The Spark of Life: Electricity in the Human Body (23 page)

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 breathe 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.

Current treatments for cystic fibrosis involve simply managing the symptoms: fighting lung infections with antibiotics, preventing the build-up of mucous in the lungs by physiotherapy, and replacing the missing digestive enzymes. But new research aims to correct the defective channel itself. About 4 per cent of patients have a mutation in CFTR (known as G551D) that reduces the time the channel spends open. Recently, a drug known as ivacaftor has been shown to coax such sleepy channels into functioning normally, and preliminary studies suggest it may be of clinical benefit. While there is still a long way to go, it is a promising new approach for treating people with the G551D mutation. Most patients, however, have a different variant of CFTR, known as F508del, that prevents the channel from ever reaching the surface membrane of the cell. In this case, drugs that correct the defective targeting of the channel are needed.

Cystic fibrosis is extremely rare in Orientals and black Africans and is highest in individuals of northern European extraction, where it is one of the most common inherited single gene diseases. Around 9,000 people in the UK have the disease and one in twenty-five of the population – over two million people – carry one copy of the faulty gene: although they are asymptomatic themselves, when two of them have a child there is a 25 per cent chance the child will have cystic fibrosis. This high frequency suggests there may be a selective advantage in having a single copy of the gene. One possibility is that such ‘carriers’ may be more resistant to the effects of diarrhoeal diseases, such as cholera.
Vibrio cholerae
, the bacterium responsible for cholera, produces a toxin that leads to opening of CFTR channels in gut cells, so that chloride rushes out of the cell, dragging water with it. This causes massive fluid loss from the gut, which results in severe diarrhoea and rapid death from dehydration. Individuals with a lower complement of CFTR channels may secrete less chloride and thus potentially be less susceptible to dehydration.

The cholera bacterium is transmitted in faeces, and any natural disaster that leads to a breakdown of sanitation, such as an earthquake or floods, brings with it the risk of a cholera outbreak. The 2010 earthquake in Haiti was no exception and was quickly followed by an epidemic of the disease. Although cholera is no longer a disease of northern Europe, being mainly confined to third-world countries, this was not always the case. One of the most notable successes of public hygiene was the removal of the handle of a water pump in Broad Street, London, by Dr John Snow in the summer of 1853.

During a severe fourteen-week-long cholera outbreak, Snow noticed that there were about ten times as many deaths in the district of Southwark than in Lambeth. He was of the opinion that cholera was spread in the water, whereas others contended it was the ‘foul miasma’ seeping from the sewers. Diligent study led Snow to discover that in one area of London the pipes from two different water companies were intermingled so that people were exposed to the same air and environment, but not necessarily the same water. By removing the handle of the pump that supplied infected water, he contained the outbreak of cholera and confirmed his hypothesis that the disease was spread in the water supply. The outbreak was eventually traced to Frances Lewis, a five-month-old baby who died of an attack of violent diarrhoea. Her mother poured the water used to rinse her daughter’s infected clothes into the gutter outside her house, which leaked into the Broad Street well and contaminated the water supply. It was a fatal mistake.

The Cell’s Plumbing System

Ultimately, both ENaC and CFTR produce disease by affecting transcellular water fluxes. For many years scientists puzzled about how water could cross cell membranes. As they are made of lipids (fats), they should be largely impervious to water, so how was it possible for water to penetrate the lipid barrier in such large amounts that it produces tears, saliva, sweat and urine? The answer is that most cells have specialized water channels known as aquaporins that conduct water across the membrane into and out of the cell. They were discovered serendipitously by Peter Agre. He called his finding, which eventually led to the award of a Nobel Prize, ‘sheer blind luck’. Having a suspicion that the protein he had discovered might be the long-sought cell water channel, he tested its ability to transport water using frog eggs, which normally live very happily in freshwater. To his excitement, frog eggs engineered to express water channels in their membranes swelled up and burst when they were placed in freshwater.

Agre’s experiment was a perfect demonstration of the power of osmosis – the tendency of water to flow from a region of low salt concentration to one of a higher concentration. Because freshwater has far fewer salts than those inside the cell, water will always attempt to penetrate frogs’ eggs but it is normally prevented from doing so by the lipid membrane. Increase the water permeability of that membrane, however (for example, by adding lots of water channels as Agre did) and water will rush in, causing the egg to swell and eventually burst.

