Saturday 28 February 2015

My successful SRC grant application

As the Cystic Fibrosis Trust announces a call for applications to form up to three more Strategic Research Centres, Dr David Sheppard of the University of Bristol explains how he went about submitting a successful SRC application.

As a scientist based at a UK university, a significant part of my time is spent applying for research funding. This funding provides salaries and bursaries for the research fellows and students that I have the privilege to work with. These highly creative individuals labour for long hours in the lab to understand better how the cystic fibrosis transmembrane conductance regulator (CFTR) works, how it goes wrong in cystic fibrosis (CF) and how drugs repair the faulty CFTR. Funding also covers the cost of all the “stuff” required to do experiments in the lab. In our case, this involves some very expensive equipment needed to monitor CFTR activity as tiny electrical currents, paraphernalia to grow cells and a battery of chemicals to stimulate CFTR and manipulate its activity. Simply put, without funding there is no research.

With my research focusing on CFTR, the CF Trust is the major funder of our work. I’m extremely grateful to the Trust for the funding that I have received over the last 20 years. The output of our research has included knowledge of how gating mutations (eg, G551D) interfere with CFTR function and the action of chemicals that act as CFTR potentiators. This information has helped the development of transformational drugs that treat the root cause of CF.

When the CF Trust announced its new research strategy in April 2013, I began to think about how to apply for a Strategic Research Centre (SRC) grant from the Trust. SRCs are virtual research centres of excellence that bring together research groups from the UK and overseas to tackle a fundamental problem in CF.

What problem to address? Great progress has been made in our understanding of F508del, the most common CF mutation, leading to clinical trials of CFTR correctors and potentiators. While very encouraging, data from the lab and clinic argue that better drugs are required to fully rescue F508del-CFTR. By focusing on F508del-CFTR, the SRC would have the potential to benefit the largest number of individuals living with CF.

Today, most research is multidisciplinary, meaning that methods from different research disciplines (eg, biochemistry and physiology) are used together to solve specific questions. While some labs successfully apply different research methods, many specialise. My own work is very highly specialised, focusing on how individual CFTR proteins work. To apply successfully for SRC funding, we would need to collaborate actively with other groups expert in studying CFTR structure, how it is made inside cells and delivered to its correct cellular location. We would also need help from pharmacologists expert in testing large numbers of chemicals for drug action.

Early in planning the application, I approached Professor Bob Ford from the University of Manchester. Bob has been at the forefront of efforts to identify the structure of CFTR. This work is fundamental to understand CFTR and its dysfunction in CF. I also approached Professor Ineke Braakman from Utrecht University in The Netherlands. Ineke and I had previously made plans to study how CFTR matures inside cells to become a gated pathway for chloride movement. When compared with other methods to study CFTR activity, those used by my Bristol colleagues are notoriously slow. Two groups studying CFTR activity would therefore be advantageous for an SRC application. Because of her expertise in studying how CFTR flutters open and closed, I approached Dr Paola Vergani at University College London. I was delighted that Bob, Ineke and Paola all readily agreed to participate in the SRC application.

Plans for the SRC were finalised at a conference in Malta organised by the European CF Society last March. Because the meeting was so intense, it was not until the day after the meeting that Bob and I finally found time to discuss, in detail, plans for the SRC, especially how the different project partners would work together to address our research goals. During these discussions, we recognised that the SRC would require a group expert in the pharmacology of CFTR. With his wide-ranging expertise in studies of drugs targeting CFTR, we both agreed that Professor Frédéric Becq from Poitiers University in France was an excellent choice. Returning to Bristol, I telephoned Frédéric to invite him to join; he agreed immediately. With the team recruited, we then set about writing the application. The initial application went smoothly, but the full application involved a lot more work; not for the first time lots of late nights and early mornings close to the deadline!

Bob, Ineke, Paola, Frédéric and I were delighted to learn that our SRC application was successful. We are excited about the studies of F508del-CFTR that we have planned. We believe strongly that they will inform the development of new drugs to benefit the majority of individuals living with CF.

Thursday 26 February 2015

Back from Boston & Bethesda

CEO Ed Owen and Director of Research Dr Janet Allen spent the first half of this week in the US, meeting with colleagues from across the American cystic fibrosis community. Ed fill us in on some of the highlights from meeting with our US counterparts.
Weeks of sub-zero temperatures and Arctic-like weather have left much of the North Eastern coastline of the US encased in ice and snow. Yet our visit this week to see Vertex and Novartis in Boston, and the Cystic Fibrosis Foundation (CFF) in Bethesda, demonstrated that the work to beat cystic fibrosis continues to generate a great deal of heat and light.

