Model Hearts and Mood Altering Microbes

05 September 2011

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This week, a computer model of the heart that could test new cardiac drugs, ancient evidence of antibiotic resistance and the tiny gold rods that may give us control over light. We find out how "friendly" bacteria, probiotics, can alter brain chemistry and calm anxiety, and Meera Senthilingam joins us for a quick flash of other science news.

In this episode

00:28 - Good News for Broken Hearts

A completely computer-generated model of the human heart that can successfully predict the effects of anti-arrhythmic drugs has been developed by scientists in the US...

Good News for Broken Hearts

A completely computer-generated model of the human heart that can successfully predict the effects of anti-arrhythmic drugs has been developed by scientists in the US.

Irregular heartbeat, or arrhythmia, occurs when there is abnormal electrical activity in the heart - if the electrical pulses among heart cells get out of sync the heart can't contract and beat normally. Drugs used to treat arrhythmia act on heart cell membrane channels to alter the flow of charged molecules called ions, which cause the electrical signals. At the wrong concentrations, these drugs can actually make arrhythmia more severe, or even lead to sudden cardiac death. Thorough testing is therefore vital to determine the doses at which they are safe to use.

Traditional methods of testing (using animal hearts or human clinical data) are incredibly inefficient, but Professor Colleen Clancy and her colleagues the University of California have come up with a completely different approach: a computerized model of the human heart.Computerized Heart

In the model, mathematical equations represent the opening and closing of ion channels in individual cell membranes.  Other equations connect these events among single cells in order to simulate a whole heart. Drugs can then be mathematically 'fed' into the framework and their effects monitored.

Two existing anti-arrhythmic drugs - lidocaine and flecainide - were tested in this way at different concentrations, and remarkably the model's predictions were validated both by human clinical data and with similar tests on a rabbit heart.

This novel approach could potentially speed up the drug development process, helping treatments get to patients faster. Professor Clancy said, "Our plan for the next phase of this work is to expand this approach to cover all the existing classes of anti-arrhythmic drugs and develop a database. Our long term goal would be to scale this up so it could be used in a high-throughput manner to screen drugs that are currently in development."

The research was published this week in the journal Science Translational Medicine.

Click to hear the full interview with Colleen Clancy

03:07 - Antibiotic resistance is ancient

Bacterial antibiotic resistance genes have been discovered in soil frozen for over 30,000 years, Canadian scientists have shown.

Antibiotic resistance is ancient

Bacterial antibiotic resistance genes have been discovered in soil Enterobacter cloacae on agarfrozen for over 30,000 years, Canadian scientists have shown.

Working at a site close to Dawson City in Yukon, Vanessa D'Costa and her colleagues drilled 6 metres into the permafrost to recover core samples from soils aged by carbon dating to concide with a time when mammoths and bison roamed the area. Using sensitive genetic techniques the team were able to recover from the samples DNA sequences of trees, animals and microorganisms.

Focusing on the bacteria, they were able to identify the genetic signatures of a range of microbial species, including genes known to confer resistance to several classes of modern day antibiotics. The VanX gene that enables bugs to evade vancomycin was one, the TetM gene, which provides tetracycline resistance also turned up, as did the beta-lactamase gene that breaks down penicillins.

The scientists ruled out contamination of their core samples by contemporary organisms by first spraying their drilling equipment with a strain of E. coli into which a glowing-green jellyfish gene had been inserted. By looking at the levels of this gene amongst the DNA they recovered from the cores they could gauge the level of contamination, which was extremely low.

To confirm that the ancient anti-antibiotic genes were functional, the VanX gene recovered from the cores was inserted into a strain of laboratory-grown E. coli bacteria, which made the gene product. This was further tested to confirm that it behaves identically to the VanX resistance genes found in hospitals today.

So, far from being a new phenomenon that has emerged only in the last eighty years over which antibiotics have become mainstream, antibiotic resistance is in fact much older.

As the researchers say in their paper in the journal Nature, "This work firmly establishes that antibiotic resistance genes predate our use of antibiotics and offers the first direct evidence that antibiotic resistance is an ancient, naturally-occurring phenomenon widespread in the environment."

This is because, after all, the antibiotics we use in hospitals today are largely "borrowed" from other microbes, which normally make these chemicals to protect themselves. Naturally, other bugs have evolved defense measures in the form of resistance genes.

