IELTS Academic Reading Practice Test 384

Akira Endo was born in 1933 into a family of farmers in northern Japan, and he later said that the years he spent working in the fields as a boy taught him the patience that research would demand. He studied agricultural chemistry at Tohoku University, where his interest in fungi began, and in 1957 he joined Sankyo, a pharmaceutical company in Tokyo. In 1966 he took leave to spend two years at the Albert Einstein College of Medicine in New York, where he worked on the way cells build cholesterol. When he returned to Japan he brought with him a question that would occupy him for the next decade.

By the late 1960s, heart disease had become the leading cause of death in many wealthy countries, and researchers had established that a high level of cholesterol in the blood was among the strongest predictors of it. Cholesterol itself is not a poison. Every cell in the body needs it to keep its membrane in working order, and the body uses it to make vitamin D and several hormones, including testosterone and oestrogen. The liver manufactures most of what we need. The difficulty is that cholesterol does not dissolve in water, and blood is mostly water, so surplus amounts cannot simply be flushed out. They circulate instead, and in some people they settle in the walls of arteries.

Endo's idea came from microbiology. Micro-organisms compete with one another by releasing chemicals that interfere with a rival's chemistry, and the antibiotics then being discovered in Japan and elsewhere were products of exactly this kind of warfare. If one mould could make a substance that blocked the construction of a bacterial cell wall, Endo reasoned, another might make one that blocked the construction of cholesterol. The most promising target was an enzyme called HMG-CoA reductase, which catalyses an early and rate-limiting step in the synthesis of cholesterol. Block that enzyme and a cell should be unable to make cholesterol at all.

Finding such a compound was slow, repetitive work. Endo, with very little help, grew several thousand moulds in flasks of nutrient broth, using samples of soil and of rice, and tested what each had produced. His superiors at Sankyo were doubtful that a drug of this kind could ever be made. The project was never a priority for the company. In the summer of 1973 a culture of Penicillium citrinum, a common blue-green mould, yielded a substance that inhibited the enzyme powerfully. The team called it ML-236B, and later compactin.

Compactin appeared to do what the theory predicted. In laboratory dishes it stopped cells from making cholesterol, and in animals — dogs, rabbits and monkeys — it produced large falls in the cholesterol carried in the blood. The results were striking, because they suggested that a single chemical, swallowed as a pill, could lower a risk factor that diet alone rarely changed very much. Endo's team also noticed something that would later prove important. Cells exposed to the compound responded by drawing more cholesterol out of the fluid around them, as though they were trying to compensate for the loss of their own supply.

By the late 1970s small studies had begun in patients, including people with an inherited condition that leaves them with extremely high cholesterol from birth and gives them heart attacks in their thirties, or even their twenties. Compactin lowered their cholesterol substantially, and the results were published. Other groups took notice. In 1978 Endo left Sankyo for a professorship at Tokyo Noko University, where he continued to study the biology of cholesterol for the rest of his working life.

Then came the setback. In 1980 a team reported that dogs given very large doses of compactin had developed cancers of the intestine and of the lymphatic system. Whether the tumours were caused by the drug itself, or by the enormous doses used, could not be settled, but Sankyo suspended development, and compactin was never marketed as a medicine. The decision seemed to many observers to mark the end of the whole approach, and for a time work on enzyme-blocking drugs stopped in several laboratories at once.

Elsewhere the work continued. In 1978 a team at the American company Merck, led by Alfred Alberts, had isolated a similar compound from a different mould, Aspergillus terreus, and named it lovastatin. Merck's own safety studies in dogs raised similar alarms, and the company paused. Its scientists argued that the doses used had been far higher than any patient would ever receive, and after a review the programme resumed. Lovastatin was approved by the United States Food and Drug Administration in 1987, becoming the first statin available to the public.

The effect on medicine was enormous. Large trials in the 1990s, involving tens of thousands of patients, showed that statins reduced heart attacks, strokes and deaths among people who already had heart disease, and later trials extended the evidence to those at raised risk who had none. Statins became among the most widely prescribed medicines in the world. Pravastatin, a compound derived from compactin, was developed by Sankyo and reached the market in the late 1980s.

Recognition for Endo came slowly. He was awarded the Japan Prize in 2006, and in 2008 he received the Lasker award for clinical medical research, an honour that had gone in 1985 to Michael Brown and Joseph Goldstein, the American scientists who explained how cells take up cholesterol through receptors on their surface.

