Match-making to find a new treatment for MND

Translating recent scientific discoveries in MND into the development of new and better treatments is a major challenge we face. To facilitate this process within the UK, we’ve recently played a role in match-making a key UK academic neuroscience department and a commercial organisation.

Pharmaceutical industry – the big, the small and the CROs

Discovery and development of a new medicine is always going to be expensive and never as rapid as everyone would like. Many major pharmaceutical companies cannot justify a large investment in a relatively rare disease like MND. They may not recover the costs even if a new drug is discovered. However, the landscape of pharmaceutical research has changed dramatically in recent years – the big multinationals are not the only players.

Smaller research companies, often termed ‘Biotechs’, have been responsible for many of the newer medicines discovered. They sometimes then collaborate with, or become a part of, a larger organisation to enable the development and commercialisation of the product. They can undertake research that larger companies, answerable to shareholders, consider too ‘risky’. The larger companies, facing decreased income as older medicines lose their patent protection, have been making cutbacks to their in-house research. However, they may be willing to take on a potential new medicine when evidence of its usefulness has already been generated.

Another group of companies, called ‘contract research organisations’ (CROs), will carry out part of the research process, typically under a contract from another company. This enables a large company to put extra people onto a project for a few months without having to employ them directly, which can be more flexible. Initially CROs undertook clinical research, testing new medicines on patients, but different CROs are now involved in all stages of the research and development process, often employing people with prior experience gained in the larger companies.

Universities

Drug discovery can also take place in University research departments. Industry has always taken advantage of the basic biological research done by academic researchers. Gradually, a few universities and institutes have become involved in other stages of drug discovery – facilitated recently by the willingness of scientists with key industry experience to move to academic roles. In the UK this has focussed on two areas: cancer (due largely to funding from Cancer Research UK) and ‘neglected diseases’ (usually diseases of the developing world, such as malaria).     

Forging a Partnership

The drug discovery CROs are now becoming interested in partnering with academic researchers, to facilitate their drug discovery. My personal industrial experience means that I know people in some of these CROs, and they know of my move to the MND Association. One particular company, Peakdale Molecular became aware of the research underway at the Sheffield Institute for Translational Neuroscience (SITraN), and were particularly keen to know more as they are based relatively close. We encouraged some of Peakdale’s scientists to join us at the recent one-day conference in Liverpool, where they heard Dr Ramesh from SITraN give a presentation about his Association-funded project to test potential drug compounds in his zebrafish model of MND. The following week I travelled north again – South Yorkshire this time – to attend the first meeting between representatives of Peakdale and some of the scientists at SITraN. 

We heard about several projects, mostly MND-related, but also one on Parkinson’s disease, and we were shown around the SITraN labs. The Peakdale managers described the ways they would be able to help an academic team, for example, to select and source compounds for testing in the various biological assays at SITraN.  They were impressed with the results shown for the various projects, and could readily see how the experience and expertise of their staff might help the academic projects. Finally – and key news for the academics – Peakdale announced they would like to start by providing some help without charge, although purchase of compounds from commercial suppliers will inevitably incur costs.

It’s only a few weeks since that first meeting in March 2012, but already a Confidentiality Disclosure Agreement has been put in place to allow the start of collaborative working between Peakdale and SITraN scientists.  Such an agreement is important if any discoveries are later considered to require protection by patent filings. 

We really hope they do, as that will be one small step forward in the search for a new treatment for MND.

Very recent update: SITraN scientists have placed an order for a test compound to be synthesised by Peakdale for their MND studies and a second meeting has taken place between SITraN scientists and the Peakdale Chemists to further forge the working partnership on a number of projects.

May The Fourth Be With You – PhD Studentship Applications

Spring has finally sprung and so it’s now time to open our online summary application form for our next round of research grant applications.

This round is for PhD studentship applications, for projects starting in October 2013. The deadline for summary applications is Friday 4 May 2012.

Attracting promising researchers
Through our successful PhD studentship programme we have a track record of attracting and funding promising young scientists to develop their careers in MND research. Since 1998 we have funded 30 studentships, 12 of these are currently ongoing.

