Book Excerpt: Supergerm Warfare- page 4 | Science | Smithsonian

Book Excerpt: Supergerm Warfare

Dragon's drool, frog's glands and shark's stomachs have all been recruited for the fight against drug-resistant bacteria

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(Continued from page 3)

By 1993, inspired by zasloff’s original paper, dozens of other scientists had gone in search of peptides in other animals. They’d found them just about everywhere they’d looked—70 different antibiotic peptides in all—in everything from insects to cows to Komodo dragons. Intriguingly, different creatures secreted peptides from different kinds of cells. Many insects made them in their white blood cells. In horseshoe crabs, they appeared in the blood elements called platelets. In the frog, as Zasloff had determined, they appeared in a part of the nervous system called the granular glands: the frog empties these glands, Zasloff found, when the animal is stressed, or when the skin is torn. As for humans, they turned out to harbor peptides of their own: in white blood cells, in the gut and, notably for cystic fibrosis babies, in certain cells of the airway called the ciliated epithelium. Perhaps, thought Zasloff, some other animal’s peptides would make a more potent antibiotic than those of the African clawed frog—potent enough to bring investors scurrying back to Magainin.

 

One day Zasloff gave his standard stump talk about peptides to a group of scientists at the Marine Biological Laboratory in Mount Desert, Maine. John Forrest, a professor at YaleUniversity’s medical school, raised his hand to say that he’d spent 19 summers studying the dogfish shark, and, by God, if the African clawed frog had peptides, so must the shark. The shark had long been Forrest’s experimental animal model, as the frog was Zasloff’s. Small and hardy, the shark had large, simple cells and organs that made it easy to study. Best of all, when Forrest operated on a dogfish shark, he could suture it up and toss it back in a tank of dirty water, as Zasloff did with his frogs. Inevitably, the shark healed without infection. Zasloff went home with a shark stomach expecting to find peptides. Instead, he found a new kind of steroid with even stronger antibacterial action—yet another element of the innate immune system. He called it squalamine. “Hey!” he told Forrest by phone. “Send me more of those shark stomachs!”

 

Eventually, Zasloff found a way to purify shark squalamine, and switched to livers, because a commercial fishery called Seatrade in New Hampshire could Federal Express him half a ton of them a week. Zasloff himself would wheel the heavy boxes of stinking shark organs in from the loading dock, then start slinging them into a giant meat grinder. The purification process involved heating the ground livers in garbage cans like great vats of soup, skimming the squalamine-rich scum from the top, then filtering the scum through a high-tech set of steps.

 

Along with squalamines, Zasloff found other steroids in the purified gunk. He figured there were more than 12 kinds in all. Each had broad antibiotic effects, but each also seemed to target a specific kind of cell in the shark’s body. Publication of the discovery of squalamines had brought calls from around the world, and these helped focus Zasloff’s study. Several of the steroids worked as anticancer agents both in dogfish sharks and in humans. One kind even prevented lymphocytes from carrying out the AIDS virus’ orders to make more virus.

 

Certain that he had found a way to save his company, Zasloff contacted Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at NIH and, as such, the top U.S. government official involved in fighting AIDS. Fauci established a Cooperative Research and Development Agreement, or CRADA, with Magainin, and Zasloff started injecting squalamines into AIDS-infected mice and dogs and monkeys. The squalamines worked brilliantly—up to a point. They stopped the growth of the lymphocytes, just as they had in laboratory experiments. Unfortunately, as soon as the treated animals were hit with the squalamines, they stopped eating and began to lose weight.

 

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