Cholesterol is a waxy substance that the body cannot do without. It stiffens cell membranes, provides the starting material for vitamin D and for hormones such as cortisol and testosterone, and helps the liver to make bile acids, the chemicals that digest fat in the intestine. Yet cholesterol has a property that makes it awkward to transport: it does not dissolve in water. Blood is a water-based liquid, so cholesterol cannot be carried in solution in the way that glucose is. Instead, the liver and the intestine package it with other fats inside particles called lipoproteins, which have an oily core and a shell of proteins and phospholipids that can mix with water.

The largest of these particles are chylomicrons, assembled in the cells of the intestinal wall after a fatty meal. They carry the fat we have eaten, together with a little cholesterol from food and from bile, into the lymph and then into the bloodstream, and they are cleared within a few hours by the liver and by fat tissue. Chylomicrons are so large that a sample of blood plasma left to stand may show a creamy layer at the top, which is one reason why patients are sometimes asked to fast before a blood test.

Between meals the liver takes over. It assembles very-low-density lipoprotein, or VLDL, whose core is mostly triglyceride, the fat that the body uses for storage and fuel. As VLDL travels through muscle and fat tissue, an enzyme removes its triglycerides, and the particle shrinks. It becomes intermediate-density lipoprotein and then low-density lipoprotein, or LDL, which is dense because it now consists largely of protein and cholesterol with very little fat. The journey also reduces the number of particular proteins on the particle's surface, and that change matters, because those proteins are what the tissues recognise.

LDL is the main carrier of cholesterol to the tissues. Cells that need cholesterol display receptors for LDL on their surface. When a particle binds to one of them, the cell swallows it and breaks it down, releasing the cholesterol inside. The liver, which carries more of these receptors than any other organ, removes a large share of the LDL particles from the blood. The number of receptors on a cell is not fixed. When a cell is short of cholesterol it makes more of them; when it has plenty, it makes fewer. This feedback keeps the whole system roughly in balance.

In the 1970s Michael Brown and Joseph Goldstein, working in Dallas, showed that this feedback explained a rare inherited disorder. People with familial hypercholesterolaemia inherit a faulty gene for the LDL receptor, so their cells cannot take LDL out of the blood efficiently. From childhood their LDL is two or three times the normal level, and many of them have a heart attack in their thirties or forties. The work won the two scientists the Nobel Prize in Physiology or Medicine in 1985. It also explained how a new class of drugs worked, because blocking cholesterol production inside the liver leaves that organ short of cholesterol and prompts it to put more receptors on its surface, which pulls more LDL out of the blood.

Not all lipoproteins carry cholesterol towards the tissues. High-density lipoprotein, or HDL, is assembled in the liver and intestine as a comparatively empty shell, and it collects cholesterol from cells as it circulates, returning it to the liver for disposal in bile. Because a higher HDL level is associated with lower rates of heart disease, it was long known as 'good cholesterol', and it seemed obvious that raising it would help. Trials of drugs that raised HDL substantially, however, produced little or no reduction in heart attacks, and one of them increased deaths. The association, researchers concluded, was largely a marker of other things rather than a cause.

Doctors usually begin with a lipid profile, a blood test that reports total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. LDL is often not measured directly but calculated from the other figures with a formula devised in the 1970s, which becomes unreliable when triglycerides are high. Even a direct measurement gives only the mass of cholesterol carried in LDL, not the number of particles, and some researchers argue that particle number, estimated from a protein called apolipoprotein B, predicts risk better. Guidelines differ on this point and the argument is unresolved. Most clinicians still treat the familiar figures as a reasonable guide to treatment.

Whatever is measured, most of the damage is done inside the artery wall. An LDL particle can cross the thin lining of an artery and become trapped in the tissue beneath it. There it is attacked by oxygen and by enzymes and is chemically altered. Immune cells called macrophages, which normally engulf bacteria, take up the altered LDL but cannot dispose of the cholesterol it contains; instead they swell into what pathologists call foam cells. Foam cells gather, attract further immune cells and provoke inflammation, and the result is a plaque: a fatty, fibrous swelling that narrows the artery and may eventually rupture, triggering a clot that blocks the flow of blood to the heart or the brain. Why one plaque ruptures and another does not remains one of the hardest questions in the field. Inflammation, rather than cholesterol alone, is now thought to drive much of the process.

