The following is an excerpt from the book Unnatural Selection by Emily Monosson (Island Press, 2016):
“I see resistant staph all the time,” says nurse practitioner Maggie G. Her enormous blue eyes convey both the compassion and the weariness of someone who has seen it all. Over the course of 25 years, the Western Massachusetts nurse has treated farmers, hill-town hippies, and teens seeking treatment for STDs and fevers, as well as men, women, and children who walk for miles and wait patiently with festering wounds and suppurating tumors in the Sierra Leone clinic that she visits once a year. One constant throughout all of Maggie’s experiences is methicillinresistant staph, or MRSA. Back in the late eighties, when Maggie was just finishing nursing school, MRSA was rare. But over the years she has witnessed the rise of this drug-resistant bug, tending to countless cases—one of the most memorable involved a young camp counselor whose infected toe turned into a life-threatening hole in her heart. When we spoke, Maggie was working with recovering addicts at a psych hospital. MRSA spreads so easily in needle-using addict populations through needle sharing or festering open wounds that Maggie says addicts are often treated “presumptively”—meaning the staff doesn’t always test but assumes drug resistance. It’s a reasonable assumption. In some places, nearly 50 percent of the needle-using population may be positive for community-acquired MRSA.
First recognized as a “healthcare-associated infection” limited to patients and caretakers, MRSA made its way out of the hospital into the community a decade or so ago. The bacteria can spread from mother to daughter, throughout a high school locker room by way of an infected towel, from pet to owner, and between hospital patients on the hands of a caregiver. It is a parent’s worst nightmare: a small bite or scrape turns into an angry red trail streaking up a child’s leg, and one antibiotic after another fails. A once easily treatable infection is now potentially fatal. Of the roughly 75,000 Americans who become infected with MRSA each year, an estimated 9,700 will die.
We live in dangerous times. Infectious diseases are rapidly evolving beyond our medicinal reach, returning us to the pre-antibiotic age. In just over a century, we have rendered impotent some of our most precious therapies, and there is plenty of blame to go around. Whether it be doctors pacifying pushy, anxious parents; the agricultural industry preventively treating livestock, or worse, simply encouraging livestock growth; or hospitals fending off recalcitrant infection—we have all contributed to the rise of the superbug. Each year nearly 37 million pounds of antibiotics are used in the United States. Some 7 million pounds go down the throats of our kids, up the arms of hospital patients, and into infected addicts; a few hundred thousand pounds are consumed by our pets; and the rest is used by the ag industry. And though MRSA is the poster-bug for resistance, it has plenty of company. A once-curable pneumonia recently killed seven patients at a well-regarded national hospital. Tuberculosis that is completely drug resistant has surfaced in India, Italy, and Iran. In Japan, a strain of gonorrhea has shaken free from all antibiotics. That a fully antibiotic-resistant STD may once again rage throughout the world ought to strike fear into all of us, even those who consider ourselves beyond its reach—if not simply because “you just never know,” then because some bacteria can easily swap resistance genes. And that means that resistance in a venereal disease may one day transfer to a bug that causes pneumonia or a skin infection. Bacteria may be among the most primitive life forms on earth, but they have proven to be among the most formidable opponents.
As the Second World War came to a close, the great technology transfer began. From nuclear power to plastics, pesticides, and antibiotics, the era of “Better Living through Chemistry” had arrived. Penicillin was ripe for exploitation. Just as everything today, from mattresses to shopping-cart handles, is impregnated with antimicrobials, industry envisioned toothpaste, chewing gum, lozenges, face creams, and even vaginal crÃ¨mes infused with penicillin. In his 1945 Nobel acceptance speech, Fleming warned that penicillin’s overuse and under-treatment of disease could result in resistant bacteria. But it was already too late. Our first lesson in moderation had come and gone, as resistant strains of staph, strep, and pneumonia cropped up during the war. Penicillin had imposed a powerful selection pressure. Pathogens that could not evolve would die. But in hospital wards both here and in Europe, penicillin-resistant staph began making the rounds, along with sulfa-drug-resistant bacteria. One could almost watch resistance evolve. Attempting to control dangerous strep infections in new recruits, the US Navy treated hundreds of thousands of trainees with prophylactic doses of the drug sulfadiazine. Rheumatic fever, scarlet fever, and respiratory disease incidence dropped almost immediately, but sulfa-resistant strep emerged just three months after the initial phase of treatment. Similarly, penicillin was losing ground. As Fleming had feared, one of the greatest factors in the decline of antibiotic effectiveness proved to be overuse.
