Do Recent Scientific and Technological Advances Lower the Threshold for the Proliferation of Biological Weapons?

Introduction

Concerns have arisen that, given the tremendous advances in genetics, analytical and synthetic biotechnologies, and the accompanying explosion in knowledge of the human genome and its function, as well as the complete genetic maps of a number of viruses and microorganisms, it may be possible for non-state parties, or states with rather primitive scientific and technical infrastructures, to develop effective biological weapons at relatively low cost and without the complex and expensive technological investment needed in the past. This paper presents an overview and assessment of the probability that such scientific and technical advances would stimulate the proliferation of biological weapons development to both states and non-state parties. In this discussion, the latter includes everything from a single individual with a cause up to highly organized and well-financed entities.

What Is a Biological Weapon (BW)?

Mother Nature has provided us with a wide range of infectious agents-bacteria, viruses and prions-that co-evolved with the human species and continue to take their toll among human, animal, and plant populations. The idea of employing a real or presumed transmissible agent to carry disease to one's enemy predates the germ theory of disease.[1],[2]

A BW can thus be defined as a living agent, or a substance produced by a living organism, together with the technology or formulation needed to deliver it, that can be used to cause deliberate harm to humans, or to the animals and plants upon which human populations depend. The powerful toxins produced by or derived from certain living organisms and that can be used in weapons (e.g., botulinum toxin produced by the soil bacterium Clostridium botulinum or ricin, a component of castor beans) are sometimes considered to be chemical weapons agents, but since they are included in the Biological and Toxin Weapons Convention (BWC), which was adopted in 1972 and entered into force in 1975, and have a biological origin, we will include them in the discussion. The BWC defines BW agents as "microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes."[3]

Ironically, the tremendous advances in genetics, molecular biology, cell biology, immunology, and related medical sciences that are thus far being applied to improve the human condition constitute a body of knowledge that also has a dark side. Thus, the list of potential BW agents now includes a vast variety of putative designer molecules and engineered microbial agents. The term currently in vogue to describe this technology is "dual-use", but since nearly all modern biotechnology may be considered "dual-use", the term is really not very useful. This hypothetical new arsenal goes far beyond the classic concept of BW as a means to spread a virulent disease or a biological toxin to a human, animal, or plant population. Fortunately, the original language agreed upon by the creators of the BWC can be interpreted to be broad enough to cover such applications not foreseen in 1972, when the treaty was adopted. Moreover, subsequent BWC Review Conferences have taken note of this explosion of knowledge and made it clear that any novel technological applications are to be covered by the BWC.

History and Current Status of BW Development

Over the past 50 years, the serious development of BW has remained within the province of states that meet two criteria: a relatively high level of scientific and technical capability and significant financial resources to be able to fund such activities. These criteria must be fulfilled even where the level of scientific sophistication being brought to bear on the weaponry is not of a particularly advanced nature (e.g., the production of Bacillus anthracis spores and their incorporation into deployable delivery systems), due in large part to the requirements for the formulation of the BW agent, often in a dispersible aerosolized form, and the manufacture of the agent itself in a manner that ensures safety for those carrying out such activities.

Many countries have been engaged in the development of BW in the past. The most extensive programs were carried out by Japan, the United States, and the Soviet Union. The U.S. program, based at Fort Detrick, near Frederick, Maryland, investigated a number of potential weapons based on highly infectious agents and potent toxins. However, the United States chose to not develop into weapons any biological agents that were either contagious (as they could not control the spread of the resulting disease) or for which there was no treatment. Several agents, including for example, highly dispersible B. anthracis spores, were deployed in actual weaponry. In the end, no BWs were ever used by the United States. As the public awareness and concomitant revulsion over such a program grew, it was abandoned unilaterally in 1969, a decision that probably reflected the potential for overkill inherent in the mounting stockpile of nuclear weapons during the peak of the cold war among other political considerations.

