July 19, 2013 6:45 pm

Science: The shape of drugs to come

Scientists discover the structure of a ‘receptor’ protein which helps regulate the body’s response to stress
The Diamond Light Source synchrotron©Diamond Light Source

The Diamond Light Source synchrotron, Oxfordshire, could help lead to new treatments

Ultra-bright X-ray beams, produced by accelerating electrons to near the speed of light in a huge synchrotron machine, are revealing the structure of important biological molecules. Knowing a molecule’s shape enables scientists to design drugs to boost or block its activity.

The latest discovery, published this week in Nature, is the structure of CRF1, a “receptor” protein in the brain, which helps to regulate the body’s response to stress. It was made by scientists from Heptares Therapeutics, a UK biotechnology company, working at Diamond Light Source, the £480m national synchrotron in Oxfordshire.

A receptor sits on the cell surface to receive external signals. CRF1 is the docking point for a stress-related hormone called corticotropin-releasing factor or CRF. Working out the structure of CRF1 is important as a possible route to new treatments for disorders such as depression and anxiety. But it also has wider implications because CRF1 is the first member of a family of molecules known as “Class B G-protein-coupled receptors” – sorry about the clunky terminology – to have its structure published.

“CRF1 will provide a template to assist in finding the structure of other Class B receptors, which could help us to design drugs for diabetes, osteoporosis and migraine,” says Fiona Marshall, Heptares’ chief scientist. The company is particularly interested in the receptors for hormones such as glucagon that is implicated in metabolic disease.

Breathless

Air pollution, smokestacks

Air pollution from human activities kills about 2.5 million people a year, says a study in Environmental Research Letters. Most deaths are in Asia and caused by fine particles lodging in the lungs.

The shape of CRF1 – and by implication other Class B receptors – turns out to be quite unlike the related family of Class A receptors, whose structures are already known. In particular, it has a binding site or pocket in a different position. Computer technology will make it possible to design small molecule drugs to fit in this pocket and therefore stop the receptor responding to the stress hormone for which nature intended it.

X-ray analysis of proteins does not produce a simple, direct image like a medical X-ray of a broken bone. First there is the hard job of getting the protein to crystallise so as to give a regular atomic structure. Then the way the atoms scatter the X-rays gives a complex diffraction pattern, from which the molecule’s 3D shape is reconstructed.

“We needed Diamond’s very finely focused beam because we had very small protein crystals and a normal X-ray beam would be too large for us,” says Marshall.

Diamond is used largely by academic researchers but Trevor Rayment, physical sciences director, says the facility is keen to double the proportion of beam time taken by industrial users – currently 5 per cent. It can be used for a range of research besides biology and health, including physics, energy and engineering.

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When snails go hitchhiking

Irish flora and fauna bear a puzzling resemblance to those of the Iberian peninsula – and human genetics has shown links between the people of southwestern Europe and Ireland.

Now a study of snails has added more evidence of movement between Iberia and Ireland. Nottingham University geneticists have discovered that Irish populations of the common land snail Cepaea nemoralis are almost identical to those in the Pyrenees between France and Spain – and quite distinct from the same species elsewhere in Europe. The research appears in the journal PLoS One.

Snails are not renowned for their speed so they are unlikely to have moved more than a thousand miles without assistance, fast enough to avoid genetic mutation. The simplest explanation is that snails hitched a ride with human migrants about 8,000 years ago.

“There is a very clear pattern, which is difficult to explain except by involving humans,” says Angus Davison of Nottingham. “If the snails naturally colonised Ireland, you would expect to find some of the same genetic type in other areas of Europe, especially Britain. We just don’t find them.”

Archaeological evidence shows Stone Age people eating Cepaea nemoralis in the Pyrenees and perhaps farming them. The main population of snails with the same genes as their Irish counterparts is along the Garonne river that flanks the Pyrenees and was an ancient trade route to the Atlantic.

Whether the snails were carried accidentally in boats from southwest France to Ireland or deliberately as food is a matter for speculation.

Other species that occur only in southwest Europe and Ireland include the Kerry slug and the strawberry tree. “It is a mystery as to why Ireland is so different from Britain. For these snails, at least, the difference may be that they hitched a ride on a passing boat,” Davison concludes.

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New satellite Euclid

Space voyager: an impression of new satellite Euclid

The universe’s dark materials

A €600m European space mission to probe the “dark universe” is moving into its construction phase, preparing to launch an observatory in 2020. The Euclid satellite, named after the Greek mathematician, will investigate the mysterious 95 per cent of the universe made up of something other than known objects such as stars, planets, gas clouds and black holes.

By its nature the dark universe is invisible, so Euclid’s instruments will map it indirectly by observing the distribution of billions of galaxies over a huge area: 40 per cent of the sky. They will see galaxies as far away as 10 billion light years, equivalent to looking back 10 billion years.

The distribution of galaxies through space and over time should enable scientists to calculate where the unseen dark matter is, from its gravitational effects. The favoured theory is that most dark matter consists of “weakly interacting massive particles”; these “Wimps” pass through ordinary matter as if it was not there, which has so far made direct detection impossible.

Dark energy, an unknown property of empty space that is driving everything apart at an accelerating pace, is more of a challenge. Astrophysicists hope to gain more insight from the changing expansion rate of the universe over billions of years.

The European Space Agency has chosen contractors Thales and Astrium, Nasa has joined as a minority participant, and university teams are beginning work on the Euclid’s instruments.

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Elderly men playing chess©Getty

Checkmate: the superior cognitive performance of the elderly

The new golden age

Encouraging news from a large Danish study of the changing mental performance of people in their nineties. Nonagenarians now are markedly superior in their cognitive skills to their counterparts a decade ago.

Kaare Christensen and colleagues studied 3,800 people in two groups through extensive physical and cognitive testing and interviews. The first cohort of 2,262 people was born in 1905 and assessed in 1998 at the age of 93. The second was born in 1915 and tested in 2010, aged 95.

People born in 1915 performed better than members of the 1905 cohort in tests of cognitive ability and activities of daily living, even though they were two years older when tested. The research is published in The Lancet.

Although average educational attainment was slightly higher in the 1915 cohort, the authors say their superior performance is unlikely to be attributable to improved education.

“Even after adjusting for the increase in education … the 1915 cohort still performed better in the cognitive measures, which suggests that changes in other factors such as nutrition, burden of infectious disease, work environment, intellectual stimulation and general living conditions also play an important part in the improvement of cognitive functioning,” they say.

“The study challenges speculations that the improving longevity is the result of the survival of very frail and disabled elderly people,” adds Christensen.

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