SCIENCE & TECHNOLOGY
DALY'S ADVENTURE N I H scientist has trekked the world to chronicle nature's own chemistry but now faces toughest road IVAN AMATO, C&EN WASHINGTON
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this month, his choice of sandals and shorts showed off athletic legs that have taken him to many faraway places in search of nature's chemistry. Daly retired in 2002—without really retiring—and is now a scientist emeritus at NIDDK. With written assurance from Gershengom and approval by N I H leadership, Daly arranged to retain an office, lab space, secretarial assistance, and the continued collaboration of two longtime staff chemists. H. Martin Garraffo and Thomas F. Spande have been with Daly, elucidating structures of hundreds of natural products, for 19 and 26 years, respectively.
W h a t bothers Daly most about these of Building 8 on the campus of the Natroubling times is that it has placed a hold tional Institutes of Health in Bethesda, on his relentless quest to uncover some of Md., stands an aging General Electric nature's most ostentatious chemical invenfreezer crammed with hundreds of tions: molecules with often scientifically vials. Housed in this single appliance is useful and sometimes deadly biological the most comprehensive and hard-won consequences that he and others have found collection offrogskin secretions in the world in frogs and other amphibians as well as arTHIS ARRANGEMENT is how Daly has kept The chemicals in some of these vials have thropods and the occasional bird. Evidence himself in the game when most scientists his sparked research wildfires. One inspired age really do retire. His love for biology an analgesic drug development program showed up as a kid in Portland, Ore., at a major pharmaceutical company. where he collected frogs and garter Some became workhorse molecular tools snakes in his backyard. His mastery of for biologists studying cell receptors and chemistry came later when he earned ion channels. The structures and value of degrees in biochemistry and organic others remain unknown. chemistry at Oregon State University and then at Stanford University. For They are the trophies that chemist, his Ph.D. dissertation at Stanford, he pharmacologist, and chemical ecologist worked out the structure of a terpene John W. Daly has been finding around alcohol in peppermint oil. After that, in the world for more than 40 years, and 1958, his supervisor helped him secure they have made him famous in the field a postdoctoral position at N I H in the of natural product chemistry. "For amLaboratory of Chemistry led by Bernphibian natural products, his work is hard Witkop. simply the best there is," saysJon Clardy of Harvard Medical School, where There, Daly had two career-definClardy investigates, among other things, ing experiences: He developed experichemicals made by marine sponges, mental skills in pharmacology while moths, and microbes. working under the tutelage of the late Julius Axelrod, who would share a NoEven so, Daly—a chemist's Indiana bel Prize for his research on the neuJones of sorts who has trekked in rain rotransmitter norepinephrine. Equally forests and other amphibian-rich venues fateful was Witkop's request to Daly in from Colombia to Thailand to Mada1963 to run a research errand: Go to the gascar to Australia—now finds himself Colombian rain forests to harvest and at the most perilous crossroads of his TREASURE CHEST Natural product chemist chemically characterize skin secretions career. In May, Daly was told by Marvin Daly shows off the world's most extensive of frogs that Indians there were using C. Gershengom, the scientific director collection of amphibian skin secretions, which is to poison their darts. From this came of the National Institute of Diabetes & stored in this freezer at NIH. the discovery of the batrachotoxins, a Digestive & Kidney Diseases (MDDK), unique class of sodium-channel activators. that funding for his laboratory there would of Daly's productivity is all over his cramped After reading about that discovery in be zeroed out at the end of this fiscal year office. Every shelf and surface is overfilled Medical World News in 1966, Charles W. because of budgetary constraints. Ever since, with laboratory and field notebooks with Myers, then a herpetology graduate student Daly and many of his collaborators and coldates spanning a half-century, manuscripts studying the reptiles and amphibians of leagues have been desperately trying to conin various stages of completion, posters with Panama, wrote to Daly. He suggested the frogs overlaid with chemical structures, vince the leadership at NIDDK and N I H to two collaborate on a study ofpoison frogs in stacks of current reprints, and chemical reverse the decision. At press time, there was Panama. "Myers became my mentor in the samples and biological specimens. talk of relocating Daly's research program field," Daly says. He adds that Myers helped to another N I H institute, but there's still no At 73, Daly is lanky with a gray-bearded him appreciate the biological, ecological, and final verdict on whether this will be Daly's face often framed by his gigantic, blackevolutionary contexts that go along with last summer of research at N I H . frame reading glasses. On a warm day earlier N A CLAUSTROPHOBIC HALLWAY NOOK
"For amphibian natural products, his work is simply the best there is." 36
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the pure chemistry of natural products. I Seeking to understand these contexts and to find new agents for biomedical research has driven Daly's work ever since. Daly's brand of retirement includes publishing papers regularly—13 in the past 18 months. He also hasn't put an end to his lifelong series of dozens of natural-product hunting adventures. Two months ago, he traveled to Costa Rica with herpetologists Maureen A. Donnelly and Ralph A. Saporito of Florida International University to investigate the flow of alkaloids from specific ants and other arthropods to the frogs that feed on the arthropods. With his name on more than 600 published papers, a handful of patents, and a long list of awards and honors—among them induction into the National Academy of Sciences and the symposium "Roots of Chemistry at NIH," which was dedicated to Daly on his 65th birthday—it would take a book to chronicle his scientific accomplishments. Consider a paper that Daly, Spande, and Garraffo published in theJournal of Natural Products (2005,68,1556). It is titled "Alkaloids from Amphibian Skin: A Tabulation of Over Eight Hundred Compounds," and the authors have had a hand in identifying virtually all of those alkaloids. Amid this bounty of chemical diversity, a few discoveries stand out even to Daly "Epibatidine is by far the most important because it has had such an impact on nicotinic receptor research," Daly says, referring to a I OFFICE
