1
The Select Agent Regulations

CHARGE TO THE COMMITTEE

In 2006, the National Science Advisory Board for Biosecurity (NSABB) released a report, Addressing Biosecurity Concerns Related to the Synthesis of Select Agents (NSABB 2006),” which considered the impact of synthetic biology and DNA synthesis technology on biosecurity and the current Select Agents Regulations (SAR). The principal concerns it addressed were that:

  • DNA synthesis technology is rapidly diminishing barriers to acquisition of pathogens, because an increasing variety of organisms may be instantiated by whole genome synthesis, rather than by transfer of samples of existing organism stocks or cultures;

  • Natural variation and intentional genetic modification blurs the boundaries around any discrete list based on taxonomic names; and

  • Synthetic biology may enable the accidental or deliberate creation of entirely novel pathogens unrelated to current ones.

The NSABB made four recommendations: (1) that the Department of Health and Human Services (DHHS) and the U.S. Department of Agriculture (USDA) clarify and harmonize guidance to investigators and synthetic DNA companies regarding genetic elements and nucleic acids subject to the Select Agent Regulations; (2) Synthetic DNA companies establish uniform and standardized policies to screen orders; (3) repeal 18 U.S.C. 175c, because current scientific insight precludes meaningful definition of an agent based solely on sequence homology; and (4) that two further studies be initiated. The first study would focus on reconciling the current Select Agent controls with advances in synthetic genomics (i.e., a new synthetic means of pathogen accessibility, other



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1 The Select Agent Regulations CHARGE TO THE COMMITTEE In 2006, the National Science Advisory Board for Biosecurity (NSABB) released a report, Addressing Biosecurity Concerns Related to the Synthesis of Select Agents (NSABB 2006),” which considered the impact of synthetic biol- ogy and DNA synthesis technology on biosecurity and the current Select Agents Regulations (SAR). The principal concerns it addressed were that: • DNA synthesis technology is rapidly diminishing barriers to acquisi- tion of pathogens, because an increasing variety of organisms may be instantiated by whole genome synthesis, rather than by transfer of samples of existing organism stocks or cultures; • Natural variation and intentional genetic modification blurs the bound- aries around any discrete list based on taxonomic names; and • Synthetic biology may enable the accidental or deliberate creation of entirely novel pathogens unrelated to current ones. The NSABB made four recommendations: (1) that the Department of Health and Human Services (DHHS) and the U.S. Department of Agriculture (USDA) clarify and harmonize guidance to investigators and synthetic DNA companies regarding genetic elements and nucleic acids subject to the Select Agent Regulations; (2) Synthetic DNA companies establish uniform and stan - dardized policies to screen orders; (3) repeal 18 U.S.C. 175c, because current scientific insight precludes meaningful definition of an agent based solely on sequence homology; and (4) that two further studies be initiated. The first study would focus on reconciling the current Select Agent controls with advances in synthetic genomics (i.e., a new synthetic means of pathogen accessibility, other 

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0 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS than by transfer of existing stocks or wild isolates). The second proposed study became the origin of our committee. This recommendation proposed that: . . . a group of experts from the scientific community be assembled to deter- mine if an alternative framework based on predicted features and properties encoded by nucleic acids, such as virulence or pathogenicity, can be developed and utilized in lieu of the current finite list of specific agents and taxonomic definitions . . . (NSABB 2006). Thus, this study was initiated with the title of “Scientific Milestones for the Development of a Gene Sequence-Based Classification System for Oversight of Select Agents” on the basis of this recommendation. The committee was specifically charged with identifying: . . . the scientific advances that would be necessary to permit serious consid- eration of developing and implementing an oversight system for Select Agents that is based on predicted features and properties encoded by nucleic acids rather than a relatively static list of specific agents and taxonomic definitions (see Box 1.1 or Appendix A). BOX 1.1 Scientific Milestones for the Development of a Gene Sequence-Based Classification System for Oversight of Select Agents Statement of Task NIH has requested the National Research Council to convene an ad hoc commit- tee to identify the scientific advances that would be necessary to permit serious consideration of developing and implementing an oversight system for Select Agents that is based on predicted features and properties encoded by nucleic acids rather than a relatively static list of specific agents and taxonomic defini- tions. The committee is asked to address several questions: • What would be the key scientific attributes of a predictive oversight system? • What are the challenges in attempting to predict biological characteristics from sequence? • Does the current state of the science of predicting function from sequence support a predictive oversight system at this time? • If not, what are the scientific milestones that would need to be realized before a predictive oversight system might be feasible? • In qualitative terms, what level of certainty would be needed about the ability to predict biological characteristics from sequence data in order to have confidence in a predictive oversight system? • In what time frame might these milestones be realized? What kinds of studies are needed to achieve these milestones?

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 THE SELECT AGENT REGULATIONS ORGANIZATION OF THE REPORT In order to think about what an alternative framework for Select Agents might look like in an era of genomics and DNA synthesis, Chapter 1 starts by presenting the rationale for and status of the current system. This chapter also discusses the consequences of the Select Agent Regulations on the gene synthe - sis industry and the research community, and the criteria that are considered when Select Agent status is determined. (Appendices for this chapter provide information regarding the Select Agent Regulations and related guidelines.) Chapter 2 presents the complexity of biology, the challenges in predicting function from sequence, and the special case of synthetic biology. (Appendi - ces for this chapter contain detailed information regarding the challenges in predicting pathogenicity from sequence, and include examples of “virulence factors” from known pathogens.) Chapter 3 explains how prediction differs from classification, outlines three threat scenarios presented by synthetic genomics, and describes how—with current technologies—a sequence based classification system might be created to address the challenges that synthetic biology and natural variation present to biosecurity. Chapter 4 summarizes key findings and conclusions, and provides near term milestones and long term areas of research that would enable a sequence based classification framework for biosecurity and biosafety. (Appendix L for this chapter presents additional milestones and issues for consideration regard - ing the development of a gene sequence based classification system.) CONTEXT OF THE SELECT AGENT REGULATIONS During the committee’s deliberations, the issues of biological weapons, biosecurity, and biosafety were each considered relevant to addressing the charge. The Select Agent Regulations, the NIH Guidelines, and the implement- ing legislation for the BWC define conditions for the legitimate, safe, and secure use of biological agents that have the potential to be used for great harm. It is important that research be conducted on microbes including those that may cause disease; biosafety rules are needed to protect the environment and the health of clinicians, researchers and the public and are therefore a necessity— even in the absence of terrorism or other security threats. As will be discussed, the biosafety system that has been in place for decades provides a framework of oversight for legitimate use of pathogenic microorganisms. The BWC, and implementing legislation,1 is concerned with illegitimate use of biological agents (i.e., as weapons). The Select Agent Regulations identify agents most likely 1 The 1989 Biological Weapons Act is the implementing legislation for the BWC. Title 18 US, Chapter 10, §175 established criminal penalties related to the development, manufacture, transfer or possession of a biological agent, toxin, or delivery system for use as a weapon; the BWC has never attempted to list BW agents.

