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Laser dissection captures cells for early cancer detection A powerful new technique for extracting a homogeneous population of cells from the heterogeneous mix obtained in a tissue biopsy has been developed by researchers at the National Institutes of Health, Bethesda, Md. Dubbed laser capture microdissection, it opens the way for earlier detection of cancer and other diseases and could lead to a revolution in the understanding of the molecular basis of disease [Science, 274, 998 (1996)]. "Having this technique gives us access to a disease while it is still in the planning stages," says Lance A. Liotta, chief of the National Cancer Institutes laboratory of pathology. That's powerful information to have in designing strategies to halt the disease process." The one-step extraction approach is simple but "extremely sophisticated," says Liotta: A thin, transparent thermoplastic film (ethylene vinyl acetate polymer) is placed on the surface of a tissue section mounted on a glass slide. The tissue region containing the cells of interest is visualized with a standard microscope. A pulse of light from a low-power carbon dioxide laser coupled to the microscope is trained on the film at this site. The light beam heats the film enough to make it sticky, so the cells underneath adhere to it. The film is lifted off the slide, carrying a patch of homogeneous tissue that can be analyzed for DNA, RNA, enzymes, or proteins. 11 1 think this is the start of a new phase of clinical diagnostics that goes beyond histology to the genetic level," comments G. Steven Bova, assistant professor of urology, pathology, and oncology at Johns Hopkins University School of Medicine.
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Cluster of homogeneous cancer cells (right) was removed from breast tissue mounted on glass slide (left) via laser capture microdissection.
The 213th National Meeting and Exposition, April 13-17, 1997, in San Francisco, California, is hosted by the American Chemical Society.
science/technolosy The device was codeveloped by Liotta's team and a group of bioengineers led by Robert F. Bonner, head of biomedical optics at the National Center for Research Resources. It can capture a small cluster of cells in less than 10 seconds. That's far speedier than manually microdissecting tissue—the only route available until now to get at specific cells. And it neatly avoids cross-contamination of cells, an ever-present challenge in manual dissection. Using laser capture microdissection, normal, precancerous, and malignant cells can be extracted from a tissue sample, their genetic material amplified, and the genetic changes that are taking place as normal cells become cancerous identified, says Liotta. "It's like being able to investigate a crime in progress rather than going back to the scene of the crime when much of the evidence has gone,'' he explains. His group has used it to extract tumor cells from breast and prostate tissue, among others, as well as to "dissect" kidney tissue for specialized cells. DNA and protein analysis suggest the laser-captured tissue is not damaged by the laser beam. Thermoplastic films absorb strongly at carbon dioxide laser wavelengths, but the underlying tissue does not, the researchers note. The diameter of a cell is roughly 10 urn, and the laser beam currently can be focused on an area just 30 urn in diameter. The group is working to refine the laser so it can be focused on one cell, says Bonner. That would be an asset in Hodgkin's disease, Liotta notes, where unusual cells known as Reed-Sternberg cells are scattered among more typical cancer cells. "If we could isolate a single Reed-Sternberg cell, it might help us understand Hodgkin's," he explains. The technique is particularly useful for tracking prostate cancer, notes team leader Michael R. Emmert-Buck. "Amplification of RNA from prostate cancer and precancerous cells is allowing us to produce a specific genetic fingerprint of the disease as it progresses," he says. Liotta's group will be using the technique to compare genetic material from diseased tissue to genes being discovered at the National Center for Human Genome Research. "We have hundreds of thousands of genes being discovered in the genome project," he says. "And we want to apply that knowledge to understanding what's happening in diseased tissue." His group also is using the new tool to study collagenases implicated in can34 NOVEMBER 18, 1996 C&EN
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more than 200 years: The university's first chemistry professor, John Maclean, was appointed in 1795. The symposium's scope—from molecules to cells and materials—reflected how the reach of chemistry has expanded since Maclean's time. "We wanted to hold up a mirror to the state of chemistry today," says chemistry professor Giacinto Scoles, who chaired the organizing committee. Of the 32 speakers, about 70% had some sort of Princeton connection—as current or former faculty, students, or postdocs. Five speakers were Nobel Laureates. One of the recipients of this year's Nobel Prize, Rice University chemistry professor Richard E. Smalley (who obtained his Ph.D. at Princeton), opened the portion of the symposium that focused on the chemical foundations of materials research with a talk on fullerenes. Peter G. Schultz, professor of chemistry at the University of California, Berkeley, kicked off the biological chemistry segment. "Chemistry has a lot to learn by studying the way nature has solved problems over millions of years of evolution," he said, drawing examples from his own research on catalytic antibodies and protein engineering. Schultz also noted how the strategies such as combinatorial chemistry, an idea derived from the immune system that chemists have been applying to attack biAs Princeton University celebrated its ological problems, can be employed in 250th anniversary last month with fire- materials-oriented research. "We haven't works and forums, the chemistry depart- even begun to look through the periodic ment held a celebration of its own. A table," he said. four-day symposium called "Chemistry: Later, Harry B. Gray, professor of chemBetween Matter and Life" showcased the istry at California Institute of Technolodiscipline's central position in science gy, pointed out that the research coming and technology. out of Schultz's lab encompassed the enPrinceton was chartered Oct. 22, tire spectrum of chemistry. "We don't 1746, as the College of New Jersey. need any more talks," Gray joked. "We Chemistry has had a presence there for can spend the next four days discussing Peter's work." s About 350 people at^ tended the 250th anniversaE ry symposium. Among them ^ were undergraduate stuo dents from colleges and uni| versifies up and down the East Coast, there as Princeton's guests. "We invited schools to send their top students," said chemistry department chairman George McLendon. "We had generous support from industrial sponsors and we wanted to share the occasion." From left, Smalley, McLendon, Scoles, and Schultz Pamela Zurer attended Princeton's 250th anniversary symposium, cer metastasis, an effort initially undertaken by Emmert-Buck that drove the development of the device. "We wanted to speed up dissection," says Liotta. Manual dissection is very tedious, requiring dexterity, skill, and a tremendous amount of patience, notes Bonner. A significant advantage of the laser technique "is that it's relatively easy to envision automating it so large numbers of samples can be handled routinely," he says. That opens a way to learn more about the science of disease pathology, he explains. The laser capture invention was "an intensively collaborative effort" between Liotta's group and his own group, Bonner notes. It represents "what you can do sometimes in the government when the stars are right "—scientists in a variety of fields work together and make very rapid progress. The National Cancer Institute plans to make the device available to researchers and clinicians nationwide after modifications and further testing have been completed, says Liotta. Mairin Brennan
Chemistry symposium marks Princeton's 250th anniversary
