Have your say on emerging technologies

The Nuffield Council on Bioethics are currently asking for views on a number of technologies that people affected by MND may have a view on. They are seeking views on both the medical and non-medical applications of neural stem cell therapy, brain computer interfaces, deep brain stimulation and transcranial magnetic stimulation.

 To find out how to take part you can visit their website and download a Word document. This gives you explanations of each technology, followed by a series of questions about your thoughts on how it is and should be used and regulated. You can choose whether to give your name or whether to submit your answers anonymously. Responses must be received by the Nuffield Council by Friday 23 April.

A quick peruse of the posters

Sometimes, presenters’ reactions to hearing that they’ve been given a poster presentation, rather than a talk is that of disappointment. I disagree. I feel it is a great opportunity to have a more in depth two way discussion than is ever possible during the 2-3 minutes allocated to questions after a talk.

There are over 200 posters being presented at this International Symposium. Before heading anywhere near the room where they’re on display I mark off a selection of posters to visit. Sometimes they are topics I know something about, or people that I know – for example MND Association grantees, or I sometimes choose topics that I don’t know anything about – the latter to find just what they are about. In one blog post (and the time available to write it) I can’t do justice to the topics that I did learn more about, but here is a bit of a taster:

Split hand wasting – this definitely fell into the latter category above! Two posters reported on how two quite closely connected muscles in your hand waste at different rates in people with MND. (The muscle groups are the thenar muscles and the abductor digiti minimum in case you want to look them up). Parvathi Menon’s poster established that it may be possible to use the ratio of the two different muscles as a way to diagnose MND and as a possible biomarker. Jocelyn Zwicker’s study investigated the electrophysiological nature of this observation.

Early conclusions from Neuralstem safety clinical trial included: Injections in the lumbar section of the spinal cord are well tolerated by people with MND are various disease stages. Participants experienced significant discomfort from the stomach / GI effects of the immunosuppressant drugs they received. Permission has been given by the FDA to advance the trial to cervical sections of the spinal cord, neuroprotection at this level may help with diaphragm function.

Does riluzole have an affect on Dexpramipexole?: Using the results from the previous, phase II, clinical trial for dexpramipexole, the authors described how the use of riluzole and dexpramipexole neither adds to, nor takes away from the effect of dexpramipexole on survival or progression. They conclude that it would be useful to confirm this in the phase III clinical trial currently underway across multiple sites across the world.

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

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

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

Read all about the New York Stem Cell Conference

 ….or at least, read even more about it!  

Back in January, we reported that sixty of the world’s leading stem cell research experts from 14 countries were brought together for the first time to shape the development of future international MND stem cell research.

The two-day conference in New York – organised by the MND Association in conjunction with the UK National Stem Cell Network; the Canadian Stem Cell Network; the New York Stem Cell Foundation; and the ALS Association of the USA (ALSA) – brought leading stem cell experts together under one roof in order to agree key areas of investigation in this exciting field of MND research.

You can catch up with what our director of research, Dr Brian Dickie said about the conference in seven Stem Cell Workshop blog posts. 

If you felt that Brian’s daily blogs from the beginning of the year weren’t enough, a more comprehensive report has just been published in the journal Amyotrophic Lateral Sclerosis, of which Brian is a co-author. The journal publishers have also kindly given permission for a version of the report to be available online, which can be downloaded from the ALS Association’s website.

The published report on the ALS Association’s website is not written in plain-english as it provides a thorough assessment of the ‘state of affairs’ of MND stem cell research for scientists – you may find it interesting none-the-less!

New unproven stem cell treatment via IV and mannitol causes concern

We have been made aware that there’s a new kid on the block in terms of unproven treatments, which is a new route of administration of stem cells at the X-Cell stem cell clinic based in Germany.

As a brief background of the story to date, last year, a group of international researchers collectively known as ALSUntangled investigated the claims of X-Cell.

ALSUntangled wrote, and published an article (in the journal ALS) on the X-Cell clinic which concluded that until they demonstrate the safety and effectiveness of their stem cell treatment through a rigorous clinical trial that they would not condone X-Cell centre’s protocol for people living with MND. We wrote about this in our ‘X-Cell Stem Cell Centre has been investigated by ALSUntangled’ blog article.

