Bioterrorism — Preparing to Fight the Next War
http://www.100md.com
《新英格兰医药杂志》
The United States has become preoccupied with the threat of bioterrorism — the potential for the poisoning of the
milk supply with botulinum toxin, the hypothetical dissemination of smallpox by self-infected terrorists, the
possibility of a massive release of aerosolized anthrax spores in the subway, even the newly raised specter of
misuse of a reconstructed 1918 influenza virus. These concerns have had important consequences for the biomedical
research agenda, funding priorities, and the regulatory environment.
In fiscal year 2003, $1.5 billion was allocated for biodefense research to the National Institutes of Health (NIH).
These new research dollars, which have been reallocated yearly, now account for roughly one third of the budget of
the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH. Although some of these funds are
intended for the study of emerging infectious diseases, unprecedented attention is being paid to pathogens that
currently cause rare diseases. For example, the number of NIH grants for work on Francisella tularensis increased
from 4 in 2001 to 71 in 2003, although there are only 100 to 150 cases of tularemia in the United States each year;
in October 2005, $60 million was awarded by NIAID for work on new tularemia vaccines.
Government concern about bioterrorism has also led to new federal restrictions on the handling of infectious
agents; such rules have hampered both the ability of U.S. researchers to participate in international
collaborations and efforts to train foreign scientists in this country. All these changes reflect a radical shift
in the political and social climate — a shift highlighted by the incarceration in 2004 in federal prison, on
charges of improper handling of Yersinia pestis, of Dr. Thomas Butler, chief of infectious diseases at Texas Tech
University and an expert on plague.
How well founded is this heightened concern about bioterrorism? If it is justified, how can we best allocate our
intellectual, technical, and financial resources, given the imminent dangers from avian influenza and other natural
threats? On what principles should we build a biodefense strategy?
Policymakers weighing the likelihood and dangers of bioterrorism tend to seek guidance from a past era of large,
state-sponsored bioweapons programs that used industrial-scale processes, emphasized quality control, and based
their projections of use on traditional military doctrine. The leaders of those programs that then viewed biologic
agents as credible strategic weapons believed that a few particular agents had the most potential for use and saw
the technology for preparing and delivering those agents as an essential component of a weapons program.
But we cannot assume that the logic behind biowarfare programs of the past will guide future misuses of the life
sciences. Indeed, the lessons of this history can be dangerously misleading. First, the notion that only a certain
few agents pose a plausible threat is largely an artifact of weapons programs that predated our current knowledge
of molecular biology and that selected agents on the basis of their natural properties and the limited technical
expertise then available. Among the agents that remain on today's threat lists, anthrax and smallpox make
particularly compelling weapons, but as science and technology advance, the number of worrisome agents is expanding
greatly.
Furthermore, large-scale industrial processes are not necessary for the development of potent biologic weapons.
Increasingly, the means for propagating biologic agents under controlled conditions are being made accessible to
anyone. Even our traditional concept of "weaponization" is misleading: nature provides mechanisms for packaging and
preserving many infectious agents that can be manipulated through biologic and genetic engineering — for example,
by enhancing the virulence of naturally sporulating organisms. Materials science and nanoscale science — advances
in encapsulation technology, for instance — will provide new ways to package such agents. And self-replicating
agents that are highly transmissible among humans, such as variola virus and influenza virus, need little or no
alteration in order to be disseminated efficiently by terrorists.
Nor should we presume, on the basis of history, that when biologic agents are used deliberately and maliciously,
they are capable of causing only relatively limited harm. The large biologic-weapons programs of the late 20th
century were never unleashed. And the use of such weapons by smaller groups, such as the Aum Shinrikyo cult, has
been relatively unsophisticated — far from representative of what moderately well informed groups might do today.
The consequences would have been far more dire, for example, had the anthrax spores circulated in the U.S. mail in
2001 been disseminated by more effective routes. Tomorrow's science and technology will present a new landscape
with features that are both worrisome and reassuring: the methods and reagents used for reverse-engineering a novel
virus, for instance, can also be used to engineer a vaccine against it.
New insights into biologic systems are emerging rapidly, and new tools for manipulating these systems continue to
be developed.1,2 Information is now disseminated globally, many relevant procedures require far fewer resources
than ever before, and much life-science technology has been miniaturized. Today, anyone with a high-school
education can use widely available protocols and prepackaged kits to modify the sequence of a gene or replace genes
within a microorganism; one can also purchase small, disposable, self-contained bioreactors for propagating viruses
and microorganisms. Such advances continue to lower the barriers to biologic-weapons development.3,4
So far, nature has been the most effective bioterrorist. In the future, however, the ability of experimenters to
create genetic or molecular diversity not found in the natural world — for example, with the use of molecular
breeding technologies — and to select for virulence-associated traits may result in new biologic agents with
previously unknown potency. Although such agents may not survive long in the natural world and could, from an
evolutionary standpoint, be dismissed as poorly adapted competitors, they may prove extremely destructive during
their lifespan.
