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http://www.nytimes.com/2002/07/12/science/12POLI.html

Scientists Create a Live Polio Virus

By ANDREW POLLACK

cientists reported yesterday that they had constructed a virus from scratch for the first time, synthesizing a live polio virus from chemicals and publicly available genetic information.

The work, conducted by scientists at the State University of New York at Stony Brook, was financed by the Pentagon as part of a program to develop biowarfare countermeasures. The scientists constructed the virus using its genome sequence, which is available on the Internet, as their blueprint and genetic material from one of the many companies that sell made-to-order DNA.

Dr. Eckard Wimmer, professor of molecular genetics and microbiology at Stony Brook and leader of the project, said they made the virus to send a warning that terrorists might be able to make biological weapons without obtaining a natural virus.

"You no longer need the real thing in order to make the virus and propagate it," Dr. Wimmer said.

The work set off a debate over whether the same technique might be applied to other viruses.

"Could someone make a highly pathogenic virus like ebola?" asked Dr. Robert A. Lamb, a professor at Northwestern University and president of the American Society for Virology. "Could you in fact make that in a rogue laboratory that doesn't need more than two skilled workers? My feeling is you probably could."

The development could also mean that even after polio is eradicated as a disease, as is expected in the next few years, vaccinations might still be needed to protect against use of synthetic polio as a bioweapon.

"This just says we're going to have to sustain some immunization for the indefinite future," said Dr. D. A. Henderson, principal adviser on public health preparedness to the secretary of health and human services.

The work, published online yesterday by the journal Science, could conceivably be classified as the first creation of life in a test tube. But most scientists say that viruses are not truly living because they cannot reproduce on their own.

The Defense Advanced Research Projects Agency said it had provided about $300,000 over the last three years for the work. "Understanding the process of viral DNA production is key to identifying new ways to kill viruses and understand how viruses could change and escape from vaccines," the agency said.

Experts agree that the research — or the synthesis of any pathogen — does not violate the 1972 treaty banning germ weapons, which gives wide latitude to all kinds of defensive research.

Stephen S. Morse, director of the Center for Public Health Preparedness at Columbia University and a former official of the defense agency, said there was nothing nefarious about the Pentagon sponsoring such research. "Hopefully, this will help people to be realistic about assessing future threats," he said.

Some scientists criticized the work. "I think it's inflammatory without scientific justification," said Dr. J. Craig Venter, who sequenced the human genome and is trying to synthesize micro-organisms for uses like cleaning the environment. "To purposely make a synthetic human pathogen is irresponsible."

Dr. Steven Block, a Stanford University expert on the applications of biotechnology to biowarfare, called the work a stunt. He played down any threat caused by synthetic viruses. "This is not the route to new kinds of terrific genetically engineered bioterror," he said.

Even if people were not vaccinated, Dr. Block said, polio would not make a good bioweapon because it was not as infectious and lethal as many other pathogens. In most cases, he said, it would be easier to obtain a natural virus than to build one from scratch. The one exception, he said, is smallpox, because the world's two known remaining stocks of the virus are closely guarded. Smallpox would be nearly impossible to synthesize from scratch using the same technique, he said.

Many viruses are simple, consisting of some genetic material, either DNA or RNA, surrounded by a coat of protein. The genetic material instructs the cells infected by the virus to produce more viruses. So if one could produce such a virus's DNA or RNA and put it in the proper cell, new viruses would be produced.

Indeed, scientists have recreated viruses this way in the past. But they started with genetic material derived from a natural virus. What is new is that the genetic material was synthesized from scratch. However, given that the naturally derived genetic material worked, it was little surprise that the synthetic material worked, too, so this was a trivial advance, some scientists said.

The polio virus genome is tiny, consisting of 7,500 chemical units, or bases, of RNA. (The human genome, by contrast, has more than 3 billion units.) Still, even assembling a genome of 7,500 units is tedious. The machines, which usually make DNA rather than RNA, can reliably make only 50 to 100 bases in a stretch. So the Stony Brook scientists ordered numerous 60-base stretches from a company that sells DNA by mail-order for as little as 40 cents a base. The stretches were then painstakingly strung together.

The DNA was then converted into RNA using a commercially available enzyme. The next step would be to put the RNA into cells to churn out new viruses. But Dr. Wimmer put the RNA instead into a mixture of proteins taken from cells, a technique he developed in 1991. That allows him to claim that the virus was made without the use of any living cells.

Making the polio took three years, though Dr. Wimmer said it could probably now be done in six months. His collaborators were Dr. Aniko V. Paul, another professor in his department, and Dr. Jeronimo Cello, a postdoctoral researcher.

The new virus, when injected into the brains of mice, gave them a paralytic disease equivalent to poliomyelitis. However, the synthesized virus was much weaker than the natural one. Dr. Wimmer said he thought that was because his team deliberately introduced mutations into it to distinguish it from the natural virus.

Dr. Wimmer said many other viruses, especially ones with small genomes like H.I.V. and hepatitis C, could be made this way. But the smallpox virus has a genome almost 200,000 bases long, putting it out of reach of current synthesis technology. Moreover, smallpox relies on some of its own proteins for replication, so just making the genes would not be enough. Dr Block said, "You can't take smallpox DNA, inject it into a cell and expect to get smallpox out."

Still, DNA synthesis technology is improving. Some experts say it will be possible to recreate smallpox someday, though it would most likely be done by making genetic changes to a related virus like cowpox, rather than synthesizing the entire genome from scratch.

The new work could intensify questions about whether biotechnology needed to be regulated, or whether the genome sequences of pathogens should be available on the Internet, as they are now.

"I think that this advance will bring the question of gene sequences more to the forefront than it was before," said Dr. Raymond A. Zilinskas, a biowarfare expert at the Monterey Institute of International Studies. He is organizing a workshop next month to advise the Defense Department on whether certain research should not be published. The National Academy of Sciences has also formed a committee to look at this question.

Dr. Joseph A. Walder, chief executive of Integrated DNA Technologies, the company that synthesized the polio DNA for Dr. Wimmer, said his company was now considering checking sequences ordered by customers against a database of pathogens.

Last year there were 480 cases of polio in the world and the World Health Organization hopes to eradicate wild polio virus by 2005, said Dr. R. Bruce Aylward, the official in charge of the project. Once that happens, he said, many countries want to stop vaccinating.

Dr. Aylward said he did not think the threat of synthetic polio would deter many countries from ending vaccinations. He said polio would not make a good bioweapon because only 1 out of every 200 to 1,000 people exposed to it suffers paralysis and only a fraction of those die.

But Dr. Wimmer said polio, as it has done in the past, could spread panic and that vaccines would have to be stockpiled if not routinely administered. "In 20 or 25 years," he said, "if a good percentage of the world is not immunized against polio virus, then the virus would be a terrible terrorist agent."

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