by Thomas Goetz
The issue, it seemed, was that in some ways antibiotics worked too well, at least in terms of patient experience. The drugs quickly pushed the disease onto its heels, and patients would feel better within days and feel cured within weeks. But the bacteria were still there, hiding in the caseous material that the body had assembled to wall them off. Now, though, that defense turned into a liability. Inside the body, the microbe was reproducing, with some generations of it creating genetic modifications that proved more resilient to the antibiotic. These new resistant microbes could remount their attack on the body, and additional rounds of streptomycin were ineffective.
The problem of resistance is one of simple math. A patient with extensive tuberculosis will have as many as one trillion bacterial cells in his body. Since microbes reproduce every few minutes or hours (tuberculosis reproduces at a rather languid fifteen- to twenty-hour cycle), there will be millions, or perhaps even billions, of opportunities for new generations of the bacterium to have slight mutations. Repeated over the course of weeks and months, the microbe might eventually find a path past a drug that may have worked just weeks before.
In the years after streptomycin was discovered, scientists were at first unworried about resistance, simply because so many other worthy antibiotics were emerging. With each one, humanity’s newfound dominant role over disease seemed to be reinforced. These new drugs—isoniazid, rifampicin, pyrazinamide—worked even better in combination therapies, where a patient would take two drugs at once for several weeks or months. This protocol quickly became the standard treatment, since the odds that bacteria could successfully generate resistance to two drugs simultaneously seemed remote. Even when these new drugs began to show resistance as well, in the late 1950s, the combination could be altered enough to beat back the disease. Meanwhile, cases of tuberculosis dropped steadily in the United States and Europe and across the globe. Within a decade or two, it seemed a relic of a premodern age.
In the developed world, the general public lost any perception of tuberculosis as a true concern. The new antibiotics, combined with postwar hygiene and sanitation standards, entirely eliminated the disease from routine experience. Tuberculosis began to seem as dated as the words that had defined it a century earlier—consumption, phthisis, scrofula. Eventually, even the National and International Lung Associations, which had formed at the beginning of the century to combat TB, shifted their mission to another insidious threat to human health: cigarettes.
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IN THE EARLY 1970S, THE US CENTERS FOR DISEASE CONTROL AND PREVENTION stopped direct funding of TB control, and Congress stopped requiring states to fund TB programs. Globally, the situation was similar, as the World Health Organization dismantled its TB program. There was little argument; the disease seemed like it was going away all on its own. In the United States, cases of tuberculosis had dipped below twenty-five thousand annually, compelling the CDC, in 1989, to release A Strategic Plan for the Elimination of Tuberculosis in the United States.
But the bacterium, unaware of humanity’s inherent inconstancy, persevered and was well situated for the lapse in attention. Between 1985 and 1992, rates among adults soared by 20 percent, and among children, by 35 percent. The cause of the resurgence was tied largely to drug use among low-income populations and to HIV infections, which lower the body’s resistance to other infections. But microbes know no class; when two Wall Street commodities traders were diagnosed with the disease in 1992, exchange officials required nearly three thousand employees to undergo testing.
Meanwhile, across the globe, new strains of tuberculosis were emerging that seemed more than just tenacious against antibiotics; they seemed downright impervious to them. These new superstrains resisted not just one but two or more antibiotics in the medicine chest. For the first time in decades, people with tuberculosis might receive a full course of treatment, yet still die—and at alarmingly high rates. As many as 80 percent died of this new form of TB, which became known as multi-drug-resistant TB, or MDR-TB.
The arrival of MDR-TB alarmed the global health community, from the CDC to the WHO. Humanity suddenly seemed outmatched in this cat-and-mouse game. The available drugs were divided into first-line, second-line, and third-line treatments, with the WHO issuing strong and precise recommendations on which drugs to take in combination and when. But as sensible as they were, these rules ran headfirst into the problem of human behavior (as baffling an adversary as germs ever were).
The fact of the matter was that taking TB drugs was (and remains) an ordeal. The drugs must be taken for at least six months, long after a patient feels better. At five hundred milligrams, the pills can be so large they are difficult to swallow. And uncomfortable side effects, including rashes, headaches, and nausea, are common. The result is that patients with TB often stop taking their pills once their symptoms wane, unwittingly affording the bacteria that essential second chance to mutate and regroup.
The arrival of MDR-TB called for a different strategy, one that required a new discipline among patients. Taking a page from the successful military-like campaign to eradicate smallpox, the WHO created a protocol for delivering antibiotics: “directly observed ther-apy, short-course,” or DOTS. The basic premise here is simple. A health official or responsible community member must witness the TB patient taking his or her medication, every day, for six months. Every day, a knock on the door, and every day, swallowing the pill, for at least six months or as long as it takes to return a clear blood test (often eighteen months or two years). Getting such a program to work, however, is onerous in countries that lack medical infrastruc-ture or the political willingness to compel their citizens to follow such strictures.
