THE NEW BIOLOGY AND CB WEAPONS


Mark Wheelis
Section of Microbiology
University of California
Davis, California


The New Biology

Biology is in the midst of what can only be described as a revolution. It began in the mid-1970's with the development of recombinant DNA technology. Slowly at first, but with rapidly increasing speed, related technologies have been developed
that have dramatically expanded the experimental capabilities of modern research biologists, and that are rapidly being adopted in applied biology, for instance for drug development. In addition to the foundational recombinant DNA technology, these
include genomics, proteomics, microarray technology, high-throughput screening techniques, combinatorial methods in both chemistry and biology, site-specific mutagenesis, knock-out mice, and many others.[1] Collectively, these technologies are referred
to as "genomic sciences," or the "new biology."
These technologies are supported by, and dependent upon, two other types of technology: high-speed computing, and an instrumentation industry. Computers increasing control the instrumentation that collects data, but more importantly computers are
necessary to interpret the data. Most of these technologies are distinguished by the enormous amount of data that they generate. For instance, the sequencing of the human genome produced a data set with about 3 billion bits of information--the sequence
of nucleotides in human DNA. If one sat down to write out that sequence, perhaps as a first step in locating genes, or to compare the human sequence to some other sequence, and if one wrote one base per second without any breaks, it would take about 100
years to complete the simple transcription task. Clearly, any analysis of this data requires very high-speed computational capabilities. Many other types of biological data besides genome sequences--proteomic data, microarray data, etc--are also
typically extremely large data sets. An entirely new discipline, termed bioinformatics, has evolved to deal with the collection and analysis of these huge databases. In fact, our understanding is often limited more by the lack of bioinformatic tools to
analyze data than by the collection of data in the first place.
The new biology is equally dependant on a sophisticated instrumentation industry. The equipment--DNA sequencers, microarray printers and readers, multiple sample screening equipment, etc--were all developed in research laboratories, but these prototypes
were necessarily slow, crude, and required highly skilled operators. Part of the reason that the new biology is developing and disseminating so rapidly is that a new industry has grown up that has refined, manufactured, and is marketing and continuously
upgrading the instrumentation for the new biology--high speed DNA sequencers, ultra-high throughput screening systems, high density microarray printers and readers, etc. Increasingly the instrumentation is controlled by computers, and operations are
performed by robotics. The scale is rapidly decreasing, so that experiments that needed milliliters or milligrams of material a few years ago now require only microliters or micrograms, or less. Although highly sophisticated, this commercially-available
equipment is reliable, increasingly affordable to individual laboratories, and operable by staff with minimal technical expertise.
Because of its power, the new biology is in a period of rapid expansion. By any measure--number of professional scientists, number of publications, new journals, funding level, etc--the growth of this field is exponential, with no sign of leveling off.
This is leading to extremely rapid production of new knowledge, and a rapid dissemination of the knowledge and technologies worldwide.

Military Applications of the New Biology

Biotechnology will clearly be one of the defining technologies of the twenty-first century, probably by the middle of the century in combination with nonotechnology, artificial intelligence, and microrobotics to form a hybrid technology of
enormous power. Even as a stand-alone technology, it will have great power for both peaceful and hostile uses.
The short- and medium-term potentials of biology and biotechnology stem from two intertwined developments. The first is the rapid development of a detailed understanding of the physiology of living organisms. Previously, attempts to manipulate
natural processes, for instance to develop safe incapacitating chemicals, or to develop pathogens with enhanced virulence, were rarely successful because of the fiendish complexity of the physiological processes underlying organismic functioning.
Attempts to manipulate systems that are imperfectly understood are only rarely, and fortuitously, successful. However, with the much more detailed understanding that is very rapidly emerging, rational manipulation becomes increasingly feasible.
The second development is a rapidly increasing understanding of receptor biology. A major component of our better understanding of physiological functioning is an increasingly detailed understanding of cellular communication systems.
Multicellular organisms are characterized by immensely complicated systems that coordinate the functioning of their constituent cells. These systems are characterized by specialized receptor proteins that are embedded in the membranes of cells. Each cell
in the body has many different receptor proteins, some of them common to most other cells, some specific to the particular tissue or organ in which the cell is located, and some specific to a group of cells within a specific tissue. Approximately one
third of the 30-50,000 different proteins encoded by the human genome appear to be receptor proteins, an indication both of the great importance of this class of proteins in human physiology, as well as the great complexity of signaling systems.
Soluble molecules termed bioregulators bind with high specificity to receptor proteins. When a bioregulator binds to its cognate receptor protein, the protein undergoes a shift in its conformation that provokes a response of some kind within the
cell--a nerve impulse may be propagated, a hormone secreted, a muscle cell may contract, etc. The bioregulators may be small molecules, like acetylcholine, serotonin, or gamma-aminobutyric acid, or they may be medium to large molecules, like endorphins.
Most pharmaceuticals are analogs of these bioregulators, that mimic or oppose the action of the natural compounds.
With the tools of modern biology, receptor protein genes can often be recognized in genomic DNA sequences, their 3D structure predicted, their binding sites modeled, and synthetic chemical compounds designed that will bind to them. This
capability, which is developing rapidly, will soon allow the rational design of new pharmaceutical agents, tailored to enhance or block specific physiological pathways. This will be a great boon for medicine, but will also allow the development of a wide
range of novel chemical and biological weapons agents.
Two applications of the new biology have particular potential for military application: understanding the functioning of the nervous system, and understanding the mechanisms of microbial pathogenesis.

