Wellcome News 58 (March 2009)

ISSUE 58 APRIL 2009

Forbidden food Will coeliac disease always mean gluten-free?

Pen-pushers Meet the winning science writers Nanotech art Small science, big ideas

Wellcome News

Editorial

Wellcome News is published four times a year and is available free of charge.

To subscribe, contact: Publishing Department Wellcome Trust FREEPOST RLYJ-UJHU-EKHJ Slough SL3 0BP T +44 (0)20 7611 8651 F +44 (0)20 7611 8242 E publishing@wellcome.ac.uk or go to: www.wellcome.ac.uk/wellcomenews We positively encourage letters to the Editor and suggestions for future articles.

Please contact: The Editor Wellcome News Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE E wellcome.news@wellcome.ac.uk Editor Chrissie Giles Writers Craig Brierley, Chrissie Giles, Mun-Keat Looi, Michael Regnier, Catherine Whitlock Design Cosima Dinkel Assistant Editor Tom Freeman Photography Richard Hall, David Sayer Publisher Hugh Blackbourn All images, unless otherwise stated, are from the Wellcome Library. Copies of images can be obtained through Wellcome Images (http://images.wellcome.ac.uk).

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 This is an open access publication and, with the exception of images and illustrations, the content may, unless otherwise stated, be reproduced free of charge in any format or medium, subject to the following constraints: content must be reproduced accurately; content must not be used in a misleading context; the Wellcome Trust must be attributed as the original author and the title of the document specified in the attribution. The views and opinions expressed by writers within Wellcome News do not necessarily reflect those of the Wellcome Trust or Editor. No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. ISSN 1356-9112. First published by the Wellcome Trust, 2009. © The trustee of the Wellcome Trust. The Wellcome Trust is a charity registered in England, no. 210183. Its sole trustee is The Wellcome Trust Limited, a company registered in England, no. 2711000, whose registered office is at 215 Euston Road, London NW1 2BE, UK. PU-4410/13.2K/04-2009/CD Cover: Foods containing gluten are harmful to people with coeliac disease. See pages 12–13.

50%

This document was printed on material made from 25 per cent post-consumer waste & 25 per cent pre-consumer waste.

WellcomeNews | Issue 58

Throughout 2009, events, exhibitions, and radio and TV programmes are celebrating the 200th anniversary of the birth of Charles Darwin, and the 150th anniversary of the publication of his great scientific work On the Origin of Species by Means of Natural Selection.

Recognising the importance of Darwin’s life and work, the Wellcome Trust has previously played a part in preserving his history. In 1996, a donation from the Trust helped English Heritage to acquire Down House, Darwin’s home for 40 years. We are a part-funder of the Darwin Correspondence Project (www.darwinproject.ac.uk), which is digitising and putting online the text of 14 500 or so of his letters. And Darwin’s walking stick formed part of Henry Wellcome’s collection; it can be seen in the Medicine Man exhibition at Wellcome Collection.

But for the Trust’s celebrations of Darwin in 2009, which form part of the UK’s Darwin200 activities, we didn’t just want to look to the past – but to ask in addition ‘how can we bring Darwin into the 21st century?’

Our most ambitious and exciting project is to deliver a free, Darwin-inspired experiment to every schoolchild in the country. For primary schools, we invited the Royal Botanic Gardens, Kew, to develop a science project, and they have created The Great Plant Hunt (www.greatplanthunt.org). Around 21 000 primary schools will receive a box – modelled on a travel chest as if from the Beagle voyage itself – containing a suite of activities for each year group, such as walks and seed banks.

For secondary schools, the Survival Rivals project (www.survivalrivals.org) provides kits allowing each year group to perform real experiments and learn about the scientific method. These include ‘I’m a Worm Get Me Out of Here’, which demonstrates the

scientific principle of natural selection through predator–prey relationships, ‘Brine Date’, which looks at sexual selection, and ‘The X-Bacteria’, which engages pupils in the very topical issue of antibiotic resistance.

We have also funded a beautiful, animated ‘fly-through’ of the Tree of Life, aired as part of David Attenborough’s recent BBC Darwin documentary. On the internet, the animation becomes a fully interactive application (www.wellcometreeoflife.org) that allows the user to explore in 3D the common ancestors of up to 400 species. Furthermore, the entire application is freely customisable, allowing users to add their own data and modify the animation for school lessons or scientific presentations.

Among our other web-based activities is Routes, a new website with eight online programmes following Katherine Ryan, a comedian, who is learning about her own genes after having had cancer twice and developing lupus. The site (www.routesgame.com) is designed to engage young audiences in contemporary scientific issues.

It’s not often that the science community gets to celebrate the life and work of one of its luminaries in such depth, and so it’s an exciting year. With The Great Plant Hunt and Survival Rivals, we are delighted to be working with schools to provide opportunities for children to learn about evolution and natural selection through practical experimentation. The Tree of Life animation and Routes website help to show how modern technology can be used to interpret Darwin’s ideas in different ways. We hope that these activities – together with the rest of the UK’s Darwin200 activities – help to enthuse the next generation about science.

Sir Mark Walport Director of the Wellcome Trust

Sir David Attenborough and primary school children launching The Great Plant Hunt.

In this issue News............................. 2–5 Funding......................... 7–8 Research................... 10–15 Features Essaying forth................6 Novel thinking................9 Gut reaction........... 12–13 From the archives........16 Noticeboard....................17

Explore animated digital sculptures of disabled motion (top), discover Julie Freeman and Jeremy Ramsden’s ‘Nano Novels’ (centre left), find out the latest on antioxidants and ageing (centre), see what’s dished up in the Wellcome Trust windows (bottom left), furrow your brow at the Wellcome Library’s archives (below), and more…

WellcomeNews | Issue 58

News Video news

Education head

Professor Derek Bell (above) is the Trust’s new Head of Education. In his previous role as Chief Executive of the Association for Science Education, he worked closely with the Trust,

including in the development the national network of Science Learning Centres. See the next issue of Wellcome News (out in June) for a detailed interview with Prof. Bell.

Wellcome windows With the new year comes a set of new window designs for the Wellcome Trust headquarters at 215 Euston Road (below), created, for 2009, by German-born product designer Julia Lohmann.

Unlike previous window designs, which were inspired by the general mission and work of the Trust, these are based on a specific scientific idea: the symbiotic relationship between the human body and the microorganisms that live there. This was inspired by a paper written by the Trust’s

Director of Technology Transfer, Dr Ted Bianco.

The windows each contain a human outline made of Petri dishes. Inside each dish is a visual representation of a microbe that can be found in that part of the body. The windows show the microbes most commonly found on the inside and outside of the body.

For the project, Julia Lohmann worked with Professor Mike Wilson, a microbiologist at University College London Eastman Dental Institute, who grew and photographed microbes in his lab for the designs.

Over the last 12 months we have been adding new video content to our website as well as launching a new channel on YouTube, the popular video sharing site.

In early 2008 we created our first filmed Annual Review, presented by Trust Director Sir Mark Walport. Soon after, we had a hit with our video report on research into paranoia that uses virtual reality, which was used on BBC London and the BBC website, as well as being picked up internationally. Our other video highlights include online features to showcase key projects on our Technology Transfer funding pages, interviews to explain the importance of stem cell research, created as part of our participation in the discussion around the Human Fertilisation and Embryology Bill, and free-to-use educational videos to support our Big Picture publication.

Go to www.wellcome.ac.uk to browse our video content, and check out www.youtube. com/wellcometrust for the latest videos on key Trust stories.

Mark of achievement Mark Walport, Director of the Wellcome Trust, received a knighthood in the 2009 New Year Honours List for services to medical research. Before joining the Trust in 2003, he was Professor of Medicine and Head of the Division of Medicine at Imperial College London, where he led a research group focusing on the immunology and genetics of rheumatic diseases.

Sir Mark is a board member of the UK Clinical Research Collaboration, the UK Research Base Funders Forum, the Health Innovation Council and the Prime Minister’s Council for Science and Technology. In 2008, at the request of the Prime Minister and Secretary of State for Justice, he co-chaired with the Information Commissioner an independent review on the use and sharing of personal information in the public and private sectors.

Grant system update The status of the project to deliver an automated grant processing system has been reviewed, and as a consequence the supply contract has been ended and the project terminated. The Trust is now carefully considering its future options.

In the meantime, applicants should continue to use our existing eGrants electronic application system. www.wellcome.ac.uk/funding 2 | WellcomeNews | Issue 58

Conference call

Web of life

Looking to enhance your public engagement skills and share your experiences with others in the field? Don’t miss the 2009 Science Communication Conference, organised by the British Science Association in partnership with the Wellcome Trust.

The conference – which takes place on 22–23 June 2009 at Kings Place, London – will bring together people working across science communication. www.britishscienceassociation.org

In review

Ernst Heinrich Haeckel’s illustrations of embryo development for hog, calf, rabbit and man, 1874. Part of the Making Visible Embryos exhibition.

We have funded two online exhibition projects. Brought to Life: Exploring the history of medicine is an online multimedia resource aimed at secondary school students and undergraduates. The project features objects – many on view for the first time – from the Wellcome Trust collection held by the Science Museum in London. They cover centuries of medical history from around the world. Subjects include diseases and epidemics, medicine and belief, and the pioneers of medical science.

