HHMI investigator Carolyn Bertozzi, University of California, Berkeley

Ha's graduate advisor, Shimon Weiss, now at the University of California, Los Angeles, considers Ha exceptional. "Taekjip has the rare ability to identify the bottlenecks in any problem he attacks, and then come up with the most correct, simple way to overcome those bottlenecks. Never overdesigning to solve a problem, he optimizes his work investment and stops where the solution is just adequate."

Ha says he has developed an instinct for choosing people with a similar bent to work in his lab—and he pushes them to use it. "I tell my students to find ways to reduce the setup time for their experiments by a factor of two to four. I encourage them to change the whole process of doing measurements to make things more reliable and efficient so they can do better science." There's no need for him to push them very hard, Ha adds. "We always have pressure to do more tinkering."

Carolyn Bertozzi's penchant for technical ingenuity showed itself when she was a youngster playing dolls with her sisters. "We had great fun taking dolls apart and reassembling them as alien creatures," she recalls. The gadgets that her father, a physicist at the Massachusetts Institute of Technology, brought home were also an outlet. "A great favorite was a strong magnet. My sisters and I used it to build strange sculptures from nails, staples, nuts, and bolts."

Now a chemist and an HHMI investigator at the University of California, Berkeley, Bertozzi exercises her creativity in the field of glycosylation—the cellular process by which sugars are added to proteins or other molecules. The resulting "glycans" govern a variety of cell-to-cell interactions. Scientists had known for decades that changes in glycosylation were associated with cancer, bacterial infections, and other illnesses, but they had no way of studying how molecules at the cell surface use sugars. Bertozzi's lab devised a method of imaging glycosylation—something not thought possible.

		1 millimeter = 0.03937 inch 1 nanometer = 0.000001 millimeter 1 angstrom = 0.1 nanometer or 1/250 millionth of an inch

Her group developed a chemical reporter, or label, that can be installed in the glycans of cells in culture or in living animals, such as worms, zebrafish, and mice. The reporter, linked to a simple sugar and introduced into the media of worms or fish, or injected into mice, is metabolized and incorporated into cell-surface glycans. After chemical reaction with a probe molecule, the reporter can be visualized by using an imaging technique such as fluorescence microscopy or positron emission tomography.

Bertozzi says her inspiration for building gadgets comes from "the demands of research at the interface of disciplines," whereby members of one community express a need that can be met by another. As director of the Molecular Foundry at the Lawrence Berkeley National Laboratory—a user facility that supports research in nanoscience worldwide—she orchestrates that kind of interaction, and participates herself. "Of the many tools my group has worked on," she says, "the coolest is probably the carbon nanotube-based 'nanoinjector,' which we developed with Alex Zettl's lab in the Physics Department here at Berkeley."

In this case, carbon nanotubes served as new building blocks for injecting imaging agents, called quantum dots, into cells, and conducting surgery on single cells. Carbon nanotubes, being harder than steel and manipulable with angstrom-resolution precision, make ideal injectors for delicate cell membranes.

In collaboration with Zettl, Bertozzi's lab mounted a single carbon nanotube to an atomic force microscope (AFM)—a widely used instrument that scans surfaces by manipulating a probe at subnanometer scales. The tip of this "nanomanipulator" can be moved in three dimensions—X, Y, and Z. After loading the carbon nanotube with quantum dots and other molecules, the device can be positioned just above a cell. The AFM can then push the carbon nanotube through the cell membrane and deliver the load of quantum dots, bright enough to track single particles, into the cell's interior. The nanoinjector is described in detail in the May 15, 2007, issue of the Proceedings of the National Academy of Sciences.

Photo: Barbara Ries

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