Changes to the
NIH Guidelines
- What They Mean to You David W. Emery, PhD
Research Associate Professor of Medicine
&
Chair, Institutional Biosafety Committee
Eric Stefansson
Manager
EH&S Research and Occupational Safety
BioSafety-’13-Outreach
Outline
• Refresher - Oversight of research with biohazardous
agents at the University of Washington
• Changes to the NIH Guidelines
• What you need to do
• Resources for help
BioSafety-’13-Outreach
Types of Biohazardous Research
• Infectious agents
- Microorganisms (E. coli → Tuberculosis)
- Viruses (AAV → HIV)
- All human source materials (including cell lines)
• Recombinant DNA
- Transfer DNA/RNA to or from microorganisms
or any living cells
- Transgenic mice
- Transgenic plants
- Clinical gene therapy trials
- Synthetic DNA (PCR, sequencing, etc…)
• Select Agents (high security)
• Laboratory settings
• Live animals
• Clinical trails & Field tests
BioSafety-’13-Outreach
Oversight of Biohazardous Research
- a team approach -
EH&S
Research
& Occupational
Safety (ROS)
Institutional
Biosafety
Committee
(IBC)
Investigator
BioSafety-’13-Outreach
EH&S / ROS
• Staffed by biosafety professionals
• Responsible for administrating biosafety programs and
monitoring compliance with applicable regulations & policies.
• Key Functions:
• Facility design review
• Review research protocols and identify hazards
• Provide training, consultation, clearances and set OH
requirements
• Site assessments/inspections
• UW Biohazard Safety Manual
• Support IBC
BioSafety-’13-Outreach
Institutional Biosafety Committee
• Composed of faculty, staff, and community members
• Committee meetings open to public - public trust!
• Key Functions:
• Review & recommend institutional policies for research
involving rDNA and biological agents.
• Review individual research proposals for compliance with
Federal, State, local, and institutional regulations:
- Biosafety containment levels (BSL1, 2, 3)
- Adequacy of facilities, SOPs, training
• Independent approval authority for specific proposals.
• Monitor and assure compliance with the NIH Guidelines
BioSafety-’13-Outreach
Federal Authority for IBC
 Institutions receiving funding from the National Institutes
of Health must assure that ALL research is carried out in
compliance with the NIH Guidelines for Research Involving
Recombinant DNA (& Infectious Agents).
(http://oba.od.nih.gov/rdna/nih_guidelines_oba.html)
 Assurance of compliance is accomplished through the
Institutional Biosafety Committee (IBC) in collaboration
with the Institutional Health and Safety Departments.
(http://oba.od.nih.gov/rdna/nih_guidelines_new.htm#_Toc331174013)
BioSafety-’13-Outreach
Investigator Obligations
(per NIH Guidelines)
•
•
•
•
•
Wait to initiate or modify recombinant DNA research that
requires IBC approval until approval is granted.
Identify which section(s) of the NIH Guidelines apply to
their research and notify the IBC as appropriate.
Be adequately trained in good microbiological techniques
(and adequately train lab personnel).
Adhere to IBC determinations for containment and plans
for spills and personnel contamination.
Report any significant problems or violations to the IBC
and NIH Office of Biotechnology Activities within 30 days
(immediately in cases of exposure).
BioSafety-’13-Outreach
Biosafety Standards
Biosafety standards are defined and codified:
•
•
•
•
•
•
•
•
Institution (Administrative Policy, EH&S/ROS, IBC)
NIH Guidelines
CDC/NIH BMBL Biosafety in Microbiological and
Biomedical Laboratories
US Department of Agriculture
Select Agent Rule, 42 CFR Part 73
WISHA/WAC Occupational Health & Safety Standards
WAC 296-820 Bloodborne Pathogens Standard
Seattle Municipal Code Infectious Waste Management
BioSafety-’13-Outreach
Biosafety Standards
Biosafety standards are defined and codified:
•
•
•
•
•
•
•
•
Institution (Administrative Policy, EH&S/RBSO, IBC)
NIH Guidelines
CDC/NIH BMBL Biosafety in Microbiological and
Biomedical Laboratories
US Department of Agriculture
Select Agent Rule, 42 CFR Part 73
WISHA/WAC Occupational Health & Safety Standards
WAC 296-820 Bloodborne Pathogens Standard
Seattle Municipal Code Infectious Waste Management
BioSafety-’13-Outreach
What Changed ?