Making Visible Embryos is an online exhibition developed by the University of Cambridge, exploring images of embryos, and the issues surrounding their depiction, throughout history. The exhibition aims to illuminate key questions and concerns by contextualising images that have become iconic or were especially widely distributed in their time. www.sciencemuseum.org.uk/broughttolife www.hps.cam.ac.uk/visibleembryos/

Peter Ratcliffe prize

By the book

Professor Peter Ratcliffe, Head of the Nuffield Department of Clinical Medicine at the University of Oxford, has been awarded the 2009 Louis-Jeantet Prize for Medicine.

Professor Ratcliffe, who has received Trust funding for almost 20 years, was recognised for his research into the mechanisms used by cells to detect oxygen levels. He shares the prize with Swiss-American researcher Michael Hall. They will each receive 700 000 Swiss Francs (£420 000), the bulk of which will be used for their research, at an award ceremony in Geneva in April 2009.

The prize is awarded annually to outstanding biomedical researchers in Europe, to encourage the continuation of research projects that are of major importance to medicine. Previous winners include Trust Governor Professor Adrian Bird.

The Wellcome Trust Annual Review 2008 is now available in print and online. This review provides an accessible overview of our work during the year, with short summaries of research and other projects we fund. It also highlights the progress we have made towards fulfilling our mission. The online version (www.wellcome.ac.uk/annualreview) includes a video summary of our key achievements, presented by Sir Mark Walport, Director of the Trust. The full Annual Review is available to download as a PDF or to order.

Also available online are our Annual Report and Financial Statements 2008 (www.wellcome. ac.uk/annualreport), and our Strategic Plan updates (www.wellcome.ac.uk/strategicplan), summarising our activities over the last year and setting out priorities for the coming year.

A taxidermist who writes essays on her blog about 17th-century anatomists and embalmers; an achondroplasic academic who works on the mathematics of quasicrystals; and a widowed sheep farmer who lost her stock during the 2001 foot and mouth crisis in Cumbria. What do these three characters have in common?

They’re all brought together in The Embalmer’s Book of Recipes, a new novel by Ann Lingard (aka Ann Lackie).

A History of Medicine Research Expenses Grant in 2001 supported some of the research for the novel, which is published

by IndepenPress.

For more details and to see some images that inspired the writing of the novel, visit www.annlingard.com.

WellcomeNews | Issue 58 | 3

News

Get engaged A selection of the fascinating projects and events supported by our People and Arts Awards, funded through our Engaging Science programme.

Theatre The Devil’s Doctor (Shifting Sands Theatre) Paracelsus, alchemy and the birth of medicine.

Touring the UK February to May 2009. www.shiftingsandstheatre.co.uk The Last Women (Triangle Theatre Company) A powerful interpretation of the stories of condemned women.

Belgrade Theatre, Coventry, 20–25 April 2009. www.belgrade.co.uk

Events and exhibitions For the Best (Mark Storor and Anna Ledgard, in collaboration with the Unicorn Theatre, in association with artsadmin) Created with children receiving dialysis who attend the school at the Evelina Children’s Hospital, London.

The Cutting Edge: Surgery and the nature of healing (Hollie Smith) Dialogue events and an outdoor anatomy demonstration.

Unicorn Theatre, London, 2–28 June 2009.

http://cheltenhamfestivals.com

www.unicorntheatre.com

Bugs R Us (Michael Wilson) A travelling exhibition that explores the microbial communities that live in our bodies.

Kursk (Sound&Fury) An immersive theatrical experience inspired by the tragic Russian submarine explosion of 2000.

Young Vic, London, 3–27 June 2009.

Cheltenham Science Festival, 3–7 June 2009.

Showing at the Cheltenham Science Festival, 3–7 June 2009, and across the UK. http://cheltenhamfestivals.com

www.youngvic.org

Collect yourself

‘Day 25’. © Bobby Baker 2009 Photograph © Andrew Whittuck

4 | WellcomeNews | Issue 58

Among the Wellcome Collection exhibitions for 2009 is Bobby Baker’s Diary Drawings: Mental illness and me, 1997–2008. This exhibition features pages from the sketchbooks of Bobby Baker – one of the most widely acclaimed and popular performance artists working today – who has, in her own words, “periodically gone barking mad”. The drawings from Bobby’s sketchbooks, which were not initially for public display, helped her to communicate to family, friends and professionals thoughts that were hard to put into words. They also chart the ups and downs of her recovery, family life, work as an artist, breast cancer and, as she says, just how funny all this harrowing stuff can be at times.

Diary Drawings runs from 19 March to 2 August 2009. Accompanying free events at Wellcome Collection include ‘Bobby Baker in Conversation’ (16 April) and ‘Peas, Placards and Protest’ (18 April), a day of workshops and protesting peas.

Madness and Modernity, an exhibition exploring the visual arts in fin-de-siècle Vienna, will run from 1 April to 28 June 2009. www.wellcomecollection.org

Bamako 2008

Motion Disabled enabled

The Global Ministerial Forum on Research for Health is the premier meeting for decision makers in research funding and policy to focus on improving the health of poor populations. We supported the 2008 Forum, which was held in Bamako, Mali, and Trust staff took part in sessions on research priorities, pandemic preparedness, best practice for data sharing, and civil society engagement in research for health.

The Forum culminated in the release of the ‘Bamako Call to Action’. www.bamako2008.org

Motion Disabled, an animated digital sculpture that explores ideas of normality and difference, has opened at Wolverhampton Art Gallery.

To create the exhibition, artist Simon Mckeown worked with 11 people with physical disabilities including spina bifida, cerebral palsy and brittle bone disease. He recorded their everyday movements using motion capture technology – a means of recording movements digitally, often used in the making of animated feature films.

The resulting motion capture animations were applied to simple human figures

(avatars) to create five 15-minute films.

Simon Mckeown said: “I used this technology to capture for now and the future the motions of ‘difference’, in order to ask questions including: do we value difference?

How do disabled people’s bodies fit into current notions of normality? And, is physical diversity about to become virtual?” The exhibition, which was part-funded by a Trust People Award, will run at the Wolverhampton Art Gallery until 25 April 2009. www.wolverhamptonart.org.uk/ exhibitions/003808.html.

Winning technology Two Trust-funded projects have won national awards. RegenTec, a spin-off company from the University of Nottingham, won a Medical Futures Award for its ‘injectable bone’ scaffold, which helps fractured bones heal. Another team, led by John Stokes from Nottingham University Hospitals NHS Trust, won an NHS Innovation Award for their prototype surgical device that simplifies cataract surgery.

Image of kickboxing, created using motion capture technology. Simon Mckeown

Making a change 2009 has been designated the ‘Year of Climate Change’. To date, much of the debate on this subject has focused on the environment, but it is now becoming clear that climate change is also likely to affect the health of millions of people. Threats include heat waves and flooding, changing patterns of infectious diseases such as malaria and dengue, and water scarcity and rising sea levels, which could displace hundreds of thousands of people. The impacts will be greatest in developing countries.

But it may not all be doom and gloom – some of the strategies to tackle climate change could also have positive implications for health. Encouraging people to walk rather than take the car could make populations more physically active, reducing obesity while also cutting urban pollution and road traffic accidents. Similarly, moving to cleaner fuels could reduce outdoor air pollution, thereby improving public health.

We are supporting work to explore such ‘co-benefits’ in more detail, in partnership

Big is better with the Royal College of Physicians, the Economic and Social Research Council, the Department of Health, the National Institute for Health Research and the Academy of Medical Sciences.

An international team, led by the London School of Hygiene and Tropical Medicine, will model the impacts of policy choices aimed at reducing greenhouse gas emissions in key sectors, including energy, transport, housing, and food and agriculture. Case studies will consider the impacts in both developed and developing countries.

This work will contribute to the discussions at the UN climate change conference in December 2009 in Copenhagen, when political leaders meet to agree targets post-Kyoto. We will be working with the World Health Organization and other stakeholders, such as the UN Foundation, to raise awareness of this research, and the health impacts of climate change, during the course of the year.

Big Picture: Health and climate change is out now. The Big Picture educational series, a free post-16 resource for teachers that explores issues around biology and medicine, has a new look. The latest issue includes a fullcolour classroom poster that explores the connections between the carbon cycle and climate change.

Visit the redesigned Big Picture web pages at www.wellcome.ac.uk/bigpicture to order a free copy of the magazine and access exclusive online content, including extra articles and Climate Health Challenge, an interactive activity in which students must make policy decisions to try to sustain the health of the world population.

Glen McBeth

WellcomeNews | Issue 58 | 5

Essaying forth Science isn’t just about hypotheses and experiments: communicating research is also vital for advancing knowledge.

The Wellcome Trust and New Scientist Essay Competition has, for over a decade, encouraged postgraduates and postdoctoral researchers in science, engineering and technology to communicate their science and explore the possible implications of their research for society.

For some past winners, the competition provided a springboard to a career in science journalism or broadcasting, while for others it reaffirmed their passion for research.

Mun-Keat Looi asked some previous winners about their experience of the competition, the impact it had on their careers and their tips for science writing.

