Ernst Boris Chain
CHAIN-FLOREY Clinical Research Fellowships
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Introduction
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Dr Amit Patel Dr Thomas Oates Dr Philip Webster Dr Allifia Abbas Newsholme Dr Eleanor Sandhu Dr Andrew Innes Dr Antonio de Marvao Dr Parvin Begum Dr Jennet Williams Dr Elizabeth Byrne Dr Harpreet Lota
Sponsors and Advocates Professor Sir John Savill Professor Dame Sally Davies Professor Jonathan Weber Professor Dame Kay Davies Professor Sir Andrew McMichael Professor Chris Bunce Professor Sir Stephen O’Rahilly Professor Benjamin Chain
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Mentors Professor Irene Roberts Professor Charles Pusey Professor Anne Soutar
Current Fellows
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Alumni Dr Jonathan Bond Dr Tomoki Arichi Dr Jess Zhao Dr James Tomlinson
- Introduction -
Chain-Florey Clinical Research Fellowships offer medical graduates PhD opportunities in basic science laboratories at the MRC Clinical Sciences Centre In 1940 Howard Florey, Professor of Pathology at the University of Oxford, elevated penicillin from scientific curiosity to medical revolution. The collaboration between Florey and the biochemist Ernst Chain, supported by the practical knowledge of Norman Heatley, resulted in the isolation and first medical application of an antibiotic. Against the backdrop of World War II, Chain and Florey worked in a makeshift lab on a shoestring budget to unravel the secrets of penicillin.
drug discovery – stand as a tribute to the importance of the culmination of scientific endeavour and medical purpose. The Chain-Florey Fellowship Scheme brings medical graduates into the basic science laboratories of the MRC Clinical Sciences Centre (CSC) for three-year PhDs. The scheme is jointly funded by the MRC and NIHR through the Imperial BRC. Founded to spur the development of the next generation of world-class academic clinicians in the UK, the Chain-Florey Fellowships are an investment in the future of academic medicine. In previous decades, the relationship between science and medicine was arguably more transparent. This Fellowship reignites that longstanding collaborative tradition and provides medical graduates with the opportunity to undertake cutting edge fundamental research. Over three years in the CSC at the Hammersmith Hospital campus, Fellows develop their research skills and become as comfortable in the laboratory as they are on the ward. Close mentoring on both the clinical and scientific side ensures Fellows keep constant touch with their medical roots.
Alexander Fleming had stumbled upon the antibiotic potential of penicillin a decade earlier, with no inkling that his serendipitous discovery would lay the foundation for one of the most important medical advances of the 20th Century. Its power was only harnessed long after Fleming had abandoned the project. At a time when hundreds of lives were being lost every day, and a simple scratch could open the door to fatal infection, the combined expertise of a clinically trained pathologist and a biochemist changed the medical world. From the first miraculous demonstrations of the life-saving potential of penicillin on mice in May 1940, Ernst Chain and Howard Florey worked tirelessly to optimise its production, saving millions of human lives in the process.Their achievements were recognised in 1945, when they shared the Nobel Prize in Physiology or Medicine with Alexander Fleming.
Since the scheme’s inception in 2009, 15 Fellowships have been awarded.The first Fellows are now emerging, ready to apply their skills to tackling clinical research questions with scientific precision.The experience affords Fellows the skills required to bridge the boundary between the clinic and lab, and drive medical science forward by studying the basics of health and disease.
It is in celebration of this unique collaboration that the Chain-Florey Clinical Research Fellowships are named. Antibiotics – perhaps the most important 20th Century
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Professor SIR JOHN SAVILL Chief Executive, Medical Research Council
CHAIN-FLOREY
The Chain-Florey scheme provides a fantastic opportunity for clinical Fellows to work with outstanding basic biomedical scientists at the MRC Clinical Sciences Centre. A key focus for MRC is to ensure that we are developing clinical academic leaders for the future who are grounded in excellent science, which they can link to their own clinical expertise. Such clinicians will play a critical role in developing knowledge and in ensuring translation of research findings into clinical situations.
Clinical Research Fellowships
Sponsors & Advocates
The MRC Clinical Sciences Centre is a unique discovery science laboratory embedded in Imperial College at the Hammersmith Hospital campus. This site has a long tradition of excellence in training clinicians in research and fostering cross-disciplinary collaborations. I and many of my colleagues have benefited enormously from the opportunities offered here. This scheme does a fine job of providing support for clinicians to gain robust scientific training while retaining relationships with their clinical mentors. There are many challenges in ensuring that both sides of this equation are delivered effectively and I am delighted with the success of this scheme in this regard. The Fellowship is a tribute to Professor Fisher, her team and of course to the Fellows who have embarked on this challenging but exciting course – it is a real pleasure to read their profiles, which reflect their commitment and enthusiasm – I wish them and all their successors well.
“ We are developing clinical academic leaders for the future ”
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- Sponsors Advocate & Advocates -
Professor Dame Sally Davies Chief Medical Officer and Chief Scientific Adviser, Department of Health
Cell and molecular biological research powers advances in medical practice. The development of innovative medicine is reliant on fluent communication between scientists and doctors, and I am in full support of any scheme that fosters such collaboration. The training that these Chain-Florey Fellows receive in the basic science laboratories of the CSC will give them the perfect foundation to build careers that bridge the medical and scientific worlds. For these Fellows, keeping a firm grip on their clinical work while adapting to the novel challenges of academic life is challenging. I am strongly in support of mentorship schemes for young medical professionals, and this one is paving the way for great futures. The CSC is ideally located at the Hammersmith Hospital, and the clinical mentorship ensures that while they grow as scientists, the Fellows’ clinical skills don’t wane. Translational research in this country is an absolute priority, so fostering the links between the academics and practitioners of public health is vital. The Chain-Florey Fellows are developing strong relationships with worldclass biomedical researchers, and those bonds will last throughout their careers. Training our brightest clinicians in the art of fundamental science will be productive for practical medicine and biomedical science. This scheme is a shining example of the sort of career-shaping programme we are in need of.
