BWC/CONF.IV/4/Add.1 21 November Original: ENGLISH. Geneva, 25 November - 6 December 1996

Transcription

1 FOURTH REVIEW CONFERENCE OF THE PARTIES TO THE CONVENTION ON THE PROHIBITION OF THE DEVELOPMENT, PRODUCTION AND STOCKPILING OF BACTERIOLOGICAL (BIOLOGICAL) AND TOXIN WEAPONS AND ON THEIR DESTRUCTION BWC/CONF.IV/4/Add.1 21 November 1996 Original: ENGLISH Geneva, 25 November - 6 December 1996 BACKGROUND PAPER ON NEW SCIENTIFIC AND TECHNOLOGICAL DEVELOPMENTS RELEVANT TO THE CONVENTION ON THE PROHIBITION OF THE DEVELOPMENT, PRODUCTION AND STOCKPILING OF BACTERIOLOGICAL (BIOLOGICAL) AND TOXIN WEAPONS AND ON THEIR DESTRUCTION Prepared by the Secretariat 1 In paragraph 21 of its report (BWC/CONF.IV/1), the Preparatory Committee for the Fourth Review Conference of the Parties to the Convention on the Prohibition of the Development. Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on their Destruction decided to invite States parties that wished to do so, including the Depositary Governments, to submit to the secretariat information on new scientific and technological developments relevant to the Convention. This information should cover the applications being made of such developments and their relevance to various aspects of the Convention. 2 The present document contains the information provided by States parties to the secretariat, as of 21 November 1996, pursuant to paragraph 21 of the report of the Preparatory Committee. GE (E)

2 page 2 Sweden BACKGROUND INFORMATION ON NEW SCIENTIFIC AND TECHNOLOGICAL DEVELOPMENTS RELEVANT TO THE BIOLOGICAL AND TOXIN WEAPONS CONVENTION Introduction Sweden has prepared the following paper on background information since 1991 in response to a request by the Preparatory Committee for the Fourth Review Conference and to facilitate the Conference consideration of article XII in the Final Document of the previous Review Conference. During the last decades biotechnology and genetic modification of microorganisms and mammalian cells have revolutionized many areas of biological and medical science. The huge amount of knowledge conesrning basic principles of life have found worldwide applications in solving problems of global interest, such as public health, animal health, agriculture and protection of the environment. Advances in molecular biology are providing new insights into the molecular pathology of diseases and have already affected the way drug discovery is undertaken. The research is focused on molecular targets and is organized around the mechanisms underlying disease processes. Co-evolution of mammalian cells and microorganisms has ensured that virulence factors are extremely well adapted and the study of the interface between cell biology and microbiology is one driving force in this development. Gene therapy is another area of research that is important in the characterization and validation of potential molecular targets. While these developments have been and are beneficial in the context of public health, animal health and agriculture, it has also the potential, if misused, to be a base for development of new or modified BW agents or toxins. Disease-causing mechanisms Our understanding of the molecular mechanisms of microbial infections has increased immensely over the last five years. A number of intriguing methods have been developed which allow studies of the development of infectious diseases at the molecular level. This has allowed the identification of many of the key molecules (virulence factors) that pathogens use to cause disease. In many cases the mode of action of the virulence factors and their interaction with host factors has been established. This increased knowledge is of fundamental importance for the development of new means to defeat infectious diseases. However, it is obvious that the increased knowledge also can be used to manipulate microorganisms to increase their attraction as BW agents. Another major development is the finding that a number of unrelated bacterial pathogens have a shared strategy for causing disease, e.g. Yersinia sp.. Salmonella sp., Shiqella sp. and Pseudomonas sp. but also a number of plant pathogens. All these bacteria have a common secretion system

