ISSUE 61 DECEMBER 2009

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Life with sleep apnoea

Rude awakenings

At the heart of scientific advance is individual creativity, and our responsibility as a funder is to create space and opportunity for this to occur. We want to provide the researchers we fund with the means to take on challenging research questions. We are therefore establishing a new scheme – the Wellcome Trust Investigator Awards – to replace our existing project and programme grant schemes. These emphasise flexibility and individually tailored support, and will mean that we will fund larger grants that can deliver our resources more strategically and effectively, and in a way that will bring a greater impact from our funding.

So why change our funding methods? To sum up our thinking, I offer you two quotes that I am sure will resonate with many researchers. The first, from Sydney Brenner – “It is only through the use of subterfuge such as applying for money for work already done that innovative research can be freely pursued” (Science, 1998) – aptly describes the problems of project and programme grants, which require applicants to prescribe in detail what they intend to achieve and do not readily embrace the unexpected twists and turns that research often takes. Furthermore, as many of our project grants are funded for only three years, it requires researchers to submit multiple, successive applications.

Contrast this with Joshua Lederberg’s comment: “simply put, the best way to administer a creative research environment is to find people of great talent and reasonable ambition – whatever their specific disciplines – and leave them to their own devices” (The Scientist, 1991). This is the essence of our Investigator Awards, which will provide substantial long-term support to the very best researchers and their teams, and will give them the freedom to explore riskier, more speculative lines of enquiry.

We already take this approach for our successful and popular Fellowship schemes, which provide researchers with the resources and flexibility to pursue their individual vision. A key difference, of course, is that our Fellowships are not open to researchers with established positions; now, through Investigator Awards, we will be bringing this ethos to a wider community of researchers who are salaried by their university or research institute.

Studies of the age at which researchers publish the discoveries that are later recognised by major awards, such as Lasker and Gairdner Awards and Nobel Prizes, show a peak of creative output for individual researchers in their late 30s, though the spread is wide. It is a paradox that it is precisely the researchers who are at the peak of their creativity who find it hard to obtain project and programme grants and, in the USA, RO1 grants from the National Institutes of Health. For this reason we will be offering two categories – Investigator Awards and Senior Investigator Awards – for researchers at different stages of their careers; the former will be targeted specifically at creative researchers at the start of their independent research careers.

The Awards will open for applications in October 2010. We will also be offering two final rounds of project and programme grants in 2010/11 before the final closure of these schemes. Wellcome Trust Investigators, Senior Investigators and fellows will be able to apply for Enhancement Awards, which will provide additional funding to explore new opportunities that arise as their work unfolds, or to support significant unanticipated costs such as access to equipment or resources. Furthermore, as part of the Trust’s commitment to developing a community of research leaders, we are exploring opportunities to offer tailored leadership training to those who would benefit from it.

Over time, we believe that backing talented researchers who can demonstrate a clear scientific vision, creativity and potential for leadership, rather than a skill in methodological detail and the traditional conventions of grant writing, will be the best strategy to generate breakthrough improvements in global health.

WellcomeNews | Issue 61

Sir Mark Walport

Director of the Wellcome Trust

Wellcome News

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The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. www.wellcome.ac.uk

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Cover image: blackred/iStockphoto. See pages 4–5.

Editorial

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Features

Obstructive sleep apnoea 4

Wellcome Film puts history online 9

Henry Wellcome’s star collector 12

News

Nobel win for Trust-funded scientist 2

Making a drama of e-health 3

Jo Brand announces Book Prize winner 3

8

10

9

Funding

Neurodegenerative Diseases Initiative 6

Studying health impacts of climate change 6

Thailand Programme hits 30 7

Research

Conceptualising dogs 8

‘My UKPMC’ helps grant reporting 8

Investigating influenza 10

Q&A with Matt Hurles 11

Noticeboard 13

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3WellcomeNews | Issue 61 | 1

In this issue

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News

What’s on at Wellcome Collection

Ramakrishnan celebrates Nobel win Trust support for new UK drug development campus

Although it may be wintry outside, there’s plenty to fire up your imagination at Wellcome Collection. Don’t miss our current exhibition – Identity: Eight rooms, nine lives – which explores how science has tried to determine human identity, from fingerprinting to DNA sequencing. A number of related events are taking place in early 2010. You can also come and explore the world of Ismond Rosen, distinguished psychoanalyst, gifted artist and a pioneer of scientific and artistic collaboration. His works are on show throughout Wellcome Collection from 2 December to 21 March.

Wellcome Collection has teamed up with the new Times monthly science supplement for an exciting new series of debates. Eureka Live, which launched on 10 December, hosts a panel of experts to discuss the latest science in the headlines.

Lastly, our ‘Packed Lunch’ series of enlightening lunchtime talks continues to highlight the work of local scientists.

We have committed £6 million to a new £37m Bioscience Campus in Stevenage, Hertfordshire, in partnership with the UK government, GlaxoSmithKline, the Technology Strategy Board and the East of England Development Agency. The project aims to create a world-leading hub for early-stage biotech companies, operating under a model of open innovation and collaboration. Each company at the Campus will have access to specialist skills, equipment and expertise to help to stimulate innovation in drug development. By sharing knowledge, each company will also increase its chance of success while retaining its independence so entrepreneurship can flourish.

“The Stevenage Campus represents a huge investment in the future of Britain’s bioscience industry and is a strong new platform for the work of our Office for Life Sciences,” said Lord Mandelson, Secretary of State for Business, Innovation and Skills. “It will leverage our existing strengths as a world leader in the sector, helping it to grow and reinforcing our international competitiveness. And ultimately it will help us build towards a stronger UK economy coming out of the global downturn.”

The development is expected to house around 25 companies initially and to create up to 1500 new jobs, with plans to increase capacity five-fold over the next ten years.

