Transcript Table 1. Estimates of casualties from a hypothetical

National Security and Openness of
Scientific Research
Ronald M. Atlas
University of Louisville
President Elect--American Society for Microbiology
National Security and Openness of Scientific Research
Are new mechanisms needed to govern scientific research
so as to lessen the probability of the development of
advanced biological weapons?

If so what should be done?
The research and national security communities have
different objectives, cultures, and norms, and are likely to
weigh the costs and benefits of proposed policy measures
differently

What should the National Academy and scientific societies like the
American Society for Microbiology do to foster the critical dialog
among these communities?
Controlling Biological Warfare Threats: Resolving Potential Tensions Among the Research
Community, Industry, and the National Security Community. Gerald L. Epstein. Critical
Reviews in Microbiology, 27 (2001)
Suggested Policy Mechanisms to Reduce
Future Biological Weapons Threats
Tighten restrictions on access to dangerous
pathogens
Impose restrictions on the conduct and publication
of “contentious research,” i.e. fundamental
biological or biomedical investigations that produce
organisms or knowledge that could have immediate
weapons implications
Restrict access and dissemination of “relevant
information”
Controlling Biological Warfare Threats: Resolving Potential Tensions Among the Research
Community, Industry, and the National Security Community. Gerald L. Epstein. Critical
Reviews in Microbiology, 27 (2001)
Restrictions on Access to Select Agents
 Possession of potentially dangerous biological agents
should be regulated more tightly
 Are there individuals that should not be permitted to
conduct certain categories of research, or that should not
be given access to dangerous pathogens?
Physical security at institutions that maintain cultures of
potentially dangerous biological agents needs to be
reexamined to provide not only legal but also physical
barriers to help prevent unauthorized individuals from
obtaining such agents
 Are locks enough?
 Should armed guards secure laboratories with select
agents?
CDC Laboratory Registration/
Select Agent Transfer Program
These regulations place shipping and handling
requirements on laboratory facilities that transfer or
receive select agents capable of causing substantial
harm to human health. They are designed to ensure
that select agents are not shipped to parties who are
not equipped to handle them appropriately or who
lack proper authorization for their requests.
Currently regulates shipment of 42 select agents
Requires adherence to CDC biosafety manual
In effect since April 1997
USA Patriot Act
Imposes restrictions on who may possess select
agents
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Possession must be for legitimate bona fide reasons
Restricts aliens from countries designated as supporting
terrorism from possessing select agents within the United
States
Restricts individuals who are not permitted to purchase
handguns, e.g. some individuals with a history of mental
illness or a criminal record, from possessing select agents
No provision for exemptions under any circumstances
Does not require registration for possession of select
agents
In effect since October 26, 2001
Definition of a Restricted Person
 is under indictment for a crime punishable by imprisonment for a term
exceeding one year;
 has been convicted in any court of a crime punishable by
imprisonment for a term exceeding one year;
 is a fugitive from justice;
 is an unlawful user of any controlled substance;
 is an alien illegally or unlawfully in the US;
 has been adjudicated as a mental defective or has been committed to
any mental institution;
 is an alien who is a national of a country as to which the Secretary of
State has made a determination (that remains in effect) that such
country has repeatedly provided support for acts of international
terrorism; or
 has been discharged from the Armed Services of the United States
under dishonorable conditions.
Regulation of Possession of Select Agents
 On December 4, 2001, the Senate Appropriations Committee
approved HR 3338, the DOD Appropriations Bill for FY 2002,
which Senator Diane Feinstein (D-CA) and Senator Judd Gregg
(R-NH) amended to include Section 8134 Regulation of Biological
Agents and Toxins. (same as Section 216 of S l765, the
Bioterrorism Preparedness Act of 2001, which was reintroduced by
Senator Frist and Senator Kennedy on December 4, 2001)
 Restates CDC select agent transfer rules and requires safeguards
to prevent access to such agents and toxins for use in domestic
or international terrorism or for any other criminal purpose
 Mandates biannual updating of select agent list
 Mandates regulations and standards for possession of select
agents that ensure exclusion of individuals restricted by the USA
Patriot Act and provide for traceability of select agents
 Mandates appropriate security requirements for persons
possessing, using, or transferring biological agents and toxins
ASM Positions on Antiterrorism Legislation

ASM supported regulating shipment of select agents
• Assisted CDC in defining the select agent list
• Publicized select agent rule to scientific community and
exhorted microbiologists to adhere to all requirements