The Soviet Union also had a very large BW development program that started in the 1920s[4] and continued up to the time of the dissolution of the Soviet Union in 1991. The Soviet program evidently did pursue the development of weapons based on contagious agents, such as the smallpox virus. Programs that existed in the past in western European countries, Canada, South Africa, and Japan have all been abandoned. However, during the 1980s and 1990s, several states continued or started new programs and at present, the number of countries known or strongly suspected of pursuing the development of BW is probably around 12-14, although this number could be higher.[5]

The capabilities of different states known or suspected to have an interest in BW research and development vary tremendously. The level of relevant technical expertise and infrastructure is high in the United States even though, publicly at least, it has abandoned the pursuit of offensive BW. In recent years, however, the United States has expanded research into defensive biological warfare, especially using the expertise of civilian research facilities, which is a cause of concern to many.[6] Russia, Israel, China, and Cuba could certainly be considered at the "high" end of the technological spectrum. India, Pakistan, and Iran possess a moderate level of such capacity (certainly high enough to produce "conventional" BW), with Libya, and Sudan at the low end. Those states having only a marginal level of biotechnological sophistication (e.g., Sudan) would certainly have difficulties making anything strategically useful.

While most countries purported to have been engaged in BW development are probably capable of at least some level of success, there is simply no hard evidence that those at the lower end have ever succeeded in producing anything that could be considered a realistic, usable weapon that would be effective against an adversary in armed conflict or against a population of civilians. Iraq, for example, manufactured explosive artillery shells containing B. anthracis spores, without being aware that a detonation would incinerate most of the spores. In any case, there is a cut off point, below which the shortage of technical, human and financial resources will limit a state's ability to produce usable BW.

Future Directions

The scope of potential biological weaponry-including that which has already been developed and that is now technologically possible-is vast indeed and goes well beyond infectious agents and biological toxins. In order to assess which BW development strategies might be practical enough for an organization with limited scientific and technical resources to consider their pursuit, or what technological advances might facilitate the production of "conventional" microbial BW, we must examine those recent scientific and technical developments that are most likely to be applied to the design and manufacture of new weaponry by any party. We must then assess how much is needed in the way of highly trained personnel, specialized equipment, energy, acquisition of strategic materials, and financial investment to make the development of such advanced BW practical.

An exhaustive analysis of all of the new findings and technical advances would be beyond the scope of this issue brief. Accordingly, some representative areas will be discussed from which it is possible to draw some general conclusions.

Infectious Agents

The selection of which organisms to develop and perhaps modify depends on their properties and, of course, the purpose for which they would be used. The goal may be the incapacitation of the enemy for a period of some days, or the quick death of whoever comes in contact with the agent.

B. anthracis was an early choice of the programs in the United States and Soviet Union. Especially attractive was that it is a sporulating bacterium, the spores of which are highly stable over a wide range of temperature and moisture conditions. This is perhaps the simplest and first choice for a BW novice. The disease caused by the anthrax bacterium is not contagious from person to person, but can cause cutaneous, gastrointestinal, or pneumonic infections in those who come into direct contact with the spores. The mortality rate of untreated anthrax is quite high.

Agents that are highly infectious, of course, require very careful handling. Fatal accidents among those who have worked with such are well known, and in at least one instance, the surrounding community was adversely affected by B. anthracis spores that escaped from a manufacturing facility, causing many deaths.[7]

