Vol. 23 No. 6 · 22 March 2001

They reproduce, but they don’t eat, breathe or excrete

James Meek

2846 words
The Invisible Enemy: A Natural History of Viruses 
by Dorothy Crawford.
Oxford, 275 pp., £14.99, September 2000, 0 19 850332 6
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Last September, the Royal Society organised a conference to discuss Edward Hooper’s book The River, which promoted the theory that HIV was accidentally spread to humans from chimpanzees through a polio vaccination programme in Africa in the 1950s. Coincidentally, or not, on the eve of the conference, a British TV channel screened the 1995 Hollywood thriller Outbreak, starring Dustin Hoffman as a maverick military virologist given hours to find a vaccine to halt the spread of a deadly African virus in California before the military obliterates the town where it has taken hold. The film’s opening is set in Africa and based on the emergence of the Ebola virus, which was first recorded in northern Zaire in 1976, where it infected 318 people, 280 of whom died. Outbreak then goes astray: rather than portraying years of clinical trials and exhaustive lab work, the movie locates the key to getting the vaccine for the fictional virus in the ability of Hoffman and Cuba Gooding Jr to dodge heat-seeking missiles in a tree-top helicopter chase.

It’s a silly film, except in one sense. There is a long, old and dramatic human struggle against viruses. Hollywood may have smothered it in melodrama, but the enemy is real enough to draw virologists to the movie – Dorothy Crawford refers to it in her introduction – and to contribute to the brittle atmosphere of the Royal Society conference. It was like a meeting of leaders in wartime, pleased to be there, but anxious at spending time away from work while lives were being lost on the front line.

The military analogy isn’t out of place. The flu pandemic of 1918-19 killed 100 million people, more than died in the war which had just ended. In the late 20th and very early 21st centuries, when full-on warfare has become rarer and remoter for Westerners, disease is now the area where we experience the feelings of emotional intensity associated with war, the crushing communal defeat, sudden personal loss, plodding hardship and hysterical relief at victory. Man has smallpox on the run; polio emerges. Polio is almost beaten; HIV begins its offensive. A vaccine against HIV may be within reach; what next? (The current foot and mouth epidemic is a reminder that viruses which afflict people are not the only enemy.)

The story goes back to our ancient hominid ancestors, sitting in the darkness around a fire, afraid of the predators out there in the night. A million years later, we have killed or corralled all the big beasts which could hurt us, but the predators are still out there. We have shrunk the jungles, and think we have mastered all wild things, but those shrunken forests conceal the carriers of viruses which could wreak terrible destruction. There is a theory that some viruses are not just harmless to their hosts, but may even be beneficial to them because they cause deadly disease in their enemies – such as man. We still do not know the animal or insect which carries the Ebola virus, and one of the reasons could be that the virus has killed the few who have disturbed the animal’s habitat. The closer man gets to the last wild strongholds, the closer he may be getting to the ultimate predator. Imagine a virus with the effect and latency period of HIV which could be spread by a sneeze.

Viruses are hard to describe. They aren’t exactly alive: their structure is non-cellular, and they can’t survive for long without a host; they reproduce and evolve, but they don’t breathe, eat or excrete (as bacteria do, after a fashion). One way to think about them is by a reverse analogy: a computer virus is nothing but a piece of code, a series of letters and numbers. To exist, the code doesn’t even have to be on a disk: you could write it down in a notebook; you could memorise it. As long as it isn’t inside a computer’s operating system, it’s harmless, dormant, abstract. Once the code is in a computer, however, it does three things. It acquires a host, it begins to make the computer run wrongly, and it can reproduce itself to spread to another computer. Biological viruses are similar. Outside living cells, they’re not much more than a piece of information, a scrap of nucleic acid in an envelope of protein. But even if the HIV virus were one day wiped from the face of the earth, it would still be possible to write down the chemical sequence required to re-create it in a string of letters about as long as this article.

The goal of a virus is to break into a cell, use the cell’s facilities to reproduce itself, and then spread to the next host. If the cell (and the host) is damaged or dies as a result, too bad. I say ‘goal’, because it is hard not to see viruses as ingenious workers towards an end, so cunning are their methods. Colds and flu make you sneeze in order to spread themselves. The rabies virus travels in the saliva of an infected animal, which is why it’s transmitted by biting. Once inside the new victim, the virus particles enter local nerve endings. With the host apparently unharmed apart from the bite, the virus slowly works its way up the nerves to the brain. It can take days; sometimes it takes years. But eventually the virus reaches the cells of the brain itself, where it causes encephalitis, driving the infected animal or person mad, often violently so. When the rage is at its height, the virus returns to the highway of the nervous system, heading for the salivary glands, where it reproduces. Just when the rabid animal’s brain, inflamed by the virus, is most likely to drive it to turn its fangs on any creature within range, the virus has made sure its saliva is brimming with copies of itself.