Understanding the Nervous System

Among the physiological systems of greatest interest to biologists is the nervous system. This interest is both because of its great intrinsic interest, and because there is a huge economic market for the development of new pharmaceutical
compounds for the treatment of mental illness, pain, and other medically important problems. Anesthetics, analgesics, tranquilizers, stimulants, antidepressants, etc are all analogs of natural neurotransmitters (bioregulators that mediate communication
within the nervous system). As we come to understand the detailed physiological pathways that underlie pain, depression, panic attacks, post-traumatic stress, anxiety disorder, schizophrenia, sleep disorders, etc., and as we identify and characterize
their specific receptor proteins (neuroreceptors), we will be able to design new medications that will offer much greater effectiveness and specificity than current ones, and that will have much reduced side effects. A combination of humanitarian and
economic incentives insures that progress will be very rapid.
Of course, the capabilities that emerge will, like all advanced technologies, be capable of hostile as well as peaceful exploitation.[2] Hostile applications include:

· manipulation of humans to increase their effectiveness as soldiers
· novel weapons for combat use, including a range of non-lethal incapacitating biochemicals
· new agents for interrogation

For at least half a century, militaries have used pharmaceutical compounds to enhance effectiveness of troops in certain situations; amphetamines as stimulants for pilots or soldiers on long missions is the primary example. In the future, we can
anticipate that at least some countries would use forced medication to produce troops who are not only alert and energetic for days at a time, but who have heightened sensory awareness, enhanced aggressiveness, decreased fear, decreased sensitivity to
pain, and a dulled moral sense. The beginnings of the understandings of the chemical bases of all of these is already emerging, and to anticipate such capabilities is not much of an extension. It might also be possible to make soldiers much stronger and
quicker than normal; the "superhuman" strength conferred by some street drugs is a common experience among law enforcement personnel, and suggests that a biochemical basis for temporary enhancement of physical capabilities might emerge.
Many of the new analogs of bioregulators will be possible new biochemical weapons. It is worth remembering that the most potent existing chemical weapons, the nerve gases such as the V-agents, are analogs of acetylcholine, a neurotransmitter
used in a number of different neural and neuromuscular circuits. There is every reason to believe that newer, even more toxic, agents will become available, and some of these will have the other characteristics that make them attractive candidates for
weaponization.
Of more significance, it will most likely be possible to develop a completely new range of non-lethal disabling chemical weapons. We have already seen the use of disabling chemicals in a hostage rescue situation, in the 2002 Moscow theater siege.
Nearly 130 of the hostages in that situation died as a direct result of the agent used (an unidentified derivative of the anaesthetic fentanyl). However, much safer incapacitating agents will become available soon, and they will be very attractive to
law enforcement and military forces. Nearly instantaneous, silent weapons that incapacitate might be of particular interest to special forces, police, and prison personnel. Incapacitation could involve unconsciousness, paralysis, delirium, or other
derangements.
New pharmaceuticals could also be of great interest to interrogators who are willing to ignore legal limits on the bounds of interrogation. While a genuine "truth serum" may not be possible, many pharmaceuticals would substantially reduce the
ability of a captive to resist providing information. Agents that cause submissiveness and eagerness to please are on the horizon, and would be effective for many captives. Pharmaceutical forms of torture could also be highly effective in reducing the
ability of captives to retain secrets--regimes in which depression, euphoria, panic, submissiveness, etc, are manipulated would likely prove irresistible to most.

Understanding Pathogenesis

The interactions of pathogenic bacteria or viruses with their host organisms is highly complex. It involves mechanisms by which microbes are transferred from one host to another, mechanisms by which they initially colonize the new host,
mechanisms by which they invade the host and localize in particular tissues, and mechanisms by which they evade or subvert host defenses. Very rapid progress is being made in understanding these processes, promising greatly enhanced public health and
agricultural benefits.
The tools are rapidly becoming available to produce improved vaccines (more efficient, longer lasting, and safer), produce new antibiotics and anti-virals, enhance host defenses, and protect against damage from over-reaction of defensive systems.
The same benefits may be realized in veterinary medicine, and better understanding of plant diseases can be expected to provide increased yields and improve nutritional quality.
However, as with neurobiology, hostile applications are equally enabled by a detailed understanding of pathogenesis. In the present and near term (10 years), possible military applications include:

· genetically engineered pathogens that evade diagnosis and treatment
· pathogens with exceptionally high lethality due to novel toxin combinations or to their ability to defeat host defenses
· pathogens that cause novel disabling symptoms
· pathogens with enhanced contagiousness
· pathogens with increased environmental stability

