciences Save The Sharks

When most people think of sharks, the instant image of a ruthless killer, akin to those seen in the works of Spielberg, springs to mind. But what would our oceans be without these ancient predators? Sharks are a vital part of the ocean ecosystem, as apex predators, they feed on those animals below them in the food web. This not only helps to remove the weak individuals from the population, but also regulates the balance in the marine ecosystem, preventing one species from overusing a limited resource. Predation from apex predators such as sharks leads to greater biodiversity, so without sharks there wouldnt be such a beautiful variety of fish found on coral reefs. Studies in Hawaii have revealed a larger number of fish and greater diversity around uninhabited islands, where there are more sharks, whereas on inhabited islands with fewer sharks, the diversity was much lower. The removal of sharks from an ecosystem through overfishing has already been illustrated in localised collapses of fisheries and ecosystems, such as the decline in scallop populations, following the overfishing of shark at Chesapeake Bay. Aside from the environmental importance of sharks, it is difficult to deny that the shark finning trade is barbaric, wasteful and unnecessary, with over 100 million sharks killed annually by poachers. With the reputation of sharks in the media, it is easy to see how this inhumane treatment is overlooked, in a way it wouldnt be with a cute and fury animal, like a dog (although, interestingly, you are much more likely to be killed by a dog than a shark.) A study published last month (Muter et.al) found that this could be due to the fact that most

Beth Francis Third Year Biological Sciences

of the media coverage relating to sharks emphasised the risks sharks pose to humans, such as reports of shark attacks or reviews of films featuring sharks as man-eaters, rather than the threat to sharks themselves and how they are a vital part of the ecosystem. The article suggests that this negative media coverage of sharks heavily affects social opinion and proves a real obstacle in shark conservation.

>> Gruesome shark fishing in Alabama. Photo accredited to HuntFishGuide of Flickr

With what seems to be such a widespread hatred of sharks, it is difficult to see how the general public will ever push for shark conservation and the banning of shark finning before these prehistoric creatures are hunted into extinction. I conclude by echoing the words of a man, arguably partially responsible for the widespread hatred of sharks, Peter Benchley, the author of Jaws. If I have one hope, it is that we will come to appreciate and protect these wonderful animals before we manage, through ignorance, stupidity and greed, to wipe them out altogether.

In Vivo Biological & Environmental Sciences What is The Role of Epigenetics in Cancer?
Caroline Anderson Third Year Biological Sciences
example, Weber et al (2005) compared the methylation content of a colon cancer cell line compared to a normal cell line using ChIP-on How is it that monozygotic twins differ in their chip. They found that the transformed cell susceptibility to diseases such as diabetes line contained regions of hypomethylation and asthma despite sharing identical in gene-poor regions of DNA not apparent genome sequences? This phenomenon is in the normal cell line. Chromosomes 7 easily explained by epigenetics: The study and 14 in particular displayed high levels of mitotically and/or meiotically heritable of hypomethylation and were trisomic changes in gene function that cannot be compared to non-cancer cells, suggesting explained by changes in DNA that DNA hypomethylation sequence. (Russo et al, Epigenetics: The contributes to genome 1996). Altered epigenetic study of mitotically and/ instability. In addition, profiles have been identified DNA hypomethylation has or meiotically heritable in the DNA of cancer cells in also been associated with comparison to normal cells. changes in gene function reactivation of transposable Given that methylation of that cannot be explained elements and loss of genomic CpG dinucleotides in human by changes in DNA imprinting or monoallelic somatic cells is thought to sequence. gene expression. affect 70-80% of the genome, there is a large scope for aberrant In contrast, DNA hypermethylation in tumours changes to occur which further implicates is thought to inhibit the transcription of key a role for epigenetics in carcinogenesis cell cycle regulators and DNA repair genes. (Esteller, 2008). Aberrant methylation of CDKN2A/p16 is found in 40% of colorectal carcinomas (Khare Normal non-cancerous cells are subject and Verma, 2012). This tumour suppressor to a number of epigenetic modifications gene regulates the activity of cyclin D/CDK4 which serve to co-ordinately regulate and thus regulates the expression of genes gene expression. One of the most studied required for the G1/S transition and cell alterations is DNA methylation whereby a cycle progression. There is interest within methyl group is added to the 5 cytosine the cancer research field surrounding the use residue of DNA nucleotides by DNA of DNA hypermethylation as a prognostic methyltransferase (DNMT) enzymes. factor. For example, hypermethylation of Methylation is abundant at CpG dinucleotide death-associated protein kinase (DAPK) and sequences throughout the genome however p16ink4a is linked to poor outcomes in lung, unmethylated CpG islands also exist in colorectal cancer and brain cancer (Esteller, the regulatory promoter regions of genes 2008). in normal cells. Such modifications affect the transcription of genes by altering the Histone modification is another epigenetic chromatin structure and as a consequence mechanism intimately involved in the the accessibility of the transcriptional regulation of gene expression. DNA is machinery to the DNA. organised into nucleosome structures which in turn form the chromatin of chromosomes. Many groups have demonstrated Within nucleosomes DNA is wrapped around widespread DNA hypomethylation in octomeric histone cores. The C-terminal tails tumour cells compared to normal cells. For of the individual histone proteins making up

