Presentation on theme: "What are the NIH Guidelines for Research Involving Recombinant DNA Molecules?"— Presentation transcript:
1 Overview of the NIH Guidelines for Research Involving Recombinant DNA Molecules
2 What are the NIH Guidelines for Research Involving Recombinant DNA Molecules? These guidelines specify practices for constructing and handling:Recombinant DNA (rDNA) moleculesOrganisms and viruses containing rDNA moleculesHistory:Guidelines originally established in 1975 at the Asilomar Conference on Recombinant DNAEstablished recommendations to perform rDNA experiments in a manner safe for researchers and the publicRevised as needed, most recently in Sept. 2009
3 What are rDNA molecules? Definition of rDNA molecules:Molecules constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cellSynthetic DNA segments, likely to yield a potentially harmful polynucleotide or polypeptide, are considered equivalent to their natural DNA counterpart.Examples:Human gene transferCloning plasmidsViral or bacterial vectorsTransgenic animalsGenetically modified cell lines
4 Who must comply with the NIH Guidelines? Guidelines are applicable to all rDNA research at any institution that receives NIH support for rDNA research.This includes:NIH-funded projects involving rDNANon-NIH funded projects involving rDNAResearch with HUMANS involving rDNA materials developed with NIH fundsOnly if the institution sponsors, participates, or collaborates in any way to those projectsNot the mere provision of research materials*Individuals receiving NIH-funds for rDNA research must be associated with or sponsored by an institution*
5 What if we don’t comply with the NIH Guidelines? Non-compliance can result in:Suspension, Limitation, or Termination of NIH financial assistance forThe non-compliant research projectANDALL other rDNA research at the institutionImposition of NIH overview and approval for all rDNA projects before they are started
6 What does all of this mean for Haverford researchers? Haverford receives NIH funding for projects involving rDNA research, therefore:ALL researchers at Haverford must comply with the NIH GuidelinesEven those not directly receiving NIH funding.ANDJust one non-compliant researcher could jeopardize NIH grant funding for the entire college
7 How can Haverford stay in compliance with the NIH Guidelines? The NIH Office of Biotechnology Activities (OBA) fosters awareness of and adherence to the NIH GuidelinesOBA periodically conducts site visits to review how institutions follow the NIH GuidelinesCompliance with the NIH Guidelines is the responsibility of:The InstitutionThe Institutional Biosafety Committee (IBC)The Principal Investigator
8 The Institution’s Responsibilities Provide training tools to researchers on the safe use of rDNAInform Principal Investigators of their responsibilities outlined in the guidelinesForm an Institutional Biosafety Committee (IBC)
9 Institutional Biosafety Committee (IBC) Functions to review, approve, and oversee projects in accordance with the responsibilities defined in NIH Guidelines Section IV-B-2Committee membership requirements specified in Section IV-B-2 include:Individuals with expertise in rDNA technologyIndividuals with expertise in human gene transferScientist with expertise in animal containmentBiosafety officerCommunity members not affiliated with institution
10 Institutional Biosafety Committee (IBC) Responsibilities On behalf of the institution, the IBC is responsible for:Reviewing rDNA research conducted at or sponsored by the institutionSetting containment levelsNotifying PI of the results of the IBC’s review and approvalReporting significant problems or violations with the NIH guidelines to NIH/OBADeveloping emergency plans covering accidental spills and personnel contamination resulting from rDNA research
11 Principal Investigator (PI) Responsibilities Make an initial determination of the required levels of physical and biological containmentSupervise the safety performance of the laboratory staffEnsure the integrity of the physical containment (e.g. biological safety cabinets)Ensure integrity of the biological specimens (e.g. purity and genotypic/phenotypic characteristics)Be adequately trained in good microbiological techniquesAdhere to IBC approved emergency plans for handling accidental spills and personnel contaminationComply with applicable shipping requirements for recombinant DNA molecules.