The first of these is nothing new. The ability to create antibiotic-resistant pathogens by selection or plasmid transfer predates the development of genetic engineering, and selection of mutants with altered surface antigens to confuse diagnosis
is also not new. The new technologies, however, make the construction of such altered pathogens easier and faster, and provide a range of new options. Furthermore, one of the inhibiting factors has always been the probability of secondary effects of
changes of pathogen properties--frequently a change in, for instance, surface antigens, would result not only in a pathogen harder to detect, but also in one of reduced virulence, since surface antigens often have roles in pathogenesis. Better
understanding of pathogenesis allows such changes to be targeted to sites that will not compromise pathogenicity.
In nature, the virulence of pathogens is the result of a complex selective process which often limit virulence in favor of transmissibility: a pathogen that kills its host so quickly that it has little chance to transfer to a new host will
quickly die out.[3] However, engineered strains that are perpetuated in the laboratory are free of such selection, and thus genetically engineered strains offer the potential of lethality that is exceptionally high and rapid compared to existing
pathogens. There are many routes to the construction of such pathogens, such as the combination of novel toxins into a pathogen, or the incorporation of bioregulators that allow the pathogen to defeat host defenses. For the former, consider the
possibility of a common virus that produces botulinum toxin; the latter has already been done: a benign mouse-pox virus with very low lethality become highly lethal when the gene for a bioregulator of the immune system was incorporated into its DNA. Many
more such strategies could be developed by any medial microbiologist, and the options will increase rapidly.
Many bioregulators are proteins or peptides, and thus benign viruses could be engineered to produce them. Others are relatively simple chemical compounds, and viruses could be engineered to contain the enzymes for their synthesis, thus allowing
the production of these bioregulators as well. In this way, viruses (or cells, for that matter) that are normally benign could be engineered to be lethal. Perhaps more disturbing, they could instead produce severe disabling effects, covering a wide range
from mild disorientation to severe psychosis. Such viruses could be contagious, and could persist for years in the body (like herpes viruses and retroviruses), causing infectious, permanent mental or physical disability.
Many pathogens have limited capacity to transfer from host to host. The detailed reasons vary among pathogens, and from one mode of transmission to another (airborne, direct contact, fecal-oral, or vectored), but have to do generally with two
properties. The first is the number of viable pathogens that are released from an infected host in respiratory droplets, secretions, or excrement, or that can be picked up by a vector. The other is the number of viable pathogens necessary to initiate an
infection, a statistical requirement that has to do with the efficiency of early host defenses, and with the efficiency of early steps in pathogenicity. Both of these properties are amenable to engineered change, once their basis is clearly understood.
It should thus be possible, at least for some pathogens, to create variants with increased (or decreased) contagiousness. Of course, this could be combined with increased lethality. For instance, a monkeypox virus, engineered to be contagious among
humans, and incorporating human immune modulators to enhance lethality, could be a fearsome weapons, perhaps worse than wild-type smallpox.
One of the obstacles to making microbes into military weapons has always been the limited environmental persistence of many, sometimes measured in minutes in an aerosol exposed to sunlight. Limited persistence may be desirable in a military
weapon to prevent continued reinfection, but persistence of many natural pathogens is so low as to prevent use as a weapon. Plague, for instance, has a fearsome lethality in the pneumonic form, but is transmissible only over very short distances (a few
feet) because it is so short-lived in respiratory droplets. For this reason, it was not successfully weaponized by the US during its offensive BW program, although it is claimed that the Soviet Union did so. Better understanding of the reasons that some
bacteria persist for long times while others do not will very likely allow the modification of pathogens to persist longer, and thus become candidates for easy weaponization.
In the longer term (20 years or so), options for all of the short-term capabilities can be expected to be dramatically broadened. In addition, new one will become possible. It is not possible to foresee in detail what will become feasible, but
we can certainly guess with confidence at some of the likely developments. Our uncertainty lies more in our failure to anticipate important developments, rather than in the failure of ones we do anticipate to materialize. Likely capabilities include:

· synthetic prions and viruses
· synthetic cellular pathogens of exceptional virulence
· synthetic, non-replicating cell-like entities as vectors for biochemical agents
· stealth pathogens
· genotype-specific pathogens of crop plants and domestic animals
· ethnic-specific human pathogens
· pathogens that cause ethnic-specific autoimmune diseases with effects such as sterility

One of the most dramatic developments of the new biology is the impending capability to create synthetic living systems (living by the criterion of self-replication based on known life processes involving nucleic acids and proteins). Already
synthetic replicas of existing viruses have been created chemically, and scientists are actively working on the synthetic creation of cellular life. It will not be very long before completely synthetic, designed-from-scratch viruses are produced. The
capability to produce effective, synthetic new viral pathogens will follow. Such agents would have significant utility in biocontrol of pests (such as weeds, rodents, or insects), so their development is likely to be pursued vigorously, but the lessons
learned will be easily transferable to the construction of synthetic human pathogens as weapons. Synthetic viruses could be designed to be contagious or noncontagious, lethal or disabling, acute or persistent, etc, and they could be engineered to lack
the usual targets of antiviral therapy and to be invisible to the immune system. They would be very hard to diagnose on first use. Similarly, as understanding of the biology of the self-perpetuating prions (infectious protein agents) deepens, it may be
possible to develop novel, synthetic prion agents.
Fully living synthetic cells will likely be made in the next decade; synthetic pathogens more effective than wild or genetically engineered natural pathogens will be possible sometime thereafter. Like synthetic viruses, such synthetic cellular
pathogens could be designed to be contagious or noncontagious, lethal or disabling, acute or persistent, etc. They would lack the usual targets of antibiotic therapy, they would be invisible to the immune system, and they would be very hard to diagnose
on first use.
It will also be possible to create novel, cell-like entities that could serve as sophisticated vectors for bioregulator analogs. These would be cell-like in the sense of having a bounding membrane with receptor and other proteins, motility
systems that allow them to move, energy-generating systems to power that movement, tactic systems to direct the movement towards specific targets, and specific binding and fusion proteins in the membranes to catalyze the injection of the biochemical
cargo into specific cells in specific tissues. Such entities would differ from living cells only by lacking the machinery for self-replication. They would have great utility in medicine by allowing pharmaceuticals to be targeted to specific tissues, but
they would have equal potential for facilitating the delivery of weapons agents.
It might also be possible to engineer stealth pathogens. These would be pathogens (natural or synthetic) that are engineered to become latent after a period of mild or asymptomatic replication, but to be reactivated later for symptomatic
replication in response to a particular stimulus. Such a pathogen would spread unnoticed through a susceptible population, and all infected people could at a later time be induced to display symptoms in response to, for instance, an otherwise benign
chemical compound added to water supplies, imported food materials, etc. Symptoms could be lethal or disabling.
There has been much talk of "ethnic-specific" (more properly "genotype-specific") biological weapons, and they are likely to become technically feasible in the future. Their development will be easiest for agricultural targets, due to the high
level of genetic homogeneity of cultivated plants and animals. Such genotype-specific weapons could, for instance, specifically target a cultivar of corn widely planted in the US, but not in other countries. The rapidly increasing use of genetically
engineered crop plants in the developed world provides genetic targets for such designed pathogens, or natural genetic sequences unique to specific cultivars could be targeted. Most domestic animals are more heterogeneous than crop plants, but they too
tend to be highly inbred, and genotype-specific biological agents are likely to be feasible there too.
Engineering an ethnic-specific weapon targeting humans is much more difficult, as human genetic heterogeneity is very high, and the intra-ethnic heterogeneity is generally as high, and of the same nature, as the inter-ethnic. Nevertheless, it is
possible to find combinations of traits, no one of which correlates highly with ethnicity, that together do. Using such combinations as a basis for pathogen specificity makes for a formidable problem in genetic engineering, but there is no reason to
believe that it will not eventually be possible. If so, pathogens could be designed that are essentially restricted to one race or ethnic group, but which would only infect a limited proportion of that group (probably on the order of 10% or so of the
targeted group).
If such weapons are ever contemplated, it is likely that one effect sought after will be sterility, mental illness, or other disability that is not obviously the result of biological attack. Mental illness could be produced by designing the
pathogen to produce bioregulators, as described above. Sterility could be induced by causing autoimmune reactions to sperm or egg proteins, an approach that is already being actively pursued for biocontrol of pest animals. Such infectious sterility, if
coupled with ethnic-specific targeting, could go undetected for a long time, as fertility rates in the target group gradually fell.