3 page 3 for virulence factors. These complex systems have in some cases been shown, to function interchangeably between different pathogens. This shared strategy for virulence has led to an intense research where the goal is to target components of this system and to develop a common strategy to prevent infections by several different pathogens. But also here there is a potential threat that this knowledge can be misused to change the virulence of pathogens. Recent progress has also been made in the research on pathogenic viruses. Many of the receptors used by viruses to infect host cells have been identified. Of major importance has been the development of methods to genetically manipulate new groups of highly pathogenic viruses, such as Rabies, Marburg and Ebola. With these new methods it is now possible to study these viruses at the molecular level and it is also possible to construct viruses with improved potential as vaccines. Drug design The new insights into the molecular pathology of diseases have already affected the way drug discovery is undertaken. Many different strategies, e.g. screening libraries of organic molecules and peptides, structure-based drug design as well as identifying genes for inherited diseases, are utilized. Recombinant antibodies, vaccines, enzymes and growth factors targeting a variety of medical conditions have reached the clinic and many are already on the market. The diversity of product types reflects the wide range of therapeutic strategies that have been developed by using recombinant proteins. Among these are recombinant vaccines that produce immunity against specific pathogens, others are proteins functioning either by binding to cell surface molecules to regulate cell functions or by catalytically modifying specific substances e.g. toxins and other toxic compounds. Protein engineering is becoming more sophisticated and second-generation products have already been developed. The identification of novel genes by the Human Genome Programme as well as the gene therapy research will reveal more potentially useful protein products for therapy. Gene therapy, still in its infancy, has been discussed in the context of gene delivery to cancer cells as well as to cells lacking a gene function. In either case, considerable challenges remain. However, the second generation of viral and non-viral vectors are already under development as well as methods for transfer to stem cells. Another rationale that is considered important in cost-effective drug design is pharmacogenetics. The consequence of polymorphism on drug action will probably become more relevant to control, as small-molecule drugs are increasingly targeted at specific proteins encoded by disease genes. Populations with different geographic origins, have in this context different frequencies of most alleles studied, so far, in the Human Genome Diversity Programme. A consequence of this ethnic variation will probably be a broad variation in the drug response. Pharmacogenetic studies may in this way improve the safety and the efficiency profile of drugs and can also lead to market segmentation. This development should be kept in mind and closely followed.

4 page 4 This vast development of new therapeutic agents will lead to fine-tuned control of human diseases. Their range of activity covers the entire living system and even a small imbalance in these substances could have serious consequences. The worldwide increase in knowledge in this area of research increases the risk of hostile use of biological active agents, whether naturally occurring or not. Large-scale production Over the past decade, technological advances associated with the commercial biotechnology industry have made it possible to produce large quantities of microorganisms and biological products in small facilities. The introduction of continuous-flow fermenters with mass flow control, compact ultrafiltration methods has vastly increased the productivity. This has made it possible to significantly reduce the size of a fermenter compared with conventional batch fermenters that give the equivalent production. Real-time sensors and feedback loops under microprocessor control have also optimized culture conditions, resulting in much higher yields and better quality products. New cell-culture techniques greatly simplify the production of e.g. viruses and intracellular parasites. For example, allowing the cells to grow on surface of beads suspended in culture medium or by using hollow -fibre technology has permitted the scaling up of production. Advantages include economy and high concentration and purity of the end-product. Large-scale production of different biological active substances, in relatively small production facilities, has thus been made possible by the biotechnological development. Within the pharmaceutical industry research is intense for methods to stabilize drugs for aerosol delivery of, for example, toxins, chimeric toxins, modulators of the immune system and bioregulators. The outcome of this research could also increase the attraction to develop more stable BTW agents. With the advanced fermentation techniques available today, a military significant supply of BTW agents, with increased stability, could be produced over a short period, obviating the need for the long-term stockpiling of agents. As a result, a BTW production facility could be used for other purposes during peacetime. Release of genetically modified microorganisms in the environment One of the factors that constrains usage of biological weapons is their unpredictability. Of major concern in that respect is the survival of released microorganisms in the environment. The application of living microorganisms in medicine, industry and agriculture is increasing. Examples are use of living vaccines, biopesfcicides and bioremediation. This has put an increasing demand on control of survival, spread and development of microorganisms under different conditions. In recent years, considerable research has also been done on risk-assessment of GMO in the environment. Taken together, this development has increased the knowledge of the behaviour of microorganisms in different environments. There are several potential implications with regard to biological weapons that can emerge from this.

5 page 5 Techniques to predetermine the survival of microorganisms has been developed and several different approaches have been used. If minimized contamination of the environment with the released microorganisms is desirable, survival could be impaired by the introduction of specific mutation in genes important for survival, e.g., sporulation mutants of Bacillus thuringensis. The environmental impact of Bacillus thuringensis spores is difficult to assess and is therefore not well documented. This is also the reason why full-scale release of viable spores of Bacillus thuringensis (1015 spores per hectare, when used as insecticide) is not authorized in several countries. Another approach to control survival of different microorganisms is to introduce suicide-systems. Such a suicide-system could, hypothetically, be used to control the spread of bacteria in the environment. If increased survival is desirable, knowledge from studies of bacterial survival strategies in response to starvation could be used to achieve this. It is now a well-known fact that controlled starvation of different bacteria could increase their resistance towards UV -light and desiccation. Another emerging field with significance for biological warfare and public health is the viable but non-culturable state (VBNC) of many bacteria. At least 30 different species of bacteria, many of BW-importance, have been shown to be able to enter a viable but non-culturable state. In this state the cells are viable and in many cases virulent but not able to grow artificially. An example is Vibrio cholerae which could enter VBNC-state in the environment and hence would not be possible to detect by conventional techniques in the laboratory. However, if passed through the human intestine it can revert to a cultivable state and again cause infection. The VBNC state most likely represents a programmed physiological response to allow survival during a potentially letlial environmental stress. This would imply increased survival and persistence in the environment. Formulations, targeted for release, prepared to induce VBNC bacteria could potentially be used to mask deliberate dissemination of BW-agent. New antibacterial and antiviral agents The progress in developing truly new antibiotics has been rather slow for several decades. However, the resurgence of resistant organisms that cause tuberculosis, pheumonia and other severe diseases again emphasized the need for antibiotic development. Four major and truly different categories of antibiotics have been introduced during the last decade: imipenems, monobactams, augmented penicillins and fluoroquinolones. Where the last group, the fluoroquinolones, have out-standing antibacterial activity and cause limited problems with transferable resistance, another avenue that has been explored is combining existing antibiotics with substances that interfere with the bacterial mechanisms of resistance. The development of new antiviral agents has overall been slow due to the complex interactions betw een viruses and eucaryotic cells. However, a considerable number of drugs have been introduced, during the last decade for clinical use. These include treatments for severe respiratory virus infection in children and for serious forms of hemorrhagic fevers. All types of