In Vivo Biological & Environmental Sciences

these octomers may undergo a variety of modifications including lysine acetylation, serine phosphorylation and arginine and lysine methylation. These modifications act as binding sites for enzymes of the epigenetic machinery and again affect the openess of the chromatin. Typically euchromatin, the open chromatin structure, is acetylated and lacks methylation whereas heterochromatin, or closed chromatin, is predominantly hypermethylated. Fraga et al (2005) demonstrated through comparison of histone H4 tail modification in normal and transformed leukemia cells that particular histone modifications may be common hallmarks of cancer. In particular they found that loss of acetylation of Lys16 and loss of trimethylation of Lys20 of histone H4 was associated with hypomethylated repetitive DNA sequences, indicating that this signature may affect chromosome instability. Much of the excitement surrounding epigenetics in relation to cancer is due to the fact that epigenetic modifications are reversible and therefore may be targeted for cancer therapy. Two FDA-approved DNA methyltransferase inhibitory drugs (Vidaza, Decitabine) are currently in use for the treatment of myelodysplastic syndrome and leukemia whilst histone deacetylase inhibitors such as Vorinostat show promise for the treatment of cutaneous T cell lymphoma (Esteller, 2008). Given the genome-wide action of DNMTs, however, the non-specific effects of inhibitory drugs are a valid concern. Another proposed avenue for the application of epigenetics in cancer therapy is in the early diagnosis and prognosis stages of the disease. For example, the identification of hypermethylation in carriers of highpenetrance mutations of tumour suppressor genes such as BRCA1 is an early indicator of cancer (Esteller, 2000). In the modern post-genomic era the generation of individualised epigenome profiles is not a distant prospect. Differential epigenomic landscapes are apparent in a number of diseases in addition to cancer, including asthma, arthritis and diabetes. As such it is conceivable that epigenetic analysis may soon become established as a diagnostic and therapeutic tool for the management of a number of debilitating diseases.

>> Schematic representation of epigenetics associated with active and silenced loci. From Clinical translation of epigenetics in cancer. Mol Cancer Ther November 2005 4; 1810

