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The word ‘metal’ conjures up images of machines and heavy industry but metals are also intimately involved in the biological processes that regulate our bodies and underpin new energy technologies.

‘Nearly half of all enzymes require metals to function in catalysing biological reactions,’ Kylie Vincent, of Oxford University’s Department of Chemistry tells us. ‘Both the metal and the surrounding protein are crucial in tuning the reactivity of metal catalytic centres in enzymes.'

These ‘metal centres’ are hives of industry at a microscopic scale, with metals often held in a special protein environment where they may be assembled into intricate clusters inside proteins.

'Chemists are interested in understanding the effects of the protein environment on the chemistry of the metal centres, and are also fascinated by the synthetic challenges of mimicking the structure and function of metal sites in proteins by smaller molecules,’ comments Kylie.

Understanding these effects is important because metal-containing proteins are involved in many biological energy cycling reactions, including the oxidation or production of hydrogen and the conversion of carbon dioxide into organic carbon molecules.

Kylie has written a review of advances in this area of chemistry published in this week’s Philosophical Transactions of the Royal Society A.

The article explores how chemists are looking beyond X-ray based techniques to find new ways to capture enzymes at work, she explains:

‘X-ray crystal structures of metal-containing proteins provide snapshots of the positions of atoms, but proteins are dynamic systems and structural changes are often crucial to their function.’

‘Information on the many intermediate states involved in catalysis of complex reactions at metal centres in enzymes is key to understanding enzyme function and for synthesising catalysts that mimic enzyme function.’

Now infrared spectroscopy using lasers is helping to deliver snapshots of chemical changes in enzymes at the pico- or even femto-second scale. These infrared methods should capture fast chemical reactions occurring at metal centres in proteins, revealing information about intermediate species formed during catalytic reactions.

‘Many groups are trying different approaches, but at Oxford we are combining infrared spectroscopy with electrochemistry so that we can control the state of metal-containing proteins at electrodes and, at the same time, measure infrared spectra to obtain information on the structure and function of the protein,’ Kylie tells us.

‘This should provide structural insight into states of metal-containing proteins that are only formed at precise potentials - revealing details of reactions occurring during respiration, metabolism or photosynthesis.’

The knowledge gained from such experiments should help chemists to design new catalysis for ‘green’ electricity generation in fuel cells or the clean production of fuels. And because metal-centres in proteins also bind small molecules that send signals in biological systems, infrared spectroscopic experiments should help us to understand and control these types of processes.

Kylie adds: ‘There is much that we can learn from the way that micro-organisms use readily available metals to carry out these reactions while chemists often require rare and expensive metals for the same chemistry.'

'Advanced infrared spectroscopic experiments should also give us a fresh perspective on fundamental questions about the functioning of metal-containing proteins in biology.’

If you want to see how volcanoes interact with their surroundings then get a view from space.

That’s what Juliet Biggs, of Oxford University’s Department of Earth Sciences, and colleagues have been doing by using satellites to investigate volcanic rifts in intimate detail.

I asked Juliet about how satellite radar images are giving insights into what’s happening beneath our feet, and could even help us to tap geothermal energy from inside the planet…

OxSciBlog: Why do we need satellites to study volcanic activity?
Juliet Biggs: The East African Rift extends for over 3000 km, from Mozambique to Djibouti; many of the volcanoes are in remote areas which can be hard to access on the ground and even fewer have ground-based monitoring networks.

Satellite measurements offer a unique opportunity to study the East African Rift on the plate-boundary scale, giving us insight into the development of magma activity as the rift matures and the behaviour of individual volcanic systems.

Even where available, ground-based measurements of surface deformation are taken at a limited number of stations (usually less than 10 per volcano) so satellite images give a much higher measurement density.

OSB: How is radar used to pick up very small changes on the ground?
JB: A radar image can be divided into two components, the amplitude and phase of the radar wave. By taking the difference between the phase of two radar images, we can measure the change in the distance between the satellite and ground surface to an accuracy of better than 1cm.

The resulting map is called an interferogram (see image above) and shows the ground displacement at high resolution (<100m) over large areas.

OSB: What is the significance of the tiny changes you've found?
JB: We have so far detected surface deformation at four of the volcanoes in the Kenyan Rift and two in the Main Ethiopian Rift. Although these volcanoes are not currently erupting, these observations show there are significant pressure changes going on in the plumbing system.

