Features

Reviving a gene which is 'turned down' after birth could be the key to treating Duchenne muscular dystrophy (DMD), an incurable muscle-wasting condition that affects one in every 3,500 boys.

Boys with DMD have difficulty walking between the ages of one and three and are likely to be in a wheelchair by age 12. Sadly, they rarely live past their twenties or thirties.

For the past 17 years, Professor Dame Kay Davies and Professor Steve Davies at Oxford University have been working on treatments for the condition, which is caused by a lack of the muscle protein, dystrophin.

In recent months they have found a number of new groups of molecules which can increase the levels of utrophin, a protein related to dystrophin. Greater levels of utrophin can make up for the lack of dystrophin to restore muscle function. They have worked with Isis Innovation, Oxford’s technology transfer arm, to strike a deal with Summit, a drug development company with a focus on DMD.

'Duchenne muscular dystrophy is a devastating muscle wasting disease for which there is no known cure,' said Professor Kay Davies. 'These boys all still have the utrophin gene – and that’s what we’re taking advantage of. In adult muscle, utrophin is present in very low amounts, and we aim to increase the amount to levels which will help protect the muscle in these boys.

'If this approach, called utrophin modulation, really works as we hope, we could treat these boys very early on, increase their quality of life and length of life. They would walk for longer.

'This is a disease that really needs effective treatment – it takes many families by surprise because of the high new mutation rate which occurs in dystrophin protein such that boys with no family history of the disease can be affected.'

The Oxford team have been working with Summit, an Oxford spin-out company, to develop their first drug for Duchenne Muscular Dystrophy, SMT C1100. In 2012, SMT C1100 successfully completed a Phase 1 trial which showed the drug could safely circulate through the bloodstreams of healthy volunteers. It is now about to enter clinical trials in people with DMD.

Professor Kay Davies said: 'In our ideal world the first molecule we developed with Summit plc, SMT C1100, will have a beneficial effect in these patients. But although SMT C1100 looks promising, we asked ourselves - can we find other drugs that might do even better?'

The new deal will see a research collaboration formed between the University of Oxford and Summit to further the development of the new set of molecules.

Professor Steve Davies said: 'We want to ensure that this utrophin modulation therapeutic approach has the best chance of success in the shortest time for treating Duchenne Muscular Dystrophy. We are delighted to join forces with Summit plc in developing, alongside first in class SMT C1100, these back-up and potentially best in class candidates.'

Tom Hockaday, Managing Director of Isis Innovation, said: 'Isis is delighted to support Professors Kay Davies and Steve Davies in this vital work. Having a number of potential drug candidates in development greatly increases the chances of reaching the ultimate goal, which is to successfully treat this incurable disease.'

Glyn Edwards, Chief Executive Officer at Summit, said: 'The alliance provides access to differentiated classes of utrophin modulators, potentially with new mechanisms, to complement our clinical candidate SMT C1100 while also establishing a strong drug pipeline for the future. Importantly, the alliance cements our long-term relationship with two scientific leaders at the University of Oxford.'

Michael Faraday or Michael Flatley? Science or dance? The latest Science video competition shows that the two go hand in hand...

A creative video on sperm competition [watch the video], which sees swimming cap-clad sperm chasing a water-borne egg through a lake, scooped top prize in Science magazine's 2013 Dance your PhD contest.

The film was created by Dr Cedric Tan from Oxford University's Department of Zoology, who has previously won the 2012 NESCent Evolution Video Contest and the Biology category of Science's 2011 Dance your PhD contest.

I caught up with Cedric to find out how he took his ideas from the lab to the lake...

OxSciBlog: Could you tell us a little more about the concepts shown in the film?
Cedric Tan: There were two main ideas in this film. First, a male invests more sperm in the females that have mated with his brother. This was an interesting finding in the red jungle fowl where females mate with multiple males, creating episodes of competition between sperm of different males. Second, the female ejects a higher proportion of sperm from the brother of the first male mate and favours the sperm of the non-brother, facilitating a higher fertility by the non-brother's sperm.

OSB: Why are non-brother sperm more successful, and are there evolutionary reasons for this?
CT: The non-brother sperm is probably more successful as a result of female preference and ejection of a larger proportion of sperm from any of the brothers. We are not sure why females behave as such but a probable reason is that the females are mating with the male that is different from the brothers in order to increase the genetic diversity of the offspring.

OSB: What challenges did you face trying to explain these concepts through dance?
CT: A major challenge is definitely the fact that dance is a non-spoken art and we had to use our bodies to convey the scientific idea. However, through movements inspired by chickens and sperm, we were able to illustrate sexual behaviour of the chicken and some interesting characteristics of sperm biology.

