Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (6 page)

If you are host to 100 trillion microbes and each microbe is a tiny genetic machine, how many genes are cranking away within your resident microbes and what are those genes doing?

As discussed above, among the goals of NIH’s Human Microbiome Project was to sequence the genetic material of microbes taken from healthy young adults. Not only was a census conducted that defined which microbes were present (“who is there”) but also the genes that they carried and their functions (“what is there”). The main findings suggest that your microbes and mine have millions of unique genes, and a more current estimate is 2 million. Your human genome, by comparison, has about 23,000 genes. In other words, 99 percent of the unique genes in your body are bacterial, and only about 1 percent are human. Our microbes are not mere passengers; they are metabolically active. Their genes are encoding products that benefit them. Their enzymes can produce ammonia or vinegar, carbon dioxide, methane, or hydrogen that other microbes use as sources of food and, in ways we are still working out, they also make many more complex products that benefit us.

A recent survey conducted by a large group of scientists in Europe (begun as the MetaHit consortium) showed something else. A census of nearly three hundred Europeans showed that the number of unique bacterial genes in subjects’ guts varied dramatically. The distribution of individuals wasn’t normal; it was not a bell curve. Instead, researchers found two major groups. The larger group of 77 percent of the people had an average of about eight hundred thousand genes. The smaller group (23 percent of the subjects) had only about four hundred thousand genes. Two distinct groups; this was not expected. But the most interesting observation is that the people who had the low gene counts were more likely to be obese. This was a striking result, which we will discuss in more depth later.

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Understanding the ecological structure of our resident microbes presents a tricky puzzle. In a large ecosystem, say a forest, ecologists can directly observe numerous individuals and species behaving and interacting in real time, on daily, seasonal, and annual scales. But we can’t yet study microbial ecosystems in anywhere near the same way. As mentioned above, one of our best current methods is to count and identify all the genes in a given community. As a task, that is a bit like scooping up an acre of forest, putting it through a gigantic blender, and then counting the leftover fragments of leaf, wood, bone, roots, feather, and claw, and deducing from the detritus what we can about the woodland’s species and their interactions.

We can figure out some functions of our bacterial genes by comparing them with other known genes. Initial findings from the Human Microbiome Project and from the European MetaHit program account largely for what we call “housekeeping” genes, because they are both routine and necessary for life. For example, genes for cell-wall manufacture and maintenance abound since all bacteria have to build cell walls. Similarly, all bacteria must have genes that allow them to replicate their own DNA so they can reproduce. Genes that code for a crucial enzyme, DNA polymerase, needed for making new strands, have been identified. Humans have several varieties of this gene, whereas your resident microbes may have thousands, each one slightly different, depending on which bacterium it comes from.

There also are less subtle differences in the genes of microbes found in different areas of the body. While genes for housekeeping tasks remain consistent, skin bacteria have more genes related to oils than do bacteria living in the colon. Vaginal bacteria have genes to help them create and deal with acidic conditions. At this point in our knowledge, we can safely predict that bacteria will carry out specialized functions in each of the body’s habitable niches and that the differences involved are much greater than those seen in the human genome. For example, the difference in height between the tallest and the shortest adult on Earth is perhaps two- or threefold. Organisms in a typical microbiome may range, in their individual representation, by a staggering ten million–fold. Bacterial specialization is a thrilling and largely unexplored realm in uncovering what makes each of us distinct in terms of our health, metabolism, immunity, and even cognition.

While we have yet to identify the function of some 30 to 40 percent of bacterial genes identified by the large projects, we do know that some species are rare and vulnerable to extinction. As with vaginal microbes, bacterial populations can be extremely dynamic. The number of cells representing a particular species can vary from, say, one cell to a trillion. Let’s assume an animal is exposed to a new food that contains a chemical never before encountered. The bacterial species that is today represented by one hundred cells could, given a triggering change in the intestinal environment such as the new food, become billions of cells within a few days. If faced with loss of a prized food or with competition by its hungry fellow bacteria, the numerically dominant species could then drop in numbers several thousand fold or more. It is this dynamism and flexibility that are at the heart of the microbiome and contribute to its staying power. But the species represented by a hundred cells in normal times doesn’t have a big margin for error. It could also encounter an antibiotic that wipes it out permanently.

I call these rare species contingency microbes. Not only can they exploit an unusual food chemical (which more common bacteria cannot), but they may provide genetic protection against threats, such as a plague that humans have not before encountered. To me, this is a flashing red light. Diversity is essential. What if we lose critical rare species? What if human keystone species disappear? Would there be cascading effects leading to secondary extinctions?

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The fact that we can coexist with bacteria raises a profound set of questions. Why don’t they wipe us out? Why do we tolerate them? In the dog-eat-dog world of Darwinian competition, how have we achieved a stable relationship with our microbes?

Public-goods theory provides clues. A public good is something that everyone shares, such as the clean air you breathe at the seacoast, a bright sunny day, a local street built with your tax dollars, or your favorite public radio station. But nothing is ever really free. Public radio must be supported; someone has to pay. Even if clean air is public, your car might emit pollution that affects my clean air. My breathing and your driving occur in the same space.

In a smoothly functioning social world, each individual is expected to contribute to the public interest. You can listen to public radio and not pony up but, if everyone did that, public radio would go bankrupt. If everyone had a car out of tune, our common air and sunlight would be degraded. In this sense, people who use a public good but don’t give sufficiently, or who add to the common expense, may be considered “cheaters”; they benefit but do not pay their fair share of the enterprise.

