Dual Use Research of Concern

1. Dual Use Research of Concern Environment, Health & Safety University of North Carolina @ Chapel Hill

2. Overview – The Fink Report • 2003 - The National Research Council’s “Committee on Research Standards & Practices to Prevent the Destructive Application of Biotechnology” published a report entitled “Biotechnology Research in An Age of Terrorism: Confronting The Dual Use Dilemma”.(Fink Report) • The Committee recommended the creation of the National Science Advisory Board for Biosecurity (NSABB) to educate scientists & advise the government on the oversight of “dual use” research.

3. National Science Advisory Board for Biosecurity (NSABB) • The NSABB provides advice, guidance, and leadership regarding biosecurity oversight of dual use research to all Federal departments and agencies with an interest in life sciences research (including Institutional Biosafety Committees-IBCs).

4. Dual Use Research vs. Dual Use Research of Concern • “Dual Use Research” is research that has the potential to be misused for nefarious purposes. • Almost all life science research has some potential for misuse and therefore can be considered to be Dual Use Research. • The NSABB thus defined a special category: “Dual Use Research of Concern”, or DURC that warrants particular attention.

5. Dual Use Research of Concern (DURC) * “The National Science Advisory Board for Biosecurity (NSABB) has defined Dual Use Research of Concern (DURC) as: “research that, based on current understanding, can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment or materiel”. *NSABB 2004

6. USG Policy on Dual Use Research of Concern (1) Partly in response to public concerns over experiments aimed at broadening the host range of highly pathogenic avian influenza to mammals, the U.S. Government issued a policy on oversight of dual use research of concern (DURC) in March 2012. This new policy requires funding agencies to review ongoing research for DURC and to establish criteria for the management of any research that is identified as DURC. oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_oversight_of_durc_final_version_032812.pdf

7. USG Policy on Dual Use Research of Concern (2) Although all life sciences research has the potential to meet NSABB’s definition of DURC, this new USG policy on DURC applies only to research with certain infectious agents and toxins. In the future, the policy is likely to be broadened to other life sciences research, and will likely require academic institutions to review their research for DURC locally. oba.od.nih.gov/oba/biosecurity/pdf/united_states_government_policy_for_oversight_of_durc_final_version_032812.pdf

8. Dual Use Research Concern PolicyUnder the new policy, review will focus on research that involves one or more of the following select agents or toxins: • Avian influenza virus (highly pathogenic) • Bacillus anthracis • Botulinum neurotoxin • Burkholderia mallei • Burkholderia pseudomallei • Ebola virus • Foot-and-mouth disease virus • Francisella tularensis • Marburg virus • Reconstructed 1918 Influenza virus • Rinderpest virus • Toxin-producing strains of Clostridium botulinium • Variola major virus • Variola minor virus • Yersinia pestis

9. Experiments of Concern NSABB identified 7 categories of experiments that may meet the definition of DURC. Such experiments are not “prohibited” but their risks vs. benefits, and how to communicate the results, should be carefully considered before starting the research. Note that these are not restricted to select agents and toxins. 1. Enhances the harmful consequences of an agent or toxin. Example: Information on how to make a seasonal strain of the influenza virus as deadly as the 1918 pandemic strain. 2. Disrupts the immunity or the effectiveness of an immunization without clinical and/or agricultural justification. Example: Information on the insertion of an immunosuppressive cytokine into a viral genome to render the antiviral immune response less effective. 3. Confers to the agent or toxin resistance to clinically and/or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies. Example: Information on how to confer doxycycline resistance to Vibriovulnificus or antibiotic resistance to agriculturally relevant microbes, such as rendering Erwiniaamylovoraresistant to streptomycin.

10. Experiments of Concern 4. Increases the stability, transmissibility, or the ability to disseminate a biological agent or toxin. Example: Information on changing genetic factors to increase transmissibility & altering the route of transmission or vector to increase the ease & effectiveness by which an agent may be transmitted. 5. Alter the host range or tropism of the agent or toxin Example: Knowledge of how to convert nonzoonotic agents into zoonotic agents, altering the tropism of viruses& expanding the varieties of the same plant that an altered pathogenic agent could infect. 6. Enhance the susceptibility of a host population to an agent or toxin. Example: Information on how to create a stable recombinant Lactobacillus caseithat could effectively block the host’s ability to synthesize an important immune signal, such as a tumor necrosis factor alpha, which may directly facilitate the evasion of normal host defenses. 7. Generates or reconstitutes an eradicated or extinct agent or toxin. Example: Information on how to construct a de novo microbial pathogen using unique gene sequences or combinations of sequences that do not exist in nature; or on how to reconstitute a pathogen that no longer exists in nature, such as the 1918 pandemic influenza virus.

11. Case Study #1 • Reconstruction of the 1918 Spanish Flu (2005) • Dual use concern: The information obtained could be misused and the virus could be bioweaponized • Biosecurity/Biosafety issues: Were appropriate precautions taken for containment & security? Were the results communicated in a way to enhance public understanding of the need for the research?

