PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Custom Oligos: Is Screening for Bioterrorist Threats Possible? by Richard McDonald, J.D., PH.D. At first glance, the idea of commercial suppliers screening custom oligonucleotide orders for potential biosecurity threats seems like a great idea, as one can develop complex algorithms (i.e., bioagent screening algorithmic software) to determine biosecurity threats. However, what seems good on paper (i.e., an academic answer), in the real world is too narrow and misguided to work. Like DNA sequences, music notes have a wide range of possibilities. Depending on how those notes are expressed and articulated, the notes can be part of classical, rock & roll, hip-hop, country, or religious music. While the notes can mean something spiritual to one group, those same notes can signify “rock and roll all day and party all night” to others depending on how the notes are played. Similar to music notes, DNA sequences have a wide range of possibilities depending on how they are used. Although it is true we can develop the best complex algorithms in order to determine biosecurity threats, this proposal has four inherent flaws that cannot be solved. The first fundamental flaw in suppliers screening custom oligonucleotides is the inability to fix false-positives and false-negatives stemming from its sequence fragment analyses. For example, it is possible for an oligonucleotide supplier to issue a bioalert to the appropriate government agency from a short biological benign sequence requested by a diabetes type I or a C. elegans researcher because its profile “fits” a bioagent profile. In this situation, the issue of a false-positive arises. Invariably, that bioalert could be leaked to the press, and that is usually enough (Just Cause) for some to destroy the career of the diabetes type I/C. elegans researcher. Similarly, an inherently benign microbial sequence can be modified post-oligonucleotide supplier synthesis (e.g., by site-directed mutagenesis) to a bioagent on the government’s list. In this situation, the issue of a false-negative arises. Would the supplier screening custom oligonucleotides then be held liable for failing to detect that bioagent threat? These scenarios are real, to include the more complex issue of altering benign microbial genetics post-oligonucleotide supplier synthesis that causes symptoms related to another biological agent (i.e., genetic mimicry) or that causes symptoms to appear later than usual (i.e., genetic masking) (1 ). No reliable bioagent screening algorithmic software can be developed that has sufficient safeguards to prevent such false-positive and false-negative scenarios. Second, the idea of commercial suppliers screening custom oligonucleotide orders for potential biosecurity threats implies that the algorithms developed will be based on researchers not cross-talking with others in unrelated fields. For example, the possibility of the government investigating a researcher when the researcher requests custom oligonucleotides for diabetes type I research purposes, but the sequence requested is for the coxsackie virus is likely. In this theoretical example, this type of cross-field fertilization would seem appropriate for the researcher; but for the government investigators it may not be considered appropriate. Taking solutions from one field of study and applying it to another is not unusual. Developing a useful one-round PCR program in the development of a full-length HIV-1gp160 clone from a sea urchin gene PCR protocol (2) may trigger an alert with any algorithmic software program. Insight, experience, gut feeling, or whatever one calls it, gives an edge to some, as innovative science [and medicine] begins where textbooks end. The problem then is explaining to authorities the kind of scientific logic without having data. How does one convince authorities that an unusual PCR protocol loosely based sea urchin gene may work on HIV-1 isolates without any direct, or at least applicable, data? Lack of applicable data is also one reason, of twenty-one, why good ideas on grant applications are not funded. Science is not an exact science, and sometimes ideas (and solutions) are developed or found in other fields of study. Without real data, criticism of any idea is easy to do, just as it is easy from a legal viewpoint to second-guess any medical outcome. No reliable bioagent screening algorithmic software can be developed that takes into account the types of cross-field fertilization existing among scientists. Third, the idea of commercial suppliers screening custom oligonucleotide orders for potential biosecurity threats implies that the algorithms developed will be based on the assumption that only certain microbial profiles--those on the government’s biothreat list--pose biothreats. Just as it was incorrectly assumed that bioagents, such as Bacillus anthracis, could only be delivered by planes or rockets, so is the assumption that only government-restricted microbes are problematic. The anthrax letters showed that bioterrorism can be low-tech, and it showed that a bioagent does not have to cause thousands of deaths to be considered problematic. As with dirty bombs, disease outbreaks with common microbes can result in fear, confusion, and economic problems rather than thousands to millions of deaths. For example, the biodisruption of an industry, such as the milk and cheese industries, is possible from a microbe not listed on the government’s bioagent list. The milk and cheese industries could be disrupted (and ultimately destroyed) with Staphylococcus aureus, yet it