Kerri Smith First place 2005, for ‘FOXhunting: Exploring the genetics behind speech and language’

Golkin Oleg/iStockphoto

James Randerson

Jon Copley First place 1997, for ‘The secret life of shrimp’

Third place 2001, for ‘Military ecology’

Then: MSc student at

Then: PhD student at

Then: PhD student at the

the University of Oxford Now: Podcast Editor for Nature

the University of Bath Now: Environment Website Editor at the Guardian

Now: Lecturer in Marine Ecology

“The competition gave postgrads an opportunity to convey their passion about what they’ve been doing. If you are working in science, there aren’t too many opportunities – the media in general is not that science-friendly. Even student papers tend to look at broadsheets as their models, and the people that run them are likely to be humanities students who might not be that into science, so it’s quite hard to get stuff published.

“Whatever anyone’s PhD or Master’s is on, there’s always an angle that people will think is interesting. It just depends on how you express it.

“Quotes also help to bring things to life. Speak to your lab head or someone who’s just reviewed your paper to see what they liked about it, what they think is fascinating about your particular field.”

“During my PhD, I wrote popular science articles for a student magazine and for publications like BBC Wildlife Magazine.

I entered the Wellcome Trust and New Scientist competition on the off chance that, if I placed well in it, it would enhance my CV and help me get into science journalism. After my PhD I applied for an internship with New Scientist and ended up working there for five years, becoming Deputy News Editor before moving on to the Guardian as a science correspondent.

“One piece of advice is to really step back from your project as far as you can.

Try not to say too much. Communicate clearly and without jargon, so you can get your message across in a way that is accessible to someone who is interested but not an expert in the subject.”

University of Southampton at the National Oceanography Centre “For me, science without science communication is like the sound a tree makes when it falls in the woods with no one around to hear it. The competition raises the profile of science communication as an important part of how we do research. All who take part benefit from the experience of communicating with non-specialists about their work, a vital skill for a modern research career.

“The skills involved are highly transferable for a research career. My colleagues and I recently received funding to explore the world’s deepest undersea volcanoes and I am sure that writing a decent ‘non-specialist’ summary in the application helped. And the same skills are involved when communicating with colleagues from other disciplines.”

To read further interviews and writing tips from other winners, see www.wellcome.ac.uk/past–winners.

For details of the competition, see www.wellcome.ac.uk.scienceessay.

6 | WellcomeNews | Issue 58

Funding New antibiotics

Enhancing ethics We have made three Enhancement Awards in Biomedical Ethics, totalling more than £1 million, to UK research groups. Through this funding, Professor Michael Parker, Director of the Ethox Centre at the University of Oxford, and colleagues will focus on the ethics of international research. At the Centre for Family Research, University of Cambridge, researchers will explore new family forms arising from assisted reproductive technologies. And a collaborative group of researchers from the Universities of Bradford, Exeter and Bath will examine the ethical dimensions of the socalled ‘dual use’ issue, i.e. the risk that biomedical science could be used for malign as well as benign purposes.

We have awarded £4.1 million to biopharmaceutical company Achaogen, to support the discovery of new drugs for treating bacterial infections. Achaogen specialises in developing broad-spectrum antibiotics called aminoglycosides to combat a variety of multidrug-resistant bacteria.

Aminoglycosides are still in extensive clinical use; however, there has not been a new aminoglycoside approved for decades, and the effectiveness of existing drugs is declining rapidly, owing to the expansion of resistant bacterial strains.

The award, made through our Seeding

Drug Discovery initiative, will support ongoing preclinical studies of two of Achaogen’s drug candidates that have shown promising activity against bacterial infections, including the highly resistant Enterobacteriaceae (which include E. coli) and the multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa.

Both new chemical entities are being studied by Achaogen with the expectation of entering an initial product candidate into phase 1 clinical development later in 2009. www.wellcome.ac.uk/techtransfer

Matter of principal Professor Margaret (‘Scottie’) Robinson (right) has had her Wellcome Trust Principal Research Fellowship renewed. Her research, carried out at the University of Cambridge, explores how proteins get to the right part of the cell. She will use this funding to study further the ‘adaptors’ (including AP-1 and AP2) that recognise sorting signals on proteins.

These signals indicate which part of the cell the proteins are destined for.

This latest award marks some two decades of Trust support for Professor Robinson. She held a Senior Research Fellowship from 1989 to 1999, and was awarded her first Principal Research Fellowship in 1999. During this time, Professor Robinson and her lab members have been highly involved in public engagement – something set to continue.

Their engagement activities have included working closely with primary and secondary

schools to provide hands-on experience in cell biology, and taking part in a schools’ roadshow as part of the Cambridge Science Festival.

Scene from Yerma’s Eggs, a Trust-funded play exploring issues around assisted reproductive technologies.

Ethical tour Wellcome Trust staff have recently completed a tour of the Asia-Pacific region to raise awareness of our support for biomedical ethics research in developing countries (www.wellcome.ac.uk/ internationalethics).

Jacob Leveridge and Liz Shaw began in Auckland at the Ninth Global Forum on Bioethics in Research. Supported by the Trust, the Forum focused on the ethics of research involving indigenous peoples and vulnerable populations. A highlight was a presentation from Melanie Cheung, who spoke on the ethical dilemmas she faced as a Maori researcher using postmortem human brain tissue to study Huntington’s disease.

From New Zealand, Jacob went on to the University of the Philippines, Manila, then the newly established Centre for Biomedical Ethics at the National University of Singapore, and finally Vietnam, where he spoke at the Institute of Biotechnology and Vietnam National University in Hanoi, and visited the Trust’s Major Overseas Programme and the University of Medicine and Pharmacy in Ho Chi Minh City.

WellcomeNews | Issue 58 | 7

Funding Driven to drink Among the new projects funded through our Neuroscience and Mental Health stream is a study into the way heavy drinkers think about alcohol. A team led by Dr Matt Field from the University of Liverpool will use questionnaires and computer tasks to study whether the craving for alcohol and the desire to stop drinking can be separated. They hope to help explain why alcoholics struggle to stop drinking, which could have implications for the management of alcohol-related problems.

Dr Andrew Glennerster from the University of Reading and Professor Andrew Parker from the University of Oxford will use virtual reality to investigate how the brain generates a stable visual representation of the world even though our eyes are continually moving. The research should improve our understanding of how the brain normally perceives size, distance and visual direction.

Kate Whitley

A probing partnership We have invested £4.1 million in a new initiative to generate small molecule inhibitors – ‘chemical probes’ – for 25 proteins involved in epigenetic signalling, and to release these probes into the public domain with no restriction on use.

The initiative is a public–private partnership, to be led by the Structural Genomics Consortium and also involving GlaxoSmithKline, the National Institutes of Health Chemical Genomics Center in Bethesda, USA, and the Departments of Chemistry and Biochemistry at the University of Oxford.

The partnership, which brings medicinal chemistry expertise within industry together with biological expertise from academia, aims to develop chemical probes that can affect the activity of proteins involved in epigenetic control. The probes will complement genetic knockouts and RNAi approaches to understanding the role of these proteins in biology, and it is hoped that some probes may be a starting-point for drug discovery.

8 | WellcomeNews | Issue 58

Targeting cancer

Human colon cancer cells. Annie Cavanagh

The quest for personalised cancer treatments has been boosted by the announcement that we have funded an £8.5 million UK–US alliance to find the best ways to treat the disease.

Scientists will use high-throughput research to test the sensitivity of 1000 cancer cell samples to hundreds of known and novel molecular anticancer treatments. They will correlate these responses to the genes known to be driving the cancers, producing a catalogue of the most promising treatments or combinations of treatments for each of the cancer types, based on the specific genetic alterations in these cancers.

The five-year project, funded by a Wellcome Trust Strategic Award, is being led by Professor Mike Stratton and Dr Andy Futreal of the Wellcome Trust Sanger Institute and by Professors Jeff Settleman and Daniel Haber of the Massachusetts General Hospital Cancer Center in Boston, USA. The teams will make extensive use of the genetic information being produced by the Sanger Institute’s Cancer Genome Project.

Professor Stratton said: “Our emerging understanding of cancer mutations, allied to our abilities to carry out large-scale research, means that we can develop screening techniques to find the most effective treatments for a whole variety of cancers.”

Molecules, Genes and Cells Among the awards made through our Molecules, Genes and Cells stream is a project grant to researchers at the University of Oxford. They will develop statistical and computational methods to analyse data from the 1000 Genomes Project, an international collaboration to create a detailed catalogue of human genetic variation.

Also at Oxford, Professor Peter Cook has received funding to examine how the location of a gene in the nucleus affects its activity. This research is relevant to the development of gene therapies, for which it is important to know how an inserted gene will behave in a new nucleus.

Dr Helen Arthur from Newcastle University and Dr Marcus Fruttiger at University College London will use knockout mice to investigate the protein endoglin and its role in blood vessel formation – work that could have implications for the treatment of heart disease and cancer.

Colour-enhanced electron micrograph of cells, nuclei in green. University of Edinburgh

Novel thinking Artist Julie Freeman made the world of nanotechnology larger than life as part of her residency at Cranfield University. Chrissie Giles talked to her.