Still, for those willing to endure it, the DOTS therapy has good odds of success, as high as a 95 percent cure rate. But inevitably, as many as one-third of patients drop out, becoming unwitting allies to the disease. Following the now-inevitable pattern, this created a new strain of the bacterium: extensively drug-resistant, or XDR-TB, which the WHO first classified in 2006 as TB resistant to the standard first-line and at least one second-line treatment. To have XDR-TB is to be almost without hope of a cure at all. One drug after another is tried (always in combination), in a course of highly toxic chemicals that goes on for as long as two years. Even after all that, as many as half of patients will not be cured. In some countries, such as those in Eastern Europe, rates of MDR-TB or XDR-TB are as high as 20 percent of all reported cases. For the first time in sixty years, people can once again come down with tuberculosis and have no chance of a cure.
Still, the science continues. On the last day of 2012, the US Food and Drug Administration approved bedaquiline, a new drug to fight against TB. Known commercially as Sirturo and manufactured by Johnson and Johnson, the drug is considered the first new therapy to be developed against TB in some forty years. It works by inhibiting an enzyme the microbe needs to replicate and spread throughout the body.
As promising as the drug is, it is being reserved strictly for patients with MDR-TB, and then only in combination with traditional antibiotics. The concern isn’t so much that it won’t work. Rather, it’s that if it is used too much and stops working, there will be simply nothing else left on the shelf.
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THERE IS ANOTHER CONSIDERATION, ONE THAT SHOULD ONCE AND for all compel us to rethink our supposed war against microbes (if the saga of antibiotics has not done so already). It is simply this: Yes, the classic infectious diseases such as tuberculosis and cholera and diphtheria have mostly vanished from our everyday experience. But the diseases that have replaced them and that now account for the majority of deaths in developed countries—heart disease and cancer, primarily—even these so-called noninfectious diseases may turn out to have an infectious component to them.
The clues have been accumulating for decades. As far back as 1976, the German virologist Harald zur Hausen observed that cervical cancer, then a major cause of cancer deaths among women
, was largely associated with the human papillomavirus, or HPV. A vaccine against the virus was developed in 2006, allowing for a population-wide prevention campaign. (In 2008, Dr. zur Hausen won the Nobel Prize in medicine.) In the United States, rates of cervical cancer have fallen by 75 percent since the 1970s, but the disease continues to kill hundreds of thousands worldwide each year, an entirely preventable toll. Meanwhile, HPV is increasingly associated with throat and other cancers.
Some diseases once considered the result of human behavior and lifestyle also appear to be caused, in truth, by pathogens. In 1982, Australian scientists Barry Marshall and Robin Warren discovered Helicobacter, a microbe that was persistently present in patients with chronic gastritis and gastric ulcers. In an echo of the early days of the germ theory, experts in the field gave Marshall and Warren’s discovery little credence; it seemed absurd that a bacterium could cause something so well associated with stress and human biology.
Frustrated with the naysayers, Marshall decided to prove his point. In a classic demonstration of self-experimentation, Marshall swallowed a vial of Helicobacter bacteria and promptly developed a nascent ulcer. A subsequent round of antibiotics cleared the condition. Other, more traditional research bore out his and Warren’s hypothesis that ulcers were caused by Helicobacter. Yet it would be a decade before other scientists replicated their findings and changed the consensus opinion.
In 2005, Marshall and Warren would be recognized with the Nobel Prize. Their work was among the first to establish the significance of what is today known as the microbiome—the ecosystem of microbes in and on our bodies that may have a profound impact on our health, for good and for ill. Other diseases that are now believed to have at least some microbial association include Alzheimer’s, asthma, dementia, diabetes, and as much as 20 percent of all cancers.
The research into the microbiome had perhaps its most profound demonstration, though, when the first convincing association between bacteria and heart disease emerged. Heart disease, of course, kills more people than any other condition worldwide, including 47 percent of Europeans; globally, it causes 30 percent of all fatalities. But nearly all research has gone to establish some sort of behavioral or environmental link (smoking, diet, exercise, stress, and so on down the list), with a smaller fraction of known genetic causes. Except in rare cases of acute infection, such as infectious endocarditis, microbes have been largely thought irrelevant.
But in 2013, at least one such association revealed itself, in the form of trimethylamine-N-oxide, or TMAO. TMAO isn’t a microorganism itself; rather, it’s a product created by bacteria when they digest lecithin, a fatty substance common in certain foods such as eggs, milk, and some nuts. In a study published in The New England Journal of Medicine, a team led by Cleveland Clinic’s Stanley Hazen found that human subjects with the highest levels of TMAO in their blood had about twice the risk of having a heart attack, stroke, or death compared with those who had the lowest TMAO levels.
The association between microbes and human disease here is less straightforward than in the case of tuberculosis. In TB, the causal mechanism is fairly obvious: TB bacteria directly attack and injure human tissue. In Dr. Hazen’s research on heart disease, though, the chain of argument requires a few more links. First the human has to eat a diet high in lecithin, then the gut bacteria must feed on the lecithin and generate a sufficient level of TMAO as waste, and then the TMAO must circulate in the body over time. Only then, the theory goes, does the actual damage happen, when TMAO allows cholesterol to get into artery walls and prevents the body from shedding extra choles-terol. Once there, the cholesterol accumulates in the blood vessels, causing atherosclerosis. This is a complicated histology from microbe to diseased tissue, and one that is a long way from being proven convincingly, let alone to a level of proof akin to Koch’s postulates.
