Shining a light on our non-clinical fellow: Using blue light to control muscle movement

The MND Association is proud to support the brightest minds of MND research. Outside of general healthcare and biomedical project grants that are usually awarded to senior researchers, we also offer opportunities to young researchers – these take the form of PhD studentships and fellowships.

Fellowships are awarded to post-doctoral researchers who are able to support a research project as the leading investigator. Depending on their qualifications, the fellowship can either be clinical (for healthcare professionals) or non-clinical (for researchers with purely academic background). In the last round of non-clinical fellowship applications in October 2016, the MND Association awarded a senior fellowship to Dr Barney Bryson of University College London. In his upcoming project, due to start in August 2017, he will follow up on the findings he found together with his team, led by Prof Linda Greensmith.

Using light to move muscles

The idea behind Dr Bryson’s innovative project is that we can use a stimulator that emits light to create electrical signals in motor neurones (that form connections with affected muscles), rather than attempting to create long nerve connections between the muscles and the spinal cord.

We could think of this as creating a new electrical circuit from a power supply to an electric motor after lots of the wires have been damaged. Instead of reconstructing the long wires from the power supply to the motor, the researchers can directly plug in a new device that is capable of controlling the motor (or muscle in their case).

How can we use light to move muscles?

To control muscle movement by blue light, the researchers first had to create specially-modified stem cells from mice, from which specialized motor neurones could be generated. These motor neurones produce a specific neurotrophic factor and a gene that is sensitive to light, which enables them to survive longer after their implantation, and their activity to be controlled using pulses of light, respectively.

After these cells had been constructed, they were implanted into damaged sciatic nerves (one of the nerves controlling movements of the leg) in mice. Due to the survival-promoting neurotrophic factor, the implanted motor neurones were able to establish strong connections (innervation) with an atrophied muscle. Once innervated, an optical stimulator was then used to activate the transplanted motor neurons, creating electrical impulses that directly led to contraction of the connected muscles. They are now using a sophisticated implantable optical stimulator that was developed by Prof Ada Poon at Stanford University (Montgomery et al., 2015).

Optical stimulator implant (£1 coin for scale)

Optical stimulator implant (£1 coin for scale)

 How will this work be followed up now?

Much work still remains to be done before this approach could work effectively in human patients, which is a major focus of Dr Bryson’s fellowship project. Specifically, he will investigate how to best promote innervation of muscle fibres once the motor neurones are implanted. This will be done by closely observing the process of innervation in a laboratory dish and identifying the factors that promote best neurone-muscle connectivity. This part of the project is of great importance as strong connections are necessary for the muscles to receive an electrical instruction to contract.

How will this help people with MND?

While still at an early, pre-clinical stage, this project has a potentially immense impact for people with MND as it could re-establish electrical signals to the diaphragm, our main breathing muscle. When this muscle is affected, the person’s breathing ability deteriorates and an artificial way to support breathing has to be implemented (eg non-invasive ventilation). By implanting light-sensitive motor neurones to the phrenic nerve, which controls the diaphragm muscle, an optical stimulator emanating blue light could then directly control contractions of this muscle, greatly improving the person’s ability to breathe as a consequence. The hope is to also use this mechanism for peripheral muscles in order to improve person’s movement abilities.

Dr Barney Bryson

“This exciting project represents the next step in the continued development of an entirely novel strategy to overcome the progressive loss of ability to control specific muscles that occurs in MND.

“Although this future therapy is not aimed at preventing or slowing down the progressive loss of motor neurons that occurs in MND, it effectively circumvents the problem and could enable specific muscle functions and movements to be restored in an artificial manner in MND patients whose muscles have been paralysed, thus improving their quality of life.” Dr Barney Bryson

 

To find out more about MND Association-funded clinical fellowship projects, you can read about Dr James Bashford’s project investigating muscle fasciculations, or Dr Pietro Fratta’s project looking at understanding the role of RNA in MND.

Many thanks to Dr Bryson for his input and comments on this article.

To read more about the development of the optical stimulator that Dr Bryson uses, see the original research paper by Montgomery et al. (2015).

 

A PERK for neurodegenerative disease?