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS BOX 1.2 Presidential Executive Order When the committee’s report was in the final stages of completion, the White House issued on July 2, 2010, a new Executive Order, “Optimizing the Security of Biological Select Agents and Toxins in the United States” (see Appendix M). Although the committee did not have time to consider fully the implications of this Executive Order, it notes that several issues are particularly relevant to this report: 1) Sec. 4. Risk-based Tiering of the Select Agent List. “Tiering and potential reduction of the Select Agent List: HHS and USDA will, through their current biennial process of reviewing the Select Agent List, tier the existing list based upon the risk posed by the pathogen or toxin in enabling a mass casualty incident through deliberate misuse. For those pathogens and toxins in the highest risk tier, HHS and USDA will evaluate options for the targeted application of physical security and personnel reliability measures in a manner commensurate to risk. HHS and USDA will also consider reducing the number of agents and toxins on the Select Agent List.” This is in good agreement with near-term milestone d (see Chapter 4), which discusses stratification or reduction of the Select Agent list. Prioritizing the Select Agent list based on risk would make any sequence-based approach to oversight more feasible. 2) Sec. 7. Implementation. (a) Establishment, Operation, and Functions of the Federal Experts Security Advisory Panel. “A panel of Federal security and scientific experts will serve as the principal security advisory body to the SAP. The Panel will advise the SAP on a range of topics, including considerations in the tiering and/or reduction of the Select Agent List, best practices regard- ing physical security and personnel reliability that should be considered in the revision of the SAR and related Rules and guidance, and other topics as determined by HHS and USDA. The Department of Homeland Security will chair a sub-Group of the Panel that will advise the SAP on recommended physical security practices for high-risk pathogens and toxins. In addition, the EO directs the National Science Advisory Board for Biosecurity to serve as a source for external advice and input on SAP/SAR policies and practices.” As discussed in the present report, (Chapter 3; Appendix L, near-term mile- stone f) a classification or yellow flag system would depend on the techni- cal expertise of Scientific Workgroups and Advisory Panels. The Federal Experts Security Advisory Panel described in the EO could, if appropriately staffed with knowledgeable experts, be compatible with such scientific workgroups and advisory panels. For instance, the DHS sub-group is con- sistent with “Security Advisors” presented in Fig 4.1, 2b. It appears that the Federal Experts Security Advisory Panel could also include a sub group of “Scientific Advisors” as presented in Fig 4.1, 3b. (However, the FESAP may not be appropriate to perform the function of the yellow flag “Scientific Advisors,” shown in Fig 4.1, 9b.)

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 THE SELECT AGENT REGULATIONS to be used illegitimately, as weapons, restrict access to these microorganisms and their toxins to certain individuals, and specify conditions under which legitimate research use may occur. (See Appendix F for relevant legislation, regulation and guidelines.) Biological Weapons Pathogens have a long history of being investigated as potential offensive weapons for military purposes. It is well documented that the United States, the former Soviet Union, Great Britain, France, Germany and other countries maintained offensive biological warfare programs until signing of the Biological Weapons Convention of 1972.2 In at least one case, that of the former Soviet Union, clandestine research and development continued well beyond this date and it was only in 1992, following the collapse of the Soviet Union, that Rus- sia fully renounced biological weapons and opened some of its facilities to inspection by the international community. Other clandestine research is still the subject of considerable speculation but not unequivocally documented (Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism 2008). Nations party to the BWC agreed to destroy or divert to peaceful pur- poses any existing weaponized biological agents or delivery systems within nine months of signing the convention. Violation of the terms of the treaty are not directly actionable by any oversight force; rather signatories are responsible for implementation through national means, which are disclosed on a regular basis.3 2 The earliest global prohibition against the use of biological weapons is the 1925 Geneva Proto - col. This treaty was augmented via the Convention on the Prohibition of the Development, Produc- tion and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction (BWC), which was signed at London, Moscow, and Washington on 10 April, 1972, and entered into force on 26 March, 1975. Article I of the BWC states that: “Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or otherwise acquire or retain: (1) Microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes; (2) Weapons, equipment or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict.” 3 “The United States Congress passed the Biological Weapons Anti-Terrorism Act of 1989 (Public Law 101-298, May 22, 1990), which established penalties for violating the Convention’s prohibi - tions, unless “(1) such biological agent, toxin, or delivery system is for a prophylactic, protective, or other peaceful purpose; and (2) such biological agent, toxin, or delivery system, is of a type and quantity reasonable for that purpose.” In keeping with the treaty, the legislation focused on the purpose for which agents or toxins were possessed, rather than the agents themselves. The law authorizes the government to apply for a warrant to seize any biological agent, toxin, or delivery system that has no apparent justification for peaceful purposes, but prosecution under the law

