Cells on the edge - Part 1 (of many?)

I'm wanting to try out what it's like to write about the science of MND. There are so many ideas that interest me but it feels difficult to absorb and distil what has already been written, while also adding something of my own... Here goes with an intro to why motor neurones have it tough.
"If you're not living on the edge, you're taking up too much space...."

Whoever said that - maybe a branding agency - might have been talking about evolution rather than extreme sports.  Across the board, natural selection hones biological systems to perform as well as possible in a given context, often with little extra slack.  What I'd like to start to explore in this post (it's a big topic, and it's going to be a bit clunky!) is whether the forces of evolution drive motor neurones to the limits of their capability, and whether this therefore makes them particularly easy to push 'over the edge', as happens in Motor Neurone Disease (MND).

As the name suggests, motor neurones are the primary cells that fail in MND.  The 'lower motor neurones' are huge cells with their bodies in the spinal cord, and with their long axons (the cables that carry the nerve impulses) travelling out to the muscles all over the body.  A millivolt nerve impulse propagates its way down the axon, and when it reaches the end - the terminal - it causes a squirt of chemical onto the muscle and causes the muscle fibre to contract.  This exquisitely organised hybrid of electrical and chemical signalling is played out in the synapse, with every motor neurone making hundreds or thousands of synapses onto each of our many millions of muscle fibres.  And every time  a neurone fires it has to be reset immediately afterwards, ready for the next nerve impulse.

Firing a few nerve impulses now and again doesn't sound too stressful for a cell, but in fact the energetic demands of this process are huge.  Neurones are constantly working to maintain a different balance of chemical ions inside the cell than outside (giving rise to a charge, or potential difference across the cell), without which they would not be able to fire the millivolt electrical pulses that encode their signals to the muscles.  Added to that, the chemical that the motor neurone releases onto the muscle - acetylcholine - has to be manufactured, released and recaptured, many thousands of times over a day.  Motor neurones - like all other neurones - have their own inbuilt energy generation mechanism in the form of mitochondria, and in motor neurones these are found both in the cell body and in the terminals, providing the power needed to keep the synapses going.

Not only are the energetic demands of neurones huge - the brain uses an estimated 20% of all of the energy in the body - but motor neurones seem to have it particularly tough.  They are huge, complex cells, and they fire almost constantly.  Neither of those factors makes for an easy life.

A sense of scale might help here.  The longest motor neurones start in the base of the spinal cord, and reach their axons to the tip of the big toe.  If that motor neurone cell body was the size of a cricket ball (10 cm in diameter), the cable running to the furthest muscle in the body would be 1km long!  1 km long, but only 1 cm wide.   That sounds like a very vulnerable route for all of the essential supplies - including the energy generation machinery - that have to travel from one end of the cell to the other.

So why might having a high energy demand - as we'd expect for a large, complex cell that fires all the time - be problematic?  Well, as anyone who has a toddler knows, lots of energy causes lots of mess.  The energy generation process creates toxic byproducts that have to be cleaned up, constantly.  If they are not the cell will suffer damage, and over time that damage can accumulate and kill the cell.

What we understand so far about MND (see here for a good synopsis of what goes wrong in motor neurones) is that something often goes wrong with energy generation and housekeeping in the motor neurone.  This may be a cause or a consequence of the illness - we don't know - but diseased motor neurones show a variety of different signs that all is not well.  They may have clumps of defective proteins, evidence of damage by 'free radicals', or other signs of stress.  In other words, something is pushing them to the brink of what is survivable.  And sometimes that will be too much.

I can see there's a lot more to explore here....!  In the next post about cells on the edge, I'll explore some of the questions that take us beyond the fundamental biology of the system.  If motor neurones are so close to the edge, then why wouldn't everyone get MND?  Or maybe everyone would if they lived long enough.  Are motor neurones more vulnerable than other cells?  And why might a system be 'designed to fail'?

If this has piqued your interest, you might want to read more about motor neurones in general, or specifically about alpha motor neurones (the ones that innervate our muscle fibres).  Please share other resources you think are good!

Learning from others

I've been finding it hard to get to writing - all too easily distracted (the 'part time' job expanding to fill more space than I am willing to give it), poor time management, and perhaps the slightest edge of fear all stopping me from throwing myself headlong into this project.

So this evening I thought that if I couldn't write, at least I would read - The Long Goodbye by Meghan O'Rourke - a recommendation from my friend Nicole.  I've devoured half of it in almost a single sitting, between my garden and my sofa.  There's a wonderful review of it here on Brainpickings.

It's a memoir by a woman a little younger than me, who lost her mum from cancer at the age of 55.  O'Rourke was so attentive and present through her mum's illness, death, and the aftermath.  And I recognise so many things she describes beautifully in her vivid, honest and raw prose.  It's almost her throwaway comments that catch me the most - "Time doesn’t obey our commands. You cannot make it holy just because it is disappearing."

I remember being struck by that as my mum came to the end of her life.  There were still the banal things to do, and in a sense it was the banal that held the world together.  Washing, dressing, walking in the garden, making and eating food, sleeping.  All of these things have to be done, or were things that she could and wanted to do.  Every day.  Until her very last day.

But she also had a way of making all time holy.  Such that eating a slice of hard-boiled egg on our patio, in the sunshine, just a few days before she died, had a reverence and a joy that I might never know.  She could be transported into raptures by a beautiful moment, and would just close her eyes and smile.  She wrote:

Yes,life is uncertain and life is fragile.To be reverent of it is to show gratitude for this precious gift of life.