News from the Medical Research Council network Autumn 2014 Leading science for better health Shining light ondrug design The power of crystallography

The glorious future of biostatistics: Staying one step ahead of the curve Opinion: Arming doctors with the best trials

Network can also be downloaded as a PDF at: www.mrc.ac.uk/network CONTENTS NEWS COMMENT FROM News Seven pharma companies offer up Seven pharma companies offer up compounds compounds to UK researchers to UK researchers 3 John The MRC has formed a partnership with seven global Minister meets macaques 4 drug companies to grant researchers access to pharmaceutical compounds which stalled in early Savill industry testing but which may be of great value for CHIEF EXECUTIVE People improving our understanding of diseases. We’ve become complacent about AstraZeneca, GlaxoSmithKline, Janssen Research & Development LLC, received less attention from industry. And because all of the molecules African leaders of tomorrow 5 bacterial infection; we expect that Lilly, Pfizer, Takeda and UCB will each offer up several molecules for have undergone some degree of early testing, treatments arising from there will always be a cure. But now, use in research. the research could reach patients faster. due to the threat of microbes becoming resistant to the drugs that Many of the compounds were not fully developed because they were The collaboration builds on the success of a previous compound-sharing should destroy them, we’re facing a found to be insufficiently effective against the disease in question. initiative between the MRC and AstraZeneca (AZ) launched in 2011. Latest discoveries scenario in which even the simplest However, academic researchers can use them to understand how a Projects from this partnership are starting to bear fruit, including the scratch could kill. disease takes hold in the body, how it might be stopped or slowed down, first human trials of a new treatment for chronic cough, using a New trigger for ovulation could make IVF safer 10 or to study diseases with shared biological pathways. compound which was originally developed by AZ to treat gastro- In the UK alone the research community has spent £275m oesophageal reflux disease. Nipping the malaria parasite in the bud 11 researching antimicrobial resistance since 2007. Yet, to date, Repurposing such compounds could ultimately lead to new drugs for a no effective solutions have been found. wide range of conditions including rare diseases that in the past have Find out how MRC researchers are designing new drugs on page 6

Thanks to work by Chief Medical Officer for England – and member of MRC Council – Professor Dame Sally Davies, the Funding idea that we must act urgently is gaining traction, and a coordinated approach is being put into action. Mapping out the future of molecular pathology UK to revolutionise fight against cancer and The MRC has undertaken a review which has highlighted the UK’s capabilities in molecular pathology – the analysis rare diseases 17 In July we announced the MRC-led Antimicrobial Resistance Funders’ Forum, an antimicrobial resistance ‘war cabinet’ of the molecules within tissue and body fluids to allow more accurate diagnosis and monitoring of disease. Funding for women and children’s health research 17 which brings together all seven of the research councils, eight government bodies and the Wellcome Trust, to tackle The review identifies areas which, if not addressed, could hold back the benefits that stratified medicine has to offer. I fully support the antimicrobial resistance with research in four themes. £25m is development of new diagnostic tests that would capitalise on the UK’s recommendations and am pleased that the MRC can commit funding to available to fund work in the first two. excellent science base and benefit research, health and the economy. deliver these.” The review also makes recommendations about how to tackle these That all seven research councils are uniting to fight areas of concern. With joint funding of up to £17.5m, the MRC and Engineering and Physical Features antimicrobial resistance serves to highlight the Sciences Research Council have joined forces to establish regional interdisciplinary of the problem. Each council has Sir John Savill explained: “UK Government and charitable funders, Molecular Pathology Nodes – centres of excellence that will bring clinical Shining light on drug design: the power of something to offer, from developing new techniques to study including the MRC, have committed more than £200m to stratified and research skills and expertise closer together. The investment will crystallography 6 bacteria in the laboratory to studying the social aspects of medicine in the last four years. However, for the UK and patients to fully support around eight awards, which will bring together molecular antibiotic use. benefit from this investment, we must create the very best environments pathology diagnostic research, development and service delivery across The glorious future of biostatistics 8 for the discovery, development and uptake of new therapies and a common infrastructure, with industry engagement. You can read more about the funders’ forum, and the range diagnostic tests. Joining forces in the antimicrobial arms race 12 of antimicrobial resistance research being carried out, in a For more information, visit www.mrc.ac.uk/molecularpathologyreview feature article on page 12. The MRC has undertaken a review of the challenges facing those Working life: Professor Dame Carol Robinson 14 developing novel diagnostic tests, so we can better understand what is Opinion: Arming doctors with the best trials 18 Sir John Savill needed for the UK to fully capture the clinical, economic and research MRC Chief Executive

2 | MRCNetwork MRCNetwork | 3 NEWS PEOPLE

Industry and academia join forces to unravel dementia A century of science for health African leaders of tomorrow