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS Nevertheless, concern about the use of biological weapons persists, as noted by the Commission on the Preention of WMD Proliferation and Ter- rorism co-chaired by former Senators Bob Graham and Jim Talent. The 2008 report, The World at Risk (Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism 2008),4 stated that “Unless the world community acts decisively and with great urgency, it is more likely than not that a weapon of mass destruction will be used in a terrorist attack somewhere in the world by the end of 2013.”5 More recently, the White House National Security Council issued “The National Strategy for Countering Biological Threats (Na- tional Security Council 2009)” at the December 2009 BWC meeting in Geneva. This report again addresses concerns that the life sciences might be misused. Biosafety (and Categorization of Microorganisms) In the United States, the Select Agent Regulations and other current legal mechanisms to control development, stockpiling, access, and use of specific biological agents had their roots in public health laboratory practices. In 1974, the Centers for Disease Control and Prevention (CDC) sought to limit the occurrence of laboratory-acquired infections by issuing guidance in the form of lists of microorganisms entitled, “Classification of Etiologic Agents on the Basis of Hazard” (CDC 1974). While adherence to safe practices was strongly encouraged, no federal requirements were imposed. However, these guidelines played an essential role in the development of the original National Institutes of Health (NIH) Guidelines for Research Inoling Recombinant DNA Molecules issued in 19766 (NIH 1976). The same concerns for public health and safety led to promulgation of rules governing the packaging, labeling and transport of in - fectious agents shipped in interstate commerce (DHHS 1979). First published in 1984 by the CDC and National Institutes of Health (NIH), the document, “Biosafety in Microbiological and Biomedical Laboratories” (BMBL) defines the principles of biosafety for research and clinical laboratories around the globe. The BMBL describes safe handling practices and identifies four levels would require the government to prove that an individual did not have peaceful intentions (Atlas 1999)” (NRC 2009b). 4 See also, The Clock is Ticking: A Progress Report on America’s Preparedness (Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism 2009). 5 The validity of this statement is much debated. See for instance, “Does Threat Reduction Re - quire Threat Inflation?” by Micheal Krepon and “Biological threats: A matter of balance,” from the Bulletin of Atomic Scientists. 6 The Recombinant DNA Advisory Committee (RAC) advised the NIH in the development of the NIH Guidelines for Research Inoling Recombinant DNA Molecules, which have become the stan- dard of safe scientific practice in the use of recombinant DNA. Institutional Biosafety Committees (IBCs), which are mandated by the NIH Guidelines, are charged with reviewing research involving recombinant DNA, although many IBCs have chosen to review other forms of research that involve potential biohazards—including research involving Biological Select Agent and Toxins (BSATs). Institutions are required to register their IBCs with NIH’s Office of Biotechnology Activities.

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 THE SELECT AGENT REGULATIONS BOX 1.3 The Nuclear Paradigm Although biological materials have the potential for misuse and could be devel- oped and employed as Weapons of Mass Destruction, it should not be assumed that biological agents are similar to nuclear WMD threats. Biological agents have unique attributes that are considered in order to develop an effective oversight strategy. Characteristics of Fissile Materials and Pathogens Fissile Materials Pathogenic Microorganisms • Do not exist in nature in readily • Generally found in nature and often concentrated form appropriate for widely distributed globally weapons • Non-living • Living, replicative • Difficult and costly to produce • Easy and cheap to produce • Not diverse: plutonium and highly • Highly diverse enriched uranium are the only fissile materials used in nuclear weapons. • Can be inventoried and tracked in a • Vials containing pathogen cultures quantitative manner may be inventoried and tracked, however, because pathogens repro- duce, exact pathogen quantification is unreliable. • Can be detected at a distance from • Cannot be detected at a distance the emission of ionizing radiation with available technologies • Weapons-grade fissile materials are • Pathogens are present in many stored at a limited number of military types of facilities (e.g. hospitals and sites schools) and at multiple locations within a facility • Few non-military applications (such • Many legitimate applications in bio- as research reactors, thermoelec- medical research and the pharma- tric generators and production of ceutical biotechnology industry. radioisotopes). (Modified from Tucker 2003) of containment based on risk criteria of infectivity, transmissibility, severity of illness, and the nature of work being performed. As a guideline, the BMBL maintains the flexibility needed to evolve along with the pathogens it describes. Though not a regulation, many choose to follow the BMBL’s recommendations. Moreover, Select Agent Regulations part 73.12(c)(1) requires such consider-

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS BOX 1.4 NIH Guidelines—Risk Groups Although not specifically targeted to Select Agents, the NIH Guidelines for Re- search Involving Recombinant DNA Molecules (NIH Guidelines) specify bio- safety and containment practices for constructing and handling recombinant DNA. Agents are classified into four risk groups (RG) based upon their potential hazard. Select Agents are found in categorizes RG2, RG3, or RG4. Risk Group 1 (RG1): Agents that are not associated with disease in healthy adult humans. Risk Group 2 (RG2): Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available. Risk Group 3 (RG3): Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk) Risk Group 4 (RG4): Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk) The NIH Guidelines are normally enforced locally by Institutional Biosafety Com- mittees (IBC), and each institution performing research with Select Agents usually have a dedicated Biosafety Officer who is responsible for ensuring regulatory compliance, reporting problems to the IBC, and serving as a technical resource for questions regarding biosafety. If Select Agents are present, the Biosafety Officer often serves as the first line of oversight in the management of research, transport and handling of Select Agents. A Responsible Official (RO) is designated for each entity holding Select Agents, and the Biosafety Officer may serve as the RO, or will work in close association with the RO. ation as a result of a contractual requirement or best practices; thus in this case, the BMBL can be interpreted as having the force of law. The BMBL, like the NIH Guidelines, stipulates four biosafety levels (BSL- 1, -2, -3, -4) (Box 1.5). Increasingly stringent safety and containment criteria govern each biosafety level so that the pathogens with high mortality rates and no known treatment or prevention are designated BSL-4 agents. All BSL-4 agents have been designated as Select Agents; however, not all Select Agents require BSL-4 containment.7 The CDC conducted an assessment of the potential for biological agents to impact public health (Rotz, Khan et al. 2002). Criteria for classification included potential impact on public health, dissemination potential, public 7 Anthrax, considered among the greatest security threats, requires only BSL-2/3 containment for biosafety, according to the BMBL.

