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The Eureka Facilitator
Deep in the bowels of the Physiology Building, scientists witness what they have only suspected.

Doug Murphy packed up his own cellular biology lab to become full-time director of the Microscope Facility.
The idea of resounding yelps coming from the somber basement corridors of the Physiology Building may seem peculiar, but such outbursts don't surprise Doug Murphy. In his three years as director of a School of Medicine service known as the Microscope Facility, located in a special nook down in those subterranean parts, he's heard a good many triumphant Eurekas! "Important discoveries take place here all the time," Murphy says, because in this lab, with its armament of microscope technology, scientists frequently witness in front of their eyes what they only suspected was taking place in a test tube.

Here, for instance, psychiatrist Christopher Ross's lab confirmed exactly where in a cell the critical proteins that cause Huntington's disease could be found. (That discovery was announced first in Science.) One of oncologist Stephen Baylin's graduate students also left the Microscope Facility last year with a new piece of knowlege: "It was the first time," Baylin says, "we began to understand how key proteins interact to silence genes abnormally in cancer cells. We knew we were onto something big."

The fact is, the technology in this isolated corner of the basic sciences complex goes far beyond anything that many scientists might even imagine. The site boasts two confocal microscopes that offer rare views of an interior layer of a specimen without destroying any of the surroundings. There are two scanning electron microscopes, a transmission electron microscope and a fluorescence imaging laboratory, all essential tools for tracking down the whereabouts of elusive molecules. The techniques keep getting smarter: This winter, the facility acquired a deconvolution microscope. Like a standard confocal microscope, this piece of equipment can home in on a tiny slice within a specimen and then, through a series of computerized calculations, reconstruct a view of surrounding layers that would otherwise be out of focus.

The Microscope Facility is a core resource, where scientists share equipment that would be far too expensive for any one lab to afford. This kind of pooling happened as far back as 1989, but three years ago, with funding from the basic science directors and the dean's office, the facility expanded to 2,000 square feet and began vaunting its technological capabilities. It earned NIH grants to purchase the latest, most sought-after equipment. Meanwhile, Murphy, a cellular biologist, packed his own lab into cardboard boxes and put his research in limbo in order to become the full-time director.

"I saw it as a challenge," he says, "to provide a site for the entire School of Medicine that would be absolutely cutting-edge."

Today, the Microscope Facility is used by researchers from more than 150 labs, as many as half of whom are from clinical departments.

Getting a good view of a biological phenomenon, however, is a learned craft. Murphy, who's recently published a textbook on the fundamentals of microscopy, offers graduate students, fellows and faculty three eight-week courses in using the 'scopes. He covers everything from choosing the appropriate technique to interpreting the images. The course even touches on the ethics of microscopy.

"It's possible," Murphy cautions, "to enhance an image in such a way that you're overstating what you think you see."

But the real punch behind the facility is the staff: Mike Delannoy, Carol Cooke and Brad Harris. Working with researchers individually, these microscopy specialists show them how to puzzle through their imaging problems. Even some of the best wet-lab scientists have botched the preparation of a specimen by using a fixative that happens to destroy the structure they want to see or a less-than-optimal antibody-tagging technique to mark a particular protein.

Cooke, an immuno-electron microscopy expert, says each investigation comes with a new twist. Jeremy Nathans' molecular biology lab, for instance, had cloned a protein but struggled to get a good look at how it affected a layer of photoreceptor cells in the retina. The images weren't definitive. But Cooke had heard about a light-weight gold-tagging formula and found that it bonded well to the protein and created the appropriate shadow effect necessary to make the molecules visible.

The facility is still developing. "We have to stay on top of the technology," Murphy says. "I'm constantly thinking, "Are we cutting-edge? Do our scientists have state-of-the-art equipment? A top-notch facility can really catapult research."

-Kate Ledger



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