Annual Review 2012

Connecting science, health and society

Highlights of the ’s work in 2012, a year in which we helped to bring together researchers, teams and centres to better tackle the complex challenges of health research. Executive Board Wellcome Trust

Mark Walport We are a global charitable foundation Director of the Wellcome Trust dedicated to achieving extraordinary Ted Bianco Director of Technology Transfer improvements in human and animal John Cooper health by supporting the brightest minds Chief in biomedical research and the medical Operating Officer and Deputy Chief Executive Officer humanities. Simon Jeffreys Chief Operating Officer Our ten-year Strategic Plan for 2010–20 David Lynn Director of Strategic Planning provides the framework for how we intend and Policy to evolve our support to be even more Clare Matterson effective in achieving this aim. Director of Medical Humanities and Engagement Kevin Moses Our funding focuses on: Director of Science Funding 1. Supporting outstanding researchers Danny Truell Chief Investment Officer 2. Accelerating the application of research Susan Wallcraft 3. Exploring in historical and General Counsel and Company cultural contexts. Secretary

As at December 2012 Our five major challenges are: 1. Maximising the health benefits Board of Governors of genetics and genomics 2. Understanding the brain , Chairman 3. Combating infectious Peter Rigby, Deputy Chairman Alan Brown 4. Investigating development, ageing and chronic disease 5. Connecting environment, nutrition Michael Ferguson and health. Anne Johnson Eliza Manningham-Buller This Annual Review covers the period Peter Smith 1 October 2011–30 September 2012.

As at December 2012 Contents

Year in brief 02 02

Director’s statement 04 04

Supporting outstanding researchers 08 08

Accelerating the application of research 12

Exploring medicine in historical 16 and cultural contexts

Maximising the health benefits 20 20 of genetics and genomics

Understanding the brain 24

Combating infectious disease 28

Investigating development, ageing and 32 chronic disease

Connecting environment, nutrition 36 and health

Advisory committees 2011/12 40 40 Year in brief

An overview of some of our activities in 2011/12, from research successes and public engagement campaigns to the grants we have awarded and the performance of our investments.

Mitochondrial research In the Zone Brains exhibition UK opens A new centre at Newcastle Inspired by the London ’s most Researchers can now apply is developing ways to 2012 Games, the Wellcome popular exhibition to date to use the UK Biobank stop children inheriting Trust combined sport and explored the history of database, with health mitochondrial . physiology in a touring human efforts to information and samples exhibition and experiment understand the brain’s from 500 000 volunteers. Research leaders of the kits for schools. mysteries. future therapy successes The first ten Sir Henry Dale Tracking MRSA Stem Institute Research teams have made – early-career Rapid whole-genome As pioneering striking progress in researchers with the sequencing shows success research wins a Nobel developing gene therapies potential to become world in identifying, tracking and Prize, a new institute is – including, for the first leaders – have been named. stopping hospital outbreaks launched to advance our time ever, treating a genetic of MRSA. understanding of stem eye disease. Stevenage Bioscience cells and their potential Catalyst Urbanisation and health use in medicine. The UK’s first open An Indian study is revealing innovation bioscience the full implications for campus has received its health when people migrate first tenants from industry to cities. and academia.

Funding and achievements 970 28 492 053 Total grants awarded Countries receiving funding Wellcome Collection visits 12 600 £185m 4433 Items of media coverage finance Scientific research papers associated relating to the Wellcome Trust secured by grantholders for with the Wellcome Trust commercialisation of R&D (Published in calendar year 2011, indexed on PubMed and in Thomson Reuters databases)

2 | Annual Review 2012 Online content

For more content related to the stories featured in the Annual Review, see www.wellcome.ac.uk/ annualreview.

Key financials at a glance

Financial summary Net asset value Our ability to support research and other charitable activities depends on the success of our investment portfolio. We invest globally across £13.3bn a very broad range of assets and As at 30 £13.3bn strategies. In 2011/12, we were £12.0bn £11.9bn £12.7bn £12.4bn September. pleased that our investment portfolio recorded a total return of 12%.

We have returned a total of 27% (annualised 8%) over three years 2008 2009 2010 2011 2012 and 145% (annualised 9%) over ten years to September 2012. Since the inception of our investment portfolio in 1985, it has provided Charitable funding committed in year a total return averaging almost 14% a year.

Our annual grant-making budget is £746m £746m £702m £720m set by reference to a three-year For the year ended £678m £642m weighted average of our portfolio’s 30 September. value in order to smooth the effects of short-term volatility. Over the next five years we aim to commit in excess of £3 billion for charitable activities, but this will depend on our investment performance. 2008 2009 2010 2011 2012

For more details, see our Annual Report and Financial Statements at www.wellcome.ac.uk/annualreport.

Annual Review 2012 | 3 Director’s statement

This year, we have created more opportunities for researchers to build connections with each other and across all parts of society – vital for improving health in the future.

In October 2012, the Nobel Prize in the same immature state as our Physiology or Medicine was awarded natural stem cells and using them for to Sir John Gurdon and regenerative medicine. Professor Professor Shinya Yamanaka. Their Yamanaka’s share of the Nobel Prize work, 50 years apart, showed that was for his work published in 2006, mature cells can be reprogrammed which honed an innovative yet and used to generate so-called induced practicable technique for genetically pluripotent stem cells. John’s engineering mature cells into induced experiments in the late 1950s pluripotent stem cells. overturned theories of cell development and opened up new Building on this pioneering research, possibilities in biological research we announced a new centre in and medicine. Since then, he has Cambridge this year: the Wellcome continued a highly successful research Trust–Medical Research Council Making connections career, was a co-founder and the first Cambridge Stem Cell Institute. It director of the Wellcome Trust/ draws on our existing strengths in Researchers do not work in isolation: Research UK , the field, uniting many world-class productive collaborations, strong and has also served as a Governor of research groups in their efforts to leadership and a supportive the Wellcome Trust. advance our understanding of stem infrastructure are vital parts of any cells and how we can use these to treat researcher’s success. Similarly, science This year’s Annual Review is all about a range of human illnesses. does not operate in a vacuum. The connecting science, health and society. Wellcome Trust works across many John’s story reflects this theme in One example of such an application sectors to connect science, health many ways: the connections from his was published this year by a team at and society so that the fruits of original discovery to the development the and the biomedical research are fully able to today of new stem cell therapies; the nearby Wellcome Trust Sanger contribute to better health for all. connections he fostered between Institute, who combined stem cell scientists at the Gurdon Institute; and, biology and gene therapy to correct a through the influence of his work on faulty gene that can cause cirrhosis of cloning and stem cell technologies, the the liver and emphysema in the lungs. wider connections that exist between They took skin cells from patients, science and society. These connections reprogrammed the cells into stem resonate with the stories of the Trust’s cells and replaced the gene. Then they work over the past year, which you can used the corrected stem cells to read about in this Review. generate healthy liver cells. Such techniques – almost unimaginable Connecting science and health just a few decades ago – bring us closer John’s experiments showed that an to safe and effective treatments based animal’s mature, specialised cells all on our growing understanding of retain its entire genetic code. The genetics and stem cells. genetic information in any one cell could be used to create a new, fully Connecting researchers formed organism. This finding The Gurdon Institute celebrated its sparked interest in the potential for 21st anniversary this year. Established cloning animals, and raised the by a small group of researchers led by prospect of reprogramming cells into John, it adopted his name in 2004,

4 | Annual Review 2012 after he had stepped down from the position of director, recognising his guiding influence in developing a creative and productive environment for developmental biology and cancer research. From the start, his leadership style was inclusive, open and democratic, and this philosophy continues there today. It helped to forge strong links between Gurdon researchers and has inspired similar approaches at other research centres.

Such leadership can sometimes be Scanning electron micrograph of human embryonic stem cells. Professor Miodrag Stojkovic/SPL overlooked in research – it is certainly not something that can be recognised by Nobel Prizes. While we need scientists to be able to do science, The rapid development of team from a drug and medical device they cannot do it in isolation. Most communications technology in recent development company, moved in this modern biomedical research requires years has made the world smaller and year, and the University of Cambridge a team of scientists, with a number of extended the range of collaborations announced that it would establish a international collaborations, the right available to researchers. However, centre of innovation for its researchers infrastructure to support them, and we must not forget that strong on the campus. As more tenants move someone providing a unifying vision relationships form more readily when in, opportunities for collaboration and and direction to the research. people work near each other. This is innovation will multiply. particularly important for creating With this in mind, many of our an environment that promotes Connecting with the public fellowship schemes are designed to innovation, which often arises when At the Trust, we firmly believe that help develop leadership skills, people make unpredictable science flourishes most when the including a new scheme launched connections. public can feel a connection with it, this year in partnership with the relate it to their own lives, participate Royal Society. Sir Henry Dale Research centres and institutes in informed debates and share in the Fellowships are named after one of encourage such interactions, but there delight of scientific discoveries. We the most eminent neuroscientists of are fewer examples when it comes to support artists, broadcasters and the 20th century, who also served as collaboration in applied research. educators who engage people of all Chairman of the Wellcome Trust and Stevenage Bioscience Catalyst is a ages with biomedical research and the President of the Royal Society. The new approach to fostering ‘open issues around it. Fellowships are for researchers at an innovation’ between academic early stage of their careers who already researchers and industry scientists. We also hold exhibitions and events at show exceptional potential. The Supported by the Wellcome Trust, our own venue, Wellcome Collection. fellows receive generous resources GlaxoSmithKline and government For example, Brains: The mind as to focus on exciting and important agencies, it is a site where researchers matter examined not what we know research questions while developing from the public, private and charitable about how the brain works, but rather the skills, networks and collaborations sectors can come together and share the methods by which researchers necessary to become world leaders expertise in early-stage drug discovery through history have tried to find out. in their fields. and development. The first tenants, a It was our most popular exhibition to

Annual Review 2012 | 5 Director’s statement cont.