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 THE SELECT AGENT REGULATIONS BOX 1.5 BMBL Biosafety Levels Biosafety “BSL-1 is suitable for work involving well-characterized agents not Level 1 known to consistently cause disease in immunocompetent adult hu- mans, and present minimal potential hazard to laboratory personnel and the environment.” Biosafety “BSL-2 is suitable for work involving agents that pose moderate Level 2 hazards to personnel and the environment.” Biosafety “BSL-3 is applicable to clinical, diagnostic, teaching, research, or Level 3 productions facilities where work is performed with indigenous or exotic agents that may cause serious or potentially lethal disease through inhalation route exposure.” Biosafety “BSL-4 is required for work with dangerous and exotic agents that Level 4 pose a high individual risk of life-threatening disease, aerosol trans- mission, or related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 containment must be handled at this level until sufficient data are obtained either to confirm continued work at this level or re- designate the level.” (CDC/NIH 2007) perception, and special public health preparedness needs such as stockpile requirements, enhanced surveillance or diagnostic needs required to mitigate harm or respond following an attack. Public perception in this case refers to the ability to engender widespread panic or concern about the safety of products including food, thus precipitating a major impact even if an event does not cause direct or significant harm to human health. Individual pathogens were classified as Category A, B, or C, with Category A agents having the greatest potential to cause widespread casualties and requiring the largest public health preparedness efforts. Category B agents were also deemed to have a potential for large-scale dissemination, although generally with documented lower rates of illness and death. Agents not currently recognized as significant bioterrorism risks, but with attributes that might enable their future weaponization, were classified as Category C agents (Box 1.6). The National Institutes of Health (NIH), National Institute for Allergy and Infectious Diseases (NIAID) has also developed a classification of pathogens using a Category A, B, and C system; however, this system is used to set research priorities and the criteria for classification was different. The NIH criteria stressed ease of dissemination, associated mortality rates following infection, potential for public health impact, social disruption, and required special action

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8 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS BOX 1.6 CDC Bioterrorism Agents / Diseases by Category Category Ca Criteria Category A Category B Variablea Ease of Easily Moderately easy dissemination Variablea Mortality rates High Low Variablea Morbidity rates Variable Moderate Variablea Potential for social Possible Variable disruption Specific enhancements Variablea Action for Requires special public health actions of CDC’s diagnostic preparedness capacity and enhanced disease surveillance aCategory C considers emerging pathogens that could be engineered for mass dis- semination in the future because of availability, ease of production and dissemination, and potential for high morbidity and mortality rates and major health impact. SOURCE: Modified from Rotz, Khan et al. 2002). for public health preparedness. A larger universe of pathogens was included in the NIH assessment such that some agents appear on the NIH list that were not captured on either the CDC classification or Select Agents list. Biosecurity and the Select Agent Regulations Biosafety and biosecurity8 are related and complementary concepts; how- ever, there are important distinctions. The fifth edition of the BMBL defines 8As discussed in NRC report 2009, “[i]t should be noted that the use of the term “biosecurity” presents a number of difficulties. At its most basic, the term does not exist in some languages, or is identical with “biosafety”; French, German, Russian, and Chinese are all examples of this im - mediate practical problem. Even more serious, the term is already used to refer to several other major international issues. For example, to many “biosecurity” refers to the obligations undertaken by states adhering to the Convention on Biodiversity and particularly the Cartagena Protocol on Biosafety, which is intended to protect biological diversity from the potential risks posed by living modified organisms resulting from modern biotechnology. (Further information on the Conven - tion may be found at and on the Protocol at .) “Biosecurity” has also been narrowly applied to efforts to increase the security of dangerous pathogens, either in the laboratory or in dedicated collections; guidelines from both the World Health Organization (WHO 2004) and the Organization for Economic Cooperation and Devel- opment (OECD 2007) use this more restricted meaning of the term. In an agricultural context, the

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 THE SELECT AGENT REGULATIONS biosafety programs as those that “reduce or eliminate exposure of individuals and the environment to potentially hazardous biological agents,” while the “objective of biosecurity is to prevent loss, theft or misuse of microorganisms, biological materials, and research-related information” (CDC/NIH 2007). Bi - osecurity rose to public prominence in 1995, when three vials of an inactivated form of the organism that causes plague (Yersinia pestis) were illegally obtained by an alleged white supremacist (NRC 2009b). The perpetrator was charged with mail fraud as it was not a crime to possess these materials. This incident highlighted the need for a fundamental change in regulation of biological agents, which stimulated congressional interest culminating in the passage of legislation entitled “The Antiterrorism and Effective Death Penalty Act of 1996” (P.L. 104-132). This Act made it a federal crime to use or threaten to use a weapon of mass destruction including biological weapons and “directs the Secretary of Health and Human Services to promulgate regulations identifying biological agents that pose a potential threat to public health and safety and governing their intentional or inadvertent transfer.” Accordingly, CDC promul- gated regulations for facilities transferring or receiving select infectious agents and toxins as defined by the Secretary of Health and Human Services. However, it wasn’t until Bacillus anthracis was sent through the U.S. Postal Service in October 2001, resulting in five deaths, that a broader system of controls on the possession, use and transfer of Select Agents was established, carrying with it severe criminal penalties, including imprisonment and fines. The National Select Agents Registry Program (Select Agent Program) was formally established to execute provisions of the USA PATRIOT Act and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 regarding biological agents. Biological Select Agents and Toxins (BSAT) are defined by DHHS and the USDA as pathogens or biological toxins that have the “potential to pose a severe threat to public health and safety.” 9 The USA PATRIOT Act (Public Law 107-56) made it an offense for a person to knowingly possess any biological agent, toxin, or delivery system of a type or in a quantity that, under the circumstances, is not reasonably justified by prophylactic, protective, bona fide research, or other peaceful purpose. The Act also prohibited the possession or transfer of Select Agents by “restricted persons.” A restricted person is defined by the Act (18 U.S.C. 175b) as an individual who: • is under indictment for a crime punishable by imprisonment for a term exceeding 1 year; term refers to efforts to exclude the introduction of plant or animal pathogens. (See NRC 2009a:8-9 for a discussion of this and other issues related to terminology.) Earlier NRC reports (2004ab, 2006, 2009ab) confine the use of “biosecurity” to policies and practices to reduce the risk that the knowl - edge, tools, and techniques resulting from research would be used for malevolent purposes.” 9 Both the 1996 and the 2002 legislation mandated a list of regulated agents, subject to biennial review and revision, or as needed.