In Vivo Biomedical Sciences Of Mice and Men - JQ1 the First Male testosterone levels; mainly decreased sex Contraceptive drive, behavioural effects and increase in
By Katie Pantelli Third Year Biomedical Science In 1999, the Economist declared that the female contraceptive pill was the most important scientific advancement of the 20th century. From pills to patches, coils to implants, women have been burdened with the responsibility of birth control since the 50s. The scientific and social impacts of contraception are huge; in 2010 118m was spent on abortions in the UK. There are 34 million unplanned pregnancies a year and thousands of women die due to complications from unwanted pregnancies and unsafe abortions. Many argue that the lack of contraceptive options for men contributes heavily to these figures. the risk of prostate cancer. The only other option is a vasectomy, which is permanent and requires surgery. After years of different attempts for a male contraceptive, all still in the pipeline with no real improvements, a molecule has been found which is causing a buzz amongst scientists. Research has found that infertility, for many men, is associated with a modification in the sperms tail that alters the sperms ability to swim efficiently. Cue the development of JQ1, a non-hormonal compound that alters sperm on a molecular level, targeting the male germline. JQ1 targets the testis specific bromodomain-containing protein BRDT, which is expressed in spermatocytes and spermatids and is critical during spermatogenesis for chromatin remodelling. It results in decreased sperm production and sperm that are not very motile. Studies in mice have shown that once the JQ1 compound is removed, normal fertility is restored. The mice also have a normal sex drive, which will put some worries to rest. Time for men to take responsibility in controlling their own fertility? Judging by reactions on the Internet, its a yes from the men. Male Birth Control Pledges are appearing everywhere, with men publicly sharing that they promise to use FDA (food and drug administration) approved methods, if and when they become available.
>> JQ1 reverisbly creates a depletion in spermatid levels.

Since the condom, pharmaceutical companies havent been able to find a reversible contraceptive for men that doesnt have a knock-on effect on

Lets hope this new group of self-dubbed pioneers help to make sure this revolutionary pill takes off. Even if they decide that it isnt for them, they will have more choice and more control over their futures.

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In Vivo Biomedical Sciences Does Chewing Gum Aid Concentration?

By Charlotte Leigh Second Year Biomedical Science Once again there is speculation that chewing gum may improve concentration. A recent Japanese behavioural study (Hirano et al, 2013) suggested that chewing increases arousal and thus temporarily improves blood flow to certain parts of the brain. This claim is based on a very small study assessing whether chewing gum improves attention and reaction times in healthy adults in a specific cognitive task and its >> The results so far are inconclusive results were fairly inconclusive. Similarly, other recent studies (Stephens during chewing condition, their Maybe & Tunney, 2004) have found accuracy did not change. evolution provided varying results when exploring this mechanism for the link between chewing and Following a study in 2002 into the completely different link between chewing gum and cognitive processing speeds, reasons although Tucha et al. (2004) memory, psychologist Dr Andrew claimed that alertness was Scholey said, Maybe evolution adversely affected by chewing. provided this mechanism for completely different reasons and this rather bizarre The Hirano et al. study went like this: 17 habit of chewing gum is tapping into them. healthy young adult volunteers were asked This is a thought-provoking concept and this to perform a cognitive task involving a area of science is undoubtedly interesting as screen flashing images of five arrows. The there does seem to be some sort of tenuous volunteers had to press a button with their link between chewing and increased arousal; left/right thumb, in response to the direction but as the Hirano (2013) study only assessed the middle arrow pointed. Speed and 17 healthy young adults, their results may not accuracy was recorded both while chewing apply to other groups of people, and their gum, and not chewing gum. results are somewhat unconvincing, without any tangible improvement in concentration. Using functional MRI (fMRI), the volunteers brains were monitored while they performed On-going research the tasks. This technique shows blood flow Other recent studies have reported a in the brain, with increased blood flow beneficial effect (Onyper et al, 2011) and they indicating more activity in a specific region suggested that chewing influences arousal of the brain. The fMRI analysis yielded mixed via the reticular activating system and thus results; with some alertness-associated areas accelerates cognitive processing, and yet of the brain (such as the anterior cingulate there was no concrete evidence observed cortex) becoming more active, while when tested on volunteers. This is a curious similar areas actually became less active. and well-funded area of neuroresearch so Thus the results can be seen to be overall hopefully we shall know soon if chewing gum inconclusive. The reaction-time results were does in fact improve cognitive function, and similarly inconclusive, as although mean if it does, prepare for gum sales in Costcutter reaction time was signicantly decreased to shoot through the roof!

