Outbreak! Plagues That Changed History

by Bryn Barnard

  As it turns out, only a single infectious genie—smallpox—has been successfully stuffed back in its bottle. By 1991, the disease disappointments of the late twentieth century would prompt weary Columbia University physician Harold Neu to this rueful wisdom: “Bacteria are cleverer than men.” By 2002, Flinders University microbiology professor Peter MacDonald would make an even more sweeping admission: “Germs are smarter than people and getting smarter all the time.”

  Part of the problem is that since the days of Koch and Pasteur, we’ve thought of our relationship with disease as a kind of war. In the bloody twentieth century, where war was ubiquitous, disease was yet another enemy. Military terms began to define illness. Today the metaphors are pervasive: the human body is a fortress; microbes are the enemy; medicine is our weapon. In a time when everyone “fights” a cold, it’s hard to think of infectious disease any other way. The problem with this kind of thinking is that it suggests that in disease, as in war, we can beat microbes and they’ll stay beaten. Problem is, no one told the microbes.

  Our relationship with pathogens is a never-ending competition. As we develop new measures to keep pathogens at bay, they evolve countermeasures to outwit us. So far, germs have proven smarter.

  Paging Doctor Told-you-so

  In hindsight, our current dilemma could have been predicted. As we have seen before, antibiotics don’t kill off all microbes, just the weak ones. A few resistant microbes survive, reproduce, and become dominant. This is evolution, the force that is the real “invisible hand” pushing variation among and between all living things. Human beings, like microbes, have been pressured to change by evolution. We have evolved skin to keep microbes out, an elaborate internal immune system to neutralize those that get in, and sexual reproduction to shuffle our descendants’ genetic makeup, rendering them less vulnerable hosts. For both people and microbes, the process of change occurs over thousands of generations. The difference is that microbes reproduce in hours, not years. In an evolutionary race, they always win.

  To improve our odds, we’ve added antibacterials, antivirals, antibiotics, and other medicines to our evolutionary armamentarium. But as early as 1946, only three years after the first use of penicillin, staphylococcus bacteria began showing resistance. With the mass deployment of the drug worldwide to treat a variety of infections, resistance increased. By 1952, three-fifths of all staph infections were resistant to penicillin. Today the figure is 95 percent.

  In October 1943, a second antibiotic was discovered. It was called streptomycin, and it proved to be a total cure for tuberculosis. Soon the new drug was being sold by the ton around the world; by 1955, microbes began showing resistance. With the initial success of penicillin and streptomycin, drug companies began testing soil samples from all over the world to find new antibiotic-producing bacteria and fungi to replace them. Ultimately some eight thousand antibiotics were described, a fraction of which were safe enough to be used on people. Once a commercially useful antibiotic was isolated, it was mass-produced and deployed.

  In every case, bacteria adapted and became resistant. Methicillin was deployed in 1960 to treat penicillin-resistant infections. Resistance showed up the following year. Vancomycin, a powerful, expensive antibiotic, was first deployed in 1956, and by the 1960s it was being used to treat methicillin-resistant staph. By 1986, some microbes actually thrived in the poison. Resistance to vancomycin’s replacement, linezolid, started showing up in 1999.

  Today more than a hundred thousand tons of antibiotics are produced worldwide with annual sales of almost $5 billion. With so many pharmaceuticals flooding the environment, antibiotics have become a global evolutionary force. Hospitals, where bacteria and viruses have multiple opportunities to swap useful traits, have become centers of bacterial resistance and disease amplification. Each year millions of patients contract nosocomial (hospital-acquired) infections. Tens of thousands die. This is true in industrialized countries like the United States, where budget cuts have compromised basic hygiene procedures like sterilizing hospital laundry and isolating infectious individuals. It is also the case in Russia and Africa, where hospital poverty means vaccination syringes have to be reused hundreds of times, in effect injecting diseases from one patient into many others.

  Bad as this is, it gets worse: some scientists are deliberately accelerating microbial evolution in novel directions. Around the world, military bioweapons laboratories are trying to create new pathogens with the characteristics of several different microbes (imagine plague, smallpox, and cholera deployed in a single organism). These perverse “chimeras” are engineered to overwhelm both human resistance and antibiotics. Released into the environment, either accidentally or on purpose, such pathogens could kill us all.

  For a graphic reminder of what the world might be like were we to return to an age without modern hygiene and antibiotics, we have the example of the horrific Asian tsunami that occurred on December 26, 2004. In a few moments, a series of huge earthquake-generated waves killed over 150,000 people living around the Indian Ocean rim. In the days, weeks, and months that followed the disaster, thousands of injured survivors had no access to simple first aid: clean water, soap, bandages, and antibiotics. Simple wounds that could usually be treated with a twenty-five-cent pill became gangrenous. With no alternative, doctors had to do as they did during the American Civil War: cut off the dying limb to save the patient. In Indonesia, a month after the tsunami, doctors were performing so many amputations they started to run out of usable surgical saws.