 In September 2012 the National Institutes of Health (NIH)
Office of Biotechnology Activities (OBA) published final changes
to the NIH Guidelines which it deemed necessary to reflect the
emerging technologies involving "synthetic DNA"...
 Prior to these changes, recombinant DNA was defined, in part,
as "joining segments of DNA from different sources"; the new
rules were necessary to capture the use of recDNA generated by
artificial synthesis (synthetic DNA).
 This precipitated several other changes to NIH Guidelines...
BioSafety-’13-Outreach
What Changed ?
(continued)
• Synthetic DNA is treated the same as Recombinant DNA
• Recombinant DNA outside of cells remains "exempt" from
the NIH Guidelines, with some exceptions
• New rules for recDNA prepared in liposomes, other "vehicles"
• New definition and rules for "safe" recDNA inside cells
• New rules for chemically modified recDNA
• New rules for drug resistance genes in pathogenic agents
• New rules for synthetic DNA that exists in nature
• New rules for clinical gene therapy
• New rules for risk assessment
• Reconfirm concept that all recDNA is hazardous
BioSafety-’13-Outreach
Synthetic DNA = Recombinant DNA
Old Definition
(Recombinant DNA)
New Definition
(Recombinant & Synthetic
Nucleic Acid Molecules)
(i) molecules that are
constructed outside of living
cells by joining natural or
synthetic DNA segments to
DNA molecules that can
replicate in a living cell, or
(i) molecules that a) are constructed by joining
nucleic acid molecules and b) can replicate in
a living cell, i.e., recombinant nucleic acids;
(ii) molecules that result from
the replication of those
described in (i) above.
(ii) 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 acid molecules,
i.e., synthetic nucleic acids; or
(iii) molecules that result from the replication
of those described in (i) or (ii) above.
BioSafety-’13-Outreach
recDNA Outside Cells Remains Exempt
New Section III-F-2
(exempt from the NIH Guidelines)
Synthetic or recombinant nucleic acids "that are not in
organisms, cells, or viruses and that have not been
modified or manipulated (e.g., encapsulated into synthetic
or natural vehicles) to render them capable of penetrating
cellular membranes" are exempt from the NIH Guidelines.
BioSafety-’13-Outreach
recDNA Prepared in "Vehicles"
New Upgrade from Section III-F to III-E
Synthetic or recombinant nucleic acids that are
"encapsulated into synthetic or natural vehicles" so as to
render them "capable of penetrating cellular membranes"
are no longer exempt from the NIH Guidelines, but instead
fall under Section III-E (must be reported to the IBC).
Examples: - Liposomes / polyplexes
- Nanoparticles
- Synthetic scaffolds
A new section on the Biological Use Authorization (BUA)
application specifically asks about this work
BioSafety-’13-Outreach
"Safe" recDNA
New Downgrade from Section III-E to III-F
Oligonucleotides or other synthetic nucleic acids (<100 bases)
that meet the following criteria:
a) Do not contain an origin of replication or elements known to
interact with either DNA or RNA polymerase, and
b) Are not designed to integrate into DNA, and
c) Do not produce a toxin that is lethal for vertebrates
(LD50 < 100 ng/Kg)
Examples: - siRNA, even when administered to animals
- nucleic acid adjuvants for immunization
- short morpholinos
BioSafety-’13-Outreach
Chemically Modified recDNA
New Upgrade from Section III-F to III-E
Recombinant or synthetic nucleic acid molecules that are
chemically modified but can still "base pair with naturally occurring
nucleic acid molecules" now must be treated the same as their
unmodified "functional equivalent".
Examples: - morpholinos not fitting the category of "safe"
- bioengineering studies with base analogs
BioSafety-’13-Outreach
Drug Resistance Genes in Pathogens
Section III-A - Review by the NIH RAC
Old Definition
The deliberate transfer of a drug
resistance trait to microorganisms
that are not known to acquire the
trait naturally, if such acquisition
could compromise the use of the
drug to control disease agents in
humans, veterinary medicine, or
agriculture...
New Definition
The deliberate transfer of a drug resistance trait to
microorganisms that are not known to acquire the
trait naturally, if such acquisition could compromise
the ability to control disease agents in humans,
veterinary medicine, or agriculture...
