Saturday afternoon saw the 25th International Symposium on ALS/MND expand from two to three sessions running in parallel. Times have changed from the early years of the meeting when sessions finished at lunchtime on the second day because there wasn’t enough stuff to talk about! Rather than flitting between three different lecture halls, I opted to immerse myself in the Biomarkers session, especially since the session was being kicked off with presentations from MND Association funded investigators. Read More »
Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Senior Clinical Research fellow, Dr Martin Turner writes about recent developments in his BioMox study.
My first ever blog. I decided to share developments in ‘BioMOx’ – the Oxford Study for Biomarkers in MND, which has been funded through the MND Association’s pioneering Lady Edith Wolfson Fellowship scheme (in conjunction with the Medical Research Council).
Between 2009 and 2013, over 70 people living with MND (and some healthy people of similar age for comparison), took part in a new type of patient-based study. Men and women of all ages (from 28 to 86), some with primary lateral sclerosis (PLS) as well as a range of the more common amyotrophic lateral sclerosis (ALS) types, all gave up their time to attend for a day or two of tests in Oxford. Read More »
To end volunteer week, Katy Styles, who is a Campaigns contact for the East Kent Development Group of the MND Association, blogs about her and her husband Mark’s experience of volunteering to take part in the Biomarker’s in Oxford (BioMOx) study.
It started as an innocuous question following a neurology appointment at the Oxford MND Care Centre, Mark and I asked “Now what can we do for you?”
Following a phone call and some form filling, Mark and I had volunteered to take part in Dr Martin Turner’s BioMOx Project. Mark as a person with MND and me as a control of the same age.
We didn’t know what to expect as we were scheduled to take part in two days worth of tests, which included two scans and a written test. In between time in the scanners however, we were able to enjoy everything Oxford has on offer.Read More »
Plenary speaker Dr Massimo Filippi put this question to delegates on the second day of the 24th International Symposium on ALS/MND.
Opening the session on neuroimaging, Dr Filippi gave an excellent review on what we currently know about this area of research, and ultimately answering whether or not we can see more clearly in MND?
It’s all in your head – Magnetic Resonance Imaging (MRI)
Over the past ten years there have been significant advances in the identification of neuroimaging patterns in MND. Dr Filippi focused mainly on the use of MRI neuroimaging (a technique used to visualise changes in the brain). He stated: “Through the use of MRI we have been able to detect cortical thickness of the Cerebral cortex (the outermost layer of the brain), which is significantly reduced in MND”.
There’s a scene in the 1969 film Battle of Britain where Laurence Olivier, who plays the Air Chief Marshal, is in a meeting with his two Vice Marshals. One of them complains that they don’t have enough planes; the other is more concerned with keeping the airfields working. Olivier silences them both by telling them that the fight will be won or lost on one key factor – the number of trained pilots.
It’s a rather cheesy film, but I used that story earlier this month to illustrate the importance of investing in bringing through the next generation of researchers in our battle to defeat MND. We organised a ‘get together’ of our Lady Edith Wolfson Clinical Fellows at the Sheffield Institute for Translational Neuroscience (SITraN) to share their research findings with the donor who has so generously supported the scheme. The ‘get together’ also provided a wonderful opportunity for them to exchange information and expertise with each other, as well as all the staff of SITraN, who over the course of the day were frequently shuttling between the lecture room and their labs.
The Fellowships are aimed at attracting and training the brightest and the best Clinician-Scientists (or ‘Doctor-Doctors’ as I sometimes call them – with both a medical degree and a science PhD). Even so, I couldn’t resist using this cartoon in my introduction, although the reality is very different for our Fellows – the bar is set very high and even applicants for the Junior Fellowships need to have considerable research experience and be fully ‘lab tested’.
