Only two places on Earth are known to retain live smallpox virus samples. As nations spar over the fate of these tiny vials, the World Health Organisation gets set to make some tough decisions this month.

In 1978, Janet Parker became the last known person to die of smallpox. Caused by a virus called variola, the disease is documented to have killed hundreds of millions in the 20th century alone. Parker's case, however, is particularly tragic, and is bound to be brought up more this month as WHO’s decision making body, the World Health Assembly (WHA), gathers for its 67th meeting to discuss, among other issues, the highly contentious debate of whether the last 571 samples of living smallpox virus should be destroyed or preserved.

So long and good riddance

Smallpox was declared by WHO to be eradicated on December 9, 1979.

This was two years after the last known natural case, that of Somalian hospital cook Ali Maow Maalin, who survived and went on, until his death from malaria in July 2013, to play a significant role in his country's polio eradication campaign.

It was a year after Maalin’s case that British medical photographer Janet Parker contracted the disease. The reason she does not qualify as a "natural" case is because she got it not from the wild but from the lab she was working at. The head of the university's microbiology department who was in charge of conducting the smallpox research at the lab had once been warned by WHO about inadequate safety standards. He committed suicide at his home on finding out Parker was infected. A few days later she succumbed, but not before her father died of cardiac arrest while visiting her at the hospital and her mother caught the virus from her.

Horror stories and happy endings

Smallpox remains the only human disease ever to have been eradicated by deliberate intervention. “Eradication” means that the prevalence of the disease among the host population (humans) has been reduced to zero. The cattle disease rinderpest is the only other one to have been wiped out.

It's been nearly 35 years since anybody has suffered from small pox, but as incredible as this may sound: there's actually a flipside to that. Most of the world's current population has no immunity to the disease, as vaccinations are no longer given.

Why does it matter, you may wonder, if we are or are not immune to a disease that no longer exists? That's because there still are living smallpox viruses in the world today -- 571 known samples, to be exact. They are preserved in two specially designated laboratories -- a Russian lab called Vector in Siberia (120 samples), and the Center for Disease Control lab in Atlanta, U.S.A. (451 samples).

Deadly souvenirs

When smallpox was eradicated in 1979-80, the plan was to destroy all remaining stocks of the virus, or transfer them to one of only four WHO-designated laboratories situated in U.K., U.S., South Africa and Russia. By 1983, all stocks in South Africa were destroyed and the U.K. ones were transferred to the CDC lab in the U.S.

The plan was to eventually destroy all available stock -- after all, you wouldn't want to have a repeat of the Janet Parker episode, would you -- but a portion of the scientific community (not surprisingly, mostly from U.S. and Russia) are of the opinion that it would be unwise to do so for a number of reasons.

Firstly, there is a fear that there might be undisclosed or forgotten sources of the virus. As this Frontline article says, this could be in the form of a corpse of a smallpox victim buried in permafrost, a vial of the virus retained by mistake in some laboratory, samples deliberately retained by some country which suspects the motives of the Russian and U.S. governments, or by individuals out of intentions of bio-terrorism. If, in this way, any variola escapes into the wild, it will leave entire human populations susceptible to a highly contagious virus they have no immunity against.

There are not enough doses of vaccine left to treat a massive outbreak since 1990 when, according to this New Yorker article, WHO decided to destroy 9.5 million out of the 10 million doses after declaring smallpox was no longer a threat. So, in the chance that any future outbreak does happen, we risk being completely ill-prepared.

Because WHO said so

Since 1980, several WHA meetings have addressed the issue of how long to wait before destroying the samples, but the U.S. and Russia have been stalling setting the date just yet. They argue that declaring those possessing the virus as guilty of crimes against humanity (as it will be after destruction) will not deter terrorists from doing so.

Moreover, as synthetic biology gains ground (Craig Venter and team became the first to create a self-replicating bacterial cell from scratch in the lab in 2010), the possibility of creating variola from scratch in the lab is becoming a reality. If the bad guys find a way to do this first, and governments have no live samples to base their defense on, then the result could be catastrophic. Destroying the viruses before developing a better, safer and more efficient vaccine (the original vaccine, though effective, would not have passed today's safety standards) and a drug to treat the disease, they say, could backfire badly on us.

But for countries in Africa and Asia where the memory of the terror of the disease is still ripe, and which are much less equipped than richer nations like U.S. and Russia to handle an accidental release, retaining the virus is plain bad news. In fact, a 1998 WHA survey of the positions of its 191 members revealed that out of the 79 countries that responded, only Russia was against destruction (camp “retentionists”). U.S., U.K., and France were undecided and the rest of the 74 were in favour of destruction (camp “destructionists”).

In the 1999 WHA, however, the Bill Clinton government sought for a delay in destruction, heralding a change in U.S. position that has been much read into.

“He started it!”

