Bacillus anthraces — more commonly known as anthrax — is not to be trifled with. Once the bacterium enters the blood stream, it releases a lethal cocktail of toxins that spreads rapidly throughout the body, leading to severe tissue damage, bleeding, and respiratory collapse. The fact that anthrax spores can infect a host via inhalation have made it a popular biological weapon in recent years.


Some people, however, demonstrate a natural resistance to anthrax, although the reasons for this have remained largely unknown. Now, researchers have discovered that how resistant you are to anthrax's effects likely depends on specific components of your genetic makeup. What implications do their results have for biodefense and biosecurity? Is our understanding of infectious agents advancing to a point that could soon make genetic-specific bioweapons a reality?

A genetic basis for anthrax resistance

The results of the anthrax study are published in this week's Proceedings of the National Academy of Sciences, by a team of Stanford geneticists led by researchers Mikhail Martchenko and Stanley Cohen.


SciAm's Katherine Harmon provides a tidy summary of their findings:

The researchers used cells from 234 people from African, Asian, European and North American descent whose tissues were taken for the HapMap Project, a freely available genome database. Of those cells, most fell to assaults from the anthrax bacterium. But cells from three people-of European descent-required hundreds or even thousands more times as much anthrax toxin to kill them.

This staggering range in lethality was certainly unexpected; but believe it or not, the fact that the toxin was more deadly to some cells than it was to others was not, in and of itself, surprising.

Whether these variations were due to genetic or environmental factors, however, was unclear, which is why the real surprise came when Martchenko and Cohen managed to trace the broad range in anthrax sensitivity to the regulation of a specific gene, named capillary morphogenesis gene 2, or "CMG2" for short. (CMG2 codes for a protein that controls anthrax's ability to access human cells.)


The researchers found that the cells of people who were closely related expressed the CMG2 protein in similar quantities, and had comparable reactions to the toxin, leading the researchers to conclude that a person's sensitivity to anthrax is, in fact, a heritable genetic trait. By extension, some ethnic/geographical groups are likely to be more susceptible to lethal anthrax infection than others.

This study therefore belongs to a small handful of investigations that have managed to identify a strong genetic basis for person-to-person variations in toxin resistance, which make its findings especially relevant in the context of international biosecurity — i.e. how we go about protecting ourselves from biological warfare.


A brief introduction to biological warfare

Why these findings are so important in the context of international security requires a bit of background. The first thing you should understand is that biological weapons have been around for a very long time, and come in many different forms.


As early as the 5th century BC, Greco-Roman soldiers were deliberately contaminating their enemies' water sources with animal carcasses. By 400 BC, Scythian archers had managed to effectively weaponize biological agents by dipping the heads of their arrows in feces or decaying cadavers, recognizing that their projectiles would inflict more harm if they were first tainted by human waste of one form or another.


Two hundred years later, Hannibal — the legendary Carthaginian general — would weaponize biological agents, as well, cramming large clay pots full of venomous snakes before launching them aboard the ships of his enemies.

It seemed at first ridiculous to Hannibal's opponents that he should fight with earthen pots, "[as though his men] could not fight with the sword," writes Roman biographer Cornelius Nepos, in an account of Hannibal's unconventional tactics. "But when the ships began to be filled with serpents, and they were thus involved in double peril, [Hannibal's enemies] yielded the victory."


Over the course of history, biological warfare has evolved, and with it its methods of implementation. At the 1346 Siege of Caffa, Mongol forces are believed to have used enormous trebuchets — many capable of hurling loads well over 200 pounds — to pitch plague-ridden cadavers over the walls of the well-guarded the city.

"[These corpses] could easily have transmitted plague, as defenders handled the cadavers during disposal," writes Mark Wheelis — an historian of biological warfare and microbiologist at UC Davis — in an analysis of the tactics employed at Caffa. He continues:

Contact with infected material is a known mechanism of transmission; for instance, among 284 cases of plague in the United States in 1970–1995 for which a mechanism of transmission could be reasonably inferred, 20% were thought to be by direct contact. Such transmission would have been especially likely at Caffa, where cadavers would have been badly mangled by being hurled, and many of the defenders probably had cut or abraded hands from coping with the bombardment.