Policy Reponses to the Prospects of the New Biology

The preceding analysis has outlined some of the hostile applications of the revolution in the biological sciences. It is far from exhaustive; many other applications can be imagined, and many more that we cannot yet imagine will soon become
possibilities. These are all natural applications of knowledge that will be acquired as the inevitable result of peaceful medical, veterinary, and agricultural efforts. There is no way to avoid the knowledge that will make new hostile applications
possible while still enjoying the benefits of the peaceful applications; the knowledge is the same. Thus if we wish to enjoy the benefits and avoid the perils offered by new biological knowledge, a coherent policy of controlling the applications of this
knowledge is necessary.
First, of course, it is necessary to decide whether the hostile applications outlined above, and others that will emerge in the future, are desirable or not. The creation of novel pathogens is clearly not in the interests of the United States.
The US abandoned its offensive BW program over 30 years ago, and the wisdom of that policy decision is still widely respected. Like their natural predecessors, the biological weapons that will become possible in the future are more valuable to our
enemies than to us; it is in our security interest to make sure that no-one creates them.
One class of weapon enabled by biological sciences has some appeal, however, and is under active investigation by several countries, including the US. These are the disabling biochemical compounds, currently taken from the existing pharmacoepia,
and suffering from the problem of causing significant lethality along with disablement.[4] However, developments in pharmaceutical sciences will likely allow rapid development of disabling chemicals with very low lethality under conditions of use. Are
these desirable?
Proponents of the "non-lethal," or "less-than-lethal," weapons argue that for conditions in which combatants and non-combatants are mixed, as in hostage situations, or urban combat, these weapons would offer valuable options. There is no doubt
that there may be situations in which the use of disabling biochemicals would be the most humane and sensible option. However, the costs of world-wide development of these weapons may outweigh the advantages. Careful policy analysis, with due
consideration to the long-term implications rather than just the immediate benefits, is warranted before any country embarks on the development of disabling biochemicals as weapons for law enforcement or military forces. In performing such an analysis,
it would be wise to assume that if they are developed, they will become readily available to unfriendly nations, terrorists, and organized crime, and that protective measures will also be widely available. It will also be necessary to consider the threat
to peace and democracy that they might pose in the hands of dictators, and the damage they might do to the ban chemical and biological weapons in general.[5]
Clearly it will be desirable to prevent many, perhaps all, of the hostile applications of the new biology. Many of the international legal tools are already in place, notably the Biological Weapons Convention and the Chemical Weapons Convention,
which together ban military use of all of the weapons imagined here. However, these may prove insufficient to prevent proliferation, and the US should not shy away from new international treaties as necessary. Foremost among the new treaties the US
should consider, or reconsider, would include ones that would (1) add a verification regime to the Biological Weapons Convention; (2) make development, possession, or use of chemical or biological weapons a crimes over which nations may claim universal
jurisdiction (like piracy, airline hijacking, torture, etc);[6] and (3) impose a single control regime over the possession and transfer of dangerous pathogens and toxins.[7]
However, no treaties by themselves, even with sustained political commitment to ensuring compliance, will be sufficient to prevent determined nations from secretly developing prohibited weapons. A variety of other means will need to supplement
the international legal regime. Many of these are already in place, such as export controls. Others will be needed. Perhaps foremost would be a system of review and prior approval for potentially dangerous experiments, whose results might be readily
applied to weapons development.[8] Such a system would usefully begin as national programs in the US and other countries with strong biomedical research communities, but would have to ultimately become international, or at least be widely implemented in
a harmonized fashion, to truly contribute to addressing the problem.
One of the most significant contributors to interest in new weapons is always suspicion that other nations may be developing them. The development and production of chemical and biological weapons has an increasingly small footprint, and may
become nearly invisible to national technical means of intelligence. It is thus increasingly difficult to have confidence in the compliance of many countries with the BWC and CWC. This problem will become worse as the technology becomes more
sophisticated, production facilities decentralized, miniaturized, and robotically controlled, and the potential weapons more potent. For this reason, and others, serious consideration should be given to making transparency in biodefense and chemical
defense a central component of US efforts in counterproliferation. This would allow the US to take a leadership role in encouraging other to be transparent, and to offer incentives to those that do and sanctions on those that do not. A world in which
biology and chemistry are maximally transparent, without betraying important vulnerabilities or clues to offensive technology, is much more likely to deter proliferation of biological and chemical weapons, and to be able to detect when nations cheat,
than one in which military biology and chemistry are shrouded in secrecy.

Conclusion

The revolution in the biological sciences is making it possible for biology, especially medical and pharmaceutical sciences, to become fully-fledged military technologies. This raises the specter of a new generation of biological and chemical
weapons, as well as a sophisticated capability to manipulate the physiology of human beings for military purposes. Designing and weaponizing these agents would require a substantial investment of time, expertise, and money; it is not a feasible option
for terrorists, although with time, some terrorist groups might be able to develop some of the simpler alternatives. However, these new weapons will lie well within the capabilities of any country with a reasonably sophisticated biomedical research
community, an increasingly large number of states that include many suspected of current and past interest in biological and chemical weapons. The implications for weapons proliferation are thus grave.

