Tracking the Daily Microbiome

human microbiome by Hank Osuna

Human Microbiome by Hank Osuna

Humans are essentially 90% bacteria. These bacteria pepper our skin and hang out in our digestive tracts, helping to break down complex carbohydrates and keeping bad bugs in check.

We know how the human microbiome (our collection of bacteria) gets seeded during the birth process, and we know how bacterial populations change in the aftermath of a biological apocalyse, such as their human host taking a course of antibiotics. Yet we know very little about how the microbiome changes on a day-to-day basis.

Now, a team of scientists at Massachussetts Institute of Technology (MIT) have changed that by recruiting two individuals to provide samples of their poop and saliva every day for a YEAR to track their gut and oral microbiome signatures, and correlate them with lifestyle and activities.

Overall, microbe communities remained remarkably stable for months at a time. The three big variables – sleep, exercise and mood – failed to make much of an impact on microbe populations. Yet small dietary and lifestyle changes prompted rapid (next day) changes. Increasing fibre intake boosted populations of fibre-sensitive Bifidobacteria, Roseburia and Eubacteria. Bifidobacteria levels were similarly enhanced after eating live yoghurt cultures. Eating citrus fruits led to a jump in levels of Clostridiales bacteria, while dental flossing decreased saliva levels of the dental pathogen, Streptococcus mutans.

bacterial bodies bryan christie scientific american june 2012

Bacterial Bodies by Bryan Christie

The biggest changes in microbiome signatures happened in the wake of relatively rare life events. Travelling from a developed to a developing country caused numbers of Bacteriodes microbes to swell (as the host ate new foods) and increased Proteobacteria populations (as the host experienced bouts of diarrhea). These bacteria settled back down to normal levels when their host returned home. On the flip side, a bout of Salmonella food poisoning permanently wiped out a subset of native Firmicutes bacteria, which eventually got replaced by other similar species.

It appears, then, that our microbes generally go about their business in a happy, unpeturbed state. Yet inadvertently introducing them to a new experience can either result in a benevolent (often temporary) change, or a tremendously negative wipe-out event.

You can read the original #openaccess article free here.

David LA, Materna AC, Friedman J, Campos-Baptista MI, Blackburn MC, Perrotta A, Erdman SE, & Alm EJ (2014). Host lifestyle affects human microbiota on daily timescales. Genome biology, 15 (7) PMID: 25146375

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Plastic bags responsible for outrageous lack of cute pink piglets

Margaret Ackland, Plastic Bag, Oil on Linen

Margaret Ackland, Plastic Bag, Oil on Linen

Most of us now subscribe to the idea that plastic bags are bad for the environment. Hence, droves of people turn up at their local supermarket with a sturdy jute bag in tow. Now, there’s evidence that the items that get placed into plastic bags also have a terrible time, especially if they’re biological in origin.

Take the case of pig farmers in Spain. In Spring 2010, 41 farms across Spain reported issues with their lady pigs failing to get pregnant after artificial insemination. The ensuing biological detective hunt found that sperm quality was high (it was good and wriggly, and donated from many different boars, ruling out a genetic incompatibility) and the fertility of the potential mama pigs was good. All the animals were in good health, and they were kept in comfortable, well-fed conditions.

One of the factors that all the farms had in common was the brand of plastic bag being used to store the boar semen until it got shot into the lady pig. In fact, the longer the semen was kept in these bags, the greater the decrease in fertility.

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Plastic bags: a chemical cocktail

Concerned that a nasty chemical contaminant may be to blame, scientists at the Universidad de Zaragoza passed an old batch of “good” bags and a new batch of “suspicious” bags through a mass spectrometer (a machine that breaks materials up into their chemical components). They found that the “suspicious” bags contained five extra chemicals that weren’t present in the “good” bags: 1) octyl phthalate, 2) 13-docosenamide, 3) BADGE (a derivative of Bisphenol A), 4) 1,4-trioxacyclotridecane-8,13-dione (a cyclic lactone) and 5) diethylene glycol cyclic phthalate. These chemicals formed part of the adhesive used to manufacture the multilayer bags.

Three of these chemicals (BADGE, 1,4-trioxacyclotridecane-8,13-dione and diethylene glycol cyclic phthalate) were actually capable of leaching out of the bags into the fluid they contained (sterile water was used as a less messy substitute for boar semen). Yet in a dish, mixing these three chemicals with boar semen had no impact on sperm quality: no overt abnormalities were observed, and the sperm were still able to penetrate their egg targets.

Finally, the ultimate test was performed: if semen spiked with these three chemicals was infused into a lady pig, would there be an outrageous lack of cute pink piglets born? Sure enough, there was a drop in the fertility rate from 84% to 58%, and the number of piglets being born fell from 231 to 70.

About your plastic water bottle…

This study didn’t go as far as identifying exactly how these chemicals were messing up fertilisation: the authors speculate that blastocyst implantation or early development may have been affected. However it happened, though, this is definitely a cautionary tale for using plastic bags as storage containers, with significant relevance for human artificial insemination. The leaching of such chemicals into the environment as plastic bags break down on landfill remains a sure source of concern to humans and pigs alike.

Nerin C, Ubeda JL, Alfaro P, Dahmani Y, Aznar M, Canellas E, & Ausejo R (2014). Compounds from multilayer plastic bags cause reproductive failures in artificial insemination. Scientific reports, 4 PMID: 24810330

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The science behind FIFA’s footballs

Football_soccer_futbol_by_walexxx19Lovers and haters of the World Cup alike can’t fail to be amazed by the skills of some professional footballers. Like David Beckham or Cristiano Ronaldo. But while some footballers have been blessed by biology, it’s not just the combined genetic talent of a player or a team that leads to a stunning win or a sorry loss. According to scientists at the University of Tsukuba in Japan, the aerodynamic performance of a football can introduce a skill set all of its own.

The football has evolved substantially from its vaguely nauseating origins (an inflated sheep’s bladder) to the shiny polished orb in use today. A typical football is made from 32 five- and six-sided panels stitched together to form a pleasingly spherical shape. In recent years, this basic design has developed towards minimising the number of panels and changing the pattern in which they’re stitched together to boost aerodynamic performance and consistency. Adidas, who ride at the forefront of innovative football design, have created the Cafusa (32 panels; currently used by many football leagues), the Teamgeist 2 (14 panels; the official ball of the 2008 EURO cup) and the Jabulani (8 panels; the official ball of the 2010 FIFA World Cup). Now, for the FIFA World Cup 2014, they’ve made it to the 6 panel ball: the Brazuca.

The team of Japanese scientists wanted to find out how these different balls – the Cafusa, Teamgeist 2, Jabulani, Brazuca and the traditional Molten Vantaggio 32-panel ball – behaved in flight, and how this affected shot accuracy on goal. To do this, they employed a wind tunnel, a kick robot and a whole bagful of beautiful balls. To take into account the difference in panel stitching design, they looked at the ball’s performance when it was kicked off from two orientations: normal (head on) or tilted 180 degrees (see below).

balls

They found that the different balls experienced substantially different aerodynamic forces as they were “kicked” into the wind tunnel. The Brazuca was the most stable ball in flight, followed by the conventional ball, Cafusa, Teamgeist 2 and Jabulani.

When the balls were travelling at higher speeds (the equivalent of a good hearty kick, or a “power shot”), the Cafusa generated the biggest increase in lift and side force – which could allow the ball to travel a greater distance. The Jabulani put in the worst performance in this category, and behaved “irregularly” when it was in flight.

The scientists then launched balls from both orientations at 30m/s towards a goal 25m away, and plotted the hits on target (see graphs below; blue is head on, red is tilted 180°). The Brazuca and the conventional ball gave the best performances, hitting the target most consistently regardless of the orientation of the ball (the blue and red spots cluster together). For the Cafusa, the Jabulani and the Teamgeist 2, the flight paths and in-flight behaviour varied hugely depending on which orientation the ball was in when it set off towards the goal (the blue and red spots are far apart). Even when the number of panels were the same (Cafusa vs. Conventional ball; both 32 panels), differences in panel orientation and stitching design meant the conventional ball hit the target more consistently than the Cafusa.

accuracy on goalThese results – particularly the importance of panel orientation on performance – will undoubtedly be used to inform the design of the next generation of footballs with an eye to improving shooting accuracy and enhancing player performance. Ultimately, though, the conventional 32 panel ball performed just as well – if not better – than most of the innovative new footballs tested, suggesting that at some point it’s not that easy to improve upon design perfection.

Hong S, & Asai T (2014). Effect of panel shape of soccer ball on its flight characteristics. Scientific reports, 4 PMID: 24875291

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Watching it Burn: Soil Microbes vs. Wildfires

Los Angeles County "Station Fire" view from LAXWildfires can devastate ecosystems across the world. In 2012, over 67,000 wildfires raced across more than 9 million acres of land in the US alone. Fuelled by wind and parched vegetation, wildfires burn through everything in their path: plants don’t stand a chance, and even mobile animals struggle to outpace the flames.

But what impact do wildfires have on the beasties that live deep down in the soil? For example, soil-dwelling microbes, like bacteria? These incredibly important organisms help ecosystems to flourish, but their ability to recover after a forest fire – and to help other parts of the ecosystem recover, too – has been largely uncharacterised. Until now.

A team of scientists in China recently calculated that 70-80% of soil microbial biomass (the organic material made up of bacteria and fungi) was lost after wildfires swept through forests in the Greater Khingan mountains. But the flames didn’t fry the bacteria directly. Rather, the fire dramatically altered the soil biochemistry, most importantly changing its pH but also impacting moisture content, carbon/nitrogen ratio’s and ammonium levels.

This meant that the classes of bacteria that were more flexible at growing at an increased pH – like Bacteriodetes and Betaproteobacteria – were able to persist in the soil after the wildfire had swept through. The populations of other bacteria, like Acidobacteria, plummeted, since they were less equipped to grow in their newly scorched and acidified home.

It took 11 years for the original community of bacterial species to re-establish themselves. While this seems staggering, it’s actually a lot quicker than the above ground vegetation, which typically takes 20-100 years to reappear. Intriguingly, the bounce back of soil bacteria and the gradual re-emergence of a happy soil environment probably plays a huge role in the re-establishment of plants, and the animals that eat them.

This research may help to guide environmental efforts by aiming to adjust soil environments to help ecosystems make a speedy recovery after a wildfire.

Xiang, X., Shi, Y., Yang, J., Kong, J., Lin, X., Zhang, H., Zeng, J., & Chu, H. (2014). Rapid recovery of soil bacterial communities after wildfire in a Chinese boreal forest Scientific Reports, 4 DOI: 10.1038/srep03829

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Swimming with Viruses

8641509698_ac47920d89_bYou can find viruses everywhere: in the soil, in the clouds and in animals. According to scientists from the University of Oldenburg in Germany, there are also a ridiculous number of viruses buried at sea, in the sediments of the oceans.

These sedimentary viruses don’t lie dormant on the seabed, but actively replicate down in the fathoms, even in the gyres of the ocean where most forms of life can’t be sustained since organic carbon is a scarce commodity. By infecting and killing prokaryotic cells (bacteria, archaea) in ocean sediments, viruses act as efficient organic carbon recycling machines.

Scientists found that in every sediment tested, from active tidal flats, open oceans and nutrient-poor gyres, viruses vastly outnumbered prokaryotic host cells. Active viruses didn’t just exist in the oceanic topsoil, but rather permeated through deep layers laid down millions of years ago. Bacteriophages (viruses that infect bacteria) could be found in layers of sediment 320m deep, and in ancient layers from ~14 million years ago.

These exciting findings mean that viruses are actively replicating in buried ocean sediments all the time, and are thus making a huge contribution to the maintenance and carbon cycling of oceanic microbial communities.

Engelhardt T, Kallmeyer J, Cypionka H, & Engelen B (2014). High virus-to-cell ratios indicate ongoing production of viruses in deep subsurface sediments. The ISME journal PMID: 24430483

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More evidence that red wine and aspirin protect against cancer

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Cancer is a disease of genes. DNA mutations mess with the genetic content of a cell, enabling it to escape the normal controls that restrict their growth.

Now, a team of scientists led by Delphine Lissa and Guido Kroemer at the French Institute of Health and Medical Research in Paris have begun exploring ways to slow or stop the formation of cells containing multiple copies of chromosomes, which they think are an essential intermediate in cancer formation.

Normal healthy cells are diploid, which means they have two copies of each chromosome, one from each parent. But during cancer formation, early malignant cells are often tetraploid, with four sets of chromosomes—the extras are either mistaken copies created in-house or genomes picked up from other cells.

Most cells deal with tetraploidy by committing suicide before they become malignant. These genomically deviant cells can also get removed by the immune system as part of its routine cancer surveillance program. But sometimes, these cells are not dealt with, allowing them to continue accumulating chromosomes and acquiring new genetic mutations, transforming them into dangerous cancer cells.

Enjoying that drink

In their study, published in the Proceedings of the National Academy of Science, Lissa and colleagues looked for drugs that could kill tetraploid cells, but leave healthy diploid cells relatively intact. After screening a panel of 480 bioactive chemicals from a database at Harvard Medical School, they came up with two hits: aspirin and resveratrol.

Aspirin is a common presence in the medicine cabinet, and has an excellent record against disease. Almost all of us have enjoyed its headache-relieving properties, and many old people are advised to take small doses of aspirin to protect their hearts. There is also evidence that aspirin can prevent colon cancer.

Those of us who enjoy red wine are ingesting resveratrol on a regular basis. It is also found in red grapes, peanut butter, dark chocolate, and blueberries. While it is still not certain exactly what protective effects resveratrol has against disease, there are suggestions that it can prolong lifespan, protect the heart, and prevent certain forms of cancer.

When researchers looked closely at the fates of both dangerous tetraploid or normal diploid cells treated in a dish with their two drug hits, they observed that unhealthy cells were controlled at least partially through the activation of signals that coaxed them into committing suicide.

Lissa also looked at the use of statins, which work through some biological pathways that may overlap with those tweaked by aspirin and resveratrol (they are commonly prescribed to control high cholesterol levels and minimise the risk of heart disease and stroke). In mixed populations of diploid and tetraploid cells, statins selectively induced more tetraploid cells to die. Several agents, then, could suppress the growth of genetically unstable cells capable of causing cancer.

Stopping cancer in its tracks

After establishing that their drugs had useful effects against fully-formed tetraploid cells, Lissa looked into whether the team could prevent such dangerous tetraploid cells from forming in the first place. Seems it can be done—resveratrol, aspirin, and their biochemical derivatives also reduced the formation of tetraploid cells.

When tested in mice prone to intestinal cancer, either oral resveratrol or aspirin lowered cancer rates. By probing gut cells with fluorescent tags, they saw that fewer dangerous tetraploid cells formed in treated animals. So both drugs could normalise the gut environment to minimise the likelihood of cancer.