“ This is paving the way for great futures ”
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Sponsors Advocates- Sponsorsand & Advocates
Professor Jonathan Weber Director of Research, Imperial NIHR BRC
“ We’re now using the ChainFlorey model as a template for many other schemes ”
I am a tremendous enthusiast of this scheme. Clinician scientists are in short supply, and are a very difficult group to train. With these posts, we agreed from the very beginning that they’d have to be held in a non-clinical lab, but that there would be a clinical mentor to bridge the divide. The Fellows would need strong mentoring, but with the right support it would be an extremely productive programme. The Clinical Sciences Centre is the jewel in the crown for Imperial College in terms of fundamental discovery biology, and we’re delighted to have this landmark scheme there. We’re now using the Chain-Florey model as a template for many other schemes. The advantage of these Fellowships is that clinicians and scientists learn to communicate. That communication is bilateral and durable. It can last a whole career, and is the key to this sharp end of translational medicine. This experience will give Fellows not only the skills, but also the tools to ask fundamental questions about clinical issues in the most rigorous way. The next step for the Chain-Florey Fellows is for us to be able to support the most successful in their post-doctoral careers, where the restrictions of clinical training challenge time for research. I am therefore delighted by the creation of the Chain-Florey lectureships which will guarantee the research career progression of our most able Fellows.
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- Sponsors & Advocates -
Professor Dame Kay Davies Director, MRC Functional Genomics Unit, Dr Lee’s Professor of Anatomy, University of Oxford
“ This is a very exciting scheme, and incredibly important ” “I’ve always worked very closely at the interface between science and the clinic, and I don’t think that would be possible without having clinical training Fellows in the lab,” says Professor Dame Kay Davies. “When you get to the translational part of research, it’s a completely different way of thinking. That’s why the links between the clinician at the bedside, the basic scientist in the lab, and the clinical Fellows in between is very important indeed. A gap develops when basic scientists work on a problem in isolation, with no feeling for patients’ needs. You need a full understanding of the clinical phenotype before you can design a research strategy. A clinically trained person adds a tremendous amount. They bring with them a breadth of knowledge about the whole body that simply doesn’t exist without them. Of course, they have no idea of the basic science, so it really is an exciting two-way process. Some of them take to it like a duck to water, but not all. But they’re consistently very bright and highly motivated, so they more than make up for it. If you’re trying to practise and do research, you need a clinic within running distance, as it is at the Hammersmith. The Chain-Florey scheme is ideally placed to promote and support these Fellows. Now more than ever, it’s a challenge for a clinician to take time off during their career. But being in a lab broadens their outlook tremendously. This is a very exciting scheme, and incredibly important.”
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- Sponsors Advocate & Advocates -
Professor Sir Andrew McMichael Professor of Molecular Medicine, University of Oxford “This scheme is very attractive,” says Professor Sir Andrew McMichael. “I have great admiration for the Fellows. They’re doing the sort of things I’ve done in science, but at a far more advanced stage in their clinical training. They will emerge highly qualified both as scientists and clinicians, and there’s always a need for more of those people. When I first went into a non-clinical institution, it was fairly accidental. It was good to be able to concentrate entirely on learning how to do research without having to worry about going to clinics and ward rounds. Now clinical training has become much more formalised, and it can be hard to meet all the requirements to keep your clinical career on track and carry on your work as a scientist. However, this kind of scheme makes it possible. Getting people started on this career path gives them choices. If you’re really going to advance translational medicine, these are the people who will be the leaders. They are mature, highly motivated, and learn very quickly. They have skills that are very useful for practising as a scientist, but have respect for the full time clinicians dealing with patients. Being able to appreciate their difficulties is very important. My father was a Professor of Medicine at Hammersmith Hospital, so I grew up there. I’ve seen it develop, and with this top class research centre – the CSC – in the grounds it is a fantastic place to work. This whole scheme is excellent, and I wish all the Fellows good luck.”
“ Getting people started on this career path gives them choices ”
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- Sponsors & Advocates -
Professor Chris Bunce Research Director, Leukaemia & Lymphoma Research
“ It exposes talented, motivated, well-trained individuals to stateof-the art technologies ” Schemes like the Chain-Florey Fellowship programme are essential in promoting translational research and addressing the cultural and language barriers between medicine and basic science. This pro-active initiative recognises that basic and clinical scientists often need some kind of encouragement to make contact with each other. Translational research has never been so strong. Today it’s possible for non-clinical and clinically trained researchers to build teams, make discoveries and personally drive them all the way to early-phase trials. It feels a bit like a ‘perfect storm’. In the past, translational research was viewed as perhaps not the highest of academic pursuits. Today the ethos across academia and industry is changing. Universities are being assessed not on publication prowess alone, but impact, the extent to which their research actually changes something. The pharmaceutical industry used to translate basic research. Today there is more of a desire to move the risk-taking into academic institutions, which empowers the whole movement towards translational medicine. Science is developing at such a great pace and the technologies that are evolving alongside are challenging. If the power of those technologies is not understood within the clinical community, there is a danger that the gap between basic and clinical science will open up again. The whole concept of a scheme like this is that it exposes talented, motivated, well-trained individuals to state-of-the-art technologies. This removes the fear of these technologies and empowers clinicians to embrace the possibilities so that they can be as at home in a lab as they are in a ward. This is really exciting.