"[this] predicts that new antibiotics will select for pre-existing resistance determinants that have been circulating within the microbial pangenome for millenia. The reality must be a guiding principle in our stewardship of existing and new antibiotics."

05:36 - Controlling light wave by wave

Tiny gold rods may give us almost complete control over light waves.

Controlling light wave by wave

Scientists have unveiled a way to control light beams, wave-by-wave.

Light is vitally important, not only in our everyday lives to avoid bumping into things, but to our technology, ranging from transmitting our phone calls down optic fibres to making computer chips. So any improvement in our control of light should help in all sorts of different ways.

Light will travel at right angles to its wave fronts, a wave front is the line Argon-ion and He-Ne laser beamsalong the top of a wave). Normally you do this with a mirror, or by using a material that slows down light like glass, allowing you to bend the wavefronts and therefore light in lenses or prisms, but this is very limited in what you can do with the light.

Federico Capasso and collegues have managed a much finer control, they have managed to make tiny gold rods onto a silicon wafer that are smaller than the wavelength of light, which when they are hit by light have electric currents induced in them which slosh up and down the rods. Depending on the  shape of the rods, these currents interact with the light and can slow down the wave fronts by different amounts.

This means that the wavefronts can be controlled by changing the pattern of rods. They have made light leaving the silicon bend in a direction they can control, and they have made the light form a spiralling pattern by creating a circle of different rods with different delays at different angles. This spiralling light will cause molecules it hits to spin and is useful for controlling individual atoms or even cells, and in quantum computing.

But the real power of this technique is that they have managed to produce a generalised form of the equations of reflection and refraction which will allow them to have almost complete control of light, so it should be possible to make patterns on a scale smaller than light's wavelength, completely flat lenses, perfect absorbers, and may other useful devices. Though it might be a while before they get used in glasses, as the present design will work differently for different colours.

08:49 - Mood Altering Microbes

Probiotics, the "friendly" bacteria, seem to have the potential to treat anxiety and depression related disorders due to the effects they have on brain activity...

Mood Altering Microbes
Professor Paul Forsythe, McMaster University

Chris - Researchers from University College Cork and McMaster University in Canada have found that the so-called good bacteria, also known as probiotics, don't just affect the digestive tract. They can also affect mood and potentially have an impact on stress and depression. Joining us now to discuss how they've down this work and what they've discovered is Professor Paul Forsythe and he's at McMaster University.Probiotic Drink Hello, Paul.

Paul - Hi, there.

Chris - So first of all, what was the question you started out by asking when you were doing this work?

Paul - Well, over recent years there's been real increase in our understanding of the importance of the normal bacteria in the intestine, the gut microbiota, and how it influences a range of physiological systems. What particularly interested us was evidence emerging that these bacteria could influence the brain and brain development. We've been investigating the particular bacteria that we used in the study for some time, and we had demonstrated it could actually alter the activity of nerve cells in the intestines of mice. But what was really interesting is we could actually reduce the perception of pain signals coming from the gut and we took that as a good indication that it was modifying the communication between the gut and the brain. So we wanted to explore this further and to see if we could actually detect changes in brain neurochemistry and subsequently whether these changes in brain neurochemistry might alter the behaviour of these animals.

Chris - So the bacteria that go into the intestine in some way change the chemical environment in the tissue of the intestine, which in turn changes the activity of the nerve cells in the intestine. You're saying that can then be propagated, or at least you speculated that it could be propagated, up to the brain and, in turn, alter neurochemistry in the central nervous system?

Paul - That's it and actually what we demonstrated was that the Vagus nerve, which has already been and shown to be an important communication system between the gut and the brain, was critical to mediating the signals from the bacteria to the brain. So when there was no signalling going along the vagus nerve we didn't see the changes in the brain when we fed the bacteria.

Chris - So talk us through the experiment. You did this in mice.

Paul - We did, yes. So we fed mice with a particular strain of lactobacillus, Lactobacillus rhamnosus, and we fed them for 28 days. We then conducted a number of behavioural tests looking for things like anxiety and then we looked at the brains of these animals. We initially focused on the GABAergic system in the brain and so we looked at receptors for the neurotransmitter GABA and we saw changes in these receptors in the brain.

