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Introduction

THE LIFE-SCIENCE REVOLUTION

The ultimate goal of biology, medicine, and other life sciences is to build a complete understanding of the function of all living things, both as discrete molecular components and as integrated complex interactive systems. Until recently, such an ambitious undertaking has been little more than a distant dream. That dream began to take shape in the 1950s and 1960s when the DNA code was deciphered, and its realization accelerated in the 1970s as new tools that were developed to read and manipulate gene sequences increased the pace of discovery many times over (Hood and Galas, 2003).

The revolution in the life sciences that began to take shape in the 20th century is no longer a promise; it is happening now. The major technologies catalyzing this revolution are sequencing of the entire genetic codes of organisms (including humans), mapping of genome variability between individuals of a species, and microarray technology that allows observation and analysis of genome-wide patterns of gene activity under different conditions. All those technologies allow the rapid analysis of the entire repertoire of proteins and other macromolecules produced by a cell, and they have generated very large biological databases and associated analytic software tools. Those and other advances now allow life scientists to assemble the mass of new data into an accurate and detailed way to reach the goal of understanding how organisms function.

All branches of the life sciences have entered a period of unprecedented research productivity, and the pace will only increase. As a result,



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Seeking Security: Pathogens, Open Access, and Genome Databases 1 Introduction THE LIFE-SCIENCE REVOLUTION The ultimate goal of biology, medicine, and other life sciences is to build a complete understanding of the function of all living things, both as discrete molecular components and as integrated complex interactive systems. Until recently, such an ambitious undertaking has been little more than a distant dream. That dream began to take shape in the 1950s and 1960s when the DNA code was deciphered, and its realization accelerated in the 1970s as new tools that were developed to read and manipulate gene sequences increased the pace of discovery many times over (Hood and Galas, 2003). The revolution in the life sciences that began to take shape in the 20th century is no longer a promise; it is happening now. The major technologies catalyzing this revolution are sequencing of the entire genetic codes of organisms (including humans), mapping of genome variability between individuals of a species, and microarray technology that allows observation and analysis of genome-wide patterns of gene activity under different conditions. All those technologies allow the rapid analysis of the entire repertoire of proteins and other macromolecules produced by a cell, and they have generated very large biological databases and associated analytic software tools. Those and other advances now allow life scientists to assemble the mass of new data into an accurate and detailed way to reach the goal of understanding how organisms function. All branches of the life sciences have entered a period of unprecedented research productivity, and the pace will only increase. As a result,

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Seeking Security: Pathogens, Open Access, and Genome Databases the idea of obtaining a reasonably complete understanding of living systems, although still some distance off, is in view (Kanehisa and Bork, 2003; Venter et al., 2003). And just as it was difficult even a decade ago to envision all the changes that the widespread use of computers and global computer networks would bring, it is impossible now to foresee all the effects that the life-sciences revolution will have over the next decade. The rapidly growing understanding of natural systems has tremendous potential to create better lives for people the world over. For example, understanding fully how pathogens and hosts interact is a major long-term research goal. To reach it, scientists must gain a detailed understanding of what makes the immune response effective and of how pathogens cripple or evade the immune response to cause disease. As more details of the interplay between pathogenic microorganisms and the immune system become known, scientists will probably be able to create new and powerful strategies to fight infection, create better vaccines, and develop faster, more precise diagnostic tools (Moxon and Rappuoli, 2002; Rappuoli and Covacci, 2003). Perhaps scientists will someday be able to deliver those benefits in a matter of days or weeks, so that when new pathogens emerge, treatments and vaccines will become available quickly enough to contain what might otherwise be catastrophic outbreaks of infection and disease. The benefits of the life-science revolution are broad and include treatments and preventive measures for conditions as varied as sudden infant death syndrome, cancer, autoimmune diseases, infectious diseases, and such neurological disorders as Alzheimer’s disease. In addition, agriculture, energy production, chemical manufacturing, and even computing all stand to be transformed by the genome revolution. Of course, such powerful technology can also be used for destructive purposes. This is the “dual-use” problem familiar to those who work on arms-control and disarmament issues: most technologies that are important in the peacetime economy—including communications, cryptography, computers, materials science, aeronautics, and nuclear energy—are also technologies for weapons. The products of life-science research must be included prominently in any list of technologies that can be used for good or ill. Just as fundamental knowledge about how pathogens interact with the immune system will lead to new ways to prevent and cure infections, it could also help someone bent on designing genetically altered versions of natural pathogens that could be exploited as weapons by governments or terrorists. Some types of research has been called “contentious research” (Epstein, 2001) or is said to fall into a gray zone where the benefits of publication may not outweigh the dangers. In a 2001 publication, Gerald Epstein described this category as “fundamental biological or biomedical investigations that produce organisms or knowledge that could have immediate weapons implications and that therefore raise questions