What we heard from all those we saw gives me renewed confidence about the future prospects of research. But, while competition in the pharmaceutical industry is an important driver in pushing the development of new drugs, this needs to be matched by new forms of international collaboration and partnership that pools effort and resource in the best interests of people with cystic fibrosis.

Our strong relationship with the CFF is crucial here. We have shared goals, represent communities of people who are themselves increasingly interconnected, and both have access to key clinical, academic and business expertise. We can bring this together on tackling the big issues facing people with cystic fibrosis so the potential for greater and quicker advances becomes a reality.

The Foundation’s success in helping to develop and promote new therapies in cystic fibrosis has been extraordinary.  We in the UK owe a great debt to them – and their $3.3bn windfall late last year resulting from the selling of their Kalydeco royalty rights gives them significant new resource to invest in new research to bring hope to everyone with cystic fibrosis wherever they live.

But, as the Foundation will readily admit, they do not have a monopoly on wisdom or expertise – and are keen, too, to explore areas of collaboration with the Cystic Fibrosis Trust in particular areas that can bring impact.

At our meeting, we therefore discussed a range of areas of potential joint research activity. One was tackling the challenges posed by what are called ‘nonsense mutations’ of cystic fibrosis, and developing novel treatments that would benefit around 1,000 people here in the UK alone. The existing pipeline of small molecule therapies being developed by Vertex and other pharmaceutical companies would not affect this group so it is an important area for ourselves and the Foundation.

A further area we explored was transformational work in gene therapy and stem cell research. The UK has particular expertise here, not least that generated by the Gene Therapy Consortium, supported by the Trust over many years and soon to publish the results of its Phase 2b study. In stem cells too, the UK has a strong scientific base and we are keen to see more of this focused on cystic fibrosis over the coming years.

We also discussed joint approaches to tackling emerging infection threats to people with cystic fibrosis such as NTM and aspergillus. The CFF is supportive of the Strategic Research Centre on NTM being funded by the Trust, and keen to follow its progress.

Finally, we talked about our SmartCareCF programme and working together to harness new technology to give people with cystic fibrosis the tools to take greater control of their lives, as well as increasing access to clinical trials here in the UK.

I believe that in these and other areas we can demonstrate real collaboration over 2015 to bring together the greatest possible expertise and resource in our collective fight to beat cystic fibrosis for good

Tuesday 24 February 2015

Moving Mountains - “Making the impossible possible with exercise”

Last Friday saw Churchill College, University of Cambridge, host the Moving Mountains conference on how sport and exercise can benefit those with long-term health conditions, such as cystic fibrosis.

Our own, Paul Rymer, Head of Principal Involvement attended from the Trust and has given us a flavour of the informative, interesting and exciting events there

In the next year fitness and sport will be an increasing focus for the Trust. Last week I attended a conference highlighting the benefits of exercise, including better mental health, less reliance on drugs, and increased feelings of confidence and social inclusion.

The event was organised by Dr Jonathan King, who has CF, in partnership with others living with chronic conditions.

Jonathan used a slide presentation and props (bottles of water) to engagingly describe lung function, his treatment regime, what happened when things went badly wrong during a holiday, and then the months of recovery. With persistence, and support from his care team, Jonathan managed to avoid a lung transplant by gradually improving his lung function though exercise. At first he could barely move, but over a period of months he gradually increased his physical activity, from walking a few steps, to trying a treadmill, to jogging and then to running 4K. Jonathan now uses regular exercise to maintain his health. His next endeavour is to cycle 1,200 miles from London to Barcelona in support of the Cystic Fibrosis Trust.

Nick Talbot gave an extremely funny account first of his experience as a young man with CF, including dating, relationships and work. He then shared his experiences climbing mountains in the Himalayas, and the challenges of doing that with cystic fibrosis. Where Jonathan’s story was one of survival against the odds, Nick’s was an example of someone not accepting the perceived limitations of cystic fibrosis. Nick is aiming to climb Everest in support of the Trust in April–May.

Charlotte Wells, a specialist respiratory physiotherapist, talked engagingly about her experience working with CF patients, and the benefits of exercise from a clinical perspective.