A £16 million public-private partnership to speed up research into dementia has been launched by the MRC. July saw current and past researchers attend a symposium at the National First MRC/LSHTM West African Fellow appointed Institute for Medical Research (NIMR) to celebrate its 100-year history. Announcing the launch at the Global Dementia Legacy Event in June, To find out more, visit www.mrc.ac.uk/ukdp The MRC and the London School of Hygiene & Tropical Medicine (LSHTM) Health Secretary Jeremy Hunt stressed “the desperate need for Featuring contributions from NIMR researchers, past and present, the have appointed Dr Brenda Kwambana of MRC Unit, The Gambia, as the first continued investment in dementia”. symposium covered research topics from infectious disease, West African Global Health Research Fellow. and structural biology to neuroscience and developmental biology. It The aim of the UK Dementias Research Platform (UKDP) is to enable ended with a talk and film about the history of the NIMR, followed by the The fellowship scheme, aimed at attracting outstanding early career earlier detection of dementia, improve treatments and ultimately ceremonial cutting of an anniversary cake. postdoctoral researchers, offers funding for two candidates from West prevent the disease by looking not only at what is going wrong in the Africa and one from the EU over a three-year period. brain, but also studying the brain in the context of the whole body. A new book, A Century of Science for Health, tells the story behind the Causes of dementia will be investigated across a range of NIMR’s scientific achievements. Providing insights into the atmosphere and Since gaining her PhD in 2011, Brenda has developed her skills as the neurodegenerative conditions including Alzheimer’s, Parkinson’s and changing attitudes at NIMR, it gives a compelling account of what it takes Gambia site coordinator of the Bill and Melinda Gates Foundation motor neuron disease. to create – and hold together – an institute over 100 years. Paediatric Microbiome Project and coordinator of the unit’s Genomics Interest Group. The UKDP brings together expertise from six companies and investigator Access the book, A Century of Science for Health, at teams from eight UK universities with over two million research www.historyofnimr.org.uk Brenda said: “Thank you to all the people who worked so hard to put this volunteers who have taken part in existing population studies such as UK scheme in place, targeting West Africans in particular. It demonstrates Biobank. UKDP researchers will be able to link a wealth of medical and the MRC’s and LSHTM’s commitment to meaningful capacity building in lifestyle data to emerging biological data from genetic studies, brain the sub-region.” imaging and cognitive testing. This will provide a better understanding of who is at risk of getting dementia, how it might be triggered, and what Read more in TAMA, the Gambia unit’s newsletter www.mrc.gm/tama might speed up or slow down its progression.

Prestigious Royal Society prize for African research leader MRC fellows of the British Academy Minister meets macaques Dr Faith Osier, a recipient of an MRC/DFID African Research Leader award in 2013, has been awarded the Royal Society Pfizer Prize. The prize Minister of State for Crime Prevention the Rt Hon Norman Baker MP, who Mr Baker met the centre’s Chief Operating Officer, David Farningham; Two MRC directors have recently been made recognises African researchers early in their career who are making is responsible for regulating the use of animals in science, visited the MRC research fellow Claire Witham; the centre’s Named Veterinary Surgeon; fellows of the British Academy – an accolade innovative contributions to biological sciences and building scientific Centre for Macaques in July. and technical staff. which recognises outstanding research in capacity in Africa. the humanities and social sciences. Describing the visit, David said: “We toured the animal facility where Faith’s research focuses on how people develop immunity to the malaria Mr Baker was interested in the variety of the diet and forage on offer and MRC Cognition and Brain Sciences Unit parasite, and how this knowledge might be used to develop malaria seemed very surprised to see a member of staff sitting in an animal room Director Professor Sue Gathercole has been vaccines. She is based at the KEMRI-Wellcome Trust Research Programme socialising with macaques.” made a fellow in recognition of her Professor Sue Gathercole in Kenya. pioneering work on developmental disorders Human contact and familiarity is essential to the wellbeing of animals in cognition, and implications for education. Faith said: “I am delighted and excited by the Royal Society Pfizer Prize that will spend much of their lives working one to one with scientists. award, which I see as an award to my whole research team. It is our dream Developing scientific methods of welfare assessment is essential to Francesca Happé, Director of the MRC Social to build strong science in Africa which contributes to solving Africa’s major improving the environment of primates within the laboratory. Genetic and Developmental Psychiatry health problems.” Centre at the Institute of Psychiatry at King’s As part of the MRC’s commitment to openness, the centre recently took College London, has been made a fellow in Applications for the next round of the MRC/DFID African Research Leader part in Understanding Animal Research’s Open Labs event. More about recognition of her academic distinction in scheme opened on 18 September 2014. For more information visit the work of the centre and the science it supports can be seen in recent the field of Autism Spectrum Disorders. Professor Francesca Happé www.mrc.ac.uk/arl Norman Baker MP with the videos produced by the MRC at http://mrc.io/1aYI3uK centre's COO, David Farningham. Read more about Faith’s work on our MRC Insight blog http://mrc.io/osier2