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Seeking Security: Pathogens, Open Access, and Genome Databases concerning whether and how that research should be conducted and disseminated” (Epstein, 2001). The conduct of such contentious research is beyond the charge to this committee, but the dissemination of the results falls within our purview. Two examples of such potentially contentious research are given later in the report: work with a fungal pathogen of plants and work with a virus of mice. RELATED NATIONAL ACADEMIES PROJECTS On January 9, 2003, the National Academies convened a workshop titled “Scientific Openness and National Security.” The day-long workshop had sessions on assessing the threat posed by life-science knowledge and current policies related to openness, and four case studies of how “sensitive” information could be handled were discussed. Two members of the committee that wrote the present report participated in that workshop. On January 10, 2003, a meeting of journal editors was held in Washington, DC. The editors discussed their role in determining which articles are published, including decisions as to what constitutes sensitive or dangerous information and what steps journal editors might take to decrease the chances that published material would facilitate efforts of bioterrorists. These editors later published a joint statement in three journals (Science, Nature, and the Proceedings of the National Academy of Science; Atlas et al., 2003a,b,c). The statement indicated that the scientific review process must be safeguarded and issues of security risks acknowledged. They called for journals to devise appropriate procedures for reviewing security risks and to encourage scientists to communicate their data in ways that minimize risk and maximize benefits. On October 8, 2003, the National Academies released a report, Biotechnology Research in an Age of Terrorism, written by the Committee on Research Standards and Practices to Prevent the Destructive Application of Biotechnology, chaired by Gerald Fink, of the Whitehead Institute in Cambridge, Massachusetts. The report examined the dual-use problem as related to applications of life-science research. The charge to that committee was to “consider ways to minimize threats from biological warfare and bioterrorism without hindering the progress of biotechnology” (NRC, 2003a), and the committee’s report identified seven categories of “experiments of concern.” They included experiments that would Demonstrate how to render a vaccine ineffective. Confer resistance to therapeutically useful antibiotics or antiviral agents.

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Seeking Security: Pathogens, Open Access, and Genome Databases Enhance the virulence of a pathogen or render a non-pathogen virulent. Increase transmissibility of a pathogen. Alter the host range of a pathogen. Enable the evasion of diagnostic or detection methods. Enable the weaponization of a biological agent or toxin. The same report proposed modifications of the system of review of biological experiments that would address concerns about misuse of results without unduly limiting work in the life sciences. Among several recommendations, the report urged that The Department of Health and Human Services (DHHS) expand and augment its system of scientific review to include the consideration of the potential for misuse of results of proposed research. Life scientists educate themselves and policy-makers about the kinds of misuse of scientific results that are possible. A permanent expert committee be set up in DHHS to provide advice and leadership for the expanded system of review. An international forum be convened to attempt to harmonize policies on dangerous life-science research results around the world. CHARGE TO THE COMMITTEE Discussions among members of the National Interagency Genomics Sciences Coordinating Committee (NIGSCC), which comprises representatives of several federal agencies that have an interest in genome research, had been held on the topic of the release to the public domain of genome data as it pertains to likely agents of bioterrorism. Given that complete genomes of more than 100 microbial pathogens—including those for smallpox, anthrax, Ebola hemorrhagic fever, botulism, and plague—are already in Internet-accessible databases freely open to all and that the genomes of hundreds more pathogens will be sequenced with the support of government funds in the next few years (Fraser, 2004), representatives of those agencies discussed whether current policies regarding release of genome sequence data were appropriate. As a result of the discussions, some NIGSCC members decided to seek advice from the scientific community. The National Science Foundation, the National Institutes of Health, the Department of Homeland Security, and the Central Intelligence Agency funded the National Academies to convene a committee, to hold a workshop, and to produce a report about how biological scientists view the potential for misuse of genome sequence data and the policies governing access to databases that contain them.

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Seeking Security: Pathogens, Open Access, and Genome Databases At the first meeting of the committee, the sponsors indicated that they hoped the report would present the perspective of working biological scientists so that readers in the policy and intelligence communities could use the report when considering potential changes in policy regarding access to genome sequence data. The sponsors specifically requested that the report capture input from presentations and discussions by workshop participants, identify general issues surrounding the publication of genome data on bioterrorism-threat agents, develop a list of pros and cons associated with the release to the public domain of such data, and present recommendations for policy options and decision-making frameworks concerning release to the public domain of genome information. The National Academies Committee on Genomics Databases for Bioterrorism Threat Agents organized a 1-day workshop on the public release of genome data on bioterrorism-threat agents, which was held in Washington, DC, on October 1, 2003. About 40 invited scientists and policy experts who work in government, private industry, and academic laboratories attended. Workshop participants were asked to address three questions concerning genome data on possible biological-weapons agents: What categories of genome data present the greatest concern? What are the pros and cons of unlimited vs. restricted access to such data, including threats posed to the scientific community or to national security? What are some options for making decisions about release to the public domain? The genome data considered at the workshop included not only raw DNA sequences but also annotated sequences and interpretations of sequence data (for example, identification of protein motifs or functional genomics data). Proteome data (for example, data on protein expression patterns) was also be considered by the participants. Various venues for publication of such data (such as deposition into electronic banks and publication in mainstream journals) were considered, as well as possible mechanisms to constrain access to data. The workshop agenda and a list of the participants are appended to this report. Although the questions posed to the committee were limited to consideration of genome sequences of bioterrorism-threat agents, these were by no means the only kind of data that workshop participants discussed. The broader context is complex, and there is no clear demarcation between bioterror-agent genome sequences and other genome data, gene-expression data, protein structures, and other kinds of research results. The key advances in modern life science are not readily apparent in any particular piece of genome data. Instead, the growing set of full-length

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Seeking Security: Pathogens, Open Access, and Genome Databases sequences of many organisms can be thought of as “raw material” for modern biological research or as the platform from which research can be launched. Data on one organism often prove to be invaluable for building a better understanding of other organisms, and data from many organisms taken together and compared, analyzed, and applied to new questions will allow new and fundamental insights into biological processes.