Our host for the day was one of the world’s most respected MND ‘Doctor-Doctors’, SITraN Director Prof Pam Shaw, who welcomed everyone to the meeting and provided an overview of the multidisciplinary expertise and collaborative philosophy that underpins SITraN. Prof Shaw also has a great belief in the importance of nurturing the next generation of talent and it is no surprise that almost half of the Clinical Fellows in the programme are based at SITraN.
Are fit and active people more likely to develop MND?
Our first research presentation was from Dr Ceryl Harwood (Sheffield) who is carrying out research on the epidemiology of MND. Specifically, she is addressing the question of whether physical activity is a risk factor for MND. As she explained, this has been a long standing theory, showing us a quote from a medical journal written over 50 years ago which stated:
”Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases”
She outlined the plausibility that physical activity may contribute to a complex interplay between biological and genetic processes that may predispose an individual to develop the disease. Generating the evidence, however, is no easy matter, but she has developed and validated a novel questionnaire to measure physical history in adulthood, using data from a diabetes study in the 1990s where over 1,000 people had detailed measures taken of their actual energy expenditure.
A hundred of these participants have recently agreed to undergo rigorous face-to-face interviews and their responses were correlated with actual physical measures from over 15 years previously. In other words, she can now assess how accurately peoples’ recollection of their physical activity – both day to day work and vigorous exercise – links with their actual energy expenditure at the time. This questionnaire is now being used to compare the physical activity profiles in up to 350 people with MND and 700 control participants in Yorkshire and surrounding counties.
Should the results support the theory that physical activity is a predisposing factor in MND, she will be perfectly placed to delve into the genetic factors that underpin the selective vulnerability of motor neurons.
Repetition is bad….
Next up to the lectern was Dr Pietro Fratta, (University College London) who has been immersing himself in the mysteries of how the C9orf72 gene can cause neurodegeneration – especially MND and a related condition called Frontotemporal Dementia (FTD).
Like a needle on a vinyl record can sometimes stick and repeat the same fragment of music again and again, this gene sometimes carries a repeat in its genetic code – specifically with the letters GGGGCC occurring again and again. Dr Fratta has examined many DNA samples from MND and FTD patients and finds that these ‘repeat expansions’ are very large indeed, occurring between 700 and 4000 times!
The process through which these repeat expansions cause nerves to die is still a mystery, but Dr Fratta showed results from his lab which suggests that rather than losing its normal function, the C9orf72 gene gains some additional activity, turning it into a ‘rogue’ gene. He and his colleagues have recently shown that the repeat expansions can lead to the formation of very stable chemical structures called G-quadruplexes that have been implicated in causing nerve damage in other disorders.
He is currently studying how these structures interact with other cellular components, interfering with normal neuronal function. He is also starting to look at possible therapeutic approaches in a collaboration with the UCL School of Pharmacy to develop compounds that will bind to and hopefully inactivate these structures.
Over lunch, we were given a guided tour of the superb SITraN labs by Prof Shaw. Although I strongly believe that research is only as good as the researchers doing the work, there’s no doubt that having a purpose built institute filled with state-of-the art technology certainly doesn’t do any harm!
Then it was back into the lecture room for our afternoon presenters.
A Sheffield double act
The post-lunch session was kicked off by Dr Robin Highley, a neuropathologist who has recently completed his Fellowship and now divides his time equally between pathology duties and MND research. Dr Highley’s area of expertise is in how neurons edit the genetic instructions into precise ‘blueprints’ to make proteins, the essential building blocks of every cell in our body.
He used an entertaining analogy of making dresses form a pattern to describe the process of how DNA is made into RNA copies which can be ‘tailored’ into slightly different protein designs (to find out more about how DNA makes RNA and subsequently proteins see our earlier blog post).
Using a variety of approaches he has looked at gene expression (which genes are being switched on and off) and gene splicing (how the RNA copies are edited) patterns in both inherited and non-inherited MND, as well as in non-MND states. He finds changes occurring in thousands of genes, but by performing searches on databases of the ‘function’ of each gene he can then sort them into different groups (which are then involved in key cellular processes). This provides important clues as to which cellular pathways are altered in MND, which will help researchers around the world to focus their attention on the most common changes and hopefully start addressing the question of how these may be slowed or stopped.