The volcanoes are neither dormant nor extinct, with active magma systems at depths of 2-5 km. Along with colleagues specialising in volcanology, petrology and seismology and structural geology, we are still trying to understand the mechanism behind the deformation: is it the result of new magma moving into the system, the build-up and release of gases, or an unstable hydrothermal system?

The high percentage of volcanoes which have been seen to be deforming is surprising and indicates a ubiquitous magma supply with implications for models of continental rifting, caldera volcanoes, geothermal resources, and volcanic and seismic hazard.

OSB: How could these findings help us understand volcanic activity near Nairobi/Addis Ababa?
JB: Several of these volcanoes lie close to the heavily populated capital cities of Nairobi and Addis Ababa. There is little information available about the eruptive history of most of these volcanoes, but widespread ash layers show they have the potential for major explosive eruptions.

The satellite observations can help us identify the presence of active magma chambers and understand the patterns of magma recharge. Several of these volcanoes are potential sites for geothermal power stations, so a clearer understanding is necessary to determine the level of risk for personnel, infrastructure and productivity.

OSB: What do you hope the rest of your studies will reveal?
JB: These observations formed part of the pilot study on the Kenyan Rift: I am currently working with ESA as part of the Changing Earth Science Network to produce a map of the spatial and temporal distribution of activity along the East African Rift.

When complete, this map will show the role of magmatic fluids in continental extension with implications both for the East African Rift and the development of other rift systems. The map will also provide a database of information for seismic hazard, volcanic hazard and geothermal exploration.

In December 2009, a sequence of four medium earthquakes hit Northern Lake Malawi causing significant damage and killing four people. The deformation patterns seen in the satellite images are consistent with the rupture of a shallow, west-dipping fault, which had not been previously mapped. Although previous studies have shown that magma has an important influence on continental rifting even in immature sections of the East African Rift System, the satellite images show no evidence for the involvement of magmatic fluids in these events.

I’ve been looking to write about Moon Zoo for a while now: it’s a new citizen science project that enables web users to become virtual lunar explorers.

Visitors to the site get the chance to examine the lunar surface in unprecedented detail, thanks to new high-resolution images taken by NASA’s Lunar Reconnaissance Orbiter [LRO].

And, like Galaxy Zoo, users don’t just get the chance to spot things that have never been seen before - everything from lost Russian spacecraft to previously unseen geological features -  they help to answer vital scientific questions.

In fact the Moon’s history is written on its surface: by counting craters visitors will make it possible to determine how old a particular region is and the depth of the lunar ‘soil’ (regolith). Finding fresh craters left by recent impacts could also tell us a lot about the risk of meteor strikes here on Earth.

And understanding craters will be vital for any return to our nearest neighbour:

‘There’s tremendous variation in the Moon’s craters from faint old ones you can hardly see to fresh new ones that sparkle in the sunlight,’ Moon Zoo team leader Chris Lintott, of Oxford University’s Department of Physics, tells me.

‘If we’re to identify safe landing sites for future missions it’s vital that we know about craters with boulders and where meteors have smashed though the lunar surface creating large holes that would make landing a spacecraft very difficult.’

The lunar surface also holds a unique record of previous missions.

Not only can users browse unseen images of the Apollo landing sites, spotting abandoned rovers and equipment and trails left by the astronauts, but they could stumble across lost Russian spacecraft - such as Luna 9 and Luna 13 - that crash landed on the Moon but have never been found.

As you can see from the image gallery above, captioned by Rob Simpson of Oxford’s Department of Physics, visitors are already alerting the team to some fascinating images of rolling boulders, vast pits, and possible lava flows. You can even see where users are on the lunar surface right now through the fantastic Moon Zoo Live.

I’ll be blogging more about Moon Zoo later in the year when we have something a bit special planned but, for now, if you’re intrigued by the snapshots above, you should join our crew of intrepid virtual astronauts. 

A new, dispassionate analysis is needed of all the available data on breast cancer screening programmes and their effectiveness, says an Oxford University researcher in an article today in the BMJ medical journal.

Although it saves lives, the benefits and harms of breast cancer screening are perhaps more evenly balanced than many of us might naively imagine.

This has led to increasingly heated debates among specialists in the field who take one side or the other, says Professor Klim McPherson in his BMJ article. These polarised arguments are not helping women to make an informed decision about screening, he argues.

It can be a very difficult thing to assess the benefits of cancer screening programmes – something OxSciBlog has looked at before.