In devising a robust biodefense strategy, a key challenge will be to define the optimal balance between fixed and
flexible defenses. The Maginot Line built by the French in the 1930s serves as a symbol of static defenses designed
to protect against known threats. Although these elaborate fortifications bought the French some time, the
advancing German army maneuvered around them. Similarly, the creation of static defenses can be justified for
clear, imminent, and potentially catastrophic biologic threats — including avian influenza virus and prominent
drug-resistant bacteria, such as Staphylococcus aureus, as well as anthrax and smallpox.
For the vast array of other potential threats, however, we should invest even more in flexible, dynamic defenses,
which will rely on integrative science, new insights into biologic systems, and advancing technology. We need
methods and technologies that can generate effective diagnostics, therapeutics, and prophylactics against a new or
variant infectious agent within days or weeks after its characterization.
Lists of specific agents and the scrutiny of past events can inhibit creative thinking about universal tools and
generic approaches for a dynamic world. A robust biodefense plan must be anticipatory, flexible, and rapidly
responsive. It should exploit crosscutting technologies and cross-disciplinary scientific insights and use broadly
applicable platforms and methods that offer substantial scalability. Examples include the use of "lab-on-a-chip"
technology, based on advances in microfluidics, for rapid, sensitive, point-of-care diagnostics; computational
approaches for predicting drug–ligand interactions; genomic tools such as microarrays and genome-wide screening
for protective antigens; and automated robotic systems for rapid, high-throughput drug screening and the scale-up
of vaccine production. Efforts to understand microbial virulence should emphasize the study of mechanisms and
structures that are shared by a variety of agents.
Given the importance of early intervention, a greater emphasis should be placed on approaches to diagnosing
diseases early and specifically. We need such tools now for naturally occurring microbial diseases, if only to
reduce the inappropriate use of antibiotics. For example, analyses of host responses to infection in which advanced
mass spectroscopy or DNA microarray technology is used to assess patterns of protein abundance or genome-wide
patterns of transcript abundance may lead to a new capability for diagnosing presymptomatic disease and predicting
clinical outcomes or responses to therapy. The NIH, the Centers for Disease Control and Prevention, the Department
of Homeland Security — in response to the federal strategic plan for defense against biologic weapons outlined in
Homeland Security Presidential Directive 10 — and other agencies have discussed these needs,5 but investments in
these broad approaches have been insufficient.
Such efforts will require strengthening our public health infrastructure, especially in terms of personnel,
communications, and surge capacity. Scientists and clinicians will need to play a bigger role in biodefense
planning, including the articulation of needs, policymaking, and the assessment of future threats.
It is often said that military forces are trained to fight the last war, not the next one. The same may be true of
public health officials and scientists working to strengthen the public health infrastructure. But given the pace
of change in the life sciences, we cannot afford to be constrained by the past, nor can we afford to make
incremental, short-term fixes. Recent investments in biodefense offer immense potential benefit, if guided by a
creative, future-oriented perspective. Now is the time to begin making serious, sustained investments in the
science and technology on which we can build agile defenses against an ever-evolving spectrum of biologic threats.
Source Information
Dr. Relman is an associate professor in the Departments of Medicine and of Microbiology and Immunology, Stanford
University, Stanford, Calif., chief of infectious diseases at the Veterans Affairs Palo Alto Health Care System,
Palo Alto, Calif., and a member of the National Science Advisory Board for Biosecurity.
An interview with Dr. Relman can be heard at www.nejm.org.
References
Segal E, Friedman N, Kaminski N, Regev A, Koller D. From signatures to models: understanding cancer using
microarrays. Nat Genet 2005;37:Suppl:S38-S45.
Tully T, Bourtchouladze R, Scott R, Tallman J. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov
2003;2:267-277.
Petro JB, Relman DA. Understanding threats to scientific openness. Science 2003;302:1898-1898.
Petro JB, Plasse TR, McNulty JA. Biotechnology: impact on biological warfare and biodefense. Biosecur Bioterror
2003;1:161-168.
