HHMI investigator Carlos Bustamante, University of California, Berkeley

Tinkerers fiddle and adapt, look across disciplines, test and redesign, and ultimately devise methods to explore areas of research that once seemed unapproachable. For example, the semiconductor industry, which continues to find ways to cram more information onto a computer chip, has some lessons to teach the alert biologist interested in observing life at its smallest scale but stymied by the capabilities of modern microscopes. Similarly, bulky needles used to inject labeling molecules can damage cells, but scientists who dabble in nanotechnology are producing thinner and stronger materials that are less likely to disturb the sample.

HHMI investigators Carlos Bustamante, Taekjip Ha, and Carolyn Bertozzi, and Janelia Farm scientist Herschel Marchman, are making such innovations. They craft tools to help explore the scientific mysteries that compel them personally, but their gadgets are enabling a far broader community of researchers to address diverse and intriguing biological questions.

Carlos Bustamante grew up in Peru, where his knack for tinkering became apparent at a very young age. Playing with his toy cars meant taking them apart and putting them back together. As the space age dawned, his interests turned skyward. He built rockets and experimented with different types of fuels. But his world changed at about age 12 when his father, a physician, brought him a microscope from the United States.

"I thought it was the most marvelous thing. You could peer into this microscopic world, where all these exciting things were happening," says Bustamante, now an HHMI investigator at the University of California, Berkeley, and head of the Advanced Microscopies Department at Lawrence Berkeley National Laboratory.

In the late 1980s at the University of New Mexico, he and his colleagues used fluorescence microscopy and wire electrodes to coax DNA to "inch along like a caterpillar," enabling real-time study of DNA movement through a gel during electrophoresis. Then he added magnetic tweezers, figuring out how to anchor one end of a DNA molecule to a glass slide and attach magnetic beads to the other end to characterize the elastic response of the molecule—a first.

Bustamante is probably best known for tinkering with optical tweezers—a laser-based technique physicists invented in 1970 that uses the minute forces exerted by light waves to manipulate molecules. He adapted optical tweezers in the 1990s so that a molecule, trapped in a kind of Star Trek tractor beam, can be poked, prodded, and analyzed. This method has become a standard for measuring single molecules.

Because good can always be better, the upgrading in Bustamante's lab continues—at smaller and smaller scales. He says his most exciting invention so far is an ultra-high-resolution optical tweezers machine. "Measuring changes down to the angstrom, it opens up a way of following the dynamics of biological systems," says Bustamante. He is currently searching for nanoscale handles he can attach to molecules to obtain even more precise information. Those handles will likely be carbon nanotubes, he says—cylindrical carbon molecules 1–3 nanometers in diameter that are unusually strong and have unique electrical and heat-conducting properties.

Bustamante says he was deeply inspired in his youth, and adulthood, by two of humanity's greatest scientists—and tinkerers extraordinaire. "Galileo, my all-time hero, was a professor of mathematics, but he was always building things. It is breathtaking the way he put reasoning into instruments that allowed him to arrive at such profound conclusions as the law of inertia."

Photo: Andrew Nagata

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