A key aim of current cardiac research is to develop a real-time computer model of the heart. The principal exponent of this approach has been the Oxford professor Denis Noble. His ‘virtual heart’ model is good enough to model the normal heartbeat, the effects of a heart attack, of genetic mutations that cause human disease, and the actions of drugs that block HERG channels. It is even sometimes used by drug companies to help explain the mechanism of action of novel drugs.
Some years ago, when his model was in an earlier version, the pharmaceutical company Roche asked Noble to appear in person at a hearing of the Federal Drug Administration in Philadelphia. To his surprise, he found the back of the hall was filled with traders clutching mobile phones and listening to the proceedings. The price of Roche stocks on Wall Street rose and fell as new evidence was presented and forwarded to the New York stock exchange. After the professor’s presentation, one member of the FDA remarked, ‘I want my hands on that program.’ ‘No problem’, came the laconic reply, ‘but you will need to buy a supercomputer costing £5 million [£10 million in today’s prices] to run it.’
Computing power has increased so rapidly that today the same simulations can be run on an ordinary desktop computer. But to simulate the activity of the heart in real time, as the drug companies desire, is still beyond the capability of most modern supercomputers (at least for now).
8
Life and Death
Life and death are balanced on the edge of a razor.
Homer, The Iliad
In 1970, about 15 per cent of the maize (corn) crop in the United States succumbed to an epidemic of Southern Corn Leaf Blight, caused by the fungus Bipolaris maydis. An estimated one billion bushels of maize were destroyed at a cost of over a billion dollars, and many small farmers went out of business. The disease was first reported in the USA in 1969, but cases were isolated and it was not considered of major importance. That all changed in 1970. The warm humid weather that year provided ideal conditions for the rapid spread of the fungus. The epidemic started in Florida and by June it had reached Alabama, southern Louisiana, much of the Mississippi basin and parts of Texas. By September the disease had spread throughout the Corn Belt and as far as Wisconsin in the north and Kansas in the west.
It caused extensive devastation of the corn crop. The first signs of infection were a reddish discoloration of the leaves, rapidly followed by yellowing of the whole plant. In the worst cases, the ears of corn rotted and fell to the ground, where they crumbled into pieces. Some fields were so heavily infested that when they were harvested clouds of spores boiled blackly above the machines.
The destructive effects of Southern Corn Leaf Blight resulted from the unhappy combination of a toxin produced by the fungus and an ion channel that is only found in certain self-sterile strains of maize. The disease reached epidemic proportions in 1970 because most of the maize planted that year was of the self-sterile variety. The reason for this genetic uniformity has its origins in the 1800s. Like many plants, maize is a hermaphrodite and has both male and female parts. The male parts are the tassels, which stick up from the top of the plant and release pollen grains into the air. The female parts are found in the ear of the corn; they develop into the maize kernels following fertilization. Wild maize is self-fertile and, because of the proximity of the male and female parts, most plants are self-fertilized. However, the best maize is a hybrid, obtained when the female plants are fertilized by pollen from a different strain. This was discovered toward the end of the nineteenth century, when plant breeders found that hybrid plants tended to be taller and more vigorous than either of their parents and, more importantly, had larger ears and kernels. Gradually, the use of hybrid maize spread. The farmers were impressed by the superior properties of the hybrid seed and the seed merchants who supplied them encouraged the use of hybrid strains, as it meant that farmers had to buy new seed each year.
To obtain hybrid plants it is necessary to prevent self-fertilization. Historically, this was done by removing the tassels by hand, a time-consuming and laborious operation, since it had to be done for many thousands of plants each year. Crop breeders were therefore delighted when they came across varieties of maize that produced no pollen. They realized immediately that these plants, known as cytoplasmic male sterile (CMS) strains, would be ideally suited for cross-breeding and they were soon widely adopted by seed companies. All that was necessary was to plant the CMS strain adjacent to a pollen-producing variety of maize and the wind would do the rest: the CMS plants would produce only hybrid seed. However, there was a hidden cost. Unlike normal maize plants, and unbeknownst to the plant breeders, the male-sterile CMS varieties were susceptible to Southern Corn Leaf Blight because they carried a specific type of ion channel in all of their cells.
