August 13, 2006
By ROBIN MARANTZ HENIG
In the 30-plus years that Richard Atkinson has been studying obesity, he has always maintained that overeating doesn’t really explain it all. His epiphany came early in his career, when he was a medical fellow at U.C.L.A. engaged in a study of people who weighed more than 300 pounds and had come in for obesity surgery. “The general thought at the time was that fat people ate too much,” Atkinson, now at Virginia Commonwealth University, told me recently. “And we documented that fat people do eat too much — our subjects ate an average of 6,700 calories a day. But what was so impressive to me was the fact that not all fat people eat too much.”
One of Atkinson’s most memorable patients was Janet S., a bright, funny 25-year-old who weighed 348 pounds when she finally made her way to U.C.L.A. in 1975. In exchange for agreeing to be hospitalized for three months so scientists could study them, Janet and the other obese research subjects (30 in all) each received a free intestinal bypass. During the three months of presurgical study, the dietitian on the research team calculated how many calories it should take for a 5-foot-6-inch woman like Janet to maintain a weight of 348. They fed her exactly that many calories — no more, no less. She dutifully ate what she was told, and she gained 12 pounds in two weeks — almost a pound a day.
“I don’t think I’d ever gained that much weight that quickly,” recalled Janet, who asked me not to use her full name because she didn’t want people to know how fat she had once been. The doctors accused her of sneaking snacks into the hospital. “But I told them, ‘I’m gaining weight because you’re feeding me a tremendous amount of food!’ ”
The experience with Janet was an early inkling that traditional ideas about obesity were incomplete. Researchers and public-health officials have long understood that to maintain a given weight, energy in (calories consumed) must equal energy out (calories expended). But then they learned that genes were important, too, and that for some people, like Janet, this formula was tilted in a direction that led to weight gain. Since the discovery of the first obesity gene in 1994, scientists have found about 50 genes involved in obesity. Some of them determine how individuals lay down fat and metabolize energy stores. Others regulate how much people want to eat in the first place, how they know when they’ve had enough and how likely they are to use up calories through activities ranging from fidgeting to running marathons. People like Janet, who can get fat on very little fuel, may be genetically programmed to survive in harsher environments. When the human species got its start, it was an advantage to be efficient. Today, when food is plentiful, it is a hazard.
But even as our understanding of genes and behavior has become more refined, some cases still boggle the mind, like identical twins who eat roughly the same and yet have vastly different weights. Now a third wave of obesity researchers are looking for explanations that don’t fall into the relatively easy ones of genetics, overeating or lack of exercise. They are investigating what might seem to be the unlikeliest of culprits: the microorganisms we encounter every day.
Jeffrey Gordon, whose theory is that obesity is related to intestinal microorganisms, has never had a weight problem. I went to meet him and his colleagues at the Center for Genome Sciences at Washington University, which he directs. I wanted to find out everything Gordon knows about the bugs in our guts, and how those bugs might contribute to human physiology — in particular, how they might make some people fat.
Of the trillions and trillions of cells in a typical human body — at least 10 times as many cells in a single individual as there are stars in the Milky Way — only about 1 in 10 is human. The other 90 percent are microbial. These microbes — a term that encompasses all forms of microscopic organisms, including bacteria, fungi, protozoa and a form of life called archaea — exist everywhere. They are found in the ears, nose, mouth, vagina, anus, as well as every inch of skin, especially the armpits, the groin and between the toes. The vast majority are in the gut, which harbors 10 trillion to 100 trillion of them. “Microbes colonize our body surfaces from the moment of our birth,” Gordon said. “They are with us throughout our lives, and at the moment of our death they consume us.”
Known collectively as the gut microflora (or microbiota, a term Gordon prefers because it derives from the Greek word bios, for “life”), these microbes have a Star Trek analogue, he says: the Borg Collective, a community of cybernetically enhanced humanoids with functions so intertwined that they operate as a single intelligence, sort of like an ant colony. In its Borglike way, the microflora assumes an extraordinary array of functions on our behalf — functions that we couldn’t manage on our own. It helps create the capillaries that line and nourish the intestines. It produces vitamins, in particular thiamine, pyroxidine and vitamin K. It provides the enzymes necessary to metabolize cholesterol and bile acid. It digests complex plant polysaccharides, the fiber found in grains, fruits and vegetables that would otherwise be indigestible.
And it helps extract calories from the food we eat and helps store those calories in fat cells for later use — which gives them, in effect, a role in determining whether our diets will make us fat or thin.
In the womb, humans are free of microbes. Colonization begins during the journey down the birth canal, which is riddled with bacteria, some of which make their way onto the newborn’s skin. From that moment on, every mother’s kiss, every swaddling blanket, carries on it more microbes, which are introduced into the baby’s system.
