NIH Office of Science Policy

• Oversees recombinant or synthetic nucleic acid research, including human gene transfer.
• Manages the Recombinant DNA Advisory Committee (RAC), a public advisory committee that advises the Department of Health and Human Services and NIH about recombinant nucleic acid research.
• Administers the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.
• Partners with Institutional Biosafety Committees in the oversight of recombinant nucleic acid research.

History of the Guidelines Development

With the emergence of recombinant DNA technology in the mid-1970s, the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules grew out of concerns by scientists and the general public for public health and safety, environmental impact, and the ethical and social implications of such research.

The original guidelines were issued in 1976. Multiple revisions have been issued since, with the most recent amendment effective as of April 2016.

Scope of the Guidelines

The purpose of the NIH Guidelines is to specify practices for constructing and handling:

1. Recombinant nucleic acid molecules
2. Synthetic nucleic acid molecules
3. Cells, organisms and viruses containing recombinant or synthetic nucleic acid molecules
4. Transgenic animals

Definition: Recombinant Nucleic Acid Molecules

• Molecules that are constructed by joining natural or synthetic nucleic acid molecules to nucleic acid molecules that can replicate in a living cell
• Molecules that result from the replication of the molecules described above
• Recombinant nucleic acid segments likely to yield a potentially harmful polynucleotide or polypeptide (i.e. toxin) are exempt unless they are expressed in vivo as a biologically active product.
• Genomic DNA of plants and bacteria that have acquired a transposable element (even if it was donated from a recombinant vector that is no longer present) are exempt unless the transposon itself contains recombinant nucleic acid molecules.

Definition: Synthetic Nucleic Acids

• Nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acids.
• Molecules that result from the replication of the molecules described above
• Synthetic techniques may enable the synthesis of more complex chimeras containing sequences from a number of different sources.

Definition: SiRNA

• Small interfering RNA are a class of 20-25 nucleotide-long double-stranded RNA molecules involved in the RNA interference (RNAi) pathway and interferes with the expression of a specific gene.
• Recombinant DNA experiments include inserting DNA encoding siRNA targeting the gene of interest into an expression vector.

Definition: Transgenic Animals

• Animals that have been modified by stable introduction of recombinant or synthetic nucleic acid molecules, or DNA derived therefrom, into the germ-line.
• Foreign nucleic acid molecules are introduced into the animal using recombinant nucleic acid technology, and then must be transmitted through the germ line so that every cell, including germ cells of the animal, contain the same modified genetic material.

Example: Cre/loxP System

• Mice can be made transgenic for the gene encoding Cre attached to a promoter activated only when bound by the appropriate transcription factors:
  • A "target" gene is flanked by loxP sequences.
  • Transcription of the Cre gene. Its protein will then remove the "target" gene under study.
  • The result: a mouse with a particular gene knocked out in only certain cells.