Wellcome NEWS

Issue 67, summer 2011

MEMORIES ARE MADE OF THIS

Eleanor Maguire talks taxis, amnesia and getting lost.

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Wellcome Trust Investigator Awards

Nothing has such power to broaden the mind as the ability to investigate systematically and truly
Marcus Aurelius
We have expanded our Investigator Awards to cover the medical humanities, bioethics and aspects of the social sciences. We are inviting applications from world-class scholars asking the most important questions at the interface of science, medicine and the wider humanities. The scheme will cover two categories Medical History and Humanities, and Ethics and Society enabling scholars to pursue bold individual visions with greater flexibility. Applications now open.

www.wellcome.ac.uk/mhinvestigators/wn
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Pasieka/SPL

Deejpilot/iStockphoto

14 Eleanor Maguire: mapping memories

CONTENTS

INSIDE THIS ISSuE

In brief Message from the Director Funding news Research news In depth How I Got Into the biology of bee brains: Dr Chris Connolly Eleanor Maguire: mapping memories Any questions? Taking part in Im A Scientist Blog and film update Q&A: Dr Gareth Owen Smooth Operator: Making the i-Snake Opinion Dogma on mental illness is a threat to progress Appliance of Science: music festivals and science Picture features Hijacking natural systems Nuts and Bolts: MRI From the Archive: Ann Fanshawes recipe book 22 26 32
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4 6 8 10 14 20 24 25 28 13 34

Wellcome NEWS
Telling the stories of the Wellcome Trusts work Editor Chrissie Giles Assistant Editor Tom Freeman Writers Craig Brierley, Chrissie Giles, Mun-Keat Looi, Jen Middleton Design Anja Fouad Photography David Sayer Publisher Hugh Blackbourn Contributors: Chris Connolly illustration Bret Syfert MRI illustration Malcolm Chivers Ideas, comments, suggestions? Get in touch: Wellcome News Wellcome Trust Gibbs Building 215 Euston Road London NW1 2BE E wellcome.news@wellcome.ac.uk www.wellcome.ac.uk/wellcomenews To subscribe: T +44 (0)20 7611 8651 E publishing@wellcome.ac.uk www.wellcome.ac.uk/subscribe All images, unless otherwise stated, are from the Wellcome Library. You can get copies through Wellcome Images (images.wellcome.ac.uk). Wellcome Trust We are a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests. 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, 2011. Wellcome News is the Wellcome Trust and is licensed under Creative Commons Attribution 2.0 UK. The Wellcome Trust is a charity registered in England and Wales, no. 210183. Its sole trustee is The Wellcome Trust Limited, a company registered in England and Wales, no. 2711000 (whose registered office is at 215 Euston Road, London NW1 2BE, UK).
PU-5122/15K/06-2011/AF
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MESSAgE FROM THE DIREcTOR SIR MARK WALPORT

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

Much of the scientific process is inherently repetitive. There are days, perhaps even years, of developing and refining techniques, checking controls and ensuring that results are replicable. But this repetition is punctuated with moments of inspiration when a new idea strikes, of delight when an experiment finally works, and of serendipity when something unexpected sparks a completely new line of enquiry. It is such moments that make science come alive. The first 75 years of the Wellcome Trust the anniversary we celebrate this year are full of examples of this. Take Graham Mont Liggins, whose work we funded from the 1960s. His moment of revelation came from the unexpected breathing of a newborn lamb. As part of his research into what triggers labour, he infused a pregnant ewe with cortisol. This led to a successful birth 37 days before full term, when the lambs immature lungs should have been incapable of inflating. This led to the development of corticosteroid treatment for women showing signs of giving birth prematurely, estimated to have helped save hundreds of thousands of newborn infants by accelerating maturation of the lungs. Nick Whites key moment came in 1979 when he chanced upon a dog-eared paper in a Chinese scientific journal detailing the antimalarial properties of a herb called qinghao, derived from sweet wormwood. By tracking down the authors and building on their work, he and his team proved that derivatives of qinghao (artemisinin) are indeed powerful antimalarial drugs. These are now frontline treatments for the disease. I am immensely proud of the progress made possible by the Wellcome Trust over its first three-quarters of a century. This anniversary affords a great opportunity not only to reflect on the considerable achievements made in science, medicine and the medical humanities in this time, but also to recognise the great personal effort and dedication behind each one. This anniversary is also an opportunity to look to the future, and consider how contemporary research may produce great stories in coming years. I have invited researchers from nine of our biggest funded initiatives across the uK (holders of Wellcome Trust Strategic Awards) to run events for the general public during the second half of 2011. These will showcase the best of their fields of science, showing how these have developed during the last 75 years and what further progress may be possible.

Cover: Professor Eleanor Maguire, who works on the neuroscience of memory. See page 14. Wellcome Images

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Investigator Awards in biomedical science announced

The microscope of Ronald Ross, who made the connection between mosquitoes and malaria. Audio Visual, LSHTM/Wellcome Images

We have awarded the first Wellcome Trust Investigator Awards in biomedical science. In total, 20 Senior Investigators and seven New Investigators were named, and 26 awards were made (one being a joint Senior and New Investigator Award). The Investigators come from 12 institutions across the uK and one in Brazil. The New Investigators include Dr Pedro Hallal from the Federal university of Pelotas in Brazil, who will be studying the effects of exercise in pregnancy on the future health of the child. Dr Christopher Thompson from the university of Manchester will use his New Investigator Award to understand the factors behind cell fate during development. At the Liverpool School of Tropical Medicine, Professor Alister Craig has been made a Senior Investigator, and will be exploring the role of cytoadherence when red blood cells stick to capillaries in cerebral malaria. Senior Investigator Professor Sara Rankin from Imperial College London is building on previous Trust funding, including a Research Career Development Fellowship and a university Award, to research the pharmacology of the mobilisation of stem cells from bone marrow and their use in tissue regeneration. We are accepting applications for Investigator Awards on a rolling basis. For more information see www.wellcome.ac.uk/investigators

Director of Science Funding named

The summer the new Wellcome Trust Director of Science Funding, Dr Kevin Moses, arrives, following the departure of Dr Alan Schafer last year. Kevin takes up his post in July. The key function of the Director of Science Funding is to continue to find, support and rigorously assess the best scientists. The best scientists make the best science, he says. I find the breadth of opportunity at the Wellcome Trust to be very exciting. Kevin joins us from Janelia Farm/Howard Hughes Medical Institute, where his most recent role was Chief Administrative Officer. His responsibilities included faculty recruiting, mentoring and review, and training programmes. His background is in academic research. After studying at the university of Cambridge for his degree, MA and PhD in natural sciences, he spent over 20 years studying the developmental biology and molecular genetics of Drosophila. I am very pleased that we have made such a strong appointment to this post, and look forward to welcoming Kevin, says Sir Mark Walport, Director of the Wellcome Trust.

New writing prize

Comedian Dara O Briain, Editor-in-Chief of Guardian News & Media Alan Rusbridger and Director of the Wellcome Trust Sir Mark Walport are among the judges of the first Wellcome Trust Science Writing Prize. The competition invites non-professional science writers based in the UK or Republic of Ireland to submit articles of up to 800 words on an area of science. Entries are now closed for this years competition. The winners, who will be announced at an ceremony in October 2011, will have their work printed in the Guardian or Observer, receive a 1000 cash prize and a science writing workshop at the Guardian.

Test your reflexes

If you happen to pass by our headquarters on Euston Road, London, keep an eye out for the new interactive window display, Reflex by rAndom International. This light installation contains LEDs that respond to the movements of people walking past the windows, emulating the collective decision-making processes of swarming animals such as bees.

