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Curious snake-like forms have been spotted in cells from many different species across the evolutionary tree. Now Oxford scientists have shown they exist in human cells as well.

This apparent ubiquity across species from bacteria to mammals suggests the structures perform a crucial function in the cell. But how and why they form, and what role they play in the cell remain anyone’s guess.

Three groups reported observations of the snakes in cells from a whole range of different species at around the same time in 2010, including Dr Ji-Long Liu’s group at the Department of Physiology, Anatomy and Genetics in Oxford.

Ji-Long and colleagues named the structures ‘cytoophidia’ because of how they looked under the microscope: cytoophidium is ‘cell snake’ in Greek.
‘Cytoophidia have heads and tails and can move around. They really do look like snakes,’ explains Ji-Long Liu.

‘I reported the finding in fruit flies early in the summer of 2010,’ he says. ‘Two months later, two papers – one from Zemer Gitai’s group in Princeton and the other from James Wilhelm’s group at the University of California, San Diego – reported similar snake-like structures in bacteria, brewer’s yeast, flies and rats.’

Ji-Long’s group has now reported the first observation of these cellular structures in human cells in the Journal of Genetics and Genomics.

‘Amazingly, these snakes occur across the tree of life, from bugs to humans,’ he says. ‘Cytoophidia are found inside cells, and sometimes they stay near the surface of cells. It looks like the number of snakes in a cell is tightly controlled.’

But what are they? Having initially observed the snakes in cells from fruit flies, Ji-Long got curious and decided to follow up the chance observation. He took advantage of a collection of fruit flies at the Carnegie Institution Department of Embryology [CIDE], where he worked before moving to Oxford.

In this collection, individual proteins in the fruit flies had been labelled with a fluorescent green marker, allowing Ji-Long to identify the cell snakes as containing the enzyme CTP synthase.

CTP synthase is a crucial but not necessarily glamorous enzyme, one of many such enzymes involved in necessary biological processes that keep our cells ticking over. In this case, the enzyme plays a role in making the molecule CTP, a building block that helps make up DNA and RNA. The CTP molecule also crops up in fat metabolism.

‘If the generation of CTP goes wrong, it could cause a lot of damage to the cell,’ Ji-Long says.

It is possible to speculate about why an enzyme would form these long filament structures in cells. For a start, cells are a long way from just being bags of biological molecules and enzymes that float around freely, magically carrying out their many functions, reactions and chains of metabolic processes.

The cell needs an organised structure to bring this industry of biochemical reactions under control, with many processes cordoned off in separate chambers, capsules and compartments. It allows related reactions to be better controlled and regulated, with the right concentrations of the different molecules brought together in the right environment. After all, you don’t just bung all the ingredients into a chemical engineering plant, a brewery or a baking tin imagining that the recipe will be fine.

‘The beauty of a well-organised cell has not been appreciated by everyone. Without the structure, a bag of the same amounts of all the molecules would not do the same thing as a living cell,’ explains Ji-Long. ‘Compartmentation could be a general feature for many enzymes in a cell,’ he believes.

He notes that six enzymes that produce a set of biomolecular building blocks called purines are known to cluster in a specific compartment, and studies have shown that many proteins are found localised in just one part of a cell. ‘It seems to us that the filaments are necessary for the CTP synthase enzyme activity,’ he says. ‘We are trying to understand the relationship between filament-forming and the overall function of the enzyme in a cell – but we have no clear answer yet.’

His research group has found some drugs that affect the assembly of the CTP synthase enzyme into snakes, making the filaments appear in human and fruit fly cells. This approach could give a new handle to study the snakes’ function in the cell.

Another interesting question is why the enzyme forms a snake-like filament or rings rather than spheres or just irregular capsules. These shapes have different surface-to-volume ratios, which might give some clues as to the difference this makes to the activity of the enzyme.

‘It would be fascinating to know more about what the role of the cytoophidium plays in regulating the production of CTP,’ says Ji-Long. He notes that the CTP synthase enzyme is found in larger amounts in many types of cancer cells, and that his group has shown that some potential anti-cancer drugs can promote the formation of cytoophidia. But that’s still a long way from showing that this is important clinically or that there might be medical applications in understanding more about these cell snakes.

At the moment the existence of these snakes is an interesting observation that opens up intriguing new research questions, but what role the snakes play in our cells is unknown. Ji-Long also suggests that it’s ‘very likely’ there are other enzymes packaged up in structures in the cell that we don’t know about yet. ‘Time will tell!’ he says.

A project in which volunteers hunt online for new planets NASA may have missed is publishing its first results which show some remarkable finds.

Planethunters.org, which was set up by Oxford University physicists, working with colleagues at Yale University and the Adler Planetarium, has enabled over 45,000 armchair astronomers to find candidates for new alien worlds by searching data from the Kepler mission.

Reporting on just the first month of the project, which was launched in December 2010, researchers believe there is a ‘95% chance or greater’ that volunteers have already spotted two new exoplanets NASA originally discarded: other finds include a previously unknown eclipsing binary star system.

