The Spark of Life
Electricity in the Human Body
FRANCES ASHCROFT
Line drawings by Ronan Mahon
W. W. Norton & Company
New York • London
For Rosy and Charles
‘Man is no more than electrified clay’
Percy Bysshe Shelley
Contents
Introduction: I Sing the Body Electric
1 The Age of Wonder
2 Molecular Pores
3 Acting on Impulse
4 Mind the Gap
5 Muscling in on the Action
6 Les Poissons Trembleurs
7 The Heart of the Matter
8 Life and Death
9 The Doors of Perception
10 All Wired Up
11 Mind Matters
12 Shocking Treatment
Notes
Further Reading
Acknowledgements
Credits
Index
Cautionary Note
Electricity is highly dangerous when used incorrectly. The reader is strongly advised not to try any of the experiments described in this book on themselves, on others, or on animals. The author and publishers accept no responsibility for any resulting harm if the reader should fail to heed this advice.
Introduction
I Sing the Body Electric
Then felt I like some watcher of the skies
When a new planet swims into his ken;
Or like stout Cortez when with eagle eyes
He star’d at the Pacific – and all his men
Look’d at each other with a wild surmise –
Silent, upon a peak in Darien.
John Keats, ‘On first looking into Chapman’s Homer’
When he was just a few months old, James suddenly developed diabetes so severe that he required hospitalization. He faced a lifetime of insulin injections. Over the course of the next few months it became clear that he was also developing more slowly than most children and that he had problems with walking and talking. By the time he was five years old, he had only just started to walk, he was still unable to communicate and he had the temper tantrums of a two-year-old. Life was far from easy for his anxious parents.
It was later discovered that James has a very rare form of diabetes caused by a genetic defect (a mutation) in a protein known as the KATP channel that is important for both insulin secretion and brain function. Some mutations in the KATP channel simply cause diabetes, but around 20 per cent of them, including the one James has, also produce a constellation of neurological difficulties, including developmental delay, hyperactivity, behavioural problems and muscle dysfunction. All of these symptoms arise because the KATP channel influences the electrical activity of the insulin-secreting cells as well as that of the muscles and brain. It turns out that James’s story is closely entwined with my own, for the KATP channel has been my life’s work and understanding how it operates has enabled James to replace the multiple daily insulin injections he once needed to control his diabetes with just a few pills.
Diabetes occurs when the beta-cells of the pancreas do not release enough insulin for the body’s needs, so that the blood sugar level rises. Back in 1984, I discovered that the KATP channel sits in the membrane that envelops the beta-cell and regulates its electrical activity and thereby insulin release. The channel functions as a tiny, molecular pore that is indirectly opened and closed by changes in the blood sugar concentration: when the pore is closed insulin secretion is stimulated and when it is open insulin release is inhibited.1
I vividly remember the day I made that discovery. As so often happens, the breakthrough came late at night when I was working alone. I had hypothesized that adding glucose to the solution bathing the beta-cells would cause the channel to shut. Yet when it did, I felt certain it must be a technical error. So certain, in fact, that I almost ended the experiment. But just in case I was wrong, I tested the effect of removing the sugar, reasoning that if glucose were indeed regulating the channel activity its removal should cause the pore to reopen, whereas if it were simply a technical problem the channel should remain closed. After several agonizingly long minutes the channel opened once again. I was ecstatic. I was dancing in the air, shot high into the sky on the rocket of excitement with the stars exploding in vivid colours all around me. Even recalling that moment sends excitement fizzing through my veins, and puts a smile on my face. There is nothing – nothing at all – that compares to the exhilaration of discovery, of being the first person on the planet to see something new and understand what it means. It comes all too rarely to a scientist, perhaps just once in a lifetime, and usually requires years of hard grind to get there. But the delight of discovery is truly magical, a life-transforming event that keeps you at the bench even when times are tough. It makes science an addictive pursuit.
That night I felt like stout Cortez, silent upon his peak in Darien, gazing out across not the Pacific Ocean, but a landscape of the mind. It was crystal clear where my mental journey must take me, what experiments were needed and what the implications were. Next morning, of course, all certainty swept away, I felt sure my beautiful result was merely a mistake. There was only one way to find out. Repeat the experiment – again and again and again. That is the daily drudgery of a scientific life: it is very far from the ecstasy of discovery.
Even all those years ago, it was obvious that if the channel failed to close when the blood glucose level rose, insulin secretion would be prevented and the result would be diabetes. To prove it, we needed to find mutations in the DNA sequence that encodes the KATP channel protein in people with diabetes. It took ten years of work by many people throughout the world to identify that DNA sequence, and when we finally screened it for mutations we found . . . nothing!
It was my friend Andrew Hattersley who eventually found the first mutations, another ten years later. Andrew is a very special person. Tall, slim and sandy-haired, with an incisive mind and a warm compassionate nature, he is both a wonderful doctor and a brilliant scientist. He not only recognized that the mutations we were seeking would be more likely to be found in people who were born with diabetes (rather than those who developed it later in life); he also instigated a worldwide search to find them. When he and his associate Anna Gloyn identified the first mutation in 2003, he phoned me and invited us to collaborate with him. It was a call I will never forget.