Summer at Wellcome Collection

As featured in Wellcome News 66, Wellcome Collections Dirt Season is well underway. You can catch the Dirt exhibition until 31 August, as well as a host of events. These include the Evolution of Disgust debate on 14 July, the exploration of unclean Beings on 1516 July and Archaeological Dirt on 21 July. There are also two family days, on 23 July and 20 August. If you are not near London, then keep an eye out for some dirt-related fun at a number of festivals over the summer, and the closing of the Dirt Season in Glasgow. You can also test your own filthiness by playing Filth Fair, our hidden word game, available online and as an app for Phone and iPad. Find out more at www.wellcomecollection.org/dirt

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FUNDINg NEWS

Investigators expand
We have expanded the new Wellcome Trust Investigator Awards scheme to cover the medical humanities and bioethics, inviting applications from worldclass scholars asking the most important questions at the interface of science, medicine and the humanities. The latest set of Investigator Awards covers two categories Medical History and Humanities, and Ethics and Society enabling scholars to pursue bold individual visions more flexibly. Our current bioethics programme has expanded to include the social aspects of biomedical research and health interventions more broadly, as well as research evaluating public engagement and health communication interventions. Applications for Investigator Awards are now open and the deadline for the first full applications will be 2 September 2011. For more, see www.wellcome.ac.uk/funding

Primitive Streak grows

Heart Tube Hat. Photo: Justine; model: Korinna at Models 1

Parasite prizes
Professor Hector Hugo Garcia has celebrated receiving the prestigious 2011 Prix Christophe Merieux from the Institut de France. Professor Garcia is our first Senior Fellow in Public Health and Tropical Medicine. He works on neurocysticercosis, a widespread, serious infection of the brain caused by the larvae of the pork tapeworm, Taenia solium. The 500 000 prize is awarded to a researcher or team studying infectious diseases in lowincome countries. Congratulations to Dr Simon Brooker, a Wellcome Trust Research Career Development Fellow based at the KEMRI Wellcome Trust Research Programme in Kenya, on being awarded the CA Wright medal by the British Society of Parasitology. The award is made to a mid-career scientist who, it is considered, will confirm their already outstanding achievements to become a truly distinguished future leader of their field. Previous recipients include our own Director of Technology Transfer, Ted Bianco.
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In 1997, we awarded Sciart funding to artist and former fashion designer Helen Storey and her developmental biologist sister, Kate Storey, for their project Primitive Streak. Together they created a series of textile and fashion designs that spanned the first 1000 hours of human gestation. Now, some 14 years on, they have received further funding to add new dresses to their collection. The new pieces explore the development of the lungs and incorporate bespoke textiles that evoke the feel and function

of respiratory surfaces. Over the spring, ten of the original 27 dresses and the new item, the Lung Dress, have been exhibited in Sheffield, Newcastle and London. Helen and Kate Storey will be speaking about Primitive Streak at Wellcome Collection on 28 July, where the Lung Dress will be on display for a short period. Find out more about the designs and the science that inspired them at www.primitive-streak.org

Funding for infection response

The theme for the latest round of funding from the Health Innovation Challenge Fund has been announced. Applications are now welcome for developing infection response systems scalable solutions that will better prepare the uK for the next public health emergency. The Health Innovation Challenge Fund (HICF) is a funding partnership between the Wellcome Trust and the Department of Health. It is making up to 15 million available for healthcare innovators who can offer solutions for improved detection, prediction, prevention and management of infectious diseases. Applications are due by 2 September 2011. This is the fifth call for proposals from the HICF, which stimulates the creation of innovative healthcare products, technologies and interventions, to benefit patients in the NHS and beyond. www.wellcome.ac.uk/hicf

FuNDING OPPORTuNITIES
www.wellcome.ac.uk/funding

Children of the 90s come of age

The Children of the 90s study is celebrating 20 years of research into the health of thousands of people in and around Bristol, and is now covering the children of the original children studied. The project formally the Avon Longitudinal Study of Parents and Children (ALSPAC) recruited over 14 000 pregnant women in 1991 and 1992 and has charted the health of the women and their children ever since. Now, with 6 million from the Wellcome Trust, the Medical Research Council and the university of Bristol, the project is planning to continue studying the original participants as well as involving all other interested family members, including grandchildren and other children of the study mothers. This additional funding means that we can investigate how the health of subsequent generations depends in part on what happens in the early life of future parents, says Professor George Davey Smith, Scientific Director of Children of the 90s. Contributing to improved health of current and future generations is our ultimate goal. The findings of the project to date include that fathers can suffer from postnatal depression and that taking paracetamol in pregnancy can lead to childhood asthma. Watch a short film on ALSPAC: www.wellcome.ac.uk/ News/2011/News/WTVM050756.htm

Wellcome Trust Genome Campus

Advanced Courses and Scientific Conferences

At the cutting edge of biomedical training, discussion and debate. Wellcome Trust Advanced Courses and Scientific Conferences are hosted in dedicated facilities at the Wellcome Trust Genome Campus in Hinxton a short distance from the historic city of Cambridge. Funding is now available for new Advanced Courses and to seed the developemnt of new Scientific Conferences. Please contact Dr Rebecca Twells, Programme Manager, for more information (rt@hinxton.wellcome.ac.uk). For details of all upcoming Advanced Courses and Scientific Conferences, please visit: www.wellcome.ac.uk/hinxton

New medical history fellows

We have awarded five new Medical History and Humanities Fellowships. The recipients include Dr Mingji Cuomu, a trained Tibetan medical practitioner working at the university of Oxford. She will explore, evaluate and document current educational methods used for Tibetan medicine, to ensure that traditional techniques do not die out. Dr Sarah Walters from the London School of Hygiene and Tropical Medicine will apply methods used to study historical populations in Europe to five countries in Africa. She will use parish registers to explore how populations have changed in sub-Saharan Africa over the 20th century, to boost our understanding of the impact of colonial rule on mortality and fertility. At the university of Cambridge Dr Hannah Newton will be looking at recovery from illness in England between 1580 and 1720, a time when contrary to popular understanding most ailments ended in recovery rather than death. She will investigate how doctors, patients and their families understood, experienced and responded to recovery, using sources including personal and legal documents, religious literature and medical texts.

Tibetan anatomical figure, c.1800. Wellcome Library

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RESEARcH NEWS

Solving structures for nicer gnashers

Cancers linked
The first genome scan for womb cancer, part-funded by us, has identified a genetic region linked to susceptibility to the disease. The region, which overlaps with the gene HNF1B on chromosome 17, has previously been linked to prostate cancer risk in men. This is the first region common to both cancers to be discovered, something that could indicate shared mechanisms of disease.
Spurdle AB et al. Nat Genet 2011;43:45154. Computer-generated graphical view of glucansucrase forming the glucan from sucrose. Fructose is the residual product of the reaction. Sohei Ito, University of Shizuoka, Japan

Weight-loss surgery
Supported by a 1 million Wellcome Trust Strategic Translation Award, Irish company Crospon has launched a new tool, an imaging catheter called the EF-620, the latest addition to the companys existing EndoFLIP imaging system. The catheter will give surgeons a consistent and reliable way of measuring the size of a sleeve they create during weight-loss surgery. It is hoped this will help surgeons create sleeves in real time, safely and consistently, and better understand why some weight-loss procedures fail. www.crospon.com

Scientists have solved the 3D structure of an enzyme involved in tooth decay, information that should prove useful in the design of new inhibitors that could be added to toothpaste and mouthwash to help protect teeth. Tooth decay can occur when dental plaque a biofilm containing bacteria and food debris is formed by a large glucose polymer called glucan on the tooth surface. Acid secreted by the bacteria breaks down the tooths enamel. Scientists using Diamond Light Source, the uKs national synchrotron science facility, worked with researchers

from the Photon Factory in Tsukuba city, Japan, to study how the enzyme GTF-SI forms glucan. Several inhibitors that prevent this type of enzyme forming glucan have been identified but to date there has been little structural information available, says the projects lead researcher, Sohei Ito from the university of Shizuoka in Japan. We now have a better understanding of how the enzyme functions and how it can be stopped.
Ito K et al. Crystal structure of glucansucrase from the dental caries pathogen Streptococcus mutans. J Mol Biol 2011;408(2):17786.

Tracking a killer
An international team including Sitali Simwami and Dr Matthew Fisher from Imperial College London has studied the evolution of the fungus that causes cryptococcal meningitis, responsible for a third of all AIDS-related deaths. The researchers showed that the Cryptococcus neoformans variety grubii found in Thailand exhibits significantly less genetic diversity than that elsewhere, especially in Africa consistent with the idea that that the pathogen was introduced from Africa to Asia at some point within the past 7000 years.
Simwami SP et al. PLoS Pathog 2011;7(4):e1001343.

