Features

Research published last week in the journal PNAS may have identified a promising new target for developing drugs against one of the most common types of lung cancer.

Oxford University researchers have helped a team at biotech company Genentech in South San Francisco look at the role of a protein called PAK1 in the growth of tumours.

PAK1 is a protein involved in a biochemical cascade used by cells in the body to control things like cell growth, division, and survival. Other proteins in this pathway have been implicated in cancer – when these controls go wrong, they can lead to uncontrolled cancerous growth.

Dr Adrian Jubb and colleagues at the Weatherall Institute of Molecular Medicine at Oxford were able to develop a test to look at levels of PAK1 in lung tissue samples from a tissue bank in Oxford. They showed that PAK1 was found at higher levels in one type of lung cancer, specifically the squamous type of non-small-cell lung cancer.

Building on these observations, the Genentech team were then able to show that knocking out the PAK1 protein stopped the growth of cells from these human lung cancers in the lab. Similarly, inhibiting PAK1 could impair growth of these tumours in mice.

Importantly, results also showed that combining an attack on PAK1 with other targeted therapies that Genentech is developing might kill off the cancer cells.

This suggests that such combination drug therapies might be a promising new avenue in searching for new treatments for non-small-cell lung cancer.

Certainly, lung cancer (of all types) is one of the most difficult cancers to treat, and has one of the lowest survival rates of any type of cancer. Fewer than 10 per cent of lung cancer patients survive the disease beyond five years after diagnosis. It is often diagnosed at a late stage and it tends to occur in older people who may also have other medical conditions.

Non-small-cell lung cancer accounts for around 85 per cent of all lung cancer cases, with around 30,000 people are diagnosed with this form of the disease each year in the UK.

Non-small-cell lung cancers can be further divided into three types: squamous cell carcinomas, adenocarcinomas, and large cell carcinomas.

Squamous cancers are the most common type of lung cancer, and are often due to smoking. It is squamous cancers that have been identified as having raised levels of PAK1 in this study.

Beyond doing what’s already possible with surgery, radiotherapy and chemotherapy, options for drug treatments of non-small-cell lung cancer are limited.

‘Non-small-cell lung cancer is an unmet clinical need,’ says Adrian Jubb. ‘We simply need more effective treatments.

‘We have demonstrated that targeting PAK1 has antitumour activity. And we now have a platform for assessing whether PAK1 is also worth pursuing for other squamous cancers, such as head and neck cancers, or other tumours including melanoma and pancreatic cancer.’

The Oxford work was supported by Cancer Research UK, the Oxford Biomedical Research Centre and the Pathological Society of Great Britain.

Birds willing to move around and take risks are better at finding the best places to live, researchers have found. Those with ‘fast-exploring’ personalities – birds tending to be hyperactive – are far more likely to end up in areas providing enough food, shelter and reproductive opportunities, a new study shows.

The research, led by scientists at Oxford University, has also found that smaller immigrant birds – those flying into, and staying, in a better habitat – are likely to have faster personalities than those born in the better habitat.  

‘If you’re quite big, your personality probably doesn’t matter because you’re likely to be able to secure a territory anyway, or a mate with a territory,’ said Dr John Quinn of Oxford University's Department of Zoology. ‘But if you’re quite small you have to have a big personality to join a new population.’

Researchers from the Edward Grey Institute in the Department of Zoology have been studying great tits  – a common garden and woodland bird – for more than 50 years and Wytham Woods near Oxford, an oak woodland that is comparatively rare near Oxford, is one of the best local habitats for the species.

‘Great tits can probably see the woods from several kilometres away and we think the immigrants were born in towns or hedgerows where the habitat quality is not so good,’ Dr Quinn says. His study showed that immigrant birds flying into Wytham were likely to have fast personality types.

The research by Dr Quinn and colleagues was published this week in the BES's Journal of Animal Ecology. The birds were housed overnight in a field station near to Wytham and in the morning placed in a room with artificial trees ‘so that we could determine their behaviour in these unusual circumstances,’ Dr Quinn explains.

Great tits are generally calm, and readily adapt to captivity, but there were clear differences between fast and slow personalities. ‘The slow types just sat on the trees and did very little while the hyperactive types moved around constantly.

‘This behaviour is consistent throughout an individual bird’s life and even predicts whether birds are assertive, aggressive or promiscuous in the wild.’

The scientists also assessed whether the fast-exploring trait was passed onto offspring. ‘Overall in Wytham, exploration behaviour is heritable – it is spurred partly by “nature” - but the difference between immigrants and residents seems primarily to be driven by environmental conditions, or “nurture”. Although this trait stays with an individual for life, we found that the offspring of immigrant birds behaved in the same way as the residents.’

The ability of birds, and other animals, to relocate to better sites is often important for gene flow, Dr Quinn adds. ‘Immigration generally increases the genetic variation and makes populations more resilient to environmental change and inbreeding’. But while immigrants to Wytham may bring in new genes for some kinds of traits, this does not appear to be the case for genes normally associated with personality.

