The Spark of Life: Electricity in the Human Body (29 page)

Touched

From the caress of a loved one, to the feel of the wind on our cheek or the crush of a bear-hug, touch plays an important part in all our lives. Sense organs in our skin respond to such mechanical forces with an electrical change, triggering nerve impulses that relay information back to the spinal cord and brain. Like other sensory nerves, impulse frequency is graded according to the stimulus strength, with lighter touches evoking fewer impulses than stronger pressures. Touch receptors also adapt to continuous stimulation, which explains why we do not notice the pressure of the clothes we wear.

Exactly how mechanical energy is transformed into electrical energy remains a puzzle, but it is clear that mechanically sensitive ion channels are somehow involved. Recent studies suggest that these channels are attached to the extracellular surface of the cell by a gating tether, in an arrangement similar to that found in the hair cells of the ear. Pressure on the cell membrane is thought to tug on the tether, distorting the structure of the channel so that it opens. The more the membrane is deformed, the more channels are likely to be activated and the greater the excitation of the nerve. Sometimes nerve endings sensitive to mechanical force are packaged into specialized structures that enhance their ability to detect changes in pressure or vibrations such as those that arise when you stroke your fingers across a rough surface. However, the end result is the same: a mechanical stimulus elicits an increase in action potential frequency in the sensory nerve.

Some Like it Hot

Our skin not only contains receptors sensitive to pressure, but also to temperature and painful stimuli. Bite into a habenero chilli pepper and it explodes in your mouth like a firebomb. Its burning pain comes from the chemical capsaicin it contains and different varieties of pepper have different amounts of capsaicin, which explains their very different potencies. In 1912, Wilbur Scoville calibrated the strength of chillies by measuring how much an extract of the pepper must be diluted until it was barely detectable when placed on the tip of the tongue. On the Scoville scale, the mild bell pepper notches up less than one heat unit, a jalapeño pepper has 2,500 to 5,000 units, and the famously incendiary Bhut Jolokia well over a million. The potency of pepper sprays used to repel grizzly bears, elephants and human attackers can be even higher: the weapons-grade pepper spray used by the Indian army cracks in at two million Scoville units.

When Mike Caterina and David Julius first isolated the capsaicin receptor, it turned out to be an ion channel. Binding of capsaicin opened the pore and stimulated electrical activity in the sensory nerve. The channel was also opened by noxious heat. So the reason chilli peppers taste so hot is that they open the same ion channel as high temperature and because the brain cannot tell the difference between the two stimuli it interprets them both as heat. These channels are not just found in the tongue, they are also present in the skin of your fingertips, face and other sensitive parts of the body – as unfortunate men who have been chopping chilli very quickly find out if they forget to wash their hands before visiting the lavatory. Unlike humans, birds are not sensitive to chilli because they have a mutation in the channel that renders it less sensitive to capsaicin. This is highly advantageous to the plant, for their seeds are spread by wild birds. It is also why it is recommended to deliberately add chilli powder to bird food to deter squirrels from stealing it.

Just as chilli stimulates hot receptors, so other chemicals interact with receptors that sense cold, fooling the body into thinking the substance is cool. The minty, fresh taste of menthol, found in peppermint oil, arises from the fact it activates an ion channel that detects cold temperatures. This channel is structurally very similar to the capsaicin receptor and in fact we now know that there is a whole family of such channels, called TRP channels, each of which detects a different shade of temperature. Many of these channels are also sensitive to a range of pungent or painful chemicals – not just capsaicin, but substances such as wasabi (the hot Japanese horseradish), mustard, garlic and camphor.

Some snakes have exploited the ability of TRP channels to sense heat to produce natural thermal-imaging cameras that enable them to detect the body heat of their prey and so track their movements and strike accurately even in the dark. The Western diamond-backed rattlesnake, a pit viper, is unmatched in its sensitivity to infrared radiation, being able to detect a change in temperature as small as 0.01 °C. It has two exquisitely sensitive heat sensors, known as pit organs, which lie on either side of its head. These consist of spherical pits, open to the outside, within which a thin heat-sensitive membrane is suspended. Sensory nerve endings ramify through the membrane, their tips crowded with a type of TRP channel known as TRPA1, which serves as the heat sensor.
¹²
It is postulated that heat activates the TRPA1 channels, stimulating firing of the sensory nerve and alerting the snake that its prey – or a predator – is present. Vampire bats also use TRP channels to home in on their warm-blooded prey; they are found in specialized heat-sensing organs located around the bat’s nose.

