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'Roots of Chemistry at NIH' Revealed

By Sharon Ricks

Nobel Laureate Julius Axelrod and 100 government, academic and industrial scientists gathered at the Natcher conference center recently to celebrate the "Roots of Chemistry at NIH" and NIDDK's Dr. John W. Daly's 40-year career.

"What his life and this symposium demonstrate is the essence of what makes good science," said NIDDK Scientist Emeritus J. Edward Rall. "This symposium and John's life demonstrate that basic science is fun and, in the long haul, profitable."

The symposium opened with remarks by Dr. Phil Skolnick, one of Daly's former postdocs who now works at Eli Lilly and Co. Skolnick said Daly has made remarkable contributions to the biologist's toolbox. He cited Daly's studies on adenosine's role as a transmitter in the central nervous system and his discovery that adenosine receptors can be physically labeled. He also praised Daly's work on the behavioral actions of methyl xanthines and his discovery that forskolin, a compound from a medicinal plant, can activate adenylyl cyclase.

Symposium honoree Dr. John Daly tries out an authentic poison dart blowgun, a gift from Dr. Bernhard Witkop presented by Dr. Julius Axelrod.

"Daly was for the expression of molecules what Darwin was for the evolution of man," remarked Dr. Edson Albuquerque, chairman of the department of pharmacology and experimental therapeutics at the University of Maryland's School of Medicine and a collaborator with Daly for 25 years.

In the 1960's, Daly began to hunt the Central and South American rain forests for poisonous neotropical frogs whose skins proved to be filled with novel biologically active compounds. His work has led to the discovery of more than 400 alkaloids in over 20 structural classes. Many are widely used as research tools for studying nerve and muscle function.

In 1978, Daly found that one of these alkaloids, epibatidine, is 200 times more effective than morphine as a painkiller. "Certainly, when Daly got interested in these crazy frogs, he had no idea that the secretions would possess a compound with analgesic properties," said Rall, who was NIDDK scientific director then. "You don't know where basic research is going, but if you've got people who are smart and think it's fun and work day and night, something is going to happen."

At the time, Daly could not obtain quantities necessary to determine the structure, so the original trace amount sat in a freezer for 13 years. In 1991, the power and sensitivity of nuclear magnetic resonance allowed Daly and his colleagues to determine the structure of epibatidine. They found that its analgesic action occurs via nicotinic receptors. Recently, researchers at Abbott Laboratories announced the development of an experimental drug with a chemical structure similar to epibatidine. This new painkiller is in early human safety testing in Europe.

"The breadth and significance of his discoveries is dazzling, especially when you consider that most of it spawned from an esoteric interest in the skin of exotic frogs," said Dr. Michael Gottesman, NIH deputy director for intramural research, who added that such "arcane research" might not have been easily funded extramurally at NIH. "He is a very successful example of what we wish to foster in the intramural program and the perfect example of the type of scientist NIH will need to find more of, if we're going to succeed in the future in creating multidisciplinary groups to attack complicated problems."

Daly said he came to NIH in 1958 because he wanted a career in biomedical research. He joined Dr. Bernhard Witkop's Laboratory of Chemistry in the National Institute of Arthritis and Metabolic Diseases, now NIDDK, as a postdoctoral fellow. Axelrod had a strong, seminal influence on Daly's career as a chemist/pharmacologist. "Julius took a naive chemist and taught him how to think about science," said Daly. He and Axelrod collaborated on studies on the methylation of catecholamines. "John somehow drifted to our lab, and I was struck by his intense interest in research," said Axelrod, who won the 1970 Nobel Prize in Medicine for discoveries on catecholamines as transmitters in nerve terminals. "Over the years, I have valued his advice on chemical problems."

During the 1980's, Daly was among the 100 most-cited scientists worldwide as documented in Current Contents. In his 40-year career, he has published 500 papers and written 75 chapters and a book. "What makes John tick?" asked Gottesman. "What has made him so creative and productive over these years? Those who know him know it's not an ego trip or name recognition, and considering what industrial chemists make today, I'm sure he didn't stay at the NIH because of the money you could make here. The important thing for John is the joy of the discovery, be it a new species of frog, the NIH Shift [a novel migration observed in deuterium, tritium, halogens and alkyl groups with arene oxides identified as the reaction intermediates] or 400 new alkaloids in 20 structural classes. Our thanks go to John for serving as a model chemist and a model NIH scientist."

"It is a great honor," Daly said about the symposium. "I am kind of overwhelmed. I'm a private person. I am more at home on the jungle trail or in my boat. I'm known to avoid social gatherings, but this is a special one. My life has prospered because of your contributions, and I hope yours has prospered because of mine."

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