It turns out that there are many different kinds of aquaporin channels and they are present in many types of cells, including brain cells and red blood cells, and even the cells of plants and microorganisms. One of the most important (known as aquaporin 2) sits in the collecting ducts of the kidney tubules and is responsible for reabsorbing the final thirty-five litres of water that the kidney filters every day, and thus for our ability to make a concentrated urine.
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Approximately three billion water molecules a second pass through a single aquaporin channel. It is highly selective as, due to the unique architecture of the pore, only water – and not ions – can pass through. Water channels are also unusual in that they do not open and close like ion channels, but are permanently locked open: instead the amount of water taken up is regulated by shuttling the channels in and out of the cell membrane. When the body needs to conserve water, extra water channels are inserted. Conversely, if you drink too much fluid, water channels are removed, so that less of the water filtered by the kidney is reabsorbed and it simply flows away as urine. This endless cycling of water channels into and out of the cell membrane is under hormonal control and occurs continuously. It is happening in your own kidneys, right now.

Interestingly, the process can be disrupted by alcohol. A few pints of beer prevent the release of the anti-diuretic hormone that causes water channels to be inserted into the kidney tubules, which is why you produce copious amounts of dilute urine. The result is that the morning after a binge you wake up in a partially dehydrated state, which contributes to the headache. As all the alcohol has now been metabolized (one hopes), hormone levels will be higher, water channels will be mobilized into the tubule membranes, and the increased water uptake will result in a concentrated urine. You can even observe the phenomenon for yourself for the concentrated urine you produce the morning after an evening out is a far darker colour than the dilute pee of the night before.

People who lack functioning aquaporin 2 channels produce large amounts of dilute urine – as much as 25 litres a day – and quickly become seriously dehydrated and very thirsty. This can happen because of a rare genetic mutation, in which case the disease manifests at birth; it can be hard for parents to spot, for urine-soaked nappies are far from uncommon in babies.

Lethal Agents

Ion channels are not only crucial at the start of life – they are also intimately involved in its end. Many cells and organisms use ion channels as offensive weapons. These act as molecular hole-punches, inserting themselves into the membrane of the target cell and forming a huge hole – a giant pore so big that not only ions but also small molecules and essential nutrients can leave the cell. Water rushes in, causing the cell to swell up so much that it eventually explodes (lyses) and dies. Channels used as lethal agents in this way are particularly interesting as they are packaged within the aggressor cell in an inactive form in which they do no harm. Once released, they reassemble themselves into a structure that is able to embed itself in the membrane of their prey. They are true transformers, shape-shifting from a harmless inactive form to a highly lethal one in matter of seconds.

Such channel-forming molecules play important roles in our immune system, defending us against invading pathogens. One type, appropriately named defensins, is found in our skin and the lining of the airways, where they act as natural antibiotics with a broad spectrum of action against bacteria, fungi and some viruses. Others are released by specialized white blood cells known as killer T-cells (or natural killer cells). Killer T-cells kill viruses and bacteria in a number of different ways, but one of them is by releasing perforins – ion channels that punch holes in alien cell membranes. Another pore-forming weapon in the arsenal of our immune system is complement, which produces even larger perforations in invading cells.

Bacteria also indulge in incessant chemical warfare with one another, secreting channel-forming proteins that kill other bacteria. Unfortunately, some of these also attack human cells. Alpha toxin, secreted by
Staphylococcus aureus
, is one of the largest, most lethal and most beautiful of all. It is a mushroom-shaped channel, with the stalk spanning the membrane and the cap resting on its outer surface, projecting out from the cell. To avoid damaging the bacterium itself the channel is made of seven separate subunits, which are secreted individually and subsequently co-assemble to form a giant pore that punctures the target cell.
Staphylococcus
bacteria cause skin infections such as carbuncles, boils, abscesses, wound infections, and, most seriously of all, systemic infections in which the bloodstream carries the toxin and bacteria to all tissues and both red and white blood cells may be damaged (causing blood poisoning). The ability of alpha toxin to lyse red blood cells gives rise to its alternative name, haemolysin.

Staphylococcus pyrogenes
, the bug that causes scarlet fever, also a produces a toxin that bursts red blood cells, causing a characteristic fine red rash all over the body and a bright strawberry-red tongue. It can be fatal – the mother of the nineteenth-century American novelist Louisa May Alcott died of the disease, a traumatic event that the writer subsequently used in her novel
Little Women
. Other ion channels, such as those released by the protozoan that causes amoebic dysentery, wreak havoc in our guts.

Battling Bugs

Humans have harnessed such channel-forming bacterial toxins for their own purposes. Some, which attack bacterial cells but not mammalian ones, have been exploited as antibiotics. Others are used as insecticides. The best known is that secreted by the bacterium
Bacillus thurigiensis
, which inserts itself into the cells lining an insect’s gut, causing them to lyse, so that the insect eventually dies of dehydration. The toxin is released as an inactive precursor that must be activated in the insect gut and so is harmless to humans.