The three-foot-high sculpturette of some 20 base pairs of DNA — a tiny fraction of the 3 billion nucleic building blocks that make up the human genome — has a sort of Henry Moore bulbosity to it, coupled with the graceful, emergent torque of the Venus de Milo. All very sinusoidal and maternal: just what one would expect of the famed Molecule of Life and the mother of all cookbooks. Yet as Dr. Barton speaks of her studies about how DNA might keep itself fit and fiery by shooting electrons up and down its span, the familiar object on her table begins to evoke a very different image: that of a lightning bolt, a crackling zigzag of opportunity. Far from being a couch-bound custodian of information, it seems, the molecule of life is the original live wire. "What many people don't realize is how dynamic the structure of DNA is," said Dr. Barton, her fingers fluttering lightly over the model. "The base pairs are always moving and vibrating, electrons are migrating, holes are opening up and closing through the center of the DNA." It's like a cocktail party or a kindergarten class, she said. "Nothing stays still for more than a femtosecond here or a millisecond there." Yet for all the squirm and spark, DNA, the ultimate source of information on how cells and bodies should behave, remains a remarkably stable presence throughout one's terrestrial tenure, and even beyond. It's because the molecule is so substantive and slow to degrade, said Dr. Barton, "that you can still look at dinosaur DNA." Dr. Barton, 51, and her colleagues are seeking to understand just how the double helix manages to be at once so twitchy and so reliable, capable of constant interchange with tens of thousands of proteins and other small characters in the cell, hammered at by blistering chemicals, ultraviolet rays and corrosive free radicals, and expected to split and split and split again, spawning numberless generations of daughter DNA molecules in the course of cell division; and all the while still staying sane and functional and relatively error-free. Dr. Barton proposes that the DNA molecule polices itself electronically, periodically delivering a flow of charged particles from Point A to Point B to check for mutant, misplaced bases that might be skulking in the corridors. If the electrons proceed unimpeded, she suggests, all is well. But if there is a kink in the sequence, the smallest sign of a nascent mutation, the flow would short-circuit. That break would in turn sound an alarm, alerting the cell's DNA repair crew to fix the mess now, or at least sometime before lunch. The work is part of Dr. Barton's larger exploration of the electrical properties of DNA, and how the trafficking of charged particles in and around its zigs, swags and crevasses may help mold the contours of the master macro-molecule or set its timbre twanging. Dr. Barton is a heavy-metal fan. She and her lab mates have created metal-studded molecular probes that allow them to generate electrons when and where they want them, and to follow the migration of the particles as they ping their way through DNA. By taking an electron's eye view of the double helix, she hopes to help solve a mystery of molecular biology: how all the tens of thousands of tiny proteins responsible for servicing the genome and carrying out its encoded directives find their correct genetic targets along an otherwise forbidding spaghetti of chromosomal coils. On a practical note, Dr. Barton has designed tiny metal-based probes to test the integrity of a given DNA sample as quickly and cheaply as possible. A company that she founded in San Diego, GeneOhm Sciences Inc., is now working to translate some of her ideas into a simple laboratory assay that could detect disease mutations in a patient's DNA by simply running a current through it and seeing if anything trips it up. Such a procedure would be much simpler than using biochemical methods to spell out, or sequence, thousands of DNA subunits in search of the occasional miscreant. Her work is also attracting attention from experts in the fashionable field of nanotechnology, the science of the extremely tiny, who would dearly love to exploit nature's microcircuitry in devices of their own. Dr. Barton has long been a high-wattage figure on the chemistry circuit. She is a MacArthur fellow, a member of the National Academy of Sciences and a winner of laurels from the National Science Foundation, the American Chemical Society and the American Philosophical Society, to name a few. Like the molecule she studies, Dr. Barton is a braid of contradictions: animated and composed, optimistic and pragmatic, genial and driven. "If the house were to burn down, if things were going badly in the lab, if a paper wasn't accepted by the right journal, she wouldn't get angry or frustrated or wear it on her sleeve, the way I might," said Dr. Peter Dervan, 58, her husband and also a professor of chemistry at Caltech. Dr. Barton is compact, dark-eyed, dark-haired, and, true to her New York roots, she likes dressing in black. She walks briskly, as nearly all scientists do, but with a decided bounce in her step. "What can I say?" said Dr. Robert