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Sponsors - Sponsorsand & Advocates Advocates-
professor sir stephen o’rahilly Director, University of Cambridge Metabolic Research Laboratories; and MRC Metabolic Diseases Unit I have benefited enormously from working in an environment where basic and clinical scientists rub shoulders with each other on a day-to-day basis. It really helps to foster cross-disciplinary thinking. It can bring to basic scientists clinical perspectives they may not have. The rigour and technologically innovative aspects of contemporary science can enlighten the clinician, who may not have previously appreciated what was possible. Some inquisitive and smart doctors have gone into science early after training in medicine and stopped practicing. Several such people such as Mike Brown, Joe Goldstein and Harold Varmus have won Nobel Prizes. What we have now is the opportunity to create a cadre of doctors whose science continues to be driven forward by their active clinical practice. The challenge is to retain clinical credibility and skills in a time of changing knowledge and pressures, while remaining at the scientific cutting-edge. The Hammersmith has been a Mecca for clinical science for many decades. What it’s done very well over the past 10 or 20 years is to strengthen fundamental science, ensuring it doesn’t lose links with the hospital. The raw brain-power of many of the young doctors that are attracted to undertake a period of research training is pretty formidable.When you combine that with some of the best scientists in Britain, then that’s a recipe for new ventures and points of light. This is the kind of environment that the MRC Clinical Sciences Centre and the broader Imperial College campus can provide.
“ The raw brain-power of many of the young doctors attracted to research training is pretty formidable ”
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- Sponsors Advocate & Advocates -
Professor Benjamin Chain Professor of Immunology, UCL
“ My father would have been very supportive of this scheme ”
“I once met the doctor who administered the first injections of penicillin, when he was a very old man,” recalls Professor Benjamin Chain, son of Ernst. “He said it was the most exciting moment of his life. He had a patient who he knew for sure would be dead by the next morning. He gave him this stuff, and the next day the patient was sitting up in bed, chatting. At that time, the link between scientists and doctors was so close. The barrier has only emerged relatively recently. These Fellowships are breaking down a wall that was never there before. My father felt very strongly that, in principle, it was very important to have close links between the clinic and lab. He thought that a lot of scientific discoveries of medical importance had come from medical observations. This scheme is something that he would definitely have been in favour of. He spent a lot of time saying that for the vast amount of progress in scientific understanding that he saw, the actual practical medical impact was relatively limited. It wasn’t translated, and it wasn’t clear how it could be. He felt doctors were important for showing scientists the implications for the medical world. He would have been very supportive of this scheme. My father and Florey were an early example of a very successful multidisciplinary approach. The medical profession is very resistant to change, while scientists constantly want to change things. These Fellowships bridge that divide between the conservative and progressive attitude, and get somewhere in between.”
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Professor Irene Roberts Professor Charles Pusey Professor Anne Soutar
CHAIN-FLOREY Clinical Research Fellowships
“The Fellows have to learn a totally different way of thinking,” says Professor Irene Roberts. “They have to employ tremendously different skills to those that make you a successful clinician. The best part of being a mentor is seeing that change in them over the time of the Fellowship. They all approach it in different ways, but having the best scientific training at this early stage will give them flexibility. That bedrock on which they build their way of thinking about science is vital, no matter what they go on to do.”
Mentors
“Working away in a very basic science environment, it could be easy for the Fellows to lose track of their clinical training and future careers,” says Professor Charles Pusey, Director of Clinical Academic Training at Imperial College. “Having clinical mentors allows the Fellows to discuss their progress and get impartial advice from a senior academic clinician. The success of mentoring depends on the relationship that develops between mentor and mentee. The frequency of meetings is variable, and driven by the Fellows. They generally find it helpful and reassuring to speak to an independent and experienced clinician who understands the clinical academic career path.” “Of course, the Fellows have two academic mentors, as do all PhD students at the CSC, but the clinical mentors are key to the success of this scheme,” agrees Professor Anne Soutar, Director of Postgraduate Studies at the CSC. “The Fellows are in a strange environment, completely out of their comfort zone. When they start it’s an absolute sea change for them.They go from being quite senior and responsible in the clinical arena to the bottom of the laboratory hierarchy. They’re suddenly working in an environment where they’re more expected to solve problems as an individual. Having this contact with the clinical world, and with someone who speaks the same language, is extremely important.”
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Current Fellows
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“ Having a fundamental look at a major clinical problem is great �
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Dr Amit Patel • 2009 Fellow, Cell Cycle Group
Amit elected to pursue a project in the Cell Cycle Group at CSC, led by Luis Aragón. After finding his feet he started using a yeast model of DNA damage and repair to understand fundamental processes common to many diseases he has treated. “The project I’m pursuing is centred around repair of the most cytotoxic type of DNA damage, where both strands of the DNA duplex are broken just prior to cell division. Such chromosome breaks can occur in a clinical setting, for example following exposure to oxygen therapy, irradiation, or medications. We have learned that repair is mutagenic and have demonstrated the mechanism. This discovery may help us better understand how cancer might develop and progress during treatment, and potentially identify new therapeutic targets.”
“The whole experience is very different to what I have been used to practising in clinical medicine.” Dr Amit Patel, who had received a prize for his recent clinical research, approached the Chain-Florey Fellowship with little previous practical experience of basic science research. Swapping the ward for the wet-lab has presented novel challenges. The transition from his familiar clinical environment, as a specialist registrar in haematology and intensive care medicine, to the relatively foreign world of the science lab came as a significant culture shock. “I had experience of clinical research, but I’d had little practical exposure to cutting edge fundamental discovery science. It was certainly challenging when I started,” admits Amit. “But being at the Hammersmith Hospital site, where I had previously completed an Academic Clinical Fellowship, makes it easier as there are always people you know that can help you.”
“Having a fundamental look at a major clinical problem is great,” says Amit, reflecting on delving deep into the molecular basis relevant to a broad range of diseases rather than just one in particular. He remains grounded in clinical practice, working on-call once a week. “That maintains the essential connection to patients. It enables you to focus on the ultimate aim of the research, to translate advances in scientific knowledge into improved patient care. It also keeps your clinical skills sharp.” On completion of his Fellowship, Amit will be returning to sub-specialty clinical training in stem cell transplantation, and plans to continue as a clinical academic, building on the foundation established here at the CSC. “The Chain-Florey scheme paves the way for you to be as comfortable in the research lab as you are in the hospital.”
