The Calabar bean is native to Nigeria, where it has been used for centuries in tribal rituals to determine if a person is guilty of witchcraft or possessed by evil spirits. The accused is forced to swallow the chocolate-brown bean and is deemed guilty if they die, but innocent if they vomit up the beans. The outcome is actually dictated by the amount of poison the victim swallows, which depends on both the number and the ripeness of the beans, enabling those in power to manipulate the dose administered to achieve the verdict they desire. The Calabar bean is believed to have been used in a gruesome murder in which a young boy’s headless and limbless torso was found floating in the Thames in September 2001. Analysis of his gut contents by the Royal Botanic Gardens at Kew revealed the remains of the Calabar bean plant, which both helped identify the country that the child came from and led detectives to speculate he was poisoned in a black magic ritual before being dismembered.
But agents like physostigmine also have therapeutic uses. Myasthenia gravis is an autoimmune disease in which the body produces antibodies against the muscle acetylcholine receptor. Each antibody bears two arms that grab two adjacent acetylcholine receptors and link them together, whereupon they are removed from the surface membrane and destroyed by the muscle cell. Consequently the number of acetylcholine receptors is markedly reduced, impairing nerve–muscle transmission and causing severe muscle weakness, progressive paralysis, and muscle wasting. Similar muscle weakness can be caused by loss-of-function mutations in the genes that encode muscle acetylcholine receptors. Children born with this disease have droopy eyelids, dropped jaws, open mouths and find it hard to stand, let alone walk. The treatment for both disorders is to increase the time that acetylcholine lingers at the synapse by inhibiting its breakdown by acetylcholinesterases.
The use of physostigmine to treat myasthenia gravis was pioneered by Dr Mary Walker, a quiet, unassuming assistant medical officer at St Alfege’s Hospital in Greenwich. Noticing that the effects of myasthenia were similar to those of curare poisoning, she reasoned that they should be alleviated by physostigmine, a known antidote for curare poisoning. In 1934, she administered oral physostigmine to Dorothy Codling, a thirty-four-year-old chambermaid who had had the disease for six years. The effects were dramatic: previously so weak she was unable to lift a cup and confined to bed, Dorothy was able to walk shortly after being injected with the drug. It became popularly known as the ‘miracle of St Alfege’s’. The treatment Mary Walker devised is still used today.
Riding the Lightning
Chemical transmission triumphed in the war of soups and sparks. Nevertheless, electrical transmission between cells does exist. At electrical synapses, the membranes of the communicating cells come extremely close to one another and are physically joined by specializations known as gap junctions. Each gap junction is made up of several hundred channels, packed tightly together in a semi-crystalline array. Uniquely, gap junction channels come in two halves, with one half of the channel being inserted into the membrane of one cell and the other half into that of its neighbour. When they couple up, a pathway is created for ions to flow directly from one cell to another, which allows electrical signals to spread quickly between cells.
Transmission at electrical synapses is about ten times as fast as at a chemical synapse because no time is needed for the transmitter to be released, diffuse across the synaptic gap and bind to post-synaptic receptors. As a consequence, electrical synapses often mediate defensive reactions such as the jet-propelled escape response of the squid, the ink cloud released by cuttlefish to cloak themselves from their enemies and the rapid withdrawal reflex of the earthworm that facilitates its backward retreat into its burrow when a blackbird pecks.
The rapidity of transmission also means that electrical synapses are perfect for synchronizing electrical activity in adjacent cells, and they are found throughout our bodies. Heart cells are wired together by gap junctions to ensure they contract in concert; gap junctions link the insulin-secreting beta-cells of the pancreas so that they release insulin simultaneously; and neurones in certain regions of our brains are electrically coupled so that they fire together. The pore of the gap junction channel is much larger than that of most other channels, which enables intracellular signalling molecules and small metabolites, as well as ions, to pass through. Consequently, gap junctions do not just connect cells electrically – they also ensure that the biochemical activities of adjacent cells are coupled. Gap junction channels even seem to play important roles in our skin, because inherited genetic defects that lead to their loss result in skin disorders. Those affected can develop thickened skin on the palms of their hands and the soles of their feet, as well as abnormalities of their teeth, hair and nails.
Leaping the Synaptic Gap
Although this chapter has focused on how the nerve impulse leaps the synaptic gap between nerve and muscle, synapses are not confined to the nerve–muscle junction. They are also found between nerve cells and gland cells and, very importantly, between different nerve cells, as described later. In all these places, the main mode of transmission is chemical and a cornucopia of different transmitters are involved. But why should chemical transmission be preferred over electrical?
One answer is that both its slower speed and the intricacies of its mechanism are better suited where integration of a plethora of signals might be advantageous. Another is that it may simply reflect the way in which cell signalling has evolved. Many simple organisms that consist of single cells, such as bacteria, communicate with one another via chemical messengers, enabling them to act as a vast team with coordinated defensive and attack strategies. Nor is the use of chemicals to transmit information from one cell to another confined to the nervous system. Long-range chemical messengers known as hormones transmit information between cells in our bodies that lie some distance apart from one another. Many different hormones circulate constantly throughout our bodies, influencing our mood, maintaining salt and water balance, stimulating cells to grow, readying our bodies to cope with stressful situations – even regulating the secretion of many other hormones. Pheromones wafted on the air enable communication between different organisms and act as sexual attractants, territorial markers and alarm signals. It seems likely that nerves have simply co-opted this universal chemical signalling system to serve their own ends.