Dr Venkatraman Ramakrishnan (above), a structural biologist at the Medical Research Council Laboratory of Molecular Biology, was named one of the winners of the Nobel Prize in Chemistry 2009. Together with Thomas A Steitz of Yale University and Ada E Yonath of the Weizmann Institute of Science in Israel, he was awarded the Prize for mapping the structure of the ribosome at the atomic level using X-ray crystallography. The 1999 publication of the first X-ray crystallography structures of a bacterial ribosome ended a decades-long challenge in the field of biochemistry.

Dr Ramakrishnan was awarded a programme grant from the Wellcome Trust in 2007 to look more closely at

components of the ribosome structure at different stages in its working process. He also won a 2008 Wellcome Image Award for pictures of the bacterial ribosome structure (see below).

“The work by Dr Ramakrishnan and his fellow Nobel Prize winners highlights the importance of structural biology in answering some of our most important and fundamental questions,” said Sir Mark Walport, Director of the Trust. “Ribosomes are crucial for translating the DNA ‘code’ into a living organism. Understanding how they work will help unlock many of the mysteries of life and, more pressingly, provide us with targets for essential new antibiotics.”

Molecular model of a ribosome. MRC Laboratory of Molecular Biology, V Ramakrishnan

Courtesy of the Department for Business, Innovation and Skills

Artwork (top) by Ismond Rosen (above). From the printed collection of Ruth Rosen

If you’ve missed any, or aren’t based in London, all talks are available to download as free podcasts on the Wellcome Collection website.www.wellcomecollection.org

Medical Research Council

Prized reading

WellcomeNews | Issue 61 | 3

The close of 2009 brings an end to a year of celebrations for Charles Darwin and his work. While February saw the 200th anniversary of Darwin’s birth, November marked 150 years since the publication of On the Origin of Species. Wellcome Collection celebrated the latter with two evolution-themed events. ‘Should We Stop Breeding?’ asked whether, with a global population set to top 9 billion by 2050, we should put a limit on reproduction for the sake of the planet. Meanwhile, a separate event showcased the

best poetry, performance and films on evolutionary theory from the year-long Evolving Words initiative, alongside live music from hip-hop artist and jazz saxophonist Soweto Kinch.

Many of the Trust’s Darwin-themed activities can still be accessed online, including the spectacular Tree of Life animation, free experiment kits for schools, and all the webisodes and mini-games from the Routes series. www.wellcome.ac.uk/darwin200

Y Touring Theatre Company is taking a new Trust-supported production on the road. Breathing Country, by Ben Musgrave, aims to raise young people’s awareness of the new NHS Electronic Patient Record system and

its use in medical research. Each performance is followed by a live debate, using electronic voting technology, during which audience members are encouraged to explore what they think about the issues posed by the drama.

The production has been developed in partnership with the Royal Academy of Engineering. It is supported by Central YMCA and the Wellcome Trust, as part of our Electronic Patient Records and Databases in Research scheme. Breathing Country has been touring schools throughout London in late 2009, and will tour nationally in spring 2010. www.ytouring.org.uk

The inaugural Wellcome Trust Book Prize has been won by Keeper: Living with Nancy – a journey into Alzheimer’s (Short Books). Author Andrea Gillies (pictured, left) was presented with the Prize at a special awards reception at Wellcome Collection in November.

Jo Brand, comedian and former psychiatric nurse (pictured, right), chaired the judging panel for the Prize and made the announcement. She said: “Andrea Gillies’s account of living with Alzheimer’s is the perfect fusion of narrative with enough memorable science not to choke you. It’s a fantastic book – down to earth and darkly comic in places. The judges found it compelling.”

Keeper beat off strong competition from a varied shortlist featuring both factual accounts and gripping novels, including a philosophical approach to illness and a tender novel about the lives of twins that were born conjoined.

The £25 000 Prize highlights outstanding works of fiction and non-fiction on the

theme of health, illness or medicine. The judging panel for the inaugural Prize

included BBC science journalist Quentin Cooper, Welsh poet and non-fiction writer Gwyneth Lewis, physician and author Raymond Tallis and Richard Barnett, an expert in the history of modern medicine.

• The 2010 Prize is now open for submissions. For more, see: www.wellcomebookprize.org

A scene from Breathing Country. Robert Workman

Prizes and appointments

Professor John Gurdon (above), who works at the Wellcome Trust–Cancer Research UK Gurdon Institute in Cambridge, has won the 2009 Albert Lasker Basic Medical Research Award, along with Shinya Yamanaka, for “discoveries concerning nuclear reprogramming”, the process in which specialised adult cells form early stem cells. Professor Gurdon first received Trust support in 1998; his most recent grant, to explore nuclear reprogramming in Xenopus oocytes, was made in 2008.

Professor Anne Glover is the new Chair of the UK Collaborative on Development Sciences (UKCDS). We are one of the member organisations of UKCDS, which works to provide a more coordinated approach to development sciences research in the UK.

Catherine Draycott (above), Head of Wellcome Images – the Wellcome Library’s picture library (images.wellcome.ac.uk) – has won the Royal Photographic Society’s Combined Royal Colleges Medal for 2009. This award is given in recognition of an outstanding contribution to photography and its application in the service of medicine or surgery. • Check out the winners of the 2009

Wellcome Image Awards and the stories beyond the images at www.wellcomeimageawards.org.

Darwin year comes to a close

New play explores e-health

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“I worked as a tax consultant in the City of London. One day I was in a one-to-one meeting with an important client and I just dropped off – bang! Fortunately, the client thought I’d died, which was less embarrassing that the truth: that I’d fallen asleep in the meeting.”

Frank Govan, now retired, recounts one of the troublesome experiences that come from living with obstructive sleep apnoea. This common condition causes people to stop breathing in their sleep, sometimes hundreds of times a night (see box, below). They don’t remember their wakings in the morning, but can suffer extreme fatigue and sleepiness throughout the day.