Because of the risk of cross-infection, Jonathan spoke before a break time, and stayed in one area of the large venue, while Nick arrived later on, and aside from when he was speaking, remained at the back of the audience. At one point they were both in the venue, but at the widest possible distance (and it was a very large theatre). They then spoke through microphones asking each other questions. This really brought home one of the saddest aspects of living with cystic fibrosis – people unable to meet in person and share ideas, jokes and experiences.

Following the conference there was a drinks reception with special guest of honour Professor Stephen Hawking, who kindly posed with Nick and a Trust banner. In a short speech, Professor Hawking said: “You have to live life to the full. I am very aware of the preciousness of time, act now however difficult life may be there is always something you can do, be brave overcome the odds, it can be done.”.

If you have an interest in exercise, fitness or sport and would like to join me in exploring how the Trust can do more in this area, please email me at

Monday 16 February 2015

Thoughts On Stem Cell Research & Treatments

Many will have read about the story earlier this month of a young woman with cystic fibrosis, Roisin Kelleher, who travelled to the Dominican Republic in order to undergo a controversial stem cell procedure. Here, our Chief Executive, Ed Owen, reflects on the difficult issues the case raises and why the Trust cannot recommend others pursue the same course:

There’s been much interest and debate on the use of stem cells as a potential transformational therapy for cystic fibrosis in the wake of publicity around Roisin Kelleher’s story.

Roisin is 20 years old and lives in Kent. She is dependent on oxygen, has been recently diagnosed with pulmonary hypertension and has been told by her clinical team that a lung transplant is probably the only way to prolong her life. Her mum Anntoinette told me when I spoke to her this week, “our lives caved in” at the news and they were desperate to find alternative routes to bring hope for her daughter.

After undertaking a great deal of research on the internet and through other networks, Anntoinette came across the work of a Florida-based physician, Dr Zannos Grekos, who has been promoting a particular stem cell therapy for a range of debilitating conditions, including heart and lung failure. Under his procedure, patients travel to the Dominican Republic where stem cells are introduced into the body intravenously.

Roisin and Anntoinette decided to give it a chance, and raised the funds they needed to travel to the Dominican Republic and undergo the procedure. Roisin is now back home and you can read her personal story on her Facebook page, ‘Breathe Hope for Roisin’.

So what is our view of this particular therapy? It is the question we have been asked by many, including some in the same situation as Roisin who, inevitably, are asking themselves whether they too should seek to undergo this procedure as a way to bring hope of future life.

In answering this question it is important to start by saying that all of us understand the desperation felt by the Kellehers. Theirs is a heartfelt story experienced by many other families touched by cystic fibrosis – and all of us wish Roisin well over the next few weeks and months. Like every other member of the wider cystic fibrosis community, they deserve and should receive full support and love from us all.

But the Cystic Fibrosis Trust does not recommend that others follow their example because it is a procedure that has not undergone the minimum essential procedures to guarantee patient safety. Indeed, the very reason it is carried out in the Dominican Republic is because it is not authorized by the US regulators, the FDA.

I have been in contact with a number of cystic fibrosis experts in the UK and in the US over the last few days, and none believes that this procedure has any scientific or clinical basis. It should also be pointed out that, in 2013, the Florida Board of Medicine removed the medical license of Dr Grekos for committing medical malpractice in performing an “unproven” stem cell therapy on a patient who later died. The board's vote was unanimous and without discussion, although I understand he may be appealing this decision.

I admire Anntoinette’s spirit and deep love for her daughter.  She accepts their decision was a “leap of faith”, and is also keen to point out that Roisin continues to take her existing treatments and is still going through a transplant assessment here in the UK.  She also understands the position the Trust takes on this issue.

And what we all very much agree on is the need for more research into the use of stem cells in cystic fibrosis.

For all the professional scepticism about Dr Grekos’ procedure, there is a great deal of enthusiasm within scientific and clinical circles for the longer-term potential offered by stem cell research. The Cystic Fibrosis Foundation in the US is looking to invest heavily in this field  and we, too, are exploring some innovative areas of work in this area which we hope to announce soon.

This is not work that is going to bring potential clinical therapies soon, and we are some way from even early stage clinical trials. But it is a genuinely exciting area as part of our mission to beat cystic fibrosis for good, and we will not stop until we get there.

In the meantime, our hearts go out to Roisin at this time, and to all those families facing the daily battle to ensure their loved ones remain with them. You are, quite simply, our inspiration in the fight against this cruel condition.

We are continuing to look into this issue, as we do with all developments in cystic fibrosis care and research. Please do keep an eye out on the Trust’s
Facebook, Twitter and website, as well as this blog for updates.

