In a way, it all started because Dr. Michael Zasloff didn't like to kill frogs.

As a high-school science student, he raised flatworms in his Manhattan bathroom. He and his wife, Barbara, preserve and frame spiderwebs as a hobby. To his mind, a frog is not more primitive than a human; it is merely different.

In his laboratory experiments, he needed female frogs' ovaries to get the large egg cells that were ideal for studying how genetic messages travel out of the cell's nucleus.

So after he operated on his African clawed frogs, he didn't "sacrifice" them as many scientists might have done. He sutured their surgical wounds and tossed them back into their murky aquariums in his laboratory at the National Institutes of Health, deciding to let nature determine their fate.

That simple decision changed the course of his career.

Even though these post-op frogs were continuously bathed in the germ-infested water, their wounds mysteriously healed. One summer day in 1986, Zasloff suddenly asked himself why. Now, a year and a half after his first tentative attempts to probe the riddle of his frogs' surprising resistance to infections, Zasloff has become a pioneer in what he confidently predicts will be "a new biology."

He has discovered magainins, a remarkable family of natural antibiotics produced in frog skin that are the key to a previously unknown set of defenses against disease. Apparently more versatile than any other class of antibiotic, they are active in the test tube against many types of bacteria as well as fungi; protozoa, including the kinds that cause malaria; and some viruses.

Preliminary research suggests they also kill certain kinds of cancer cells and may have other important biological functions.

Zasloff now has strong evidence that magainins (pronounced mah-GAY-ninz) and related substances, which chemically are short, rod-shaped protein fragments called peptides, are also present in mice and humans. And he is intoxicated by the awareness that he is fulfilling a lifelong dream, that of making a discovery in his beloved realm of genes and molecules that promises eventually to help human patients.

A skeptic who craves certainty, Zasloff chose the field of molecular biology because it offered unambiguous clues to the fundamental workings of living things. But until he found magainins, he had been saddened by a growing suspicion that his work might never yield practical medical applications.

"As a doctor-scientist, a lot of what I have done, though it's been very basic, deep in my heart it's been somehow to have an impact in man," he said. "This is the bridge for me."

The magainin defense system has "the wonderful features of a basic problem, yet it holds the promise that we'll use it in man. That's a very rare combination. It's an extraordinary position as a scientist."

Single-Minded Devotion

At 42, Zasloff is the kind of scientist that makes the frenetic seem mellow. An enthusiastic teacher, he guzzles coffee from a scorched pot in his cluttered office and bounces up and down from his chair to pull out molecular models, graphs from his latest experiment, recent scientific articles.

Then he runs up the stairs of the NIH's Clinical Center to his laboratory to demonstrate to a visitor, through a microscope, what a drop of magainin solution does to a swimming paramecium. Even while he watches the single-celled creature slowly swell and burst as the substance's action forces it to take in excess fluid, he theorizes aloud about what might be happening on a molecular level.

By the next interview, a few weeks later, he has tested the theories and come up with more leads.

The son of a dentist and an artist, Zasloff began playing with science so early that, when he graduated from elementary school, the "gift" assigned to him in the school's yearbook was a laboratory. It was an apt choice; he had already converted the small bathroom off his bedroom in his parents' apartment on Manhattan's West Side into a makeshift lab.

"I had big-league explosions in my home," he recalled. "My parents had an enormous threshold for letting me mess up my environment. I wish I was as good with my own kids."

He did not raise frogs, but he worked with chemicals and studied protozoa and bacteria. At 12, over his parents' objections, he hoarded his allowance to buy an expensive microscope. Later, as a student at the Bronx High School of Science, he was a semifinalist in a national science fair with experiments attempting to extract the chemical that allows flatworms to regenerate lost tails. "It's probably magainins," he joked.

Barbara Zasloff, a clinical psychologist who met her husband when they were undergraduates at Columbia and Barnard in the mid-1960s, said his devotion to science was single-minded even then.

"He would draft notes in restaurants on napkins of new models he was making of whatever he was interested in at the time," she recalled. "I could have saved a stack of paper napkins with his perpetual revisions of theories."

The models are a way of ordering information, and Barbara Zasloff said they allow her husband to learn from everything he does. "What I would say about Michael probably is true for every fine scientist," she said. "Nothing is wastable. Failures aren't wastable . . . He can recall data from experiments 10 years ago, little bits of data."

Zasloff said he thinks about his research -- at the moment, about magainins -- "every minute. I wake up in the morning, I think about them. I go to bed at night, I think about them." He said his wife and three daughters have grown used to listening to him talk about his work.

Leaving the NIH Nest

The discovery of magainins comes at a time when Zasloff is crossing a professional bridge. In July, he will leave his post as a branch chief at the National Institutes of Health, where he has spent most of his scientific career, to become a professor of pediatrics and genetics at the University of Pennsylvania.

He said the move is motivated by a desire for closer contact with the patients he hopes to help, and by his belief that outside the federal government he will be better able to speed the exploration of the new substances' potential as drugs.