Hirschberg R, La Montagne J, Fauci AS. Biomedical research -- an integral component of national security. N Engl J
Med 2004;350:2119-2121.(David A. Relman, M.D.)
milk supply with botulinum toxin, the hypothetical dissemination of smallpox by self-infected terrorists, the
possibility of a massive release of aerosolized anthrax spores in the subway, even the newly raised specter of
misuse of a reconstructed 1918 influenza virus. These concerns have had important consequences for the biomedical
research agenda, funding priorities, and the regulatory environment.
In fiscal year 2003, $1.5 billion was allocated for biodefense research to the National Institutes of Health (NIH).
These new research dollars, which have been reallocated yearly, now account for roughly one third of the budget of
the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH. Although some of these funds are
intended for the study of emerging infectious diseases, unprecedented attention is being paid to pathogens that
currently cause rare diseases. For example, the number of NIH grants for work on Francisella tularensis increased
from 4 in 2001 to 71 in 2003, although there are only 100 to 150 cases of tularemia in the United States each year;
in October 2005, $60 million was awarded by NIAID for work on new tularemia vaccines.
Government concern about bioterrorism has also led to new federal restrictions on the handling of infectious
agents; such rules have hampered both the ability of U.S. researchers to participate in international
collaborations and efforts to train foreign scientists in this country. All these changes reflect a radical shift
in the political and social climate — a shift highlighted by the incarceration in 2004 in federal prison, on
charges of improper handling of Yersinia pestis, of Dr. Thomas Butler, chief of infectious diseases at Texas Tech
University and an expert on plague.
How well founded is this heightened concern about bioterrorism? If it is justified, how can we best allocate our
intellectual, technical, and financial resources, given the imminent dangers from avian influenza and other natural
threats? On what principles should we build a biodefense strategy?
Policymakers weighing the likelihood and dangers of bioterrorism tend to seek guidance from a past era of large,
state-sponsored bioweapons programs that used industrial-scale processes, emphasized quality control, and based
their projections of use on traditional military doctrine. The leaders of those programs that then viewed biologic
agents as credible strategic weapons believed that a few particular agents had the most potential for use and saw
the technology for preparing and delivering those agents as an essential component of a weapons program.
But we cannot assume that the logic behind biowarfare programs of the past will guide future misuses of the life
sciences. Indeed, the lessons of this history can be dangerously misleading. First, the notion that only a certain
few agents pose a plausible threat is largely an artifact of weapons programs that predated our current knowledge
of molecular biology and that selected agents on the basis of their natural properties and the limited technical
expertise then available. Among the agents that remain on today's threat lists, anthrax and smallpox make
particularly compelling weapons, but as science and technology advance, the number of worrisome agents is expanding
greatly.
Furthermore, large-scale industrial processes are not necessary for the development of potent biologic weapons.
Increasingly, the means for propagating biologic agents under controlled conditions are being made accessible to
anyone. Even our traditional concept of "weaponization" is misleading: nature provides mechanisms for packaging and
preserving many infectious agents that can be manipulated through biologic and genetic engineering — for example,
by enhancing the virulence of naturally sporulating organisms. Materials science and nanoscale science — advances
in encapsulation technology, for instance — will provide new ways to package such agents. And self-replicating
agents that are highly transmissible among humans, such as variola virus and influenza virus, need little or no
alteration in order to be disseminated efficiently by terrorists.
Nor should we presume, on the basis of history, that when biologic agents are used deliberately and maliciously,
they are capable of causing only relatively limited harm. The large biologic-weapons programs of the late 20th
century were never unleashed. And the use of such weapons by smaller groups, such as the Aum Shinrikyo cult, has
been relatively unsophisticated — far from representative of what moderately well informed groups might do today.
The consequences would have been far more dire, for example, had the anthrax spores circulated in the U.S. mail in
2001 been disseminated by more effective routes. Tomorrow's science and technology will present a new landscape
with features that are both worrisome and reassuring: the methods and reagents used for reverse-engineering a novel
virus, for instance, can also be used to engineer a vaccine against it.
New insights into biologic systems are emerging rapidly, and new tools for manipulating these systems continue to
be developed.1,2 Information is now disseminated globally, many relevant procedures require far fewer resources
than ever before, and much life-science technology has been miniaturized. Today, anyone with a high-school
education can use widely available protocols and prepackaged kits to modify the sequence of a gene or replace genes
within a microorganism; one can also purchase small, disposable, self-contained bioreactors for propagating viruses
and microorganisms. Such advances continue to lower the barriers to biologic-weapons development.3,4
So far, nature has been the most effective bioterrorist. In the future, however, the ability of experimenters to
create genetic or molecular diversity not found in the natural world — for example, with the use of molecular
breeding technologies — and to select for virulence-associated traits may result in new biologic agents with
previously unknown potency. Although such agents may not survive long in the natural world and could, from an
evolutionary standpoint, be dismissed as poorly adapted competitors, they may prove extremely destructive during
their lifespan.
