Biosecurity Campbell

Dual-use biomedical research and the roles of journals: 

Dual-use biomedical research and the roles of journals Philip Campbell Como, 20 March 2005

Political concerns in US: 

Political concerns in US 2002: Congress discussions stimulated by controversial papers January 2003: NAS: editors, authors and security stakeholders meet 2004-5 Development of National Science Advisory Board for Biodefense

Controversial papers: 

Controversial papers Interleukin 4 gene into mousepox virus made it more lethal (Ronald Jackson and colleagues J Virology Feb 2001) Altered smallpox gene –test-tube studies of inhibiting immune response (Ariella Rosengaard et al, PNAS June 2002) Synthesis of polio virus (Eckard Wimmer at al, Science 9 August 2002)

Information control: 

Information control How can one define what is dangerous and how can we design a system that contains that danger while allowing legitimate biomedical research to proceed in a manner acceptable to society? Should more research be declared classified? Should there be review boards to consider the national security implications of publications and presentations? Should we restrict access and dissemination of scientific information? Should scientists be constrained regarding which questions they can ask? Should journals reject papers containing potentially sensitive information? Should journals modify principles of unrestricted access to data and materials?

Journal Editors and Authors Group : 

Journal Editors and Authors Group Ronald Atlas, President ASM, Editor CRC Critical Reviews in Microbiology Philip Campbell, Editor, Nature Nick Cozzarelli, Editor, PNAS Greg Curfman, New England Journal of Medicine Lynn Enquist, Editor, Journal of Virology Gerry Fink, MIT Annette Flanagin, Managing Senior Editor JAMA, President, Council of Science Editors Jacqueline Fletcher, President, American Phytopathological Society Beth George, DOE Gordon Hammes, Editor, Biochemistry David Heyman – CSIS Thomas Inglesby, Editor, Biosecurity and Bioterrorism Samuel Kaplan, Chair, ASM Publications Board Donald Kennedy, Editor Science Judith Krug, American Library Association Rachel Levinson, OSTP Emilie Marcus, Editor, Neuron (Cell Press) Henry Metzger, NIAMS, NIH Stephen S. Morse, Columbia University Alison O'Brien, Editor, Infection and Immunity Andrew Onderdonk, Editor, Journal of Clinical Microbiology George Poste, Health Technology Networks Beatrice Renault, Editor, Nature Medicine Robert Rich, Editor, Journal of Immunology Ariella Rosengard, University of Pennsylvania Steven Salzburg, TIGR Thomas Shenk, ASM President-Elect, Past Editor, Journal of Virology Mary Scanlan, American Chemical Society Herbert Tabor, Editor, Journal Biological Chemistry Eckard Wimmer, SUNY Stony Brook Keith Yamamoto, Editor, Molecular Biology of the Cell

Meeting also included…: 

Meeting also included… OSTP, Department of Homeland Security, FBI, CIA… These ‘representatives’ were concerned that the scientific community should put its own house in order. They were not at that time advocating greater restrictions. Potential action by Congress loomed large.

Editorial controversy: 

Editorial controversy Objections to editorial censorship: Stanley Falkow in Science: need definition Public Library of Science: anti censorship Objections to openness: Richard Meyer, Center for Disease Control – restrict key details George Poste: 'collision course'

Follow-up by Nature: 

Follow-up by Nature Established informal group of advisers with defence connections, including scientists at national labs in the US and at Porton Down in the UK. Informal discussions held. Established internal framework for consultation. Published policy.

Nature journal policy: 

Nature journal policy The editorial staff of Nature journals maintain a network of advisers on biosecurity issues. All concerns on that score, including the commissioning of external advice, will be shared within an editorial monitoring group consisting of the Editor-in-Chief of Nature publications, the Executive Editor of the Nature research journals, the Chief Biological Sciences Editor of Nature, and the Chief Editor of the journal concerned. Once a decision has been reached, authors will be informed if biosecurity advice has informed that decision.