OSB: Could you tell us a bit about the accompanying music?
CT: The two original music and lyrics pieces were written by Dr Stuart Wigby, my former supervisor. The first piece 'Animal Love' is about the variety of sexual behaviour across different animal species. The second piece 'Scenester' is a piece about a girl who keeps changing her ways and males trying to keep up with her, which is especially apt for illustrating sperm competition.

OSB: How long did it take to plan, choreograph, shoot and edit?
CT: This idea was conceived last summer after I finished the previous video on 'Less Attractive Friends'. However I only started in June 2013 to plan, with the help of my Producer Sozos Michaelides and co-producer Kiyono Sekii. Choreography and training of the dancers was done with my co-choreographer Hannah Moore and lasted 4 weeks. Choreography came along quite readily as I was working simultaneously on my field experiments, in which I was deriving inspiration from the chickens and the sperm under the microscope. Hannah also worked very closely with me on synthesising sperm and chicken movements with sports actions.

After the intense training and for the following three weeks, the Director of Photography, Xinyang Hong, shot the dancing at various places, from Port Meadows to Hinksey Lake. I took about 3 weeks to edit the videos and that was a pain but looking at the outcome, I must say it was all worth it!

OSB: Do you have any plans for another video next year?
CT: Yes of course! It will sexier, stickier and sizeably bigger, and in the style of a musical. But the idea is a secret... I am already excited about creating this new piece!

OSB: Finally, how did you convince so many people to dress up as sperm and jump into a freezing lake?
CT: It took lots of bribing with food. Kiyono also religiously brought flasks of hot drinks for the dancers every time we had pool/lake filming. As for the costume, many of the sperm complained a lot, I just had to buy more food.

The video was funded by Green Templeton College, Oxford, The Edward Grey Institute of Field Ornithology and the European Society for Evolutionary Biology.

Over the last four years, solar cells made from materials called perovskites have reached efficiencies that other technologies took decades to achieve, but until recently no-one quite knew why.

Since perovskite was first used in 2009 to produce 3% efficient photovoltaic (PV) cells, scientists have rapidly developed the technology to achieve efficiencies of over 15%, overtaking other emerging solar technologies which have yet to break the 14% barrier.

Scientists at Oxford University, reporting in Science, have revealed that the secret to perovskites' success lies in a property known as the diffusion length, and worked out a way to make it ten times better.

'The diffusion length gives us an indication of how thick the photovoltaic (PV) film can be,' explains Sam Stranks, who led the discovery in Henry Snaith's group at Oxford University's Department of Physics. 'If the diffusion length is too low, you can only use thin films so the cell can't absorb much sunlight.'

So why is the diffusion length so important?

PV cells are made from two types of material, called p-type and n-type semiconductors. P-type materials mainly contain positively-charged 'holes' and n-type materials mainly contain negatively-charged electrons. They meet at a 'p–n junction', where the difference in charge creates an electric field.

The cells generate electricity when light particles (photons) collide with electrons, creating 'excited' electrons and holes. The electric field of the p–n junction guides excited electrons towards the n-side and holes towards the p-side. They are picked up by metal contacts, electrodes, which enable them to flow around the circuit to create an electric current.

'The diffusion length tells you the average distance that charge-carriers (electrons and holes) can travel before they recombine,' explains Sam. 'Recombination happens when excited electrons and holes meet, leaving behind a low-energy electron which has lost the energy it gained from the sunlight.

'If the diffusion length is less than the thickness of the material, most charge-carriers will recombine before they reach the electrodes so you only get low currents. You want a diffusion length that is two to three times as long as the thickness to collect almost all of the charges.'

The thickness of a solar cell is always a compromise – if they're too thin they won't absorb much light, but if they're too thick the charge carriers inside won't be able to travel through. Longer diffusion lengths allow for more efficient cells overall, as they can be made thicker without losing as many charge carriers. Scientists can get around this by arranging cells into complex structures called 'mesostructures', but this is a time-consuming and complicated process which has yet to be proven commercially.

Previously, researchers were able to get mesostructured perovskite cells to 15% efficiency, using a perovskite compound with a diffusion length of around 100 nanometres (nm). But by adding chloride ions to the mix, Henry's group achieved diffusion lengths over 1000nm. These improved cells can reach 15% efficiency without the need for complex structures, making them cheaper and easier to produce.

'Being able to make 15% efficient cells in simple, flat structures makes a huge difference. We've made hundreds just for research purposes, it's such an easy process. I expect we'll be seeing perovskite cells in commercial use within the next few years. They're incredibly cheap to make, have proven high efficiencies and are also semi-transparent. We can tune the colour too, so you could install them in aesthetically-pleasing ways in office windows.'

