You should spend about 20 minutes on Questions 1–13, which are based on Reading Passage 1 below.
The First Sight of Bacteria
In the autumn of 1676 a letter reached the rooms of the Royal Society in London that its fellows found hard to believe. The author, a Dutchman with no medical training, described creatures seen through a lens of his own making. They were, he claimed, so numerous in a single drop of water that they outnumbered the people of his country. Each, he added, was a thousand times smaller than the eye of a louse. The letter was written in Dutch, and the society's members, none of whom had met its author, asked for proof.
Antonie van Leeuwenhoek was born in Delft in 1632. His father, a basket maker, died while he was a small child, and the boy received only a modest schooling before he was sent to Amsterdam to learn the cloth trade. He returned to Delft, married in 1654 and spent the next twenty years as a draper, a respectable occupation with no connection to science. Of his children, only a daughter, Maria, survived infancy, and she kept house for him until the end of his life. Neighbours knew him as a quiet man who held a minor civic post and who retreated each evening to a workshop behind his house.
Drapers needed to count the threads in a piece of cloth, and the magnifying glass Leeuwenhoek used for this purpose may have prompted him to try better ones. Grinding a small but almost perfectly shaped piece of glass was slow, delicate work, and in the end he made hundreds of lenses, each mounted in a small brass frame.
In front of the lens he placed a pointed pin for the specimen, which could be moved in three directions by means of screws. He never explained how he ground his lenses and kept the details secret; only a handful of his instruments survive. Yet his single lenses, magnifying up to about 270 times, gave clearer images than the compound microscopes of the day, whose two lenses produced blurred fringes of colour.
Leeuwenhoek did not invent the microscope and he had no university education. He was brought to the attention of the Royal Society in 1673 by a Delft physician, Regnier de Graaf, who wrote to the society's secretary, Henry Oldenburg, about the amateur's skill. Oldenburg encouraged him, and for the next fifty years the draper sent letters to London, some running to many pages, describing whatever he had placed under his lens: mould, the sting of a bee, the structure of wood, the mouthparts of an insect.
His observations of 1674 were the first to astonish the society. Examining water from a lake near Delft, he saw minute organisms swimming and spinning, none of them visible to the naked eye. Others had glimpsed such things before, but his lenses showed them so sharply that he could follow their movements for hours and record their shapes. He called them animalcules, and he noted that they appeared in water left standing for a few days and vanished when it was boiled.
Then came the discovery that gave the letter of 1676 its fame. Leeuwenhoek soaked peppercorns in water to see what might live on the surface of the grains. After a few days the infusion contained organisms of an entirely different kind: smaller than anything he had described before, darting about, and present in extraordinary numbers. He later found similar creatures in material scraped from his own teeth. The society, shown drawings of organisms that nobody else could see, was openly sceptical and asked for more evidence. In 1677 another fellow, Robert Hooke, repeated the pepper-water experiment at a meeting of the society and confirmed what the letters had described.
Measuring the unmeasurable occupied much of Leeuwenhoek's energy. He compared his animalcules with a grain of sand, with a hair from his beard and with the eye of a louse, and calculated how many of them, laid end to end, would fill a familiar space. On one occasion he concluded that a single drop of water held more of them than there were people in the Dutch Republic. Modern counts of bacteria in a rich sample suggest that his arithmetic was nearer the truth than his critics supposed.
Recognition came slowly. In 1680 the society elected him a fellow, and curious travellers began to call at his house in Delft, among them the Russian tsar Peter the Great, who arrived in 1698 and spent time peering through his instruments. Leeuwenhoek never crossed the sea to attend a meeting in person, yet he never stopped writing. He described the flow of blood in the finest vessels of fish and frogs, the reproduction of aphids and the life cycle of the flea, and he argued, against the accepted view, that such creatures were not generated spontaneously from mud or decay.
He never wrote a book. His discoveries reached the world through his correspondence, which the society published in English translation and which was also gathered into printed collections. He died in Delft in 1723, aged 90, still working with his lenses. Nothing in his letters suggests that he connected the smallest animalcules with illness; the link between such organisms and disease was established a century and a half later, through the work of Pasteur and Koch. The word bacteria did not exist in his lifetime.
You should spend about 20 minutes on Questions 14–26, which are based on Reading Passage 2 below.