Imagine a man of fifty-five who feels entirely well. He plays tennis, sleeps badly only when work is busy, and has no symptoms of any kind. At a routine check his blood pressure is found to be slightly raised and his cholesterol modestly above the level considered ideal. His doctor offers him two tablets to be taken every day for the rest of his life. Nothing is wrong with him in the sense that anything hurts; he is simply being asked to take medicine in order to make an event that has not happened less likely. Decisions of this kind, once unusual, are now among the commonest in medicine.

The case for such prescribing rests on a solid foundation. High blood pressure and high LDL cholesterol are not merely statistical associations; they are causes of cardiovascular disease, and lowering them lowers the risk of strokes, heart attacks and premature death. Trials in people with established disease showed this first, and later trials in people without symptoms, but at raised risk, confirmed it. The drugs involved are mostly old, cheap and available as generic tablets, which means that a health service can treat millions of people for a modest sum. On any reasonable reckoning, the introduction of statins and of modern blood-pressure drugs has prevented a very large number of deaths.

The case against is less often stated, because it sounds ungenerous. It rests not on the claim that these drugs do not work but on the arithmetic of small effects. For a person at moderate risk, the chance that any single year of treatment will save his life is very small, and expressing a trial result as a percentage reduction makes that chance look larger than it is: a fall from two in a hundred to one and a half is a reduction of a quarter, yet the great majority of those treated are no better off. Doctors speak of the number needed to treat, which for prevention is often in the dozens.

Then there is the question of harm. Trials are designed to detect heart attacks and deaths, and they count side effects poorly. Muscle aching is a common complaint among people taking statins; its true frequency is disputed, with some careful studies suggesting that much of it is not caused by the drug at all. Aspirin offers a sharper lesson. For years it was recommended to healthy people to ward off heart attacks, until trials showed that the bleeding it caused roughly balanced the benefit, and guidelines retreated. A person who feels well has more to lose from a drug that spoils his sleep or his muscles than a person who has already had a heart attack.

Behind these calculations lies a cultural shift. When a risk factor is measured, a person who considered himself healthy becomes a patient with a condition to monitor, and the threshold at which treatment begins tends to move downwards over time. A much-cited paper in the British Medical Journal in 2002 warned about 'disease mongering', the widening of the boundaries of illness in order to enlarge the market for treatment, and though the authors wrote about several conditions, the argument applies uncomfortably well to prevention. Each lowering of a threshold may be defensible on its own; taken together, such changes steadily increase the number of people taking medicines they may not need.

Prediction itself is imperfect. Risk calculators combine age, sex, blood pressure, cholesterol, smoking and other factors into a score, and the score is a reasonable summary of a group's experience, but it cannot say what will happen to one person. Most of those labelled high risk will never have a heart attack, and some of those labelled low risk will. Presented with a percentage, patients understand it in strikingly different ways, and a consultation of ten minutes is rarely enough to explain what it means. The result is that many people consent to treatment without really knowing what they are consenting to.

There is an alternative, and it is older than the drugs. In a famous essay published in 1985, the epidemiologist Geoffrey Rose distinguished between the strategy that treats individuals at high risk and the strategy that shifts the whole population's exposure. The first is necessary for those who are genuinely vulnerable, but it leaves the causes untouched; the second changes the conditions in which everyone lives. Reducing the salt hidden in processed food, taxing sugary drinks, discouraging smoking and designing towns in which walking is normal do not require anybody to become a patient, and their effects are large because they apply to everybody. The difficulty is political rather than scientific: such measures are opposed by industries whose profits depend on the status quo.

That is not an argument for retreat. Both strategies are needed, and the pills that shift the odds for a person at genuinely high risk are among the most valuable products of twentieth-century pharmacology. What I would argue is that the decision to prescribe should rest on absolute rather than relative risk, that the numbers should be explained in plain terms, and that the smallness of the benefit should be admitted openly rather than buried in a leaflet. Patients who understand that they are taking a tablet on the chance of a modest gain are making a reasonable choice; those who believe they are preventing a certainty are not. The question is not whether prevention is good, but who should be turned into a patient in order to achieve it.