class of cellular receptors in brain and other tissues. First isolated in tiny quantities from the poison kogEpipedobates tricolor during a 1974fieldtrip with Myers to Ecuador, Daly observed in a routine pharmacology test that | a mouse injected with the extract arched its | tail over its back. Daly recognized that this 1 was the "Straub tail," a reaction associated I with opioids, not with any of the frog alkaloids he had been working with. It took a second trip to collect enough frogs to allow isolation of about a milligram of the active principle, which the researchers named epibatidine. Daly showed that epibatidine indeed was not an opioid, yet it was 200 times more potent than morphine as an analgesic. The full structure remained a challenge until years later when the increased sophistication of nuclear magnetic resonance spectrometry techniques allowed Daly and colleagues to establish the nicotine-like structure of epibatidine and report it in 1992. Within a year, the laboratory of Harvard University organic chemist and Nobel Laureate E.J. Corey had synthesized both enantiomers of epibatidine and offered Daly these and three analogs. The gift enabled Daly and colleagues to determine that epibatidine owed its analgesic activity to its potent stimulatory effect on nicotinic receptors. That finding, along with epibatidine's structure, inspired medicinal chemistry programs aimed at developing powerful new analgesics, including one at Abbott Labora-
POLITICS
Daly's Future At NIH Remains Uncertain
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ohn W. Daly, a retired yet actively researching bioorganic chemist at the National Institute for Diabetes & Digestive & Kidney Diseases, first heard the bad news during a meeting on May 11 with Marvin C. Gershengorn, NIDDK's scientific director. That's when Daly, who is universally credited as the world leader in amphibian natural product chemistry, was told that funding for his modest research program would end with the fiscal year. Without delay, Daly and outraged collaborators and colleagues began lobbying the leadership at NIDDK and its parent, the National Institutes of Health, to reverse the decision, which includes shuttering two other NIDDK research programs. In a typical tetter of protest, this one to Michael M. Gottesman, NIH's deputy director for intramural research (a copy of which was sent to NIH Director Elias A, Zerhouni), James E Barrett, president of
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the American Society of Pharmacology & Experimental Therapeutics, wrote that Daly's "program is among the best in the world in providing a model for 'drug discovery' from nature." Gershengorn told C&EN that the funding cut affecting Daly is part of austerity measures made necessary by tough budget realities. As an emeritus scientist, Daly would continue to receive NIDDK support for what Gershengorn calls "the typical package"— an office and secretarial assistance. But additional funds to pay for research, including two staff scientists, would be discontinued or applied elsewhere. Indications at C&EN press time suggest that the cry to save Daly's tab may succeed. On June 16, Daly says he learned from Griffin P. Rodgers, NIDDK acting director, that efforts are afoot to transfer his research program, including his two staff scientists, to another institute at NIH.
DOCTOR FROG Epibatidine From the frog species Epipedobates tricolor, Daly made one of his most prized natural product discoveries: epabatidine.
tories from which emerged the promising compound ABT-594. This compound is far more potent than morphine as a painkiller but later proved to have unacceptable side effects. Even so, epibatidine has become one of the most important molecular tools for scientists studying the biological role of nicotinic receptors. ANOTHER RESEARCH standout for Daly was his isolation of batrachotoxin from poison dart frogs of Colombia. With this isolated alkaloid—and crystallographic data supplied by Isabella Karle of the Naval Research Laboratory—Daly and his first postdoctoral colleague, Takashi Tokuyama, were able to establish the compound's structure. In the 1970s, after Daly and electrophysiologist Edson X. Albuquerque at the University of Maryland, College Park, revealed batrachotoxin to be a potent and specific activator of sodium channels, the agent became a widely used tool for probing interactions of anesthetics, anticonvulsants, and antiarrhythmia agents with these channels. Daly has always been fascinated by the biological and chemical ecological significance of the compounds he has been discovering. That's why one of his more recent research foci has been to track down the ecological sources of some of the toxins. "I was originally resistant to the dietary source idea," he says, referring to the possibility that the alkaloids are derived from dietary sources rather than made by some biosynthetic process within the amphibians' own cells. Now for over a decade, he and coworkers have been chronicling how poison frogs accumulate their skin alkaloids from alkaloid-containing arthropods, most notably ants, but also from beedes and millipedes. As Daly even now forges new collaborations and looks forward to new studies, NIDDK's decision to cancel his research funding leaves a bitter taste, like that of the alkaloids he has at times quickly detected in the field using a taste test. "No good science goes unpunished," reads a note on his office door. With the momentum building at N I H in mid-June to keep his lab up and running, however, he is feeling confident that his days of thrilling chemical sleuthing are not yet so numbered. • C & E N / J U N E 2 6 , 2006
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