As this story illustrates, ion channels are not limited to electrically excitable cells like nerve and muscle. They are found in every cell of our body and in every organism on Earth, from the humblest bacteria to the giant redwoods of California, and they regulate everything we do.
Turbo-charged Sperm
Ion channels play a crucial role in our lives even before conception, for they influence the outcome of the great sperm race. An arduous event with only one winner, it is the first and most important race we will ever enter and one that each of us (or rather some part of us) has won.
Sperm must swim from the moment of ejaculation, fighting their way towards the egg by lashing their tails. As they travel from the vagina into the upper regions of the woman’s reproductive tract they encounter a more alkaline environment and the hormone progesterone. This triggers a switch in the beat of the sperm’s tail from rapid wriggles to slower, larger and more forceful asymmetric whips that spur on the sperm. It’s a kind of last-minute turbo charge that kicks in just when the sperm needs more power, and it is essential – without it, the sperm would lack the thrust to penetrate the membranes surrounding the egg. This change in the beat of the sperm’s tail is produced by the opening of a specialized ion channel known as Catsper.
Catsper is the favourite channel of David Clapham, a Harvard scientist with a razor-sharp brain, a wicked grin and a salacious sense of humour. Searching through the database of the Human Genome Project for undiscovered treasures, his post-doctoral fellow Dejian Ren came across a novel ion channel that was found only in the testis. That fact immediately caught Clapham’s attention and soon, sperm, in all their many manifestations, became a focus of the lab. ‘They have’, Clapham says, ‘everything neurones have and more: they have ion channels, they get excited, they sense chemicals in their environment, they move – and they get more vigorous around an egg, just like men around women.’
The Catsper channel is one the most complex in the human genome. The channel pore is composed of four different proteins and it associates with several different kinds of accessory protein. If any one of them is absent, the channel no longer functions and the sperm fails to switch to the stronger tail lashes, resulting in infertility. As Catsper is only found in sperm, drugs that block the channel might make a perfect contraceptive. Unlike the more familiar contraceptive pill, they would not interfere with a woman’s hormonal system and they would not need to be taken orally. But such a drug would not be the long-sought male contraceptive. It would again be the woman who would have to take it, not just so she could be confident of its use, but because it is only in the her reproductive tract that the change in the sperms’ swimming occurs.
Not all sperm have Catsper channels. They are not found in the impressively giant sperm of the tiny fruitfly Drosophila bifurca, which crawl rather than swim up the female tract. These leviathans have the longest tails on Earth. They are almost six centimetres (over two inches) long, which is more than 600 times longer than their human counterparts and 20 times as long as the fly itself. Why such giant tails have evolved remains a mystery, but one idea is that the curled-up tail forms a plug that completely fills up the female tract and prevents other sperm from entering. Competition between sperm to
pass on their DNA is intense, even when they come from the same male.
Plants have a different problem, as their sperm are immotile and contained within pollen grains to protect them from desiccation. Yet they too use ion channels to facilitate fertilization. When a pollen grain lands on a plant’s female reproductive organ (the stigma) it sends out a long pollen tube that grows down towards the egg, carrying the sperm within it. The tube bursts on arrival, releasing the sperm. It turns out that the rupture of the pollen tube is caused by a chemical secreted by the cells surrounding the egg that opens an ion channel in the pollen tube membrane. As a consequence, potassium ions flood in, dragging water with them and causing the pollen tube to swell and burst. Liberated from the confines of the pollen tube, the sperm can now fertilize the egg.
