Appendix B

Official Statements

 

•    December 20, 2011, National Institutes of Health (NIH), “Press Statement of the NSABB Review of H5N1 Research.”

•    December 30, 2011, World Health Organization (WHO), “WHO Concerned that New H5N1 Influenza Research Could Undermine the 2011 Pandemic Influenza Preparedness Framework.”

•    January 20, 2012, NIH, “NIH Statement on H5N1.”

•    January 31, 2012, National Science Advisory Board for Biosecurity (NSABB), “Adaptations of Avian Flu Virus Are a Cause for Concern.” ScienceExpress January 31, 2012. Reprinted with permission from AAAS.

•    February 2012, WHO “Report on Technical Consultation on H5N1 Research Issues.”

•    March 29, 2012, NIH, “United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern.”

•    March 30, 2012, NSABB, “Findings and Recommendations, March 29-30, 2012.”

•    April 14, 2012, NIH, “Statement on NSABB’s March 30, 2012 Recommendations to NIH on H5N1 Research.”

•    April 20, 2012, NIH, “Statement by NIH Director Francis Collins, M.D., Ph.D. on the NSABB Review of Revised H5N1 Manuscripts.”



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Appendix B Official Statements • December 20, 2011, National Institutes of Health (NIH), “Press Statement of the NSABB Review of H5N1 Research.” • December 30, 2011, World Health Organization (WHO), “WHO Concerned that New H5N1 Influenza Research Could Undermine the 2011 Pandemic Influenza Preparedness Framework.” • January 20, 2012, NIH, “NIH Statement on H5N1.” • January 31, 2012, National Science Advisory Board for Bio­ ecurity s (NSABB), “Adaptations of Avian Flu Virus Are a Cause for Con- cern.” ScienceExpress January 31, 2012. Reprinted with permis- sion from AAAS. • February 2012, WHO “Report on Technical Consultation on H5N1 Research Issues.” • March 29, 2012, NIH, “United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern.” • March 30, 2012, NSABB, “Findings and Recommendations, March 29-30, 2012.” • April 14, 2012, NIH, “Statement on NSABB’s March 30, 2012 Recommendations to NIH on H5N1 Research.” • April 20, 2012, NIH, “Statement by NIH Director Francis Collins, M.D., Ph.D. on the NSABB Review of Revised H5N1 Manuscripts.” 55

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56 PERSPECTIVES ON RESEARCH  WITH H5N1 AVIAN INFLUENZA                                               

OCR for page 55
APPENDIX B 57           

OCR for page 55
  58 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA                                           

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 APPENDIX B  59                               

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60 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA NIH Statement on H5N1 http://w w w .nih.gov/about/director/01202012_h5n1_statement.htm Februray 13, 2012 The NIH Director January 20, 2012 Last month, the National Science Advisory Board for Biosecurity (NSABB)—an independent expert committee that advises the Department of Health and Human Services (HHS) and other Federal departments and agencies on matters of biosecurity—completed a review of two unpublished manuscripts describing National Institutes of Health (NIH)-funded research on the transmissibility of H5N1 influenza. The NSABB concluded that publishing the methodological and other details of this work could potentially enable replication of experiments that had enhanced transmissibility of H5N1 influenza (in ferrets) by those who might wish to do harm, and recommended that the manuscripts not be published in full. NSABB members also discussed whether there should be a temporary moratorium on the broad communication of dual-use H5N1 research until the issues raised by the research could be resolved. HHS provided the NSABB's non-binding recommendations to the authors of the manuscripts and the editors of the journals to which the manuscripts had been submitted for publication. To date, the manuscripts have not been published. Today, the authors of the unpublished manuscripts and other scientists in the H5N1 research community announced that they will voluntarily suspend certain research on the H5N1 virus for 60 days, pending a thorough international discussion about its future directions and parameters for its safe conduct and responsible communication. This suspension applies both to research that enhances the transmissibility of highly pathogenic avian influenza viruses in mammals, as well as any experiments with H5N1 viruses already shown to be transmissible in ferrets. We applaud the decision by these scientists, who have demonstrated great responsibility and flexibility in pausing their work to allow for a full dialogue about the risks and benefits of this research. NIH, the Centers for Disease Control and Prevention, and other U.S. government agencies that conduct or fund such research will also abide by this moratorium. We continue to urge the international scientific community to work toward a consensus on the future directions of such research to improve public health in light of international security implications, while ensuring the global influenza surveillance and research communities can share through appropriate means critical information about the potential transmissibility of H5N1 influenza in humans. Understanding how influenza viruses become human pandemic threats is vitally important to global health preparedness. Such research helps us to understand the ability of the virus to cross between species and enables the development of tools for the prediction, prevention, and treatment of outbreaks. To this end, officials with the World Health Organization are now working to organize a forum for the international scientific community to discuss these issues in the coming weeks. We look forward to participating in this important dialogue. Francis S. Collins, M.D., Ph.D. Director, National Institutes of Health Anthony S. Fauci, M.D. Director, National Institute of Allergy and Infectious Diseases National Institutes of Health This page last reviewed on January 20, 2012