Call to use new antibiotic in typhoid

Researchers from the Wellcome Trust Major Overseas Programme at the Oxford university Clinical Research unit in Vietnam and the Oxford university Clinical Research unitPatan Academy of Health Sciences in Nepal have conducted the largest randomised controlled trial for typhoid to date, and are now calling for the use of the drug gatifloxacin to treat young people with the disease. They compared the standard treatment for typhoid, chloramphenicol, to gatifloxacin one of a new generation of antibiotics called fluoroquinolones. Gatifloxacin was released in North America in 1999 but was withdrawn after a 2006 study claimed that it can cause serious side-effects, including very high and low blood sugar. The researchers found both drugs to be equally effective, but showed that the side-effects were significantly worse with chloramphenicol, a course of which takes longer to complete and costs more than gatifloxacin. They have now submitted evidence to the World Health Organization arguing that gatifloxacin should be retained in young people not at risk of diabetes. The drug is also in phase III trials for the treatment of tuberculosis.
Arjyal A et al. Gatifloxacin versus chloramphenicol for uncomplicated enteric fever: an open-label, randomised, controlled trial. Lancet Infect Dis 2011 [epub ahead of print].

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Limiting the effects of a loss of blood supply

The loss of blood supply to parts of the body can cause serious tissue damage, including stroke and heart attack. Now, researchers have identified a specific pathway of the innate immune system that causes an inflammatory response to oxygen-deprived cells and tissues, and have managed to block this response in mice with a single injection. This inflammatory response contributes to major loss of tissue and organ function. Now, with long-term Wellcome Trust and Medical Research Council support, an international team led by Professor Wilhelm Schwaeble from the university of Leicester has identified a new therapeutic target to limit this type of tissue loss. The target is mannan-binding lectinassociated serine protease-2 (MASP-2), a key component of the lectin pathway of complement activation. The researchers found that when this enzyme was absent or blocked, the tissue inflammation and loss that usually occurs when tissues are reperfused following a temporary loss of blood supply was significantly reduced. They also reduced tissue damage in mice using a single injection of a neutralising antibody against MASP-2. Therapies based on these findings have the potential to improve the outcomes of heart attacks, strokes and transplant surgery, and may be applicable to any surgical procedure where a temporary disruption of blood flow could put tissue at risk.
Schwaeble WJ et al. Targeting of mannan-binding lectinassociated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury. Proc Natl Acad Sci USA 2011;108(18):75238. Illustration showing the circulatory system. Medical Art Service, Munich/Wellcome Images

New target for TB vaccine

Every day, 4700 people die from tuberculosis. The only available vaccine, BCG, protects against severe disease in children but is not effective in adults. Now, scientists have discovered a protein produced by Mycobacterium tuberculosis the bacterium that causes tuberculosis that could be the key to a new vaccine. In the new study that we have funded, scientists have identified a protein called EspC that triggers a stronger immune response in people infected with M. tuberculosis than any other known molecule does. This protein is not present in the BCG vaccine, which means that a vaccine based on EspC would provide immunity over and above that provided by BCG. Weve shown that EspC, which is secreted by the bacterium, provokes a very strong immune response, and is also highly specific to MTB [M. tuberculosis], says senior author Professor Ajit Lalvani, from the National Heart and Lung Institute at Imperial College London. Surprisingly, our results also show that this molecule could underpin next-generation diagnostic blood tests that can rapidly detect latent TB infection. In other work, researchers have claimed that the standard approach to re-treating TB in low- and middleincome settings is failing. They call for improvements in the way the disease is managed, including greater access to rapid diagnostics for drug-resistant TB, second-line treatment and antiretroviral HIV therapy.
Millington K et al. EspC is a highly immunodominant E1-dependent secreted antigen specific for Mycobacterium tuberculosis infection. Proc Natl Acad Sci USA 2011;108(14):57305. Jones-Lpez EC et al. Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study. PLoS Med 2011;8(3):e1000427.

Anti-TB poster featuring Albert Calmette, co-discoverer of the BCG vaccine, 1934. Wellcome Library

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cAREERS

DR CHRIS CONNOLLY

HOW I GOT INTO... THE BIOLOGY OF BEE BRAINS

In the jokes of a certain kind of comedian, the mother-in-law comes across as part menace, part millstone. But for neuroscientist Dr Chris Connolly from the university of Dundee, his mother-in-law was the source of the impetus to open up a whole new area of research. By Chrissie Giles.
n Christmas Day 2008, my mother-in-law gave me A World Without Bees by Alison Benjamin and Brian McCallum, a book that describes the decline of the honeybee. As a neurobiologist reading, it struck me that many of the symptoms of colony collapse disorder were consistent with some kind of brain disorder. I was thinking about pesticides and realised that so-called sub-lethal doses [which dont kill pests] may affect how bees behave. I decided that this is more or less the kind of thing weve been doing on mammalian brain cells, so if we could apply this to the bee brain, we could find out if these chemicals have sub-lethal effects at the level of individual cells, neural networks [circuits of nerve cells], whole animals or entire colonies. So, I had the idea, but thought that it might be hard to get funding because I didnt work in the field. I applied as an individual to the Co-operatives Plan Bee, which funds research into the decline of the honeybee, but was unsuccessful. But something wasnt letting me drop the idea, as then I heard about the Insect Pollinators Initiative, and the 10 million of funding it was making available. This got me thinking about forming a larger, multidisciplinary team. I researched the science in more detail on PubMed, the online library of scientific papers, and thought about how Id assemble a team. Although I knew many neurobiologists who could help me with the cellular and molecular aspects of the project, I had no experience working with bees. I called up Professor Pat Wilmer, a pollination biologist at St Andrews, for some help. She put me in touch with expert neuroscientists who are using bees as models to investigate mechanisms of learning and memory. This was a fantastic advance in assembling a world-class team. We applied, and heard our proposal was one of nine chosen to be funded. Serendipitously, the proposed work on bee receptors overlapped with my work on human receptors. In bee research, there is lack of stable cell lines (different types of bee cells to grow and use in the lab), as, unlike human cell lines, these are very hard to make. Particularly tricky are insect cells studded with nicotinic acetylcholine receptors, found in the nervous systems of vertebrates and invertebrates alike. Fortuitously, in a separate project, Ive been working with Professor Neil Millar, a neuropharmacologist at university College London, on a chaperone protein that helps cells produce these receptors. Hes a partner on our pollinator project, and we will attempt to create the first ever honeybee cell line for pesticide screening. Since getting the funding, Ive given talks to many organisations and conferences, including CropWorld, the Association of Independent Crop Consultants and both the Scottish and British Beekeepers Associations quite a different circuit to what Im used to. In what private time I have, Im interested in wildlife, nature and the environment; as a professional, Im interested in the medical implications of dysfunctional neuronal communication. Reading the book on bees, bells started ringing in my head as I realised that I could join up my interests in one project. My mother-inlaw is very excited too, especially as this is all thanks to her. Of course, now I find it impossible to get that worklife balance just as I like it.
On this project, Chris is working with Dr Jenni Harvey (University of Dundee), Dr Nigel Raine (Royal Holloway, University of London), Dr Geraldine Wright (Newcastle University) and Professor Neil Millar (UCL). For more on the Insect Pollinators Initiative, see www.wellcome.ac.uk/pollinators.

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Can you contribute to our world-class image resource?

The Wellcome Images collection incorporates a broad spectrum of images, from the history of medicine to cuttingedge biomedical science. We are currently looking for new images from research scientists, clinical photographers and illustrators to expand our biomedical collection. We are particularly keen to receive high-quality images from research on stem cells, parasites, infectious diseases, neuroscience and genetics. Find out more about our collection at images.wellcome.ac.uk
Darkfield light micrograph of a sea louse, Lepeophtheirus salmonis. Pablo Rojas/Wellcome Images

Or contact Dr Laura Pastorelli: E l.pastorelli@wellcome.ac.uk T +44 (0)20 7611 8347

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Dogma on mental illness is a threat to progress

