Guardian on pain

Once again the Guardian (5th September) has provided me with an interesting scientific pointer, in the margins of a piece about photographing black holes, to one David Julius, one of this year’s winners of a 2020 Breakthrough Prize in Life Sciences – a win worth $3m. I don’t yet know what he will do with it – or whether he will share it with his colleagues. See references 1 and 2. A story which played both to my interest in neurons and to that in city walls, this last being last noticed at reference 3, and which has provoked a crash course in neural communications.

Figure 1

So, for example, I have been reminded that a lot of neural communication works by opening and shutting ion channels – with positively charged ions flowing through open channels and sometimes so generating action potentials. With the positive ions mostly being potassium and sodium and with an influx of sodium ions often being the proximate cause  of an action potential. The negative ion chlorine also gets into the mix – with sodium and chlorine, as it happens, being the active ingredients of sea water.

And while all sorts of tricky things, often involving neurotransmitters – natural or pharmaceutical – are involved in opening and shutting all these gates, the actual action potential is just a flow of electrical charge. As is said in another context, money has no smell. And as far as trying to explain consciousness is concerned, perhaps concentrating on these action potentials will turn out to be right.

Eventually I was led to the Julius paper at reference 5, about things called TRP channels (Transient Receptor Potential channels, named for electrical activity in the eyes of fruit flies (drosophila melanogaster)) and pain. Where the story is that while analgesics like morphine are tremendously powerful, they also act centrally and come with all kinds of unwanted side effects. So, for example, as well as damping down pain, morphine also damps down bowel movements, resulting in constipation. The hunt is on for analgesics which act peripherally and which are more specific. TRP channels may provide the answer, with the work that Julius, his colleagues and others have done showing that there are various specialised TRP channels dealing with pain and that particular sorts of TRP channels tend to be concentrated in particular neurons. So that shutting down one particular sort of TRP channel in one particular place, might deal with one particular sort of pain – with rather fewer side effects than might come with getting morphine to do the job.

I imagine that reference 5 is one of Julius’s more accessible papers, accessible both in that I could understand parts of it and in that it had leaked out into the public domain – and while a lot of it was not accessible to me, I did learn some interesting bits and pieces, some of which I share in what follows. I also share the results of my crash course more generally. In which sharing, I should say that I stray out of my comfort zone, so any facts therein ought to be checked before being passed on…

Channels turn out to be proteins embedded in the membranes of cells, with the cells of particular interest here being neurons. Membranes which are the boundary between the interior of the cell and the outside world. Proteins which are both chemicals and structures.

Figure 2

Proteins are chains of amino acids, more precisely amino acid residues, from tens to several thousand of them. With these chains of acids being specified by chains of genes in chromosomes. This is the view on the left of the figure above. But as proteins get bigger there gets to be a hierarchical structure, often a very repetitive structure. So a large protein, called a protein complex might be made up of a number of domains (very independent, usually labelled with Greek letters, for example α, β, γ) or sub-units (less independent, usually labelled with Latin numbers, for example I, II, III) . These in turn are made up of helices, sheets and turns. This is the view of the right of the figure above. But while the protein is, on this view, a linear structure, in vivo it is folded into a complex three dimensional structure.

Figure 3

With Bing offering this picture of three of the ways of looking at that three dimensional structure. Left we have a rod and ball diagram, not necessarily exhaustive. Right we have an impression of how the collection of atoms might look from the outside if we were to be scaled down appropriately. In the middle we have a representation of what is called the secondary structure of helices (purple), sheets (yellow) and turns (blue).

Figure 4

While the puff for Julius offered by his institution, UCSF, offers a picture of the channel involved in detecting wasabi, to which I shall return below.

Figure 5

So our ion channel is a molecule of a protein (blue in the figure above) embedded in the cell membrane (yellow). A molecule with, in this case, five domains labelled with Greek letters. With the letter being repeated where the domain repeats. With the ions flowing, one at a time, up or down through the pore in the middle – at rates which can be as high as millions of ions per second. With the opening and shutting, the gating of these pores being managed, in part, by neurotransmitters, here called messengers, locking onto receptors on the outer rim of the channel. So neurotransmitters – and their pharmaceutical fakes (recently noticed at reference 8) are important. Noting that some messengers turn channels on (agonists) and some turn them off (antagonists) – and I imagine the differences between the two are sometimes very modest.