12 Principal Investigator (PI) Responsibilities Submit an initial registration to the IBC for review and approval or disapprovalReport any subsequent changes to project (e.g. changes in the sources of DNA or host-vector system)Remain in communication with the IBC throughout the duration of the projectReport to the IBC, NIH/OBA and other appropriate authorities:Any significant problems, violations of the NIH GuidelinesAny significant research-related accidents and illnessesWithin 30 days of incident
13 Principal Investigator (PI) Responsibilities On behalf of the institution, the PI is responsible for full compliance with the NIH guidelines in the conduct of rDNA research.PIs must be knowledgeable about the different types of rDNA work and their registration requirements:rDNA work requiring NIH/OBA and IBC approval before initiationRegistration document requiredrDNA work that must be approved by the IBC before initiationrDNA work that requires notification to the IBC simultaneous to initiationrDNA work that is exemptWhile a registration document is NOT required by NIH, Haverford policy requires a record of all rDNA workNo rDNA work requiring IBC review beforeinitiation may be started or modified until fullIBC approval is granted.
14 Haverford’s rDNA Registration Document You will be required to complete a registration document that looks like this:
15 Know the NIH Guidelines “Section III” It is the PI’s responsibility to know which section of the NIH Guidelines covers his or her rDNA workPenn’s registration form asks you to properly identify this informationThe following slides will help you determine appropriate categories
16 Know the NIH Guidelines “Section III” NIH Guidelines “Sections III-A, III-B, III-C”rDNA work requiring NIH/OBA and IBC approval before initiationNIH Guidelines “Section III-D”rDNA work that must be approved by the IBC before initiationNIH Guidelines “Section III-E”rDNA work that requires notification to the IBC simultaneous to initiation
17 Experiments that require NIH/OBA and IBC approval before initiation: NIH Guidelines “Sections III-A, III-B, III-C” covers:Experiments that require IBC and IRB and RAC review before research participant enrollment.Experiments involving the cloning of toxin molecules with LD50 of less than100ng/kg body weight.Experiments involving the deliberate transfer of rDNA, or DNA or RNA derived from rDNA, into one or more human research participants.
18 Examples of work under “Sections III-A, III-B, and III-C” Examples include but are not limited to:III-A-1: Major actions requiring IBC, RAC, and NIH Director approvalIII-A-1a: The deliberate transfer of drug resistance to microorganisms not naturally acquiring that resistanceIf the resistance trait can could compromise the use of a clinically significant drugIII-B-1: Formation of rDNA containing genes for toxin molecules that are lethal to vertebratesToxins that have an LD50 of less than 100ng/kg body weightEx) Botulinum toxins, tetanus toxins, diphtheria toxin, Shigella dysenteriae neurotoxinIII-C-1: Experiments involving the deliberate transfer of rDNA into human research participants (human gene transfer)
19 “Section III-C-1”: Human Gene Transfer Research involving the deliberate transfer of rDNA or DNA/RNA derived from rDNA into human research participantsNO research participants may be enrolled until the rDNA Advisory Committee (RAC) review has been completedRAC review requirements outlined in “Appendix M” of the GuidelinesFor clinical trial sites added after RAC review:Clinical trial site must submit the following documents to NIH OBA:IBC approvalIRB approvalIRB approved informed consent documentsCurriculum vitae of the PI (no more than 2 pages in biographical sketch format)NIH grant number (if applicable)
20 “Section III-C-1”: Human Gene Transfer NIH Guidelines apply if the institution:Participates in projectIncluding research collaboration and contractual agreementsNOT merely providing research materialsPIs engaging in human gene transfer projects may delegate to another party the reporting functions set forth in “Appendix M”This may be a corporate sponsor.Written notification to NIH/OBA is required.
