Germs that make you fat? An idea that would have seemed nuts not long ago has suddenly become respectable. Although by no means proven, it is no longer in the same outlandish class as the dog that ate homework and other butt-covering fictions.
The possible connection between a pathogen and obesity is just one more example of a startling revisionist hypothesis that is, well, infecting biomedical research: the notion that germs cause, or at least contribute to, an increasingly long list of chronic diseases, many of them exceedingly common. With the help of new molecular techniques, scientists can now easily zero in on disease organisms in human patients and, using statistical methods, link them with particular maladies. Infection is suspected of being at least partly responsible not only for metabolic disorders like diabetes and mental disorders like schizophrenia, but also for the two ailments that will eventually kill most of us: cancer and heart disease.
"In my medical school I was taught that gastric ulcer is due to hurry, worry and curry," says Nikhil Dhurandhar, Ph.D., who was educated in Bombay and is now an assistant professor at Wayne State University in Detroit. He is talking about the disease that is everybody's favorite example of biomedicine's new infectious paradigm. For decades the medical party line was that ulcers were stress-induced and incurable, the archetypal ailment of the Age of Anxiety -- except that almost all ulcers are caused by a bacterium, Helicobacter pylori, and can be easily, permanently and inexpensively cured in less than a month with antibiotics. Researchers first described the relation between H. pylori infection and ulcers in 1983, but their findings were scoffed at for years and incorporated into the medical canon only recently.
Dhurandhar is on a similar mission, but meeting less resistance. Backed by a powerful mentor, obesity researcher Richard Atkinson of the University of Wisconsin, Dhurandhar is slowly amassing evidence that some proportion of obesity -- at this point his work suggests, scarily, that it may be a very large proportion -- is the consequence of infection by a virus.
Most of this research has been done in animals, but some small human studies, so far mostly unpublished, back it up. The latest published contribution appeared last month in the International Journal of Obesity and Related Metabolic Disorders. The paper reported on experiments in which Dhurandhar and his colleagues inoculated chickens and mice with a human virus they suspect of promoting fat gain. It did: The infected animals gained two-thirds more fat than uninfected control animals.
The virus, designated Ad-36, is one of 50 adenoviruses known to infect people. In an electron microscope, adenoviruses look a bit like the World War II mines used to block shipping channels -- spherical and studded with spikes that help them attach to host cells. Despite that ominous configuration, most appear to be benign. A few cause respiratory infections, pinkeye and diarrhea.
As for Ad-36, it doesn't seem to give diarrhea or colds to Dhurandhar's birds and rodents, at least. "They are quiet for a day or so, and then they bounce back," he says.
A handful of viruses are known to make animals fat, which is how Dhurandhar -- who operated obesity treatment centers in India before he came to the U.S. nearly a decade ago -- got interested in them. An unexpected characteristic of these infections is that when the animals get fat the levels of cholesterol and triglycerides in their blood plummet. Increased body fat is generally accompanied by increased cholesterol and triglycerides, which ferry fats around in the blood.
In a study published in 1997, Dhurandhar examined blood from patients in Bombay looking for antibodies against an adenovirus that was epidemic among Indian chickens -- and which killed them after making them fat. He found viral antibodies in 10 of his 52 human patients, evidence that they had been exposed to the virus at some time in their lives. The 10 tended to be fatter than the other patients, and also tended to have lower cholesterol and triglycerides.
Dhurandhar says he has strengthened the case in a U.S. study. In findings presented at conferences and in a paper Dhurandhar says has been submitted for publication, Ad-36 antibodies turned up in 100 of 313 obese subjects, but in just four of 92 lean controls. In short, nearly one in three fat Americans in Dhurandhar's study showed evidence of prior infection with the virus, compared with only one in 20 slim ones. Moreover, the infected subjects also had lower-than-usual cholesterol levels.