Amit has little time to spare, between the demands of professional and family life. He is widely involved in all aspects of undergraduate and postgraduate medical education for many organisations, and was recognised as a Local Teaching Hero by Imperial College London for undergraduate teaching at Imperial College Healthcare NHS Trust. He also manages a small medical education company, holds leadership and management roles for medical professional organisations, and still finds time to entertain his two baby daughters.
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Dr Thomas Oates • 2010 Fellow, Integrative Genomics and Medicine Group Dr Thomas Oates had his introduction to science during the summer of 2001. “I’ve always felt strongly compelled to do research,” he says. “I spent a summer in Paul Greengard’s lab at the Rockefeller University, New York, the same year Greengard won the Nobel Prize. There is no doubt he was doing ‘big-shot science’,” he smiles, “I was just some 21 year old who got a salary and an apartment. It was great fun. They were all very driven, so it gave me an insight into goaloriented science.”
“ The highest quality research is always going to come from people trained in high quality labs, from the basics upwards ”
Renal specialist Tom started his Chain-Florey Fellowship in September 2010. “I’m far enough down the line with my medical career to know what is useful and interesting for me, and now seemed the best time.” The CSC was an important part of the attraction for Tom. “The highest quality research
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“Patients with glomerulonephritis get bombarded with treatment, so the goal is to develop more tailored therapies, and reduce side-effects. Targeting epigenetic modifications would certainly be novel as a therapeutic approach and that is something I have been able to do in the course of my thesis as well.”
is always going to come from people trained in high quality labs, from the basics upwards.” The work life of a scientist is not the same as that of a medic. “In medicine the work never stops – it comes to you. When you start in science, the self-start determination is a challenge. The experiments don’t do themselves, choose themselves, or make themselves work. But now I’m used to that, I enjoy it.”
The nature of his research means Tom has not only had to hone his lab skills, but his computing abilities too. Previously, he asserts these extended not far beyond reading his emails. Now comfortable with programming and computational statistics, Tom adds that he, “got a real kick out of learning to properly harness the power of computers and the vast sources of information available.”
Tom works in Enrico Petretto’s Integrative Genomics and Medicine Group on glomerulonephritis (GN), an inflammatory disease of the kidneys, predominantly of autoimmune aetiology. “In my clinical work I see patients with severe GN. Their kidneys are severely damaged by the accumulation of macrophages. I’m looking at DNA methylation in macrophages and how this might play a role in susceptibility to glomerulonephritis.” Tom has used whole-genome sequencing to identify differences in DNA methylation in macrophages between two rat strains – one that develops glomerulonephritis and one that does not.
Being the only medic in a lab of scientists may have made Tom “the butt of a lot of scientific jokes”, but that’s done nothing to dissuade him from pursuing basic research. “Doing this very basic work provides an excellent grounding, no matter what you go on to do.”
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Dr Philip Webster • 2011 Fellow, Cancer Genomics Group
“When you start, it’s a real baptism of fire,” muses Dr Philip Webster, casting his mind two years back to when he began his Chain-Florey Fellowship. “I’d spent a little bit of time in a lab before, but there was still plenty of floundering. You come in really knowing nothing.” And if the challenges of lab life aren’t enough, Phil has a three year old daughter at home, although he finds the flexibility of lab work a boon. “In clinical medicine you can be constrained,” he explains, “I still work long hours but I’m more in control of my time. My wife is a full time clinician, so now I can work around her if I need to.”
few people in renal medicine have done basic science research in oncology. It’s an unfilled niche.” Phil is looking at the mechanisms of lymphoma – a cancer of the white blood cells that can affect immunosuppressed patients. His project uses a technique called insertional mutagenesis to inject a retrovirus into newborn mice. Insertion of the virus genome into the mouse genome causes mutations of neighbouring genes, which drives lymphoma development.“We identify the regions of the genome where the virus inserted, then sequence these regions to identify nearby genes.” In this way the team can detect common insertion sites, before analysing how genes at these sites are involved in lymphoma development. One specific gene, BCL-2, is involved in preventing apoptosis (programmed cell death). If overexpressed, cells remain alive for too long, leading to cancers and autoimmune diseases. By identifying genes that are commonly mutated with BCL-2, Phil will alter their expression in lymphoma cells, to see what role they play in lymphomagenesis. “If we can find groups of genes that are interacting to produce disease,” he clarifies, “then we could develop patient targetted therapy.”
Phil trained at Nottingham University Medical School and has worked across the UK and beyond, including a somewhat traumatic stint in a hospital in the Australian outback: “Running a hospital single-handed, hundreds of miles from anywhere was terrifying at the time, but brilliant experience in hindsight.” In 2007 he came to London, and later began his specialist training as a nephrologist. He simultaneously embarked on an Academic Clinical Fellowship, before being accepted to the Chain-Florey scheme in 2011. With an interest in immune-mediated diseases, Phil was attracted to the Cancer Genomics Group, led by Anthony Uren. “Lots of renal diseases are autoimmune,” he explains, “in which the body makes antibodies and literally attacks itself.” Immunosuppression drugs are used to treat these conditions, and also to prevent organ rejection after kidney transplantation, although patients are at risk of side-effects from a ‘squashed’ immune system. “Cancers are more common in immunosuppressed patients,” he reveals, “but
“The last two years have been difficult at times due to the uncertainty involved in developing novel techniques,” says Phil, “but we now have a customised next-generation sequencing protocol working reproducibly and have identified a number of new gene candidates mutated alongside BCL-2 to study in more detail. It’s been hard work but I’ve really enjoyed it.”