Some 2–4 per cent of younger adults and over 15 per cent of elderly people have the condition. Overweight men make up the majority of cases, although it is not clear how many women are affected. Research into sleep apnoea has improved our understanding of the condition, and there is a cost-effective treatment that works for many people: continuous positive airway pressure (CPAP).

The years of intense tiredness – or feeling “zombified”, as Mr Govan describes it – takes its toll on patients and their families. Mr Govan’s sleepiness had become a standing joke among his friends. He was frequently so exhausted that he would fall asleep mid-meal at dinner parties: “I never saw dessert,” he says.

Research shows that obstructive sleep apnoea is a known risk factor for road accidents (see box, far right). Indeed,

Mr Govan once fell asleep at the wheel while driving his family in the fast lane of the M6. Luckily, no one was hurt.

Spurred by this to seek help, Mr Govan saw his GP. Unfortunately, years of fruitless visits followed as a diagnosis remained elusive. In the end it was a chance comment made by his wife to an ear, nose and throat consultant at a dinner party that led to a referral to a sleep specialist and a diagnosis of obstructive sleep apnoea.

Mr Govan now uses a CPAP machine and a mask over his nose whenever he sleeps. A continuous stream of air is delivered, which keeps his airway open without interfering with breathing. The effects of just one night of CPAP were spectacular. “I felt refreshed and my energy had returned,” he says. “I had my life back.”

Sleep studiesAround the same time as Mr Govan was diagnosed, Mary Morrell was completing her PhD, studying the changes in breathing that occur during sleep. With a Wellcome Trust International Travelling Fellowship, she then worked at the University of Wisconsin-Madison in the USA with a group at the forefront of research into the control of breathing during sleep.

“The Fellowship introduced me to large-scale sleep and breathing studies,” she says. “At that time there wasn’t an equivalent group in the UK researching the causes of sleep apnoea, so I went to the USA to get experience.”

Inspired by her Fellowship, Dr Morrell and colleagues in 1997 established the

Take my breath awayWaking hundreds of times a night, gasping for breath, but with no recollection in the morning sounds like the stuff of nightmares, yet for thousands of people with obstructive sleep apnoea, this is a nightly reality. Chrissie Giles talked to a man with the condition and a researcher who has dedicated her career to studying it, to find out what can be done to secure a good night’s sleep.

Ina Peters/iStockphoto

Sleep apnoea at a glanceSleep apnoea occurs when a person’s airway becomes blocked as they sleep, causing them to stop breathing. These pauses can last from a few seconds to over a minute.

What causes this? When we sleep, our muscles relax. The upper airways (behind the tongue) are not reinforced with cartilage, so can go floppy. In extreme cases, the airway collapses entirely and blocks, preventing air from reaching the lungs. If this happens, the brain eventually detects the struggle for breath and the resulting drop in blood oxygen levels, triggering the person to wake up and breathe – often with a loud gasp or snort.

Sleep apnoea is more likely in people with narrowed airways, caused, for example, by large tonsils or a set-back lower jaw. Being overweight is also a risk factor, as the weight of fatty tissue around the neck can promote airway collapse. The bigger your collar size, the greater the risk of sleep apnoea.

Johanna Viljakainen/iStockphoto

WellcomeNews | Issue 61 | 5

Clinical and Academic Unit of Sleep and Breathing at the Royal Brompton Hospital, National Heart and Lung Institute, Imperial College London. The Unit is dedicated to studying the control of breathing during sleep in patients, focusing particularly on sleep apnoea.

“The effects of sleep apnoea are particularly devastating,” says Dr Morrell. “It’s like putting a pillow over somebody’s face and asking them to breathe.”

Extreme fatigue is not the only effect of sleep apnoea. Waking up after each ‘apnoea’ (period without breathing) causes a surge in blood pressure and heart rate around twice as great as that caused by spontaneous waking. Cumulatively, these surges can lead to high blood pressure, meaning an increased risk of cardiovascular disease, including stroke and heart attacks, and memory problems.

Dr Morrell and colleagues set out to investigate what factors in the body affect these surges. In a study of young adults they made a surprising discovery: the size of the surge in blood pressure and heart rate was not affected by respiratory factors such as low blood oxygen or a blocked airway, which can occur in obstructive sleep apnoea.

The researchers recognised that there was a lack of data about these surges in older people. When they studied healthy over-60s, they found that the surge in heart rate and blood pressure after waking was lower than in younger people, suggesting that it decreases with age.

The implications of this finding aren’t clear – a lower surge could mean that the cardiovascular impacts of sleep apnoea are reduced in older people. Alternatively, given that many older people have ‘stiff’ arteries that predispose to heart disease, the effects of sleep apnoea on the risk of stroke or heart attacks could still be substantial.

The National Institute for Health and Clinical Excellence (NICE) guidelines published in 2008 recommend CPAP for adults with moderate–to-severe sleep apnoea. As Dr Morrell’s work shows, the causes and consequences of sleep apnoea are different in older people, so we can’t assume that CPAP will be as effective for elderly patients.

Dr Morrell has recently been awarded funding from the UK NHS Health

Technology Assessment Programme for PREDICT, a UK-wide, randomised controlled trial of CPAP in people over 65 with sleep apnoea. The primary outcome measure of the trial is an improvement in sleepiness, but the study will also include a measure of cost-effectiveness, to ensure that the economic impact of the findings can be calculated.

With a research portfolio that combines studies of respiratory physiology with investigations into the clinical consequences, particularly in older people, Dr Morrell is building on our understanding of obstructive sleep apnoea and helping to guide future treatments. Thanks to her work, people such as Mr Govan can get a good night’s sleep at last.

Selected references

Peppard PE et al. The impact of obesity on oxygen desaturation during sleep-disordered breathing. Am J Respir Crit Care Med 2009;180(8):788–93.

Goff EA et al. The cardiovascular response to arousal from sleep decreases with age in healthy adults. Sleep 2008;31(7):1009–17.

Morrell MJ, Badr MS. Effects of NREM sleep on dynamic within-breath changes in upper airway patency in humans. J Appl Physiol 1998; 84(1):190–9.

