Scientists in Canada have used commercially available genetic material to piece together the extinct horsepox virus, a cousin of the smallpox virus that killed as many as a billion human beings before being eradicated.
He has not yet published his findings in a scientific journal — how to report this kind of research is necessarily fraught for the editors of such journals — but he did discuss them at a meeting on smallpox research last November at the World Health Organization in Geneva. A report on the meeting published by the WHO noted that Evans had received approval from regulatory authorities for his work, but the report added that those authorities may not have fully appreciated the need for regulation of the steps involved in synthesizing a virulent horse pathogen.
Evans said he has applied for a patent and is collaborating with a commercial company, Tonix Pharmaceuticals. In a news release, Tonix said it hopes to use horsepox virus to develop a new vaccine for smallpox that is safer than the one currently available, which can have serious side effects.
Evans said he was not trying to prove a point, but he acknowledged that he has long argued that it would be possible to synthesize a pox virus through laboratory techniques.
Smallpox, the deadliest disease in human history, was formally declared eradicated in 1980. Government officials and virologists have long debated whether to destroy the existing samples of smallpox kept under close guard at the U.S. Centers for Disease Control and Prevention, as well as in government facilities in Russia. One argument against doing so, advanced by Evans and others, is that destroying the known stocks would not conclusively get rid of smallpox, because there could be unknown caches of the virus hidden somewhere, and that, in any case, modern techniques would be able to synthesize the virus based on already published genetic sequences.
Evans's experiment, according to Science, required about $100,000, a relatively modest sum, and used commercially available genetic material. Companies sell scraps of cloned DNA that scientists stitch together. Laws restrict access to smallpox genes, however, and Evans said that even a highly credentialed researcher would not be able to obtain such material: “You’d probably get a call from the FBI if you tried.”
Evans said the creation of synthetic horsepox “isn't trivially easy.” He said he was not seeking publicity and wished that news organizations would not make a “fuss” about his work.
“Whether you can make the virus, or whether there are these hidden stocks of virus, doesn’t change the fact that in the case of smallpox, we have to be prepared for it,” he said. “I don’t know whether the risk has gone up or not. The fact we’re talking about it is to some extent increasing the risk.”
Tom Frieden, former head of the CDC, said the breakthrough was not surprising but probably makes the debate over destroying the existing smallpox stockpiles less relevant. He said it highlights the need to monitor more closely “dual-use” experiments — research that could be used either for protective purposes or, in theory, to create a deadly pathogen.
“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,” said Frieden, who favors limiting the number of such experiments and institutions where they can take place.
Frieden said this research should spur improvements in laboratory safety to prevent the accidental release of microbes — something that has happened a number of times in American facilities and others around the world. The broader story here, Frieden said, is that the U.S. and other countries need to be prepared for emerging pathogens, which can and will appear naturally — no laboratory necessary.
That sentiment was echoed by Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases.
“The danger of naturally evolving microbes, like Zika, like pandemic influenza, like Ebola, that naturally evolve, are much more of a threat to civilization than the possibility that someone might be able to synthesize a microbe,” Fauci told The Washington Post. “People should concentrate on what we’ve been talking about for a long time: getting ourselves prepared for the natural emergence in nature of microbes that could threaten us.”
Smallpox vaccination programs ceased several decades ago after the smallpox virus stopped circulating widely. Today, a majority of Americans have never been vaccinated against smallpox. That's a straightforward example of risk analysis: The potential side effects (including, in rare cases, death) from smallpox vaccination have been viewed as greater than the risk of anyone becoming infected with the virus once it stopped circulating in the population.
Ethicists have struggled with the question of how to handle dual-use biomedical research.
“We are still struggling with how to manage the dual-use dilemma. How do we get the benefit of the research without the risk of it being turned against us?” said Alta Charo, a law professor and bioethicist at the University of Wisconsin who has followed the debate closely.
She cautioned against overreaction to Evans's research. Creating a pathogen is not the same thing as weaponizing one, she said.
Peter Jahrling, director of the NIH Integrated Research Facility, praised Evans's work: “I think he did a terrific service. You had a lot of people saying this can't be done. And he said yes it can.” Jahrling added, “If he had done it with smallpox virus, that would be a real [tempest]."
Jahrling and other experts noted that a synthetic polio virus was built in a lab some years ago. The pox viruses are much larger, and their synthesis represents a breakthrough. But Jahrling said this kind of work could be replicated by other researchers.
“Maybe not some guy in a cave,” Jahrling said. “But a reasonably equipped undergraduate microbiology lab could repeat this trick.”
The smallpox virus's complete genome has been known since the 1990s. Scientists and government officials debated whether the genomic information should be published, but synthetic biology was such a primitive field at the time that few people expected anyone would be able to reconstitute the virus.
Since then, biotechnology has advanced at a stunning rate. The global health community has known for roughly a decade that synthesis of pox viruses, including smallpox, was possible, said Gigi Kwik Gronvall, a senior associate at the Johns Hopkins Center for Health Security and author of “Synthetic Biology: Safety, Security and Promise.” The Evans experiment, she said, had “no technical breakthrough.”
Still, restrictions are in place to prevent smallpox DNA from falling into the wrong hands. In the United States, experiments that are identified as Dual Use Research of Concern go through an additional round of review by funding agencies and must include a risk mitigation plan in their design. Last year, the World Health Organization recommended that no institution be allowed to posses more than 20 percent of the smallpox virus's genome. Companies that produce DNA for research are required to screen customers' orders for matches against known pathogens.
“You couldn’t have somebody just order smallpox DNA to a P.O. box,” Gronvall said.
This is not the first experimental work on engineered pox viruses. In 2001, Australian researchers manipulated the genetic code of mouse pox and showed that it could be deadly even to those who had been vaccinated or naturally immune. A researcher in St. Louis demonstrated similar alterations in mouse pox in 2003, inciting alarms about the potential misuse of biomedical experiments.
Such concerns spiked after 9/11 and the anthrax attacks of that autumn. The controversy flared again in 2011 when researchers in Wisconsin and the Netherlands conducted experiments on bird flu virus. The National Science Advisory Board for Biosecurity urged the journals Science and Nature to refrain from publishing the research, and the journals initially complied. But the researchers later revealed that their experiments did not create any killer pathogens, and publication went forward.
Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, said the breakthrough with horsepox suggests that similar work is likely to be occurring around the planet.
“The question is how many other people have done it. We never thought or expected it to come from a place like Alberta,” he said. “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?” He said the U.S. government is unprepared to handle an emergency involving a synthetic pathogen — particularly given that many senior positions haven't been filled yet by the Trump administration.
“This has been the storm coming for years,” Osterholm said. “We’ve known about it, but unfortunately, we’re not ready.”
Ariana Eunjung Cha and Sarah Kaplan contributed to this report.