date, with more than 1400 visitors about their lifestyle, diet and medical but it is as yet impossible to make a day on average. The success of history. UK Biobank is now open to confident predictions about the Wellcome Collection means that, just researchers from all over the world – precise effects. five years after it opened, we have academic and industry scientists alike decided to create new galleries and – who want to investigate how and In this area, as in so much of our spaces to meet demand. The why some people develop diseases like work, our focus is to keep making development work will take place cancer or heart disease while others connections. We are increasing our from summer 2013 to summer 2014, do not. It is a prime example of a funding of research to characterise but we plan to keep the building open project that directly connects the relationships between to the public throughout. scientific research with improving environment and health, but we are health for the good of society. also communicating about these This year, we had a singular issues, raising them up the scientific opportunity to connect new Future connections agenda, and looking for partners in audiences with science: the London I will be leaving the Trust in 2013 other sectors whose involvement will 2012 Olympic and Paralympic Games. to take up the position of Chief be essential for us to make a real As well as entering the spirit of the Scientific Adviser to the UK difference. Games and engaging the public with government. I am very proud of what the physiology and biology of athletic has been achieved in my ten years as Improving health requires more than endeavour, it was important to us that Director, but rather than reflecting on excellent science: it also requires the science should have a place in the that here, I want to look forward. capacity for technological innovation, legacy of London 2012 alongside the appropriate regulatory and legal sports initiatives and urban Whether in stem , genetics, frameworks, readiness within regeneration projects. neuroscience or any number of other healthcare systems to adopt new fields, these are exciting times in approaches, and public acceptance of Our contribution, therefore, was In biomedical science. Researchers make new treatments and policies. On top the Zone. Focusing on the science of astounding leaps forward every year, of supporting excellent research, the body and mind in motion, kits full and yet each discovery seems to therefore, the Wellcome Trust has an of ideas for inspirational, practical confirm that we are barely scratching important role to play across all these science experiments were delivered to the surface in terms of understanding sectors. We help to connect science, more than 30 000 schools across the our fundamental biology and how to health and society so that the fruits of country, as well as to teacher training apply these advances. Across medical research are accessible and available colleges, science centres and more. research, using the tools and to contribute to better health for An interactive touring exhibition knowledge we have accumulated, everyone. attracted tens of thousands of visitors there is huge potential to make truly with high-energy shows and extraordinary improvements in opportunities to test their own health in the years ahead. physical abilities. It was a fantastic way to harness the world’s greatest However, we also know that the sporting event and engage people future will bring new challenges. In Sir with science. the Wellcome Trust’s Strategic Plan Director of the Wellcome Trust 2010–20, one of the five broad areas of December 2012 Science relies on people being not research we identify as central to our just engaged with it, but willing to work this decade is the relationship participate in it as well. UK Biobank is between the environment, nutrition a major biomedical research resource, and health. Climate change, drawing on data from half a million population growth and cultural volunteers who have had biological changes such as increasing samples taken, been weighed and urbanisation will have a significant measured, and answered questions impact on health around the world,

6 | Annual Review 2012 , 1890. Annual Review 2011 | 7 Computer-generated images of how the UK Centre for Medical Research and Innovation will look. 8 | Annual Review 2011 Supporting outstanding researchers

Researchers are developing IVF techniques to stop children inheriting mitochondrial diseases from their mothers.

In January 2012, the Wellcome Trust Mitochondrial are passed people realise these techniques, based awarded £4.4 million to Newcastle exclusively down the maternal line. on existing in vitro fertilisation University, which contributed a Researchers at the new Centre have techniques, are safe and effective. further £1.4m, to establish the already developed two techniques Wellcome Trust Centre for that could prevent the transmission Mitochondrial abnormalities do not Mitochondrial Research. The Centre of mitochondrial diseases from just cause inherited diseases: will bring together ground-breaking mother to child, by using donor eggs mitochondrial failure has been seen laboratory researchers, doctors caring with healthy mitochondria. The in conditions such as Parkinson’s for patients with mitochondrial nuclear DNA, which contains the disease, suggesting that the impact of diseases, and the clinical research information for every characteristic energy failure might be greater than expertise of the Newcastle Fertility and function of the child except expected and an important factor in Centre, which has an international their mitochondria, is removed from ageing and degenerative diseases. The reputation in reproductive biology. the donor egg and replaced with Centre’s work will also investigate the nuclear DNA from one of the this aspect of mitochondrial The cells in our bodies require energy mother’s eggs. This leaves an egg function, and pave the way for to function properly. Most of this cell with the mother’s nuclear developing new ways to prevent energy is supplied in chemical form DNA and the donor’s healthy and treat such diseases. by mitochondria, small parts of the mitochondrial DNA. cellular machinery that are thought to be descendants of bacteria that The team has shown that these colonised our cells more than 2 billion techniques work in the laboratory, years ago. Mitochondria are almost and is now working on further like cells within cells, each having its experiments to assess their safety own membrane and its own genes before they can be used with patients. separate from the rest of the genome, which is stored in the cell nucleus. Professor Doug Turnbull, director of Mutations in mitochondrial genes the Centre, and his colleagues can lead to devastating diseases, recognise that such work is typically affecting tissues that use a potentially controversial, so an lot of energy, such as the heart, important focus of their work is to muscles and brain. talk to patients, the public and policy makers to make sure their work is transparent and understood, and that

Mitochondria (red) around the nucleus of a kidney cell. University of Edinburgh/Wellcome Images Annual Review 2012 | 9 From left: Data from an MRI scan. Gabrielle Voinot/ Look at Sciences/SPL Dr Venkatraman Ramakrishnan. Wellcome Images Dr Ludovic Vallier. NC3Rs Trypanosoma brucei parasites, the object of Dr Bungo Akiyoshi’s research. Gull Lab, Sir William Dunn School of Pathology/Wellcome Images

Making MRI more sensitive Expanding investigations Reducing animal use Magnetic resonance imaging (MRI) is Now in its second year, the Wellcome Wellcome Trust-funded researchers used more than 1.5 million times a Trust’s Investigator Awards scheme from several institutions won prizes year in the NHS, but there is still a lot is building a growing body of this year for their work in reducing of potential for finding new and exceptional researchers. Across four the use of animals in research. The better ways to apply the technology. rounds of funding in biomedical annual prizes are awarded by the Professor Simon Duckett and his science this year, 45 Senior National Centre for the Replacement, team at the University of York Investigators and 10 New Refinement and Reduction of received a £3.6 million Strategic Investigators were announced. The Animals in Research. They honour Award this year to radically improve successful researchers included Dr research that makes an original the sensitivity of MRI, using a Venkatraman Ramakrishnan of the contribution to scientific and technique called hyperpolarisation. Medical Research Council Laboratory technological advances in the ‘3Rs’. of Molecular Biology in Cambridge, Current MRI technology is based on who received a Senior Investigator The overall winner, Dr Ludovic detecting signals from the hydrogen award. Dr Ramakrishnan shared the Vallier from the University of in water and fat throughout the body. 2009 Nobel Prize in Chemistry for his Cambridge, published a method of This often involves injecting contrast work in revealing the structure of using human skin cells to produce agents – usually heavy metals – to ribosomes, the components within liver cells that are a model for distinguish more clearly what these our cells that translate genetic inherited liver diseases. This could signals mean. At York’s Centre for instructions to make proteins. help to replace the use of animals in Hyperpolarisation in MRI, part- early drug tests. funded by the Wellcome Trust, a new Also funded this year was Professor technology called SABRE (signal Derek Jones, a New Investigator based At the University of Edinburgh, amplification by reversible exchange) at Cardiff University, who is Dr Anna Williams and colleagues has been used to impart the developing an imaging technique to produced a cell culture model of distinctive magnetic properties to study the connections between brain repair mechanisms in multiple molecules other than hydrogen, so cells. Five joint awards were made this sclerosis, while Dr Stephen Pettitt of that they can now be detected directly year, accounting for one New and the Institute of Cancer Research and in the scanner. For example, a drug nine Senior Investigators: among colleagues from the Wellcome Trust hyperpolarised in this way could be them were William Sanger Institute described a new way tracked as it was absorbed and Cookson and Miriam Moffatt, who of developing genetically modified metabolised in a patient’s body. work together at Imperial College mice. Their innovative methods were London, looking at the genetics both highly commended for their As well as expanding the possible underlying asthma with the aim of potential to considerably reduce the applications of MRI and increasing developing new treatments. number of mice used in research. its sensitivity by several orders of magnitude, this technology could For Investigator Awards in medical also lead to the development of history and humanities, see page 18. smaller, cheaper scanners.

10 | Annual Review 2012 These extremely prestigious fellowships will give a vital boost to our most talented researchers, putting them well on the way to a highly successful career.” David Willetts, UK Minister for Universities and Science

Research leaders of the future Ten outstanding researchers received Among the first recipients was Dr Dr Maciej Boni also has a fellowship the inaugural Sir Henry Dale Jennifer Bizley, a former Wellcome with the , Fellowships this year. Run jointly by Trust-funded PhD student and although he is based at the Wellcome the Wellcome Trust and the Royal currently a Royal Society Dorothy Trust’s Major Overseas Programme in Society, the scheme was introduced in Hodgkin . Based at University Vietnam. Dr Boni uses mathematical October 2011 to identify and support College London’s Ear Institute, Dr biology to understand human health scientists at an early stage of their Bizley is looking at how we combine and infectious diseases. He will focus careers who have the potential to visual and audio information in the on determining the prevalence and become world leaders in biomedical brain. She was one of the first people severity of influenza in the region, research. The fellowships provide to demonstrate that what we see and whether conditions could generous resources to enable these affects the way our brain cells respond potentially give rise to another researchers to pursue exciting to sound. Her research will determine pandemic. Dr Boni will use his research questions, develop new how this phenomenon helps us to findings to advise on the best type skills, forge collaborations and listen in an increasingly noisy world of influenza vaccination policy become internationally competitive. and might lead to better ways of for Vietnam. helping people adjust to wearing Sir was one of the hearing aids. most eminent biomedical scientists of the 20th century. Together with With his fellowship at the University Professor Otto Loewi, he was of Oxford, Dr Bungo Akiyoshi will awarded the 1936 Nobel Prize in study chromosome segregation, a Physiology or Medicine for the mechanism that cells use to ensure discovery of acetylcholine and its genetic material is passed on actions in the body. This work accurately during cell division. When revolutionised our understanding chromosome segregation goes wrong, of the nervous system. it can cause birth defects or cancer. Dr Akiyoshi will be using a parasite Dale was the Chairman of the called Trypanosoma brucei to learn Wellcome Trust from 1938 until 1960, more about this mechanism and how and President of the Royal Society it might be exploited by drugs in order between 1940 and 1945. Today, to help treat human diseases such combining the expertise, experience as cancer. and influence of these two organisations makes the scheme named after him one of the most prestigious fellowships available to scientists early in their careers.

Annual Review 2012 | 11

Accelerating the application of research

The first tenants have moved in to Stevenage Bioscience Catalyst, a life sciences facility that aims to stimulate open innovation across all sectors of biomedical research.

The UK’s first open innovation conducted in academia, which has an associated with multinational bioscience campus welcomed its first edge in identifying new biological pharmaceutical companies, and will tenants from both industry and targets and developing assays. be able to share their knowledge of academia in 2012. The campus, called Publicly funded researchers will biology and biological systems with Stevenage Bioscience Catalyst, is have access to industry’s compound their neighbours from industry. backed by a £38 million investment libraries, its expertise in optimising from its founding stakeholders: drugs and clinical trial design, and its The founders expect that the arrival GlaxoSmithKline, the Wellcome infrastructure and state-of-the-art of the first two sets of tenants in Trust, the Department for Business, facilities. Stevenage will create momentum Innovation and Skills, the Technology that attracts other academic, Strategy Board and the East of The first tenants moved in on 23 pharmaceutical and biotechnology England Development Agency. February 2012. They are the partners. Translational and Medical Sciences Based at GlaxoSmithKline’s Stevenage Consultancy division of Aptiv facilities, Stevenage Bioscience Solutions, a company providing drug Catalyst aims to help rejuvenate and medical device development the UK’s pharmaceutical and services, with expertise in adaptive biotechnology sector. Focusing on clinical trial design, simulation early-stage drug discovery and and execution. development, it provides a collaborative environment for Later in the year, the University of researchers from the public, private Cambridge announced that it is and charitable sectors. The idea is to establishing a centre of innovation on bring together people who have the campus. The proximity of shared goals in order to capitalise on Cambridge and Stevenage means that what each partner does best. Industry the University’s researchers will have can benefit from the breadth of access to the expertise, networks and comprehensive basic research scientific facilities more often