6 page 6 interferons, alfa, beta and gamma, have been used for treating viral infections, generally in combination with antiviral agents. Thus the use of such combinations will improve the possibility to treat all types'of viral infections, even those caused by possible BW agents. Vaccines The rapid progress in biotechnology has also opened up new avenues for the development of a second generation of vaccines, subunit vaccines and recombinant vaccines. Examples of successful subunit vaccines are protein-carbohydrate complexes from Hemophilus influp.n:^ and StreptoMr^nc; pneumpniae that protect against the life-threatening diseases meningitis and pneumonia, respectively. Recombinant vaccines have been attracting a considerable interest during the last decade. Despite the fact that they in theory fulfil most requirements of an ideal vaccine, only a handful of these vaccines have been effective. An exciting new concept is the use of naked DNA for vaccination. DNA-based vaccines have advantages, such as a low cost, efficient large-scale production. Theoretically, they can also be multi-component and thereby protect against more than one disease. Administration is also relatively simple. Thus, the efficacy of the protection will determine their usefulness. It has been shown in an experimental model that they afford both humoral and cell-mediated immunity. DNA vaccines are of special promise for emerging infectious diseases as working with DNA can be done much more safely as compared to other constituents of microorganisms. There are several examples of newly discovered pathogens that first have been characterized with regard to their DNA. Thus, it is possible that DNA vaccination can be attempted even before the pathogens have been fully characterized. Identification, diagnosis and detection The diagnosis of infectious agents has traditionally relied on the association of a specific pathogenic microorganism with a characteristic clinical syndrome to diagnose an infection in any particular patient. This diagnostic process has relied on the isolation and cultivation of the presumed agent, followed by biochemical and antigenic identification. However, molecular biological techniques have led to the remarkable discovery that most environmental microbes are refractory to in vitro cultivation by current techniques. There are, for example, numerous serogroups of the diarrhoeal agent rotavirus discovered during the 1980s. Similarly, enteric adenoviruses have been identified in the last 10 years. Obviously, molecular biology will allow for a more precise and possibly more extensive array of already known genera of viruses and bacteria. This development in microbial identification and diagnosis of disease has improved prophylaxis and therapy. This development can also be beneficial for verification in making it possible to distinguish pre-existing strains of microorganisms from BW agents introduced from the outside.

7 page 7 There has also been development in the area of defence against biological and toxin warfare when it comes to methods for rapid identification and detection including for long-range, laser based systems. Conclusion The exploitation of biotechnology and the trend to establish commercial cooperations worldwide significantly contributes to the spread and increase of knowledge in this field of research and development. Continuing expansion of activities in industrial microbiology and increasing demand on control of survival and spread of microorganisms in the context of control of pests can have implications that have to be considered in relation to the BTWC. The growing knowledge about disease-causing mechanisms and about fine tuned control of processes in the human body explores new avenues for therapy and prophylaxis but also increases the risk of misuse. The consequence of polymorphism on the development of new therapeutic agents could introduce ethnic concerns that have to be considered in the future. The development in the field of identification and diagnosis can improve therapy and prophylaxis but also be of value in the context of biological defence and for verification. Vaccines based on an entirely new concept, DNA vaccines, can help to protect against newly discovered pathogens and may also fulfil the requirements of an ideal recombinent vaccine also of relevance for biological defence. The vast amount of research and development carried out has been beneficial for public health and industrial development but there is a risk that some aspects could be misused to improve the utility of biological and toxin warfare. The rapid pace of scientific and technological developments has continued during the period after the Third Review Conference up to now and will so continue. Sweden still believes that article I of the BTWC is sufficiently comprehensive and covers current developments in areas relevant to the BTWC and that all biological agents or toxins whether naturally occurring or not, including any resulting genetic modification are covered by the BTWC.