We need to continue to develop the UK basic research capacity by attracting more young scientists to develop careers in MND research. We can do this by funding PhD studentships.

Funding the best of the best
As with all of the research projects funded by the MND Association, our rigorous application process allows us to ensure we only fund studentships of the highest quality and of direct relevance to MND.

The way that we fund research starts with a summary application, which is a concise outline of the proposed project. After the deadline date has passed a decision is made as to whether the summary is relevant to ‘classical’ MND and the project aims fit with our Research Strategy. If the summary does not fit, it’s rejected. If all criteria are met, the summary is reviewed by our Biomedical Research Advisory Panel (BRAP).

The reviewer’s comments and scores are then assessed using a two thirds majority rule. Each reviewer scores the summary application. A score under 50 is classed as unsuitable for funding, if it’s over 50 then the applicant is invited to submit a full application.

We hope this year holds an exciting round of PhD studentship applications!

More information:

For further information please see the Prize PhD Studentship Flyer or visit our website www.mndassociation.org

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.

Disappointing results from UK based lithium clinical trial

Yesterday, we announced on our website the disappointing news that the UK-based lithium clinical trial showed that lithium carbonate is ineffective at treating MND.

Commenting on the lithium clinical trial, Dr Brian Dickie, our Director of Research Development said:

“As many people will know, when lithium was first proposed as having benefit in MND, a couple of small, short-term trials were performed to establish whether the drug had a large and rapid effect on physical changes in disease progression. This trial, by contrast, was developed to ask whether the drug had a more subtle benefit over a longer time course, as is the case with riluzole, using survival times as the primary measure. The only way to answer this question was by performing larger, lengthier and more comprehensive studies.

“While the result is deeply disappointing, we now have a clear answer.

“Lithium can be described as a messy drug. It can act in multiple ways in the body, producing potentially beneficial effects as well as possible unwanted side effects. An overall beneficial effect, even modest, would have refocused scientific interest in the drug to try and separate ‘the good from the bad’ with the longer-term goal of developing more effective compounds. This is a strategy that is presently being pursued with regard to riluzole, in a project co-funded by the ALS Association, the University of Reading and ourselves.

“This trial was the first of its type in the UK, devised and run by clinicians without the need for drug company funding. A number of MND clinics that previously had little or no experience in clinical drug trials for MND have developed vital expertise and confidence in delivering trials to the highest standards. This can only help make the UK a more attractive place in the future for drug companies looking to push potential treatments from lab to clinic.”    

Two hundred and fourteen people with MND took part in this trial, each giving up their time to help find us the answers. We’d like to thank those that have taken part in this trial.

One person who took part in the UK lithium clinical trial was Colin Knight. We spoke to him a few years ago about his views on taking part. Please be aware that in the film clip, Colin speaks frankly about his diagnosis.

 

Read our official press release.

Cogane produces encouraging results in MND Association-funded study

Prof Linda Greensmith

Thanks to funding and some strategic ‘match-making’ by the MND Association, a new drug may have taken one step closer to beginning clinical trials in MND after producing promising results in an animal model of the disease.

The drug, known as Cogane, was developed by the biotechnology company Phytopharm. It had already demonstrated in laboratory tests that it could help to protect neurones by promoting the production of natural, nerve nourishing substances called neurotrophic factors and early animal testing had hinted at its potential beneficial effects in MND. However, its journey towards clinical testing in MND had hit a road block because it hadn’t been extensively put through its paces in large numbers of the most widely used animal model of the disease, the SOD1 mouse. Without robust data from this model, there would have been little to encourage further investment in Cogane’s development.

So up stepped the Association to introduce Phytopharm to Professor Linda Greensmith at University College London, a leading MND researcher with considerable expertise in SOD1 mouse testing. With funding from the Association, Prof Greensmith and her team were able to conduct a rigorous study of the effects of Cogane, administered to the mice after they had developed MND-like symptoms.

