Virusphere: What doesn’t kill you makes you stronger. Frank Ryan

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,