Herpes simplex virus usually enters the body through delicate, more easily broken tissue, or where there is a natural opening – by kissing, which leads to cold sores, or through sex, which leads to genital herpes. It gets inside skin cells, starts to reproduce and attracts the attention of the immune system, which snuffs it out and prevents future infection. But the original virus hasn’t gone away. It has found another hiding place, inside nerve cells, where it can’t reproduce but where the immune system can’t detect it. The virus is there for ever, and a still poorly understood trigger mechanism will arouse it from its dormant state to produce cold sores and genital blisters again, capable of infecting others.

HIV, the most closely studied virus ever, is grimly fascinating in its slow, precise work of destruction. The cells it attacks are the very cells which must survive if the virus is to be fought – CD4 T-cells, the marshals of the immune system. It’s a retrovirus, which means it works backwards to smuggle its way inside the nuclei of human cells. Its genetic material is RNA, the chemical that normally ‘reads’ DNA; but retroviruses carry an enzyme that can copy the RNA’s information into DNA molecules which then infiltrate human DNA. An HIV-infected person’s blood may seem to have only a trace of the virus because it’s working away in the lymph glands, where most CD4 cells are found. There, 100 billion new virus particles are made each day, destroying one to two billion of the body’s CD4 cells, a third of the total, in the process. The bone marrow makes new cells to replace those lost. This battle goes on for an average of ten years before the bone marrow can no longer make good the body’s losses, the immune system begins to collapse, and Aids sets in.

There is good news from the evolutionary front, though. It’s not necessarily to the virus’s advantage to kill, or even disable, its host. Viruses which swiftly kill every host they enter are doomed because there is little chance of them being able to jump to another host. Ebola virus is a case in point. It is a fearsome disease which spreads through blood and sexual contact. For between two and 21 days, there are no symptoms. Then the infected person comes down with muscle pains, headaches and a fever. A phenomenon known as ‘crash and bleed’ sets in. Over a few days, the virus destroys the cells lining the blood vessels, and the patient suffers massive internal bleeding, accompanied by vomiting and diarrhoea: 50 to 90 per cent of those infected die. In the 1976 outbreak in Zaire, 85 women attending an antenatal clinic were given injections from the same Ebola-contaminated needle. All of them caught the virus, and all of them died. But the savagery of the illness makes it easy to spot Ebola at an early stage and to put in place containment measures. Even in this age of intercontinental air travel, the worst we can expect from Ebola is a succession of brushfire outbreaks, locally devastating but quickly identified and controlled.

Herpes is less deadly, but more successful. It has been around for hundreds of millions of years and is endemic in a vast range of species. Even oysters have herpes. It spreads fairly easily, dodges precautions by erupting at long, unpredictable intervals in infected humans and is impossible to dislodge from its hiding place in nerve cells. Most important, it causes discomfort and embarrassment rather than disability and death. It will be around as long as the host is.

HIV is an evolutionary champion. Because its information is carried as RNA rather than DNA, it has no mechanism to correct mistakes when it makes copies of itself, and the rate of mutation is fantastically high. Rapid mutation is one of the ways it escapes attack by the immune system. But this mutation rate may work to our advantage. From an evolutionary point of view, the more we practise safe sex, the more natural selection favours those HIV viruses which let the host live longer. Unprotected sex fails to punish viruses which slay their host early. HIV is young; hence its savagery. It would be much more widespread if it were less cruel to its hosts.

Humankind does have a failsafe mechanism. Although we evolve slowly, there are so many of us that there are bound to be some who, by chance, carry a natural immunity to any virus. Not many, mind: in the case of HIV, it’s about 1 per cent in people of Northern European descent, possibly as the result of natural selection during an ancient smallpox epidemic; but it’s enough to puncture the vain notion, as self-regarding as the belief that mankind is indestructible, that a disease by itself could end our reign on earth.