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS oversight of the Select Agent program (Casadevall and Relman 2010). A case in point is the stipulation in the 18 USC Part 1, Chapter 10, subsection 175 c. that established criminal penalties for the possession of biological material shar- ing 85 percent or more of the genome of variola virus, the cause of smallpox. It is unclear what “85 percent of the gene sequence” means. Does this refer to a fragment of 85 percent or more of the full-length variola virus genome? Or does it mean a full-length genome of 85 percent or greater sequence identity to variola? Moreover, several orthopoxviruses share approximately 96 percent amino identity with variola. The language is sufficiently problematic that the NSABB has recommended the repeal of the requirement because it may in - advertently criminalize work on other orthopoxviruses including vaccinia, the smallpox vaccine virus, which was surely not the intent of the legislation 17,18 (NSABB 2006). This example highlights the challenges faced in defining Select Agents based on sequences alone. Gene Synthesis Industry If genetic sequences do not suffice to define Select Agents, then a challenge arises in providing guidance to the approximately fifty companies worldwide that offer gene synthesis as a commercial service (Maurer, Fischer et al. 2009). With one exception,19 all of the gene synthesis companies are private and none publish their financial results. Several manufacturers market their services through more than one distributor. The fact that the market is largely privately held and highly dispersed makes it difficult to gauge its size with any accuracy, but estimates place its value between $50 and $80 million in 2008. This repre - sents over 50 million bases pairs of synthetic DNA, or approximately 75,000 genes. The cost of synthesis has declined rapidly, dropping by half every 18-24 months over the last ten years and will likely continue to decline for at least the next few years. Each of the top gene synthesis companies is currently capable of providing 1-2 million base pairs of synthetic DNA per month, and most are planning for rapid growth. 17 In July 2008 the Department of Justice released a memorandum clarifying the scope of the definition of variola virus under the Intelligence Reform and Terrorism Prevention Act of 2004, Sec- tion 6906, making it a criminal offense to knowingly produce, engineer, synthesize, acquire transfer directly or indirectly receive, possess, import, export or use, or possess and threaten to use, variola virus. 18 USC 175c (a) (1) exempts work conducted by or under the authority of the Secretary of HHS. The Department of Justice stated that section 175c does not apply to all orthopoxviruses, but only to viruses that cause smallpox. However, the challenge remains—how can one tell from sequence if an orthopoxvirus will cause smallpox? 18 This is still active statute; however, S.1649-WMD Prevention and Preparedness Act of 2009, was amended in mark up to include an amendment which codifies the WHO recommendations for the distribution, handling and synthesis of Variola Virus DNA and mandates regulations governing the distribution, synthesis and handling of variola virus DNA. 19 GeneArt.

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 THE SELECT AGENT REGULATIONS While gene synthesis provides many benefits to biomedical research, it also provides an alternate route of access to toxins and pathogenic organisms. Cur- rent government oversight of the DNA synthesis industry has not kept up with the pace of science in a number of important ways. First, existing regulations are difficult to interpret in the context of a series of DNA sequence orders. The Select Agent Regulations focus on species definitions of pathogens and do not define the boundaries between a pathogen and a similar sequence from a related species. (The Export Administration Regulations enforced by the U.S. Department of Commerce include phrases such as “. . . sequences associated with the pathogenicity of microorganisms . . .” that are vague and imprecise.) Second, the regulations do not address activities that have the potential to cause significant alarm in the public and the scientific community. For instance, two DNA fragments that comprise the genome of the Select Agent Omsk Hem- orrhagic Fever virus are not covered by the Select Agent Regulations when separated, but would be covered if the two fragments are joined together using simple, widely available molecular tools. Gene synthesis companies have been active in working with their respec - tive governments to promote effective regulation of the technology. All gene synthesis companies must comply with their national laws regarding pathogen and toxin DNAs.20 Most of the companies have customers in more than one country and must also comply with regulations that govern export from their country, as well as the regulations governing importation and possession of the sequences at the customer’s location. Several different industry groups have formed to promote safe, effective regulation of gene synthesis technology. Although the application of the Select Agent Regulations to cloned DNA could be interpreted in a number of different ways, the CDC has provided a guide to interpreting these rules for the gene synthesis companies (“Applica - bility of the Select Agent Regulations to Issues of Synthetic Genomics,” see Appendix E). The guidance document defines the organisms whose genomes are covered and provides examples that clarify the application of these rules. The document does not define the species boundaries in terms of sequence similarity. The gene synthesis companies therefore pragmatically must define a number of critical screening parameters on their own. However, because they must rely on sequence alone, they are faced with significant questions: Which 20 Gene synthesis companies based in the United States are affected by at least four regulations that cover the synthesis of pathogen and toxin genes; (1) the Select Agent Rules, (2) the Depart - ment of Commerce Export regulations, (3) the Biological Weapons Anti-Terrorism Act of 1989 and (4) a specific statute relating to smallpox. In addition, the World Health Organization places significant limits on the possession and end use of small pox genes, including a prohibition against the synthesis of any fragment of more than 500 base pairs. Currently, each of the approximately 40 companies worldwide that supply synthetic genes has developed an independent process to screen orders for sequences that might be covered by the laws and regulations of its own country and those of the customer’s country.

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8 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS genome should be used as a reference for the species? Is a sequence that is 99 percent identical to the reference genome covered? 98 percent? 90 percent? DHHS has recently issued a document “Screening Framework Guidance for Synthetic Double-Stranded DNA Providers,” which provides a more de- tailed methodology by which companies can screen DNA synthesis orders. These draft guidelines have been published in the Federal Register, and are cur- rently available for public comment prior to issuance of a final set of guidelines. The guidance requests that companies identify and follow up on sequences (greater than 200bp) with homology unique to a Select Agent sequence. Thus, the guidance aims to define the boundaries between a Select Agent and a simi- lar sequence from a related species. The guidance also discusses concerns that virulence genes from non-Select Agents could be used to produce biological threats: The U.S. Government acknowledges that there are synthetic nucleic acid sequences from non-Select Agents or Toxins that may pose a biosecurity concern. Synthetic nucleic acid providers may choose to investigate such sequences as part of their best practices. However, due to the complexity of determining pathogenicity and because research in this area is ongoing, a list of additional non-Select Agent or Toxin sequences or organisms to screen against would not be comprehensive and consequently are not provided by the U.S. Government in this guidance (DHHS 2009). However, the guidance does encourage companies to “exercise their due dili- gence in the investigation of screening hits against non-Select Agents and Toxins that may raise a biosecurity concern” (DHHS 2009). While the motivation for this portion of the guidance is clear, the ability to implement the suggestion is not. Companies may find it challenging to recognize a sequence that poses a biosecurity concern, readily identify virulence genes, or determine the usability of genomic sequences in predicting potentially dangerous sequences in naturally occurring, genetically modified, or synthetically derived microorganisms. 21 Impact of Select Agent Regulations on Research There is a clear recognition that research on infectious disease agents, including Select Agents, is vital to public health and national security. There is also an acknowledgement among researchers that Select Agents should be regu- lated (NRC 2009b; Sutton 2009). However, for those scientists who choose to pursue this line of investigation, it is not always clear what organisms and which 21 The draft DHHS screening guidelines were the topic of a January 11, 2010, meeting hosted by AAAS CSTSP. A summary of the “major themes of the meeting, including concerns and/or chal - lenges highlighted, and recommendations proposed by individual attendees” is available online. Berger, K. M., W. Pinard, et al. (2009). Minimizing the Risks of Synthetic DNA: Scientists’ Views on the U.S. Government’s Guidance on Synthetic Genomics.