‘Kepler's mission is to work out what kind of worlds might be out there - that's why it's so important we rescue those that have slipped through the net,’ Chris Lintott of Oxford University’s Department of Physics, one of the scientists leading planethunters.org, told me.

The Kepler telescopes detect new planets by recording tiny changes in the brightness of stars. This dimming is caused by planets crossing in front of them. Volunteers visiting planethunters.org sort through thousands of images of stars searching for examples of these dimming events (known as 'transits') which NASA’s small team of experts may have missed.

The project builds on a series of highly successful Oxford-led citizen science projects, such as Galaxy Zoo, Old Weather, and most recently Ancient Lives, which have shown that ordinary web users can beat computer algorithms at spotting patterns and interesting phenomena.

Carolyn Bol, from Helensburgh in Scotland, is one of the planethunters.org volunteers who has made a discovery that will soon see her name appear on a scientific paper.

‘The fact that all that data is readily available to everyone makes the ‘hunting’ a bit of a game thanks to all of those connected remotely from the comfort of their home,’ she explains. ‘I have a full time job as an optometrist so I really enjoy having this hobby where I spend time hunting for planets when I have some spare time.’

It was while sorting through images of stars that Carolyn made her discovery:

‘The moment I saw the pattern I screamed “A PLANET !” just because all the light curves I was classifying were very similar, some pulsating etc but there were no distinctive transits until that pattern appeared and I was sure I was watching a planet. I marked the transits, I favourite it and went to discuss it.’

It led to some interesting discussions with her work colleagues, such as whether you should name a planet when it might have been named already by an alien civilisation.

In fact Carolyn’s planetary candidate would later be found to be not an alien world passing in front of a star but something almost as exotic: an eclipsing binary system containing two stars in which one star’s orbit sees it pass in front of its companion.

It just goes to show that when you unleash an army of citizen scientists part of the fun is not knowing what they will turn up.

‘I think it's incredible that only 16 years after the first planets were discovered around other stars, it's now possible to find candidates using nothing but a web browser,’ Chris tells me.

‘With new data being released just last week, there are plenty more surprises hidden in the data for planet hunters to find.’

Technology that turns low-cost mobile phones into sophisticated stethoscopes could save thousands of lives in poor countries.

The kit, developed by Oxford University and South African researchers, enables people to record and analyse their own heart sounds using a mobile phone microphone. Patients then send the recordings to medics who can remotely monitor their condition.

The idea came from a conversation between Dr Thomas Brennan of Oxford University’s Department of Engineering Science and Professor Bongani Mayosi of the University of Cape Town about how to reduce the numbers of people dying of tuberculous pericarditis: a condition affecting up to 1-2% of TB patients where the lining of the heart becomes infected. 

‘About 40% of people die post-diagnosis, largely because the onset of symptoms is insidious and they can't get into the clinic before it's too late and they die of cardiac arrest,’ Thomas tells me.

‘We discussed various ideas of being able to remotely monitor their heart in a low-cost way to pick up early signs of deterioration. The idea of using the phone's microphone as a stethoscope to analyse and record heart sounds came after seeing the iPhone app iStethoscope, and I wondered if we could do something similar using low-cost phones.’

As half of all Africans own a mobile phone the number of patients who could potentially benefit was enormous.

Thomas teamed up with Dr Gari Clifford of Oxford’s Institute for Biomedical Engineering (IBME) who had worked with Katherine Kuan, a student at MIT, on listening technology for smart phones. They extended that work to enable low-cost phones to effectively capture and analyse the resultant phonocardiogram (PCG) recordings to assess the feasibility of the project.

‘The original idea was that a person could use their own phone to record their heart sounds,’ Thomas explains ‘and that any phone would be able to make an adequate heart sound recording at little or no cost using readily available objects, from which heart rate and abnormal heart sounds could be detected.’

Before they could create a device a number of technical challenges had to be overcome: low-cost phones are designed for voice so they had to deal with distortion introduced by the phone, signal processing techniques were needed to identify a poor recording and ask the user to try again, and algorithms had to be developed that could reliably identify heart rate and heart sounds.

‘The biggest challenge was in assessing the feasibility of the device,’ Thomas comments. In partnership with Professor Mayosi and Dr Jens Hitzeroth, the team conducted a clinical trial, in which Professor Mayosi was principal investigator and Drs Hitzeroth and Brennan were co-investigators, between January and April at the Department of Cardiology at Groote Schuur Hospital in Cape Town to compare two mobiles - a Nokia 3110 Classic and an iPhone 3G - with the £400 3M Littmann Electronic Stethoscope.

They collected phonocardiograms from 150 volunteers with a range of cardiac conditions using the Littmann, the iPhone, and the Nokia 3100 Classic. The trial showed that the Nokia actually out-performed the Littmann in estimating heart rate, although it had to discard more low signal quality recordings.

After these promising results the team are pressing ahead with the next stage of the project:

‘Alongside a MSc student, David Springer - who worked with me in developing the algorithms - we're developing an Android application to record and process the heart sounds recordings,’ Thomas tells me.