is not a government-listed bioagent. Staphylococcus aureus is already is a common contaminant source in milk and milk products. In addition, 10% to 40% of people infected with this bacterium are asymptomatic carriers (3,4,5,6). Like Staphylococcus aureus, Salmonella typhimurium is not considered a bioagent by the government, yet it was sprayed on salad bars making many sick (7). Fear and economic problems stemming from a microbe are real, just as non-vaccinees traveling overseas returning with a microbe creating health-related economic concerns (8). With common, potentially non-lethal microbes, the death rate may be close to zero, but the biodisruption any-sized industry or treatment of the sick does make an economic impact statement. No reliable bioagent screening algorithmic software can be developed that takes into account the threat--medical or economic--from the more than 10,000 microbes that are not on the government’s bioagent list. The fourth and perhaps the most fundamental flaw in the custom oligonucleotide order screening is that it does not take into account the many labs that have in-house oligonucleotide synthesizers, and consequently do not need a commercial supplier for their oligonucleotides. In addition, synthesizers can be purchased easily from primary or secondary markets. In either situation, any gene or DNA fragment can be synthesized and thus bypassing any commercial custom oligonucleotide supplier. Taking it a step further, the idea of then banning the sale of synthesizers and confiscating synthesizers in labs forcing researchers to order only through government-approved commercials suppliers is nonsensical. This creates a very long list of legal issues, from Probable Cause to a violation of the Racketeer Influenced and Corrupt Organizations Act (commonly referred to as the RICO Act) (9,10). The Patriot Act, though useful, is not a blanket Act that supersedes all laws in the U.S. [this is testable in courts, but like anything legal, heavily dependant on who does the arguing], paralleling legal arguments with gun, automotive, alcohol, and plane industries for example, on product liability uses in perpetuating crimes or the misuse of them (11,12,13,14,15,16). Just as musical notes are not inherently unsound, genetic sequences are not inherently biological threats. Bioterrorism by its nature is dynamic, that is, it is a multi-threat weapon that cannot be boxed-in neatly, as theoretical solutions can be in a PowerPoint presentation. However, bioterrorism countermeasures should be multi-tech, both low- and high-tech, but applicable in the real world. The idea of a supplier screening custom oligonucleotide orders for potential biosecurity threats is shortsighted beyond an academic interest, and in no way parallels airport security measures, as qualitative differences exist between the two. This includes the overly simplistic view of “wishful thinking” or “doing something is better than nothing.” No compelling justification exists, even in today’s environment of heightened public scrutiny, for a supplier to screen custom oligonucleotide orders for potential biosecurity threats because it fails to do what is designed to do…it cannot screen custom oligonucleotides orders for potential biosecurity threats properly in the real world. Richard McDonald, J.D., PH.D. Senior Principal Scientist and Product Development Associate Director Biomedical Health Sciences Division GenoVar Bioscience 22963 California St. St. Clair Shores, MI 48080-2503 USA voice mail/fax: 586.776.4616 mcdonald@scientist.com www.McDonaldPhD.com "Improving Life By Strengthening Science" 1. McDonald R, Cao T, Borschel R (2001) Multiplexing for the detection of multiple biowarfare agents shows promise in the field. Mil Med. 166: 237-239. 2. McDonald R and Burnett V (2005) Novel single-round PCR and cloning of full-length envelope genes of HIV-1 may yield new insight into biomolecular antibacterial drug development. J Virol Methods 126: 111-118. 3. Noble WC, ed. (1981) Microbiology of human skin. 2nd edition. London, United Kingdom: Lloyd-Luke Ltd. 4. Alterkruse SF, Timbo BB, Mowbray JC, Bean NH, Potter ME (1998) Cheese-associated outbreaks of human illness in the United States, 1973 to 1992: sanitary manufacturing practices protect consumers. J Food 61: 1405-1407. 5. Bone FJ, Bogle D, Morgan-Jones SJ (1989) Staphylococcal food poisoning from sheep's milk cheese. Epidemiol Infect 103: 249-258. 6. Johnson EA, Nelson JH, Johnson M (1990) Microbiological safety of cheese made from heat-treated milk. Part II. Microbiology. J Food Prot 53: 519-540. 7. Torok TJ, Tauxe RV, Wise RP, Livengood JR, Sokolow R, et al. (1997) A large community outbreak of Salmonellosis caused by intentional contamination of restaurant salad bars. JAMA 278: 389-395. 8. Parker AA, Staggs W, Dayan GH, Ortega-Sanchez IR, Rota PA, et al. (2006) Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States. N Engl J Med 355: 447-455. 9. VanDenBroeck v. CommonPoint Mortgage Co., 210 F.3d 696, 699 (6th Cir. 2000). 10. Agency Holding Corp. v. Malley-Duff & Assoc., Inc., 483 U.S. 143, 154 (1987). 11. Schemel v. General Motors Corp., 384 F.2d 802 (7th Cir. 1967). 12. Gardner v. Q.H.S. Inc. & J.M. Fields, 448 F.2d 238 (4th Cir. 1971). 13. Venezia v. Miller Brewing Co., 626 F.2d 188 (1st Cir. 1980). 14. Mountain v. Procter & Gamble Co., 312 F. Supp. 534 (E.D. Wis. 1970). 15. Daly v. General Motors Corp., 575 P.2d 1162 (Cal. 1978). 16. McDevitt v. Standard Oil Co. of Texas, 391 F.2d 364 (5th Cir. 1969). ### << Previous Next >> [ View All Perspectives ] |
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