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“ Few people in renal medicine have done basic science research in oncology - it’s an unfilled niche ”
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Dr Allifia abbas newsholme • 2012 Fellow, Lymphocyte Development Group “Learning the language of science has been a real eyeopener,” says Dr Allifia Abbas Newsholme, now 18 months into her Chain-Florey Fellowship. “When I first heard Amanda Fisher and Rosalind John chatting about my project, I had absolutely no idea what they were talking about.” Allifia meets the challenge with a hunger for new knowledge and a willingness to step outside of her comfort zone. “When I first came across ‘epigenetics’ I went and bought a popular science book. I found the concept just mind-blowing. The idea of jumping into something so exciting and unknown was great.”
“ Learning the language of science has been a real eye-opener ”
Originally from Dubai, Allifia took her undergraduate degree at the University of Leeds, and an intercalated BSc in immunology at the Royal Free. She has two years
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the environment may influence the nature of expression of these genes,” explains Allifia. “So we will keep mice at different stages during their pregnancy on low-, medium- or high-protein diets. We want to see whether this causes a change in the expression of these genes from monoallelic to biallelic.”
further training in her chosen specialty of Nephrology at the London Deanery. “When I came to meet CSC scientists and consider the project options, I could not decide on a project. “Meeting with Amanda and getting a sense of how she sees things was enough to convince me.” Allifia is looking at imprinted genes which are expressed in monoallelic fashion. “These genes are important in neurobehavioural development and are implicated in longterm chronic diseases,” she reveals. “My project is to devise a system to image changes in their expression.” She is using a range of molecular biology techniques including cloning, imaging and working with mice. “It involves lots of skills that are really important if I’m to have a career in basic science.” Her model gene is calle CDKN1C.
First she had to make a genetic construct with a luciferase reporter, which when added to the silent CDKN1C allele, allows gene expression to be visualised. “It took me a year to make the construct,” she admits. “But this means we can image the genes in real time. If the silent allele becomes active the luciferase reporter will switch on too.” Her construct needs to be transfected into a plasmid, which is injected into embryonic stem (ES) cells to generate mice. These can then be imaged and Allifia is hopeful this will allow them to detect tissues exhibiting biallelic expression.
“CDKN1C is expressed very widely in the brain, heart, kidney and adipose tissue,” reveals Allifia. “Mainly we know it’s important in neurobehavioural metabolism, even oncogenesis.” When faulty, the gene plays a role in Beckwith-Wiedemann syndrome, which is characterised by an increased risk of tumour formation. We believe
Now half way through her Fellowship, Allifia is surprised at how far she has come. “It’s an uncomfortable thing to unfetter yourself from your clinical preoccupations, but now I’m beginning to talk the language of science.”
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Dr Eleanor Sandhu • 2012 Fellow, Neurophysiology and Metabolic Signalling Groups “It’s fun being involved with setting up a new technique and then getting it to work,” says Dr Eleanor Sandhu a year into her Chain-Florey Fellowship. Working with Mark Ungless (Neurophysiology) and Dominic Withers (Metabolic Signalling), she is investigating what networks are involved in regulating salt appetite.“I’ve been very lucky that I’ve had the freedom to create my own project.” With an undergraduate medical degree from the University of Cambridge and clinical training at UCL, she moved to North Thames to specialise in Nephrology. Eleanor comes to the CSC with only a little former lab experience.
the networks at play in salt appetite. “From the survival point of view, reward pathways have developed in our brain to drive us to get things we need like food, salt and water,” says Eleanor, “so it looks like drugs of addiction hijack the normal reward system.” Eleanor explains how she is approaching the research. “I induce a salt appetite in mice using a diuretic – furosemide – to make them salt deplete.” The mice then feed on jellies with differing salt concentrations. “Then I can measure their salt appetite and preference.” With mice genetically modified to express Cre in dopamine neurons, Eleanor is using a virus to transfect a light sensitive channel into the dopamine neurons of the VTA. “The Cre-expressing cells then also express the light-sensitive channel. I then embed a fibreoptic into the VTA.” And finally the dopamine neurons can be illuminated and hence stimulated when mobile by attaching a laser to the fibreoptic, which allows their effect to be more easily studied.
As a doctor Eleanor has worked with patients who require dialysis because their kidneys no longer work. “People with heart failure salt retain,” she explains. “They should be on a low-salt diet but seem to have an abnormal salt appetite making it very difficult for them.” Patients with kidney failure have a similar problem. Regular dialysis relieves these patients of the water, salt and byproducts that they are unable to excrete. “But some of them just can’t stick to the low-salt diet,” says Eleanor, “so they drink too much. The excess fluid can put huge pressure on the circulatory system and heart, and they often end up with pulmonary oedema.”
The optogenetic system will allow Eleanor to see what happens to salt appetite when dopamine neurons are stimulated. “I’ve only run a pilot study, so it’s just starting to come together.” Although the system is still being perfected, she’s expecting that dopamine agonists will give the mice a bigger appetite.“But so far my mice just stopped eating,” she laughs. “I’ve got to do bigger numbers.” Eleanor hopes that there might be help for dialysis and heart failure patients if research can uncover a way to reduce their salt appetite through some form of manipulation.
Finding out what makes salt attractive could reveal a way to help these patients. Previous studies have shown that dopamine neurons are involved. The Ventral Tegmental Area (VTA) of the brain, where the dopamine neurons sit, is tied up with addiction, wanting and reward, so Eleanor’s project is probing this region of the brain with a view to uncovering
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“ It’s fun being involved with setting up a new technique and then getting it to work ”
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“ Suddenly you realise you’re doing it with everyone else, and you’ve just finished a genomewide screen ”
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Dr ANdrew innes • 2012 Fellow, Cellular Senescence Group
“When I first learned about my project and saw the others presenting in the lab meeting, I was terrified,” admits Dr Andrew Innes.“I thought there’d be no way I could do these experiments.” A year into his fellowship and Andrew is taking lab life in his stride. “Suddenly you realise you’re doing it with everyone else, and you’ve just finished a genomewide screen.” After a nine month Academic Clinical Fellowship at Imperial College with Francesco Dazzi, Andrew approached the bench with a firmer grounding in basic research than many other Chain-Florey Fellows.
genomewide viral screen to knock down every known gene so that we can figure out which ones are important.We use next generation sequencing to identify the most important ones.” While the project is still in its early stages, he hopes the findings will be relevant to his clinical interest. “Senescence is well known for its role in controlling cancers, but its role in fibrotic disorders is less well understood,” he confirms. “I’m interested in post-transplant fibrotic disease, specifically Graft Versus Host Disease (GVHD).There’s a lot of evidence that this is essentially an autoimmune problem, but there is also evidence that could link it to senescence.”
