In 2003, the Human Genome Project (HGP) announced that it had completed sequencing every base pair of DNA from an individual human and mapping all the genes—together known as the genome—of our species, Homo sapiens. This was touted as a major breakthrough in understanding our development, our evolution, and very importantly, our health. The HGP has revolutionized medicine, and gene-sequencing technology has since become far more common and less expensive.
From the Human Genome Project we learned that the human genome has about 20,000 protein-coding genes—no more than a mouse has, and fewer than some common laboratory plants! How could such intelligent exquisite, complicated beings as ourselves get by with so few genes? It turns out that we humans are not simply just humans. Each one of us is an ecosystem with an estimated one trillion other microscopic organisms living in and on us at any given time. And these organisms, collectively known as our microbiome, contain about 300 times the number of genes that our own genomes express.
We are currently in the midst of another revolution, and this one is just as exciting and fast-moving as the genomic one. The more we learn about these organisms, the clearer it becomes that we are in fact superorganisms, each of us a little planet into ourselves, with residents and visitors. They affect our mood and our appearance, and play important roles in our immune systems. Yet we alter these communities in many ways, one of the most significant being the use of antibiotics. Like penicillin, one of the first antibiotics to be discovered, and Cipro, which flew of the shelves in the anthrax scares after 9/11, these are powerful and effective drugs for killing off bacteria. They’re not effective against viruses or fungal infections, however, and yet an alarmingly large number of doctors admit to prescribing them for conditions like cold viruses, because patients or parents of patients think it will make them feel better. This practice, along with other types of antibiotic misuse, does more than waste money. These practices disrupt our microbiome, with consequences for human health that we’re only now beginning to understand.
Meet Your Microbiome explores those consequences, and their potential remedies, through the research of Dr. Martin Blaser, Director of the Human Microbiome Program, NYU Langone Medical Center and author, most recently, of Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues.
— by Dr. Susan Perkins
Microbiologist Susan Perkins is Associate Curator/Professor in the Museum’s Department of Invertebrate Zoology & Sackler Institute for Comparative Genomics & Richard Gilder Graduate School. She studies parasites, the dominant form of life on Earth, with a focus on the protozoan parasites that cause malaria.
Dr. Martin Blaser on sacred cows, ear infections and the nature of science
by Ashton Applewhite
Bacteria had the planet to themselves for around three billion years, and they were busy. Dr. Martin J. Blaser puts it beautifully in his 2014 book Missing Microbes: “They made the oxygen we breathe, the soils we till, the food webs that support our oceans. Slowly, inexorably, through trial and error across the deepness of time, they invented the complex and robust feedback systems that to this day support all life on earth.” Ancient but not primitive, bacterial cells—which the infectious disease specialist calls “complete, self-contained beings”—come in all shapes and sizes and are adapted to virtually every ecosystem on Earth.
So it shouldn’t surprise us that they occupy most of the Tree of Life, which represents the evolutionary relationships between all living things. Blaser uses the example of two common bacteria, E. coli and Clostridium, to make that point. Humans are far closer on the “tree” to corn, a green plant, than the two bacteria are to each other. In other words, he writes, “Humanity is just a speck in the massively bacterial world. We need to get used to that idea.”
“Humanity is just a speck in
the massively bacterial world.
We need to get used to that idea.”
Given that fact, it shouldn’t surprise us that microbes occupy most of us as well. Seventy to ninety percent of all cells in the human body are bacterial, representing perhaps 10,000 different species. Genetically we get even less real estate: 99 percent of the unique genes in our bodies are bacterial. This population of over 100 trillion microorganisms makes up our microbiome: a collection of microbial communities that has evolved along with homo sapiens to help orchestrate basic life processes, beginning the moment we’re born.
So it really shouldn’t surprise us that the microbiome plays a major role in health, especially immunity and metabolism. Nor that disrupting this ancient equilibrium could have serious consequences. But that was the last thing on anyone’s mind when antibiotics, which destroy bacteria or slow their growth, came on the scene in the 1940s. “We’d just won World War II, we had dropped the bomb, we were invincible, and now we had these incredible drugs,” says Blaser. Formerly lethal diseases could be prevented or cured. Surgery grew far safer. Side effects appeared to be few and mild.