ASM supported regulating possession of select agents
• ASM supported USA Patriot Act that restricts possession by
individuals who might pose heightened risk of misuse but that
does not restrict all aliens
• ASM supported the Kennedy and Frist Regulation of Biological
Agents and Toxins section of the Bioterrorism Preparedness Act
of 2001and the Feinstein amendment to the DOD
Appropriations Bill that require registration for legal possession
of select agents and that mandate biosafety and biosecurity
practices for select agents
Restricting Research Publication
Opacity
 Should there be criteria that would warrant restrictions on
publication or other dissemination of research results?
 Should more research be declared classified?
 Should we stop revealing genomes?
 Should some aspects of research be withheld from
publication, e.g. methods or selective results?
 Should there be review boards to consider the national
security implications of all publications?
Antibiotic Resistance of Bacillus anthracis
 The American Society for Microbiology's Web site includes the
abstracts of the 4th International Conference that was organized by
scientists from the U.S. Army Medical Research Institute, the British
Defense Research Agency, NIH, and the Pasteur Institute.
 Board 42A. In Vitro Selection and Characterization of High-Level
Fluoroquinolone Resistance in Bacillus anthracis. L. Price, A. G.
Vogler, S. James, and P. Keim. Northern Arizona State University
• increasing exposure to ciprofloxacin resulted in evolution of
fluoroquinolone resistance in Bacillus anthracis
• antibiotic resistant B. anthracis can be intentionally produced
• multiple antibiotic treatment was warranted in cases of
inhalational anthrax
 Should this abstract have been published?
 Should it have been removed after Sept. 11?
Concern Over Scientific Information
ASM posted information about bioterrorism and anthrax at
its web site for the education of the scientific community
 “The principle right now is one of openness in science--if
someone wants to publish a legitimate research paper
we’re not going to be the censor.” Ronald Atlas-President elect ASM
Position of openness of science draws scorn
Eric Lichtblau Response to Terror: Rising Fears That What We Do
Know Can Hurt Us, Los Angeles Times November 18, 2001

