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 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

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(1-2):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?

Smallpox Virus Genome

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.

ConclusionsMajor 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 cell-

mediated 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.