December 01, 1995

Article at Science Spectra

Death and the Virus

The smallpox virus under the microscope

The killer of an estimated one billion humans over the millennia is facing extinction, the sword of medical science hovering above its head. But still the debate rages about whether smallpox should die.

by Wilson da Silva 

FRANK FENNER  is thorough. His answers are exacting and considered. In discussion, he is careful to leave no angle undebated, no avenue unexplored.

That might explain his exasperation, or such as it is for a contemplative 80-year-old. For it has been nearly 30 years since the eminent Australian virologist first joined an international task force with a seemingly impossible task – to eradicate an infectious disease from the face of the Earth.

Today, his quarry – the smallpox virus – is all but vanquished, its remnants on microbial death row in the United States and Russia. He’d like to finish the job. But he’ll be damned if he can get somebody to throw the switch.

“My personal feeling is that there’s no justification for keeping it,” Professor Fenner, of the John Curtin School of Medical Research at the Australian National University in Canberra, Australia, told Science Spectra.  “The arguments that have been put up just don’t hold water. Now, it really not a matter of science, it’s a matter of politics.”

It was in 1967 that the World Health Organization (WHO) began a ‘moonshot’ of sorts, attempting to eradicate the micro-organism. Sparked by a proposal by the Soviet Union nine years earlier, the Global Commission for the Certification of Smallpox Eradication came into being. It employed about a hundred highly-trained professionals, many of them young and idealistic, and thousands of local health workers worldwide who were pressed to the cause.

Frank Fenner

They trekked dirt roads in India or dodged civil wars in Africa, acting on reports of the disease and hunting it down. They inoculated whole villages where one case arose, at times forcibly and with the help of local police. They broke WHO regulations and flouted procedure in the search for their viral prey, and their medical superiors largely turned a blind eye to bureaucracy rather than halt the war. 

They were fighting a horrendous disease, one that had killed indiscriminately over the centuries. It was transmitted by breath, the tiniest droplet carrying more than 1,000 viruses, causing a disfiguring bulbous inflammations of the face and skin. Unlike most infectious diseases, it did not just target the most impoverished – the Roman Empire was devastated by an outbreak 165 AD that lasted 15 years, infecting across social strata and wiping out between 25 and 30 per cent of the population. 

It’s arrival on the New World solidified the feeble foothold of the Europeans in the 16th century. Cortez’s war against the Aztecs was on the verge of collapse in 1520 when his ragtag army of 400 was driven from the city of Tenochtitlan, to a field where they awaited their defeat. But it never came – the conquistadors had brought with them smallpox, and a plague befell the city. When even the nephew of the great King Montezuma died, the Aztecs took it as an omen and surrendered. It was the first time disease had been used, although unintentionally, as a biological weapon.

By the time the Russians pushed for its eradication, smallpox was present in 33 countries and was killing two million a year, despite the fact a vaccine had been available since 1796, which had now been made 99 per cent effective. 

By 1974 the teams had surrounded the last of the deadly variola major strain in Bangladesh, and were months from eradicating it. Catastrophic floods, a coup and civil war intervened, hampering the work of hunting down the last cases for another year. The only remaining but less deadly strain, variola minor, was cured from its last victim on October 27, 1977 in Somalia. Three years later, Fenner as chairman of the task force was able to announce to a meeting of the WHO: “We, the members of the Global Commission ... certify that smallpox has been eradicated from the world.”

It had taken just 11 years and cost US$760 million in today’s dollars. More than 250 million doses were dispensed annually. The virus was dead everywhere – except in laboratories, where it could always escape. And in 1978, it did: British photographer Janet Parker, taking pictures in a Birmingham University Medical School laboratory where samples were stored, was accidentally infected.

man suffering from smallpox at North Head Quarantine Station, Sydney; the bumps filled with thick fluid (National Museum of Australia)

She died, and the scientist in charge committed suicide. The last remaining stocks in Britain, Japan and the Netherlands were then transferred to deep freeze facilities kept by the high security labs of the Centres for Disease Control and Prevention in Atlanta, USA. Another collection of strains was maintained by the Institute for Viral Preparations in Moscow, Russia.

And that’s where they have been ever since. The Global Commission, since converted into the Ad Hoc Committee on Orthopoxvirus Infections, decided to keep stocks just in case the virus arose again. At the time, the only way of confirming its re-emergence would be to compare a strain against stocks of known strains. But modern genetic engineering technology did away with all that and by 1986, when the committee met again, the hibernating viruses were no longer considered necessary, and it was recommended they be destroyed.

The WHO consulted scientists around the world, and most agreed. But bureaucracy slowed to a crawl, prompting another meeting of the Ad Hoc Committee in 1990 which repeated the  recommendation made. But by then, a group of mostly American scientists were raising strong objections, among them the influential Professor Bernard Fields, former chairman of the microbiology and molecular genetics department at Harvard Medical School in Boston. 

“On a scientific basis, we’re taking an extremely precious resource and destroying it,” Fields told The Scientist newspaper last year. “Destroying it ends the whole issue of possibly understanding it in the future.”

The WHO committee had the backing of the American Society for Microbiology and the Council of the International Union of Microbiological Societies. However, to ameliorate the concerns of the eminent scientists, the 10-member Ad Hoc Committee recommended that the United States and the (then) Soviet Union begin a program to sequence the genomes of the viruses. They were given three years to do this, and the virus was then to be destroyed in late 1993.

