From Common Colds to Ebola Epidemics – Why We Need the Viruses That Plague Us
by Frank Ryan
A virologist’s insight into how viruses evolve and why global epidemics are inevitable
In 1993 a previously healthy young man was drowning in the middle of a desert, in fluids produced by his own lungs. This was the beginning of the terrifying Sin Nombre hantavirus epidemic and the start of a scientific journey that would forever change our understanding of what it means to be human.
After witnessing the Sin Nombre outbreak, Dr Frank Ryan began researching viral evolution and was astonished to discover that it’s inextricable from the evolution of all life on Earth. From AIDS and Ebola to the common cold, Ryan explores the role of the virus within every ecosystem on the planet. His gripping conclusions shed new light on the natural world, proving that what doesn’t kill you really does make you (and your species) stronger.
What are viruses?
Only in the last decade have we come to realise that, from its very beginnings, all of cellular life has inhabited not only the visible biosphere – of solid earth, air and oceans – but also a less familiar and invisible virosphere. The viruses that constitute this virosphere are not merely surrounding us, they are within us, both as evolving extrinsic organisms in themselves and as interactive symbiotic entities that are an intrinsic part of our being. We might not be aware of the presence of these minuscule passengers within us from moment to moment, but the passengers are, in their quintessentially viral way, aware of us.
This might seem somewhat daunting, even frightening, to some of us, but there is no need for alarm. They have always been there. It is likely that they preceded any origins of human life on planet Earth, or indeed, going further back, the origins of the mammals, or any animals or plants, or fungi, or, if I am right, even the single-celled amoebae. All that has changed is that the world of virology is coming to understand the role of viruses in the origins and diversity of life, and what might appear incongruous to any notion of viruses being exclusively agents of disease, the health of the biosphere.
For viruses to achieve all this they must surely possess some remarkable properties. For example, they have no means of locomotion yet they move among us: in pandemic forms they effortlessly circulate around the globe. Although they have no sense of vision, hearing, touch, smell or taste, they detect with uncanny precision the cell, or organ or tissue that is their target destination. This they achieve despite the relentless opposition of powerful immune defences designed to prevent this happening; and once arrived, they penetrate the defences of the target cell, break entry through its protective surface membrane, and once inside take over its physiological, biochemical and genetic programming to compel the cell to become a factory for the production of a new generation of themselves.
Welcome to the world of viruses!
It is, admittedly, a very strange world replete with mysteries. It becomes all the more quixotic when we attempt to examine it at the most basic level.
What then are viruses? How do we even begin to define them? What, for instance, is the difference between, say, a bacterium and a virus? While viruses and bacteria are often confused in the minds of ordinary folk, because they cause many of the common infectious diseases, bacteria and viruses are very different entities. Viruses are more difficult to define than bacteria because they are said to occupy a position somewhere between the biological notions of life and non-living chemicals. This has tempted a distinguished colleague to dismiss them as ‘a piece of mischief wrapped up in a protein’. While the hubris contains a grain of truth, there is rather more to viruses than being merely a source of mischief. So let us delve a little deeper! Do viruses rely on genes, and genomes, like all of the more familiar forms of life, from whales to humans and buttercups to the so-called ‘humble’ bacterium? The answer to that question is, ‘Yes!’ Viruses do indeed have genomes, which contain protein-coding genes. We shall discover more about those viral genomes in subsequent chapters when we shall also observe some important differences between the genomes of viruses and all other organisms.
Do viruses follow the same patterns of evolution as, say, plants and animals? The answer again is, ‘Yes!’ But the patterns of evolution – the specific mechanisms involved – are heavily influenced by a facet of their organismal existence that is confined to viruses. Viruses can only replicate by making use of the host cell’s genetic apparatus, and because of this, viruses were formerly defined as ‘obligate genetic parasites’. But with our increasing understanding of viruses, and of their complex roles in relation to the evolution of their hosts, this definition is no longer sufficient to characterise them. A more adequate definition must take on board the fact that viruses are symbionts. Indeed, we now know that viruses are the ultimate symbionts, exhibiting many examples of all three patterns of symbiotic behaviour, namely parasitism, commensalism and mutualism. Moreover, since viruses will sometimes employ aggression as an evolutionary pattern of behaviour in relation to their hosts, they are also potentially ‘aggressive symbionts’.
The more we examine viruses, in their evolutionary trajectories and in the influence of that trajectory on the evolution of their hosts, the stranger and more fascinating their story becomes. Is it reasonable to propose that viruses were born at the stage of chemical self-replicators before the actual advent of cellular life on Earth? If so, how then, from those primal beginnings, did viruses evolve, to interact with, and thus contribute to, the evolution of all of life on this planet?
The aim of this book will be to enlighten readers through a step-wise progression, starting with a familiar territory: we shall confront the wide range of illnesses that are caused by viruses. For example, we shall examine what is really going on in the common cold, the childhood illnesses such as measles, chickenpox, herpes and mumps, rubella, as well as less familiar examples such as rabies, ‘breakbone fever’, haemorrhagic fevers such as Ebola, and virus-induced cancers such as Burkitt’s lymphoma. In such an examination we shall discover what makes viruses tick, exploring what’s actually going on inside us when we encounter the virus, how this gives rise to the symptoms we get from the infection, and, key to deeper understanding, probing what the virus itself gets from the ‘interaction’ with its human host. We shall employ the same virus-orientated perspective to explore important epidemic forms such as influenza, smallpox, AIDS and polio, which will illustrate how viral infections have impacted on human social history, from the wall paintings of the Ancient Egyptians to the colonisations of the Americas, Australasia and Africa. We shall also take a close look at vaccines as a measure to prevent epidemic infections, from the first introduction of vaccination against smallpox centuries ago to the recent controversy concerning the triple vaccine and the papilloma virus vaccine.
The science of virology grew out of the study of viruses in the causation of disease. Through understanding the viruses already familiar to us, we shall widen our enlightenment by examining the role of viruses in the evolution of life, and in particular we shall explore the role of viruses in our human evolutionary history. We shall see how, throughout our prior evolution, we have shared our existence with these powerful invisible entities, and how they really have changed us at the most intimate level, to help make us human.
I hope that, like me, you will come to appreciate the enormous importance of viruses to life, in its origins and complexity, while also marvelling at the existential nature of what is one of the great wonders of life on our beautiful blue-oceanic planet. Viruses, by and large, have had a bad press. This is understandable, given the experiences of earlier generations of virologists, whose only contact with viruses was in dealing with the infections caused by them. But today a major wind of change is blowing through the world of virology – so much so that recently a distinguished evolutionary virologist declared that we were witnessing what he called ‘The Great Virus Comeback’. What does he mean by this? Why have some of the modern pioneers of virology introduced the term ‘virosphere’ as the key to a new exploration of the importance of viruses to the entire biosphere? Could it be true that, as some would have us believe, viruses should now be seen as the ‘Fourth Domain of Life’?
Coughs and Sneezes Spread Diseases
Historically, viruses were included with the so-called ‘microbes’ – tiny organisms that were originally discovered as the cause of infectious diseases in humans, animals and plants. Interestingly, there is a part of us that has long been intimately acquainted with microbes in general, and with viruses in particular. This is our inbuilt system of defences against infection: what doctors refer to as our immune system. It is perhaps as well that we possess this inbuilt immunological protection, because we inhabit a world that teems with microbes.
A veritable zoo of such microbes covers our skin and other surface membranes. Biologists call this the ‘human microbiome’. Although it might cause some of us to squirm a little just to acknowledge its existence, this secret world is no real threat to us. It is an intrinsic part of our being, comprising a variety of bacteria, as well as other microbial forms, that inhabit our surface skin, mouth and throat, nostrils and nasal cavities, and in the case of women, the genital passages. Our bodies are said to contain roughly 30 to 40 trillion cells – if you are mathematically inclined, this is 3 to 4 times 10
– which comprises the sum total of living cells that make up our living tissues and organs. Meanwhile our ‘microbiome’, which amounts to all of the microbes that inhabit our skin, gut, oral and nasal passages and throat, and genital tract in women, accounts for some ten times as many microbial cells, comprising such organisms as bacteria, Archaea and protists. It is natural enough, given our awareness of past epidemics and day-to-day troublesome infections, to assume that such microbes are invariably harmful; but these microbes that make up our personal microbiomes are not hostile. Some simply live off us in commensal fashion without causing us any harm; while many others help to maintain our normal health. For example, the zoo of microbes that inhabit our large bowels, or colons, play an important beneficial role in our human nutrition – such as in helping us to absorb vitamin B12 – as well as helping to protect us from invasion of our digestive tract by pathological visitors. The bodies of this ‘colonic flora’ account for no less than 30 per cent of the bulk of our faecal waste.
There is also growing evidence that we benefit in a number of other ways from this microbial flora of our skin, and other abdominal cavities. This holistic realisation begs a relevant question: could viruses be a part of this human biome, capable of contributing to our human health? For any group of microbes to contribute to the nutrition or general well-being of a host, this would imply a lengthy period of symbiotic evolution with the same host. Immediately we even come to consider such a curious virus–host interaction, we are obliged to consider something profoundly different about viruses when compared to cellular symbionts, such as the bacterial flora of the human intestine or skin. Viruses inhabit the landscape of the host genome.
This means that viruses are certainly not going to contribute, for example, to human vitamin digestion. What it really implies is that, if viruses are to contribute in some way to host health – or indeed host evolution – that contribution is likely to be much more subtle, involving, perhaps in the human host, an interaction with our immunological defences, or more profoundly still, an interaction with our human genetic machinery – or most profound of all, changing our very human genome, the repository of our human heredity, buried deep in the nucleus of every human cell. If this were to happen, viruses would have contributed to what makes us human.