By about the age of 2, most of a person’s microbial community is established, and it looks much like any other person’s microbial community. But in the same way that it takes only a small percentage of our genome to make each of us unique, modest differences in our microflora may make a big difference from one person to another. It’s not clear what accounts for individual variations. Some guts may be innately more hospitable to certain microbes, either because of genetics or because of the mix of microbes already there. Most of the colonization probably happens in the first few years, which explains why the microflora fingerprints of adult twins, who shared an intimate environment (and a mother) in childhood, more closely resemble each other than they do those of their spouses, with whom they became intimate later in life.
No one yet knows whether an individual’s microflora community tends to remain stable for a lifetime, but it is known that certain environmental changes, like taking antibiotics, can alter it at least temporarily. Stop the antibiotics, and the microflora seems to bounce back — but it might not bounce back to exactly what it was before the antibiotics.
In 2004, a group of microbiologists at Stanford University led by David Relman conducted the first census of the gut microflora. It took them a year to do an analysis of just three healthy subjects, by which time they had counted 395 species of bacteria. They stopped counting before the census was complete; Relman has said the real count might be anywhere from 500 species to a few thousand.
About a year ago, Relman joined with other scientists, including Jeffrey Gordon, to begin to sequence all the genes of the human gut microflora. In early June, they published their results in Science: some 78 million base pairs in all. But even this huge number barely scratches the surface; the total number of base pairs in the gut microflora might be 100 times that. Because there are so many trillions of microbes in the gut, the vast majority of the genes that a person carries around are more microbial than human. “Humans are superorganisms,” the scientists wrote, “whose metabolism represents an amalgamation of microbial and human attributes.” They call this amalgamation — human genes plus microbial genes — the metagenome.
Gordon first began studying the connection between the microflora and obesity when he saw what happened to mice without any microbes at all. These germ-free mice, reared in sterile isolators in Gordon’s lab, had 60 percent less fat than ordinary mice. Although they ate voraciously, usually about 30 percent more food than the others, they stayed lean. Without gut microbes, they were unable to extract calories from some of the types of food they ate, which passed through their bodies without being either used or converted to fat.
When Gordon’s postdoctoral researcher Fredrik Bäckhed transplanted gut microbes from normal mice into the germ-free mice, the germ-free mice started metabolizing their food better, extracting calories efficiently and laying down fat to store for later use. Within two weeks, they were just as fat as ordinary mice. Bäckhed and Gordon found at least one mechanism that helps explain this observation. As they reported in the Proceedings of the National Academy of Sciences in 2004, some common gut bacteria, including B. theta, suppress the protein FIAF, which ordinarily prevents the body from storing fat. By suppressing FIAF, B. theta allows fat deposition to increase. A different gut microbe, M. smithii, was later found to interact with B. theta in a way that extracts additional calories from polysaccharides in the diet, further increasing the amount of fat available to be deposited after the mouse eats a meal. Mice whose guts were colonized with both B. theta and M. smithii — as usually happens in humans in the real world — were found to have about 13 percent more body fat than mice colonized by just one or the other.
Gordon likes to explain his hypothesis of what gut microbes do by talking about Cheerios. The cereal box says that a one-cup serving contains 110 calories. But it may be that not everyone will extract 110 calories from a cup of Cheerios. Some may extract more, some less, depending on the particular combination of microbes in their guts. “A diet has a certain amount of absolute energy,” he said. “But the amount that can be extracted from that diet may vary between individuals — not in a huge way, but if the energy balance is affected by just a few calories a day, over time that can make a big difference in body weight.”
Gordon says he is still far from understanding the relationship between gut microflora and weight gain. “I wish you were writing this article a year from now, even two years from now,” he told me. “We’re just beginning to explore this wilderness, finding out who’s there, how does that population change, which are the key players.” He says it will be a while before anyone figures out what the gut microbes do, how they interact with one another and how, or even whether, they play a role in obesity. And it will be even longer before anyone learns how to change the microflora in a deliberate way.
There’s another way that biological middlemen might be involved in obesity — in this case, not the gut microbes (mostly bacteria) with which we co-exist but the viruses and other pathogens that occasionally infect us and make us ill. This is the subspecialty that is being called infectobesity.
The idea of infectobesity dates to 1988, when Nikhil Dhurandhar was a young physician studying for his doctorate in biochemistry at the University of Bombay. He was having tea with his father, also a physician and the head of an obesity clinic, and an old family friend, S. M. Ajinkya, a pathologist at Bombay Veterinary College. Ajinkya was describing a plague that was killing thousands of chickens throughout India, caused by a new poultry virus that he had discovered and named with his own and a colleague’s initials, SMAM-1. On autopsy, the vet said, chickens infected with SMAM-1 revealed pale and enlarged livers and kidneys, an atrophied thymus and excess fat in the abdomen.
