The cell that never grew up

With Pantomime season kicking off back home in the UK, delegates in Milan were introduced to one of the newest cellular villains in the MND story – oligodendrocytes.

Although oligodendrocytes were first identified in the 1920s and are known to be affected in multiple sclerosis, they were generally considered as ‘bit part’ players in MND rather than ‘centre stage’.

All that has started to change in the past couple of years, with researchers in the USA and Belgium independently showing that, in both SOD1 mice and human post mortem MND brain tissue, the brain was making new oligodendrocytes to replace ones that appeared to be dying off.  The problem is that the new ones being formed appear to get stuck in an immature state and therefore do not perform their role of helping motor neurons to maintain appropriate energy levels and also send electrical signals down their long nerve fibres.

So, by getting stuck in a ‘Peter Pan’ scenario of never growing up, oligodendrocytes may be at best, unable to help protect the death of motor neurons or, at worst, they may actually contribute to the degeneration. Peter Pan rather than Captain Hook as the pantomime villain is a novel twist to the script!

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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”

Anne Rowling Regenerative Neurology Symposium

The sun was (uncharacteristically!) shining on Edinburgh last week for a symposium to celebrate the launch of the new Anne Rowling Regenerative Neurology Clinic. The clinic, which opened to patients earlier this year, was founded following a donation by the author JK Rowling, in memory of her mother, who died from complications related to multiple sclerosis (MS).  Run by Professors Siddarthan Chandran and Charles ffench-Constant, the clinic aims to translate laboratory research into clinical trials for neurodegenerative diseases such as MS and MND.

Anne rowling logo

The programme for the two-day meeting was packed with ‘big hitters’ from the world of neurology. In keeping with the regenerative neurology theme, the opening session was chaired by Sir John Gurdon, recent co-winner of the Nobel Prize for physiology and Medicine, whose pioneering work on cell cloning set the foundations for the more recent development of induced pluripotential stem cells, which are currently revolutionising medical research.

Different diseases, common challenges

The first day was given over to research areas such as multiple sclerosis, Parkinson’s disease and Alzheimer’s disease, as well as spinal injury and pain. What was also apparent is that different fields of neurology are wrestling with similar challenges: to diagnose disease earlier, ideally even before symptoms occur; to find biomarkers that tell us about the changes occurring in the Central Nervous System(CNS) at different stages of disease; to really understand the order in which these different aspects of pathology (the study and diagnosis of disease) occur and, given the theme of the conference, to sift the cellular changes caused by disease from the body’s attempts at cellular repair. All of these feed into the greatest challenge – how to take this accumulated knowledge from bench to bedside.

We can learn a lot from diseases that are further ahead in this process, such as the excellent overview by Prof Alastair Compston (Cambridge) on MS. It’s becoming clear that MS has distinct disease stages, starting off as an inflammatory disease, but progressing to a more ‘traditional’ neurodegenerative disease in more advanced stages. Whist there has been some considerable success in treating the former, the approaches to the latter have, as with MND, met with very limited success.

The use of imaging techniques to work out what is happening within the brain has been a vital factor in drug development for MS. As Prof David Miller (University College London) pointed out, magnetic resonance imaging (MRI) can pick up positive changes in small MS drug trials that are not large enough to show changes in disability. This sort of biomarker-based evidence gives drug companies the confidence to invest in the larger, much more expensive trials needed to show a clinical effect.

A presentation on the imaging of pain by Prof Irene Tracey (Oxford) provided a fascinating insight into the power of the placebo effect. She explained how neuroimaging has helped researchers to identify the brain regions associated with placebo effects and also gave examples of studies where the placebo effect has performed as well as (and even outperformed) commonly used painkillers! The power of placebo can be very strong indeed and it is important to always ensure that trials are rigorously performed to account for this.

Parkinson’s disease has always been viewed as a promising candidate for cell transplantation therapy, but clinical studies over the past 30 years have produced mixed results. Profs Roger Barker (Cambridge) and Anders Bjorklund (Lund University) discussed the various reasons for this ‘heterogeneity of response’ and how these are being addressed in the plans for a pan-European study.

In terms of cell transplantation, the approaches that will need to be taken for MND are very different from those for Parkinson’s disease. In Parkinson’s disease the strategy is to try and replace some of the key neurons that have died, but due to the immense length of human motor neurons, such a strategy of rewiring the nervous system is highly unlikely to work for MND. However, there are other approaches that can be taken, as Prof Clive Svendsen (Cedars-Sinai Medical Center) explained.