‘We generally think fast-exploring birds are risk takers that prioritise finding food. But with that comes a greater chance of predation and perhaps a risk of injury from fighting. If you watched great tits at your garden feeder there’s a good chance you’d pick out the fast and slow personality types. In Wytham, fast birds tend to dominate the feeders.’

Fast personality traits are commonly seen in other animals ranging from spiders to squid and  from fish to pond skaters. ‘These wild-animal personalities are also biologically similar to those you see in pets. Some dogs for example have quite agreeable personalities, or temperaments, while others are quite aggressive,’ Dr Quinn says. ‘But while the variation you see in pets is caused by artificial selection, the patterns we see in wild birds seem to be caused by natural selection.’  

Dr John Quinn is based at Oxford University's Department of Zoology.

Technology using catalysts which make hydrogen from formic acid could eventually replace lithium batteries and power a host of mobile devices.

Edman Tsang of Oxford University’s Department of Chemistry and colleagues are developing new catalysts which can produce hydrogen at room temperature without the need for solvents or additives.

Their initial results, reported in a recent paper in Nature Nanotechnology, are promising and suggest that a hydrogen fuel cell in your pocket might not be that far away.

The new approach involves placing a single atomic layer of palladium atoms onto silver nanoparticles. ‘The structural and electronic effects from the underlying silver greatly enhance the catalytic properties of palladium, giving impressive activity for the conversion of formic acid to hydrogen and carbon dioxide at room temperature,’ Edman told us.

He explains that the storage and handling of organic liquids, such as formic acid, is much easier and safer than storing hydrogen. The catalysts would enable the production of hydrogen from liquid fuel stored in a disposable or recycled cartridge, creating miniature fuel cells to power everything from mobile phones to laptops.

Another advantage of the new technology is that the gas stream generated from the reaction is mainly composed of hydrogen and carbon dioxide but virtually free from catalyst-poisoning carbon monoxide; removing the need for clean-up processes and extending the life of the fuel cells.

The chemists have worked closely with George Smith, Paul Bagot and co-workers at Oxford University’s Department of Materials to characterise the catalysts using atom probe tomography. The underlying technology is the subject of a recent Isis Innovation patent application.

‘There are lots of hurdles before you can get a real device, but we are looking at the possibility of using this new technology to replace lithium battery technology with an alternative which has a longer lifespan and has less impact on the environment,’ explains Edman.

Professor Edman Tsang is based at Oxford University’s Department of Chemistry.

Forensic science, fossil dating and volcanic eruptions were among the topics investigated by more than 400 secondary school students at this year’s Oxford University Science Roadshow.

Students also created their own solar cells, calculated the power the cells were generating and proposed research projects that could develop their potential.

The youngsters, aged from 11 to 18 and from six Oxfordshire schools, also had the chance to study particle physics and hear how it may be used to help treat cancer. They also learnt about and the links between geology and climate.

Roadshow organiser Dr Zareen Ahmed-Stewart, of Oxford’s Mathematical, Physical and Life Sciences Division, said: 'We are taking science, new equipment and ideas into schools and providing students with hands on experience. They’re always amazed at how science can be applied to everyday life.'

‘We’ve had lots of positive feedback from schools particularly those that find it difficult to come to Oxford. Many teachers are keen for us to run similar initiatives outside of the Roadshow.'

The event ran from 14-18 March and is staged annually during National Science & Engineering Week to give students an insight into science research at the university and broaden their interest in science.

This year’s Roadshow started at Matthew Arnold School where, guided by a technician and the Department of Materials' Schools Liaison Officer, Jayne Shaw, pupils constructed their own dye sensitised solar cells.

They compared the efficiency of different dyes and assessed how solar cell research may be developed. Their work was linked to ongoing research into photovoltaics at Oxford and elsewhere. This solar cells workshop was a development from a workshop earlier in the year which was supported by the National HE STEM Programme.

Jayne said: ‘I had a great morning and was made to feel very welcome at the school. The children were an enthusiastic and bright group. Several said how much they enjoyed the work with one saying “It was fabulous!”’

At the Oxford Academy and Burford School, students worked with Sarah Lloyd, Education Officer at the Oxford University Museum of Natural History,  to date the remains of fossils. They were shown how some fossils provide better evidence than others and the large amount of evidence needed to confirm initial findings about the age of fossils.

Sarah said: ‘The students enjoyed the practical element of the work and were surprised by the diversity of fossils they managed to isolate. Their teacher described the workshop as “totally captivating.”'

The Roadshow explored the world of chemistry at Cheney School where youngsters worked with undergraduates and graduates from the University’s Department of Chemistry.

They played forensic scientists in a game of Cluedo, analysing samples found at a crime scene to solve the mystery. Later, they created their own chemical rainbows by working out how to stack organic and inorganic solvents in order of their density.

Cheney students were also joined by experts from the Department of Earth Sciences who showed them a collection of rocks from different geological ages. The rocks revealed how the UK’s climate has changed and how the changes are related to the movement of the world’s tectonic plates.