Then, in 1950, as if to throw fuel on fires of resistance, scientists discovered that antibiotics added to livestock feed accelerated growth, moving animals more quickly from farm to table. Even better, antibiotics helped cut production costs. It was an apparent win-win for the farmers struggling to meet the booming postwar demand for meat and for customers craving an affordable, protein-packed meal. Antibiotics weren’t just for the sick and dying anymore—they had become an integral part of “what’s for dinner.”
The medical world’s failure to heed Fleming’s warning was a combination of hubris and naÃ¯vetÃ© about genetics and evolution. Medicine was on a roll: if one antibiotic failed, another would surely take its place. If evolution worked to the bacterium’s advantage, human ingenuity would work toward ours. Penicillin was one of the first drugs to be improved. Under penicillin’s pressure and through the process of natural selection, bacterial populations acquired a gene for an enzyme capable of snipping apart the drug’s key chemical structure—called a beta-lactam ring. In response, drug developers created methicillin. Like having a portcullis to block the castle gate, methicillin contained a molecule that protected the bacterial-busting beta-lactam structure from destruction. This so-called super-penicillin did the trick. That was in 1959. By 1961, reports of methicillin-resistant staph emerged in England and Europe. The invaders had found another way around. By 1968, researchers at Boston City Hospital had isolated 22 methicillin-resistant strains from 18 patients. Most had become infected after admission to the hospital. It was the dawning of the age of hospital-acquired MRSA.
Several modified versions of penicillin followed, as did the discovery of other natural and synthetic drugs including bacitracin, streptomycin, rifampicin, erythromycin, and polymyxin. The majority were discovered during the antibiotic golden years, 1930–1950. Today, they are fast becoming obsolete, and unfortunately, the next best thing isn’t around the corner. Many of our current antibiotics, like penicillin, are beta-lactams that inhibit cell-wall synthesis. Some inhibit the production of proteins, and others alter bacterial cell membranes. At prescribed dosages, most target bacteria while leaving our cells intact and relatively healthy. One increasingly recognized downside of antibiotics, though, is their inability to distinguish the pathogenic bacteria from the “good” bacteria, some of which may even help fend off disease. And while most MRSA patients, including those in Maggie’s psych clinic, may benefit for now from next-generation drugs, those options are not available to all. “People in Sierra Leone die from infections,” says Maggie, weary with resignation. “We’re still using first-line antibiotics there—if we even have them.”
The majority of medically important microbes now resist one antibiotic or more, and words like “nightmare” and “catastrophic” are increasingly cropping up in the medical literature. It is not just hyperbole. Like Aesop’s Hare, whose overconfidence led to a predictable loss against Tortoise, our hubris may very well cost us our health—if not our lives. Certainly our current situation is not for lack of understanding; we know far more about bacteria and evolution than Pasteur, Koch, or Ehrlich could have even dreamed. Yet we continue to play whack-amole— simply changing antibiotics as resistance pops up. It is time to reconsider our strategy and pay homage to evolution. Not the dusty old process of evolution that we equate with the descent of man and speciation but the wild, DNA-swapping, mutating ways of bacteria.
Unveiling the Machinations of Evolution
A single Staphylococcus aureus cell, like most bacteria, can within days give rise to millions, if not billions of daughter cells. Bacteria reproduce by cloning. The parent cell divides into two daughters that in turn generate their own daughter cells on and on as one cell exponentially yields hundreds, thousands, and then millions of new cells—by any measure, an impressive amount of DNA replication. Not all of it perfect, though. With each new generation comes the potential for mutation. And mutations are a source of variation for evolution. This is true no matter the species, whether bacteria, bedbugs, elephants, or humans. Only some enjoy the advantages of new gene variants in the course of a few months or years while others like us might require centuries. And though most mutations are of little or no benefit, it only takes one alteration in the right place, and voilÃ , an enzyme is no longer a suitable target for chemical attack. When these advantageous traits are selected, evolution happens.