In devising a robust biodefense strategy, a key challenge will be to define the optimal balance between fixed and
flexible defenses. The Maginot Line built by the French in the 1930s serves as a symbol of static defenses designed
to protect against known threats. Although these elaborate fortifications bought the French some time, the
advancing German army maneuvered around them. Similarly, the creation of static defenses can be justified for
clear, imminent, and potentially catastrophic biologic threats — including avian influenza virus and prominent
drug-resistant bacteria, such as Staphylococcus aureus, as well as anthrax and smallpox.
For the vast array of other potential threats, however, we should invest even more in flexible, dynamic defenses,
which will rely on integrative science, new insights into biologic systems, and advancing technology. We need
methods and technologies that can generate effective diagnostics, therapeutics, and prophylactics against a new or
variant infectious agent within days or weeks after its characterization.
Lists of specific agents and the scrutiny of past events can inhibit creative thinking about universal tools and
generic approaches for a dynamic world. A robust biodefense plan must be anticipatory, flexible, and rapidly
responsive. It should exploit crosscutting technologies and cross-disciplinary scientific insights and use broadly
applicable platforms and methods that offer substantial scalability. Examples include the use of "lab-on-a-chip"
technology, based on advances in microfluidics, for rapid, sensitive, point-of-care diagnostics; computational
approaches for predicting drug–ligand interactions; genomic tools such as microarrays and genome-wide screening
for protective antigens; and automated robotic systems for rapid, high-throughput drug screening and the scale-up
of vaccine production. Efforts to understand microbial virulence should emphasize the study of mechanisms and
structures that are shared by a variety of agents.
Given the importance of early intervention, a greater emphasis should be placed on approaches to diagnosing
diseases early and specifically. We need such tools now for naturally occurring microbial diseases, if only to
reduce the inappropriate use of antibiotics. For example, analyses of host responses to infection in which advanced
mass spectroscopy or DNA microarray technology is used to assess patterns of protein abundance or genome-wide
patterns of transcript abundance may lead to a new capability for diagnosing presymptomatic disease and predicting
clinical outcomes or responses to therapy. The NIH, the Centers for Disease Control and Prevention, the Department
of Homeland Security — in response to the federal strategic plan for defense against biologic weapons outlined in
Homeland Security Presidential Directive 10 — and other agencies have discussed these needs,5 but investments in
these broad approaches have been insufficient.
Such efforts will require strengthening our public health infrastructure, especially in terms of personnel,
communications, and surge capacity. Scientists and clinicians will need to play a bigger role in biodefense
planning, including the articulation of needs, policymaking, and the assessment of future threats.
It is often said that military forces are trained to fight the last war, not the next one. The same may be true of
public health officials and scientists working to strengthen the public health infrastructure. But given the pace
of change in the life sciences, we cannot afford to be constrained by the past, nor can we afford to make
incremental, short-term fixes. Recent investments in biodefense offer immense potential benefit, if guided by a
creative, future-oriented perspective. Now is the time to begin making serious, sustained investments in the
science and technology on which we can build agile defenses against an ever-evolving spectrum of biologic threats.
Source Information
Dr. Relman is an associate professor in the Departments of Medicine and of Microbiology and Immunology, Stanford
University, Stanford, Calif., chief of infectious diseases at the Veterans Affairs Palo Alto Health Care System,
Palo Alto, Calif., and a member of the National Science Advisory Board for Biosecurity.
An interview with Dr. Relman can be heard at www.nejm.org.
References
Segal E, Friedman N, Kaminski N, Regev A, Koller D. From signatures to models: understanding cancer using
microarrays. Nat Genet 2005;37:Suppl:S38-S45.
Tully T, Bourtchouladze R, Scott R, Tallman J. Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov
2003;2:267-277.
Petro JB, Relman DA. Understanding threats to scientific openness. Science 2003;302:1898-1898.
Petro JB, Plasse TR, McNulty JA. Biotechnology: impact on biological warfare and biodefense. Biosecur Bioterror
2003;1:161-168.
Hirschberg R, La Montagne J, Fauci AS. Biomedical research -- an integral component of national security. N Engl J
Med 2004;350:2119-2121.(David A. Relman, M.D.)