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APPENDIX B 61 Adaptations of Avian Flu Virus Are a Cause for Concern Kenneth I. Berns,1* Arturo Casadevall,2 Murray L. Cohen,3 Susan A. Ehrlich,4 Lynn W. Enquist,5 J. Patrick Fitch,6 David R. Franz,7 Claire M. Fraser-Liggett,8 Christine M. Grant,9 Michael J. Imperiale,10 Joseph Kanabrocki,11 Paul S. Keim,12† Stanley M. Lemon,13 Stuart B. Levy,14 John R. Lumpkin,15 Jeffery F. Miller,16 Randall Murch,17 Mark E. Nance,18 Michael T. Osterholm,19 David A. Relman,20 James A. Roth,21 Anne K. Vidaver22 1 Genetics Institute, University of Florida, Gainesville, FL 32611, USA. 2Albert Einstein School of Medicine, Bronx, NY 10461, USA. 3Frontline Healthcare Workers Safety Foundation, Ltd., Atlanta, GA 30338, USA. 4University of Texas Medical Branch, Galveston, TX 77555, USA. 5Princeton University, Princeton, NJ 08544, USA. 6Battelle National Biodefense Institute, LLC, Frederick, MD 21702, USA. 7MRIGlobal, Frederick, MD 21702, USA. 8University of Maryland School of Medicine, Baltimore, MD 21201, USA. 9InfecDetect Rapid Diagnostic Tests, LLC, Princeton, NJ 08540, USA. 10University of Michigan Medical School, Ann Arbor, MI 48109, USA. 11University of Chicago, Chicago, IL 60637, USA. 12Northern Arizona University, Downloaded from www.sciencemag.org on January 31, 2012 Flagstaff, AZ 86011, and Translational Genomics Research Institute, Phoenix, AZ 85004, USA. 13University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. 14Tufts University School of Medicine, Boston, MA 02111, USA. 15The Robert Wood Johnson Foundation, Princeton, NJ 08540, USA. 16University of California–Los Angeles, Los Angeles, CA 90095, USA. 17Virginia Polytechnic Institute and State University–Virginia Tech Research Center, Arlington VA 22203, USA. 18 GE Healthcare, Princeton, NJ 08540, USA. 19University of Minnesota, Minneapolis, MN 55455, USA. 20Stanford University School of Medicine, Stanford, CA 94305, USA. 21Center for Food Security and Public Health, Iowa State University, Ames, IA 50011, USA. 22University of Nebraska, Lincoln, NE 68588, USA. *The authors are members of the U.S. National Science Advisory Board for Biosecurity. †To whom correspondence should be addressed. E-mail: Paul.Keim@nau.edu Members of the National Science Advisory Board for used for good or bad purposes. We are now confronted by a Biosecurity explain its recommendations on the potent, real-world example. communication of experimental work on H5N1 influenza. Highly pathogenic avian influenza A/H5N1 infection of humans has been a serious public health concern since its We are in the midst of a revolutionary period in the life identification in 1997 in Asia. This virus rarely infects sciences. Technological capabilities have dramatically humans, but when it does, it causes severe disease with case expanded, we have a much improved understanding of the fatality rates of 59% (4). To date, the transmission of complex biology of selected microorganisms, and we have a influenza A/H5N1 virus from human to human has been rare, much improved ability to manipulate microbial genomes. and no human pandemic has occurred. If influenza A/H5N1 With this has come unprecedented potential for better control virus acquired the capacity for human-to-human spread and of infectious diseases and significant societal benefit. retained its current virulence, we could face an epidemic of However, there is also a growing risk that the same science substantial proportions. Historically, epidemics or pandemics will be deliberately misused and that the consequences could with high mortalities have been documented when humans be catastrophic. Efforts to describe or define life-sciences interact with new agents for which they have no immunity, research of particular concern have focused on the possibility such as with Yersinia pestis (plague) in the Middle Ages and that knowledge or products derived from such research, or the introduction of smallpox and measles into the Americas new technologies, could be directly misapplied with a after the arrival of Europeans. sufficiently broad scope to affect national or global security. Recently, several scientific research teams have achieved Research that might greatly enhance the harm caused by some success in isolating influenza A/H5N1 viruses that are microbial pathogens has been of special concern (1–3). Until transmitted efficiently between mammals, in one instance now, these efforts have suffered from a lack of specificity and with maintenance of high pathogenicity. This information is a paucity of concrete examples of “dual use research of very important because, before these experiments were done, concern” (3). Dual use is defined as research that could be it was uncertain whether avian influenza A/H5N1 could ever acquire the capacity for mammal-to-mammal transmission. / www.sciencexpress.org / 31 January 2012 / Page 1/ 10.1126/science.1217994

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62 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA Now that this information is known, society can take steps mammal-adapted influenza A/H5N1 viruses for harmful globally to prepare for when nature might generate such a purposes. We believe that as scientists and as members of the virus spontaneously. At the same time, these scientific results general public, we have a primary responsibility “to do no also represent a grave concern for global biosecurity, harm” as well as to act prudently and with some humility as biosafety, and public health. Could this knowledge, in the we consider the immense power of the life sciences to create hands of malevolent individuals, organizations, or microbes with novel and unusually consequential properties. governments, allow construction of a genetically altered At the same time, we acknowledge that there are clear influenza virus capable of causing a pandemic with mortality benefits to be realized for the public good in alerting exceeding that of the “Spanish flu” epidemic of 1918? The humanity of this potential threat and in pursuing those aspects research teams that performed this work did so in a well- of this work that will allow greater preparedness and the intended effort to discover evolutionary routes by which potential development of novel strategies leading to future avian influenza A/H5N1 viruses might adapt to humans. Such disease control. By recommending that the basic result be knowledge may be valuable for improving the public health communicated without methods or details, we believe that the response to a looming natural threat. And, to their credit and benefits to society are maximized and the risks minimized. that of the peer reviewers selected by the journals Science and Although scientists pride themselves on the creation of Nature, the journals themselves, as well as the U.S. scientific literature that defines careful methodology that Downloaded from www.sciencemag.org on January 31, 2012 government, it was recognized before their publication that would allow other scientists to replicate experiments, we do these experiments had dual use of concern potential. not believe that widespread dissemination of the methodology The U.S. government asked National Science Advisory in this case is a responsible action. Board for Biosecurity (NSABB) (5), to assess the dual-use The life sciences have reached a crossroads. The direction research implications of two as-yet-unpublished manuscripts we choose and the process by which we arrive at this decision on the avian influenza A/H5N1 virus, to consider the risks must be undertaken as a community and not relegated to and benefits of communicating the research results, and to small segments of government, the scientific community, or provide findings and recommendations regarding the society. Physicists faced a similar situation in the 1940s with responsible communication of this research. nuclear weapons research, and it is inevitable that other Risk assessment of public harm is challenging because it scientific disciplines will also do so. necessitates consideration of the intent and capability of those Along with our recommendation to restrict communication who wish to do harm, as well as the vulnerability of the of these particular scientific results, we discussed the need for public and the status of public health preparedness for both a rapid and broad international discussion of dual-use deliberate and accidental events. We found the potential risk research policy concerning influenza A/H5N1 virus with the of public harm to be of unusually high magnitude. In goal of developing a consensus on the path forward. There is formulating our recommendations to the government, no doubt that this is a complex endeavor that will require scientific journals, and the broader scientific community, we diligent and nuanced consideration. There are many important tried to balance the great risks against the benefits that could stakeholders whose opinions need to be heard at this juncture. come from making the details of this research known. This must be done quickly and with the full participation of Because the NSABB found that there was significant multiple societal components. potential for harm in fully publishing these results and that We are aware that the continuing circulation of the highly the harm exceeded the benefits of publication, we therefore pathogenic avian influenza A/H5N1 virus in Eurasia—where recommended that the work not be fully communicated in an it is constantly found to cause disease in animals of particular open forum. The NSABB was unanimous that regions—constitutes a continuing threat to humankind. A communication of the results in the two manuscripts it pandemic, or the deliberate release of a transmissible highly reviewed should be greatly limited in terms of the pathogenic influenza A/H5N1 virus, would be an experimental details and results. unimaginable catastrophe for which the world is currently This is an unprecedented recommendation for work in the inadequately prepared. It is urgent to establish how best to life sciences, and our analysis was conducted with careful facilitate the much-needed research as well as minimize consideration both of the potential benefits of publication and potential dual use. of the potential harm that could occur from such a precedent. To facilitate and motivate this process, we also discussed Our concern is that publishing these experiments in detail the possibility of the scientific community participating in a would provide information to some person, organization, or self-imposed moratorium on the broad communication of the government that would help them to develop similar results of experiments that show greatly enhanced virulence / www.sciencexpress.org / 31 January 2012 / Page 2/ 10.1126/science.1217994