4 | MRCNetwork MRCNetwork | 5 FEATURE To find out more, visit www.diamond.ac.uk

Shining light on drug design:

special conditions are needed for all protein molecules in the sample says Dave, “and look at crystals that are Crystallography is vital for the to adopt the same repeating orientation and form a crystal. However, about a thousandth of a millimetre in size.” discovery of new, powerful drugs. in recent years advances in technology have speeded up these steps, ensuring that crystallography remains a leading technique in structure- Robin Owen is Principle Beamline Scientist To celebrate the International Year based drug design. on microfocus beamline I24 at Diamond of Crystallography 2014 and the Light Source. “If you have large protein Diamond Light Source is the UK’s national synchrotron facility in molecules – membrane proteins or virus surpassing of 100,000 protein Oxfordshire and used by many MRC-funded researchers. It works like a molecules – you might struggle to grow large structures in the Protein Data Bank, giant microscope, speeding up electrons to almost the speed of light crystals,” says Robin. “That’s where I24 comes so that they give off bright beams of light, which are directed into into its own because we can collect data Cara Steger finds out how this laboratories known as 'beamlines'. When a beam of light is fired from very small crystals that wouldn’t be through a protein crystal it bounces off the crystal's repeating protein possible to do elsewhere.” important technique can inform molecules and forms a pattern, allowing researchers to work out the drug design by revealing the protein's molecular structure. An MRC scientist who is using crystallography in structure-based drug design is Peter atomic structures of proteins. Dave Stuart, Life Sciences Director at Diamond Light Source, is using Fischer, Professor of medicinal chemistry crystallography to research the structure of viruses and viral proteins. from the University of Nottingham. His In 1914 the German physicist Max von Laue was awarded a Nobel Prize “The great thing about the technology at Diamond is that we can now research is focused on developing drugs that for his discovery that crystals are able to scatter X-ray light. This work get much better results giving us a tremendous amount of detail on will target orexin receptors (OXRs). OXRs are laid the foundation for the development of crystallography, a viruses in a fraction of a second,” says Dave. He compares it to the involved in a number of conditions and technique that uses powerful X-ray beams to reveal the atomic work done by one of the earliest crystallographers, Dorothy Hodgkin: diseases such as narcolepsy, attention deficit structure of crystallised matter. “We can get more in a tenth of a second than Dorothy could get in 90 hyperactivity disorder, bipolar disorder, hours! This means that now we can use viruses and viral proteins as Parkinson’s disease and obesity. He hopes “The extraordinary benefit of crystallography is that it enables us to effective targets for drug discovery.” these drugs will provide new treatments decipher protein structures and understand exactly how different for patients. components work,” says Patrick Maxwell, Chair of the MRC Molecular The sample preparation stage of crystallography has also become and Cellular Medicine Board. “It has provided remarkable faster and more efficient. The Membrane Protein Lab (MPL), situated In partnership with the pharmaceutical company Heptares, formed in Additional reporting by Isabel Baker breakthroughs in understanding normal physiology and what goes within the Diamond facility, is where crystal samples are prepared 2007 from the MRC’s Laboratory of Molecular Biology and National wrong in disease. Increasingly, it can also be used to design drugs that before they are analysed. “The MPL is important because it’s a way of Institute for Medical Research, Peter will use the facilities at Diamond are like molecular keys – precisely engineered to fit a specific lock.” helping people to get the quality of sample they need to get crystals,” and MPL to better understand how OXRs work at the molecular level. says Dave. “What we’re trying to do is design small molecule drugs that fit to

The MRC has a rich history in crystallography. MRC scientists used this specific receptors,” says Peter. “This is like designing a key that will fit Read more about Heptares Therapeutics here: technique to discover the helical structure of DNA and to work out Isabel Moraes is the MPL coordinator and group leader. “Synchrotrons into a specific lock. We can do this if we know the 3D structure of the http://mrc.io/heptares-therapeutics how haemoglobin transports oxygen in the blood. Nobel Laureate Sir like Diamond, with very specific beamlines, are the right spot for this receptor.” That is the real power of crystallography, explains Peter, it John Walker used crystallography to determine the structure of the type of work. That’s the reason why we are here, because we can easily allows us to discover this structure. In 1952, and Raymond Gosling took cell’s major energy source – ATP synthase. And this same technique access a beamline to test the crystals for further optimisation,” Photo 51, one of the most famous X-ray crystallography has revealed the structure of proteins involved in HIV infection. she says. 100 years after Max von Laue’s discovery, this remarkable technique images in the world. Read more on our MRC Insight blog continues to offer new and exciting possibilities for drug design. The http://mrc.io/10BChK5 Crystallography has historically been a lengthy process, due to the Larger crystals are more effective at diffracting X-ray light but are future looks very bright. time it takes to prepare and analyse crystal samples. Protein samples difficult to grow. Helpfully, some of the beamlines are able to analyse must be converted from a liquid to a solid state to form crystals, and increasingly smaller crystals. “Now you can get a tiny beam of X-rays,”

6 | MRCNetwork MRCNetwork | 7 FEATURE Find out more at www.mrc-bsu.cam.ac.uk

A celebration of clinical trials The glorious future of biostatistics: Leaders of tomorrow