[continued in next message]

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* Origin: fsxNet Usenet Gateway (21:1/5)

THE NEW BIOLOGY AND CB WEAPONS


Mark Wheelis
Section of Microbiology
University of California
Davis, California


The New Biology

Biology is in the midst of what can only be described as a revolution. It began in the mid-1970's with the development of recombinant DNA technology. Slowly at first, but with rapidly increasing speed, related technologies have been developed
that have dramatically expanded the experimental capabilities of modern research biologists, and that are rapidly being adopted in applied biology, for instance for drug development. In addition to the foundational recombinant DNA technology, these
include genomics, proteomics, microarray technology, high-throughput screening techniques, combinatorial methods in both chemistry and biology, site-specific mutagenesis, knock-out mice, and many others.[1] Collectively, these technologies are referred
to as "genomic sciences," or the "new biology."
These technologies are supported by, and dependent upon, two other types of technology: high-speed computing, and an instrumentation industry. Computers increasing control the instrumentation that collects data, but more importantly computers are
necessary to interpret the data. Most of these technologies are distinguished by the enormous amount of data that they generate. For instance, the sequencing of the human genome produced a data set with about 3 billion bits of information--the sequence
of nucleotides in human DNA. If one sat down to write out that sequence, perhaps as a first step in locating genes, or to compare the human sequence to some other sequence, and if one wrote one base per second without any breaks, it would take about 100
years to complete the simple transcription task. Clearly, any analysis of this data requires very high-speed computational capabilities. Many other types of biological data besides genome sequences--proteomic data, microarray data, etc--are also
typically extremely large data sets. An entirely new discipline, termed bioinformatics, has evolved to deal with the collection and analysis of these huge databases. In fact, our understanding is often limited more by the lack of bioinformatic tools to
analyze data than by the collection of data in the first place.
The new biology is equally dependant on a sophisticated instrumentation industry. The equipment--DNA sequencers, microarray printers and readers, multiple sample screening equipment, etc--were all developed in research laboratories, but these prototypes
were necessarily slow, crude, and required highly skilled operators. Part of the reason that the new biology is developing and disseminating so rapidly is that a new industry has grown up that has refined, manufactured, and is marketing and continuously
upgrading the instrumentation for the new biology--high speed DNA sequencers, ultra-high throughput screening systems, high density microarray printers and readers, etc. Increasingly the instrumentation is controlled by computers, and operations are
performed by robotics. The scale is rapidly decreasing, so that experiments that needed milliliters or milligrams of material a few years ago now require only microliters or micrograms, or less. Although highly sophisticated, this commercially-available
equipment is reliable, increasingly affordable to individual laboratories, and operable by staff with minimal technical expertise.
Because of its power, the new biology is in a period of rapid expansion. By any measure--number of professional scientists, number of publications, new journals, funding level, etc--the growth of this field is exponential, with no sign of leveling off.
This is leading to extremely rapid production of new knowledge, and a rapid dissemination of the knowledge and technologies worldwide.

Military Applications of the New Biology

Biotechnology will clearly be one of the defining technologies of the twenty-first century, probably by the middle of the century in combination with nonotechnology, artificial intelligence, and microrobotics to form a hybrid technology of
enormous power. Even as a stand-alone technology, it will have great power for both peaceful and hostile uses.
The short- and medium-term potentials of biology and biotechnology stem from two intertwined developments. The first is the rapid development of a detailed understanding of the physiology of living organisms. Previously, attempts to manipulate
natural processes, for instance to develop safe incapacitating chemicals, or to develop pathogens with enhanced virulence, were rarely successful because of the fiendish complexity of the physiological processes underlying organismic functioning.
Attempts to manipulate systems that are imperfectly understood are only rarely, and fortuitously, successful. However, with the much more detailed understanding that is very rapidly emerging, rational manipulation becomes increasingly feasible.
The second development is a rapidly increasing understanding of receptor biology. A major component of our better understanding of physiological functioning is an increasingly detailed understanding of cellular communication systems.
Multicellular organisms are characterized by immensely complicated systems that coordinate the functioning of their constituent cells. These systems are characterized by specialized receptor proteins that are embedded in the membranes of cells. Each cell
in the body has many different receptor proteins, some of them common to most other cells, some specific to the particular tissue or organ in which the cell is located, and some specific to a group of cells within a specific tissue. Approximately one
third of the 30-50,000 different proteins encoded by the human genome appear to be receptor proteins, an indication both of the great importance of this class of proteins in human physiology, as well as the great complexity of signaling systems.
Soluble molecules termed bioregulators bind with high specificity to receptor proteins. When a bioregulator binds to its cognate receptor protein, the protein undergoes a shift in its conformation that provokes a response of some kind within the
cell--a nerve impulse may be propagated, a hormone secreted, a muscle cell may contract, etc. The bioregulators may be small molecules, like acetylcholine, serotonin, or gamma-aminobutyric acid, or they may be medium to large molecules, like endorphins.
Most pharmaceuticals are analogs of these bioregulators, that mimic or oppose the action of the natural compounds.
With the tools of modern biology, receptor protein genes can often be recognized in genomic DNA sequences, their 3D structure predicted, their binding sites modeled, and synthetic chemical compounds designed that will bind to them. This
capability, which is developing rapidly, will soon allow the rational design of new pharmaceutical agents, tailored to enhance or block specific physiological pathways. This will be a great boon for medicine, but will also allow the development of a wide
range of novel chemical and biological weapons agents.
Two applications of the new biology have particular potential for military application: understanding the functioning of the nervous system, and understanding the mechanisms of microbial pathogenesis.

