Anyone who was alive during the outbreak of the bubonic plague in the 14th century experienced something terrifyingly close to the widespread death and chaos of an apocalyptic event.  

The plague, which was carried by rat-borne fleas, spread from Mongolia to the British Isles, killing at least 25 million people, possibly many times that number, as there's no comprehensive record. Governments were toppled, ethnic warfare swept across Europe, commerce stalled, and bodies were disposed of so hurriedly that they were often eaten by dogs. Death was so common, wrote one chronicler, Agnolo di Tura, that few people even wept over it anymore, “for all awaited death. And so many died that all believed it was the end of the world.”

Yet for all its horrors, the plague, also known as the black death, is considered only the second greatest scourge in human history. The worst, the deceptively mundane-sounding 1918 influenza, or Spanish flu, killed an estimated 50 million people worldwide (and, again, possibly many more). And experts say the absolute worst may be yet to come.

In an era of vastly expanded knowledge about how viruses and bacteria spread, when there are better treatments and in some cases vaccines, it is hard to fathom a pandemic on the scale of the plague (which is caused by a bacteria) or the 1918 flu (caused by a virus, which can’t be cured with antibiotics). The closest the world has come in recent memory is AIDS, a slow-motion viral pandemic that has killed an estimated 30 million people worldwide during the last three decades. The current Ebola epidemic, also viral, is not even close, with the death toll just topping 2,400 as of Sept. 12.

But the potential for another pandemic of similar scale remains real, with most experts saying it's just a question of how and when. As David Quammen noted in the New York Times on Oct. 14, 2013, “Plague is a tribulation that science, technology and social engineering haven’t fixed.”  

Left to their own devices, epidemic diseases tend to follow the same basic process: A virus or bacteria infects a host, who typically becomes sick and in many cases dies. Along the way, the host infects others. How long it takes for the host to become infected, assuming he or she does, how long the suffering lasts, and how and when the person transmits the disease to others are significant variables. But in almost every case there is a terrible, exquisite symmetry at the core of viral behavior, in which the one logical human response – to try to flee the threat – is precisely what the virus needs its host to do.

That dispersal process is now underway in West Africa as Ebola spreads from bush villages to metropolitan areas and beyond.

For an uninfected person, running away may be the best response, and it limits the spread by acting as a kind of quarantine. But if the person who flees is infected, the results can be disastrous both for that person and for others who are exposed as a result. In West Africa, “people are running away from the infrastructure where you could isolate it and give them care,” said Dr. Scott Podolsky, director of Harvard’s Center for the History of Medicine.

Podolsky pointed to a recent Washington Post article in which World Bank president Dr. Jim Yong Kim and Harvard professor Dr. Paul Farmer suggested that the Ebola outbreak now devastating Guinea, Liberia and Sierra Leone could have been easily contained had it occurred in a place with better health care, such as the United States. The outbreak of a disease similar to Ebola in Germany and Yugoslavia in 1967, for example, carried a 23 percent fatality rate, compared with an 86 percent rate for Ebola across sub-Saharan Africa. “The difference is that Germany and Yugoslavia had functioning health systems and resources to treat patients effectively,” Kim and Farmer wrote. “The West African countries coping with Ebola today have neither.”

Historically, such an outbreak would simply run its course, to whatever morbid conclusion. Without effective human intervention, epidemics and pandemics typically end only when the virus or bacteria has infected every available host and all have either died or become immune to the disease. But, as Kim and Farmer noted, society is not likely to allow that to happen today. “It would be scandalous to let this crisis escalate further when we have the knowledge, tools and resources to stop it,” they wrote. “Tens of thousands of lives, the future of the region, and hard-won economic and health gains for millions hang in the balance.”

By definition, an epidemic has exceeded the ability of people to satisfactorily contain its spread. But how it plays out is only a question of scale. Without an adequate response, an epidemic can develop into a pandemic, which generally means it has spread to more than one continent. Ebola has not reached that level, but because viruses can mutate, including in response to treatment measures, even the most educated statements about Ebola -- including conclusions about its potential to spread -- carry an asterisk.

One stage of the Bubonic plague was known as pneumonic, in which the virus infects the respiratory system, at which point the pathogen has access to a new, airborne transmission mechanism. Could such a mechanism develop for Ebola, greatly expanding its communicability and range? “That’s a good question," Podolsky said, but he was quick to add, "I haven’t heard any credible biologist say it could spread in a different way.” Similar concerns were expressed about AIDS becoming airborne during the early years of that pandemic, he said, but it did not happen.

One reason the current Ebola outbreak is so much worse than previous ones (the virus was first identified in 1976, and has cropped up numerous times, until recently primarily in Central Africa), is that it began in a new area where three nations intersect. Cross-border travel enabled it to spread to cities that offered concentrated opportunities for growth. 

Further complicating matters, Podolsky said, is that those cities, which do not have adequate health care systems to start with, had little experience with treating Ebola. In the worst-case epidemic -- what’s known as a virgin-soil epidemic -- a population caught in its grips has no experience with it at all, and therefore no physical antibodies and often little understanding of the disease’s causes or how to treat it. That is how Native American populations were decimated by the spread of European diseases like smallpox.   