‘One thing that particularly engaged many students was the moment when they realised that rather than being a boring homogenous grey lump the piece of rock in front of them was actually packed full of the fossilised remains of pre-historic creatures and told the story of an ancient tropical sea in the UK,’ said David Ferguson of the Department of Earth Sciences.

Students at Fitzharrys School in Abingdon got up close and personal with the exciting world of particle and accelerator physics. They learnt how particle accelerators can do everything from recreating conditions just after the Big Bang to finding new ways to treat cancer, as well as finding out how to drive the world's biggest machine - the Large Hadron Collider in Switzerland.

At Banbury School, Professor David Pyle from the Department of Earth Sciences explained how volcanoes form, and how they erupt as part of the cycle of tectonic movement, which in turn is driven by heat deep in the earth.

Professor Pyle said: 'My morning at Banbury School was lively not least because they have such a vibrant science area. I talked about the latest on the earthquake and tsunami in Japan and spent time with Year 12 chemists chatting about careers in science. The students listened well and fired several questions at me. It was definitely time well spent.'

An Oxford University scientist has taken our understanding of the origin of life a step further.

Professor Don Fraser from the Department of Earth Sciences has carried out neutron scattering experiments to try to find out more about the role of geochemistry in determining the origin of our amino acids – key building blocks of life on Earth – and specifically why the DNA-coded amino acids that make up our proteins are all left-handed.

There are two varieties of amino acids, known as left- or right-handed (referred to as S and R). They are mirror images of each other and both exist in nature, as shown for other substances by Louis Pasteur.

Biochemical processes in living organisms use left- and right-handed or ‘chiral’ receptors that template differently with these two forms. The olfactory receptors in our noses, for example, easily distinguish the distinct smells of the otherwise identical molecules (called carvones) of spearmint (R-carvone) and caraway (S-carvone).

Another example is the thalidomide tragedy that was related to the presence in the drug of both the mirror-image forms. One of these (S) was later understood to be harmful.

An important and outstanding mystery is why nature chooses only exclusively left-handed amino acids in forming proteins.

In the late 19th century, TH Huxley and Charles Darwin realised that life may have begun abiotically in a ‘warm little pond’ containing all the elements needed for life, ‘so that a protein compound was chemically formed ready to undergo still more complex changes,’ Darwin wrote.

Much later, in 1924, the Soviet scientist Alexander Oparin returned to the idea of spontaneous generation, suggesting that a ‘primeval soup’ of organic molecules, created by the action of sunlight in an oxygen-free environment, was the basis of all life.

Electric spark experiments subsequently carried out by Stanley Miller in model primeval atmospheres showed that amino acids form in lightning discharges. In contrast to biological systems, these show no preference for either mirror image form and are 50%:50% (racemic) mixtures.

Clay was suggested by the crystallographer John Bernal as a means of concentrating primitive biomolecules onto its surface so as to be available for further reactions. Clays again became the focus of studies more recently when James Ferris showed that they can act as catalysts for the formation of long strands of RNA, which with proteins and DNA are major compounds essential for the origin of life.

In a second paper, also published in Physical Chemistry Chemical Physics, Professor Fraser has extended these ideas to consider amino acids and to try to understand why all amino acids used to make proteins are left-handed.

With colleagues Professor Neal Skipper from UCL, Dr Martin Smalley from York University and Dr Chris Greenwell from Durham University he replaced the cations between the layers making up natural clay molecules with weakly bound organic cations, causing the clay layers to drift apart.
That created an extremely sensitive clay system with sufficient space to insert both left-handed and right-handed forms of the amino acid histidine between the layers.

‘We found that the R- and S-histidine molecules interact differently with the clay surfaces. These clays are abiotically able to select for chirality – left- or right-handedness – as well as being implicated in the abiotic synthesis of RNA,’ Professor Fraser says. ‘Our experiments were the first to show that clay molecules could do that.

‘We also found that the tiny interlayer space some 5nm wide was a very important dynamic region for studying prebiotic chemistry and that the reactions of simple chemicals there leads to the formation both of RNA oligomers and the selection of left-handed amino acids.’

Clays have also been shown by Jack Szostak and others to enable fatty acids to form primitive cells and, interestingly, clays show similar selective behaviour in space, as reported recently by the NASA scientists Glavin and Dworkin.

Amino acids contained in the meteorites Murchison and Orgueil show enrichment in S-amino acids and this correlates with the amount of intrinsic hydrous clay present in these primitive meteorites that are 4.55 billion years old. ‘The amino acid studied – isovaline – cannot be a contaminant as it is not found in terrestrial living systems,’ Professor Fraser explains. ‘We are thus building an increasingly detailed picture of the steps that lead to the origin of life.

‘We are continuing our research next month on the new NIMROD instrument at the ISIS neutron source near Oxford. This will involve amino acids enriched in deuterium, an isotope of hydrogen, and will provide a detailed atomic picture of the way amino acids interact with the layers of clay for the first time.

‘In the long term, this work could have significant applications not only for our understanding of the origin of life, but also in medicine as the design of new mineral surfaces that aid the production of chiral drugs would be of great benefit to the  pharmaceutical industry.’