Understanding the Nervous System

Among the physiological systems of greatest interest to biologists is the nervous system. This interest is both because of its great intrinsic interest, and because there is a huge economic market for the development of new pharmaceutical
compounds for the treatment of mental illness, pain, and other medically important problems. Anesthetics, analgesics, tranquilizers, stimulants, antidepressants, etc are all analogs of natural neurotransmitters (bioregulators that mediate communication
within the nervous system). As we come to understand the detailed physiological pathways that underlie pain, depression, panic attacks, post-traumatic stress, anxiety disorder, schizophrenia, sleep disorders, etc., and as we identify and characterize
their specific receptor proteins (neuroreceptors), we will be able to design new medications that will offer much greater effectiveness and specificity than current ones, and that will have much reduced side effects. A combination of humanitarian and
economic incentives insures that progress will be very rapid.
Of course, the capabilities that emerge will, like all advanced technologies, be capable of hostile as well as peaceful exploitation.[2] Hostile applications include:

· manipulation of humans to increase their effectiveness as soldiers
· novel weapons for combat use, including a range of non-lethal incapacitating biochemicals
· new agents for interrogation

For at least half a century, militaries have used pharmaceutical compounds to enhance effectiveness of troops in certain situations; amphetamines as stimulants for pilots or soldiers on long missions is the primary example. In the future, we can
anticipate that at least some countries would use forced medication to produce troops who are not only alert and energetic for days at a time, but who have heightened sensory awareness, enhanced aggressiveness, decreased fear, decreased sensitivity to
pain, and a dulled moral sense. The beginnings of the understandings of the chemical bases of all of these is already emerging, and to anticipate such capabilities is not much of an extension. It might also be possible to make soldiers much stronger and
quicker than normal; the "superhuman" strength conferred by some street drugs is a common experience among law enforcement personnel, and suggests that a biochemical basis for temporary enhancement of physical capabilities might emerge.
Many of the new analogs of bioregulators will be possible new biochemical weapons. It is worth remembering that the most potent existing chemical weapons, the nerve gases such as the V-agents, are analogs of acetylcholine, a neurotransmitter
used in a number of different neural and neuromuscular circuits. There is every reason to believe that newer, even more toxic, agents will become available, and some of these will have the other characteristics that make them attractive candidates for
weaponization.
Of more significance, it will most likely be possible to develop a completely new range of non-lethal disabling chemical weapons. We have already seen the use of disabling chemicals in a hostage rescue situation, in the 2002 Moscow theater siege.
Nearly 130 of the hostages in that situation died as a direct result of the agent used (an unidentified derivative of the anaesthetic fentanyl). However, much safer incapacitating agents will become available soon, and they will be very attractive to
law enforcement and military forces. Nearly instantaneous, silent weapons that incapacitate might be of particular interest to special forces, police, and prison personnel. Incapacitation could involve unconsciousness, paralysis, delirium, or other
derangements.
New pharmaceuticals could also be of great interest to interrogators who are willing to ignore legal limits on the bounds of interrogation. While a genuine "truth serum" may not be possible, many pharmaceuticals would substantially reduce the
ability of a captive to resist providing information. Agents that cause submissiveness and eagerness to please are on the horizon, and would be effective for many captives. Pharmaceutical forms of torture could also be highly effective in reducing the
ability of captives to retain secrets--regimes in which depression, euphoria, panic, submissiveness, etc, are manipulated would likely prove irresistible to most.

Understanding Pathogenesis

The interactions of pathogenic bacteria or viruses with their host organisms is highly complex. It involves mechanisms by which microbes are transferred from one host to another, mechanisms by which they initially colonize the new host,
mechanisms by which they invade the host and localize in particular tissues, and mechanisms by which they evade or subvert host defenses. Very rapid progress is being made in understanding these processes, promising greatly enhanced public health and
agricultural benefits.
The tools are rapidly becoming available to produce improved vaccines (more efficient, longer lasting, and safer), produce new antibiotics and anti-virals, enhance host defenses, and protect against damage from over-reaction of defensive systems.
The same benefits may be realized in veterinary medicine, and better understanding of plant diseases can be expected to provide increased yields and improve nutritional quality.
However, as with neurobiology, hostile applications are equally enabled by a detailed understanding of pathogenesis. In the present and near term (10 years), possible military applications include:

· genetically engineered pathogens that evade diagnosis and treatment
· pathogens with exceptionally high lethality due to novel toxin combinations or to their ability to defeat host defenses
· pathogens that cause novel disabling symptoms
· pathogens with enhanced contagiousness
· pathogens with increased environmental stability

