1. The Two Salmonella’s: A case history in the role of open scientific inquiry in the fight against bioterrorism and infectious disease. Eric Jakobsson, Department of Molecular and Integrative Physiology, National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign We now have the complete genomic sequences of two Salmonella’s: Salmonella typhi and Salmonella typhimurium.

2. Typhi: Causes typhoid fever, which is lethal in a high fraction of untreated cases. Is rare in industrialized countries due to public health, but kills estimated 600,000 people per year world-wide. Significant and growing fraction is multi-drug resistant. Does not persist in the food supply; needs a human as a host and vector of infection (the famous Typhoid Mary)

3. Typhimurium: Causes gastroenteritis, always miserable but rarely fatal. Persists in food supply, from which it readily spreads to humans (Salmonella typhimurium was the agent in the largest bioterrorism attack in US, which was done through restaurant salad bars in Oregon) Significant and growing fraction is multi-drug resistant

4. Comparative Facts between typhi and typhimurium Many genes are almost identical. Typhimurium genome codes for more proteins. Many genes in typhimurium are psuedo-genes in typhi. Genetic bases of virulence factors in typhi are pretty well-known. Genetic bases for typhimurium being able to persist in wider environment are not known exactly, but are presumably in the genes that typhimurium has and typhi lacks. Genetic bases for multi-drug resistance are pretty well known.

5. Weaponization of Salmonella consideration leads to: Big question #1: Would it be possible to use genomic knowledge to engineer a super-lethal Salmonella combining multi-drug resistance, typhi’s virulence, and typhimurium’s ability to persist in the food supply? AAnswer: Probably. In fact, almost certainly. Overcoming the threat of multi-drug resistant typhi and typhimurium consideration leads to: Big question #2: Since it is predictable that broad- spectrum antibiotics will become useless against both typhi and typhimurium, isn’t it necessary to use genomic knowledge to design Salmonella-specific drugs to combat naturally occurring Salmonella infections? Answer: Yes

6. The Salmonella dilemma: Dissemination of genomic knowledge of Salmonella can facilitate bio-weapons development but is necessary to combat Salmonella infection. What to do? Alternative 1: Restrict dissemination of genomic knowledge. In the short term, this may hinder development of “super-Salmonella” terror weapon, but in the long run leaves us at the mercy of multi-drug resistant Salmonella strains ranging from incapacitating to lethal. Alternative 2: Disseminate genomic knowledge, but strongly support development of Salmonella-specific drugs. The knowledge may provide a rogue state with the ability to develop “super-Salmonella” terror weapon, but it provides us with the opportunity to defend against all Salmonella infection, from either terrorist or natural source.

7. The Salmonella dilemma is not only the Salmonella dilemma. Any major bacterial disease that is common in the non-industrialized world poses exactly the same issues. Conclusion: The right policy course is to freely disseminate knowledge of bacterial genomes, at the same time embarking on a vigorous program to use that knowledge for design of specific antimicrobial drugs to replace the broad spectrum antibiotics that are predictably on a path to becoming useless.