PROFESSOR NICK CRADDOCK, CARDIFF uNIVERSITY
t is commonplace for people to hold very firm views about the nature and causes of mental illness, based on hunch, ideological perspective and anecdote. For example, some believe all mental illness is explained by adverse social circumstances; others think that it simply reflects a lack of ability to cope with lifes stresses. While many people are very supportive of the need for better understanding of mental health, even highly intelligent and otherwise open-minded individuals not infrequently hold dogmatic but ill-informed views about mental illness. This thinking extends to biological scientists, Nobel Prize winners and even members of grants panels. Many naive views seem to be based on extrapolation of knowledge of situations of relatively mild mental distress. However, this extrapolation does not work. Consider the common assumption that all depression is the result of inability to deal with life, a character weakness. While this view might be of value for mild depression, it is woefully inadequate for severe depression accompanied by stupor or delusions situations that can be life-threatening. In contrast, few people would be comfortable making similar generalising assumptions about the causes and management of severe cardiovascular disease (for example myocardial infarction) based only on their observations of people who get breathless on exercise. Within the scientific and lay press, psychiatric illnesses are discussed in a more heated, opinionated and less helpful way than nonpsychiatric illnesses. An example was the media furore surrounding the report that rare structural genomic variants are more common in cases of attention deficit hyperactivity disorder (ADHD) than controls. Despite voicing of all the caveats about the complexity of causation and importance of environmental factors, there was great disquiet voiced from some commentators that ADHD was referred to as a genetic disorder. Had similar wording been used about heart disease or diabetes, there would not have been such inflammatory debate. And yet the evidence for genetic influence on ADHD is as strong as for these physical illnesses. All involve a complex mixture of genes and environment. An increasing understanding of basic neuroscience, together with human investigative tools such as molecular genetics and multimodal brain imaging, provide the opportunity for a revolution in diagnosis and management of mental illness over the coming two to three decades. However, realising this opportunity will require us all to be open-minded and guided by evidence rather than prejudice. This includes politicians, the public, professionals, funders and grants panels, as well as researchers. For the sake of the many people whose lives are affected by severe mental illness we need to walk the walk and not just talk the talk.

OPINION

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14 | Wellcome NEWS

BRAIN RESEARcH

PROFESSOR ELEANOR MAGuIRE

MAPPING MEMORIES
From taxi drivers to people with amnesia, Eleanor Maguire has studied the brains of hundreds of people in her quest to understand how we make memories of both our personal experiences and the world around us. Roger Highfield navigated to the Wellcome Trust Centre for Neuroimaging at uCL to find out more.

Summer 2011 15 SPRINg 2011 || 15

he way that our recollections shape who we are and the way we think has long been explored in literature and popular culture, from the writings of Marcel Proust and Philip K Dick to films such as Strange Days, Memento and Eternal Sunshine of the Spotless Mind. But when Eleanor Maguire first became interested in the subject, her motivation to put memory on a scientific basis was more personal. I am absolutely appalling at finding my way around, she confesses. I wondered: How are some people so good and I am so terrible? She started out her quest to understand memory while working with patients for a doctorate at university College Dublin. Today Eleanor is still dedicated to the quest, as a Wellcome Trust Senior Research Fellow and Professor of Cognitive Neuroscience at the Wellcome Trust Centre for Neuroimaging at university College London, where she heads the Memory and Space research laboratory. She wanted to explore how our experiences, both big and humdrum, forge and sunder the vast network of connections between cells in a human brain. So, she and her colleagues are studying memory using brain scanners, notably magnetic resonance imaging (MRI) techniques. Some are tuned to reveal the extraordinary structural complexity of the brain (structural MRI), others to the tiny changes in blood flow that accompany thought (functional MRI, or fMRI). But central to her work is the field of neuropsychology, working with patients who suffer some kind of memory impairment such as amnesia. fMRI can tell you which brain areas are involved in memory but you are never sure which ones are really necessary. That is where the study of patients comes in. She is most fascinated by one region located deep in the brain, called the hippocampus. This is known to be a memory centre and is damaged in people with amnesia but Eleanors investigations suggest that its role is more subtle and interesting. She believes that it provides a kind of spatial scaffold for memories, one that is
16 | Wellcome NEWS

Cabbies often tell me about my work, not realising who I am. What is extraordinary is that they usually talk about the hippocampus.
essential if we are to make sense of our experiences. In the long run, her research will help us understand how our memories can be affected by age and shredded by dementia and developmental disorders. With that understanding may, of course, come new tests and treatments. We are all about helping patients, ultimately. But we cant come up with new kinds of rehabilitation until we understand precisely how memory works. Her first big advance came in 2000, in a study that would generate headlines worldwide, capture the public imagination and even win her a share of the highly coveted Ig Nobel Prize, a parody of the Nobel Prizes that is handed out each year for achievements that first make people laugh, and then make them think. She scanned the brains of 16 London black-cab drivers who had spent an average of three or four years learning the Knowledge the entire layout of the 25 000 streets in London. What was remarkable was

BIM/iStockphoto

that she found the taxi drivers had a larger hippocampus than control subjects, particularly on the right side. The longer they had been on the job, the larger their hippocampus. These findings seem to indicate that the hippocampus plays an important role in storing spatial memories. Furthermore, when Eleanor and colleagues followed the progress of trainee taxi drivers, they found that the drivers who successfully passed the Knowledge were those who showed the greatest alteration of the hippocampus. Experience can change the brain, she says. Do similar changes accompany other feats of memory? Not necessarily, according to Eleanors studies of participants in the World Memory Championships and of bus drivers: in neither group could she find structural changes of the kind seen in the taxi drivers. Memory champions often use

navigation strategies to boost their performance, but the amount of large-scale space memorised is small. And bus drivers use much more restricted routes than taxi drivers. So it appears that their memory feats do not place the same demands on the hippocampus. In recent years, Eleanor has focused more on the second critical role of the hippocampus, in laying down autobiographical memories of our past experiences. Here, people with anterograde amnesia have played a central role in her studies. These people live permanently in the present. Their speech and intellect tends to remain intact, because remembering facts and general knowledge is not dependent on the hippocampus. However, their experience of the world is frozen in time: they cannot remember anything

that occurs after their brain damage took place. Eleanor says: If they do a couple of hours of tests with me, for example, and I leave the room for ten minutes and come back, they cant remember anything about me or what they had been doing. In the healthy brain, many regions are involved in supporting personal, autobiographical memories, because these are coloured with emotions and depend on the spatial, temporal and social context. To understand how the brain stores and recalls this form of memory, it is important to evoke the whole memory during studies. One way of doing this is to project a photo of a party or wedding from a family album onto the screen, prompting the participant to recall and re-create this particular event in their past while their brain is being scanned. In this way, Eleanor and her team
Summer 2011 | 17

From knots to notes, people use many tricks to remember things. Eleanor Maguire says that the best way is to make a list.

Stop press
Since this interview, Eleanor Maguire has been elected a Fellow of the Academy of Medical Sciences. This honour recognises her important work in the field of cognitive neuroscience.

have investigated the episodic memories of everyday events, such as seeing someone posting a letter or preparing to ride a bike. To explore how such memories are recorded, her team showed ten volunteers three short films and asked them to memorise what they saw. The films were basic, sharing a number of similar features all included a woman carrying out an everyday task in a typical urban street, and each film was the same length, seven seconds long. The volunteers were then asked to recall each of the films in turn while inside an fMRI scanner. A computer program then studied the patterns and had to identify which film the volunteer was recalling purely by looking at the pattern of their brain activity. Remarkably, it was possible to tell which film they were thinking of. Although a network of brain areas
18 | Wellcome NEWS

support memory, the computer program performed best when analysing activity in the hippocampus itself, suggesting that this is the most important region for representing episodic memories. In particular, three areas of the hippocampus the rear right, front left and front right areas seemed to be involved consistently across all participants. This work suggests that our memories are encoded within the brain in a predictable way. While earlier fMRI work has shown the typical brain areas involved, this study, after averaging the activity in many heads, showed the precise circuits used to recall one particular memory trace in an individuals brain, down to a resolution of just over one cubic millimetre revealing much more detailed information about the hippocampus at work.