By focusing on new methodology and training a new generation of statisticians the MRC BSU is keeping pace with new developments such as genomics. Simon White, a Senior Investigator Statistician and a Pioneering work at the MRC Biostatistics Unit (BSU) on medical , member of the Young Statisticians Section of the Royal Statistical Society, is applying his knowledge of statistics to cognition and ageing. clinical studies and public health has established the modern discipline of "It’s fun and challenging to work out what you can learn from your data," he says. “There are many early career statisticians progressing through biostatistics. But with vast amounts of data arising from biotechnological the ranks. I think we’re growing as a profession but there are still advances, Isabel Baker asks are we equipped to handle the statistical challenges ahead.” demands of the future? Speakers at the 23rd Bradford Hill Memorial meeting, from left to right: Sylvia is optimistic about the future. “We have to make an impact in Linda Sharples, Stuart Pocock (this year’s lecturer), , science and we'll do that through innovative, creative thinking and , Stephen Senn, Iain Chalmers, Vern Farewell and . Statisticians at the MRC Biostatistics Unit (BSU) have been influential in Breaking new ground deep interaction with the scientists,” she says. “Statisticians are very tackling the important statistical and medical challenges of the last well equipped to do that in general, as we're collaborative people. century. From introducing the randomised controlled trial in medicine, Stratified medicine, led by programme leader Brian Tom, is another new More than 200 guests gathered at the London School of Hygiene So we have to train our young scientists to work in this way with to epidemiologist ’s ‘criteria for causality’ which research theme. This field of research involves studying large groups of & Tropical Medicine (LSHTM) this summer to celebrate the history, different disciplines.” established the causal link between risk factors and health, the BSU’s patients to better identify subgroups of patients diagnosed with the achievements and challenges of randomised controlled trials, as 100-year history is full of landmark achievements. same disease, so that treatments can be more effectively developed part of the joint history of the MRC BSU and the LSHTM. Read more about the advantages of multi-arm clinical trials in our and targeted. opinion piece on page 18 “Statistics is applicable in all aspects of medicine, epidemiology and Sir Iain Chalmers, Coordinator of the James Lind Initiative, public health,” says , director of the MRC BSU in “You need to evolve, you need to adapt,” says Brian. “We can now recounted the MRC’s pioneering work on clinical trials between 1934 Cambridge since 2012. With her wealth of experience in statistics, she interrogate data at a very fine level and look at genomic information; the and 1960. He was then joined by professors Vern Farewell and has brought a fresh perspective to how the field is developing and the data sets are huge. Peter Armitage to discuss Professor Armitage's career in challenges that lie ahead. “As the unit has consistently demonstrated, biostatistics, his work in sequential medical trials and a key Vienna statistics should be the base for designing clinical trials as well as “Dealing with all these data requires statistics, to build models and conference on controlled clinical trials in 1959. Professor Stuart evaluating the effectiveness of public policies. stratify patients into groups according to different characteristics.” Pocock, LSHTM’s current Professor of Medical Statistics, concluded Targeting treatments to subgroups of patients gives them a better the day, giving the 23rd Bradford Hill Memorial Lecture on “Statistical reasoning is very carefully applied and takes into account the chance of responding, he explains. One of Brian’s current projects is ‘Controversies, calamities and celebrations in clinical trials research’. uncertainty. It's fundamental in health, because the human body is not antimicrobial resistance; he is using genotypic information to determine a machine and we’re all different,” she says. Sylvia’s recent election as a whether bacteria will be resistant to particular antibiotics. Videos of the events, produced by the LSHTM, are available at fellow of the International Society for Bayesian Analysis is testament to vimeo.com/channels/760568 her outstanding contributions in statistics.

Equipping for the future Looking ahead Today, the MRC BSU is one of the largest groups of biostatisticians in Sylvia Richardson Europe. It is also a major centre for training and knowledge transfer. Its Anticipating emerging statistical needs is important. For clinical trials, this expertise ranges from methodological, to applied and computational is where Adrian Mander’s expertise comes in. Adrian is co-chair of the statistics. But looking to the future how is the modern practice of MRC Network of Hubs for Trials Methodology Research, and works at the statistics evolving? forefront of new clinical trial design, including adaptive clinical trials with multi-arm, multi-stage designs. “Increasingly, there are many sources of data, varying in size and Read more about the work of past BSU statisticians on our complexity and not all collected for particular purposes, being thrown “Designing new trials that haven’t yet been put into operation involves MRC Insight blog www.insight.mrc.ac.uk at us,” says Sylvia. To meet the arising research demands, she has ‘blue sky’ research and generating theoretical data to test new designs.” introduced some new themes at the unit. Groups are focusing on the According to Adrian, there’s nothing better than coming up with an idea Why study statistics? Find out in a series of videos produced by the analysis of high dimensional data – how to deal with large quantities of and then getting it into practice. “You’re making a difference to people,” Royal Statistical Society, featuring Simon White http://mrc.io/why- data – and data arising from new biotechnology, from DNA sequencing MRC Conference on Biostatistics he says. statistics to genomics, as well as their clinical implications. March 2014

8 | MRCNetwork MRCNetwork | 9 LATEST DISCOVERIES

New trigger for ovulation could Molecular ‘scaffold’ could hold Nipping the malaria parasite You are what grandma ate make IVF safer key to new dementia treatments in the bud Researchers have successfully used a new and Researchers at King’s College London have Scientists seeking new drug and vaccine targets for It’s known that when a pregnant woman is potentially safer method to stimulate ovulation discovered how a molecular ‘scaffold’, which helps malaria believe they are a step closer to disrupting undernourished, her child has a higher risk of in women undergoing IVF treatment. key parts of cells to interact, comes apart in people the life cycle of Plasmodium, the parasite that developing metabolic diseases. This is partly due to