There are several highly virulent viral diseases endemic in tropical regions, such as the Ebola and Marburg hemorrhagic fevers, which also seem to have infected the minds of the writers of popular fiction as the scariest of BW candidates. The viruses that cause these diseases tend to survive in animal reservoirs, where symptoms are mild or non-existent. Occasionally they arise in human populations, spread e.g., by a bite from an infected monkey, bat, or other animal. While the mortality rates of these infections are extremely high in humans and such outbreaks are locally catastrophic, they rarely spread beyond the site of original infection. Health workers have been infected by contact with infected patients, so human-to-human spread is possible, and should the disease occur in a densely populated urban center, the outcome could be very serious. However, it is largely because these viruses are so virulent and contagious that the naturally occurring form does not represent a good choice for a prospective BW agent. A compelling strategic reason for not choosing an agent that is extremely virulent is that the symptoms and death can occur so rapidly, that the spread throughout a population is self limiting, resulting in relatively few casualties. Moreover, safe handling of these agents is difficult under the best of conditions, requiring biosafety level 4 facilities (BSL4), which are technically complex and quite expensive. Another very strong reason for not weaponizing Ebola and similar viruses, is that there is no effective treatment for them should they infect one's own soldiers by accident.

In contrast to highly virulent viruses, an agent that is contagious for an asymptomatic incubation period of even one or two days (such as the smallpox virus), will be spread throughout a population much more extensively, with a correspondingly higher number of casualties. Accordingly, even though using contagious agents in BW at all is highly risky, this type of virus represents a significantly more rational choice for a strategic BW agent than the Ebola virus.

Influenza virus has also been discussed as a potential BW agent. There are many strains to start with, but most are genetically unstable and thus unpredictable. The so-called Spanish flu virus, responsible for a devastating global pandemic in 1918, is a variant of the seasonal type A influenza virus that is responsible for the annual "flu season" around the world. More recently, concerns have arisen about the spread of avian influenza virus to humans, where the fatality index is around 50% (an NTI issue brief on the suitability of avian influenza virus as a BW agent will be released in January, 2007). To engineer the influenza virus genetically to be more stable, or to be more virulent but containable would not be a simple undertaking.

Because the natural arsenal of infectious disease agents is so extensive, if a BW developer chooses to develop BW without advanced genetic engineering technologies, there is much to choose from without trying to improve upon what it has taken nature many millennia to perfect. Should he choose to employ new technology, the kinds of modifications that might be considered would involve genetic modifications directed at one or more of the following properties:

• alter the host range, e.g., to allow animal pathogens to infect humans more easily.
• modify the life cycle, e.g., to slow or accelerate incubation time or the development of pathology, disable contagion, etc.
• weaken the natural immune response (as in HIV infections).
• alter pathology, e.g., by adding genetic elements coding for toxins, factors regulating gene expression, colonization factors, etc.

Another logical direction that BW R&D on infectious agents could take would be the actual creation of new pathogens, e.g. by adding certain other agents to modified viral vectors used in gene transfer studies on gene therapy and transgenic animals. Here the boundary between infectious and non-infectious becomes blurred. Some examples are discussed below.

Non-infections Agents

Non-infectious agents suitable for weapons development, in addition to the "classic" microbial toxins, such as those mentioned above (ricin, botulinum toxin), may also include immunological agents, psychotropic agents, or modulators of gene expression. Immunological agents encompass a wide range of agents, including vaccines, modified or conjugated antibodies, immune modulators, oligonucleotides that modify T-cell responses, etc. Strategies for the design of new weapons could include the alteration of the host's immunity to normally harmless microbes in the environment, or the stimulation of an immune reaction against components of one's own body, including eggs and sperm. Psychotropic agents, like LSD, could alter the behavior of the people affected. And a modulator of gene expression could alter the recipient's internal biochemistry in some undesirable or even lethal manner.

Recent Scientific and Technological Advances

The United States abandoned its BW research efforts just before the real breakthroughs in genetics and molecular biology took place. The first public announcements of gene splicing occurred in the early 1970s.[8], [9] Because of the uncertainties inherent in genetic manipulation at the time, a moratorium on recombinant DNA research was self-imposed by the scientific community from 1974 to 1976, until research guidelines were formally established by the National Institutes of Health.[10], [11] Ironically, it was this act of good faith that attracted the press and when the public became informed of the remarkable achievements taking place in the research community along with the concerns of scientists themselves, widespread fear was expressed immediately, not simply because of the possibility of genetic accidents, but over the anticipation that these techniques could be used to make new generations of diabolical BW, or otherwise misused. [12]

