What goes wrong with electrical signalling in MND?

Last year, we introduced a PhD Studentship that we are funding at the University of St Andrews. Under the supervision of Dr Gareth Miles and Prof Siddharthan Chandran, the student working on this project, Amit Chouhan, is investigating why electrical signalling goes wrong in MND.

As the project enters its second year, Amit and the team have made some important discoveries… Continue reading

Using iPSCs to understand why motor neurones lose their normal function in MND

Researchers can create human motor neurones exhibiting signs of MND in the lab by taking skin cells from a person living with MND and reprogramming them into motor neurones. This is called induced pluripotent stem cell (iPSC) technology and gives an ‘in a dish’ human model of MND. iPSCs are being used by several of the researchers we fund.

GBMiles

Dr Gareth Miles

Dr Gareth Miles from the University of St Andrews, together with former PhD student Anna-Claire Devlin, has previously found that these ‘in a dish’ motor neurones lose their ability to produce an electrical nerve impulse. MND-affected motor neurones at first become overactive, and then subsequently lose their ability to produce the impulses needed to make muscles contract.

In his new project Dr Miles and PhD student Amit Chouhan, alongside Prof Siddharthan Chandran (University of Edinburgh), plans to use iPSCs to investigate why these electrical properties in nerve cells change in MND (our reference: 878-792).

The researchers will look at proteins called ‘ion channels’ that regulate the flow of electrical messages (called an action potential) which travel along the nerve cell towards the muscle. Continue reading

Using DNA Bank samples to create iPSC models of MND

Induced pluripotent stem cell (iPSC) technology has enabled researchers to create and study living human motor neurones in the lab, derived originally from patient skin cells.

DNABankLogoThis project (our reference 80-970-797) is a collaboration between the labs of Professors Chris Shaw and Jack Price at King’s College in London and Siddharthan Chandran in Edinburgh. It aims to use the already collected white blood cell samples within the UK MND DNA Bank to create a larger number of new iPSC models of MND. Ultimately creating an MND iPSC cell bank, these models will enable researchers to better understand the disease and screen potential new drugs. Continue reading

A stem cell route to the roots of MND

Nina Rzechorzek's article 'A window into brain disease is only skin deep" was shortlistedNina Rzechorzek is based at the University of Edinburgh. In 2012 Nina’s article on Prof Siddharthan Chandran’s research was shortlisted for the Access to Understanding Competition. Here she gives an update on his stem cell research.

It was a typical morning – trying to juggle experiments, trying not to make mistakes, trying hard to get results….sometimes life can be very ‘trying’ indeed… but then I’m not affected by motor neurone disease (MND) – and what a privilege it is for me to be able to rush around, to go to work and, hopefully one day, discover something that can make a difference.  I am reminded of this as I stumble out of the morning into a less ordinary afternoon – stepping away from the bench and into the world of my boss, Prof Siddharthan Chandran. Continue reading

Clinical trials in a dish?

A packed room at the 24th International Symposium on ALS/MND was given a fascinating whistle stop tour covering stem cells, robots and cellular garbage clearing, by Dr Steve Finkbeiner of the University of California, as well as a glimpse into the future of developing ‘disease in a dish’ models of MND.

Dr Finkbeiner outlined how his lab is attempting to conduct “clinical trials in a dish” by generating huge numbers of cultured neurons cells for automated ‘high throughput analysis’ of their health and death. As he says, “we’re basically trying to develop a comprehensive physical examination for nerve cells”. Continue reading

Stem cells and growth factors: from bench to bedside

After a brilliant first day at ENCALS, which included a talk by Dr Johannes Brettschneider, the second day began with a talk by Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute) arriving directly from attending at the Anne Rowling Regenerative Neurology Symposium.

Prof Svendsen gave a riveting talk to over 200 delegates, explaining his research on treating ALS (the commonest form of MND) with stem cells and growth factors, and the journey taken from bench to bedside.