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 THE SELECT AGENT REGULATIONS researchers must comply with the SAR. The regulations as currently written are open to interpretation, due to the unclear boundaries discussed above. For ex - ample, SARS-CoV is not currently a Select Agent, but may soon be designated as such. If this agent is added to the list, researchers will be required to register their SARS-CoV strains. But what does this mean? A SARS-CoV researcher is likely to have scores of related or derivative viruses, whose genomes are not identical to the ‘original’ SARS-CoV genome sequence.22 The various strains may or may not be pathogenic, and may have been obtained from the wild or via genetic modification of the ‘parent’ virus. Keep in mind that a single nucleotide change may render the organism non-pathogenic, whereas multiple- changes elsewhere could have no effect on pathogenicity.23 A researcher may need to register all of their various strains; or if none of the sequences match the ‘original’ SARS-CoV sequence, then the researcher may believe that reg - istration is not required. This is a serious concern. A misinterpretation of the requirements could lead to a substantial burden in time and resources as an investigator complies with the Select Agent Regulations unnecessarily; on the other hand, non-compliance could lead to criminal prosecution. Thus, having a clear definition of what is and is not a Select Agent, is vitally important to the responsible scientist (See Sutton 2009 and Box 1.8). The designation of certain infectious organisms and toxins as Select Agents with the potential to be used as bioweapons challenged both policy makers and the scientific community to understand better the pathogenic mechanisms of these microorganisms and toxins and to develop countermeasures to prevent, diagnose, and treat the effects of such agents. Paradoxically, the designation of these organisms and toxins as Select Agents put considerable burden on the scientific community to conduct this research while simultaneously adhering to costly and rigorous standards for security and accountability (Dias, Reyes- Gonzalez et al. 2010). The Select Agent Program was not designed to impede research but there is much concern in the scientific community that the requirements have resulted in unintended negative consequences (NRC 2009b; Dias, Reyes-Gonzalez et al. 2010). Select Agent Program criteria would be most useful if based on genomic information and a rigorous biological foundation tempered by the realities of national and international security. 22 Moreover, no reference sequences are currently provided for agents on the Select Agent list. In this regard, the agents are defined based on taxonomy and “chain of custody.” 23 As discussed in the Chapter 2, the effect that these sequence changes have on pathogenicity isn’t known until experiments are done. It should also be noted that a nucleotide sequence may contain “silent” mutations, which alter the DNA sequence, without affecting the protein sequence. Therefore, there may be dissimilarity at the DNA sequence level and identity at the protein level.

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0 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS BOX 1.8 Effect of Select Agent Regulations on Research During deliberations, the committee noted that the Select Agent Regulations have potentially significant consequences for the scientists who work in this area and on the research that is done. The Select Agent Regulations are based in law and backed by criminal penalties. Implementation of the current Select Agent Regulations was therefore discussed in the context of what a “predictive oversight system” might look like and the “level of certainty” such a system would require. The committee was aware that several issues of concern have been noted by the scientific and security commu- nities. Although the quantitative affect of the Select Agent Regulations on research is unknown, some of the concerns are briefly presented below: • Altered Research Direction—Scientists may have redirected their research to the study of attenuated strains that are not classified as Select Agents (e.g. Bacillus anthracis Sterne strain) (CDC 2005). “In our view, the most likely explanation for the 10-fold discrepancy in the number of toxin- and capsule-related papers is that capsule-related research must be carried out within the SATL-associated regula- tions. If, in fact, these regulations are hindering capsule-related research, such hindrance has direct biodefense and preparedness implications, given that capsule components have been shown to be effective vaccines” (Casadevall and Relman 2010). • Considerable costs—As noted by the NRC Responsible Research with Biological Select Agents and Toxins, “select agent laboratories have significant ongoing se- curity and safety sustainment costs that far exceed the indirect costs that grantee institutions receive to cover the costs of facilities, maintenance, and operations.” Thus, in the absence of continued federal funding, the institution must be willing and able to commit funds to meet this additional financial burden or instead deny their investigators such Select Agent research pursuits (NRC 2009b). • Inefficiency—Funds awarded to principal investigators for Select Agent research do not go as far as they would be expected to in a non-Select Agent laboratory. This may be due to the additional manpower needed for intensive recordkeeping (lab CRITERIA FOR SELECT AGENT DESIGNATION How should a “Select Agent” be defined? The registry of Select Agents is a finite list that has grown in recent years as emerging pathogens are characterized and assessed. For example, public comments are now being requested as offi- cials consider whether Severe, Acute Respiratory Syndrome (SARS) coronavirus and a recently recognized arena virus, Chapare virus, should be added to the Select Agent list. In some instances naturally occurring or derived attenuated strains of Select Agents have been removed from the list; however, despite legislation requiring periodic review of the Select Agent list, it is currently chal - lenging to subtract from the list because there are no precise biological or policy