But that was more than 30 years ago, the fears have subsided, the melodramatic scenarios postulated in the 1970s have not come to pass, and no significant negative effects of genetic engineering have been observed. The achievements in genetics and gene structure and function, molecular and cell biology, and immunology have exceeded the expectations of even the most optimistic. But there have been no publicized applications of the new technologies, even by the most advanced countries that acknowledge (or not) that they are developing BW, to design more sinister agents. That, of course, does not mean that some very new and cleverly designed weapons could not have been developed and even used covertly. While no anomalous outbreaks of disease have occurred, at least none that could not be accounted for by natural selection and the rapid evolution characteristic of microbes, the possibility remains that such weapons could have been used, for example, in a targeted assassination, to lower the vitality of a population without significantly increasing morbidity and mortality, or to reduce the fertility rate.

Let us now examine in more detail some of the specific areas regarding non-infectious agents in which such advances might be turned towards the development of a weapon.

An Anti-fertility Vaccine

A contraceptive vaccine was first developed in India in the 1980s,[13] and this approach to birth control is now under investigation in many research centers.[14] The concept behind such a vaccine is to elicit the formation of antibodies against a particular essential hormone (e.g., human choriogonadotropin (hCG), a sperm antigen, or component on the surface of the human ovum), resulting in the destruction of the mature egg. The duration of such immunization depends on the system used, but strategies are available that would significantly reduce fertility during a woman's reproductive years, possibly with a single vaccination. Many consider the use of such a vaccine unethical and its potential use as a weapon of genocide has been noted.[15] The vaccines thus far tested have been administered by injection, on a voluntary basis. However, new developments in vaccine delivery through a nasal spray or oral administration raise the possibility that such an agent could be administered clandestinely, against the will or even knowledge of the recipients. The use of such a weapon would not be the usual dramatic killing of many individuals in a single event or over a short period of time. Rather this would result in an insidious drop in birth rate, which would not only be devastatingly demoralizing in most cultures but lead, over time, to a drastic reduction of the affected population. Such a weapon could be attractive to a situation of neighboring countries or tribes that have endured centuries of war, exploitation and mutual hatred. There are many such candidate configurations around the world (e.g., Israel/Palestine, Sudan, Rwanda-Burundi, Kosovo, Sri Lanka, and Nigeria).

Agents that Control or Suppress the Expression of a Particular Gene

Considerable knowledge has accumulated over the past 20 years on the control of gene expression. The manipulation of gene expression in microbial, animal and plant systems can be carried out in a variety ways in the laboratory, and the possibility of using the up- or down- regulation of specific genes for medical interventions is under investigation. One way of blocking the expression of a particular gene is to the use of so called "antisense" DNA,[16] which can bind strongly to the messenger RNA (mRNA) coded by the gene, preventing the transcription of mRNA and hence the protein coded for by that gene. Antisense oligodeoxynucleotides might also be used to block specific regulatory genes. This emerging technology, however, also suggests that it could be used as a weapon, by introducing an antisense fragment via a viral carrier, in which the engineered viral genome would integrate into the host DNA and produce multiple copies of the gene blocking agent, producing illness or death in the host. While such a weapons strategy is, to our knowledge, purely hypothetical, it is at least, in principle, just as technically feasible as using such a strategy for therapeutic applications.

Another approach would be to create a new type of pathogen from one of the many highly engineered viral vectors constructed, for example, to introduce genes into human cells for clinical applications of gene therapy.[17] Viruses that are common but weak pathogens (e.g., rhinoviruses) might also be attractive vectors for introducing new genes or gene families into humans. Such a vector could be engineered either not to replicate into the production of mature virus particles that could infect other individuals, or as a potentially contagious agent that could be spread throughout a population.

