164. U.S. Technical Paper Submitted to the Second Review Conference of the Parties to the Biological and Toxin Weapons Convention: Scientific and Technological Developments Relevant to the Convention, September 9, 19861

1. Introduction

In preparation for the 1986 Review Conference on The Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on their Destruction (BWC),2 the Preparatory Committee requested the depositary nations to prepare national papers on new scientific and technological developments relevant to the Convention.

While nothing of the fundamental significance of the breakthroughs in recombinant DNA techniques in the 1970s has occurred since the last Review Conference, the industrial applications of these discoveries have become more and more prominent in everyday life. The applications of these discoveries to medicine, agriculture and other fields of scientific endeavour are all around us. In addition, the number of countries developing their own biotechnology industry is growing. These trends have practical significance for the BWC.

Accordingly, our examination of advances relevant to the Convention cannot be limited solely to revolutionary breakthroughs in knowledge, for it is perhaps the adaptation of these breakthroughs to everyday use that brings about the changes most relevant to the Convention. Advances have taken place in the industrial application of these discoveries to a vast array of human problems. These advances have increased our ability to manufacture new substances or modify old ones, as well as making it easier and faster to produce these products. While promising great benefits for mankind, these developments also cause concern, for they have brought about the proliferation of industrial biotechnologies, complicated verification and brought into being techniques and products that, if misused, could pose a significant biological and toxin weapons threat.

2. Advances in Industrial Application of Biotechnology

In a number of areas, the industrial application of biotechnology has relevance to the Convention.

Altered Organisms. Biotechnology enables the development of micro-organisms and products with new, unorthodox characteristics. These new microorganisms have a variety of uses, for example, in developing environmentally safer pesticides or new treatments for cancer. However, in examining these developments from the point of view of the BWC, we cannot ignore the potential misuse of biotechnology to produce new biological agents or to improve certain characteristics in those already known. Transferring certain genetic traits into

1

Department of State Bulletin, December 1986, pp. 44-46.

2 The text of the Convention may be found in Documents on Disarmament, 1972, pp. 133-138.

naturally infectious micro-organisms can potentially create organisms of greater virulence, antibiotic resistance and environmental stability. Changing the microbes genetically could alter their immunogenicity, thereby rendering vaccines and serodiagnostic techniques useless. Otherwise harmless micro-organisms could be altered into virulent ones, although the host would continue to recognize these micro-organisms as innocuous and therefore not defend against them.

Bio-engineering of micro-organisms has other implications as well. Bacteria and yeasts, genetically altered to produce products, are miniature factories by virtue of their ability to reproduce rapidly. Large quantities of compounds, previously available only in minute amounts, thus become available. Such a method of production is becoming more commonplace in civilian industry.

In addition, it is now possible to identify genes which have desirable properties and transfer them between host micro-organisms. A nearly infinite variety of biological compounds designed for specific uses and given specific characteristics is possible. Given the technical progress in this area, future developments should be of concern to the Review Conference. Within the next decade, the potential for misuse of ongoing developments in biotechnology could be most pronounced in the following areas:

Microbial pathogens could be genetically engineered to maximize infectivity and pathogenicity. Likewise they could be modified to increase or decrease their environmental stability and persistency.

Toxins. Naturally occurring protein toxins could be made in host organisms by modifying their DNA. Plant and/or fungal toxins could be mass produced. If used as an agent, the origin of these toxins could be difficult to pinpoint, given that they are already in the environment, albeit at low concentrations. Improvements in biotechnology since the previous Review Conference lead us to believe that production of potent toxins, which until now were available only in minute quantities, and only upon isolation from immense amounts of biological materials, can now be produced in kilogram quantities, which could be militarily significant.

Peptides. Peptides have been called "the antibiotics of the year 2000" because these biological materials may represent a new class of miracle drugs. Peptides are precursors of proteins made up of amino acids. They are interesting molecules for many reasons. They are active at very low concentrations (one part per billion or trillion) which makes their detection very difficult. They can be successfully modified as agonists (more active products) or antagonists (having a contrary activity). For example, modification of LHRH, a fertility hormone, by substituting a single amino acid has yielded a product 50 times more potent. Another modification of this same peptide yields a product useful in the treatment of prostate cancer.