Illustration of Stevenage Bioscience Catalyst. Bret Syfert Annual Review 2012 | 13 From left: Neural network derived from embryonic stem cells. Q-L Ying & A Smith/Wellcome Images Illustration of hearing voices in schizophrenia. Adrian Cousins/Wellcome Images Syncona will help healthcare businesses develop their advances. DNY59/iStockphoto A man giving himself an insulin injection. Ocean Photography/Veer

Pathfinders Avatar therapy Investing in new business The Wellcome Trust launched Many people with schizophrenia In March 2012, the Wellcome Trust Pathfinder Awards in February 2012. experience auditory hallucinations. established a £200 million fund to These support partnerships between They hear voices that abuse them or invest in promising healthcare academic and industry scientists to command them to harm themselves businesses. Syncona, a directly owned conduct early research and or other people. Even with drug and managed investment firm, development projects related to rare treatment, about 25 per cent of people combines the Trust’s experience in or neglected diseases. Neglected with schizophrenia continue to be the health and biotechnology sectors diseases disproportionately affect tormented by such hallucinations. with its investment expertise. people in low-income countries, and Syncona will identify and invest in – as is true for many rare diseases – At University College London, new opportunities with the aim of there is little financial incentive for Professor Julian Leff and colleagues delivering returns to the Trust while private companies to invest in are developing an unusual and supporting advances in health. research. This contributes to a lack of innovative therapy for use in options for prevention and treatment. conjunction with antipsychotic drugs Syncona offers a new source of to tackle this problem. In the therapy, finance and guidance for healthcare Pathfinder Awards are designed to patients are invited to create an avatar businesses at an early stage of their help not-for-profit teams run pilot to represent their hallucination. development. The company has research projects that could generate Voice-morphing software makes the already begun making investments, credible potential products. Further avatar sound the way the patient helping businesses turn advances in development could then be done hears the voice, while computer the life sciences into therapies that either by the industrial partner or graphics give it a face. The patient will improve patient care. through other funding schemes, such is then encouraged to enter into as the Trust’s Translation Fund. dialogue with the avatar, stand up to it and tell it to go away. A therapist The first two projects to receive modifies the avatar’s responses so Pathfinder Awards were announced that it comes to agree to stop abusing in September 2012. Researchers at the patient. Lilly and University College London are developing a line of human stem In early tests, avatar therapy reduced cells to study a rare group of severe the frequency of hallucinations and neurological disorders that affect how threatening they seemed, saving children and young adults. In the the patients a significant amount of other project, a team at Pfizer is distress. Professor Leff now has a working with scientists in the Wellcome Trust Translation Award to Structural Genomics Consortium at refine the technology and evaluate it the University of Oxford to study the in a randomised controlled trial. If enzyme affected in a rare hereditary successful, avatar therapy could be a metabolic disorder called relatively low-cost way to help people homocystinuria. with schizophrenia take control of this aspect of their condition.

14 | Annual Review 2012 This knowledge will be used in the future to help us predict who might get the disease and also to develop new approaches to prevent it.” Professor Mark Peakman, King’s College London

Immunotherapy for type 1 People who are diagnosed with type 1 The immune system operates by In people who have already have type diabetes – usually in childhood – take recognising specific peptides – small 1 diabetes, the therapy would stop daily injections of insulin to control proteins or parts of proteins – and any further loss of beta cells, and the condition. This is a lifelong attacking any cells that have these the remaining beta cells should, in treatment that does not cure the peptides on their surface. In many cases, be able to produce underlying disease or reduce all of the autoimmune diseases, the immune enough insulin to control glucose risks associated with it. A new therapy system attacks the wrong targets and, levels. This should help to prevent to cure or prevent type 1 diabetes, as a result, can kill cells that are vital associated complications, including which is on the rise around the world, for our health. Professor Peakman , loss of vision would free individuals from the and his colleagues are identifying and damage to the nerves and difficulty of managing the disease which peptides are wrongly targeted kidneys. and would remove significant in type 1 diabetes, so that they can healthcare costs. investigate whether the immune Professor Peakman’s team aims to system could be taught to tolerate develop a peptide combination that is Insulin is produced by beta cells in these peptides. This approach is suitable for testing in early clinical the pancreas, and its role is to remove called peptide immunotherapy, and it trials in people with type 1 diabetes. excess glucose from the . But if a is already being developed for other person’s immune system mistakenly inflammatory diseases including attacks and kills these beta cells, this allergies and multiple sclerosis. deprives the body of its natural insulin supply. The resulting build-up The advantage of using this kind of of glucose has effects such as weight peptide immunotherapy is that many loss and increased hunger and thirst people with type 1 diabetes have – symptoms of type 1 diabetes, an certain genetic similarities in the inflammatory autoimmune disease. immune cells that control the recognition and targeting of peptides. Professor Mark Peakman, a clinical This suggests that a therapy using a immunologist at King’s College relatively small number of peptides London, began work this year on a would be effective in a large Wellcome Trust-funded project to proportion of patients. It could even develop a therapy that ‘resets’ the be used to prevent type 1 diabetes immune system so that it no longer developing in people known to be at attacks beta cells. risk of it because of their family history, for example.

Annual Review 2012 | 15 Images: Computer-generated images of how the UK Centre for Medical Research and Innovation will look.

16 | Annual Review 20122011 Exploring medicine in historical and cultural contexts

In the Zone reached 90 000 members of the public, as well as pupils at thousands of schools and colleges, creating a lasting legacy from the London 2012 Games.

The Wellcome Trust’s In the Zone students to find out how exercise Accompanied by high-energy, project inspired people to take an affects breathing rate, test their own action-packed live science shows, the active interest in the science behind muscle strength and explore how the exhibition reached around 90 000 the record-breaking performances at cardiovascular system adapts during people at 21 community open-air the Olympic and Paralympic Games. different kinds of exercise. events, including county agricultural Sir Steve Redgrave, winner of five shows, music festivals, and balloon Olympic gold medals, launched the As well as winning an exceptionally and airshows. It arrived in east project at the Association for Science positive response from teachers and London as part of BT London Live Education conference in Liverpool in pupils alike, the kits have inspired from 27 July to 12 August before January 2012, and delivered the first further uses. The British Council is continuing its UK tour. of the In the Zone experiment kits to adapting them as an English Teaching St Paul’s Way Trust School in east Resource overseas, and the Brazilian In the Zone was part of the practical London a month later. government wants to adapt them for learning strand of Get Set – the Brazilian schools in the lead-up to the official London 2012 reward and Almost 31 000 free experiment kits Rio 2016 Games. recognition scheme for schools went to pupils aged four to 18 at and colleges demonstrating a schools and colleges across the UK. An interactive family exhibition also commitment to living the Olympic Developed in collaboration with formed part of In the Zone. Created and Paralympic values – and was Pearson Education, the kits were by At-Bristol, the exhibition toured awarded the Inspire Mark by the linked to the UK curricula and England, , Wales and London Organising Committee designed to be fun. They contained Northern Ireland from March to of the Olympic Games. equipment and activities for students September. Its high-tech, immersive to carry out hands-on experiments experience allowed visitors of all ages exploring their physiology. to test their own physical abilities, finding out how high they could jump The primary-school kits helped pupils (and how softly they could land), to investigate balance, test how quick viewing their veins, sharpening their off the mark they are and find out reaction times and sprinting for gold whether people with longer legs can along a racing track. jump further. The secondary-school kits included experiments for

The In the Zone touring exhibition at the Olympic Park in Stratford. Wellcome Images Annual Review 2012 | 17 From left: Sixteenth-century doctor William Gilbert. Professor Jonathan Barry is compiling a historical database of physicians. Wellcome Library Francis Crick’s original pencil sketch of a DNA spiral. Wellcome Library Students at Simon Langton Grammar School in Canterbury. Wellcome Images The Superhuman exhibition explored human enhancements of all kinds. Wellcome Images

Investigating medical humanities Following the successful introduction compile a database of all medical One New Investigator Award was of Investigator Awards in biomedical practitioners active in England, Wales made in medical history and science (see page 10), the Wellcome and Ireland from around 1500 to 1715. humanities this year. Dr Jessica Trust has extended the scheme to He will document their education, Reinisch of Birkbeck, University of researchers who are exploring careers and medical practice, as well London, has studied the history of questions at the interface of science, as including any major contributions international organisations in medicine, society and the humanities. to Britain’s early modern history. 20th-century Europe and the role of The same principle applies: public health crises and humanitarian supporting world-class scholars Dr Sanjoy Bhattacharya at the disasters in their development. She in established academic posts. University of York will use his Senior will now look at the short-lived Investigator Award to study in detail United Nations Relief and Professor Mary Dixon-Woods was the global movement for primary Rehabilitation Administration and among the first group of researchers healthcare in the 1970s and 1980s. its influence on ideas of nationalism to receive a Medical History and This was one of the most ambitious and international collaboration Humanities Investigator Award. She efforts to expand health coverage in Europe. leads a large programme of research equitably around the world, and at the University of Leicester on advocacy for primary healthcare patient safety, healthcare ethics and is once again rising up the World methodological innovation. With her Health Organization’s agenda. Senior Investigator Award, she aims Dr Bhattacharya’s previous work to develop principles to guide analysis on the history of smallpox and its and resolution of moral dilemmas eradication in India has shown that that arise in the effort to provide implementing global policies can be safe, good-quality healthcare. subject to complex local influences. Understanding the detailed history of While several physicians are such movements is vital to achieving prominent historical figures, there are future progress in global health. many others whose contributions to science and medicine are less well known. Professor Jonathan Barry at the University of Exeter has been given a Senior Investigator Award to In a society that constantly strives for better, faster and smarter, how much freedom should we have to take advantage of new ways to improve our mental and physical performance?” Emily Sargent, curator of Wellcome Collection’s Superhuman exhibition

18 | Annual Review 2012 Opening up geneticists’ archives Spreading school success Superhuman The Wellcome Library is bringing the At Simon Langton Grammar School Inspired by this year’s Olympic and papers of the pioneers of modern for Boys in Canterbury, nearly 100 Paralympic Games, the Superhuman genetics together for the first time. A-level students (girls and boys) are exhibition explored ways in which This is the first phase of a major using and molecular people have sought to improve on digitisation programme that will biology research techniques to nature and become something ‘more’. create an unparalleled online explore the chemical nature of myelin It ran at Wellcome Collection from repository of books, papers, films, basic protein, which is responsible for July to October 2012, attracting over photographs and audio, covering the development of some cases of 1000 visitors a day. The questions it every aspect of the history of multiple sclerosis. The project, a raised – about what is ‘normal’, where medicine and biomedical science. collaboration with the University of we should draw the line between Kent, was funded by a People Award correction and enhancement, and Foundations of Modern Genetics from the Wellcome Trust in 2008 and whether we ought to ‘play God’ like draws on material from six world- it has proved so successful that the this at all – prompted enthusiastic class libraries and archives in the teachers behind it want to encourage reviews, and thoughtful debate USA, Scotland and England, more schools to try something and analysis. including the Wellcome Library’s own similar. holdings. These collections contain called it “an tens of thousands of research notes, This year, Dr David Colthurst and his uncompromising, intelligent letters, sketches, lectures, essays and fellow teachers at the school received exhibition that will put you in the photographs from the key players in a £250 000 Society Award to extend right frame of mind to handle it”. the discovery of the structure of DNA the approach to four more schools in Many reviewers were struck by the and the subsequent development of Sheffield, London, Winchester and inclusion of items we take for genetics – including Francis Crick, Bristol. Each school has picked an granted, such as spectacles, James Watson, Sydney Brenner and area of medical research, and students smartphones and the contraceptive Lionel Penrose. All the material will and teachers will work with pill, with New Scientist commenting be freely available online. researchers at a local partner that “the exhibition reminds us that university to learn the necessary enhancement is already a part of our Crick is also the focus of the techniques and gain first-hand daily lives”. However, visitors were Wellcome Trust’s first Library Fellow, experience of working on original warned against hubris with the very Dr Christine Aicardi. She began her scientific research. first exhibit they encountered – a two-year fellowship in October 2011, small winged statue of Icarus, the boy pursuing a project on Crick’s scientific who flew too close to the Sun. career. This is part of her wider interest in how scientists work, collaborate and interact, and her work will make extensive use of content in the Foundations of Modern Genetics project.

