Furthering Franklin's Legacy

Eyewire © 2000 Harkening back to mid-18th century science, Clay M. Armstrong, professor of physiology at the University of Pennsylvania School of Medicine, tied his ground-breaking research on the ion-channel gating mechanism to Ben Franklin's famous kite and key theories as he accepted the 2000 John Scott Award on Nov. 17. The award's advisory committee also recognized Adriaan Bax for his development of nuclear magnetic resonance spectroscopy applications and Mary-Dell Chilton for her research that enabled the production of genetically engineered plants. It was particularly suitable that Armstrong called on the memory of Franklin because the John Scott Award, which is administered by the Philadelphia Board of Directors of City Trusts, was created to forward Franklin's legacy. Armstrong explained to the audience gathered at the College of Physicians in Philadelphia the connection between his research and electricity research begun more than 200 years ago: When Franklin postulated that lightning is a large electrical spark, Italian researcher Luigi Galvani used that theory to extend his experiments with the stimulation of frog legs. Galvani took frog legs outside during an electrical storm to see if they would twitch, and he found that indeed, they did. Soon Galvani discovered that the storm was unnecessary, however, and he could make the legs hop by connecting them to a copper hook on an iron rail. This he considered the manifestation of animal electricity. But another Italian, Alessandro Volta, soon suggested that the source of the electricity was not animal electricity but in fact the metal-to-metal contact, and, of course, he was right. Volta went on to develop the electrical battery. But Galvani was, in a way, also right, Armstrong said. Clay M. Armstrong "There is animal electricity. Electrical voltages are produced by all living cells," he said. "I simply can't imagine any of us without the activity of these ion channels." For almost 40 years, Armstrong has worked to unveil the mechanisms governing how ion channels--the body's equivalent of an electrical switch--behave. His work has been key to understanding the electrical underpinnings of the nervous system.1 All cells have a membrane voltage, which is needed to keep them from swelling to infinite volume from osmosis, he explained. Based on this, special proteins in the cell membrane, the ion channels, evolved a means of changing voltage suddenly and generating voltage signals. "I submit that these channel proteins are the most interesting proteins in the body," said Armstrong. "They're the ones that give us all of the characteristics that I think excite us the most." Touch and hearing are made possible by channels that are gated by mechanical pressure, Armstrong commented. Smell and taste are mediated by channels that are chemically gated; and vision, he said, results from gated channels that are operated indirectly by photons. "Every sensation, every movement, every thought, every heartbeat is governed by the activity of ion channels," said Armstrong, who also won the 1999 Lasker Basic Medical Research Award.2 Armstrong started studying gated channels in the early 1960s, after Nobel Prize-winning nerve impulse research by Alan Lloyd Hodgkin and Andrew Fielding Huxley3 inspired him to leave clinical practice for a life in science research. He has worked ever since to answer questions spurred by Hodgkin's and Huxley's research regarding how ions pass through membranes, how membranes select between sodium and potassium ions, and how membranes can change permeability. He was gratified when Roderick MacKinnon and colleagues crystallized the simple potassium ion channel in 1998,4 effectively confirming a theory of ion selectivity proposed by Armstrong and Francisco Bezanilla. Today, Armstrong is still pursuing ion channel research, trying to answer the big question in his area: What is the structure of voltage-gated ion channels? "The simple potassium ion channel that Rod crystallized does not have the fancy mechanism of voltage gating," Armstrong said. Gated ion channels detect transmembrane voltage charges and open and close the membrane accordingly. They are, Armstrong said, the key to how nerve impulses are produced. Adriaan Bax Nuclear Magnetic Resonance Spectroscopy Protein structure research is also the focus of Bax's work. In developing powerful new methods for using nuclear magnetic resonance (NMR) spectroscopy, Bax enabled the determination of atomic-scale structures of the proteins essential to life. Knowing the three-dimensional structure5 of these proteins provides the basis for understanding their function, and this knowledge is essential to predicting and modifying the properties of all living organisms. Through his ongoing research, Bax helped make NMR, which measures the effects of a large magnetic field on the nuclei of atoms associated with biological molecules such as proteins, a powerful tool to understand biology with potential for solving problems in medicine. Bax is also responsible for developing assignment procedures based on isotopes of hydrogen, carbon, and