A not-so-cheap stunt.

The recent demonstration by Eckard Wimmer and co-workers (“Chemical synthesis of poliovirus cDNA: Generation of infectious virus in the absence of natural template,” J. Cello et al. , Reports, published online 11 July, [www.sciencemag.org/cgi/content/abstract/1072266][1]) that active poliovirus could be synthesized “from scratch,” i.e., by assembling oligonucleotides into a full-length cDNA coding for the RNA of the published sequence of the poliovirus genome and then introducing this cDNA into a cell-free system derived from HeLa cells, amounts to little more than a stunt—and not a particularly cheap stunt at that, given that the effort was reportedly bankrolled by hundreds of thousands of dollars from the Defense Advanced Research Projects Agency. This work was published with considerable fanfare by Science as a Science Express paper. The criteria for Science Express papers “include timeliness and importance of the research” ([1][2]). The timeliness of this finding seems beyond question, given post-September 11 events, renewed concerns about biological weapons, and new threats posed by genetic engineering ([2][3]). Indeed, the report was immediately picked up by the news media and generated a firestorm of commentary—much of it sensational. However, I question the scientific importance of the research and, therefore, Science 's decision to publish it. A classic experiment by V. Racaniello and D. Baltimore, published more than 20 years ago, showed that cDNA derived from the poliovirus genome was sufficient to produce active virus in a transfected mammalian cell line ([3][4]), i.e., that the DNA alone is “infectious.” Wimmer's own group demonstrated in 1991 that de novo synthesis of poliovirus from a genomic clone could be achieved in a cell-free translation system ([4][5]). The recent work merely substitutes a chemically synthesized DNA for one biosynthesized from the genomic clone. But DNA is DNA is DNA, and few molecular biologists would have seriously doubted the inevitability of the results, which scarcely advance our state of knowledge. After all, DNA coding for desired gene sequences is today routinely produced by chemical synthesis and then recombined with DNA produced by biosynthetic means. Even the length of the poliovirus cDNA, at ∼7500 nucleotides, did not apparently represent that much of a technical challenge: More than half of the construction work was simply farmed out to a commercial outfit. In light of the extraordinary press coverage, there are several misconceptions worth dispelling. Entirely synthetic viruses are unlikely to present a biological weapons threat in the near term, for several reasons. Poliovirus itself causes human disease with low mortality and morbidity, weak infectivity, and limited transmissibility. For this reason, it's never been a pathogen of choice for a biological weapon, and it doesn't appear on the CDC List of Select Agents (indeed, polio is available for legitimate scientific work from the ATCC). Despite representations to the contrary by Cello et al. , it seems unlikely that the strategy of the World Health Organization's poliovirus eradication campaign now needs to be reassessed. But what about using the synthetic approach on some other virus? In most cases, it would be far easier to obtain a sample of the virus or a genomic clone of the virus than it would be to synthesize something from scratch. The single exception here would seem to be smallpox, stocks of which are held closely by the United States and Russia. However, unlike polio, the DNA of smallpox (and a good many other viruses) is not itself infectious, requiring the activity of proteins conveyed by the virion, such as polymerases. These factors might be supplied, in principle, by helper viruses or some other means, but this complicates the fabrication process considerably ([5][6]). Moreover, the genome of smallpox is among the largest of viral sequences, around 200,000 nucleotides. Anyone bent on creating smallpox would have an easier task starting from a closely related orthopox virus and introducing the necessary mutations. Also of future concern are chimeric viral constructs incorporating genes from more than one natural—or synthetic—source. It's critically important to hold a national dialog among biologists, health care experts, politicians, and the general public about the future of biological work with biological weapons implications. But publishing research like this is a poor way indeed to open the conversation. 1. [↵][7]See [www.sciencemag.org/feature/express/introduction.shl][8]. 2. [↵][9]1. S. D. Drell, 2. A. D. Sofaer, 3. G. D. Wilson , Eds. chap. 2, in The New Terror: Facing the Threat of Chemical and Biological Weapons (Hoover Institution Press, Stanford, CA, 1999), pp. 39-75. 3. [↵][10]1. V. R. Racaniello, 2. D. Baltimore , Science 214, 916 (1981). [OpenUrl][11][Abstract/FREE Full Text][12] 4. [↵][13]1. A. Molla, 2. A. V. Paul, 3. E. Wimmer , Science 254, 1647 (1991). [OpenUrl][14][Abstract/FREE Full Text][15] 5. [↵][16]1. S. J. Flint, 2. L. W. Enquist, 3. R. M. Krug, 4. V. R. Racaniello, 5. A. M. Skalka , chap. 2, Principles of Virology (American Society for Microbiology, Washington, DC, 2000), pp. 25-56. # Response {#article-title-4} Science has received a mixture of praise and criticism for publishing the paper on synthesizing poliovirus by Cello et al. The third paragraph of Block's thoughtful letter summarizes a number of reasons why the national security concerns are not worth serious consideration; we couldn't have put it better ourselves, and we are grateful for this clarification from a bona fide expert on biowarfare. This puts to rest sensationalist claims that the publication was somehow “irresponsible.” It wasn't. That leaves the claim that we have published a “stunt”—and with “fanfare” at that! Block cites previous work that would lead to a strong expectation of how the Cello et al. experiment would come out. But proof of principle sometimes involves doing all the steps, to demonstrate that the predicted outcome can actually be achieved. Certainly, this result is hardly counterintuitive. Is it a stunt? We didn't think so, and our peer reviewers didn't think so either. Sticking one's head in the sand and hoping that unpleasant realities will go away has never been a fruitful approach to science or to public policy. Nevertheless, it is surely true that there should continue to be serious conversations about the relationship between scientific research, publication, and security—in which we plan to participate in a responsible manner. 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