“If I had made only one work, it wouldn’t have been enough for a field as big as nanotechnology,” says artist Julie Freeman, who has just completed a residency at the Microsystems and Nanotechnology Centre at Cranfield University. So, working closely with Professor Jeremy Ramsden, Chair of Nanotechnology at Cranfield, she produced ‘Nano Novels’ – a series of 16 pieces of art.

This series is just part of the work produced during her residency, which was funded by a Wellcome Trust Small Arts Award.

“I began by trying to work out what to do with nanotechnology. It’s a massive field and there are lots of different areas, all of which are interesting in their own right,” says Freeman. During a year of meetings and discussions with Professor Ramsden, they created scientific descriptions of different aspects of nanotechnology. To 16 of these they added a headline, a short piece of fiction and a graphic to produce ‘Nano Novels’ (see below for an example in full).

Freeman‘s earlier works have often had a biological aspect to them, yet the form of ‘Nano Novels’ surprised her. “When the project began, we had no idea at all what we were going to produce,” she says. “As an artist I write software and do a lot of environmental sound recording. I use live data to make the artwork, which means it’s often unpredictable. In this project I ended up making large-scale images – a real departure from my normal work.”

She drew the initial images by hand and then converted them to graphics.

The resulting large-scale artworks, measuring 1.8 by 1.2 metres, were installed on the Cranfield campus in late 2008 – the first-ever art installation at the University.

Freeman and Ramsden are currently writing a paper that explores the definition of the nanoscale. To view the images and accompanying text online, along with photos of the installation and further information about Freeman’s residency, see http://in-particular.net.

Six of the ‘Nano Novels’ graphics.

In Particular Nanoparticles are pervasively invisible in our world, but their effects are obviously felt.

Naturally occurring nanoparticles include proteins within organic produce such as milk, and they are airborne in the environment; for example, soot from fires (carbon nanoparticles), bonfire smoke, and in sea spray. Non-natural examples are zinc oxide particles in suncreams for UV protection, and silver nanoparticles embedded in sticking plasters for their antibacterial properties. Everyday products such as cosmetics, medicines, and plastics can all contain nanoparticles. The most common emission of biological nanoparticles comes from something that happens billions of times every day, all over the world... ahh chooo!

Invention Recent scientific discoveries have led to a new classification for a common element not usually associated with science, love or Lo. It has been established that Lo is an essential human requirement and should be scientifically recognised as such although there is still debate whether it is an element or a compound. The oversight which has spanned centuries has been met with a combination of enthusiasm mixed with caution. Compounds already under study include precious alloyed love Au3Lo2, acid love H2Lo, toxic love LoBe, evanescent love LoNo, tungsten lovite WLoO2, tantalizing love Ta2Lo2, strange love XeLo (existence disputed).

The New Everyman Shorter English Dictionary has been updated to include this entry: ove (l˘ L uv) [Amor dominus] 1, a lubricant which forms our emotional landscape, and comes from within; a transparent, odourless compound of two volumes of heart and one of head; stable under normal atmospheric pressure but subject to enormous change if heated or cooled, can dissipate or intensify rapidly. 2, an essential common element in nearly everything; unlike oxygen, it doesn’t just affect us physically but has a guiding influence on all our daily interactions. 3, invisible, infinite and inexpensive Lo is an uncontrollable global resource, nontoxic. 4, the most widely known cause of death in humans.

The ‘Everywhere Nowhere’ artwork is accompanied by a scientific introduction to where nanoparticles can be found and how they are used, as well as a metaphorical piece exploring the elemental chemistry of love.

WellcomeNews | Issue 58 | 9

Research Depressed dads

Bombing TB Research has shown how a new drug destroys the tuberculosis (TB) bacterium from the inside, which may lead to new ways to treat latent TB and other bacterial infections.

Around a third of the world’s population has latent or dormant TB, in which Mycobacterium tuberculosis bacteria are present but not actively dividing. These people do not display any symptoms, but around ten per cent go on to develop active TB. There are no drugs for latent TB currently available, but one experimental drug, PA-824, is effective. The key event is the production of nitric oxide gas. “This highly reactive molecule is akin to a bomb blast that kills the bacteria from within,” says Dr Clifton E

Anthea Sieveking

Children whose fathers are depressed before and after birth are at a higher risk of developing emotional and behavioural problems themselves, according to a study; the more chronic the depression, the higher the risk.

The research is based on data from the Avon Longitudinal Study of Parents and Children, covering 14 000 parents and children.

Ramchandani PG et al. The effects of pre- and postnatal depression in fathers: a natural experiment comparing the effects of exposure to depression on offspring. J Child Psychol Psychiatry 2008;49(10):1069–79.

Antioxidants and ageing Diets and beauty products claiming to have antioxidant properties are unlikely to prevent ageing, according to research we have funded.

Dr David Gems and colleagues at University College London studied the action of key genes involved in removing superoxide – a reactive ‘free radical’ form of oxygen that can damage cells through oxidation – from the nematode worm Caernorhabditis elegans. By manipulating these genes, they were able to control the worm’s ability to ‘mop up’ surplus superoxide and limit potential damage caused by oxidation.

The researchers found that the lifespan of the worm was relatively unaffected by its ability to tackle surplus superoxide. The findings, combined with similar recent findings from the University of Texas using mice, imply that the free radical theory of ageing – which proposes that ageing is caused by an accumulation of molecular damage in cells from ‘oxidative stress’ – is incorrect.

Doonan R et al. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 2008;22(23):3236–41.

10 | WellcomeNews | Issue 58

Barry of the National Institute of Allergy and Infectious Diseases in the USA, who led the research.

Immune cells naturally produce nitric oxide after they engulf bacteria. PA-824 acts in a similar way, but the drug’s effect is more specific. Low-oxygen conditions, created when immune cells wall off bacteria, also aid PA-824, which interacts with bacterial cofactors and enzymes. The understanding could lead to new kinds of drug that generate nitric oxide and interact with the enzymes in other disease-causing bacteria.

Singh R et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 2008;322(5906):1392–5.

Seeing speech Professor Ruth Campbell and Dr Cheryl Capek from University College London have explored how the brain ‘sees’ language when it is presented as silent speech and sign language.

They used functional magnetic resonance imaging (fMRI) to measure brain activity as deaf and hearing participants processed silently spoken word lists. The left superior temporal cortex was strongly activated in all participants – but significantly more so in deaf people. The area that was especially strongly activated includes auditory regions, which are usually activated when hearing people perceive sounds.

When deaf people watched sign language, similar parts of the brain were activated by the hand signs and by the silent mouthing of the corresponding word, but speech-like mouthing activated the auditory regions to a much greater extent.

The parents of deaf children awaiting cochlear implants are often advised not to mouth or sign words to their children before fitting, in case this affects the sensitivity of

the auditory regions. The researchers call for a reconsideration of this practice, as their work suggests that watching speech might help children with implants to map the ‘new’ auditory stimulation to the seen speech patterns they have already been exposed to.

Also at University College London, Wellcome Trust Intermediate Clinical Fellow Dr Alexander Leff and colleagues have been using fMRI to study speech perception in the brain. Building on previous studies in the field, which have identified brain regions activated by hearing speech, the researchers have been able to model how the different regions interact and link together.

Ultimately, they hope that a better understanding of these links will be useful when developing treatments for conditions in which the brain’s speech perception system is damaged, such as stroke.

Campbell R and Capek C. Seeing speech and seeing sign: insights from a fMRI study. Int J Audiol 2008;47 Suppl 2:S3–9.

Leff AP et al. The cortical dynamics of intelligible speech.

J Neurosci 2008;28(49):13209–15.

Tomatoes: high in antioxidants, but apparently not so good at preventing ageing.

Malaria progress Significant progress has been made in the fight against malaria. The number of deaths from severe malaria in coastal Kenya has dropped by 75 per cent over the past five years, according to a study from the Kenya Medical Research Institute (KEMRI)– Wellcome Trust Research Programme. The researchers attribute this to early treatment, better drugs and better mosquito control measures.

Among the latter are insecticide-treated bednets, which protect children from mosquitoes while they sleep. A separate KEMRI study found that bednet use increased six-fold between 2000 and 2007. However, 90 million African children are still without nets – a quarter of whom are in Nigeria alone.

KEMRI is also trialling the world’s most clinically advanced malaria vaccine candidate: RTS,S. Researchers reported the success of phase II trials, showing that the vaccine provides significant protection for both infants and young children. Phase III trials are being planned across Africa.

O’Meara WP et al. Effect of a fall in malaria transmission on morbidity and mortality in Kilifi, Kenya. Lancet 2008;372(9649):1555–62.

Noor AM et al. Insecticide-treated net coverage in Africa: mapping progress in 2000–2007. Lancet 2009;373(9657): 58–67.

Bejon P et al. Efficacy of RTS,S/AS01E: clinical malaria in 5 to 17 month old children. N Engl J Med 2008;359(24):2521–32.

Q&A the protein; and a colleague developed statistical methods to ‘sort out’ the imaging of disordered, variable structures.

What’s new for this paper?

