The Obesity VIRUSes Ad-36 & SMAM-1 *old*

The Obesity Bug

By Bob Holmes
New Scientist magazine, vol 167 issue 2250, 05/08/2000, page 26


There's no doubt about it, people all over the world are getting fatter. Could a virus be to blame?, asks Bob Holmes

WHAT IF YOU COULD CATCH OBESITY as easily as you can catch a cold? Just one unlucky sneeze in a crowded railway carriage or lift, and that's it. Bang! Never mind that you've been a string bean all your life. Never mind that you've always taken plenty of exercise and watched what you eat. Pick up the wrong virus, and you're almost certain to get fat.

It sounds preposterous, but remember that only a few years ago the idea that a bacterium could give you ulcers or heart disease sounded crazy. Those theories are now well accepted-and the "obesity virus" could be the next one to become respectable. Traces of the virus show up in enough overweight people to suggest that the "epidemic of obesity" in today's world may be more than a mere metaphor. But don't sidle away from that extra-large person on the train just yet. Your greatest risk of catching obesity might come from someone you least expect.

BOMBAY, INDIA, 1988-Nikhil Dhurandhar's life was turning out just as he'd always imagined. Like his father before him, Dhurandhar was a doctor specialising in obesity. His practice was thriving and he saw a thousand patients a year. Until, one day, a casual remark changed his life forever.

A family friend, veterinary pathologist Sharad Ajinkya, mentioned that he'd been studying a viral epidemic that was sweeping through poultry flocks, killing hundreds of thousands of chickens. And oddly enough, when he examined the dead birds he'd been surprised by the large amount of body fat they were carrying. Dhurandhar was amazed. How could birds ill enough to die of a virus be overweight? "There should be little or no fat," said Dhurandhar. "They should be wasting away."

The two men decided to investigate. They injected the virus, known as SMAM-1, into some chickens in the lab. Six weeks later the infected ones had almost 50 per cent more fat in their body cavity than chickens that had not been exposed to the virus. Oddly enough, the fatter group also had less cholesterol and triglycerides in their blood. This was surprising because fat animals usually have high levels of these two molecules, which transport fat round the body in the bloodstream. Intrigued, Dhurandhar took blood samples from 52 of his obese patients and tested them for SMAM-1 antibodies. He found them in 10 of the 52, and those 10 were heavier than the other patients. They also had lower cholesterol levels-the same unusual signature he had found in the chickens. "When I got that, I thought this was something which was very important to pursue," says Dhurandhar.

But he knew, too, that he didn't have the lab space or funding to study this at his clinics in India. He started writing and phoning obesity researchers in the US, and soon realised that no one was going to take a chance on an unknown Indian scientist with an offbeat idea. He hoped there'd be a better chance of convincing someone if he went there. "So I closed my clinics-I had three at that time-got permission from my wife and my son, and we all came to the States," he recalls. "It was a big, big leap of faith."

THE WORLD has become dramatically fatter in the past few decades. Since 1980, obesity rates have risen more than 30 per cent in the US. Today, fully 23 per cent of adult Americans and about 20 per cent of adult Britons are obese, as defined by a body mass index (weight in kilograms divided by the square of height in metres) over 30, which works out to 97 kilograms for a person 1.8 metres tall. The problem is even worse in countries like Samoa, where more than half the adults are obese.

This sudden billowing of fat in rich and poor countries alike puzzles obesity experts. The usual suspects-notably poor diet and inadequate exercise-haven't worsened as rapidly as obesity has burgeoned, which has left experts with the feeling that they must be overlooking some important factor. "The fat content of the diet is too high and the level of physical activity has declined, but still we feel we cannot explain all of this obesity problem," says Arne Astrup of the University of Copenhagen.

What if the problem was, quite literally, an epidemic-a pathogen sweeping through the population, leaving obesity in its wake? The idea had always intrigued Richard Atkinson, an obesity researcher at the University of Wisconsin in Madison. Atkinson was aware that three other viruses-including canine distemper virus and Borna disease virus -had been shown to cause obesity in animals, usually by destroying the part of the brain that regulates appetite. In his lectures, he'd often joked about the possibility that fat could be contagious in humans, too. "I'd say, well, it's possible you get on an elevator, somebody sneezes on you, and you catch obesity. It got a good laugh," says Atkinson. But he'd never seriously tried to follow up on the idea.

