The Spark of Life: Electricity in the Human Body

by Ashcroft, Frances

  In contrast to the nerve–muscle junction, where acetylcholine is the main transmitter, a cornucopia of different transmitters and their receptors are found in the brain. The main excitatory transmitter in the brain is glutamate – better known perhaps as the artificial flavouring in many Chinese dishes. Too much glutamate leads to over-stimulation of the target cell and can cause its death. Glutamate is therefore something of a Jekyll-and-Hyde molecule, essential for normal brain activity, but with the potential to destroy nerve cells completely. Consequently, cells have evolved ways to rapidly reduce the brain glutamate concentration to a low level, and transporters that capture extracellular glutamate and pump it back into cells are found at all glutamate release sites. The main inhibitory transmitter in the brain is gamma-amino-butyric acid (GABA), and that in the spinal cord is glycine. Many problems arise if any of this triumvirate of transmitters, or their receptors, are altered, or if we consume drugs or toxins that interfere with their function.

  On the Horns of a Dilemma

  In 1974, and again in 1997, Ethiopia was gripped by famine. The Western world watched in shock as horrific images of emaciated children and adults were beamed straight into their living rooms by satellite television. Food aid programmes burgeoned.

  Unknown to these observers, a second tragedy was also unfolding. Many of the sufferers were reduced to crawling, not through weakness induced by starvation, but as a result of a poison contained in the only food available to them. A local doctor, Haileyesus Getahun, travelling in the remote and beautiful highlands of northern Ethiopia, described how he met a family of six, who ‘attempted to offer the traditional respect by bowing but unfortunately to no avail. All but one girl were crawlers’. The mother had to be tied with a rope to the wall of the hut to prevent her from falling down while grinding grain, and the family was totally dependent on relatives and neighbours for survival. They were tragic victims of a recent epidemic of lathryism – a crippling paralysis caused by eating the grass pea Lathyrus sativa.

  The grass pea has been cultivated in South Asia and Ethiopia for over 2,500 years. It is a popular crop because it is cheap and easy to grow, withstands drought and flooding, is resistant to insect attack and produces a good yield of highly palatable seeds. It is also often the only food plant to survive extreme drought. Thus it sounds like the perfect crop for areas prone to famine conditions – except for one small catch. The plant contains high levels of a potent nerve toxin with the unpronounceable name of β-N-oxalylamino-L-alanine (usually abbreviated BOAA). BOAA specifically damages the motor nerves that control movement for, like glutamate, it is an ‘excitotoxin’ – a poison that acts by stimulating nerve cells so much that they die.

  BOAA binds to glutamate receptors on motor nerve cells in the brain. These receptors are themselves ion channels, and glutamate binding opens the pore, allowing calcium ions to flood into the cell. Because too much calcium is toxic to nerve cells, the continuous excitation of glutamate receptors by BOAA eventually results in nerve cell death. As a consequence, those who eat the grass pea for long periods develop a flaccid paralysis of the legs and are reduced to crawling. There is little or no recovery, even after consumption ceases.

  Lathryism is the oldest neurological disease known to man. As long ago as 400 BC, the famous Indian physician Charak recognized that it was associated with excessive consumption of the grass pea, and about a century later Hippocrates wrote that at Ainos ‘all men and women who ate peas continuously became impotent in their legs’. The first account to clearly establish the link between lathryism and grass-pea consumption was that published in 1844 by Major-General William Sleeman in his book Rambles and Recollections of an Indian Official, which described an outbreak of lathryism affecting both cattle and humans in the Saugor district of Central India.

  Despite this knowledge, however, tragedies continued to happen. During World War II, the inmates of a German concentration camp at Vapniarca on the Ukrainian border were given a daily ration of grass pea and bread. Within three months over 60 per cent of them had developed lathryism. The cause was eventually identified by one of the prisoners, who was himself a victim, and the problem was solved by removing the grass pea from the prisoners’ food. This incident led to recognition that consumption of the grass pea as a major part of the diet over a three-to-four-month period is required to cause paralysis.