with dementia and motor neuron disease. causes the deadly disease. so-called ‘epigenetic’ effects where a ‘memory’ of a Doctors normally administer a hormone called hCG for this parent’s life experience is passed on to children purpose, but in some women there is a risk that this can The research looked at two components that are essential for key With MRC funding, Dr Rita Tewari’s team at the University of without any change to the DNA code. overstimulate the ovaries, with potentially life-threatening processes within cells: mitochondria, which produce energy; and Nottingham have carried out an in-depth study into the roles consequences. the endoplasmic reticulum (ER), which makes proteins and stores played by 30 protein phosphatases – enzymes that, along with An MRC- and Wellcome Trust-funded study in mice shows that the calcium for signalling processes. protein kinases, control the function of many proteins as the ‘memory’ of malnutrition during pregnancy can be passed on to Ovarian hyperstimulation syndrome (OHSS) affects around a third parasite develops. the next generation by male offspring, increasing disease risk for of IVF patients in a mild form, causing symptoms such as nausea Interactions between the ER and mitochondria enable a number of both children and grandchildren. But this effect may not be passed and vomiting. Less than 10 per cent of patients experience important cell functions, but until now the mechanism by which ER Finding new drug targets for malaria is increasingly important, down through the generations indefinitely. moderate or severe OHSS, which can cause kidney failure. and mitochondria become associated has not been fully given that the parasite has developed resistance to almost all understood. By studying cells in a dish, researchers discovered that available anti-malarial drugs. Epigenetic effects can happen via a mechanism called Kisspeptin is a naturally occurring hormone that stimulates the ER and mitochondrial proteins bind to form a ‘scaffold’, allowing methlylation, in which the molecule methyl attaches itself to our release of other reproductive hormones inside the body. Kisspeptin this close association. Using molecular cell biology and biochemical techniques to study a DNA and acts to switch genes on or off. Methylation differences is broken down more quickly than hCG, meaning the risk of species of Plasmodium that infects mice, Dr Tewari’s team found were seen in the offspring of the malnourished mice, but when the overstimulation is lower. Many cell functions controlled by these associations are disrupted that half of the phosphatase genes could not be ‘knocked out’. This researchers looked at the DNA of the next generation of mice, they in neurodegenerative diseases. The researchers were also able to highlights these phosphatases as potential drug targets, because found that the methylation changes had disappeared: the Scientists at Imperial College London and clinicians at Imperial show that a protein strongly linked to a form of motor neuron their presence is critical to parasite growth. As mouse and human ‘memory’ of the grandmother’s nutrition had been wiped, or least, College Healthcare NHS Trust gave 53 healthy volunteers a single disease and the second most common form of dementia resulted malaria parasites share many of the same genes, the research can was no longer being transmitted by methylation. injection of kisspeptin to induce ovulation, with mature eggs in a loosening of the scaffold. be translated directly to human malaria. developing in 51 of the participants. 49 women had one or two Study co-author Dr Mary-Elizabeth Patti from the Joslin Diabetes fertilised embryos transferred to the uterus, and 12 became “Our findings are important in terms of advancing our The study was carried out in collaboration with the MRC National Center and Harvard Medical School, commented: “Epigenetic pregnant, which is a good outcome compared to standard understanding of basic biology,” said Professor Chris Miller, from Institute for Medical Research, the University of Oxford, Imperial changes may in fact wear off. This could give us some optimism conventional IVF therapy. the Institute of Psychiatry at King’s, “but may also provide a College London and King Abdullah University of Science and that any epigenetic influence on our society’s obesity and diabetes potential new target for developing new treatments for these Technology in Saudi Arabia. problem might also be limited and/or reversible.” The researchers will now carry out a second study in women with devastating disorders.” polycystic ovary syndrome, who have the highest risk of OHSS.

Journal of Clinical Investigation (2014) Volume 124, p3667. Published online at www.nature.com/ncomms, June 2014 Cell Host and Microbe (2014) Volume 16, p128. Published online at www.sciencemag.com, July 2014

10 | MRCNetwork MRCNetwork | 11 FEATURE For more information, visit www.mrc.ac.uk/amr

Joining forces in the

Picture a world where a cut finger A newly launched initiative to tackle antimicrobial resistance will the different disciplines, and encourage sharing across the public and Professor David Holden, director of the MRC Centre for Molecular coordinate the work of medical researchers, biologists, engineers, vets, private sectors of tools, compound libraries and screens. Ultimately this Bacteriology and Infection, says: “This is a fresh look at the problem. By could kill you. As microorganisms economists, social scientists, mathematicians and even designers to will drive the discovery of new strategies and tools to diagnose, prevent casting the net as broadly as possible, the chances of finding a solution become resistant to antimicrobial address all aspects of this problem. It is becoming apparent that only a and treat microbial infections. are maximised. Working with the pharmaceutical industry enables multidisciplinary approach will succeed in tackling the rise in academics to focus their research on targets that have the most realistic treatments, there’s a very real antimicrobial resistance (AMR), which affects not just human health but Funding calls for the first two themes – ‘Understanding resistant bacteria chance of being used for drug development. And it enables researchers is also present in animals and the environment. in the context of the host’, and ‘Accelerating therapeutic and diagnostics to benefit from the vast amount of knowledge in screening and possibility that the drugs which development’ are already underway. The second theme focuses on the diagnostics that the industry has gained over the past 20 to 30 years.” Sir John Savill explains: “Researchers have been waging a war on AMR for development and manufacture of new antibiotics, alternative therapies we’ve come to rely upon may decades, but up until now we’ve had no war cabinet to coordinate and diagnostics – an area that will particularly benefit from a To help foster these relationships, the MRC, in partnership with BBSRC research on all fronts. This initiative is about tackling the problem at multidisciplinary approach. Partnership between industry and academia and EPSRC, is holding a series of workshops between November 2014 become obsolete. A cross-council every level and in every environment.” will also help to accelerate the translation of new therapies and and March 2015 for people from a broad range of disciplines to initiative recently launched by the diagnostic systems. encourage innovative thinking, networking and development of The research councils, along with other UK funders, have identified four proposals to address theme 2. MRC will see the seven research key priority areas, or themes. These will promote collaboration between councils join forces to tackle this global problem on all fronts. Ellen Charman reports.