One discussed reason for U.S.'s keenness to keep the virus were the revelations by Russian biological warfare expert Ken Alibek. After defecting to the U.S. in 1992, Alibek revealed to CIA officers that in the atmosphere of distrust during the Cold War, "samples of smallpox taken by Russian doctors had been turned into weapons by the Soviet military."

There have also been media reports claiming that the U.S. suspected that countries like North Korea and Iraq which do not share friendly relations with them may have hidden samples and intentions to weaponise. The Guardian has reported Russians saying that Iran had made several attempts -- some perhaps successful -- in the 1990s to recruit some of their Vector scientists.

It is no wonder, then, that African and Asian countries who have little to do with this power struggle feel unfairly burdened. According to Dr. Kalyan Banerjee, biological warfare expert and former Director of the National Institute of Virology, for India, as of today, smallpox is probably the most serious threat in terms of biological warfare. The former WHO advisory committee member echoed other destructionists when he said in 2011 to the Wall Street Journal, "To put it bluntly, it is the same logic by which the superpowers continue the possession of the nuclear weapons; they wish to hold on to the smallpox virus as a super bio-weapon."

For the sake of science

The retentionists, however, deny all of this. They maintain that their stand is motivated solely by scientific need and the demands of public health. In 1999, the WHA decided to keep the virus temporarily (“retention, up to but not later than 2002”) for research aimed at: a) developing a safer version of the vaccine b) an antiviral drug to treat the already infected, and c) to find a way to simulate human smallpox in a model animal.

Consequently, the amount of research using live virus was increased and a WHO Advisory Committee on Variola Virus Research (ACVVR) was formed to oversee the research.

2002 came and went, and though the allowed research was refined to include only those which focused on "essential public health", the date of destruction was still not set.

During the last WHA discussion it was decided that a stand would be taken in the 2014 meeting, scheduled for later this month. In this light, scientists from the Centers for Disease Control (CDC) and University of Florida in the U.S., and Universidade Federale do Rio de Janeiro in Brazil have published an opinion piece in PLoS Pathogens journal about why they think that despite considerable scientific advances, the world is not yet ready to face a new smallpox threat, and until we are, it is important to retain the virus stock.

Too far in the game?

One of the primary arguments by the CDC scientists is that even after so many years of research, science has been unable to get to the bottom of variola's ability to be a human-specific virus.

The discovery that smallpox has no carrier organisms, and humans were the only hosts, was important to devise its eradication strategy. Unless the virus is able to find and invade a human every 14 days, it would die. So, as Richard Preston, author of The Demon in the Freezer, says in a New Yorker article, if the virus could be kept from completing its fourteen-day life cycle by keeping the number of immune people high enough, then it would be unable to move to the next human host, thereby breaking its chain of infection.

Dr Inger Damon, lead author of the PLoS article, explained to me via email why scientists have for so long been unable to understand the mechanism underlying this human-specific behaviour of variola. Traditionally, questions about host-pathogen interaction are answered by knocking out specific genes until the one responsible for a particular behaviour is singled out. However, Dr Damon explains "With variola, the use of these genetic tools is not permitted by international agreements made at the end of the eradication efforts."

Nevertheless, she stressed that advances in genomics have now made it possible to answer these questions with measurements using their transcriptomes (the entire RNA content of the virus) or interactomes (all the molecular interactions in the virus). With all these at hand, scientists like Dr Damon are of the view that it would be ill-advised to destroy the viruses while we may be at the cusp of some major breakthroughs.

In search of an animal model

Responding to the issue of whether it will ever be possible to get any significant results without an animal model which adequately mimics immune response in humans, Dr. Damon remains optimistic. She informs us that an international group of scientists has reviewed animal model development, and submitted to the WHO a summary of recommendations for modifications to the existing animal models. This could, she says, result in a model which better resembles human disease.

Another reason we need variola samples, as mentioned by Dr Damon and co-authors in the article, is a re-emergence of orthopoxvirus infections in humans. Orthopoxviruses are a class of viruses which include vaccinia, cowpox, monkeypox, and variola (smallpox) viruses.

Dr. Damon says that this apparent re-emergence could be due to a variety of reasons, like the impact of stopping routine smallpox vaccination, higher diagnosis rates, or other factors such as greater animal human interface leading humans to disease exposure.

So how can the remaining variola samples help? "The research enabled by the smallpox research agenda has led to the advanced research and development of better diagnostic capabilities, as well as newer vaccines that may be used to prevent disease and antivirals which may be effective in treatment of disease."

All in WHO’s hands, now

In their article, Dr. Damon and co-authors call the notion of an ultimate final destruction of variola virus problematic. According to her, the best decision WHA could take this May is one that would allow continued use of the virus to support work to enable best practices in use of the diagnostics, vaccines and antivirals.

She adds, "This is important to maintain a “pipeline” if research studies are not supportive of their use against smallpox, or as platforms/approaches become obsolete (especially important for diagnostics). Many scientists are interested in engaging on the discussion of synthetic biology advances and how this may impact what studies are important."

How much the WHO takes these considerations into account remains to be seen when the WHA starts on May 19th.