  Unfortunately, in some circumstances, people are faced with a stark choice between starvation and lathryism. In 1997, the grass pea was the only crop that survived the severe drought in Ethiopia, and it was consumed in many different forms. Although the plant was known to be harmful, the exact nature of the problem and how to prevent its effects were only poorly understood. Health workers were at a loss and advised the community to avoid contact with the steam or the drained-off water of the cooked grass pea – a common misconception that is inaccurate and of little value. No information pamphlets were available, and many communities were so remote they could only be reached by mule or on foot. The epidemic continued for a further two years, until grass-pea consumption fell.

  Too Much of a Good Thing

  Lathryism is not the only disease caused by hyper-stimulation of glutamate receptors. Early one morning in the summer of 1961, the coastal town of Capitola in California was attacked by an enormous flock of sooty shearwaters. Hundreds of them besieged the town, slamming into houses, dive-bombing people, falling lifeless from the sky and staggering around vomiting fish. People woke to find the streets littered with dead seabirds. The event so intrigued Alfred Hitchcock that it influenced his production of Daphne du Maurier’s short story, ‘The Birds’, and he even included a reference to the Capitola attack in his film. Investigation of similar incidents that occurred subsequently showed that they were due to domoic acid, a poison that is made by phytoplankton and accumulated at high concentrations by creatures further up the food chain. The shearwaters had picked up the poison from the anchovies on which they had been feeding.

  Shellfish also accumulate domoic acid. This led to a mass outbreak of shellfish poisoning in Canada in 1987. More than 200 people who had eaten blue mussels were affected. In addition to vomiting and diarrhoea, many suffered disorientation, memory loss, seizures and coma and about a quarter of them also lost their short-term memory, in some cases permanently. Autopsies on the brains of four people who had died showed that their hippocampal neurones (which are important for memory) had been destroyed. Domoic acid kills neurones by binding very tightly to glutamate receptors of the kainate variety and causing them to open; the result is an influx of calcium ions that kills the nerve cells.

  A number of fungi also produce compounds that activate glutamate receptors, which explains why their consumption causes dizziness, delirium and euphoria. The sodium salt of glutamate (monosodium glutamate or MSG) is a flavour enhancer that is added to numerous foods, often under the name of ‘hydrolyzed vegetable protein’, to improve palatability. It has received a bad press ever since it was suggested to provoke nausea, dizziness and a splitting headache – the famous ‘Chinese restaurant syndrome’. Most of the brain is protected from the effects of MSG by the blood–brain barrier, but a few nerve cells lie outside this protective barrier. In young mice, these cells are vulnerable to the toxic effects of high levels of MSG and if they eat too much they became extremely obese as the neurones that regulate body weight are selectively killed. Numerous safety studies, however, have shown that MSG has no adverse effect in humans at concentrations very substantially higher than those used as a food additive, and double-blind trials even failed to reproducibly demonstrate that MSG causes Chinese restaurant syndrome. Nevertheless, this did not stop MSG being the focus of the ‘Soup Wars’ campaign. The battle began when the Campbell Soup Company ran an advertisement featuring its own soup as being made of 100 per cent natural ingredients and unflatteringly contended that its competitor’s Progresso line of soups tasted of MSG. The General Mills Company, who make Progresso soups, counter-attacked, pointing out that in
fact many of Campbell’s soups contained MSG, whereas many of their own soups did not. It also declared it was removing MSG from all its soups and challenged Campbell to do the same. And so it went on.

  Scared Stiff

  Sudden noises can make all of us jump. But imagine if every time you were startled your muscles seized up so severely that you froze rigid and toppled off your chair, or fell flat as a plank, like a clown in a circus act. This can happen to people with startle disease. Because they find their arms become stiffly clamped by their sides, they are unable to protect themselves when they fall and consequently may suffer multiple injuries. Babies with startle disease can be so severely affected that their spine arches backwards, as if in a tantrum, and their respiratory muscles seize up so that they suffocate and die. The disorder is sometimes known as stiff-baby syndrome.