Some research council work so far…

Biotechnology and Biological Sciences Research Council Medical Research Council (MRC): David Holden’s lab at the MRC Engineering and Physical Sciences Research Council (EPSRC): Science & Technology Facilities Council (STFC): E. coli has a (BBSRC): Co-funded by AstraZeneca, William Gaze is investigating Centre for Molecular Bacteriology and Infection has for the first time Rachel McKendry’s research at UCL aims to transform the diagnosis, characteristic outer lipid membrane which can act as a barrier to whether low levels of antibiotics in the environment could be visualised ‘persister’ cells of Salmonella during infection using a fluorescent treatment and tracking of AMR through advances in nanotechnology antibiotics. Scientists from the STFC’s ISIS facility, the University of contributing to AMR. Recent research has shown that just 100mg per protein produced by the bacteria. Persister cells are a form of bacteria and ‘big data’. She has recently determined how the antibiotic vancomycin Newcastle and the Bragg Institute in Australia have produced litre of antibiotic was enough to favour growth of resistance bacteria that don’t replicate and ‘lie low’, enabling them to evade antibiotic action. works against ‘superbug’ MRSA and developed mathematical models to membranes in the lab that mimic this bacterial membrane to use as a – the same concentration found in some rivers and lakes. Most antibiotics work only on active, replicating bacterial cells, meaning calculate relationships between antibiotic levels and how effective they model for future study into how they defy antibiotics. this work has major implications for antibiotic drug design. are at killing bacteria. 12 | MRCNetwork MRCNetwork | 13 WORKING LIFE

mass of individual molecules – to look at the structure and interaction of One of my most thrilling moments of discovery was seeing the first really Professor Dame Carol Robinson, Professor of Chemistry, protein complexes, specifically membrane proteins, which regulate the large protein complex ‘fly’ through the mass spectrometer. And more University of Oxford transport of small molecules into and out of cells. recently, discovering how membrane proteins bind to lipids, which then changes their structure and function. This exciting discovery will further Understanding how proteins interact is particularly important for our knowledge of the role of lipids in drug binding and therefore, My favourite response to the question, “Has it worked?” is “Not yet.” If you’ve got a good idea, identifying drug targets and improving drug design. I recently used this I believe, lead to better drug design in the future. believe in yourself and believe that it is going to work. technique to help understand how a membrane protein — an ABC transporter — exports lipids and drugs simultaneously. The high As told to Ellen Charman resolution of the mass spectrometry method that we developed enabled I didn’t take the conventional route to get to where I am today. I actually I found myself in the mass spectrometry lab, which I found fascinating. us to detect this small molecule even though the amount of drug left school at 16, which was a common thing to do in my school at the I was lucky in that my supervisors picked up on my obvious passion and molecules in the pocket of the protein was only around one per cent of time. I’d always been interested in chemistry, so I got a job as a lab fledgling ability early on. They encouraged me to take various part-time the total mass of the complex. technician at Pfizer which was my nearest pharmaceutical company. courses, which after seven years of hard work resulted in a degree and a place at Cambridge to study for a PhD. The other part of my job that I love is the people interaction and After working on various analytical techniques, including supporting members of my team in their careers. I have benefited chromatography, used to separate mixtures of substances, and nuclear I still feel lucky today that I get to do what I find fascinating. I’m currently enormously from the mentors I have had along the way, so I think it’s magnetic resonance to determine the structure of organic compounds, using mass spectrometry – traditionally the process used to calculate the important for me to give something back. One mentor was Chris Dobson, a Professor in the Department of Chemistry at the , who believed in me enough to give me the opportunity to get back into research, after the eight-year career break I took to bring up my three children, by offering me a postdoc position. He always encouraged me to take up the next opportunity, the next challenge. He knew I was ready even if I didn’t!

I’m not sure if I could pick one career highlight; I enjoy many aspects of my research and I wouldn’t like to say that one was more important. “I have benefited Obviously receiving my Damehood last year (for services to science and industry) was a big honour, but so was being made a professor and receiving my first MRC Fellowship… I still get a thrill each time a paper enormously from the is accepted!