Want to know more?

• Watch our video featuring Frank Govan and Mary Morrell at www.youtube.com/wellcometrust and www.wellcome.ac.uk

• The Sleep Apnoea Trust: T 0845 6060685 www.sleep-apnoea-trust.org

The exhaustion caused by sleep apnoea can make everyday tasks life-threatening ones. Research suggests that the condition is associated with an increased risk of road-traffic accidents.1 One study found that drunk healthy people performed better on a driving stimulator than sober people with sleep apnoea.2

Bus and lorry drivers are at a particular risk of sleepiness-related accidents. These professions often involve long stretches of monotonous driving and shift work, which can increase sleepiness. Such sedentary jobs also encourage weight gain, a risk factor for sleep apnoea.

“Most patients can overcome sleepiness except when doing something boring, such as driving,” says Dr Mary

Morrell from the Royal Brompton Hospital, London. “The problem is you can’t breathalyse for sleepiness – we don’t have good objective measures for it.”

Some researchers stress the need for that kind of measure. Dr Charles George, University of Western Ontario, Canada, writes: “Not all cases [of sleep apnoea] are sleepy or have crashes and more data are needed for society to establish and accept a ‘safe’ sleep apnea cutoff for driving, akin to that for alcohol.”1

References

1. George CFP. Sleep apnea, alertness, and motor vehicle crashes. Am J Respir Crit Care Med 2007;176(10):954–6.

2. behindthemedicalheadlines.com/articles/sleep-apnoea-and-road-accidents

“You can’t breathalyse for sleepiness”

Ina Peters/iStockphoto

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Dr Mary Morrell (left) and Frank Govan wearing his CPAP mask.

A gem of an idea

The Trust has launched a new scheme to support teams of UK students hoping to enter the iGEM synthetic biology competition. Run by the Massachusetts Institute of Technology, iGEM (International Genetically Engineered Machine) encourages undergraduate students to develop innovative projects based around biological building bricks in the same way that engineering students might develop a robot using standardised parts.

Previous iGEM projects have included a biosensor to detect arsenic in water supplies in developing countries, bacteria that take photographs and bacteria that smell of bananas. We are offering teams of students stipends to enable them to enter iGEM 2010. This will provide promising undergraduates with hands-on experience of synthetic biology.

“We need to attract the brightest young minds to take advantage of the rapidly emerging field of synthetic biology,” said Dr Alan Schafer, Head of Science Funding at the Trust. “We hope to foster innovative ideas from UK teams and help students to consider a career in this field.” www.wellcome.ac.uk/igem

The Trust and the Medical Research Council (MRC) are jointly funding three new research programmes focusing on key neurodegenerative diseases.

These Strategic Awards, which total just under £17 million, will support multidisciplinary collaborations to study Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and motor neurone disease. It is hoped that the research will improve our understanding of these devastating conditions and, ultimately, lead to improvements in diagnosis and therapies.

Mechanisms of neurotoxicity of amyloid aggregates: Professor Peter St George-Hyslop at the Cambridge Institute for Medical Research, University of Cambridge and colleagues from Cambridge, Bristol, Toronto and the Max-Planck Unit for Structural Molecular Biology will use novel methods from physics, chemistry and molecular biology to discover how the accumulation of amyloid beta and tau proteins results in the death of brain cells in Alzheimer’s disease and related neurodegenerative disorders.

RNA processing proteins and neurodegeneration – exploring mechanisms and modelling disease: Professor Christopher Shaw, of the MRC Centre for Neurodegeneration Research, King’s College London, and colleagues from King’s, Manchester, University of California San Diego, Cambridge and Dundee, plan to model key aspects of motor neurone disease and frontotemporal dementia, including mutations in the genes FUS and TDP43, to explore the mechanisms of disease and identify new therapeutic targets.

A systematic investigation into the pathogenesis and course of Parkinson’s syndrome: Professors Nicholas Wood, John Hardy and Anthony Schapira, Institute of Neurology, University College London, and colleagues at UCL, Dundee and Sheffield, will study Parkinson’s disease at its earliest stages. They will examine the genetic basis of Parkinson’s, to identify and characterise the biochemical pathways involved.

Funding

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Funding boost for neurodegenerative diseases research

MRI scan. Mark Lythgoe and Chloe HuttonSingle nucleotide polymorphisms.

This month, world leaders meet in Copenhagen, Denmark, to discuss how to tackle climate change. Many strategies to reduce greenhouse gas emissions, such as moving to low-carbon energy sources or encouraging cycling and walking, could also improve public health.

Now, researchers have conducted an independent scientific analysis of the potential benefits to public health of different mitigation strategies, with the results published in a series of papers in the Lancet. Funded by an international

group including the Trust, the research examines the health impacts in four sectors (electricity generation, household energy, urban land transport, and food and agriculture) in both developed and developing countries.

The findings were reported in November at simultaneous events in London and Washington DC, with speeches by the UK Secretary of State for Health and the US Assistant Secretary of Health, joined by representatives of the WHO.www.wellcome.ac.uk/climatechange

Will lower carbon mean healthier lives?

Terrance Emerson/iStockphoto

For more on this, including four background videos, see www.wellcome.ac.uk/neurodegen

In response to the pandemic H1N1 outbreak in early 2009, we are undertaking a range of funding, policy and publishing activities related to influenza. Find out more at www.wellcome.ac.uk/influenza.