The drug produced some significant improvements in muscle strength and motor neurone survival and managed to produce positive effects even in mice that had reached the later stages of the disease. To give more substance to these preliminary but very encouraging results, the research team will now go on to the painstaking work of examining more closely Cogane’s effects on the motor neurones and other key cells that play a critical role in the progression of MND. 

After the disappointment of the Trophos trial results, it’s great to be able to share some positive news on the drug development front. We know from long experience that it’s wise to limit our excitement over positive results from the mouse model – after all, plenty of drugs have shown promise at this stage and have then gone on to fail in clinical trials. However, Prof Greensmith’s experience and expertise mean that Cogane will have been tested with the utmost rigor. As she herself commented, the results indicate that “Cogane has significant potential as a therapy for ALS and merits further evaluation”.  We don’t yet know what Phytopharm’s next steps will be – these may become clearer once the more detailed data from Prof Greensmith’s work have been published, which could take the best part of a year. Let’s hope that we have a given Cogane enough of a boost to push it out of the drug development ‘doldrums’.

Read the Phytopharm press release.

Our DNA bank appeal to feature on BBC Radio 4

Sunday 8 January is not only a celebration of Prof Stephen Hawking’s 70^th birthday, it’s also the date when the MND Association’s DNA bank appeal will be launched on BBC Radio 4.

Our DNA bank contains over 3,400 samples from people with MND and their families.  By using these samples scientists in this country have already made significant discoveries into the causes of MND. To advance research into MND we now want to make the DNA bank available to researchers across the world. To do this, we’re asking people to donate funds to the BBC Radio 4 charity appeal for our DNA bank. All money raised through the appeal will go towards maintaining the samples and making them accessible to worldwide researchers. It will take a global research effort to beat MND, and the DNA bank is a very important tool in the fight against the disease.

Samples from the DNA bank will help scientists identify genes that cause familial (inherited) MND or those that influence susceptibility to sporadic MND. This will offer crucial insight into the causes of MND. Understanding the causes of MND will lead to the development of new treatments.

To listen to the broadcast narrated by Joss Ackland, listen in on Sunday 8 January at 7:55am or 9:26pm to BBC Radio 4. This will also be repeated on Thursday 12 January at 3:27pm, or you can listen again after the broadcast.

More information:
DNA bank samples are currently being used in a number of studies investigating the causes of familial and sporadic MND. For more information, please see the DNA bank pages of our website.

If you contributed a sample to our DNA bank, you can find out more about what happens to samples after they’re donated in our information sheet, and in our Thumb Print article from 2010.

Read our press release on this story.

Happy New Year – Quiz answers and round up of 2011!

And the answers to our Christmas Quiz are:

1. How many neurones does a human have? Billions
2. Which animal has the largest brain? Bottlenose dolphin
3. How much does a human brain weigh in comparison with our total average body weight (in percent)? 2
4. How many DNA samples does the MND Association’s DNA bank hold? 3,400
5. How many research projects do we currently fund? 44
6. How much does our research project portfolio currently come to? £7.6m
7. How many PhD studentships do we currently fund? 12
8. How many times a year do we have research grant funding rounds? 2
9. How many unproven MND treatments have ALSUntangled investigated so far? 13
10. How many stem cell research projects do we fund? 2

At the beginning of a new year, it’s always encouraging to look back on how far we’ve come. The list of MND research achievements continues to grow exponentially every year, and I’m pleased to say that last year was no exception, demonstrating that we really are living in exciting times.

2011 had some important discoveries in the world of MND research to find the answers to what causes MND. A number of MND causing gene mistakes were discovered including C9ORF72, Ubiquilin2 and SQSTM1. With these findings, we now know the cause of approximately 70% of cases of inherited MND – a massive leap from approximately 25-30% of known genetic mistakes the previous year.

Within the team, we’ve also made some promising headway toward our aims set out in our research strategy, by funding and promoting cutting edge research both within the UK and around the world. For example, our groundbreaking biomarker project led by Dr Martin Turner at Oxford yielded its second set of promising results, just three years into the five-year project. Dr Martin Turner also gave an enthralling talk at last year’s International Symposium on ALS/MND on neuroimaging (brain scanning) and he’s regarded as ‘the man’ to speak to in terms of MND neuroimaging on an international level.