The explosive population growth of bacteria means that a beneficial mutation can infiltrate a population within hours. Contrast that with the thousands of years required for a random yet beneficial mutation to take hold in a human population. When hospitalized patients are treated with antibiotics for weeks or months, there is potential for myriad new (or de novo) mutations, which in turn become feedstock for the evolution of resistance. As rare but helpful mutations arise—particularly in bacteria under the influence of antibiotics—resistance isn’t futile, it is inevitable. In one case, researchers caught evolution in action as the staph infecting a patient treated with vancomycin acquired 35 sequential mutations, diminishing the antibiotic’s efficacy as mutations accrued.
As impressive as rescue by de novo mutation may be, bacteria have an even more efficient means for acquiring resistance. For so-called sexless organisms, bacteria are incredibly agile genetically. Japanese researchers were the first to catch a glimpse of the acrobatics. During the Second World War, and in the years that followed, Shigella dysenteriae became epidemic in Japan. Even if dysentery didn’t kill, it knocked the survivors flat. Sulfa drugs worked at first, but by the early 1950s, Shigella had evolved resistance. Then Japanese researchers observed something that should have beat some sense into scientists and physicians around the globe. Some strains of Shigella were resistant not only to sulfa drugs but to other, newer, drugs as well. They would be the first reported multi-drug-resistant bacteria. The response by the Western medical world was underwhelming. Evolution of any resistance over the course of treatment was believed to be a low-probability event. According to antibiotic pioneer Julian Davies, “The notion of multiple drug resistance was heretical.” And that wasn’t all.
A scientist working in the United Kingdom had isolated bacteria that were, oddly enough, resisting novel antibiotics right off the bat. Resistance, it seemed, had spread from one strain to another. Follow-up studies suggested that bacteria were sharing resistance through contact. The findings, as Davies recounts, challenged the prevailing ideas about the process of evolution. If evolution simply proceeded by way of one random mutation at a time, and resistance required selection pressures like an antibiotic, then how could these findings be explained? As with the finding of multi-drug-resistant Shigella, the reception was unenthusiastic at best, doubtful at worst. But then, how else could resistance to so many drugs evolve so quickly? And why would bacteria carry resistance to a novel antibiotic? The answer lies in the so-called sex lives of bacteria.
When bacteria reproduce, much like us their genes are handed down from parent to offspring, vertically. Just as we carry our genes on linear double-stranded chromosomes, bacteria, too, carry their genes on a double-stranded chromosome—but the bacterial chromosome is a single loop of DNA. Bacteria also possess extra bits of DNA on small rounds called plasmids that are central to the DNA trade. Like modular storage units, plasmids contain 20 or 30 “auxiliary genes” that encode biological toxins, enzymes enabling the digestion of novel food, or antibiotic resistance, among other things. When bacteria reproduce, just as the single chromosome is copied and passed on to offspring, plasmids can be passed from parent to daughter. But here is where things get weird. While we humans hold tight to our genetic stock, passing it like a carefully tended trust fund vertically from one generation to the next, bacteria pass plasmids from one cell to another like day traders on the stock-exchange floor. In a process of so-called bacterial sex, when bacteria are in close proximity, a hair-like thread of cell membrane extends from one cell to another forming a “conjugal bridge.” Plasmid DNA is transferred horizontally between bacterial cells. In environments like our guts, crowded with bacteria, plasmids can be passed around like juicy bits of gossip. Even more bizarre, plasmids can pass between different types of bacteria. Unlike us, bacteria share genes with siblings, friends, and neighbors. This horizontal gene transfer provides bacteria with an unimaginably deep and interconnected gene pool. And that is a concept with which we are just now coming to grips.
If that thought isn’t enough to make us sit up straight and vow to take antibiotics only when absolutely necessary, consider the recent findings by Kiran Bhullar, Gerry Wright, and their colleagues. Deep in New Mexico’s Lechuguilla Cave is a place that has been isolated from the outside world for over 4 million years, safe from all of our chemical mayhem, including antibiotics. Yet when Bhullar and others collected bacteria from deep within the cave, they found resistance to a shopping list of antibiotics. “Like surface microbes,” they write, “. . . some strains were resistant to 14 different commercially available antibiotics.” One of those genes confers resistance to daptomycin, an antibiotic of last resort for patients suffering from MRSA. That the gene has existed for millions of years is humbling. It is as if the joke is on us. This collection of genes coding for resistance is now referred to as the resistome. Yet studies also show that some pathogenic bacteria isolated before the large-scale use of antibiotics lack resistance genes even in their plasmids. The lack of historical resistance in staph, strep, and myriad other pathogens, combined with the provenance of the resistome, raises an obvious question: Why does the resistome exist?