To work properly, proteins must fold into the correct 3D structure; misfolding can have catastrophic consequences for organisms. Helping to unravel this complex process is Professor Helen Saibil from Birkbeck, University of London. With colleagues, she has published the first structure of a newly folded protein just before it is released from a chaperonin complex, a type of chaperone that is required for protein folding in all cells.

How did this work start?

In the early 1990s we started working with crystallographers on the structure of GroEL, a chaperonin found in Escherichia coli that works with another chaperonin, GroES, to fold newly made proteins and refold those that have been damaged by stress. In 1994 we published a first, blurred image of a model protein held in the cavity of GroEL, and since then we’ve been trying to get a more detailed image of what a folding protein looks like in there.

What challenges did you face?

A mosquito on a bednet. Liverpool School of Tropical Medicine/A Stich

When insects attack Insect immune systems use natural antibiotics to ‘mop up’ the remains of infections after clearing the majority of bacteria first. This helps to prevent antibiotic resistance, suggest researchers from the University of Sheffield. Further study of antimicrobial proteins in natural settings could help to formulate new medical strategies against drug resistance.

Haine ER et al. Antimicrobial defense and persistent infection in insects. Science 2008;322(5905):1257–9.

Unfolded proteins aren’t proper structures – they are extremely disordered and variable.

Single-particle electron microscopy relies on averaging many different views, and if you average together views of unfolded proteins, the structure just blurs out. We also found that the protein complex stuck on the microscope grid in the wrong way, so we couldn’t get all the 3D information on its structure. After quite a few years’ effort, a couple of things happened that helped us: our US collaborators found a way to modify the outside surface of GroEL so it could lie on the grid in a way that meant we could get side views of

The Nature paper is a big step forward: it’s the first time we’ve been able to show a protein actually inside the folding chamber, just before it is released. We studied a protein called gp23, which forms the shell of the T4 bacteriophage. Folding in T4 requires GroEL and a T4-specific version of GroES, which is taller than the E. coli form, because – it was thought – gp23 is so big.

We found that, to our delight, that this was the case; we showed that gp23 is absolutely wedged inside the folding chamber.

What can this research tell us?

Understanding cellular protein folding is important: if misfolded proteins accumulate they aggregate and cause serious, nontreatable misfolding diseases such as Alzheimer’s. Chaperonins are one of the major components of the protein-folding system. They are activated under stress and their activation seems to deteriorate with ageing, which is why many proteinmisfolding diseases occur in old age.

How has the Trust helped you?

I’ve been supported by the Trust for many years, and recently completed a yearlong sabbatical at EMBL [the European Molecular Biology Laboratory] in Heidelberg, supported by a Trust Flexible Travel Award. During that time I worked on cryo-electron microscopy of frozen cell sections, a very recently developed technique that makes it possible to cut sections of unfixed, frozen cells or tissues.

This method allows you to look at cells and organelles closer to their native state than conventional electron microscopy does. I was keen to get back to lab work, which I never have time to do in my own lab, and the experience was tremendous. I ended up working on a yeast prion model system, and have since secured a Trust infrastructure grant to purchase equipment to permit this kind of work in my own lab.

What do you do outside of the lab?

I enjoy swimming and walking, as well as the visual arts and music.

Clare DK et al. Chaperonin complex with a newly folded protein encapsulated in the folding chamber. Nature 2009;457(7225):107–10.

WellcomeNews | Issue 58 | 11

Gut reaction Professor David van Heel is at the cutting edge of research into coeliac disease, a common and debilitating condition with no cure. Chrissie Giles spoke to him and other leading figures in the field to find out what we know about the causes and treatment of this disease.

It can prevent you from joining the armed forces, it makes eating many everyday foodstuffs impossible and it is surprisingly common. Coeliac disease is a muchmisunderstood disorder, which, often mistaken for a food allergy, is actually an autoimmune disease caused by intolerance to gluten – the major protein in wheat.

It has no cure.

Some decades ago, coeliac disease was thought of as an illness of children, causing failure to thrive. Now, doctors are finding the disease in adults more than in children (currently, there are nine adults for every child diagnosed). Coeliac disease is thought to affect 1 in 100 people in the UK, yet studies suggest only 1 in 8 affected has been diagnosed. This, in part, could be because the symptoms can vary from very mild to very severe.

As Professor of Gastrointestinal Genetics at Barts and The London School of Medicine and Dentistry, David van Heel sees hundreds of patients with coeliac disease every year.

As well as helping these people cope with their symptoms, he and his colleagues have uncovered a raft of new genetic links to the disease, helping researchers worldwide in their own research (see box, right).

Finger-like villi in the gut absorb nutrients from food (top).

Coeliac disease can flatten the villi (below), preventing the normal absorption of nutrients. Coeliac UK

12 | WellcomeNews | Issue 58

Genome-wide search Coeliac disease is highly heritable, and the involvement of certain types of key immune system genes (so-called human leukocyte antigen or HLA genes) has been known since the 1970s. But, explains Professor van Heel, it was also clear that the HLA genes were only part of the story.

“Some 99 per cent of people with coeliac disease carry HLA gene variants called DQ2 or DQ8. These types are also common in the general population, so they are necessary to cause coeliac disease, but not sufficient.”

So, with funding from Coeliac UK and the Wellcome Trust, Professor van Heel and his team carried out the first genomewide association study in coeliac disease, to try to find more genetic links to the disease.

Genome-wide association studies compare single nucleotide polymorphisms (SNPs; common DNA mutations that occur roughly once in 1000 bases) in people with and without particular traits or diseases, to try to find genes associated with them.

In a study published in 2007, the researchers found that coeliac disease was associated with genetic variation in two genes, which code for interleukin 2 and interleukin 21. “These interleukins control T-cell function,” says Professor van Heel.

“We don’t know what the T cells are ‘doing’ in coeliac disease, but we would expect them to perhaps behave more strongly or respond more easily than in people without the disease.”

A further genome-wide association study published by the group in 2008 identified an additional seven genetic variants linked to the disease, several of which had also been implicated in rheumatoid arthritis and type 1 diabetes – other autoimmune diseases.

A recent paper by Professor van Heel and colleagues from Cambridge brought the

Foods containing gluten can be hard to avoid.

number of non-HLA genetic regions associated with coeliac disease to 11, and those associated with type 1 diabetes to 21. Again, some genetic regions were involved in both diseases, bringing the total to seven. Interestingly, two of these ‘shared’ regions seemed to protect against diabetes, while conferring susceptibility to coeliac disease.

While there’s no cure for coeliac disease, there is a treatment: a gluten-free diet The researchers think that these shared genetic regions regulate the mechanisms that cause an individual’s immune system to attack the beta cells in the pancreas and the small intestine. Their results suggest that type 1 diabetes and coeliac disease not only share genetic causes but could have similar environmental triggers as well.

The Trust has recently funded a further round of genome-wide association studies, which includes research into coeliac disease.

The researchers will study SNPs in more detail, and copy number variation – where chunks of DNA are gained or lost in individuals.

“At the moment we have explained around 30 to 40 per cent of the heritability of coeliac disease, but we think that there is still a load

of genetic findings still out there,” says Professor van Heel.

“I went out for lunch and ended up in A&E...”

Cereal killer

Sue Harte, 57, from Devon, was diagnosed with coeliac disease around 18 months ago.

What do these advances in our understanding of the factors underlying coeliac disease tell us about how to treat it?

When a person with coeliac disease eats gluten, their immune system attacks the mucosa of the small intestine, preventing it from absorbing nutrients normally.

The effects, such as severe diarrhoea and vomiting, can last for days. Contamination can come from things as seemingly minor as breadcrumbs in a toaster. Professor van Heel says that while there’s no cure for coeliac disease, there is a treatment: a gluten-free diet.

Such a diet can be tricky to manage, as well as being inconvenient (see box, right). “This isn’t just a treatment,” says Professor van Heel, “it’s a morbidity in its own right.”

Other treatments in development include adding substances based on bacterial enzymes to food to digest the gluten within, as well as immune-based treatments.

But it’s not as simple as finding the genes involved and designing a treatment around them, Professor van Heel explains. “If you switch off the IL2 gene then you’re at risk of lots of horrible infections. What this kind of research does do, though, is give you new insights into the pathways primarily involved in causing the disease.”

Coeliac disease is not just down to genes; findings from twin studies – and the fact that its onset is often in a person’s 30s or 40s – suggest that environmental factors are also involved.

Researchers are trying to discover what these are and how they interact with genetics.

Other fascinating avenues that require investigation include whether breastfeeding is protective against coeliac disease when babies are weaned on to gluten-containing foods, and whether certain viral infections in infancy can predispose to the disease.

“There are some studies that have shown that, in a few children, coeliac disease seems to go away spontaneously,” says Professor van Heel.

“It appears that, in these patients, the immune system can be tipped back to tolerance. Whether we can do this clinically I don’t know, but it’s certainly an interesting question.”

Further reading van Heel DA et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 2007;39(7):827–9.

Hunt KA et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 2008;40(4):395–402.

Smyth DJ et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008;359: 2767–77.

For more information about coeliac disease, see Coeliac UK: www.coeliac.org.uk.

“I’d had the symptoms of coeliac disease since the age of 40, when I suffered severe diarrhoea for six weeks and subsequently lost 2 stone in weight. Despite this and further episodes, the symptoms were misdiagnosed several times, including as irritable bowel syndrome and stress. It was only when I moved house and found a new doctor that I was diagnosed.

