Biomedical Research and Biosecurity
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《新英格兰医药杂志》
Even as they have advanced our understanding and treatment of disease, the achievements of modern biomedical research have also increased people's ability to misuse discoveries in ways that could threaten the public health or national security. The phrase "dual-use research" attempts to capture this occasionally uneasy relation between scientific advances and the potential development of new pathogens or biologic weapons. "In the language of arms control and disarmament, dual use refers to technologies intended for civilian application that can also be used for military purposes," according to a 2003 report from a committee of the National Research Council on biotechnology research in an age of terrorism.1
In the aftermath of the attacks of September 11, 2001, and the anthrax attacks that followed them, this committee compiled a list of seven types of "experiments of concern" involving infectious agents or their products; the committee recommended that proposals for such experiments be reviewed and discussed carefully to determine whether they should even be undertaken and, if they are carried out, before their full details are published (see box).1 It recommended the creation of a specific review system for such experiments. One member of the committee, Dr. C.J. Peters of the University of Texas Medical Branch, Galveston, referred to the list as the "seven deadly sins."
Experiments of Concern.
In its report, the National Research Council committee discussed a 2001 study of an unanticipated effect of introducing the gene for interleukin-4 into ectromelia virus (mousepox). The goal of the experiments was to bioengineer a variant of the virus that, functioning as an infectious immunocontraceptive, could render mice infertile, thereby helping to reduce the mouse population in Australia. Instead, the bioengineered virus became more virulent and killed three fifths of the mice it infected, including those that had been genetically resistant to mousepox. The committee's report also discussed a 2002 article on the synthesis of the poliovirus genome from chemically synthesized oligonucleotides and the recovery of infectious viruses. While acknowledging that these examples highlight important issues, the committee also sought to put them into appropriate context — for instance, the general scientific principle behind making live poliovirus from a DNA template had been understood since 1981. Moreover, the synthetic virus was less pathogenic than wild-type strains and offered no technical advantages to a potential terrorist.
In 2005, there have been further examples of controversial research. One article, for instance, described a model of a bioterrorist attack on the United States involving the contamination of milk with botulinum toxin.2 In an op-ed in the New York Times, one of the study's authors described the analysis as a wake-up call, designed to ensure that "our milk supply is vigilantly guarded, from cow to consumer."3 Some government officials, however, viewed the analysis as a road map for bioterror and tried to prevent its publication.
The most recent examples are the reports of the complete genetic sequencing of the Spanish influenza virus that caused the 1918 pandemic and the virus's recovery by means of reverse-genetics techniques, whose scientific importance is discussed by Belshe in this issue of the Journal (pages 2209–2211). The research involving the virus was conducted in a high-containment biosafety level 3 laboratory at the Centers for Disease Control and Prevention (CDC), with additional precautions for the protection of the researchers, the environment, and the public.
At the government's request, the reports on the influenza virus were reviewed at the last minute by the recently constituted National Science Advisory Board for Biosecurity (NSABB), an advisory committee to federal departments and agencies that is chartered by the Department of Health and Human Services. The board concluded that the value of the information in helping to prevent future influenza pandemics far outweighed the potential for misuse; they therefore unanimously supported the publication of the reports. As in the case of the synthetic poliovirus, the reverse-genetics techniques that were used were not new. The editor-in-chief of Science, which published one of the articles, raised concerns about the government's authority to block the publication of a paper simply because it considered the findings "sensitive." In an editorial, he argued that "if a paper should not be published because of biosecurity risks, then it should be classified" as confidential by the federal government, which the influenza papers were not.
On October 20, 2005, the CDC designated the resurrected influenza virus as a "select agent" under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002. This classification restricted the possession, use, and transfer of the 1918 strain of influenza or its eight key gene regions to registered researchers and laboratories, as is currently the case for Bacillus anthracis, variola major (smallpox), and 39 other select agents and toxins. This classification, however, does not affect the online availability of the full genome sequence of the 1918 virus through the GenBank database at the National Institutes of Health (NIH). With rare exceptions, the federal government requires that genomic data from the research it funds be made public. The posting of the sequence has been characterized by some as "extremely foolish" and equated with broadcasting "the design of a weapon of mass destruction."4
Anticipating such concerns, another committee of the National Research Council has studied the issue. In 2004, it concluded that "policies with regard to release of genome data on microbial pathogens should not change," because preserving open access to these data is likely to "facilitate scientific and medical advances that will improve health as well as society's ability to react to biological threats."5 In September 2004, the complete genome sequences of more than 100 microbial pathogens, including smallpox, anthrax, and Ebola virus, were already publicly available in Internet-accessible databases around the world.