Now it is possible to investigate precisely which brain areas hold a given memory, how their use varies with time and what happens to these areas as a result of disease or injury. But, of course, there are even more speculative implications. Does this mean that we will one day be able to use a scanner to read a mind? Eleanor emphasises that her participants were tasked with recalling one of three short films that they had previously viewed, so the researchers were already aware of the nature of what it was they were thinking about, just not the identity. There are ethical issues but we did do the study with the cooperation of the patients and, although arguably a form of mind reading, it does take place under very controlled circumstances. While confirming the key role of the hippocampus in recalling the past,

This study, after averaging the activity in many heads, showed the precise circuits used to recall one particular memory trace in an individuals brain
whole experience in their minds eye, seeing instead just a collection of separate images. We believe this suggests a common mechanism that might underpin both recalling real memories and how we visualise imaginary and future experiences, with the hippocampus providing the spatial backdrop or context into which the details of our experiences are bound, she explains. The work closes the loop with her studies on spatial navigation, showing that space may be the key to understanding the function of the hippocampus and its role in memory. Despite these advances, huge challenges remain if she is to convince her peers that the hippocampus plays a central role in providing the spatial context for our experiences and helping us to think about the future. I believe that it is there to support coherent scenes. It is providing a spatial backdrop, or canvas, on which we play out the recall of memories, plan a route or simulate what will happen to us in the future. But that is still quite controversial and we need to link a lack of spatial representation directly to amnesia. She is also keen to apply her work in novel treatments for memory disorders. The good news is that the study of taxi drivers suggests that it is possible to train a hippocampus. For people who have hippocampal damage and associated difficulties with memory, the question of whether the brain can mend itself, and memory be recovered, is a pressing one. Today, Eleanor is gratified to find that her work has gone beyond the confines of the international conference circuit and academic journals. More than a decade after she started her pioneering research, she sometimes finds herself in the back of a London taxi. Cabbies often tell me about my work, not realising who I am. What is extraordinary is that they usually talk about the hippocampus. Read an extended version of this (from early July) and our other features to celebrate the Wellcome Trusts 75th anniversary at www.wellcome.ac.uk/75 Roger Highfield is the Editor of New Scientist. For two decades he was the science editor of the Daily Telegraph and he still contributes a column to the science page of the newspaper. He has written or coauthored several books. The latest, written with Martin Nowak of Harvard university, is SuperCooperators: The mathematics of evolution, altruism and human behaviour (Or, why we need each other to succeed). www.rogerhighfield.com Want to find out more?
Woollett K et al. Talent in the taxi: a model system for exploring expertise. Philos Trans R Soc Lond B Biol Sci 2009;364:140716. Chadwick MJ et al. Decoding individual episodic memory traces in the human hippocampus. Curr Biol 2010;20:5447. Hassabis D et al. Patients with hippocampal amnesia cannot imagine new experiences. Proc Natl Acad Sci USA 2007;104:172631.

Eleanor and colleagues went on to make a fascinating discovery when she asked amnesic patients to describe imaginary experiences. She and her team asked the patients to imagine and then describe in detail situations in commonplace settings, such as a beach, pub and forest, as well as potentially plausible future events such as a Christmas party. The patients ability to construct future and fictitious events was also severely impaired. The role played by the hippocampus in processing memory was far broader than merely reliving past experiences, she says. It also seems to support the ability to imagine any kind of experience including possible future events. That is why, in this sense, people with damage to the hippocampus are forced to live in the present. Furthermore, the patients reported that they were unable to visualise the

Summer 2011 | 19

PUBlIc ENgAgEMENT

DR JuLIAN RAYNER

ANY QuESTIONS?
To find out what working in science is like, nothing beats talking to someone who does it day in, day out. A Wellcome Trust-supported event has given this approach a reality-TV-style twist by giving students live and direct access to scientists, whom they then vote out one by one. We meet one scientist who took part to find out more.
On 14 March 2011, malaria researcher Dr Julian Rayner sat down at his desk in the Wellcome Trust Sanger Institute and flexed his fingers. The questions started to appear on the screen. Whats your favourite made-up movie chemical? How much paperwork does being a scientist involve? Do all types of mosquitoes carry malaria? Over two weeks, Julian answered these and 250 other questions, as one of the 30 contestants in the latest Im a Scientist, Get Me out of Here event. Im a Scientist was piloted in 2008, supported by a Wellcome Trust People Award. Produced by Gallomanor, its an offshoot of Im a Councillor, Get Me out of Here, launched to engage teenagers with local politics by allowing them to talk directly to councillors. The pilot of the science version was a hit, and the team has run events every March and June since 2009. The events are not just about attracting students to study and launch careers in science, but also to equip all involved with ways to think scientifically and help them become responsible citizens. Theyll all have votes to cast, goods to buy, decisions to make, says project director Sophia Collins, writing on the Wellcome Trust blog. I want them to be doing that with some ability to think about the issues surrounding science. Julian heard about the competition through a colleague in the Sanger Institutes Public Engagement team, applied, and was assigned to the Argon zone with a cell biologist, a soil scientist, a PhD student working on vitamins and a rocket engineer. Every day for two weeks they tackled students questions online and participated in at least one live 30-minute chat session.

It was quite a jump from taking questions from a small audience of students at the end of a presentation, says Julian. The chat sessions were great though: you cant prepare for them, and when theyre done, theyre done, Julian says. Theres a need to explore instant messaging more as a tool to engage busy scientists. Were there any recurring themes? The students wanted to know what its like to be a scientist what I do on a day-to-day basis, what exams I took. It seems that they know that scientist is a career, but they never get to talk to a career scientist. Its not just the students that learn a lot: Students ask great questions that can help scientists see their work differently, or think about things theyd

never considered. Scientists get lots of practice talking about their work and explaining science. The students vote out scientists from each zone one by one. The last scientist standing in the Argon zone was Julian. He plans to use the 500 prize money to cover the travel expenses of schools visiting the Sanger Institute, which already welcomes some 2000 students a year. What was the secret to victory? Winning or losing was a random process as far as I could tell, Julian laughs. But Id certainly recommend taking part to anyone!
heck out Julians answers here: C argonm11.imascientist.org.uk/profile/julianrayner he June event was just beginning as we went T to press, but its not too late for students or scientists to apply to take part in the 2012 events see more at imascientist.org.uk/about

20 | Wellcome NEWS

Wellcome Trust Translation Awards

We are a committed funder of translational R&D. We work with world-class investigators in academic institutions and companies alike, in pursuit of solutions for unmet medical needs.

We fund medical innovations in the following areas: therapeutics diagnostics enabling technologies regenerative medicines vaccines medical devices.

Bridging the gap between fundamental research and innovative health products

Next deadline for Translation Award preliminary applications: 22 July 2011

www.wellcome.ac.uk/ta
Summer 2011 | 21

22 | Wellcome NEWS

clOSE-UP

ARTS AWARDS

HIJACKING NATuRAL SYSTEMS

For one day a week over a six-month period, artist Jo Berry stepped up to the laboratory bench to get hands-on with a range of cell-imaging techniques. Working alongside scientists Dr Nicholas Holliday and Tim Self from the School of Biomedical Sciences, university of Nottingham, she conducted experiments involving the appetite hormone ghrelin. These included investigating how different drugs affect the localisation of ghrelin receptors in cells. She gained experience using a variety of imaging techniques, including live cell confocal, high content and total internal reflection microscopy. Berry, based in Carsington, Derbyshire, used the images generated during the work to create a series of short films, vinyl drawing and multilayered lightboxes. Her research produced more than fascinating imagery, though she was lead author on a poster and abstract presented at the British Pharmacological Society Winter Meeting 2010 (www.pa2online.org). Her project, Hijacking Natural Systems, goes on show in Derby from July 2011, before moving to Nottingham. The project was funded in part by a Wellcome Trust Arts Award. Find out more at www.joberry.co.uk and joberry-artist.blogspot.com

5 1 2 36 Vinyl artwork created for the exhibition at the Derby Art Museum and Gallery. Movement of HL60 cell projections called filapodia. Based on fluorescence images of the cellular trafficking of ghrelin and its receptor.