Working together, we showed that the KATP channel mutations cause diabetes because they lock the channel permanently open, preventing electrical activity and insulin secretion. Even more excitingly, we found that the defective channels can be shut by drugs known as sulphonylureas that have been safely used for more than fifty years to treat type 2 (adult-onset) diabetes and which we already knew closed normal KATP channels.
In the past, patients who were born with diabetes were treated with insulin injections, as their symptoms suggested they had an unusually early-onset form of type 1 (juvenile) diabetes. In this disease the beta-cells are destroyed by the body itself and lifelong insulin is essential. Thus James and others like him were not given drugs, but immediately started on insulin. Our research suggested that instead such patients could be treated with sulphonylurea tablets and to everyone’s delight the new therapy not only worked, but actually worked much better than insulin. Over 90 per cent of people with neonatal diabetes have been able to make the switch.
It is a rare privilege for a research scientist to see one’s work translated into clinical practice, and even rarer to meet the people whose lives have been affected, so I have been extremely fortunate. Words cannot convey the extraordina
ry emotional experience of meeting the children and families whom your work has helped. To have, for example, a pretty young teenager turn to you and say ‘Thanks to you I can wear a dress’. ‘Why?’ I inquired, puzzled. ‘Because,’ she replied, ‘I no longer need a skirt or trouser waistband from which to hang my insulin pump.’ An insulin pump, I quickly appreciated, is something of a constraint. Dashing in and out of the waves in the summer sea is simply not possible – each time the pump must be removed and reattached – and its bulky shape ruins the line of figure-hugging clothes. Drug therapy obviates these problems and banishes painful injections. But it also has more important benefits. For reasons still unclear (but which we are of course exploring), sulphonylureas produce a far more stable blood glucose level than insulin. Dramatic fluctuations in blood sugar become a thing of the past, and hypoglycaemic attacks are much less frequent (and in some cases virtually vanish). Unexpectedly, the average blood sugar level also decreases so that the risk of diabetic complications (kidney disease, heart disease, blindness and amputations) is reduced.
People with neonatal diabetes, and their families, have hailed the new therapy as a miracle. But this is no miracle: it is merely science. It is knowledge of exactly how ion channels regulate the electrical activity of the pancreatic beta-cells, and thereby insulin secretion, that has made it possible for patients to throw away their needles and insulin pumps and switch to tablets. And it is only by understanding more clearly the mechanisms underlying the electrical activity of nerve and muscle cells that eventually it may be possible to develop better therapies for their neurological problems.
We’re all familiar with the fact that machines are powered by electricity, but it’s perhaps not so widely appreciated that the same is true of ourselves. Your ability to read and understand this page, to see and hear, to think and speak, to move your arms and legs – even your sense of self – is due to the electrical events taking place in the nerve cells in your brain and the muscle cells in your limbs. And that electrical activity is initiated and regulated by your ion channels. These little-known but crucially important proteins are found in every cell of our body and in those of every organism on Earth, and they regulate our lives from the moment of conception until we draw our last breath. Ion channels are truly the ‘spark of life’ for they govern every aspect of our behaviour. From the lashing of the sperm’s tail to sexual attraction, the beating of our hearts, the craving for yet another chocolate, and the feel of the sun on your skin – everything is underpinned by ion channel activity. Not surprisingly, given their ubiquity and functional importance, a multitude of medicinal drugs work by regulating the activity of these minute molecular machines, and impaired ion channel function is responsible for many human and animal diseases. Pigs that shiver themselves to death, a herd of goats that falls over when startled, people with cystic fibrosis, epilepsy, heart arrhythmias or (as I know only too well myself) migraine – all of us are victims of channel dysfunction.
An unusual tribute to the scientists and philosophers who contributed to the discovery of electricity hangs in Musée d’Art Moderne in Paris. A giant canvas known as ‘La Fée Électricité’, which measures 10 metres high and 60 metres long, it was commissioned by a Paris electricity company to decorate its Hall of Light at the 1937 world exhibition in Paris. It is the work of the French Fauvist painter Raoul Dufy, better known for his wonderful colourful depictions of boats, and it took him and two assistants four months to complete. The Electricity Fairy sails through the sky at the far left of the painting above some of the world’s most famous landmarks, the Eiffel Tower, Big Ben and St Peter’s Basilica in Rome among them. Behind her follow some 110 people connected with the development of electricity, from Ancient Greece to modern times. As time and the canvas progress, the landscape changes from scenes of rural idyll to steam trains, furnaces, the trappings of the industrial revolution and finally the giant pylons that support the power lines carrying electricity to the planet.