2009-04-03T14-53-19 IMG_9796Out of the other 478 screened drug candidates, most had no differential impact on dangerous versus normal cells. Several other agents, including the chemotherapeutic agent cisplatin, the food supplement quercetin, and the herbicide paraquat, preferentially killed normal diploid cells but allowed the dangerous tetraploid cells to continue growing.

This study shouldn’t be viewed as justifying opening a bottle of red wine. Lissa didn’t investigate the effects of these drugs on normal cells that are meant to contain more than two pairs of chromosomes—certain cells in the liver, heart, immune system, and reproductive organs all normally have extra chromosomes. Also, aspirin may have limited use as a long-term anti-cancer agent due to its serious side effects (causing bleeds in the stomach). Finally, it’s not clear whether tetraploid cells are a necessary intermediary to cancer.

Still, beyond cancer, Lissa’s method shows that approved drugs could be screened for treating other diseases, reducing the cost of finding new treatments.

Originally published on The Conversation UK.

Lissaa, D., Senovillaa, L., Rello-Varona, S., Vitalee, I., Michauda, M., Pietrocola, F., Boilèvea, A., Obrist, F., Bordenave, C, Garcia, P., Michels, J., Jemaà, M., Kepp, O., Castedo, M., & Kroemer, G. (2014). Resveratrol and aspirin eliminate tetraploid cells for
anticancer chemoprevention PNAS DOI: 10.1073/pnas.1318440111

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Bright Night Lights: Tracking Light Pollution from Space

6483519343_0199a1c7f1_bThe creep and sprawl of artificial urban lighting is probably the most pervasive technological innovation of the 20th century. Keeping track of how artificial light is changing Europe’s nightscape is important, since more light is typically associated with greater economic development and urban expansion, but moderating light consumption helps to stabilise the ecosystem and energy security.

Scientists have recently used satellite night images going back as far as 1992 (publicly available from the Defense Meterological Satellite Program databank) to analyse how artificial light coverage across the European landscape has changed through the years.

light in europeOverall, light brightness across Europe increased over the years (shown above), with Liechtenstein showing the strongest surge. Conversely, certain countries showed substantial drops in brightness, most notably Slovakia. Small spots puckering the UK, Belgium, Denmark, Finland, Germany, Norway and Sweden also dimmed over time, and often corresponded with a loss of industrial manufacturing, the closure of military sites, the modernisation of lighting infrastructures or deliberate money-saving measures. In other areas, darkness coincided with a loss of economic stability, for example when Ukraine and Moldova became independent from the Soviet Union.

This extremely cool research shows that it’s possible to track changes in light brightness across the European night sky, giving us an excellent tool to help develop interventions that minimise the effects of light pollution and re-establish the ability to enjoy the sensational stars hanging over our heads.

Bennie J, Davies TW, Duffy JP, Inger R, & Gaston KJ (2014). Contrasting trends in light pollution across Europe based on satellite observed night time lights. Scientific reports, 4 PMID: 24445659

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Where in the body do our emotions lie?

lego emotions cc danielito311

Emotions are strange things, bursting over us as we react to life’s joys and challenges. While they might be thought of as ethereal entities with no fixed form or function, emotions actually produce very tangible physical reactions throughout the body.

These emotionally-driven physical reactions are important for surviving in the real world. For example, fear generates a helpful physical response that prepares your body to fight or flee. But we don’t really know if an emotion can fuel a reaction in a certain body part, or if regional body sensors can dictate our conscious emotional experiences.

A team of Finnish researchers were interested in finding out more about this, so they showed 701 volunteers an outline of the human body, and asked them to point out spots on that body where they felt a change in activity (either growing stronger or weaker) after they experienced an emotion generated by a certain word, story, film or facial expression.

They exposed the volunteers to six “basic” emotions (anger, fear, disgust, happiness, sadness and surprise) and seven “complex” emotions (anxiety, love, depression, contempt, pride, shame and envy), and tried their best to weed out the inherent bias of using emotive words that are culturally and lingustically associated with body parts, like “heartache”.

feeling emotions

After mapping out the results as emotional activity charts across the human body, they found that positive emotions like happiness, love and pride all looked very similar, with a suffusion of high activity (shown in yellow, above) around the heart, head, and, ahem, nether regions (for love). These associations were supported by some lovely quantitative cluster analysis.

Several of the negative emotions assembled into similar patterns: fear and anger increased activity in the chest, anxiety and shame increased activity in the torso, sadness and depression severely decreased activity in the arms and legs (shown in blue, above), while disgust, contempt and envy increased activity in the head and hands.

So, clearly, emotions can pin themselves quite reliably and reproducibly to certain areas of the human physical form, in a way that transcends cultural heritage (both Western European and Eastern Asian volunteers reacted in the same way). Such bodily associations and sensations likely have a key part in the emotional experience, and may have a core role in helping us to understand emotions in others.

Nummenmaa L, Glerean E, Hari R, & Hietanen JK (2013). Bodily maps of emotions. Proceedings of the National Academy of Sciences of the United States of America PMID: 24379370

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Antibiotics release death sugars that help bad bugs to grow

4619706028_7c9e124627_bIn the 1940’s, antibiotics were hailed as wonder drugs. “Syphilis is now curable!”, ran the posters. Yet in modern times, several dark sides of these drugs have come to light.

The widespread overuse of antibiotic therapy has driven the emergence of superstrong bacteria, like MRSA, that resist the activity of conventional antibiotics.

Antibiotic therapy is also troubled by the problematic core concept that it lacks specificity, and wipes out good and bad bugs alike. This is particularly worrying as we continue to discover just how much the trillions of good bugs that live in our gut contribute to our health and wellbeing, absorbing vitamins from our food, breaking down tough fibrous vegetables, working to prevent allergies and keeping bad bugs in check.

When good bugs are killed off by antibiotics, the gut ecosystem becomes remarkably disturbed. Large pools of sugary nutrients that the good bugs normally eat suddenly become available, forming an all-you-can-eat buffet for surviving bacteria. Unfortunately, the post-antibiotic apocalypse scavengers are often bad bugs, like Salmonella enterica and Clostridium difficile, which can cause unpleasant disease.

New research from Stanford University School of Medicine shows that both Salmonella enterica and Clostridium difficile use the same strategies to access these free pools of death sugars. Using genetic profiling, they found that in the wake of antibiotic therapy, the bad bugs increased their capacity to snack on fucose and/or sialic acid. Consequently, they were able to overgrow in the intestine to cause pooping nastiness.

While the community of good bugs began to be re-established around three days after antibiotic therapy, and the balance of good and bad bugs stabilised, eating probiotics packed with good bugs that are particularly adept at eating fucose and sialic acid during antibiotic therapy may prevent such pathogenic disturbances happening at all.

Ng KM, Ferreyra JA, Higginbottom SK, Lynch JB, Kashyap PC, Gopinath S, Naidu N, Choudhury B, Weimer BC, Monack DM, & Sonnenburg JL (2013). Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature, 502 (7469), 96-9 PMID: 23995682

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A Marvellous Month of Science

fungusFungal extracts prevent hepatitis C virus infection

Hepatitis C virus (HCV) is a huge cause of liver cancer, but current treatments are very expensive and not that great. Since HCV is a cunning little virus capable of quickly evolving drug resistance, simultaneously attacking it at several key points during its life cycle has the best chance of resolving infection. Researchers in Japan have now created and screened a library of 300 natural drugs isolated from fungi found on seaweed, mosses and other plants, and tested their ability to shut down HCV infection. One of their best hits, sulochrin, repelled several strains of hepatitis C virus, and was free from any toxic side effects. When they combined sulochrin with the traditional HCV drug, telaprevir, results were even better. Although any potential off-target effects of sulochrin still have to be ruled out, this research highlights that the natural world is a tremendously rich source of new drugs that should continue to be mined.

unwindingUnwinding shielded DNA attacks the root cause of prostate cancer

Most organs in the human body, including the prostate gland, contain a tiny population of stem cells that replace old defunct cells with shiny new ones. If these stem cells get damaged, they can become carcinogenic machines, dividing uncontrollably to form a tumour. Such cancer stem cells are thought to be the driving force that creates prostate tumours. Cancer stem cells are very difficult to kill, since they have excellent inbuilt safety features, one of which is very tightly coiled DNA that rebuffs normal treatments. Researchers at the University of York have now shown that treating prostate cancer stem cells with drugs that unwind and relax DNA sensitises them to common chemotherapies, allowing them to be destroyed and ultimately preventing tumour relapse.

Chilly temperatures help cancers to grow

7041602511_b7b65fc443_bAt low temperatures the human body has a hard time, entering a state of thermal stress  where only the most vital systems, like the brain, are left switched on. Now, a paper published in PNAS suggests that cold has yet another disadvantage – it changes the way cancer cells grow and spread, at least in mice. Mice living in a relatively cold environment (around 22°C) had cancers that grew more quickly and aggressively than mice living at a nice thermally comfortable temperature (around 30°C). Both the cold and the comfortable mice had the same numbers of potential cancer-fighting immune T cells when they were healthy, but when they got sick, the T cells in the comfortable mice were quicker and better at burrowing into the tumour to attack it. They also secreted more cancer-fighting substances than the cells from cold mice. In the tumours of cold mice, there were greater numbers of suppressive cells capable of shutting down normal immune responses. Cold temperatures, then, shifted the body’s response from fighting the tumour to accepting it. This suggests that the benefits of heat therapy for cancer may have been largely overlooked. Adapted from an article originally published on The Conversation.

HSVCommon chemotherapy drug helps oncolytic viruses kill tumours

There is a lot of excitement in the world of cancer immunotherapy over the potential utility of oncolytic viruses – that is, viruses that specifically infect and destroy cancer cells with the help of the immune system. Since a tumour is essentially a big chunk of overgrown tissue, the immune system often continues to see it as a normal part of the body (although sometimes, the sneaky tumour simply makes itself invisible to the immune system). Even after immune-activating oncolytic virus treatment, properly re-educating the immune system to see the tumour as a malignant intruder is a very difficult process. Researchers at McMaster Immunology Research Centre now show that administering an oncolytic virus together with a chemotherapy drug that triggers the immune system as it kills cancer cells finally allows the tumour to be recognised as a threat. Once that biological brake has been removed, cancer-fighting immune cells can pour into the tumour and secrete cancer-busting substances. Such exciting new combination therapies can help retrain the immune system to identify developing malignant disease.

Originally published on Scizzle.

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Chilly temperatures help cancers grow

7041602511_b7b65fc443_bAt low temperatures, the human body has a hard time. As the cold sets in, blood vessels constrict to maintain heat and some body parts – like fingers and toes – begin to suffer. Metabolism ramps up to fight the cold and shivering sets in. As these conditions continue, everything becomes sluggish as the cells of your body do not work as well. The body enters a state of thermal stress and only the most vital systems, like the brain, are left switched on.

Now, in a paper just published in the Proceedings of the National Academy of Sciences, Elizabeth Repasky at Roswell Park Cancer Institute in the US and colleagues suggest that cold has yet another disadvantage – it changes the way cancer cells grow and spread, at least in mice. This raises interesting questions about cancer therapies and many cancer studies, which tend to use mice as animal models.

Repasky found that mice living in a relatively cold environment (around 22°C) had cancers that grew more quickly and aggressively than mice living at a nice thermally comfortable temperature (around 30°C). A cold environment boosted the growth of several different types of cancer, including breast, skin, colon, and pancreas.

It did not matter if mice had lived in the cold for a lifetime before they got cancer—a chilly exposure even after their cancer had become established still made their tumours grow more quickly.

The body’s anti-cancer responses are mostly driven by the immune system’s T cells, which recognise and destroy tumor cells based on the altered proteins they produce. Tumours often react to a T-cell attack by producing signals that trick the body into suppressing these immune cells. This battle continues until one side outpaces the other – a lot of anti-cancer treatments given in the clinic help to swing the balance in favour of the immune system.

Both the cold and the comfortable mice had the same numbers of potential cancer-fighting T cells when they were healthy. But the tumour-seeking T cells in the comfortable mice were quicker and better at burrowing into the tumour to attack it. They also secreted more cancer-fighting substances than the cells from cold mice.

In the tumours of cold mice, there were greater numbers of suppressive cells capable of shutting down normal immune responses. Cold temperatures, then, shifted the body’s response from fighting the tumour to accepting it.

Most animal research facilities follow the same housing guidelines, and thus keep mice at colder-than-comfortable temperatures. This could introduce a systemic bias to animal testing where studies are done in conditions that aren’t entirely relevant. For example, what if you were trying a therapy that boosted immune function but did it in mice whose immune function was naturally tamped down? You might see no effect, when it could still be a useful drug. In contrast, something that causes tumour DNA damage might not have the same problem.

Cancers are cold

When we feel cold, we engage in warming behaviours – turning the thermostat up a notch, or thriftily putting on an extra layer of clothes. Mice are exactly the same – if they feel cold, they move to a warmer spot. When healthy mice get to choose what temperature they want to hang out at, with options at 22, 28, 30, 34 or 38°C, they typically migrate into the comfortable 30°C room. Mice with tumours tend to choose the hottest 38°C room. Cancer patients also commonly report suffering deep chills, especially following treatment.

It’s possible that growing tumours may induce a cold stress that probably promotes their own survival. We do not know exactly how this works yet, but this research still has important implications for cancer patients and their treatments. Could administering cancer therapies in a sauna – like setting improve their tumour – fighting potential and slow cancer growth?

Such approaches have been tried in small trials for breast cancer, angiosarcoma and sarcoma. They show that increasing body temperature to a mild fever over the course of a few hours improves response rates to radiation therapy.

Without large-scale studies no firm conclusions can be drawn, but this evidence suggests that the benefits of heat therapy for cancer may have been overlooked. Perhaps it is time we paid heed to the words of the ancient Greek physician Hippocrates:

Those who cannot be cured by medicine can be cured by surgery. Those who cannot be cured by surgery can be cured by heat. Those who cannot be cured by heat are to be considered incurable.

Originally published on The Conversation UK.

Kokolusa, KM, Capitanoa, ML, Leea, CT, Enga, JWL, Waighta, JD, Hylandera, BL, Sexton, S, Hong, CC, Gordon, CJ, Abrams, SI, & Repasky, EA (2013). Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature PNAS : 10.1073/pnas.1304291110

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Creepy crawly centipedes are a source of new high-strength painkillers

13161493I’m dreading the day I get knocked up, since I know that my incredibly low pain threshold will have trouble dealing with the crazy horror that is childbirth.

That’s why I was overjoyed to hear of some new research from Australia, where a new high-strength painkiller has been isolated from the venom of the Chinese red-headed centipede, Scolopendra subspinipes mutilans.

Scolopendra_subspinipes_mutilans_DSC_1438

In the insect world, centipedes are king of the hill – their venom is debilitating to their prey, helping them to capture fish, lizards, frogs and even small mammals.