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APPENDIX B 63 or transmissibility of such potentially dangerous microbes as the influenza A/H5N1 virus. until consensus is reached on the balance that must be struck between academic freedom and protecting the greater good of humankind from potential danger. With proper diligence and rapid achievement of a consensus on a proper path forward, this could have little detrimental effect on scientific progress but significant effect on diminishing risk. There are many parallels with the situation in the 1970s and recombinant DNA technologies (6–8). The Asilomar Conference in California in 1975 was a landmark meeting important to the identification, evaluation, and mitigation of risks posed by recombinant DNA technologies. In that case, the research community voluntarily imposed a temporary moratorium on the conduct of recombinant DNA research until they could develop guidance for the safe and responsible Downloaded from www.sciencemag.org on January 31, 2012 conduct of such research. We believe that this is another Asilomar-type moment for public health and infectious- disease research that urgently needs our attention. References 1. National Research Council, Biotechnology Research in an Age of Terrorism (National Academies Press, Washington, DC, 2004); www.nap.edu/catalog.php?record_id=10827. 2. National Research Council, Globalization, Biosecurity, and the Future of the Life Sciences (National Academies Press, Washington, DC, 2006); www.nap.edu/catalog.php?record_id=11567. 3. NSABB, Strategic Plan for Outreach and Education on Dual Use Research Issues (NSABB, NIH, Bethesda, MD, 2008); http://oba.od.nih.gov/biosecurity/PDF/FinalNSABBReport onOutreachandEducationDec102008.pdf. 4. World Health Organization, Confirmed human cases of H5N1 2003–2012; www.who.int/influenza/human_animal_interface/EN_GIP _20120116CumulativeNumberH5N1cases.pdf. 5. Office of Biotechnology Activities, About NSABB, http://oba.od.nih.gov/biosecurity/about_nsabb.html. 6. M. Singer, D. Soll, Science 181, 1114 (1973). 7. P. Berg, D. Baltimore, S. Brenner, R. O. Roblin, M. F. Singer, Proc. Natl. Acad. Sci. U.S.A. 72, 1981 (1975). 8. M. Singer, P. Berg, Science 193, 186 (1976). 9. R. G. Webster (St. Jude Children's Research Hospital, Memphis, TN) and J. W. Curran (Emory University, Atlanta GA) contributed substantially to the content of this Policy Forum. Published online 31 January 2012; 10.1126/science.1217994 Comment on this article at http://scim.ag/yZJTt9 / www.sciencexpress.org / 31 January 2012 / Page 3/ 10.1126/science.1217994

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64 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA Report on technical consultation on H5N1 research issues Geneva, 16–17 February 2012 Context Approximately 60% of persons known to have been infected by the avian influenza A(H5N1) virus have died from their illness. To date, most known human infections have occurred through contact with, or exposure to, infected birds. The prospect that H5N1 viruses circulating in nature might evolve and acquire the ability to spread with ease from person to person is a serious public health concern. Research on the genetic basis of the transmissibility of H5N1 by two groups (one in the Netherlands and the other a joint Japan/USA group) resulted in laboratory-modified H5N1 viruses capable of respiratory transmission between ferrets. These mammals are often used in influenza research because, in some respects, ferret influenza infection shows similarities to human influenza infection. The results of these two studies demonstrate that relatively few genetic changes in H5N1 viruses can enable transmission via the respiratory route in these animals, and, in turn, suggest that H5N1 viruses could become more easily transmissible from person to person. The findings suggest that such changes could occur in nature, but do not provide an estimate of the likelihood that they will occur. During the autumn of 2011, after manuscripts describing the research studies and their findings were submitted to scientific journals, the papers were reviewed by the National Science Advisory Board for Biosecurity (NSABB) in the United States, which recommended against publishing some details of the work. Specifically, the NSABB recommended publishing the general conclusions, without details of the research methods used or the specific mutations, to reduce the possibility that anyone seeking to do harm could replicate the experiments. On January 20, 2012, the researchers who conducted this work and some other research groups announced a 60-day voluntary research moratorium to allow time for organizations and governments to “find the best solutions for opportunities and challenges that stem from the work”. The scientific journals to which the papers had been submitted for publication also voluntarily deferred publication. In light of the global relevance of these issues, WHO convened a preliminary technical consultation on 16–17 February 2012. The purpose was to clarify key facts about the studies and to address the most urgent issues concerning the management of these laboratory-modified viruses, and how access to and dissemination of any findings should be handled. Twenty-two participants1 were invited, including those with direct involvement in, or knowledge of, the content, oversight, or potential dissemination of this work. Representatives from countries where H5N1 is currently circulating were also present. Participants reviewed the chronology of the transfer of the H5N1 viruses used in the research studies, from country of origin to the research laboratories; the associated agreements regarding use of the samples; how the research proposals were reviewed; and the oversight of the work. Under conditions of stringent security, they read the full and redacted versions of both unpublished research reports, and also heard brief presentations by the researchers, summarizing their work. Further, the participants were asked to recognize that while this research had elicited important scientific and social concerns from a number of different perspectives, the purpose of this meeting was not to debate these broader perspectives, but to find See http://www.who.int/influenza/human_animal_interface/list_participants/en/index.html for the full list of participants.