Dufy’s magnificent painting celebrates the scientists and engineers who shaped the world we live in today – Archimedes, Ampere, Edison, Franklin, Faraday, Ohm and others. But there is also a less well-known gallery of scientists who are the scientific descendants of Galvani, the discoverer of animal electricity. To these men and women we owe the drugs and technologies that we take for granted in our modern hospitals and our knowledge of how our bodies work. This book tells their stories. It charts the development of our ideas about animal electricity and shows how these are intertwined with our growing understanding of electricity itself. It explains how the electrical activity of our bodies is generated, and tells the dramatic, fascinating and sometimes tragic stories of what happens when things go wrong. What happens when you have a heart attack? Can someone really die of fright? Why are some people unable to stand when they eat a banana? What does Botox actually do? How does an electric eel give you a shock? How do vampire bats sense their prey? Is the red I see the same as you do?
This book provides the answers to these and other questions. It explains how ion channels work and how they give rise to the electrical activity of our nerves and muscles. It shows how ion channels act as our windows on the world and how all our sensory experience – from listening to a Mozart quartet to judging where a tennis ball will fall – depends on their ability to translate sensory information into electrical signals that the brain can interpret. It explores what happens when we fall asleep, or lose consciousness, and it discusses how our increasing knowledge of the electrical activity of the brain has stimulated and illuminated the link between mind and brain.
In essence, this book is a detective story about a special kind of protein – the ion channel – that takes us from Ancient Greece to the forefront of scientific research today. It is very much a tale for today, as although the effects of static electricity and lightning on the body have been known for centuries, it is only in the last few decades that ion channels have been discovered, their functions unravelled and their beautiful, delicate, intricate structures seen by scientists for the first time. It is also a personal panegyric for my favourite proteins, which captured me as a young scientist and never let me go; they have been a consuming passion throughout my life. In Walt Whitman’s wonderful words, my aim is to ‘sing the body electric’.
1
The Age of Wonder
I am attacked by two very opposite sects – the scientists and the know-nothings. Both laugh at me – calling me ‘the Frog’s Dancing-Master’, but I know that I have discovered one of the greatest Forces in Nature.
Luigi Galvani1
‘It was on a dreary night of November, that I beheld the accomplishment of my toils. With an anxiety that almost amounted to agony, I collected the instruments of life around me, that I might infuse a spark of being into the lifeless thing that lay at my feet. It was already one in the morning; the rain pattered dismally against the panes, and my candle was nearly burnt out, when, by the glimmer of the half-extinguished light, I saw the dull yellow eye of the creature open; it breathed hard, and a convulsive motion agitated its limbs.’ Thus did Victor Frankenstein, in Mary Shelley’s great gothic novel Frankenstein, written in 1818, record his creation of a monstrous being.
It is widely believed that electricity, in the form of a lightning bolt, was used to waken Frankenstein’s creature to life. But this is a misconception that probably originates with the famous 1931 film in which Boris Karloff played the monster. Shelley herself was far more circumspect and refers only to the ‘instruments of life’. Nevertheless, the novel leads us to infer that electricity was used to instill the monster with ‘a spark of being’, for Frankenstein gives a dramatic description of a lightning strike he witnessed as a young man that blasted an ancient oak tree to smithereens; and on inquiring about the nature of lightning from his father, he was informed it was ‘Electricity’. Shelley also uses her preface to make a marriage of physiology and electricity – ‘perhaps a corpse would be reanimated; galvanism had given a token of such thi
ngs’.
Indeed, both Mary and her lover Percy Bysshe Shelley took a keen interest in the emerging science of electricity and its effects on the human body. Percy was a particular enthusiast having experimented with electricity at Eton, at Oxford and even at home – his sister recounts how she was terrified of being ‘placed hand-in-hand round the nursery table to be electrified’. Percy was eventually sent down from Oxford for his atheist views and in 1810, during the winter vacation before his last term, he wrote to his tutor that he supposed man to be ‘a mass of electrified clay possessing the power to confine, fetter and deteriorate the omnipresent intelligence of the universe’. Over 200 years later, ‘electrified clay’ remains a fair description of the human brain.
Although we may scoff at the idea that electricity could animate a lifeless creature and know that a lightning strike is often lethal, even today we are not immune from the idea that electricity is the spark of life. A late-night arts programme on British television (The South Bank Show) is introduced by a modified version of Michelangelo’s famous painting of God creating Adam, in which an electric spark leaps from God’s outstretched finger. Nor is the idea entirely fanciful for, like almost all organisms, humans are electrical machines. As this chapter shows, the development of our knowledge of ‘the body electric’ is intimately entwined with our understanding of electricity itself.
The Dawn of Understanding
On a dry wintry day you may receive a sharp electric shock when you open the car door or grab a metal doorknob, and find that sparks fly and crackle when you pull off a nylon shirt. Petticoats that cling to your legs, clothes fresh from the tumble dryer that stick together, hair that stands on end when you remove your hat, an electric jolt when you kiss someone, the faint battle-rattle of electric sparks, like ‘tiny ghosts shooting’, as you comb your hair – all these phenomena happen because static electricity builds up on our bodies. In humid atmospheres the charge dissipates quickly, but under dry conditions it can build up to thousands of volts. Close proximity to metal, however, or even another person, will cause it to discharge. Direct contact is unnecessary, as the electricity will jump the gap, generating a spark in the process. The ‘electricity’ between two people, that special spark, may be more than just lovers’ talk.
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