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In Vivo Biomedical Sciences Whats Your Poison? The Damaging Effects of-control youths and the third worst of Alcohol binge drinkers in Europe, not the best title,

but is the occasional binge OK? 20% of men By Rebecca Crosby and 13% of women are reported binge Third Year Biomedical Science drinkers quantified as more than twice the A glass of red wine a day can help you live recommended daily limit, with the highest longer or more than one glass a day will amounts found within the 25-44 age bracket increase cancer, which is the truth? Mixed for men and 16-24 for women. Some of the messages about alcohol are commonplace more immediate risks include: unintentional in the media generating confusing advice on injuries such as traffic accidents or how to stay healthy. The maximum violence, risky sexual behaviour recommended alcohol limit in A sharp and alcohol poisoning, resulting the UK is 21-28 units/week for rise in liver cancer in a trip to hospital. But bingeing men and 14-21 for women. But is blamed on can also impose long-term health what is a unit? Most people particularly liver believe that one drink is one binge drinking and problems, damage leading to liver disease, unit. However, it depends on the obesity obesity and cardiovascular strength and size of the drink of disease. choice. One unit is actually 10ml or 8g of pure alcohol one drink is not Social Impacts one unit! The graph below shows just how In the 21st century, especially whilst at confused the headlines can be. university, most people like to go out and drink. They lose social inhibitions and have a Bingeing crazy time without having to remember any British teenagers have been labelled outembarrassing events or consequences the

>> Figure 1 Graph showing the proportion of good, neutral or bad press coverage alcohol has in relation to numerous different risk factors (y axis)

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In Vivo Biomedical Sciences

next morning. But these social norms have some quite severe consequence - the risk of violence dramatically increases under the influence of alcohol. Alcohol has topped the list of dangerous drugs; this includes harder drugs such as cocaine and heroin! Although alcohol is third highest for individual risks, when combined with social risks, it easily tops the leader-board. Yet alcohol is legal and is the most easily available drug on the market, so the consequences are further enhanced. it takes the liver one hour to process one unit of alcohol. Liver Alcohol is processed by the liver; consequently, increased alcohol consumption puts increased strain on the liver to cope. A sharp rise in liver cancer is blamed on binge drinking and obesity (August, 2009). Drinking excess alcohol does not only increase risk of liver cancer but also liver damage and disease. Liver disease What happens to our body? only causes mild symptoms In 2009, 90% of adults in until it is quite advanced; this England drank alcohol and the makes it a dangerous killer. average weekly consumption Deaths from liver disease in for adults (16+years) was >> Figure 2: The structure of alcohol the UK have doubled since found in drinks, ethanol. 16.4 units for men and 8.0 for 1986, rising from 4.9 to 11.4 women. However, this study deaths per 100,000 people and is flawed, since it includes non-drinkers. are expected to kill 250,000 people in the So how is alcohol dealt with in the human next 20 years (18.1 deaths per 100,000). This body? Alcohol (see figure 2) is absorbed rise in the UK is paralleled by a decline in from the stomach and small intestine into liver disease in France, thought to be due the bloodstream within minutes, with levels to increased knowledge of the effects and peaking 45-90 minutes after drinking. This risks of alcohol, and recent strict marketing process is quickened further if you have regulations for alcohol. an empty stomach, the drink is strong or carbonated, if you are a women or even Cardiovascular just small. Alcohol is poisonous to the body Studies show that alcohol causes twice in high quantities and therefore needs to as many deaths from heart disease as it be eliminated rapidly. Small amounts are prevents. It is important to remember that excreted through urine and breath, but most CHD is a multi-factorial disease with a large is broken down by the liver into substances number of contributors: smoking, blood that can be stored or excreted. On average, pressure, diabetes and cholesterol all have

