A DNA sequence-based system to better define when a pathogen or toxin is subject to Select Agent regulations could be developed, says a new report from the National Research Council, which adds that this could be coupled with a "yellow flag" system that would recognize requests to synthesize suspicious sequences and serve as a reference to anyone with relevant questions, allowing for appropriate follow-up.
Select Agents are defined in regulations through a list of names of particularly dangerous known bacteria, viruses, toxins, and fungi. However, natural variation and intentional genetic modification blur the boundaries of any discrete Select Agent list based on names. Access to technologies that can generate or "synthesize" any DNA sequence is expanding, making it easier and less expensive for researchers, industry scientists, and amateur users to create organisms without needing to obtain samples of existing stocks or cultures. This has led to growing concerns that these DNA synthesis technologies might be used to synthesize Select Agents, modify such agents by introducing small changes to the genetic sequence, or create entirely new pathogens. Amid these concerns, the National Institutes of Health requested that the Research Council investigate the science and technology needed to replace the current Select Agent list with an oversight system that predicts if a DNA sequence could be used to produce an organism that should be regulated as a Select Agent.
The committee that wrote the report found that replacing the current list of Select Agents with a system that could predict if fragments of DNA sequences could be used to produce novel pathogens with Select Agent characteristics is not feasible. However, it emphasized that for the foreseeable future, any threat from synthetic biology and synthetic genomics is far more likely to come from assembling known Select Agents, or modifications of them, rather than construction of previously unknown agents. Therefore, the committee recommended modernizing the regulations to define Select Agents in terms of their gene sequences, not by their names, and called this "sequence-based classification."
The committee was concerned that a dedicated research agenda to improve prediction of Select Agent properties from gene sequence could actually empower those set on misusing synthetic biology, and therefore argued against such security-driven research.
A sequence-based classification system could be used to determine if a DNA sequence might be hazardous and close enough to that of a listed Select Agent -- although not falling within the criteria -- to raise a cautionary alert or "yellow flag," the report says. This could help address biosafety goals in addition to biosecurity. For instance, a DNA synthesis company might use the system's database to screen their orders and investigate who placed a questionable order and why. The committee emphasized that the system would not be regulatory in nature but intended to serve as a resource for information sharing that would not restrict access to the sequence.
Although the sequence-based classification system could be developed and may improve the current practice, the committee noted that such a system does have limitations and potential negative consequences. Therefore, the committee did not specifically recommend that either the classification or yellow flag system be implemented, nor did it address whether the additional administrative structure needed to maintain such a classification system would be justified. Rather, it provided information about what is technologically feasible and emphasized that the potential benefits of such a system should be considered and weighed against the cost and complexity of implementation.
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