“I feel so much better now that I’m on a gluten-free diet, and suffer symptoms only if I eat food that has been cross-contaminated.

I had a carvery meal and ended up in A&E with severe vomiting and diarrhoea, because the serving spoons for the leeks (served in a sauce containing flour) and plain vegetables had been swapped.

“I miss the freedom of being able to eat whatever I want, or spontaneously deciding to go out for a meal or pick up a takeaway, but feeling better far outweighs these disadvantages.

“Some people think a gluten-free diet is a bit of a fad or conscious choice, but it’s more than that. It might not be life-threatening like a peanut allergy, but for coeliacs eating gluten can really make you ill and have other health implications. After years of misdiagnosis I have early osteoporosis, caused by malabsorption of nutrients, particularly calcium.

“I get some gluten-free foods on prescription, but I’m surprised there’s not more available to buy, at a reasonable price.”

Making an impact What have the short-term effects of Professor van Heel’s research been? We asked two of the world’s leading researchers working on coeliac disease for their thoughts.

Professor Ludvig Sollid is Director of the Centre for Immune Regulation at the University of Oslo and the Rikshospitalet University Hospital, Norway.

Dr Bob Anderson is a Lab Head at the Autoimmunity and Transplantation Division at the Walter and Eliza Hall Institute, Parkville, Australia.

“Professor van Heel’s work has definitely had a big impact on the field. Since the discovery of HLA-DQ2, studies into the genetics of coeliac disease have more or less led nowhere – until his genome-wide association study. We are experiencing a revolution in the field of coeliac disease, similar to that being seen in many other multi-gene disorders.

“The susceptibility genes identified by Professor van Heel provide a roadmap for further investigation, and my group is particularly interested in finding out what these genes might be doing.

“What’s been disappointing is that the effects of the novel genes in terms of genetic risk are small. There are some 11 genes associated with coeliac disease, excluding HLA-DQ2, but a huge number are needed to fill the gap – perhaps hundreds – we just don’t know yet.”

“The funding available for research into coeliac disease has always been limited, and the main challenge for researchers in the field has been to secure research support. An effect of Professor van Heel’s genetics studies has been to save considerable resources by ending the smallscale genetics research that had many false starts and produced findings that have not been replicable.

“The genes implicated by Professor van Heel’s work emphasise the other components of the immune system that influence T-cell behaviour. In the longer term, knowledge of these genes may guide the therapy prescribed for patients. Coeliac disease has become a wonderful testing ground to understand the biology of, and to develop therapeutics for, chronic immune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis.”

Professor David van Heel’s lab is based at Barts and The London School of Medicine and Dentistry. For more details of its work, see http://vanheelgroup.googlepages.com.

WellcomeNews | Issue 58 | 13

Research Wise up

Photomicrograph of a developing human fetus.

A study at King’s College London has shown that a molecule called Wise controls tooth development by linking together signalling pathways outside cells. The researchers found that Wise, secreted by mesenchymal cells, can modulate the activity of signalling pathways in nearby epithelial cells by binding to the surface protein Lrp4; without Wise or Lrp4, extra teeth develop and teeth fuse together.

“The regulation of signalling pathways outside cells is not well understood,” says co-author Professor Paul Sharpe. “By linking two pathways together outside the cell, Wise provides cells with information about what’s happening in their surrounding environment.”

Ohazama A et al. Lrp4 modulates extracellular integration of cell signaling pathways in development. PLoS ONE 2008;3(12):e4092.

European genes

Moved to grow The normal development of an embryo’s bones requires the action of muscles.

Now, scientists in Dublin have used a novel method to identify two genes that are involved, Collagen X (ColX) and Indian hedgehog (Ihh). The results show that ColX and Ihh expression is altered when muscle movement is reduced, implicating them in the regulation of bone growth through movement in the embryo.

A study of DNA samples from over 1000 Spanish and Portuguese men reveals that one in five has a Jewish paternal ancestor and one in ten has North African paternal ancestry.

The researchers, led by Professor Mark Jobling from the University of Leicester, suggest that this is the result of a history of religious persecution, culminating in the Spanish Inquisition’s activities in the 15th century, which forced Muslims and Sephardic Jews in the region to convert, leave or be killed.

The integration of those who converted into the population left a lasting genetic legacy.

Separately, a team of researchers have used samples from the Wellcome Trust Case Control Consortium to show a strong correlation between the genetics and physical location of Europeans. This could be used to map where unknown genome

samples come from. The study confirms gradients of genetic variation spanning from Russia to Spain, and from Norway and Sweden to Romania and Spain.

The authors say that their method could aid disease association studies, allowing scientists to predict the ethnic origin of samples without the need for genotype data from individuals. Newly genotyped samples from people with a particular disease can also be matched to pre-existing control samples, avoiding the need for expensive collection and genotyping of additional controls.

Adams SM et al. The genetic legacy of religious diversity and intolerance: paternal lineages of Christians, Jews, and Muslims in the Iberian peninsula. Am J Hum Genet 2008;83(6):725–36.

Heath SC et al. Investigation of the fine structure of European populations with applications to disease association studies. Eur J Hum Genet 2008;16(12):1413–29.

Nowlan NC et al. Identification of mechanosensitive genes during embryonic bone formation. PLoS Comput Biol 2008;4(12):e1000250.

African genome Researchers have decoded the first African human genome using a new, faster and lower-cost sequencing method. The team, including scientists from the Wellcome Trust Sanger Institute, identified significantly more polymorphisms than in a European human genome, with many variants previously unknown. The researchers say the new techniques make whole human genome sequencing potentially feasible as a clinical tool in the near future.

Bentley DR et al. Accurate whole human genome sequencing using reversible terminator chemistry.

Nature 2008;456(7218):53–9.

14 | WellcomeNews | Issue 58

A woman brought before the Spanish Inquisition. Aquatint by Jazet after S J E Jones.

Waist watchers

Libby Welch

A study part-funded by us shows that larger waistlines significantly increase the risk of death. Researchers from the German Institute of Human Nutrition Potsdam-Rehbruecke and colleagues looked at waist circumference and waist-to-hip ratio for almost 360 000 individuals from nine European countries over a ten-year period.

Pischon T et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med 2008;359(20):2105–20.

Treating eating disorders A new form of psychotherapy has the potential to treat more than eight out of ten cases of eating disorders in adults, a study reports. This new ‘enhanced’ form of cognitive behavioural therapy builds on and improves the current leading treatment for bulimia nervosa (as recommended by the National Institute for Health and Clinical Excellence).

Professor Christopher Fairburn – a Wellcome Trust Principal Research Fellow at the University of Oxford – and colleagues found that the enhanced treatment could also be used to treat both bulimia nervosa and atypical eating disorders, making it suitable for over 80 per cent of cases of eating disorders.

“Eating disorders are serious mental health problems and can be very distressing for both patients and their families,” says Professor Fairburn. “Now, for the first time, we have a single treatment that can be effective at treating the majority of cases without the need for patients to be admitted into hospital.”

The research is the culmination of a sevenyear study funded by us.

Fairburn CG et al. Transdiagnostic cognitive-behavioral therapy for patients with eating disorders: a two-site trial with 60-week follow-up. Am J Psychiatry 2008 [Epub ahead of print].

Under pressure Putting on weight generally leads to a rise in blood pressure. Now, a study of a particular group of obese individuals has shown that this association is controlled by the melanocortin system in the brain.

Dr Sadaf Farooqi and colleagues at the University of Cambridge found that people with an inherited form of obesity, caused by mutations in the MC4R gene, have lower blood pressure than other obese people.

Conversely, when the researchers stimulated the melanocortin 4 receptors (which are produced by the MC4R gene) of obese people without MC4R mutations, blood pressure increased. The melanocortin 4 receptor is found in the brain and is involved in the control of weight and appetite; mutations in the MC4R gene are present in up to 6 per cent of obese individuals and lead to problems controlling weight.

“We’ve now shown that the link between gaining weight and increased blood pressure is through the melanocortin system,” says Dr Farooqi. “What happens in the brain is likely to be key to understanding obesity and its associated complications.” Many obese people are susceptible to diabetes, and raised insulin levels had previously been associated with raised blood pressure. However, this study found that insulin levels did not explain the association between blood pressure and obesity.

Weighty findings Researchers studying the genetic risks of obesity have found six new genetic regions that may affect our behaviour rather than the way fat is digested or stored. The study, involving scientists at the Wellcome Trust Sanger Institute, looked at the DNA of over 90 000 people. The regions identified contain genes that are expressed in the hypothalamus, a part of the brain that regulates body functions such as hunger.

The findings suggest that genetic variation affecting how the brain behaves in response to food influences the risk of obesity.

Willer CJ et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009;41(7):25–34.

Greenfield JR et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 2009;360(1):44–52.

Risky business There are marked differences in mortality from coronary heart disease between people from high and low socioeconomic groups.

Most of these differences could be eliminated if current best-practice interventions to reduce coronary risk factors (such as smoking and high blood pressure) are applied to both groups, according to estimates made by a team of researchers working in the UK and France, including Wellcome Trust Career Development Fellow Dr David Batty.