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APPENDIX B 65 practical, feasible, ad hoc solutions to the questions of access to research findings and management of the laboratory-modifed viruses. Overview of the research findings The studies indicated that different experimental methods can generate viable H5N1 or other influenza viruses with certain H5 characteristics, which demonstrate increased transmissibility in ferrets. In each study, the increase in capacity for transmission by the respiratory route was associated with a group of specific mutations, although these differed between the two studies. Both studies were essentially proof-of-principle experiments, and thus were not designed to elucidate the pathogenicity or degree of transmissibility of the laboratory-modified viruses. It was noted that the research methods used in these studies are not novel and are widely used in biomedical research. Participants agreed on the public health value of the data on genetic modifications for improving the existing surveillance performed by both the human public health and animal health sectors, so as to monitor for variants that may be indicative of important changes among circulating H5N1 viruses. The findings of these studies provide a valuable complement to the accumulating data on virus evolution occurring in nature, and to ongoing analyses of in-host pathogen evolutionary dynamics. Participants noted that the research findings had to be considered within a social context. The studies had raised concerns about the potential misuse of the viruses and the research findings. The participants also noted that, if disseminated to the public health and scientific community, the results would offer significant benefits to global health. Specifically, the findings could be used to improve the sensitivity of public health surveillance, facilitate the early detection of potentially pandemic H5N1 strains, and might aid the development of vaccines and the assessment of the potential value of other countermeasures. Overview of options discussed Several issues relating to publication were considered: • If the research were to be published in redacted form, would genetic sequence data and/or the research methods remain completely restricted, or should the information be made available to a limited audience, after a public health justification for use of the information? • If the latter, what workable mechanism would allow selective access to this information by laboratories involved in public health surveillance and legitimate research? • What criteria would be required for access, and which organization would exercise governance over access? • How could dissemination to those permitted access be performed securely? • Could the confidentiality of the information be maintained? On the question of limiting access to the results through publication of redacted versions, some participants observed that there was no current practical mechanism to limit access. Further, it would not be difficult for knowledgeable scientists to determine the information that had been removed, as novel methods had not been used. Limiting access to those with a need for the information would pose insurmountable practical problems. Chief among these problems are the development and implementation of a mechanism to disseminate the information to diverse and geographically distributed groups while maintaining the confidentiality of the detail. Therefore, such a mechanism would not realistically resolve concerns about dual-use research. There may be benefit in creating such a mechanism to deal with other dual-use research information in the future. However, this will require thorough consideration of and international agreement on practical issues such as security, access requirements, governance, and liability.

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70 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA 2 health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security 1. 2) “Life sciences” pertains to living organisms (e.g., microbes, human beings, animals, and plants) and their products, including all disciplines and methodologies of biology such as aerobiology, agricultural science, plant science, animal science, bioinformatics, genomics, proteomics, synthetic biology, environmental science, public health, modeling, engineering of living systems, and all applications of the biological sciences. The term is meant to encompass the diverse approaches for understanding life at the level of ecosystems, organisms, organs, tissues, cells, and molecules. 3) Extramural research is that which is funded by a department or agency under a grant, contract, cooperative agreement, or other agreement and not conducted directly by the department or agency. 4) Intramural research is that which is directly conducted by a department or agency. Section III: Scope Under this Policy, review will focus on research that involves one or more of the agents or toxins listed in Section (III.1) below, which pose the greatest risk of deliberate misuse with most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence, and produces, aims to produce, or is reasonably anticipated to produce one or more of the effects listed in Section (III.2) below: 1) Agents and toxins 2: a) Avian influenza virus (highly pathogenic) b) Bacillus anthracis c) Botulinum neurotoxin d) Burkholderia mallei e) Burkholderia pseudomallei f) Ebola virus g) Foot-and-mouth disease virus h) Francisella tularensis i) Marburg virus j) Reconstructed 1918 Influenza virus k) Rinderpest virus l) Toxin-producing strains of Clostridium botulinum m) Variola major virus n) Variola minor virus o) Yersinia pestis 2) Categories of experiments: a) Enhances the harmful consequences of the agent or toxin; b) Disrupts immunity or the effectiveness of an immunization against the agent or toxin without clinical or agricultural justification; c) Confers to the agent or toxin resistance to clinically or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies; d) Increases the stability, transmissibility, or the ability to disseminate the agent or toxin; e) Alters the host range or tropism of the agent or toxin; 1 This definition of DURC is derived from the NSABB definition, but is modified for purposes of this Policy. 2 These agents and toxins are regulated by the Select Agent Program under Federal Law (7 C.F.R. part 331, 9 C.F.R. part 121, and 42 C.F.R. part 73), and have the potential to pose a severe threat to human, animal, or plant health, or to animal and plant products.