To develop such a novel pathogen that worked by suppressing the expression of one or more specific (and essential) genes would indeed require highly trained individuals working in very well equipped laboratories. It could however, be the sort of weapon that a country with such advanced facilities and expertise could provide to a terrorist organization with which it sympathized. Such a made-to-order microbe could have considerable advantages over natural pathogens as a BW agent, but unanticipated risks as well. Risks could include instability of the genetic modifications, where e.g., a non-contagious agent might become contagious, exchange of genetic material with naturally occurring microbes, disruptions in some aspect of microbial ecology, etc.

Immunological Agents

Scientists have long sought to develop the concept of a targeted cancer therapeutic. The principle used is to find one or more antigens that are expressed uniquely on the surface of tumor cells but not on any other cells. Antibodies against such unique antigens, or better yet, a cytotoxic agent linked to a monoclonal antibody against a specific tumor antigen, could in principle, kill only the cells expressing that gene and leave all non-tumor cells unharmed. This seems like a dream strategy, in view of the fact that the current crop of chemotherapeutics, for the most part powerful antimetabolites, attack healthy cells as well as cancer cells, but because the cancer cells are dividing much more rapidly than healthy cells, they are more susceptible to the drug.

The idea of a targeted immunotoxin has been around for many years, but only relatively recently have any specific applications been promising. Success has been reported with an immunotoxin tailored to attack cells carrying a gene that is expressed only in a particular type of breast cancer. Other immunotoxins show promise against prostate cancer, malignant melanoma and others [18],[19]

The application of such technologies for weapons purposes is easy to imagine. However, to be a useful weapon and not merely an expensive and complicated poison (cyanide is simple, cheap, and effective; so is botulinum toxin, relatively speaking) the application of a new technology must have some unique advantage. For example, one perhaps would want to design an agent that could be disseminated in a clandestine manner to trigger an immune response against a particular normal cell type, eventually leading to disability and possibly death over a period of time. A variety of autoimmune diseases occur naturally. Others are triggered by infections where a microbial antigen resembles a natural cellular antigen. Rheumatic fever, which can be a sequela of severe streptococcal infections, is an example of this type of effect. An effective immunological weapon could thus contain an immunological agent such as a subunit or cell-free vaccine, or a microbe engineered to produce either a specific kind of immune response, or to disable one or more of the body's innate immune mechanisms that prevents the immune system from attacking the body's own cells and tissues. Because such immune responses occur naturally, the perpetrators could thus disguise a BW as a naturally occurring disease. As such, for example, if the incidence of diabetes were to rise significantly among members of a specific population, a BW would not be the first thing to suspect as the cause.

In this respect, it is worth noting that there have been suggestions that HIV is really a BW agent. While that possibly may be ruled out for several reasons, HIV is a remarkable end product of microbial evolution, where the survival and propagation of the virus depends upon (a) infection of and ultimately disabling an important class of T-cells, and (b) the capacity for rapid genetic rearrangement, which alters the antigenic properties of the virus, a combination that confounds the cell-mediated immune system. Many see HIV as being far too clever to have been designed by a human being.

What Advances May Lower the Threshold for Proliferation of BW?

The above are just a few examples of how recent advances in biomedical sciences can also have a dark side. Virtually all knowledge can be misused, and this is true of the remarkable advances in genetics, immunology, neurobiology, and medical sciences in general. However, the degree of expertise and the level of sophisticated hardware and facilities needed to engineer a BW is probably quite similar to that required to create a novel pharmaceutical. In spite of the tremendous advances in knowledge that have taken place over the past 30 years, a well-funded research community in many parts of the world, and the spawning of a very innovative biotechnology industry, useful medical advances have not been easy to bring into practice. The relatively small number of successes (among a much larger number of failures) have taken many years of innovative research and technical problem-solving before they finally emerged, usually after many blind alleys and false starts. Therefore, it is unreasonable to expect the development of highly sophisticated biological weaponry to proceed any faster, and if it should, only where the scientific and technological infrastructure and level of training and expertise are high. Accordingly, it is far more likely that such techniques would be put to nefarious use, not by a non-state or state with relatively low technological capabilities, but rather by the most technically advanced countries whose political conscience would not preclude going down this road.