As well as the research projects that we fund yielding positive results, and following progress on an international level, we’re also a major player in promoting research. The key to defeating MND lies in fostering strong collaboration between leading researchers around the world  and sharing new understanding of the disease as rapidly as possible. In 2011, we made two huge steps in this:

In January 2011, in conjunction with two leading members of the International Consortium of Stem Cell Networks (the Canadian Stem Cell Network and the UK Stem Cell Network), The New York Stem Cell Foundation and the ALS Association of the USA, we organised an MND stem cell conference. Our workshop brought together 60 of the world’s leading stem cell research experts to shape the development of future international MND stem cell research and to form new research collaborations. We were privileged to organise this event and the research community now have a solid foundation of understanding of where we are in terms of MND stem cell research. Dr Brian Dickie, our Director of Research now also has the honour of being a co-author on the scientific paper from the conference – published in the journal ALS.

In July 2011, we made a further step forward in sharing new understanding rapidly by joining a group of research-funding organisations to fund UK PubMed Central, an online research database containing over two million research articles. This is the first step in the Association’s aim to establish a comprehensive resource for the global MND research community.

We also had a fantastic year for improving the way we fund research and maintaining our high standards.

For our first grants round of the year, a record-breaking 19 full applications were considered for funding by our Biomedical Research Advisory Panel. Only one in five research applications is considered of a high enough standard for funding, but through our rigorous process we can provide our donors with the assurance that they are supporting the ‘very best of the best’ MND research.

Before our second grants round, we announced the successful launch of our online summary application form for researchers applying for grants and PhD studentships. By evolving our summary application process to use an online system, we are able to ensure that our high standards are maintained and that we are using our time efficiently and effectively to fund high-quality research.

We also proudly received our certificate for best practice for our rigorous procedures for funding research from the Association of Medical Research Charities (AMRC) in the UK with a comment saying that we are “considered as setting the standard within the audit”.

You can find out more information on the research projects we currently fund on our research we fund information sheet.

One of our highlights from last year, and the result of over a year’s work in preparation from the research team and our conference team, was the International Symposium on ALS/MND held in Sydney, Australia. We are proud to organise this vital worldwide event every year, and are pleased that last year was successful. Holding the event in different countries around the world enables us to draw new people into the international research community, bringing new ideas and expertise to the field and creating new alliances in the fight against MND.

We took you behind the scenes of last year’s symposium by writing daily blog articles on a multitude of topics. If you’ve not already read these, you can find an introduction to these with links on our blog. Please remember to complete our survey on what you thought of our reporting, as it really helps us to determine whether we should continue to report from the symposium, and whether we should change anything.

We’ve definitely set the bar in 2011 and have a lot to live up to in 2012. We’re really looking forward to see what 2012 holds for MND research, and we hope that you’ll continue to follow our progress on our blog throughout the year.

We wish you a very Happy New Year from all of us in the Research Development Team at the MND Association.

Why we need biomarkers

Yesterday’s announcement by the biotechnology company Trophos SA of the lack of effectiveness of their compound olesoxime adds to the long list of drugs that have failed to live up to their early promise in the lab.

It’s a story that’s common across the world of neurodegenerative disease, including common conditions such as Parkinson’s disease and Alzheimer’s disease. The path from bench to bedside is fraught with pitfalls….

In their press release, Trophos suggested that trials have to be conducted when the ‘window of opportunity’ is greatest – the sooner a drug is administered the better its effect is likely to be. Otherwise, we don’t know whether these treatments genuinely do not work or is it simply a case of ‘too little, too late’?

Certainly, companies such as Biogen Idec have picked up on this, restricting the time limit for inclusion in their trial of dexpramipexole to two years from symptom onset, as opposed to the three year (and sometime longer) limit that has been used in previous trials. It means that Biogen Idec has to involve more local MND clinics to recruit the numbers needed, for the trial, which increases the cost, but they view this as necessary if they are to increase the chances of a positive result.