Monday 9 February 2015

SRCs: What’s so good about them?

The Cystic Fibrosis Trust has just announced it's two newest Strategic Research Centres. Senior Research Manager, Dr Anoushka de Almeida-Carragher explains why they're so great!

Our Strategic Research Centre (SRC) programme is one of the main initiatives which have come about following the launch of our Research Strategy,
'Investing in Research to Change Lives', a couple of years ago. SRCs are virtual centres of excellence made up of a unique consortia of scientists in the UK and overseas, using their wide knowledge and expertise to crack serious problems in cystic fibrosis (CF). SRCs also bring together established academics from different disciplines like chemistry and neuroscience; this much-needed extra set of skills, into CF research, is of profound importance. Not only do SRCs give the opportunity to partner up with pharmaceutical companies, thereby facilitating translating bench science to bedside clinical practice, but they also inspire the next generation of bright, young scientists to focus their research in CF, thus paving the way to a future of global research excellence in CF.

We have recently awarded two world class SRC programmes. Dr David Sheppard at Bristol University will be leading one of them. His multidisciplinary team is made up of renowned scientists from the UK, France and The Netherlands. The team will perform an innovative series of basic science studies which will provide an in-depth understanding of what is going wrong in the cells of CF patients. Specifically, his research aims to promote the development of new drugs to treat the most common cause of CF called F508del.  CF is caused by defects in the protein CFTR that forms a gated pathway for chloride, one part of salt, to cross cell borders lining ducts and tubes throughout the body.  The F508del defect prevents CFTR assembling correctly within the cell.  As a result, few CFTR proteins reach the cell border.  Those that do are fragile; they do not transport chloride properly and they quickly fall apart, losing altogether the ability to do useful work.  The team will investigate the structure of CFTR and learn how it is affected by the F508del defect.  Aided by this knowledge, they will then go on to search for chemicals that repair all the faults in CFTR caused by the F508del defect, so that CFTR is correctly made and delivered to the cell border to form a stable gated pathway for chloride movement.  Thus, the results will inform the development of new drug therapies to benefit the majority of people living with CF.

The second SRC will be led by Prof Di Bilton and her colleagues at Imperial College, London (The Royal Brompton Hospital). Her research team is made up of respiratory medicine experts, epidemiologists, medical statisticians and health economists, widely spread throughout the UK and in Canada. The project will enhance the use of the UK CF Registry data (containing information for over 99% of the UK CF population) so that better use of the information can be made to help answer important CF-related questions. When the data is analysed by cutting edge techniques, the team will be able to identify therapies and make recommendations regarding best use of therapies at critical stages and planning of care, for the increasing adult CF population.

Later this week, we will be inviting researchers to apply for a SRC grant, for the next round. This is a great opportunity for world class research academics in CF research, and other related disciplines, to ‘bang heads’ and work together to answer the critical questions we face in the field of CF, today

Find out more about our existing SRCs at

Thursday 5 February 2015

Three Parent Babies and Stem Cells

With three parent babies passed by MPs earlier this week and stem cell treatments in the news, Dr Janet Allen gives insight on how this all applies to cystic fibrosis.

This week there was another landmark decision as MPs approved legislation to help people who carry mutations in a small subset of genes, contained in a part of the cell called mitochondria. This is clear evidence that the UK is once again leading the way in developing and implementing novel approaches that can help people who carry genetic conditions. It is a testimony to the UK’s pioneering work, by thought-leaders such as Dame Mary Warnock, which allows ethical issues to be debated alongside scientific advances. The Human Fertilisation and Embryology Authority, formed in the ‘90s, continues to provide an excellent framework for this debate and ensures new approaches to treatments are introduced in a safe and considered fashion.
The news of the three-parent babies debate has received a lot of press attention this week. So what is meant by three-parent babies? It is really a misnomer. There are 37 genes that are found in specific organelles called mitochondria, inside cells. These organelles have been referred to as ‘the power battery for cells’.  Their role is to provide the energy to allow cells to function. Mutations in this small number of genes lead to dysfunctional mitochondria and so genetic conditions. Mitochondria are present in the human ova (eggs) but lie outside the cell nucleus and are not involved in the fertilisation process at conception. In contrast there are over 20,000 genes found in the cell nucleus, which are derived from the father and mother and come together during fertilisation to form the genetic make-up of the child. This fact is unchanged by the recent news.