This act of biological warfare, concludes Wheelis, "appears to have been spectacularly successful in producing casualties."


More detailed accounts of biological warfare in the pre-modern and modern eras are available elsewhere. (The figure featured here, which highlights notable instances of biowarfare throughout history, is taken from "Feces, Dead Horses, and Fleas: Evolution of the Hostile Use of Biological Agents," and is available via the National Institutes of Health.)

An Unruly Weapon

For now, however, the most important thing to take away from these accounts is how every single one of them points to an overall lack of understanding and sophistication surrounding the weaponization of biological agents. Did armies recognize that arrows dipped in feces would inflict more harm upon their targets, or that plague-ridden bodies could act as vectors of illness and disease? Almost certainly — at least on some basic level. But remember: these tactics of biological warfare predate the germ theory of disease by hundreds, even thousands of years; whatever understanding these civilizations possessed, it lacked the epidemiological sophistication of modern science and medicine.


Granted, all of these examples took place a long, long time ago; our understanding of biological agents and how they affect the body has come a long way since we were hurling disease-ridden bodies over city walls, right? Absolutely — but in many ways, humanity's relationship with biological warfare is defined by a lack of understanding even to this day. Consider, for example, that one of the major hurdles facing biological warfare's effective implementation is the issue of target specificity — or, rather, the lack thereof.


"Among weapons of mass destruction, biological weapons are more destructive than

chemical weapons, including nerve gas," writes David Siegrist, a professor of biodefense at George Mason University, in an article published in Emerging Infectious Diseases.

"In certain circumstances," Siegrist continues, "biological weapons can be

as devastating as nuclear ones — —a few kilograms of anthrax can kill as many people as a

Hiroshima-size nuclear weapon."


Their potential to wipe out thousands of people while leaving infrastructure intact has led some to refer to biological weapons as "the poor man's neutron bomb." But these powerful weapons differ on one subtle, albeit crucial point: nuclear arms were specifically designed to deliver wholesale devastation; in contrast, widespread pestilence — the kind brought about by a biological weapon — is defined by a lack of design on humanity's part, by our outright inability to wield its power with deliberation.

What does the future hold?

Which brings us back to why the findings of Martchenko and his colleagues are so important in the context of international biosecurity.


Speaking to the implications of their results, the authors note:

Our findings, which reveal the previously unsuspected magnitude of genetically determined differences in toxin sensitivity among cells from different individuals, suggest a broadly applicable approach for investigating pathogen susceptibility in diverse human populations.


Such investigations could inform our ability to determine which members of a population are most likely to fall ill following exposure to a biological weapon. On one hand, this is the kind of information that a bioterrorist could use to "custom tailor" a toxin or infectious agent to inflict harm on a specific subset of people — what is sometimes referred to as an ethnic or biogenetic weapon. At a Department of Defense news briefing held in 1997, then Secretary of Defense William S. Cohen described such weapons as a conceivable risk, remarking that there are "plenty of ingenious minds out there that are at work finding ways in which they can wreak terror upon other nations." To assume that these "ingenious minds" will not take interest in a study that demonstrates a genetic basis for susceptibility to anthrax toxin would be exceedingly foolish.


On the other hand, this kind of information will also prove incredibly useful for those working to improve our ability to defend against lethal pathogens, anthrax or otherwise.

This discovery, notes Relman, who was not involved in the research, "could lead to the development of novel treatment strategies, perhaps by blocking the interaction between the toxin and the receptor or by down-regulating its expression."


"The findings could also provide a possible means for predicting who is likely to become seriously ill after exposure, which could be extremely useful when faced with a large number of exposed people."

So what's the upshot of all this? If the anthrax findings published in this week's PNAS have brought us one step closer to a future where custom-made biogenetic weapons are a reality, they have also narrowed the gap that separates us from effective defenses against those weapons.


The researchers' findings are published in the latest issue of PNAS.

DNA and Gas mask via Shutterstock; Hannibal via Wikimedia Commons; All other figures via their respective papers