The Spark of Life: Electricity in the Human Body (12 page)

A disaffected group of conscientious objectors are reputed to have hatched a bizarre plot to kill the British Prime Minister Lloyd George using curare. Mrs Alice Wheeldon, her daughters Winnie and Hettie, and her son-in-law Alfred Mason all belonged to the No Conscription Fellowship that campaigned against compulsory military service (introduced because of very heavy losses on the Western Front) and the punishment and imprisonment of conscientious objectors (COs) during World War I. Alfred, a qualified chemist and a lecturer at Southampton University, obtained the curare. In late December 1916, the group was successfully infiltrated by two secret agents, Alex Gordon and Herbert Booth, who posed as conscientious objectors. Herbert Booth testified that he was given an airgun and pellets tipped with curare and detailed to shoot the Prime Minster as he walked on Walton Heath. There was enough curare to kill several individuals and, despite their protestations that the drug was intended to kill dogs guarding CO internment camps rather than the Prime Minister, and that this course of action had been suggested to them by Booth and Gordon, Alice, Winnie and Alfred were convicted of conspiracy to murder. Whether the assassination attempt could have been successful is unclear. Equally uncertain is if this was a genuine assassination attempt or a government plot to discredit the anti-conscription movement and the anti-war factions – were Booth and Gordon in fact agents provocateurs?

What is more definite is that the US government gave curare to operatives on covert operations, in case they were caught and had to take their own life to avoid being tortured. When Francis Gary Powers flew his U2 spy plane over Russia during the Cold War he carried with him an American silver dollar that had a small straight pin inserted in the side. The pin consisted of an outer sheath covering a fine sharp needle with a grooved tip coated with a brown sticky substance that Powers states he was told was curare. When he was shot down and captured, the Russians found the pin and tested it on a dog, which stopped breathing within a minute of being pricked and was dead thirty seconds later. It is questionable, however, whether curare was the sole ingredient on the pinhead as its action appears to have been unusually fast.

The poison hemlock (
Conium maculatum
) contains several alkaloids, but one of the most potent, coniine, acts like curare by blocking the action of acetylcholine and paralysing the respiratory muscles. The plant was used as a means of judicial execution in Europe for centuries. Its most famous victim was Socrates, whose death is described in the
Phaedo
, which details how the paralysis developed, beginning with the feet and moving gradually upwards towards the chest.

Curare-like drugs, such as vecuronium, are often used in operations as muscle relaxants to enable the surgeon to operate more easily and to allow a lower level of anaesthesia to be used. This is especially important during abdominal surgery because contraction of the abdominal muscles might make it difficult for the surgeon to gain access without the intestines being squeezed out of the wound. Although the respiratory muscles are those least affected by curare, patients are usually artificially ventilated to help them breathe. The caveat with the use of curare-like drugs is that if anaesthesia is inadequate, the patient may be awake but unable to move, speak or communicate their distress. Each year, this happens to about 0.1 per cent of people undergoing surgery in the United States – approximately 25,000 people. About a third of them can feel the pain associated with their operation and the remainder have some awareness of what is going on without suffering pain. It is a particular problem during Caesarean sections when a lighter level of anaesthesia may be used to avoid anaesthetizing the unborn child.

Nerve Gas

Clearly, if a muscle is to be able to respond to a second nerve impulse, the first signal must be switched off rapidly. This is achieved in two ways. First, the transmitter remains attached to its receptor for only a short time before it spontaneously detaches. Secondly, the transmitter is rapidly removed. At the nerve–muscle junction, acetylcholine is destroyed within about five milliseconds of its release by an enzyme called acetylcholinesterase that sits in the synaptic gap.

Agents that inhibit the action of acetylcholinesterase are lethal. The most famous is the nerve gas sarin. The
Aum Shinrikyo
sect came to public notice in 1995 when they released an impure form of sarin in the Tokyo Metro, killing twelve people, seriously injuring fifty and temporarily affecting the sight of almost a thousand more. The terrorist attack was timed to coincide with the morning rush hour. Equally horrendous were the tests conducted forty years earlier by the British government.

In May 1953, a number of young servicemen were asked to participate in trials for a new cure for the common cold. But the volunteers were misled in a brutal and unforgivable fashion, as they were not exposed to the cold virus but to the nerve gas sarin. Twenty-year-old Ronald Maddison died horribly forty-five minutes after the agent was dripped onto his skin, suffering from convulsions so severe it appeared to an eyewitness that he was being electrocuted. His lungs became clogged with mucous and he died of asphyxiation. Maddison was used as a human guinea pig to determine how much of the lethal agent was required to kill the enemy. His death was witnessed by a young ambulance man, Alfred Thornhill, who was traumatized by what he saw and afraid to speak out because the authorities threatened him with prison if he did so. The incident was quickly hushed up and only became known fifty years later when the Wiltshire police finally opened a second inquest into Maddison’s death. The previous verdict of death by misadventure was overturned and replaced by one of unlawful killing. Maddison’s sister said that until the inquest she and her family had never known the truth about how her brother died. Britain was not alone in wishing to test sarin on troops. Extraordinarily, in the 1960s, US military scientists requested permission from the Australian government to test the nerve agent on Australian troops.

Inhibition of acetylcholinesterase is fatal because it leads to a build-up of acetylcholine in the synaptic gap. The consequence is overstimulation of acetylcholine receptors, which results in muscle convulsions. Because acetylcholine is the transmitter at the nerves that innervate the glands, acetylcholinesterase inhibitors also cause excessive salivation, drooling and watering eyes. The symptoms of acute poisoning by sarin and other nerve gases are well described by the mnemonic SLUDGE: salivation, lacrimation, urination, diarrhoea, gastrointestinal upset and emesis (nausea and vomiting). The victim can also suffer from dizziness, skin irritation, tightness of the chest and involuntary muscle twitching. In the worst case, they may die by suffocation from convulsive spasms of the chest muscles.

Atropine is used to treat patients who have been poisoned by nerve agents. It acts by blocking acetylcholine receptors and thus reduces the ability of excess acetylcholine to exert its effect. Military personnel carry autoinjectable ‘Combo’ pens, consisting of a spring-loaded syringe containing a needle and a barrel filled with atropine which can be used to self-administer the drug rapidly in an emergency. The top of the pen also contains a Valium tablet to reduce levels of stress (which is probably much needed!). Too much atropine, however, can also incapacitate the soldier because it knocks out acetylcholine action too effectively. In this case, nerve–muscle transmission is prevented, resulting in muscle weakness.

Oximes are also used as antidotes to nerve gases, but are generally given in advance of a possible nerve agent attack. They reactivate acetylcholinesterase by removing the phosphate molecule that is added to the enzyme by the nerve agent.

The Deadly Calabar Bean

Another substance that inhibits the action of acetylcholinesterase is physostigmine, the active ingredient of the Calabar bean,
Physostigma venenosum
. The Nigerian name of the plant is esere, from which its alternative scientific name, eserine, is derived. It was eserine that enabled Feldberg and Dale to demonstrate that acetylcholine was released from nerve terminals, by preventing its breakdown by endogenous acetylcholinesterases.

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.