Stem cells have also been in the news this week. The use of these cells in tissue repair processes is the subject of much research. Initially, stem cells were derived from embryonic sources (eSC) but this was very controversial and restricted their application. In recent years, a new source of stem cells has been identified, known as inducible pluripotent stems cells or iPS or iPSC.  These iPS cells can be derived from mature blood cells.

So what are iPSCs? Normally, when a blood cell divides it creates more blood cells of the same type. However, scientists have worked out how to convert a blood cell to a stem cell in the lab. Once an iPS stem cell, it can then be converted in to another cell type, say a liver or lung cell. So for any one individual, their own blood cells can be converted to the specific cells required for tissue repair. In the context of CF, it is important to understand that this process alone will not fix the gene mutation, cells that carry the CFTR mutation following this process will continue to carry the CFTR mutation. We have just started to fund a research programme where we will aim to correct the mutation in these iPS stem cells. Only then will it be possible to use stem cells as a therapy for cystic fibrosis. Achieving this in the laboratory is relatively straightforward. The big challenge is how to convert this to help people directly.

Stem cell therapies hold enormous promise for the future.  However, at the moment, the work is still at an experimental stage and is not available as a routine.  It is very important that any claims for success are properly evaluated and subject to critical review by independent experts.  Stem cell therapies need to be scrutinised as rigorously as any new treatment for cystic fibrosis.  After all, no one would accept that a new drug be used in people with cystic fibrosis without the proper safety and efficacy measures required by the European Medicines Agency and the Food and Drug Administration in the US.  These agencies have been set up to protect us all and ensure any new treatments, including stem cells, are used appropriately.
If you want to learn more about how three parent babies work, you can find some good lay explanations over on the BBCThe Independent and Buzzfeed

Wednesday 4 February 2015

Genotype Matters

Yesterday we launched 'Genotype Matters', allowing people with cystic fibrosis to learn more about their genotype, and how it is important in the era of personalised medicine. Dr Janet Allen, Director of Research & Care, has been overseeing the project at the Cystic Fibrosis Trust and here gives some background to it.

I am delighted to announce that we have launched our Genotype Matters campaign. We have been working with the CF centres in this area for a while. We ran a very successful pilot last year where we were able to pay for some of those whose genotype was unknown to have a blood test, and now we are able to extend the offer to all those who have a question mark about their genotype in the CF Registry. Cystic fibrosis is a clinical diagnosis made by expert CF specialists. In the past, the genotype information was provided afterwards and recorded in the CF Registry. However, the early genotyping panels only covered three or four common genotypes. As our knowledge of cystic fibrosis has increased, it has become clear that there are many different CF-causing mutations and not all of these are on the most recent standard test as they are very rare. So, we know that there are about 900 patients in the CF registry (out of just over 10,000) where the genotype record is missing for one or both genes (entered as ? or ??). In the past, knowing the exact genotype was not a high priority as treatment had nothing to do with knowing the genotype.

However, the picture changed with the appearance of ivacaftor (Kalydeco) which is prescribed for people who carry the G551D mutation. This is the first genotype-specific treatment and we anticipate that others will appear in the next few years that are targeted to other mutations. What’s more, it has become clear that ivacaftor (Kalydeco) can have beneficial effects on some people with a limited number of very rare mutations (so called non G551D gating mutations) and is already being used in the US for these very rare mutations. So it now becomes important that everyone wherever possible knows their genotype. Clearly, for the vast majority of people with CF this information is available and in their medical notes. We believe it is your right to know this information, and if you don’t we urge you to ask at your next clinic visit. If your doctor says the record in the registry says “?” or “??”, then we will cover the costs of the most up-to-date test that covers the rare genotypes. This is quite an expensive test so we are asking your doctor to double check with us and the CF Registry to make sure we don’t waste this opportunity.

In the pilot study, we found it was not always possible to identify the genotype even with the most modern test, because for technical reasons the test isn’t able to cover the entire gene. So our aim this year is that everyone with cystic fibrosis knows their genotype based on the most up-to-date test but recognise that for a small number of people this information will still remain unknown.

Why does this matter? Ivacaftor is the first of a new generation of treatments that help certain genotypes. However, even more exciting is the possibility to correct the mutation in the person’s own gene – so called genetic editing. For this, the precise genotype information is required. The approach works in the laboratory but as usual it will take some time before this lab-based work becomes reality.

You can find out about your genotype, or if you don't know it, learn how to get tested for it, at