Emerging ‘line in the sand’: 

Emerging ‘line in the sand’ General consensus: open publication of pathogenic genomes key to public health Details of pathogenic mechanisms used by organisms to outwit the immune system are necessary to develop new treatments Some experiments with hybrid pathogens against scourges that currently kill many worldwide (like the flu) are worth the risk Properly contained experiments in appropriate facilities are crucial Details of methods required for replication and progress Public outreach and education crucial to avoid misunderstandings and inappropriate regulation

Biosecurity & openness: 

Biosecurity andamp; openness Publication of infectious mechanisms and genomes, as SARS genome has already proven, can have almost immediate health benefits Increase economic health and academic quality Openness attracts talent Openness encourages international cooperation

Science is international:consensus: 

Science is international: consensus International activities like science need international consensus in what constitutes appropriate action Overly harsh regulation of publication in one country will be ineffective Classifying certain research unilaterally would also create incentives for scientists to move research programs elsewhere

Science is international:trust: 

Science is international: trust Non-US editors and scientists becoming wary - need to build-up trust again Visas - news reports that visa situation affecting decisions to enroll in US institutions and business Could have consequences for academic, technologic and economic strength in coming decades Access to government-run information - could PubMed, a critical information resource run by NLM, excise controversial papers at request of US government?

So what has happened?: 

So what has happened? Nature journals: several papers sent out for dual-use assessment, no decisions affected. Science: no decisions affected. PNAS: Many occurrences of Category A agents, no decision not to publish or to delay or modify papers ASM: 500 select-agent ms reviewed by journal editor and chair of publications board, none withheld. 60% ASM submissions have international or non-US authorships

What is “it”?: 

What is 'it'? 2002 meeting at Monterey Institute Center for Non-Proliferation Studies considered placing restrictions on research that involves a Select Agent and that aims to achieve one or more of six weaponization-related goals: 1.   Enhance pathogen infectivity, pathogenicity, antibiotic resistance, or resistance to host immunological defenses Improve the ability of a microbial pathogen to remain viable and virulent during prolonged storage and/or after release into the environment Facilitate the dissemination of biological agents as a fine-particle aerosol Facilitate the dissemination of a biological agent by contamination of food or water sources Create a novel pathogen or one with characteristics that have been altered to evade current detection methods or host immune defenses Assemble oligonucleotides to synthesize the genome of a pathogenic microorganism.

Other bio-weaponry to come?: 

Other bio-weaponry to come? George Poste, NAS meeting 2003 (not formally published): Microbiology just a part of the landscape Deliberate engineering of immune escape, stealth viral vectors Overproduction of host inflammatory mediators to produce toxic shock Knocking out genes that regulate key cell processes such as cell proliferation. Small molecules that disrupt molecular circuits, eg networks in immune response, blood clotting system, higher brain function Acoustic disruption – bone pain, airway modulation, ultrasonic skin heating. 'Sophisticated, but not beyond the bounds of state actors'

Manuscripts of concern: Fink: 

Manuscripts of concern: Fink October 2003 US National Academy of Sciences committee chaired by Gerald Fink Identified some categories of experiments should be cause for concern: Render vaccines ineffective Confer resistance to useful antibiotics or antivirals Enhance virulence of microorganisms Increase transmissibility of pathogens Alter host range of a pathogen Render a pathogen harder to detect ‘Weaponize’ biological agents or toxins

More ‘dual-use’ publications: 

More ‘dual-use’ publications After the Jan 2003 meeting dual-use publication continues May 2003 Nature - anthrax genome May 2003 Science - SARS sequence Mar 2004 Science - crystal structure of 1918 pandemic influenza hemagglutinin Aug 2004 Nature - anthrax toxin-receptor structure Oct 2004 Nature - construction of virulent flu in mice with 1918 HA Dec 2004 Nature – gene synthesis