Similarly, the way MND manifests and progresses can be so different in one individual compared to the next, meaning that trials need to recruit large numbers of participants to reduce the statistical ‘noise’ – once again increasing the already high cost and complexity of the trial.

We will only make major inroads into earlier diagnosis and more accurate predictions of how the disease will progress if we can identify biomarkers – specific biochemical and/or structural changes that occur within the brain and spinal cord that provide us with a unique ‘fingerprint’ of MND. 

Biomarkers can also be tailored to look at the effects of specific drugs in trials. Even if it is unclear whether a drug is working on the ‘outside’ (on muscle function for example) it would at least be possible to confirm it was working on the ‘inside’ by reaching the right parts of the brain and spine and acting on the correct chemical processes.

In a nutshell, biomarkers would likely lead to smaller, faster and more accurate trials. That would mean trials could be performed more cheaply – and cheaper trials would almost certainly mean more trials.

This is why the MND Association sees biomarker research as so important. We are currently supporting three clinical biomarker projects (in London, Oxford and Sheffield) which are among the most comprehensive examples of this research in the world. Without the commitment and enthusiasm of those who participate, we wouldn’t be able to create these vital research resources which, as highlighted in previous postings, are beginning to generate promising early results.

But these projects are just the start. Their findings will need to be confirmed in much larger studies, involving the collaboration of MND clinics across many countries, collecting clinical data and samples to precise scientific protocols. This was the rationale behind a major biomarker funding initiative announced earlier this year under the European Union Joint Programme in Neurodegenerative Diseases (JPND). Established by 23 European countries, the JPND Research Call invited funding bids to assist the harmonisation of biomarker collections and the development of new methods of analysing the samples.

On Friday, JPND announced the four projects shortlisted on the basis of “scientific excellence” for a share of the €15 million (approx £12.6 million) research fund. One of these projects is SOPHIA (Sampling and biomarker OPtimisation and Harmonisation In ALS).

Co-ordinated by Prof Leonard van den Berg, the SOPHIA initiative will span up to 16 centres across 12 European countries, including the MND Association’s Sheffield and Oxford Care Centres. The precise level of funding has not yet been determined, but nonetheless this provides a fantastic platform on which major international biomarker research can be developed. We will of course keep you posted once the final outcome is known.

If you were a car, would you be a Ferrari or a Focus?

People at increased risk of MND might be the human equivalent of high performance cars – built for speed and agility but becoming unreliable once they reach a high mileage.

There is much anecdotal evidence amongst MND clinicians and those affected by the disease that people who develop MND tend to have been relatively physically fit before their diagnosis, often having been involved in various athletic pursuits throughout their life. This prompted MND Association-funded researcher Dr Martin Turner to ask the intriguing question: Is an athletic physique an outward sign of a subtle predisposition to MND? But how could he make a sensible measurement of ‘athletic physique’ in order to answer such a question? Or as he put it in his presentation on Thursday morning, do people with MND have motor system run to death, or is it a motor system born to run?

A pragmatic way of looking at this was to look at the history of coronary heart disease and whether this is linked to a likelihood of developing MND later in life. Dr Turner has recently published this study in the Journal of Neurology, Neurosurgery and Psychiatry). Through very careful examination of hospital medical records, he and his colleagues compared numbers of MND cases in over a hundred thousand people with a history of coronary heart disease to an even larger group with no known heart problems.

The study did reveal a slightly increased occurrence of MND in the group with healthy hearts, providing indirect evidence that MND is more likely to occur in people with greater levels of ‘fitness’. Dr Turner’s results were in fact corroborated by the findings of another more general study of lifestyle and environmental factors presented in the same session. Dr Marc Huisman’s meticulously executed and much admired questionnaire-based study of the Dutch population also suggested that people with MND were less likely to have relatives with heart disease, indicating a more genetically robust cardiovascular system, amongst many other findings.