You have to be clear that picking up breast cancer early on through screening leads to improved outcomes (fewer deaths) for those women. You also have to be wary of false positives, or treating cases where perhaps there was no need – the type of cancer involved may not have progressed, for example. This is known as over-diagnosis and over-treatment, and can potentially be harmful.

The BMJ’s press release today also highlights the number of women that need to take part in a screening programme before lives are saved:

'A recent US report on screening for breast cancer estimated that the mortality reductions attributable to breast screening are 15% for women aged 39–49, 14% for those aged 50–59, and 32% for those aged 60–69. Worse still, estimated numbers of women needed to be invited to a US screening programme in order to save one life are high. For the younger group it is nearly 2,000 while in those aged 60–69 it is still nearly 400. In the UK, the figure is around 1,600 for women aged 40–55.'

Klim McPherson, visiting professor of public health epidemiology at Oxford’s Nuffield Department of Obstetrics and Gynaecology, tells OxSciBlog that: ‘There has been a debate about whether the actual benefit of mammography in earlier diagnosis justifies the risk of over-diagnosis and over-treatment it may cause.

‘The evidence on breast screening programmes is that the chance of saving a woman's life is small but real, and the chance of unnecessary anxiety and treatment is also low and real – and not properly discussed. The uncertainty is in the relative size of these two risks for a woman.’

This uncertainty does need addressing, he says, and it may be time to look again at the NHS screening programme thoroughly.

The burden of breast cancer is unremitting and we must do anything we can to contain it, he is clear. But screening for a progressive disease is justified only if earlier diagnosis and treatment improve disease progression enough to justify the harms of screening.

‘Breast cancer screening is no panacea, is expensive and it is irresponsible not to properly assess it, so that women can be better informed,’ says Professor McPherson.

‘The problem is that the debate between cynics and enthusiasts is going nowhere and getting more and more heated. It needs to be properly resolved by, for example, the National Institute for Health and Clinical Excellence (NICE) using all the available data dispassionately.’

In the last of a series of articles marking the 10th anniversary of the first draft human genome, OxSciBlog talks to Professor George Ebers about what we know now about the genetics involved in multiple sclerosis.

Since the sequencing of the human genome, our understanding has greatly increased of the subtle interplay between our genes, our lifestyles, and all that we encounter and are exposed to as we grow up and develop.

We know more about the interactions between our genes, the intricate control systems within the body that switch them on and off, and have some evidence of the way outside factors can link to our genes and make us more susceptible to some conditions.

The idea that we are at the mercy of our genes, that all we are is hard-written into our DNA – if it ever truly held sway – has long gone. It is clear that genetic and lifestyle or ‘environmental’ factors are both important in many complex diseases, from heart disease to obesity and mental health conditions.

Multiple sclerosis, the complex and devastating neurological disease which leads to progressive loss of function in the nervous system, is one condition which offers a clear illustration of this.

Genes linked to MS
Professor George Ebers of the Department for Clinical Neurology says: ‘The sequencing of the human genome has provided a vital tool for understanding the interactions between genes and the environment, how “nature” and “nurture” are bound up together, in many human diseases such as multiple sclerosis.

Over the past 15 years and more, George Ebers has amassed a large database of genetic and lifestyle information from Canadian patients with multiple sclerosis and their families. This has proved to be very powerful in answering many questions about MS.

It’s been known for a long time that multiple sclerosis is associated with the major histocompatibility complex (MHC), a big player in the human immune system. Work by George Ebers and colleagues, though, has demonstrated that the picture is more complicated than originally thought.

They pinpointed the single strongest genetic effect in MS to a variation in one gene called HLA-DRB1 that is involved in the MHC. This is a highly variable genetic region, but one variant that may be present, called HLA-DRB1*15, is strongly linked to susceptibility to the condition.

Unfortunately it’s not quite as simple as having one or two copies of this genetic variant increases your risk of MS by a certain amount. Other variations present in this tight cluster of genes appear to modify further a person’s risk of developing MS. They could increase or decrease the risk associated with HLA-DRB1*15. Further genetic variations in this region appear to affect the severity of the condition where it develops.

It’s a complex picture of genes influencing the effects of other genes – a phenomenon called epistasis. You can’t just consider the effects of each gene individually in isolation.

Getting more sun
But there’s yet more to it than just genes. Where you live in the world has an effect. The further you are from the equator, the greater is your risk of MS. That is, there are more cases in Edinburgh than Marseilles and more in Sydney than North Queensland.