Nonetheless, this research is captivating and persuasive—and it gestures toward a new germ theory. This new germ theory would allow that direct connections between microbes and human health are less evident—or at least require more examination. It would grant that the dependencies and effects between microbe and humankind are more complicated and that new relationships will emerge.
This new germ theory is based on the growing awareness of a microbiome—those one trillion microorganisms that live in our guts and on our skin, a trillion organisms that unwittingly affect the larger organism that is the human body. The science of the microbiome—a concept that was first coined in 2000 but that has gained mainstream traction only since 2010 or so—is devoted to the possibility that these microbes play a far more nuanced role in human health than ever conceived, even more than the great microbiologists such as Koch and Pasteur may have imagined. Where Koch believed in the linearity of bacteriology (if the germ existed in the body, he believed, then the disease must also exist, and vice versa), this new science of microbiomics assumes that there are myriad influences and interactions at work. Some are directly causal, as with Helicobacter and gastritis. But others, as described in the TMAO research, are far more complicated and potentially more profound.
Teasing out the possibilities and implications of these more tentative associations will likely occupy the next century of scientists. This new generation of germ theorists will have to contend with the many microbes that exist in us but have yet to be identified. They will have to sort out the consequences of our overuse of antibiotics. And they will have to provide a more nuanced but still convincing argument against eradication: the increasingly discredited and potentially self-destructive notion that all germs are dangerous and must be eliminated (as if such a thing were even possible).
Like their predecessors in the nineteenth and twentieth centuries, this century’s scientists must explain to a skeptical public why such a thing as germs matter, and why our understanding of these invisible beings demands to be reconsidered. If it remains necessary to learn what role they play in disease, it will also increasingly be essential to learn how they affect our health.
As any microbiologist or infectious disease expert will tell you, if we treat disease as a battle against microbes, we are destined to lose. The bacteria precede us. They outnumber us. And they will outlast us.
ACKNOWLEDGMENTS
This book wouldn’t exist without The New England Journal of Medicine. On December 8, 2005, the journal ran a handful of essays on “medical detectives,” including a tribute to Berton Roueché, a brilliant New Yorker reporter who, for several decades, spun urban outbreaks into gripping mysteries. When I was growing up, Roueché’s stories were a favorite in our house, and my father, a physician and lifelong subscriber to NEJM, sent me the issue. In a note, he drew my attention as well to a brief essay by Howard Markel concerning a certain coincidence involving Robert Koch and Arthur Conan Doyle.
I filed away the issue and, five years later, realized that this historical footnote was in fact a book begging to be written. Though my father is not alive to read this book, I’m grateful that before he died at age ninety he was able to read the original proposal. Nor would I have been so inspired if Conan Doyle’s detective stories weren’t also family favorites, particularly beloved by my sister Cecilia in our youth. Cecie’s work in public health and her death during a global health project inspired my own efforts in the field. I dedicate this book to both of their memories.
The library at the University of Minnesota (where my father taught medicine for forty years) contains a splendid Sherlock Holmes collection, and the staff there, including Timothy Johnson and Arvid Nelson, were generous with their time and counsel. Heide Tröllmich, the curator of the Robert Koch collection at the Robert Koch Institute in Berlin, likewise contributed her time and expertise. I am also indebted to Christoph Gradmann and Thomas D. Brock, whose scholarship on Koch has been indispensible to my own efforts. I wrote much of this book at the Community Library in Ketchum, Idaho, a splendid institution.
It’s also essential to acknowledge the help
I received from today’s technologies. I thank Twitter for finding me Marco Kalz of the Open University of the Netherlands, who generously translated several of Koch’s early letters. Likewise, only with the Internet would I have found Annelie Wendeberg, a microbiologist at the Helmholtz Institute for Environmental Research in Leipzig, Germany, whose keen read of my manuscript helped me skirt several errors. I am also glad for the existence of Google Books, without which I would’ve never discovered many significant sources and archival materials.
There have been crucial readers, beginning with Chris Calhoun, my agent and—more vitally—my friend. Steven Johnson, whose brilliant work has influenced my own, generously contributed a thorough read and crucial improvements. Conversations with Bill Wasik helped me navigate several challenges, and Alison Byrne Fields lent an eye as well. As always, my sister Laura contributed sage advice on medical matters. There were also the master readers I held in mind as my ideal audience: Mary Rose Goetz (who knows mysteries!), Sue Wright, and Lynda Chittenden.
At Gotham, Megan Newman has been an astute editor, and this book is the better for her efforts. Thanks also to Bill Shinker for recognizing the potential of this unusual story and how deep it might go. I’m proud to be in their house.
I’m grateful for support from my friends at the Robert Wood Johnson Foundation, especially Brian Quinn, Steve Downs, Paul Tarini, and John Lumpkin. Matt Mohebbi, my cofounder at Iodine, kindly tolerated my excursions into the nineteenth century as we build something for the twenty-first. Tom Neilssen and the team at the BrightSight Group have been brilliant at helping me spread these ideas to the public.