These are weighty questions. Perhaps many of my readers might be inclined to make the point that, so far as they are aware, only the less helpful kinds of viruses appear to have come their way.
In this book we shall explore the truly strange, and intriguing, world of viruses. We might make a start by dispelling a common misconception; many people tend to confuse viruses with bacteria. This is perfectly understandable since viruses, like bacteria, cause many of the common ailments that afflict us in our ordinary lives, and particularly so the fevers that beset the lives of our children. Family doctors deal with these common ailments on a day-to-day basis, and they tend to treat them in similar ways, with antibiotics for bacterial illnesses and vaccination programmes or antiviral drugs aimed at protecting kids from the common viral infections. It is little wonder that people are apt to confuse viruses with bacteria. What then is the difference between the two?
In fact there are major differences between bacteria and viruses. The most obvious difference is one of scale: most viruses are much smaller than bacteria. We readily grasp this if we take a closer look at what is going on during those coughs and sneezes that we recognise as the harbingers of that bothersome cold. While a few other viruses can cause an illness resembling a cold, the majority of colds are caused by a particular virus, which goes by the name of ‘rhinovirus’. If one harks back to the sneezing, snuffling and nose-blowing that are the familiar symptoms of that developing cold, the name rhinovirus is apt, since ‘rhino’ derives from the Greek word, rhinos, for nose. Rhinoviruses are the commonest virus infections to afflict humans worldwide, with a seasonal peak in the autumn and early winter. The more we learn about the rhinovirus, the more we witness how well-suited it is to its natural environment, and to its life cycle of infectious behaviour and spread.
The rhinovirus is exceedingly tiny, at about 18 to 30 nanometres in diameter. A nanometre, or nm, is one-thousand-millionth of a metre. This clearly tells us that a single rhinovirus organism – it is referred to as a ‘virion’ – is absolutely minuscule. In the evolutionary system of classification known as ‘taxonomy’, rhinoviruses are classed as a genus within the family of the ‘picornaviruses’, a word derived from pico for small, and rna, because the rhinovirus genome is made up of the nucleic acid RNA rather than the more familiar DNA. Let us put aside any discussion of these genetic molecules for the moment, but we shall return to consider some remarkable implications of RNA-based viral genomes in subsequent chapters.
Returning to the differences in scale between viruses and bacteria, rhinoviruses are far too small to be seen under the ordinary laboratory light microscope. The virions can only be visualised under the phenomenal magnification of the electron microscope, when they appear to be roughly spherical in shape, resembling tiny balls of wool. In fact, if we examine the individual virions more closely under the electron microscope, we see that they are not really spheres but have multifaceted surfaces, rather like cut diamonds. In the technical jargon, the multifaceted surface of the rhinovirus is the viral ‘capsid’, which is the viral equivalent of a human cell’s enclosing membrane. This capsid has a striking mathematical symmetry comprising 20 equilateral triangles. All viruses have genomes, made up of either DNA or its sister molecule, RNA. The protein capsid acts as a protective shell that encloses the viral genome. It is the capsid that gives rhinoviruses their quasi-crystalline appearance, known as ‘icosahedral’ symmetry – the term is simply the Greek for ‘twenty-sided’. The multifaceted symmetry is not comprised of diamantine crystal, however, but constructed by a biochemical protein assembly.
Microbiologists had long recognised the presence of viruses before the electron microscope was invented. They found ways of detecting the presence of viruses from their effects on host cells, and they could even count their precise numbers from their cytopathic effects in cultures. It will come as no surprise to discover that the best cultures for growing rhinoviruses are cells derived from the human nasal lining, or the lining of the windpipe, or trachea. We are equally unsurprised to learn that the best temperature at which to culture cold viruses is between 33°C and 35°C, which is the temperature found within our human nostrils on a cold autumnal or winter’s day.
Rhinoviruses are highly adapted for survival in their host environment. They are also highly adapted to infect a specific host. This became apparent when scientists attempted to infect laboratory animals, including chimpanzees and gibbons, with a variety of different subtypes of rhinovirus that readily infected humans. They could not replicate the symptoms of a typical cold in any of the animals. From this we glean an important lesson about viruses: the rhinovirus is most particular when it comes to its choice of host, which is exclusively Homo sapiens. This has a pertinent significance; it means that human infection is vitally important to virus survival. Only through human to human contagion can the virus be passed on and breed new generations of rhinovirus. We are the natural reservoir of the cold virus.
But a moment or two of reflection on such exclusivity provokes a tangential thought – and a pertinent question. These minuscule polyhedral balls have no obvious means of locomotion. How can they possibly move about through our human population to effortlessly spread their infection across national and even international boundaries?
In fact, we already have the answer: it is implied in the very title of this chapter. Why do we cough and sneeze? We do so because this is what happens when our noses, throats and windpipe passages feel irritated. It is part of the natural defences against foreign material entering passages where it could block our airways and, implicitly, obstruct them and threaten our breathing. What rhinoviruses do is to provoke the same physiological responses by irritating the linings of our nasal passages. The viruses spread from person to person because they are explosively ejected into the ambient air with every cough and sneeze, to be inhaled and subsequently infect new hosts. And here, once again, we learn something vitally important about viruses. The viruses do not need any mechanism of locomotion because they hitch a ride on our own locomotion, and everywhere we go, we further oblige them by spreading their contagion by coughing and sneezing.
How clever, we are inclined to think, are viruses!
But viruses could not possibly be clever. They are far too simple to be capable of thinking for themselves. We are instead confronted by another of the numerous enigmas in relation to viruses. How, for example, could an organism some paltry 30 nanometres in diameter acquire such devious but also such highly effective patterns of behaviour as we discover in the common cold? The answer is that viruses do this through their evolution. Indeed, viruses have an extraordinary capacity to evolve. They evolve much faster than humans, even much faster than bacteria. Over subsequent chapters we shall see how that viral employment of host locomotion is one of many such evolutionary adaptations.
What then do rhinoviruses do when they get inside us?
We have seen that the rhinovirus has a specific target cell, the cilia-flapping cells lining the nasal passages. Once inhaled, the virus targets these lining cells, discovering a specific ‘receptor’ in the cell’s surface membrane, after which the virus uses the receptor to break through the membranous barrier and gain entry into the cell’s interior, or cytoplasm. Here the virus hijacks the cell’s metabolic pathways to convert it into a factory for the replication of daughter viruses. The daughter viruses are extruded into the nasal and air passages, there to search out new cells to infect and continue the invasive process. It seems to require only a tiny dose of virus to be inhaled from the expelled cough or sneeze of an infected person to initiate infection in a new individual. After arrival, the incubation period from virus entry to infected nasal cells exuding new daughter viruses can be as little as a day. We don’t have much of a chance of escaping infection once the virus has been inhaled. Virus replication peaks by day four.
Fortunately, it isn’t all one way. Even as the virus is launching its attack, the human immune system has registered the threat, and it has recognised the viral antigenic signature – what we call the serotype. The problem is that the arrival of a new serotype requires time for the immune system to recognise the threat and to build up a formidable arsenal of responses. By day six the nasal passages are the focus of a virus versus immunological war zone, with no quarter asked or given on either side. This intense immune response causes the nasal passages to shed most of their lining cells, exposing highly inflamed raw surfaces, with narrowed breathing passages exuding copious mucus, which contains rising levels of antibodies to the virus. The rhinovirus is eventually killed off by the neutralising antibodies and the ‘war detritus’ is cleared away by the gobbling action of phagocytic white cells. During this immunological conflagration the new host follows the same unfortunate cycle of being infectious to others, through coughing and sneezing, for a period of anything from one to three weeks.
There is an adage that colds will not kill you. This is largely true, but colds can make children more liable to sinusitis and otitis media, a nasty bacterial infection of the middle ear. Colds can also precipitate asthma in people constitutionally prone to it, and they can provoke secondary bacterial chest infections in people suffering from cystic fibrosis or chronic bronchitis. Nevertheless, the salutary consolation is that, in the great majority of human infections, the rhinovirus eventually passes on by and we make a complete recovery.
Is there anything we can do to minimise the risk of contracting that cold – or is there any effective treatment when we are afflicted?
In Roman times, Pliny the Younger recommended kissing the hairy muzzle of a mouse as a remedy for colds. Benjamin Franklin was more sensible, suggesting that exposure to cold and damp in the atmosphere was responsible for the development of a cold. He also recommended fresh air and avoiding the exhaled air of other people. More modern times have seen a veritable cornucopia of quack remedies for prevention or treatment of colds. One of the most popular was vitamin C, championed by the distinguished American chemist, Linus Pauling. But alas, when subjected to scientific scrutiny it proved no more effective than the mouse’s whiskers. Perhaps we should focus more on common sense? Colds are contracted from the coughs and sneezes of infected people. People in congested offices, or even relatives who find themselves ill at home, should follow the old adage: trap your germs in a handkerchief. If an individual is deemed to be at a particularly high risk from a cold, wearing a virus-level face mask would certainly reduce the likelihood of infection when exposed to an infectious source.
A pertinent question remains: why, then, if our immune system has come to recognise and react to the rhinovirus, are we still susceptible to further colds during our lifetime? In fact, there are roughly 100 different ‘serotypes’ of the rhinovirus, so immunisation to any one type would not provide adequate protection from the others. Added to this is the fact that serotypes are capable of evolving so that their antigenic properties are apt to change.