Centipede venom is made up of a complex cocktail of proteins, each designed to disengage a particular biological pathway. Researchers isolated one of these proteins, µ-SLPTX-Ssm6a, and found that it blocked a specific pain receptor known as the voltage-gated sodium channel, Nav1.7.

For several types of chemical-, temperature- or acid-based pain, µ-SLPTX-Ssm6a provided better pain relief than the current gold standard, morphine. Happily, no side effects were observed.

So, µ-SLPTX-Ssm6a is a great new drug candidate for human pain relief. And since other beastie-derived venom proteins are already in clinical use – like PRIALT from the marine cone snail – µ-SLPTX-Ssm6a could make it to market before I find me a baby daddy.

Yang S, Xiao Y, Kang D, Liu J, Li Y, Undheim EA, Klint JK, Rong M, Lai R, & King GF (2013). Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models. Proceedings of the National Academy of Sciences of the United States of America, 110 (43), 17534-9 PMID: 24082113

Posted in Analgesics, Bioengineering, Disease, Medicine, Science | Tagged , , , , , , , , , | 2 Comments

Pumping out Petrol with Bioengineered Bugs

petrol

One of the terribly tricky questions in this ol’ world of ours is how to sustain a species that likes to extract toxic crude oil from the ground and use it in a way that’s disturbingly damaging to the environment they inhabit.

But imagine how much closer we would be to a renewable energy eutopia if instead of sucking fossil fuel out of the earth, there was an alternative way to satisfy our hunger for fuel.

Enter: microbes.

We’ve already created genetically engineered bacteria that produce diesel, but not our favourite fuel, petrol. The difficulty lies in convincing bacteria to produce the short-chain hydrocarbons that form part of the petrol cocktail, since they much prefer making longer chains.

Researchers in South Korea have now addressed this issue by creating two different strains of friendly Escherichia coli bacteria. After engineering in lots of additional hardware – including genes from Clostridium, Arabidopsis and Acinetobacter species – they substantially bumped the bacteria’s capacity to produce short-chain hydrocarbons.

The first strain, Gas-2, produces a steady stream of short-chain free fatty acids, which are intermediate products in the petrol creation process, while the second strain, Gas-3, churns out short-chain hydrocarbons (i.e. petrol) at a rate of 580 milligrams per litre.

This work represents an excellent new starter platform for the sustainable production of biofuels.

Choi YJ, & Lee SY (2013). Microbial production of short-chain alkanes. Nature, 502 (7472), 571-4 PMID: 24077097

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“Grape-like aromas” keep mosquitoes at bay

mosquito_terror_by_kittenmittenmuffin-d5bgh44The mosquito is my dad’s nemesis in the insect world. He will go to extraordinary lengths to secure his person from mosquito attack, roaming the corridors on night patrols and jamming mosquito repellent devices into every possible plug socket.

Such devices are usually based on the chemical, N, N-diethyl-meta-toluamide, or DEET. The problem with DEET is it’s expensive, it has nasty effects on our own skin and mosquitos are evolving resistance to it.

But replacing DEET has proven a tricky business, since we don’t really know exactly how it prevents mosquitoes zeroing in on their bloodbag human targets.

Until now.

A team of researchers from the University of California found that mosquito nerve cells in the antenna expressing the receptor Ir40a were crucial for the anti-DEET effect. When this receptor was blocked, mosquitoes became resistant to DEET – and in a nightmarish twist, some became more drawn to its scent.

They then used a computer algorithm to screen over 3000 “natural odours”, including extracts from plants, insects or vertebrates, and ones already approved for use in perfumes, cosmetics and food additives, for their predicted ability to block Ir40a receptors.

Three promising compounds with a “grape-like aroma”, plus a fourth that ants secrete to mark their trail, had strong effects on nerves expressing Ir40a and repelled mosquitos.

Since these compounds already have WHO and FDA approval, they are exciting new candidates for an improved class of bug repellents that could be speedily translated to market.

Kain, P, Boyle, SM, Tharadra, SK, Guda, T, Pham, C, Dahanukar, A, & Ray, A (2013). Odour receptors and neurons for DEET and new insect repellents Nature : 24089210

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How to: boost resistance to tuberculosis

Mycobacterium tuberculosis

Most kiddies receive the very effective Bacille Calmette-Guérin (BCG) vaccine against tuberculosis during childhood, but as they grow up, the protection afforded by this vaccine wanes.

Since cases of adult TB are on the rise, receiving an immune upgrade would be a great benefit to boost immune protection.

One team of researchers at McMaster University, led by Professor Zhou Xing, have now developed a new booster vaccine based on adenovirus, which causes the common cold.

In 26 healthy adults, they showed that this vaccine could generate robust immune responses against TB. Anti-TB immune cells created by the booster vaccine performed better in people that had previously received the childhood BCG vaccine, secreting a wider range of protective immune factors.

Since this novel booster vaccine has proven safe and very effective at reawakening TB immunity in BCG-vaccinated healthy adults, it will now move on to the next stages of clinical trials.

Smaill F, Jeyanathan M, Smiejal M, Medinal MF, Thanthrige-Don N, Zganiacz A, Yin C, Heriazon A, Damjanovic D, Puril L, Hamidl J, Xie F, Foley R, Bramson J, Gauldie J, & Xing Z (2013). A Human Type 5 Adenovirus–Based Tuberculosis Vaccine Induces Robust T Cell Responses in Humans Despite Preexisting Anti-Adenovirus Immunity Science Translational Medicine, 5 (205) DOI: 10.1126/scitranslmed.3006843

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A Marvellous Month of Infectious Science

Cold weather helps to spread flu across the country

snowA very cool new study from McMaster University researchers shows how weather patterns impact the spread of influenza A virus across Canada. Using outbreak data gathered over more than 13 years, the virus could be tracked over time and space. Influenza A tended to first emerge in the colder, less humid provinces of Western Canada (British Columbia and Alberta), and then spread across the country to the East. Schools also represented hotbeds of infection – when they were shut during the Summer, there were significantly fewer cases of flu recorded.

Investigating the ‘ouch’ factor during a bacterial infection

nerveWhen a bacterial infection takes hold, it’s usually a painful experience. During a normal immune response, immune cells infiltrate the infected area, pummel the invading bacteria and in doing so release molecules that cause swelling and pain. Yet new research from Harvard Medical School shows that it’s not only the immune system that is to blame: at least some of the pain comes from the bacteria themselves secreting factors that can interact directly with our nervous system.

The immune system’s need for speed

speedOur beautiful human bodies have several portals where nasty pathogens, such as bacteria, can enter and wreak havoc. Once inside the human body, bacteria start reproducing straight away, doubling their numbers around once every 20 minutes. Yet our immune T cells constantly patrol such vulnerable open-access areas, sampling their environment to identify threatening material. A reassuring new study has now come out showing that reactive T cells sense such foreign material within a few seconds, and make the decision to respond to malevolent threats within a speedy minute.

Edible vaccines, om nom nom!

OLYMPUS DIGITAL CAMERARotavirus infection is one of the major nasty causes of childhood diahorrea, but can happily be prevented with an oral vaccine. Vaccinated children in industrialised countries develop 85-98% immune protection, while those in the third world develop a much lower protection level of 50-60%. The reasons behind this startling difference are not well characterised, but third world kiddies would obviously benefit from a boost in their rotavirus immune protection.

One team has come up with a new way of administering such an immune upgrade – by loading rice, a staple food in the third world, with anti-rotavirus immune-boosting antibodies. This tasty dish could conceivably be consumed regularly during childhood to maintain protection levels.

Originally posted on Scizzle.

Posted in Bacteria, Disease, Immunology, Microorganisms, Science, Vaccines, Viruses | Tagged , , , , , , , , , | Leave a comment

The fairly depressing picture of pesticide pollution in British rivers

2405003862_2c3ece1e79_bLots of pesticides – such as the organochlorine insecticide, DDT – that were widely used in the fairly recent past are now banned after having serious effects on the health of humans and other species.

Yet old and new pollution of rivers and streams is still an issue across Europe, since waste water treatment practises don’t remove potentially harmful substances like pesticides, toxins, synthetic hormones and pharmaceutical drugs.

One team of researchers wanted to assess the levels of contaminants and the state of river recovery across 33 rivers in South Wales, UK, that were badly polluted in the past. To do this, they sampled toxin levels in the eggs of the Eurasian dipper (Cinclus cinclus), a waterbird that is well known to act as a pollution bioindicator.

cinclus_cinclus_2332They found that eggs from urban areas contained higher levels of modern pollutants, like toxic PCBs and PBDEs, while eggs from rural areas had higher levels of old agricultural pollutants, such as the pesticides DDE (a breakdown product of DDT) and dieldrin.

When the team compared current pesticide levels with those recorded 20 years ago, there was little or no reduction, and the concentrations of some pesticides – such as HCB and lindane –  had actually increased to levels high enough to affect bird development.

This research indicates that British water wildlife is not being properly protected by current legislation governing levels of toxic substances in rivers, and a new approach to water security is badly needed.

Paper: http://goo.gl/OZ6Dtj

Morrissey CA, Stanton DW, Pereira MG, Newton J, Durance I, Tyler CR, & Ormerod SJ (2013). Eurasian dipper eggs indicate elevated organohalogenated contaminants in urban rivers. Environmental science & technology, 47 (15), 8931-9 PMID: 23819781

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Magnificently Mathematical Mussels

2898357773_22f8feafb3_bDespite the ease with which mussels can be cooked and eaten with chips, harvesting these tiny shelled bivalves from the seashore requires a certain amount of industrious prising.

That’s because mussels use multiple thin byssus threads to securely fasten themselves to different surfaces along the coastline. These threads have a sticky plug at one end, with the mussel’s body dangling off the other (shown below).

musselScientists have found it difficult to explain how mussels tolerate the forces generated by constantly crashing waves and strong sea currents, since the calculated strength of the byssus threads alone is too low to withstand them.

So, how exactly do mussels manage to stay attached to a rocky coastline, or the hull of a fast-moving ship?

Researchers at MIT explored this question by collecting mussels from Boston harbour, and testing them under different conditions.

They found that byssus threads are not made up of the same material all the way through. Instead, the thread sports a mixture of soft and hard material that optimises its ability to resist impact forces.

The soft material nearer to the body of the mussel deforms as mechanical forces are applied, while the hard material closer to the sticky plug stays in a very relaxed state until substantial force is applied.

This geometric structure results in a 900% increase in the mussel’s ability to withstand repeated bashing by waves (dynamic strength) compared to its ability to resist constant pressure (static strength).

This arrangement also conspires to create the least amount of force at the junction between the mussel’s body and the byssus thread, minimising the likelihood of a horribly wrenching separation.

Other animals using this ingenious materials design include the mantis shrimp and certain ancient fish.

This research has wonderful implications for the bio-design of new materials that need to withstand significant push/pull forces, such as submarines, wind turbines and materials going into space.

Qin Z, & Buehler MJ (2013). Impact tolerance in mussel thread networks by heterogeneous material distribution. Nature communications, 4 PMID: 23880603

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Particle accelerators: making life better since 1932

(cc) dvarg

(cc) dvarg

Atoms form the building blocks of everything that exists in the world, holding chairs, rocks, water and our bodies together in strong, stable structures.

But atoms themselves are made up of lots of composite parts, called sub-atomic particles. Such particles exist in high energy states, and we can find out much more about them using huge particle accelerators, like the Large Hadron Collider. In these machines, atoms are smashed together to leave behind a big pile of sub-atomic debris. This can be sifted through to identify the pieces that are left behind, and to find out exactly how atoms stick so tightly together.

Although it’s fun to hammer atoms together at close to the speed of light, learning more about the structure of matter also impacts our everyday lives. High energy particles are used in electronics, medicine, environmental clean ups and energy production, and exciting new particle accelerator discoveries can be expected to supply a steady stream of future advancements.

Particle accelerators improve medical treatments

High energy particle beams created by miniaturised particle accelerators are currently used in several cancer clinics to shrink tumours. These beams deliver an incredibly precise dose of radiation to cancerous tissue, and come with fewer side effects than traditional therapies. Fourteen centres across Europe currently offer particle accelerator cancer treatments.

Particle accelerators make chocolate smoother

chocolate

Particle accelerators can unravel the molecular structures of different objects. For food scientists, the edible structures of tasty treats can be analysed to discover how different recipes produce the best flavours. For example, particle accelerator experiments have shown that fat-free chocolate CAN be tasty, depending on its atomic structure. Reducing the fat content typically leads to issues that scientists refer to as “poor in-mouth melting properties“. Chocolate recipes made with varying proportions of fats produce bars with different sub-atomic structures, some of which always go down smooth.

Particle accelerators help to clean up the planet

Toxic sludge can spill into the water, land and air, and cleaning it up is a chemically complicated problem. Analysing contaminated samples in a particle accelerator can tell us the exact blend of dirty elements present, what state they exist in and the best ways to purge them from the environment. Such analyses helped to clean up large spills of heavy metals in Hungary after tanks storing contaminated red mud excavated during mining operations accidentally failed.

Allison RR, Sibata C, & Patel R (2013). Future radiation therapy: photons, protons and particles. Future oncology (London, England), 9 (4), 493-504 PMID: 23560373

Do TA, Hargreaves JM, Wolf B, Hort J, & Mitchell JR (2007). Impact of particle size distribution on rheological and textural properties of chocolate models with reduced fat content. Journal of food science, 72 (9) PMID: 18034724

Burke IT, Mayes WM, Peacock CL, Brown AP, Jarvis AP, & Gruiz K (2012). Speciation of arsenic, chromium, and vanadium in red mud samples from the Ajka spill site, Hungary. Environmental science & technology, 46 (6), 3085-92 PMID: 22324637

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A Marvellous Month of Science

Taking vitamin supplements might not be as healthy as you think

vitaminsAntioxidant vitamins, like vitamin C and E, are thought to boost health by reducing the creation of DNA-damaging free radicals that can contribute to the ageing process. In lab mice, there is some suggestion that vitamin supplements can extend lifespan, but since laboratory-bred mice are genetic clones, such studies may bear little relevance to a hugely genetically diverse human population.

Giving wild animals, such as the short-tailed field vole, either vitamin C or E supplements has now been shown to have a less positive impact on health. Animals taking either vitamin had a decreased lifespan compared to their non-vitamin chowing counterparts. This aligns with a Cochrane analysis that suggests the same thing happens in humans.

How does the naked mole rat stay cancer-free?

Naked Mole-ratThe naked mole rat is an object of scientific fascination, not just for rocking a quirky look but also for its biological anomalies. In the world of small mammals, it has a remarkably long lifespan (more than 30 years), paired with a complete inability to develop cancer.

Now, a team of researchers led by Xian Tian have shown that the fibroblasts of the naked mole rat, which act as nurturing cells that provide structural and chemical support to other specialised cells, secrete a wonderful version of hyaluronan to produce this anti-cancer effect. Hyaluronan forms part of the extracellular matrix that sticks cells together in a nice ordered pattern. It builds up in naked mole rat cells to protect them by dampening cellular proliferation and inflammation. Removing hyaluronan from these cells renders them sensitive to malignant transformation. Using hyaluronan in the clinic may prove useful for preventing cancer and extending lifespan.