Consideration should be given as to whether the
drug resistance trait to be used in the experiment
would render that microorganism resistant to the
primary drug available to and/or indicated for certain
populations, for example children or pregnant
women.
Special provisions are provided for consulting the
Office of Biotechnology Activities.
BioSafety-’13-Outreach
DNA Sequences that Exist in Nature
Old Definition
New Definition
(Exempt, Section III-F-2)
(Exempt, Section III-F-3)
Research with DNA molecules that
are essentially copies of DNA found
in nature (paraphrased).
Research with recombinant or synthetic nucleic
acids "that consist solely of the exact recombinant
or synthetic nucleic acid sequence from a single
source that exists contemporaneously in nature."
Rational: Assure that attempts to reanimate extinct
pathogens (e.g. 1918 influenza) are reviewed by
the IBC prior to initiation of the research.
BioSafety-’13-Outreach
New Rules for Clinical Trials
New rules exempt clinical trials with "safe" recombinant
and/or synthetic DNA from review by the RAC
a) Less than 100 nucleotides
b) Do not contain an origin of replication or elements known to
interact with either DNA or RNA polymerase, and
c) Are not designed to integrate into DNA
Note: All clinical trials with recombinant and/or synthetic
DNA, even if meeting the criteria for "safe", must still be
reviewed and approved by the IBC prior to initiation.
BioSafety-’13-Outreach
New Rules for Risk Assessment
1) The Institution, IBC, and Principal Investigators must adhere to the
intent of the NIH Guidelines as well as to its specifics.
2) For organisms containing recDNA from multiple sources, the risk
assessment should include both the origin of those sources and
function of the individual genes.
3) Both the Principal Investigator and the IBC should consider whether
the "combination of certain sequences in a new biological context may
result in an organism whose risk profile could be higher than that of the
contributing organisms or sequences".
In short: The PI and the IBC need to carefully assess the potential
hazard of highly engineered organisms based on expected biology as
well as by category.
BioSafety-’13-Outreach
All recDNA Still Deemed Hazardous
Even though much work with recombinant and/or synthetic
nucleic acids remains exempt from the NIH Guidelines:
1) Contact EH&S Research and Occupational Safety (ROS)
to help determine if your research is exempt.
2) ALL forms of recombinant and/or synthetic DNA, no
matter how trivial or exempt from the NIH Guidelines, are
considered a biohazard and must be handled and disposed
of in an appropriate manner!
BioSafety-’13-Outreach
What You Need To Do
• Review your research program to determine if these
changes to the NIH Guidelines apply to your research.
• If you received Biological Use Authorization during the past
three years and you believe your research approval would be
impacted by these changes, please submit a Request for
Change form no later than February 28.
• If you are currently working without an EH&S Biological Use
Authorization and you believe your research falls under the
amended NIH Guidelines, please submit a BUA application
no later than February 28.
• Please keep these changes in mind as you plan your future
research efforts.
BioSafety-’13-Outreach
Examples
• You use liposomes or other forms of DNA "vehicles"
(may raise containment level)
• You use siRNA or other forms of "safe" recDNA in animals
(may lower containment level)
• You work with recombinant / synthetic nucleic acids and
have never registered with EH&S.
• EH&S Research and Occupational Safety will be reviewing
past approvals for these and other specific types of
research and may contact you if needed.
BioSafety-’13-Outreach
Deadlines
• All new applications and change forms must be submitted
no later than February 28, 2013.
• If you miss this due-date, your application my not be
reviewed and approved be the end of March 2013
(the due-date set by the NIH).
• Please remember that failure to comply with the NIH
Guidelines, including properly registering your research,
puts your funding, and that of your colleagues, at risk.
BioSafety-’13-Outreach
References / Contacts
• EH&S Research and Occupational Safety:
206-221-7770, ehsbio@uw.edu
• Biological Use Authorization applications:
http://www.ehs.washington.edu/forms/rbs/bua.docx
http://www.ehs.washington.edu/forms/rbs/buachange.docx
• NIH Guidelines:
http://oba.od.nih.gov/rdna/nih_guidelines_oba.html
• FAQs for changes to the NIH Guidelines:
NIH: http://oba.od.nih.gov/oba/faqs/Synthetic_FAQs-Sept-2012.pdf
EH&S: http://www.ehs.washington.edu/rbsresplan/rdna.shtm
BioSafety-’13-Outreach
? QUESTIONS ?
BioSafety-’13-Outreach