Preparing for the windy city: Symposium update

Every year we are responsible, as an Association, for organising the BIGGEST international conference event of the year on MND. The 23rd International Symposium on ALS/MND will return, after 16 years, to the windy city of Chicago from the 5-7 December this year.

This event is one of the most exciting events in the research calendar for those involved in MND research, and it promises to be full to the brim with exciting, cutting edge presentations. Scientists, clinicians and health care professionals across the globe come together every year for this stimulating event.

The deadline for abstract submission was back in May and we’ve been incredibly busy since then in compiling the abstracts for this year’s Symposium.

This year we received 419 high quality abstracts from across the globe, totalling 172,581 words! The Symposium Programme Committee, chaired by Prof. Wim Robberecht, had to review every single one of these in order to compile a stimulating and varied programme.

This year the Symposium will consist of a total of 96 oral presentations, with joint opening and closing plenary sessions on risk factors of the disease and the challenges of translating knowledge to treatment. There will be parallel scientific and clinical sessions exploring a wide variety of topics from target pathways, disease models and biomarkers, through to cognitive changes, multidisciplinary management and clinical trials. The final programme offers plenty of new ideas and key insights, particularly into the newly discovered C9ORF72 gene.

The Symposium will also see 251 poster presentations, and 55 work in progress poster presentations, showcased on a wide range of scientific and clinical themes that all sound incredibly interesting!

Me and Kelly have spent the past several weeks editing, formatting, proof reading and compiling all of these abstracts, which were sent to the publisher last week. The final document was 290 pages long and consisted of 150,096 words! The next stages of this process for us are to receive the proofs back from the publisher so that we can double, and triple, check them before they are ready for the Symposium. We will also be letting authors know their final poster numbers and timings so that they can get their presentations in order for the big event.

The full Program is available NOW on our website to give you an insight into the themes, and topics, that will be presented this year

Sharing and networking in Liverpool

From Sunday morning to Tuesday evening last week, there was a lot of talk of MND research going on in Liverpool. The reason for this ‘hotspot’ of discussions was due to the annual meeting of an international consortium of MND researchers taking place at the University of Liverpool. The 10th International Consortium on SOD1 and ALS (ICOSA) meeting took place last weekend (4 – 5 March).

In 2001, five laboratories came together to form ICOSA, where the aim was to share knowledge to design better-informed experiments to understand the rare, inherited SOD1 form of MND. MND Association grantee, Prof Samar Hasnain was one of its founding members. Success of this philosophy of sharing knowledge prior to publication has resulted in several leading groups joining the effort, looking at other causes of inherited MND too.

A tradition of ICOSA meetings is to hold an open meeting for sharing latest results with a wider audience, following their closed meeting. Thus, on Tuesday 6 March, an open meeting was held to allow the exchange of the latest results and ideas between ICOSA members and the UK MND research community.

I attended this one day meeting in Liverpool and I’ve written a mini report on the meeting below, including a couple of highlights.

The first few presenters demonstrated the truly international nature of this collaboration – they had travelled from the snowy landscape of northern Sweden, the sweltering heat (at least in August!) of mid-state Florida and from RIKEN, the large natural sciences research centre, in Japan .

The researchers represented were a mixture of physicists, biochemists and neurologists – an unusually broad spectrum of knowledge and speciality for an MND research meeting. Essentially, their core, joint interest was in understanding how the structure of a protein has such a marked change leading to MND developing or the disease progressing.

The structure of a protein is essentially about folding. The correct folding will mean that the protein can do its job. Folded incorrectly the protein won’t be able to work. An example of incorrectly folded protein is the protein clumps or ‘aggregates’ seen within motor neurones in MND. There is a whole chain of events that lead the appearance of these clumps of protein – and researchers at the meeting discussed every step along the way.

How do proteins fold and why is it important?

When the instructions for making a protein (ie genes) are read and edited by DNA and RNA respectively, they are reading or editing instructions to arrange a set of building blocks in a particular order – there are 20 different types of building block – our amino acids. ALL of our proteins within our bodies are made from specific arrangements of this core set of 20 building blocks. The arrangement of the building blocks determines where the protein folds, in which direction and the shape it makes. There are many possible folding arrangements a protein could make, but it will always try and fold itself into the lowest energy shape (a good way to think about this is the shape where the protein is ‘most comfortable’).

Geneticists know a lot about the beginning of the process (what the sequence of building blocks will be) and biochemists and pathologists know a lot about the end of this process (what the protein does and a what it looks like in the cell when it clumps together) – but the physicists of the MND research world are working on the bit in the middle (precisely where which building block is, in the folded protein).

A change to the sequence of the building blocks, as seen in the proteins made from mutated genes that cause MND, will lead to unusual folding, and damage to the cell – due to the loss of normal function or a trigger for toxicity. So having a complete picture of a protein ‘lifespan’ is really important in understanding what goes wrong in MND and how to fix it.