Presenting: the first ultrahigh resolution atlas of the human brain!

Image converted using ifftoanyThe human brain is a fascinating organ that shapes, defines and controls us as individuals. Yet its structure remains frustratingly complex to dissect, and we are only just beginning to understand the anatomical features that can easily be seen by the naked eye. Analysing fine ultrastructural details, including how more than 170 billion neural cells are connected, has proven a tricky task.

To address this issue, a single human brain donated by a 65 year old woman was cut into 7,400 thin slivers, which were stained, photographed and painstakingly fitted back together to create the first high definition 3-D reference map of the human brain. Lovingly known as, “BigBrain”, this new publicly available biological encyclopedia should help us better understand the nature of language, emotions and consciousness.

You can watch a video of the 3-D BigBrain map here: http://youtu.be/nJpFvQ0YZLk

Visit the database here: https://bigbrain.loris.ca/main.php

Stem cells work in shifts to replenish immune patrols in the blood

4. Hemo-StemB and T cells are lethal immune warriors that circulate in the blood and vanquish pathogenic invaders. Yet they don’t live forever, and have to be periodically replenished to maintain immune protection. The sources of this renewal are the haematopoietic stem cells (hSCs) that reside in the bone marrow, where they proliferate to generate their warrior progeny.

A team of researchers from The Netherlands looked at how many fresh B or T cells each individual haematopoietic stem cell added to the total immune cell pool. They found that the contribution of each hSC expanded and declined at different times. When one stem cell was churning out a large number of progeny, the others rested before taking their turn later on. Each stem cell also appeared to be dedicated to producing either B or T cells, and wasn’t able to swap between the two.

Originally posted at Scizzle Blogs

Selman, C., McLaren, J.S., Collins, A.R., Duthie, G.G., & Speakman, J.R. (2013). Deleterious consequences of antioxidant supplementation on lifespan in a wild-derived mammal Biology Letters, 9 (4) DOI: 10.1098/rsbl.2013.0432

Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, Mao Z, Nevo E, Gorbunova V, & Seluanov A (2013). High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature, 499 (7458), 346-9 PMID: 23783513

Amunts K, Lepage C, Borgeat L, Mohlberg H, Dickscheid T, Rousseau MÉ, Bludau S, Bazin PL, Lewis LB, Oros-Peusquens AM, Shah NJ, Lippert T, Zilles K, & Evans AC (2013). BigBrain: an ultrahigh-resolution 3D human brain model. Science (New York, N.Y.), 340 (6139), 1472-5 PMID: 23788795

Verovskaya, E., Broekhuis, M.J.C., Zwart, E., Ritsema, M., van Os, R., de Haan, G., & Bystrykh, L.V. (2013). Heterogeneity of young and aged murine hematopoietic stem cells revealed by quantitative clonal analysis using cellular barcoding Blood, 122 (4), 523-532 DOI: 10.1182/blood-2013-01-481135

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Clouds of decoy viruses help cure genetic disease

Helpful viruses get protected by decoy viruses in the bloodstream. Maddy Cow.

Helpful viruses get protected by decoy viruses in the bloodstream. Maddy Cow.

The presence of foreign objects, like viruses, in our bloodstream is usually a bad thing. Evolution has created some extremely efficient immune cells that patrol the blood, seeking out material that should not be there, and shutting it down.

Sometimes, though, viruses circulate in the blood for beneficial purposes. Gene therapies often deliver viruses as couriers to deliver new DNA to repair faulty cells. Getting viruses into the bloodstream is simple, but keeping them “active” during their time inside the body is difficult. This is particularly true if the immune system has encountered them before. Even though therapeutic viruses are engineered to be beneficial, the immune system doesn’t recognise the difference, and starts a defensive response.

Now a team led by Federico Mingozzi at the Children’s Hospital of Philadelphia has come up with a way of preventing such therapeutic viruses from being decommissioned by the immune system, by hiding the virus particles inside a cloud of decoy empty virus particles.

As they report today in the journal Science Translational Medicine, the team developed an engineered version of adeno-associated virus (AAV) as a genetic courier for the treatment of haemophilia B. This disease stems from a mutation in the DNA of liver cells that prevents them from producing normal levels of an enzyme called coagulation factor IX. Such patients can bleed to death without proper treatment.

Mingozzi’s AAV was designed to deliver a DNA payload to the liver. This DNA contained instructions to produce the correct version of coagulation factor IX, a crucial protein involved in blood clotting, in the hope that it would cure this genetic disease.

Stealth tactics

Viruses consist of two parts: a genetic core (either DNA or RNA) and a protective protein shell. When a virus infects a human, the host immune system typically triggers a cascade of defensive reactions. One of the most effective responses is the production of neutralising antibodies that recognise and attach to the virus shell and squelch its activity.

Mingozzi’s choice of AAV as a genetic courier would seem counter-productive then, since between 30% to 60% of the human population has previously been exposed to AAV. Thus, their immune systems have learned to recognise AAV shells. In such immune individuals, even though the engineered version of AAV contains beneficial genetic information, it gets quickly tagged for destruction and obliterated long before it reaches its target destination (the liver).

Even when a large number of AAV particles are administered to improve the odds of some getting through, the immune system mops them up. The few particles that do survive the journey initiate the production of normal coagulation factor IX in liver cells, but only manage to reconstitute around 10% of the normal volume of the coagulation factor IX pool.

So Mingozzi came up with an idea to fool the immune system. He mixed therapeutic AAV particles containing the right genetic information with lots of empty AAV shells lacking a DNA core, and injected them into mice (used as a proxy for humans). This created a smokescreen, allowing the therapeutic AAV particles to dodge the immune system’s attack.

This new approach enhanced AAV survival in the bloodstream of mice. Depending on how immune each individual mouse was to AAV, a personalised ratio of empty AAV particles to real AAV particles was administered. Mice with higher levels of AAV antibodies received more empty decoy shells.

Circulating AAV antibodies, which exist in immune individuals, attacked both empty and active versions of AAV, but enough active virus got to the liver to boost coagulation levels beyond those seen in an average mouse. These beneficial effects lasted up to four weeks – an excellent timeframe given that a severely affected haemophilia B patient has to inject themselves every day.

They also tested out the same idea using animals more closely related to humans – rhesus macaques – where the presence of decoy virus gave real AAV particles the same survival extension, and boosted coagulation factor IX levels to a similar degree.

Importantly, when different monkey tissues were examined after administering empty and real AAV formulations, all the activity predominantly happened in the liver, with no unsafe, off-target effects in other organs.

Perfecting the decoy trap

The first generation of decoy viruses used in this study were designed to be exact replicas of AAV, but without the DNA payload. Unfortunately, these decoy viruses behaved too much like the real thing, attaching to target liver cells and by virtue of their overwhelming numbers, out-competing the binding of real, therapeutically-relevant virus. Once inside liver cells, bits of these empty viruses then presented enticing foreign targets to the immune system.

Tweaking the design of the empty virus shell in the second generation of decoy viruses prevented it from binding liver cells, boosted the binding of real virus and replicated the rise in coagulation factor IX levels. It also had the happy consequence of dampening certain sections of the immune response.

Using fake viruses as bodyguards is an ingenious way of protecting therapeutic viruses in the bloodstream. This approach could represent the start of a therapeutic revolution for haemophilia B patients, and others with genetic diseases.

(Originally posted on The Conversation).

Mingozzi, F., Anguela, X.M., Pavani, G., Chen, Y., Davidson, R.J., Hui, D.J., Yazicioglu, M., Elkouby, L., Hinderer, C.J., Faella, A., Howard, C., Tai, A., Podsakoff, G.M., Zhou, S., Basner-Tschakarjan, E., Fraser Wright, J., & High, K.A. (2013). Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys Science Translational Medicine, 5 (194)

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Gene therapy using stem cells prevents inherited diseases

Originally written for The Conversation.

Gene therapy: not just for mice. J. Bradbury.

Gene therapy: not just for mice. J. Bradbury.

Genetic traits like a bulbous nose or balding give some people reasons to moan about what they inherited from their parents. But more serious genetic flaws can cause debilitating disease. Now, Italian researchers have come up with a way of treating one such inherited disease and reversing another using a promising new method of gene therapy.

The idea behind gene therapy is to replace a faulty gene with a shiny new version that works properly. Modified versions of viruses, which have been sculpted by millions of years of evolution, perfectly penetrate human cells. They act as couriers delivering DNA payloads to defective cells and ensure it is stably inherited.

This deceptively simple idea, though, has been challenging to achieve in practice. The first commercial gene therapy product, Glybera, only received regulatory approval in 2012.

Part of the reason for this is the difficulty of successfully clearing three hurdles at once: delivering replacement genetic information to the exact cells that need help, getting this information safely translated in high enough volumes to overcome the defects and stopping the immune system from reacting to “normal” genes when it has grown used to only seeing mangled ones.

Now, a team led by Alessandra Biffi at the San Raffaele Scientific Institute in Milan, Italy reports in the journal Science that they have developed a new approach that navigates each of these hurdles to treat three children with metachromatic leukodystrophy (MLD), a devastating inherited disease that affects around 1 in 40,000 people.

Engineered stem cells

MLD usually manifests in early childhood and kills patients just a few years after the first symptoms appear. It is caused by a defect in a single gene, ARSA. This gene encodes information used by the lysosome, a piece of recycling machinery used by human cells to break down unwanted material. When this recycling process does not work properly in nerve cells, as is the case with MLD patients, they become filled with rubbish and begin to slowly decline, leading to brain and spinal cord degeneration, as well as sensory deprivation.

Defects in a single gene knock out lysosomal activity in nerve cells of the central and peripheral nervous system in metachromatic leukodystrophy patients. Peter Brophy, Wellcome Images.

Defects in a single gene knock out lysosomal activity in nerve cells of the central and peripheral nervous system in metachromatic leukodystrophy patients. Peter Brophy, Wellcome Images.

Supplying a replacement ARSA gene to affected cells in the nervous system is a tricky task, because these areas are heavily protected. To overcome these defences, the team employed haematopoietic stem cells (HSCs), which can usually be found nestling quietly in the bone marrow, as stealthy genetic couriers. A tiny number of these cells were harvested from each patient, loaded with benign viruses carrying a working copy of ARSA and put back into the bloodstream.

These engineered cells either lodged in the bone marrow or continued to travel around the body in the blood, where they corrected defective cells in the nervous system by supplying the normal version of ARSA. Because these were stem cells, they also reproduced to form new blood cells that themselves took on the same supportive roles.

Resurrecting lysosomes from the dead

Most MLD patients produce a garbled version of ARSA that has a very low level of activity, nowhere near enough to let the lysosome carry out its normal job. Restoring partial activity is not enough to make a clinical impact – levels must be hiked to make an obvious difference.

One way of maximising activity is to pack defective cells with lots of normal copies of the same genetic message. In this case, haematopoietic stem cell couriers were loaded with two to four copies of the same virus, introducing multiple reproductions of the normal ARSA gene into the host cell genome.

To check that these viral inserts did not cause any unintended biological disruptions, which could lead to very serious side effects (like leukaemia), every individual founder cell infused into the patients was tracked using a genetic barcode. While some original cells generated large pools of daughter cells early on, which could be a sign of dangerously uncontrolled growth, none of them continued to dominate the blood cell pool as time went by.

In the patients, levels of ARSA quickly skyrocketed to above-average concentrations in both the original courier stem cells and their progeny. More than a year after treatment, normal ARSA levels were detected in the cerebrospinal fluid of all three patients, a clear sign that the central nervous system had stabilised. All these kids, who have older siblings badly affected by the same disease, can now think, run, jump, sit, crawl, kneel, jump, roll and speak like similarly aged average preschoolers.

Using the same technique, in a separate paper in Science, a team led by Alessandro Aiuti of the same institute in Italy showed reversal of the Wiskott-Aldrich syndrome (WAS) in three other young patients.

Like MLD, WAS is also a disease caused by a defect in a single gene. The disease causes immune system dysfunction that leaves kids at high risk of infections, bleeding and being harmed by their own immune system. But HSCs loaded with viruses containing the correct version of the faulty gene were able to restore a properly functioning immune system.

Using this stem cell-based gene therapy technique, both these new studies have either prevented the onset of a serious neurodegenerative disease, or reversed existing immunological disease. These are a testament to the tremendous potential of gene therapy and they represent a great step towards long-lasting cures for single-gene diseases.

Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, & Naldini L (2013). Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy. Science (New York, N.Y.) PMID: 23845948

Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee P, Orange J, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, & Naldini L (2013). Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome. Science (New York, N.Y.) PMID: 23845947

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MESSENGER spacecraft helps uncover Mercury’s pummelled past

mercuryIn our solar system, Mercury is the teeniest planet, and nestles closest to the sun. Understanding how Mercury developed as the solar system formed is an intriguing question for space science, and a surprising amount of information can be uncovered by analysing the topographical atlas of Mercury’s surface.

The Mariner 10 spacecraft, which launched in 1973, sent back photographs of just under half of Mercury’s surface. Now, American researchers have used images from the glossy, ultramodern MESSENGER spacecraft (launched in 2004) that visualise the entire surface to identify new landscape features that might help to explain more about Mercury’s history.

They found that the oldest areas of Mercury were pockmarked with huge craters (10 – 1,000 km wide) that hail from an intense period of history around 4 billion years ago known as the Late Heavy Bombardment. This was a time when huge fields of asteroids and comets travelled through space and cannoned into different planets of our solar system, including Mercury and the moon (interestingly, Earth doesn’t show much evidence from this period since active tectonic plates and erosion constantly resculpt the planet’s surface).

Then, around 3.8 billion years ago, several areas of Mercury’s terrain appear to have been smoothed out by intense volcanic activity extending across the planet, erasing evidence of past craters. Since such smoothened areas mostly peter out towards the end of the Late Heavy Bombardment period, these volcanoes were likely activated by the constant impact of asteroids and comets.

Paper: http://goo.gl/PoHep

Marchi S, Chapman CR, Fassett CI, Head JW, Bottke WF, & Strom RG (2013). Global resurfacing of Mercury 4.0-4.1 billion years ago by heavy bombardment and volcanism. Nature, 499 (7456), 59-61 PMID: 23823793

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A huge variety of fungi call your feet home

Skin Fungal DiversityHuman skin is a hardy, water-resistant covering that keeps important biological stuff from falling out of the body. It’s also a camping ground for millions of bacteria (picked out in magenta, above), fungi (seen in blue-green, above) and yeast that mostly hang out minding their own business and getting on with their lives. Sometimes, though, in particularly warm and moist areas, they grow a bit overexuberantly and cause problems.