The first of these is nothing new. The ability to create antibiotic-resistant pathogens by selection or plasmid transfer predates the development of genetic engineering, and selection of mutants with altered surface antigens to confuse diagnosis
is also not new. The new technologies, however, make the construction of such altered pathogens easier and faster, and provide a range of new options. Furthermore, one of the inhibiting factors has always been the probability of secondary effects of
changes of pathogen properties--frequently a change in, for instance, surface antigens, would result not only in a pathogen harder to detect, but also in one of reduced virulence, since surface antigens often have roles in pathogenesis. Better
understanding of pathogenesis allows such changes to be targeted to sites that will not compromise pathogenicity.
In nature, the virulence of pathogens is the result of a complex selective process which often limit virulence in favor of transmissibility: a pathogen that kills its host so quickly that it has little chance to transfer to a new host will
quickly die out.[3] However, engineered strains that are perpetuated in the laboratory are free of such selection, and thus genetically engineered strains offer the potential of lethality that is exceptionally high and rapid compared to existing
pathogens. There are many routes to the construction of such pathogens, such as the combination of novel toxins into a pathogen, or the incorporation of bioregulators that allow the pathogen to defeat host defenses. For the former, consider the
possibility of a common virus that produces botulinum toxin; the latter has already been done: a benign mouse-pox virus with very low lethality become highly lethal when the gene for a bioregulator of the immune system was incorporated into its DNA. Many
more such strategies could be developed by any medial microbiologist, and the options will increase rapidly.
Many bioregulators are proteins or peptides, and thus benign viruses could be engineered to produce them. Others are relatively simple chemical compounds, and viruses could be engineered to contain the enzymes for their synthesis, thus allowing
the production of these bioregulators as well. In this way, viruses (or cells, for that matter) that are normally benign could be engineered to be lethal. Perhaps more disturbing, they could instead produce severe disabling effects, covering a wide range
from mild disorientation to severe psychosis. Such viruses could be contagious, and could persist for years in the body (like herpes viruses and retroviruses), causing infectious, permanent mental or physical disability.
Many pathogens have limited capacity to transfer from host to host. The detailed reasons vary among pathogens, and from one mode of transmission to another (airborne, direct contact, fecal-oral, or vectored), but have to do generally with two
properties. The first is the number of viable pathogens that are released from an infected host in respiratory droplets, secretions, or excrement, or that can be picked up by a vector. The other is the number of viable pathogens necessary to initiate an
infection, a statistical requirement that has to do with the efficiency of early host defenses, and with the efficiency of early steps in pathogenicity. Both of these properties are amenable to engineered change, once their basis is clearly understood.
It should thus be possible, at least for some pathogens, to create variants with increased (or decreased) contagiousness. Of course, this could be combined with increased lethality. For instance, a monkeypox virus, engineered to be contagious among
humans, and incorporating human immune modulators to enhance lethality, could be a fearsome weapons, perhaps worse than wild-type smallpox.
One of the obstacles to making microbes into military weapons has always been the limited environmental persistence of many, sometimes measured in minutes in an aerosol exposed to sunlight. Limited persistence may be desirable in a military
weapon to prevent continued reinfection, but persistence of many natural pathogens is so low as to prevent use as a weapon. Plague, for instance, has a fearsome lethality in the pneumonic form, but is transmissible only over very short distances (a few
feet) because it is so short-lived in respiratory droplets. For this reason, it was not successfully weaponized by the US during its offensive BW program, although it is claimed that the Soviet Union did so. Better understanding of the reasons that some
bacteria persist for long times while others do not will very likely allow the modification of pathogens to persist longer, and thus become candidates for easy weaponization.
In the longer term (20 years or so), options for all of the short-term capabilities can be expected to be dramatically broadened. In addition, new one will become possible. It is not possible to foresee in detail what will become feasible, but
we can certainly guess with confidence at some of the likely developments. Our uncertainty lies more in our failure to anticipate important developments, rather than in the failure of ones we do anticipate to materialize. Likely capabilities include:

· synthetic prions and viruses
· synthetic cellular pathogens of exceptional virulence
· synthetic, non-replicating cell-like entities as vectors for biochemical agents
· stealth pathogens
· genotype-specific pathogens of crop plants and domestic animals
· ethnic-specific human pathogens
· pathogens that cause ethnic-specific autoimmune diseases with effects such as sterility

One of the most dramatic developments of the new biology is the impending capability to create synthetic living systems (living by the criterion of self-replication based on known life processes involving nucleic acids and proteins). Already
synthetic replicas of existing viruses have been created chemically, and scientists are actively working on the synthetic creation of cellular life. It will not be very long before completely synthetic, designed-from-scratch viruses are produced. The
capability to produce effective, synthetic new viral pathogens will follow. Such agents would have significant utility in biocontrol of pests (such as weeds, rodents, or insects), so their development is likely to be pursued vigorously, but the lessons
learned will be easily transferable to the construction of synthetic human pathogens as weapons. Synthetic viruses could be designed to be contagious or noncontagious, lethal or disabling, acute or persistent, etc, and they could be engineered to lack
the usual targets of antiviral therapy and to be invisible to the immune system. They would be very hard to diagnose on first use. Similarly, as understanding of the biology of the self-perpetuating prions (infectious protein agents) deepens, it may be
possible to develop novel, synthetic prion agents.
Fully living synthetic cells will likely be made in the next decade; synthetic pathogens more effective than wild or genetically engineered natural pathogens will be possible sometime thereafter. Like synthetic viruses, such synthetic cellular
pathogens could be designed to be contagious or noncontagious, lethal or disabling, acute or persistent, etc. They would lack the usual targets of antibiotic therapy, they would be invisible to the immune system, and they would be very hard to diagnose
on first use.
It will also be possible to create novel, cell-like entities that could serve as sophisticated vectors for bioregulator analogs. These would be cell-like in the sense of having a bounding membrane with receptor and other proteins, motility
systems that allow them to move, energy-generating systems to power that movement, tactic systems to direct the movement towards specific targets, and specific binding and fusion proteins in the membranes to catalyze the injection of the biochemical
cargo into specific cells in specific tissues. Such entities would differ from living cells only by lacking the machinery for self-replication. They would have great utility in medicine by allowing pharmaceuticals to be targeted to specific tissues, but
they would have equal potential for facilitating the delivery of weapons agents.
It might also be possible to engineer stealth pathogens. These would be pathogens (natural or synthetic) that are engineered to become latent after a period of mild or asymptomatic replication, but to be reactivated later for symptomatic
replication in response to a particular stimulus. Such a pathogen would spread unnoticed through a susceptible population, and all infected people could at a later time be induced to display symptoms in response to, for instance, an otherwise benign
chemical compound added to water supplies, imported food materials, etc. Symptoms could be lethal or disabling.
There has been much talk of "ethnic-specific" (more properly "genotype-specific") biological weapons, and they are likely to become technically feasible in the future. Their development will be easiest for agricultural targets, due to the high
level of genetic homogeneity of cultivated plants and animals. Such genotype-specific weapons could, for instance, specifically target a cultivar of corn widely planted in the US, but not in other countries. The rapidly increasing use of genetically
engineered crop plants in the developed world provides genetic targets for such designed pathogens, or natural genetic sequences unique to specific cultivars could be targeted. Most domestic animals are more heterogeneous than crop plants, but they too
tend to be highly inbred, and genotype-specific biological agents are likely to be feasible there too.
Engineering an ethnic-specific weapon targeting humans is much more difficult, as human genetic heterogeneity is very high, and the intra-ethnic heterogeneity is generally as high, and of the same nature, as the inter-ethnic. Nevertheless, it is
possible to find combinations of traits, no one of which correlates highly with ethnicity, that together do. Using such combinations as a basis for pathogen specificity makes for a formidable problem in genetic engineering, but there is no reason to
believe that it will not eventually be possible. If so, pathogens could be designed that are essentially restricted to one race or ethnic group, but which would only infect a limited proportion of that group (probably on the order of 10% or so of the
targeted group).
If such weapons are ever contemplated, it is likely that one effect sought after will be sterility, mental illness, or other disability that is not obviously the result of biological attack. Mental illness could be produced by designing the
pathogen to produce bioregulators, as described above. Sterility could be induced by causing autoimmune reactions to sperm or egg proteins, an approach that is already being actively pursued for biocontrol of pest animals. Such infectious sterility, if
coupled with ethnic-specific targeting, could go undetected for a long time, as fertility rates in the target group gradually fell.

