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Who will create the next mutant virus?

In the face of experiments on the H5N1 bird flu virus that transformed it into mutant forms,scientists worry that it might become easier than ever to make a deadly virus

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 recently in favour 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 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 DIY biology movement,the website 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.

Advocates of DIY 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.

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There are many ways to make a virus. The simplest and oldest way is to get the viruses to 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.

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’ 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 email. “Such work is outsourced to companies that do this for a living,” said Steffen Mueller,a virologist at Stony Brook University on Long Island,who regularly synthesises 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.

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.