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By David J. Craig

	Selim Ünlü, an ENG professor of electrical and computer engineering (left), Anna Swan, an ENG research assistant professor of electrical and computer engineering, and Bennett Goldberg, a CAS professor of physics, share a lab in the Photonics Center, where they conduct interdisciplinary research in nanoscience. Photo by Kalman Zabarsky

By developing new microscopy techniques that peer deep inside living cells, an interdisciplinary team of BU scientists and engineers soon could enable medical researchers to better understand the subcellular processes in pathogens such as E. coli, salmonella, and shigella.

The innovative subcellular imaging project is led by Bennett Goldberg, a CAS physics professor, and Selim Ünlü, an ENG professor of electrical and computer engineering. Goldberg and Ünlü, who share a laboratory at the BU Photonics Center, are experts in nano-optics, a field that uses light in new ways to see tiny objects in ever-finer detail.

In 2002, their research team received a $1.7 million grant from the National Institutes of Health to develop a technique called high-resolution spectral self-interference fluorescence microscopy, which has the potential to produce images of biological phenomena where points as close as a few nanometers apart can be clearly differentiated. Currently, the researchers are developing methods for observing the structure of the dysentery-causing shigella bacteria, showing how proteins and other molecules within shigella cells go about their work.

Fluorescence microscopy, one of the primary tools for probing biological systems, involves imaging molecules that emit light when excited by an outside source, like a fluorescent watch dial. These fluorescent molecules, or fluorophores, can occur naturally within cells or be introduced into cells. At present, the technique allows researchers to see things as small as 300 nanometers (a nanometer is one billionth of a meter, or about 1,000 times smaller than the width of a human hair). “That sounds like a short distance, but there are many processes inside cells that happen at much smaller length scales,” says Goldberg. “We want to bring that resolution down to 10 or 20 nanometers so we can observe things like transmembrane activity, where the membranes may be only 15 nanometers thick, and activities in the cell where multiple proteins may be working very closely together.”

Existing instruments such as electron microscopes already can render images of biological features at resolutions of just a few nanometers. The problem with that technique, Goldberg explains, is that it requires killing the cell, freezing it, and slicing it thinly before bombarding it with high-energy electrons, which damage the sample as they bounce off it. His goal is to develop an instrument that can locate, in real time and three-dimensional space, the precise position of certain proteins in living bacteria and viruses.

A key innovation of Goldberg’s and Ünlü’s technique is that unlike standard fluorescent microscopy, which uses a single lens to collect light emitted in one direction, it uses an additional lens or mirror to collect light emitted from fluorescent particles in both upward and downward directions. The way these light emissions interfere with each other provides a new level of accuracy about the location of the fluorescent particles and their actions within the cell.

“ Fluorescence microscopy is an old technique that we’re using in a new way,” says Goldberg. “The trick is figuring out how to view multiple fluorophores in one area, and to understand in spatial terms what you see in the spectral domain.”

That’s one of the technical challenges Goldberg and Ünlü are tackling with Clem Karl, an ENG professor of electrical and computer engineering, and Anna Swan, an ENG research assistant professor of electrical and computer engineering. The team also is collaborating with researchers at Massachusetts General Hospital who have expertise in the biological structures of shigella bacteria and similar pathogens. Such cross-pollination among disciplines, Goldberg says, is essential to solving problems in nanoscience, which involves the study of phenomena at the atomic and molecular levels.

“ The real breakthroughs in nanoscience are going to happen at the boundaries between disciplines,” says Goldberg, who with Ünlü formed the BU Nanoscience Working Group in 2002 to encourage physicists, chemists, biologists, engineers, and computer scientists working in nanoscience to collaborate, share lab space, and jointly fund postdocs. Currently they are preparing to form a center for nanoscience research at BU.

“ It’s pretty unusual for a condensed-matter physicist like myself to have an NIH grant to do biological imaging,” Goldberg says. “My expertise extends up to the edge of molecular biology, and that’s where I look to collaborators who can help develop the biological model systems to test a new microscopy, and who know the critical biological questions to ask.”

Interdisciplinary nanoscience research at BU has been given a boost in recent years, he says, by the dramatic growth of ENG’s biomedical engineering department, which in 2001 received a $14 million Whitaker Leadership Development Award (see related story on page 3). “The strength of ENG’s biomedical engineering department is part of what makes Boston University uniquely suited for this type of research, because researchers doing material and device-level science in areas like physics and engineering have colleagues they can talk to who understand biological applications,” Goldberg says. “The department’s enormous growth, and all the work being done there on drug delivery, tissue engineering, and other human physiology applications, is going to make a big difference in the success of nanoscience research at BU.” For more information about Goldberg’s and Ünlü’s research, visit ultra.bu.edu.

14 November 2003
Boston University
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