Their range of activity covers the entire living system, from mental processes (e.g., endorphins) to many aspects of health such as control of mood, consciousness, temperature control, sleep or emotions, exerting regulatory effects on the body. Even a small imbalance in these natural substances could have serious consequences, inducing fear, fatigue, depression or even causing death.

The predictable modification of peptide and protein structure and function (i.e., protein engineering) is in its infancy. Computer-aided molecular design will

rapidly develop, enabling molecules to be manipulated for varying degrees of physiological activity, specificity and stability. Technologies permitting the direct chemical synthesis of peptides and proteins in large yields will, in the more distant future, augment or replace microbial production of these molecules. Advances in Production. As mentioned above, once a suitable recombinant organism has been engineered, exploiting it becomes a matter of using established procedures. Biological production technology has proceeded to the point where large quantities of biological products can be produced quickly in small facilities. Long term storage, in some cases, will not be needed because large quantities can be produced very quickly. Several relevant technological considerations regarding biological production are discussed below.

Mammalian Cell Culture. Recent advances in mammalian cell culture make possible the growth of mammalian cells on the surface of minute beads, rather than on the inner surface of glass roller bottles. These cell culture systems provide the ideal environment for the growth of viruses. The new techniques greatly simplifies virus production and allows large scale yields in facilities for very modest size. As another example of advances in this field, the amount of tissue culture media needed to produce antibodies has been reduced a hundredfold by the use of encapsulated hybridomas. Such developments are eroding the distinction between production facilities and small laboratories.

Continuous Flow Fermentors. The introduction of computer controlled, continuous flow fermentors has dramatically increased productivity. Most likely the size of fermentors operating by batch process can be reduced a thousandfold by conversion to a continuous flow process.

Safety Standards. Pharmaceutical plants around the world increasingly have incorporated safety provisions akin to those which were once unique to BW production facilities, making it increasingly difficult to distinguish between permitted and prohibited activities.

Hollow Fibre Technology. Hollow fibre technology provides an example of the industrial production potential of the new technologies. This technology permits a far greater concentration of cells with a markedly increased rate of recovery in a shorter time than previously obtained using roller bottles. This equipment occupies less than one twentieth the volume of the previous technology. In the isolation of such cellular biomaterials as pyrogens, a similar transformation has taken place. Separation and reconstitution of the product can now be accomplished in about an hour using new compact ultrafiltration methods, whereas older methods took as much as four days.

Though not without constraints, developing biological and toxin weapons is an easier task than developing adequate defenses against them. However, the very advancements in biotechnology that have caused increased concern have also put new tools in the hands of those conducting permitted biological defense research. In particular, gene splicing techniques can have an impact on development of effective vaccines against those disease agents already identified. Advances in production of biological materials can greatly facilitate production of vaccines, once these have been developed. Development and production of highly specific antibodies using recently developed techniques may provide the hope of more rapid identification of biological agents and toxins. Nevertheless, these positive

developments represent a partial and incomplete response to the potential dangers resulting from advances in biotechnology.

Improvements in equipment, speed of production and quality of product are a common occurrence in the history of the commercial development of any new technology. Because of the large number of technical innovations in biotechnology, especially in the area of industrial microbiology, the BWC has become more difficult to verify since its signature in 1972.

Developments intended to increase production, decrease cost and create safer conditions for handling biological materials have blurred former distinctions important for purposes of verification-for example, between a large production facility and a laboratory. Also, capabilities to break out of the Convention in a very short time have increased.

3. Outbreaks of Infectious Diseases

Acquired immune deficiency syndrome (AIDS) represents a newly recognized epidemic illness since the last Review Conference in 1980. Rift Valley Fever (RVF) represents a classic example of a long-known disease which spreads into a new geographical area with relatively disastrous results.