A Plague Upon a Plague
In 1994 the East African nation of Rwanda erupted onto the world’s news and television screens when a simmering civil war between the major population of Hutus and minority population of Tutsis erupted into a genocidal slaughter of the minority population. But despite the deaths of half a million Tutsis, the Hutu perpetrators lost the war, causing more than two million of them to flee the country. Roughly half of these fled northwest, across the border of what was then Zaire, these days the Democratic Republic of the Congo, where they ended up around the town of Goma. Up to this point Goma had been a quiet town of some 80,000 people, nestling by Lake Kivu in the lee of a volcano. Goma now found itself overwhelmed by a desperate torrent of refugees, carrying everything from blankets to their meagre rations of yams and beans. Two hundred thousand arrived in a single day, confused, thirsty, hungry and homeless. They camped on doorsteps, in schoolyards and cemeteries, in fields so crowded that people slept standing up. Agencies from the world’s media flocked to the vicinity, reporting the chaos and the urgent need for shelter, food and water.
A reporter for Time magazine estimated that the volume of refugees needed an extra million gallons of purified water each day to prevent deaths from simple thirst, meanwhile the rescue services were managing no more than 50,000. Desperate people foraged for fresh water, scrabbling hopelessly in a hard volcanic soil that needed heavy mechanical diggers to sink a well or a latrine. Human waste from the relief camps fouled the waters of the neighbouring Lake Kivu, creating the perfect circumstances for the age-old plague of cholera to emerge. Within 24 hours of confirmation of the disease some 800 people were dead. Then it became impossible to keep count.
Viruses are not the only cause of plagues, which include a number of lethal bacteria, such as the beta-haemolytic streptococcus, tuberculosis and typhus, as well as some protists, which cause endemic illnesses such as malaria, schistosomiasis and toxoplasmosis. Cholera is a bacterial disease, caused by the comma-shaped Vibrio cholerae. The disease is thought to have originated in the Bengal Basin, with historical references to its lethal outbreaks in India from as early as 400 CE. Transmission of the germ is complex, involving two very different stages. In the aquatic reservoir the bug appears to reproduce in plankton, eggs, amoebae and debris, contaminating the surrounding water. From here it is spread to humans who drink the contaminated water, where it provokes intense gastroenteritis, which proves rapidly fatal from massive dehydration as a result of the fulminant ‘rice-water’ diarrhoea. This human phase offers a second reservoir for infection to the bug. If not prevented by strict hygiene measures, the extremely contagious and virulent gut infection causes massive effluent of rice-water stools that are uncontrollable in the individual sufferer, so that they contaminate their surroundings, and especially any local sources of drinking water, leading to a vicious spiral of very rapid spread and multiplication of the germ.
During the nineteenth century, cholera spread from its natural heartland, provoking epidemics in many countries of Asia, Europe, Africa and America. The massive diarrhoeal effluent of cholera is unlike any normal food poisoning. An affected adult can lose 30 litres of fluid and electrolytes in a single day. Within the space of hours, the victims go into a lethargic shock and die from heart failure.
The English anaesthetist, John Snow, was the first to link cholera with contaminated water, expounding his theory in an essay published in 1849. He put this theory to the test during a London-based outbreak around Broad Street, in 1854, when he predicted that the disease was disseminated by the emptying of sewers into the drinking water of the community. Snow’s thoughtful research led to the civic authorities throughout the world realising the importance of clean drinking water. Today the life of an infected person can be saved by very rapid intravenous replacement of fluid and electrolytes, but the size of the outbreak around Lake Kivu, and the relative paucity of local medical amenities, limited the clinical response. The situation was made even worse by the recognition that the cholera in the Rwandan refugee camps was now confirmed as the 01-El Tor pandemic strain of Vibrio, known to be resistant to many of the standard antibiotics. This presented immense problems for the medical staff from local health ministries and those arriving from the World Health Organization. Even though the response was one of the largest relief efforts in history – involving the Zairian armed forces, every major global relief agency and French and American army units – the spread of cholera was too rapid for their combined forces to take effect.
Three weeks after the outbreak began, cholera had infected a million people. Even with the modern knowledge and the desperate efforts of civic and medical assistance, the disease is believed to have killed some 50,000. It is hard to believe that so resistant a plague bacterium as the Vibrio cholerae might itself be prey to another microbe. But exactly such an attack, of a mystery microbe upon the cholera vibrio, had been recorded in a historic observation by another English doctor close to the very endemic heartland of the disease, a century before the outbreak at Lake Kivu.
In 1896 Ernest Hanbury Hankin was studying cholera in India when he observed something unusual in the contaminated waters of the Ganges and Yamuna Rivers. Hankin had already discovered that he could protect the local population from the lethal ravages of the disease by the simple expedient of boiling their drinking water before consumption. When, in a new experiment, he added unboiled water from the rivers to cultures of the cholera germs and observed what happened, he was astonished to discover that some agent in the unboiled waters proved lethal to the germs. It was the first inkling that some unknown entity in the river waters appeared to be preying upon the cholera bacteria.
Hankin probed the riddle further. He found that if he boiled the water before adding it to the cholera germ cultures this removed the bug-killing effect. This suggested that the agent that was killing the cholera germs was likely to be of a biological nature. He needed to know if it was another germ – sometimes germs antagonised one another – or if it was something completely different, a truly mysterious agent, that was killing the germs. Hankin decided that he would set up a new experiment using a device known as a Chamberland-Pasteur ‘germ-proof’ filter, which had been developed 12 years earlier by the French microbiologists Charles Chamberland and Louis Pasteur. The Chamberland-Pasteur filter was a flask-like apparatus made out of porcelain that allowed microbiologists to pass fluid extracts through a grid of pores varying from 0.1 to 1.0 microns in diameter – from 100-billionths to 1,000-billionths of a metre – that were designed to trap bacteria but allow anything smaller to pass through. Two years after the filter’s invention, a German microbiologist, Adolf Mayer, showed that a common disease of tobacco plants, known as tobacco mosaic disease, could be transmitted by a filtrate that had passed through the finest Chamberland-Pasteur filter. Unfortunately, he persuaded himself that the cause of the disease must somehow be a very tiny bacterium. In 1892 a Russian microbiologist, Dmitri Ivanovsky, repeated the experiment to get the same results. He refuted a bacterial cause, but still arrived at the mistaken conclusion that there must be a non-biological chemical toxin in the liquid extract. Finally, in 1896, the same year that Hankin was looking for his mystery agent in the Indian river waters, a Dutch microbiologist, Martinus Beijerinck, repeated the filter experiment with tobacco mosaic disease; but Beijerinck concluded that the causative agent was neither a bacterium nor a chemical toxin but rather ‘a contagious living fluid’. Although Beijerinck was closest of all to the truth, he was once again wrong. Today we know that the cause of tobacco mosaic disease is a virus – the tobacco mosaic virus. But thanks to Beijerinck’s mistaken finding of a ‘contagious fluid’, the current Oxford English Dictionary definition of a ‘virus’ has it as: ‘a poison, a slimy fluid, an offensive odour, or taste’.
Viruses are not poisons, or slimy fluids, or offensive odours or tastes, but rather organisms – truly remarkable organisms – that are different from bacteria, indeed utterly different from any other organisms on Earth. The great majority of viruses are very small, tiny enough to pass through Chamberland-Pasteur filters.
Of course, Hankin knew nothing of the existence of viruses when he passed the river water through the refined sieve of a Chamberland-Pasteur filter. Although he was in no position to offer a likely explanation or name for the mystery agent, he had discovered one of the most important and ubiquitous of viruses on Earth: a member of the group known today as ‘bacteriophage’ viruses, so-named from the Greek phagein, which means to devour. That is exactly what was happening to the cholera germs in Hankin’s experiments: they were being ‘devoured’ by bacteriophage viruses.
The true nature of Hankin’s discovery remained a mystery until 1915, when English bacteriologist Frederick Twort discovered a similarly minuscule agent that could pass through the Chamberland-Pasteur filters and yet remained capable of killing bacteria. By now viruses were known to exist even though biologists knew very little about them. Twort surmised that he was observing either a natural phase of the life cycle of the bacteria, the result of a fatal enzyme produced by the bacteria themselves, or a virus that grew on and destroyed the bacteria. Some two years later, a pioneering, self-taught, French-Canadian microbiologist, Félix d’Herelle, finally solved the mystery.
D’Herelle was born in the Canadian city of Montreal but considered himself a citizen of the world. Before becoming involved with viruses, he had already travelled widely, working in numerous American, Asian and African countries, to finally settle at the Pasteur Institute in Paris. At this time the discipline of microbiology was a fashionable scientific research endeavour and it was rapidly expanding its knowledge base. During his researches in Tunisia, d’Herelle had come across what was probably a virus infecting a bacterium that itself caused a lethal plague in locusts. Now working at the famous Institute, even as the First World War raged nearby, he took a particular interest in the grimy disease known as bacterial dysentery, which was killing soldiers in their muddy trenches.
Bacterial – as opposed to amoebic – dysentery is caused by a genus called Shigella, which is passed on from the infected individuals through faecal hand-to-mouth contagion. The resultant illness ranges from a mild gut upset to a severe form, with agonising griping spasms of the bowel accompanied by high fever, bloody diarrhoea and what doctors call ‘prostration’. In July and August 1915 there was an outbreak of haemorrhagic bacterial dysentery among a cavalry squadron of the French army, which was stalemated on the Franco-German front little more than 50 miles from Paris. The urgent microbiological investigation of the outbreak was assigned to d’Herelle. In the course of intensive investigation of the bugs responsible, he discovered ‘an invisible, antagonistic microbe of the dysentery bacillus’ that caused clear holes of dissolution in the otherwise opaquely uniform growth of dysentery bacteria on agar culture plates. Unlike his earlier colleagues, he had no hesitation in recognising the nature of what he had found. ‘In a flash I understood: what caused my clear spots was … a virus parasitic on the bacteria.’
