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NIDDK's Daly Delivers NIH Director's Lecture, Jan. 21

On Jan. 21, the NIH Director's Lecture series will feature internationally known chemist/pharmacologist Dr. John W. Daly speaking on "Natural Products: Impact on Biomedical Research," at 3 p.m. in Masur Auditorium, Bldg. 10.

Now a scientist emeritus in the National Institute of Diabetes and Digestive and Kidney Diseases, Daly was chief of NIDDK's Laboratory of Bioorganic Chemistry, a laboratory he founded and headed from 1981 to 1997. Natural products discovered through the research of Daly's lab, primarily alkaloids derived from amphibian skin, have had a major impact on knowledge of how the nervous system functions and how drugs interact with the nervous system.

Dr. John W. Daly
During Daly's 40-year tenure at NIH, his numerous accomplishments have included: the discovery of the "NIH Shift" — an unexpected molecular process involved in the conversion of the amino acids phenylalanine and tryptophan to the important neurotransmitters dopamine, norepinephrine and serotonin; the discovery that forskolin, from the Indian medicinal plant Coleus forskohlli, is a potent activator of adenylyl cyclase, an enzyme responsible for the formation of the intracellular messenger cyclic adenosine monophosphate (cyclic AMP) from ATP; the demonstration that the central stimulant effects of the alkaloid caffeine are due to blockade of adenosine receptors; the discovery and introduction of batrachotoxin as a specific activator of sodium channels in nerve and muscle, and of epibatidine as a potent analgesic acting through nicotinic receptors; the discovery and characterization of over 600 new biologically active alkaloids from the skin of poisonous frogs in the forests of Central and South America, Madagascar and Australia.

Daly's University of Maryland collaborator Edison Albuquerque says of him, "Daly was for the expression of molecules what Darwin was for the evolution of man."

Daly describes himself as "a pharmacologist with a strong background in chemistry." Born and reared in Portland, Ore., he received his bachelor's degree in biochemistry and his master's degree in organic chemistry at Oregon State College. After completing his Ph.D. in organic chemistry at Stanford University in 1958, he came to NIH as a postdoctoral chemist in Dr. Bernhard Witkop's Laboratory of Chemistry, where he studied the inactivation of catecholamines along a methylation pathway, mentored by future Nobel laureate Dr. Julius Axelrod. From the beginning, Daly was interested in the discovery of "small molecules" as research tools, in particular for research involving the function and diseases of the central nervous system.

Two years after his arrival, he joined the permanent staff at NIH. In 1965, Dr. Gordon Guroff of the National Heart Institute was puzzled by results obtained while working on an assay for phenylalanine hydroxylase, an enzyme involved in the metabolic disease phenylketonuria. Discussions and collaboration with Daly led to the discovery of intramolecular hydrogen migration during enzymatic hydroxylation of aromatic compounds, a phenomenon that was to be named the "NIH Shift." This discovery opened an entire new field of research, allowing Daly's former close collaborator on the mechanism of the "NIH Shift," Dr. Donald M. Jerina, to delineate the metabolic pathways that form dihydrodiol carcinogens from the polycyclic hydrocarbons found in cigarette smoke and automobile exhaust. Currently, Jerina's group in NIDDK is showing how these dihydrodiol metabolites react with DNA and interfere with repair mechanisms, potentially providing insights into how to prevent chemical carcinogenesis.

Daly's pioneering discovery of the enzyme target for the plant diterpene forskolin changed the course of pharmacology by providing researchers with a selective tool for studying the second messenger system that generates cyclic AMP, itself a key regulator of physiological functions in all cells.

In 1963, when his lab chief Witkop needed someone to collect poison dart frogs in western Colombia and investigate the nature of the toxins in such frogs, Daly proved to be the perfect choice. The batrachotoxins in the extracts he brought back were shown to have unique structures and to be specific and potent activators of sodium channels responsible for nerve conduction. Batrachotoxin and a radioactive analogue (batrachotoxinin-A benzoate) developed by Daly's group have been used in hundreds of studies to better understand the function of sodium channels and how they are affected by other agents.

A career-long collaboration between Daly and field biologist Charles Myers, begun in 1966, led to the discovery of several new species of poison frogs and hundreds of new bioactive alkaloids. One trace alkaloid from an Ecuadorian frog, epibatidine, was shown by Daly's group to be 200 times more potent than morphine, and just as effective as a pain-killer. Moreover, because epibatidine acts through nicotine rather than morphine receptors, it has the potential for pain relief without the addiction and tolerance associated with opiates. An analogue has been in clinical trials for the treatment of chronic pain. In a recent review, noted nicotine researcher Richard Glennon said, "It is difficult to say where nicotine research would be today without the discovery of epibatidine."

Daly is currently tracing the sources of these frog skin alkaloids through to their diet of insects and other arthropods. "We now realize that the frogs are really the true bioprospectors," he says, being careful to give credit where credit is due. "Without the frogs, hundreds of bioactive insect alkaloids would remain undiscovered, and possible sources for genes responsible for the biosynthesis of such alkaloids would be unknown." Among his many collaborators, NIDDK chemists Drs. H. Martin Garraffo and Thomas F. Spande continue to contribute much to the research on the frog alkaloids.

Author of over 500 research papers, a book (Cyclic Nucleotides in the Nervous System) and many book chapters, Daly was elected to the National Academy of Sciences in 1997. Among his many other honors are: the Hillebrand Award from the American Chemical Society in 1978, the Research Achievement Award from the American Society of Pharmacognosy in 1997, the Karl Wilhelm Scheele Award from the Swedish Academy of Pharmaceutical Sciences in 1999 and in 2002, the American Chemical Society's Ernest Guenther Award in the Chemistry of Natural Products. That same year, he was also named among the 200 most-cited pharmacologists in the world.

For sign language and reasonable accommodation, or for more information, call Hilda Madine, (301) 594-5595.

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