Annual Review 2012 | 19 Images: Computer-generated images of how the UK Centre for Medical Research and Innovation will look.

20 | Annual Review 20122011 Maximising the health benefits of genetics and genomics

Two Wellcome Trust-funded projects tested world-first gene therapies this year, for diseases of the eye and the liver.

Researchers at the University of partnership between the Wellcome removed all trace of the genetic Oxford and Trust and the Department of Health, manipulations except for the are making the first ever attempt to trials began in autumn 2011. While corrected gene. treat choroideraemia, a genetic the initial signs are promising, it will disease causing blindness, in human take two years to know for sure Next, they converted the treated patients. Choroideraemia, currently whether the treatment is successful. hIPSCs into liver cells and showed incurable, results from a deficiency of If so, the team will then treat the that the corrected gene was working the REP1 gene on the X chromosome, second eye (currently acting as a normally and producing normal which leads to the degeneration of control) of each of the 12 volunteers. alpha1-antitrypsin protein. Finally, the light-sensitive cells of the . they took stem cells directly from a Men who have the deficient gene lose Another group of researchers, at the patient with the alpha1-antitrypsin their sight gradually until they are Wellcome Trust Sanger Institute and deficiency and successfully corrected inoperably blind, usually by their 40s. the University of Cambridge, have the mutation using the same method. developed a technique to correct a The trial involved injecting a virus defective gene causing liver and lung Combining the potential of gene into one eye of each of 12 men with disease. A mutation in the alpha1- therapy and stem cells in this way choroideraemia. The virus carried a antitrypsin gene means the protein brings us a step closer to the segment of DNA that included a it codes for is not able to leave the possibility of making treatments healthy copy of the REP1 gene, and cell in which it is made, causing specific to individual patients. had been engineered to infect the inflammation that can lead to light-sensitive photoreceptor cells in cirrhosis of the liver and emphysema the retina. Once it had ‘broken into’ in the lungs. the cells, the REP1 gene inserted itself into the existing cell genome and In Nature in October 2011, the became active. scientists described how they took human induced pluripotent stem cells The researchers believe the gene will (hIPSCs) containing the defective remain in the retinal cells indefinitely, gene and used ‘molecular scissors’ to preventing any further degeneration cut the genome at precisely the right in sight. Funded through the Health place. They inserted a correct version Innovation Challenge Fund, a of the alpha1-antitrypsin gene, then

Photograph of an eye. Alloy Photography/Veer Annual Review 2012 | 21 Gene linked to stroke Cellular celebration Ancient viruses in our genomes A genetic variant that increases the Cell! Cell! Cell! showcased the Our genomes are riddled with ancient risk of a common type of stroke was innermost workings of our bodies viral DNA, and, in April 2012, a discovered in a study funded by the on a grand scale over summer Wellcome Trust-funded study shed Wellcome Trust and published in 2012. Developed for 360-degree light on how it got there. Researchers February 2012. It is one of very few planetariums, the film tells the story from the University of Oxford, the genetic variants that have been of the trillions of cells that make up Aaron Diamond AIDS Research found to be associated with stroke, our bodies and the genes that control Center in New York and the Rega so it could have implications for them. With funding from the Institute in Belgium compared the future treatments. Wellcome Trust, it was created by genomes of humans and 37 other Intech Science Centre in Winchester, species of mammal, including mice More than a third of strokes are in collaboration with the Wellcome and elephants, and collected caused by a blockage to one of the Trust Centre for Human Genetics in information about the viral DNA large arteries that supply blood to the Oxford and NSC Creative at the they contained. brain (large artery ischaemic stroke). National Space Centre in Leicester. Scientists at St George’s, University of They found that millions of years ago, London, and the Wellcome Trust The show launched in June 2012, one group of viruses had lost the Centre for Human Genetics at the taking children and adults on a ability to infect new cells but adapted University of Oxford, together with journey through DNA, exploring its to surviving in just one cell, collaborators around the globe, role in determining the fate of all our replicating and spreading viral compared 10 000 stroke patients’ cells and how these cells make us who genetic material throughout the host genetic make-up with that of we are. Colourful 3D graphics capture animal’s genome. DNA from these 40 000 healthy people. the incredible detail of the molecular viruses was much more abundant in machinery within our bodies. Cell! mammalian genomes than that of They found that an alteration in a Cell! Cell! has been shown in digital other viruses. The scientists think gene called HDAC9 increased the risk planetariums across the UK, and that these viruses were forced to of stroke: people with two copies of there are also related online resources choose between spreading among the variant gene were almost twice as that explore genetic inheritance, the animals and spreading throughout a likely to suffer large artery ischaemic DNA double helix and other single genome. In opting for the stroke as those with two normal important cell structures. latter, they effectively became copies. The mechanism by which ‘epidemics’ that have been running in HDAC9 affects stroke risk is not yet our genomes for 100 million years. clear, but the discovery could lead to new methods of screening and new treatments to prevent some of the 6 million caused by stroke around the world each year.

22 | Annual Review 2012 I look forward to the day whenever I stop treating cancer patients as if they’re all the same, and begin dividing patients into groups which are going to be treated more effectively.” Dr Ultan McDermott, Wellcome Trust Sanger Institute

Genetic clues to new cancer treatments Not all patients with a particular type The genetic make-up of a cancer cell Such pronounced sensitivity of a type of cancer respond to the same drugs determines how it responds to cancer of cancer to a drug used for other in the same way. By examining the drugs that target certain genes or the purposes is unlikely to be common, effectiveness of drugs on large proteins they regulate. The Cancer but the project is shedding light on numbers of cancer cells with different Cell Line Screening Project is a the many factors that determine how genetic mutations, we might be able five-year collaboration between the sensitive cancer cells are to particular to explain why patients’ responses to at the Sanger drugs. This information will help to these drugs differ, and to find ways to Institute and researchers at the guide future drug development, and determine the best treatment for an Massachusetts General Hospital especially the use of biological individual patient. Cancer Center. They are cataloguing markers to identify which drugs are how more than 600 distinct cancer most likely to help which patients. Cancer is a genetic disease: it is cell lines – derived from cells taken caused by mutations in genes that from real tumours and cultivated in control the behaviour of a cell, the laboratory – respond to 130 causing it to grow, multiply or move established and experimental drugs. around the body in a dangerous way. The work draws on high-throughput A study published in the New England screening and next-generation Journal of Medicine in March 2012, by genome-sequencing techniques scientists at the Wellcome Trust developed at the Sanger Institute. Sanger Institute and Cancer Research UK, found extraordinary variation in Initial results, published in Nature in the patterns of genetic mutations in April 2012, were promising. For cancer cells, even within a single example, the analysis suggested that a tumour. Only by understanding these class of drugs called PARP inhibitors, mutations and their effects on drug currently used to treat breast and sensitivity or resistance can we begin ovarian , might also be to develop ‘personalised medicine’, effective as a therapy for a bone tailored to each patient based on the cancer called Ewing’s sarcoma. This specific characteristics of their illness. will be tested in clinical trials and could lead to a new treatment for Ewing’s sarcoma, which affects children and young people.

From left: A cast of blood vessels in the brain. Gordon Museum, King’s College London A still from the Cell! Cell! Cell! planetarium show. NSC Creative Mammalian genomes contain ancient viral DNA. dra_schwartz/iStockphoto A lung cancer cell. Anne Weston, LRI, CRUK/Wellcome Images

Annual Review 2012 | 23 Images: Computer-generated images of how the UK Centre for Medical Research and Innovation will look.

24 | Annual Review 2011 Understanding the brain

This year, basic research into deafness was recognised with an international neuroscience prize, while a stem cell treatment restored hearing in gerbils, raising the prospect of a new therapy for some forms of human hearing loss.

Impaired hearing is a common This year, Professor Steel was The gerbils’ deafness was the result condition, with a wide range of awarded the Brain Prize, sharing it of damage to the nerves that carry possible causes including infections, with French scientist Professor signals from the ear to the brain. This noise and drugs. There is also a Christine Petit for their contributions is a model of auditory neuropathy, a strong hereditary component to to our understanding of the ear and human condition that accounts for up hearing loss: several hundred genes the causes of inherited deafness. to 15 per cent of people with profound may be involved, but we are only just The €1 million prize is given each hearing loss. Unlike deafness caused beginning to understand which they year by a Danish charity, the Grete by the loss of sound-detecting hair are and what role they play. Lundbeck European Brain Research cells in the inner ear, auditory Foundation, and Queen Margrethe II neuropathy cannot be helped by Professor Karen Steel, working with of Denmark presented the awards cochlear implants. So this stem cell Professor Steve Brown (currently at a ceremony in Copenhagen in therapy may have the potential to director of the Medical Research May 2012. repair damaged hearing in humans, Council Mammalian Genetics Unit), although it will be many years until identified the first mouse gene In September 2012, research such a treatment is ready. involved in deafness, Myo7a, in 1995. published in Nature described how It is one of many genes she has scientists led by Dr Marcelo Rivolta A growing body of research in worked on that have also been found at the Centre for Stem Cell Biology, genetics, neuroscience, stem cells and to underlie deafness in human. Since University of Sheffield, used a form other fields of science has expanded 2003, Professor Steel has worked at of stem cell therapy to restore hearing our understanding of hearing and the Wellcome Trust Sanger Institute, in deaf gerbils. deafness, suggesting new ways to help studying mice with single-gene people who lose their hearing, mutations that have caused loss of The study, funded by Action on whether from birth or later in life. hearing. Her team examines what has Hearing Loss, Deafness Research UK, changed in these mice by measuring the Wellcome Trust, the Medical the function of the cochlea and Research Council and the Royal other hearing structures in the ear Society, was the first time stem cells and brain. had been differentiated into the necessary types of progenitor cell and successfully transplanted into animals. Their hearing improved within weeks.