D’Herelle’s hunch proved to be correct. Indeed, it would be d’Herelle who would give the virus the name we know it by today: he called it a ‘bacteriophage’. Then the French-Canadian microbiologist had an additional stroke of luck. When studying an unfortunate cavalryman suffering from severe dysentery, he performed repeated cultivations of a few drops of the patient’s bloody stools. As usual, he grew the dysentery bug on culture plates and passed a fluid extract through a Chamberland-Pasteur filter, thus obtaining a filtrate that could be tested for the presence of virus. Day after day, he tested the filtrate by adding it to fresh broth cultures of the dysentery bug in glass bottle containers. For three days the broth quickly turned turbid, confirming teeming growth of the dysentery bug. On the fourth day new broth cultures initially became turbid as usual, but when he incubated the same cultures for a second night he witnessed a dramatic change. In his words, ‘All the bacteria had vanished: they had dissolved away like sugar in water.’
D’Herelle deduced that what he was witnessing was the effects of a bacteriophage virus, which must also be present in the cavalryman’s gut – a bacteriophage virus that was capable of devouring the Shigella germ. But then he had an additional stroke of genius. What if the same thing was happening inside the infected patient? He dashed to the hospital to discover that during the night the cavalryman’s condition had greatly improved and he went on to make a full recovery. At this time bacterial infections, such as dysentery, typhoid fever, tuberculosis and the streptococcus, were a major cause of disease and death throughout the world. With no known antibiotics to treat infections, there was a desperate need for any form of therapy. His observations with the dysentery bug bacteriophage gave d’Herelle the idea that, perhaps, phage viruses might be cultivated with the express purpose of treating dangerous bacterial infections.
During the 1920s and 1930s, d’Herelle conducted extensive research into the medical applications of bacteriophages, introducing the concept of phage therapy for bacterial infections. This therapy saw widespread use in the former Soviet Republic of Georgia, and also the United States, continuing in use until the discovery of antibacterial drugs in the 1930s and 1940s. The use of drugs was much simpler to apply and proved dramatically effective, thus supplanting bacteriophage therapy. But this did not stop d’Herelle from continuing to study this marvellous if deadly entity that was so very tiny that it was completely invisible even to the most powerful light microscope, and yet appeared to be so powerful when it came into contact with its prey bacteria.
In 1926, d’Herelle published a now-historic book, The Bacteriophage, in which he described his work, and thoughtful extrapolations, concerning bacteriophage viruses. As we shall duly discover, the importance of the bacteriophage, as we recognise it today, has eclipsed all that even its pioneering researcher, Félix d’Herelle, could possibly have imagined in those early years.
In retrospect, it is remarkable that, even so many decades ago, d’Herelle clearly grasped that he was dealing with a wonder of the natural world, declaring in his book that these agents that were so dreadfully lethal to bacteria were also capable of exerting an extraordinary balancing effect in the interactions between the bacteriophage virus and its host bacterium. In his words: ‘A mixed culture results from the establishment of a state of equilibrium between the virulence of the bacteriophage corpuscles and the resistance of the bacterium. In such cultures a symbiosis obtains, in the true sense of the word: parasitism is balanced by the resistance to infection.’ This is the first use of the term ‘symbiosis’ in reference to viruses in microbiological history. In a footnote, d’Herelle took the implications further by drawing a parallel between what he was observing in the interaction of the bacteriophage virus and bacterium and the symbiosis that had recently been discovered in all land plants, where fungi in soil invade the plant roots to form a ‘mycorrhiza’, whereby the fungus feeds the plant with water and minerals and the plant feeds the fungus with the energy-giving metabolites that derive from the photosynthetic capture of sunlight. In d’Herelle’s words: ‘The respective behaviour between the bacterium and the bacteriophage is exactly that of the seed of the orchid and the fungus.’
D’Herelle is now recognised by many scientists as the father of both virology and molecular biology. But it would take many years before the world of virology, and microbiology in general, would come to rediscover d’Herelle’s original vision of the symbiotic nature of the bacteriophage.
Every Parent’s Nightmare
Parents will be familiar with the anxiety that comes with childhood rashes and fevers. How natural that our hearts should falter with the beloved child tossing in a perspiring fever, the restless anxiety, racking coughs, or sickness and vomiting. We can hardly sleep with worry that something worse might happen in the dark of night. That worry is, perhaps, a residuum of a fear from times only recently gone by when unpleasant things really did happen in the dark of night to those we loved. How fortunate we are now that our families are protected by antibiotics, antiviral drugs and the vaccines that keep such terrors at bay. But these advances are relatively new to medicine and to society. We should not forget that as recently as the 1950s most of humanity, even in developed countries, ultimately died from infection.
Before its prevention, using the triple vaccine, one such major cause of parental anxiety was measles, a commonplace and highly contagious childhood fever. How astonishing it is that this appears to be a relatively new disease in humans. Hippocrates, who wrote about the common diseases in Ancient Greece in the fifth century CE, recorded clearly recognisable descriptions of common infections such as the virus-caused herpes and the protist-caused malaria, yet this very knowledgeable ancient authority gave no description to match the symptoms and signs of measles. It is hardly a disease that would be readily missed, with its striking rash and fever, high contagion and common association with childhood. There is a clue in the name, ‘measles’, deriving from an Anglo-Saxon word maseles, which means ‘spots’. The first written description of measles is attributed to the tenth-century Persian physician, Abu Becr, also known as Rhazes, who cited a seventh-century Hebrew physician, El Yehudi, as providing the first clinical description of the disease. Rhazes recognised measles as an affliction of children and he distinguished it from the equally prevalent but far deadlier rash-provoking disease of smallpox.
Symptoms typically include a high fever, with a temperature often greater than 40°C, a racking cough, runny nose and inflamed eyes. Two or three days after the start of the fever, small white spots on a red inflamed background can be seen in the mucous membranes inside the cheeks. These are known as Koplik’s spots and are diagnostic of the disease. At much the same time a flattish, bright red rash invades the skin, usually beginning on the face and then spreading to the rest of the body. The rash, and causative illness, usually persists for seven to ten days and, in fit and well-nourished children, is usually followed by a full recovery. But in a minority of cases, most commonly seen in malnourished children, and in particular children in less-developed countries with poorly developed health care facilities, measles can lead to serious complications.
Like the common cold, measles is specific to humans, although it can be artificially transmitted to monkeys by laboratory experiment. This means that we are the reservoir of measles in nature – we are the natural host. The only place measles virus can spread its infection, and produce its new brood of new daughter viruses, is in us. It really is that up close and personal. And this means that the relationship – the symbiosis – between humans and the measles virus has been evolving for a long time, and in symbiological parlance with evolutionary implications for both ‘partners’. The causative virus, or morbillivirus, comes in a variety of groups, known as ‘clades’, within the broader family of viruses, called the paramyxoviruses. Individual measles virions are spherical, rather like cold viruses, with a genome made up of a single strand of RNA. The viral genome is contained within a similar capsid type of coat, but in this case the capsid is enclosed in an additional surface ‘envelope’, which carries multiple spike-like projections that play a key role in the infectious process.
Measles is a highly infectious virus with a worldwide distribution, but it can only survive in populations as an ‘endemic’ contagion, in populations where there is a continuous supply of susceptible children. We shall return to this observation when talking about the measles vaccine. The measles virus spreads by aerosol inhalation, much like the common cold. Its initial target cells are, once again, the lining cells of the respiratory tract. But unlike the cold virus, with its focus on the nose and throat, measles heads down into the lower respiratory tract. For some unknown reason, the virus also has a predilection for the cells of the conjunctivae, which explains the inflamed eyes that are a common sign of the clinical presentation. During the first two to four days of infection, the virus multiplies locally in the target cells. The alien presence of the virus provokes local inflammation and this in turn attracts the attention of white blood cells, known as macrophages, which normally gobble up unwanted debris, dead and diseased cells and invading parasites. This process is known as phagocytosis. Unfortunately – or alas perhaps knowing a little about viruses and their behaviour, predictably – these same phagocytes now become the final target cells of the measles virus.
The virus hijacks the phagocytes, invading and then replicating inside them, and then taking advantage of their natural locomotion to the regional lymph glands, where a second phase of viral replication takes place. From the lymph glands, the virus invades another variety of white blood cells, known as leukocytes, and once again it hitches a ride aboard these infected cells into the bloodstream, thus spreading to every cell and tissue, notably the skin. It is at this stage of bloodstream spread, or ‘viraemia’, that the typical rash and high fever appear.
Just as we saw with the cold virus, the measles virus doesn’t have things all its own way. Those same cells targeted by the multiplying virus, the macrophages, are the first line of defence in our immune system. Besides phagocytosis, the macrophages play a critical role in our inbuilt ‘innate’ immunity. They also play a key role in triggering an even more powerful defence system, our ‘adaptive’ immunity, identifying foreign antigens on the surface membranes of the virus as ‘alien’ to the body’s notion of ‘self’, and presenting these foreign antigens to cells, such as lymphocytes, that set off a process of specific immune recognition followed by the production of antibodies to the virus. The antibody response is also combined with yet another key element of our immune defences, known as ‘cellular immunity’. All of these powerful elements of our immune response will ultimately work together to destroy the foreign threat.