In his new job as director of the Division of Genetics at Children's Hospital of Philadelphia, he plans to strengthen genetics research at one of the nation's premier pediatric hospitals.

The patents for magainins and several related substances belong to the government, and Zasloff hopes they will soon be licensed to a drug company. Then he will probably serve as a consultant in their development. "I'm going to see this to the bedside," he said of the discovery.

Zasloff grew up as a scientist at the NIH, and he said the decision to leave was a difficult one. The government paid for his graduate education in a combined MD-PhD program at New York University, and he came to the NIH as a research associate in 1975, fresh from a residency in pediatrics. He has headed the pediatric genetics branch of the National Institute of Child Health and Human Development since 1982.

"I've put off going to universities over the past several years because I didn't feel, scientifically, that I could do there what I can do here," he said. "At a certain point in one's career, where you really want to do daring things that people would laugh at, the NIH is terrific."

Now, however, he feels he can move his research to Penn without losing momentum, and he said he will be freer, outside the federal government, to consult with manufacturers in the magainins' development. He said he also looks forward to approximately doubling his salary -- currently about $60,000 -- and escaping from the NIH's cramped laboratory quarters, chronic shortage of secretarial help and perennial dependence on the vagaries of the federal budget.

At the same time, he expects to maintain strong ties to NIH. "I'm really proud that I was a part of this institution," he said. But he added, "I think I'm going to have more freedom. I don't want to be owned anymore. If I go, I want to go like a cowboy."

For Zasloff, the move to Penn and the discovery of magainins are variations on a single theme -- the exercise of maximum scientific freedom. It has been a way of life for him since childhood.

He has a word for it: play.

"Science is an expression of creativity," he said. "The ultimate pleasure that a scientist or a child exploring has is being given the freedom to do whatever it wants," he said. "Everything less takes away.

"It has to be wasteful. It has to be self-indulgent. You have to say, 'I'm going to do this because this is what I want to do.' Because, ultimately, it's my hand and mind that are supposed to move the problem forward. Otherwise, I'm just a technician."

Solving the Frog Riddle

Like other scientists, Zasloff is a skeptic. "I start out by not believing it," he said. "It's so easy to believe everything. You never believe yourself. You can't take yourself too seriously in this business."

His skepticism came through a few weeks ago when he was leading a teaching session for research scientists on the NIH Clinical Center's ninth-floor genetic disease ward. He raised a cautionary note on the conclusions of two recent, favorably received scientific papers on the biological basis of Duchenne's muscular dystrophy, an inherited disease.

"The biology is so obscure," he said. "They're trying to explain a disease at the point where {knowledge} is still fuzzy" even of how normal muscles work."

Afterward, he said he applies such skepticism to all research, including his own. As his wife put it: "He'd rather not have an answer than have an answer he can't trust."

It was the determination to solve a biological riddle that led Zasloff to his latest discovery. Recognizing that his frogs somehow resisted infection was a chance observation that started him down a scientific path that led to his isolation of magainins. But he had been curious for many years about whether animals might have natural, undiscovered barriers against infection.

Barbara Zasloff dates his fascination with that question to his pediatric residency, when he began to wonder why the lungs of young patients who had cystic fibrosis, a genetic disorder that produces abnormally thick mucus secretions, routinely harbored disease-causing bacteria that are rarely present in normal lungs.

To Zasloff, the more fundamental biological question was why areas of the body that are moist and constantly exposed to germs, such as the bronchi, the intestinal lining or the eye, can remain free of infection at all. "The issue of how any creature can survive is the intriguing question for him," said his wife.

His interest quickened when he read a 1981 article by a Swedish researcher, Hans Boman, describing a new family of natural antibiotics Boman had discovered in Cecropia moths. Dubbed cecropins, the new substances were peptides that disrupted bacterial membranes but did not harm the insects' own cells. "That, to me, was too beautiful," Zasloff remembers thinking. "I realized that nature wouldn't throw that away."

When Zasloff noticed the rapid healing of his frogs' wounds, he quietly began to make chemical extracts of their skin, using an adaptation of Boman's method to search for an antibacterial substance. He worked alone, confiding his hunch only to Dr. James Sidbury, a fellow pediatric geneticist at NICHD.

"He was absolutely confident," Sidbury recalled. "I didn't say anything because I've been wrong so many times. Sure enough -- boingo!"

Zasloff first isolated two short peptides, each composed of a chain of 23 amino acids, that were able to kill numerous types of bacteria. To his astonishment, they also proved active against disease-producing fungi, protozoa like those that cause malaria, and certain viruses.

But he was not yet satisfied that they were the natural antibiotics produced by the frog skin. Using modern molecular biological techniques, he isolated the genetic message from frog skin cells that coded for the two peptides, showing that they were indeed natural products rather than experimental contaminants.

Finally, he had a biochemical company make synthetic versions of the two peptides and proved that their chemistry and antibiotic action were identical to the natural versions.