Dr Turner’s findings are intriguing but there is still plenty more work to do and many questions are left unanswered. There are other studies that support the possibility of an increased MND risk in people with a healthy cardiovascular system and lean build but of course these two characteristics are also a result of undertaking higher levels of exercise – the question of whether exercise itself contributes to MND still won’t go away. However, Dr Turner’s work supports the concept that if you’re born with a natural leaning towards athletic prowess, you may excel at sport (or in evolutionary terms, hunting down your dinner) but your nervous system wiring may also be more vulnerable to MND as you age – a factor that’s only become problematic with the dramatic increases in life expectancy that have come about in the last couple of hundred years.

As Dr Turner put it at one our spring conferences this year, people with MND may well come from amongst the Ferraris of the human race. With clearer identification of risk factors, prevention of MND becomes a more realistic possibility. It may be that in future the Ferraris can undertake a specialised servicing schedule to ensure they have a greater chance of breaking the 100,000 mile barrier with their electrics in good working order!

Read our official press release on day two of the symposium.

Copying, transporting and creating proteins – what could possibly go wrong?

Proteins are the building blocks of our cells and have a variety of important roles within our bodies. The instructions for how to build our proteins sit within our DNA, our genetic code in the control centre of our cells (the nucleus). There are many steps to go through from reading that ‘raw’ instruction to ending up with a fully functioning protein.
However, the amount of information held within our genetic code is so huge that only small segments of it are read and transferred to the factory floor, as and when they are needed. These copies, known as messenger RNA, are small enough to be transported to the ‘factory floor’ of the cell to large machine-like entities called ribosomes where the copy is read, and used to create the resulting protein.
When I was doing my A levels and later at University (yes, that long ago!), we were taught that only 1% of the genetic code ever made it to the factory floor. This held true until a couple of years ago. However, as explained by Professor Bob Brown in his presentation at the ‘RNA and protein processing’ session this afternoon, such is the change in our knowledge in that area, we now know that 95% of our genetic code makes it through to the first step of making proteins.
This was a key piece of context in trying to understand the role that TDP43 plays in functioning cells – never mind specifically in motor neurones or in cases of the presence of damaged TDP43 in MND!
Professor Brown, University of Massachusetts Medical School, Boston, USA went on to give an enlightening review of what has been uncovered about this fascinating protein (TDP43) so far. Once the protein of TDP43 has been correctly made, its function is to go back and ensure that other proteins are correctly made too – the so called ‘reading helpers’ of the cells, or ‘editors of instructions’. Another new fact to me from this talk was that TDP43 is involved in editing or reading up to ONE THIRD of all proteins within the cell. That’s a city fat cat type of job! So how is it all related to it’s function in MND?
Some elegant experiments have shown that TDP43 regulates how many copies of it’s own protein are made. However, the regulation takes place in the control centre of the cell (see the top of this blog). If TDP43 gets stuck or waylaid on the factory floor, it can’t get back to press the stop button in time. So it’s thought that more and more protein is made, accumulating on the factory floor until that accumulation can be seen as the protein deposits so characteristic of what you see of motor neurones affected by MND down the microscope.
Part of the editing work that TDP43 does so well is known as ‘splicing’. In true ‘Blue Peter’ style, here is a description of that process that Kelly prepared before I flew out to Sydney:

Alternative protein
One gene can hold the instructions for a number of different versions or variants of a protein. These variants are created when different parts of the gene are used in alternative combinations. This is a normal process and it’s called ‘alternative splicing’. This complicates matters in terms of genetic research, as even though we have approximately 20,000 genes, we could potentially have a much higher number of functional proteins because of alternative spliced variants.

How does alternative splicing work?
The picture (below) depicts a simple version of how a gene can be alternatively spliced, given three ‘parts’. The example demonstrates that the first version of the protein is made up of parts 1, 2 and 3, whereas version two is made up of only parts 1 and 3. These resulting proteins would go on to function in our bodies in potentially different ways. It is therefore possible for a number of different proteins to be created given one set of original instructions in the genetic code.

 

 

Read our official day one symposium press release on our website.