Dr Highley focused his talk mainly on the TDP-43 and SOD1 forms of inherited MND, with his colleague and fellow ‘Fellow’(!) Dr Johnathan Cooper-Knock, concentrating on the C9orf72 form (the most common cause of inherited MND). Through the MND Association’s DNA Bank he has been able to obtain a large number of cell lines from patients with C9orf72 MND, along with detailed clinical information, which will allow him to compare patterns between those with fast progressing and those with more slowly progressing disease.
Although at a much earlier stage in his research, having started only 6 months ago, Dr Cooper-Knock has already identified some specific gene expression effects that may be distinct to the C9orf72 form of the disease. For more details about Dr Cooper-Knock’s work see our earlier blog post about his fellowship.
BioMOx and beyond
It was fitting that Dr Martin Turner (Oxford) gave the closing presentation. Not only was Dr Turner the first recipient of a Lady Edith Wolfson Fellowship, but he has recently been awarded a new five-year Senior Clinical Fellowship through the programme – these are highly prestigious awards, with only one in seven applicants successful.
Titling his talk ‘BioMOx and beyond’ Dr Turner outlined the challenge of identifying a specific signature of MND. He showed that whilst there is unlikely to be a single test for MND, a combination of tests (involving brain scanning and eye tracking techniques together with chemical analysis of blood, urine or cerebrospinal fluid) are showing some promise in aiding and speeding up the diagnosis, as well as predicting how the disease is likely to progress within an individual.
He highlighted the importance of international collaboration, such as the new formal link with Dr Mike Benatar in Miami, who for several years has been studying people at risk of developing inherited MND. Indeed, Dr Turner apologised for missing the morning speakers at Sheffield as he had been busy with one of Dr Benatar’s study participants in his MRI scanner at Oxford!
On the subject of international collaboration, our most recent Clinical Fellow, Dr Jemeen Sreedharan, was unfortunately unable to attend as the first two years of his Fellowship is based at the University of Massachusetts, returning to the University of Cambridge to complete his research. We look forward to having him at the next Fellows get-together!
Every March, Brain Awareness Week (11 – 17 March 2013) unites people of all ages worldwide to raise awareness of brain research. There are 45 free events across the UK, including seminars and school visits.
On the evening of the 11 March Belinda attended the free award ceremony for the winner of the Europe PubMed Central-led science writing competition ‘Access to understanding’, which included a large number of entries on an MND paper.
On the 13 March University College London (UCL) will be running a free public symposia on ‘Degenerating Brains’. As well as talks on Alzheimer’s and Parkinson’s disease, Prof Chris Shaw (King’s College London) will be speaking about MND. Due to the popularity of this event it is now fully booked.
Our Brain Research
Dr Martin Turner’s BioMOx project MND Association funded researcher Dr Martin Turner at the University of Oxford has identified a pattern of degeneration in the brains of people with MND that is linked to the level of disability.
Continuing and expanding BioMOx Dr Martin Turner has also been awarded his second MRC/MND Association Lady Edith Wolfson Clinical Research Fellowship to carry on his BioMOx project which is to begin in August 2013.
Dr Turner will be broadening the BioMOx project to include people identified as being at risk of developing MND from families with a history of the disease but who are not yet showing symptoms.
Dr Tennore Ramesh’s interneuron findings A recent study by Association funded researcher Dr Tennore Ramesh from the Sheffield Institute for Translational Neuroscience (SITraN) has shown that even before the symptoms of MND occur, at the earliest stages of the disease, ‘connector neurones’ known as interneurons are already becoming damaged in the zebrafish.
Prof Mara Cercignani’s MRI scans project Starting in October 2013 Prof Mara Cercignan’s Association funded PhD studentship will use brain magnetic resonance imaging (MRI) scans that have already been obtained from many studies at King’s College London over the past 16 years.