Among the research projects prioritised are two grants co-funded by the Medical Research Council (MRC) and us. Professor Peter Openshaw from Imperial College London and colleagues have received £2.7 million to establish a network of research centres to conduct detailed investigations on severe, hospitalised cases of H1N1 influenza. Meanwhile, Dr Andrew Hayward from University College London and colleagues will use their £2.1m grant to lead a community initiative to study virus transmission. They aim to recruit 10 000 people – representing about 4000 households – who will be followed up

throughout the pandemic period. With co-funding from the MRC, the

Biotechnology and Biological Sciences Research Council and the Department for Environment, Food and Rural Affairs, we have awarded £500 000 to support two complementary grants that will inform the control and management of the epidemic in pig populations. The research groups, led by Dr James Wood from the University of Cambridge and Dr Ian Brown from the Veterinary Laboratories Agency, will investigate the transmission of pandemic H1N1 in pigs in the laboratory and in the field, and will analyse the risk to farm workers of pig-to-human transmission. They will also study the development and extent of the disease and the immune response in pigs.

The Trust’s Major Overseas Programme in Thailand is celebrating its 30th anniversary this month. The Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme opened in 1979 as a collaboration between scientists from the University of Oxford in the UK and Mahidol University in Bangkok, Thailand. Today, it is recognised internationally for excellence in tropical disease research, having made numerous vital discoveries including the development of artemisinin combination therapy, now the frontline treatment for

uncomplicated malaria.Several celebratory activities are planned,

including the opening of new laboratories – with a traditional Buddhist ceremony – at the Bangkok site, a cultural retreat to Khao Yai National Park and a book marking the anniversary.

We have provided £21.6 million of funding to the Thailand Programme since 2005. This core support, as well as support for the Major Overseas Programme in Vietnam, has just been renewed for the period 2010–15.

H1N1 influenza virus. Digital artwork. Anna Tanczos

Funding to fight flu

Thailand Programme celebrates 30 years

WellcomeNews | Issue 61 | 7

New Strategic Award for Oxford

In partnership with the Gatsby Charitable Foundation, the Trust is funding a new institute for neuroscience at the University of Oxford, which is expected to open in late 2010. Part-funded by a £5 million Wellcome Trust Strategic Award, the institute will help to build research capacity in a key area of neuroscience concerning the networks and circuits within the brain.

Professors Gero Miesenböck, Nicholas Rawlins and Jonathan Flint from Oxford are applicants on the award, which will support research into adaptive behaviour – understanding how activity in our nerve cells leads to intelligent behaviour.

The award will build infrastructure in four main areas: neuroanatomy, gene expression, optogenetics and behaviour. Researchers will focus on the mechanisms of adaptive behaviour from the level of individual synapses to whole organisms, using models including the fruit fly, mouse and zebrafish. Further capacity building comes in the form of advanced training – a number of postdoc positions will be made available.

The Gatsby Charitable Foundation is also contributing £5m to the award, and the University of Oxford is providing a building and £5m for refurbishment.

A researcher at the Thailand Programme. Joss Dimock

A frontal view of the fly brain showing two groups of dopamine-producing neurons. Confocal images: Adam Claridge-Chang; photomontage: Robert Roorda and Gero Miesenböck. From Science 2009;326(5951). Reprinted with permission from AAAS

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If it barks like a dog…

Research

One of the defining characteristics of human intelligence is our ability to use prior knowledge when dealing with new situations through the development of concepts. For example, we know that an animal that barks, has four legs, is furry and has a snout is likely to be a dog.

Researchers from the Wellcome Trust Centre for Neuroimaging at University College London have revealed that this ability is underpinned by a coupled circuit involving the hippocampus (an area of the brain responsible for learning and memory) and the ventromedial prefrontal cortex (used in decision making). Their findings suggest that the hippocampus creates and stores these concepts, and passes this information to the prefrontal cortex where it can be put to use, for example in making choices where rewards are at stake.

“Our study offers neurobiological insights into the remarkable capacity of humans to develop concepts based on their visual experiences,” said Dr

Dharshan Kumaran, who led the study. “It reveals how so-called ‘memory’ regions like the hippocampus team up with ‘decision modules’ in the prefrontal lobe to put this information to use.”

Kumaran D et al. Tracking the emergence of conceptual knowledge during human decision making. Neuron 2009;63(6):889–901.

Annette Shaff/iStockphoto

Want a simpler way to complete your end-of-grant reports and keep track of your citations? ‘My UKPMC’, a new grant-reporting tool from UK PubMed Central (UKPMC) can help. Through My UKPMC, Trust grantholders can report on and share the outcomes of grants via publicly available web pages that update dynamically whenever a new publication is added to PubMed or UKPMC. The ‘My Impact’ report shows the number of citations for each paper, counts that are updated continuously using data from the Thomson Reuters Web of Knowledge and Scopus citation services.

Dr Tim Hubbard, a researcher at the Wellcome Trust Sanger Institute who sits on the UKPMC Advisory Board, says that the service should make it easier for researchers to see which of their publications are popular, and will help others in the field to discover papers of interest quickly. “My UKPMC will help save time for researchers, who always have too much to read, and should, ultimately, improve the progress of science.”

UKPMC is a free digital archive of biomedical journal literature set up by leading UK research funders in partnership with the British Library. It is open to grantholders funded by the member organisations, including the Trust. Manuscript submission and grant reporting services are available at: ukpmc.ac.uk/ukmss

Citizen-scientists unite!

Schoolchildren and members of the public will be able to help collect data for scientific projects using a new mobile phone application designed to help scientists in the field to analyse their data remotely. EpiCollect (above), developed by researchers at Imperial College London, is a free smartphone application that allows the user to collect and record data, photos and videos and send this to a central web-based database. Users can request and view all analyses through their phones, allowing researchers a quick and easy way to build up and share maps of, for example, disease cases or the distribution of endangered species, to identify patterns in the data.

“EpiCollect could be used for community projects, for example projects that ask members of the public to track sightings of birdlife in their garden,” said David Aanensen from Imperial College. “It should be much quicker and simpler to submit sightings to the website by phone than email or the post.”

The software runs on the Android open-source operating system developed by Google and the Open Handset Alliance, with an Apple iPhone version currently in beta testing (consumer testing prior to official release).

Aenensen AM et al. EpiCollect: linking smartphones to web applications for epidemiology, ecology and community data collection. PLoS One 2009;4(9):e6968.