After training in Dundee, Glasgow and Manchester, Andrew moved to London in 2008 to specialise in Haematology. “I’m already almost four years into that,” he reveals, “so I’ve only one more year to do.” An intercalated BMedSci in Pharmacology and Neuroscience gave him his first taster of basic science. “I did a project looking at the anti-platelet effect of chocolate.” Discovering that dark chocolate inhibits platelet clotting cemented Andrew’s desire to pursue a career in clinical research.
The project has introduced Andrew to host of new techniques. “I’d done some PCR and flow cytometry before and a little bit of cell culture,” he says,“but I’d never done any RNA knockdown-based techniques, confocal microscopy or Western blots.” Faced with a steep learning curve, which introduced him to lentiviral and retroviral infection biology among other things, Andrew was undaunted by the challenge. “Maybe I was extra prepared because former Fellows had warned me how tough it would be. You don’t get the immediate self-gratification that comes with working on the ward, making sick people better,” he adds, “you have to wait weeks for experimental results.”
Working with Jesús Gil at the CSC, the goal is to uncover the genes that regulate replicative senescence. “When you culture cells, they only grow for a certain amount of time and then stop growing. But like the cells in our bodies, they remain metabolically active and can still influence cells around them.” Andrew’s project will look at what controls senescence in the natural ageing process. “We’re using a
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dr antonio de marvao • 2012 Fellow, Molecular Cardiology and Integrative Genomics and Medicine Groups “The Chain-Florey Fellowship scheme was the obvious choice for me when I decided I wanted to do research,” says Antonio. Born and bred in Lisbon, he explains his welldeveloped Scottish lilt,“I moved to Glasgow when I was 17.” Graduating from Glasgow Medical School in 2007 he was to remain in Scotland for two further years to complete house officer training. Antonio then made the move to London in 2009 to complete his core training at Imperial College London.
“ Ultimately, we’d like to understand how specific genes and gene pathways affect disease progression ”
With no former experience in a research environment, Antonio was inspired to visit the CSC when he rubbed shoulders with colleague and Chain-Florey Fellow, Dr Phil Webster, at the Hammersmith campus. A conversation with CSC Director, Amanda Fisher, and Director of Postgraduate
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Studies, Anne Soutar, led to a decision to carry out two months work experience with James Leiper (Nitric Oxide Signalling Group), to help equip Antonio with basic lab skills, and give him a taster of what was to come. He was hooked, although he says of the Fellowship, “This is the hardest thing I’ve done in my career.”
influence the shape and function of the heart. Antonio sums up. “Ultimately, we’d like to understand how specific genes and gene pathways affect disease progression, so we can give patients an accurate prognosis and choose the most appropriate treatment.”
Working with systems-geneticist Enrico Petretto (Integrative Genomics and Medicine Group), clinicianscientist cardiologist Stuart Cook (Molecular Cardiology Group) and radiologist Declan O’Regan (MR Facility), Antonio’s clinical interests are well matched to his research project. “I’m a cardiologist, and am particularly interested in the use of imaging as a tool to investigate cardiac patients and guide their treatment.” His PhD involves looking for genes that influence heart shape and function. “We’re analysing a cohort of 1,500 healthy human volunteers,” he explains. “Each volunteer is being scanned with traditional cardiac MRI techniques and state-of-the-art 3D approaches. Scans will help create a much more detailed 3D model of the heart than has previously been possible.” After having manually created 20 cardiac atlases that provide prior anatomical knowledge he can now use automated software to analyse new scans. “Each 2mm3 point (pictured) in these high resolution scans is labelled as either muscle or blood and given a co-ordinate (XYZ) in space. We then co-register each point with corresponding points in other hearts. Finally we pool the data for all 1,500 people into one 3D model.” With some 11,000 points on the outer surface and 8,200 on the inside, the model harnesses a powerful dataset. “We can look at these data any way we want,” says Antonio, “to probe wall thickness, for example.” The team can then group members of the cohort, who share features of interest, and then investigate any genotypic similarities.
Cardiac atlas
For each volunteer, next generation targetted sequencing is being performed on a panel of 200 genes, which have previously been linked to cardiomyopathies. Thanks to additional support from the BHF, Wellcome and the NIHR a large bioinformatics and sequencing infrastructure was created at Imperial with Stuart Cook providing the link to clinical cohorts from the Brompton NHLI site. The goal is to identify common and rare genotypic variants that
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Dr parvin begum • 2012 Fellow, Gene Regulation and Chromatin Group “The best thing about the Chain-Florey Fellowship is having the time to concentrate on a completely new area,” says Dr Parvin Begum, now almost a year into her PhD with Niall Dillon in the CSC’s Gene Regulation and Chromatin Group. “As a doctor you can do some clinical research on the side of your day to day work, but to have robust scientific training in a place like this is a great opportunity.” With an NIHR Clinical Academic Fellowship under her belt, Parvin comes to the institute with some previous lab experience. “I had a little time in the lab as part of my NIHR fellowship but it was enough to give me the exposure I needed to consider a basic science PhD rather than a predominantly clinical one.”
entering quiescence. “Deregulation of that process may be important in cancer,” explains Parvin. She is trying to find out more about the transcriptional regulation of this gene. “Cancer patients with tumours that overexpress Aurora B have a poor prognosis compared to those who don’t but we know little about the mechanisms underlying this,” Parvin comments. “I want to look specifically at the epigenetic effects of Aurora B in lung cancer ” Parvin has had to get to grips with lab techniques including cloning, transfection, Western blotting, chromatin immunoprecipitation, RNA analysis and gene reporter assays. “Thanks to my former lab stint, I didn’t feel too uncomfortable at the bench,” she says. “But it’s a completely new venture. There’s a lot to learn. You do some basic science in your medical degree, although nothing this in depth.” During her first year she’s been using mouse cells. “We had ChipSeq data for that, so I’ve been cloning and modifying parts of the genome that potentially control the Aurora B kinase gene in mouse to see what’s important. I am now focusing on the human system and starting experiments with lung cancer cells.”