However, out in the jungle, where “survival of the fittest” rules supreme, “cheating” seems like a pretty good strategy. The cheater might be able to lay more eggs or find better nesting sites and, over generations, be more successful (have more offspring) since its ratio of benefit per cost is more favorable. The cheater has a selective advantage. However, if “cheaters” always won, cooperation would fall apart. Why wouldn’t everyone cheat and not pay for public radio? How can different life-forms live together if there is a built-in selective advantage for breaking the rules? Cheating has the power to make the whole system break down.

Yet clearly cooperation occurs everywhere we look: bees and flowers; sharks and pilot fish; cows and their rumen bacteria allowing them to create energy from grass, termites, aphids. As far as we know, ruminants have existed for millions of years and insects like termites and aphids even longer. This tells us that cheaters don’t always win. Simply put, the penalty for cheating must be sufficiently high that cheating is disadvantageous, so that cheaters don’t triumph. If there were no consequences, more people would speed when they drive. Penalties work.

The same holds true for you and your microbes. Natural selection favors hosts that have a system of penalties in place that cannot be evaded: the more the cheating, the higher the penalty. Such penalties can deflect the spoils of “ill-gotten” gains. Thus a bacterium in the termite gut that oversteps its bounds can trigger a very strong immune response, putting it back in its place. This works, but it can be expensive for the host to have such a system. Some might die fighting off cheaters with an overly aggressive immune response. When the host dies, so do all of its inhabitants. When this happens, all of the genes, from both the host and its residents, are lost for all of posterity. Other termites that did not have a cheater arise and take up the niche vacated by their newly deceased sibling. The tension between competition and cooperation plays out on a thousand stages.

Game theory, inspired by the great economist and mathematician John Nash (whose story has been told in the book and movie
A Beautiful Mind
), sheds light on the phenomenon of cooperation, on why coevolved systems appear to select for individuals who largely play by the rules. It is a way of understanding behavior in social settings—how people make decisions to optimize outcomes and how markets operate. Nash envisioned a situation that has since been called the “Nash equilibrium.” It can be summarized as a strategy in a game with two or more players in which the outcome is optimized by playing within the rules; if you cheat, your outcome is worse than if you played fair and square.

Ecosystems that have been around a long time, like our bodies, have solved this fundamental tension between conflict and cooperation. We have persevered. But this theory has relevance as we consider our changing world. What that means is that cooperation is tenuous: don’t mess with it, because then all bets will be off. I worry that with the overuse of antibiotics as well as some other now-common practices, such as Cesarian sections, we have entered a danger zone, a no-man’s-land between the world of our ancient microbiome and an uncharted modern world.

4.

THE RISE OF PATHOGENS

When I was a medical student, I spent the summer assisting a doctor whose job was to examine workers in a West Virginia Job Corps program. It was a great experience, because it was intensely clinical. I learned to do careful physical exams on a large number of basically healthy young people. My teacher, Dr. Fred Cooley, was practical, smart, and funny. My job with him ended at about one in the afternoon, so I could head over to the hospital and work with other doctors seeing all kinds of patients. They didn’t have many medical students, so they welcomed me with open arms, a trainee with lots of questions.

One afternoon, we were called to see an eleven-year-old boy who had become acutely ill and was hospitalized. He lived in a small, very conservative, Baptist community. He had been perfectly well until about two days earlier, when he began to feel achy; he developed a fever and an upset stomach. The next day his fever worsened, and he had a headache. On the third day, he developed small purplish dots all over his body. His parents were scared and brought him to the hospital, which was a good thing. The emergency room doctors quickly diagnosed Rocky Mountain spotted fever, a disease caused by a bite from a tick infected with a type of bacteria called rickettsia. Although first discovered in the Bitterroot Valley in Montana, hence its name, it is much more common in the eastern half of the country.

The bacterium multiplies within cells lining blood vessels, invoking a vigorous immune response. That explains the rash, since the blood vessels get inflamed and break. And it explains the headache, since the brain’s blood vessels are involved, causing a form of encephalitis. The boy was started on tetracycline, a life-saving antibiotic. If treatment isn’t given immediately, or is started too late, RMSF is fatal in up to 30 percent of people.

I accompanied the doctors up to see him. His hospital room was darkened because light hurt his eyes, indicating that his brain was affected. His body was covered in purple spots, more than I have seen in anyone since. Some of the spots ran together, producing big blackish purple patches. His hair was matted. He was drenched in sweat as he thrashed from side to side, his hands tied to the bed rails so he would not hurt himself and others. He was yelling at the top of his lungs, hallucinating, completely incoherent. From time to time, a recognizable word would emerge, but they were all curses: “shit, fuck, you fucking bastard, tits, cunt, fuck.” This went on continuously. In the corner of the room, his parents were cowering. Where had he learned these words? We knew that the encephalitis was causing his lack of inhibition.

Fortunately, with treatment, he turned the corner, gradually got better, and was discharged from the hospital five days later to complete his treatment at home. He didn’t remember anything that happened, but I am sure his parents never forgot it, not just the horror of his illness but the miracle of his cure.

Pathogens like rickettsia are microbes that make you ill. They bring the fevers, chills, pains, and aches that keep you bedridden for days. They can kill you—slowly or rapidly. You might die alone or alongside thousands of others. We usually call them germs and have, since their discovery about 150 years ago, done everything in our power to kill them. For the past 70 years we have waged an aggressive war against pathogenic bacteria using a slew of antibiotics, saving millions of lives worldwide. But to our chagrin, this battle seems to have no end. Bacteria mutate with lightning speed and have developed resistance against some of our most effective antibiotics. Even more worrisome, the battle we wage against pathogens has led to serious unintended consequences for our health and well-being.