MEANWHILE, Dhurandhar's big gamble had not paid off. He had landed a job as a researcher at North Dakota State University in Fargo. But as he neared the end of his second bitterly cold winter, he still had found no one willing to support his work on the chicken virus . Discouraged, he decided he'd pack up and move back to Bombay. But just before he gave up, one of his letters ended up on Atkinson's desk. A few months later Dhurandhar moved to Madison to take a research position in Atkinson's new lab.

The collaboration almost ended before it ever began. "The plan was that we would import SMAM-1 and start working on it," recalls Dhurandhar. "Of course, you need permission from the US Department of Agriculture to import a virus. We applied for a permit, and they very promptly refused it." Not all that surprising since the virus would devastate chicken flocks if it got out and maybe even make people fat.

Unable to do the research they had planned, the researchers decided to try their experiments with a different virus. Since SMAM-1 belonged to a group of virus es called adenoviruses, they scanned a list of the 50 or so commercially available human adenoviruses, which cause colds, diarrhoea and conjunctivitis. They decided to start with one called Ad-36, mostly because it was different enough from other adenoviruses to make antibodies formed against it easy to recognise. Scientists knew almost nothing about Ad-36 except that it had originally been isolated from a German girl with diarrhoea.

It turned out to be a lucky choice. After just three weeks, chickens inoculated with Ad-36 had two-thirds more abdominal fat than chickens without the infection-and once again, they had unusually low cholesterol. The new virus they had picked out of a catalogue, in other words, had exactly the same effect as their banned Indian virus . "We should have bought a lottery ticket on that day," says Dhurandhar, who suspects that their good fortune must mean that at least a few other viruses have similar effects.

When the researchers gave Ad-36 to mice, the effect was the same: two-thirds more abdominal fat than controls, and lower cholesterol levels. In a pilot experiment with marmosets, three animals infected with the virus put on three times as much weight over a six-month span as monkeys not exposed to the virus , Dhurandhar and Atkinson reported in May at the European Obesity Congress in Antwerp. And, as with the chickens and mice, their cholesterol went down. The monkey experiment should go a long way towards convincing sceptics that the animal experiments are relevant to people, says Atkinson. "People can dismiss chickens, and they have. They can dismiss mice, and they have. It's a lot harder to dismiss monkeys," he says.

But even if Ad-36 can make chickens, mice and monkeys pile on the fat , could it really do the same thing to people? To find out, Dhurandhar and Atkinson collected blood samples from 313 obese people and 92 lean ones in Wisconsin, Florida and New York. They found antibodies to Ad-36 in just four of the lean people but in 100-that's 32 per cent- of the fat ones. Once again, the obese people exposed to Ad-36 had unusually low cholesterol levels.

What those numbers suggest is frightening: should you be unlucky enough to get the virus, you're overwhelmingly likely to end up fat. "That's pretty scary," says John Foreyt, an obesity researcher at Baylor College of Medicine in Houston, Texas.

Could it be that fat people are just more likely to get the virus than skinny folks? After all, obesity often leads to a depressed immune system. To test this, Dhurandhar and Atkinson also looked for antibodies to three other adenoviruses-Ad-2, Ad-31 and Ad-37. All three turned up equally often in lean and obese people, and none was associated with the telltale signature of lower cholesterol.

And Dhurandhar keeps accumulating more evidence. Recently, he looked for antibodies in blood samples drawn from 86 pairs of identical or fraternal twins. In the 26 pairs where one twin had antibodies to Ad-36 and the other didn't, the one who had been exposed to Ad-36 proved to be significantly heavier, with a body mass index 1.5 points higher, on average. Once again, there was no such pattern with the other three adenoviruses.

Even with this growing weight of evidence, though, Dhurandhar and Atkinson have had trouble convincing their colleagues to accept their theory. "We've had people laugh at us," says Atkinson. "One of the most frustrating things I've ever done in my life is trying to get this stuff published. We're getting nit-picked to death."

That's not too surprising, says Frank Greenway, an obesity expert at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. "I think that's typical in the scientific community," he says. "People aren't comfortable with taking quantum leaps. The guy who decided that Helicobacter pylori was responsible for ulcers had a terrible time."

