Visions of a new frontier

Revolutionary microscope helps researchers make
giant leaps in everything from birth defects to cancer

This article, and the one accompanying it, were written by Seattle Post-Intelligencer business reporter Warren Wilson. Originally published Nov. 20, 1995, they appear here courtesy of the Seattle Post-Intelligencer.

In 1683, Dutch researcher Anton van Leeuwenhoek ushered in a new age of science when he peered through a hand-ground lens and, for the first time, described a living cell.

Three centuries later, biologists in Seattle are using an innovative high-tech microscope to make a similar leap forward, peering deep inside cells to study structures and processes never seen before - the delicate machinery that controls birth defects and infertility, how some cancers begin, even the details of how we hear.

Paul Goodwin revels in his "incredible good fortune" to manage the Image Analysis Laboratory at the Fred Hutchinson Cancer Research Center, where the microscope, called a DeltaVision, is installed.

"I get to do the 'Aha!' part," says Goodwin, whose casual, blue-jeans-and-no-necktie manner belies the seriousness and passion he brings to his work.

He compares the moments of discovery in his lab to "the feeling that Balboa had when he crossed the Isthmus of Panama and saw the Pacific Ocean, or that Galileo had when it finally dawned on him that the Earth was not the center of the universe."

The microscope was developed by University of California-San Francisco researchers Dr. John Sedat and Dr. David Agard and by Applied Precision Inc., a Mercer Island company that makes high-precision equipment for the semiconductor and biomedical industries.

It takes advantage of new developments in several different fields, including an almost miracu lous image-processing technique called "deconvolution." The combination yields sharp, three -dimensional images of objects as small as 200 nanometers in size one five-hundredth the thick ness of a typical human hair. One of the first of these microscopes was installed last year at the Center under an agreement that it be made available to researchers from other institutions as well.

That suits Goodwin. He enjoys the variety of people who gather around the microscope in the basement of the brick-and-glass research center on Lake Union. He likens his laboratory to a jungle watering hole that draws all sorts of creatures together ­ and where some interesting encounters occur.

"Even people next door to each other may not know what the other person's working on," Goodwin says, "but they run into other critters at the watering hole and start exchanging information ... and they realize, 'You have the same problem we have, we can help each other out.' "

One of the regular visitors is Dr. David Battaglia, an obstetrical-gynecological faculty member at the University of Washington, who for several years has sought to understand the causes of mis carriages and birth defects and why such problems become more common as women get older.

Some of the problems involved damage to the chromosomes, the rod-shaped bodies in the cell nucleus that carry the genes. So Battaglia decided to examine human egg cells at the critical stage just before fertilization, when the 23 pairs of chromosomes divide into two matched sets.

He collected eggs from two groups of 20 women one group 20 to 25 years old, the other 40 to 45 and cultured them until they were mature.

Working before the DeltaVision was installed, he used a confocal microscope and found strik ing differences among the two groups of eggs.

Of those from the younger women, 83 percent were textbook perfect; the chromosomes had divided into two disc-shaped "plates," each a mirror image of the other.

Among the older group, however, only 11 percent were normal; in the others, the plates were misshapen.

Battaglia wondered if the cause might lie in the cell spindle, a system of tiny protein fibers arranged somewhat like the spokes of a bicycle wheel. The fibers attach themselves to the chromo somes and gently tug them apart to form the two plates.

He tried to examine the fibers through a confocal microscope, but its intense laser light de stroyed the specimens. Then he heard about Sedat and Agard's deconvolution scope, the DeltaVision's precursor, and sent some old slides off to San Francisco to see what it could do.

Battaglia said he sent a specimen that had been heavily damaged by the confocal microscope, yet he got back "unbelievably clear images."

"That was the first demonstration to me that this system would be a far better tool than anything else out there," he says.

Subsequent images captured on the DeltaVision in Goodwin's lab have allowed Battaglia to identify, for the first time, the specific protein fibers linking the spindle's poles to individual chromosomes.

They also revealed the first signs that the abnormal eggs had one or more extra poles, each apparently producing its own fibers and upsetting the delicate balance of tension required to separate the chromosomes evenly.

Moreover, Battaglia says, the DeltaVision images showed that within the two plates, the chromosomes were not arrayed randomly but organized in a pinwheel pattern that hadn't been recog nized before.

All three results help advance scientists' understanding of how normal fertilization occurs, what happens when it goes awry and, potentially, how to solve or prevent such problems.

"You try not to overdramatize," Battaglia says, "but this has brought kind of a revolution in thinking about how optical microscopy should be done."

Another regular visitor to Goodwin's lab is Rissa Sanchez, a researcher for UW molecular biologist Dr. Brian Reid.

Their work focuses on a condition called Barrett's esophagus that can lead to one of the most lethal and rapidly increasing cancers in developed countries: adenocarcinoma.

They are searching, she says, for specific "markers on the road to cancer" early warnings that, if heeded, would detect the process before the cancer stage.

One involves a gene labeled p53, which they found either missing or mutated in nearly every patient they studied who had adenocarcinoma.

To better understand the process that a normal cell undergoes in becoming cancerous, they studied mouse tissue from which the p53 gene had been deliberately removed. Sure enough, they found cells distorted by numerous extra poles, called centrosomes, in their spindles.

The next question was whether the same link existed in human tissue. Last summer, Sanchez and Goodwin succeeded in capturing an image of a human cell with abnormal p53 that had devel oped numerous extra centrosomes.

Goodwin was ecstatic.

"We caught it in the act" of progressing toward cancer, he says.

Sanchez called the images "spectacular," particularly since they involve structures so delicate that a confocal microscope would make them "fizzle in front of my eyes."

The pictures that emerge from the DeltaVision scope are as varied as they are striking.

Drs. Hao Wang and Bruce Tempel, researchers at the UW's Virginia Merrill Bloedel Hearing Research Center and the Veterans Administration Medical Center in Seattle, have used it, literally, to see how we hear.

They captured images showing the location of specific ion channels in the fine neuron exten sions of the inner ear. These channels help us hear by transmitting electrically coded information generated by sound waves from the ear to the brain for interpretation.

The DeltaVision images show the "very, very fine processes of the nerve that we weren't able to see with other types of imaging," Tempel says.

Another set of images that was captured last summer is shifting the standard view of mitochon dria, the tiny engines inside our cells that convert sugars into the cell fuel called ATP.

From two-dimensional microscope images, scientists for decades have thought that mitochon dria were rod-shaped, like tiny pills, Goodwin said. The new, three-dimensional images showed that they are instead long and tangled, like noodles.

Not all of what goes on in the image lab is pure work.

One day recently, Goodwin and Sanchez were poring over slides, painstakingly searching for cells with extra poles, when suddenly Goodwin cried out, "Oh, cool!"

He directed a reporter's eye to what looked like a gossamer veil, glowing yellow-orange with fluorescent dye, floating gracefully in an ink-black sea.

Nothing significant, he admitted. Just strikingly beautiful.

But if the researchers occasionally take a moment to enjoy their art, they are driven by the urge to learn, to discover, to solve problems.

"I hate cancer," Goodwin says. "Cancer took my mom."

With the DeltaVision images, he says, "I think we got a little handle on the bugger."

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