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 THE SELECT AGENT REGULATIONS access, equipment access, reagent use, etc.), and the extensive recurrent training necessary for Select Agent registration compliance. There is inherent down time during which individuals must wait to be cleared by the CDC and FBI to begin work in the Select Agent areas. As noted by Dias et al., “the most striking effect observed was not associated with individual authors or institutions; it was a loss of efficiency, with an approximate 2- to 5-fold increase in the cost of doing select agent research as measured by the number of research papers published per millions of U.S. research dollars awarded”(Dias, Reyes-Gonzalez et al. 2010). • Personnel Issues—As noted by the NSABB, “Certain research facilities (notably federal) have instituted formal Personnel Reliability Programs (PRPs) to provide additional measures to help ensure that individuals with access to select agents meet additional standards of reliability . . . . “The promulgation of additional reli- ability measures could serve as a powerful disincentive to those who wish to and would responsibly conduct research on select agents because the most talented young researchers, those with many options for research paths, may be far more likely to enter fields with less onerous regulatory requirements. Thus, a burdensome national personnel reliability program may not only drive scientists from important select agent research, but also drive select agent research out of academia and potentially out of the U.S. into countries with less stringent regulations (NSABB 2009). • Collaborations may be affected between Select Agent laboratories and non-Select Agent-certified collaborators and trade partners, especially overseas. The develop- ment of diagnostics and vaccines may require the sharing of samples, recombinant DNA, or toxins in quantities above Select Agent limits. Commercial partners may view the requirement of being Select Agent-registered as a disincentive to collabo- ration and development of essential biodefense-related preventives, therapeutics, and diagnostics. This concern has again been expressed in response to a proposal of adding SARS-CoV to the SA list, “The ASM believes the proposal to add the SARS-CoV virus to the HHS list of select agents and toxins deserves further de- liberation . . . consider the impact on international collaboration and public health efforts.” criteria to do so. Nor are there precise, quantitative criteria for inclusion. Select Agent status has generally been conferred on an ad hoc, case-by-case basis, using a combination of the following considerations.24 24 “[T]he Act requires the HHS Secretary to consider the following criteria in determining whether to list an agent or toxin: (1) The effect on human health of exposure to the agent or toxin; (2) the degree of contagiousness of the agent or toxin and the methods by which the agent or toxin is transferred to humans; (3) the availability and effectiveness of pharmacotherapies and immunizations to treat and prevent any illness resulting from infection by the agent or toxin; and (4) any other criteria, including the needs of children and other vulnerable populations, that the Secretary considers appropriate” (DHHS 2005).

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS • Virulence, pathogenicity, or toxicity of the organism; its potential to cause death or serious disease. • Availability of treatments such as vaccines or drugs to control the consequences of a release or epidemic. • Transmissibility of the organism; its potential to cause an uncontrolled epidemic. • Ease of preparing the organism in sufficient quantity and stability for use as a bioterrorism agent; for example, the ability to prepare large quantities of stable microbial spores. • Ease of disseminating the organism in a bioterrorism event to cause mass casualties, for example by aerosolization. • Public perception of the organism; its potential to cause societal dis - ruption by mass panic. • Known research and development efforts on the organism by national bioweapons programs. Thus, there are multiple factors that are considered before adding an agent to the Select Agent list. Simply possessing the capability of causing a significant threat to public health and safety does not meet the threshold for designation as a Select Agent. For example, seasonal influenza causes an average of 35,000 deaths annually in the United States, yet it is not considered a Select Agent (an effective vaccine is available). Historically, pathogens that were previously weaponized either by the United States or other countries are considered to be the greatest risk,25 even when subsequent scientific findings suggest otherwise. Potential biological weapons threats are uniformly discussed (See, for example, Kortepeter and Parker 1999), as possessing attributes that would enhance their appeal to terrorists as a weapon. Since the 1950s these attributes include the ability to incapacitate affected individuals or cause highly lethal infections in a short period of time, lack of availability of preventive or therapeutic measures, ease of production, stability as an aerosol, and ability to be dispersed as small particles, all characteristics that could lead to significant loss of life, overwhelm the healthcare system, and cause social disruption and panic. For example, variola (the virus that causes smallpox) is perhaps the clearest and least contro - versial agent on the Select Agent list; smallpox virus has the potential to cause a catastrophic epidemic if it were released. It also seems clear that the aim of the Select Agent Regulations is not to regulate all organisms that could be used by bioterrorists, even if the organism has already been used for bioterrorism. Salmonella typhimurium was the agent used in a 1984 incident in Oregon by followers of Bhagwan Shree Rajneesh, but 25 Those pathogens most often considered as greatest threats included anthrax ( Bacillus anthracis), botulinum toxin, tularemia (Francisella tularensis), plague (Yersinia pestis), and smallpox (variola virus), among others.

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 THE SELECT AGENT REGULATIONS the resulting cases of food poisoning were on a scale similar to many normally occurring food contamination events and readily handled by the normal public health system. One useful source for understanding the rationale for the current Select Agents list is the commentary on 42 CFR Part 73, the DHHS implementation of provisions of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (DHHS 2002), describing some of the considerations that led to the Select Agents list that superseded the 1997 list in 42 CFR 72.6. For example, “viruses causing hantavirus pulmonary syndrome” were removed from the CFR 72.6 Select Agent list because they “are difficult to propagate and there is a lack of data establishing laboratory acquired infections.” Yellow fever virus was removed because “there is a safe and effective vaccine.” Histoplasma capsulatum and Blastomyces species were considered but not included because “they are difficult to cultivate and do not sporulate readily.” Aflatoxins were not included because “the acute toxicity is too low to pose a significant mass casu - alty threat.” The published discussion in the Federal Register does not include any examples in which DHHS considered public perception of the organism or known bioweapons development programs in its decision making. It explicitly lists “effect on human health” (pathogenicity), “contagiousness,” “methods by which the agent or toxin is transferred to humans,” (dissemination) and “the availability of pharmacotherapies and immunizations” as criteria, and the dis - cussion includes more than one example in which ease of preparation of large quantities of the organism was considered. All in all, the decision to include a microorganism or a microbial product as a Select Agent is based on a variety of factors, including past medical experience, partial laboratory evidence, and historical precedent. From this perspective it is worth considering which properties (or general criteria) can be predicted from genome sequence now, which ones might be predicted in the future, and which ones will never be predictable from genome sequence because they are not biological properties. Non-Biological Criteria As mentioned, non-biological information is considered when determining if an agent should be designated as a Select Agent or Toxin. Factors such as trade policy, the availability of therapeutics, natural prevalence of the micro - organism, and historical use of an agent as a bioweapon can all effect whether or not a microorganism poses a threat to national security (Table 1.1). Because such factors are not inherent biological properties, they can never be deter- mined by a biological agent’s genome. For example, USDA animal pathogens are included in the Select Agent list because the diseases they cause have significant economic and trade repercus -