Athlete’s foot and toenail infections are two common examples of fungi gone wild. One team of researchers from the National Institutes of Health in Bethesda, USA, were interested to find out if the levels and types of fungi found on the foot predisposed it to fungal disease. So, they recruited 10 healthy adults, swabbed them in 14 different anatomical areas, including the feet, and ran genetic analyses on the sampled fungi.

8 of those 14 swabs were taken from core body parts – the inner ear, behind the ear, chest, back, nostril, scalp, the crease between the thigh and torso and the space between the eyebrows. These areas were totally dominated by fungi from the Malassezia genus, with an average of 6 different types observed.

3 of those 14 swabs were taken from the arm – at the elbow crease, palm and forearm – and these showed a richer level of fungal variety, with an average of 25 types identified.

The final 3 swabs were taken from the feet – the heel, toenail and between the toes – and returned a huge spectrum of fungal types. On average, 50 different varieties were found.

Fungal DiversityWhen some of the volunteers returned a few months later to be freshly swabbed, the core body and arm sites still housed the same types of fungi. On the feet, though, while there was still a huge assortment of fungi present, they were not the same communities that had previously been sampled.

This suggests that the normal exposure of the foot to the outside world causes constant shifts in microbial ecosystems that present opportunities for pathogenic fungi to become established. So, the relatively high propensity for fungal outbreaks on the foot – where up to 60% of “healthy” people have underlying infections – could definitely be explained by the highly changeable nature of the fungi that live there.

Paper: http://goo.gl/SfVSs

Findley K, Oh J, Yang J, Conlan S, Deming C, Meyer JA, Schoenfeld D, Nomicos E, Park M, NIH Intramural Sequencing Center Comparative Sequencing Program, Kong HH, & Segre JA (2013). Topographic diversity of fungal and bacterial communities in human skin. Nature, 498 (7454), 367-70 PMID: 23698366

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Vaccine delivers an immune double whammy to fight tuberculosis

TB chest X-Ray

Vaccination is a hugely important public health intervention, perhaps the biggest in the history of mankind. While many childhood diseases are now effectively controlled by immunisation programs (as long as parents vaccinate their kids), there is still no effective vaccine for other serious infections like adult tuberculosis (TB).

Most adult TB vaccines under development focus on boosting the “adaptive” immune response to generate highly activated immune cells to fight off M. tuberculosis bacteria. New research has now revealed that it’s also important to consider how such vaccines impact the “innate” immune response, which exists in a state of constant readiness to repel pathogenic invaders.

In a collaborative effort from the McMaster Immunology Research Centre in Canada, researchers first administered a basic TB shot to set up a foundation level of anti-TB immunity. Then, since tuberculosis-causing bacteria enter the human body via the lungs, the team delivered a second inhaled vaccine designed to boost immune cells at the site of pathogen invasion. Two different inhaled vaccines were used, based on adenovirus or vesicular stomatitis virus (VSV).

While both inhaled vaccines generated similar levels of adaptive immunity, the VSV vaccine was not as good as adenovirus at producing robustly activated, multi-functional innate immunity. This led to a poor anti-bacterial effect, and a lack of protection against M.tb bacteria.

The unique nature of each inhaled vaccine appears to be responsible for this difference in outcome. VSV enters lung cells in a certain way, attaching at different sites, activating different intracellular pathways, expressing different viral products and consequently engaging different parts of the immune system. The two different vaccines programmed the two arms of the immune system differently, and the vaccine that engaged adaptive and innate immunity together did the best job at controlling tuberculosis infection.

This research should help to drive the intelligent design of future vaccines against pathogens like HIV and chlamydia, which enter at similar interfaces where the body meets the outside world.

Jeyanathan M, Damjanovic D, Shaler CR, Lai R, Wortzman M, Yin C, Zganiacz A, Lichty BD, & Xing Z (2013). Differentially imprinted innate immunity by mucosal boost vaccination determines antituberculosis immune protective outcomes, independent of T-cell immunity. Mucosal immunology, 6 (3), 612-25 PMID: 23131783

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Fish parasite inspires sticky surgical tissue patch

organs

(c) Myotis

Surgeons still find it tricky to quickly and reliably stick a wet, slippery organ back together during invasive procedures. The currently available selection of ‘stick-you-together’ products – staples and chemical glues – do a decent job, but make a bit of a mess of nearby nerves and blood vessels, and often cause swelling, itching, scarring and, sometimes, infection.

Yet lots of parasitic organisms have evolved excellent ways of entering – and sticking to – their host. The freshwater fish parasite, Pomphorhynchus laevis, also known as the spiny-headed worm, gets eaten by an unsuspecting fish and travels through the digestive tract. Once it reaches a prime spot, it anchors itself firmly in the slippery intestines, ramming its proboscis deep into the intestine wall, inflating the tip, and forming a tight, interlocking grip on the tissue.

A team of researchers from Harvard have taken inspiration from this ingenious design to develop a small microneedle patch (shown below) to hold together organs. The patch glides smoothly and non-invasively into tissues and, once embedded, the tips of each tiny needle absorb water from the interstitial fluid that bathes every cell. These tips swell to their maximum size within 10 minutes, forming a bulbous end like an arrow head that gives the patch great sticking power.

microneedle matIn a test run on a pig, the microneedle patch attached skin grafts better than the current gold standard (staples), and there was less associated contamination from nasty bacteria. After the tissue healed, the microneedle mat could be easily removed, and the tiny holes it left behind sealed within a few hours. Once out of the liquid tissue environment, the swollen tips shrank back to their original size and shape, and were ready to be sterilised and re-used.

All-in-all, a mightily impressive bit of bioengineering!

Yang SY, O'Cearbhaill ED, Sisk GC, Park KM, Cho WK, Villiger M, Bouma BE, Pomahac B, & Karp JM (2013). A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue. Nature communications, 4 PMID: 23591869

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It’s great to be a woman scientist; it’s challenging to be a woman scientist

RosieTechI recently volunteered to help organise an event run by the Canadian Science Policy Centre that looked at the status of women in science and technology. To be frank, I was mightily fearful about participating in such an event. I had the idea that it would quickly degenerate into a depressing evening of man-bashing.

Yet, as it turned out, it was actually a wonderfully empowering, evidence-based look at women working in STEM fields (or maybe I just thought so because I travelled to the meeting listening to the Spice Girls – the ultimate in female power).

Wendy Cukier and Dr. Maydianne Andrade first described that while overt gender discrimination no longer exists (for a recent convert to the ridiculously sexist show Mad Men, this is good news), subtly muted gender discrimination does. We have to acknowledge this reality, even if it doesn’t affect us personally.

Gender bias almost appears to be written into our basic subconscious – and the fabric of our society. It flows in many different directions: it doesn’t just come from men directed at women. Some fields are overtly biased against men – 2012 was the first year a male midwife graduated from a Canadian university. And women can be biased against other women. So improving everyone’s awareness about gender balance is important. As Dr. Robin Duncan said, being self-perceptive about your own biases can help you to consciously counter them. Dr. Maydianne Andrade suggested taking Harvard University’s online test Project Implicit as a first step in that direction.

A remarkably soothing message that came through was that You. Are. Not. Alone. Every person in every workplace in the world encounters the gender issue, although it’s more evident in certain fields – such as computing, engineering, maths and the physical sciences. While women have made inroads into the life sciences (left graph, in purple, below), it is pretty depressing to see how few women go into and stay in other scientific fields (right graph, in purple, below).

stemgraphs2Being apathetic about balancing out the ratio of men to women in the workplace is remarkably easy. I used to be solidly indifferent myself. Wendy Cukier underscored that the decision to instigate change comes from essentially political powers, who are often resistant to such turbulence until enough pressure, advocacy and active engagement occurs.

One particular area in academia that was highlighted as prime for change was the way that in-house applications for pots of research funding get reviewed. Inherent bias in this system was first outlined in 1997 in a paper that analysed outcomes of postdoctoral grant applications to the Swedish Medical Research council. In these reviews, female applicants were consistently ranked lower in all categories, even though their research had the same level of scientific impact, and these review panels were made up of both men and women.

This is startling. Yet the solution is stunningly simple: to blind grant reviewers to the names (and consequently, genders) of the applicants. Research shows that this approach works. Yet few institutions seem to do it. This is unacceptable. Academic and private institutions have a stern responsibility to do all they can to minimise the potential impact of prejudice, and to seek out and put forward diverse candidates to fill new roles. Such problems and overt barriers are real. There is substantial evidence for their existence. And they need to be addressed.

Under the steam of this event, I came to realise that every minority – be it defined by gender or otherwise – still needs help to reach parity in the workplace. Without extending this help, new points-of-view and fresh, enriching ways of thinking are lost. This comes along with an inherent cost to our country and our society, which loses the capacity to achieve maximum innovation, creativity and output, all major factors that drive the economy.

For such help to be of any use, though, requires that women put themselves forward to advance in their career and fill new positions. The Hon. Lorna Marsden described a 2008 scheme run by the government of Canada to create and fill a new research chair position. Designed to attract international scientific experts, hundreds of people applied, 19 were selected, and all were men.

So, why is this? As Sheryl Sandberg, COO of Facebook, recently alluded to in her TED talk, such situations can stem from women being shy at owning their strengths, their successes and their ambitions. It is not bragging or self-aggrandising to recognise that you have done a good job.

Another piece of the reason pie is the inner working of a treacherous brain. Dr. Shiva Amiri mentioned the insidiously self-obstructive imposter syndrome, feeling like you don’t know anything and are going to be found out as a fraud. As Dr. Dawn Bowdish recommended, even if you don’t feel it, fake it – a great piece of advice. Wendy Cukier also made a good case for a proactive approach: seeking people out, asking them questions, taking the initiative and actually asking for things. Gender issues are only partly down to a biased system; the rest is not asking for what you want.

Seeing this team of six wonderful women (Hon. Lorna Marsden CM, Wendy Cukier, Dr. Maydianne Andrade, Dr. Dawn Bowdish, Dr. Shiva Amiri and Dr. Robin Duncan) getting to the bottom of a shared issue was a great experience. Knowing how the gender issue looks these days, compared with its past guises, is simultaneously a wonderful win and a sorry ongoing saga. There’s definitely much more to do – and I’m in for doing it.

Wenneras C, & Wold A (1997). Nepotism and sexism in peer-review. Nature, 387 (6631), 341-3 PMID: 9163412

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How to survive the bacterial antibiotic revolution

superbugs

These days, we have a pretty serious problem when it comes to our ability to kill resistant bacteria causing serious illness. People petition governments to urge action, while drug companies lament over how those pesky bacteria evolved to defeat their beautiful antibiotics – and their projected profit margins.

Yet, it’s not all bad. There are a few little ways that us humans can fortify our bodies with a sturdy shield against nasty bugs.

Nurture good bacteria

Keeping your good bacteria, especially the ones in your gut, happy, robust and numerous is a great way to deflect nasty microbial attacks. Eating live good bacteria in an effort to boost health was first documented by Suleiman the Magnificent (1494-1566), a Turkish emperor who prescribed yoghurt as a cure for the severe diarrhoea experienced by King Francis I of France.

Yoghurt, or rather the active bacteria in yoghurt, promotes a healthy microbe balance in the gut. Farm animals routinely fed dried versions of probiotics have a tremendously diminished rate of nasty Salmonella infection outbreaks, and for humans, eating probiotics has been promoted by scientists as a good way to control Clostridium difficile outbreaks, reducing the number of cases by around 65% in nursing homes and hospitals.

Probiotics thus appear to have the admirable ability to suppress the growth of dangerous bacteria, while nourishing our happy, friendly bacteria.

Give bad bacteria a hard time

While chefs rub a nice pork loin with garlic to infuse it with a tasty flavour, a great side benefit is that garlic seriously slows the growth of contaminating bacteria. What’s good for a pork loin is also good for tender humans. Physicians in the Roman army used fresh crushed garlic to cure illness, harnessing its ability to fight not just bacteria, but fungi, viruses and protozoa to boot.

Garlic has little effect on good bacteria, like the helpful lactic acid ones in our gut, but packs a punch with bad bacteria – perhaps because their slightly different biologies affect susceptibility to garlic’s active chemical ingredient, allicin. Pathogenic bacteria, such as E.coli, Shigella and Salmonella, isolated from the poop of patients suffering severe bouts of diarrhoea, can be effectively killed by garlic, at least as well if not better than antibiotics. Even multi-drug resistant bacteria succumb upon exposure to crude garlic extracts.

Protect places where bacteria are likely to breed

There are plenty of nasty bacteria present on or in our bodies all the time. Only when damage occurs – say, when you fall over rollerskating and scuff your knee – do these bacteria get an opportunity to wreak havoc. But open wounds can be effectively treated with a protective glaze from the kitchen cupboard. Honey, the sweet and viscous liquid produced by honey bees, has a potent natural antimicrobial activity, packed full of bee proteins, like defensin-1, which punch holes in bacterial membranes and recruit immune cells to battle invaders.

The gooiness – and high sugar content – of honey, especially Manuka honey, also sucks moisture out of injured tissues where bacteria could thrive, seals off damaged areas and stops wounds from festering. Honey is capable of efficiently killing tough disease-causing bacteria, like methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, a tricksy little bug that often plagues cystic fibrosis patients.

So, with bacteria currently outmanoeuvring us in the antibiotic arena, exploring the world of natural antimicrobials, perhaps by simply adding a little yoghurt, honey and garlic into our lives, might be a great way to strengthen our individual biological shields.

Johnston BC, Ma SS, Goldenberg JZ, Thorlund K, Vandvik PO, Loeb M, & Guyatt GH (2012). Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis. Annals of internal medicine, 157 (12), 878-88 PMID: 23362517

Karuppiah P, & Rajaram S (2012). Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens. Asian Pacific journal of tropical biomedicine, 2 (8), 597-601 PMID: 23569978

Kwakman PH, te Velde AA, de Boer L, Speijer D, Vandenbroucke-Grauls CM, & Zaat SA (2010). How honey kills bacteria. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 24 (7), 2576-82 PMID: 20228250

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Stem Cells Wanted: Alive Not Dead

adult_stem_cell_0527Stem cell therapies are taking off, in a surprisingly unregulated way. While most humans have to go to places like South Korea to receive them, horses, dogs, cats, pigs and tigers are already being treated in North America. The most overzealous stem cell companies bluster about their currently unlicensed ability to beat down cancer, diabetes, blindness and a whole raft of other diseases, a stretch given the paucity of clinical data available, yet such therapies are nevertheless generating a new buzz in the treatment world.

For all this showboating, stem cell therapies remain incredibly difficult to implement, with lots of practical problems still facing a system usually based on harvesting a patient’s stem cells, modifying them, bulking up their numbers in a dish, then reinfusing them to try and repair damage or disease. One of the biggest challenges is keeping stem cells alive and in their natural immature state once they’re outside the body, where they inhabit a specially-designed cosy little niche that keeps them well-fed and happy. Re-creating such a niche in a dish is hard.