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APPENDIX B 71 3 f) Enhances the susceptibility of a host population to the agent or toxin; or g) Generates or reconstitutes an eradicated or extinct agent or toxin listed in Section (III.1) above. Section IV: Department and Agency Responsibilities 1) Federal departments and agencies that conduct or fund life sciences research should implement the following actions: a) Conduct a review to identify all current or proposed, unclassified intramural or extramural, life sciences research projects that fall within the scope of Section III. This review will include, at a minimum, initial proposals and any progress reports. b) Determine which, if any, of the projects identified in Section (IV.1.a) meet the definition of DURC in Section (II.1) of this document. c) Assess the risks and benefits of such projects, including how research methodologies may generate risks and/or whether open access to the knowledge, information, products, or technologies generates risk. d) Based on the risk assessment, in collaboration with the institution or researcher, develop a risk mitigation plan to apply any necessary and appropriate risk mitigation measures. In addition: i) For DURC that is proposed and not yet funded, departments and agencies will assess whether to incorporate risk mitigation measures in the grant, contract, or agreement. ii) For currently funded DURC, funding departments and agencies will consider modifying the grant, contract, or agreement to incorporate risk mitigation measures. If such modifications are not possible or desirable, departments and agencies will seek voluntary implementation of mitigation measures by the institution. e) A risk mitigation plan may include, but not be limited to, the following risk mitigation measures: i) Modifying the design or conduct of the research. ii) Applying specific or enhanced biosecurity or biosafety measures. iii) Evaluating existing evidence of medical countermeasures (MCM) efficacy, or conducting experiments to determine MCM efficacy against agents or toxins resulting from DURC, and where effective MCM exist, including that information in publications. iv) Referring the institution to available DURC educational tools such as: http://oba.od.nih.gov/biosecurity/biosecurity.html v) Regularly reviewing, at the institutional level, emerging research findings for additional DURC. vi) Requesting that institutions notify funding departments or agencies if additional DURC is identified, and propose modifications to the risk mitigation plan, as needed. vii) Determining the venue and mode of communication (addressing content, timing, and possibly the extent of distribution of the information) to communicate the research responsibly. viii) Reviewing annual progress reports from Principal Investigators to determine if DURC results have been generated, and if so, flagging them for institutional attention and applying potential mitigation measures as described above, as necessary. ix) If the risks posed by the research cannot be adequately mitigated with the measures above, Federal departments and agencies will determine whether it is appropriate to: (a) Request voluntary redaction of the research publications or communications 3; (b) Classify the research: (i) In accordance with National Security Decision Directive/NSDD-189, departments and agencies will make classification determinations within 3 Actions taken to restrict the publication of technology may have implications under export control laws and regulations (e.g., 15 CFR parts 730-774 and 22 CFR parts 120-130).

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72 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA 4 the scope of their classification authorities and appropriate classification guidelines or may consult with other departments and agencies to make these determinations. (ii) Departments and agencies may consider whether to refer classified research to another department or agency for funding. (c) Not provide or terminate research funding. 2) Federal departments and agencies are requested to report the following to the Assistant to the President for Homeland Security and Counterterrorism: a) Within 60 days of issuance of this Policy, the following results of the review conducted in response to Section (IV.1.a): i) Aggregate number of current and proposed unclassified, intramural, and extramural research projects identified that include work with one or more of the agents and toxins in Section (III.1). ii) Aggregate number of current and proposed unclassified, intramural, and extramural research projects that include work with one or more of the agents and toxins in Section (III.1) and produces, aims to produce, or are reasonably anticipated to produce one or more of the effects listed in Section (III.2). b) Within 90 days of issuance of this Policy, the following results of the review conducted in response to Sections (IV.1. b. c. and d): i) Number of unclassified current and proposed DURC projects. 4 ii) Number of current projects identified as DURC through initial proposals versus progress reports.5 iii) Summary of risks, mitigation measures already in place that address those risks, any additional mitigation measures that have been proposed or implemented, and number of projects to which each mitigation measure would be applied. 3) Following completion of the reporting requirements in Section (IV.2), Federal departments and agencies are requested to submit periodic reports on items in Section (IV.2.a. and b) biannually. 4) Federal departments and agencies should implement Section IV in accordance with their relevant and applicable authorities, regulations, and statutes. 5) For additional guidance on how to conduct the risk assessment identified in Section (IV. 1.c), departments and agencies may refer to the “Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information,” which identifies useful assessment tools and is available at: http://oba.od.nih.gov/biosecurity/biosecurity_documents.html . Section V: Consultation As necessary and appropriate, the United States Government will continue to consult with the NSABB (in compliance with provisions of the Federal Advisory Committee Act) or convene the Countering Biological Threats Interagency Policy Committee for guidance on matters relating to the review and conduct of DURC and the mitigation of DURC risks. 4,5 Report the number of projects by agent and/or toxin plus the category of experiment.

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APPENDIX B 73 National Science Advisory Board for Biosecurity Findings and Recommendations March 29‐30, 2012 Summary On March 29‐30, 2012, the National Science Advisory Board for Biosecurity (NSABB or Board) convened to examine two revised manuscripts regarding the transmissibility of highly pathogenic avian influenza A virus H5N1 (H5N1) in ferrets. After careful deliberation, the NSABB unanimously recommended that the revised manuscript submitted by Dr. Yoshihiro Kawaoka be communicated in full. The NSABB also recommended, in a 12‐to‐6 decision, that the data, methods, and conclusions presented in the revised manuscript submitted by Dr. Ron Fouchier be communicated after appropriate scientific review and revision. Background In the Fall of 2011, the NSABB reviewed manuscripts from Dr. Ron Fouchier, Erasmus Medical Center, and Dr. Yoshihiro Kawaoka, the University of Wisconsin, reporting the transmissibility of H5N1 in mammals. The manuscripts, submitted for publication in Science and Nature respectively, described the generation of mutations in H5N1 that enable the airborne transmission of the virus between ferrets. Ferrets are commonly used as an animal model for influenza transmissibility in humans. At that time, the Board recognized the importance of the research in advancing knowledge of influenza transmission and supporting public health efforts. Specifically, the Board recognized that the experiments confirmed that H5N1 had the potential to become mammalian transmissible and thus posed a threat of a future pandemic. This information was significant because until then it had been uncertain whether this virus had the evolutionary capacity to adapt to mammalian transmissibility. The Board understood, however, that the specific findings would enable others to synthesize and express an H5N1 strain with mammal‐ to‐mammal airborne transmissibility, and thus it had significant concerns that the information in the manuscripts could be misused to endanger public health and national security. Given these dual use concerns,1 the Board recommended that the information in these manuscripts be published in a redacted form with the omission of certain details that could enable the direct misuse of the research by those with malevolent intent. The goal was to deliver the critical information about the H5N1 potential for pandemic spread while minimizing the possible risk that the information could be used for nefarious purposes. In February 2012, the World Health Organization (WHO) convened a technical consultation to “clarify key facts about the studies and to address the most urgent issues concerning the management of these laboratory‐modified viruses, and how access to and dissemination of any findings should be handled.”2 At this meeting, additional non‐public data were presented and discussed, and key clarifications were made by the authors, who subsequently revised the manuscripts. In light of this, the United States Department of Health and Human Services convened the NSABB in a closed session March 29‐30, 2012, to review the newly revised manuscripts and to recommend whether and/or how the information 1 In the Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research information, the NSABB defined “dual use research” as “[r]esearch yielding new technologies or information with the potential for both benevolent and malevolent applications." 2 WHO Report on Technical Consultation on H5N1 Research Issues http://www.who.int/influenza/human_animal_interface/mtg_report_h5n1.pdf 1