The talk began with Prof Svendsen explaining his earlier research into Spinal Muscular Atrophy (SMA) – a genetic disease which causes severe paralysis in children. He explained how he and his collaborators took skin cells that had been banked for over 10 years from a patient with SMA and ‘reprogrammed’ them back into stem cells which were then pushed forward again into motor neurones. Stem cells are ‘immature’ cells, which have not yet ‘matured’ into a specific cell type (eg nerve cell or heart cell). Prof Svendsen’s research was similar to that by Prof Chandran (who did a post-doc with Prof Svendsen) who took skin cells from an MND patient.

Mo Le Cule on our stand at ENCALS

Mo Le Cule on our stand at ENCALS

A little bit of everything is good for you

Like red wine and chocolate (which are both allegedly good for us in moderation) Prof Svendsen highlighted that “a little bit of everything is good for you ” particulary with regards to radiation.

Radiation is a word that people associate with cancer and being dangerous but Prof Svendsen explained that low doses of radiation actually increases DNA repair.  Work by Dr. Seigo Hatada at the Cedars-Sinai Regenerative Medicine Institute has shown that when induced pluripotent stem (IPS) cells are given a low dose of radiation in the lab this enhances the ability to put new genes into the stem cells (homologous recombination) an important technique needed to either label the cells or correct bad mutations.   This is a very important new finding that may help the stem cell field in the future.

Ageing astrocytes

Astrocytes are support cells that are known to play an important role in keeping motor neurones healthy. SOD1 astrocytes (positive for the SOD1 MND-causing gene) were previously found to be toxic to motor neurones but TDP-43 astrocytes were found not to be toxic. Prof Svendsen showed that aged wild type (normal ‘healthy’) astrocytes were also toxic to motor neurones, suggesting that ageing of these cells may have an important role in MND.

Not only were the aged adult wild type cells toxic, they were almost as toxic  as a SOD1 astrocyte (upto 40% more than foetal wild type astrocytes)!

Astrocytes are the key

Replacing damaged motor neurones with stem cells, or healthy motor neurones, is just not possible today”. This is because motor neurones have incredibly long connections and replacing them in the body is a hard thing for researchers to do.

Prof Svendsen explained that replacing astrocytes offered a much better alternative. This is because astrocytes are easy to transplant and are sick and aged in MND. His approach, as described previously at the Anne Rowling Regenerative Neurology symposium, involves a combination of gene therapy and stem cells. Prof Svendsen converted human stem cells into astrocytes and then genetically modified them to produce large quantities of a nerve protecting factor called glial-derived neurotrophic factor (GDNF).

Genetic modification of these astrocytes was carried out by infecting them with a harmless virus. This virus then inserts a gene into the astrocyte, which enables it to produce and secrete GDNF. These modified astrocytes are then inserted into one side of the spinal cord of a SOD1 rat (expressing signs of MND). Prof Svendsen successfully showed that these astrocytes secreted GDNF and protected the motor neurones in the rat at the side of the transplant.

Prof Svendsen explained that the modified astrocytes do not seem to cross to the other side of the spinal cord and are only a ‘partial protection mode’ which means they don’t affect paralysis. They do, however, protect the healthy motor neurones. It is important to note that these experiments used the SOD1 rat model. Only 20% of inherited MND cases have the SOD1 MND-causing gene so this model is not a complete representation of other inherited and sporadic MND cases.   It is now important to try these exciting new stem cell and growth factor treatments directly in patients – they are the only real representation of the disease.

A phase I clinical trial after twelve years of research

Prof Svendsen concluded his talk by mentioning that with funding from the California Institute for Regenerative Medicine (CIRM) he is seeking U.S Food and Drug Administration (FDA) approval for a phase I/IIa clinical trial, which aims to transplant these genetically modified astrocytes into the lumbar (lower) spinal cord of ALS patients.

This trial plans to begin in 2015 by transplanting the GDNF secreting astrocytes into one side of the spinal cord to see the effects on the patient’s legs. Because, the astrocytes can’t cross the spinal cord, this will mean that the researchers will be able to compare both legs to look for differences in disease progression. The trial is double-blinded (with only the surgeon knowing which side the astrocytes are transplanted) and is across three centers in America. Prof Svendsen mentioned that he is on track for the first patient in 2015 providing the safety studies in animals work out as planned.

Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute)

Thierry Latran Speaker Prof Clive Svendsen (Director of the Cedars-Sinai Regenerative Medicine Institute)

Prof Svendsen stressed that this has been a long road and shows just how long it takes to go from making observations in the lab to a clinical trial (he started this work back in 2003).

What next?

Prof Svendsen’s research has shown a great deal of work; including how he converted stem cells into astrocytes, showed that aged wild type and SOD1 astrocytes are toxic to motor neurones, found that GDNF prevented motor neurone death and the start of his clinical trial in 2015.

Prof Sevndsen commented on what the future might be. “If this therapy is found to be effective in ALS patients during this phase I/IIa trial we plan a much bigger trial!! We would aim to move from protecting the legs to protecting respiration – as we have shown the cells can work there too.”

Finally, Prof Svendsen stated what this research means to people living with MND with two simple words. “New hope”

Prof Siddharthan Chandran talks about the recipe for stem cell success at our Annual Conference

Neural progenitor cells, courtesy of Chandran lab, University of Edinburgh

Neural Progenitor cells, courtesy of Prof Chandran lab, University of Edinburgh

We invited Prof Siddharthan Chandran to be our keynote speaker at our Annual Conference and below we’ve provided a brief overview of his presentation which we hope you’ll find useful as either a recap if you attended or as an insight into MND and stem cells if you couldn’t make it on the day.

About Prof Chandran

Prof Chandran is Professor of Neurology at the University of Edinburgh and Director of the Euan MacDonald Centre for MND Research which is based at the university. He is leading the Association’s largest stem cell research programme which pulls together world-class researchers from leading institutes in Edinburgh, London and New York. Working together, the international research teams are manipulating stem cells to provide a unique tool for studying MND and developing new drugs. It’s research programmes like this, that really demonstrate our role as a leader in funding and promoting cutting-edge MND research. Naturally we were only too pleased to introduce Prof Chandran to our conference delegates.

Origins of understanding the power of stem cells

Prof Chandran began his talk on a mythological level with the story of Prometheus, who was punished by the Greek God Zeus by being chained to a rock and having his liver eaten daily by an eagle, only to have it grow back the next day to endure the torture again. Not a very nice story, but Prof Chandran went on to explain that through this myth, the Greeks had stumbled onto the origins of understanding the nature of stem cells. The liver is one of the only solid organs that we have that has the power to regenerate itself when damaged. Although this wasn’t the moral of the myth, it’s still an important historical reference that demonstrates that the potential of stem cells as a regenerative tool is not a new concept.

From science fiction to science fact

If Prof Chandran, while at university, had suggested that in the future it would be possible to create stem cells from a skin sample, he said that he would have been ridiculed and the idea would’ve been seen as pure science fiction. Yet here we are, now living in ‘the future’ and this technology is a reality, the newest finding of which was the discovery of stem cell-like cells called ‘induced pleuripotent stem cells’ (or iPS cells for short) in 2008 by a Japanese research group. By delivering a cocktail of chemicals to skin cells donated by a living person, they were able to turn back the clock of the skin cells to turn them into iPS cells. This finding is now the cornerstone of many new stem cell research projects, which has arguably revolutionised the field.

Future treatment potential, but currently regeneration is impractical

There are many ways that stem cells could be used in the future to treat MND, but using them to regenerate motor neurones is not currently a practical solution. But why isn’t this practical? In his talk, Prof Chandran explained…

Crossing wires

The brain is a very complex organ and can be related to a ball of wiring, with each wire being linked to a specific place within the brain and body. If this were to be wired up inaccurately, then it would cause pandemonium in our bodies, with movement instructions meant for our feet to possibly end in our hands, mouth or elbow for example – something we’d definitely not want to happen!

Prof Chandran went onto explain that each neurone has its own ‘postcode’ in the brain, and depending on where it ‘lives’, he explained that its function will vary.