Unravelling questions about SOD1

People with the SOD1 form of the rare, inherited type of MND have a mistake in the assembly of one building block in the instruction to make the SOD1 protein. Over 160 different, single building block mistakes have been found in this form of MND so far. All of them lead to the development of MND. So that means 160 damaging variations in the folding of the SOD1 protein.

Over 70 other delegates and I heard the latest on how mimicking the effects of these mutations (by changing building blocks of the protein) in SOD1 mouse models tells us more about this cause of MND. It’s even possible to study the different effects of the toxic protein on different cell types essential for motor neurone function. (Although motor neurones carry the messages, they are supported by groups of ‘glia’ cells around them).

Where (the) ‘FUS’ is

Prof Larry Hayward presented his research on a protein called ‘FUS’; mutations in this gene causes another form of the rare inherited MND. The damaged ‘FUS’ protein is found in a completely different place in motor neurones than usual. Images of motor neurones where the FUS is in the centre of motor neurones, as usual, looked a bit like fried eggs; but the location of the damaged FUS in the outside of the cell reminded me of ring donuts! By stressing motor neurones, he showed a video of the proteins moving from the centre to the outside of the cell; and back to the centre when the stress was removed. This all happens very quickly, in a matter of minutes!

C9orf72 – a hot topic

Another highlight of the meeting was the presentation by MND Association grantee Prof Huw Morris on both how the C9orf72 gene mistake was found last year, and also on what’s happened since the results of this finding were announced. In the five and a half months since the 21 September announcement, another 26 reports have been published in this area of MND research. That’s slightly more than one report a week! (To put this in context there are roughly 36 MND reports published a week, total, across a broad range of topics). He commented that one factor that kept him focussed in the long search for this gene defect was the people with MND in his care.

Drug scaffolding to correct damaged folding

Above I mentioned that the physicists work out the precise folding of proteins, knowing where each of the building blocks is within its final shape. They do this by isolating the protein they want to study and placing it in increasingly high concentrations of salt solution to remove literally every molecule of water, until the protein itself comes out of solution and forms crystals. These crystals are then analysed by x-ray crystallography and other analytical chemistry techniques.

For a protein made from a mutated SOD1 gene, x-ray crystallography studies found a hole in the protein folding that may explain why it forms clumps within motor neurones. MND Association funded researcher Dr Neil Kershaw from the University of Liverpool presented the latest results from his research in designing a drug that will ‘prop up’ incorrectly folded SOD1, in the hope that this will remove its damaging effects.

I hope that this report demonstrates that in between the ‘big news’ stories about MND research, steady progress continues to be made in understanding MND and searching for treatments for it.

Chromosome 9 finally reveals its secrets

It’s taken a huge international collaboration, including 3 MND Association-funded scientists, to discover a genetic mistake that appears to cause almost 40% of cases of familial (inherited) MND – that’s nearly twice as many as are caused by mutations in the SOD1 gene and more than three times as many as are caused by TDP-43 and FUS combined. Yet despite the fact that it’s relatively common, the rogue gene proved especially difficult to find.

Digging for genes

Our genetic code is arranged into 23 pairs of subunits called chromosomes. Earlier work had homed in on an area on chromosome 9 that appeared to be significantly associated with both MND and the related neurodegenerative disease frontotemporal dementia (FTD), but nobody could drill down as far as the problem gene itself. As a result, chromosome 9 became something of an ‘archaeological dig site’ for MND researchers, with several groups using cutting edge techniques to try and excavate the elusive causative gene that they knew was lurking somewhere in the short arm of this chromosome. The successful international team, which included almost 60 scientists at 37 institutes, finally discovered the exact location and nature of the aberrant genetic code by looking in the most unlikely of places – in the stretches of DNA that do not actually provide any instructions for building proteins, otherwise known as non-coding DNA.

What did the researchers unearth?

The research team studied DNA samples from a Welsh family affected by inherited MND and FTD that was already known to be associated with chromosome 9, as well as samples from a similar Dutch family and a large number of Finnish inherited and non-inherited MND cases. In among the non-coding DNA in a chromosome 9 gene called C9ORF72, the researchers found a 6-letter genetic ‘word’ which, in healthy individuals, is consecutively repeated up to about 20 times. However, in the Welsh and Dutch families and a large proportion of the Finnish familial cases, the 6-letter word was repeated as many as 250 times. This phenomenon is known as a ‘repeat expansion’. The researchers went on to check for this repeat expansion in familial MND cases from North America, Germany and Italy, and found it cropped up in 38% of them. They even found it in a much smaller proportion of sporadic cases from Finland, suggesting that it could be an important risk factor in at least some people with the  non-inherited form of the disease.

What does the discovery mean for MND research?