Professor Karen Steel. Wellcome Images Annual Review 2012 | 25 Brains: The mind as matter Over 100 000 people came to see idea that the shape of the skull task of making as many of the brain’s Brains: The mind as matter, which ran reflected a person’s brain and 100 trillion connections as they could from 29 March to 17 June 2012 at therefore their character – and by clicking on protein targets. It was Wellcome Collection. The exhibition trepanning, drilling holes in the skull played over 4 million times in its first explored human attempts to unravel to relieve pressure on the brain. There three months and continues to the mysteries incorporated in the were anatomical models of the brain attract gamers. organ that governs our body, mind and a film of a modern brain and soul. dissection. A wide programme of events accompanied the exhibition, Famous and infamous brain Brains garnered five-star reviews and including Mind Over Matter, a ground- specimens – including those of Albert glowing plaudits. Time Out called it a breaking show at Shoreditch Town Einstein, Charles Babbage and “must-see”; Metro said that “much of Hall featuring photographs and audio William Burke – were on display it [was] jaw-dropping…some of it narratives from 12 people who had alongside works by contemporary breathtaking”. The New Statesman, elected to donate their brains after artists offering personal responses to Guardian and New Scientist called for research. At Wellcome the physical form and matter of the the exhibition “incredibly moving”, Collection, visitors could watch brain, and reflections on its nature “exquisite” and “compelling” ‘Brains on Film’, a programme of and meaning from famous thinkers. respectively. Hundreds of articles short films and features, including appeared online across the world, and the classic B-movie Donovan’s Brain, The exhibition’s aim was to explore there was extensive international and a series of ‘Brain Matters’ talks what we have done to the brain in broadcast coverage. explored the impact of how we the name of medicine, science and understand the brain on issues culture, as opposed to what it does A free online game exploring the of identity and ethics. for us. Exhibits explored historical brain’s structure was launched on concepts such as phrenology – the the Wellcome Collection website to complement the Brains exhibition. Developed by BAFTA-winning games studio Preloaded, Axon set players the

Brains goes beyond just a visual feast, and quietly adds to the sense of gravitas with which we approach our most mysterious organ.” Claire Ramtuhul, New Statesman

26 | Annual Review 2012 From left: A still from the ‘Dissecting Brains’ film shown at Wellcome Collection. Martha Henson A zebrafish. Wellcome Images Symptoms of psychological distress have been linked to lower life expectancy. Fancy Photography/Veer Professor Daniel Pick. Matchbox Video

High-resolution brain activity Mental health and life expectancy Analysing the Nazi mind A technique for measuring the A link between mental health and The Allied Forces’ deployment of activity of thousands of individual life expectancy has been found in psychological techniques in World brain cells simultaneously was research led by Wellcome Trust War II is not widely appreciated. reported in Nature in May 2012. Dr Fellow Dr David Batty. The study, However, the British and Americans Misha Ahrens, a Sir Henry Wellcome published in the British Medical made extensive use of psychoanalysis Postdoctoral Fellow based at Harvard Journal in July 2012, analysed ten years and psychiatry to probe the Nazi state University and the University of of data from the Health Survey for of mind as part of an urgent mission Cambridge, developed the technique England, covering more than 68 000 to understand more about the enemy. with colleagues and used it to study individuals. It showed that people the role of different cells when a with symptoms of psychological Professor Daniel Pick of Birkbeck, zebrafish adapts its movement in distress were about 20 per cent more University of London, was supported response to external stimuli. The likely to die over a given period than by the Wellcome Trust to investigate findings offer an insight into how people of the same age and sex who this episode of history, leading to the human brains might work when we reported no such symptoms. There publication this year of The Pursuit of adapt our movements to cope with a was an effect even when the distress the Nazi Mind: Hitler, Hess and the change in conditions, such as walking symptoms were relatively mild, but analysts. The book includes discussion on a slippery surface. it became more marked as the of the British Army’s attempts to severity increased. understand the behaviour and mental Zebrafish are naturally transparent state of the Deputy Führer, Rudolf during the larval stage of The mechanism underlying this Hess, who was captured in Scotland development, so the researchers relationship between mental health in 1941. introduced a protein that fluoresces if and life expectancy is not clear. It is a brain cell is active. Using a laser- possible that even mild mental health Professor Pick believes that many of scanning microscope, they could see problems produce biological changes the psychological themes examined which cells were active, looking at up in the body that increase the risk of during the War are still relevant to 2000 cells at the same time. The certain diseases, such as heart today, despite the very different zebrafish were paralysed but given disease. More research will be needed context. visual feedback corresponding to to see whether treating mild mental how their brains thought they were health problems reduces these risks. swimming. While neural activity can be studied in other animals, such as rats, their brains are larger – and not transparent – so only a small number of brain cells can be observed. The zebrafish model creates new opportunities for studying complete brain circuits.

Annual Review 2012 | 27 Images: Computer-generated images of how the UK Centre for Medical Research and Innovation will look.

28 | Annual Review 2011 Combating infectious disease

Rapid whole-genome sequencing could be used to identify infectious outbreaks earlier, potentially ending them more quickly.

Methicillin-resistant Staphylococcus The researchers showed that, unlike The approach was verified when the aureus (MRSA) is a major public health current laboratory techniques, infection control team at another problem, with people often becoming sequencing technology could hospital in Cambridge identified 12 infected while in hospital for other distinguish between people whose patients with MRSA infections. reasons. Its antibiotic resistance MRSA infection was part of the larger Sequencing demonstrated that the makes MRSA slower and more outbreak and those who had been bacteria in all 12 cases were closely expensive to treat than other infected by an unrelated strain. This related and that this was an outbreak. infections. Genome sequencing could is critical because it can help to It also revealed that the outbreak help to reduce the spread of MRSA by identify how a specific strain is covered more than twice as many identifying outbreaks more quickly, spreading between people. They also people as previously realised. and by helping to understand how an found that they could have identified outbreak is being transmitted and the outbreak at an earlier stage than While this work was still underway, a how it can be effectively controlled. current clinical testing – an new case was identified in a different advantage that could have helped unit of the hospital. Despite there To test this approach, researchers at to end the outbreak sooner. being no apparent links between the the Wellcome Trust Sanger Institute, previous patients and this unit, the University of Cambridge and In addition, the team was able to sequencing showed that this case was biotechnology company Illumina compare the genome of the outbreak also part of the outbreak. Hospital used whole-genome-sequencing MRSA strain with MRSA genes that workers were screened and one was techniques to retrospectively analyse are known to confer resistance to found to be carrying MRSA. Again, an outbreak of MRSA in a Cambridge antibiotics. This would have allowed sequencing confirmed the bacteria hospital. They obtained samples and them to say which antibiotics were were related to those in the outbreak. sequenced them as if the outbreak most likely to work in treating the The member of staff was treated, were happening right then, in real infection during the outbreak. As well preventing further transmission of time. The project was supported by as guiding treatment for individual the infection. This episode, described the Wellcome Trust and other patients, this sort of analysis – in the Lancet in November 2012, funders, including the UK Clinical published in the New England Journal clearly shows the potential of Research Collaboration, which itself of Medicine in June 2012 – could help advanced genome sequencing to is Trust-funded. to discover new mechanisms of identify and control infectious drug resistance as they evolve in outbreaks more effectively than is the bacteria. currently possible.

Methicillin-resistant Staphylococcus aureus bacteria. Annie Cavanagh/Wellcome Images Annual Review 2012 | 29 Flu severity depends on host Vitamin D and TB Key to HIV infection genes too South Africa has the third-highest Scientists have found the ‘key’ that People who have a particular burden of tuberculosis (TB) in the HIV uses to enter the nucleus of an variant of a gene called IFITM3 are world, and infection rates are highest infected cell and integrate itself into significantly more likely to require in Cape Town, where there are greater the cell’s DNA. This is how HIV a stay in hospital when they get seasonal variations in people’s replicates and spreads through the influenza. The finding, reported in vitamin D levels than in other parts of body, but how it passes through the Nature in March 2012, helps explain the country. In a paper published in nuclear pore complex – a gateway into why flu can be life-threatening for Proceedings of the National Academy of the nucleus – has been unclear. In some people but has only mild effects Sciences in November 2011, Wellcome December 2011, a team led by in others. Trust Senior Research Fellow Professor Greg Towers, a Wellcome Professor Robert Wilkinson and Trust Senior Research Fellow, A team of scientists at the Wellcome colleagues showed that black people published research showing that a Trust Sanger Institute led work on the in Cape Town were about five times specific part of the virus called the IFITM3 gene after it was implicated more likely to be infected with TB capsid protein binds to a component in mechanisms of resistance to if they had low levels of vitamin D. of the nuclear pore complex, opening influenza A and other viruses. They The number of new TB cases in the gateway and letting HIV in. discovered that disrupting the gene Cape Town is highest in the months in mice led to more serious and following winter and lowest after The finding provides a potential new prolonged illness in response to summer, suggesting that low vitamin target for drugs to combat HIV relatively mild strains of influenza. In D levels are directly responsible for infection. HIV evolves rapidly and so humans, the researchers found that the increased susceptibility. it quickly develops resistance to drugs some patients admitted to hospital in that target the virus itself. Treatments 2009–10 – with either seasonal flu or In a paper published in the same targeting the human nuclear pore the pandemic H5N1 strain – had rare journal in September 2012, Professor complex – in effect, changing the variant forms of IFITM3 that made Wilkinson and colleagues also locks – might be harder for the virus them more susceptible. described how giving vitamin D to beat. supplements to people with TB Knowing more about the interactions affected the response of their immune between viruses and the human systems to the infection. Overall, immune system will help us prevent vitamin D reduced the time it took for infections in the future. inflammation to clear, suggesting it might be a useful addition to standard TB treatments.

From left: Influenza B virus particles. R Dourmashkin/Wellcome Images Cape Town. Joseph Ferris III on Flickr Internal structure of HIV, showing the capsid protein in red. Stephen Fuller/Wellcome Images Work at the Shoklo Malaria Research Unit in Mae Sot, Thailand. Mads Monsen 30 | Annual Review 2012 Malaria already kills hundreds of thousands of people a year – if our drugs become ineffective, this figure will rise dramatically.” Professor François Nosten, Shoklo Malaria Research Unit

Antimalarial resistance The spectre of untreatable malaria region. But a study published in Fears about resistance to ACT have loomed this year as researchers the Lancet in April 2012 suggests been fuelled by the findings of published evidence that resistance that, while that approach may well another study, by Trust-funded to artemisinin, the recommended help, containing the spread of researchers who have been examining treatment, has spread across resistance will be harder than the ingredients of antimalarials on Thailand. originally thought. sale in Africa. In January 2012, they reported in Malaria Journal that some Over the last two decades, clinical And, 800 km away on Thailand’s of those contained active trials by researchers at the Wellcome northern broder with Myanmar, pharmaceutical ingredients that Trust Major Overseas Programmes in researchers at the Trust’s Shoklo would not cure malaria but could Thailand and Vietnam have shown Malaria Research Unit have also cause serious side-effects. Others that therapies based on artemisinin, reported cases of resistance to contained small amounts of an ancient Chinese herbal remedy for artemisinin. They found that the artemisinin derivatives – enough fevers, are more effective than other average time it took ACT to clear to pass simple authenticity tests antimalarials. As a result, in 2006 parasites from patients’ bloodstream but not enough to rid the body of the World Health Organization had increased between 2001 and 2010. malaria parasites, creating ideal recommended artemisinin-based This rise in cases of slow-clearing circumstances for the parasite to combination therapies (ACTs) as infections is a clear sign that the develop resistance to the drug. first-line treatments for the most drugs are becoming less effective. deadly species of malaria parasite, The research confirms that we are Plasmodium falciparum. In another study published on the in a race against time to prevent the same day in Science, in collaboration spread of drug-resistant malaria. In 2009, there were unsettling reports with scientists at the Texas Urgent coordinated action by that artemisinin-resistant malaria Biomedical Research Institute, San scientists, medics, public health parasites had emerged in western Antonio, the same researchers organisations and policy makers is Cambodia, near the southern border provided compelling evidence that needed to prevent one of the world’s of Thailand. Researchers at the the decline in the parasite clearance major killers from becoming much Trust’s Thailand Programme had rates was due to genetic changes in more dangerous. hoped it would be possible to a region on chromosome 13 of the prevent the spread of resistance by P. falciparum genome. eliminating P. falciparum from that

Annual Review 2012 | 31 Images: Computer-generated images of how the UK Centre for Medical Research and Innovation will look.