X-Cell has now adapted their strategy to use intravenous (IV) administration for stem cells, meaning that the cells are delivered into a vein in the arm rather than via surgery on the brain or spine. X-Cell claim that they are able to use this new, far less invasive route of administration because they also give patients IV mannitol to help the stem cells gain access to the central nervous system. Mannitol is a drug used to draw water out of the brain in cases of cerebral oedema (swelling of the brain). There has been research into mannitol use to ‘open’ the blood brain barrier for chemotherapy to improve delivery of drugs to tumors in the brain. However, there is a big difference in trying to get a reasonably small chemical through the blood brain barrier – which in real life terms is like a sieve from the blood through to the brain, and trying to get comparatively huge stem cells through the blood-brain barrier. Unless research is published to demonstrate that this is possible, then it is an unproven method.

We are aware that unproven treatments can seem attractive to people affected by MND given the lack of a treatment. However, they often come at a large cost and have not demonstrated their effectiveness in rigorous clinical trials. To find out more about what makes a good clinical trial, visit our website: ‘what makes a good clinical trial’, or ‘unproven treatments’.

If you are considering an unproven treatment and would like to know the facts about the information they provide, please contact us at research@mndassociation.org. We provide the facts so that people affected by MND can make up their own minds about whether it’s an option they would like to consider.

*Updated – the X-Cell centre has now been closed due to the German Government tightening the loophole that allowed the centre to offer unproven stem cell treatments.

Painting the way to new motor neurones from stem cells

A study led by MND Association funded researcher Prof Siddharthan Chandran from the University of Edinburgh has developed a new method to create a diverse group of motor neurones from stem cells. The research, published in the journal Nature Communications could be used to create more accurate and clinically relevant laboratory dish models to learn more about the differences in vulnerability and connectivity of motor neurones in MND.

 Why are the subtypes of motor neurones important to MND research?
When we first start to develop as embryos in the womb, chemical messages are used as cues to tell our cells what to turn in to. At the start of this process our cells can be thought of as blank canvases that have the potential to turn into any type of cell. Mixtures of ‘colourful’ chemicals are then used to create a unique ‘hue’ signal in order for the cell to know what to become.

So, depending on the ‘hue’ of chemicals around them, neuronal precursor cells will turn into different subtypes of motor neurone. In their fully formed state, these motor neurones subtly vary in their chemical makeup (due to acting on the different ‘hue’ signals given), their vulnerability to degenerate in MND, as well as the way they connect and communicate with other cells.

The subtle differences in subtypes of motor neurone have not been replicated in a laboratory dish model of MND to date. However, being able to develop such a model would provide MND researchers with a true spectrum of the way that MND affects the different subtypes of motor neurones. They would then also be able to develop new and better treatments that can target specific types of motor neurones that may be more vulnerable to MND.

What did the researchers do to find this?
The collaborative research group from Universities of Edinburgh, Cardiff and Cambridge tested a new method for creating different types of motor neurones in a dish from human embryonic stem cells.

To do this, they first added a chemical that accelerates the process of turning stem cells into neurone precursor cells – it’s the equivalent of being able to add a ‘quick drying’ additive to a painting. By adding this chemical, which has been given the catchy name of SB431542, the process of changing an embryonic stem cell into motor neurone progenitor cells is sped up from approximately 30 days to just 12 days.

They then tested whether a certain chemical called ‘retinoic acid’ is needed for the process of making different types of motor neurone. By measuring the chemical makeup of the functional motor neurones produced without retinoic acid, they were able to determine that they had produced a different type of motor neurone that is different from those created with the use of retinoic acid.

What’s next?
By defining a new process to create new and better models using stem cell technology, a new multi-motor neurone type model could be created for MND to study the similarities and differences between motor neurones in MND.

By learning more about these differences, we could learn more about how and why some motor neurones remain spared in MND.

To find out more about the future of stem cell research, please read Dr Brian Dickie’s account of the recent stem cell conference. Or, download a copy of our stem cell information sheet.

Journal Reference: Patani, R. et al. Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state. Nat. Commun. 2:214 doi: 10.1038/ncomms1216 (2011).