A year’s speciality training in respiratory and general medicine has led to her clinical interest in lung cancer. “I’ve always been interested in genetics, and then started to become really interested in epigenetics. That combination of interests brought me to the CSC at Imperial, because there is such a strong epigenetics section here.” She is investigating the role of a mitotic kinase in lung cancer. “The kinase is known to be involved in cell cycle regulation, having important functions in mitosis. Recently the lab discovered that Aurora B kinase also plays a role in regulating quiescence.” Quiescence describes a resting state where cells are not actively dividing but retain the ability to reenter the cell cycle. “It’s important in maintaining tissue homeostasis.”
“It’s fascinating to be able to physically manipulate gene sequences to try to answer questions you’re interested in.” In the future she hopes to continue with research. “It’s great being at the CSC.There’s so much expertise and technology available if you want to use it.”
Parvin is looking at whether Aurora B may be involved in mediating the choice between cells continuing to cycle or
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“ It’s fascinating to be able to physically manipulate gene sequences to try to answer questions you’re interested in ”
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DR jennet williams • 2013
DR elizabeth byrne • 2013
Jennet Williams trained in Wales and is now more than half way through her training as a Medical Oncologist. She became a Chain-Florey Fellow early in 2013. Her first real exposure to life in the lab was working as an Academic Clinical Fellow at the Wellcome Trust Centre for Human Genetics. She is fascinated by the Warburg effect – the observation that cancer cells metabolise glucose differently from normal cells – and was therefore thrilled to join Dave Carling’s Cellular Stress Group, experts on AMP-activated protein kinase (AMPK), a key enzyme in energy homeostasis. The role of AMPK in cancer, specifically whether it is a friend or foe, is still uncertain and Jennet is investigating this question in hepatocellular cancer.
Elizabeth Byrne moved from a small village on the outskirts of Manchester into the heart of the city, to complete her medical degree and BSc in Pathology. She undertook an academic foundation programme in East London before moving to Leeds to begin her histopathology specialist training. She returned to London to take up an Academic Clinical Fellowship, and has worked at Hammersmith Hospital for two years. Elizabeth’s project is not yet confirmed and she approaches the Fellowship with an open mind while she decides on her speciality. She hopes that taking this time to focus on the basic science of one area in depth will equip her with the skills to grapple with both diagnostic and research work in the future.
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Chain-florey clinical fellows 2014 and beyond Eligibility Criteria • Practicing Medic in training in the UK • Hold a National Training Number and be eligible for ‘OOPE’ (Out of Programme Clinical Experience for Postgraduate Doctors in training) • Would normally have passed Membership exams Chain-Florey Clinical Research Fellowships are for medical graduates pursuing a career as an academic clinician. Fellows carry out their research in one of the MRC Clinical Sciences Centre’s world-leading basic science groups. Chain-Florey projects must involve human tissues or samples or be otherwise related to human disease of relevance to the Academic Health Science Centre strategy. Fellows have 3 years to complete their PhD before returning to their postgraduate clinical training.
DR harpreet lota • 2013 Harpreet Lota graduated from Imperial College in 2005 and is currently a respiratory specialist trainee in London. Her training at the Royal Brompton Hospital sparked her interest in the interstitial lung diseases and she chose to get involved in a basic science project due to her scientific curiosity into the pathogenetic mechanisms underlying this devastating group of disorders. Her research will investigate the role of methylarginine metabolism in the context of pulmonary fibrosis and will hopefully allow the development of future therapeutic pathways. She hopes that taking time out of clinical training to complete this work will equip with her invaluable skills for her future career. Harpreet is looking forward to starting her Chain-Florey Fellowship in October 2013.
The CSC is looking for candidates with a genuine interest in doing scientific research, and an open and enquiring mind. Previous laboratory experience is helpful but not essential. Fellows will receive sound scientific training on an interesting project in an internationally competitive research institute that will equip them with the scientific skills and experience needed for a high-flying career in academic research medicine. The CSC plans to offer 3 posts each year to European Economic Area nationals.The posts are jointly funded by the MRC, Imperial College London and the NIHR Biomedical Research Centre at Imperial College NHS Trust. For further information, visit www.csc.mrc.ac.uk/ChainFlorey
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“ I gradually became aware throughout the Chain-Florey Fellowship that I wanted to stay with research ”
makes that very amenable.” Following on from his PhD, which looked at gene transcriptional regulation in normal B cells and B cell leukaemia, he is keen to explore possibilities for new therapeutics for this disorder.
DR jonathan bond • 2009-2012
“The chemotherapy used for leukaemia treatment hasn’t changed much in the last 40 years,” he explains. “I’m looking at very immature leukaemia cells since they can help us to understand why normal blood cell development gets blocked and causes leukaemia. If we understand this then we can target the block more specifically.” Jonathan is particularly interested in the role of the Core Binding Factor (CBF) protein in these immature leukaemias. “Around 20% of myeloid leukaemias have abnormalities in CBF,” he explains, “so I’m currently exploring how genetic abnormalities in this transcription factor affect early blood cell development.”