But TRP channels are not only used to sense temperature. Those sensitive to thermal extremes also serve as pain receptors and when they are stimulated we feel it hurts. This explains why it is difficult to discriminate between extreme heat and intense cold – between fire and ice. One feels only pain. As Shelley eloquently put it, ‘the bright chains eat with their burning cold into my bones’.

Such a Pain

Pain can be extremely useful – it is a valuable alarm system that signals danger. It tells us that the pan is hot; that our toes are in the fire; that straining too hard will tear our muscles; that we have an infection or a wound. Without it you may be burnt, develop suppurating sores, or walk around with broken limbs, causing further damage. Pain also reminds us to allow damaged parts of the body to heal. A common side-effect of diabetes is the loss of sensation in the feet and legs. As a consequence, blisters, sores and minor injuries can go unnoticed, leading to infections that ultimately may necessitate amputation of the affected limb.

In addition to TRP channels, one of the ten kinds of human sodium channel is involved in the perception of pain. This channel, known as Nav1.7, fails to work in some people. Because their pain nerve fibres can no longer conduct action potentials, they are unable to feel pain, although their sensitivity to touch, temperature, pressure and so on is completely normal. This is far from a blessing, for pain is a valuable warning and bruised and broken limbs may go unnoticed in people who lack functional Nav1.7 channels. Indeed, scientists first identified the role of the channel in pain sensation by studying the family of a young Pakistani boy who made a living by stabbing knives into his arms, or walking on burning coals, in a gruesome form of street theatre. On his fourteenth birthday he jumped off a house roof to prove just how tough he was. He died from his injuries, which mercifully he was unable to feel.

Equally disabling is the opposite condition in which the Nav1.7 sodium channels are permanently activated. This condition is known as erythermalgia and it runs in families. Patients suffer episodes of intense debilitating pain, associated with redness and burning sensations in their hands, arms and legs. They complain that they feel as if hot lava had been poured over their body, as if their feet were on fire or of the sensation of walking on hot sand. These symptoms tend to be provoked by warm weather, exercise and the use of bed sheets, and many sufferers are unable to wear shoes because of the pain. It seems Nav1.7 sets the gain on pain – too much channel activity and you will be in permanent pain, too little and you will be always anaesthetized. Interestingly, a common variant in the Nav1.7 gene alters your pain threshold and could explain why the same stimulus feels more painful to some people than to others.

All pain comes from the brain. It is our brain that receives messages from nerve fibres, telling us we have stubbed our toe, and many brain areas are involved in our experience of pain; they tell us where the pain is, how much it hurts, and what kind of pain it is – sharp, burning or just a dull ache. Our perception of pain is also highly variable. Even if the input signal from our sensory nerve endings is identical, the way the signals are processed is powerfully influenced by our attention, mood and expectation and this can dramatically alter the pain we experience. Our emotions can make a placebo pill an effective painkiller even though it contains no active ingredient, and, conversely, fear of pain can sharpen its impact.

The main problem with pain is that once we have registered its message we are unable to switch it off. Worse still, in some unfortunate people the pain may remain even after the body has healed. Such chronic pain is very common, and is experienced by as many as 15 per cent of adults. This can be devastating and may ruin their lives. Billions of dollars are spent on pain medication every year, but many painkillers are not very effective and some of them, such as those derived from opium, have addictive properties. Better drugs are urgently needed, especially for treating chronic pain, which is often not ameliorated by current therapies. Because Nav1.7 is mainly confined to pain neurones, a drug that specifically blocks these channels might be able to tune out pain without causing side-effects.

What a Relief

When I was a child, I dreaded a visit to the dentist as it was often a painful experience. No longer. Modern dentistry has been completely transformed by the introduction of new and better local anaesthetics. Even the removal of a nerve from a root canal is painless – the worst sensation is the sharp pinprick as the injection is given, and that too is partially numbed by application of a topical anaesthetic. Most local anaesthetics act by blocking sodium channels, preventing conduction of nerve impulses from local nerve endings in the teeth to the brain. Dentists commonly use lidocaine because it acts very rapidly. The problem with such drugs, however, is that they do not just inhibit electrical activity in pain fibres, they also affect the other sensory and motor nerve fibres so that some hours after we have visited the dentist we still have a lopsided smile and our jaw feels numb. What is needed is an anaesthetic that is specific for the sensory nerves.