21 Experiments that require IBC approval before initiation: NIH Guidelines “Section III-D” covers:Experiments using risk group 2, 3 or 4 or restricted agents as host vector systemsExperiments in which DNA from risk group 2, 3 or 4 or restricted agents is cloned into nonpathogenic prokaryotic or lower eukaryotic host-vector systemsExperiments involving the use of infectious DNA or RNA viruses or defective DNA or RNA viruses in the presence of helper virus in tissue culture systemsExperiments involving whole animalsExperiments involving whole plantsExperiments involving more than 10 liters of cultureExperiments involving influenza virus
22 Examples of work under “Section III-D” Examples include but are not limited to:III-D-1: Using lentiviral or adenoviral vectorsIII-D-2: Gene inserts used are from pathogenic microorganismsIII-D-3: Helper virus is used in tissue culture to enhance pathogenicity of viral vectorsIII-D-4: ANY rDNA materials that are going into animalsDOES NOT include making transgenic rodentsOne of the most common categories of work at PennIII-D-5: Genetically engineering plants using rDNA and/or using these plants in experimentsIII-D-6: rDNA experiments using >10L of cultureIII-D-7: rDNA work with all influenza viruses with special consideration of:human H2N2 ( )fully reconstructed H1N1Highly Pathogenic Avian Influenza (HPAI) H5N1 (Goose/Guangdong/96-like lineage)
23 Experiments that require IBC notice simultaneous with initiation NIH Guidelines, “Section III-E” covers:Only experiments that require BSL-1/ABSL-1 containmentIf BSL-2/ABSL-2 containment is required, it cannot be “Section III-E”rDNA molecules of eukaryotic viruses that contain no more than 2/3 of the viral genomeIn tissue culture only andRequire BSL-1 containmentMust demonstrate the lack of helper virus for certain families of defective viruses being usedExperiments involving whole plantsExperiments involving transgenic rodentsGeneration of transgenic rodents by altering genome through stable introduction of rDNA into germ-line
24 Examples of work under “Section III-E” Examples include but are not limited to:III-E-1: Recombinant eukaryotic virus containing < 2/3 of its genome is propagated in tissue cultureIII-E-2: rDNA plant experiments requiring BSL-1 containmentIII-E-3: Experiments with transgenic rodents requiring BSL-1 containmentCreating a transgenic mouse (BSL-1 containment)
25 NEW Exemption: Change to Section III-E-3 Requirements (as of January 19, 2011) Old Requirement:Breeding of one or more transgenic rodents to create new transgenic rodents using BSL-1 conditionsFell under section III-E-3Previously required registration
26 NEW Exemption: Change to Section III-E-3 Requirements (as of January 19, 2011) New Requirement:Breeding of almost* all transgenic rodents that require BSL-1 housing is exemptExempt under section III-F-6No registration document required*Exceptions*The following must be registered:Rodents that contain a transgene encoding >50% of an exogenous eukaryotic virusTransgenic rodents in which the transgene is under control of a gammaretroviral promotorAny breeding experiments that require BSL-2 conditions
27 Exempt rDNA Experiments NIH Guidelines “Section III-F” covers exempt experimentsRegistration with the IBC is not requiredExempt experiments are those involving rDNA molecules that:III-F-1: are not in organisms or virusesIII-F-2: consist entirely of DNA from single nonchromosomal or viral DNA sourceIII-F-3: consist entirely of DNA from a prokaryotic host when propagated only in that hostIII-F-4: consist entirely of DNA from an eukaryotic host when propagated only in that host (excluding DNA from viruses)III-F-5: consist entirely of DNA from different species that exchange DNA by known physiological processes (list periodically updated in Appendices A-I through A-VI)III-F-6: do not present significant risk to health or to the environment as determined by NIH Director with the advice of RAC
28 Dual Use ResearchDefinition: “Research that yields information or technologies with the potential to be misused to threaten public health or other aspects of national security.”Identify this on Haverford’s rDNA registration form :
29 Training Requirements All personnel who are listed on a registration document must complete training, including:PIAnyone directly involved in rDNA experimentsRegistrations will not be approved until all training is completeThis module satisfies the knowledge portion of training on the NIH GuidelinesPI is responsible for “hands-on” training of personnel
30 Haverford’s rDNA Registration Review Process Submit the completed and signed registration forms to the chair of the IBC (see Provost’s Office if you are unsure who is the current chair of the IBC - for ,it is Rob Fairman)A member of the IBC will review the registration form and contact you with any questions or necessary revisionsThe IBC reviews registrations as neededThe IBC is not permitted to review registrations outside of a fully convened meetingSOPlease be sure to submit registrations in a timely fashion, allowing enough time for a full meeting of the IBC to be arranged and convened
31 Haverford’d rDNA Registration Review Process If the IBC approves your registration, you will receive an approval letter with:IBC registration number (ex. #11-805)The biosafety level (BSL) requiredThe animal biosafety level (ABSL) requiredRegistrations must be renewed every 3 yearsIf your registration is for work requiring IBC approval BEFORE initiation (Sections III-A, III-B, III-C, III-D), you may not start work until an official approval letter has been received
32 Additional Resources to Foster NIH Guideline Understanding Office of Biotechnology Activities website•NIH GuidelinesOffice of Environmental Health and Radiation Safety’s (EHRS) website for Biological Safety at U. PennShirly Mildiner-Earley,Contact the IBC at Haverford (see Provost’s Office)