5
Muscling in on the Action
Under a spreading chestnut tree
The village smithy stands;
The smith, a mighty man is he,
With large and sinewy hands;
And the muscles of his brawny arms
Are strong as iron bands.
Henry Wadsworth Longfellow, ‘The Village Blacksmith’
Deep in the farmlands of rural Tennessee live some very unusual goats. Variously known as fainting goats, stiff-legged goats or myotonic goats, they topple over when startled. Their first name is misleading as the goats do not faint or even lose consciousness. Rather, they find it difficult to walk normally and often fall over when they are frightened because their muscles seize up and their legs become rigid. It resembles a kind of extreme cramp in which the muscles lock up so tightly that the animal can even be picked up without its legs bending – they are literally scared stiff. The attacks last only a few seconds and afterwards the goat is none the worse for its experience.
Mystery surrounds the origin of the myotonic goats. Anecdotal stories relate that in 1880 a man named Tinsley arrived at a farm in central Tennessee with a few goats and a zebu. He never said where he got the goats, or where he himself came from, and a year later, he moved on, leaving the goats behind. Another apocryphal story has it that their peculiar behaviour was discovered when one of them was shot for dinner and the rest of the herd collapsed in unison. What is certain is that a sudden stimulus such as a loud noise or an unexpected movement causes them to fall over – such as when a Tennessee marching band goes past, or a passing train sounds its whistle. In some Tennessee towns a ‘fainting’ contest even forms par
t of an annual goat festival, with the prize being awarded to the goats that fall over the fastest and stay down the longest. Predictably, perhaps, animal rights protesters argue that scaring goats stiff is cruel. But myotonic goats are usually much-loved pets, kept for their novelty value rather than their meat.
Wiring our Muscles
The muscles that move our limbs are made up of many individual muscle cells, known as muscle fibres. These are grouped together into bundles, which gives meat its stringy texture. The nerve cells that control our muscles are known as motor neurones. If they are damaged or work imperfectly, our muscles are no longer able to respond when we wish to move them and gradually waste away from lack of use. This happens, for example, in motor neurone disease, where progressive degeneration of the motor neurones leads to weakness and muscle wasting, which results in a gradual inability to move the limbs and difficulties with speaking, swallowing and ultimately breathing.
Three motor units, shown in dark grey, pale grey and white. Each motor nerve originates in the spinal cord and innervates many muscle fibres, located throughout the muscle.
Each muscle cell is innervated by a single motor nerve fibre, which has its cell body in the brain or spinal cord. However, one nerve cell can innervate several thousand muscle fibres because its terminal end splits into numerous branches. The nerve and its attendant muscle fibres are collectively called a motor unit and when the nerve fires all the muscle fibres it innervates will twitch in synchrony. The muscle fibres that make up the motor unit lie dispersed throughout the muscle, often quite distant from one another. Although this may seem strange, there is a good reason for it. It ensures that the force generated by stimulating a single motor nerve is spread throughout the whole muscle, and not focused in one place, which could cause the muscle to tear itself apart. In muscles that require fine control of movement, each motor unit is composed of a smaller number of muscle fibres: your finger muscles, for example, have fewer fibres per motor unit than your leg muscles.
The nerve contacts the muscle close to the centre of the fibre, where it splits into several fine branches, each of which forms a synapse with the muscle, as explained in the previous chapter. The muscle membrane opposite the nerve ending is thrown into numerous folds, which increases its surface area and enables many more acetylcholine receptors to be accommodated. Stimulation of the nerve releases a flood of acetylcholine, which diffuses across the synaptic gap and binds to these receptors.
Like a nerve fibre, and indeed all other cells in your body, muscle fibres have a voltage difference across their membranes, with the inside of the cell being more negative than the outside. Opening of the acetylcholine receptor channels dissipates this voltage difference, driving the membrane potential positive. Just as we saw with nerve cells, the change in membrane voltage opens muscle sodium channels and so sets off an electrical impulse (an action potential) that propagates along the muscle fibre in both directions from its point of origin. The action potential spreads rapidly over the surface of the muscle cell and then down into a network of tubular invaginations of the surface membrane, which penetrate right into the centre of the fibre. These conduct the action potential deep into the fibre interior, thus ensuring that all the contractile filaments contract in a single concerted step. The fact that an individual muscle cell contracts in an all-or-none fashion – completely or not all – was shown long before the all-or-none nature of the action potential was appreciated.
