Office of Biotechnology Activities
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Subject: Response to request for comments on the proposed revisions to the NIH Guidelines for Research Involving Recombinant DNA Molecules, published in the March 4, 2009 Federal Register, 9411-21

The American Society for Microbiology (ASM) is submitting the following comments on the proposed revisions to the NIH Guidelines for Research Involving Recombinant DNA Molecules, published in the March 4, 2009 Federal Register, 9411-21:

Revision to Section III-A-1 Major Actions Under the NIH Guidelines. The proposed revised section states that all experiments involving “the deliberate transfer of a drug resistance trait to a microorganism, if such acquisition could compromise the ability to treat or manage disease agents in human and veterinary medicine or agriculture,” will receive RAC review and NIH Director approval. The current NIH Guidelines state that if the microorganism is known to acquire the trait naturally, then transfer of the drug resistance may not need RAC review. The NIH is now proposing to delete the phrase “that are not known to acquire the trait naturally,” in Section III-A-1.

Further discussion of this stringent review policy and assessment of the presumed risk to the public and the environment posed by antibiotic resistance markers in basic and pathogenic bacteriology research is needed. If interpreted literally, as it likely will be, this language could have a chilling impact on microbiological research where antibiotic resistance is routinely used in molecular and genetic studies. Given that no documented harm has come from laboratory research using antibiotic resistance markers, the question must be asked as to why a change in the Guidelines is warranted. Any change in Section III-A-1 should clarify and narrowly focus on areas of concern. The proposed language does the opposite. By broadening the activities that require approval, it will have an adverse impact on microbiological research and public health.

The stated purpose of the revision to Section III–A–1 is to clarify the current guidelines for local Institutional Biosafety Committees (IBCs). The NIH Guidelines are based on the premise that local oversight is the best approach to biosafety. However, the work of the IBCs will be more complicated if the proposed change is adopted. While we agree that whether or not an organism acquires the trait naturally is not the critical factor in evaluating the safety of the experiment, broadening the range of concern to include consideration of possible rare uses of an antibiotic that is not a ‘‘drug of choice,’’ will only confound the work of the IBCs.

Selectable antibiotic resistance markers introduced into bacteria via plasmids, transposons, or by homologous recombination are the most conventional, versatile, and widely used tools in the study of bacterial pathogenesis and bacterial physiology. Such antibiotic resistance genes have been used to replace or inactivate bacterial genes to elucidate key physiological or pathogenic traits. Such mutant traits are then complemented with a replacement copy of the gene borne on a plasmid that is maintained under antibiotic selection, an essential step in fulfillment of Molecular Koch’s Postulates. The applications for antibiotic resistance selection are so numerous that it is impossible to envision the study of bacterial genetics without the use of antibiotic selection markers. The real question is whether such antibiotic resistance markers pose an actual risk in treatment of infections with the bacterial strains and pathogens we study.

Previously, researchers took into consideration the likelihood that the selection agent would be clinically used as a therapy for infection. However, concerns about multiply resistant agents of all types, the “drugs of choice” and the threat to the public posed by resistant bacteria are more difficult to determine. Nonetheless, the emergence of multiple drug resistance in bacteria is universally regarded as a product of the indiscriminant use of antibiotics in humans and in agriculture worldwide. Therefore, bacteriologic strains developed during the course of basic scientific research and tested in vitro or in vivo in laboratory animal models are relatively unlikely to pose any threat to the population or environment at large.

Given the value of antibiotics in the study of bacteria, and the mechanisms already in place through other federal regulations to protect the public from agents in the research laboratory environment, we consider this revision to the RAC Guidelines as ill-defined in purpose and counterproductive to the generation of helpful science in the interest of public health.

The ASM supports the proposed revisions to Section I-B, Basic Research with Recombinant and Synthetic Nucleic Acids, which clarifies the applicability of the NIH Guidelines to research with synthetic nucleic acids, and Section III-E-1, Experiments Involving DNA Molecules Containing No More Than One Half of the Genome of Any Eukaryotic Virus, which changes the level of review for recombinant or synthetic experiments involving more than half but less than two thirds of the genome of certain viruses.

We appreciate the opportunity to comment on the proposed changes to the RDNA Guidelines.

Sincerely,

Alison O’Brien, Ph.D., President, ASM
Ronald M. Atlas, Ph.D., o-Chair, Committee on Biodefense
Kenneth I. Berns, M.D., Ph.D., o-Chair, Committee on Biodefense

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