nitrogen that elucidate protein research. One of the most cited chemists6 in the entire literature of science, he is chief of the section on biophysical NMR spectroscopy at the National Institutes of Health. In accepting his award, Bax attributed his success in research to luck, at least in part. "It's not so much intelligence or deep thinking that has really helped me. It's really a long string of lucky events," he said. In explaining the turns in his career, he expressed particular gratitude to his colleagues for using the techniques he developed. "Methods are useless until put to use. Fortunately, my colleagues have put them to use. I am indebted for this," he said. Mary-Dell Chilton Chilton's Research Benefits For Chilton, evidence of how her research has been used is becoming increasingly widespread. She developed the process that enables the production of genetically engineered plants. Her research made it possible to grow crops with improved yields, resistance to insects and disease, and the ability to withstand adverse environmental conditions. But when Chilton started her research into crown gall disease back in the 1970s,7 such practical results were unimaginable. Crown gall disease causes serious damage to crops when the bacterial pathogen, Agrobacterium tumefaciens, enters the plant and causes uncontrolled cell division. Chilton focused her research on identifying the bacterial genes responsible for the disease, and determining the mechanism of their transfer to the plant cell. Drawing on findings that the genes are located on plasmid DNA, Chilton and colleagues carried out a series of experiments that demonstrated that a region of the bacterium plasmid is in fact incorporated into the chromosome of the infected plant. Much further research was required before it was possible to exploit this natural system of gene transfer to introduce other genes into the plant that, instead of producing tumors, would produce desirable traits. In 1983, Chilton and colleagues published a landmark paper demonstrating how plants could incorporate foreign genes and transmit them to their progeny.8 Since then, she has worked with genetic engineering techniques to make the tumor-inducing plasmids a powerful tool for the genetic modification of plants. In accepting her award, Chilton, senior staff scientist at Novartis Agricultural Biotechnology Research Inc., expressed gratitude for the recognition that gene transfer technology has received, and hope that it will benefit the environment. "We know that plants have the natural ability to pick up and incorporate genes. The process is probably the same one that plants use to repair genetic damage. I hope that people who share my concerns about the environment will come to agree with the technology for gene transfer in plants is a clean, safe and natural process." Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor for The Scientist. References 1. (A) F. Bezanilla, C.M. Armstrong, "Inactivation of sodium channel.1. Sodium Current Experiments," Journal Of General Physiology, 70: 549-66 1977 (Cited in 513 papers). (B) C.M. Armstrong, F. Bezanilla, "Inactivation of sodium channel.2. Gating Current Experiments," Journal Of General Physiology, 70:567-90, 1977 (Cited in 544 papers). 2. E. Russo, "The 1999 Lasker Awards," The Scientist, 13[21]:1, Oct. 25, 1999. 3. A.L. Hodgkin, A.F. Huxley, "A quantitative description of membrane current and its application to conduction and excitation in nerve," Journal of Physiology-London, 117:500-44, 1952 (Cited in about 5,600 papers). 4. J.H.M. Cabral et al., "Crystal structure and functional analysis of the HERG potassium channel N terminus: A eukaryotic PAS domain," Cell, 95:649-55, 1998. 5. (A) L.E. Kay et al., "Practical aspects of 3D heteronuclear NMR of proteins," Journal of Magnetic Resonance, 84:72-84, 1989 (Cited in 233 papers). (B) L.E. Kay et al., "3-domensional triple-resonance NMR-spectroscopy of isotopically enriched proteins," Journal of Magnetic Resonance, 89:496-514, 1990 (Cited in 429 papers). 6. (A) A. Bax, D.G. Davis, "MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy," Journal of Magnetic Resonance, 65[2]:355-60, 1985 (Cited in 2,648 papers). (B) A. Bax, M.F. Summers, "H-1 and C-13 assignments from sensitivity-enhanced detection of heteronuclear multiple-bond connectivity by 2D multiple quantum NMR," Journal of the American Chemical Society, 108:2093-4, 1986 (Cited in 2,030 papers). 7. (A) B. Watson et al., "Plasmid required for virulence of Agrobacterium-Tumefaciens," Journal Of Bacteriology, 123:255-64, 1975 (Cited in 480 papers). (B) M.D. Chilton et al., "Stable incorporation of plasmid DNA into higher plant-cells-molecular-basis of Crown gall tumorigenesis," Cell, 11:263-71, 1977 (Cited in 529 papers). 8. M.W. Bevan et al., "A chimaeric antibiotic-resistance gene as a selectable marker for plant-cell transformation," Nature, 304:184-7, 1983 (Cited in 181 papers). For more information on the John Scott Award, go to www.eugenegarfield.org, and click on "John Scott Award."

Furthering Franklin's Legacy

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