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74 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA should be communicated. Taking into account the additional information in the revised manuscripts, new non‐public epidemiological information, and security information to be presented in a classified briefing, the NSABB was charged with:  Assessing the dual use research implications of two unpublished, revised manuscripts on the transmissibility of highly pathogenic avian influenza A virus H5N1;  Considering the risks and benefits of communicating the research results; and  Developing findings and recommendations regarding whether the information should be communicated, and if so, to what extent. NSABB Approach On March 29‐30, 2012, the NSABB members read the revised copies of the manuscripts, heard presentations, and discussed the findings with the authors. The Board also engaged public health officials, influenza experts, journal editors, security experts, and individuals involved in the oversight of H5N1 research both from the United States and from the international communities. The Board’s discussions were informed by the analytical frameworks3 that it previously developed for considering the risks and benefits associated with the communication of dual use research of concern.4 Findings The NSABB strongly supports the unrestricted communication of research information unless that information could be directly misused to pose a significant and near‐term risk to public health and safety or if the risks associated with misuse of the information are so significant that no amount of potential benefits can justify the risks. The Board concluded that the communication of the information in these revised manuscripts still presents dual use research concerns. The risks and benefits associated with communicating, or not communicating, these findings were considered in light of additional information and key clarifications. The majority of the members of the NSABB concluded that:  The data are not immediately enabling. As currently written, the revised manuscripts do not appear to provide information that would enable the near‐term misuse of the research in ways that would endanger public health or national security. The mutations described in the manuscripts do not appear to result in H5N1 viruses that are both highly pathogenic and transmissible between ferrets through the air. The Board emphasized that if additional information were included that would enable the construction of an H5N1 virus that was both highly pathogenic and transmissible between mammals through the air, then the information in the manuscripts would have more implications for misuse and would require additional consideration regarding communication. 3 www.biosecurityboard.gov, see the Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information in the NSABB Documents link. 4 In the Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information, the NSABB defined “dual use research of concern” 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.” 2

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APPENDIX B 75  These data may benefit public health and surveillance efforts. New information regarding epidemiology and the natural evolution of the virus in the field has emerged that underscores the fact that understanding specific mutations and the biologic properties associated with these mutations may improve international surveillance and public health efforts. While more research needs to be conducted to validate these ideas, potential public health benefits may include enhanced surveillance of viruses in birds and humans and other mammals (e.g., possible reassortment viruses in pigs) and improved risk assessment of circulating strains. The information in the manuscripts also may help inform public health decisions regarding pandemic preparedness (e.g., maintenance or strengthening of vaccine stockpiles and strain selection for vaccine development). The revised manuscripts provided a greater appreciation of the direct applicability of the information to ongoing and future influenza surveillance efforts.  Global cooperation is essential for pandemic influenza preparedness. The Board recognizes that international cooperation is critical to ensuring public health and safety on a global scale and that such cooperation is predicated upon the free exchange of information. The Board’s discussions underscored the risks associated with not sharing the information, which could jeopardize pandemic influenza preparedness efforts. Specifically, there was concern that the United States would be perceived as redacting information with potential public health benefits and that this could undermine valuable international collaborations. The information in these manuscripts will help public health officials prepare for influenza outbreaks in parts of the world where the virus is endemic.  The research was conducted under appropriate conditions. The NSABB noted during its review of the initial and revised manuscripts that both studies were conducted under rigorous biosafety conditions, including appropriate biosafety containment, practices, training, and occupational‐ health programs. Because the research involved the use of a select agent, the research also was conducted under the oversight of the Select Agent Program, including periodic inspection of the facilities and biosecurity review by the United States Centers for Disease Control and Prevention (CDC) and/or the United States Department of Agriculture (USDA). However, the Board recognized that biosafety requirements might be different if the engineered viruses had greatly altered properties. A review of the biosafety regulations would be prudent, should be performed by qualified professionals, and should be based upon a risk assessment of the work environment and the altered viruses.  There is an urgent need for effective United States and international policies for the oversight and communication of dual use research of concern. The NSABB has noted previously that it is important that dual use research issues are identified and managed early in the research process rather than after the research has been conducted, let alone when a manuscript is ready for publication. The newly released United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern5 was based upon this principle and the urgency of the recent deliberations. This policy applies to life sciences research funded by the United States and will ensure that dual use concerns are addressed during the evaluation of ongoing and 5 http://oba.od.nih.gov/oba/biosecurity/PDF/United_States_Government_Policy_for_Oversight_of_DURC_FINAL_v ersion_032812.pdf 3