UKPMC report showing articles linked to a specific grant.

Easier grant reporting with UKPMC

Lucy Goodchild/Imperial College London

WellcomeNews | Issue 61 | 9

The black-and-white film begins with a caption explaining that you’re about to watch an operation to remove a brain tumour. Next comes an X-ray, clearly showing a dark area at the front of the patient’s head. Then the operation begins.

The eight minutes that follow are fascinating, unflinching and, it has to be said, pretty hard to stomach in places, particularly when the top of the skull is opened up. The Prefrontal Tuberculoma film, made in Britain in 1933, is the most viewed video on the Wellcome Film YouTube channel (www.youtube.com/wellcomefilm).

This channel is one way to watch the videos and films made available through Wellcome Film – the Wellcome Library’s film digitisation project. Eventually, over 450 of the most frequently requested films and videos from the Library’s Moving Image and Sound Collection will be made freely available online, under Creative Commons licences and in a number of digital formats. So far, around 360 films are available, and the full complement is expected to be online by spring 2010.

The Moving Image and Sound Collection includes material from a variety of sources: broadcast television programmes, departmental collections from universities, professional associations, charities and individuals.

Possibly next in line for digitisation are some of the 1500 or so audio titles held in the Moving Image and Sound Collection. Stand-out items in the collection, which contains broadcast and non-broadcast material, include 1890 recordings of

Florence Nightingale’s appeal on behalf of the veterans of Balaclava, and a short audio interview with Alexander Fleming broadcast by the BBC in 1945 where he speaks prophetically about the dangers of overexposure to antibiotics. library.wellcome.ac.uk/wellcomefilm www.youtube.com/wellcomefilm

A moving sightAs part of its digitisation programme, the Wellcome Library is making over 450 films and videos on 20th-century healthcare and medicine freely available online. We have a look at what’s available so far through Wellcome Film.

Five not to miss A pick of some of the highlights of Wellcome Film:

• �A�day�at�Gebel�Moya,�season�1912–13: Experience life at one of Sir Henry Wellcome’s archaeogical sites in Sudan (1912–13)

• Conditioned�reflexes�and�behavior: Reconstructed experiments in Ivan Pavlov’s laboratory (c.1930)

• The�Both�mechanical�respirator: Forgotten treatment regimens for respiratory paralysis caused by polio (1950s)

• �Dying�for�a�smoke: UK public health information film on smoking (1967)

• The�story�of�the�Wellcome�Foundation�Ltd: Explore the origins of the Wellcome Trust (1955).

Vital statisticsThe Moving Image and Sound Collection is the largest compilation of film, video and audio of 20th-century medicine and healthcare in Europe. It contains:

• over 1300 films, mostly on 16 mm but with a few examples on 8 mm, 9.5 mm and 35 mm

• 3500 videos in many formats, including ¼" open reel tape, U-Matic and Betacam SP

• 1500 sound recordings, mostly held as audio cassettes and CDs.

library.wellcome.ac.uk/misc.html

WellcomeNews | Issue 61 | 9

10 | WellcomeNews | Issue 61

Research

Scientists have managed to extend the lifespan of mice by up to a fifth and reduce the number of age-related diseases the animals suffer. The research, which involved blocking a key molecular pathway, mimics the health benefits of reducing calorie intake and suggests that drug treatments for ageing and age-related diseases are feasible.

In a study primarily funded by the Trust, scientists from the Institute of Healthy Ageing at University College London discovered changes in the ageing process in a strain of knockout mice, which were unable to produce a particular protein known as S6 kinase 1 (S6K1).

“Blocking the action of the S6K1 protein helps prevent a number of age-related conditions in female mice,” says Professor Dominic Withers, who led the study. “The mice lived longer and were leaner, more active and generally healthier than the control group. We added ‘life to their years’ as well as ‘years to their lives’.”

The effect was dramatic in female mice,

Knockout mouse leads leaner, longer life

but not so in males, who showed some of the health benefits but little difference in lifespan. The reasons for these differences are unclear.

Selman C et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009;326(5949): 140–4.

Pandemic swine flu can infect cells situated deeper in the lungs than seasonal flu, according to researchers from Imperial College London. Seasonal influenza viruses infect cells by attaching to receptors found on the outside of cells in the nose, throat and upper airway. The researchers found that H1N1 swine flu can attach to those receptors, but also to a receptor found on

cells deep inside the lungs, which can result in a more severe lung infection. If an influenza virus is able to bind to more than one type of receptor, it can attach itself to a larger area of the respiratory tract, infecting more cells and causing a more serious infection.

“Receptor binding determines how well a virus spreads between cells and causes an infection,” says Professor Ten Feizi, one of the researchers from Imperial College. “Our new study adds to our understanding of how the swine-origin influenza H1N1 virus is behaving in the current pandemic, and shows us changes we need to look out for.”

In a separate study, researchers found consistent evidence that influenza triggers heart attacks. The researchers conducted a systematic review of 39 studies, investigating links between influenza infection and acute myocardial infarction. They say that influenza vaccines should be encouraged, particularly for patients with established cardiovascular disease.

Childs RA et al. Receptor-binding specificity of pandemic influenza A (H1N1) 2009 virus determined by carbohydrate microarray. Nat Biotechnol 2009;27(9):797–9. Warren-Gash C et al. Influenza as a trigger of acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet 2009;9:601–10.

Round-up

Negative signalsSubliminal messaging – images shown so briefly that the viewer does not consciously ‘see’ them – is most effective when the message is negative, according to researchers from University College London. Participants asked whether a fleetingly shown word was ‘neutral’ or ‘emotional’ answered most accurately when responding to negative words, even when they believed they were merely guessing.Nasrallah M et al. Emotion 2009;9(5):609–18.