32 | Annual Review 20122011 Investigating development, ageing and chronic disease

We are beginning to realise the potential of stem cells for use in therapies, as recognised by the 2012 Nobel Prize in Physiology or Medicine, shared by Sir John Gurdon and Shinya Yamanaka.

In August 2012, the Wellcome Trust the Prize with Professor Shinya and could also be used to test and the Medical Research Council Yamanaka, who transformed skin potential new treatments for the announced a new institute for stem cells back into stem cells using genetic disease when they are in the early cell biology and medicine at the engineering. This work, published stages of development. University of Cambridge. The in 2006, opened the way to using a £8 million centre will build on patient’s own tissue to create stem The UK is recognised as one of the existing investment by the two cells that can be used to replace best places in the world for stem cell funders in stem cell research, uniting damaged or faulty cells. For example, research and the new Wellcome 25 leading research teams working in October 2011, researchers used Trust–MRC Cambridge Stem Cell across the three main types of stem human induced pluripotent stem Institute is intended to make sure cell: embryonic, adult and induced cells to correct a gene mutation that this continues, attracting the pluripotent cells. The teams’ work responsible for a type of liver disease best international researchers in will advance our understanding of the (see page 21). stem cell biology and regenerative roles stem cells play in our bodies and medicine. their potential to treat a range of As well as innovative forms of life-threatening conditions. treatment, stem cells offer us new ways to understand the basic biology It was 50 years ago that Professor of disease. In February 2012, scientists Sir John Gurdon first proved that at the Wellcome Trust/Cancer mature, specialised cells could be Research UK Gurdon Institute reprogrammed to become immature – named in honour of Sir John – took cells capable of developing into all donated skin cells, reprogrammed tissues of the body. This achievement them into stem cells and used them to was recognised in October 2012, when generate large numbers of nerve cells it was announced that he had won the that behave just like the cells in the Nobel Prize in Physiology or Medicine human brain. These populations of would. Sir John, also a former nerve cells are being used to model Wellcome Trust Governor, shared the progression of Alzheimer’s disease

Professor Sir John Gurdon. Wellcome Images Annual Review 2012 | 33 From left: UK Biobank gives a picture of health and disease across the British population. Ocean Photography/Veer A fibroblast, involved in wound healing. Matthew Daniels, University of Oxford/Wellcome Images Respiration monitor. Covidien plc Richard Tyrone Jones holding a model heart. Andrew Crowe

UK Biobank opens After spending six years amassing Researchers took measures of height, Researchers can now able to apply to a unique repository of health weight, body fat, hand grip strength, use the database. They are not given information and samples from bone density, lung function and blood access to the volunteers, who will 500 000 volunteers, UK Biobank pressure. Blood and samples remain strictly anonymous; only opened to researchers on 30 March were also taken and preserved so that information that does not identify 2012. Funded by the UK Department it will later be possible to extract DNA participants is provided to of Health, the Medical Research and measure other biologically researchers. Scientists from the UK Council, the important substances. The final and overseas, from academia and and the Wellcome Trust, and based in 100 000 participants to be recruited industry, will be able to use the Stockport, UK Biobank is a valuable also had hearing, fitness and eye tests. resource to find out why some people scientific resource. Studies using data As a result of this initial data develop particular conditions and from people’s biological samples, collection phase, UK Biobank now others do not, paving the way for new medical histories and lifestyle holds more than 1000 separate pieces ways to prevent and treat diseases. questionnaires will help to unravel of information on each of its 500 000 genetic and environmental volunteers. They include 26 000 contributions to the development people with diabetes and 50 000 with of many diseases. joint disorders, 41 000 teetotallers and 11 000 survivors of heart attacks. Half a million volunteers aged between 40 and 69 were recruited This information will grow as the from Scotland, England and Wales participants’ stored samples are over four years from 2006. They were analysed and their health is followed invited to assessment centres, where over the next 25 years. In this time, all they completed a questionnaire and changes in their health, medical tests, were interviewed about their lifestyle, drug prescriptions and deaths will medical history and diet. , be added to the database, taking early life factors and psychosocial advantage of the UK’s centralised events, such as how often people NHS and electronic records such see family and friends, were as cancer and death registries. also recorded.

Even if I can’t benefit from the results personally, I know my children, my children’s children and perfect strangers will.” Barbara Collins, a UK Biobank volunteer from London 34 | Annual Review 2012 Helping wounds heal Monitoring respiration Living with heart failure Recovering from an injury, illness In 2003, the Wellcome Trust and ‘Richard Tyrone Jones’s Big Heart’ is or surgery involves the repairing the Scottish Government invested a solo show of poetry and comedy all of damaged tissue. In October 2011, £1 million in CardioDigital Ltd, based around the fact that, at the age researchers at the University of a Scottish company developing of just 30, Jones found out he had Bristol and the Wellcome Trust electronic medical devices. The heart failure. Funded through a Centre for Cell-Matrix Research company had found that a pulse Wellcome Trust People Award, the at the University of Manchester oximeter – a sensor placed on a show covers the poet’s attempts to described how cells detect and patient’s finger to measure oxygen educate himself and others on the respond to tissue damage, which levels in the blood – could be used body’s ‘engine room’. He discusses could open up new opportunities for to measure breathing rate as well. how and why he was diagnosed with improving the healing of wounds. the condition at such a young age, The Trust supplemented the funding and talks about the experience of When blood vessels are broken, in 2005 and 2006, as CardioDigital his heart stopping for four seconds. plasma leaks out of them and causes developed software that could turn fibroblast cells to migrate to the pulse oximeter data into accurate Jones performed the show at the damaged tissue, where they make clinical information about Edinburgh Fringe Festival, Liverpool’s the wound contract and plug it with respiration. CardioDigital’s assets Dadafest and around the UK in collagen and other structural were acquired in 2008 by Covidien autumn 2012. It was both poetic molecules. Every step of the healing plc, a leading global healthcare and scientifically accurate, while process requires cells to repeatedly products company, which integrated maintaining a sense of humour stick to and unstick from other cells. the respiration rate software with its throughout. It even included a Using atomic force microscopy, the own leading pulse oximetry products. biomedical cover of Tom Lehrer’s scientists revealed the signalling ‘The Elements’ song, using 48 pathway that controls the ‘stickiness’ In March 2012, Covidien announced tongue-twisting genetic conditions. of fibroblasts in response to changes that the technology had received outside the cells. Blocking these regulatory appproval to be used in signals stopped tissue from repairing the USA and the European Economic properly, suggesting that modulating Area. The sensor can make several them with drugs or other therapies measurements simultaneously, could help to improve the way our freeing clinicians from having to wounds heal. count the rise and fall of a patient’s chest to measure breathing rate. The system also provides data about trends, to help clinicians detect and respond to dangerous respiratory events more quickly.

Annual Review 2012 | 35

Connecting environment, nutrition and health

Not only is the global population continuing to increase, but also the way we live is changing, which could have a considerable effect on our health.

More than half the world’s population Initial results from the study, similar but lower levels. The pattern now lives in cities or other urban published in 2010, showed that was the same in women but with environments. This is mostly driven migration to cities was associated slightly lower levels of activity overall. by migration – people want to live with increases in obesity within ten Another paper, published in early 2012 where there are jobs, resources and years, which drove other changes that in the National Medical Journal of other opportunities. But moving to also raised the risk of cardiovascular India, looked at diet. The researchers the city brings pressures on the way disease. Further analysis in 2011 were able to identify a number of we live, which can significantly affect showed that the urban environment specific foods that obese people ate our health. might affect the way a gene called more of than their normal-weight FTO contributed to the likelihood of neighbours. In 2005, the Wellcome Trust-funded obesity in India. The researchers’ Indian Migration Study began conclusion was that rural migrants These studies may point the way recruiting workers in four urban rapidly adopt lifestyles that put them towards methods of encouraging factories who had moved to the city at the same risk of disease as the people to change their physical from the countryside and still had a indigenous urban population. activity and food consumption, which brother or sister living in their home The strength of the Indian Migration would help to slow the rise in diabetes village. The factories were in four Study is that, by using pairs of and obesity in Indian cities. different cities around India but the siblings, it accounts as far as is pairs of siblings were from 20 of the feasible for confounding factors such 29 states in the country, reflecting as genetics or early life experiences. It how far people are willing to move to reveals the likely impact of increasing find work. The researchers measured migration on the health of individuals the nearly 7000 participants’ and the healthcare systems that cardiovascular risk factors, recorded support them. whether they were obese or had diabetes, assessed their diet and levels More research from the Indian of physical activity, determined their Migration Study was published this socioeconomic position, and year, including a paper in PLoS ONE performed several laboratory tests. in October 2011 showing that the migrants quickly adapted to urban levels of physical activity. Rural men had the highest levels of physical activity, whereas those born in the city and those who moved there had

Indian city illustration. Bret Syfert Annual Review 2012 | 37

From left: A gray wolf. US Fish and Wildlife Service (Midwest Region) on Flickr Sir David Attenborough in conversation. Leishmaniasis is moving into cities in Brazil. Ocean Photography/Veer Artworks from the Dekha Undekha exhibition.

Modelling population change Environmental changes can have In a paper published in Science in The wide range of population profound effects on a species, December 2011, Professor Coulson responses to environmental changes influencing population numbers described a model that allows makes accurate prediction and physical characteristics – even researchers to test how changes in challenging. It may be that the best the frequencies of certain genetic environment would affect the size of we can do with our current variants within the species. These the wolf population and, through information and technology is to effects can be documented when they changes to the gene pool, factors such explore possible consequences of occur, but it is difficult to predict as the frequency of black or grey coats different scenarios of environmental what impact a specific change in over centuries. The model treats change, using models such as this environment will have because there the population as a collection of one. The framework used to develop are so many interacting variables. individuals, each with many the model can naturally be applied to attributes. Distributions of these any species, and Professor Coulson’s Professor Tim Coulson of Imperial attributes can then be constructed colleagues have already begun College London seeks to understand that change over time according to applying it to insect and plant the consequences of environmental their association with survival, populations. Meanwhile, he is change on the characteristics of a development and reproduction. collaborating with a team at Stanford whole population. In a Wellcome One interesting finding was that University, using data from the Trust-funded project, he used changes in the average value of an Framingham Heart Study, to apply data from a population of wolves environmental factor had a greater the model to human populations. in Yellowstone National Park, impact across the population than Such work means researchers will be Wyoming, to construct a model of increased variability in that factor. able to start asking questions such as environmental change. Changes in For example, an increase in the what the long-term effects on life the depth of snow in winter, the average temperature in Yellowstone expectancy might be if obesity rates availability of prey and the occurrence would be more significant to the continue to rise. of disease, for example, can all affect wolves than larger swings in the wolves’ survival, reproduction, temperature around the same growth and even the colour of their annual average. coats. Information about all these variables has been rigorously recorded in Yellowstone since the wolves were reintroduced to the habitat in the mid-1990s.