One way to find this is to identify the types of ion channels specific to sensory nerves and then find a drug that selectively blocks them. Currently, the best target seems to be Nav1.7, and several drug companies are currently seeking specific inhibitors of this channel. This is far from easy as the drug must also be able to penetrate the sheath surrounding the nerve, must not be broken down by the body too quickly, and preferably should retain its activity when taken by mouth. Developing any new drug also takes a long time and is extremely expensive. Consequently, it may be some time before we no longer suffer a frozen jaw after a visit to the dentist.

The Sensational Brain

Information from our sense organs travels via the sensory nerves to the brain encoded as electrical impulses. Bypassing the sense organs and stimulating the sensory nerves directly therefore evokes a sensation, as Isaac Newton vividly demonstrated in the mid-1660s. He records how he slid a bodkin (a small needle) between his eyeball and the back of the eye socket and found that when he pressed on it ‘there appeared severall white darke & coloured circles’. It is not necessary to perform such a dangerous experiment, however, to see coloured circles – simply gently pressing on the closed eyelid will do it. The pressure stimulates the retina, and thus the optic nerve, and is seen as light. Direct electrical stimulation of the region of the brain concerned with vision has the same effect, even in the blind.

Newton also records how the ‘circles were plainest when I continued to rub my eye [with the] point of [the] bodkine, but if I held my eye & [the] bodkin still, though I continued to presse my eye [with] it yet [the] circles would grow faint & often disappeare untill I removed [them] by moving my eye or [the] bodkin’. As you will by now appreciate, a common theme in the nervous system is that the response to a continuous stimulus gradually weakens. We are preprogrammed to respond most strongly to changes in our environment and cease to pay attention if nothing new happens, a phenomenon that has a clear evolutionary advantage.

Sensory experience, then, is coded in electrical signals. It is the brain that interprets this barrage of nerve impulses, and deduces – on the basis of where they come from – what they mean. When the brain fails to attend to its inputs we may stare at the world but fail to see what is there, and illusions arise when signals conflict. Nor is the brain merely a receiver, for it can tune the sensitivity of our sense organs and modify the information they receive. Our perception of sights, sounds, scents and so on is thus the result of a two-way collaboration between our sense organs and the brain. So let us next look at the role the brain plays in this sensational dance and how it modifies and shapes the fractured information supplied by our sense organs, and weaves it together to produce a complete sensory picture of the world. To do so, we must first understand how the brain is wired up.

10

All Wired Up

Men ought to know that from the brain, and from the brain alone, arise our pleasures, joys, laughter and jests, as well as our sorrows, pains, griefs and tears. Through it in particular, we think, see, hear, distinguish the ugly from the beautiful, the bad from the good, the pleasant from the unpleasant.

Hippocrates,
On the Sacred Disease

Hello. I am delighted to meet you – and particularly pleased you have made it this far. I hope it has been an interesting journey. Or perhaps you have just picked up this book and, riffling through the pages, have arrived at this one? Whichever it is, take a moment to consider how astonishing it is that I can communicate with you so easily across space and time. A vast number of obscure electrical miracles taking place in your brain enable me to do so.

As you read (or listen) to my words, the sensory cells in your eyes or ears are busily engaged in detecting information encoded as light or sound and transforming it into electrical signals. But that’s only the start of the process – that information is then converted into a chemical signal and back again into an electrical one multiple times as it travels from sense organ to brain. And information that was first deconstructed into small manageable chunks of data is then processed and reassembled to form several sensory maps in the surface layers of your brain. Even more extraordinary, this information – this pattern of electrical signals flying around your nerve cells – is then interpreted as language and yet more sparks fly as you recognize my words and understand what I mean. If you like what I say, you might smile; and if you don’t understand me or think my words facile you may by now be feeling frustrated or irritated – you may even (I hope not) be bored. And this too, these emotions my words trigger, are again produced by chemicals sloshing around your brain stimulating yet more nerve cells to fire. But the truly astonishing thing, most extraordinary of all, is that the person talking to you, writing these words – and indeed you yourself – is locked inside a small lump of jelly that fits neatly into your cupped hands and weighs no more than about 3 pounds: the brain. We are electrical beings, you and I, and we constitute no more than an unimaginably complex and continuously changing pattern of electrical and chemical signals.