Anthrax genome (Nature, May 2003): 

Anthrax genome (Nature, May 2003) Provides ability to identify signatures of various strains Insights into possible pathogenic mechanisms Improved vaccines Risk: possible development of more lethal varieties

SARS sequence (Science, May 2003): 

SARS sequence (Science, May 2003) Clear identity of virus International comparison of isolates Immediate effects on outbreak control Better tracking and diagnosis Potential vaccines Learn pathogenic mechanisms, leading to treatments Risk: sequence available for negative purposes

Anthrax toxin-receptor(Nature, Aug 2004): 

Anthrax toxin-receptor (Nature, Aug 2004) New insights into toxicity Possible treatment leads, with agents that interfere with mechanism Risk: tweaking toxin to improve its efficacy

Virulent flu in mice from 1918 strain proteins(Kobasa et al, Nature, Oct 2004): 

Virulent flu in mice from 1918 strain proteins (Kobasa et al, Nature, Oct 2004) H5N1 (haemagglutinin 5, neuraminidase 1) rampant in birds in SE Asia, human pandemic predicted. Single anti-flu drug on market. Need new antivirals to attack virus from various angels to avoid escape, and immunomodulators to enhance antiviral host defence mechanism. Reverse genetics technique to clone cDNA to generate infectious virus - previously published. Pinpointed haemagglutinin gene as responsible for high pathogenicity out of those previously identified in PNAS. Inconclusive as it’s mouse model. Underlying mechanism – neutrophil influx and associated inflammatory foci in lungs – novel and important for drug design even if we don’t know how particular haemagglutinin modulates effect.

Virulent flu in mice from 1918 strain proteins(Kobasa et al, Nature, Oct 2004): 

Virulent flu in mice from 1918 strain proteins (Kobasa et al, Nature, Oct 2004) Post-publication concern in media about safety, but was level 4 and enhanced level 3 labs. Concern as to why do the work. See previous justification, but maybe journals and/or authors need to provide more explicit justification. Concern over lack of transparency and democratic accountability of journal’s dual-use risk assessment. (Paper was seen by experts within the US risk assessment community.)

Accurate multiplex gene synthesis from programmable DNA microchips.Tian et al, Nature 432 1050-4 2004: 

Accurate multiplex gene synthesis from programmable DNA microchips. Tian et al, Nature 432 1050-4 2004 Testing the many hypotheses from genomics and systems biology experiments demands accurate and cost-effective gene and genome synthesis. Here we describe a microchip-based technology for multiplex gene synthesis. Pools of thousands of 'construction' oligonucleotides and tagged complementary 'selection' oligonucleotides are synthesized on photo-programmable microfluidic chips, released, amplified and selected by hybridization to reduce synthesis errors ninefold. A one-step polymerase assembly multiplexing reaction assembles these into multiple genes. This technology enabled us to synthesize all 21 genes that encode the proteins of the Escherichia coli 30S ribosomal subunit, and to optimize their translation efficiency in vitro through alteration of codon bias. This is a significant step towards the synthesis of ribosomes in vitro and should have utility for synthetic biology in general.

Protein-mediated error correction for de novo DNA synthesis Carr et al (MIT), Nucleic Acids Research 32 e162 (2004): 

Protein-mediated error correction for de novo DNA synthesis Carr et al (MIT), Nucleic Acids Research 32 e162 (2004) The availability of inexpensive, on demand synthetic DNA has enabled numerous powerful applications in biotechnology, in turn driving considerable present interest in the de novo synthesis of increasingly longer DNA constructs. The synthesis of DNA from oligonucleotides into products even as large as small viral genomes has been accomplished. Despite such achievements, the costs and time required to generate such long constructs has, to date, precluded gene-length (and longer) DNA synthesis from being an everyday research tool in the same manner as PCR and DNA sequencing. A critical barrier to low-cost, high-throughput de novo DNA synthesis is the frequency at which errors pervade the final product. Here, we employ a DNA mismatch-binding protein, MutS (from Thermus aquaticus) to remove failure products from synthetic genes. This method reduced errors by andgt;15-fold relative to conventional gene synthesis techniques, yielding DNA with one error per 10 000 base pairs. The approach is general, scalable and can be iterated multiple times for greater fidelity. Reductions in both costs and time required are demonstrated for the synthesis of a 2.5 kb gene.