“We have to get away from the ethos that knowledge is
good, knowledge should be publicly available, that
information will liberate us...Information will kill us in
the techno-terrorist age, and I think it's nuts to put that
stuff on Web sites.” Arthur Caplan--U. Penn. bioethicist
Smallpox Virus Genome
 The entire DNA genome of a highly virulent Variola is
constituted of 186,102 base pairs
 Sequence analysis shows 187 closely spaced open reading
frames specifying putative major proteins containing >= 65
amino acids.
 150 proteins have > 90% identity to major gene products
encoded by Vaccinia virus, the smallpox vaccine.
 Variola virus has a group of proteins that are truncated
compared with Vaccinia virus counterparts and a smaller group
of proteins that are elongated.
 The terminal regions encode several novel proteins and
variants of other poxvirus proteins potentially augment variola
virus transmissibility and virulence for its only natural host,
humans.
Massung RF., et al. Analysis of the complete genome of smallpox
variola major virus strain Bangladesh-1975. Virology.
201(2):215-40, 1994 Jun.
 Should the genome have been published?--ASM position was Yes
Smallpox Virus Genome
 Analysis of variola virus nucleotide sequence revealed proteins
belonging to several families that provide the virus with the
possibility of overcoming the barriers of specific and non-specific
host immune defense against viral infection.
 The complement-binding proteins, lymphokine-binding proteins,
serine protease inhibitors, and proteins providing the
orthopoxviruses with resistance to interferon are of this type
Shchelkunov SN, et al. Genes of variola and Vaccinia viruses necessary
to overcome the host protective mechanisms. FEBS Letters. 319(12):80-3, 1993 Mar 15.
Conclusions
 Genome analysis shows basis for smallpox viral virulence
 Genome shows immunomodulation is critical for smallpox virulence
 Genome analysis reveals targets for vaccine, drug, and detection
development
Should the genome have been published? Is the information
of more value for improving medicine or to terrorists?
Bacillus anthracis genome
 Bacillus anthracis plasmid pXO1 contains a "pathogenicity island,"
with the three toxin genes (cya, lef, and pagA), regulatory
elements controlling the toxin genes, three germination response
genes,19 additional ORFs and 3 sequences that may encode
enzymes responsible for the synthesis of a polysaccharide capsule
usually associated with serotype-specific virulent streptococci.
Okinaka RT. Cloud K. Hampton O. Hoffmaster AR. Hill KK. Keim P. Koehler
TM. Lamke G. Kumano S. Mahillon J. Manter D. Martinez Y. Ricke D.
Svensson R. Jackson PJ. Sequence and organization of pXO1, the large Bacillus
anthracis plasmid harboring the anthrax toxin genes. Journal of Bacteriology.
181(20):6509-6515, 1999.
Conclusions
Major virulence elements of Bacillus anthracis are plasmid encoded
 Should the genome have been published?
 Should the information be expunged from the open
literature?
 Should the full genome of B. anthracis be released?
Single Genes/Reverse Genetics
 As demonstrated by reverse genetics, a single mutation at position
627 in the PB2 protein of an H5N1 influenza A virus influenced the
outcome of infection in mice, i.e one mutation can greatly increase
virulence.
 High cleavability of the hemagglutinin glycoprotein was an
essential requirement for lethal infection.
Hatta M, Gao P, Halfmann P, Kawaoka Y. Molecular basis for high virulence of Hong
Kong H5N1 influenza A viruses. Science. 2001 Sep 7;293(5536):1773-5
Conclusions
 Single gene modification can greatly increase pathogen virulence.
 A knockout can produce a highly lethal strain of influenza.
 May be simple to create more virulent biothreat agents
 Should this information have been revealed?
 Should journals censor information in such articles?
ASM Publication Board Statement
 “The ASM recognizes that there are valid concerns regarding the
publication of information in scientific journals that could be put to
inappropriate use. The ASM hopes to participate in the public debate
on these issues. Until a national consensus is reached, the rare
manuscript that might raise such issues will be reviewed by the ASM
Publications Board prior to the Society proceeding to publication."
This statement with an accompanying introduction will be sent to all
Editors of all ASM journals in order that they be alerted as to their
responsibilities in this matter.”
 The editors of the ASM journals are trying to be responsible stewards
of scientific information and communication by carefully balancing
national security with the value of advancing science for the benefit of
humanity.
Restrict Research Conduct
Constraint
 Are there areas of research or types of experimentation
that they should not be conducted at all?
 Are there others that should require advance approval?
 Is molecular biology a threat--Will recombinant DNA
technology be used to create horrific biothreat agents?
 Should certain molecular biology experiments and
methodologies be prohibited?
Mousepox--Immune System Suppression
 Expression of IL-4 by a thymidine kinase-positive mousepox virus
suppresses cytolytic responses of natural killer (NK) and a strong
CD8(+) cytotoxic T-lymphocyte (CTL) and expression of gamma
interferon.
 Genetically resistant mice infected with the IL-4-expressing virus
develop acute mousepox accompanied by high mortality.
Jackson RJ. et al. 2001. Expression of mouse interleukin-4 by a recombinant
ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic
resistance to mousepox. J. Virology 75:1205-10.
Conclusions
 Virus-encoded IL-4 not only suppresses primary antiviral cellmediated immune responses but also can inhibit the expression of
immune memory responses.
 A poxvirus can be simply genetically engineered for which
immunization will be totally ineffective.
 Should this research have been permitted?
DNA SHUFFLING--Power to Create New Biothreat Agents?
 "DNA shuffling" is a method of in vitro recombination that
relies on the ordering, trimming, and joining of randomly
cleaved parental DNA fragments annealed to a transient
polynucleotide scaffold.
 Generates chimeric libraries averaging 14.0 crossovers per
gene, a several-fold higher level of recombination than
observed for other methods.
Coco WM., et al. DNA shuffling method for generating highly
recombined genes and evolved enzymes. Nature Biotechnology.
19(4):354-9, 2001 Apr.
Conclusions
 Allows generation of diverse recombinant organisms
 Allows potential rapid production of numerous biothreat
agents with enhanced virulence
 Increases threat of being able to create a deadly new
pathogen intentionally or accidentally
 Should this methodology be banned? Is it too
powerful
Role of Scientific Community in
Identifying Misconduct
Responsibility
 What obligation do members of the research community
have to identify, call attention to, or clarify activities of
others that may appear suspicious?
Transparency
 Are there areas of research or types of experiment that
pose such sensitivity regarding potential bioweapons
application that they merit extraordinary obligations for
transparency and openness?
ASM Resolution on Bioethics
The Council Policy Committee of the American Society for
Microbiology affirms the longstanding position of the
Society that microbiologists will work for the proper and
beneficent application of science and will call to the
attention of the public or the appropriate authorities misuses
of microbiology or of information derived from
microbiology.
ASM members are obligated to discourage any use of
microbiology contrary to the welfare of humankind,
including the use of microbes as biological weapons.
Bioterrorism violates the fundamental principles expressed
in the Code of Ethics of the Society and is abhorrent to the
ASM and its members.