Wednesday, March 26, 2014

What Accidental Amplification of Virulence Teaches us about Biological Weapon Development


"Many analysts rank cultured and genetically engineered biological organisms as the most dangerous of all existing weapons technologies, with the potential for producing more extensive and devastating effects on human populations than even fusion nuclear weapons (Henderson, 1999)." See:http://bioscience.oxfordjournals.org/content/52/7/583.full


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In 2001, the New Scientist (4) published an article on a deadly virus created accidentally by an Australian research team trying to genetically engineer a contraceptive vaccine for mice."They spliced a gene for the protein interleukin-4 (IL-4) into the relatively harmless mousepox virus (ectromelia virus) in the hope that IL-4 would boost the immune system to make more antibodies. When the researchers injected this vaccine into mice, all the mice died. In fact, this synthetic virus was so lethal that it also killed half of all the mice that had been vaccinated against mousepox.The work published in the Journal of Virology (http://jvi.asm.org/content/75/3/1205.long) revealed that hte mice used were genetically resistant to the mousepox viruis in the first place. Genetic resistance to mousepox varies among inbred laboratory mice, and depends on natural killer (NK) cells and cytotoxic T-lymphocytes (CTL) responses to viral infection, both of which destroy cells that have been infected with virus so as to clear the body of the virus. The researcher found that expression of IL-4 suppressed both NK and CTL. Genetically resistant mice infected with the IL-4 expressing virus developed symptoms of acute mousepox accompanied by 100% mortality, similar to the disease seen when genetically sensitive mice are infected with the virulent Moscow strain. Strikingly, infection of genetically resistant mice recently immunised against mousepox also resulted in significant mortality. These findings suggest that virus-encoded IL-4 not only suppresses primary antiviral immune responses but also inhibits the expression of immune memory responses.  In previous investigations (6,7), the IL-4 gene inserted into another virus used in vaccinations against smallpox, the vaccinia virus, delayed the clearance of the the virus from experimental animals and undermined the animals' anti-viral defence. These results suggest that IL-4 may function similiarly in all viruses in the same family, which also contains the human smallpox virus. These findings raise the spectre of biological warfare. But the far greater danger lies in the unintentional creation of deadly pathogens in the course of apparently innocent genetic engineering experiments. Genetic engineering involves facilitating horizontal transfer and recombination of genetic materials across species barriers, precisely the conditions favouring the creation of new viruses and bacteria that cause diseases.We now know of cases in the laboratory where such viruses have been created. (http://www.twnside.org.sg/title/twr127i.htm)
But what does the IL-4 study teach us in terms of modern and advanced biological weapon development? "The scene on the far horizon is much harder to discern simply because the current rapid pace of technological advance suggests that new technologies are likely to be developed in the coming years that will completely change the landscape for biological warfare offensive and defensive possibilities. Even without envisioning new biological agents such as those that could be generated by synthetic biology, the technology already exists for significantly enhancing the lethality of biological weapons. The introduction of antimicrobial resistance genes into bacterial agents could significantly enhance their lethality by reducing treatment options. In this regard, it is relatively easy to generate B. anthracis resistant to first line antimicrobial therapies such as ciprofloxacin (athamna et al., 2004). It is noteworthy that microbial modifications to increase lethality is only one possible outcome for engineering biological weapons since these could also be designed to incapacitate instead of kill. Given the enormous universe of microbial threats, the power of modern biology to enhance the microbial virulence and the high likelihood that biological weapons will continue to threaten humanity one must face the question of how best to protect society. The sheer number of threats and the availability of technologies to modify microbes to defeat available countermeasures suggests that any attempt to achieve defence in depth using microbe-by microb approaches to bio-defence is impractical and ineffective." See: http://onlinelibrary.wiley.com/doi/10.1111/j.1751-7915.2012.00340.x/full 

Arturo Casadevall's paper, quoted above, posits several possible countermeasures worth considering:

  1. Continued development of specific diagnostic assays and countermeasures (vaccines, drugs, antibodies) for high risk threats identified by current matrix threat analysis. This is essentially a continuation of the major societal response to perceived biological threats in the first decade of the 21st century when a significant proportion of government supported research has focused on known agents such as variola major, B. anthracis and other high risk agents. This approach makes sense given that known agents will continue to be the most likely threats in the near horizon.
  2. Develop host-targeted interventions that enhance immune function against a wide variety of threats. In other words, develop therapies that produce temporary increases in immune function that would protect against known and unknown threats. This approach would provide defensive options against yet to be identified microbial threats.
  3. Develop new ways to assess the healthy state that could allow monitoring of the population to identify the appearance of new agents. Although physicians can readily identify the disease state and surveillance systems for known agents are critically important for identifying a biological attack, such approaches may not suffice for all threats. For example, consider the situation with the outbreak of the HIV epidemic. The epidemic was identified in 1981 as a consequence of clusters of cases with known infectious diseases that did not fit known epidemiological parameters for such maladies as they included rare diseases in individuals with no predisposing conditions. However, we now know that AIDS can follow many years after the HIV infection and the interval between infection and disease is characterized by a slow decline in immune function during which the individual does not exhibit signs of disease. Arguably, the existence of methodology that could assess the healthy state might have identified the silent spread of the virus in certain populations years prior to the onset of the epidemic.
  4. Obtain a better understanding of microbial diseases in animal species and especially those that come in close contact with humans. Given that 72% of emergent infectious diseases described in recent decades have been zoonosis (Jones et al., 2008), it is reasonable to assume that wildlife will continue to be source of new pathogenic microbes for humans and a potential source of biological weapons. Consequently any effort to design a system for defence in depth should include efforts to describe, catalogue and study microbial diseases in wildlife.
  5. In preparing for known and unknown threats the availability of a vigorous scientific research establishment that can respond rapidly is an essential component for any effort to defend society. The rapid identification of HIV as the cause of AIDS and the development of effective anti-retroviral therapies was made possible by prior societal investments in studying the biology of retroviruses at a time when these were not associated with human diseases. Hence, continued investments in basic research with emphasis on fostering a better understanding of host–microbe interactions is an essential cornerstone for any effort to defend in depth against biological weapons.
See: Arturo Casadevall, "The Future of biological warfare", Microbial Biotechnology, Vol.5, Issue 5,584-587, September, 2012.


Jill Bellamy is an internationally recognized expert on biological warfare and defence. She has formerly advised NATO and for the past seventeen years has represented a number of bio-pharmaceutical and government clients working on procurement strategy between NATO MS and Washington DC. Her articles have appeared in the National Review, The Wall Street Journal, The Washington Post, The Sunday Times of London, Le Temps, Le Monde and the Jerusalem Post among other publications. She is a CBRN SME with the U.S. Department of Defence, Chemical, Biological, Radiological and Nuclear Defence Information Analysis Center and CEO of Warfare Technology Analytics, a private consultancy based in the Netherlands. She is an Associate Fellow with the Henry Jackson Society, UK.



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