It's been described as the deadliest disease in human history, and scientists are warning the world may have just inched closer to seeing its revival.
Smallpox claimed as many as 500 million lives in the 20th century alone before it was eradicated, and scientists fear controversial experiments in which researchers recreated a related horsepox virus from scratch could make its deadly cousin equally replicable.
Researchers at the University of Alberta created an uproar last year when news broke that they had pieced together the extinct horsepox virus – which does not pose a direct threat to humans – by assembling fragments of DNA purchased over the internet for around US$100,000.
By stitching these disparate sections of genetic material together, the researchers reconstituted what they claim is the largest virus assembled to date using chemically synthesised DNA – but not everybody was happy about it.
While the purpose of the exercise was ostensibly to investigate how the synthetic horsepox virus could help us research safer new forms of smallpox vaccines, critics of the research say it serves as a dangerous example of how to engineer deadly viruses that could harm people, like smallpox.
"It is a brave new world out there with the ability to re-create organisms that existed in the past or create organisms that have never existed," former head of the Centres for Disease Control and Prevention (CDC), Tom Frieden, told The Washington Post in July.
The critics have not changed their tune in the interim.
They argue that existing safe vaccines are already available, citing Modified Vaccinia Ankara (MVA) – some 28 million doses of which are already stockpiled by the US government – and a Japanese vaccine called LC16m8.
In light of these readily available alternatives, some researchers are saying the 'smallpox vaccine' justification for the horsepox research doesn't make sense.
One commentator, infectious disease specialist Thomas Inglesby from Johns Hopkins University called the publication of the paper "a serious mistake".
"The world is now more vulnerable to smallpox," he told Science.
Of course, this kind of critiquing is par for the course when it comes to so-called "dual-use research": scientific experiments that stand to improve our understanding for the positive, but which could also be abused to create harm and danger.
That latter potential is what most seem to be focussing on with regards to the publication of the synthetic virus study.
"If anyone wants to recreate another poxvirus, they now have the instructions to do that in one place," said virologist Andreas Nitsche from the Robert Koch Institute in Germany.
Indeed, that's exactly what the senior researcher behind the poxvirus study, virologist David Evans, intends to do next – albeit with a view to discovering more vaccines.
"We are invested as a research laboratory in taking that same technology and applying it to other poxviruses," Evans explains in a press release.
Evans, who is listed as co-inventor on the patent for this synthetic version of horsepox – called vaccine candidate TNX–801 – has previously expressed some ambivalence about whether his reconstituted virus research could be used for the wrong reasons.
"Have I increased the risk by showing how to do this? I don't know," he told Science last year.
"Maybe yes. But the reality is that the risk was always there."
That's because another aim of the research is to show just how far virus recombination and biotechnology at large have leapt forward in the past couple of decades.
The smallpox genome has been fully understood since the 1990s, but back then nobody imagined researchers would any time soon have the expertise or equipment to be able to stitch together pieces of synthetic virus – let alone fragments they'd ordered over that new computer system called the internet.
The world has changed a bit since then.
"The question is how many other people have done it? We never thought or expected it to come from a place like Alberta," the director of the Centre for Infectious Disease Research and Policy at the University of Minnesota, Michael Osterholm, told The Washington Post last year.
"It's not one of the leading universities in the world for microbiology and synthetic biology. If it came out of there, how many other places like this are also doing the same work right now?"
The findings are reported in PLOS One.