The majority of antibiotics in circulation today did not originate through human invention but rather through human discovery. Like penicillin, many antibiotics are derived from chemicals that we’ve co-opted and then spread around the world in unprecedented quantities. Some may well be chemical-warfare agents evolved long ago by biota engaged in perpetual conflict. It’s not difficult to imagine fungi in nature like penicillin sparring with bacteria over limited resources. But other antibiotics, suggests Julian Davies, may simply be part of a chemical messenger system. Life has a long history of signaling from one cell to another, and small antibiotic-like molecules are their language. Once a message has been sent and received, a cell would do well to destroy it rather than allowing such messages to build up like so much chemical noise, or worse, as constant stimulants. Consider the neurotransmitter acetylcholine, which signals many of our muscles to contract. Continuous stimulation can be lethal. Organophosphate pesticides kill by inhibiting acetylcholine breakdown. Our cells have evolved plenty of enzymes devoted to chewing up and destroying chemical messages. It makes sense that bacterial cells, too, carry genes for chewing up and spitting out naturally occurring antibiotics—no matter their role in nature. As Bhullar and colleagues write, there is increasing evidence that these nonpathogenic bacteria provide “a reservoir of resistance genes.”
Our dependence on antibiotics, combined with the promiscuity of plasmids, is moving resistance into pathogenic bacterial populations. Even synthetic antibiotics based on novel mechanisms do not guarantee victory. There too, bacteria can make an end run. Consider ciprofloxacin, a powerful second-generation synthetic antibiotic, once the answer to resistance. Pathogenic bacteria are now resisting even this powerful drug; one strategy, explains Julian Davies, is by co-opting an existing enzyme that has deactivated antibiotics with no structural similarity to cipro. This is like using a wrench to do the job of a screwdriver—a testament to nature’s ingenuity.
But wait, there’s more: as resistance circulates around hospitals, communities, and local farms, some geneticists suggest that antibiotic overuse may even increase the evolutionary potential of bacteria—their “evolvability.” Bacteria were already masters of evolution, but we may have made them even better. Our use of antibiotics has given pathogenic bacteria no other option but to evolve into superbugs; and we are inching backward toward the days when disease triumphed and families hid in their homes, away from diseased neighbors, wary of catching their death.
We are circling back toward the pre-antibiotic age. As Maggie and other health-care workers around the globe struggle to hold the line against pathogenic bacteria, we must alter course. In today’s highly traveled and far more populous world—when infection can spread around the globe in a day—prevention and cure are more critical than ever. In the fall of 2012, Srinivasan hoped to capture the public’s attention when he declared: “The threat of untreatable infections is real. Although previously unthinkable, the day when antibiotics don’t work is upon us.” In 2014, a World Health Organization report reiterated the sentiment, stating that antibiotic resistance around the world has reached alarming levels. But it is not like we haven’t been warned before. First there was Fleming. Decades later another Nobel Prize winner, Joshua Lederberg, similarly warned that “we live in evolutionary competition with microbes. . . . There is no guarantee that we will be the survivors.”
We carry around a huge load of bacteria, many of which may shape our lives in ways we have yet to understand. Indiscriminately killing all of them while aiming at only one or two no longer makes sense. The modern age of discovery has laid bare the power of evolution and provided insight into its inner workings. We now know that no matter how many new antibiotics we discover, there will always be resistance. We must rebalance our relationship with the world of microbes—pathogens, essential and nonessential bacterial—perhaps someday even pitting our resident bacteria against disease-causing bacteria. The evolution of resistance is inevitable but its pace is not. We have imposed powerful selection pressures. It’s time to discover a new way: a way to save the patient without killing the antibiotic.
From Unnatural Selection by Emily Monosson. Copyright © 2015 Emily Monosson. Reproduced by permission of Island Press, Washington, D.C.