I greatly appreciate the flexibility that working in academia has given me. mentors I have had along It was incredibly important to me that when the children were at school I was able to attend their parents’ evenings and sports days. And in turn, the way, so I think it’s they now support me. On one occasion, when I was appointed as a Fellow of the Royal Society (in 2004), one of my teenage sons decided he would rather go bowling but in the end he came to the ceremony. All important for me to give three came to watch me receive my Damehood despite the fact that they now live all over the world. When my son, now 30, spread the news of my Damehood on Facebook I knew that I had made it in his eyes! something back”

Academia has allowed me to follow my instincts, even if something doesn’t seem right at first or is a bit risky. That was actually how I came Career in brief to study protein complexes. I was originally looking at protein folding pathways, but then I noticed that some of the complexes were • PhD in mass spectrometry at the University of Cambridge maintained in the gas phase of the mass spectrometer. At first I didn’t • MRC research grant: Mass spectrometry at the frontiers of molecular medicine believe this, but I started studying these complexes and found I could rationalise them, despite it being a controversial area of research at • Notable accolades: First woman to secure a full female professorship of chemistry at both On 22 July, Carol featured on the BBC’s ‘The Life Scientific’, describing her the time. Oxford and Cambridge universities. journey from lab technician to Professor of Chemistry. Listen to the interview at www.bbc.co.uk/programmes/b049yhcn

14 | MRCNetwork MRCNetwork | 15 FUNDING £48m Biomedical MRC Board and Panel Funding for women and Catalyst funding Recruitment 2015 children’s health research The MRC is currently inviting applications from scientists with the Funding for research addressing the health needs of New ways to tackle the symptoms of Parkinson’s disease, relevant experience and expertise to become members of MRC Boards women and children in low resource settings is now and Panels from April 2015. We are seeking to fill 24 vacancies on our available under a joint call launched by the MRC, the eczema and tinnitus are just some of the projects being four research boards and 21 vacancies on our six panels. The deadline for funded through a £48m investment, making up the fourth applications is 4pm, 6 October 2014. To find out more and apply, UK Department for International Development and the round of Biomedical Catalyst funding, announced by the visit www.mrc.ac.uk/board-panel-vacancies Department for Biotechnology, Government of India. previous Universities and Science Minister, David Willetts, What’s it like being a board member? Read about Professor Kim Graham’s The Global Research Program call provides opportunities for in June. experience on our MRC Insight blog http://mrc.io/17z4JOf researchers to work in trilateral partnerships with academics from India, the UK and low income countries. Proposals should focus on The scheme, run jointly by the MRC and the UK’s innovation agency, issues relating to maternal, newborn and child health (including Innovate UK, supports the best life science opportunities in the UK to women’s and girls’ sexual health); nutrition; and infectious diseases. help speed up the transition from discovery science to clinical application. UK to revolutionise The closing date for applications is 4pm, 21 October 2014. For more information visit: www.mrc.ac.uk/jght The funding will support more than 70 research projects at UK small and fight against cancer and medium sized enterprises (SMEs) and universities.

University of Edinburgh researcher Professor Alasdair MacLullich with the rare diseases In the latest rounds of funding, awards have ranged from £60,000 to 'Delbox', an early prototype of the smartphone app his team plans to develop £4m. Grant funding through the Biomedical Catalyst is available to UK to detect and monitor delirium. A £24m MRC investment, part of a package of Improving trials to businesses and academics looking to develop innovative solutions to investment worth more than £300m, was announced healthcare challenges either individually or in collaboration. Support is by Prime Minister David Cameron on 1 August to improve health available for projects arising from any sector or discipline. Some Biomedical Catalyst innovations in brief transform how cancer and rare diseases are diagnosed and treated. In 2009, the MRC established a network of Hubs for Trials Sir John Savill said: “Since its inception, the Biomedical Catalyst has • U niversity of Edinburgh scientists plan to develop a smartphone app Methodology Research to conduct, promote and awarded over £170m to UK scientists and businesses, which has been to detect and monitor delirium. Delirium is often under-detected due The investment will provide computing power to help ensure that disseminate research – to improve health by improving matched by an additional £97m of private investment. The academic- to a lack of diagnostic tests, with severe consequences, including data from participants will be properly analysed and interpreted, clinical trials. industry partnerships forged through this investment will help to improve increased risk of death. Using a computerised neuropsychological test and made available to doctors and researchers securely. It will set lives by delivering the next generation of innovative therapies.” to measure inattention, a symptom of delirium, the scientists plan to the UK up to become the world leader in ground-breaking genetic Through collaborative methodological studies the network has provided conduct clinical trials to see if the smartphone app can be used research into cancer and rare diseases. a great contribution to the evidence base for robust and reliable trials. By effectively in a hospital setting. accelerating the implementation of effective and appropriate methods Mr Cameron pledged that the UK will map 100,000 human the network has improved the quality of trials, saving resources and • A team at the University of Essex plan to develop a one-size-fits-all, genomes by 2017, and described a new partnership between benefiting patient care on the national and international scale. third generation artificial blood substitute with a shelf life of up to two Genomics England and Illumina that will deliver infrastructure and years. This artificial blood substitute is a safe, long-lasting, virus-free expertise to turn the plan into reality. Those interested in finding out more can visit the 4th COMET Initiative alternative to current blood transfusions. The innovation is based on (Core Outcome Measures in Effectiveness Trials) Meeting in Rome on haemoglobin, the key protein in red blood cells that carries oxygen The landmark project is on a scale not seen anywhere else in the 19-20 November www.comet-initiative.org/meeting or attend the 3rd around our body, and could be made available to all countries, world. Sequencing the genome of someone with cancer or a rare International Clinical Trials Methodology Conference in Glasgow on immediately accessible at the site of natural disasters as a substitute disease will help researchers and doctors understand how these 16-17 November 2015 (registration opens early 2015). for blood lost in surgery or trauma. The work at Essex is co-funded by diseases work. the Biotechnology and Biological Sciences Research Council. To find out more about the network, visit Mr Cameron said: “I am determined to do all I can to support the • U niversity of Southampton researchers have developed sensors to health and scientific sector to unlock the power of DNA, turning an www.methodologyhubs.mrc.ac.uk, or contact the Network Coordinator, prevent pain for amputees. They have developed a new ‘second skin’ important scientific breakthrough into something that will help Emma Tomlinson, at [email protected] which can sense the build-up of pressure between an amputee’s deliver better tests, better drugs and above all better care stump and the socket of their prosthetic leg. The lining, which will for patients.” Turn to pages 8 and 18 to read more about clinical trials help prevent discomfort and dangerous pressure sores via a sensor resembling a ‘golden postage stamp’, may be useful in other areas of healthcare.