  The symptoms of this extraordinary disease are similar to those of strychnine poisoning, which provides a clue to its origin. The common cause is loss of glycine receptor function – either due to a mutation, as in startle disease, or to inhibition by strychnine. Glycine is one of the main transmitters at inhibitory synapses in the spinal cord and brain stem. It is released from inhibitory nerve cells and interacts with glycine receptors in the post-synaptic nerve cell membrane, opening an intrinsic ion channel that is permeable to chloride. This damps down the electrical activity of the target cell and prevents it from responding to excitatory inputs. Such inhibition is essential for normal function. The muscles that move our limbs tend to come in opposing pairs, one of which flexes the limb and the other which extends it. It is crucial that when one muscle is stimulated to contract the other relaxes, for if both contract simultaneously the limb becomes stiff and cannot move. People with startle disease cannot respond to the glycine released from their inhibitory nerves, so their opposing muscles fail to relax. As both muscles contract simultaneously, they become rigid when surprised.

  Although this disease has some similarities with that of the Tennessee myotonic goats described earlier (in both cases the muscles stiffen up) it has a very different origin. Startle disease is a problem of the central nervous system, which fails to provide the muscles with the correct signals. The muscles themselves are normal. In contrast, the nerves of the myotonic goats are unaffected; it is the muscles that are defective.

  ‘The Mysterious Affair at Styles’

  Late one night, Mrs Emily Cavendish, a wealthy widow, was found dying at her Essex country manor house, Styles Court, from what later proves to be strychnine poisoning. Agatha Christie’s famous detective Hercule Poirot unravels a series of intricate twists and turns in the novel to prove that her new husband and his lover are the culprits. Strychnine has been used in many famous cases of poisoning, both real and fictional. The Lambeth serial killer, Dr Thomas Neill Cream, invited prostitutes to take a drink with him, spiked their drinks with strychnine and left them to die in agony. As strychnine is one of the most bitter substances known, the drinks must have been sweetened to disguise its taste, or the girls must have been sufficiently inebriated not to have detected it. It was also once used as a rat poison.

  Strychnine poisoning resembles startle disease because the drug blocks glycine receptors, rendering them non-functional. The toxin was first isolated from the beans of the plant Strychnos ignatia, which was named after Saint Ignatius of Loyola, the founder of the Jesuits. It is also found in the seeds of the Strychnine tree (Strychnos nux-vomica). Intriguingly, strychnine was once used as a stimulant, albeit at concentrations lower than that which cause severe toxicity. As might be expected, this sometimes led to accidental overdoses. A medical student, writing in 1896, described how he took it while studying for an examination because he was feeling run down. His calf muscles began to stiffen and jerk, his toes curled up, he saw flashing lights and he broke out in a cold sweat. He wrote that he ‘knew something serious was developing’ and so crawled to his medical case and drank potassium chlorate (an anaesthetic). He quickly lost consciousness and fell into a profound sleep ‘awaking in the morning with no unpleasant symptoms’ but a desire to be on the move and a temporary stiffness in the jaw. Not, one imagines, an experience he wished to repeat.

  Brain Storms

  Loss of inhibition in certain brain circuits can also trigger epilepsy, a sudden uncoordinated burst of excess electrical activity that resembles an electrical storm of the brain. Fyodor Dostoyevsky was probably the most famous epileptic in history. He recorded 102 seizures in his notebook and incorporated his experiences into his novels. Fits or seizures tend to be unique to the individual, for there are many types of epilepsy and many causes, but they can be broadly grouped into two main kinds. In petit mal or absence seizures, the patient goes blank for a few seconds, staring into space and seemingly switching off from the world around them. More dramatic are the convulsive seizures in which the victim’s limbs twitch and shake uncontrollably because the electrical storm influences the nerve cells that regulate their limb muscles. In some people the convulsions are highly localized and affect only a small group of muscles, whereas others may experience a grand mal seizure that is associated with generalized convulsions and often loss of consciousness.