The drugs were so effective and so apparently risk-free that both doctors and patients began using them even when the malady wasn’t likely to be caused by bacteria: to treat upper respiratory infections, for example. The vast majority of ear infections, sore throats and coughs are caused by viruses and get better on their own. “But if your kid’s taken amoxicillin, it’s human nature to credit the drug,” says Blaser. “It’s human nature to see what we want and expect to see.” The difficulty lies in distinguishing between serious and mild illnesses, and in factoring in the risk to the community as a whole. Whether or not the drug helps that one kid with the ear infection, Blaser makes the case that “cumulatively, across society, all of those doses do hurt.”
On average, Americans take about 30
courses of antibiotics before age 40.
He’s equally clear about the fact that antibiotics are invaluable for treating many serious infections, and continue to save countless lives. The problem is not use, but overuse. On average, Americans take about 30 courses of antibiotics before age 40. They also come our way in nonorganic meat, farmed fish, milk and eggs, because about 70 percent of all of the antibiotics sold are fed to commercially farmed animals to fatten them up. They’re in our tap water too. Trace amounts, but as Blaser points out, it all adds up. Overuse of antiseptics and sanitizers, and the rising rate of cesarean sections also contribute to an assault on the microbial diversity on and within us. We are only beginning to apprehend the health consequences. Missing Microbes documents a relation between what Blaser calls “modern plagues”—obesity, childhood diabetes, asthma, hay fever, food allergies, esophageal reflux and cancer, celiac disease, Crohn’s disease, ulcerative colitis, autism, eczema—and widespread antibiotic overuse.
In retrospect Blaser asks, “How can we have missed this for so long? How could we have used something so powerful, so widely, and think nothing was going to happen?” He attributes it to “sacred cows everywhere”—ideas, often unreasonable ones, that nevertheless go unquestioned. “It’s still true that antibiotics are so effective and safe, but it’s not 100 percent true. There is biological cost, particularly for children, in ways that we didn’t foresee.”
Skeptics point out that studies conducted by Blaser’s lab show correlation, not causation. For example, 2010 CDC maps of the US show the incidence of both obesity and antibiotic use to be markedly higher in the South. Describing the evidence as “strikingly nonrandom,” Blaser says, “If you can show enough associations in enough different directions, it begins to form a causal argument.” Take smoking, he suggests, which has never been proven to cause lung cancer. Plenty of smokers never get cancer and there are non-smokers who do. “The point is that smoking is such a strong risk factor that we now assume it’s a cause, but in the technical sense, it’s never been shown in humans.”
Blaser is quick to acknowledge that science is about testing hypotheses, so it’s appropriate for new ideas to face skepticism. Research into the role of Helicobacter pylori, a bacterium that’s been carried around in the human gut for at least 100,000 years, is a case in point. Medical dogma long held that the stomach was sterile and the way to treat ulcers was to reduce acidity by drinking milk and reducing stress. Then two Australian doctors noticed an S-shaped bacterium (which we now know as H. pylori) in the stomach and were able to establish a groundbreaking link to both gastritis (stomach inflammation) and ulcers—work that won them the Nobel Prize for Medicine in 2005. Blaser’s lab, which began studying H. pylori in 1985, went on to prove that the microbe could cause gastric cancer, a leading cause of cancer death.
The dogma shifted, to “the only good H. pylori is a dead one.” But as Blaser began to see how profoundly the microbiology of the human stomach had changed in just a few generations, he began wondering whether that was actually the case. The bacterium probably became less prevalent in the early 20th century, as water grew cleaner and families grew smaller, and the widespread use of antibiotics after 1940 accelerated the trend. The effects are lifelong. New diseases related to the loss of H. pylori are on the rise.
Beginning in 1996, and in the face of considerable and ongoing skepticism, Blaser theorized that H. pylori also serves a positive role in human health. He and his colleagues have shown that the bacterium protects against GERD (gastroesophageal reflux disease), asthma, and esophageal cancer. “Helicobacter is a very complicated issue,” he says. “Everyone’s trying to get rid of it, but its disappearance could be just as important. I’ve had people come up to me privately and say, ‘We agree with you.’”