>> How many units are in your drink? Image from drinkaware.co.uk

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In Vivo Biomedical Sciences

a major impact on cardiovascular health. One study did find a link between a higher alcohol intake and reduced risk of CHD in men, but it had many limitations, including a major mishap the researchers did not examine participants for CHD before the study! In the most recent and extensive look at 30 years of alcohol research, involving more than a million adults, it was found that light to moderate drinkers had a reduced risk of having a heart attack or dying from heart disease/stroke, compared to nondrinkers. However, they were not any less likely from stroke. Cancer The World Cancer Research Trust (WCRF) recently added alcohol to a list of risk factors increasing the chance of cancer, independent of whether you spread the units over a week or a day. Undeniable evidence suggests a link between alcohol and cancer is stronger than ever, including cancer of the pharynx, larynx, oesophagus, breast (women) and bowel (men). The important factor is the amount of alcohol consumed, not the type of drink or strength. There is no evidence to suggest a safe level of consumption, due to the suggestion that any alcohol directly damages DNA, causing uncontrolled growth and cancer. Pregnancy There is no question, in the scientific mind, that alcohol freely passes across the placenta to the foetus and that heavy drinking can damage foetal development, leading to foetal alcohol syndrome, characterised by low birth weight and intellectual/physical abnormalities. Experts agree that drinking large amounts of alcohol during pregnancy has serious detrimental effects on the health of the baby. There are many raised concerns that alcohol may be associated with slow growth, risk of miscarriage, stillbirth and premature birth. There is, however, no evidence of any threshold level for safe alcohol consumption, but low to moderate consumption (1.5 units a day) was not linked with harm but there was not strong enough evidence to rule out any risk. Obesity Alcohol has a large calorific tag alongside it. Middle-aged heavy drinkers are stereotypically of overweight or obese stature, and so even if it is not the alcohol directly causing the obesity and associated health risks, the amount of sugar and calories included do. On average, a spirit will contain 60-80 calories with no mixer, add in an energy drink and that rises to 125 per drink! A standard glass of white wine has about 180 calories and an alcopop will contain about 240. It all adds up! Conclusions In a country where people enjoy drinking, a headline suggesting this habit is beneficial will always be more appealing than one describing adverse and risky effects. However, shouldnt the government take greater responsibility to represent the scientific community and raise awareness rather than allowing media scandal and confusion?

>> Figure 3. Graph showing the proportion of different types of cancer estimated to be attributable to alcohol overall and drinking more than the recommended limits

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In Vivo Microbiology & Virology Call for Universal HPV Vaccination

By Kathryn Maskew Second Year Biomedical Sciences The Human Papillomavirus (HPV) is a member of the papillomavirus family and establishes infection primarily in keratinocytes of the skin or mucous membranes. backed by over 150 medical professionals, claims the HPV vaccine should be rolled out to all 12 year old boys to protect against cancer, and in particular throat cancer. In the USA, HPV associated oropharyngeal cancer represents 60% of all oropharyngeal cancers, compared to 40% in the previous decade (Adelstein et al). Recent statistics show that 35% of all throat cancers, and 25% of all mouth cancers are associated to HPV in the UK, particularly becoming prominent in young men (Throat Cancer Foundation). It has been stated that if the current trends of HPV and related cancers continue, the number of cases of throat cancer will exceed those of cervical cancer by 2020 (Throat Cancer Foundation). Jamie Rae, head of The Throat Cancer Foundation, described HPV as a ticking time bomb and called the current girl-only vaccination scheme discriminatory. However, a representative of the Department of Health has stated that There are currently no plans to extend HPV vaccination to males. So far, Australia is currently the only country to routinely offer the vaccination against HPV to both girls and boys, with Gardasil being used predominantly. Professor Christopher Nutting from the Royal Marsden Hospital in London stated that the national programme in Australia led to a 90% drop in genital warts in men and women, showing that the vaccine is effective in reducing the spread of HPV. The Throat Cancer Foundation has lodged an Early Day Motion with the Houses of Parliament, in a bid to raise awareness of cases of throat, penile, anal, vulval and cervical cancers which could be prevented through a more comprehensive and genderneutral HPV immunisation programme.
For more information about HPV visit: www.parliament.uk/edm/2012-13/980 www.throatcancerfoundation.org