Stem cell conference part seven: Creating new and better models for MND

It was then back to the science. Prof Frank Soldner (Massachusetts Institute of Technology) provided an overview of a new and exciting way in which MND-causing genes can be introduced into human embryonic stem cells in order to study the disease. Traditional gene transfection techniques are rather uncontrolled, resulting in multiple copies of the gene being introduced in random parts of the human genome – both of which can affect normal cellular functioning. A new genome-editing technique allows the existing ‘normal’ gene within the stem cells to be converted directly into a ‘mutant’ gene, which should result in the creation of stem cell-derived motor neurones that are much more representative of those in the patient.

Of course, the other way of getting to this point is not to use embryonic stem cells, but instead to use induced pleuripotent stem (iPS) cells, generated from skin samples taken from inherited ALS patients with a known gene mutation. Prof Jeff Rothstein (Johns Hopkins University) provided an update on the US National ALS Cell Bank which to date has produced 30 iPS cell lines from patients with various known MND gene mutations. He stressed the need for a large number of well characterised  cells to be made available to the research community, as each one will be slightly different, putting it very succinctly with the statement: “You need more than one ‘human’ to test a hypothesis or a compound.”

The National ALS Cell Bank will create both motor neurones and a type of neurone support cell called ‘astrocytes’ from each iPS cell line.

We know very little about the different subtypes of astrocytes that are present in the central nervous system – we know that brain astrocytes are different from those in the spinal cord. Both Prof Rothstein and Prof Su-Chun Zhang (University of Wisconsin) highlighted recent research showing that there are marked ‘regional differences’ within the spinal cord itself.

Using different ‘cues’ Prof Zhang is able to develop subtypes of astrocytes similar to those found in different parts of the spinal cord. This information may be very important in understanding why the disease progresses so differently between one person and the next. As the emerging stem cell trials in MND are based on replacing and improving the astrocyte populations in the spinal cord, it is also likely to be important in maximising the chances of success in altering disease progression, by ensuring the stem cells turn into the right type of astrocyte, best able to support motor neurones around the site of injection.

Stem cell conference part six: unregulated treatments

The room was crowded at 8am for the first presentation of day two, from Dr Doug Sipp (RIKEN Institute, Japan) on ‘Unregulated ALS/MND treatments and public education’.  Dr Sipp provided an insightful and entertaining overview of the plethora of self-styled stem cell ‘clinics’ and the tactics they employ to attract business. During the talk, the song Snake Oil, by the country singer Steve Earle, kept going round my head…. 

“Ladies and gentlemen, attention please
Come in close so everyone can see
I got a tale to tell
A listen don’t cost a dime
And if you believe that, we’re gonna get along just fine….”

Time was given over for a discussion on the issue of unregulated treatments, moderated by Dr Rick Bedlack (Duke University) and involving myself and Steven Byer of the US charity ALS Worldwide. Dr Bedlack is one of the founders of ALSUntangled, a consortium of ALS clinicians that used the Internet and social media to investigate alternative and off-label ALS treatments. Although in its early stages of development, ALSUntangled is fast becoming a very important resource to people with MND, providing the sort of objective information that helps people to come to an informed choice on whether or not to pursue alternative approaches to treating their disease.

There was clear consensus among those in the room that clinicians, scientists and patient associations need to find mechanisms for working more closely together – in separating ‘hope from hype’ and providing a more accurate explanation of the potential uses of stem cells in both basic science and disease treatment. Stephen Byer talked about the two C’s: the need for closer Collaboration and sharing of information; and better methods of Communication. I added a third – Consistency – to the discussion. We don’t necessarily all need to be providing exactly the same message, as different individuals and organisations we may well have differing opinions, but we should be basing those opinions on the same level of information and understanding.

Stem cell conference part five: safety first for current human stem cell trials

One human neural stem cell line that has cleared the US Government’s regulatory hurdles is that developed by the biotechnology company Neuralstem. To date, nine patients have received implants of these cells with few complications reported. Two of the clinicians leading the study at Emory University, neurologist Jonathan Glass and neurosurgeon Nick Boulis, outlined the system that has been developed to ensure extremely accurate implantation into the spinal cord. Both clinicians stressed the importance of safety – the spinal surgery procedure was constantly tested, evaluated and refined, along with the creation of clear ‘stopping criteria’ during the three-hour period of surgery. In this trial, the central tenet of the hippocratic oath – primum non nocere (first, do no harm) – is taken very seriously indeed.