One of the ways to improve stem cell survival in the lab is to mix them with a supportive layer of nanny cells that nourish, cuddle, calm and generally look after the cells. One team of researcher’s in Massachusetts found that adding fat cells in this nannying role kept stem cells alive longer, perhaps due to the unique spectrum of fatty proteins they secreted, such as adiponectin and TNFa. Another team found that adding specialised blood vessel cells, called perivascular cells, as nanny cells drastically improved the survival and usefulness of their stem cells, and did this much better than the standard MSC’s currently used by many stem cell research labs. In both cases, the nanny cells had to be in direct contact with the stem cells in order to exert their positive effects.

The sum of this research implies that generating a really good niche in a dish might involve mixing lots of nanny cells of different origin, like fat, bone and blood, in one big culture to capture as many aspects of the biological stem cell home as possible.

Corselli, M., Chin, C., Parekh, C., Sahaghian, A., Wang, W., Ge, S., Evseenko, D., Wang, X., Montelatici, E., Lazzari, L., Crooks, G., & Peault, B. (2013). Perivascular support of human hematopoietic stem/progenitor cells Blood, 121 (15), 2891-2901 DOI: 10.1182/blood-2012-08-451864

Glettig, D.L., & Kaplan, D.L. (2013). Extending Human Hematopoietic Stem Cell Survival In Vitro with Adipocytes BioResearch Open Access

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Eating too much salt sends immune system haywire

salty salt

When it comes to knowing whether eating too much salt is a bad thing, there is a surprising lack of “verified-by-science” information available*. A certain level of salt, or sodium chloride, is a biological necessity that keeps muscles pumping and nerves firing off electrical signals. Yet lots of studies have suggested that high levels of dietary salt could contribute to problems with blood pressure and heart disease, which is why the CDC (and probably your mum) tells you to reduce your salt consumption. On the flip side, a study undertaken in 2011 by the Cochrane Collaboration (an international not-for-profit that performs unbiased reviews of existing experimental data to answer important public health questions) concluded that it is still unknown if low salt diets have positive or negative impacts on health.

Research has now been published that places an intriguing new entry onto the “salt is bad” list, linking high levels of salt to the development of autoimmunity – that is, your own immune system reacting against you. Rates of autoimmune disease have rocketed in the last 50 years, and while some of this is due to genetics, the sheer scale of the problem strongly suggests that modern lifestyle factors, such as diet, play a huge role.

Many autoimmune syndromes, like psoriasis, multiple sclerosis and arthritis, are driven by issues with a population of immune cells known as TH17‘s. Researcher’s have now observed that feeding mice a high salt diet, within relevant consumer levels, leads to an overproduction of these TH17 cells that are horribly dysfunctional, and induce earlier onset, more severe autoimmune symptoms in animal models of multiple sclerosis. While this research doesn’t go far enough to directly link high salt intake with autoimmunity, it does give serious credence to that notion.

*This New York Times article does an excellent job of putting it all in one place

Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, & Hafler DA (2013). Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature PMID: 23467095

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The Evolution of the Impenetrable American Bedbug

ugly bugMost of us are quite content to share our beds with a partner or a kitty, but are less inclined to extend the same warm welcome to the common bedbug, Cimex lectularius. These parasitic insects, which feed exclusively on blood, have undergone a population explosion since the mid-1990’s, with infestations recently hitting the headlines all over the globe. Buildings full of warm and cosy human nests, such as blocks of flats and hotels, are enticing bedbug havens. Although pesticide sprays are deployed as control measures, research from Denmark has already suggested that this isn’t a viable long-term solution, since bedbugs quickly develop resistance to common insecticides like chlorpyrifos, permethrin and deltamethrin.

New research from a team at the University of Kentucky, USA, has now revealed how bedbugs evolve such resistance. Pesticide-resistant bedbugs can exhibit changes in up to fourteen key sections of DNA compared to those that are pesticide-susceptible. Individual bedbugs isolated from 21 test locations across the midwestern USA (including LA, Cincinnati, Lexington, Plainview, Louisville and Chicago) all had at least two of these fourteen genetic modifications, most of which bolstered the shell, stopping or slowing chemical penetration. Changes in other genes increased the activity of pesticide-detoxifying metabolic pathways, or improved the ability of bedbug nerve cells to spit out chemicals targeted to the central nervous system. This knowledge could help to devise useful new bedbug control strategies.

Zhu F, Gujar H, Gordon JR, Haynes KF, Potter MF, & Palli SR (2013). Bed bugs evolved unique adaptive strategy to resist pyrethroid insecticides. Scientific reports, 3 PMID: 23492626

Kilpinen, O., Vagn Jensen, K.-M., & Kristensen, M. (2008). Bed Bug Problems in Denmark, with a European Perspective Proceedings of the Sixth International Conference on Urban Pests

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Making Pretty, Meaty, Friendly Animals (on Scientific American)

Head on over to Scientific American to read our second guest blog post!

toy farm

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Converting weeds into flowers: artificial stem cells create a blood supply for bioengineered organs

Regenerating the human body by growing whole new organs or patching up damaged ones from just a few cells scraped from your own tissues is a fascinating area of science known as bioengineering. Every living cell in such an organ is sustained by the blood, which supplies food and gases and flows through a conduit network of hollow vessels. Successful organ bioengineering relies on establishing such a system of blood flow capable of reaching and supporting the energy demands of every living cell.

lung vesselsSprawling throughout our bodies, blood vessels have walls several cell layers thick, incorporating endothelial cells, smooth muscle cells and many others, all woven together and poised in a harmonious balance with their neighbour. Artificially creating something with such natural complexity is a tricky business. The developing human embryo is naturally pre-programmed to form a huge variety of cells from a single founder population, the pluripotent stem cells. These come equipped with a weighty tome of instructions that direct the formation of cellular offspring that populate the various parts of the body. Yet harnessing the capabilities of pluripotent stem cells for organ bioengineering churns up some serious ethical and moral issues, since the only real human source is the developing foetus. The established human body also contains a source of stem cells, known as adult stem cells, which are usually mobilised when organs require maintenance or repair. The problem with using these cells for organ bioengineering is that they are confined to producing cells from a designated category, so aren’t quite as pliable, and are also incredibly rare, so it’s almost impossible to safely harvest a good chunk of starting material. You can get around this by bulking up cell numbers in a dish, but this can be time-consuming (most material harvested from humans grows slowly) and expensive. More than that, manipulating cells in this way often changes their very nature, and once they have been convinced to start growing, what if they don’t stop?

So, clearly, obtaining enough primitive, malleable source material to effectively vascularise a bioengineered organ is an issue. An ideal solution would be to take a common adult cell that has already reached its full potential, is easily harvested and grows like a weed outside the body, and turn it back in time to resemble something like its primordial ancestor, the pluripotent stem cell. Advancing this concept, researcher’s from the UK and China have now developed a totally new type of bioengineering starter cell, the partially-induced pluripotent stem cell, which can create lots of different sorts of cells, but happily lacks the potential for uncontrolled growth and tumour formation. Starting off with fibroblasts (see image, below), widespread cells that provide structure and support in every organ, the team supplied four lots of DNA-targeted instructions designed to reset the cells to a more primitive state. This prompted cells to enter a genetically liquid phase where multiple cell outcomes were possible, including bone, cartilage, fat, nerves or blood vessels. Reset cells underwent rapid changes in how they moved, grew, divided and survived, yet they were also very well-behaved and showed no signs of losing growth control. Several reset cells began to spontaneously form hollow, tube-like structures and expressed genes classically associated with endothelial cells, one of the main cell components of a blood vessel.

fibroblasts

Could these reset cells, then, which had already shown a natural inclination to form cells of a vascular origin, be coaxed to focus their development more specifically down this pathway? To test this possibility, reset fibroblasts were fed a tasty molecular soup designed to encourage conversion into endothelial cells. Cells emerging under these conditions built up into multi-layered blood vessel structures, which were robust, stable and able to perform normal functions, such as taking up low-density lipoprotein (LDL), an important part of circulatory health. When cells were seeded onto an artificial bioengineering scaffold, they were able to form nice, native vessels composed of an extensive repertoire of vascular cell types. Perhaps most impressively, these cells also performed admirably when tested for their ability to restore damaged blood vessels in a living animal: when injected into an injured mouse leg, cells were able to attach and integrate into the muscle to improve blood flow, re-establish circulatory system connections and restore oxygen supply to the muscle.

Thus, manipulating a common cell to acquire specialised vascular functions is entirely possible and reprogramming cells in this way is a great step forward in terms of bioengineering safety and feasibility. While researcher’s have not yet tried this with human material, the short time it took to reprogram cells (~2 weeks) suggests that this could be a viable approach to personalised regenerative therapy, which could ultimately render organ donation totally redundant.

Margariti A, Winkler B, Karamariti E, Zampetaki A, Tsai TN, Baban D, Ragoussis J, Huang Y, Han JD, Zeng L, Hu Y, & Xu Q (2012). Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels. Proceedings of the National Academy of Sciences of the United States of America, 109 (34), 13793-8 PMID: 22869753

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Ivory DNA sequencing tracks elephant poaching hotspots

savannah elephants

The illicit trade in elephant ivory has been a ridiculous problem since the 1980’s, when Asian and African elephants were decimated to such a level that they made it onto Appendix One (“most endangered species”) of CITES. While all trade in their ivory was banned in 1989, poaching is still a huge issue, especially in the dense forests of Africa that camouflage a multitude of illegal activities. Large seizures of black market ivory have been made over the years, but without knowing precisely where in the world these materials are originating from, tracking – and stopping – poachers is a tricky business.

Scientists have made this challenge a little bit easier by developing a test that combines genetics with statistics to match ivory DNA sequences to within 500-1000km of the originating elephant’s habitat. Working up the method on tissue and poop samples from forest and savannah elephants at 28 locations throughout Africa, a team led by Dr. Samuel Wasser correlated sixteen regions of DNA, known to show heady levels of variation between individuals and to act as a unique genetic fingerprint, with location. On a blinded test, their strategy was able to correctly identify the geographic area of origin of forest elephants 83% of the time, and of savannah elephants 35% of the time. Even in the savannah elephants, the 65% of “incorrectly assigned” locations were typically still pretty near the actual location. This approach was then used as part of a criminal investigation into a 6.5 tonne illegal shipment of ivory seized in Singapore, shipped from Malawi, and estimated to be poached from 3000-6500 elephants. While it was suspected that the tusks had been widely culled from across Africa, researcher’s showed that almost all of it came from savannah elephants in Zambia.

This innovative method should make it possible to trace the origins of elephant ivory all over the world, enabling the focussed deployment of anti-poaching efforts. It could also conceivably be expanded to include other endangered species in the illegal wildlife trade.

Wasser SK, Shedlock AM, Comstock K, Ostrander EA, Mutayoba B, & Stephens M (2004). Assigning African elephant DNA to geographic region of origin: applications to the ivory trade. Proceedings of the National Academy of Sciences of the United States of America, 101 (41), 14847-52 PMID: 15459317

Wasser SK, Mailand C, Booth R, Mutayoba B, Kisamo E, Clark B, & Stephens M (2007). Using DNA to track the origin of the largest ivory seizure since the 1989 trade ban. Proceedings of the National Academy of Sciences of the United States of America, 104 (10), 4228-33 PMID: 17360505

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Supporting Miss. Muffet in the sixth millenium BC

cheeeeeseI love cheese. Oh, how I do. Hard cheese, soft cheese, hole-y cheese, crumbly cheese, squidgy cheese – all of them will find a warm and welcoming home in my mouth. While deliciousness alone seals the place of cheese at my table, historically, converting milk into a processed dairy product like cheese had a lot of benefits. Cheese kept a lot longer without going off (a big deal when you didn’t have any way to keep food cool and fresh), was easy to transport and trade, and was digested much more easily by the human gut. It also meant a continuous supply of food throughout the year without needing to kill animals for meat.

Making cheese back in prehistoric times was not a trivial process: first, milk had to be coagulated to produce a mixture of semi-solid curds and liquid whey. Then, the liquid had to be strained off, and the remaining curds pressed to solidify into cheese. There is now delicious historical evidence that in early Neolithic times, small pottery vessels poked through with lots of randomly-placed holes were used as designated cheese strainers. Researcher’s analysed and compared shards of pottery from either these sieve-like vessels or from three ‘general’ types of cooking pots, bowls and collared flasks, all of which were unearthed in archaeological digs along the Vistula river in Kuyavia, Poland, and dated to around 5000 BC. Fats extracted from the surfaces of these different pot shards showed a marked concentration of fresh dairy animal fats and fatty acids from milk bacterial populations in the vessels with holes, but not in the general pots, bowls and flasks. These specialised kitchen tools currently represent the earliest evidence for the innovative introduction of cheese making in humans.

Salque M, Bogucki PI, Pyzel J, Sobkowiak-Tabaka I, Grygiel R, Szmyt M, & Evershed RP (2013). Earliest evidence for cheese making in the sixth millennium BC in northern Europe. Nature, 493 (7433), 522-5 PMID: 23235824

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Semi-retired cells repair our damaged hearts

Repairing or replacing damaged cells keeps our organs in tip top working condition. For a long time, we thought that only the incredibly rare stem cells in adult organs were able to create brand new cells to replace injured ones and fix damaged areas. Yet some tissues definitely don’t conform to this autocratic model: following liver damage, for example, mature hepatocyte cells that normally exist in a semi-retired state re-engage their cell cycle and undergo a huge amount of cellular proliferation to patch up affected sections.

Body Works HeartFor other organs, such as the heart, it’s still unknown if stem cells or mature cardiomyocyte cells are responsible for performing such repairs. One team of researcher’s recently got to grips with this question by supplying cells in the heart with thymidine, one of the building blocks of DNA, tagged with a stable isotope of nitrogen, 15N. Since DNA is duplicated during cell division, heart cells that are actively dividing incorporate the 15N-thymidine and can be tracked. After suffering a heart-damaging myocardial infarction, mature cardiomyocyte cells immediately next to the affected area incorporated the trackable thymidine. Around 15% of these mature cells came out of semi-retirement and actively re-entered the cell cycle, dividing to generate fresh new cells. The other 85% simply got bigger to take on more work, compensating for the lost cells and maintaining cardiac output. No stem cells were observed to incorporate 15N-thymidine in a substantial way.

So, it’s not just jazzy, energetic stem cells that can support the biological business of tissue repair. The heart, like the liver, contains established, mature cells capable of producing lovely new cells. This knowledge could help to identify new ways of speeding up the healing process.

Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, & Lee RT (2013). Mammalian heart renewal by pre-existing cardiomyocytes. Nature, 493 (7432), 433-6 PMID: 23222518

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Antibiotics hit your gut microbes hard

batman doesn't like antibiotics being overused

These days, most doctor’s are acutely aware of the problems of overprescribing antibiotics. Historically given as more of a placatory gesture – ‘I have to prescribe something, else this patient will think I’m an incompetent buffoon’ – their overuse almost single-handedly drove the rapid development of antibiotic-resistant bacteria, like MRSA. Yet we’re becoming more and more aware that antibiotics don’t only drive huge reactive changes in the bugs that we’re trying to kill, but also in our own bodies. Because the problem with antibiotics is their broad approach to killing – they don’t only target the ‘bad’ bugs, but also the trillions of happy, healthy bugs that live in our gut and work with us to digest food that we couldn’t process alone. The collective term for this huge community of microorganisms inhabiting our digestive tract is the, ‘microbiota‘, and it’s vital for maintaining a healthy gut.

intestinal-bacteria-670

We don’t really know much about the reactions of gut bacteria to antibiotic therapy, but since around 60% of faecal matter is made up of these microbes, your poop gives a good indication of what’s going on in the digestive tract. Researcher’s at the University of València in Spain analysed microbial changes in the faeces of one individual undergoing a 14 day course of beta-lactam therapy, a common class of antibiotics that control bacteria by interfering with their ability to build cell walls. The first bugs to be affected by the antibiotics were the gram-negative ones, whose numbers dropped off rapidly. The overall diversity of the gut microbiota plummeted, as only bugs that were naturally resistant to beta-lactams were able to survive: they began thriving after the death of antibiotic-susceptible bugs freed up large pools of nutrients. Then, gram-positive bugs began to overpopulate the gut. This bacterial imbalance hampered the metabolism of vitamins D and B12, cholesterol, hormones and iron, leading to potential dietary deficiencies. Four weeks after antibiotic treatment had finished, gut digestive function improved as surviving gut microbes began to re-establish normal service, but certain ‘good’ bugs that had been present before antibiotic therapy began did not reappear and likely had been permanently wiped out.

This research builds up an intriguing picture of how the gut microbiota changes during antibiotic therapy. It also suggests that antibiotics should continue to be reserved for only the most compelling bacterial diseases, since such disturbances in the gut microbiota are likely to drive the acquisition of antibiotic-resistance, the overgrowth of dangerous bacteria and the unhealthy loss of ancient ‘good’ gut bacteria.

Pérez-Cobas AE, Gosalbes MJ, Friedrichs A, Knecht H, Artacho A, Eismann K, Otto W, Rojo D, Bargiela R, von Bergen M, Neulinger SC, Däumer C, Heinsen FA, Latorre A, Barbas C, Seifert J, Dos Santos VM, Ott SJ, Ferrer M, & Moya A (2012). Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut PMID: 23236009

Posted in Bacteria, Ecology, Microorganisms, Science | Tagged , , , , , , , , , , | 1 Comment

24 hours in the life of HIV

HIVHuman immunodeficiency virus, or HIV, only emerged in humans relatively recently, yet already represents a big public health threat. When HIV enters the human body, often through sexual contact or the sharing of needles between drug users, it shows a remarkably focussed preference for infecting a certain population of immune cells, known as CD4+ T cells. Since these cells usually play a major role in vanquishing a viral foe, this is the perfect spot for HIV to hide out, since it essentially disappears behind an immune firewall.

Once HIV infects a CD4+ T cell, it often stays silent for long periods of time. Eventually, though, it will begin to multiply in a process known as replication. We know that it takes about 24 hours for HIV to complete its replication cycle, producing lots of progeny viruses that spread through the entire body. Yet the exact stages and timings of this replication process are not very clear. Researcher’s in Switzerland have now determined that nine intermediate stages occur through a single 24 hour replication cycle. Timewise, 3 hours after first entering the CD4+ T cell, the virus begins processing its own genetic material to make it compatible with that of the host cell. At 4 hours, the virus orchestrates a huge shutdown of all normal host cell functions. Any host genes with the ability to attack and subdue HIV are particularly targeted. At 8 hours, the viral genetic material is forced into the DNA of the host cell. Viral data starts to be decoded, forming a blueprint that will guide construction of new HIV particles. At this point, the virus begins to switch certain cellular functions back on, to help viral replication. By 15 hours, all the component parts necessary to build new virus particles have been produced and at 18 hours, fully completed viruses are coming off the production line. They leave the nursery cell where they were created, and set about finding a new CD4+ T cell to start up their own replication cycles.

This research gives us an excellent insight into the life cycle of a single HIV particle. Knowing when each stage emerges during replication could help us apply targeted interventions, aimed at preventing the transition between certain stages and thus blocking viral reproduction. This may ultimately help to guide the development of better treatments.

Mohammadi P, Desfarges S, Bartha I, Joos B, Zangger N, Muñoz M, Günthard HF, Beerenwinkel N, Telenti A & Ciuffi A (2013). 24 Hours in the Life of HIV-1 in a T Cell Line PLOS Pathogens, 9 (1) : 10.1371/journal.ppat.1003161

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The journey to parasite egg paradise

liver meal

The parasite, Schistosoma mansoni, is a remarkably cunning and efficient worm. It spends the first part of its life infecting freshwater snails, where it vigorously multiplies to bulk up numbers. This parasite army then marches out of the snail and into the river, encounters an unsuspecting human, latches on to their skin and burrows its way inside, more often than not through a hair follicle. Schistosomes infect more than 200 million people a year, in many parts of the world, and since most worms live for more than 10 years, infection with this pathogen is a long-term health problem.

In the human body, the parasite lives most of its life in the bloodstream, but when it comes time to produce tiny parasite offspring, this is a bad neighbourhood to bring up the kids. A much more nurturing location is the human gut, a stable, moist and nutrient-rich environment. Eggs are first laid in the veins carrying blood from the gut, and from there, they hop into the intestines, finally being pooped out from the host to continue their life cycle back in the freshwater snail. Exactly how the eggs migrate from the vein to the gut has been a vaguely grey area, but now a team of researcher’s at the University of York have shown that a big part of this journey involves the eggs accumulating in Peyer’s Patches. These are small pockets of immune tissue in the gut wall that maintain immune surveillance, and are particularly well supplied with extra energy and nutrients. Once the eggs are settled in these cosy patches, they secrete factors that force the area to undergo an extensive biological remodelling, making it easier for the eggs to slip out of the host once they’ve reached full maturity.

Thus, the dastardly schistosome is an excellent example of a human pathogen that can commandeer our natural anatomical and biological features, manipulating them to its own advantage to improve the chances of reproductive success.

Turner JD, Narang P, Coles MC, & Mountford AP (2012). Blood Flukes Exploit Peyer's Patch Lymphoid Tissue to Facilitate Transmission from the Mammalian Host. PLoS pathogens, 8 (12) PMID: 23308064

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What makes the smallpox vaccine so great?

Perhaps one of the most incredibly effective vaccines ever used, against smallpox, has completely eradicated a terribly nasty human disease. Yet the way in which vaccinia virus, the live poxvirus contained in the smallpox vaccine, actually orchestrates a protective immune response is still mostly unknown. The live virus component is a major reason why the smallpox vaccine is so good – instead of having some crusty bit of dried up dead protein in there, there is a real virus that looks a bit like smallpox and properly challenges the immune system.

smallpox vaccine vials

Once the smallpox vaccine is administered, vaccinia begins replicating in the human body, causing a mild infection, and soon begins to exist in two different forms: one lives outside the cells of the body, milling about and spreading to infect new cells, while the other hides out inside the cells of the body and spawns lots of new viruses. The one that lives on the outside of cells is typically exposed to and controlled by the immune system, and is made up of five major surface protein components (A33, A34, A36, A56 and B5), as well as a lipid membrane that surrounds the entire virus particle, all of which can be targeted by immune cells.

smallpox virus

Researcher’s have been trying to understand how one part of the immune system, the antibodies, drive protection against vaccinia virus – and thus against smallpox. Typically, if enough antibodies bind to enough important virus proteins, this blocks virus accessibility and shuts down infection. Yet this does not seem to be the case with vaccinia. One team in California recruited nine people who had previously received the smallpox vaccine and looked at antibody responses in their blood. In all nine individuals, antibodies recognising vaccinia struggled to inactivate the virus on their own, only working properly to suppress viral infection in the presence of another immune system component, complement. Complement is a series of proteins in the blood, which help antibodies by attracting other immune cells to neutralise foreign material. Four individuals controlled the virus almost exclusively through neutralising antibodies targeted against the virus protein B5, while other donors had a minimal contribution (15-28%) from B5 antibodies; their protection, instead, was supplemented by antibodies against a second virus protein, A33. The only effective antibodies against either B5 or A33 were the ones that bound vaccinia virus very tightly, in a destructive huggy embrace.

This suggests that, contrary to current theories in vaccine development, antibodies don’t have to be able to work alone to bring about viral destruction in order to effectively control disease. While antibodies are important in establishing immunity against smallpox, multiple parts of the immune system work together to protect against such pathogens.

Benhnia MR, Maybeno M, Blum D, Aguilar-Sino R, Matho M, Meng X, Head S, Felgner PL, Zajonc DM, Koriazova L, Kato S, Burton DR, Xiang Y, Crowe JE Jr, Peters B, & Crotty S (2013). Unusual features of vaccinia virus extracellular virion form neutralization resistance revealed in human antibody responses to the smallpox vaccine. Journal of virology, 87 (3), 1569-85 PMID: 23152530

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Colonised livestock transmit MRSA to farmers

These days, most people are aware of the increasing development of antibiotic resistance in bacteria that cause human disease, which is at least partially driven by the overprescription of antibiotics. Even our most robust antibiotics, active against a wide range of bacterial species, are not up to the task of controlling certain infections, making the push to develop new ones – or antibiotic alternatives – particularly compelling. One exceptionally well-publicised antibiotic-insensitive bacteria is the methicillin-resistant Staphylococcus aureus (MRSA), which spreads throughout hospitals, communities and, interestingly, farms.

The first reports of livestock-associated MRSA (LA-MRSA) were published in 2003, after isolation from Dutch pigs. From there, it was identified in pigs across Europe, in Singapore and in North America. And it wasn’t only pigs becoming colonised, either: in the United Kingdom in 2009, LA-MRSA was identified in horses, and towards the end of 2012, in the cattle population. Unfortunately, livestock don’t keep these social microorganisms to themselves – the bacteria are more than happy to transfer onto humans coming into contact with carrier animals. Although the prevalence of LA-MRSA in the general human population is low, there is certainly evidence for it causing disease in people closely associated with agriculture and livestock. In one Dutch study, around 38% of cattle farmers were colonised with LA-MRSA, and the bacteria were more prevalent after longer periods of time spent around animals.

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While the appearance of this bacteria in food-producing animals and the substantial exposure risk for people who work with them is a definite public health concern, following healthy guidelines in the preparation and consumption of animal products – such as only drinking pasteurised milk and checking that meat is thoroughly cooked –  should ensure that LA-MRSA has little general human impact.

Paterson G, Larsen J, Harrison E, Larsen A, Morgan F, Peacock S, Parkhill J, Zadoks R, & Holmes M (2012). First detection of livestock-associated meticillin-resistant Staphylococcus aureus CC398 in bulk tank milk in the United Kingdom, January to July 2012. Euro surveillance : bulletin europeen sur les maladies transmissibles = European communicable disease bulletin, 17 (50) PMID: 23241232

Golding GR, Bryden L, Levett PN, McDonald RR, Wong A, Wylie J, Graham MR, Tyler S, Van Domselaar G, Simor AE, Gravel D, & Mulvey MR (2010). Livestock-associated methicillin-resistant Staphylococcus aureus sequence type 398 in humans, Canada. Emerging infectious diseases, 16 (4), 587-94 PMID: 20350371

Graveland H, Wagenaar JA, Bergs K, Heesterbeek H, & Heederik D (2011). Persistence of livestock associated MRSA CC398 in humans is dependent on intensity of animal contact. PloS one, 6 (2) PMID: 21347386

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Zinc takes the sting out of jellyfish venom

For me, there are three extremely good reasons never to go to Australia – huge furry-bodied poisonous spiders, venomous lightning fast snakes and sharks with great mouthfuls of serrated teeth. After reading a recent article, I am now happy to add a fourth to the list: the Australian box jellyfish. Your average run-of-the-mill jellyfish sting is definitely an unwelcome arrival, delivering a sharp, searing pain and leaving your skin all red and puckered, but it doesn’t usually require medical intervention. A sting from the Australian box jellyfish, Chironex fleckeri, a beastie with up to sixty 2-metre long tentacles, each capable of injecting hundreds of thousands of tiny poisonous capsules, can result in the rather more serious outcome of total shutdown of heart and lung function, and death. While there is a general anti-venom available, it’s not very effective, and there is definitely room for therapeutic improvement.

chironex_fleckeri_by_demonicsyco-d4tv4gk

A team of researcher’s from the University of Hawaii wanted to get to grips with the constituents of box jellyfish venom, how they worked to generate such a serious reaction in the human body and more importantly, how to counteract these effects. The venom of the box jellyfish is a complex mixture of proteins, fats and other active molecules. The most severe biological consequences are caused by the porin proteins, which are designed to create fluid-filled passages through cells that allow molecules to pass in and out. Just five minutes after box jellyfish venom is delivered, these porins begin to punch holes in red blood cells travelling round the circulatory system, allowing first potassium and then haemoglobin to leak out. After twenty minutes, this steady leakage causes red blood cells to pop, rendering them entirely useless as oxygen couriers. This is all accompanied by a steady decrease in heart function, including electrical abnormalities and arrhythmic contractions.

Zinc, one of the metallic elements, is already known to interfere with the ability of porins to burrow tunnels through cells. Mice were exposed to box jellyfish venom and then given an injection of zinc gluconate, an FDA-approved natural dietary supplement, immediately afterwards. This slowed and reduced the level of molecular leakage from red blood cells, maintained the heartbeat in a more normal state and ~60% of mice survived (none survived without the treatment). Zinc is therefore at least partially able to counteract the actions of box jellyfish venom, and could represent a useful new frontline treatment for box jellyfish sting victims.

You can read the original article in full here.

Yanagihara AA, & Shohet RV (2012). Cubozoan venom-induced cardiovascular collapse is caused by hyperkalemia and prevented by zinc gluconate in mice. PloS one, 7 (12) PMID: 23251508

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British Sheep vs. Chernobyl Radiation

chernobyl

The explosion of reactor number four of the Chernobyl nuclear power plant in 1986 is widely regarded as the worst radiation disaster in human history. The radioactive fallout spread from Northern Ukraine throughout Northern Europe, dispersing large quantities of radioactive elements, including two caesium isotopes, Cs-134 and Cs-137. In the United Kingdom, this radiocaesium-laden cloud mingled with heavy rain falling in mountainous areas of North Wales and Cumbria, depositing substantial quantities of radioisotopes in uplands areas and introducing radioactivity into the food chain: plants took up the radiocaesium deposited in topsoil, livestock ate the plants and humans ate the livestock. In response, the Food Standards Agency (FSA), the independent authority that makes sure all food in the UK is safe and hygienic, implemented a series of laws restricting the movement, sale and slaughter of livestock grazed on contaminated uplands pastures. For sheep, a Summer monitoring program was designed to remove highly radioactive animals from the food chain.

welsh sheep

More than 25 years later, a government report released in November 2011 showed that although environmental radiocaesium still persists in Welsh and Cumbrian farms, levels found in sheep have gradually declined over time, with recorded measurements (on average 0.09 mSv per year) now well below the safe limit established by the ICRP (1 mSv per year). No radioactively unsafe animals have been identified for several years in Cumbria, and less than 0.5% (out of ~75,000 sheep) in North Wales. This is partly due to the common farming practice of fattening up sheep for several months on tasty lowland protein-rich, clover-heavy pastures before taking them to market. Lowland grasses contain much less radiocaesium, and since its biological half-life (the time required for the amount of active radionuclide to be reduced by 50%) is only 10-20 days, lengthy periods of grazing in these areas allows the natural process of radioactive decay to lower whole body levels.