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76 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA future federally funded research on H5N1 influenza virus. The Board’s discussion was informed by this new policy initiative. The Board also noted the need for guidelines to aid in the determination of how/whether certain types of “gain‐of‐function” experiments with influenza should be conducted or communicated. These two H5N1 studies both used well‐known techniques to change the mode of transmission of H5N1 avian influenza virus from fecal‐oral to respiratory and from avian‐avian transmission to mammal‐mammal transmission. Further gain‐of‐function experiments of this type are likely to be contemplated by these and other laboratories around the world. Experiments that change the mode of transmission or host range of a zoonotic agent are of particular concern and require detailed analyses of risks and benefits before they are conducted or communicated. At the present time, no specific guidelines exist to aid in these analyses for future studies of influenza virus. Since scientific research and protecting public health are global endeavors, the Board urges the U.S. Government to closely engage the international community during the policy‐development process so that scientific information can be shared between and among appropriate global partners. To this end, the Board will soon consider the findings and recommendations of its Working Group on Global Engagement, which has been charged with addressing the communication and other challenges presented by H5N1 dual use research of concern, challenges that are inherently international in scope.  There is a critical need for a mechanism for disseminating sensitive scientific information. There remains a pressing need for an effective and feasible mechanism to provide controlled access to scientific information that has potential public health benefits but poses a significant risk for misuse if broadly disseminated. There are complex questions involved in developing such a mechanism, many of them legal issues. Nonetheless, a feasible, secure mechanism for sharing sensitive scientific information with individuals who have a legitimate need to know in order to support public health, safety, and security efforts is essential. In contrast, a minority of members of NSABB concluded that:  The data in the newly‐revised Fouchier manuscript are immediately and directly enabling. As currently written, the revised Fouchier manuscript provides information that would enable the near‐term misuse of the research in ways that would endanger public health or national security. The mutations described in this manuscript appear to result in modified H5N1 viruses that are transmissible between ferrets by respiratory route, as claimed by the authors, and in modified viruses that appear to be as pathogenic as the parental H5N1 strain, which in nature is known to be highly pathogenic in humans. The data in the Kawaoka paper, however, are less immediately and directly enabling because the approach involved the use of less virulent viral strains.  While the data in the two manuscripts may benefit public health and surveillance efforts, these data may not be directly relevant or immediately helpful to the current public health or surveillance infrastructure. The evolutionary paths taken by naturally occurring H5N1 viruses may not be similar to those selected under these laboratory conditions. The relevance of the laboratory‐derived mutations and their meaning for the evolution of H5N1 viruses in natural environments are unclear. Excessive attention to these mutations may in fact distract 4

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APPENDIX B 77 surveillance efforts from what might be the naturally occurring mutations of greater interest. Furthermore, the current surveillance infrastructure is ill‐equipped to detect the emergence of highly transmissible influenza viruses in real‐time prior to their dissemination in nature. While there may be benefits to the dissemination of the mutation data in the Fouchier manuscript and global cooperation is essential for pandemic influenza preparedness, it is unlikely that the benefits will be fully realized in the near‐term. These Board members agreed with the rest of the Board about the general importance of global cooperation, the urgent need for effective policies for the oversight and communication of dual use research of concern, and the critical need for a mechanism for disseminating sensitive scientific information. Recommendations The Board considered the manuscripts separately and after careful deliberation made the following recommendations:  The revised Kawaoka manuscript should be communicated in full. The NSABB unanimously recommended the full communication of this revised manuscript.  The data, methods, and conclusions presented in the revised Fouchier manuscript should be communicated, but not as currently written. In a 12‐to‐6 decision, the NSABB recommended communicating the data, methods, and conclusions presented in this revised manuscript. However, the Board identified a number of scientific clarifications that should be made prior to publication of the manuscript. Importantly, the Board also noted that additional information that would enable the construction of an H5N1 virus that is both highly pathogenic and transmissible between mammals through the air should not be included in the manuscript. Such information could conceivably be directly misused to threaten public health or national security and additional considerations regarding communication would be necessary. Six of the 18 voting members felt that the data, methods, and conclusions presented in the revised Fouchier manuscript should not be communicated.  The U.S. Government should continue to develop national, and participate in the development of international, policies for the oversight and communication of dual use research of concern. The newly released United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern is an important first step in ensuring that dual use concerns associated with federally funded life sciences research will be addressed and managed early in and continuously during the research process. This policy will apply to H5N1 research as well as other agents and toxins that pose the greatest risk of misuse. In implementing this policy, the U.S. Government should monitor how effectively it facilitates the identification and timely management of dual use research of concern. However, it is essential that such oversight does not unduly burden or slow the progress of life sciences research. The oversight process should be periodically and robustly reviewed and modified as necessary to address these issues. The U.S. Government should also provide guidance on how to deal with “gain‐of‐function” studies that increase pathogenesis of zoonotic agents, particularly avian influenza viruses. Experiments that change the mode of transmission or host range of a zoonotic agent are of 5

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78 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA particular concern and require a detailed analysis of risks and benefits before they are conducted or communicated. Scientific research and protecting public health and safety are global endeavors. It is therefore critical that the U.S. Government continue to work with its international partners to develop, enforce and continually review consistent policies for the oversight of dual use research that enable the effective management and sharing of sensitive research information.  The U.S. Government should expeditiously develop a mechanism to provide controlled access to sensitive scientific information. The majority of the NSABB recommends that the information contained in these revised H5N1 manuscripts should be communicated in full, but the Board also recognizes that research findings will likely emerge in the very near future that should not be widely disseminated because of a high risk of misuse but that nevertheless should be made available to certain researchers and public health officials around the world who have a legitimate need to know. The need for an effective, practical, and feasible mechanism for selectively sharing sensitive scientific information has never been more apparent. In order to manage the risks posed by communicating future cases of dual use research of concern, the Board strongly urges the U.S. Government to develop in an expeditious manner a practical and secure mechanism for sharing sensitive scientific information in order to support public health, safety, and security efforts. 6