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ONlINE HIgHlIgHTS

STEM CELLS, ELEMENTS AND MORE

BLOG & FILM

Wellcome Trust blog One of the aims for our blog is to provide a place where the many researchers we support can tell stories about their work. Over the last few months we have been delighted as more and more of our researchers whether PhD students or research fellows have written for us, covering everything from the neuroscience of language (wp.me/pJJaZ-1dZ) and masculinity and madness in the Victorian age (wp.me/pJJaZ-1bn) to stem cells (wp.me/pJJaZ-18Y) and centrioles, via a Lord of the Rings pun (wp.me/pJJaZ-19B). We have been honoured to host established bloggers such as Dorothy Bishop (wp.me/ pJJaZ-1gz) and Daniel Macarthur (wp.me/pJJaZ-1hU), but equally proud to give a voice to so many first-time bloggers. If you have a story to tell, email m.looi@wellcome.ac.uk. Wellcome Trust and Wellcome Collection films The new films added to our YouTube channels deal with topics as varied as bipolar disorder, the secrets of chemical elements and life as a medical photographer. Ever wondered what colour oxygen is? What solid iodine looks like? Why mercury is so important to chemists? In three short films, Dr Andrea Sella gives the lowdown on these three elements, demonstrating how to turn oxygen into a liquid and iodine into a purple gas, and taking a look at the beautiful but deadly mercury. www.wellcomecollection.org/elements In the early 1990s, more than 14 000 mothers were recruited to the Children of the 90s project, which aimed to study parents and children at a level of biological, behavioural and psychological detail never seen before. Project director Professor George Davey Smith shows us around the studys base in Bristol. www.youtube.com/watch?v=xjOf0GTTliE The Bipolar Blues features Twink, former photographer for The Jam, who has experienced the extremes of bipolar disorder for more than two decades, and Professor Nicholas Craddock (see page 13), the principal investigator for bipolar disorder in the Wellcome Trust Case Control Consortium. This film garnered over 1000 views in its first week on YouTube and was featured in several science blogs and the Guardian website. www.youtube.com/watch?v=pAIJGX3RICA Finally, look behind the scenes of a 2011 Wellcome Image Awards winner in a film that follows medical photographer David Bishop, to give you a taste of what its like to be an observer during surgery. www.youtube.com/watch?v=b0s3-XSKhB0

Contact us on 020 7611 2200 or email conferencecentre@wellcome.ac.uk www.wellcomecollectionconference.org

Wellcome Collection Conference Centre is operated through two companies: The Wellcome Trust Limited, a company registered in England and Wales (no. 2711000), as sole trustee of the Wellcome Trust (a charity registered in England and Wales, no. 210183); and Wellcome Trust Trading Limited, a non-charitable company registered in England and Wales (no. 3227027), controlled by the Wellcome Trust. The registered offices of both companies are at 215 Euston Road, London NW1 2BE, UK. PU5122.9/05-2011/AF

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IN THE HOT SEAT

DECIDING WHOS FIT TO MAKE DECISIONS

DR GARETH OWEN
Dr Gareth Owen completed a degree in philosophy and physics before becoming a psychiatrist. He has recently completed a Wellcome Trust-funded fellowship at the Parliamentary Office of Science and Technology (POST) looking at the ethical, practical and legal issues surrounding decision making by people with mental disorders. He has produced a POSTnote to get us all to think about who should make decisions for us when were deemed unfit to do so.

What area do you work in? Im an academic psychiatrist at the Institute of Psychiatry, Kings College London working to understand how people with mental health disorders make decisions, and the problems they can have with decision making. This is now operating within a new legal framework the Mental Capacity Act 2005 (MCA) which specifies the rules under which people should be assessing anothers ability to make a specific decision (their capacity). The new Act challenges the idea that people with mental health problems are just unsound of mind, and tries to focus more closely on which decisions can and cant be made by people with conditions like schizophrenia or brain injury. What does the law say about this? Weve got two pieces of mental health law now. The Mental Health Act is based on the idea of protecting individuals and society; the newer MCA is based on peoples right to decide for themselves. When the MCA was a Bill, many of the debates were about whether it would permit euthanasia by the back door. Post-legislatively, thats not the debate at all. Now, were trying to understand how this Act fits with the Mental Health Act and deal with the confusion that this causes on the ground. The MCA also introduced the idea of devolved decision making via a legal instrument called lasting power of attorney for health and welfare, which is completely new for England. Adults can appoint a trusted friend or relative to become their health decision maker for when they lose capacity. People are starting to think about the consequences of that now.

What were your priorities for the POSTnote? For the last five years or so, Ive been interviewing people to build up a better picture of what capacity looks like on the ground. The POST fellowship was a chance to look at this at the policy level. I have interviewed parliamentarians, philosophers, lawyers and those working across medicine, which produced a massive amount of material. Compressing that into a four-page POSTnote was a job! I tried to tell the story of the MCA and put it into the context of mental health law in general. What do the changes mean for us? The MCA makes decisions around capacity a responsibility of all of us as citizens, because it acknowledges that much of the care for people that might not have capacity is given in the community. In practice though, most assessments of decisionmaking capacity are carried out by healthcare or social workers, because these issues come out in clinical settings. Another part of the Act is to try and change peoples mindsets and get them to plan for any future loss of capacity, particularly in the elderly. Its exciting that society is now much more face-to-face with these issues. Theyve been slightly repressed in the past, consistent with the history the Mental Health Act came out of the asylum tradition and its out of sight, out of mind mentality. Capacity is an evolving area, its definitely not game over!
ead Gareths POSTnote at www.parliament.uk/post R

Summer 2011 | 25

NUTS AND BOlTS

IMAGING TECHNIQuES

MRI SCANNER
On 3 July 1977, the first magnetic resonance imaging scan on a human was performed. Today, MRI is used widely in both medicine and research. This quick guide explores the science behind the ubiquitous technology that can get right under our skin. By Mun-Keat Looi.
MRI (magnetic resonance imaging) is commonly used in hospitals to look at what is happening inside the body for example, to monitor blood flow and to diagnose or stage tumours. The technique (and variations of it such as functional MRI) has also been used extensively in biomedical research, for everything from exploring how the brain interprets speech and music to seeing how taxi drivers brains differ from other peoples (see pages 1419). Compared with other imaging methods, MRI has plenty of advantages: it is non-invasive, and does not use potentially harmful radiation, as X-rays and many other imaging techniques do. It also does better for looking at soft tissues and, with one scan, allows you to view the body from multiple angles. But how does it work? MRI is all about magnets and radio waves. It relies on the fact that atoms (in this case, hydrogen atoms) are constantly spinning; most of them will fall into synch when you put them in the scanners magnetic field. Then, you send in radio waves to make them spin in a new direction, and when they afterwards return to their previous alignment, they emit energy (i.e. waves are bounced back the resonance in MRI). This energy is what the scanner uses to create an image. The lower the water content of a body area, the fewer hydrogen atoms there will be emitting signals. The weaker the signal, the darker the area appears on the scan. The result is various shades of grey: fat is quite light, but bone is dark.

Mini MRI
The Wellcome Trust recently awarded a Strategic Translation Award worth almost 2.5 million to GE Healthcare to investigate the use of MRI for newborns at high risk of brain injury. In the UK, approximately five in every 1000 babies born suffer brain injury, and of those, approximately one in five dies. Getting faster and more accurate diagnosis of brain problems in babies is essential for making treatment more effective. While MRI is widely accepted as a better diagnostic tool than ultrasound, it is often not practical to take babies out of neonatal intensive care to the MRI scanner, which is often in another part of the hospital or a different centre altogether. This funding will initially be used to investigate how MRI could be placed within the neonatal unit itself, removing the need to take babies out of intensive care.

Want to know more? Florida State university Magnet Lab: www.magnet.fsu.edu/education/ tutorials/magnetacademy/mri fMRI for newbies: psychology.uwo.ca/fmri4newbies/

Patient platform
This is where the patient lies, with the body part to be scanned in the exact centre of the magnetic field. The amount of water and fat in our bodies means that were full of hydrogen atoms, and its these that MRI targets.

26 | Wellcome NEWS

5
Most magnets used today are superconducting, so contain liquid helium as a coolant (at 269C). In the case of a quench, when the helium boils, helium gas is directed out of the room via a quench pipe.

Magnet
Magnets commonly used in MRI scanners today are 0.53.0 tesla strong, but some research uses magnets as powerful as 60 T (a fridge magnet is about 0.005 T). No metal is allowed anywhere near the scanner. Coins, jewellery and other objects accidentally left in scanning rooms become potentially dangerous projectiles when close to the magnet. And any bankcards will be erased

Radio frequency coil

This directs a radio wave at the area you want to examine and detects the waves bounced back. The room is shielded so that other radio waves (e.g. those carrying The Archers) dont interfere. With MRI, you can use different dyes to alter the magnetic field and produce a wider range of contrasts, which can make it easier to distinguish between normal and abnormal tissue.

Gradient coils
These are other magnets within the main magnet. Lower in strength than the main magnet (typically 0.0180.027 T), they are arranged to alter the magnetic field. This helps to focus in on the area you want to look at, literally slicing the image any way you want.