Bringing Bacteria into Focus
A bacterium is a very small object. Most of the species that live in and on the human body are between one and two micrometres across, far narrower than a human hair and about a fifth of the diameter of a red blood cell. A light microscope can, in principle, distinguish two points about 0.2 micrometres apart, so bacteria can be seen with an ordinary instrument, but only as rods, spheres or commas. Their internal structure, and the differences between one species and another, remain hidden.
For two centuries after Antonie van Leeuwenhoek first described them, bacteria were studied with instruments that had changed remarkably little. The compound microscope, with one lens close to the specimen and another near the eye, had been used by Robert Hooke in the 1660s. Nineteenth-century improvements in lens design and in staining allowed Robert Koch to identify the bacterium that causes tuberculosis in 1882, an achievement that depended as much on dyes as on glass.
The optical arrangement of a modern instrument follows the same path. At the base sits a small lamp. Beneath the stage, a condenser concentrates the light into a cone that passes through the slide. The slide itself rests on a flat stage, held by clips and moved by two knobs. The objective, the lens nearest the specimen, is screwed into a revolving nosepiece so that several powers can be exchanged. At the top, the eyepiece magnifies the image formed by the objective for the observer's eye. Total magnification is simply the product of the two: a 100× objective with a 10× eyepiece enlarges a thousand times.
Magnification is the least interesting property of a microscope; resolution matters more. However large an image is made, two objects closer together than about half the wavelength of the light used to view them will merge into a single blur. This limit, described by the German physicist Ernst Abbe in the 1870s, means that a light microscope using green light of 550 nanometres cannot separate details much smaller than 200 nanometres. The figure can be improved by using light of a shorter wavelength and by increasing the numerical aperture of the objective, a measure of how wide a cone of light it can gather. A drop of oil with the same refractive index as glass stops light from bending away between the specimen and the lens.
None of this would help if the specimen were invisible. Bacteria are almost transparent, and the early microscopists therefore killed and coloured them. The most durable of these methods was devised in 1884 by the Danish bacteriologist Hans Christian Gram, who found that bacteria treated in a particular sequence of dyes were either purple or pink, depending on the structure of their cell wall. The Gram stain still divides bacteria into two great groups and is still the first step in most hospital laboratories. The dyes, however, usually kill the cells they colour.
Seeing bacteria alive required a different approach. The Dutch physicist Frits Zernike worked out in the 1930s that light passing through a transparent object is slowed slightly, and that this difference in phase can be converted into a difference in brightness. Phase contrast requires no dye at all, and it allows a living cell to be watched as it divides. Zernike received the Nobel Prize in Physics in 1953.
Fluorescence microscopy added colour and specificity. Certain molecules absorb light of one wavelength and emit it at another, so a dye attached to an antibody, or a fluorescent protein produced by the cell itself, can make a chosen structure glow against a dark background. The green fluorescent protein, first isolated from a jellyfish, has been used in this way since the 1990s, and its development as a research tool was recognised with a Nobel Prize in 2008.
Fluorescence also provided the route past Abbe's limit. In the 1990s Stefan Hell showed that a second beam of light could switch off the glow everywhere except in a tiny spot, and other groups found ways to build an image from the positions of individual molecules recorded one at a time. These techniques, known collectively as super-resolution microscopy, resolve details only tens of nanometres apart. The Nobel Prize in Chemistry in 2014 was awarded for their development.
Electron microscopes abandon light altogether. A beam of electrons has a wavelength thousands of times shorter than that of visible light, and the first instruments, built by Ernst Ruska and others in the 1930s, soon revealed details far beyond the reach of any lens. The price is a loss of life: electrons scatter in air, so the specimen must be dried or frozen and placed in a vacuum, and it is examined as a still image rather than a living cell. Cryo-electron microscopy, which preserves frozen specimens in a near-natural state, was recognised with a Nobel Prize in 2017.
Where does that leave the study of bacteria today? Light microscopy remains the only way to watch a living cell in real time, and it is now used to follow the effects of antibiotics on individual bacteria within minutes of treatment. The difficulty is that the brightest techniques damage the cells they illuminate, and that super-resolution methods combine many separate images, so that anything moving quickly becomes a blur. How far these methods can be pushed before the light itself alters what is being observed is a question that laboratories are still working to answer.