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APPENDIX B 79 Statement on NSABB's March 30, 2012 Recommendations to NIH on H5N1 Research April 14, 2012 On March 29-30, 2012, the National Science Advisory Board for Biosecurity (NSABB) was convened to examine two revised manuscripts regarding the transmissibility of the H5N1 avian flu virus in ferrets. The NSABB is an independent federal advisory committee chartered to provide advice and guidance to the Secretary of the Department of Health and Human Services, the Director of the National Institutes of Health, and all Federal entities that conduct, support, or have an interest in life sciences research regarding biosecurity oversight of dual use research, defined as biological research with legitimate scientific purpose that may be misused to pose a biologic threat to public health and/or national security. After careful deliberation, the NSABB unanimously recommended that the revised manuscript submitted by Dr. Yoshihiro Kawaoka be communicated in full. The NSABB also recommended, in a 12-to-6 decision, that the data, methods, and conclusions presented in the revised manuscript submitted by Dr. Ron Fouchier be communicated after appropriate further scientific review and revision. A final recommendation of these two revised manuscripts regarding the transmissibility of the H5N1 avian flu virus in ferrets will be made by the HHS Secretary and brought to the broader U.S. government. In addition, in their final recommendations submitted to NIH yesterday, the NSABB also made two other thoughtful recommendations about future approaches to the challenges presented by oversight of dual use research. Those recommendations are being carefully reviewed and considered. HHS will continue to work with scientific and national security experts, the public, and the international community regarding the long term recommendations on dual use research. I want to take this occasion to express my sincere gratitude to the NSABB members, who have worked tirelessly to study the issue carefully, hear directly from the experts, and weigh the benefits and risks of making the research data public. The full NSABB recommendations can be found at http://www.nih.gov/about/director/03302012_NSABB_Recommendations.pdf. (PDF - 268 KB) Francis S. Collins, M.D., Ph.D. Director, National Institutes of Health http://www.nih.gov/about/director/04142012_NSABB.htm 4/16/2012

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80 PERSPECTIVES ON RESEARCH WITH H5N1 AVIAN INFLUENZA Statement by NIH Director Francis Collins, M.D., Ph.D. on More Informatio the NSABB Review of Revised H5N1 Manuscripts Statement on NSABB' Recommendations to Research, April, 14 2 April 20, 2012 National Science Adv Biosecurity Findings a On March 29 and 30, the National Science Advisory Board for Biosecurity (NSABB), an independent expert Recommendations committee that advises the National Institutes of Health (NIH), the Department of Health and Human Services March 29-30, 2012 (HHS) and other Federal departments and agencies on matters of biosecurity, convened to review unpublished revised manuscripts describing NIH-funded research on the transmissibility of H5N1 influenza virus—the strain Press Statement: Mee commonly referred to as "bird flu." One manuscript, “Aerosol transmission of avian influenza A/H5N1 virus,” to Review Manuscript Transmissibility Rese contained research findings by Dr. Ron Fouchier. The other manuscript, “Haemagglutinin mutations that confer 2012 human-type receptor recognition and support respiratory droplet transmission of H5N1 influenza A virus in ferrets,” contained research findings by Dr. Yoshihiro Kawaoka. To clarify the results of their research findings, NIH Statement on H5 both authors revised their manuscripts from versions reviewed earlier by the NSABB. The NSABB reviewed the Health Organization revised manuscripts to make recommendations as to whether, and if so how, they should be communicated. 17, 2012 NIH Statement on H5 This line of research is critically important because it will help public health officials understand, detect, and 2012 defend against the emergence of H5N1 virus as a human threat, a development that could pose a pandemic scenario. The value of this research notwithstanding, certain information obtained through such studies has the potential to be misused for harmful purposes—a characteristic associated with what is referred to as “dual use research of concern.” These particular manuscripts include the important finding that the H5N1 virus has greater potential than previously believed to gain the capacity to be transmitted among mammals, as assessed by experiments with ferrets. The manuscripts describe some of the genetic changes that appear to correlate with this potential. During its March meeting, the NSABB took into account the new and clarified information in the manuscripts, additional perspectives provided by influenza biology experts, highly pertinent but as yet unpublished epidemiologic data, and relevant security information. After careful deliberation, the NSABB unanimously recommended the revised manuscript by Dr. Yoshihiro Kawaoka be communicated in full. The NSABB also recommended, in a 12-to-6 decision, that the data, methods, and conclusions presented in the revised manuscript by Dr. Ron Fouchier be communicated fully after a number of further scientific clarifications are made in the manuscript. The recommendation to communicate the research was based on the observation that the information in the revised manuscripts has direct applicability to ongoing and future influenza surveillance efforts and does not appear to enable direct misuse of the research in ways that would endanger public health or national security. The HHS Secretary and I concur with the NSABB’s recommendation that the information in the two manuscripts should be communicated fully and we have conveyed our concurrence to the journals considering publication of the manuscripts. This information has clear value to national and international public health preparedness efforts and must be shared with those who are poised to realize the benefits of this research. The Secretary’s decision takes account of relevant U.S. law, international obligations, and a rigorous analysis of the benefits and risks of publication. The work in the Netherlands by Ron Fouchier is subject also to laws and regulations of the Netherlands, and the Dutch government is conducting its own review of Dr. Fouchier’s work. We respect that process and value the dialogue we have with Dutch authorities toward our common goals of encouraging scientific inquiry, advancing global health, and protecting the safety and security of our populations and the wider global community. In addition, the recently released Federal policy on dual use research of concern is an important step in enhancing the oversight of federally funded life sciences research going forward. Through implementation of this policy, the U.S. Government aims to preserve the benefits of vitally important life sciences research that holds the promise of enhancing quality of life for all of us, while minimizing the possibility that the knowledge, information, products, or technologies provided by such research could be misused for harm. Statement by the NSABB members for the time andM.D., they have dedicated to considering the complex Page 2 of 2 I am grateful to NIH Director Francis Collins, effort Ph.D. on the NSABB Review of Revis... issues pertinent to dual use research generally, and for working so tirelessly on developing the most thoughtful recommendations possible regarding these two manuscripts. Francis S. Collins, M.D., Ph.D. Director, National Institutes of Health http://www.nih.gov/about/director/04202012_NSABB.htm This page last reviewed on April 15, 2012 National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, Maryland 20892 NIH…Turning Discovery Into Health