G. Shulman, an emeritus professor of molecular biophysics and biochemistry at Yale. "We were all jealous of her husband when they got married." As one of the very few women ranking as a full professor at Caltech, and in the chemistry trade generally, Dr. Barton has perhaps inevitably become a role model to young women in science. Later this month, for example, she is participating in the first Rosalind Franklin International Lecture Program at the Imperial College in Britain, devised "to expose young scientists" to that wondrous sight, "internationally recognized women scientists." Dr. Shana Kelley, an assistant professor of chemistry at Boston College, said, "I tell people she's found out how to do it all, that you don't have to choose between career or family, and that's what I want for myself." "I might have had more doubts if I hadn't watched her," she added. Dr. Anna Marie Pyle, a professor of molecular biophysics and biochemistry at Yale who studied under Dr. Barton, said: "Jackie conveys to her students the importance of creativity and imagination in science. Women need to have somebody express confidence in their creative abilities, not just their ability to work harder." The good life has its grindstones and metronomes, though. The couple's time is so tightly scheduled, admitted Dr. Dervan, "that I can tell you where we'll be to the day, to the hour, for the next 12 months." When they are at work, they work, and when they are at home, they are parents. (They have two children — Elizabeth, 13, and Andrew, 21, Dr. Dervan's son from his first marriage.) "People assume that because Peter and I are both chemists, we talk all the time about chemistry," said Dr. Barton. "In fact, we almost never talk shop. If we go out to dinner together, we talk about Elizabeth." They travel often for work, but they are zealously efficient in those jaunts. Dr. Barton has been known to fly back and forth to Europe in a single day, alighting abroad just long enough to deliver a two-hour talk. "Who wants to sleep in a hotel alone," she said, "when you can sleep at home with your family?" One of the few things that gets her ever so wryly ruffled is the public's attitude toward her beloved discipline, chemistry. "People hear the word `chemical' and they automatically think it's bad," she said. "Even my daughter, when she was in kindergarten, came home and said she'd learned that there were too many chemicals in the world. I told her, Elizabeth, we're all chemicals! Everything is made of chemicals!" Dr. Barton is also skeptical whenever laypeople tell her they "flunked chemistry" in high school. "Not everybody could possibly have flunked chemistry," she said. "Surely someone somewhere got a B." For that matter, she said, why do people so readily confess to their complete ignorance of chemistry and other science, even to the point of sounding boastful? "People are perfectly willing to say to me at a party, I haven't the foggiest idea what you're talking about, which they would never do if we were discussing current events," she said. "Why aren't they embarrassed? Why don't they think, Gee, maybe this is something I ought to know a little bit about?" Fear is no excuse. For all its daunting reputation, she said: "Science really isn't that hard. I don't think it's more difficult than anything else." Born and raised in New York City, she attended the Riverdale Country School for Girls. Back then, she said, "young girls didn't take chemistry." The first chemistry course she took was in college, at Barnard. It became her major; she graduated summa cum laude. She earned her Ph.D. in inorganic chemistry from Columbia, and did a postdoctoral fellowship at Bell Labs and Yale. Dr. Barton then took a position as assistant professor of chemistry at Hunter College in New York. She soon moved to Columbia, where her research using metal ions to study DNA began attracting considerable attention, from her future husband, among others. She and Dr. Dervan knew each other for years professionally before they began dating, and when Caltech sought to woo Dr. Barton from Columbia, she told the recruiters of the potentially confounding fact that she was in love with a member of their faculty. "Their response was, well, that's further incentive for you to come here," Dr. Dervan said. Soon after moving to Caltech, Dr. Barton gave birth to her daughter, and within short order learned of her MacArthur "genius" award. "That came at a good time for me," she said. "I was wondering if people might think, oh, she's a mother now, is she going to start slowing down? The MacArthur gave me the reassurance that I was probably O.K., and that I could go on to do interesting stuff." So long as it doesn't require an overnight stay.
March 2, 2004
Constantly in Motion, Like DNA Itself
ASADENA, Calif. — Like many a bio-minded scientist in this gilded age of the genome, Dr. Jacqueline K. Barton, a professor of chemistry at the California Institute of Technology here, considers the double helix so aesthetically pleasing that she keeps a chubby, cheery model of it smack in the middle of her office table.
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