>> An EM of the HPV viral particle. This image was released by the National Cancer Institute

HPV can cause minor problems such as common skin warts and verrucas. However in more serious cases, infection with certain types of HPV can lead to abnormal growth of tissues and changes to cells, which in turn can lead to cervical, anal, penile and vaginal cancers. In 2008, there were 957 deaths from cervical cancer in the UK, with 7% of cervical cancer deaths occurring in women under the age of 35. Worldwide there are over 273,000 deaths from cervical cancer each year and this accounts for 9% of female cancer deaths (Cancer Research UK). The Current Vaccine In autumn 2008, a national HPV vaccination programme was unveiled for girls aged 1218, aiming to prevent cervical cancer; three injections were to be delivered over a 6 month period. Vaccines that are currently in use, such as Gardasil and Cervarix, are highly effective in preventing infections with HPV types 6, 11, 16 and 18. It is types 16 and 18 which are the more high risk strains, causing cervical, anal, penile and vaginal cancers. The Proposed Vaccine The Throat Cancer Foundation, a charity

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In Vivo Microbiology & Virology Measles Hits 18 Year High in The UK

By Ed Sullivan Third Year Medical Microbiology and Virology In 2012 the cases of Measles reached over 2000, the highest in 18 years. This has been aided by large outbreaks in Merseyside and Surrey, and smaller outbreaks in traveller populations. Measles cases have been on the increase in recent years, with numbers increasing dramatically in both 2011 and 2012. Vaccination is both possible and effective in the prevention of the disease. A live attenuated version of the virus is injected into patients as part of the MMR jab, between the ages of 12 to 16 months. After a booster jab, typically before the child enters school, they gain lifelong protection against the virus. These are enveloped single-stranded, negative-sense RNA viruses. Measles virus is spread via the inhalation of infected droplets and is highly infectious. Symptoms of measles include; cold-like symptoms, fever, sensitivity to light and greyish spots in the mouth and throat. These then progress to the characteristic rash of red-brown spots. Complications can occur including pneumonia and meningitis. Measles is particularly dangerous if caught during pregnancy. The infection can be passed to the foetus and cause miscarriage, premature labour or low birth weight.

Dr Mary Ramsay of the Health Protection Agency (HPA) has cautioned against assuming measles is a disease of the past and has warned that the virus can prove fatal in severe cases. The HPA continues to urge parents to ensure that their children are fully A large percentage of the >> The distinctive rash caused by vaccinated against the disease. reported cases of measles in measles. Picture by the CDC. The total number of cases of the last two years have been in measles in England and Wales in 2012 was young adults. It is possible that this is linked 2,016 the highest volume since 1994. Dr to the MMR-Autism scandal of the 1990s. Ramsay went on to explain that Coverage In 1998 Dr Andrew Wakefield published an of MMR is now at historically high levels but article in The Lancet in which he suggested measles is highly infectious and can spread that receipt of the MMR jab, the combined easily among communities that are poorly vaccine that protects against measles, vaccinated, and can affect anyone who is mumps and rubella, was associated with susceptible, including toddlers in whom development of autism spectrum disorders. vaccination has been delayed. Measles Although this was widely proved incorrect, itself is still prominent in other countries and Wakefield was later struck off the medical within Europe with over 26,000 cases of register, it was followed by a significant drop measles reported from 36 countries in off in the number of children receiving the Europe with 83% of these cases coming from vaccine. Many of those being infected and Western Europe in 2011. The high levels of developing the disease now are those that measles in Europe further emphasises the did not get vaccinated and have remained need to maintain routine MMR vaccinations unprotected since. within the U.K. and the constant surveillance of cases to ensure that any individuals at risk Measles is a viral disease caused by a are vaccinated, preventing the spread of the paramyxovirus of the Morbilivirus genus. virus.

