This Eradicated Disease Could Come Back as a Terrifying Biological WeaponA Discovery series released Thursday produced by Steve Rivo, Invisible Killers, explores in one episode how smallpox—eradicated in 1980—could make a surprising, deadly comeback.

That might seem inherently at odds with what we think about smallpox, a disease that starts as a fever with red bumps that become painful blisters within and outside the body, ultimately causing up to half of people afflicted with it to die.

There is no cure, and smallpox permanently scars not only the body but a person’s organs.

But thanks to a staggering effort fronted by the World Health Organization, the disease was eradicated in 1980.

The disease isn’t dead, however. Labs around the world hold vials of smallpox in the event of an emergency, stockpiles that were supposed to be destroyed by 2002 but weren’t after 9/11 and the subsequent anthrax attacks made bioterror a real, looming threat.

The CDC still holds reserves, in addition to enough vaccinations and treatments in the event of a surprise eruption of smallpox.

It would seem to suggest the disease and all its future iterations would be under control, but a brewing debate among policymakers and those who study smallpox biology suggests the possibility of a weaponized new strain of smallpox.

In January, David Evans, a virologist at the University of Alberta in Canada, and his colleagues, published a paper in PLOS One that shook national security experts.

In it, Evans described how he and two colleagues went about ordering DNA fragments on the Internet, carefully pieced them together, created horsepox (a smallpox cousin that can’t affect humans), and published their work—to much backlash.

Why? Security experts and public health officials argued that what Evans and his team had essentially published was a recipe for making smallpox at home and disseminating it.

Evans refused to comment on his study to The Daily Beast, instead pointing questions to a colleague unrelated to the study, an emeritus professor of molecular genetics and microbiology at the University of Florida, Richard Condit.

Condit’s laboratory studied smallpox, among other pox viruses, for nearly 40 years. “I actually think it’s fair to say I played a role in helping to develop a lot of the techniques used to create synthetic pox virus,” he told The Daily Beast while driving from his home in Austin back to Gainesville.

Condit wasn’t drawn to virology, but said that he was “interested in how genes work, studying how genes work.” “Viruses are simple genetic systems,” he said.

That doesn’t mean that viruses like smallpox should be overlooked or scoffed at, however: Their operation is extremely complex and intricate. “The most unusual thing about pox viruses is that they are the only viruses that contain DNA and don’t replicate outside of the cell,” he explained.

Smallpox is also unique in that it has its own complete replication system. That’s unusual among viruses, which normally have to encode DNA outside the cell. Smallpox, however, is autonomous, encoding this replication machinery within the cell. This leads to smallpox’s biochemical complexity; according to Condit, the simplest viruses have five genes. Smallpox contains about 200.

“As viruses go, it’s a relatively complex organism,” he said. “I don’t think any one can tell you why it’s so deadly”—and a lot of that probably has to do with the fact that it’s so complicated.

But reproducing it? Not so hard. Condit described it as such: “The technology that is used to make the synthetic virus really has to do with introducing segments of DNA into a cell under conditions where they will join up with each other to make a complete genome…

What you have to do is infect cells with a closely related pox virus to provide the machinery that’s necessary to join fragments and launch the infection. You let the DNA fragments join and the helper—the initial virus you added—provides the machinery to launch the infection.”

That, in a nutshell, is how to make a smallpox virus.

Condit insisted that the technology to create the virus has actually existed for decades, but that what’s different now is the fact that DNA fragments are available, viable, and can be bought on the Internet.

That accessibility is in fact what makes many policymakers nervous. Condit said that if his lab were still running, it would take just some scientists and money to throw a virus together.

“First you have to have a laboratory that is equipped to do biomedical science, with incubators to grow a million cells, supplies, personnel that is knowledgeable,” he ticked off.

“Setting that up is $1 to $2 million. David [Evans] told me the DNA fragments he bought were about $100,000. If my lab were starting from scratch to do the experiment, it would take six months, probably a year, could turn into two years. Finding the personnel could run about $200,000 a year, with appropriate expertise, $300,000, but it could be twice that when you’re finished.”