Dr Jonathan Bond, the first ever Chain-Florey Fellow, is set on being a clinician-scientist.Well into his second fellowship (this time at postdoctoral level), he continues to build on work carried out in the Gene Regulation and Chromatin Group at the CSC under Niall Dillon. “I gradually became aware throughout the Chain-Florey Fellowship that I wanted to stay with research. I was lucky to find the project that I’m working on now since it is exactly what I wanted to do.” “The Chain-Florey Fellowship helped me with technical approaches to experiments, and also in learning how to pose the right kinds of questions,” says Jonathan. Although not currently working in the clinic, he says, “I want to continue in science doing 80% research and 20% clinical work. My clinical role would be in diagnostics. Haematology
Jonathan is based in Elizabeth Macintyre’s lab at l’Hôpital Necker-Enfants Malades in Paris and is supported by a Kay Kendall Leukaemia Fund Intermediate Research Fellowship. He continues to work in collaboration with Professor Niall Dillon, to whose lab he will return for the latter part of the project.
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“ It’s been a challenge to go from recently completing a PhD to supervising doctoral students ”
develop robotic tools to support his research. “These tools are essentially intelligent toys with movement sensors” he reveals. “We’re using them to accurately measure and understand whether children who’ve suffered a stroke use their hands and limbs differently, before it becomes obvious to their parents and doctors.”
DR tomoki arichi • 2009-2012 Since he completed his Fellowship in 2012, Dr Tomoki Arichi is very clear he wants to be a clinical academic. Having recently been appointed an NIHR Clinical Lecturer, he says, “it’s been a challenge to go from recently completing a PhD to supervising doctoral students.” The academic side of his lectureship will “build on the functional MRI studies in new born infants that I did for my Chain-Florey Fellowship.”
Diagnosing neonatal stroke earlier opens up a whole new window to potential treatments. “There’s a lot more plasticity in the developing brain, which we could take advantage of to rehabilitate the children. They could use specially developed robotics to passively move limbs or to help with sensation,” hopes Tomoki. The experience he gained in imaging at the CSC will be essential to the project. “We can use fMRI to track any changes in the brain and understand the underlying pathophysiology.”
His current research could bring benefit to 1 in 3,000-4,000 children who suffer stroke around the time of birth. “Lots of these children aren’t diagnosed with cerebral palsy until they’re two or three years old,” explains Tomoki. “We’re interested to see whether any asymmetry in the way they use their hands might be detectable earlier.” With a visiting position in the Bioengineering Department at Imperial College London, Tomoki’s in the perfect position to
Tomoki is a Clinical Lecturer in Paediatric Neurology at Kings College London.
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“ I would definitely recommend the Chain-Florey Fellowship to doctors with an interest in basic science ”
“I particularly remember the feeling I had when we discovered CaMKK beta had a significant effect on sepsis outcome in the mouse model we were using,” she recalls. Mice lacking the protein kinase were found to be resistant to septic shock. A pharmacological inhibitor of CaMKK beta already exists, so her project has the potential to yield tangible results.
DR jess zhao • 2010-2013 “The Chain-Florey Fellowship has given me the opportunity to work in a fantastic lab and has confirmed my aim of becoming an academic clinician,” says Dr Jess Zhao who recently completed her PhD research project in the CSC’s Cellular Stress Group with Dave Carling. She is now aiming to complete her PhD by the end of the year.
Finding the right balance of clinical and research work has been more challenging than I expected,” says Jess. “It’s still something I’m working on.” Having returned to complete her core medical training, she hopes to pursue a career in academic medicine in the future, and is particularly interested in specialising in care for the elderly.
Following an infection, patients can develop septic shock, an inflammatory response and massive drop in blood pressure that can lead to multiple organ failure and death. Jess wanted to find out how a protein kinase called CaMKK beta might be involved in mediating the process. “When I started the investigation into the underlying molecular interactions, I had that mixture of excitement and uncertainty that you feel when heading out into the unknown.”
“I would definitely recommend the Chain-Florey Fellowship to doctors with an interest in basic science. It provides an excellent opportunity to carry out exciting research supported by experts in their fields.” Jess is currently a trust doctor in the stroke unit at Charing Cross Hospital, Imperial College Healthcare NHS Trust.
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“ It’s only towards the end of the three years that you start to appreciate what you’ve actually done ”
For James the critical lab results came right at the end of his project. “I worked very hard to develop a transgenic mouse model to look at kidney disease. We discovered that mice, which cannot make DDAH (dimethylarginine dimethylaminohydrolase), an enzyme involved in nitricoxide signalling, are protected against renal fibrosis.” Being able to correlate this basic finding to relevant human clinical data has been an extra boon. “The mouse model is now being used by collaborators in the US to better understand the kidney physiology and the role of DDAH in nitric oxide signalling.”
DR James tomlinson • 2010-2013 “The Chain-Florey Fellowship changed me a lot,” says Dr James Tomlinson, who completed the practical side of his PhD in April 2013. “Doing the Fellowship gave me time to stop and think. Working on the wards, you don’t get much time to pause or reflect.” With a BMedSci under his belt, James was no stranger to the lab, but admits even so that, “It’s only towards the end of the three years that you start to appreciate what you’ve actually done.”
While it can be difficult to strike the balance between research and clinical work, James is keen to keep both within his sights. “I’d like to continue collaborating with the research scientists I’ve met at the CSC. In the future, I’m keen to develop my own research niche, to develop my academic prowess and ultimately become more autonomous.”
“It’s a complete career change,” he adds. “And it’s very difficult to get through, in terms of feeling competent and doing the lab-based work.” James has since returned to complete his final three years of clinical training, but admits that the Chain-Florey experience has cemented his decision to pursue a career as a clinician-scientist. “I’d like to finish writing up by September this year so that I can start applying for lectureships.”
James is currently completing his registrar training in renal medicine at Epsom and St Helier University Hospital NHS Trust in Carshalton.
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Inside cover image courtesy of Professor Benjamin Chain. Inside back image Š National Portrait Gallery, London. Produced by the Public Engagement Media & Grants Facility, MRC Clinical Science Centre. Printed by ScanPlus.
Howard Walter Florey
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