Many years ago, as a medical student at the University of Sheffield, I conducted an experiment aimed at testing how the mammalian immune system would respond to exactly such a viral invasion into our bloodstream. With the help of my mentor, Mike McEntegart, Professor of Microbiology, I injected viruses into the bloodstream of rabbits and then observed how the rabbit immune system dealt with them. I started with a primary dose and followed this up a week or so later with a booster dose. Some readers might react with concern about hurting experimental animals, but the virus I used was a bacteriophage, known as ΦX174 – a virus that only attacks E. coli bacteria – so the rabbits suffered no illness. But their adaptive immune system responded in exactly the way a mammalian immune system should respond to any alien invader entering the bloodstream, with a build-up of antibodies in two waves, rising to a peak by 21 days, by which time a single drop of the now-immune rabbit serum was seen to inactivate a billion viruses in mere minutes. With the help of other colleagues at the university, we obtained pictures of what was actually happening under the electron microscope, which showed the syringe-shaped phage virus being overwhelmed with antibody molecules and gathered up in sticky antibody-wrapped aggregates that would have been readily mopped up and cleared from the system by the ever-vigilant phagocytes.
What I observed in the phage virus experiment is similar to what would be expected to happen in a child suffering from measles. There is an incubation period of one to 12 days after exposure to the virus, during which it is passing through the target cells in the respiratory tract, through the lymph glands and entering the bloodstream. At this stage the illness becomes obvious, with fever, cough, runny nose and inflamed eyes. Two or three days later, the Koplik’s spots appear on the inner lining of the cheeks and the rash appears on the face and spreads over a day or two to be confluent over the skin. Ironically the striking symptoms and signs, including the fever and the rash, are actually produced by the attack of the immune system on the virus. Through the actions of that same immune system, the majority of children go on to make a full recovery – after which the immune system retains its memory of the antigens on the surface of the virus. In most cases, this will ensure that the sufferer is resistant to any future infection with measles. But further complications bedevil the recovery in a tragic minority of infected children, which include diarrhoea, pneumonia, blindness and, most serious of all, the inflammation of the brain called encephalitis.
Readers may be astonished to read that before the introduction of the measles vaccine, in 1963, major epidemics of measles swept through the global population every two to three years, causing some 2.6 million deaths. Even today, measles is still one of the leading causes of death in young children, despite the fact that a safe and cost-effective vaccine is available to prevent the infection. Between the years 2000 to 2016, the World Health Organization estimated that measles vaccination had prevented some 20.4 million deaths; but, tragically, in 2016 some 90,000 people still died needlessly from this preventable infection.
Unlike my generation, in which measles infection was commonplace, most parents in developed countries these days will have little or no experience of dealing with measles in the family. This, thankfully, is through the benefit of the MMR vaccination programmes which are now governmental policy in many countries. MMR vaccines protect children against three different viral illnesses: measles, mumps and rubella. But as a result of so-called ‘MMR misinformation scares’, the triple vaccine has been the subject of controversy in different countries, with some misguided parents withdrawing their children from the vaccination programmes.
I shall return to this important topic later in this chapter, but first I would like to examine the other two viruses involved in the vaccine.
The infection we call ‘the mumps’ probably derives its name from an old word meaning ‘to mope’ – an apt description of the afflicted child, struck down by malaise and fever and, a day after the onset, the painful swelling of one or both parotid glands within the cheeks, a condition known clinically as ‘parotitis’. The causative virus, the mumps virus, is another paramyxovirus, which is also global in distribution. Unlike measles, mumps was familiar to Hippocrates, some two and a half millennia ago. Mumps is also specific to and dependent on the human host, which, in symbiological parlance, is its co-evolving partner, and sole natural reservoir. Once more, the mumps virus is usually spread by the respiratory route, but it can also be spread through contamination with virus-infected saliva.
Fortunately, in most cases the illness is quickly dealt with by the immune system, with the symptoms settling within a few days, so that recovery is usually uneventful. In some cases the illness is so slight that the sufferer doesn’t even realise he or she has encountered the virus. But in 20 per cent of males who contract mumps after the age of puberty, the virus causes inflammation of the testes, clinically known as ‘orchitis’. This manifests as local pain, which can be severe, accompanied by the swelling of one or both testes some four or five days after the onset of the parotitis. Though some testicular atrophy may result, thankfully the orchitis doesn’t usually cause subsequent sterility. Though uncommon, mumps can occasionally cause inflammation in the ovaries in females, and equally rarely cause pancreatitis in either sex. Mumps may also cause a viral, or ‘aseptic’, meningitis and, like measles, it may also cause encephalitis. Meningitis and encephalitis are serious medical complications, which will usually result in hospitalisation and, in some cases, mortality.
Rubella, or the so-called ‘German measles’, is not a German contagion at all but rather a globally distributed infection. The illness just happened to be first described by two German doctors back in the eighteenth century. No more does it have anything to do with measles. The causative virus is in fact a ‘togavirus’, and an interesting example of this family of viruses since it is the only togavirus that isn’t spread by biting insects. Rubella is a contagious, generally mild, viral infection that mostly afflicts children and young adults. But if the virus infects women in early pregnancy, at a key time when major embryological development is taking place in the foetus, it can cause foetal death or a range of severe congenital defects known as ‘congenital rubella syndrome’ (CRS). These include hearing impairment, eye and heart defects, autism, diabetes mellitus and thyroid malfunction.
The key fact here is that rubella, like measles and mumps, is exclusive to humans. It means that we are the only reservoir or host of all three viruses – in the symbiological lexicon, we are the exclusive partner. That means that if the reservoir were to be closed down, for example through vaccination, the diseases would disappear.
The risk of all three of these viruses – measles, mumps and rubella – has been greatly reduced in developed countries by preventive vaccination, which, in the UK, the US and many other countries, is achieved using the combined MMR vaccine. It is important, given various misinformation scares, that we grasp the purpose of such a vaccine, and indeed the way in which vaccination works.
Vaccines use either a live, but harmless, variant of a live virus, or a killed virus – or even antigens extracted from parts of a virus – to protect children from the suffering and potential complications of virus infection. The MMR triple vaccine, which employs all three live attenuated viruses – measles, mumps and rubella – has greatly reduced the prevalence of all three viral diseases in the countries where it has been introduced. Unfortunately, a scientifically disproven claim that the MMR vaccine increases the risk of autism has persuaded some parents to forgo vaccinating their children.
People really do need to sit up and take notice of the advice of doctors and health authorities and ignore the misinformation coming from unreliable sources. Not doing so has the potential for unpleasant consequences. In a recent case involving the Somali-American community in the state of Minnesota, the local population, being misguided into believing that the vaccine had increased the frequency of autism in their children, stopped vaccinating their children with MMR. The real truth was exposed by a joint study by the University of Minnesota, the Centers for Disease Control in Atlanta, and the US National Institutes of Health, which showed that the incidence of autism in the Somali-Americans was no different from the vaccinated city’s white population. Alas, in May 2017 Minnesota saw the biggest outbreak of measles in the state for 27 years. State officials recommended that the Somali children be protected as soon as possible with vaccination booster shots.
America is far from alone in the resurgence of this dangerous and highly infectious disease of childhood. In May 2018, the British newspaper, the Daily Telegraph, reported a resurgence of measles throughout the continent of Europe, with the disease increasing in Belgium, Portugal, France and Germany. Once again, the efficacy of MMR vaccination was being undermined by the same baseless linking of the measles vaccine to autism, which had resulted in a rise from a record low incidence of measles Europe-wide, with 300 per cent rise in cases from 2017 to an estimated 21,000 cases in 2018, and some 35 reported deaths. In the UK, following years of similar misinformation about a link between the MMR and autism, many people of late teenage years to early twenties had not been vaccinated in their childhood years, making them now susceptible to this unpleasant and potentially dangerous viral infection. In July 2018 The Times reported a national alert being sounded out to family doctors throughout the UK, warning them to be on the alert for the disease in families returning from holidays in Italy. In England alone some 729 cases had already been reported in the first half of the year, when compared to 274 in the whole of the previous year.
Parents with any due concerns should seek the advice of their knowledgeable family doctors.
A Bug Versus a Virus
One of the commonest errors people make in relation to microbes is to confuse viruses with bacteria. It is important that we recognise the differences since this is the first step towards understanding the vital role of the interactions between the two very different organisms – bacteria and viruses – in the great ecological cycles that are central to life on the planet. One of the commonest of bacterial species found in the healthy colon of mammals is Escherichia coli, usually diminished to E. coli. The most widely studied bacterium in laboratory experiments, E. coli is also an important member of the symbiotic gut bacteria, helping in the production of vitamin K and the digestive uptake of vitamin B12, meanwhile also helping to reduce the threat of invading pathogenic bacteria. E. coli colonises the baby’s gut within 40 hours of birth, gaining access through hand-to-mouth human contact – most likely the mother during her fondling and feeding of the child. This, of course, is no threat, but rather the beginning of an important symbiotic interaction between human and bacterium.
The E. coli species is divided into a number of serotypes, most of which are either harmless or symbiotic to humans. This is why contamination of the skin with human waste is a question of hygiene rather than a cause for alarm. However, there are pathogenic serotypes of E. coli that can cause gastroenteritis, and these serotypes may be involved in food scares and product withdrawal from food outlets. More virulent strains of the pathological serotypes can cause urinary tract infections and, rarer still, life-threatening bowel necrosis, peritonitis, septicaemia and fatal cases of haemolytic-uraemic syndrome. Thankfully these serotypes are very rare, so that, under normal circumstances, E. coli is a beneficial contributor to the human gut flora.