But again, opponents won a stay of execution – the issue was hotly debated at a meeting of the International Biological Congress that year, where U.S. scientists argued to retain it so they could study the unusual way it interferes with the human immune system. They said new information about the way the virus worked might help in the battle against the human immunodeficiency virus (HIV). That convinced the WHO, and deferred the destruction. But after studying the arguments for its retention, the Ad Hoc Committee recommended again in September 1994 that the stocks be destroyed.

A decision was to be made by the WHO’s legislative body, the World Health Assembly. But at a meeting in January 1995 of the executive board preparing for the assembly four months later, Britain and the United States led a rebellion against the agenda item, and a vote on a decision to destroy smallpox was removed from the document. This time, it was the military who led the charge: British chemical and biological defense officials thought the virus might one day be resurrected and used for terrorist purposes, and they were backed by U.S. defense officials.

They argued that all known anti-virals should be tested to see if one exists that was effective against smallpox, just in case the virus was ever used in biological warfare. And group argued pathogenesis – studies to see how the virus kills – should be conducted to better understand smallpox’s mechanism.

“The reasons given by the British officials at first were ludicrous, they were not scientific at all,” said Fenner. “The ideas that are being circulated now not very convincing but they’re a bit better than they were.” There are no really good experimental animals other than humans for pathogenesis studies, he said. “Those investigations could be done much more readily with other viruses of the same family ... rather than having to use these special, high security labs for handling smallpox.”

A number of strains of the virus have been completely sequenced by the two centres, and proponents of destruction say that fragments of the virus genetic material be cloned and kept for study, up to 20 per cent of the whole DNA strand in any one lab. Dr Bernard Moss, of the National Institute of Health in Bethesda, Maryland, USA, said the WHO committee was now “fully satisfied that the genetic blueprint of variola (smallpox) virus has been properly archived for posterity.  Should the need arise, we will be able to conduct diagnostic tests with 100 per cent accuracy,”

But smallpox defenders decry this as inadequate. “Anyone who says the sequence is enough doesn’t understand virology, and that includes some famous virologists,” Fields has said. “We have to understand holistic parts of this virus and how these work together. There are many other poxviruses (to experiment on), but not this one. This one is the key pathogenic virus in its family. It’s qualitatively different.”

Biosafety Level 4 lab at the Centres for Disease Control and Prevention where smallpox is studied

Ironically, Fields – the main witness for the defense – has himself passed away recently. His cudgel has been taken up by Wolfgang Joklik, Professor of Microbiology at Duke University in Durham, North Carolina, USA. 

“The complete virus is required, not just plasmid clones and a sequence,” he said. “How viruses cause disease at a biochemical and molecular level is little understood, and in smallpox, viral proteins mimic or interfere with host immune and regulatory functions. Clones don’t suffice for study because encoding regions of the smallpox DNA are separated from regions that control expression.”

“Twenty years ago we thought all the information present in a  viral genome was only to enable the virus to multiply,” said Joklik. “Now we know that half the information is to defeat the human defense mechanism.”  

For Fenner and other members of the Ad Hoc Committee, the possibility that smallpox stocks might be used by terrorists is the most worrisome. “It’s greatest threat is as a terrorist weapon. Somebody could use it, for example, in airport lounges with aerosol dispensers – which wouldn’t be hard to do – and it could cause a lot of panic. That means that the virus has to be kept under military as well as microbiological security – for ever, if you’re going to keep it.”

It’s a scenario that also worries David Baltimore, Professor of Molecular Biology and Immunology at the Massachusetts Institute of Technology near Boston, USA,. “In a perfect world, we would have a perfect repository where we could keep it just in case we were wrong.” While he agrees that referring to gene sequences or toying with clones may not be the best way to study with the virus, “Balance that against the fact that there are nuts in the world, and I would just as soon get rid of it.”

But just the act of getting rid of it bothers scientists on both sides, since it would be the first conscious destruction of a species – in effect, genocide. 

“I don’t think we should destroy them,” Joklik said. “With the variola virus, obviously it’s taken millions of years for nature to make it, and why should 10 guys sitting around a table say, ‘Let’s destroy it’?”

“There is concern about that,” Fenner admits. “But maintaining it in deep freeze isn’t preserving life. To preserve life, you would need to return it to its ecological niche, which is to cause continuous infections to human beings. This isn’t what anybody wants.”

One irony is that Joklik, the man now leading the save smallpox, was a student for eight years under Fenner, the man charged with its eradication. The two met again late last year in Australia, and both agreed the sudden military interest was unfathomable, Fenner said. “I really can’t understand what’s behind it. I don’t think they want to use it themselves as a biological agent for war, since a vaccine could be made in large quantities very quickly and inoculated very quickly.” 

The WHO has provided for 500,000 doses of the vaccine always be available just in case the virus does break out again. It is taking seriously not just the threat of terrorist action or an accident, but that some of the virus might harboring in preserved corpses buried deep in the permafrost, or in forgotten or hidden stocks, or otherwise preserved in some corner of the world, from whence it would escape to plague humanity again.

“It’s a pretty lethal disease,” Fenner said. “Even in India, where people have been exposed to it for a couple of thousand years – and you think there would have been some natural selection for resistance – the Asian strain killed on average 20 to 25 per cent of people not vaccinated. For babies and older people it was about 40 per cent.

“You wouldn’t want that to come back,” he said.

As for the Ad Hoc Committee, Fenner suspects it will continue in name only, until its mandate is finally carried out. It has already outlived the virus in the wild by 18 years.  “It was really set up as a self-destruct committee,” he muses. “We’ve been going over the same ground for so long. I think they’ve got to decide now.”