Chris - Which bits of the brain did you look at and which bits of the brain showed those changes? More critically, were they the bits of the brain that would be consistent with the observed behavioural effects you saw in mood, stress, depression, that kind of thing?

Paul - We did. So, we focused on the hippocampus and the medulla. They have both been related to changes in things like depression and anxiety. So, the changes we saw were consistent with the sorts of changes we were getting in behaviour - so reductions in anxiety-like behaviour.

Chris - So how do you know that the link in the chain was gut to nervous system i.e.  Vagus nerve to brain? How did you rule out the fact that the animals weren't just feeling better and healthier because they have these bacteria in their guts, and this was impacting on their behaviour?

Paul - So what we actually did is we divided [cut] the vagal nerve so there was no signalling going from the intestine to the brain through the vagus nerve. We lost the behavioural effects and lost the changes in the brain chemistry, indicating that this signal through the Vagus was critical. And animals that were fed with just broth without the bacteria, they had no changes in their behaviours at all.

Chris - So that's pretty encouraging isn't it? It shows that there is definitely some kind of connection going on - via that Vagus nerve - between the gut and the brain. You only looked at one nerve transmitter chemical though, and there are many others in the brain. Are you now going to go ahead and  look at some of the other, what we know are mood-related, nerve transmitter chemicals and see if they also get changed?

Paul - Exactly. I mean, we focused just on the GABAergic system in this study, but, as you said, there is a whole range of nerve transmitters involved. We don't know the extent of the changes caused by feeding these bacteria and that's definitely something we're actually looking at, at the moment.

Chris - And what about in humans? Is there similar clinical data that it has the same effects when humans consume these bacteria in the yoghurt drinks and things?

Paul - The studies in humans are very limited and tend to be looking at reducing anxiety or chronic fatigue and things like that. But the studies have been quite small and the data is limited, so we don't really know what the effect of these bacteria would be on humans. That's obviously something that we want to look at.

Chris - And of course related to that is what actually are the bacteria doing to have that effect in the gut itself, and is there some other way of mimicking their presence, or mimicking their effects? For instance, if you ate something different, would that have the same sort of impact on the gut as these bacteria do?

Paul - Sure, exactly. I mean, looking at the bacteria itself, so what are the characteristics of that bacterium that allow it to mediate these signals? Is it something to do with the cell wall of the bacteria, or is it a product that that bacterium produces. And then how does it transmit the signal to the Vagus nerve? Does this involve other cells in the gut - immune cells perhaps - or is it a direct effect on the nervous system? And then we're also interested in looking at what's the nature of the change of the signal along the Vagus nerve that mediates these effects. I mean, it's interesting to note that electrical stimulation of the Vagus is actually an approved treatment for depression. And so it's quite encouraging that it seems our bacteria are acting on that same signalling pathway.

Chris - Alright. We must leave it there. Thank you, Paul. I think it's very good proof that you are, genuinely, what you eat. That was Paul Forsythe. He's an Assistant Professor in the Department of Medicine at McMaster University and he's published that study he was discussing, this week, in the journal PNAS.

14:52 - Nitrogen, Mobile Phones and Anti-cancer traps

How dead dinosaurs fertilise forests, why mobile phones answer the call in emergencies, a DNA trip-switch for cancer and a Star Trek style "sick bay" beams down to Leicester Royal Infirmary...

Nitrogen, Mobile Phones and Anti-cancer traps
Naked Scientists NewsFlash!

The Rocky Road to Fertilising Forests

Meera -   Scientists studying how forests develop have discovered a new source of nitrogen that plants and trees can tap into, helping to boost their growth and so remove more carbon dioxide from the atmosphere.

By analysing samples of soils from coniferous forests in Northern California, a team at the University of California, Davis found that the underlying bedrock leaches nitrogen-containing chemicals into the soil, nourishing the plants and trees growing above. This source of nitrogen was previously unknown, according to Professor Benjamin Houlton who was part of the study...

Benjamin - It was thought for a long time that the way nitrogen comes in to our environment is from the atmosphere only, and especially by way of a couple of interactions. One interaction involves bacteria known as Rhizobium and, in addition, nitrogen can come in from rain water. But it turns out that there's a tremendous amount of nitrogen that's in rock material. This is kind of a new discovery that nitrogen actually is in the rock material and it's also available to forests and other types of plant ecosystems.