This project will apply new ideas in medical computing to old data in order to identify how MRI changes in the brains of people with MND evolve. This will then enable the development of a new method to ‘stage’ MND progression so that brain abnormalities can be detected earlier.
Tissue Donation and MND
Tissue donation is a generous gift that can make a vital contribution towards MND research. Researchers investigating MND are particularly interested in the whole of the brain and spinal cord tissue, otherwise known as the central nervous system (CNS).
A brain and spinal cord tissue donation is made from either a healthy individual or somebody with MND after their death. To find out more information about tissue donation please see our information sheet on our website.
Raise Awareness of MND
Our 2013 Awareness Month campaign is focussed around a film called I Am Breathing. The hard-hitting documentary tells the story of Neil Platt, who was diagnosed with MND just after his son, Oscar, was born.
Neil wanted to leave a legacy for Oscar and also raise awareness of MND. We hope that thousands of people will see the film on or after a special Global Screening Day, Friday 21 June, Global MND Awareness Day.The Association has joined forces with the film makers, the Scottish Documentary Institute, and with Neil’s family to make sure this powerful story is shared as widely as possible when the film is released during the Awareness Month in June 2013.
You can help fulfil Neil’s goal of raising awareness by hosting your own screening of I Am Breathing on 21 June 2013 – MND Global Awareness Day.
Two MND clinicians have been awarded Medical Research Council (MRC) /MND Association Lady Edith Wolfson Clinical Research Fellowships to help advance our understanding of MND while moulding future experts.
The MND Association Lady Edith Wolfson Clinical Research Fellowship scheme plays a vital role in helping us strengthen and translate emerging knowledge from the lab to treatment strategies for people living with the motor neurone disease, while creating new innovative and exciting scientific leaders in the field.
These new fellowships, granted to Dr Martin Turner and Dr Jemeen Sreedharan will drive us forward to achieve the Association’s aim of unlocking the secrets of this cruel disease to identify promising new treatments.
Our Director of Research Development Dr Brian Dickie commented, “These new fellowships represent £2.6 million of investment not only in cutting-edge science, but also in the career development of two future leaders in MND research and treatment.”
Read more about this story on our website: MND Association fellowships awarded to promising clinicians | 2013 | MND Association.
MND Association funded researcher Dr Martin Turner at University of Oxford has identified a pattern of degeneration in the brains of people with MND that is linked to the level of disability.
This finding brings us closer to identifying a biomarker that can be used to speed up the diagnosis of MND, which can be delayed on average by a year since first symptoms.
This is the third finding to be announced since Dr Turner was awarded with the MRC/MND Association’s Lady Edith Wolfson Clinical Research Fellowship in 2008.
You can read more about this exciting finding on our website:
Reference: Stagg CJ, Knight S, Talbot K, Jenkinson M, Maudsley AA, Turner MR, Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS. Neurology 2013; DOI 10.1212/WNL.0b013e318281ccec
Delegates to last weekend’s ENCALS (European Network for the Cure of ALS) meeting in Dublin were met with uncharacteristic hot and sunny weather – enjoyed by the numerous Stag and Hen parties wandering the city centre, but not by the 200 people ensconced in the impressive, new Biomedical Sciences Institute at Trinity College, from 8am to 7pm, for a packed programme of presentations and debate.
ENCALS was established to help develop the standards of clinical and biomedical MND research across Europe and create a more collaborative environment for researchers, industry, funding agencies and Patient Associations. However, the meeting had a very transatlantic flavour, thanks to the participation of several of the leading researchers from North America.
With around 40 speakers, as well as numerous poster presentations, there is too much to cover in a few hundred words, so I’ll focus on just a few of the key themes that were covered. I also apologise for the quite technical language, which may make for hard reading, but is a positive in that it reflects the increasing complexity and sophistication of MND research.