Our bodies need to be able to make new proteins, to maintain long term memory. So if the ability to make new proteins is switched off, does this cause Alzheimer’s Disease? New research findings published yesterday by scientists based in Leicester take us closer to answering this question. Journalist are describing this as a step forward for all neurodegenerative disease, so I wanted to explain what the researchers found, and what it might mean for MND.

What’s the story?

The activated form of a chemical called ‘eIF2’, is found in higher levels than normal in the brains of Alzheimer’s Disease patients. (In it’s turn, eIF2 is activated by an enzyme called PERK – hence the name of the blog post.. !).

Last month (September 2013) researchers found that genetically blocking the activation eIF2 prevented memory problems in a mouse model of Alzheimer’s Disease. The research published yesterday showed that in a mouse model of prion disease, chemically blocking eIF2 (as opposed to genetically blocking it) helped prevent the development of prion disease (Variant CJD or ‘mad cow disease’ is an example of a prion disease).

The chemical block was given to mice orally (one of way of doing this is to give it to them in their food). It got to the brain OK and effectively blocked eIF2, but the chemical did have serious side effects. So it’s a possible turning point for drug treatment for Alzheimer’s Disease and prion disease, but not the answer.

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One week on – Reflections on my first experience of the International Symposium on ALS/MND

Our recent blog articles describe lots of fascinating science and the progress in the care and treatment of MND/ALS that was presented at the symposium.  Personally, another really positive aspect was the opportunity to meet some of the researchers face-to-face. This included several senior scientists and clinicians whose work we support, some of whom gave lectures or chaired sessions. The symposium also gave presentation opportunities to PhD students and post-doctoral scientists, some of whom were attending their first International Symposium. We invited several from the UK to an ‘ice-breaker’ social on the Friday evening before the main lecture sessions began. Not all were able to attend, but a good group gathered with us, getting to know each other, and we met others later as they presented their posters. 

Sheffield University was well represented, including current grantees Emily Goodall and Clare Wood-Allum who both presented posters. Newer to ALS research was Guiseppe (‘Bepe’) Battaglia part of a cross-disciplinary group of collaborators who call themselves ViNCeNS for ‘Virus-like Nanoparticles for targeting the Central Nervous System’ with a website at www.vincens.group.shef.ac.uk/index.htm.

‘Fishing’ for new animal models of MND

Two others at our ‘ice-breaker’ gave lectures during the Saturday session on ‘Emerging Disease Models’.   Marc Da Costa (also from Sheffield) described some outcomes of his PhD project developing a new zebrafish with a mutated SOD1 gene.  Zebrafish are popular models for neurological conditions (there was a second presentation from an US-based group), as the fish embryos are transparent, so their neurones can be studied easily under the microscope.  Their muscular strength can be judged by the amount they move (studied by automated analysis of video) or by their progress swimming against a ‘current’ in a tube.  Marc studies the differences between fish with normal or mutant SOD1.  The latter have more difficulty swimming, and are more vulnerable to stress (for example, added toxic chemicals).  Marc can test the effects of potential drugs on the stressed fish, and has already seen some promising results.

Looking in a ‘library’ for MND mice

Another new animal model was presented by Peter Joyce (MND Association funded, based at the Medical Research Council Laboratories near Oxford).  His mouse strain carries a mutation (mistake) in its native (mouse) SOD1 gene, matching one recently reported from a human family with ALS.  This is different from the more established SOD1 mouse model, in which the MND-like symptoms develop as a result of multiple copies of an added human mutant gene.  Peter is studying the timescale in which muscle problems develop, relating these to changes in the neurones.  The MRC has a huge ‘library’ of mouse mutations available, so Peter will be investigating if others match mutations reported in different ALS families, possibly looking for collaborators to work on these.

Presenting the impact of healthcare decisions

A completely different type of research was presented as posters by two researchers working with Carolyn Young at the University of Liverpool.  Hikari Ando has been studying the reasons why some people with MND decide not to accept the offer of non-invasive ventilation (NIV), and the extent to it is actually used by at home.  Chris Gibbons’ work covered the assessment of quality of life for people with MND, particularly the role of fatigue and depression. 

Final thoughts

It was particularly inspiring to meet so many UK-based researchers, filling all of us from the MND Association with more incurable optimism.  Of course we also met many other people too – the attendees, many of whom collaborate internationally, came from more than 30 countries.