That perovskite cells are showing commercial potential after such a short time is a testament to their fantastic properties. We could well be seeing perovskite cells with efficiencies of 20-30% within the next few years, offering the same power as standard silicon-based cells at a fraction of the cost.

'Now is a truly exciting time to be working in the field,' says Sam. 'It's such a rapidly-emerging field, I expect to see it evolve even further over the next couple of years. What's incredible is that all of these advances have been made in academic environments so far, but it won't be long before industrial manufacturers start looking at perovskite cells as serious contenders.'

This week, scientists and engineers from Oxford University and around the world will start work on the final designs for the Square Kilometre Array (SKA), soon to become the world's largest and most sensitive radio telescope.

The SKA will cover a combined collecting area equivalent to a dish of about one square kilometre using thousands of dishes and millions of linked antennae spread across Australia and in Southern Africa. It will be able to detect radio waves more accurately and sensitively than ever before, helping to answer some of the biggest questions in physics and astronomy. These include questions about dark matter and dark energy, and perhaps even the biggest question of all: is humanity alone in the universe?

'After many years of planning and preparation it is very exciting that the SKA project is now moving in to the detailed design phase,' said Professor Michael Jones, principal investigator of SKA at Oxford. 'In a few years this amazing scientific instrument will no longer be the stuff of dreams but will start to become a reality.'

The Oxford team will lead the design of electronic systems to digitise and combine signals from millions of low-frequency antennae and allow the telescope to point in multiple directions at once. This will be done in collaboration with the Rutherford Appleton Laboratory along with partners from industry and other universities.

Oxford is also one of the key universities involved in preparation for the scientific exploitation of the SKA, with members on several of the SKA Science Working Groups. They will play a major role in the development of the signal processing systems that will search for pulsars, one of the SKA's key science goals, and in the development of software and high-performance computing systems for the project.

Proteins which reside in the membrane of cells play a key role in many biological processes and provide targets for more than half of current drug treatments. These membrane proteins are notoriously difficult to study in their natural environment, but scientists at the University of Oxford have now developed a technique to do just that, combining the use of sophisticated nanodiscs and mass spectrometers.

Mass spectrometry is a technique which allows scientists to probe molecular interactions. Using a high-tech 'nanoflow' system, molecules are transmitted into the instrument in charged water droplets, which then undergo evaporation releasing molecules into the gas phase of the mass spectrometer.

But membrane proteins are difficult to measure in this way, as they are hydrophobic: they don't dissolve in water. One way to overcome this problem is to mix them with detergents. Detergents work by surrounding insoluble substances with a water-friendly shell. Each detergent particle has two ends – the heads are attracted to water and the tails are attracted to insoluble regions of the membrane protein. The tails stick to the hydrophobic parts, leaving a shell of water-loving heads around the outside. The molecules can then easily dissolve in water.

Although detergents can be used to get membrane proteins to dissolve in water, these artificial chemicals can damage protein structures and do not faithfully mimic the natural environments in which they are normally found. The Oxford group, led by Professor Carol Robinson, has utilised a technique which allows them to study membrane protein structures by mass spectrometry from their natural environment. Their new method, published in Nature Methods, uses tiny disc-like structures made from molecules called lipids, as first author Dr Jonathan Hopper explains:

'Membrane proteins are naturally found in flat structures called lipid bilayers. Lipids are a bit like nature's detergents, in that they have water-loving heads and fat-loving tails. Lipid bilayers are made up of two sheets of lipids with their tails pointing inwards.

'The nanodiscs we use are made from lipids, the same material that membrane proteins occupy in the body. It's essentially as if you took a round cookie cutter to remove a section of the natural bilayer, so the conditions are just like they would be in the body. The discs are stabilised by wrapping a belt of proteins around them to keep the exposed lipid tails from the water.

'Aside from the nanodiscs, we actually got great results from 'bicelles', which are made in a similar way.  The main difference is that instead of putting a belt of proteins around the edge, we plug the gap with short-chain lipids instead. This actually gives us much more control over the size and structure of the disc.'

These innovations enable researchers to study membrane protein structures using sophisticated mass spectrometry, in environments as close to the human body as possible.

'I am delighted that this has worked, it is completely unexpected given the difficulties we have had in the past in studying these complexes in lipidic environments,' says study leader Professor Carol Robinson. 'The breakthrough enables us to study membrane proteins in a natural environment for the first time. We believe this will have a great impact on structural biology approaches, and could in turn lead to better-designed drug treatments.'