Another problem from antibiotic overuse, and the first to be recognized, is antibiotic resistance: the emergence of “superbugs” immune to the most powerful drugs in our small arsenal. Lethal microbes like C. difficile and MRSA, the infection due to antibiotic-resistant Staphylococcus, first emerged in hospitals. This makes sense, but why have they begun to escape into the community? Because of antibiotic pressure, says Blaser, drawing an analogy to living below sea level in Holland. “The dyke protecting you has to be really solid, because the pressure of the sea is so strong that any little leak could end up inundating you. When it comes to these powerful pathogens, the pressure is generated by all the antibiotic products in use since WWII—not just antibiotics but all the antibacterials we’re washing with and putting on our clothes. A colleague of mine found an ad for an antibacterial stapler!”
The frankly terrifying rise and spread of these lethal microbes may be what drives change, and there’s evidence that we can change our ways. It’s apparent that Americans are addicted to antibiotics, but other societies are way less so. The Swedes, for example, use only 40 percent as many antibiotics as Americans (and are at least as healthy). Likewise, the rates at which doctors prescribe antibiotics have been shown to vary widely across a single type of medical practice. Blaser wrote Missing Microbes to influence the public and medical practitioners about all the risks of antibiotic use. He’d like to develop a program to educate people about the health consequences of children receiving antibiotics early in life. And he’d like to encourage the development of narrow-spectrum antibiotics, which affect only a few types of bacteria. Because antibiotics are much less profitable than drugs for chronic diseases, pharmaceutical companies have stopped developing them. Blaser suggest that people tell Congress, “I have kids and grand kids and I want them to get narrow spectrum antibiotics—and I want them to be safe.”
View a slideshow of the Antibiotics and Obesity lecture
A promising avenue for restoring the microbiome is remediation—replacing some of the organisms that are lost when someone takes an antibiotic. One method is fecal transplant (FT): transferring stool from a healthy person to replace good bacteria that have been killed or suppressed. FT has been highly effective at eradicating debilitating C. difficile infections. In theory, the more microbially diverse the sample the better, but in practice just about every healthy person’s stool will transform a weird microbiome into a normal one. “It’s amazing,” Blaser comments. “We think it’s because there’s a fundamental equilibrium.”
He also cautions that it’s the early days of FT, and possibly also the late days, because safer and more precise treatments are in the works. Again, it’s a question of assessing risk. “There are seriously ill people who really need it, but other people who are mildly ill ask me how they can get one.” Blaser is seeing good results from oral cocktails that contain much more defined bacterial cultures. Those are scientifically developed probiotics, he emphasizes, not the poorly studied compounds that fill shelves in grocery stores and health food stores and drug stores.
“We also need to enhance some of the organisms that are present, but depleted, with prebiotics,” says Blaser. (Prebiotics are specific chemicals that promote the growth of beneficial organism—either your own or ones given as probiotics.) “Maybe we have to do a reversal, replace some of those vanished organisms, perhaps with isolates from the Amazon or from Africa. And ultimately, we have to monitor.” The medical frontiers are many. “We know that antibiotics affect the development of metabolism (as in obesity) and immunity (as with asthma or Type 1 diabetes), so it’s not a stretch to think they affect the complex development of the brain as well,” the doctor writes in Missing Microbes. He also sees a potential connection to estrogen status.
“We need to enhance some of the organisms that are present, but depleted ... Maybe we have to replace some of those vanished organisms, perhaps with isolates from the Amazon or from Africa. And ultimately, we have to monitor.”
Are all biological systems potentially affected by the microbiome? Blaser thinks that it probably plays a role in almost every aspect of health and disease, and that the bigger question is one of magnitude. “Is the microbiome involved in one percent of the biological process—whether development, for example, or heart failure—or most of it?” Just about any disease would be worth study, because all vary in course and outcome, and in how well or poorly people respond to therapy. Doctors devote a lot of time to studying this human variation, and Blaser thinks it’s reasonable to ascribe some of that variation to the metabolic status of the individual microbiome. He and his colleagues are particularly interested in kidney failure, which causes some patients to progress to dialysis faster than others. “We’re at the very early stages of determining whether the metabolic activities of the microbes in our gut play a role in that variation.”
It’s a fascinating research frontier. “We have early evidence that there’s gold out there,” Blaser says. “We don’t know where it is yet.” What he does know is that well-reasoned scientific arguments backed by data make eyes light up.
Dr. Blaser is the Muriel and George Singer Professor of Medicine, Professor of Microbiology, and Director of the Human Microbiome Program, at NYU Langone Medical Center. He is the author of over 500 scientific publications and 14 books, most recently Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues.
Ashton Applewhite is a staff writer at the American Museum of Natural History.