The Little Grey Cells

Your brain is one of the most sophisticated machines on the planet. It has over 100 billion nerve cells and each of them communicates with many thousands of others. There are trillions of connections, as many as in the whole of the world’s telephone system and far too many to fully comprehend. But the brain is not simply a great mass of interconnected nerve cells. It is a highly organized structure, with different parts being specialized for different purposes.

The most important bit of the brain – that responsible for our thoughts and actions – is the forebrain or cerebrum. It makes up about 80 per cent of the weight of the human brain and is divided into two mirror-image cerebral hemispheres, each of which primarily interacts with one side of the body. For unknown reasons, the wiring is crossed, with nerves from the left side of the body going to the right side of the brain and vice versa. The cerebral hemispheres are wired together by the corpus callosum, the brain’s information superhighway: cut it, and you cannot name what lies in the left half of your visual field because the image is presented to the right side of your brain whereas language is processed on the left side of your brain.

The outer layer of the forebrain, known as the cerebral cortex, is made up of a thin sheet of nerve cells that is thrown into numerous folds to increase its surface area and enable more to be packed into the skull. Its highly convoluted structure makes it look rather like a walnut kernel. It is this four-millimetre thick layer of cells that mediates thinking, conscious actions, sensation, learning and memory, and different parts of it are specialized for different functions. Below the outer shell of nerve cells the forebrain is packed with nerve fibres that run to and fro wiring the nerve cells of the cortex together. So vast in number are these interconnections that the cortex spends most of its time talking to itself.

Cross-section of the human brain showing the major regions.

Below the forebrain lie regions of the brain that are involved in controlling the emotions, in regulating appetite and sleep, and that act as relay centres for processing information coming in from the sense organs and handing it on to the cerebral cortex. Even further down, at the base of the brain, sits the brainstem, which connects the upper parts of the brain to the spinal cord. It controls all your unconscious actions: here is where breathing, blood pressure, heart rate, digestion and so on are regulated. These regions may continue to survive and function even when higher brain functions have ceased, a condition known as a persistent vegetative state, in which the patient is often referred to as a vegetable. This bit of the brain is similar in structure to that found in many other creatures, and serves the same role: indeed, it is sometimes known as the reptilian brain.

Curled up at the back of the brain at the top of the brainstem is the cerebellum (or ‘little brain’), which helps control balance and coordinates movements. It is involved in learning skilled motor tasks such as riding a bicycle, driving a car, and dancing
Les Sylphides
; damage it, and you cannot walk properly, but stagger around as if drunk.

Agatha Christie’s famous detective Hercule Poirot was very proud of his ‘little grey cells’. He was referring to the fact that although the living brain is a pinky-brown colour, when it is pickled the nerve cells turn grey, and hence are known as the grey matter. Nerve fibres, on the other hand, appear white and shiny when pickled (because of their myelin coats) and are called the white matter. But the brain does not consist solely of nerve cells. There are almost as many supporting cells, called glia, which help guide developing nerve cells on their way, supply them with nutrients, envelop them within a myelin sheath and guard them against infection. The delicate brain tissues are enveloped by membranes (the meninges) and shielded by a protective skull; within it, the brain floats in a sea of cerebrospinal fluid that cushions it and prevents it being damaged if the head is accidentally knocked, in the same way that the amniotic fluid protects the developing baby in the womb.

The brain has a large blood supply and many people will die, and an even larger number will be permanently handicapped, by blockage or rupture of the cerebral blood vessels, such as occurs in a stroke. Loss of the blood supply in this way leads to death of nerve cells in the local environment through lack of oxygen and nutrients and the build-up of toxic waste products. However, brain cells are not in direct contact with the bloodstream, but are protected by the blood-brain barrier. This is formed from the layer of cells that line the smallest blood vessels, which are so tightly knit together that they prevent substances leaking between the bloodstream and the cerebrospinal fluid. This blood–brain barrier is an important defence against noxious substances and infectious agents, such as bacteria and viruses, which drift around in the bloodstream.