The biggest impact I’ve seen on human health is slums…Huge areas occupied by people living, whole families, in tiny little apartments with no sanitation – and no future.” Sir David Attenborough

38 | Annual Review 2012

Man of the (natural) world Sex pheromones in the city Art and health in the slums Environmental change can manifest Before the 1980s, leishmaniasis was In February 2012, an ambitious art itself in different ways in different a rural disease in Brazil. A potentially exhibition funded by the Wellcome parts of the globe, but the naturalist fatal parasitic infection transmitted Trust opened in Dharavi, one of the and broadcaster Sir David by female sand flies, it was a risk most disadvantaged areas of Mumbai. Attenborough, who has seen more for people in the countryside, Dekha Undekha (Seen Unseen) of the globe than most people, is particularly the forests. But as people brought together residents, artists adamant that the major issues affect have migrated to the cities, so the and health professionals to express us all. These include the challenge of disease has followed. For example, concerns affecting many of Dharavi’s producing enough power to support there is evidence that leishmaniasis million inhabitants. Together, they the ever-increasing population and is spreading from the south-west state explored issues such as sanitation, ensuring that everyone has access to of Mato Grosso do Sul, moving along personal hygiene, domestic violence, clean water and sanitation to prevent the highways towards the east, maternal health and superstitions. the spread of infectious diseases. threatening in particular São Paolo, the largest city in the southern The project aimed to help local Sir David says the fundamental hemisphere and the seventh most residents develop skills in source of the environmental problems populous city in the world. Another photography, ceramics and textile art, we face is the rapid growth of the factor in the spread of the disease is and discuss urban health issues more human population. In an interview the environmental degradation of the openly – informed by input from filmed this year by the Wellcome forests, which has led to the insects health experts. Through a series of Trust, he says that the number of that carry the parasite becoming the workshops over a year, participants people in the world has tripled in dominant species in their habitats. created a joint exhibition at a Dharavi his lifetime and that many of our primary school, including cushions problems would be made more This year, field trials of a new reflecting female health conditions, manageable if we could slow that approach to controlling sand flies a street play on safe sex, and dreams rate of growth. But another critical began in Brazil with the support of a moulded on ceramic slippers. These aspect of solving these problems Wellcome Trust Translation Award. activities brought visitors into the is to persuade politicians and the The project uses a combination of a urban slum and encouraged them people who elect them that action is synthetic sand-fly sex pheromone and to engage with the reality of the required. The Trust is expanding its a pesticide to lure and then kill female residents’ lives. activities in areas where health sand flies. The scientists hope to intersects with issues of the demonstrate that this strategy can environment and nutrition, and reduce the transmission of a large part of this work will be to leishmaniasis to humans. communicate the problems and the potential solutions.

Annual Review 2012 | 39 Advisory committees 2011/12

We are indebted to the researchers and experts who give up their time to sit on our advisory committees or review our grant applications.

Advisory Committee for the B Johnson Professor S Phillips (Co-Chair) Clinical Interview Committee Wellcome Trust–National Graphic Science Ltd Research Complex at Harwell Institutes of Health Four-year Professor B R Walker (Chair) PhD Studentship Programme S Willson Professor T Aitman University of Edinburgh Clod Ensemble Imperial College London Dr G Felsenfeld (Chair) Professor C Boshoff NIH, Bethesda, USA Dr R Wingate Professor R Baldock University College London King’s College London University of Edinburgh Dr C Blackstone Professor M Botto NIH, Bethesda, USA Professor S Brunak Imperial College London Basic Science Interview Technical University of Denmark Dr J Brenchley Committee Professor H D Critchley NIH, Bethesda, USA Professor N Bulleid University of Sussex Professor C Kleanthous (Chair) University of Glasgow Dr J Clarke University of Oxford Dr I S Farooqi University of Cambridge Professor P R Burton University of Cambridge Professor R Allshire University of Leicester Dr D C Douek University of Edinburgh Professor M Husain NIH, Bethesda, USA Professor Z Chen University College London Professor W Barclay University of Oxford Dr F Gribble Imperial College London Professor J Iredale University of Cambridge Dr J Christodoulou University of Edinburgh Dr S Gamblin University College London Dr M M S Heck MRC National Institute for Professor H McShane University of Edinburgh Medical Research, London Professor D F Cutler University of Oxford University College London Dr S Muller Professor A J King Professor T Skerry University of Glasgow University of Oxford Professor I Davis University of Sheffield University of Oxford Dr J R Sellers Professor L M Machesky Professor P G Smith NIH, Bethesda, USA University of Glasgow Professor P Elliott London School of Hygiene Imperial College London and Tropical Medicine Dr J-P Vincent Professor R Noelle MRC National Institute for King’s College London Professor J Frampton Professor R L Smyth Medical Research, London University of Birmingham University of Liverpool Professor M J Shattock Dr T Wolfsberg University College London Dr A J Greenfield Professor H J Willison NIH, Bethesda, USA Medical Research Council University of Glasgow Dr M Tobin University of Leicester Dr A Holder Arts Award Funding Committee MRC National Institute for Ethics and Society Interview Professor S W Wilson Medical Research, London Committee A Ledgard (Chair) University College London Dr J Rappsilber Professor B Farsides (Chair) Dr M J Gorman University of Edinburgh University of Sussex Trinity College Dublin, Ireland Biomedical Resources and Professor R Razavi Multi-user Equipment Professor P Braude King’s College London M Govinda Committee King’s College London Artsadmin, London Professor R J Read Professor J Parkhill (Co-Chair) Professor A J Clarke University of Cambridge G Henderson Wellcome Trust Sanger Institute, Cardiff University House of Illustration Cambridge Professor S R Williams Dr S Cunningham-Burley University of Manchester University of Edinburgh

40 | Annual Review 2012 Dr M Quigley Professor C ffrench-Constant Dr J Langhorne Professor A J Knox University of Manchester University of Edinburgh MRC National Institute for University of Nottingham Medical Research, London Professor D Schroeder Professor G Miesenboeck Professor P Martin University of Central Lancashire University of Oxford Professor F Powrie University of Bristol University of Oxford Dr I Singh Professor T Owens Professor A M Prentice London School of Economics University of Southern Denmark Dr F Randow London School of Hygiene and Medical Research Council Tropical Medicine Professor S Wilkinson Professor G Schiavo Keele University Cancer Research UK Professor A Rudensky Professor M D Schneider Memorial Sloan–Kettering Imperial College London Professor C Williams Professor B Schwappach Cancer Center, New York, USA Brunel University University of Goettingen, Professor J Seckl Germany Professor D C Wraith University of Edinburgh Professor S Yearley University of Bristol University of Edinburgh Professor L Wilkinson Cardiff University Expert Review Group 7: Cell Expert Review Group 5: and Developmental Biology Expert Review Group 1: Pathogen Biology and Genetics, Genomics and Expert Review Group 3: Disease Transmission Professor F Grosveld (Chair) Population Research Cognitive Neuroscience Erasmus University, Rotterdam, and Mental Health Professor G Dougan (Chair) the Professor A D Morris (Chair) Genome Research Limited University of Dundee Professor D Bishop (Co-Chair) Dr J Briscoe University of Oxford Professor G S Besra MRC National Institute for Dr I Barroso University of Birmingham Medical Research, London Wellcome Trust Sanger Institute, Professor R N Lemon (Co-Chair) Cambridge University College London Professor S P Borriello Professor K E Kadler Veterinary Medicines Directorate University of Manchester Dr E Birney Professor A Ehlers European Bioinformatics King’s College London Professor E Carniel Professor R Krumlauf Institute Pasteur Institute, Paris, France Stowers Institute for Medical Professor D K Jones Research, Kansas City, USA Professor J Danesh Cardiff University Professor K Gull University of Cambridge University of Oxford Professor P Parker Professor M J Morgan King’s College London Professor G Davey Smith City University of London Professor J Hemingway University of Bristol Liverpool School of Tropical Professor Dame L Partridge Professor A Nobre Medicine Max Planck Society Professor C Lewis University of Oxford King’s College London Dr A Holder Dr C Rabouille Professor D J Porteous MRC National Institute for Hubrecht Institute, Utrecht, the Professor J Lupski University of Edinburgh Medical Research, London Netherlands Baylor College of Medicine, Texas, USA Dr E R Watkins Professor M J Keeling Professor M S Robinson University of Exeter University of Warwick University of Cambridge Professor G McVean University of Oxford Professor S C Wessely Professor G L Smith Professor G B Warren King’s College London University of Cambridge Max F Perutz Laboratories, Professor N Rahman Vienna, Austria Institute of Cancer Research Professor D Wolpert Professor R Weiss University of Cambridge University College London Professor F M Watt Dr C Stoltenberg University of Cambridge Norwegian Institute of Public Health Expert Review Group 4: Immune Expert Review Group 6: System in Health and Disease Physiology in Health and Disease Expert Review Group 8: Molecular Basis of Cell Function Expert Review Group 2: Cellular Professor P J Lehner (Chair) Professor P J Ratcliffe (Chair) and Molecular Neuroscience University of Cambridge University of Oxford Professor A Lamond (Chair) University of Dundee Professor D Attwell (Co-Chair) Dr B Arnold Professor W Arlt University College London German Cancer Research Centre, University of Birmingham Professor D Barford Heidelberg, Germany Institute of Cancer Research Professor D Rubinsztein Professor D C Crossman (Co-Chair) Professor P R Crocker University of East Anglia Professor W Bickmore University of Cambridge University of Dundee University of Edinburgh Professor A K Daly Professor Z Bashir Professor T J Elliott Newcastle University Dr J Molloy University of Bristol University of Southampton Medical Research Council Professor A T Hattersley Professor P F Chinnery Professor D Goldblatt University of Exeter Newcastle University University College London

Annual Review 2012 | 41 Advisory committees 2011/12

Professor H Saibil Professor C Gradmann Professor W J Graham Health Innovation Birkbeck, University of London University of Oslo, Norway University of Aberdeen Challenge Fund