Delivery serviceIndigenous Peruvian women with little formal education do use childbirth delivery services if their needs are met, say researchers from Salud Sin Límites Perú and the London School of Tropical Medicine and Hygiene. This contradicts common attitudes that ascribe high levels of home births to cultural preferences or ignorance. Introducing an appropriate model for childbirth to a Peruvian community led to a 77 per cent increase in births delivered at a health facility between 1999 and 2007. Gabrysch S et al. Bull World Health Organ2009;87(9):724–9.

HIV failA substantial number of children still do not have access to life-saving HIV treatment, according to researchers from the Africa Centre for Health and Population Studies in South Africa. They found that, despite progress in improving the availability of free HIV services, fewer than predicted HIV-infected children under one had started essential antiretroviral treatment. Cooke GS et al. PLoS One 2009;4(9):e7101.

Faruk Ulay/iStockphoto

Jeroen Peys/iStockphoto

Fred Goldstein/iStockphoto

Rob Owen-Wahl

Influenza insights

WellcomeNews | Issue 61 | 11

Q&A

In 2006, the first map of human copy number variants – lengths of DNA lost or duplicated in the genome – was published. Now, a more detailed map has been released, revealing more about this type of genetic variation. Dr Matt Hurles from the Wellcome Trust Sanger Institute, a leader on the project, talks us through the highlights.

What are CNVs?CNVs, or copy number variants, are relatively long sections of DNA gained or lost in one individual relative to another. They’ve been known about for a long time but, until the last couple of years, we haven’t really had the tools to get a sense of how prevalent they are in the genome.

What was the aim of the study?In 2006, we published a ‘first-generation’ map of the largest CNVs that could be seen with the technology of the time. Since then we’ve been working to produce a more comprehensive map that captures the majority of common CNVs, and provides the resources to be able to incorporate those into genetic studies: essentially, a reference map for CNVs to drive research.

To do this, we had to screen the genome at much higher resolution than has been done before. We split the genome into 20 different segments and put each on to its own microarray. We ended up screening the genome with 42 million probes – at least a 20-fold higher density than has been done previously. We looked at CNVs bigger than 443 bp [base pairs] occurring in one in 20 individuals.

What did you find?We’ve discovered some interesting things about CNVs, such as how they arise and how frequently – at least one in 17 children every generation will have a new CNV. Something that previous CNV

maps haven’t shown is that some duplicated sections of DNA have jumped to new locations within the genome, sometimes on to a different chromosome.

CNVs seem to be less common in introns [non-coding DNA sequences within a gene] – they’re selected against. It is known that deletions in these regions can cause disease but we don’t fully understand the mechanism behind this yet.

Was there anything unexpected?Studies of SNPs [single nucleotide polymorphisms, sequence variations at a single DNA base] have gone some way to explaining why diseases cluster in families, but the majority of this clustering is not explained. It was thought that CNVs might account for this so-called ‘missing heritability’, but we found that it’s highly unlikely that common CNVs explain a significant proportion of it, although rare CNVs may still play a significant role.

Where is the missing heritability?We think that it’s most likely to be rare variation that hasn’t been well captured by the approaches currently available. We do point out in the paper that, because of the negative selection acting on some CNVs, many of these variants will necessarily be rare. Also, the fact that they’re being selected against suggests that they may have an effect on disease.

What’s next for CNVs?One of our next steps will be to look for these rarer variants. Ideally, we’ll do this in a way that allows us to capture SNPs and CNVs, so we’ll be maximising the power to identify any region of the genome that happens to harbour rare variants. It should be possible, but it is a work in progress. While the new sequencing technology can be very good at capturing sequence variation, it’s an open question to what degree it can capture structural variation.

What do you do outside of the lab?I enjoy spending time playing with my young children, and sculling on the river Cam.

Conrad DF et al. Origins and functional impact of copy number variation in the human genome. Nature 2009 [Epub ahead of print].

Short-sighted view on sports

Scientists studying children from the Avon Longitudinal Study of Parents and Children found that short-sighted children were less physically active than those without short-sightedness. In the study, researchers studied the short-sightedness of nearly 5000 children aged 10, and fitted the same children with accelerometers to measure their physical activity at age 12.

Short-sighted children had lower total activity, lower levels of moderate-to-vigorous activity and were more sedentary than those without short-sightedness. Although short-sighted children may be reluctant to join in with vigorous activities if they wear glasses, adjusting for glasses wearing in this study made little difference to the results, indicating that other factors may be responsible.

The authors suggest that interventions targeted at short-sighted children are required, to make them aware of the risks of low physical activity, particularly as there is evidence that childhood behaviours can be carried into adulthood.

Deere K et al. Myopia and later physical activity in adolescence: a prospective study. Br J Sports Med 2009;43:542–44.

A rare form of testicular tumour could help to explain why certain genetic diseases are more common in the children of older fathers.

The link between the genetic conditions and the tumour are the germ cells that produce sperm. If certain genetic mutations arise in these cells, they can be passed on to offspring and cause conditions including achondroplasia and Apert, Noonan and Costello syndromes. As these mutations happen to be in genes that are involved in controlling cell multiplication, they also encourage the mutant cells to divide and multiply, causing tumours to develop.

When these mutant cells divide, they copy the mutation to each daughter cell. So, the number of mutant cells – and hence the number of mutant sperm produced – increases with age, raising the risk that older fathers will have affected children.

Professor Andrew Wilkie from the University of Oxford, who led the study, explains: “We think most men develop these tiny clumps of mutant cells in their testicles as they age. They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm – causing children to be born with a variety of serious conditions.”

Goriely A et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009;41(11):1247–52.

Older dads, greater risk?

Reddoch Graphics/iStockphoto

12 | WellcomeNews | Issue 61

In her new book, An Infinity of Things: How Sir Henry Wellcome collected the world, Frances Larson explores the fascinating collection of the Wellcome Trust’s founder. In this abridged extract, she looks at the career of expert collector Peter Johnston-Saint, a respected colleague of Henry Wellcome.