Policy Reponses to the Prospects of the New Biology

The preceding analysis has outlined some of the hostile applications of the revolution in the biological sciences. It is far from exhaustive; many other applications can be imagined, and many more that we cannot yet imagine will soon become
possibilities. These are all natural applications of knowledge that will be acquired as the inevitable result of peaceful medical, veterinary, and agricultural efforts. There is no way to avoid the knowledge that will make new hostile applications
possible while still enjoying the benefits of the peaceful applications; the knowledge is the same. Thus if we wish to enjoy the benefits and avoid the perils offered by new biological knowledge, a coherent policy of controlling the applications of this
knowledge is necessary.
First, of course, it is necessary to decide whether the hostile applications outlined above, and others that will emerge in the future, are desirable or not. The creation of novel pathogens is clearly not in the interests of the United States.
The US abandoned its offensive BW program over 30 years ago, and the wisdom of that policy decision is still widely respected. Like their natural predecessors, the biological weapons that will become possible in the future are more valuable to our
enemies than to us; it is in our security interest to make sure that no-one creates them.
One class of weapon enabled by biological sciences has some appeal, however, and is under active investigation by several countries, including the US. These are the disabling biochemical compounds, currently taken from the existing pharmacoepia,
and suffering from the problem of causing significant lethality along with disablement.[4] However, developments in pharmaceutical sciences will likely allow rapid development of disabling chemicals with very low lethality under conditions of use. Are
these desirable?
Proponents of the "non-lethal," or "less-than-lethal," weapons argue that for conditions in which combatants and non-combatants are mixed, as in hostage situations, or urban combat, these weapons would offer valuable options. There is no doubt
that there may be situations in which the use of disabling biochemicals would be the most humane and sensible option. However, the costs of world-wide development of these weapons may outweigh the advantages. Careful policy analysis, with due
consideration to the long-term implications rather than just the immediate benefits, is warranted before any country embarks on the development of disabling biochemicals as weapons for law enforcement or military forces. In performing such an analysis,
it would be wise to assume that if they are developed, they will become readily available to unfriendly nations, terrorists, and organized crime, and that protective measures will also be widely available. It will also be necessary to consider the threat
to peace and democracy that they might pose in the hands of dictators, and the damage they might do to the ban chemical and biological weapons in general.[5]
Clearly it will be desirable to prevent many, perhaps all, of the hostile applications of the new biology. Many of the international legal tools are already in place, notably the Biological Weapons Convention and the Chemical Weapons Convention,
which together ban military use of all of the weapons imagined here. However, these may prove insufficient to prevent proliferation, and the US should not shy away from new international treaties as necessary. Foremost among the new treaties the US
should consider, or reconsider, would include ones that would (1) add a verification regime to the Biological Weapons Convention; (2) make development, possession, or use of chemical or biological weapons a crimes over which nations may claim universal
jurisdiction (like piracy, airline hijacking, torture, etc);[6] and (3) impose a single control regime over the possession and transfer of dangerous pathogens and toxins.[7]
However, no treaties by themselves, even with sustained political commitment to ensuring compliance, will be sufficient to prevent determined nations from secretly developing prohibited weapons. A variety of other means will need to supplement
the international legal regime. Many of these are already in place, such as export controls. Others will be needed. Perhaps foremost would be a system of review and prior approval for potentially dangerous experiments, whose results might be readily
applied to weapons development.[8] Such a system would usefully begin as national programs in the US and other countries with strong biomedical research communities, but would have to ultimately become international, or at least be widely implemented in
a harmonized fashion, to truly contribute to addressing the problem.
One of the most significant contributors to interest in new weapons is always suspicion that other nations may be developing them. The development and production of chemical and biological weapons has an increasingly small footprint, and may
become nearly invisible to national technical means of intelligence. It is thus increasingly difficult to have confidence in the compliance of many countries with the BWC and CWC. This problem will become worse as the technology becomes more
sophisticated, production facilities decentralized, miniaturized, and robotically controlled, and the potential weapons more potent. For this reason, and others, serious consideration should be given to making transparency in biodefense and chemical
defense a central component of US efforts in counterproliferation. This would allow the US to take a leadership role in encouraging other to be transparent, and to offer incentives to those that do and sanctions on those that do not. A world in which
biology and chemistry are maximally transparent, without betraying important vulnerabilities or clues to offensive technology, is much more likely to deter proliferation of biological and chemical weapons, and to be able to detect when nations cheat,
than one in which military biology and chemistry are shrouded in secrecy.

Conclusion

The revolution in the biological sciences is making it possible for biology, especially medical and pharmaceutical sciences, to become fully-fledged military technologies. This raises the specter of a new generation of biological and chemical
weapons, as well as a sophisticated capability to manipulate the physiology of human beings for military purposes. Designing and weaponizing these agents would require a substantial investment of time, expertise, and money; it is not a feasible option
for terrorists, although with time, some terrorist groups might be able to develop some of the simpler alternatives. However, these new weapons will lie well within the capabilities of any country with a reasonably sophisticated biomedical research
community, an increasingly large number of states that include many suspected of current and past interest in biological and chemical weapons. The implications for weapons proliferation are thus grave.

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