AIDS. AIDS in a short period of time has become a major worldwide health problem. AIDS is caused by human T-Cell lymphotrophic virus (HTLV-III), a retrovirus. The disease results from virus infection and destruction of T-helper cells, an important component of the immune system that helps the body ward off disease. Without these cells the patients is susceptible to a wide variety of opportunistic pathogens such as pneumocystis, fungi, and mycobacteria.

HTLV-III first entered the USA in 1977. HTLV-III antibodies have not been detected in serum specimens collected and frozen in the USA before 1977. HTLV-III probably evolved as a mutant of an African retrovirus. Serum specimens obtained from Ugandan children in 1973 had antibodies to HTLV-III or an HTLV-III-like virus. Epidemic AIDS was first recognized in 1981. Cases characteristically occurred among homosexual males, haemophiliacs, Haitianborn immigrants and intravenous drug abusers. Approximately 16,000 cases have been reported to date in the United States.

AIDS is a classic example of a new disease that has now become pandemic and which arose either from a mutational event of an existing human virus or introduction of an animal (monkey) virus into the human population.

Rift Valley Fever (RVF). RVF has long had a major role as a domestic animal and human pathogen in sub-Saharan Africa. RVF virus was first discovered in Kenya in 1931 as a consequence of a major epizootic in sheep with secondary human infections. There is no evidence that there has been geographic spread of the virus within Africa with two exceptions: (a) the 1977 Egyptian epidemic with the 1951 epizootic to be discussed below and (b) recognition of RVF in South Africa.

Sudan-reared sheep were being transported in 1977 from north central Sudan to live animal markets in southern Egypt at a time when sheep in Sudan experienced signs consistent with RVF. Rapid transport of sheep from epizootic areas allowed infected sheep to survive the trip to southern Egypt where RVF virus was spread to local animals.

Once introduced, the RVF virus spread rapidly and caused an impressive epizootic epidemic. In 1977, 18,000 human cases with 598 deaths were officially reported. There may have been more than a million infections in humans. Viral activity declined with onset of cool weather, but transmission of virus reoccurred in the warm season of 1978 and the disease extended its geographic distribution within Egypt. During 1979, there were occasional outbreaks and a few RVF virus isolations with further decline of virus activity in 1980. The potential for RVF infection in Egypt continues to exist, but for no documented reason, disease activity has diminished and perhaps even disappeared.

4. Summary

The past ten years have witnessed impressive strides in the fields of molecular biology and biotechnology. As the two juxtaposed words "molecular biology" imply, the distinction between biology and chemistry is becoming blurred. However, the US continues to believe that Article I, which defines the scope of the Convention, has proved sufficiently comprehensive to have covered recent scientific and technological developments relevant to the Convention. In many ways, recent progress in biological technology affects the ease of concealment of manufacturing plants and the availability of new delivery systems, particularly for biological chemicals such as toxins and peptides. Verification of the Convention, always a difficult task, has been significantly complicated by the new technology. The confidence derived from the belief that certain technical problems would make biological weapons unattractive for the foreseeable future has eroded. The ease and rapidity of genetic manipulation, the ready availability of a variety of production equipment, the proliferation of safety and environmental equipment and health procedures to numerous laboratories and production facilities throughout the world are signs of the growing roles of biotechnology in the world's economy. But these very same signs also give concern for the possibility of misuse of this biotechnology to subvert the Convention.

165. U.S. Background Document Submitted to the Second Review Conference of the Parties to the Biological and Toxin Weapons Convention: U.S. Compliance With the Convention, September 9, 19861

Article I

The United States is in full compliance with the obligations contained in Article I. Facilities previously used for development, production or stockpiling of biological weapons are now devoted to peaceful purposes. The United States biological defense programme is limited to research on strictly defined prophylactic, protective or other peaceful purposes, such as immunization.

1 Department of State Bulletin, December 1986, pp. 46-47.