Mathematical modelling estimates that even extremely hungry people who eat more than 25 kg of delicious sheep products per year couldn’t begin to approach unsafe levels of radiation exposure, thus all Chernobyl livestock legislation was recently fully revoked in the UK. While other areas of Europe, such as Scandinavia, continue to record substantial levels of radioactivity in stock animal populations, the UK has provided happy evidence that the impact of Chernobyl radiation is diminishing.

You can read the original FSA report in full here.

Field, A. (2011). An Assessment of Radiocaesium Activity Concentrations in Sheep in Restricted Areas of England and Wales and Potential Consumer Doses Food Standards Agency

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Sea creatures dissolve as oceans acidify

There’s little doubt that increasing carbon dioxide (CO2) emissions through human industry contribute to the changing of the Earth’s climate. Excess CO2 is absorbed by our ocean’s, changing their chemical composition and driving more blustery ocean winds that force deeper areas of sea water, which are naturally more acidic, to mix with shallower layers. The net outcome is ocean acidification, which can affect resident sea creatures. In particular, levels of aragonite, a naturally ocurring form of calcium carbonate used by plankton, fish and shellfish to build their skeletons and shells, drop severely in acidic sea water, making it difficult for organic calcification to proceed.

Limacina-helicina-antarctica-rangiOne species that incorporates aragonite into its shell is the sea butterfly, Limacina helicina antarctica, seen on the right. This creature lives in the Antarctic Ocean, has a lifespan of around 2 years and grows to be around 1 cm in diameter. As part of the British Antarctic Survey, researcher’s analysed how the sea butterfly was affected by ocean acidification in a test area located in the Scotia Sea. Specimens plucked from particular geographical quadrants where ocean winds caused more deep water upwelling and greater acidification exhibited substantial shell damage and dissolution (see image left; the top is a shell from Untitleda section with normal acidity levels, while the bottom is a shell from an acidic section). Furthermore, shells only had to bathe in such water for eight days to show significant signs of dissolution. While this doesn’t necessarily kill the little beasties, it does mean they are more vulnerable to attacks by hungry predator’s, and are more susceptible to infections, since they are in a weakened state.

Thus, as the acidic areas of the ocean continue to expand, populations of aragonite-shelled organisms will likely diminish and further affect global climate flux.

Bednaršek, N., Tarling, G., Bakker, D., Fielding, S., Jones, E., Venables, H., Ward, P., Kuzirian, A., Lézé, B., Feely, R., & Murphy, E. (2012). Extensive dissolution of live pteropods in the Southern Ocean Nature Geoscience, 5 (12), 881-885 DOI: 10.1038/ngeo1635

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Forensic evidence links badgers and cows in British tuberculosis infections

Bovine tuberculosis (bTB) is a serious disease that threatens the health of livestock, wildlife, and the agricultural economy, particularly in the United Kingdom. Although every cow in the UK is subjected to a yearly bTB test, and those with positive results are slaughtered, efficient disease containment and control has yet to be achieved. This suggests that there is a source of the causative agent, the bacterial pathogen, Mycobacterium bovis (M. bovis), maintained somewhere outside of the cattle population that allows the bTB epidemic to be sustained. M. bovis is a member of the same complex that includes human tuberculosis, and can be transmitted between cows and humans, often through drinking unpasteurised milk. Controlling and eradicating bTB is therefore an important public health and economic issue.

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Historically, the badger (Meles meles) has been implicated as a wild reservoir for M. bovis. This has mostly been based on circumstantial evidence: for example, large badger populations have been noted in areas where bovine tuberculosis outbreaks frequently occur. Ultimately, the role of badgers in transmitting bTB has not been well defined and remains very controversial. Badger infection control strategies have nevertheless been implemented, ranging from vaccination to licensed culls. Now, recently published research shows very clearly that the exact same strains of M. bovis bacteria can be found in infected badgers and infected cattle living in the same place at the same time. A forensic genetic analysis, known as whole genome sequencing, was carried out on the DNA of M. bovis bacteria isolated over a period of 10 years from both badgers and cows living in a test area of neighbouring farms in Northern Ireland where outbreaks of bTB were common. Genetically matched variants of M. bovis were identified in both species, meaning one of two things: either the bacterium had been directly transmitted between badgers and cows, or both animals had stumbled upon and been exposed to the same infectious source somewhere in their habitat (M. bovis can survive for months in the soil).

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By modelling the transmission of the 31 identified strains of M. bovis, it was apparent that different patterns of bacterial circulation could drive bTB outbreaks: transmission in some herds was sustained through cow-to-cow infections, while in other herds, transmission was heavily influenced by new interactions with a local reservoir of unknown origin. Thus, local rather than distant interactions were the principal drivers of M. bovis infection outbreaks, with very little transmission being attributed to the movement of livestock between farms or hidden low levels of infection being missed by the annual bTB test.

This is the first direct evidence that badgers infected with M. bovis show a genetic interaction with persistently infected herds of cows, suggesting the potential for direct transmission of bTB between these two species.

Biek R, O'Hare A, Wright D, Mallon T, McCormick C, Orton RJ, McDowell S, Trewby H, Skuce RA, & Kao RR (2012). Whole Genome Sequencing Reveals Local Transmission Patterns of Mycobacterium bovis in Sympatric Cattle and Badger Populations. PLoS pathogens, 8 (11) PMID: 23209404

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Nerve growth factor: not just for nerves anymore

The male ejaculate, semen, is an eclectic mix of proteins, chemicals and hormones, all in a nicely fluid solution ideally suited to transporting spermatozoa during the process of reproduction. While many seminal fluid components and their corresponding biological functions have been well described, a team at the University of Saskatchewan in Canada has recently characterised a new molecule in semen that induces ovulation and persuades the ovary to ramp up production of pregnancy hormones in llamas.

While most mammalian species (such as cattle, mice and humans) work on the ‘spontaneous ovulation’ model of reproduction, where at a specific point in the menstrual cycle, hormonal and developmental conditions harmonise to allow follicle release, some mammals (such as the llamas used in this study, as well as camels, cats, rabbits and koalas) work on the ‘induced ovulation’ principle, where both the physical stimulation of intercourse and seminal fluid factors are necessary to encourage the ovary to release a ready-to-be-fertilised ovum.

This newly-established seminal fluid factor has been identified as nerve growth factor (NGF), and is present in semen from both induced ovulator and spontaneous ovulator species. NGF has previously been known for its direct role in the survival and growth of neurons in the central nervous system. This is the first documented evidence that NGF can have a direct biological effect on influencing ovarian function in the female reproductive tract. The findings of this study may have relevance for human fertility issues.

Read the original article here.

Ratto MH, Leduc YA, Valderrama XP, van Straaten KE, Delbaere LT, Pierson RA, & Adams GP (2012). The nerve of ovulation-inducing factor in semen. Proceedings of the National Academy of Sciences of the United States of America, 109 (37), 15042-7 PMID: 22908303

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The (genetic) answer to the polar bear (evolution) question

When did polar bears evolve to form a separate and distinct species from their relatives, the brown and black bears? Researchers from China, Norway, Iceland, Denmark, Singapore, Canada, Mexico and the USA have recently collaborated to address this very question using whole genome sequence analysis. The team compared both mitochondrial and nuclear DNA extracted from modern day polar, brown and black bears with DNA retrieved from an ancient polar bear jawbone (115-130,000 years old) excavated in Svalbard, Norway. Their results suggest that polar bears and brown bears have had largely independent evolutionary histories for the last 4-5 million years, with black bears having split off even further before this. However, a detectable level of gene flow has continued between polar and brown bears since then, suggesting interbreeding events: indeed, brown bear/polar bear hybrids have recently been identified in arctic Canada, where territory ranges of both species overlap.

The team also identifed a few polar bear genes that were hugely changed from those seen in black or brown bears, which may have enabled polar bears to adapt to their harsh arctic lifestyle. Genes involved in skin pigmentation and coat colour patterns were altered, which could have allowed the polar bear to develop the dark black skin that is perfect for absorbing heat and keeping warm. Genes involved in metabolism and weight gain were also modified, potentially leading to improved storage of the large fat reserves necessary to maintain both energy levels and core body temperatures. Finally, changes in genes involved in hair follicle development and function were evident, and may have led to the polar bear developing the highest mean hair density of all ursid bears, a very useful adaptation in an extremely cold environment.

Read the original article here.

Miller W, Schuster SC, Welch AJ, Ratan A, Bedoya-Reina OC, Zhao F, Kim HL, Burhans RC, Drautz DI, Wittekindt NE, Tomsho LP, Ibarra-Laclette E, Herrera-Estrella L, Peacock E, Farley S, Sage GK, Rode K, Obbard M, Montiel R, Bachmann L, Ingólfsson O, Aars J, Mailund T, Wiig O, Talbot SL, & Lindqvist C (2012). Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change. Proceedings of the National Academy of Sciences of the United States of America, 109 (36) PMID: 22826254

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Helpful skin bacteria take charge of local immune responses

Humans have evolved a symbiotic relationship with ‘good’ bacteria over the millions of years that both have been around. The gut is the most heavily colonised spot, where bacteria assist in the digestion process and help to regulate immune function, and in return siphon off a tiny proportion of the nutrients they help to release. The skin, which represents a major practical barrier that protects you from your environment, is also colonised by bacteria, which sit on the outer skin layer, and in sebaceous glands and hair follicles. Researcher’s at the National Instutite of Allergy and Infectious Diseases in Bethesda, USA, have shown for the first time that skin-bourne bacteria play a major role in helping to control the patrolling immune cells that are poised to respond to pathogenic invasions. Local skin immune responses to the protozoan parasite, Leishmania major, were much more robust and protective in colonised mice (who had the helpful bacteria, Staphylococcus epidermidis, on their skin) compared to germ-free mice (who had no helpful bacteria on the skin). So, treat your skin gently, and protect your caring, sharing bacterial communities.

Read the original article here.

Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, Spencer S, Hall JA, Dzutsev A, Kong H, Campbell DJ, Trinchieri G, Segre JA, & Belkaid Y (2012). Compartmentalized control of skin immunity by resident commensals. Science (New York, N.Y.), 337 (6098), 1115-9 PMID: 22837383

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Cool bananas! – genetically speaking

Scientists at the Université d’Evry in France have sequenced the genome of the wild banana, Musa acuminata, the species that gave rise to the commonly eaten Cavendish and other varieties. The banana plant is the largest herbaceous flowering plant, whose ancestor came into existence in the Jurassic period, more than 125 million years ago. The 523 Mbp (523,000,000 base pair) sequence, which contains 36,542 protein-coding genes, was decoded not only to classify the evolutionary history of the banana, but also to identify ways to genetically advance it, improving resistance to pests, expanding the environmental conditions in which it can grow and enhancing the ripening process.

Some very interesting findings that came up along the way include the identification of banana streak virus sequences inserted into the banana’s DNA, presumably following a nasty infection. These viral genomic integrations were found in 10 out of the banana’s 11 chromosomes, but were fragmented and likely incapable of producing live infectious virus. This is ancient evidence that the banana was once under a strong infectious threat, but survived in all its deliciousness until the present day.

Read the original research article here.

D'Hont A, Denoeud F, Aury JM, Baurens FC, Carreel F, Garsmeur O, Noel B, Bocs S, Droc G, Rouard M, Da Silva C, Jabbari K, Cardi C, Poulain J, Souquet M, Labadie K, Jourda C, Lengellé J, Rodier-Goud M, Alberti A, Bernard M, Correa M, Ayyampalayam S, Mckain MR, Leebens-Mack J, Burgess D, Freeling M, Mbéguié-A-Mbéguié D, Chabannes M, Wicker T, Panaud O, Barbosa J, Hribova E, Heslop-Harrison P, Habas R, Rivallan R, Francois P, Poiron C, Kilian A, Burthia D, Jenny C, Bakry F, Brown S, Guignon V, Kema G, Dita M, Waalwijk C, Joseph S, Dievart A, Jaillon O, Leclercq J, Argout X, Lyons E, Almeida A, Jeridi M, Dolezel J, Roux N, Risterucci AM, Weissenbach J, Ruiz M, Glaszmann JC, Quétier F, Yahiaoui N, & Wincker P (2012). The banana (Musa acuminata) genome and the evolution of monocotyledonous plants. Nature, 488 (7410), 213-7 PMID: 22801500

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Mercury in vaccines – is it really a concern?

We are all exposed to mercury in our lives, through consumption in the diet, in some vaccines, at the dentist’s (those silver fillings) and through environmental exposure. High biological levels of mercury lead to serious health problems, including loss of memory, depression and dementia. Indeed, Environmental Protection Agency guidelines to limit the amount of mercury in your diet are probably sound, especially during pregnancy when exposure to even small amounts of mercury can harm the developing foetus.

When it comes to vaccines, since 2001, any new FDA-approved vaccine has to be mercury-free. However, the yearly-formulated seasonal flu vaccine is an exception to this rule, but only on a ‘bulk use’ basis: single dose vials that are intended to be opened and used once do not have a mercury component, but multi-dose vials are supplied with a mercury-containing preservative, thimerosal. In multi-dose vials, repeated doses of vaccine are withdrawn during a mass immunisation session, putting the contents at a higher risk of contamination, even though vials are discarded at the end of the session or after 6 hours (whichever comes first). Thimerosal prevents the growth of dangerous microorganisms, such as bacteria and fungi. Other vaccines approved before 2001, such as the pertussis (whooping cough), tetanus and meningococcal vaccines, also contain low levels of thimerosal (~0.01%).

Many different governmental and independent bodies, including the World Health Organisation (WHO), the Center for Disease Control and Prevention (CDC), the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), have reviewed current evidence to determine if inclusion of thimerosal in vaccines is harmful to human health: all have concluded that there is no scientifically-sound evidence that links exposure to thimerosal through vaccines with disease (including autism).

Visit http://www.fda.gov/food/foodsafety/product-specificinformation/seafood/foodbornepathogenscontaminants/methylmercury/ucm115644.htm to find out which fish contain the highest levels of mercury, helping to manage a healthy level of consumption in your diet.

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