Under the light microscope, the bacterium is visible as a single-celled sausage-shaped bacterium roughly 2.0 micrometres long. A micrometre, or μm, is one-millionth of a metre. E. coli has no nucleus and so it is an example of a prokaryote, which translates from the Greek to mean ‘before nucleated life forms’. The bacterial body is enclosed in a membrane, or cell wall, which contains the protein antigens that separate it into different serotypes. The cell wall does not take up the commonly used dye for testing bacterial types, known as a Gram stain, so it is classified as Gram-negative. This same cell wall is capable of acting as a barrier to certain antibiotics, so for example E. coli is resistant to the action of penicillin. Many strains of the bug have flagella and so they can be seen to wriggle about in search of nourishment. The bug is attuned to living in the anaerobic environment of the human intestine, where it sticks on tight to the microvilli of the intestinal wall. When passed out of the body, in faeces, the bug is capable of surviving for some time even when exposed to the oxygenated environment. This is why pathological serotypes can cause food contamination in the home and in food-processing environments.
We are somewhat inclined to see all microbes as potential pathogens. But outside the medical world, microbiologists have long been aware that microbes play much wider roles in nature. For example, the bacteria in soil are essential to the normal cycles of life, helping to break down organic matter to its elemental components, which are then made available for recycling to supply the basic requirements of other living beings. So essential are these soil bacteria that if they were to disappear, the vast majority of life on Earth would follow their example. Such living interdependency is known as symbiosis. We humans are apt to confuse symbiosis with notions of ‘friendliness’ or ‘togetherness’, thereby grafting human attributes onto situations where such human notions do not apply. Perhaps it might be a good idea to clarify what the concept of symbiosis actually means to the biological sciences.
Bugs, such as bacteria and viruses, do not think. No more do they have feelings. Their behaviour among themselves, and in relation to their hosts, is driven by a mixture of happenstance and the fundamental mechanisms of evolution. Symbiosis is not about Mr Friendly Guy who shakes the hand of Ms Friendly Lady and everything is hunky-dory from then on. It is about survival in what Darwin called ‘the struggle for existence’. In 1878 a professor of botany in Berlin, called Anton de Bary, defined symbiosis as ‘the living together of differently named organisms’. A modern interpretation might rephrase his definition as ‘living interactions between different species of organisms’. The interacting partner species are called ‘symbionts’ and the interaction as a whole is called the ‘holobiont’.
While symbiosis includes parasitism, which is defined as a symbiotic interaction in which one or more of the partners benefits from the partnership at the expense of another, symbiosis also includes commensalism, where one or more partners gains without detriment to the others; and it also includes mutualism, where two or more of the interacting partners gain from the partnership without harm to the other partner, or partners. It is important to grasp that mutualism often begins as parasitism – indeed in nature many relationships involve situations somewhere between the extremes of parasitism and mutualism. This broader umbrella of living interactions offers the necessary scope for understanding the enormous variety of living interactions, involving microbes and their hosts, in nature. It allows us to compare and contrast a bacterium, E. coli, with a virus that also has a predilection for the human gut: the so-called winter vomiting bug, known as the norovirus.
The norovirus is the commonest cause of gastroenteritis in the world, familiar to most of us with its unpleasant manifestations of diarrhoea, vomiting and stomach cramps. It is extremely contagious by the faecal-oral route, whether through contaminated food or water, or direct contact contamination from another sufferer. Once again, we humans appear to be the only host. This, in turn, means that we are the natural reservoir in nature of the virus. Symptoms usually develop some 12 to 48 hours after exposure to infection, often with a low fever and headache. The gut irritation is rarely severe enough to provoke the bloody diarrhoea that is sometimes seen in dysentery, and recovery usually follows within a few days. Since the condition is usually self-limiting, diagnosis tends to be made on the basis of symptoms alone, especially when it occurs during a local recognised outbreak. No specific treatment is usually necessary, although sufferers may be helped by increasing fluid intake to avoid dehydration, together with non-specific anti-fever and anti-diarrhoeal medication. Laboratory confirmation is not usually necessary although public health authorities may sometimes make use of it for contact tracing purposes.
Prevention is the judicious policy, through careful hand-washing and disinfection of potentially contaminated surfaces. Unfortunately, alcohol-based hand sanitisers of the sort dispensed in hospitals are, reportedly, ineffective.
Noroviruses comprise a genus within the family of calciviruses, so-called because they have cup-like depressions in their capsids and so were named after the Greek word calyx, which means a cup or goblet. Since they cannot currently be cultured in the usual laboratory media, the single species is divided into six genetically distinct ‘genogroups’, which infect mice, cows, pigs and humans. The human genotypes are extremely infectious even from minute numbers of the virus, so much so that it has been calculated that a single tablespoonful of diarrhoeal effluent from an infected individual would contain enough viruses to infect everyone in the world many times over. But this is no cause for alarm. Thankfully there is rather more to infectious spread than such theoretical extrapolations. A more practical consideration is the fact that affected individuals can remain infectious for several days after the symptoms have settled. This means that they might feel well enough to return to normal life, including work premises, when they are still capable of passing on the virus. It might also contribute to the tendency for outbreaks to occur in closed communities, such as hospitals, cruise ships, schools and residential care homes, where communal food preparation, and common dining areas, make transmission of the virus more likely. Readers may be surprised to learn that, in spite of the relatively mild nature of the illness, the ease of transmission, combined with the prostration of the vomiting and diarrhoea, has led to the norovirus being classed as a Category B bio-warfare agent.
Globally it is estimated that norovirus infects some 685 million people a year, most of whom go on to make a full and speedy recovery. Unfortunately, in a small minority, it can result in a life-threatening illness, with some 200,000 or so deaths worldwide each year. Children under the age of five years are most susceptible, especially in developing countries, where it causes as many as 50,000 paediatric deaths annually. It is worrying that the number of reported outbreaks has been rising since 2002, warning health authorities, if they weren’t sufficiently alarmed already, that we need to treat the norovirus as a dangerous ‘emerging infection’, and one that may be evolving even more highly infectious strains.
The causative virus is globular in shape and between 20 and 40 nanometres in diameter. This means that the norovirus is somewhere between a hundredth and a fiftieth the size of the E. coli bacterium. Viruses lack the enclosing cell wall seen in bacterial, or indeed human, cells. But under the powerful magnification of the electron microscope we see that the norovirus possesses an icosahedral capsid, which encloses and protects the viral RNA-based genome. E. coli, like all bacteria, and indeed all cellular forms of life, has a DNA-based genome.
If we compare and contrast the bacterial and viral genomes, we come across gargantuan differences between bacteria and viruses at every level of their structure and organisation. The E. coli genome is coiled into a single, very lengthy circle of DNA that is attached to the inner aspect of the bacterial cell wall at a single point. This bacterial genome contains roughly 4,288 protein-coding genes, as well as coding sequences for other key metabolic functions involved with the handling of gene expression. This is comprehensive enough for the bacterium to store the memory of its genetic heredity as well as to allow it to carry out numerous internal metabolic functions involved in its internal physiology and biochemistry. One such key function is the control of the processes involved in its budding pattern of reproduction, to produce daughter bacteria.
When compared to the bacterial genome, the norovirus counterpart is frugal in the extreme. The viral genome comprises regulatory regions at either end of a compact linear string of RNA, which codes for a minimum of eight proteins, two of which code for the protein structures of the viral capsid, and six concerned with viral replication. A key difference between the bacterium and the virus is that the bacterium has all it needs to reproduce itself, but the virus can only replicate to produce daughter viruses by making use of the genetic and biochemical properties of its cellular host. In the case of the human strain of norovirus, these genetic and biochemical properties are those of the human target cell.
The norovirus genome codes for a singular aggressive viral protein known as the ‘protein virulence factor’, or VF1. This menacing entity localises to the human mitochondria during infection with the virus, where it antagonises the infected person’s innate immune response to the virus. While some viruses are capable of commensalism or even mutualistic interactions with their hosts, we see little evidence for this in the norovirus. Its symbiotic interaction with humans appears to be exclusively parasitic. Unlike the bacterium, it has no genes devoted to nutrition, or to internal metabolic pathways, since, unlike the bacterium, it has no internal metabolic pathways. Its genome is designed to take advantage of the physiology, metabolic pathways, genetic pathways, and even the very locomotion and life-style patterns of human behaviour in order to replicate itself and transmit its contagion as widely as possible.
So now we see that viruses are not fluids or poisons. They are organisms that follow a wide range of symbiotic interactions, each virus usually associated with a highly specific host, a tiny minority of which happen to be human. They are clearly very different in size, genomic organisation and life-cycle patterns to bacteria. The fact that most viruses do not possess their own internal metabolic processes does not imply that viruses do not utilise metabolic processes. On the contrary, viruses take advantage of their host’s metabolic pathways. This is why it is a mistake to think of viruses in isolation from their hosts. Outside their hosts viruses are biologically inactive: but this does not mean that they are inorganic chemicals.
Outside the target cells of their hosts, viruses have evolved stages that are somewhat equivalent to suspended animation. This stage is well-suited to being ejected in the aerosol created by a cough or a sneeze, or excreted in faeces, or in sexual secretions, or surviving being transferred by a secondary carrier, such as a biting insect or a rabid dog; or in the case of plant viruses, being carried to new hosts on the wind, or through water, or through a miscellany of other avenues of transmission, to find new hosts. Only when they enter into their obligate symbiotic partnership with the new host do we witness viruses behaving with the genetic and biochemical subtlety and efficiency we might expect of biological organisms.
The norovirus is no exception to such symbiotic evolutionary behaviour. So specific is the virus in its symbiotic interaction with its human host that different human-associated viral genotypes have affinities for specific ABO blood group proteins on cell membranes, these protein ‘receptors’ binding with one of the two proteins of the viral capsid as an integral step in the infectious process. On passing into the bowel, the virus has a predilection for the upper small bowel, or jejunum. How, exactly, the virus then penetrates the intestinal wall is not fully understood, but it would appear that it preferentially infects the immune lymphoid follicles in the gut wall, which are known as Peyer’s patches, while also searching out a type of intestinal cell, known as H-cells. After making its way through the gut wall, the virus is identified as alien by the innate immune defences of the gut, which might be just fine as far as the virus is concerned, since these may be its target cells. Whatever the target cells, we can anticipate that the virus will hijack their genetic and metabolic pathways in order to replicate itself, thus establishing its cycle of infection and multiplication, generation after generation.