The brainstem is directly connected to the spinal cord. When you decide to wriggle your fingers and toes the brain sends signals down the spinal cord and out along the peripheral nerves to command your muscles to move. The nerves that come out of the spinal cord in the small of the back and below serve the muscles of the legs; those higher up in the neck region signal to the arms. Damage to the nerves in the spinal cord means that electrical signals will be disrupted leading to paralysis and loss of sensation, as everything below the injury ceases to function properly. People who sever their spinal cord in the middle of their back can no longer walk but will still be able to breathe and move their arms. Break your neck, however, and you may be unable to move or feel anything in your arms as well. Depending on the exact location of the break, you may also be unable to breathe unaided.

Damaged nerve fibres in the brain and spinal cord never recover, leaving the patient permanently disabled. This was known even to the Ancient Egyptians, who declared that a person having ‘a dislocation in a vertebra of his neck’ is unaware of his legs and arms and cannot be treated. Over 3,700 years later, it is still the case. Not so for the peripheral nerves. My father severed the nerves in his fingers when adjusting the blade on an old lawn-mower and was left with no sensation in his fingertips, a devastating blow for a potter. Within a year or so, however, he was able to feel his fingertips once again as the nerves had grown back: but the regrowth was a slow process, inching forwards at less than two millimetres a day.

Seeing Single Cells

Individual brain cells are so tiny that it was not possible to see them until the invention of the microscope. Even then, the huge interconnected mass of cells within the brain and nerve trunks meant that special stains were needed to visualize individual cells clearly. In 1871, Camillo Golgi developed just such a stain.

While working as a medical officer in a psychiatric hospital in northern Italy, Golgi pursued his real passion – unravelling the anatomy of the brain – in a makeshift laboratory converted from an old kitchen. After a long series of attempts he discovered that a combination of potassium dichromate and silver nitrate stained a very few nerve cells randomly, but in their entirety. Paradoxically, the most important thing about Golgi’s method was that it hardly ever worked, for the fact that only a few cells were stained meant that for the first time it was possible to see the spidery shape of a single nerve cell in all its glory, with its multiple, delicate dendrites and long, thread-like axon.

The great Spanish anatomist Santiago Ramón y Cajal subsequently made a series of stunningly beautiful drawings of nerve cells visualized using Golgi’s silver-staining method. He was a gifted draughtsman and had originally wished to be an artist, but his father persuaded him to study medicine. In the event he combined both professions. Based on his observations, Cajal proposed that each nerve cell is a distinct entity and physically separate from its neighbour. This led to a dispute with Golgi, who had a different idea. In the end, however, Cajal turned out to be right.

While silver staining enables a small number of neurones to be visualized in exquisite detail, it is not possible to see how neurones are connected together. What is needed is some way of colour-coding adjacent cells with different stains. This was achieved in 2007, using genetic techniques to label neurones with multiple different colours. In the same way that a television uses only three colours to produce many different hues, three different genetically encoded fluorescent dyes were used to paint the brain of a mouse. In one region of the ‘brainbow’ mouse brain over ninety different colours were distinguished, enabling the connections between neurones to be traced. It was not just clever science – it was also a work of art.

Drawing of Purkinje nerve cells (A) and granule nerve cell (B) from a pigeon brain by Santiago Ramón y Cajal, 1899. The cells were stained with the silver stain developed by Camillo Golgi. The small ‘knots’ on the dendrites are dendritic spines.

Taking the Brain Apart

Understanding how the brain is wired up, how information flows from one region to another, and how information is coded and processed is one of the most challenging and complex tasks in neuroscience. In an electronic circuit, such as that of a radio, the wiring diagram details the connections between individual components and how information flows around the circuit. There is only one animal on the planet for which the complete wiring diagram of the nervous system is known and that is a microscopic nematode worm called
Caenorhabditis elegans
that lives in the soil. It is a scientific supermodel and has received even more attention than the catwalk variety. Because it is so small and has such a simple nervous system, every single nerve cell and every connection is known. It has 302 neurones, about 5,000 chemical synapses, 600 electrical synapses and 2,000 nerve–muscle connections.