  Epilepsy has been known since antiquity. Hippocrates referred to it as the ‘sacred disease’, and correctly argued that it was caused by a disturbance of brain function. Nevertheless, for many centuries the view that epilepsy was a medical problem coexisted with the idea that epileptic individuals had been cursed by the gods or were possessed by evil spirits. Epileptics were often ostracized and by the sixteenth century were even branded as witches. Gradually, it was recognized that epilepsy was an illness, but it still carried a negative aura. When Prince John, the youngest son of King George V, developed epilepsy he was hidden away in a cottage on the Sandringham estate. Fortunately, these days there is no stigma attached to the disease.

  The origins of epilepsy are still not fully understood. In some cases it results from a traumatic brain injury, a tumour that presses on the brain, or brain damage sustained during birth. In other cases it is inherited and caused by mutations in specific genes, many of which are ion channels. Most of these mutations impair the electrical activity of inhibitory nerve cells that normally exert a brake on brain activity. Release the brake and the brain goes into overdrive as excitatory circuits then become over-stimulated.

  Early treatments for epilepsy were bizarre, ranging from Pliny’s advice to drink the blood of gladiators to Robert Boyle’s suggestion to eat crushed mistletoe, ‘as much as can be held on a sixpence coin’, when the moon was full. A landmark in therapy came when it was recognized in the late nineteenth century that removal of the trigger area could help treat epilepsy. Surgery is not always possible, however, and other parts of the brain may be damaged when removing epileptic foci. Current therapies often involve drugs that reduce the frequency and intensity of seizures. Many act by enhancing the release or action of the inhibitory transmitter GABA, which prevents excess electrical activity by holding nerve cells at a more negative level. Others suppress the activity of excitatory neurones directly by acting on the sodium and potassium channels involved. However, as epileptic seizures can damage the brain, such therapies may only have partial success unless the patient can be treated early.

  Some unfortunate children have intractable epilepsy that is unresponsive to drug therapy and involves parts of the brain inaccessible to surgery. An old treatment that is surprisingly effective in some of these patients is to severely restrict their consumption of carbohydrates. Known as the ketogenic diet because it leads to the rise of metabolic by-products known as ketone bodies in the blood, it stops most seizures in about a third of patients and reduces their frequency in a further third. Why it works is far from clear, but the patients and their parents are not bothered about that. It is not an easy diet to stick to, however, and consumption of a single chocolate bar or other carbohydrate treat can precipitate a seizure.

  Wiring the Brain

  As this chapter ha
s shown, the way the brain is wired up determines the intricate pattern of electrical impulses and ‘chemical kisses’ between cells, and so influences how we move our limbs and sense our environment. But it has a still more important and extraordinary function. As we shall see next, it determines our emotions, thoughts, personality, consciousness – our very sense of self.

  11

  Mind Matters

  O body swayed to music, o brightening glance,

  How can we know the dancer from the dance?

  W. B .Yeats, ‘Among Schoolchildren’

  Joy, sadness, fear, anger, exhilaration, despair; our emotions fluctuate like sunshine and clouds in a British summer. They influence our thoughts, dictate our actions and form the basis of our personalities. But we are not mere puppets of our emotions. We are also capable of reasoned argument, of rational thought and action, of creative ideas that seem to come from out of the blue. Contrary to the mediaeval view, there is not some homunculus sitting in our brain pulling the strings. Rather, blind evolutionary forces have shaped our brains so that everything we think, feel and do is governed by the electrical and chemical events taking place in our nerve cells. It may seem uncomfortable to consider that your thoughts and feelings are determined simply by clouds of chemicals washing through your brain, and by the changing patterns of electrical activity they produce. Yet with a moment’s thought you will recognize that this is indeed the case, for drugs, hormones and diseases that alter the levels of neurotransmitters in our brain affect us deeply, transforming our emotions and our behaviour.