‘The next step is to expand the scope of the device to see if it can be used as a screening tool for patients with heart disease, particularly rheumatic heart disease, which has a particularly high prevalence in southern Africa.’

The genomes of 18 different and varied strains of the thale cress, Arabidopsis thaliana, have been sequenced by an international group lead by Oxford University scientists.

Arabidopsis is standard in plant genetics labs in the same way that other scientists might study E. coli, yeast and fruit flies as models from which they can draw general lessons about the way genes and biological pathways work. And the genome of the thale cress was decoded in 2000 to act as a reference for studies in plant genetics.

Oxford Science Blog asked lead researcher Professor Richard Mott of the Wellcome Trust Centre for Human Genetics about the current study providing 18 new genomes, and what it offers the field.

The research is published in Nature and also included Oxford scientists from the departments of Plant Sciences and Statistics.

Oxford Science Blog: Why is Arabidopsis so important in understanding plant genetics?
Richard Mott: Arabidopsis has become the standard model for much of plant genetics research.

It is small and grows quickly, it has an accurately sequenced reference genome that is relatively compact and there is a wealth of molecular tools with which to probe gene function.

Arabidopsis is a brassica – that is, a member of the cabbage family. But most of its genes are similar to those found in other plants, including important crops. It is generally much easier to figure out the functions of genes in Arabidopsis and apply this knowledge to other species.

OSB: I thought its genome had been sequenced already. What does this new study add?
RM: Arabidopsis is a highly variable species, at both the genetic and phenotypic [observable characteristic] level.

Several recent studies have begun to catalogue this genetic variation. Our study differs in that rather than interpret this variability in relation to the reference genome sequence (called Col-0), we have assembled 18 Arabidopsis genomes very accurately, so that we could determine the gene content of each.

What we found was quite surprising. If we had simply lifted over the genes annotated in the reference Col-0 onto each genome, then we would have predicted that about a third of the genes were severely altered (or even non-functional) in at least one of the 18 genomes.

But because we also collected gene expression data (essentially the sequences of the protein-coding genes), we could see that in many cases the gene structures changed in a way that mitigated these effects.

This means that we need to move from a view of Arabidopsis where we interpret the effects of variation relative to the reference, to one where each genome is treated on an equal footing. It will be interesting to see if this also applies to other species.

OSB: What has been learned about the genetic variation between different strains of this species?
RM: Along with several other recent studies, we found there is a lot of variation in this 119 Mb genome, not only single-letter changes in the DNA code (about 3 million) but also many insertions and deletions (over 1 million).

We also found about 100,000 ‘imbalanced substitutions’, where a stretch of reference genome was replaced with an entirely difference sequence of a different length. Only about 7% of genes were completely conserved between the genomes.

OSB: What does this tell us?
RM: One important reason for studying these particular 18 genomes is that they are the progenitors of a much larger population of over 700 inbred lines, called ‘MAGIC’. (MAGIC stands for Multi-parental Advanced Generation InterCross).

The MAGIC lines are being used in a number of labs around the world to study a wide range of phenotypes, such as growth and disease resistance.

Each MAGIC genome is a mosaic of the genomes we sequenced, so by stitching together these genomes in the right way, we can predict the genome sequences of a much larger population. In effect we have sequenced the genomes of all these lines for the price of sequencing 18.

OSB: Are the findings relevant for other plants?
RM: Arabidopsis is primarily used to understand fundamental mechanisms in plants. This includes the response to the environment. For example, the most variable genes in our study are those whose function relates to response to the biotic environment – disease-resistance genes and so on. This is going to be relevant to studies on disease resistance in the MAGIC lines.

It is expected that lessons learned in Arabidopsis will translate to crops. In fact, there similar populations of MAGIC lines being made in crops such as wheat. But the wheat genome is about 80 times larger than the Arabidopsis genome and much harder to assemble, so the work we have done here may inform studies in these other populations.

Marine algae that turn carbon dissolved in seawater into shell will produce thinner and thinner shells as carbon dioxide levels increase.

The algae, called coccolithophores, have floated in our oceans for over 200 million years Hoovering up carbon and turning it into coccoliths - overlapping plates of calcium carbonate.

Predicting how these algae, an important part of the carbon cycle, will react to rising CO2 levels has always been a puzzle. Now a team including Ros Rickaby from Oxford University’s Department of Earth Sciences, has found strong evidence that as CO2 concentration in seawater increases so calcification decreases and coccolith mass declines.

The findings, reported in a recent Nature paper, suggest that entire communities of marine organisms, such as coral, are threatened by rising CO2 and ocean acidification.

The new evidence comes from studies of half a million coccoliths from hundreds of seawater samples and ancient marine sediments cores taken from all over the world.

The research shows much greater variations in coccolith mass than previous lab-based studies, as, in the ocean, rising CO2 causes populations of algae to favour smaller, lightly calcified species over heavily calcified ones.

Further work is now needed to understand how the algae will respond to the changing marine environment and what impact a rise in thinner-shelled species will have on our oceans and the planet.