Lack of past exposure was also a factor in the spread of the Bubonic plague. Though plagues had occurred before, with the earliest recorded in the second century A.D., the Bubonic strain was unprecedented. It originated in the Asian steppes and spread to new areas with developing trade; ships carried it from port to port, and from there it traveled inland in every direction, eventually killing as much as half of the population of Europe. Because the carnage occurred during the Middle Ages, in the mid-14th century, the exact number of deaths is unknown, but estimates range from 25 million to several hundred million.

The 1918 flu – misnamed the Spanish flu during World War I by enemy nations that found it mutually convenient to associate the disease with neutral Spain – was even more deadly, in part because influenza is extremely contagious and easily transmitted by air, through body fluids and by direct contact with contaminated surfaces. Ebola, by comparison, requires direct contact with the body fluids of someone who has it, or who died from it. The Bubonic plague, with its multiple transmission mechanisms, did not stop until it had crossed Asia and Europe and reached the British Isles on the west and the frigid Scandinavian region to the north. By then, essentially everyone in its path had been exposed and had either died or developed immunity.

The 1918 flu seems to run counter to the notion that nations with good health care are less prone to epidemics. As John Barry noted in his 2004 book “The Great Influenza,” the world’s worst pandemic is believed to have originated at an army camp in Kansas, spread from base to base and to Europe with U.S. troops, then exploded, killing as many as 100 million people worldwide, including an estimated 675,000 in the U.S.  

Barry wrote in the January 2004 Journal of Translational Medicine that the World Health Organization and other public health authorities have responded to more-recent flu outbreaks with vaccines and treatments that prevent the viruses “from adapting to man and igniting a new pandemic.” But, he added, only 83 countries in the world – less than half – participate in WHO’s surveillance system, which means diseases that could spread are not uniformly monitored. In Barry’s view, “unless WHO gets more resources and political leaders move aggressively on the diplomatic front, then a new pandemic really is all too inevitable.”

Flu viruses constantly change and mutate, which is how different strains move from animal to human populations. Some mutations happen often enough that human immune systems cannot recognize them from year to year, which is why seasonal flus require new vaccinations. Others happen suddenly and result in new flu subtypes, which is the kind that could spark a severe epidemic or pandemic.

According to WHO spokesperson Dan Epstein, the greatest danger today is the potential for a disease to become resistant to antibiotics that enable human populations to control or at least to dramatically influence the spread of epidemics.

“The world is more prepared than it’s ever been, but diseases are tricky -- they can cross borders at any time,” Epstein said. “We’re able to track and detect very well, but the response is dependent upon what tools we have available.” In the case of the Ebola epidemic, “we don’t really have any effective medicines available,” he said.

The quarantine of a U.S. air marshal in Houston after a syringe attack Wednesday by an unknown assailant at the Lagos, Nigeria, airport -- involving suspected but unconfirmed Ebola -- highlights a secondary threat of the epidemic in West Africa: the potential for a contagious disease to be weaponized with the aim of creating an epidemic or even global pandemic. How easily such a pandemic could be artificially manipulated remains open to debate, but the debate is no longer confined to sci-fi readers, survivalists and board game geeks. The U.S. Centers for Disease Control includes on its list of potential bioterrorism agents with the greatest potential for widespread deaths an untreatable form of botulism, coronaviruses like SARS, one strain of avian flu, smallpox and pneumonic plague, the latter 100 percent fatal if not treated within 48 hours.

The flu is an endemic disease, meaning it is always present in human populations, and in some areas, so is the plague. Both are kept at bay through sanitation and medical treatments. Yet, Epstein pointed out, when considering the potential for a new disease pandemic, “There’s a huge danger of antibiotic resistance. There are bacteria that are developing that, and that’s one of the biggest dangers. If all the antibiotics become ineffective, then any little infection that has resistance could lead to death.”

Already, mutations have resulted in antibiotic-resistant strains of tuberculosis and malaria, and similar treatment mutations are being found in certain strains of HIV and influenza. Treatment failures owing to resistance may soon make the sexually transmitted disease gonorrhea untreatable, because no new drugs are in development, according to the WHO website. Given that, Ebola – for which there is no cure or vaccine -- may be far less a concern than a familiar disease that develops resistance.

WHO’s 2014 report on global surveillance of antimicrobial resistance noted that “antibiotic resistance is no longer a prediction for the future; it is happening right now, across the world, and is putting at risk the ability to treat common infections in the community and hospitals.”

According to National Geographic, the last reported serious outbreak of plague was in 2006 in the Democratic Republic of the Congo in Central Africa, where at least 50 people died. Plague has also been confirmed in China, India, Mongolia, Vietnam and the U.S. Most infected people survive if given the proper antiviral medications in time, the article noted. But there is a major caveat.

As WHO’s 2014 report warned, “Without urgent, coordinated action, the world is heading toward a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill.”