Maybe it's their restricted quarters, their bland diet or their monotonously comfortable lifestyles.
But researchers have puzzled for more than a decade over why the vividly colored poison dart frogs, which secrete a variety of noxious and even deadly alkaloids when they are born in the wilds of Central and South America, are about as toxic as Sesame Street's Kermit when hatched in captivity.
Baltimore's National Aquarium, which has an internationally known breeding program for the creatures, has even released some of its captive-bred and therefore toxin-free poison dart frogs to scamper among the foliage of the walk-through rain forest exhibit, officials said.
To try to uncover the missing ingredient the frogs need to produce their venoms, researchers have hatched their eggs under special full-spectrum sunlamps, originally designed to treat people with depression. The amphibians have been given PTC the run of large outdoor enclosures called "vivariums" in Hawaii to test the role of environmental stress.
They've been injected with liquid from the stomachs of wild frogs, to see if some rare protozoan helps produce the venoms. They've even been fed free-range ants flown in from the wilds of Central America, to determine whether the insects might contain some substance crucial to the process.
"Our bottom line, after several years of working on this question of why they don't produce the alkaloids in captivity, is we don't know," said Dr. John W. Daly, chief of the bio-organic chemistry laboratory at the National Institutes of Health in Bethesda.
"It's a fascinating question," said Dr. Daly, who along with Jack Cover, director of the rain forest exhibit at the National Aquarium, has studied specimens from each of the 19 poison dart frog species raised at the Aquarium. "It's something that has evolved in these frogs and is important for their survival," but vanishes in the first generation raised outside its natural habitat.
Take the Tyrannosaurus rex of the frog world, Phyllobates terribilis -- Latin for "terrible frog."
Most poison dart frogs produce alkaloids potent enough to sicken any predator bold enough to try to eat them.
But a few species are deadly. P. terribilis -- discovered by Dr. Daly and his longtime collaborator, Charles W. Myers, a herpetologist with the American Museum of Natural History in New York -- can secrete enough highly potent toxins to kill several hundred people. The Choco Indians in Colombia simply wipe their blow-gun darts on the frog's back to make their projectiles lethal.
In captivity, though, even this ferocious frog is born to be mild.
Dr. Daly and Mr. Cover have written an article formally documenting some of their research into this puzzling phenomenon, based on work with poison dart frogs raised at the Aquarium, for a future edition of the scientific journal Toxicon.
Scientists have known for more than a decade that captive frogs produce no poison. Amateur herpetologists who collect the frogs soon recognize that their captive-bred animals lose their sting.
The mystery of the missing frog poison isn't just an intellectual puzzle. Dr. Daly spends a lot of time traipsing around Latin America trying to capture these frogs so he can study the 300 alkaloid compounds produced by about half the 135 species.
(Despite their family name, half the poison dart frog species produce no poisons at all, even in the wild).
Breeding poison-producing frogs in the laboratory would give Dr. Daly a reliable source of these chemicals, including some rare compounds with chemical structures that have not yet been deciphered.
These substances may one day be a source of new drugs. Dr. Daly and the National Institutes of Health have just patented a poison dart frog alkaloid compound, called Epibatidine, which acts as a pain killer that is many times more powerful than morphine. The NIH hopes to persuade a drug company to manufacture the substance.
Since the loss of toxins was first discovered, researchers have settled on two basic theories to explain it.
Dr. Daly said one theory holds that the wild diet may include some "co-factor," an organism or other substance that is not an alkaloid itself but is needed to produce the frogs' alkaloids. The other theory suggests the frogs need some kind of environmental trigger to produce the toxins, such as a combination of sunlight and variable temperatures, or the stress of hunting for food.
The diet theory "certainly remains a good possibility," Dr. Daly said."That's because the insects they eat in the wild will have their guts full of who knows what." The captive-raised crickets, fruit flies and ants fed to poison dart frogs in terrariums eat rabbit pellets or some other commercial feed.
The environmental stress idea intrigues Dr. Daly, because captivity restricts the frogs' complex behavior.