But their persistence may finally be paying off. Dhurandhar and Atkinson's first peer-reviewed paper, on their animal experiments, appeared this month in the International Journal of Obesity (vol 24, p 989). And none of the obesity experts contacted by New Scientist thinks the idea that a virus might cause some cases of obesity ridiculous, though most still say the idea is "not proven" in humans. "I think we can say for the moment that this virus induces obesity in some animals, but that this is not yet found to be true in humans," says Luc Van Gaal of the University of Antwerp. Even Dhurandhar agrees. "Everybody wants me to say this virus causes obesity in humans for sure. I'm not prepared to do that yet," he says.

Truly convincing proof in people may be hard to come by, though. "In the theoretically ideal world, you'd take a bunch of people and infect half of them and see what happens," says Greenway. "That's clearly unethical, so the next best thing is to understand the mechanism." Once scientists know what molecular triggers the virus trips to make animals fat, they can look to see if the same triggers are active in humans.

Dhurandhar is beginning to see the first hints of how the virus might make people fat. In test-tube experiments, he added Ad-36 to cultures of immature fat cells of mice. The infected cells were three times as likely as uninfected ones to mature into fully fledged fat cells, he found. Sure enough, he also found that Ad-36-infected animals have more fat cells in their bodies. Once formed, these still-slender fat cells begin doing their job, sending out the hormonal signals to gather and store fat. Which means that you're more likely to put on weight.

This summer, Dhurandhar-who moved last autumn to take up a professorship at Wayne State University in Detroit-is beginning a new set of experiments to try to understand how the virus lowers cholesterol even as it increases obesity. He's now testing to see whether hamsters- the lab animal of choice for cholesterol researchers-respond to Ad-36 in the same way as chickens, mice and monkeys. If researchers can figure out how the virus lowers cholesterol, they will know whether this reduction benefits the individual or not. "Where does it go? If it's going into arterial walls, that's not good," says Dhurandhar. On the other hand, if the liver breaks it down and excretes it-or if the liver simply produces less, scientists may eventually be able to treat high cholesterol with drugs that mimic the virus's action.

IF DHURANDHAR and Atkinson's work eventually proves that the Ad-36 virus is responsible for some proportion of the obese people we see today, what happens then? To begin with, Dhurandhar has seen some hints that obese people with antibodies to the virus may respond better to anti-obesity drugs. Perhaps, he guesses, such people lack any genetic predisposition to obesity, they simply had the bad luck to catch the virus, so their obesity is easier to reverse. And antiviral drugs or, eventually, a vaccine might prevent the disease altogether in such people. Dhurandhar is already working with a company, which he won't name, to develop an antiviral drug which is effective against Ad-36.

Governments should also begin screening blood donors for the virus, suggests Dhurandhar. His experiments show that the virus remains infectious in human blood even after long storage, meaning that someone could become infected after a blood transfusion.

If obesity does prove to be infectious, the researchers hope this knowledge may help erase some of the stigma that surrounds fat people. "Obese people suffer huge discrimination, and it's because of this moralistic Judaeo-Christian ethic that you must be greedy, you must not have any self-discipline, and so therefore you must be a bad person," says Atkinson. "If people understood that there but for the grace of God go they, because somebody didn't sneeze on them in an elevator-they might have a bit more compassion."

But might obese people just be trading one stigma for another? After all, most human adenoviruses are highly contagious. And Ad-36 clearly spreads easily in animals. For example, Dhurandhar can detect viral DNA in the blood of previously uninfected chickens just 12 hours after housing them in the same room as chickens carrying the virus. And birds that catch the virus in this way get fatter, just like ones that Dhurandhar inoculates directly with the virus. "They caught obesity just from being in the same room," says Dhurandhar.

So what does this mean for people who must share buses, offices and theatres with potential carriers? Should people play it safe and shun fat people even more than they do already? Dhurandhar thinks not. "The virus is highly infectious, for sure," he says. But so far he has only found antibodies to the virus in obese people, not the live virus itself. "The million-dollar question is, does the person carry the virus intact for many years or not, and are obese people carrying the virus more than lean people?" The marmosets, for example, stopped releasing live virus in their faeces after 60 days. If that's typical, people who have become fat because of the virus are likely to be long past the infectious stage, even though their blood still carries antibodies as evidence of their past infection.

As Atkinson says: "A fat person who's gotten fat because of this virus isn't going to hurt you. It's that skinny guy with a cold who's sneezing on you. Watch that guy. Discriminate against him."