Nonetheless, there is continuing concern about the possible misuse of rapidly developing commercial technologies for synthesizing genes and genomes from sequence information. When I spoke to him in October, Dr. Dennis Kasper, a professor of medicine, microbiology, and molecular genetics at Harvard Medical School and the chair of the NSABB, said, "If someone wants to buy the genome for the smallpox virus or the genes that make pertussis toxin or diphtheria toxin or anthrax toxin, do you sell it to them? These are heavy-duty questions."
The NSABB, which is managed within the National Institutes of Health, first met in the summer of 2005 and is just beginning its work. In its initial phase, it is primarily a forum for the development of guidance for federally supported research, not for the review of individual research proposals or manuscripts — although it may serve as a review committee in additional instances. It is not a law-enforcement committee or a committee to prevent biologic warfare. In some ways, its role resembles that of the Recombinant DNA Advisory Committee that was established within the NIH in 1974 and that played an important part in setting guidelines and reviewing research protocols. Although the types of experiments the board will consider have implications for medicine and public health, the research itself will be mostly basic science at the outset. Eventually, it may include more studies involving human subjects.
Among the matters that the NSABB is discussing are the definition of dual-use research, how such research should be reviewed within institutions and the government, the types of research that might be problematic for journals to communicate and how specific instances should be addressed and resolved, international cooperation in the development and acceptance of guidelines, and the possibility of a code of conduct for federally funded scientists and laboratory workers with regard to dual-use research activities. According to Kasper, the advisory board "is really focusing on the creation and use of potential biologic weapons. The concern is that a clever scientist working for an evil agency could pick up some information and use it." For instance, there will always be unexpected research findings — like the accidental creation of the hypervirulent viral strain that occurred in the mousepox case.
Establishing biosecurity policies for biomedical research without obstructing scientific progress or disrupting the usual procedures for scientific communication is a complex matter. At the moment, however, it is far easier to describe the challenges than to resolve them.(Robert Steinbrook, M.D.)
In the aftermath of the attacks of September 11, 2001, and the anthrax attacks that followed them, this committee compiled a list of seven types of "experiments of concern" involving infectious agents or their products; the committee recommended that proposals for such experiments be reviewed and discussed carefully to determine whether they should even be undertaken and, if they are carried out, before their full details are published (see box).1 It recommended the creation of a specific review system for such experiments. One member of the committee, Dr. C.J. Peters of the University of Texas Medical Branch, Galveston, referred to the list as the "seven deadly sins."
Experiments of Concern.
In its report, the National Research Council committee discussed a 2001 study of an unanticipated effect of introducing the gene for interleukin-4 into ectromelia virus (mousepox). The goal of the experiments was to bioengineer a variant of the virus that, functioning as an infectious immunocontraceptive, could render mice infertile, thereby helping to reduce the mouse population in Australia. Instead, the bioengineered virus became more virulent and killed three fifths of the mice it infected, including those that had been genetically resistant to mousepox. The committee's report also discussed a 2002 article on the synthesis of the poliovirus genome from chemically synthesized oligonucleotides and the recovery of infectious viruses. While acknowledging that these examples highlight important issues, the committee also sought to put them into appropriate context — for instance, the general scientific principle behind making live poliovirus from a DNA template had been understood since 1981. Moreover, the synthetic virus was less pathogenic than wild-type strains and offered no technical advantages to a potential terrorist.
In 2005, there have been further examples of controversial research. One article, for instance, described a model of a bioterrorist attack on the United States involving the contamination of milk with botulinum toxin.2 In an op-ed in the New York Times, one of the study's authors described the analysis as a wake-up call, designed to ensure that "our milk supply is vigilantly guarded, from cow to consumer."3 Some government officials, however, viewed the analysis as a road map for bioterror and tried to prevent its publication.
