Researchers de-extincted a killer Pox virus for $100k using mail order DNA

Eradicating smallpox, one of the deadliest diseases in human history, took humanity decades and cost billions of dollars, but by using exponential technologies and tools bringing the scourge back would probably take a small scientific team with little specialised knowledge half a year and cost about $100,000. Furthermore though over time even those relatively menial resource requirements will look overkill compared to what happens when an Artificial Intelligence (AI), like this one from ETH Zurich, can autonomously design synthetic viral genomes, and the cost of manufacturing them drops to hundreds then just tens of dollars – both of which will happen sooner than you think and ultimately “democratise” everyone’s ability to manufacture deadly viruses at will. Unless, of course, regulators figure out a way to stop it, which they’re notoriously bad at.

The conclusion comes from an unusual and as yet unpublished experiment performed last year by Canadian researchers after a group led by virologist David Evans of the University of Alberta in Canada, managed to re-synthesise the horsepox virus, a relative of smallpox which became extinct last century, using little more than genetic pieces ordered in the mail.

Horsepox is not known to harm humans, and like smallpox researchers believe it no longer exists in nature, nor is it seen as a major agricultural threat. But the technique Evans used could be used to recreate smallpox, a horrific disease that was declared eradicated in 1980.

"No question. If it’s possible with horsepox, it’s possible with smallpox,” says virologist Gerd Sutter of Ludwig Maximilians University in Munich, Germany, who wasn’t involved in the experiment.

In order to accomplish their feat Evans and his team purchased overlapping DNA fragments, each about 30,000 base pairs in length, from Geneart in Germany, a company that synthesises DNA commercially that allowed them to stitch together the 212,000-base-pair horsepox virus genome.

Introducing the genome into cells infected with a different type of poxvirus then led these cells to start producing infectious horsepox virus particles, a technique first shown to work in a 2002 paper in the Proceedings of the National Academy of Sciences. The virus was then “grown, sequenced and characterised,” the report notes, and then became viable and active.

Evans hopes the research, most of which was done by research associate Ryan Noyce, will help unravel the origins of a centuries old smallpox vaccine and lead to new, better vaccines or even cancer therapeutics. Scientifically, the achievement isn't a big surprise. Researchers had assumed it would one day be possible to synthesise pox viruses since virologists assembled the much smaller poliovirus from scratch back in 2002. But the new work, like the poliovirus reconstitutions before it, is now obviously raising troubling questions about how terrorists or rogue states could use modern biotechnology to create the next generation of bioweapons after the UN recently declared the world’s deadliest weapons, putting even nuclear weapons in the shade.

Given that backdrop, the study marks "an important milestone, a proof of concept of what can be done with viral synthesis,“ says bioethicist Nicholas Evans, who's not related to David Evans, of the University of Massachusetts in Lowell.

The study seems bound to reignite a long-running debate about how such science should be regulated, says Paul Keim, who has spent most of his career studying another potential bioweapon, Anthrax, at Northern Arizona University in Flagstaff.

"Bringing back an extinct virus that is related to smallpox, that's a pretty inflammatory situation,” Keim says. "There is always an experiment or event that triggers closer scrutiny, and this sounds like it should be one of those events where the authorities start thinking about what should be regulated.” And that’s before we even consider the possibility of using new AI tools to not just re-create extinct deadly viruses but to create even deadlier ones which, as the recent global Coronavirus pandemic COVID-19 has shown, would be incredibly difficult if not nearly impossible to counter and eradicate.

David Evans acknowledges that the research falls in the category of dual-use research, which could be used for good or bad.

"Have I increased the risk by showing people how to do this? I don't know," he says. "Maybe yes. But the reality is that the risk was always there."

Evans first discussed the work in 2016 at a meeting of the Advisory Committee on Variola (Smallpox) Virus Research at the World Health Organization (WHO) in Geneva, Switzerland. Worringly for all of us a report from that meeting, posted on WHO's website, noted that Evans's effort "did not require exceptional biochemical knowledge or skills, significant funds or significant time,” and it didn’t draw much attention from biosecurity experts or the press.

Also little noticed was a press release issued by Tonix, a pharmaceutical company headquartered in New York City with which Evans has collaborated, which also mentioned the feat. Tonix says it hopes to develop the horsepox virus into a human smallpox vaccine that is safer than existing vaccines, which cause severe side effects in a small minority of people. Evans says it could also serve as a platform, like DARPA’s P3 pandemic research platform, for the development of vaccines against other diseases, and he says poxvirus synthesis could also aid in the development of viruses that can kill tumors, his other area of research.

"I think we need to be aware of the dual-use issues [weaponisation]," Evans says. "But we should be taking advantage of the incredible power of this approach [for good].”

The double-stranded variola genome is 30 times bigger than the poliovirus genome, which Eckard Wimmer of State University of New York at Stony Brook assembled from mail-ordered fragments in 2002. Its ends are also linked by structures called terminal hairpins, which are a challenge to recreate. And though simply putting the poliovirus genome into a suitable cell will lead to the production of new virus particles, that trick does not work for poxviruses. That made building variola "far more challenging," says Geoffrey Smith of the University of Cambridge in the UK, who chairs WHO's variola advisory panel.

As far back as 2015 a special group convened by WHO to discuss the implications of synthetic biology for bringing back smallpox from the dead concluded that “the technical hurdles to re-creating these viruses had been overcome.”

"Henceforth there will always be the potential to recreate variola virus and therefore the risk of smallpox happening again can never be eradicated,” the group's report said. But Evans felt like the matter was never really put to rest. "The first response was, ‘Well let's have another committee to review it,’ and then there was another committee, and then there was another committee that reviewed that committee, and they brought people like me back to interview us and see whether we thought it was real,” he says. "It became a little bit ludicrous.”

Sadly, this governmental led-by-committee response is all too common and is often ultimately toothless and ineffective as we’ve seen with similar committee-led debates on the future of AI and even facial recognition and privacy where consensus is hard to come by and action is nowhere to be seen – that is at least until a catastrophic event occurs and then all of a sudden heads turn and policies change.

Evans says he did the experiment in part to end the debate about whether recreating a poxvirus was feasible, he says.

"The world just needs to accept the fact that you can do this and now we have to figure out what is the best strategy for dealing with that,” he says.

Today, producing the variola virus in the same fashion would be prohibited under WHO regulations because labs are not allowed to make more than 20 percent of the variola genome, and the companies that make and sell DNA fragments have voluntary checks in place to prevent their customers from ordering ingredients for certain pathogens unless they have a valid reason. But, that said, controlling every company in the world that produces nucleic acids is impossible, Keim says.

"We’ve recognised for quite a few years that regulating this type of activity is essentially impossible,“ he says – all of which means it’s no longer a case of if we’ll see the emergence of a new synthesised deadly virus, but when.

However, that said, let’s all hope that this research, and the research that follows it is used wisely, with the right safe guards in place and for benign purposes, and fingers crossed it doesn’t get into the wrong hands.