12. Case Study #2 • Mousepox Experiment - A strain of ectromelia virus (mousepox) was bioengineered in an effort to sterilize mice in Australia. The strain killed 60% of the infected mice. (2001) • Dual use concern: Many feared that publication of this research would provide a blueprint for those with malevolent intentions and a more virulent strain of smallpox could be created to infect humans.

13. PI Responsibilities -Assess their own research and the research of those under their supervision for dual use potential and report as appropriate; -Stay abreast of literature, guidance, and requirements related to dual use research, and particularly Dual Use Research of Concern (DURC); -Ensure that their lab personnel are able to identify DURC and manage it properly; -Conduct research responsibly, especially research that may meet the criteria for DURC; -Give thought as to how the results of such research should be communicated to others, including the public; and -Always be alert to potential misuse of research. PIs/Researchers should cultivate and sustain a culture of responsibility, accountability and safety!

14. UNC’s Responsibility • UNC’s Institutional Biosafety Committee (IBC) and Environment, Health & Safety (EHS) Biological Safety section currently reviews research proposals (Schedule G) & determines if they might meet the NSABB definition of DURC. • If a protocol meets the criteria for DURC, a risk assessment is done and a mitigation plan is developed. Further safety measures may be taken or if necessary the protocol may be revised or retracted.

15. Framework for assessing & managing risk: *5 Key Questions: • Could this research yield information that could be intentionally misused to threaten public health, safety and security? • What is the nature of the threat that could be posed from intentional misapplication of the information & what are the potential consequences? • Based on questions 2&3, how reasonably anticipated is it that the information could be used to pose a threat to public health, safety and/or security? *http://oba.od.nih.gov/oba/biosecurity/documents/B_Dual_Use_Educational_Module_FINAL.pdf

16. Framework for assessing & managing risk:5 key questions (cont’d) 4. Could this research yield information that could potentially benefit the life sciences and/or public health, safety or national security? 5. Do the potential risks outweigh the potential benefits?? Framework for assessing & managing risk: If potential risks outweigh the potential benefits, determine whether research should be modified, delayed or discontinued.

17. Hypothetical Cases -Although the new USG policy on DURC that was issued in March 2012 calls for review and oversight only of research involving certain select agents and toxins, the NSABB and others have made it clear that DURC is not restricted only to such research but can exist in other types of life sciences research. - The NSABB has highlighted the need to broadly educate life science researchers about DURC and to increase their awareness of the issue. Such efforts could enhance public confidence in research, and possibly forestall additional draconian regulation or oversight measures. - To aid in these efforts, the NSABB has prepared a series of hypothetical cases and related questions for discussion. http://oba.od.nih.gov/oba/biosecurity/documents/B_Dual_Use_Educational_Module_FINAL.pdf

18. Hypothetical Case #1* Ann, a post-doctoral fellow, is working with Peter, a senior researcher, on a study of antimicrobial resistance in gram-positive pathogenic bacteria. Ann is studying recently isolated strains of Streptococcus pneumoniae that have developed antibiotic resistance & cause significantly increased pneumonia morbidity & mortality. She has identified a gene that she believes is responsible for the resistance, one that encodes part of a membrane-bound pump that removes materials from bacterial cells. With that gene, she has created a variant with increased capacity and heightened resistance. * http://oba.od.nih.gov/oba/biosecurity/documents/B_Dual_Use_Educational_Module_FINAL.pdf

19. Questions -This research has the clear potential to yield public health benefits, but it could also be used for malevolent purposes. What, if anything, should Ann & Peter do to minimize the risks of misuse of the research? They should contact their local IBC for an evaluation of their research & if necessary risk mitigation procedures should be established. -Should Ann & Peter be held responsible if the findings of their research are maliciously misused? No, not if they have gone through the proper channels of having their research reviewed and approved by the IBC.

20. Hypothetical Case #2* Clostridium botulinum produces a toxin that causes ~150 cases of food poisoning a year in the U.S. Bioterrorists could exploit several of the bacterium’s properties as it is accessible & easy to prepare in large quantities. To counteract the effects of such an attack, a research team screened a library of compounds with the potential to inhibit the activity of botulinum toxin to determine if they could be used therapeutically after an attack. During the studies, a small molecule scaffold that strongly enhances the catalytic activity through an apparent increase in binding affinity was discovered. This finding could yield both benefits & harms. In small doses, botulinum toxin is used to treat cerebral palsy. This finding could allow for it to be used therapeutically for other conditions. However, this discovery could also be used malevolently. * http://oba.od.nih.gov/oba/biosecurity/documents/B_Dual_Use_Educational_Module_FINAL.pdf

21. Questions -Should these researchers share the results of their research at a scientific conference? What considerations should they take into account when making a decision on whether to share the findings? Yes. If they have been evaluated by the IBC & a researcher who specializes in dual use research. -Are there ways to share findings while minimizing the risks of misuse? Yes, the findings can be shared however, the details should be limited.

22. Fink Committee of the National Research Council of the National Academies, USA (2003): “Even experiments that have the greatest potential for diversion to offensive applications or terrorist purposes may also have potentially beneficial uses for public health promotion and defense”.

23. If you have any questions regarding your research and its dual use research potential, please contact UNC’s Institutional Biosafety Committee dmhoward@ehs.unc.edu