Dhurandhar's provocative results, especially the human studies, must, of course, be replicated before they can be fully accepted. But the reactions of other obesity researchers, at first skeptical, have become cautiously friendly, at least in public. One measure of Dhurandhar's increasing credibility is that top obesity researchers have joined the advisory board of the Rochester Center for Obesity Research, the nonprofit center he has set up to do human studies in collaboration with the weight management center at Crittenton Hospital in Rochester, Mich. These scientists include Atkinson, who is president of the American Obesity Association, and John P. Foreyt, a professor at the Baylor College of Medicine in Houston. The National Institutes of Health has given Dhurandhar money to screen other human adenoviruses for fat-promoting effects.
But as Dhurandhar points out, even if the results of his studies hold up, many questions remain. "We don't know what role the virus plays. Is it that you need a viral infection and a high-fat diet? If you have just the infection but not a high-fat diet, maybe you won't gain weight. Or is it some other factor that has to go together with viral infection for obesity to be expressed? We don't know."
To add, um, weight to his thesis, Dhurandhar and his colleagues have also studied twins, a traditional means for ferreting out genetic and environmental causes of disease. They screened a group of 90 pairs of identical twins for Ad-36 antibodies, throwing out the pairs in which both twins tested the same -- positive or negative -- for the virus. In the remaining 26 twin pairs, where one twin possessed the antibodies and the other did not, the positive subjects had significantly higher body weight and body fat than the antibody-negative twins, says Dhurandhar, who is seeking funding to expand the twin study. "I believe that's the closest one can come to showing the role of this virus in humans," he says.
This sort of indirect evidence of a relation between viral infection and obesity in humans is probably the best we can expect. One of the Australian researchers who finally established that ulcers are caused by a bacterial infection got so fed up with being hooted at by his colleagues that he put his mouth where his convictions were. He swallowed some H. pylori -- and promptly got ulcers. But he also had faith that his stomach pain could quickly be vanquished with antibiotics. There is no such magic bullet for infectious adiposity, if it exists. And even if regulatory agencies would permit direct human tests, it's hard to imagine thin people volunteering to swallow Ad-36 and then sit around -- perhaps for years -- waiting to get fat.
"In humans we say we have a strong association, not a causation," says Dhurandhar. "So we have to collect circumstantial evidence, something like smoking and cancer." The circumstantial evidence includes continuing searches for viral antibodies and traces of the virus itself. The virus has been detected in infected animals but, so far, not in people.
Dhurandhar is also doing laboratory investigations of how a virus might make people fat. In these studies, Ad-36 seems to speed up the conversion of a kind of pre-fat cell into full-fledged fat cells, known as adipocytes. His hypothesis is that the virus is doing what viruses do, commandeering human DNA and getting it to make viral proteins, in the process ratcheting up the adipocyte production rate.
Dhurandhar has been inundated with beseeching e-mails from hundreds of distended and desperate people. Sadly, he has nothing to offer them -- for now, at least -- except the conventional, notoriously unsuccessful advice: diet and exercise.
But some day, if the infection theory of fatness holds, Dhurandhar thinks it would not be too difficult to develop an Ad-36 vaccine that could be administered to everybody early in life, like polio vaccine. "But right now we are far from that," he cautions.
Another possibility is antiviral drugs. But before developing a pill, scientists would want to know how long the virus remains in the bodies of the fat. "Does this virus just turn genes on or off, and go away, but the body goes on to become obese? That's one scenario," says Dhurandhar. "The other is that the virus stays in your body and continues to make you fat. In that case one could add an antiviral to other therapies."
If researchers continue to fail to find traces of the virus itself in the antibody-positive obese, that could mean that the infection itself is long gone, rendering antiviral drugs useless. On the bright side, it could also mean that virally induced obesity isn't contagious.
"At this point we don't know whether it's an acute or a chronic infection," Dhurandhar says. "It may be that a virus makes a person fat, but once they're obese, then what they've got to do is eat less and exercise more."
In a slightly cheering bit of news, he says, a small pilot study of people undergoing drug treatment for obesity has shown that those with the Ad-36 antibodies lost weight faster than those who were antibody-free. Dhurandhar thinks that might mean that someone who gets fat as a result of a viral infection may not be predisposed to gain weight -- unlike those of us who chose our ancestors unwisely and are therefore genetically more resistant to weight loss.
Which might mean that fat germs are less fateful than fat genes.
"Maybe," says Dhurandhar, "but we don't know right now."