Study: Sting’s venom hid fat-fighting secret

A mouse made chubby on a high-fat diet, left, stands next to a mouse that lost weight after being treated with a drug derived from sea anemone venom. COURTESY OF GEORGE CHANDY, UC IRVINE

A drug derived from sea anemone venom can make fat mice thin – with potentially powerful implications for treating obesity and diabetes in humans.

The compound, called ShK-186, not only reduced weight, but cholesterol and blood sugar as well. What's more, the drug had no effect on regular mice fed a normal diet – suggesting its effects are only triggered in mice on an obesity-inducing diet.

The discovery was recently published by a UC Irvine team, whose work has been leading up to it for 30 years; human trials of the drug's effects on obesity could begin in a few years.

"This is a drug that both affects fat metabolism and diabetes," said George Chandy, a UC Irvine physiology and biophysics professor who led the team. "There aren't any drugs that do both."

How Chandy and his science team found their way to the discovery is at least as interesting as the discovery itself.

Chandy and a colleague, Michael Cahalan, began their journey in 1984 when they traced out a molecular pathway shared by immune cells that cause multiple sclerosis, diabetes and rheumatoid arthritis.

The pathway, in fact, is a kind of superhighway for immune cells run amok. A protein called the Kv 1.3 potassium channel, which is found on the surface of one class of immune cells, allows the cells to attack.

They attack the brain, along with a nerve-insulator known as myelin, in MS patients, the pancreas in children with type 1 diabetes and the joints of rheumatoid arthritis sufferers.

The next link in the chain came in the 1990s. That was when the potentially beneficial effects from nasty stings first caught the attention of Chandy's team.

According to reports in the press and the medical literature, stings from anemones and scorpions sometimes had an astonishing effect on people with multiple sclerosis.

"One doctor from England said he had very severe MS," Chandy said. "He's taken to the Bahamas, gets into the water and is stung by a sea anemone. He comes out with his whole back full of rash, terrible pain – then, 48 hours later, surprise! This guy who could not walk could now run a mile."

Another case involved a woman with severe MS who was stung by a scorpion while vacationing in Arizona, according to a study published in the early 1980s. Her MS symptoms vanished for eight to 10 weeks.

In most cases, the effects wore off after a few weeks, though often leaving the patient with less-severe symptoms.

"We started wondering, 'What is in venoms that can do this?'" Chandy said. "Venoms are known to paralyze people, and the way they do this is by blocking channel proteins."

They began trying to find out if the venom might, just possibly, block the pathway they discovered in 1984.

"We started playing around with scorpion toxins," he said. "We found one that blocked Kv 1.3."

Things began to move more quickly. A Cuban researcher had isolated a sea anemone peptide, a type of amino-acid compound; other colleagues of Chandy's, including Michael Pennington, created a synthetic version that hit pay dirt.

It was "so potent," Chandy said. "Kv 1.3, it just hammers it."

They were hot on the trail that would lead to the big discovery. But there was one nagging problem. The peptide not only attacked the channel they were after, on immune cells called effector memory T-cells. It attacked brain channels as well.

"The peptide was very potent, but not selective," he said. "I spent 10 years with Mike Pennington trying to make it selective, so that it only blocked the Kv 1.3 channel on the effector memory T-cells, without touching the brain."

The answer turned out to be a kind of molecular attachment: another amino-acid called L-phosphotyrosine.

The anemone peptide was now tamed, Chandy said.

"It suddenly became very selective," he said, attacking only the Kv 1.3 channel.

"It took us 10 years, but actually, to be honest, it was a mistake," he said. "We discovered it by random chance."

A Seattle company, Kineta Inc., licensed the compound from Chandy and his team and began trying to develop it into a drug to combat auto-immune disease.

The next revelation came from Kineta's lab.

"About a year ago, they noticed something really funny with monkeys," Chandy said. "When you give them the drug, the monkeys seem to have lowered cholesterol."

A post-doctoral researcher who had just joined Chandy's lab, Sanjeev Upadhyay, suggested testing the compound on mice.

A different science team, from Yale, had previously found that mice with genes for the Kv 1.3 channel knocked out of their DNA failed to gain weight, despite being placed on high-fat diets.

"This champ joins my lab and says, 'Why don't we just take mice, put them on a junk-food diet, high fat – McDonald's burgers, fructose, corn syrup in Coke – give them our drug, and see what happens.'"

The fattened animals lost nearly 30 percent of their weight in 10 weeks.

Chandy split the mice into two groups, one that received the drug and one that received only saline injections.

"The ones given saline got fatter and fatter," he said. "The ones given the drug stopped gaining weight."

The fat mice that became diabetic also saw diabetes symptoms disappear when given the drug.

Animals that were "good-looking, thin mice," meanwhile, were put on a healthy diet, and given the drug once more.

The drug had no effect. Apparently, only a junk-food diet could make the mice sensitive to the drug.

Chandy believes the compound works by activating the body's brown fat, which can burn away calories, helping to reduce the white fat that accumulates in the belly and in the liver.

Testing on humans can potentially leap ahead of the normal, lengthy approval process, he said. Trials already conducted by Kineta, part of its effort to test the drug on auto-immune disease, have proven that the drug is safe for humans.

Chandy said he hopes his discovery won't lead to fad diets.

"I'd like it to be used for people who are really obese – cardiovascular risk, stroke risk, diabetes risk – to try and get them over the hump, while they are changing their lifestyle," he said. "Patients who need stomach stapling: We (could) give them the drug for about six months while we coach them to change their diet and start exercise, and change their lifestyle."

Though no one knew quite where it would lead when they began, the UC Irvine team's scientific pursuit ends up sounding a little like a detective story.

"It's been a fun 30 years," Chandy said.

When he started his career, he had to make a choice between becoming a practicing physician and conducting basic research.

"I made this calculation that a physician normally serves about 100,000 people in his or her lifetime," he said. "And I had a dream that if I could treat more than 100,000 people, through a discovery like this, then my life would be useful."

The study, "Selective Kv 1.3 blocker as therapeutic for obesity and insulin resistance," was published in the Proceedings of the National Academy of Sciences on June 11. Authors included Sanjeev Kumar Upadhyay, Kristin L. Eckel-Mahan, M. Reza Mirbolooki, Indra Tjong, Stephen M. Griffey, Galina Schmunk, Amanda Koehne, Briac Halbout, Shawn Iadonato, Brian Pedersen, Emiliana Borrelli, Ping H. Wang, Jogeshwar Mukherjee, Paolo Sassone-Corsi and K. George Chandy. The paper was edited by Michael D. Cahalan.

Contact the writer: 714-796-7865 or

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