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HHMI investigator Taekjip Ha, University of Illinois at Urbana-Champaign
Louis Pasteur's elegant logic similarly impressed Bustamante. Pasteur discovered stereochemistry when he precipitated tartaric acid crystals from a solution and, to his surprise, found two mirror-image shapes. Curiosity piqued, Pasteur used a small stick to separate the crystals in two bunches, using his microscope, and proceeded to dissolve them and study further. He found the solutions identical in all aspects, except that one rotated the plane of polarization of light clockwise and the other counterclockwise. "Pasteur arrived at the remarkable conclusion that molecules can exist in two different forms that are mirror images of one another. That's tinkering for you, at its best."
A scientist can accomplish remarkable results just by reflecting that same curiosity-driven spirit, according to Bustamante. "There is nothing written—no rule—that says scientists should work only with instruments that exist. You start with a need and develop the instrument to fit that need," he says.
"Oftentimes, tinkering doesn't involve sophisticated thinking," he insists. "It involves simple logic, and the simpler a system is the better it will be."
As a young student in Korea, Taekjip Ha was a self-described "test taker." He didn't discover his inventive side until he became a researcher with goals that were unattainable with existing technologies.
"I was just a very good student who did what I was told to do," he recalls. "But once I began to work on my own projects, it was a whole new world. I began to think 'How can I do measurements?' That is when I became a tinkerer," says Ha, a biophysicist and HHMI investigator at the University of Illinois at Urbana-Champaign. Since then, he has immersed himself in the role, even ordering off-the-shelf parts to build a microscope from scratch.
Ha's overriding goal has been to observe single molecules in action. For example, his group recently devised the "nanocontainer"—a nanoscale test tube with a diameter one-thousandth that of a human hair—to enable scientists to observe the behavior of single molecules of DNA, RNA, or proteins. In the June 11, 2007, issue of the Proceedings of the National Academy of Sciences, the team described how they intentionally made the nanocontainers porous; the large subject molecules cannot escape, but smaller molecules such as ions and the cellular energy source ATP can be added to start reactions. Ha calls the technique "another cool addition to the tool set that is being made available by our research."
That tool set got its start when Ha was challenged to improve fluorescence resonance energy transfer (FRET) as an optical measurement technique. At the time, FRET could measure the distance between only two points. The "donor" and "acceptor," two different colors, are attached to two points on a molecule, or on two molecules. If the distance between them remains larger than 10 nanometers, their colors do not change. But if the dyes come into closer proximity, indicating the molecules are interacting, the ratio of the two colors—and thus the intensity—changes.
Unsatisfied, Ha continued to experiment, building an apparatus that combines single-molecule FRET with optical tweezers. Today he is performing FRET in three colors, allowing measurements of three different molecular distances at a time. "With complex molecules there is more than one moving part," he explains.
"My ultimate goal is to reconstitute the entire DNA replication system," says Ha. "When all these proteins are labeled with different molecules and we have nanoscale handles to manipulate and study their coordination in great detail, we will see how molecules really work."
John Dixon / AP, © HHMI