Despite the fact that the repeat expansion does not directly affect the instructions for building a protein, there is good reason to believe that it can still lead to significant neuronal damage. At the moment it is not fully understood how this happens, but one possibility is that it leads to the production of excessive and consequently toxic quantities of RNA, the molecule that provides the cell with a more usable copy of DNA. Disruption to RNA processing has already been implicated as a disease mechanism in MND – this is the pathway through which faulty TDP-43 and FUS are thought to exert their effects – so C9ORF72 may provide scientists with another piece of the RNA jigsaw.

The effect of the repeat expansion is clearly open to influence. Among those people with the repeat expansion, some experienced only FTD, others showed only muscle weakness, and some had both MND and FTD.  The reasons for this variation in symptoms will be just one area that scientists will now want to look into. This overlap between MND and FTD is something that researchers are very keen to understand, and the C9ORF72 discovery may be the key to solving this puzzle. They will also want to better understand how the repeat expansion causes damage, and that will include trying to find out what C9ORF72 actually does – at the moment this is unknown. (Maybe it’ll get a more interesting name along the way!) Building on the new finding in this way could help move us closer to an effective treatment.

For now, a more tangible consequence of the discovery could be a genetic test for people already diagnosed with familial MND who want to understand more about the basis of their disease. Such a test will take a little time to develop but should become available in the UK in the next few months. When it does, it will be accessible to genetics labs across the country. Anyone interested should speak to their doctor or specialist nurse.  

Dead heat

Just as archaeologists might question whether a newly discovered artefact is the real thing, so scientists need double-checking when they claim to have made a new discovery. Fortunately, a second team hit upon C9ORF72 at exactly the same time, and their results will be published alongside the work described here, in the journal ‘Neuron’. The race to the ‘Lost Ark’ of chromosome 9 ended in a tie, but has provided the research community with a major piece of the MND puzzle on which to build future discoveries.

Article: Renton A, Majounie E, Waite A et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. Neuron (2011).

Read our press release on the C9ORF72 story.

Updating our research strategy

Our Research Strategy has recently been revised and can be downloaded from our website:

 Although it can seem that MND research moves at ‘glacial’ speed, the fact that we have had to update the strategy to take into account new gene discoveries, new laboratory models of MND, advances in stem cell technology and the upsurge in research activity around the world, all serve as reminders that scientists and clinicians are continuously chipping away at the disease and probing for a weakness that can be turned into a potential treatment.

 There is no getting away from the fact that MND is a complex disease: the causes are complex, the biochemical pathways underpinning motor neuron degeneration are complex and the treatment approaches are likely to be complex. But if we can continue to put the right building blocks in place – to understand the causes; develop laboratory models that truly represent the human disease; improve diagnosis and measuring disease progression; ensure consistent high quality care; attract the best researchers to work on MND and encourage greater international collaboration – the challenge will be that much easier.

 At the Association’s International Symposium, a few years ago, Prof Bob Brown (a senior ALS neurologist from the USA) commented: “There’s a ‘sea change’ coming in MND research.”   We still have a voyage to make, but perhaps we are just beginning to feel the breeze in the sails…?

Marion – incurable optimist

My reasons for being an ‘incurable optimist’ is the increasing amount of research being carried out and the number of researchers interested in MND and in collaborating to solve the mystery of this terrible disease.  

The difference now from when I started with the Association over 20 years ago (as a very young woman!) is huge. At that time, among other things:

  • there were no clinical trials at all and none in the pipeline
  • no gene mutations had been identified
  • researchers hardly ever collaborated and were a very select few
  • the symposium was in it’s embryonic stage
  • generally people just diagnosed were told to go home and put their lives in order – nothing could be done
  • I think the number of staff was around 13
  • Care and research centres were just the beginnings of a twinkle in the eye of Peter Cardy the Director (C.E.) at the time.

Progress, of course, has not been fast enough and it would have been brilliant if the cause/s, more effective treatments and ultimately the cure had been found.  However, we are moving in the right direction:

  • in 1989 around 40 UK researchers came together for a research conference in Solihull. This was the start of what today is the International Symposium on ALS/MND which includes around 300 presentations, attracting on average 800 delegates from around the world, all under the same roof for one reason. To fight MND and the effects of the disease
  • The budget for 22 research projects in 1989 was £211K, today the annual expenditure is around £2m on 45 research projects (this includes small grants)
  • 1996 Riluzole was licensed for the treatment for MND
  • There have been numerous clinical trials since – sadly mainly negative in terms of stopping or changing the course of the disease – but each adding a small amount of information to the bigger picture and helping to plan and develop future trials
  • There are now 18 care centres where people with MND can get the help and treatments available under one roof and health care professionals can call upon their expertise
  • Because of the above and the continued work and influence of the Association, people with MND and their families/carers now, in the main, get better treatment and are provided with more information to help them cope with the devastating news of being diagnosed with MND.

 Lots more needs to be and is being done and with the MND Association being the driving force, to ensure the needs of people living with MND are considered and met at every level there are reasons to be optimistic.

Follow our incurable optimism campaign