Just how easy is it to make a deadly virus?
This disturbing question has been on the minds of many scientists recently, thanks to a pair of controversial experiments in which the H5N1 bird flu virus was transformed into mutant forms that spread among mammals.
After months of intense worldwide debate, a panel of scientists brought together by the World Health Organization recommended last week in favor of publishing the results. There is no word on exactly when those papers — withheld since last fall by the journals Nature and Science — will appear. But when they do, will it be possible for others to recreate the mutant virus? And if so, who might they be and how would they do it?
Scientists are sharply divided on those questions, as they are on the whole complex of issues surrounding the mutated virus known as mutH5N1.
On the question of who, while terrorists and cults have long been a concern in biosecurity circles, some scientists also fear that publication may allow curious amateurs to recreate the mutated virus — raising the risk of an accidental release.
Over the past decade, more amateur biologists have started to do genetic experiments of their own. One hub of this so-called D.I.Y. biology movement, the Web site DIYbio.org, now has more than 2,000 members.
“I worry about the garage scientist, about the do-your-own scientist, about the person who just wants to try and see if they can do it,” Michael T. Osterholm of the University of Minnesota said last week at a meeting of biosecurity experts in Washington.
Dr. Arturo Casadevall of the Albert Einstein College of Medicine in New York City, who along with Dr. Osterholm is a member of the scientific advisory board that initially recommended against publishing the papers, agreed. “Mike is right,” he said in a telephone interview. “Humans are very inventive.”
Advocates of D.I.Y. biology say such fears not only are wildly exaggerated, but could interfere with their efforts to educate the public.
“I am really sick and tired of folks waving this particular red flag,” said Ellen D. Jorgensen, a molecular biologist who is president of Genspace, a “community biotechnology lab” in Brooklyn.
There are many ways to make a virus. The simplest and oldest way is to get the viruses do all the work. In the 19th century, doctors produced smallpox vaccines by inoculating cows with cowpox viruses. The viruses replicated in the cows and produced scabs, which were then applied to patients, protecting them from the closely related smallpox virus.
By the turn of the century, scientists had discovered how to isolate a number of other viruses from animals and transfer them to new hosts. And by midcentury scientists were rearing viruses in colonies of cells, which made their study far easier. (Viruses have to infect host cells to reproduce; they cannot replicate on their own.)
More recently, scientists discovered how to make new viruses — or at least new variations on old ones. The biotechnology revolution of the 1970s enabled them to move genes from one virus to another.
Flu vaccines can be made this way. Scientists can move some genes from a dangerous flu strain to a harmless virus that grows quickly in chicken eggs. They inject the engineered viruses into the eggs to let them multiply, then kill the viruses to prepare injectable vaccines.
Scientists have also learned how to tweak individual virus genes. They remove a portion of the gene and then use enzymes to mutate specific sites. Using other enzymes, they paste the altered portion back into the virus’s genes.
Another way to make altered viruses is to harness evolution. In a method called serial passage, scientists infect an animal with viruses. The descendants of those viruses mutate inside the animal, and some mutations allow certain viruses to multiply faster than others. The scientists then take a sample of the viruses and infect another animal.
Viruses can change in important ways during this process. If it is done in the presence of antiviral drugs, scientists can observe how viruses evolve resistance. And viruses can become weak, making them useful as vaccines.
At the biosecurity meeting in Washington last week, Ron Fouchier, who led the Dutch team that created one of the mutant H5N1 viruses, described part of the experiment.
The scientists used well-established methods: First they introduced a few mutations into the H5N1 flu genes that they thought might help the bird flu infect mammals. They administered the viruses to the throats of ferrets, waited for the animals to get sick and then transferred viruses to other ferrets. After several rounds, they ended up with a strain that could spread on its own from one ferret to another in the air.
If trained virologists could see the full details of the paper, there would be several ways they could make mutH5N1 for themselves. The most sophisticated way would be to make the viruses from scratch. They could take the publicly available genome sequence of H5N1 and rewrite it to include the new mutations, then simply copy the new sequence into an e-mail.
“It’s outsourced to companies that do this for a living,” said Steffen Mueller, a virologist at Stony Brook University on Long Island, who regularly synthesizes flu viruses to design new vaccines.
A DNA-synthesis company would then send back harmless segments of the flu’s genes, pasted into the DNA of bacteria. The scientists could cut out the viral segments from the bacteria, paste them together and inject the reconstructed virus genes into cells. If everything went right, the cells would start making mutH5N1 viruses.
The synthesis companies are on the lookout for matches between requested DNA and the genomes of dangerous pathogens. But some experts say such safeguards are hardly airtight. “You could imagine a determined actor could cleverly disguise orders,” Dr. Casadevall said. “I have a lot of respect for human ingenuity.”
Synthesizing viruses has a high-tech glamour about it, but trained virologists could use a simpler method. Knowing the mutations acquired by mutH5N1, they could simply alter ordinary H5N1 viruses at the same sites in its genes to match it.
Virologists might even be able to figure out how to make mutH5N1 from the few details that have already emerged. According to reports, there were only five mutations in the Dutch viruses, and these were most likely at key sites involved in getting viruses into host cells.
Matthew B. Frieman, a virologist at the University of Maryland School of Medicine, said that a review of the scientific literature could point to where the mutations were inserted. “It’s not like nuclear fission,” he said.
Some of the equipment that scientists use to work on viruses has grown so inexpensive that it is no longer limited to university labs. Devices for duplicating pieces of DNA sell for a few hundred dollars on eBay, for example.
Those falling costs have spurred the rise of the D.I.Y. biology movement; they have also generated concerns about what a do-it-yourselfer might be able accomplish.
D.I.Y. biologists sometimes laugh at the sinister powers people think they have. “People overestimate our technological abilities and underestimate our ethics,” said Jason Bobe, a founder of DIYbio.org.
Todd Kuiken, a senior research associate at the Woodrow Wilson Center in Washington who specializes in the movement, points out that typical D.I.Y. projects are relatively simple, like inserting a gene into bacteria to make them glow. Producing viruses involves much more expensive equipment to do things like rearing host cells. “It’s not going to happen in someone’s basement,” he said.
Nor do these amateurs have the years of training it takes to grow viruses successfully. “It’s like I say, ‘I want to be a four-star chef,’ ” said Dr. Jorgensen, the president of Genspace, who worked with viruses for her Ph.D. “You can read about it, but unless someone teaches you side by side, I don’t think you’re going to get far.”
It is hard to predict how the future evolution of biotechnology will affect the risk of homegrown pathogens.
“There ought to be oversight down the road,” Mr. Bobe said. But he and others question whether holding back scientific information can reduce the risk. While it might be challenging to make one particular flu virus, like mutH5N1, it is not hard to try to breed new flu viruses.
“If you are a farmer somewhere in China, you could do it,” said Dr. Mueller, the virologist at Stony Brook. All that would be necessary is to bring some sick chickens in contact with ferrets or other mammals. “Without knowing what you’re doing, you could do it anyway.”
Of course, someone trying to make a new flu this way might well end up its first victim.
And some experts say that regardless of how a lethal virus might arise, the important thing is to be able to defeat it when it appears, so that we can avoid a global catastrophe like the 1918 flu pandemic, which killed 50 million people.
“The only thing that can be done, and to my mind should be done,” said Ron Atlas, a University of Louisville microbiologist and expert on bioterrorism, “is to have a vaccine that protect against this. We need an urgent program for a generalized influenza vaccine. We would take off the table another 1918-type event.”
Carl Zimmer, NY Times