The evidence is accruing that the amount of sunlight people get influences the number of cases of MS that are seen. Sunlight helps the body produce vitamin D, and those populations with lower levels of the vitamin do have more cases of MS. This and other potential health benefits has led to suggestions in Scotland (where rates of MS are the highest in the world) of widely distributing vitamin D supplements.

The group has also identified a modest ‘month of birth effect’, where babies born in May have slightly higher risk of MS than those born in November. One possible reason? Mothers who are pregnant over winter months see less sun and have lower vitamin D levels.

Last year, George Ebers, Julian Knight and colleagues made a direct connection between these observations and the genetics of MS. They showed that vitamin D binds to a section of DNA next to the important genetic region for MS – HLA-DRB1 – and alters the amount of protein that’s produced from the gene.

Here is a route by which genes and the environment (the amount of sunlight a person experiences and their vitamin D levels) interact, and where they are both known to influence MS risk. How this process increases MS risk is unknown, but the finding suddenly allows new studies to investigate.

Enter epigenetics
However, George Ebers thinks this is only one way in which genes and environmental factors interact in multiple sclerosis. ‘Epigenetics – an emerging field that moves beyond the sequence of the DNA code alone to consider other changes in the chemical and physical structure of our genes – is turning out to be the most important of these gene-environment interactions,’ he says.

There are a number of processes occurring on a DNA molecule that can switch genes on and off, controlling their effect. These modifications can be added or removed, so can be temporary, and do not involve changes in DNA sequence. Jane Mellor has described many of these processes previously on OxSciBlog and the effects they can have in disease, in growth and development and across generations.

Epigenetics adds yet another level of complexity, and geneticists are increasingly moving away from considering DNA sequence alone to include these additional chemical markers on the DNA.

Epigenetics is likely to be behind what are some otherwise surprising observations in multiple sclerosis. Data from George’s Canadian study has revealed that mothers tend to contribute more to disease development than fathers. Comparing where nieces and nephews are affected and where there’s also an uncle or aunt with the condition shows this effect. The parent connecting the niece/nephew through the family tree to the uncle/aunt is found to be more likely the mother than the father.

His team are now looking at how the genetic region important for MS might be chemically modified, and how these epigenetic markers get passed down the generations. Such epigenetic changes to the DNA might occur in response to environmental factors to predispose people to disease, perhaps they could occur in the womb for example. Even more confusingly, the genetic trait mysteriously disappears after two or three generations. An article by Michael Gross in a recent issue of Oxford Today explains it like this:

'These epigenetic markers can remain on a gene long enough to be passed on to the next generation or two, but they don't last forever. Studying large families in North America descended from one European and one Native American parent - which is of particular interest, as the MS susceptibility trait is virtually unheard of among Native Americans - Ebers' group found that the disease hit two generations with the predicted pattern, but then disappeared in the third.

Ebers says his group has now shown three ways in which the environment interacts with the genes to influence MS risk. 'Firstly, gene expression in the main genetic region for MS risk is regulated by vitamin D. Secondly, the month of birth effect maps to the same genetic region, and finally we have shown that epigenetic modifications determining MS risk take place in this same region.'

These findings, says Ebers, confirm that the 'genetic cause' that scientists were hunting for so long, really reflects environment-gene interaction, an epigenetic pattern that is passed on for one or two generations but then tends to disappear. 'Multiple sclerosis is the first common disorder with an important epigenetic mechanism', Ebers concludes.'

To investigate the epigenetic changes that are having an effect on MS will be a challenge, however. New experimental techniques will be required to identify and pinpoint those extra chemical or structural modifications to the DNA that are important in disease, says George Ebers.

‘We can recognise clues from genetic epidemiological studies that epigenetics is playing a role in disease, and it is possible to identify disease-specific epigenetic markers. But the pressing challenge in this field is to come up with efficient and reliable sequencing methods for detecting the key epigenetic changes.’

He is confident this will happen. ‘We can expect many new insights from epigenetics in the coming years, in areas from cancer to multiple sclerosis, continuing to build on the knowledge we have gained from the human genomics studies of the last ten years,’ George Ebers says.

‘My hopes are very high and I believe the understanding of epigenetics will represent and embody the most important contributions genetics has to offer. Epigenetics is the interface between genetics and the environment and its understanding holds the key to preventing many common diseases.'