The most recent examples are the reports of the complete genetic sequencing of the Spanish influenza virus that caused the 1918 pandemic and the virus's recovery by means of reverse-genetics techniques, whose scientific importance is discussed by Belshe in this issue of the Journal (pages 2209–2211). The research involving the virus was conducted in a high-containment biosafety level 3 laboratory at the Centers for Disease Control and Prevention (CDC), with additional precautions for the protection of the researchers, the environment, and the public.
At the government's request, the reports on the influenza virus were reviewed at the last minute by the recently constituted National Science Advisory Board for Biosecurity (NSABB), an advisory committee to federal departments and agencies that is chartered by the Department of Health and Human Services. The board concluded that the value of the information in helping to prevent future influenza pandemics far outweighed the potential for misuse; they therefore unanimously supported the publication of the reports. As in the case of the synthetic poliovirus, the reverse-genetics techniques that were used were not new. The editor-in-chief of Science, which published one of the articles, raised concerns about the government's authority to block the publication of a paper simply because it considered the findings "sensitive." In an editorial, he argued that "if a paper should not be published because of biosecurity risks, then it should be classified" as confidential by the federal government, which the influenza papers were not.
On October 20, 2005, the CDC designated the resurrected influenza virus as a "select agent" under the Public Health Security and Bioterrorism Preparedness and Response Act of 2002. This classification restricted the possession, use, and transfer of the 1918 strain of influenza or its eight key gene regions to registered researchers and laboratories, as is currently the case for Bacillus anthracis, variola major (smallpox), and 39 other select agents and toxins. This classification, however, does not affect the online availability of the full genome sequence of the 1918 virus through the GenBank database at the National Institutes of Health (NIH). With rare exceptions, the federal government requires that genomic data from the research it funds be made public. The posting of the sequence has been characterized by some as "extremely foolish" and equated with broadcasting "the design of a weapon of mass destruction."4
Anticipating such concerns, another committee of the National Research Council has studied the issue. In 2004, it concluded that "policies with regard to release of genome data on microbial pathogens should not change," because preserving open access to these data is likely to "facilitate scientific and medical advances that will improve health as well as society's ability to react to biological threats."5 In September 2004, the complete genome sequences of more than 100 microbial pathogens, including smallpox, anthrax, and Ebola virus, were already publicly available in Internet-accessible databases around the world.
Nonetheless, there is continuing concern about the possible misuse of rapidly developing commercial technologies for synthesizing genes and genomes from sequence information. When I spoke to him in October, Dr. Dennis Kasper, a professor of medicine, microbiology, and molecular genetics at Harvard Medical School and the chair of the NSABB, said, "If someone wants to buy the genome for the smallpox virus or the genes that make pertussis toxin or diphtheria toxin or anthrax toxin, do you sell it to them? These are heavy-duty questions."
The NSABB, which is managed within the National Institutes of Health, first met in the summer of 2005 and is just beginning its work. In its initial phase, it is primarily a forum for the development of guidance for federally supported research, not for the review of individual research proposals or manuscripts — although it may serve as a review committee in additional instances. It is not a law-enforcement committee or a committee to prevent biologic warfare. In some ways, its role resembles that of the Recombinant DNA Advisory Committee that was established within the NIH in 1974 and that played an important part in setting guidelines and reviewing research protocols. Although the types of experiments the board will consider have implications for medicine and public health, the research itself will be mostly basic science at the outset. Eventually, it may include more studies involving human subjects.
Among the matters that the NSABB is discussing are the definition of dual-use research, how such research should be reviewed within institutions and the government, the types of research that might be problematic for journals to communicate and how specific instances should be addressed and resolved, international cooperation in the development and acceptance of guidelines, and the possibility of a code of conduct for federally funded scientists and laboratory workers with regard to dual-use research activities. According to Kasper, the advisory board "is really focusing on the creation and use of potential biologic weapons. The concern is that a clever scientist working for an evil agency could pick up some information and use it." For instance, there will always be unexpected research findings — like the accidental creation of the hypervirulent viral strain that occurred in the mousepox case.
Establishing biosecurity policies for biomedical research without obstructing scientific progress or disrupting the usual procedures for scientific communication is a complex matter. At the moment, however, it is far easier to describe the challenges than to resolve them.(Robert Steinbrook, M.D.)