In short: Even on the expensive side, recreating a synthetic smallpox virus in a lab would take trained professionals around $3 million to do.

That’s cheap—especially for a state sponsored terrorist organization.

Michael Osterholm, director at the University of Minnesota’s Center for Infectious Disease Research and Policy, thinks that horsepox is a gateway virus of sorts towards manipulating what we know about smallpox into a viable strain that would wreak havoc.

What especially concerns Osterholm is the fact that the recipe for creating smallpox is out for the taking. Evans’ paper made ripples not only because he was able to create horsepox from scratch but moreso because it was published—which means people with nefarious intent could reproduce horsepox and tweak it enough to become smallpox. “The principles of making horsepox virus are not different [from smallpox],” Osterholm said.

“Do you want to lay out a roadmap for the bad guys?” Osterholm asked. “The work in Canada [by Evans] is virtually a road map. Now every Tom, Dick, and Harry can do it.”

According to Condit, that’s not quite true. Condit emphasized that smallpox is a complex virus whose evolution and synthetic reproduction will likely also be complex and said that creating a new smallpox virus that would be both synthetic and something we’d never seen before that would harm humans was “beyond our capability.”

“Nature has worked on this [smallpox] for a long time,” Condit argued. “My guess is that most things you created in the lab would be less lethal than smallpox.” That’s because half of the 200 genes are for “tinkering” with the immune system to replicate the host’s immune system response. “It’s an enormously complicated process.”

Evans’ lab was not the first to piece together DNA to create a pox. In 2001, Australian researchers published a paper in The Journal of Virology that pointed to experiments done in 1998 and 1999 where researchers—who were actually trying to make mice infertile and didn’t publish results for a couple years because they were debating if it was morally responsible to do so—dropped a gene into the mousepox virus.

The mice, even if they were vaccinated, were eviscerated.

Experiments like Evans and the mousepox virus that was adjusted to become deadlier show Osterholm that it’s very much in the realm of possibility for humans to make a smallpox virus that’s much more frightening than its original form, despite the fact that Condit invoked a common phrase in science—“mice lie and monkeys exaggerate”—to suggest animal experiments aren’t necessarily translatable to humans.

“The principles are no different,” Osterholm stressed. “Surely government sponsored labs could do it. You’d clone the public sequences. Someone can take that and alter it. We can surely guarantee with ongoing improvements in lab science that we can see a potential for more harm.”

One thing both Condit and Osterholm do agree on is the relative ease by which a state-sponsored actor could replicate smallpox. “The tools are readily available now to allow us to do something with viruses that we can’t even imagine,” Condit said. “With well supported laboratories and new molecular genetic tools, this is Pandora’s box.”

Condit echoed this statement. “Sure, that’s right—a well-equipped and knowledgeable lab could do this,” he said. “David’s [Evans] experiment is proof of principle.” The only thing a group would have to do to create smallpox that wasn’t horsepox? According to Condit, it would be to use synthetic DNA instead of fragments that previously already existed.

Osterholm and Condit also differ in their thoughts about the future of smallpox in being used as a bioweapon is our preparedness.

“There was a major initiative launched to get a new and better vaccine [to cover a potential crisis in the aftermath of 9/11],” Osterholm said. “It [stockpiles of smallpox vaccine] would cover the U.S. population, and a little more. But it’s surely not adequate for the world should smallpox come back.”

Osterholm added that while smallpox could be contained quickly in the United States thanks to established public health measure practices, an incident in a region where an immunological response plan isn’t set up could be dangerous, particularly in an age of air travel.

Osterholm said that in a scenario where a smallpox virus was created in a laboratory the creator might not be able to remain anonymous; the genes would be able to be traced, the methods and strains used found. “It would be a blowback if an epidemic was traced back to a government,” he said, changing a world order where such an attack would be considered a blatant human rights offense.

The recent attack allegedly by Russia of a spy and his daughter using the nerve agent novichok, however, has turned that over, though. “It’s possible,” Osterholm said. “I can’t think of too many things that would cause panic than the return of smallpox.”