Raising the Barriers
It is vital that only a single sperm fertilizes an egg because if multiple sperm do so the resulting cell fails to develop normally. Thus the egg has developed defences to ensure that only the first sperm to arrive is welcomed and that all subsequent hopefuls are excluded. How this block to polyspermy is produced was first studied in sea urchin eggs, which are easier to work with, as they are very large and can even be seen with the naked eye. Back in 1976, while still a young student, Rindy Jaffe discovered that as soon as the first sperm penetrates a sea urchin egg, the potential across the egg membrane rapidly flicks from being negatively charged on the inside to being positive. This voltage difference prevents further sperm from entering.
The surprise came when scientists looked at mammalian eggs and discovered that the mechanism was different. Here, the block to polyspermy is not an electrical but a physical one – a mechanical barrier that the sperm cannot penetrate, which develops only slowly after fertilization. The difference in strategy reflects the very different environments in which fertilization takes place. In the ocean, many millions of sperm arrive almost simultaneously at the egg so an electrical block to polyspermy is ideal as it is very fast. In mammals, the long and difficult journey up the female tract ensures that only a few sperm make it to the egg and that they rarely do so simultaneously. Hence a slower block is adequate.
Drawing Life from Death
Aya Soliman had a most unusual start in life, being born by Caesarean section two days after her mother Jayne was declared brain dead. Jayne, a champion ice skater, had a fatal brain haemorrhage when she was twenty-five weeks pregnant. She was flown by air ambulance to hospital in Oxford, but died shortly after arrival. Although Jayne’s brain was dead, doctors decided to keep her body alive to provide vital time for her daughter’s lungs to mature.
Within the womb, the fetus floats in a cushioning sac of water. Its developing lungs are filled with fluid and it does not breathe air, but obtains all the oxygen it needs via the umbilical cord that links it to the placenta. At birth, the water within the lungs must be rapidly removed as the newborn child switches over to breathing air. This is achieved with the help of specialized epithelial sodium channels (ENaC channels) that are present in the cells that line the lung. At birth the ENaC channels open, allowing sodium ions in the lung fluid to flow down their concentration gradient into the lung cells. Because sodium ions drag water with them, the lungs quickly dry out and so long as ENaC channels are present and functional, the lungs are rapidly cleared of fluid. Without ENaC, however, babies are at risk of drowning in their own fluid at birth and may suffer from ‘wet’ lungs.
During normal development, a rise in steroid hormones switches on ENaC production a few weeks prior to birth, ensuring the lungs are fully mature when the baby is delivered. At twenty-five weeks of pregnancy, however, lung development is incomplete and the number of ENaC channels in the cells lining the lung is still very small. A chemical called surfactant that reduces the surface tension of the tiny air sacs in the lungs and so prevents their collapse is also low. Thus if a baby must be delivered early, and conditions permit, steroids are administered to the mother before birth. These cross over the placenta and help her premature baby’s lungs mature. As a mother’s womb is the optimal incubator for a baby, Jayne’s body was kept alive on a life-support machine while steroids were given to provide her daughter with the best possible chance of life.
There is a further twist to this story. It turns out that at birth ENaC channels are stimulated to open more completely by the stress hormone adrenaline, which rises dramatically in the mother’s blood during the trauma of labour. This may explain why babies born by Caesarean section, where this stimulus is lacking, may have more difficulty clearing their lungs than those born naturally, and why they experience a higher incidence of respiratory complications in the postnatal period.
Piling on the Pressure
ENaC’s tasks do not end at birth. It plays a vital role in regulating the amount of sodium in your blood and this, in turn, determines your blood pressure. If ENaC channels malfunction, your blood pressure can skyrocket, putting you at risk of a stroke.
Your kidneys are sophisticated machines that clean the blood, continuously filtering out toxins and waste products and flushing away excess water. Waste processing takes place in about a million individual units known as nephrons, where tufts of fine blood vessels, known as capillaries, are entwined with tiny tubules that act as urine-collecting devices. Amazingly, the whole of your blood passes through the kidney twice every hour. The red blood cells and plasma proteins are retained in the capillary, but the salts and water are forced out into the kidney tubule. Almost all of the sodium and much of the water that is filtered are subsequently reabsorbed as the fluid passes down the kidney tubules. What remains is stored in the bladder and excreted as urine.