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In Vivo Microbiology & Virology Overcoming Drug Resistance in Influenza

By Adrian Robertshaw Third Year Medical Microbiology and Virology Like a broken key, stuck in a lock. This is how Professor Steve Withers from the University of British Columbia described a new antiviral being developed to treat influenza. The new type of antivirals called 2,3-difluorosialic acids (DFSAs) may prevent drug resistance in influenza. The new drug acts by inhibiting the neuraminidase enzyme antigen on the outside of the viral particle, which under normal circumstances allows for influenza to leave the infected cell. This is an essential enzyme, as it facilitates viral progeny leaving the host cell, without it new viruses cannot leave the cell and so the infection fails to spread. Current neuraminidase inhibiting antiviral drugs, such as Zanamivir (trade name Relenza) and Osteltamivir (Tamiflu), block the essential function of the neuraminidase enzyme. However, the virus can become resistant to these drugs over time, as mutations accumulate that prevent the drug from binding to the target site on the neuraminidase enzyme. The accumulation of mutations is caused by antigenic drift and is a process which selects antigenic structures, resistant to antibodies or drugs with which the virus species is currently in contact. Drug resistance is a major problem, the World Health Organisation estimates that Influenza causes 3 -5 million cases of disease every year and can cause major pandemics. When influenza pandemics occur, they can cause significant numbers of deaths and place a significant strain on healthcare services; therefore it is vitally important to have an arsenal of antiviral drugs to protect individuals from severe disease and to prevent deaths. The DFSAs are neuraminidase inhibitors which bind to a different target site of the neuraminidase antigen and prevent viral progeny from leaving the cell. The drug permanently binds to the neuraminidase enzyme, however the binding site of this family of drugs is in an important region of the viral neuraminidase and any mutation in this region, to avoid the effects of the drug, renders the virus incapable of producing an infection. Results have so far been positive in studies with mice and the antiviral drug has been shown to work effectively on current drug resistant strains of influenza A and B. Research now needs to be conducted in other animal species to confirm that DFSAs have the same effect. This drug family is currently a promising candidate to combat future influenza pandemics, however it is still in an early stage of testing and it could be six to seven years until the drug comes into general use. It is predicted that a flu pandemic will occur again in the future and it is therefore of the upmost importance that new antiviral medications are produced to help protect the worlds population from a potentially deadly disease.

>> The antiviral drug Oseltamivir (Tamiflu, yellow sphere) placed in the free space of the neuraminidase (yellow grid) inhibits the enzyme and blocks the replication of the virus. Picture accredited to PharmaInformatic.

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In Vivo Microbiology & Virology Novel Coronavirus Infections in the UK

By Samuel Rollins Third Year Medical Microbiology and Virology Over the past few weeks there has been increased media attention on the spread of a new coronavirus, with the media heralding it as the new SARS. How true is that statement and what are the realistic risks to the population at present? actually infected by the virus. At present there has been a reported twelve cases of the coronavirus infection across the globe. Six of the twelve have died due to complications caused by the virus. In the UK there have been four reported cases of the virus, three of those in UK nationals and one is a Qatari citizen. The point of concern is that the three UK nationals are in fact related and only one of them has recently travelled to the affected area suggesting humanto-human transmission. Out of this cluster, the patient who travelled is still receiving treatment for the infection, the second only had a mild infection, and has fully recovered, and the third has died. The Health Protection Agency has continued to follow up these cases in the UK, by monitoring the person-to-person contacts of the three related cases. Through monitoring these contacts, the Health Protection Agency has tested more than 100 people and in every single case the tests have reported back negative for novel coronavirus infection. Professor John Watson, head of the respiratory diseases department at the HPA, said: The routes of transmission to humans of the novel coronavirus have not yet been fully determined, but the recent UK experience provides strong evidence of human-to-human transmission in at least some circumstances. This lack of evidence for sufficient humanto-human spread suggests that at present the media is simply scare mongering. Professor John Watson went on further to state that The risk of infection in contacts in most circumstances is still considered to be low and the risk associated with novel coronavirus to the general UK population remains very low. Once the receptor of the virus is fully identified the risk to the population will be better understood.