Synthetic biology: 

Synthetic biology Engineering as well as science Precision design, not 'DNA bashing' Focus on artificial production of cell components (genes, networks) Methods literature Cost reductions: technology widely available within two years of publications Registration of equipment? Do we need Asilomar-type moratorium?

Synthetic biology visions Oliver Morton, Wired January 2005: 

Synthetic biology visions Oliver Morton, Wired January 2005 'The goal, as Endy puts it, is nothing less than to 'reimplement life in a manner of our choosing.' 'And what might the practitioners of this emerging science do with such godlike capability? Within a decade, some hope to create bacteria able to mass-produce drugs that currently have to be painstakingly harvested from rare plants. Others talk about making viruses encased in protein sheaths that can be used to produce fabric with molecular circuitry woven into its warp and weft. 'In the more distant future, synthetic biologists envision building more complex organisms, like supercoral that sucks carbon out of the biosphere and puts it into building materials, or an acorn programmed to grow into an oak tree - complete with a nifty tree house. 'And there's the opportunity to add new chromosomes to the human genome, ushering in a panoply of human augmentations and enhancements.'

Possible restrictions processes: 

Possible restrictions processes Prime responsibility on funding agency at outset At publication stage, submission of paper about 'Restricted' research project accompanied by a letter from the funding agency denoting which portions of the paper were sensitive and warranted restrictions on distribution. Dissemination of the embargoed material to legitimate scientists (identified through a simple vetting process) would then be controlled by the journal editor, in cooperation with the funding agency. For example, access to sensitive data might be provided through secure, password-controlled websites, with substantial fines and other sanctions (such as denial of access) imposed in cases of unauthorized transfers. [Monterey workshop August 2002]

Restrictions problems: 

Restrictions problems Needs to be international Does not prevent internet distribution or conferences Who would be allowed access? Who’d pay to maintain the restricted archives? Could be impractical See ‘Limiting the contribution of the open scientific literature to the biological weapons threat’ by RA Zilinskas and JB Tucker, J Homeland Security, December 2002 And……

Slide30: 

Still no further definition of restricted research!

NSABB: 

NSABB Screening of nominees First meeting hoped in June Driven by communications concerns above all: publications, conferences, informal Likely to review the Fink criteria, review codes of conduct, communication Sensitive information: crescendo of discussion Draft set of principles But recipe impractical. Each manuscript is like an individual person. Advisory only

Issues: 

Issues GM agents: restrictions eg on % of genome? Depends on bio context in which its expressed. Critical paths in food production Evolutionary biology of virus strains: basic science, vaccine application, dual use risk. Pathogen synthesis

Summary of journals’ duties: 

Summary of journals’ duties Be alert to papers whose risks of publication might outweigh benefits. Be alert to papers whose research materials’ dissemination might cause hazard. Ensure papers’ protocols adhere to ethics rules (local – so far) Keep in touch with debate Be transparent Journalism: scrutinize biodefence developments

Key considerations: 

Key considerations Journal editors must show responsibility Scientists must show responsibility Science’s integrity needs to be preserved: 'The traditions and structure of research in the U.S. today depends on replication and refutation, which means that sufficient data and methods to allow that must be published in peer-reviewed journals. Such publication also mitigates fraudulent results, sloppy science, and political biases guiding important policy decisions. Recent, well-publicized incidents of scientific misconduct underscore the merits of this system.' MRC Greenwood, Chancellor, UC Santa Cruz