16 | MRCNetwork MRCNetwork | 17 OPINION

Arming doctors with the best trials “If you increase the number Multi-arm clinical trials – which allow several new treatments to be tested of new treatments you at once – are more efficient than traditional two-arm trials and can bring are testing in a trial, new treatments to patients faster, argues Annabelle South from the you increase the MRC Clinical Trials Unit at UCL. chances that one

Randomised controlled trials are the best way of finding out if new Multi-arm trials allow you to test many more treatments than would of them will treatments are better than the current standard treatment. But trials take ever be done in two-arm trials – you don’t have to guess in advance a long time to set up and run, and can be expensive. which new drug is most likely to work, you can test several good be better” candidates at once. At the MRC Clinical Trials Unit at UCL we are keen to find faster and more efficient ways of working out which treatments work best, so And there are major cost savings from adopting the multi-arm approach. patients can benefit sooner. That’s why we are urging researchers and We estimate that costs are halved, because it’s much cheaper to assess drugs companies to move away from the traditional ‘two-arm’ approach several new treatments simultaneously in one multi-arm trial, rather than to trials, and adopt more innovative, efficient approaches like the running several separate ones. multi-arm trial. Some people have been concerned that multi-arm trials may be too The usual design for a randomised controlled trial is to randomly allocate complex for doctors and patients to understand. But our experience patients to receive either the new treatment or the current standard one. shows this is not the case – in fact, patients and doctors are very The trial doctors and nurses closely monitor both groups (or arms). At the supportive of multi-arm trials, asking “why don’t you do all your trials this end of the trial, we analyse all the data to see if the new treatment works way?” Our multi-arm trials recruit patients faster than comparable better than the old one. two-arm trials.

This design does work – it tells us whether the new treatment is effective Multi-arm, multi-stage (MAMS) trials take this one step further. They not and safe. But about half of trials find the new treatment is no better than only test several treatments at once, but can also stop recruiting patients the existing one, leaving us back at the drawing board. to a particular arm part way through, if a treatment is not looking promising enough. They even allow us to add new treatments to the trial Multi-arm clinical trials offer several advantages over two-arm trials. when they are ready for testing. This approach is even more efficient, Perhaps the most compelling is that they increase the chance of finding meaning you don’t have to have gaps between stopping a trial and an effective treatment. If you increase the number of new treatments starting a new one, and may not need to set up a separate new trial to you are testing in a trial, you increase the chances that one of them will test a new treatment. This saves many years. be better. This means that at the end of all your efforts you are much more likely to have discovered something that can improve the lives of One example of this is the STAMPEDE trial, looking at how to treat people with the disease. prostate cancer. It has stopped and added arms as it’s gone along. It now has more than 5,500 participants, making it the largest prostate cancer treatment trial ever. It will assess eight new treatments in 15 years – something that would have taken at least 40 years in separate The full comment piece ‘More multiarm randomised trials of superiority are needed’, is published online at www.thelancet.com sequential trials.

Find out more about the MRC’s important role in developing clinical The advantages of multi-arm trials over two-arm trials are such that trial methods in the 1940s and 1950s in an article by Sir Iain two-arm trials should be the exception, not the rule. We urge doctors Chalmers, on our MRC Insight blog http://mrc.io/clinical-trial-methods and patient groups to push for more multi-arm trials, and fewer two-arm trials, so we can identify effective new treatments faster and Annabelle South is Policy, Communications more efficiently. & Research Impact Coordinator at the MRC Clinical Trials Unit. This piece was originally published on our MRC Insight blog.

18 | MRCNetwork MRCNetwork | 19 YOUR FEEDBACK

Network is for anyone who has an interest in the work of the MRC, including scientists, doctors and health professionals involved in medical research, government departments and parliamentarians, and university staff and students. The aim is to provide a quick, easy-to-read summary of activities across the MRC, from research news through to funding, grant schemes and policy issues, with pointers to more in-depth information on websites and in other publications.

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