  Just getting started

  Viruses can evolve even more quickly than bacteria. The story of HIV, the human immunodeficiency virus, is well known. HIV is the virus that causes acquired immune deficiency syndrome (AIDS). AIDS destroys the body’s immune system, opening the door for infection by other parasites, like tuberculosis (AIDS has been instrumental in accelerating the current TB epidemic). Currently about forty million people are infected with the virus. About four million new cases occur each year, and the rate is accelerating. Since 1981, when AIDS was identified, twenty million people have died of the disease.

  HIV probably jumped to us from primates, most likely in Africa, where it is now a leading cause of death. The disease is transmitted from person to person by the exchange of bodily fluids. HIV evolves so rapidly that one person may host thousands of different HIV variants. Resistance to a single drug treatment evolves not in years or months but in days. There’s no cure, but HIV evolution can be temporarily arrested with an arduous, unpleasant “triple-drug cocktail.” It has to be taken several times a day, every day, for the rest of an infected person’s life. At current prices, it costs over $18,000 per patient per year. Recently, a variant of the virus was discovered that is immune even to this extreme treatment.

  The human immunodeficiency virus

  As with other plagues, AIDS has evoked the usual dismal catalog of human responses: fear, greed, humiliation, anger, blame, hate, and violence. But this unhappy record has been balanced by reason, compassion, and astonishing scientific effort. We now know the cause of AIDS, we know how to prevent it, and we know how to treat it. We don’t know whether this knowledge will be enough to stop the epidemic, nor can we predict the long-term effects it will have on our social relations, political choices, and economic development. It is clear, however, that human beings need not die helplessly from AIDS. That they continue to do so is a measure of how little we have really changed since the age of the Black Death.

  Scrub-a-dub-dub

  As the example of AIDS shows, racing to keep up with all this human-generated evolution is expensive—by some estimates more than $100 billion per year in the United States alone. More importantly, as the cost of treating resistant microbes rises, more and more people cannot afford the drugs. In impoverished Haiti, that includes virtually everyone except a tiny elite. In the United States, where over forty-two million people do not have health insurance, that’s nearly a fifth of the population.

  Is there an alternati
ve? Of course. Resistance is a useful trait, but it exacts a cost. Remove evolutionary pressures like antibiotics and pesticides, and resistant microbes lose their advantage over their less hardy relatives. Resistance fades. The catch is, we’ve gotten complacent. We need to change our behavior. Outdoors, this means a return to disciplined mosquito control, removing stagnant water sources where the insect vectors for yellow fever, West Nile virus, and malaria can breed. In hospitals, this means a return to more basic hygiene: rigorous sterilization and plain old Semmelweis hand washing. Astoundingly, American doctors comply with rigorous hand-washing procedures only 40 to 60 percent of the time. The supposedly squeaky-clean Swiss are just as bad.

  Poor hand-washing habits among the general population (that means you) are responsible for the spread of many microbes, including Toxoplasma gondii, a protozoan that infects half the world’s human population (in some places over 80 percent) with results we are only beginning to understand. Toxoplasma lives in the soil and in many kinds of mammals, especially cats. We usually become infected with toxoplasma when we change kitty litter and don’t stop to clean our hands. Contaminated meat is an-other route. Toxoplasma is dangerous for pregnant women: it can damage the fetus. It’s also bad for AIDS patients, in whom toxoplasma can cause dementia. Most people, however, are utterly unaware they host the parasite, even though it has subtle effects on personality and responses to stimuli. People infected with toxoplasma have more sluggish reaction times than the uninfected. Consequently, they are twice as likely to be involved in a traffic accident.

  Many pathogens can modify our behavior. Toxoplasma gondii changes people’s personalities and slows their reactions, making their driving more dangerous for everyone. The parasite infects half the world’s human population. We get it from infected food and used kitty litter.

  End of the line

  Agriculture can also play a role in slowing microbial evolution. Industrial farming relies on precisely applied fertilizers, poisons, and drugs to keep high-density monocultures of animals and plants disease-free. Some cattle ranchers and chicken farmers are experimenting with a low-tech alternative. They have switched back to old-fashioned free-range grazing and organic feed. Although herds and flocks are smaller, the need for antibiotics and chemicals is less. Ditto for potato farmers. Most American potato farms now grow Russett Burbanks, the raw ingredient for McDonald’s fries. The only way to keep at bay the pests and blights that specialize in this potato variety is to drench the crop in deadly pesticides, herbicides, and fungicides. The ancient Inca method—a mix of many different organically raised potatoes—uses no expensive poisons, so farming costs are lower. In the end, fewer microbes are pressured to evolve. The food sells for more. Profits are higher. Everyone wins—except, of course, the folks selling chemicals and antibiotics.

  In a few cases, some microbes may actually be eradicated, bringing their evolution to a dead stop. Through the vaccination efforts of the World Health Organization, by 2004 polio was nearly wiped out, confined to a small part of Africa. A few officials there stopped cooperating, however, and polio has once again begun to spread to other continents. If governments can cooperate, it may disappear. River blindness, another mostly African disease, is a happier tale. It may vanish due to the “strategic philanthropy” of pharmaceutical giant Merck. Free annual treatments with the company’s drug Ivermectin (developed for canine heartworms) paralyze the microscopic worms that cause the disease. They can neither move nor reproduce. If all goes well, in about a decade the parasite will be extinct. The benefit to Merck? Good works, of course, but also good public relations. Such positive image building helps offset negative publicity, like the bad ink that accompanied the 2004 recall of Merck’s controversial painkiller Vioxx.

