[Obesity Discussion]

In another line of research, Gordon and his postdoctoral researcher Ruth Ley compared the microflora in two kinds of mice: normal-weight mice and mice with a genetic mutation that made them fat. Like humans, the mice had microflora consisting almost exclusively of two divisions of bacteria, the Bacteroidetes and the Firmicutes. But the proportions differed depending on whether the host was thin or fat. The normal-weight mice had more Bacteroidetes than Firmicutes in their gut microflora. The genetically obese mice had the opposite proportions: 50 percent fewer Bacteroidetes, 50 percent more Firmicutes.

It isn’t clear what the functional significance is of having more Firmicutes in the gut, nor whether the observed difference is a cause of the obesity or an effect. But Gordon wanted to see whether something comparable happened in humans of different weights. Over the past year, he and his colleagues have evaluated stool samples from 12 obese patients at a weight-loss clinic at Washington University, along with some normal-weight controls. They want to see if there’s such a thing as lean-type and obese-type microflora, and whether weight loss leads to a change in a person’s microbial community.

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.


You might think a microbial theory of obesity could change people’s views about the obese, perhaps even lessen the degree to which people think that obesity is the fat person’s own fault. But anti-fat sentiments seem to be deeply ingrained and resistant to change, as reflected in a rather unlikely place: New Scientist, a British magazine. In an article last year describing the work of Gordon and two groups of researchers in England who were also investigating the link between obesity and gut microflora, the author, Bijal Trivedi, was quite sympathetic to Gordon’s hypothesis. But the article — which is, remember, about a possible biological cause of obesity — was presented with a headline that still managed to depict obese people as lazy and gluttonous. It was called “Slimming for Slackers” and was illustrated with a fat man in a sweatsuit — the “slacker” of the title — sitting beside a partly eaten chocolate doughnut, waiting passively for thinness to arrive.

This is not to single out the New Scientist editors; they are just reflecting the generalized belief that there’s an element of laziness in anyone’s obesity. “Gluttony and sloth are two of the seven deadly sins,” said Ellen Ruppel Shell, author of “The Hungry Gene.” “We ascribe obesity to a character flaw.” This is what leads to the psychic pain of being fat, the social isolation of having a condition that everyone believes to be completely within your control — as if it were a voluntary purgatory, a case of willfully digging your own grave with your dinner fork.

I found that this attitude exists even among obese people, including a woman who was a research subject in Gordon’s clinical study. Joan was one of the obese patients at Washington University who sent Gordon stool samples as she lost weight (15 pounds over the course of a year, which she eventually gained back when she stopped dieting) so they could be tested for various microbes. She said she hasn’t been curious enough to try to find out about her microflora; she’s too busy, and besides, she already knows where to place the blame for her excess weight — not on a microbe but on herself. “I know that I’m not being obedient, I’m not using my body the way God intended,” said Joan, who asked me to refer to her only by her middle name. “I know how I’m supposed to eat, but I’m not having a healthy appetite, you know what I’m saying? I’m not wanting to be obedient.”

But it’s not about obedience — or at least not only about obedience. “The biochemistry of the body of the obese person is very different from that of a lean person,” said Richard Atkinson, Janet S.’s former physician. “If the obese person gets down to a lean person’s weight, their biochemistry is not the same.” Losing weight is hard, keeping it off is harder and, especially for some unfortunate souls, the body seems to work against itself in the struggle.


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.”

Dhurandhar’s battle against the conventional wisdom was reminiscent of the struggle a decade earlier of two Australian scientists, who were also proposing an infectious cause for a chronic disease, in their case, a bacterium that causes ulcers. The Australians were met with skepticism at first, but eventually they accumulated enough evidence to make it hard to ignore the connection between ulcers and the bacterium, Helicobacter pylori. It helped that one of them, Barry J. Marshall, dramatically swallowed a pure culture of H. pylori — and promptly came down with symptoms of gastritis, the first stage of an ulcer. (The H. pylori story ended with the ultimate vindication: Marshall and his collaborator, J. Robin Warren, won the Nobel Prize in 2005.)

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.