Computer system
(not shown) This takes the signals from each point and maps the tissue, creating 2D and 3D models using a mathematical formula. Standard MRI forms a static image of a body part. Functional MRI looks at brain activity. By measuring the amount of oxygenated blood flowing around the head (the blood oxygenation level dependent or BOLD response), it follows brain functioning. This allows researchers to track which areas are active when people perform a specific task.

Summer 2011 | 27

TEcHNOlOgy TRANSFER

MEDICAL DEVICES

SMOOTH OPERATOR
Robots in the operating theatre may sound like the stuff of science fiction, but robotic devices are being used more and more, promising safer, more accurate and even scar-free surgery. Chrissie Giles meets a team from Imperial College London working on i-Snake, a robotically controlled snake that could transform surgery.

eoples dedication to their work comes out in all kinds of ways. Today, there are six of us and a camera crammed into the mechatronics lab at the Hamlyn Centre, Imperial College London. As we chat about how some of the machines are used in the jewellery trade, engineer and Co-Director of the Centre Professor Guang-Zhong Yang slips off his wedding ring and passes it around. It seems his passion for engineering extends even to the symbolism of love, as he explains that the ornate ring has been made with one piece in three dimensions using a technique called electric discharge machining. I note this down on a growing list of things Im learning this afternoon. Our visit here to a department that develops technology to minimise the
28 | Wellcome NEWS

physical and psychological impact of surgery began in much the same vein, with my colleague and me struck dumb by the labs rapid prototyper. Rapid is right: in front of our gaping eyes, it produced a fully formed mechanical component, three-dimensionally printed in layers just 16 microns deep. You could even scan your head and get a model of that printed, one of the projects engineers tells us. In the next office, a surgeon talks to us as he assembles an endoscope from a large case. In an engineering lab across campus sits a large plastic box with small holes in the lid, used to train surgeons in keyhole surgery. Inside, garish latex organs wobble ominously. Its becoming clear that this is no ordinary engineering project. The project funded by a Strategic Translation Award made by the Wellcome Trusts Technology Transfer

division aims to transform keyhole surgery. Such minimally invasive techniques have already improved the care of many patients. Instead of having to cut open the body to expose the organs, surgeons can slide cameras and surgical instruments into the body, through tiny incisions, on the end of flexible rods. Led by Guang-Zhong and his colleague surgeon (and former health minister) Professor Lord Ara Darzi, the team of engineers and surgeons are developing a robotic snake-like device called i-Snake. It will be self-propelled, able to move through the body to its target, where the surgeon can operate it by remote control. This project is about advancing the current generation of keyhole surgery into something thats more accessible and more flexible in the long term, says Guang-Zhong.

Professor Guang-Zhong Yang (far right) and other members of the i-Snake team.

Robots in surgery using robots in the operating theatre is not new. At St Marys Hospital we were the first group in the uK to use robots to help us do some surgical procedures, says Ara. The robotically assisted platform was itself quite a big step in allowing us to do surgery much more precisely, even more than through a keyhole or open approach. St Marys Hospital, part of Imperial College, acquired in 2001 a da Vinci surgical robot, made by Intuitive Surgical. used originally in cardiac surgery, the robot was adopted by surgeons removing the prostate gland a procedure that carries the risk of leaving the patient incontinent and impotent, with huge implications for their future quality of life. There are many proposed benefits of the da Vinci, but there are costs too, explains Mr James Clark, a surgeon and

PhD student on the i-Snake team. In the uK, the robot is predominantly used for removing the prostate for prostate cancer, although some groups are exploring its potential in other fields including bowel and thyroid surgery. It enhances the surgeons precision, and reduces the chance that vital nerves close to the operation site will be damaged. For many operations, only specific parts of the procedure require such precision. With i-Snake were trying to exploit this and see if we can develop a device that is not only compact but that can be used on an on-demand basis. We are always looking for new surgical applications that could be derived from this sort of technology. Keyhole surgery is not the only potential use of i-Snake it may also be useful in an emerging field of surgery called natural orifice transluminal endoscopic surgery (NOTES), in which

surgeons operate through body orifices such as the mouth or vagina. This means that no incision is required so there will be no scar (see panel, page 31). The robotic snake is not just about improved access to distant tissues, but also about augmenting the surgeons own senses acting as an extension of their eyes and hands. i-Snake stands for imaging-sensing navigated and kinematically enhanced, says GuangZhong. We use imaging and sensing so that it can view the tissue its touching and can see where it is going. Imaging will be a major benefit of the robot. When removing a tumour, for example, clinicians could scan the tissue before surgery to differentiate between cancerous and healthy tissue. Then, during the operation, the tissue could be overlaid with the scans, to help ensure that all the cancer is removed and that healthy tissue is spared.
Summer 2011 | 29

Before coming to this group, I would see a virtual robot moving on the screen, but to control a real robot using my algorithms is a whole different story. Its very exciting, but challenging too. Valentina Vitiello (above left)

Its really opened my eyes. While all your attention might be directed to some technical problems, a clinician might come to you and tell you that some situations will never exist in a clinical scenario. Ka-Wai Kwok (above right)

getting into trials early in the design process

an engineers view on working with surgeons

The collaboration works so well because were able to tell each other where the limitations are. Its easy for an engineer to build a device thats wonderful, but that when its put into a real surgical environment has no clinical relevance. Mr James Clark (left)

a surgeons view on working with engineers

Surgeons will also be able to use real-time imaging during the operation to see beyond the tissue theyre working on. This will help to stop them damaging tissues, such as blood vessels, that they cant see, and will obviate the need for other imaging, such as histopathology, to be performed before the operation. Taking control Visions of slithering reptiles are put to rest as we are shown a prototype a long, thin metal device made of narrow jointed segments connected in a line. The robot is just over 1 cm wide, and hollow, so that instruments can be put inside, emerging from the tip when required. The length of the robot will vary from 20 cm to two or three times this, depending on the type of operation and how the organ is accessed. Although the word robot implies automation, with this device, the
30 | Wellcome NEWS

surgeon is always in control. It is, essentially, a telemanipulator something that you control manually but that works remotely. Balancing what the surgeon can and cant do with the robot, the so-called humanrobot interface, is a major activity for some of the engineers working on the project. i-Snake consists of many articulated parts. Its not efficient to control the joints one by one, so my work is to design a control scheme for the operator to manipulate those joints simultaneously, says medical robotics engineer and PhD student Ka-Wai Kwok. His colleague and fellow PhD student Valentina Vitiello adds: We consider the head of the robot to be controlled by the surgeon we dont want to make the whole thing automatic. However, while the surgeon is carrying out the procedure we need to make sure that the rest of the articulated body is not

causing tissue damage. To do this, the engineers can set a limited workspace, which means that certain body areas are made physically out of bounds to the snake. Safety is always our concern, says Ka-Wai. Thanks to advanced medical imaging we can frequently update the allowable workspace of the surgical robot inside the body to provide appropriate guidance to the robot. Were doing more than making the robot avoid obstacles, were preventing tissue damage and controlling the force the robot applies to the tissue. A testing environment While some engineering projects can run for years before the product is tested in a real-life environment, i-Snake couldnt be more different. In the three years of the project so far, six different iterations of the snake robot have

The best thing that you can actually do is to try and make things that can help people. Its obviously very interesting to build a robot that will drive around a corridor, but if its a practical application using the same technology inside a human, it has potentially much more benefit. The word multidisciplinary is rhetoric some departments use the term to attract money but they dont know what theyre talking about. This project is very, very different. Prof. Ara Darzi (above) David Noonan (above right)

Taking NOTES What is it? NOTES (natural orifice transluminal endoscopic surgery) is an emerging surgical technique in which surgeons go through a natural orifice (such as the mouth, rectum or vagina) instead of making an incision on the outside of the body. What benefits does it offer? No incision means no incisionrelated complications and no visible scars. What about the risks? It can be difficult to navigate precisely to the target organ with current instruments. There is still an access hole (albeit inside the body) that needs to be closed safely.

on translational research

on multidisciplinary working

existed, each tested in surgical trials using pigs. Each trial sees the team test the previous and the new model of robot. The reality is that were constantly refining and improving, says engineer and research assistant David Noonan. Well improve the actual robot, the articulated sections, but also the software, the driver electronics to control it, the user interface. Its almost a complete overhaul of the system each time. Its also the time that the surgeons get to be hands-on with the device, which can be nerve-wracking for the engineers. We had one trial where the system was damaged by the surgeon testing it. Its not their fault although we do joke about it with them within the team. The team hopes to complete the design and engineering in the next 18 months, and the next stage is to seek regulatory approval to test the device in

humans. ultimately, it could have multiple applications: gastrointestinal, gynaecological and, eventually, cardiothoracic surgery. But will surgeons adapt to the new technology? Clinicians are a fairly conservative bunch they dont like change, says Ara. When laparoscopic surgery first emerged, people thought I was mad. He tells of several other occasions in his career when new technologies received a frosty welcome from some, including the introduction of surgical robots. He sees i-Snake as the next advance in line, but is adamant about the need to innovate: If Henry Ford had taken the advice to invest in a cart, not in a car, wed be in a very different place now.
or more on the Hamlyn Centres research, see: F www3.imperial.ac.uk/roboticsurgery/research or a film on this project, see: F www.wellcome.ac.uk/isnake

Whats happening at St Marys? There is a clinical trial of NOTES underway. To date, two gallbladder removals have been completed, with access via the vagina.