It is quite probable that if a state were to engage in producing new generations of weapons, especially a State Party to the BWC, it would be more likely to supply a group or individuals with a ready-to-use kit, rather than to use it under its own identity. Death squads are ubiquitous, and their equivalents, under one name or another, have been hired or assembled by governments of all persuasions, including the United States.[20] This then is the most probable route by which such weapons would ever be deployed and how non-state groups, including ad hoc ones assembled for the purpose, might be involved in the development and use of a new generation of BW.

Can Improved Education and Technical Training Lower the Entry Threshold for BW?

The level of scientific training and capabilities of research communities around the world continue to increase. This reflects rapid economic development is certain parts of the world (e.g., China, India, and South Korea), international initiatives in research[21] and training[22] that target developing countries, and the fact that bright young scientists from anywhere in the world can now train at the best universities and research centers.

Does this mean that while non-state entities are precluded from developing weapons based on the most advanced and newest science, is it still possible that because more people are trained in bioengineering and fermentation, that it would be easier to set up a production plant (e.g., for B. anthracis spores in any part of the world) than it was 20 or 30 years ago? Probably it is. We know that, with a very great economic incentive, methamphetamine is produced in laboratories sometimes small enough to fit into the trunk of a car, and the cocaine factories in the hinterlands of South America are infamous. How much more difficult would it be to produce the simplest of traditional BW? More difficult, yes, but not that much more difficult. A meth lab is basically a chemical and purification operation. Controlled fermentation, purification equipment, and the attendant safety facilities would be required for BW production, but there are probably people with the requisite level of skill to operate such facilities throughout most of the world, and the financial resources would probably not be an issue. Fermentation facilities do require a significant input of energy. But when seen as comparable to the facilities in a brewery, which include large-scale fermentors, it is immediately apparent that, like beer production, BW activities could be carried out nearly anywhere in the world.

Deterrents against BW Development and the Position of Non-states

It should be kept in mind that there is enormous international pressure not to develop or use BW at all. Period. As noted above, the BWC entered into force in 1975. The Fourth Review Conference in 1996 reconfirmed its intent and acknowledged the potential for the nefarious applications of advances in genetics and molecular biology. The Fifth Review Conference held in 2001 was a contentious affair (largely due to what was seen as a lack of cooperativeness by the delegation from the United States) and the conference was adjourned, then resumed in November 2002, but without reaching consensus on key issues. The United States delegation proposed that any kind of strict regulation of BW research development was not realistic in that any rules would be essentially unenforceable, and that on-site inspections of research facilities or biotechnology R&D centers of private companies would not reveal the true nature of any weapons development, should the perpetrators choose to conceal it (a valid point). Inspections of research labs were viewed as an intrusion into privacy that could compromise intellectual property rights and in any case, would not be effective. The results of the Sixth Review Conference, held during November 20 – December 8, 2006, are not known at the time of this writing.

The effectiveness of the BWC, since it contains no enforcement mechanisms, rests primarily on the good will and trust of the 155 States Parties (plus 16 signatories) and, because the use of BW is considered so morally repugnant, their use, it is assumed, would evoke the condemnation of the global community. Some countries, including those suspected to be developing BW (e.g., Israel) have simply not signed the convention and have not participated in the international deliberations to strengthen it. The BWC, of course, does not apply to either non-signatory states or to non-state groups. As mentioned above, the latter could include anything from well financed organizations with militant political agendas, known to carry out terrorist activities and suicide bombings, to a single misguided individual (e.g., the Unabomber).