The function of each motor neurone will also intuitively denote what muscle it’s supposed to connect to. The way that our neurones grow toward a muscle is an extremely well orchestrated affair, with chemical messages throughout the body that either attract, or repulse it. However, as our bodies develop in the womb, this system is switched off – meaning that any new motor neurones trying to grow from scratch in the brain will find it near to impossible to know where it’s supposed to go.

It is therefore a very complicated issue to try and regenerate motor neurones in humans to ensure that the motor neurone firstly starts in the right place, and secondly that the neurone has the right instructions in place to guide it toward its target muscle.  However, these aren’t the only issues that researchers face…

Being sure it’s a motor neurone

In our search for using stem cells as a treatment for MND, there is also an issue of making sure that stem cells turn into the cells you want them to be, and Prof Chandran eloquently explained this by using a video of heart cells, generated using stem cell technology and saying that you definitely wouldn’t want these cells beating away in your brain instead of your motor neurones!

But how do researchers turn stem cells into the ‘right’ sort of cell? Prof Chandran explained that this is done quite simply, by giving them the right recipe of chemical ingredients to tell them what to become when they’re older.

Neurones are slow growers

Even if researchers could somehow ensure that ‘new’ motor neurones could be created and would connect to the right ‘postcode’ of the brain, neurones are very slow growing. As some of our motor neurones would have to grow over a metre to reach its target muscle, the amount of time that it would take to regenerate motor neurones would be implausible in terms of using them as a treatment. There just isn’t a way to speed this up at the moment.

For all of the above reasons, this is why stem cells cannot currently be used to regenerate motor neurones as a treatment for MND. However, this is not to say that they don’t have other uses…

Using stem cells to learn more about MND

Stem cells are great tools for recreating diseases in a dish, as they are able to divide to create large numbers of cells and are able to turn (with the right receipe) into any type of cell, such as a motor neurones.

In his laboratory, Prof Chandran’s research group have created living human motor neurones grown in a dish from skin cells donated by people with an inherited form of MND using iPS cell technology. In his presentation, he showed us that within 100 days, his laboratory is able to create a billion (1012, referred to as a trillion in USA) cells from a stem cell. He has also shown that these motor neurones generated from stem cells connect to muscle cells and are electrically active – which means that to all intents and purposes, they are real motor neurones.

He then explained that his MND Association funded project is creating these motor neurones and support cells from a skin biopsy of somebody with MND with faults in a gene called TDP-43. They can then use these new cells as a tool to investigate the disease process and hopefully in the future to test the effectiveness of therapies in this model.

Realising the potential of stem cells

As well as using stem cells to create new models in the laboratory, to discover new medicines, stem cells could potentially be used in a different way to treat the disease. These treatments would not aim to regenerate the motor neurones, but instead would attempt to slow down, or even stop the disease.

Realistically, researchers could use neurone support cells to provide a protective environment to lasting motor neurones – in fact, there are plans in place to test such a treatment which is estimated to being enrolling in 2014 (see stem cell conference blog article for more information).

Overall, Prof Chandran’s talk was extremely well received with delegates commenting to us that “Prof Chandran was the best speaker I can recall” and Prof Chandran’s talk was: “clear, hopeful, excellent. He inspired confidence and spoke in language I could understand”

We’re pleased that so many people who attended our AGM and Annual Conference enjoyed Prof Chandran’s talk, with 91.2% of delegates saying that it was “excellent” (from our survey of 57 people who attended).

Find out more about stem cells on our website.

Stay up-to-date with news on our next conferences by following our conference team on Twitter @mndconference

Stem cell conference part two: How are motor neurones created from stem cells?

Creating motor neurones for research is a lengthy and expensive process, so Prof Kevin Eggan from Harvard University  Massachusetts, asked whether we can predict at an early stage which stem cell lines will be the most useful in generating the best quantities of motor neurones, saving time, effort and money. He has been developing a ‘scorecard’ which he believes will help work out which cell lines are most useful.