Figure 6

Given the vertical, trans-membrane organisation of the domain or sub-unit, it is often easier to work with a diagram expanded in the way of the figure above, with the channel, as it were, unrolled. In this case, with four sub-units. Note the four (P) loops dipping down into the membrane layer, loops which form the outer opening of the pore through which the ions flow.

My understanding is that it is description at this sort of level which gives rise to the identification, the designation of the group of channels called TRP channels.

So just as with other complex systems, like large computer systems, we need to tune the method of visualisation to the task at hand. No one visualisation is going to be able to capture and project the whole story; there is just too much of it.

But at least we are now in a position to drill down into membrane proteins. With a membrane protein being any protein apt to be found embedded in the outer membrane of a cell. With a membrane channel being a large and complicated protein which spans the membrane which encloses a healthy cell – to be contrasted with something like a sweat duct which is a layered sheet of cells folded into a tube – something which is built of cells rather than being built into a cell wall – but which might still come in at hundreds to the square centimetre of skin. With orifices in general coming in all kinds of shapes and sizes. Another striking fact is that an ion channel, despite its small size, might pass millions of ions a second, which makes it very fast compared with some other kinds of channel - which makes them important in the all-important, very fast communications needed between the billions of neurons of the human brain.

Figure 7

And there are lots of other membrane proteins, doing all kinds of different jobs, with the ion channels we are interested in here appearing bottom right. Passive, in the sense that once open, ions just flow with the prevailing winds, as it were. No expenditure of energy. Active in the sense that the ion (or whatever) has to be carried through the pore, possibly against the prevailing wind. Which does involve the expenditure of energy. Note that, confusingly, prefixes like α and β tend to be used in a lot of different ways.

Figure 8

And there are lots of different kinds of ion channels, with TRP channels just being one family in the order. A family which itself breaks down into hundreds of species. With nomenclature, again as with large computer systems, being something of a problem. With the bottom row of the figure above being the sort of thing that Julius writes about in reference 5.

His story majors on these TRP channels, much involved in a great deal of pain. Furthermore, in the sort of chronic pain which is apt to increase in our aging populations.

Figure 9

The TRP channels we are interested in here are the ones near the periphery, for example in hands and feet, belonging to terminals of primary sensory nerves which go on to ascend to the spinal cord, from where they are relayed up to the head. Also known as afferent neurons.

Some of these channels are sensitive to, that is to say they are gated by, vegetable irritants and toxins, for example capsaicin (as in red hot chillies), menthol, camphor, wasabi and garlic, and some are sensitive to animals toxins, for example those from spiders and snakes. Interestingly, some of these irritants and toxins are paired with heat and some of them are paired with cold. And some of them are very much involved in the sensation of pain, not only because they are sensitive to tissue damage, potential or actual, but also because they are involved in nerve sensitisation, whereby, for example, even moderate heat can cause immoderate pain.

Presumably, the finer one grinds one’s pepper, one’s capsaicin, the more likely it is to find its way to the front door of one of these channels. While birds, unlike mammals, are OK with capsaicin as they lack the relevant channel.

And having often wondered about how it was that some toxins worked so fast, in minutes if not seconds, I was interested to read that many of them interfere with the workings of some neurotransmitter or other, thus disabling some important part of the target’s life support system.

But curiously, while both salt and chilli were once rubbed into open wounds by way of torture, say after a flogging – giving us the common locution ‘rubbing salt into the wound’, there are also plenty of hits from both Bing and Google suggesting that such rubbing is useful as a way to staunch moderate bleeding, as antiseptic and as local anaesthetic. To be fair, a fair proportion of such hits attract adverse comment.

In any event, studying the effects of all these irritants and toxins on both humans and other animals does seem to be a route to understanding.