Since non-state groups are not bound by the constraints that generally are brought to bear in international diplomacy, and overt "terrorist" acts committed around the world with considerable loss of life continue apace, there are genuine concerns that if such groups could obtain or manufacture BW, they would not hesitate to use them. For some groups even sacrificing the lives of their own members (for example, if it means disseminating a virulent agent in a population they wish to harm) is deemed acceptable.

Resolution 1540 (UNSCR 1540), which was adopted by the United Nations Security Council in April 2004, is an important piece of international law, specifically designed to address the fact that non-state groups are not bound by international treaties and conventions. It requires all states to refrain from supporting "non-state actors" in the proliferation of weapons of mass destruction (WMD), including BW and their means of delivery. Under the provisions of the resolution, states must make national laws to criminalize WMD proliferation, as well as implement accounting and other measures to ensure that WMD technology does not enter the private sphere.[23] It is likely that a non-state organization seeking to develop BW would not be directly deterred by the knowledge that their activities are illegal in their country of operation. However, the implementation of accounting measures, physical protection, and export controls on sensitive technologies will make BW-related materials and technology much more difficult to acquire, thus preventing proliferation (and use) through a supply-side mechanism.

The fact that non-state groups have not used BW implies that this nonproliferation mechanism has thus far been successful: they can neither obtain existing weapons from their supporters, who currently supply them with explosives and conventional weapons, nor can they make such weapons themselves. This suggests that even though the technology to make BW is well known, even setting up and running the most primitive of facilities to manufacture a BW of the simplest type is considered too risky, too difficult, or too expensive when weighed against the effectiveness and ease of obtaining of conventional explosives and military hardware with which to achieve their objectives.

But the question remains: Are there any advances among the many that have been achieved in the biosciences that would lower the threshold for entry by new entities into the BW "community"? The answer has to be a highly qualified yes, in that it is not the spectacular gains in molecular genetics and cell biology that will lower the threshold, but advances in engineering, such as developments in instrumentation and information technology (including automation) that can facilitate the manufacture of BW agents, reduce costs, and decrease the requirement for expertise.[24] These technological developments may also extend to BW delivery systems. But in the event that new players should decide to enter the game, the BW agents themselves are still far more likely to be based on yesterday's biology than on the science at the frontiers of knowledge.

Conclusion

Whether or not any state or organization would engage in the use of new technologies to produce advanced BW is dependent on a number of factors, but the limiting step is neither the skill of the technologists nor access to materials and equipment. Most important is the motive: whether or not it makes sense to take a strategic decision to develop and deploy BW based on infectious agents or biological toxins in view of all of the other strategic options available, and what objective one is trying to achieve. Explosives, and even chemical weapons are simpler and, if inflicting injury and death is the prime objective, then is there any real advantage to using a BW that is more difficult to control and in fact could accidentally attack your own people? Usually not. The advantage of a BW over other weapons would come in the form of applications of the advances in biology, some of which are discussed here, where the objective would be, for example, a long-term insidious weakening of an adversary, disseminated by some covert means, rather than applications where an immediate effect is desired. But without a willing, technically sophisticated, and very wealthy partner, and plenty of time to perfect and test such a weapon, this scenario is unlikely.

Perhaps the most dangerous nefarious use of new biomedical technologies would come from the stereotype of a disgruntled, and very brilliant scientist, who, having a job in a top medical research center and working by him/herself, makes the wonder weapon and, with no fear of his/her own death, uses it, perhaps convinced that the apocalypse is coming anyway. If such a person is a charismatic spiritual leader, and has a cult of followers to do his bidding, the chance of them working to develop such weapons is far higher.

In conclusion, it is the opinion of the authors that while recent advances in the biomedical and genetic sciences do indeed greatly expand the range of possible BW, they do not, per se, make it easier or lower the threshold for the proliferation of BW to either technologically less advanced states or non-state parties, unless they are working in close cooperation with a technologically advanced entity capable of pursuing this strategy effectively.