His approach involves a combination of gene therapy and stem cell therapy. By converting human stem cells into astrocytes, which are cells known to play an important role in keeping neurons healthy. By genetically modifying these cells to produce large quantities of a nerve protecting factor called glial-derived neurotrophic factor, and injecting them into the spinal cord of SOD1 rats, he has shown that the surviving motor neurons can be protected. He is in the process of gearing up for a phase 1 therapeutic trial in up to 18 carefully selected MND patients.neuron

Disease in the dish

Prof Svendsen also briefly spoke about the promising research arising from the use of induced pluripotential stem cells (iPSCs) to study MND – a topic taken up in much more detail by Prof Jeff Rothstein (Johns Hopkins University) who highlighted recent advances in understanding the C9orf72 form of the disease.

It may be possible to create specially tailored gene therapy approaches for some forms of familial (inherited) MND, as is currently being attempted in SOD1 MND. Prof Rothstein’s initial work using iPSC-derived motor neurons suggests that this approach is also worth considering for the more common C9orf72 from as well.

Prof Steve Finkbeiner (University of California) who is collaborating in the Association-funded international stem cell initiative elaborated on the use of iPSCs as a tool for drug discovery, demonstrating how fully-automated robot-based systems can be used to follow the fate of thousands of individual human motor neurons in the dish over a prolonged time period. The great thing about robots is that they don’t need sleep, so can analyse the cells at all times of day and night. They do, however, have Twitter accounts, so they can report in to the centre staff when they have completed their experiments!

One of the exiting prospects of using these automated systems is the potential to screen thousands of compounds. If human motor neurons can be protected in the dish, there are no guarantees, but it at least shortens the odds that the human motor neurons can be protected in the human as well. There are still many improvements that can be made to the process, but screening work is underway, with a particular focus on drugs that stimulate cellular process called autophagy (a process in which a cell breaks down damaged components), which is believed to be protective across a number of neurodegenerative diseases.

There were many take home messages from this meeting, but what was abundantly clear from all the work presented was the enthusiasm of each speaker for their field of research and an optimism that we are on the cusp of major advances in understanding neurological conditions. Sharing of new knowledge across the various diseases and disciplines can only bring those advances closer.

Changing fashions of MND models

Models of MND are important both to understand the causes of MND and to quickly, efficiently and accurately screen and develop new treatments for it.

A number of key developments both in terms of technological know-how and new understanding of genetics of MND have led to the development of new models discussed at on the last day of the symposium.

Stem cells
The session was opened with a presentation on what is arguably the most glittering and exciting of these new models, that of using so called ‘iPS’ cells. The principle behind iPS cells (induced pluripotent stem cells to give them their full name), is that it’s possible to take a skin cell from someone with MND, coax it back into basic stem-cell-like state and then change it into motor neurones. The idea that this was even possible was scientific heresy say five years ago. The beauty of this technique is that you then have living human motor neurones in dish in the laboratory.

Dr Kevin Eggan from Harvard University Massachusetts USA is one of the leading lights in this technology and he treated us to an update of his latest research. “In itself, ALS is an interesting test tube for stem cell research” he said, adding “this is my first ALS meeting, I’ve enjoyed it and learnt a lot”. Aswell as being the first time that it was possible to study the cells directly affected in MND (motor neurones), iPS techniques also allow researchers to study the behaviour of motor neurones at as close to the actual disease conditions as possible.

Are they really motor neurones?
In the first part of this talk Dr Eggan explained and demonstrated that the cells that he and his colleagues have grown really are motor neurone-like and that they do behave like motor neurones. However he did caution that this model is not the panacea of ALS models, it’s an arrow in a quiver of techniques.

How do these motor neurones behave?
The second half of his talk concentrated on whether these human motor neurone models behave differently to motor neurones grown from skin cells of unaffected people.

When given the same growing conditions, motor neurones derived from people with SOD1 mistakes (mutations) were found to be less plentiful when growing ‘in a dish’ than those derived from healthy individuals. The SOD1 motor neurones also display a different pattern of electrical activity (transmitting electrical activity, is, after all, one of the main functions of motor neurones). The next steps of this research will be to double check that the effects seen in cells with SOD1 mutations really are due to this faulty gene and investigate the effects of other known genetic causes of MND in these cells.

Of mice and men
Moving from a new model to an old and arguably less fashionable one, Dr Greg Cox was given the title of “Are mice a good model for human ALS”. His first slide was to turn this question on its head and state that humans are a terrible model for mouse ALS! His point was that there are so many things that are unknown in human MND that generating a truly accurate mouse model for it was an almost impossible task. Saying this, he went on to discuss three key essentials for any mouse model, so called face, construct and predictive validity. Towards the end of his presentation he shared some results of one of this own studies, explaining that there is an area of our genetic code, not identified in MND before, that seems to carry a mistake that causes symptoms of MND.

Read our press release from day three of the symposium.

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!