Since we don’t yet have suitable tissue cultures or animal models to study the norovirus, we are not in a position to examine the ways in which it provokes the vomiting and diarrhoea, which play a key role in spreading the virus far and wide throughout the world. Currently there is no preventative vaccine, but trials of an oral vaccine are taking place as I write. Let us cross our fingers and hope that these trials are rewarded with an early success!
A Coincidental Paralysis
In the summer of 1921 the 39-year-old Franklin D. Roosevelt fell overboard from his yacht on the Bay of Fundy, a beautiful if freezing inlet between the eastern Canadian provinces of New Brunswick and Nova Scotia. The following day he was tormented by pain in his lower back and then, as the day progressed, he felt his legs grow increasingly weak until they could no longer sustain his body weight. This was the onset of Roosevelt’s poliomyelitis, at this time known as ‘infantile paralysis’. Poliomyelitis is caused by a virus that goes by the same name. In 1921 doctors were limited in their knowledge of the poliovirus, or indeed viruses as such. They might, however, have known that the virus did not infect Roosevelt while he was struggling in the cold water – the only infectious source of poliomyelitis virus is another person who has already contracted it. Once again, we are looking at an exclusively human reservoir. Moreover, the paralytic disease has an ancient pedigree.
Infantile paralysis was familiar to physicians in the time of the pharaohs of Egypt, since the effects of the disease were painted, with stunning accuracy, on the walls of their tombs. In 1921, as indeed today, there was no cure for the paralytic effects of the virus once it had afflicted a victim. Fortunately, Roosevelt was gifted with an extraordinary vitality and courage, enabling him to overcome the lifetime of paralysis that would result from his illness. It is to his credit that despite this handicap he became the 32nd President of the United States and he continued to serve the American people for an unprecedented four terms in office.
Viruses do not follow our human notions of rules and so they are apt to surprise us. One such surprise is that those viruses that replicate primarily in the gut – the so-called ‘enteroviruses’ – do not cause the usual symptoms of gastroenteritis. Instead, the viruses that do cause gastroenteritis are a miscellaneous group with members coming from widely different viral families. Of course, these include the genus of noroviruses within the family of calciviruses. Another group of gastroenteritis-associated viruses are the rotaviruses, a genus within the family of reoviruses, which cause vomiting, diarrhoea and fever in babies under the age of two years. Other similar offenders include adenoviruses, coronaviruses and astroviruses. We are sometimes inclined to joke about the clinical effects of gastroenteritis, but the truth is that this is a distressing condition in people of any age. Moreover, in less developed countries, gastroenteritis is one of the commonest causes of death in children, a tragic situation complicating poor hygiene and contaminated water supplies. As we might anticipate, these illnesses are transmitted by the faecal-oral route.
The ‘enteroviruses’ are also transmitted by the faecal-oral route and the viruses also replicate within the intestine, but curiously they do not present with the typical fever, vomiting and diarrhoea that typifies gastroenteritis. Instead they cause less predictable and often complex patterns of illness that affect various organs and tissues, for example, the brain and meninges, or the heart, skeletal muscles, skin and mucous membranes, the pancreas, and so on. The most familiar of this strange gamut of enterovirus-linked illnesses is poliomyelitis. All three ‘serotypes’ of the poliovirus, which have slight differences in their capsid proteins, are ‘enteroviruses’ within the family known as the picornaviruses. We might recall that these belong to the family of very small RNA-based viruses that includes the rhinoviruses. A cardinal feature of enteroviruses is that they are resistant to acid, so they can pass through the human stomach to replicate further down the alimentary tract. The poliovirus was the first of the enteroviruses to be discovered, earning its finders – Enders, Weller and Robbins – a Nobel Prize in 1954.
We should not be too surprised to discover that humans are the exclusive host of the poliovirus. The individual virion is a mere 18 to 30 nanometres in diameter. Under the electron microscope it has a capsid with the familiar icosahedral symmetry, which encloses a relatively simple RNA-based genome. In the small intestine, the virus binds to a specific receptor molecule in the lymphoid tissues of the pharynx and the ‘Peyer’s patches’ of the gut. Here the virus hacks its way into the interior of the cells, where it takes over the genetic processes to convert the cell into a factory for manufacturing daughter viruses. The daughter viruses are released through rupture of the infected cell, after which they re-invade neighbouring cells and repeat the process.
All of this sounds a trifle horrific and even potentially deadly. But in reality the great majority of individuals infected by poliovirus show little or no signs of disease other than, perhaps, a mild looseness of the bowels. But the stools of an infected individual will now be swarming with virus, which will be passed on to contacts through the faecal-oral route. Polio characteristically moves through populations in epidemic waves, with most of the infected unaware that they have encountered the virus. Only in a tiny minority does the virus make its way to the anterior horn nerve cells in the spinal cord, where infection and subsequent death of the nerve cells gives rise to the paralysis we saw in President Roosevelt. Bizarre as it might seem, the infection of the nerve cells appears to serve no purpose as far as virus transmission or evolutionary pathways are concerned. Indeed, this most dreaded complication of poliomyelitis appears to be coincidental.
The incubation period of poliovirus infection is usually a week to two weeks and, in the minority that show symptoms of infection, this involves a minor malaise, fever and a sore throat. These reflect the virus entering the bloodstream and will usually resolve without requiring any treatment and with no long-term consequences. Only in a small minority of those infected does polio give rise to a more severe illness. The onset is usually abrupt with headache, fever, vomiting – in some this may be accompanied by the neck stiffness typical of meningitis. Even still, the majority of symptomatic cases will go on to make a good recovery. But in the tiny but highly significant minority the paralysis of poliomyelitis sets in.
Paralytic poliomyelitis gets its name from the Greek polios for ‘grey’ and muelos, for marrow. This derives from the fact that the paralysis results from destruction of the grey marrow of the anterior horns of the spinal cord, which contain the cell bodies of the nerves that supply the muscles of arms, legs, chest and remainder of the trunk. The death of those cell bodies in the spinal cord causes a floppy style paralysis of the affected muscles, which is usually apparent within two or three days of the onset of the disease. In children affected by paralysis, this will have secondary long-term effects on limb growth and development. Bulbar poliomyelitis, a similar infection, causes damage to the nerve bodies of the cranial nerves, which results in paralysis of the pharynx and possibly accompanying difficulty with the muscles involved in breathing. This dreadful complication is why, before the advent of vaccination, some unfortunate patients ended up having to be supported by ‘iron lungs’.
We do not know why this unfortunate minority of infected individuals develop serious disease, including paralysis, from the poliovirus. There is some evidence that the virus gets into the central nervous system more commonly than is suggested by clinical signs. Indeed, as we shall see, this pattern of unwanted penetration into the central nervous system can feature in illnesses caused by other enteroviruses. One wonders if some genetic propensity might perhaps play some role, but it may be no more than bad luck. As we saw above, this pattern of paralysis in children, with its effects on limb growth, was recognised in the wall paintings of the tombs of pharaohs from Ancient Egypt. How puzzling then that such an ancient and easily recognisable disease was unfamiliar to European doctors until the latter years of the nineteenth century, when the first epidemics began in the cooler climates of industrialised Europe and the United States!
Such has been the dramatic success of vaccination programmes, using live attenuated viral vaccines taken by mouth, that polio has been largely eliminated from developed countries. In 2018, according to the Global Polio Eradication Initiative, the disease is now endemic in just three countries: Afghanistan, Nigeria and Pakistan. But, given the ease and extent of modern travel, we cannot rest assured until this historic and maiming disease is completely eradicated in these remaining pockets of potential contagion.
While poliomyelitis is now approaching global control, it is not the only enterovirus to afflict humanity. Other members of this virus family are still commonly encountered in developed countries, including viruses that can be baffling in their presentations and clinically unpredictable in the course of their illnesses. Perhaps the best known of these are the Coxsackie B viruses, which sometimes present with a condition known to doctors as epidemic pleurodynia. Also known as ‘Bornholm disease’, after the Danish island where it was first recognised, this can present as severe chest pain arising from inflammation in the intercostal muscles of the chest wall. Popularly known as ‘the devil’s grip’, the sudden onset and severity of the pain can mimic a heart attack. Coxsackie B viruses can occasionally cause inflammation of the brain, presenting as the condition known as myalgic encephalomyelitis, or ‘Royal Free disease’, named after the London teaching hospital where it first presented. The same enterovirus may also present with inflammation of the heart muscle, or myocarditis, coupled with inflammation of the membrane surrounding the heart, known as pericarditis, a combination that presents in both children and adults and can very occasionally prove fatal. Other enteroviruses, including the echoviruses and types 70 and 71 enteroviruses, can cause chest infections and various patterns of muscle, meningeal and brain infections, where the diagnosis of the causative virus may be exceedingly difficult to pin down.
Viruses and their associated illnesses can be very puzzling. Ever since we first discovered their enigmatic presence among us, questions have inevitably arisen as to the evolutionary purpose behind their behaviours. When faced with the unpleasant, sometimes life-threatening, effects of virus infections, we are inclined to wonder what possible benefit such behaviour might confer on the virus. In the case of the poliovirus we saw how it appears to be mere happenstance that the virus causes serious illness in a tiny minority of those it infects. But there are other viruses that sweep through the human population and inflict dreadful patterns of illnesses in the majority of those infected, sometimes accompanied by a high mortality. This is all the more baffling since all that matters to the virus is its survival and successful replication. Survival of the virus must surely be threatened by killing its host. When one views the same question from a medical perspective, we are inclined to question: why are some viruses so deadly?