Meera - This new source of nitrogen is released by the rocks as they erode according to the groups paper published in Nature this week. More nitrogen, which is an essential ingredient for the formation of proteins and DNA, means that plants and trees grow faster, storing more carbon dioxide from the atmosphere as a result. The findings could therefore be used, say the scientists, to identify fertile areas in which to site forests intended to function as carbon-offset schemes in the future.

Increased forest ecosystem carbon and nitrogen storage from nitrogen rich bedrock, Scott L. Morford, Benjamin Z. Houlton & Randy A. Dahlgren, Nature Volume: 477, Pages: 78-81 (01 September 2011)

Mobile Phones in Emergencies

Mobile PhoneUsing mobile phones to track how people move about in emergencies has enabled scientists to develop better ways to target aid to where it's most needed.

Although relief agencies have contingency plans in place for tackling a range of disasters, the way victims actually behave under these circumstances remains poorly understood.

But now, publishing in the journal PLoS medicine, Linus Bengtsson and colleagues from the Karolinksa institute in Sweden used mobile phone signals to follow the movements of more than 1.9 million people affected by the 2010 Haiti earthquake and the ensuing cholera outbreak, to predict, with very high accuracy, where people will go, in what sorts of numbers and over what time period following an emergency...

Linus - What characterises a disaster is often total chaos and it's very, very difficult to understand where people are. Since we know which tower each mobile phone used, we can sort of follow each phone as it travels across the country. We could see that approximately 600,000 people left Port au Prince 19 days after the earthquake. So, our hope is that this will contribute to making aid delivery much more efficient.

Gething PW, Tatem AJ (2011) Can Mobile Phone Data Improve Emergency Response to Natural Disasters? PLoS Med 8(8): e1001085. doi:10.1371/journal.pmed.1001085

Anticancer Traps

A DNA-based "circuit" that "trips", and kills cancerous cells, has been engineered by scientists at the Swiss Institute of Technology and MIT.Described this week in the journal Science, the new system looks for specific microRNA molecules that are known to be present at higher-than-normal levels within cancer cells.

Mouse TrapOnce a threshold level of the microRNAs is detected, a DNA domino effect is triggered causing the cell to self-destruct by a process called apoptosis. Although the team have yet to solve the problem of how to achieve safe and large-scale delivery of these cancer-preventing trip-switches into a patients' cells, Lead Scientist Yakov Benenson believes the work could be a strong contender in the search for new, more specific, cancer therapies...

Yakov - If we think about what would be the ideal anti-cancer therapy, it has to be something that looks at each cell and determines whether it should be destroyed or should be left alone. We don't have any good ways right now to do so. I think our study shows how to look inside the cell and detect what's going on with the cell with high precision, based on the integration of multiple cancer signals and markers.

Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells, Zhen Xie, Liliana Wroblewska, Laura Prochazka, Ron Weiss, Yaakov Benenson, Science, 2 September 2011: Vol. 333 no. 6047 pp. 1307-1311

&nb

Star-Trek Style Sick Bay

A team of scientists at the University of Leicester have used space technology to develop a "Star Trek" style "sick bay" that can non-invasively detect a variety of illnesses, all at once.

Co-inventor Professor Paul Monks explains that how the technology can see, smell and feel diseases...

Paul - The first uses imaging technology, which has really been developed for use on the Mars rovers, to look at the colour of people's skin for instance, to see whether we can pick up disease from that. The second suite of  technology looks at the composition of people's breath. From that, you can actually tell how well people are. The third suite of monitors really looks inside the body, but non-invasively, to look at blood flow and how much oxygen is in the blood and muscles and skin at any given time. Put together, it's the first time that you'll get this holistic measure of a patient's well-being.

Meera - The whole diagnostic process should take just 15 minutes. and will be based at the Accident & emergency department of the Leicester Royal Infirmary, which sees 150,000 patients coming through its doors annually. 

The developers expect to be using the system to pick up a range of diseases including infections, heart disease, skin conditions, respiratory problems and some cancers.  Liver disease,  asthma and even MRSA are earmarked for the future.So what was once considered to be science fiction looks set to become reality....

University of Leicester scientists deploy space-age technologies to detect illness at science-fiction style 'sick bay'

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