But if you make motor neurones from skin cells, are they really motor neurones? At the moment there is no consensus on what makes a neurone a motor neurone, so Prof Eggan outlined a series of tests used in his lab that “provide confidence that these have more than a passing resemblance to motor neurones”. Additional encouraging results suggest that motor neurones created from ‘adult’ iPS cells are “pretty indistinguishable from those obtained from embryonic stem cells”. There are some differences, so comparative work using both types will need to continue for the forseeable future.

Prof Siddharthan Chandran, MND Association funded researcher at Edinburgh University then posed the question: “Do they reflect the different types of motor neurone found in the human body? There is no such thing as a ‘generic’ motor neurone, each one has its own postcode.”

So, can stem cell-derived motor neurones reflect the diversity of subtypes found in the human body? For example, the motor neurones that control eye movement are much more resistant to the disease than other motor neurone types, and motor neurone controlling limb muscles can behave differently from those controlling the trunk muscles.

The answer is preliminary, but encouraging.

Prof Hynek Wichterle, from the Columbia University New York, presented research showing that embryonic stem cells can be turned into different subtypes of motor neurone and Prof Chandran has been working on the same issue using iPS cells.

There is a lot of work to do, but having human motor neurones in a dish that faithfully reflect the diversity of types found in the body will greatly assist understanding of MND and may also help in identifying potential drugs that might target highly vulnerable motor neurone populations in patients with different clinical patterns of disease.

Mixing with the media

Brian with Profs Chandran and Wilmut

It’s Friday afternoon and I’m just back from a press briefing in London, where we were unveiling an exciting new stem cell research programme. I’ve just realised that we’ve put a press embargo on until Monday, so this won’t be posted until Monday morning – otherwise I’ll be breaking our own embargo…..

The press briefing was held in the Science Media Centre  . The SMC plays a vital role in bringing scientists and the media together, to assist with the accuracy of reporting of scientific issues in the public eye. We’ve developed a very good relationship with them, having held several press conferences at the SMC offices over the years. They were having a frenetic time of it this morning – not only were they setting up our press conference, but they were also dealing with the story of Craig Ventner creating a ‘man-made’ bacterium, which was all over the papers (“Dr God creates artificial life in lab”, was the none-too subtle heading in my morning paper).

‘Dr God’ probably had an impact on the number of journalists in attendance, as many were still out and about following up other reporting angles, but we still managed to attract quite a few of the top science correspondents from TV and radio (BBC, Channel 4) newspapers (Telegraph, Times, Daily Mail) medical press (BMJ) as well as the Press Association (which ensures that the story will go out on the newswire).

By the time I arrived, two of the researchers involved in the project (Prof Siddarthan Chandran and Prof Ian Wilmut from Edinburgh University) were already there. It was straight into the press briefing, where Siddarthan led off by setting out the background to the research programme, for the assembled reporters. Recent advances in stem cell research mean that researchers are now able to model human MND in the lab. Siddarthan explained the promise that research using induced pluripotential stem cells holds for advancing our understanding of MND and for developing methods for the efficient screening potential therapeutic compounds. This is a field that is moving quickly – less than a couple of years ago, the idea that a skin cell could be turned back into a stem cell and then into a motor neuron, would have graced the pages of a Sci-Fi magazine rather than a medical journal.

Prof Ian Wilmut explained in more detail how the stem cells are created in the Edinburgh lab and I followed up by outlining how the other research teams in this initiative, led by Prof Chris Shaw (King’s College London) and Prof Tom Maniatis (Columbia University, New York) would analyse how the cells react under healthy conditions and also under conditions that mimic the damaging cellular environment that occurs in the brain and spine of people with MND. A key message that all three of us put across the importance of international collaboration – if we are going to crack this disease, we have to ensure that the best researchers in the world are working together on the big questions.

You could tell it was a collection of science reporters in the room by the high percentage of intelligent questions – not something you always get when discussing science with the media. Hopefully this press briefing will be the first of many as this and complementary MND research programmes around the world, start to gather pace.

PS – Monday morning. Quite a bit of press coverage, some accurate (well done The Scotsman!) some not quite on the button, but all helping to raise awareness of MND!