  It’s the poverty, stupid

  Such efforts will come to naught without addressing the elephant in our collective living room: unequal access to health care among rich and poor. Global wealth has reached unprecedented concentrations. The net worth of the world’s 350 top billionaires exceeds that of the bottom two and a half billion people. The best medical care is lavished on the rich. Pharmaceutical companies cater to them. The poor get the crumbs. Problem is, the poor are the ones with the most serious medical problems. Most of the millions of people dying from TB, cholera, yellow fever, malaria, dengue, AIDS, and other epidemic illnesses are poor. Because those at the bottom can only afford a portion of the needed drugs (or bogus drugs, or expired drugs, or the wrong drugs), they help spread multiple-drug resistance. While this “epidemiological divide” remains, quickened microbial evolution will eventually negate all the advances of the last century. Even unlimited wealth can’t stop a microbe that is resistant to everything.

  Microbes exploit human inequality. The epidemiological divide between rich and poor—with some people receiving excellent treatment while most people receive mediocre treatment or none at all—helps spread deadly diseases to everyone.

  In countries where multi-drug-resistant microbes are prevalent, a tuberculosis treatment idea called DOTS-Plus offers a template to slow microbial evolution and save lives. DOTS (which stands for “directly observed therapy, short course”) was an aggressive tuberculosis treatment strategy pioneered in New York during the 1990s after the onset of the current epidemic. DOTS requires public health workers to find TB patients wherever they are and watch them take their meds, time after time, pill after pill, until a six-month regimen is completed. It works, and the DOTS model has now been exported around the world. But as more and more TB microbes have become resistant to several drugs, DOTS has become less useful. A new therapy, DOTS-Plus, deploys several powerful and expensive TB drugs at once in a patient for up to two years. The therapy kills all the TB microbes, not just the weak ones.

  Initially, DOTS-Plus was only available to the wealthy or the well-insured. Curing poor people with multi-drug-resistant TB was not considered “cost-effective,” an idea born of lingering middle-class prejudices: the lives of the poor were too chaotic, they moved a lot, they couldn’t adhere to elaborate multi-drug treatments over months and years. More importantly, they couldn’t pay. But a Boston-based organization, Partners in Health, working in impoverished regions of Peru, proved that the poor are just as capable as the rich—often more capable—of following complex drug regimens. With that evidence in hand, a consortium of health organizations called the Green Light Committee pressured pharmaceutical companies to drop their prices for expensive TB drugs by up to 99 percent. DOTS-Plus is now being deployed around the globe by the World Health Organization. TB evolution has been slowed, benefiting everyone, rich and poor.

  Wealth or health

  Profit is a great motivator. It drives the capitalist economy. Many of the world’s medical breakthroughs have been pioneered by altruistic people with noble intentions. Many more have been made by people who wanted to get rich. There’s no shame in that. The problem comes when medicine focuses so exclusively on taking care of the wealthy minority of patients who can afford the best that the majority of humanity is left out. We ignore this disparity at our peril. Pathogens are equal-opportunity infectors: they don’t discriminate based on address, education, skin color, or credit limit. They exploit the inequalities we have built into our health care environment to their advantage.

  When health is a public good, not a private perk, everyone is better off. Retargeting health care funds from the few to the many may be one of the most effective ways to slow microbial evolution. Some countries have already approached this goal: Sweden, Singapore, Canada, and Cuba have each tried different approaches to marrying private medicine and public health. Sweden, Singapore, and Canada are wealthy nations. Cuba is quite poor. Despite these differences, each of these countries has created a health care system with greater access to better care for more people than the United States, where health care is the most expensive in the world. As you might imagine, the health care systems in Sweden, Singapore, Canada, and Cuba have problems and critics. But the results speak for the
mselves, especially in rates of infant mortality, in that period at the beginning of life when immune systems are fragile and people are easy prey for lethal infectious diseases. Infant mortality in all these countries is lower, and achieved at lower cost, than in the United States. Singapore’s infant mortality rate, 2.2 deaths per thousand births (about a third of the American rate), is the lowest on earth. Clearly they’re doing something right.

  Run, Alice, run!

  If we’re really going to change the way we deal with human health, we may need to think differently about disease. It turns out that the victor-and-vanquished military metaphor is not a terribly useful way to imagine microbial parasites. A better way to understand our evolutionary relationship with microbes comes, of all places, from a classic children’s story. It’s called the “Red Queen hypothesis,” and it goes like this: as we evolve, so do pathogens; as pathogens evolve, so do we. Medicines like antibiotics and poisons like chlorine give us temporary protection from these predators. But eventually a microbe evolves that can overcome these measures. Its descendants then put the pressure back on us. Round and round we go. Like the Red Queen Alice meets in Lewis Carroll’s Through the Looking-Glass, we’re running as fast as we can just to stay in one place.