Wellcome’s collector

A suave and well-connected ex-army officer, Peter Johnston-Saint (above) was one of Henry Wellcome’s most trusted collecting agents. In his role as Foreign Secretary for the Wellcome Historical Medical Museum between 1927 and 1935 he travelled all over Europe, North Africa and the Middle East.

Saint bought thousands of manuscripts, books and artefacts for Wellcome. Amongst his acquisitions were Turkish shoes made from an old motor tyre, an eighteenth century boot-shaped bath equipped with a furnace (used by a French doctor who suffered from leprosy), the doorway to a school for training Buddhist monks as doctors in Lhasa, an account of King Louis XIV’s last illness written by one of his doctors at Versailles, and a single hair from the head of St Catherine of Siena held in a small piece of paper sealed with a cardinal’s seal.

Saint was the perfect ambassador. He had a wide social circle, but he was not a pretentious man. He was equally happy talking to the King of Spain, whose wife he had known since childhood, or drinking with locals in a remote tavern in the Sicilian mountains in the company of “goats, fowls and diminutive asses”. (Each of these encounters, incidentally, yielded new accessions for the Museum to Wellcome’s great satisfaction.)

Johnston-Saint’s travel reports are littered with the names of European politicians and members of the aristocracy. Spanish dukes and duchesses, Italian cardinals, Indian maharajahs and French princes all grace the pages of his diaries, but he could also find himself in rather unsavoury quarters.

At Lisieux, in Normandy, where pilgrims worshipped at the Shrine of Saint Teresa of the Infant Jesus, he found a house that “was occupied by a sort of dealer in junk and odds and ends”, but he did not stay long,

“because the stench was so dreadful. A dreadful old woman with whiskers came to see what I wanted, and assuredly she did not add to the relief of the situation.”

One bookshop in Valencia, which he found in March 1928, was in fact “a junk shop of the first order.”

“It was in a narrow dirty street and it was lighted by one gas jet. The proprietor was reclining in a broken wicker chair smoking the stump of a cigar. All around him in the small room, some 12' x 10' were piles of rubbish, loose leaves, pamphlets, vellum bound books and such like which you had to walk on indiscriminately.”

Here, Saint unearthed medical books from the sixteenth and seventeenth centuries that were virtually impossible to find in Spain. He purchased about 150 titles there and then.

“It has always been a matter of surprise to me,” Saint wrote, “to find that in some squalid ramshackle shop which resembles more a go-down than a shop, the owner produces most wonderful objects – jewels worth many thousands and objects of art of

great beauty and value.”In 1934 Saint was promoted to

Conservator of the Wellcome Historical Medical Museum, a post he held until his retirement in 1947. He was one of the last people to have talked to Wellcome before he died in 1936. Saint’s constancy, his diligence, and his delight in artefacts of all kinds must have left little doubt in Wellcome’s mind that his great collection was in safe hands.

Johnston-Saint’s sketches of objects from Rome. Henry Wellcome (left) and Johnston-Saint .

Oxford University Press is pleased to offer Wellcome News readers a special price of £18.99 (inc. free UK p&p) on An Infinity of Things by Frances Larson.

To order your copy, visit www.oup.com/uk, add this title to your shopping basket and enter promo code WEBWTFL09. Alternatively, telephone 01536 741727 or email bookorders.uk@oup.com, quoting promotion WEBWTFL09. Offer ends 31 January 2010.

WellcomeNews | Issue 61 | 13

Courses, conferences and workshops

March 2010

1–3Therapeutic Applications of Computational Biology and ChemistryConference GC

GC: Event takes place at the Wellcome Trust Genome Campus, Hinxton, Cambs.

For information on Wellcome Trust Conferences, see www.wellcome.ac.uk/conferences.

For information on Advanced Courses and Open door Workshops, see www.wellcome.ac.uk/advancedcourses.

‘Engineering DNA’ digital artwork. Oliver Burston

9–12 Working with the Human Genome SequenceAdvanced Course, Instituto de Higiene, Montevideo, Uruguay18–19Perspectives in Clinical ProteomicsConference GC

April

17–21Working with Parasite Database ResourcesWorkshop GC

May

9–15Molecular Basis of Bacterial Infection: Basic and applied research approachesAdvanced Course GC10–12Working with the Human Genome SequenceWorkshop GC

June

5–8The Evolutionary Biology of Caenorhabditis and Other NematodesConference GC9–13Genomics of Malaria EpidemiologyConference GC19–26Molecular Neurology and NeuropathologyAdvanced Course GC

July

18–24Next Generation SequencingAdvanced Course GC21–27Human Genome Analysis: Genetic analysis of multifactorial diseasesAdvanced Course GC

Students should be undergraduates in the middle (i.e. not the first or last) years of their first degree studies.

They should be registered for a basic science, medical, dentistry or veterinary degree at a university within the UK or the Republic of Ireland (RoI).

Projects must be undertaken at a UK or RoI university.

Preference will be given to undergraduates without previous research experience. Students are encouraged to arrange their scholarship away from their usual place of study.

Application forms and further details are available from the Wellcome Trust website at www.wellcome.ac.uk/vacation

Applications must be submitted on behalf of the student, by the project supervisor.

Forms must be returned by 15 February 2010.

Wellcome Trust Biomedical Vacation Scholarships 2010

Applications are invited from biomedical and veterinary science departments for undergraduates to work on a biomedical science research project during their summer vacation. Scholarships provide the student with a stipend for up to eight weeks.

Research expenses are not provided.

The Wellcome Trust is a charity registered in England, no. 210183.

PROLIFIC VICTORIAN SCIENTIST FRANCIS GALTON WAS DRIVEN BY THE IDEA THAT HUMANS COULD BE DIVIDED INTO TYPES. SOLDIERS, PUBLIC SCHOOLBOYS AND MURDERERS WERE AMONG THOSE HE OBSESSIVELY MEASURED, PHOTOGRAPHED AND COMPARED.

A FREE DESTINATION FOR THE INCURABLY CURIOUS

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