Mankind’s relationship with viruses in the past few hundred years has followed parallel tracks: exterminate and propagate. Caroline, Princess of Wales in the early 18th century, had a robust attitude towards medical ethics. Introduced to smallpox inoculation by Lady Mary Wortley Montagu, who had seen it used in Turkey (scrapings from the pocks of the infected were dabbed onto a lightly bleeding cut), she was keen to use it on her own daughters. But she wanted to test it on someone else first, so she tried it on six condemned prisoners at Newgate jail. When they survived, just to make sure, she tried it out on 12 orphans. That was good, too. So, in 1723, the young princesses were inoculated, 75 years before Edward Jenner discovered that vaccination with cowpox would do to the job just as well, and the smallpox virus, which once killed 400,000 people a year in Western Europe alone, was on its way to extinction.

In 1763, the British military commander in North America, Sir Jeffrey Amherst, became the first practitioner of viral warfare when he authorised the distribution of blankets contaminated with smallpox to American Indians who were making life difficult for European settlers in Pennsylvania. And this is how it has been: on the one hand, steady progress in understanding and defeating viruses; on the other, human actions that have led to the emergence, spread or survival of viruses – if more by accident than Amherstian design.

The roll of honour in the war against yellow fever, which decimated the population of Philadelphia in four months in 1793, begins with Jesse Lazear, head of the clinical laboratories at Johns Hopkins Medical School. He was one of three American doctors who volunteered as guinea pigs on an expedition to Cuba in 1900 to test the theory, widely ridiculed, that mosquitoes spread the disease. He caught yellow fever and died; the link was soon proved and the importance of draining mosquito marshes realised. In 1937, a vaccine was developed. A success story. Yet increasing international trade and travel still threaten to give yellow fever a new lease of life, by spreading it across the Indian Ocean to Asia, where, Crawford warns, ‘the virus would find a wholly unprotected population to infect.’

The struggle against polio, which has triumphed to the point where it will soon, like smallpox, be declared extinct, is another remarkable story. Yet the disease, which spreads when traces of infected faeces are ingested, acquired an epidemic nature in the 20th century only in developed countries when strict hygiene had become the norm. Previously, polio had been endemic, and most children had caught mild, symptomless forms of the disease before they were five, gaining immunity. It could be argued that a victory had been gained over an epidemic humankind unwittingly brought on itself.

Polio carries with it another lesson. It was still not clear by the end of the Royal Society conference whether there is a link between the African polio vaccinations and the success of the different strains of HIV in jumping species from monkeys and chimpanzees into humans and then spreading. What is known is that huge numbers of people – 98 million in the US alone – were given polio vaccine infected with another simian virus, known as SV40. The vaccine was grown in rhesus monkey cells at a time when the risk of animal viruses spreading to humans was poorly understood. So far there is little evidence that SV40 has done any harm, but it was a lucky escape. Our shifting of wildlife to the margins, our host of domesticated animals, our fondness for pets, our provision of new evolutionary niches for pests and our use of animals in medicine, all these offer new ways for viruses to move between species, whether by way of a deadly seal plague involving a virus caught from pet dogs, as happened in Northern Europe in the 1980s; or a new, severe flu pandemic from viruses found in Europe’s overcrowded pig population; or the devastating consequence of viruses which have long been harmlessly carried by swine being transferred to humans as a result of future pig to human organ transplants.

The dangers seem as great as ever. But our recently acquired knowledge of how viruses and cells work on a molecular level, particularly the breaking of the genetic code of different organisms, has greatly advanced the field of virology. New vaccines are being made which consist of nothing more than part of the chemical signature of a virus. The role of viruses in provoking cancer and auto-immune diseases – could a virus be responsible for multiple sclerosis? – is being explored. And modified versions of viruses, with their ability to break into cells and plant DNA there, are being used in gene therapy, to get properly working genes into the cells of people who don’t have them.

There are two ways of looking at this burgeoning medical revolution. One is as a set of many different potential medical breakthroughs, all offering hope for a cure of this or that disease. The other is as the beginnings of a complete understanding of how life on earth (in this context, everything from viruses to people) works as a single biochemical machine. We are already at the point where there are many more things we could do (clone human beings, tinker with our inheritable DNA) than we do do, either because they are morally unacceptable, not useful, or because the consequences are in doubt. This gap between what is doable and what is done, in terms of medicine, is certain to widen. But one day we may find ourselves invited to cross that gap, from a world of incomplete, fuzzy solutions to disease, where solving one problem may lead to another, to a world whose entire ecosystem, including mankind itself, is continually being genetically redesigned. Already we’re seeing the mass failure of antibiotics, with bacteria out-evolving our means to control them. It seems likely that viruses have more unpleasant surprises in store, and yet here we are, addicted to being cured. If scientists begin telling us that the only sure way to defend ourselves and our children is to modify ourselves genetically, will we find it in ourselves to say no?

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