You should spend about 20 minutes on Questions 27–40, which are based on Reading Passage 3 below.
Should Antibiotics Be Sold Only on Prescription?
The arguments for and against restricting access to antibiotics
In a pharmacy in many parts of Africa or South Asia, a customer with a sore throat can buy a strip of amoxicillin over the counter, without a prescription and often without seeing anyone trained to diagnose. In most of Europe the same transaction is illegal. The difference is not a small administrative detail. It shapes how much of the world's antibiotic supply is consumed, and therefore how quickly bacteria lose their susceptibility to it.
The argument for prescription-only sale rests on a simple piece of biology. Every course of antibiotics applies pressure to a bacterial population: the susceptible die, and any that happen to resist survive and multiply. The more a drug is used, the stronger that pressure becomes. Resistant bacteria do not stay where they arose; they travel with people, with animals and in food, which is why the problem is treated as a global one. Restricting sales to prescription has curbed unnecessary use wherever it has been enforced, because it places a trained person between the patient and the drug. The cost of failure is measured in lives: an analysis published in 2022 attributed about 1.27 million deaths in 2019 directly to infections that resisted the drugs used against them.
Alexander Fleming, who discovered penicillin, saw the danger clearly. In his Nobel lecture in 1945 he described a hypothetical patient who buys the drug cheaply without a prescription, takes too little to kill the bacteria, and thereby teaches them to resist. His warning has lost none of its force; the behaviour he imagined is exactly what a prescription requirement is designed to prevent. What he did not consider was the patient for whom no prescriber exists.
That patient is not unusual. In much of the world the nearest clinic is a long and expensive journey away, while the pharmacy is at the end of the street. In rural districts of low-income countries, a clinic may have no doctor at all for most of the week. A child with pneumonia needs the right antibiotic within hours, and a rule that delays it may cost more lives than it saves. The World Health Organization has repeatedly pointed out that, for all the concern about excess, a great many people still die for want of antibiotics that exist. Any policy that treats restriction as an end in itself will be judged by that failure.
Then there is the question of enforcement. In many countries a prescription is already required by law, yet the law is routinely ignored, and a rule that everyone breaks teaches people that rules do not matter. Worse, prohibition pushes the trade towards sellers who ask no questions, keep no records and stock whatever is cheapest, including tablets with too little active ingredient to cure anything and just enough to encourage resistance.
Doctors are not blameless either. Surveys of prescribing in hospitals and clinics repeatedly find that a large share of antibiotic courses are unnecessary, or use drugs broader in spectrum than the infection requires. A prescription requirement does nothing to correct this; it merely moves the decision into a consulting room, where it may still be made badly. Education and feedback for prescribers matter as much as any rule about who may hand over the box.
Projections are hazardous, but they frame the debate. A review chaired by the economist Jim O'Neill, published in 2016, estimated that resistant infections could cause ten million deaths a year by 2050 if nothing changed. That figure is a model, not a measurement, and the assumptions behind it have been questioned. Even so, its direction is hard to dispute.
What would a workable policy look like? The World Health Organization's classification of antibiotics offers a starting point: it sorts the drugs into three groups, named Access, Watch and Reserve, according to how urgently they need to be preserved, and it argues that the Access group should be widely available while the Reserve group is tightly controlled. Trained pharmacy staff could dispense a short list of first-line medicines for common infections, referring everything else to a clinic. Controls would then fall hardest on the drugs that matter most.
Rapid diagnostic tests would help, by separating bacterial infections from viral ones that antibiotics cannot touch. Several such tests exist, and a few can be used in a consulting room rather than a laboratory. None is yet reliable enough to replace clinical judgement, however, and the tests that work best are the ones least likely to be available where the need is greatest. A test that costs more than the course of tablets it replaces will not be bought by a clinic with a fixed budget.
The sensible aim, then, is not a prescription for every packet. It is a system in which the drugs that matter most are tightly controlled and those that people need are within reach. Prescription-only dispensing should remain the goal, but it should be reached by training and equipping the people who already sell medicines, not by pretending that they do not exist, and not by insisting on a clinic in every district when no country could afford one. A rule that people cannot comply with is not a policy but a formality.
Tip: select any text in the passage to highlight it in one of four colours. Click a highlight to remove it.