Vitiello V et al. DOF minimization for optimized shape conformance under active constraints for a hyper-redundant flexible robot. In: P Jannin et al. (eds). Information Processing in Computer-Assisted Interventions 2011 (Lecture Notes in Computer Science). Springer: Berlin/Heidelberg; 2011. Kwok KW et al. Control of articulated snake robot under dynamic active constraints. Med Image Comput Comput Assist Interv 2010;13(pt 3):22936. Noonan DP et al. Gaze contingent control for an articulated mechatronic laparoscope. IEEE International Conference on Biomedical Robotics and Biomechatronics, Tokyo, Japan. IEEE; 2010. Shang J. et al. An articulated universal joint based flexible access robot for minimally invasive surgery. IEEE International Conference on Robotics and Automation (accepted).

Summer 2011 | 31

FROM THE ARcHIVE

DIGITISED MANuSCRIPT

ANN FANSHAWES RECIPE BOOK

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Helen Wakely shows us one of the Wellcome Librarys most mouth-watering treasures. What is it?
Lady Ann Fanshawe compiled this recipe collection from 1651, and passed it on to her daughter Katherine shortly before she died in 1680. The volume is a vast accumulation of culinary and medicinal knowledge, and reflects Fanshawes intense interest in testing out a broad range of recipes, from ice cream to perfumes to cures for melancholy.

Why is it so special?
Fanshawes volume is just one of nearly 300 recipe manuscripts held in the Wellcome Library, but hers stands out as it reflects her time in Spain and Portugal as the wife of Charles IIs ambassador. During her travels Fanshawe noted down several unusual recipes (including instructions on how to dress chocolatte, or make drinking chocolate). But her everyday recipes are equally interesting, as they shed light on 17th-century medical knowledge and the role of women as household physicians.

can you see it?

The manuscript is kept in a climatecontrolled strongroom, but you can view it in the Library by ordering it through the Library catalogue. You can also access it digitally (along with 75 other recipe manuscripts in the collection) from the Librarys website.

Want to know more?

Then come along to Wellcome Collections Recipes and Remedies events this autumn. A series of discussions, talks and tasting events will explore the cultural, economic and scientific aspects of food and health over time, and uncover the surprising resonances of 17th-century recipes for our 21st-century lives.

Find out more at library.wellcome.ac.uk/recipebooks

Summer 2011 | 33

Music festivals are an ideal place to share science

JEN WONG, GuERILLA SCIENCE
usic festivals are places of wonder. They provide a riot of live art, performance and playful mayhem that stimulates the mind, body and soul. The curious and the quirky come together to explore this transient world where everyone desires to escape the confines of their everyday existence and experience something new, captivating and exciting. It seems natural to me that science communication would therefore thrive in this kind of eye-opening space. After all, science reveals the unimaginable realities of our universe that many of us can only wonder at. Since 2007, Guerilla Science has brought bespoke activities, performances and events to unconventional habitats for science. Theres always a demand for novelty and surprise at music festivals, and science provides huge inspiration for this. By blending science with art, music and play we attract a target audience of young artsy adults with little background in science. Independent evaluation shows around 80 per cent werent expecting to encounter science at a festival. Many remarked that theyd come across our activities by chance and stayed because they looked fun. All surveyed said they would like to see more. The informal, open-minded and slightly bizarre nature of our activities helps them remain meaningful. Aiming to embed science into culture, we take researchers out of the lab and into the festivals places that inspire. The unique opportunities we create provide scientists with the chance to engage with people they might never otherwise come across. Eighty-four per cent of surveyed participants involved in 2010 said they would definitely take part again. Scientists favourite aspects included the questions people asked. This forced me to think on my feet and put across a view of my subject which challenged some of my assumptions as well, said one scientist. An audience member said: I loved the way people got enthusiastic about stuff that they might not normally think about or care about. The interdisciplinary space we work within also shows how much science needs the arts to be inspired and remain inspiring, and vice versa. Our Experimental Ward within Secret Cinemas One Flew Over the Cuckoos Nest production introduced practising psychiatrists into an abandoned nursing-home-cum-Oregon State Hospital. Actors portraying mental health conditions were trained by psychiatrists, while our psychosurgical classes were informed by both patient and psychiatric perspectives. Participating psychiatrists and actors all remarked how valuable they had found the encounter. The 1500-strong audience raved about the event. The outcome was a richer experience for all. guerillascience.co.uk

APPLIANCE OF SCIENCE

Plus Catch Guerilla Science at Glastonbury in June, the Secret Garden Party in July and Bestival in September, commissioned as part of the Wellcome Trusts Dirt Season.
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DIARy courses, conferences and workshops

Wellcome Trust Genome Campus, Hinxton, unless otherwise specified. For more, see www.wellcome.ac.uk/ advancedcourses and www.wellcome.ac.uk/conferences Epigenomics of Common Diseases Conference, 1316 September Practical Aspects of Biopharmaceutical Drug Discovery Course, 1924 September Design and Analysis of Genetic-based Association Studies Workshop, 2630 September UK Pharmacogenetics and Stratified Medicine Network Conference, 28 September Pharmacogenomics and Personalised Medicine 2011 Conference, 29 September2 October Next Generation Sequencing Workshop, 210 October 2011 Working with Parasite Database Resources Workshop, 37 October Working with the Human Genome Sequence Course, KEMRIWellcome Trust Research Programme, Kilifi, Kenya, 31 October2 November Working with Pathogen Genomes Workshop, 2026 November Genomic Epidemiology of Malaria Course, Mahidol university, Bangkok, Thailand, 27 November2 December Functional Genomics and Systems Biology Conference, 29 November1 December Protein Interactions and Networks Workshop, 1117 December Mathematical Models for Infectious Disease Dynamics Course, 1224 February 2012

Science Policy in the News (Spin)

Science knows no country, because knowledge belongs to humanity, and is the torch which illuminates the world
Louis Pasteur Keep up to date with worldwide biomedical science policy through our free weekly newsletter Science Policy in the News (Spin). Sign up to receive Spin straight to your inbox and access our free, searchable archive dating back to 1992. www.wellcome.ac.uk/spin/wn

Wellcome collection events and exhibitions

Euston Road, London. www.wellcomecollection.org Wellcome Image Awards 2011 Exhibition, until 10 July Dirt: The filthy reality of everyday life Exhibition, until 31 August Medicine Man and Medicine Now Permanent exhibitions Event listings See website for details

IN YOuR NEXT ISSuE

Exploring a career in medical engineering, plus updates on our funding and research activities.

Summer 2011 | 35

Human embryo. Yorgos Nikas/Wellcome Images

A FREE DESTINATION FOR THE INCURABLY CURIOUS

TUESDAYSUNDAY (UNTIL 18.00) LATE-NIGHT THURSDAY (UNTIL 22.00) 183 EUSTON ROAD, NW1 EUSTON, EUSTON SQUARE

The Filthy Reality of Everyday Life

Free exhibition Until 31 August

This exhibition and accompanying events are part of a Wellcome Trust season of activity at special dirty locations across the UK, including the Eden Project, Glasgow, Glastonbury and other summer festivals. Wellcome Collection is part of the Wellcome Trust.

www.wellcomecollection.org/dirt
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The Wellcome Trust is a charity registered in England and Wales, no. 210183. PU-5047.36/03-2011/MD