Can we block the ‘molecular funnel’?
The opening speaker, Prof Teepu Siddique, from Northwestern University in Chicago, spoke on The molecular funnel of neurodegeneration. His view of MND is that it may have a large number of different causes, but the way a motor neurone dies will probably be similar, no matter what the original cause. We’re currently finding lots of new genetic factors involved in the disease, but we don’t understand how many of these genes work in health, much less how they malfunction in disease. So, the mouth of our funnel is getting wider.
Prof Siddique’s view is that by focusing on the cellular changes that are common to all forms of the disease, it gives us possible therapeutic targets that could be relevant to all forms of MND. It’s easier to block the funnel at its narrowest point.
He discussed how the degradation of incorrectly formed or damaged proteins is a classic hallmark of all forms of MND. While the way in which the proteins are damaged may differ from one form of MND to the next, it’s the cell’s inability to correctly deal with these proteins that may be a good target. If we can normalise or improve this process, it may keep the motor neurones functioning for longer.
Prof Orla Hardiman, the meeting organiser from Dublin, discussed the need for much larger and more detailed study of large numbers of patients, to attempt to unpick the environmental influences that undoubtedly exist.
A question that many people often ask is whether MND is occuring more often in younger people that in the past. Intriguingly, Prof Hardiman’s ‘population-based’ research using the Irish MND Register suggests the opposite – the average age of symptom onset is getting older. She suggests that continued improvement in medicine and diet means that the population in general is healthier, so our ‘biological age’ is slowing. If age-related diseases such as MND are linked to ‘biological age’ rather than ‘actual age’, it would explain this surprising trend.
Good Genes/Bad Genes
While factors that cause or predispose towards MND are clearly the subject of intensive research, there is of course also interest in factors that might prevent or slow the disease. Some of these potentially ‘good’ genetic variants are being explored:
- Prof Wim Robberecht’s group (University of Leuven) is examining the function of a gene called ephA4, which appears to correlate with longer survival in humans. This work is supported by studies in zebrafish and mouse models of MND.
- Prof Kevin Talbot (University of Oxford) showed data that suggests that by increasing activity of a gene called smn1 might be beneficial to motor neurones. This is a strategy that is being followed for a predominately childhood motor neurone disease called Spinal Muscular Atrophy, so if these approaches work in this particular condition, they might be of benefit in other, adult onset motor neurone diseases.
- Prof Robert Brown (University of Massachusetts) presented early data from a study of a variant in a gene called sarn1, which appears to protect motor neurones from damage….at least in fruit flies and mice. Work is ongoing to see whether it also has relevance in humans.
In contrast, Dr Andrea Calvo (University of Torino) provided information from Italian patients confirming studies in other populations that a variation in the unc13A gene can speed up disease progression. However, the important issue about these disease-modifying genes – and it doesn’t matter whether they speed up or slow down MND – is that they all represent potential therapeutic targets.
Not just about the motor neurones!
We know that motor neurones do not die alone. Other parts of the brain and spine can be affected, but it’s the motor neurones that ‘bear the brunt’.
Dr Sharon Abrahams (University of Edinburgh) provided an excellent overview of the range of cognitive and behavioural changes that can occur in the disease, indicating damage to other part of the brain, in particular the frontal lobe. Thankfully, the ‘real world’ effects of frontal lobe changes are usually subtle, but the fact that they can be picked up by psychological tests and MRI scans will help in defining specific ‘subtypes’ of MND which may require additional approaches to managing the disease.
Dr Martin Turner (University of Oxford) outlined evidence from a number of clinical research studies, including his own that nerve cells, called interneurones, might be involved early in the disease. These particular neurones usually play a role in calming down motor neurones, so if they are damaged or lost, the motor neurones themselves become over-excited and stressed, which leads ultimately to their degeneration.