>> EM of the new coronavirus from the BBC

The new coronavirus, HCov-EMC, was first isolated in a sputum sample from a sixty year old patient in Saudi Arabia in June 2012. The patient was referred to hospital on the 13th of June 2012 and unfortunately, due to the virus and other health complications, passed away eleven days later. In the lab scientists found the virus readily replicates within a cell culture, causing a cytopathic effect. Sequence analysis of the virus showed it closely related to the bat coronaviruses, HKU4 and HKU5. The clinical presentation of the virus in the patient was incredibly similar to that seen nine years earlier with the SARS coronavirus. The HCov-EMC however appeared to lack the ability to spread between humans, as none of the health care professionals treating the patient displayed any symptoms related to a coronavirus infection; it should be noted however, that none of the professionals actually underwent antibody screening to see if they were or had been

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In Vivo Careers
Vivo interviews Professor Keith Leppard Professor Keith Leppard In on his career in research and academia.
His current research into adenoviruses The things we are interested in at the moment are really two areas; the first is looking at a promoter we discovered in the viral genome about five years ago and trying to understand the cellular factors that regulate it. We think that this promotor might be important in determining whether an infection progresses all the way through to productivity or whether it stalls and becomes an abortive infection in some cell types. The other area looks at interactions with PML nuclear bodies, which are probably important in the innate immune response. American scientists. The following year it was in Cold Spring Harbor New York, where I actually presented a talk (which was very traumatic). It became the norm to think of doing that, and I was lucky enough to get the chance.

Whats your favourite discovery that youve made so far in your career? In terms of novelty, although I dont anticipate its going to be anything earth shattering, the new promoter in the adenovirus genome. I am really pleased with it because adenovirus molecular biology was kind of seen as a done deal as of the mid 1980s. The genome had been sequenced, all the promoters had been mapped, What inspired you to do a PhD? the RNA and gene expression was When I was doing my undergraduate known. Everyone thought we know degree [Biochemistry at Oxford] I >> Professor Keith Leppard it. Through a chance discovery, which was really fascinated by the kinds of related to our work trying to make adenovirus things that were coming along new then. One vectors for gene therapy about ten years ago, of the things that was discovered whilst I was we saw something that made me think ah, okay an undergraduate was splicing. Prior to that maybe there is something different there, so everyone thought mRNA was co-linear with the we pursued it and actually found it. DNA. I remember reading that paper and being fascinated by it and of course it was a discovery What advice would you give to undergraduates made in adenoviruses, which although it didnt wanting to following in your footsteps? influence my choice of PhD at the time, its come Its a hard life, so think carefully about it. I think back into my life in a big way. Nonetheless I the positives of being a researcher are that you weighed research against possibly a career in IT have probably more freedom within a fairly and I remember considering applying to IBM for secure employment than you might have in a job, but quite what swayed me to make a PhD many other careers. You get all that pleasure of application Im not sure. discovery, so I would encourage somebody who really positively wanted to do it, but I would also You took a postdoctoral position at Stoney caution that its tough and a fairly low proportion Brook (NY) and then at Princeton. Why did of those that do a PhD end up in the seat Im you want to work in the US? sitting in today. I suppose it was something my PhD environment encouraged me in. I did my PhD at what was Another very positive thing about this career is then the Imperial Cancer Research Fund (now that you have the opportunity to meet a huge Cancer Research UK) at Lincolns Inn Fields, number of people, not just through the fact London and the person I was working for, a man that you have new students coming through called Dr Lionel Crawford, had spent time in the the door every year, which is nice, it keeps you US. The whole area of tumour virus biology was grounded, but also internationally, you have a an international field. network of research colleagues and friends who are based in lots of different places all over the The first year I was doing my PhD I went to an world. Thats a nice feeling to have. international conference, which happened to be in Cambridge England, but I met various

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