So any one sensory nerve or neuron will have lots of these channels, but it seems that, to some extent at least, different subjective sensations come from different populations of nerves and neurons. Nerve type A does X and nerve type B does Y, rather than just having nerve type C which codes for X with  2Hz bursts of activity and codes for Y with 4Hz bursts of activity. And to the extent that this is true of pain, targeting the relevant type of nerve might be a useful complement to morphine – which as noted above is powerful, but is rather crude and has unhelpful side effects. With a word of warning being that turning off the sensation of hot, along with that of some sort of pain, would be a mixed blessing.

At which point, I decided I could let the matter rest.

Other gleanings

Along the way I came across something called the Goldman equation for resting membrane potential, an equation including temperature as one of its terms. Suggestive of the way a change in temperature might disrupt the workings of the brain. Which bears on the homeostasis of reference 3.

I was struck by the number of unpleasant diseases, complaints and symptoms which are put down to disturbances of neurology. Even allowing for the vagaries of description and classification, the list offered by Wikipedia at reference 6 is a long one – with a chunk of the ‘A’ part of the list being: Allan–Herndon–Dudley syndrome, alternating hemiplegia of childhood, Alzheimer's disease, amaurosis fugax, amnesia, amyotrophic lateral sclerosis, aneurysm, Angelman syndrome, anosognosia, aphasia, aphantasia, apraxia, arachnoiditis and Arnold–Chiari malformation. In which list one might argue about aneurysm and in which arachnoiditis is so named for the spiders’ web like appearance of part of the arachnoid mater – and one might argue about that one too. Nevertheless, there is still a lot of it.

An outing which has drawn my attention to the differences between an encyclopaedic standard text, such as that at reference 4, and an online, crowd populated encyclopaedia like Wikipedia. On the plus side for the standard text, the 1,400 pages of it are well presented and appear to be well written by the 45 contributors (to the fourth edition). Not to mention the management team. It is in book form, which older readers at least are likely to be more comfortable with than a screen – and on the minus side for Wikipedia, sometimes this last gets a bit too carried away with helpful pop-ups as one’s mouse wanders over the screen. But the text is updated on a roughly ten year cycle, while the more democratic, crowd populated Wikipedia can be updated much more frequently, a difference which is important in a field moving as fast as this one. Differences which might explain why I got my near 20 year old fourth edition of the former for a knock down price, a fraction of what the current edition would have cost. I might add that as far as accuracy is concerned, the few serious checks that I have come across suggest that Wikipedia does well enough – and the advantages of crowd sourcing seem to balance those of centralised control and management. The wisdom of crowds (for which see reference 9)? And for those interested in the history of science, or perhaps the sociology of science, it would be fascinating to be able to explore, compare and contrast the two populations of scientists and others involved in the production of the two encyclopaedias. Presumably there is a fair bit of overlap.

PS: a homely example of the effect of temperature on chemistry, is the ease with which one can clean a tea-stained mug with warm water, compared with cleaning with cold water. And a homely example of the importance of the city walls and their city gates of reference 3, one metaphor for cells and their channels, is the fascination of three year olds with inside, outside, doors, gates and windows.

References

Reference 1: https://profiles.ucsf.edu/david.julius.

Reference 2: https://breakthroughprize.org/. Funded by a clutch of successful hi-tech entrepreneurs – including the man from Facebook.

Reference 3: https://psmv4.blogspot.com/2019/07/more-city-walls.html.

Reference 4: Principles of Neural Science – Eric R. Kandel, James H. Schwartz, Thomas M. Jessell – 2000.

Reference 5: TRP channels and pain – Julius D – 2013.

Reference 6: https://en.wikipedia.org/wiki/List_of_neurological_conditions_and_disorders.

Reference 7: https://en.wikipedia.org/wiki/Principles_of_Neural_Science. The story, according to Wikipedia, of the standard text at reference 4.

Reference 8: http://psmv4.blogspot.com/2019/09/fake-85.html.

Reference 9: https://psmv4.blogspot.com/2018/11/a-last-outing.html. This is the madness of crowds. Dig a bit and you get to the wisdom of crowds.