Dr Turner’s evidence comes mainly from clinical imaging and electrophysiology studies in MND patients, but his theory was supported by a presentation from Dr Tennore Ramesh (University of Sheffield) who works with zebrafish models of MND. He showed results using zebrafish that carry a human SOD1 gene known to cause MND. The fish develop a form of MND in adulthood, but the very earliest signs of nerve damage actually occurs in specific types of interneurones that connect with the motor neurones, with the motor neurone damage occurring much later, closer to the onset of symptoms.
Presentations also covered the role of non-neuronal support cells, such as microglia and astrocytes, both of which have been the subject of extensive research in recent years, as they appear to play a role in the speed of progression of the disease. Prof Jeff Rothstein (Johns Hopkins University) introduced a new cellular player to the MND field, called the oligodendrocyte. These specialised cells have been known for many years to play a role in helping neurones to carry electrical signals, as well as helping them to maintain energy levels. Although they are known to be involved in multiple sclerosis, they hadn’t attracted much attention in MND.
Prof Rothstein showed that in human post mortem MND brain tissue, there is evidence that the brain has been making oligodenrocytes. This is certainly very clear in SOD1 mice, where a massive production of new oligodendrocytes occurs. However the total number of these cells was not increased in the mice, suggesting that older oligodendrocytes were being killed and getting replaced.
He suggested that the new ‘immature’ oligodendrocytes are not nearly as efficient in their supporting role, especially when it comes to supporting motor neurones in maintaining their energy balance. This provides two possible treatment approaches – either try to keep the existing oligodendrocytes healthier or find a way of making sure that their replacements reach their full functional maturity.
I’ve no doubt we’ll be hearing a lot more about these cells in the future.
We’re pleased to announce that Dr Martin Turner has been awarded with the European Network for the Cure of ALS (ENCALS) Young Investigators Award 2012.
Dr Turner was awarded with the MRC/ MND Association Lady Edith Wolfson Clinical Research Fellowship in 2008 for his study to identify biomarkers in MND (called BioMOx). Since then, Dr Turner has already published two findings from his five-year disease marker study in the prestigious journals Neurology and Brain. Using advanced brain scanning technology, his study has identified a common pattern of nerve damage in the brains of MND patients. This holds the promise of a much-needed disease marker.
Talking about why he thinks the ENCALS award is so important, Dr Turner said:
“The ENCALS award marks a major highlight in my career.”
“I am passionate about MND, and feel privileged to help care for those living with the most challenging of diseases. To be recognised as having made a useful contribution to research as well, by international leaders in the field, means an enormous amount.
“It is 13 years since I began as a PhD student under Professor Nigel Leigh, whose ground-breaking ideas about brain changes in MND first sparked my interest. I was fortunate to meet Professor Kevin Talbot in 2003, and through his support and partnership I have been able to develop these ideas alongside leading brain imaging neuroscientists at Oxford University.
“I have never felt more sure that progress is accelerating in MND research, and I am pleased to be adding something to the wider global effort.”
Funding promising researchers
One of our research aims, is to develop the research workforce. Dr Turner talks more about how our funding has helped to develop his career:
“The Lady Edith Wolfson Clinical Research Fellowship scheme, uniquely linked to the Government-funded Medical Research Council through the MND Association, has been critical to my development as an MND researcher.
“These highly competitive 5-year Fellowships don’t simply provide the funding for the experimental studies, but crucially allow me to devote most of my time as a consultant neurologist solely to the care and research of MND patients. There is no simple way to specialise like this within the standard NHS framework, and such schemes are a vital way to help develop a strong UK academic neurology workforce in MND.”
Commenting on this story, our Director of Research Development, Dr Brian Dickie said “We’re delighted that one of our Lady Edith Wolfson Fellows has won this prestigious international award. The Fellowships were created to attract and retain the brightest and the best young clinicians to MND research and it is a fitting tribute to the knowledge, expertise and dedication that Dr Turner brings to this important field of MND research.”
Go to the BioMOx website to find out more about this project
Find out more about ENCALS
Our research aims