The finding of abdominal fat intrigued Dhurandhar. “If a chicken died of infection, having wasted away, it should be less fat, not more,” he remembered thinking at the time. He asked permission to conduct a small experiment at the vet school.
Working with about 20 chickens, Dhurandhar, then 28, infected half of them with SMAM-1. He fed them all the same amount of food, but only the infected chickens became obese. Strangely, despite their excess fat, the infected obese chickens had low levels of cholesterol and triglycerides in their blood — just the opposite of what was thought to happen in humans, whose cholesterol and triglyceride levels generally increase as their weight increases. After his pilot study in 1988, Dhurandhar conducted a larger one with 100 chickens. It confirmed his finding that SMAM-1 caused obesity in chickens.
But what about humans? With a built-in patient population from his clinic, Dhurandhar collected blood samples from 52 overweight patients. Ten of them, nearly 20 percent, showed antibody evidence of prior exposure to the SMAM-1 virus, which was a chicken virus not previously thought to have infected humans. Moreover, the once-infected patients weighed an average of 33 pounds more than those who were never infected and, most surprisingly, had lower cholesterol and triglyceride levels — the same paradoxical finding as in the chickens.
The findings violated three pieces of conventional wisdom, Dhurandhar said recently: “The first is that viruses don’t cause obesity. The second is that obesity leads to high cholesterol and triglycerides. The third is that avian viruses don’t infect humans.”
Dhurandhar, now 46, is a thoughtful man with a head of still-dark hair. Like Gordon, he has never been fat. But even though he is so firmly in the biological camp of obesity researchers, he ascribes his own weight control to behavior, not microbes; he says he is slim because he walks five miles a day, lifts weights and is careful about what he eats. Being overweight runs in his family; Dhurandhar’s father, who still practices medicine in India, began treating obese patients because of his own struggle to keep his weight down, from a onetime high of 220.
Slim as he is, Dhurandhar nonetheless is sensitive to the pain of being fat and the maddening frustration of trying to do anything about it. He takes to heart the anguished letters and e-mail he receives each time his research is publicized. Once, he said, he heard from a woman whose 10-year-old grandson weighed 184 pounds. The boy rode his bicycle until his feet bled, hoping to lose weight; he was so embarrassed by his body that he kept his T-shirt on when he went swimming. The grandmother told Dhurandhar that the virus research sounded like the answer to her prayers. But the scientist knew that even if a virus was to blame for this boy’s obesity, he was a long way from offering any real help.
In 1992, Dhurandhar moved his wife and 7-year-old son to the United States in search of a lab where he could continue his research. At first, because infectobesity was so far out of the mainstream, all he could find was unrelated work at North Dakota State University. “My wife and I gave ourselves two years,” he recalled. “If I didn’t find work in the field of viruses and obesity in two years, we would go back to Bombay.”
One month before his self-imposed deadline in 1994, Dhurandhar received a job offer from Richard Atkinson, who was then at the University of Wisconsin, Madison. Atkinson, always on the lookout for new biological explanations of obesity, wanted to collaborate with Dhurandhar on SMAM-1. But the virus existed only in India, and the U.S. government would not allow it to be imported. So the scientists decided to work with a closely related virus, a human adenovirus. They opened the catalogue of a laboratory-supply company to see which one of the 50 human adenoviruses they should order.
“I’d like to say we chose the virus out of some wisdom, out of some belief that it was similar in important ways to SMAM-1,” Dhurandhar said. But really, he admitted, it was dumb luck that the adenovirus they started with, Ad-36, turned out to be so fattening.
By this time, several pathogens had already been shown to cause obesity in laboratory animals. With Ad-36, Dhurandhar and Atkinson began by squirting the virus up the nostrils of a series of lab animals — chickens, rats, marmosets — and in every species the infected animals got fat.
“The marmosets were most dramatic,” Atkinson recalled. By seven months after infection, he said, 100 percent of them became obese. Subsequently, Atkinson’s group and another in England conducted similar research using other strains of human adenovirus. The British group found that one strain, Ad-5, caused obesity in mice; the Wisconsin group found the same thing with Ad-37 and chickens. Two other strains, Ad-2 and Ad-31, failed to cause obesity.