Deadly Viruses (#u05bbd12e-fc53-5e94-91fc-1b07bdd2ba3c)
The Four Horsemen of the Apocalypse feature in the biblical Book of Revelation, where, having been released by the opening of seven seals, they ride out on red, white, black and pale horses. Theologians differ in their interpretations of what these riders might signify, but one of the four is commonly interpreted as pestilence, which, in modern terminology, would be interpreted as plague. While the common childhood infections, caused by viruses, are usually self-limiting, some viruses are truly dreadful in their capacity for death and suffering. In the recorded pages of history, two plagues of humanity would justify the term ‘apocalyptic’: these are the bacterial pandemics known as bubonic plague, as seen in the Black Death in the Middle Ages, and its viral counterpart, the plague of smallpox. Both have tormented humanity from ancient times, bequeathing a grim legacy in historical records and grave pits.
The Black Death was named after the festering swellings, or ‘buboes’, where lymph glands in the groin or armpit became swollen with pus and erupted onto the skin of victims. The causative bacterium, Pasturella pestis, is transmitted by the bite of an infected rat flea. Although the public commonly assumes that bubonic plague has gone away, in fact a milder form of the illness is still endemic in rural parts of the United States, South America, Asia and Africa. The viral apocalypse, smallpox, was named after the rash that accompanied the disease, which resulted from pustular blistering in the skin that healed with deep circular scars, or ‘pocks’.
It is comforting to use the past tense here since, mercifully, smallpox has been eradicated as a plague. The clinical term for smallpox was ‘variola’, and the disease followed two very different patterns of virulence, depending on the causative virus. Variola major and Variola minor are species within the family of poxviruses. The poxviruses infect a wide variety of animals, but only three species infect humans: namely the two variola viruses and a related species, Molluscum contagiosum, which causes minor blisters on the skin of children. We shall confine our attentions to the variola viruses, which have a number of unusual features.
Humans are the only hosts for smallpox, so we are the exclusive reservoir of the two variola viruses in nature. The individual ‘brick-shaped’ virions are relatively large, measuring 302 to 350 by 244 to 270 nanometres. Before being displaced by the discovery of the ‘Megaviruses’, poxviruses were the giants among the viruses, being big enough to be seen as tiny cytoplasmic inclusions under high magnification of the light microscope. This feature alone alerts us to the fact that we are dealing with a relatively complex virus. The variola genome is predictably large and DNA-based. Unusually for a virus, it contains the genetic wherewithal for the manufacture of its own virus messenger, RNA, which takes care of the manufacture of viral proteins. This virus also has its own coded enzymes and transcriptional factors which control the manufacture of daughter viruses within the cytoplasm of infected host cells.
Smallpox viruses are extremely contagious, spreading by that most infectious route of all, aerosol inhalation. The viruses are also capable of spread through skin contact with the blistering rash, or through contaminated clothing, bed linen, utensils or dust. Infection usually begins with the arrival of the virus into the air passages of the throat and lungs of a susceptible individual, where they penetrate the superficial lining cells to be ‘discovered’ by the tissue macrophages, the first line of the human immunological defences. The stage of infection within the macrophages is asymptomatic, but accompanied by stealthy advance of the virus towards its ultimate goal. By about the third day after infection, the ‘virus-factories’ within the macrophages journey on to the lymphatic stream and local lymph glands, from where the viruses spread to the other key elements of the ‘reticuloendothelial system’, in particular the bone marrow, spleen and circulating blood. This triggers a massive immune counter-attack on the virus, including cytotoxic T-cells and interferons. But, as the history, and the grave pits, suggests, this counter-attack is unsuccessful in the majority of sufferers. Symptoms begin with a severe sore throat at much the same time that blood-borne spread carries the viruses to the skin, where they produce the blistering and scarring rash, with its predilection for the face and limbs. The blisters are the result of direct viral invasion of the skin and they teem with viruses.
Historically it is thought that smallpox first arrived among humans about 10,000 years ago in the agricultural settlements in northeast Africa, spreading to India through trade with Ancient Egypt. It grieves one to imagine such a disease spreading through such populations of naïve people, and impossible to imagine exactly what they thought was among them. No doubt they had some simple rules for dealing with contagion, and, equally likely, they would have blamed some occult cause. We discover the pathognomonic pocks in the mummified skin of Ancient Egyptian mummies, such as the Pharaoh Rameses V, who died in 1156 BCE.
Smallpox, or the ‘small pocks’, was a clinical term that came into usage in the sixteenth and seventeenth centuries to differentiate it from the inch-or-more-diameter ‘great pocks’ that medical historians assume were pathognomonic of tertiary syphilis, a bacterial plague that may have been imported into Europe from the Americas. The viral plague of smallpox arrived into Europe much earlier, sometime between the fifth and seventh centuries CE, where it persisted as an infection, giving rise to repeated epidemics during the Middle Ages. Estimates suggest that it killed some 400,000 Europeans annually in the late 1700s, affecting all levels of society, including five reigning monarchs, and was responsible for a third of all cases of blindness. The same plague played a key role in the Conquistador subjugation of the Aztecs and Incas of South America, during the sixteenth and seventeenth centuries, when it may have dominated the history of encounters between Eurasian adventurers and the stricken native and hitherto ‘virgin’ peoples.
Today we can scarcely imagine the terror of living through a major epidemic of plague or smallpox sweeping through such a ‘virgin’ population. They would have been very quickly aware that a pestilence was among them, with panic-stricken populations in the grip of raging fever and, in case of smallpox, a virulent rash, which, when severe, caused the entire skin to boil with blisters and carried with it a horrific lethality, at its worst as high as 90 per cent. It must surely have seemed as if a pitiless demon had entered their world, intent on wiping out entire families, and even entire villages, towns and cities.
But smallpox was never a uniform death sentence. We cannot be certain of the actual levels of lethality of smallpox in various parts of the Americas, though we are informed that it was as high as 60 to 90 per cent in the worst-affected populations, falling to 30 to 35 per cent in some of the lesser-affected regions. This lower lethality was in fact similar with the calculated overall mortality of Variola major in concurrent Eurasian populations, suggesting that the virus had already become endemic in those regions. Meanwhile, even in the Americas, the Variola minor virus caused a much milder disease, with a mortality of about 1 per cent. It is somewhat ironic that smallpox, one of the deadliest plagues in history, was the first to be subdued by the use of a vaccine. Many readers will be familiar with the discovery of cowpox vaccine by the English physician, Edward Jenner, and this more than a century before the world even realised the existence of viruses.
In such less-enlightened times various therapies that we would now dismiss as ‘quack’ were touted as preventions or curatives for every frightening illness. In seventeenth-century England, for example, Dr Sydenham, an eminent physician in his day, treated patients in the throes of smallpox by allowing no fire in the room, leaving the windows permanently open, drawing the bedclothes no higher than the patient’s waist and administering ‘twelve bottles of small beer every twenty-four hours’. If nothing else, the beer would have dampened consciousness of the suffering – and perhaps the discomfort of the therapeutically induced hypothermia in winter. But it was famously known from ancient times that survivors of smallpox were immune to further infection. A hazardous treatment, involving inoculation of non-immune individuals with a scalpel wet with material from the ripe pustule of an infected patient, was variously employed in Africa, India and China long before Jenner introduced his vaccine.
History has it that Jenner overheard a dairymaid say, ‘I shall never have smallpox for I have had cowpox.’ Cowpox, a milder pox infection in cattle, was known as vaccinia, after the Latin, vacca,for cow. In 1796 Jenner conducted a now-famous experiment in which he inoculated an eight-year-old boy with pus from a vaccinia blister, obtained from a dairymaid with cowpox, and, having waited for the boy to develop immunity, subsequently tested this by inoculating him with smallpox. Thank goodness that the boy now proved to be immune. Although Jenner had rivals, who dismissed the importance of his discovery, the cowpox inoculation was soon taken up as a preventive measure against smallpox. We still refer to it today with the term Jenner coined for it: ‘vaccination’.
When I was a child, it was still mandatory to be vaccinated against smallpox. I still bear the scar, which is a pock-shaped irregular oval about half an inch in diameter, on the skin of my upper left arm. Today children are no longer vaccinated against smallpox because the disease was eradicated from the global human population by a ten-year international programme of smallpox vaccination, headed by the American physician, Donald Ainslie Henderson, who worked under the auspices of the World Health Organization. This was formally signed off with the confirmed eradication of the disease in 1979.
There can be no denying that the eradication of smallpox was an extraordinary achievement. Ironically, however, this very success makes our modern populations unduly susceptible to a malicious attack involving a potentially bioengineered smallpox virus that might be deliberately created to be as lethal as possible. New generations, who have never been vaccinated, would have no inbuilt protection to such a spreading lethal strain. This is why the smallpox virus is now included in the list of Category A bio-warfare agents. Following smallpox eradication, it was agreed by international treaty that samples of the smallpox virus should only be retained in two maximum security laboratories – one at the CDC in Atlanta, in the United States, and one at similar facilities in Moscow, in Russia. The plan was to allow some continuing research aimed at countering any attempt to use the virus for bio-warfare, whether through terrorism or through formal hostilities between nations. We must hope that, if the worst comes to the worst, the officially sanctioned research in this small number of biosafety laboratories will come to our rescue with a modern vaccine, which will need to be spread globally with more efficiency than we have ever seen with any previous vaccination programme.
Beyond COVID-19 編集委員会 委員長