Select agents should be defined by DNA sequence in today’s era of synthetic biology

WASHINGTON — 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.

The report was sponsored by the National Institutes of Health. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies. They are independent, nonprofit institutions that provide science, technology, and health policy advice under an 1863 congressional charter. Committee members, who serve pro bono as volunteers, are chosen by the Academies for each study based on their expertise and experience and must satisfy the Academies’ conflict-of-interest standards. The resulting consensus reports undergo external peer review before completion. For more information, visit http://national-academies.org/studycommitteprocess.pdf. A committee roster follows.

Copies of SEQUENCE-BASED CLASSIFICATION OF SELECT AGENTS: A BRIGHTER LINE are available from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at HTTP://WWW.NAP.EDU. Reporters may obtain a copy from the Office of News and Public Information (contacts listed above).

[ This news release and report are available at HTTP://NATIONAL-ACADEMIES.ORG ]

NATIONAL RESEARCH COUNCIL

Division on Earth and Life Studies

Board on Life Sciences

COMMITTEE ON SCIENTIFIC MILESTONES FOR THE DEVELOPMENT OF A GENE SEQUENCE-BASED CLASSIFICATION SYSTEM FOR OVERSIGHT OF SELECT AGENTS

JAMES W. LEDUC (CHAIR)

Professor of Microbiology and Immunology,

Chair in Global Health, and

Associate Director

Galveston National Laboratory

Medical Branch

University of Texas

Galveston

RALPH BARIC

Professor

Department of Epidemiology and Department of Microbiology and Immunology

University of North Carolina

Chapel Hill

ROGER G. BREEZE

Chief Executive Officer

Centaur Science Group

Washington, D.C.

R. MARK BULLER

Professor

Molecular Microbiology and Immunology Department

School of Medicine

Saint Louis University

St. Louis

SEAN EDDY

Group Leader

Janelia Farm Research Campus

Howard Hughes Medical Institute

Ashburn, Va.

STANLEY FALKOW 1,2

Professor

Department of Microbiology and Immunology

Stanford University

Stanford, Calif.

RACHEL E. LEVINSON

Director of Special Projects and Research Initiatives

Office of Vice President for Research and Economic Affairs

Arizona State University

Washington, D.C.

JOHN MULLIGAN

Chairman and Chief Scientific Officer

Blue Heron Biotechnology

Bothell, Wash.

ALISON D. O’BRIEN

Professor

Microbiology Department

Uniformed Services University of the Health Sciences

Bethesda, Md.

FRANCISCO OCHOA-CORONA

Assistant Professor

Entomology and Plant Pathology

Oklahoma State University

Stillwater

JANE S. RICHARDSON 1,2

James B. Duke Professor

Department of Biochemistry

Medical Center

Duke University

Durham, N.C.

MARGARET RILEY

Professor

Department of Biology

University of Massachusetts

Amherst

TOM SLEZAK

Program Leader

Global Security Program

Lawrence Livermore National Laboratory

Livermore, Calif.

RESEARCH COUNCIL STAFF

INDIA HOOK-BARNARD

Study Director

1 Member, National Academy of Sciences

2 Member, Institute of Medicine

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