 

Daniel Offen, a representative from the Israeli company, Brainstorm, presented the strategy for their planned clinical studies using patients’ own stem cells from bone marrow (so called ‘mesenchymal’ stem cells), which have been modified to become more-‘astrocyte-like’ and have also been demonstrated to secrete neurotrophic factors.  

These cells will be administered by intrathecal or intramuscular injection. It is important to reiterate that the above preclinical and clinical studies mentioned above are not trying to create new motor neurones to ‘re-wire’ the nervous system.  Instead, the aim is to provide the surviving motor neurones with a supportive environment to try and fight off whatever is causing them to become damaged. It is also important to stress that the primary outcome of these early studies is to ensure the implants are safe.

 

Of course, implantation of mesenchymal stem cells have been tested before – albeit, not in the modified form that Brainstorm has developed. Dr Letizia Mazzini from University of Novara Italy has experience of performing such studies and has published her research in medial journals over the past few years. There have been no serious adverse events in the short or long-term related to the technique. Unfortunately, there was no strong evidence of any beneficial effect and it is not clear whether the cells actually survived long-term, once implanted. 

By 7pm, the presentations for Day 1 drew to a close, but a few glasses of wine in the next room ensured continued discussion. My brain was suffering from information overload…

 

And we still had another day to go…..

Stem cell conference part four: Laying the foundations for future stem cell clinical trials

The remainder of the morning covered some of the preclinical research that has laid the foundations for current and forthcoming clinicalstudies. Prof Clive Svendsen, from University Wisconsin-Madison, gave an overview of the strategy that helped lay the foundations for the current Neuralstem trial. This strategy involves the implantation of support cells (astrocytes) into the spinal cord. These astrocytes produce important nourishing (neurotrophic) factors that are essential to maintain the health of neurones. The strategy therefore is not about rewiring the nervous system, but instead providing the surviving motor neurones with a ‘boost’ to aid their survival.

He stressed the need for long and detailed study of the astrocyte cell lines if they are to be seriously considered as candidates for transplantation studies, using the comment “rubbish in, rubbish out”. He also provided very useful cautionary information in that some of the human cell lines show a tendency towards developing genetic changes over time, reminiscent of some types of tumours. By careful characterisation of the cell lines, his team was able to select only cells that demonstrated they were extremely stable. He has grafted these cells into the spinal cords of SOD1 rats, which does indeed help to protect the motor neurones.

However, it does not markedly alter the survival of the animals, probably due to the fact that the implanted cells can take months to mature into functional astrocytes, plus the fact that the motor neurones were still drawing back from the muscles and losing their connection. He is therefore looking at a ‘two-pronged attack’, treating both ends of the motor neurone through astrocyte implantation into the spinal cord, combined with nerve growth factor injections into the muscle.

Why stem cells derived astrocytes?
Astrocytes vastly outnumber neurones in the brain and spine: they are the cells that make up most of the ‘cellular neighbourhood’ and it is believed that in diseases such as MND, that neighbourhood is toxic to motor neurones. Prof Don Cleveland from University of California San Diego believes that if healthier, correctly functioning, astrocytes can be implanted into the spinal cord, it could turn the cellular neighbourhood into one that will protect the motor neurones and alter disease progression. The question is whether we can engraft enough cells to radically change the neighbourhood for good?

In colaboration with Prof Larry Goldstein, also from University California San Diego, his studies in SOD1 rats showed that injection of embryonic stem cell-derived human astrocytes can ‘clear the hurdles’ that need to be overcome in order to get astrocyte implantation studies into the clinic. Studies will move to a larger animal model and further work on producing, purifying and screening the cells needs to be done, in order to satisfy strict regulatory conditions.

He stressed the importance of setting milestones and getting the administration in place to deal with these hurdles. If all goes well in achieving these milestones, the plan is to be able to perform the first clinical studies in the next four years.