Kivimäki M et al. Best-practice interventions to reduce socioeconomic inequalities of coronary heart disease mortality in UK: a prospective occupational cohort study. Lancet 2008;372:1648–54. iStockphoto/Sascha Burkard

‘Hearing Voices’ – man with schizophrenia. Stevie Taylor

Insomnia and paranoia A link between sleeplessness and paranoid thinking has been found. The study – the first to examine insomnia and persecutory thoughts – found that in the general population individuals with insomnia were five times more likely to have high levels of paranoid thinking than people who were sleeping well. In an extension of the research, over half the individuals attending psychiatric services for severe paranoia were found to have clinical insomnia.

Freeman D et al. Insomnia and paranoia. Schizophr Res 2009;108(1):280–4.

WellcomeNews | Issue 58 | 15

From the archives The Wellcome Library’s extensive collections – which include everything from ancient Egyptian manuscripts to the latest films on biomedical issues – are packed with fascinating items that give us an insight into medicine across the ages and around the world.

Wellcome News asked some of the Library’s archivists and librarians to share a selection of their favourite items.

A recipe for success

Unearthing the plesiosaur

Perfect for the nosey parkers among us, the Wellcome Library’s unsurpassed collection of nearly 300 manuscript recipe books provides a chance to peer into women’s households as far back as the late 1500s. The 17th-century recipe books, 74 in all, are now fully digitised and available on the Library’s website.

But forget Jamie, Gordon and Nigella – these recipe books contain more than just food, including healing, cosmetics, religious and intellectual interests, family and social networks, and household and veterinary management. The disconcerting mix of culinary and medical recipes in Grace Acton’s 1621 volume (above) is typical: her flamboyant recipe for roast peacock is followed by an unappetising way to cure bed-wetting, by feeding a child a mouse boiled in urine.

The manuscripts are accumulations of knowledge passed from one generation to the next, and their numerous annotations give a sense of individual women’s experiences.

With their limited circulation, they allowed their compilers the freedom to explore their interests in a way unthinkable in published works. Ironically, however, they also served to reinforce social norms, providing role models for the next generation of women. For more, see: http://library.wellcome.ac.uk/doc_ WTD041747.html.

Christy Henshaw and Helen Wakely

The 19th century was the golden age of the fossil hunter: there were many new species to describe for the first time, all over a background of fierce debate about what these remains meant for biology and geology.

Finding the specimens that fed this debate could be a lucrative business, if you had a knack for it.

One of the earliest and greatest fossil hunters was Mary Anning, born in 1799 to a working-class family in the palaeontologically fertile Lyme Regis, Dorset. She was barely into her teens when she discovered what was later to be named ichthyosaurus, following this in December 1823 with the first complete plesiosaurus.

In two letters to a potential buyer, written a week after she discovered the plesiosaur, she describes the specimen and includes a wonderful pen-and-ink sketch of the bones and their disposition (below). These letters, along with thousands of others bought by Henry Wellcome, have been fully catalogued and their descriptions are available online.

Chris Hilton

Why not try this 17th-century recipe for ‘Sugar Cakes’ from Lady Ann Fanshawe’s collection?

“Take 2 pound of Butter, one pound of fine Sugar, ye yolkes of nine Egs, a full Spoonfull of Mace beat & searsed [sifted], as much Flower as this will well wett making them so stiffe as you may rowle it out, then with the Cup of a glasse of what Size you please cutt them into round Cakes & pricke them and bake them.”

16 | WellcomeNews | Issue 58

Anthea Sieveking

To the fore(head) Metoposcopy may sound like an unpleasant medical procedure, but it is, in fact, the art of divining a person’s character by ‘reading’ their forehead. The Library has recently purchased the only known copy of a German pamphlet from 1785 that still contains two original ‘forehead-reading’ templates.

These hand-coloured templates are designed to fit snugly over the forehead; there is one for males and one for females.

Readers would look through the slits to reveal the exact position of lines underneath, and record and measure them.

This information would then be interpreted with reference to the seven planets known at that time and their associated mythologies.

The 12 signs of the zodiac were delineated by markings along the lines, so the lines’ beginnings and ends would have significance to the star signs. This is a wonderful example of transposing the ideas of astrology into the area of metoposcopy in a new and fun way. Such novelties were probably inspired by the runaway success of Johann Caspar Lavater’s influential work Essays on Physiognomy, which was published in 1775.

Danny Rees

Want to know more?

You can search the Library’s archives catalogue at: http://archives.wellcome.ac.uk and view many of the objects on Wellcome Images at: http://images.wellcome.ac.uk.

Keep up to date with the Wellcome Library blog at: http://wellcomelibrary.blogspot.com.

Sign up to receive our free Wellcome Trust publications Up-to-date news and features highlighting the Trust’s wide-reaching science and public engagement activities, grant schemes, policies and more.

Published four times a year.

ryry toto om isis eH eH om lclc elel WW ISSUE 39 WINTER

ISSUE 39 WINTER

2008

2008

Feature article Feature article n Face transplantatio Face transplantatio n uNit MaNcHeSter MaNcHeSt er uNit care Intensive Intensive care illness AbdominalAbdominal illness n NHS reorganisatio NHS reorganisatio n Animal testing Animal testing

2

Connective tissue

Animal suicide Connective tissue

2

13

rePOrt 4 cONFereNce Animal suicide reSearcH reSOurceS cONFereNc e rePOrt 13 database

4

Italian charlatans reSearcH reSOurceS

bOOk reviewS Italian charlatans database caleNdar bOOk reviewS caleNdar

16

16

Aimed at medical historians, this engaging newsletter contains a lively mixture of features, research updates, conference reports, book reviews and more.

Published three times a year.

18 24

18 24

To receive copies of any of these publications, please let us know your name, address, email and occupation and the titles you would like. Call, email or write to us, quoting WN58: Publishing Department Wellcome Trust FREEPOST RLYJ-UJHU-EKHJ Slough SL3 0EN T +44(0)1753 688684 E publishing@wellcome.ac.uk

See the full range of Wellcome Trust publications online: www.wellcome.ac.uk/publications To unsubscribe from any publications please contact us on any of the above.

The Wellcome Trust regards the lawful and correct treatment of personal information as very important and to this end is fully committed to the principles of data protection, as set out in the Data Protection Act. Our full privacy statement can be found online at www.wellcome.ac.uk/aboutthissite/privacy

Courses, conferences and workshops June 2009

August

14–17 Genomic Epidemiology of Malaria Wellcome Trust Conference GC

9–16 Wellcome Trust School on Biology of Social Cognition GC

17–22 Genomic Epidemiology of Malaria Advanced Course GC 17–26 Functional Genomics and Systems Biology Advanced Course GC

Transgenic Drosophila expressing gene marker GFP in its eyes and ocelli. Derric Nimmo and Paul Eggleston

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.

9–23 Drosophila Genetics and Genomics Advanced Course GC

July

16–21 Wellcome Trust School of Human Genomics GC

1–5 Biobank Summer School Wellcome Trust–Public Population Project in Genomics GC

26–30 Applied Bioinformatics and Public Health Microbiology Wellcome Trust Conference GC

5–10 Practical Aspects of Small Molecule Drug Discovery Advanced Course GC

September

22–28 Human Genome Analysis: Genetic analysis of multifactorial diseases Advanced Course GC

2–6 Mouse Genetics and Genomics: Development and disease Wellcome Trust Conference GC

