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By Christopher Vaughan Professor Carlos J. Bustamante’s eyes light up as he describes one of his first dramatic research discoveries. As a 12-year-old boy growing up in Peru in the early 1960s, he and his friends used to make rockets out of aluminum cigar tubes. When one of his chemistry teachers told the class that mixing together potassium chlorate, sugar, and sulfur would produce an explosion, Bustamante shot an excited glance at his rocketry compatriots. “I knew immediately that this was the solid rocket fuel we had been looking for,” he recalls. At their soonest opportunity, they packed the cigar tubes with potassium salt and sugar and then injected sulfuric acid through a long tube. The rocket went up with a roar. The boys survived. As a self-described member of the “Sputnik Generation,” enthralled by space and beguiled by rockets, Bustamante might easily have become involved in aerospace research as an adult. But, instead of exploring the vastness of outer space, he became ever more fascinated by inner space--the microscopic world of individual molecules. He has succeeded in opening up a whole new field of research, pioneering new methods that will ultimately require chemists and biologists to rewrite their textbooks. So great is the importance of his work in molecular mechanics that he was recently elected to the National Academy of Sciences and named one of “America’s Best” in science and medicine by Time magazine. What Bustamante does is simple to describe, but fiendishly difficult to do. Classically, chemists have understood chemical reactions by looking at the behavior of groups of molecules. “When you do what I call ‘bulk studies’ of molecules, you get beautiful, smooth signals,” Bustamante says. The breakthrough that Bustamante has engineered is a way of looking at single molecules during chemical reactions, and this creates a quite different picture of what’s going on. “The reality is that it’s chaos,” he says. “Individual molecules are doing all sorts of things at different times, often for no apparent reason.” One might be tempted to think this is a trivial finding, that knowing exactly what an individual molecule does for a few nanoseconds in the midst of a reaction makes little difference, as long as all the molecules do the same thing by the time the reaction is finished. But the world is rife with examples of important differences between average effects and individual instances. A fire department that plans for fires in buildings of average height will find its ladders short if a fire breaks out in the tallest building in town. A man who plans a beachside snack bar just above the average high-water mark will find his snack shack soaked when a big storm hits. “There are some things you can’t understand by looking at an average molecule,” Bustamante notes. His lab is currently studying one of those things: how an enzyme called RNA polymerase walks along a strand of DNA during the early stages of protein synthesis in a cell. The classic picture is that the enzyme moves smoothly along DNA, steadily reading off its sequence. But what Bustamante has found is that RNA polymerase really acts in fits and starts, moving quickly sometimes, while at other times moving slowly or not at all. The speed change, he says, is probably related to changes in the enzyme’s shape. “This suggests that molecules are not static structures.” X-ray crystallography--the traditional, bulk method of looking at molecular structure--produces pretty snapshots of proteins, says Bustamante. “People look at [these] and say, ‘That’s what the protein looks like.’ But that’s not really accurate.” In fact, it may be quite common for proteins to suddenly change shape, allowing them to either speed up reactions or slow them down. “What this might do is give the reaction another level of regulation,” explains Bustamante. “RNA polymerase [might] move quickly when the cell needs to produce a lot of protein and slowly when it doesn’t.” Such differences are not only important for understanding cell function, they might also be of practical interest to bioengineers who want to produce large amounts of protein in industrial biotechnology applications, he adds. Bustamante’s interest in the microscopic world took root in his father’s library, where he discovered a biography of the great neurologist Santiago Ramón y Cajal, a Spanish scientist who won the Nobel Prize in 1906 with Camillo Golgi. The two had developed a way of staining cells that allowed them to see the inner structures of neurons. “I was interested to find out that this guy was a big scientist and also Spanish, like me,” recalls Bustamante. His father, a physician, got him an old microscope; young Carlos began doing experiments with protozoans and looking for a cell stain as useful as those that made Cajal famous. At one point, Bustamante observed that cell membranes contain fatty molecules called lipids. “I thought I had made a great discovery, but then my father showed me in a book that this had been known for 30 years,” he says. “But these experiences motivated me because I found I could ask a question and then answer it.” Bustamante’s pleasure in asking and answering scientific questions became more apparent to him after he enrolled in medical school. “I realized I was fooling myself [about wanting to become a doctor] and that what I really wanted was to be a researcher,” he recalls. “So I quit medical school and began studying chemistry.” After earning a master’s degree in chemistry in Peru, Bustamante realized that to study chemistry at the highest levels he would have to leave the country. “Training to be a biochemist in Peru was like training to be a sailor in Switzerland,” he says. Bustamante was drawn to Berkeley immediately. “The ethos, the collective attitude at Berkeley is wonderful,” he says. “Berkeley attracts some of the best people in the world, and the quality of your work is always potentiated by the quality of the people with whom you work.” He first came