ENaC channels in the membranes of the kidney tubule cells are responsible for reabsorption of sodium. As in the lung, sodium uptake is accompanied by water, which leads to an increase in blood volume and, because the circulation is a closed system, raises the blood pressure. A diet high in salt (sodium chloride) is bad for you because more sodium is taken up, which drags more water with it, increasing your blood volume and therefore your blood pressure. Conversely, if blood sodium levels are low, insufficient water is retained by the body, leading to a fall in blood pressure. This is why it is important to ensure that you eat enough salt in a hot climate, where a lot of salt is lost through sweating.
Mutations in any of the three genes that make up the ENaC channel affect blood pressure. Those that lead to increased ENaC activity cause a hereditary form of hypertension known as Liddle’s disease, whereas those that reduce ENaC activity result in low blood pressure. The latter are particularly dangerous as they lead to a life-threatening salt-losing syndrome in newborns and infants. Because sodium uptake is reduced, less water is reabsorbed, so that the child quickly becomes dehydrated and the blood concentration of other ions (especially potassium) becomes unbalanced. The disease is fatal unless it is quickly recognized and treated.
Fortunately, mutations in ENaC are rare. However, it is thought that one reason for the greater incidence of high blood pressure and its attendant complications in black people than in Caucasians is because they have relatively common variants in their ENaC channel genes that predispose them to increased sodium uptake. Why this is the case is uncertain, but one suggestion is that people living near the Sahara evolved very efficient mechanisms for absorbing salt as it was in such short supply. While this is advantageous when salt is only rarely obtainable, it becomes a handicap in our present world where much processed food is very high in salt.
A Salty Tale
In mediaeval times, kissing a child’s forehead was held to foretell its fate, for those that tasted salty were considered to be bewitched and at risk of dying young. The association between a salty skin and an early death is not mere myth, however, but an early description of the disease we now call cystic fibrosis. People with this disease have very salty sweat and fail to secrete certain digestive enzymes. Most serious of all, their lungs get clogged up by thick, sticky, mucous secretions that make it hard to breath
e and lead to chronic infection, inflammation and a slow progressive destruction of the lungs. There still is no cure. It is a life-threatening condition and even with today’s advanced technologies over half of those born with the disease are likely to die before they reach the age of forty.
Cystic fibrosis was first recognized as a distinct disease in 1938, when Dorothy Andersen published the first comprehensive description of the disorder. Several years later, during a heatwave in New York City, the paediatrician Paul di Sant’Agnese noticed that many children admitted to hospital with heat prostration also suffered from cystic fibrosis. An insightful physician, he recognized that their collapse was probably precipitated by excessive salt loss and he analysed their sweat. It contained an abnormally high level of sodium chloride, a finding that forms the basis of the ‘sweat’ test that is still used today in the diagnosis of the disease.
Mutations that ablate the function of an unusual ion channel lie at the heart of the problem. Its full name is the cystic fibrosis transmembrane conductance regulator, but as this is such a mouthful it is always abbreviated to CFTR. This channel resides in the cells that line the lungs and the ducts of organs such as the sweat glands, pancreas and testes, and it shepherds chloride ions across the cell membrane. Secretion of chloride ions is vital for formation of the fluid that carries the digestive enzymes into the gut, for the seminal fluids, and for sweat. It is also essential for fluid secretion in the lungs, where a thin film of fluid is used to entrap bacteria and move them from the base of the lungs up the airways to the mouth, where they are swallowed and safely destroyed. Without this escalator, the airways clog up with a thick, sticky mucous in which bacteria breed. Such infections eventually damage the lungs.
The Spark of Life: Electricity in the Human Body Page 18