WellcomeNews | Issue 58 | 17

EUROSCIENCE SUBLIMINAL INVITING SUPER FASCINATING NEURON HIEROGLYPHICS ANEURYSM CHARIOT RETICENT PHOTO RESERVATION LADYBIRD OPSONISATION PERSPICACITY SOLUTIONS MILLION MATERIA MEDICA NURSE FROND NINETEEN MO ORTURE REVOLUTIONARY INSPIRATION EMBRYO PHLEBOTOMY ANKLET LYMPH NODE OPERATION GLUCOSE GLORIFICATION ANELLING DRAWER MICROSCOPE QUERIST ICONOGRAPHIC NEUROFIBROMATOSIS CURIOUS NUDE GENETICS CENTURY ANT OSMOPOLITAN PAINTING FORAYS COIFFURE SCAMPER EUGENICS LONG RECEIPT UNUSUAL BULLET INFORMING DECORATED ORANUS JOINTS MONUMENTAL MUSCULOSKELETAL IMPROVING ROSES ANIMAL SUBSTITUTE KING ENLIGHTEN ENGAGEMEN OSSET RESTORATION PLETHORA NOMENCLATURE ORIENTAL HIPPOCRATES SYLLOGISM MICROBIOLOGIST IMPROVEMENT AR RANSCRIPTION KNOCKOUT INTERIOR SOURCE SNAPSHOT APOCALYPTIC VALUE CANON FLOATING OPTOMETRY PROTEINS S DUCIARY SOMMONTE SWIM CANOPIC ACADEMY CHALLENGE MYOCARDIUM ALLEGORICAL ILLUMINATIVE CONSERVATION BL OUNTERPOINT PROPERTY FIFTEENTH BIRD DEPICTING SILVER COMPARTMENT INTESTINE CADUCEUS ALLOPATHIC JEWEL TIM CROLLS CHILD MONOCHROME BIOHAZARD NEOCLASSICAL EARCAP IMPRESSED ANTRUM NOTEBOOK SCALABILITY CONFOC HASTITY BIOARCHAEOLOGY MASK FIGURE STILL ZOONOSES FETUS PEOPLE ODDITY SANDAL BRUSH SCIENTIST MENDELIAN RAHMAN REVEAL FRAGMENT AMAZON COLOSSUS SCAR RENOVATION SHRUNKEN BIBLIOMANIA CANVAS ARTIFICIAL APPETIT OREHEAD FRESCO BEZOAR ERYTHROCYTE ALCOHOL CARVING PAROCHIAL DEPICTION MAGNILOQUENT ABSCESS ORNAMEN ONCEPTUAL SPEAR BORBORYGMI BOTTLES ABUNDANCE RECIPES DANCERS PUBLIC FILM ANAMORPHIC DIAGONAL DEVELO POTHECARY WIND AMALGAMATION MUTATION EFFIGY ESOTERICA DELICATE CHRYSALIS VIRUSES ELIXIR CLASS PHARMACOL WITCH WOODEN STUCCOWORK OBSTETRIC ALBUMINOUS PARCHMENT BLOODLETTING SCOLD GESTATION ABRACADABRA BR ONTINGENCY CONGENITAL RENAISSANCE SYMBOLISM MODERN MACHINE RITUALISED AMITOTIC DHARMA PLASTINATE PSEU ULSATING ANATOMY VEINS WAR DYNAMO BORDERS HUMUNGOUS PLASTINATION NUTRITION PHARMACEUTICAL SERVE SPH EHYDRATE MOLOCHISM MINNESOTA RETROVIRAL EXQUISITE ABSTRACTION TATTOO CHALLENGING BODIES MALARIA EMBRY MANUSCRIPT SNUFFBOX PHTHISIS ZYGOTE SHARING GARMENT SCENES EXPRESSION BABY DRUGS WHIMSICAL PHILANTHRO ERENDIPITOUS SPECIMEN UNREQUITED SNORING ANOMALY ANTHROPOMORPHIC EMBALM WATERCOLOUR SCULPTURE STA KELETON AMPUTATION TESTOSTERONE SILAS MAINVILLE BURROUGHS FLUORESCENT DATA CLASSICAL GRAVE FIGMENT VIT ISTORICAL ICONOCLASTIC GROTESQUE CURIOSITY DREAM SMOKE MUSEUM SHRINE CADAVER HEAD ANTAGONIST DOCTOR LEPTOMANIAC SKETCHING BRAIN HEAL ANTIDEPRESSANT SURGEON EASEL ARMS WILL STASIS FLUX ANTIBODIES CERAMIC MUMMY ALCHEMY DECAY GERATOLOGY TINNITUS TOILET ACUPUNCTURE DEAD SALVAGE MANIKIN STYLE MUSE HENRY SOLO WELLCOME NUCLEUS CALCIUM BRAND INLAY FLEETING MOLECULAR TORTURE VARIEGATED QUIRKY LEGACY EROTIC DISTILL NTIQUITY WATER VISIONARY SEQUENCING HUMANE HERITAGE MECHANICAL TRUTH PIONEER ELABORATE MAJESTIC METAPH MALADIES TOXICOLOGY DIGITISATION TRIBE VENTRICLES PSYCHIATRY CULTURE PHYSICK NURTURE PAIN TISSUE ARTEFACTS ELIC GALVANIC BREASTS HUMAN MYTHOLOGY LEATHER LABORATORY GUILLOTINE EPISTEMOLOGY PROSTHETIC PHYSIOLO ALATE OESTROGEN ORTHOPAEDICS SHIELD STETHOSCOPE OXYGENATED OBESITY LEECHES SPECTACLE HOLY MEDICINE BL ATHOLOGICAL FORGET POLYMATH LISTERIA LIVES CABINET STONE HIPPOPOTAMUS FASHIONABLE MYRIAD GROWTH TREASU EONATOLOGY CURING ARCHITRAVE RENAISSANCE MAN HISTORIC ILLNESS FERTILISATION PARAGON COLOSSAL INVASIVE AN RADLE HEARTBURN EXCAVATION ENIGMATIC ENEMA PRAYER ACQUISITION EXPERIMENT EPIDEMIOLOGY SEX BIOPSY COMPO ORPSE CONCEALED MUSCLE ALIVE HEALTH MEMORY CHAIR TONGUE AGONIST ITALIAN GENITALIA WONDER SCIENCE IMAGIN ALEN NATURE SESQUIPEDALIAN ORGAN RANDOM VENEER BRAINSTEM DENTIST GENE TOOTHPICK VESSELS VISTAS FUNCTIO ISEASE GROTTO DRAGON ARCHAEOLOGICAL FERTILITY STICK END ECCENTRIC RHETORIC PANORAMIC MYSTERY STIRRING A EATHERS GASTROSTOMY TABLET MELLIFLUOUS GLOW FREAKS INSTRUMENT GILDED SYRINGE NARRATIVE INSPIRING VAULT ILL MASTERPIECE PHARMACY ARTERIES UPPER INSTALLATION PLACEBO FANTASY HYSTERIA MASTURBATION ANTEDILUVIAN HRENOLOGY HOMOEOPATHIC ARTERY IVORY TRACHEA HISTOIRES PRODIGIEUSES NEOTERIC COLLAGEN MOLECULAR TORTU IAGNOSTIC BIENVENIDO UTERUS VIRTUE INSOMNIA PREGNANT STURGEON BEQUEST FEET GARGANTUAN HAIR CATACOMB IN EPOSITORY TALISMAN TEXTILE SLEEP APNOEA PIPE PERSONAL SHAVING DEPICTED BACTERIA ENGRAVING URINAL HEREDITY LTRASOUND FRANCIS CRICK PHYSICIAN ARCHETYPES FOCUS HISTORY ILLUMINATION VERTIGO MULTIFARIOUS GUARDIAN E X-VOTO METICULOUS DEDICATED IMAGINATIVE SEEK BIOTECHNOLOGY EMPOWERING CHALONES INTERGALACTIC FUNERAL OTHECA ECLECTIC AVANT-GARDE RESEARCH AMULET PORTRAIT GEOMANCY TRANSPLANT RAZOR PHYSICIST DISSECTION L ELP ECUADORIAN WOOD WADE INVESTIGATE VISCERA TECHNOLOGY DIASPORA XENOTRANSPLANTATION ORNAMENTAL VIVID AINTED BOUND BLADDER PASSION BEHEMOTH BAROQUE CAPILLARIES HYPNOTIC PHANTOM FRAME FREE RADICAL BEAUTY NCOGNITA GLAZE BELT GASTRIC JUICE ANOREXIA LUMINOSITY CAVITY METHOD INVISIBLE WOMAN SCARIFICATION SPECIOUS US ALCHEMIST EMPATHIC OESOPHAGUS MEDIA TRANSCENDENTAL STAINED PERUVIAN GLOBES CHAETAE REMEDIES HERED HRONOLOGICAL FRIEZE AMPHORA AUTHORITIES INMATE EMULSION SERENDIPITY OFFERING EXTREMITIES CHINESE YAGE C Open until 18.00 Tuesday–Sunday HAMBER ANTHROPOMORPHISM TSANTA WALKING CATHOLIC STUDIO CHROMATOPSIA DUODENUM REGENERATION CATALYS until 22.00 GENOME FIGURATIVE ATTACK PERCEPTION DROSOPHILA REASONABLENESS SUBLIMATE CINN YGMY Thursday SAW SINUSES STELLAR ONICITY NARCOLEPSY ARTIST FANTASTICAL ELECTROTHERAPEUTIC FACILITIES BILLIONS ASYLUM POSTERITY TRANSFORMA Book now for weekly events HIPPOCAMPUS FORM SAINT LINEAR LANDSCAPE YELLOW FEVER ZYGOSIS SHUAR G ONDITION ENZYMES AORTA SENSIBILITY WALLOWING DISCOVERY BLEIGIESSEN TEXT REALIST SOUP CARDIOVASCULAR SABALOKA CELESTIAL PAPER BAZOMBO COM www.wellcomecollection.org LZHEIMER’S ROCOCO DYNAMIC CONNECTIVE ELECTRON GAMMA RAY NATURALISM GAS CHROMOSOME DOTTY UNICORN AP IM FORCEPS RECEIVE EMBROIDERED FACILITATE THUMB PROGRESS MEDIEVAL VOMITING SHINGLES GROUNDBREAKING THI 183 Euston Road, London NW1 2BE HELERETHISM GENETICIST ROSACEA FISSIPAROUS ASTROLABE CHEMOTAXIS CHEQUERED TIN BIOCHEMISTRY DRAWN ARCH Warren Street HELIX HYDROCHLORIC ACID NOK CULTURE POLITICAL WESOMEEuston, METLAKAHTLA LACHRYMAL

BOBBY BAKER’S DIARY DRAWINGS: Mental illness and me, 1997–2008

Free exhibition, 19 March–2 August

‘Day 12’ © Bobby Baker 2009 Photograph © Andrew Whittuck