In 2004, Atkinson and Dhurandhar were ready to move to humans. All of the 50 strains of human adenoviruses cause infections that are usually mild and transient, the kind that people pass off as a cold, a stomach bug or pink eye. The symptoms are so minor that people who have been infected often don’t remember ever having been sick. Even with such an innocuous virus, it would be unethical, of course, for a scientist to infect a human deliberately just to see if the person gets fat. Human studies are, therefore, always retrospective, a hunt for antibodies that would signal the presence of an infectious agent at some point in the past. To carry out this research, Atkinson developed — and patented — a screening test to look for the presence of Ad-36 antibodies in the blood.
The scientists found 502 volunteers from Wisconsin, Florida and New York willing to be screened for antibodies, 360 of them obese and 142 of them of not obese. Of the leaner subjects, 11 percent had antibodies to Ad-36, indicating an infection at some point in the past. (Ad-36 was identified relatively recently, in 1978.) Among the obese subjects, 30 percent had antibodies— a difference large enough to suggest it was not just chance. In addition, subjects who were antibody-positive weighed significantly more than subjects who were uninfected. Those who were antibody-positive also had cholesterol and triglyceride readings that were significantly lower than people who were antibody-negative — just as in the infected chickens — a finding that held true whether or not they were obese.
As for the other pathogens implicated in infectobesity — nine in all — certain viruses are known to impair the brain’s appetite-control mechanism in the hypothalamus, as happens in some cases of people becoming grossly obese after meningitis. Scientists also point to a commonality between fat cells and immune-system cells, although the exact significance of the connection is unclear. Immature fat cells, for instance, have been shown to behave like macrophages, the immune cells that engulf and destroy invading pathogens. Mature fat cells secrete hormones that stimulate the production of macrophages as well as another kind of immune-system cell, T-lymphocytes.
Another line of investigation in the field of infectobesity concerns inflammation, a corollary of infection. Obese people have higher levels of two proteins related to inflammation, C-reactive protein and interleukin-6. This may suggest that an infectious agent has set off some sort of derangement in the body’s system of fat regulation, making the infected person fat. A different interpretation is not about obesity causation but about its associated risks. Some scientists, including Jeffrey Gordon’s colleagues at Washington University, are trying to see whether the ailments of obesity (especially diabetes and high blood pressure) might be caused not by the added weight per se, but by the associated inflammation.
The thrifty-genotype hypothesis holds that there was, once upon a time, an adaptive advantage to being able to get fat. Our ancestors survived unpredictable cycles of food catastrophes by laying down fat stores when food was plentiful, and using up the stores slowly when food was scarce. The ones who did this best were the ones most likely to survive and to pass on the thrifty genotype to the next generation. But this mechanism evolved to get through a difficult winter — and we’re living now in an eternal spring. With food so readily available, thriftiness is a liability, and the ability to slow down metabolism during periods of reduced eating (a k a dieting) tends to create a fatter populace, albeit a more famine-proof one.
Obesity has turned out to be a daunting foe. Many of us are tethered to bodies that sabotage us in our struggle to keep from getting fat, or to slim down when we do. Microbes might be one explanation. There might be others, as outlined in June in a paper in The International Journal of Obesity listing 10 “putative contributors” to obesity, among them sleep deprivation, the increased use of psychoactive prescription drugs and the spread of air-conditioning.
But where does this leave us, exactly? Whatever the reason for any one individual’s tendency to gain weight, the only way to lose the weight is to eat less and exercise more. Behavioral interventions are all we’ve got right now. Even the supposedly biological approach to weight loss — that is, diet drugs — still works (or, more often, fails to work) by affecting eating behavior, through chemicals instead of through willpower. If it turns out that microbes are implicated in obesity, this biological approach will become more direct, in the form of an antiviral agent or a microbial supplement. But the truth is, this isn’t going to happen any time soon.
On an individual level and for the foreseeable future, if you want to lose weight, you still have to fiddle with the energy equation. Weight still boils down to the balance between how much a particular body needs to maintain a certain weight and how much it is fed. What complicates things is that in some people, for reasons still not fully understood, what their bodies need is set unfairly low. It could be genes; it could be microbes; it could be something else entirely.
According to Rudolph Leibel, an obesity researcher at Columbia University who was involved in the discovery of the first human gene implicated in obesity, if you take two nonobese people of the same weight, they will require different amounts of food depending on whether or not they were once obese. It goes in precisely the maddening direction you might expect: formerly fat people need to eat less than never-fat people to maintain exactly the same weight. In other words, a 150-pound woman who has always weighed 150 might be able to get away with eating, say, 2,500 calories a day, but a 150-pound woman who once weighed more — 20 pounds more, 200 pounds more, the exact amount doesn’t matter — would have to consume about 15 percent fewer calories to keep from regaining the weight. The change occurs as soon as the person starts reducing, Leibel said, and it “is not proportional to amount of weight lost, and persists over time.”