Nevertheless, we would be remiss not to acknowledge the globalization of knowledge and the fact that the Internet constitutes a vast "how-to" manual for doing just about anything. Moreover, the level of skill available worldwide has increased considerably over the past several decades, now enabling parties who could not have undertaken this kind of activity in the past to engage in bioengineering and large scale fermentation, and to produce microbes or microbial products in large quantity. Even so, barring the lone perpetrator or cult leader, it is unlikely that most non-state groups with a political agenda, regardless of the means they consider ethically acceptable, would give the pursuit of BW a high priority.

Sources:

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[10] C. Grobstein, "Asilomar and the Formation of Public Policy" in Raymond A. Zilinskas and Burke K. Zimmerman, eds., The Gene Splicing Wars, (New York: AAAS/MacMillan, 1986) pp. 3-26.
[11] Graham Chedd, "Genetic Engineering: Cautious agreement at Pacific Grove" New Scientist, (18-24 November 2006) p. 19.
[12] B.K. Zimmerman, "The Fear and Trembling" in B.K. Zimmerman, Biofuture, (New York: Plenum Press, 1984), pp. 141-177. Also see discussion in R. Zilinskas and B.K. Zimmerman, The Gene Splicing Wars.
[13] "Indian Scientists Report Breakthrough in Attempt to Develop a Reversible Vaccine Against Pregnancy"
International Family Planning Digest, Vol. 2, No. 1 (Mar., 1976), pp. 11-12; G.P. Talwar, ed., Immunological Approaches to Contraception and the Promotion of Fertility (New York: Plenum Press, 1986).
[14] P.D. Griffin, "Contraceptive Vaccines," Geneva Foundation for Medical Education and Research, www.gfmer.ch.
[15] A.S. Gupta, "Research on Hire," Indian Journal of Medical Ethics 9 (Oct-Dec 2001); Daniel Reyes, "The Ethics of Biowarfare," American Institute of Biological Sciences, (February 2003), https://actionbioscience.org.
[16] N. Dias and C.A. Stein, "Antisense Oligonucleotides: Basic Concepts and Mechanisms," Molecular Cancer Therapeutics 1, (2002), pp. 347-355.
[17] For summary of early work on viral vectors, see W.F. Anderson, "Prospects for Human Gene Therapy," Science 226, (1984), pp. 401-409; L. Naldini, U. Bromer, P. Gallay, D. Ory, R. Mulligan, F.H. Gage, I.M. Verma, and D. Trono, "In-vivo Gene Delivery and Stable transduction of nondividing cells by a lentiviral vector," Science 272, (1996), pp. 263-267.
[18] D. Schrama, R.A. Reisfeld, and C. Becker, "Antibody targeted drugs as cancer therapeutics," Nature Reviews/Drug Discovery 5, (2006), pp. 147-159.
[19] P.J. Carter, "Potent antibody therapeutics by design," Nature Reviews/Immunology 6, (2006), pp. 343-357.
[20] American Defense Monitor, "School of the Americas: At War with Democracy?" (transcript), (October 9, 1994), www.cdi.org.
[21] For example, the International Center for Genetic Engineering and Biotechnology was established by UNIDO in 1985, with facilities in New Delhi, India, and Trieste, Italy, with the objective of bringing a high level of biotechnology to bear on the needs of developing countries. Numerous national research centers have been established in many countries during the past twenty years.
[22] In 1987, the Gesellschaft für Biotechnologische Forschung (Now the Helmholtz Zentrum für Infektionbiologie), Braunschweig, Germany, began an advanced training program in modern biotechnology for scientists from developing countries. While this program has been recently discontinued, training supported by UNESCO, national governments and private foundations has enabled promising scientists form all over the world to obtain advanced training.
[23] UN Security Council Resolution 1540, April 28, 2004.
[24]; Relman, David A., "Bioterrorism – Preparing to Fight the Next War,"  New England Journal of Medicine, 354, 113-115 (2006)