In Michael Creighton’s 1969 best selling thriller, “The Andromeda Strain” a satellite crashes back to Earth carrying with it an extraterrestrial pathogen that threatens all human life. For genetic researchers in Canberra Australia no such dramatic entrance was needed to come face to face with a similar scenario, instead they just tried to create a mouse contraceptive.
Around the turn of the century the government of Australia turned to genetic researchers for help in trying to control an overabundant mouse population that was plaguing the Australian countryside. The researchers formulated a reasonable plan, they would use the mousepox virus joined to the gene for a protein expressed in mouse eggs to illicit an immune response in female mice to their own eggs. In this way, while otherwise being unharmed the female mice would be sterile and would reduce the mouse population. The early studies however, did not show a sufficient immune response against the mouse ovary to prove effective. So, going back to the drawing board, the researchers now decided to also include the gene for the cytokine interleukin 4 (Il-4) in the mousepox virus along with the gene for the mouse egg protein. IL-4 was known to be involved in immune regulation and it was speculated it would serve as a sort of vaccine adjuvant, something that would increase the mouse’s antibody immune response to the mouse egg protein.
When they did this something curious, unfortunate and totally unexpected happened. Every single mouse who received the modified mousepox virus died. While mousepox certainly can kill mice, it is far from uniformly fatal. Indeed the whole point and intent of this experiment was to create a non-virulent virus, so that sterile mice could then be released into the wild after exposure to the engineered mousepox virus. The researchers, quite alarmed by this dramatic turn of events, carried out a subsequent experiment. By administering a mousepox vaccine, they immunized the mice against mousepox and again introduced the modified mousepox virus. Even in this case, 50% of the immunized mice died.
It is hard to overstate the impact smallpox (the strain of pox virus specific to humans) has had on human history and development. Smallpox was one of the most contagious and virulent diseases ever known. It mercilessly killed countless millions across the world throughout recorded history, especially in Europe, India and China. The Pharaoh Ramses V is believed to be a very early case, dying of smallpox in 1157 BC. The disease reached Europe in 710 AD and was transferred to America by Hernando Cortez in 1520. Some historians believe as many as 3.5 million Aztecs succumbed to smallpox over the 2 years after its introduction. In the cities of 18th century Europe, smallpox often reached plague proportions and was a feared scourge. Five reigning European monarchs died from smallpox during the 18th century alone. In Europe, the majority of people caught it at some stage in their lives. About 10-20% of infected people died as a result. Of the survivors, around 15% were permanently disfigured by the scars left from the pustules that covered the body. By some estimates smallpox has likely killed more people than all other epidemics and wars combined.
Smallpox is also the first disease to have been prevented through vaccination, when Edward Jenner followed up on a dairy maid’s comment that she would never have the small pox as she had had the cowpox. So successful was this new approach of vaccination (vacca being latin for cow) that smallpox is believed to have been entirely eradicated, primarily through vaccination. This initial success has led to a whole industry of subsequent vaccines, though often for less urgent indications and of quite debatable efficacy and safety (see Gardasil is a Bad Idea).
Back to our story, the researchers in Australia agonized for many months over whether to go public with their findings, realizing the potential harm such knowledge could have if in the wrong hands. However, in the end they decided it was better to warn the community of the potential dangers from their work than to try to hide the results. They published the findings of their work in 2001 in the Journal of Virology. Subsequently some three years later their findings were replicated by another research team in the United States.
There are many differences between the mouse immune system and that of humans. It is not certain that the introduction of Il-4 into human smallpox would bring about the same horrific results seen with mousepox. However, shortly after their research gone awry, Dr. Ron Jackson, who co-engineered the modified mousepox virus stated,
“It would be safe to assume that if some idiot did put human IL-4 into human smallpox they’d increase the lethality quite dramatically…Seeing the consequences of what happened in the mice, I wouldn’t want to be the one who’d want to do the experiment.”
As if this isn’t concern enough it is also worth noting that since the eradication of smallpox the world population is neither naturally exposed nor immunized to the smallpox virus, it is a totally “immune naive” population to use the medical term. If there were no possibility for immunization, even normal smallpox, with its fatality rate of some 10-30%, could cut through the immune naive world population like a hot knife through butter. If Il-4 has anywhere near the effect on human smallpox as it did on mousepox, such an organism truly would deserve the moniker of an Armageddon Bug.
The researchers in Australia did not set out to discover some horrifying bioweapon. They stumbled upon this new virus entirely by accident and that is also terribly concerning. There are currently dozens if not hundreds of genetically modified organisms, mixing and matching genes across species, genus, phyla and kingdom like some sort of genetic fondue menu. These organisms have been released into the wild and are self-replicating, they cannot be recalled. Just maybe we should stop playing at being the Sorcerer’s Apprentice long enough to prevent another accident as happened in Australia from turning us all into rat food.