In a normal muscle fibre, a single nerve stimulus elicits a single muscle action potential that gives rise to a single contraction, such as when you blink your eye. It takes some time for the muscle to relax so that the duration of a muscle twitch is much longer than that of the electrical impulse. This means that if the muscle is stimulated repetitively, the twitches will summate to produce a sustained contraction of the muscle, known as a contracture. This enables you to apply a steady force to an object. The force a muscle can apply can be increased not only by stimulating an individual muscle fibre more frequently, but also by recruiting more motor units. Any sort of movement – from typing these words to hitting a squash ball – involves the complex coordination of a multitude of muscles and the precise control of their contraction by a myriad of electrical impulses in your nerves and muscles.
The muscle action potential is similar to that of nerve cells, in that it is initiated by the opening of sodium channels and terminated by opening of potassium channels. However, different genes code for the ion channels involved, which explains why a mutation in the muscle sodium channel does not affect nerve sodium channels (or vice versa) and why toxins that act on our nerves do not always affect our muscles. Muscle action potentials also involve more types of ion channels than those of axons. Of particular importance are the calcium and chloride channels, so-called because they are selectively permeable to these ions. Mutations in any of the different kinds of channel that shape the muscle action potential can cause muscle disorders.
Impressive: A Trojan Horse
Quarter horses were originally bred for quarter-mile racing (hence their name) and for handling cattle because they are very fast over short distances. Nowadays, they are more favoured as show horses. Some of the most beautiful have a mutation in their muscle sodium channel gene that causes a disorder known as hyperkalaemic periodic paralysis (or HYPP). Horses who carry the HYPP mutation are very sensitive to the concentration of potassium ions in their blood, and they become paralysed when this increases. Unfortunately, high concentrations of potassium are naturally present in alfalfa, so that eating hay made from alfalfa often causes attacks of flaccid paralysis. These start with muscle trembling and weakness, progress to swaying and staggering, and sometimes can be severe enough to cause the horse to collapse and fall over. Afflicted animals normally survive these attacks, but those that have the disease often have a shorter life span.
The mutation that causes HYPP prevents the muscle sodium channel from closing completely. Consequently, sodium ions continuously leak into the cell, decreasing the potential gradient across the muscle membrane and enhancing muscle excitability. This can cause the muscle to contract even when the horse is standing still. These spontaneous muscle contractions produce the peculiar impression of worms writhing just beneath the animal’s skin. They also result in a striking muscular physique because the animal is, in effect, performing continuous isometric exercises. During an attack, the potential across the muscle membrane is reduced so much that the sodium channels shut down (they are said to be inactivated). Thus the muscle cannot sustain the contraction however much it is stimulated, the muscles become weak and floppy, and the horse falls to the ground.
Well-developed musculature is a highly desirable trait in a show horse, and animals with HYPP win many prizes. As a result of a programme of selective breeding for muscular physiques, 4 per cent of quarter horses are at risk of the disease. All of them can be traced to a single ancestor, a stallion called Impressive – named not for the quantity of offspring he sired, but rather for his powerful muscles. His majestic physique and the fact he always won his show classes meant he was in great demand as a stud. It was only later that it was appreciated that his offspring inherited more than his impressive muscles, for, like the original Trojan horse, Impressive’s appearance concealed a more sinister gift.
Because only a single copy of the mutant gene is needed to cause the disease, roughly half of Impressive’s offspring were susceptible to HYPP. Animals that carry two copies of the mutant gene are more severely affected. As a simple genetic test can provide a definitive diagnosis of HYPP, the disease could be easily eliminated if owners agreed not to breed from animals carrying a single copy of the mutant gene. However, this idea has proved somewhat difficult to enforce since affected horses win more prizes and are consequently more valuable. Nevertheless, since 2007, foals that carry two copies of the mutant gene are no longer eligible for registry with the American Quarter Horse Association.
Humans can also suffer from a similar condit
ion. Those affected become weak and cannot move if they eat potassium-rich foods, like apricots and bananas, when they stop to rest after strenuous exercise or when they awake. During an attack their limbs become flaccid and floppy, like those of a rag doll. In a rare variant of this disease, known as paramyotonia congenita, people develop muscle stiffness when they get cold and it gets even more pronounced if they also exercise. The condition is not life-threatening, but it can be decidedly inconvenient to find that your hands become clamped to your spade when shovelling snow, that you cannot let go of your bicycle’s metal handlebars when bicycling in cold weather, that you get stiff and weak when running in cold weather or that your jaw muscles stiffen up so much when you eat ice cream that you are unable to speak.
Many different mutations can cause HYPP in humans but, like the equine disease, they all make the muscle sodium channels leaky. In some cases, this causes the muscle fibre to become hyperexcitable, producing muscle trembling or stiffness, as in paramyotonia congenita. Other mutations render the muscle completely inexcitable so that it can no longer contract and the individual is paralysed. All of these conditions are precipitated by a small increase in the blood potassium concentration, which is why eating potassium-rich foods can trigger an attack. Although all of us will develop muscle weakness if the potassium levels in our blood increase too much, people with HYPP mutations are unusually sensitive.
Scared Stiff
The Spark of Life: Electricity in the Human Body Page 11