Once he had that incontrovertible evidence, Zasloff announced his findings. Last August, he published his first report on the frog peptides -- which led to a wave of publicity over the discovery of these new biological agents.

Four months earlier, a group of biochemists at Cambridge University in England had reported isolating the same two new peptides, as well as others, from frog skin. But they failed to make the key discovery that these two peptides had antibiotic properties.

Zasloff dubbed the substances magainins, from the Hebrew word for shield. "Tradition would have it that he would have given it a Latin or Greek name," said Barbara Zasloff. "We both felt that he comes from a Hebrew tradition and it would be very appropriate to give it a Hebrew name."

Since last summer, Zasloff has continued to explore the biological action of magainins and several related peptides, seeking to learn more about their purpose in cells and about how they behave on a molecular level.

"The analysis of the mechanism is very critical to me," he said. "It's behaving in such a strange way, with such breadth, that unless it had a very novel mechanism I'd be very worried."

The peptides' structure allows them to twist into spiral-shaped molecules with two sides, one side soluble in fat and the other side soluble in water. Their length, just right for spanning the membrane that surrounds all living cells, led Zasloff to suspect they might form bridges or channels across the membranes of bacteria, viruses or animal cells.

Zasloff consulted Richard Feldmann, an NIH computer scientist. Feldmann used a sophisticated computer program to construct a model of how six or eight magainin molecules might line up to form a circular tube or tunnel. The outside of the tunnel would be soluble in a cell membrane, which is made of fat and electrically neutral.

The portions of the molecules facing the tunnel's interior would be positively charged, attracting negatively charged cellular components such as chloride ions. The model predicted that magainins might work by forming channels to move such ions, which are critical to cellular function, in or out of a cell.

Next, Zasloff collaborated with NIH specialists in the field of electrophysiology to test this theory. Together they designed a set of so-called "patch clamp" experiments, in which a tiny piece of cell membrane can be placed on a special instrument that measures the movement of electrically charged ions across it.

Preliminary results suggest that magainins do form channels that move chloride ions across cell membranes.

Zasloff theorizes that the ability of magainins to form such channels in some kinds of cells but not others may help explain their ability to kill disease-causing organisms without harming the animal that produces them.

"I think it's going to be what defends wet mucosa," the layer of cells lining an animal's lungs and digestive system, forming the barrier between the organism and its environment, he said.

He suggested that the evolution of magainins may be what allowed amphibians -- and perhaps other aquatic animals -- to survive in ponds teeming with bacteria and protozoa.

The fact that magainins work equally well at cold temperatures may explain why they are especially important in cold-blooded animals. The cells of the immune system -- which, in mammals, provide the major defense against infections -- require warmth to work. Zasloff said that if the body temperature of a tropical frog drops below room temperature, its white blood cells stop functioning. "The chemical {defense} system has to be very dominant in such a species," he said.

In his admiration for the beauty of such a system and for its potential role in the survival of many kinds of animals, Zasloff waxes almost mystical. "He feels as if he's observing good work, work so splendid that it was able to survive thousands, millions of years," explained Barbara Zasloff. "Pieces of it worked so well that they're repeated again and again" in different species. "It's like all of an artist's work has some similarity to itself."

A Long Way From Treatment

If preliminary evidence that magainins affect chloride transport is confirmed, the finding will bolster Zasloff's hunch that a deficiency or abnormality of a related substance in humans may someday be found to explain why children with cystic fibrosis are so vulnerable to infections. The cells lining the respiratory system in such patients show abnormal chloride transport, and measuring the chloride concentration in a child's sweat is the standard diagnostic test for the disease.

But he emphasized that much more must be learned about magainins, and extensive testing must be done in animals, before the peptides can be tried to treat disease.

All the publicity that attended Zasloff's initial report has had both amusing and uncomfortable repercussions, he said. He was feted by Jewish organizations both for the discovery itself and for his choice of a Hebrew name. He has also been besieged by patients with cancer and hard-to-treat infections who are desperate for a miracle drug that, if it ever appears, is still years away.

What's more, he has emerged as the nation's premier frog lover. From across the country has come a motley collection of toy frogs, frog statues and frog-related artifacts from wellwishers. His favorite was an honorary membership in the Watts Island Bullfrog Club, whose location was identified only by its longitude and latitude.

He said he enjoyed the recognition, especially the praise of his colleagues. But, for Zasloff, the play's the thing.

"This problem has permitted me to go completely freewheeling in the lab," he said. "It's so new. This is the most fun you can have as a scientist.

He added, "I'm somewhere between heaven and earth right now."

Rod-shaped molecules called magainin, shown in a computer model at right, are naturally occurring antibiotics discovered in the skin of frogs. Scientists theorize that magainin molecules kill enemy cells, such as bacteria or certain cancer cells, by forming a circular tunnel or doorway through the cell's outer layer, or membrane (below).

Inside the circle of magainin molecules, a tiny channel is created. Variations in electrical charges and concentrations could then cause chloride ions to either enter or leave the cell via this channel, upsetting the cell's chemistry and killing it.