Professor A Sharrocks Professor L Jordanova Professor T Jafar W Burns (Chair) University of Manchester King’s College London Aga Khan University, Karachi, Pakistan Professor Sir J M Brady Professor D J Sherratt Professor J Macnaughton University of Oxford University of Oxford Durham University Professor G T Keusch Boston University, USA Dr U Gebhardt Professor J M Thornton Professor J H Mills European Bioinformatics University of Strathclyde Professor D Lalloo T Haines Institute Liverpool School of Tropical Abingworth LLP Professor S Swain Medicine Professor D W Tollervey University of Warwick Professor S H Ralston University of Edinburgh Professor B I McPake University of Edinburgh Professor G Williams Queen Margaret University Professor S Urbe University of Bristol Professor M Singer University of Liverpool Dr K M V Narayan University College London Emory University, Atlanta, USA Expert Review Group 11: Dr J Smith Expert Review Group 9: Ethics and Society Professor J Newell West Wireless Health Institute, Population and Public Health University of Leeds San Diego, USA Professor T Marteau (Chair) Dr J Koplan (Chair) University of Cambridge Professor A Nunn Professor S W Smye Emory University, Atlanta, USA Medical Research Council Leeds Teaching Hospitals Professor M Dixon-Woods NHS Trust Professor A Barnett University of Leicester Professor B S Ramakrishna London School of Economics Christian Medical College, Dr W Geissler Vellore, India Medical History and Humanities Professor Z A Bhutta London School of Hygiene and Interview Committee Aga Khan University, Karachi, Tropical Medicine Professor A Stein Pakistan University of Oxford Professor J N P B Horden (Chair) Professor J Harris Royal Holloway, University of Dr G Tomson Professor R M Campbell University of Manchester London University of Bristol Karolinska Institute, Stockholm, Dr T Lewens Sweden Professor D J Arnold Professor K K Cheng University of Cambridge University of Warwick University of Birmingham Professor F Wabwire-Mangen Professor A Lucassen Makerere University, Kampala, Professor D Bhugra Professor J G Cleland University of Southampton Uganda King’s College London London School of Hygiene and Tropical Medicine Professor M Parker M Warren Professor P Biller University of Oxford AVAC Global Advocacy for HIV University of York Professor A F Glasier Prevention, New York, USA University of Edinburgh Professor R Scott Professor L W B Brockliss King’s College London University of Oxford Professor A O House H3Africa Initiative Committee University of Leeds Professor G A M Widdershoven Dr C Cox Vrije University Medical Centre, Professor S B J Ebrahim (Chair) University College Dublin Professor H Rees Amsterdam, the Netherlands London School of Hygiene and University of Witwatersrand, Tropical Medicine Dr G L Davis Johannesburg, South Africa University of Edinburgh Global Health Trials Committee Professor R Chadwick Professor N Sewankambo Cardiff University Dr M Gorsky Makerere University, Kampala, Professor J Darbyshire (Chair) London School of Hygiene and Uganda Professor R Cooper Tropical Medicine Dr S Abdulla Loyola University, Maywood, USA Ifakara Health Institute, Dar es Professor M Harrison Expert Review Group 10: Medical Salaam, Tanzania Professor M Levin University of Oxford History and Humanities Imperial College London Professor R Araya Dr S Hodges Professor M Harrison (Chair) University of Bristol Professor C Victora University of Warwick University of Oxford Universidade Federal de Pelotas, Dr A Bhuiya Brazil Professor H King Professor A Borsay International Centre for Open University Swansea University Diarrhoeal Research, Dhaka, Dr C S Yajnik Bangladesh King Edward Memorial Hospital, Dr J B Reinarz Professor S Gilman Pune, India University of Birmingham Emory University, Atlanta, USA Professor U d’Alessandro Prince Leopold Institute of Professor J W Stewart Tropical Medicine, Antwerp, Glasgow Caledonian University Belgium

42 | Annual Review 2012 Professor P J Van Der Eijk Dr P Marrack Research Resources in Medical Professor D Rubinsztein Humboldt University of Berlin, Howard Hughes Medical History Funding Committee University of Cambridge Germany Institute, USA Professor M A Jackson (Chair) Professor E Simpson University of Exeter Imperial College School of Medical Humanities and Public Health and Tropical Medicine Engagement Capital Awards 2012 Medicine Interview Committee Dr M Barfoot Professor J C Smith J Vitmayer (Chair) Professor M Egger (Chair) Professor V Berridge MRC National Institute for Horniman Museum, London University of Berne, Switzerland London School of Hygiene and Medical Research, London Tropical Medicine Professor S Duensing Professor M Bockarie Professor M Yaniv King’s College London Liverpool School of Tropical Dr G Browell Pasteur Institute, Paris, France Medicine King’s College London Dr D Edwards University of Leicester Professor J K Cruickshank Dr G L Davis Seeding Drug Discovery King’s College London University of Edinburgh Committee Dr M J Gorman Trinity College Dublin Professor H M Dockrell Dr C Fletcher Dr A Baxter (Chair) London School of Hygiene and University of Oxford Stevenage Bioscience Catalyst Professor A McFarlane Tropical Medicine Royal Botanic Gardens, Kew I Milne Dr F Brown Professor D Dunne Royal College of Physicians of ViComm Pharma Consulting, Dr N Merriman University of Cambridge Edinburgh Alamo, USA University of Manchester Professor C H D Fall Dr M P Thomson Professor J H Griffin University of Southampton University of Warwick Numerate, Inc., San Bruno, USA Medical Humanities Selection Panel Dr G Kang A Walker Professor P F Leadlay Christian Medical College, British Library University of Cambridge Professor C Jones (Chair) Vellore, India Queen Mary, University Dr D Marquess of London Professor P Mugyenyi Science Funding Interview Panel Theravance, Inc., Half Moon Bay, Joint Clinical Research Centre, USA Professor J Bourke Kampala, Uganda Professor Sir P Nurse (Co-Chair) Birkbeck, University of London Royal Society Dr F Marshall Professor M Newport Heptares Therapeutics Ltd Professor J Browne University of Sussex Professor D F Smith (Co-Chair) Harvard University, Cambridge, University of York Dr H E Moser USA Professor P A Winstanley Achaogen, Inc., San Francisco, University of Warwick Professor D Altshuler USA Dr N Hopwood , Cambridge, USA University of Cambridge Dr J Rex R&D for Affordable Healthcare Professor W Arlt AstraZeneca Pharmaceuticals Professor A Hyder in India Committee University of Birmingham Johns Hopkins University, Professor W Bickmore Baltimore, USA Dr R Parekh (Chair) Sir Henry Dale Fellowship University of Edinburgh Advent Venture Partners Ltd Interview Committee Professor M Leach Professor N Chaturvedi Institute of Development Studies, Dr A Allsop Professor J C Smith (Chair) Imperial College London Brighton MRC National Institute for Dr W Luyten Medical Research, London Professor R Dolan Professor R Tallis IriDM, Leuven, Belgium University College London Professor R Allshire Professor J Wolff Professor Sir R N Maini University of Edinburgh Professor T Hunter University College London Imperial College London Salk Institute for Biological Professor A H Brand Studies, La Jolla, USA Dr G Michel University of Cambridge Principal Research Fellowship Foundation of New Innovative Professor P Ingham Interview Committee Diagnostics, Founex, Switzerland Professor A D Hingorani Institute of Molecular and Cell University College London Biology, Singapore Professor T Hunter (Chair) Dr J Mountford Salk Institute for Biological University of Glasgow Professor A J King Professor C Lewis Studies, La Jolla, USA University of Oxford Professor M Singer King’s College London Professor P Ingham University College London Professor P F Leadlay Professor I Mattaj Institute of Molecular and Cell University of Cambridge EMBL Heidelberg, Germany Biology, Singapore Dr A J Wood Professor L M Machesky Professor E J Robertson University of Glasgow University of Oxford

Annual Review 2012 | 43 Advisory committees 2011/12

Professor M H Malim Society Awards Funding Technology Transfer King’s College London Committee Strategy Panel

Professor C J Marshall Dr S Webster (Chair) Dr A J Wood (Chair) Institute of Cancer Research Imperial College London Idfac Ltd

Professor M S P Sansom R Gould Dr A Baxter University of Oxford Stevenage Bioscience Catalyst Professor H Marland Professor R Sauerborn University of Warwick Dr K Bingham University of Heidelberg, SV Life Sciences (UK) Ltd Germany Professor A McFarlane Royal Botanic Gardens, Kew Dr D Brown Professor Dame J O Thomas University of Cambridge G Page W Burns Science and Plants for Schools Professor A Waters University of Glasgow L Smith Veterinary Fellowships Interview Dundee Science Centre Professor D Wigley Committee Institute of Cancer Research Dr J Thomas Professor E Simpson (Chair) Imperial College London N Ware Sir Henry Wellcome Postdoctoral Professor J L Fitzpatrick Fellowships Interview Moredun Research Institute Committee Technology Transfer Challenge Committee Professor I R Hart Professor J C Buckingham (Chair) Queen Mary, University of Imperial College London Professor M Brown London University of Hertfordshire Professor D Barry Professor A R McLean University of Glasgow Dr S N Chatfield All Souls College, Oxford Emergent BioSolutions Professor W Earnshaw Professor E M Riley University of Edinburgh Dr M Claybourn London School of Hygiene and HORIBA, France Tropical Medicine Professor P C Fletcher University of Cambridge Professor M Feldmann Professor T Skerry Imperial College London University of Sheffield Professor G Griffiths University of Cambridge Dr A Hudson

Professor A D Hingorani Dr K Johnson University College London Index Venture Management LLP

Dr C McBain Dr W Luyten NIH, Bethesda, USA IriDM, Leuven, Belgium

Professor N Papalopulu Dr G Michel University of Manchester Foundation of New Innovative Diagnostics, Founex, Switzerland

Dr J Mountford University of Glasgow

Dr J Rasmussen psi-napse

Dr M Skingle GlaxoSmithKline

Professor M M Stevens Imperial College London

Dr T Wells Medicines for Malaria Venture, Geneva, Switzerland

Dr K Zinkewich-Peotti IPSEN, France

44 | Annual Review 2012 We are grateful to the many The Wellcome Trust Annual Review researchers and members of is available in PDF form at Wellcome Trust staff who helped www.wellcome.ac.uk/annualreview to produce this volume, everyone who agreed to be reviewed in this ISBN 978 1 84129 092 8 issue, and everyone who supplied images or gave us permission for The Wellcome Trust is a charity their images to be used. registered in England and Wales, no. 210183. Its sole trustee is The Editor Wellcome Trust Limited, a company Michael Regnier registered in England and Wales, no. 2711000 (whose registered office Assistant Editor is at 215 Euston Road, London Tom Freeman NW1 2BE, UK).

Writers First published by the Wellcome Trust, Penny Bailey 2012. Michael Regnier Nancy Wilkinson © The trustee of the Wellcome Trust, London, and licensed under Creative Design Commons Attribution 2.0 UK. Malcolm Chivers This is an open access publication and, Photography with the exception of images and David Sayer illustrations, the content may, unless otherwise stated, be reproduced free Editorial Team Manager of charge in any format or medium, Dr Giles Newton subject to the following conditions: content must be reproduced accurately; Publisher content must not be used in a Mark Henderson misleading context; and the Wellcome Trust must be attributed as the original Comments on the Wellcome Trust author and the title of the document Annual Review are welcomed and specified in the attribution. should be sent to: Wellcome Trust Publishing Department Gibbs Building Wellcome Trust 215 Euston Road Gibbs Building London NW1 2BE, UK 215 Euston Road London NW1 2BE, UK T +44 (0)20 7611 8888 F +44 (0)20 7611 8242 F +44 (0)20 7611 8270 E [email protected] E [email protected] www.wellcome.ac.uk

Many of the images used are from Wellcome Images, available at images.wellcome.ac.uk.

Cover illustration by Bret Syfert Wellcome Trust Annual Review 1 October 2011–30 September 2012

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-5548.3/1K/12-2012/MC WellcomeTrust GibbsBuilding Euston 215 Road LondonNW1 2BE, UK 8888 7611 (0)20 +44 T Wellcome TrustWellcome areWe a global charitable foundation dedicated toachieving extraordinary improvements in humanand animal health. support We the brightestminds in biomedical research and the medicalhumanities. Our breadth of support includespublic engagement, education and the applicationof research to improve health. are We independent ofboth political and commercialinterests. 7611 +44F 8545(0)20 [email protected] www.wellcome.ac.uk