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS TABLE 1.1 Prospects for de Noo Prediction of “Select Agent-ness” from Sequence Predictable Foreseeable Maybe Property Now? Future? Someday? Never Pathogenicity X Transmissibility X Available treatments X Ease of preparation X Ease of dissemination X Public perception X Historical bioweapon X Economic impact X Natural prevalence X sions for U.S. Agriculture.26 A few years ago U.S. international trade in beef was halted for approximately two years at a cost of billions of dollars to U.S. farm - ers due to the occurrence a single case of bovine spongiform encephalopathy (BSE)—commonly known as “mad-cow disease.” This response was the result of international trade rules—long supported by the U.S.—that mandate that all animal product exports being halted in the event of a single case of foot and mouth disease or BSE (or other transboundary livestock and poultry diseases listed by the World Animal Health Association27). The concept of “increased virulence” is thus intriguing in regard to these non-zoonotic animal Select Agents; if the catastrophic response is triggered, as for BSE, by even one case, then the biological characteristic of virulence is not an issue. What could pos - sibly be made worse? Even a totally synthetic foot and mouth virus designed for enhanced virulence would have no increased impact from the point of view of international trade rules. Because it is not U.S. policy to vaccinate animals to control the disease, FMD is already the most infectious animal virus known (a single pig is estimated to produce 100 billion cattle infectious doses per day and there are approximately 24 million pigs in Iowa) and the international trade consequences would be the same as a natural FMD virus. Thus, these agents are designated as Select Agents not because they pose a threat to human health, or even animal health. Rather, these agents pose a threat to national security, and are designated as Select Agents because of potential economic consequences, international trade agreements, and vaccination policy. Thus, criteria that are considered in designating a microorganism as a “Select Agent” include biological and non-biological data. While it is not cur- 26 The international trade rules for animal agriculture are set by the International Office of Epizootics in Paris (recently retitled the World Animal Health Association), an arm of the World Trade Organization. 27 Formerly called the International Office of Epizootics (OIE).

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 THE SELECT AGENT REGULATIONS BOX 1.9 Non-Biological Factors for Select Agent Designation—Smallpox and Polio Smallpox was declared eradicated by the World Health Assembly in 1980, a mo- ment that is recognized as one of the most important achievements of humankind. Routine smallpox vaccination ceased in the United States in 1980, and earlier in some countries. Almost half the world’s population is currently immunologically naïve to the disease. At the same time, the rise of diseases such as HIV/AIDS that weaken the immune system, as well as the prevalence of atopic dermatitis (the vaccine is contraindicated for individuals with atopic dermatitis), would make resumption of routine vaccination difficult. There are today no licensed therapeu- tics for the treatment of smallpox, and currently licensed vaccines, while effective, are contraindicated for immunocompromised individuals. Historical anecdotes, while not confirmed, suggest that contaminated materials could be used to spread smallpox in target populations. Both the United States and the Soviet Union have engaged in research aimed at weaponizing smallpox (NRC 2009b). While variola’s virulence makes it a threat to public health, these other non-biological factors make smallpox an obvious candidate for use as a bioweapon. Thus, both biological and non-biological factors contribute to this once endemic pathogen being designated a Select Agent. In contrast, polio is not a Select Agent despite its ability to cause crippling disease and death. Polio virus is endemic in some countries, and is therefore difficult to restrict. Moreover, the availability of effective vaccines reduce the threat posed by this virus. However, if vaccination were to cease, this virus could be viewed as a potential bioweapon and designated as a Select Agent. Clearly, the non-biological context can never be predicted from the viral sequence. rently feasible to predict the biological characteristics from sequence, it is not even theoretically possible to predict the non-biological considerations from sequence. Ultimately, designation of a microorganism as a “Select Agent” is a judgment call and a policy decision. “Select Agent-ness” is not a strictly bio - logical property. Biological Criteria With the multiple non-biological factors that contribute to Select Agent designation, it is clear that “Select Agent” is a regulatory term, rather than a biological one. However, the central criteria for a Select Agent are biological attributes. At the time when the Select Agent list was devised by DHHS, some 60 or so full bacterial genomes were known and annotated as well as a score of viruses.28 Hundreds of bacterial genome sequences are now available for com- 28 The first complete sequence of a bacterial genome was published in 1995.

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 SEQUENCE-BASED CLASSIFICATION FOR SELECT AGENTS parative genomics. Genomic information was not employed in the initial defini- tion of Select Agents. However, from the outset it was asked, to what degree can genomic sequences be used to detect Select Agents now and, for the future, to what degree can genomic sequences be used to predict potentially danger- ous sequences in naturally occurring, genetically manipulated or synthetically derived microorganisms? These questions are the focus of this committee. In examining the sequences from several hundred bacterial genomes, it is impressive just how much diversity is seen—even in different genomes from the same bacterial species. If one considers the general biological criteria used to designate a microorganism as a Select Agent and then asks, to what degree could these attributes be deduced from sequence, the answer is quite clear. Prediction of pathogenicity, transmissibility, ease of preparation, and ease of dissemination is not possible now or in the foreseeable future (see Table 1.1). In part, this is because we lack the basic biological information, and in part it is because our current predictive algorithms are not sufficiently robust. Infection of a susceptible host by a Select Agent may lead to morbidity and mortality by many different mechanisms, be it “hemorrhagic fever” due to some viral infections or neurological disease following exposure to a bacterial toxin. With the exception of some toxins, the genetic basis for the disease or death that may follow infection with or intoxication by a Select Agent is, however, not well defined. Pathogenicity seen in a susceptible host is the result of a complex interaction between a pathogen and a host defense system, as well as an envi - ronmental context (e.g. age, sex, nutrition, health, immune status, and others). As will be discussed subsequently, pathogenicity of an organism may be the result of a specific sequence and gene, or more frequently the result of interac- tions between several genes, various sequences, structural characteristics, and host characteristics. There are too many variables involved on the host side alone to be able to accurately predict whether any given nucleic acid change in the pathogen will involve greater or lesser pathogenicity. The complexity of these systems argues against a simple gene-sequence basis for “predictive oversight of Select Agents” without substantial new information. As will be discussed in Chapter 2, there is no current way in which a complex biological factor such as pathogenicity can be predicted from genome sequence. Predicting the function of an individual protein, or single microor- ganism is daunting. Moreover, the nature of infectious disease is such that ac - curate prediction of microbial pathogenicity is not possible without information concerning the host and the environmental context.