to Berkeley as a Fulbright scholar in 1975 and stayed until he earned his doctorate in biophysics in 1981. Cal chemistry professor Ignacio Tinoco, in whose lab Bustamante worked at that time, remembers his new student as very smart, very hardworking, and a bit of a dreamer. “He always had his head in the clouds--the other students sometimes kidded him about it.” But that dreaminess was not the product of a disorganized or unfocused mind, says Tinoco, it was just his creative engine at work. Although he had always intended to return to Peru after his Ph.D., upon learning that he would earn just $80 a month as a Peruvian professor, Bustamante decided to stay in the United States--first as an associate professor at the University of New Mexico, and later as a professor at the University of Oregon. Bustamante was again working with microscopes, albeit far more sophisticated ones than those of his youth--signal fluorescence microscopes, spectroscopic microscopes, and atomic force microscopes (which are capable of “feeling” the atomic structure of a surface). Each microscope in turn allowed him to discern ever smaller details of molecular structure, but he was still looking at collections of molecules. It was during this time that Bustamante began to think of using these instruments to look at or even manipulate single molecules. In the early 1990s, Bustamante fixed one end of a DNA molecule to a magnetic bead and pulled on the other end with magnets. This allowed him to measure the strength and stretchiness of a single DNA molecule under different conditions. “This really broke a psychological barrier, when we showed it was possible to do this with a single molecule,” Bustamante says. Shortly afterward, he modified his atomic force microscope so that it could be used with a pair of laser tweezers to grasp single molecules, to play with them, or even to pull them apart. All the time that he was working on these techniques, Bustamante was hoping to get back to Berkeley. His wish was finally granted in 1998, when he was offered the position of professor of molecular and cell biology. Not only was this a lucky break for Bustamante, it was good for Cal, says Professor Robert Tjian, who was involved in his hiring. “He is a positive force on campus, one of the major pieces of the effort in structural biology that we were trying to build on campus,” Tjian says. “He brings a lot of energy, vision, and originality to biology.” Another positive for Cal has been Bustamante’s commitment to developing interest in science among Hispanics, says chemistry professor and friend Graham Fleming. While at the University of New Mexico, Bustamante had taken part in an NIH-sponsored program to help minority undergraduates choose scientific careers, and in Oregon he had been involved in recruiting minority students for the Institute of Molecular Biology. “A big part of coming back to Berkeley was that he felt he would have more influence here in that role,” Fleming says. “I believe that science is still alien to the Hispanic culture in the U.S.,” says Bustamante. “And I think that role models in science can be extremely important. It’s easier for people to go along paths that have already been walked by others.” Bustamante’s move back to Berkeley was also a happy occasion for his family. “My wife Silvia and I love the climate in the Bay Area, and we love the beach,” Bustamante says. “Here we are on the same ocean as we were in Lima, and the sun sets in the correct place.” His son Carlos Jr., 20, and daughter Fernanda, 22, also feel at home in Berkeley--both are now Cal students. Since returning to Berkeley, Bustamante has been working on a number of projects, including the RNA polymerase research and an experiment in which he plays tug-of-war with a virus. “We grab one end of a strand of DNA and pull on it as a viral protein sheath is trying to pull it in,” he says. By measuring the force they need to stop the virus from pulling in the DNA, they can learn exactly how strong the virus’s molecular machinery is. This information may be extremely important in the future if scientists are to create molecular motors to power microscopic machines. Other scientists at Berkeley have already shaped microscopic gears and rods out of silicon; molecular motors that mimic this virus may be just what is needed to get those gears turning. The virus that they are studying, says Bustamante, has proven to have the strongest molecular motor yet discovered. In addition to his molecular work, Bustamante has also been thinking on a grander scale. He has played a key role in a California initiative called QB3--shorthand for the Institute for Quantitative Biomedical Research, a complementary effort by scientists at three University of California campuses (Berkeley, San Francisco, and Santa Cruz) to apply research in mathematics, physics, chemistry, and engineering directly to biological problems. QB3 hopes to form the foundation of the next stage in the biotechnology revolution. Graham Fleming, leader of QB3 on the Cal campus, says he often consults Bustamante when thinking about the future of the initiative. “He’s one of the people I rely on when making plans for QB3,” says Fleming. “He’s always thinking about the future and keeping steps ahead of where the field is.” Work like Bustamante’s allows scientists to take a nuts-and-bolts, engineering approach to biological problems. Having made it back to Berkeley at last, Bustamante is leaving the University again, but only for a sabbatical in Madrid this year. During his time in Spain, Bustamante will put the field he created under the microscope: He is writing a book to illuminate the world of single-molecule biophysics for other scientists. As someone who enjoys good living as much as good science, Bustamante says he chose to go to Spain to write because, like California, it also has good weather and good food: “I thought if I was going to be writing, I might as well go to a place where they have good tapas!” |
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