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Cutting-Edge Tissue Arrays Increasingly Help Researchers Observe Gene Function in Action

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Lately, researchers have been looking beyond gene expression arrays for parallel analysis of the gene’s function in a cell. At the cutting edge of tools that enable this further analysis are tissue arrays: wafer-thin sections of tiny bits of tissues arranged on a slide.

The first “tissue arrays” — carrying several tissues, but with no particular orientation — were manufactured about 15 years ago. But it was only about four years ago that Olli Kallioniemi at the NIH and his colleagues in Switzerland and Finland developed chips with up to 1,000 tissue biopsies in an array format. Since then, their popularity among researchers has steadily increased.

“It’s taken off like an insanity,” said Stephen Hewitt, who runs the Tissue Array Research Program (TARP) laboratory, a collaboration between the NCI and the NHGRI. The lab was founded in the summer of 2000 to provide researchers, both in and outside the NCI, with multi-tumor tissue microarrays. Meanwhile the number of extramural users has grown to more than 300, most of them basic scientists, said Hewitt.

 

Spatial Exploration Technology

Tissue chips usually carry between a few dozen and several hundred samples of normal or diseased tissue from humans or animals. Researchers use them to measure gene expression, gene amplifications, or protein expression. Determining the spatial distribution of proteins within tissues and cells, they hope, can give clues to their function. Also, any changes in location in response to a disease or a treatment may serve as diagnostic or prognostic marker.

The methods used with tissue arrays are the same ones that were developed for traditional tissue sections: fluorescence in situ hybridization, PCR, immunohistochemistry, and other staining methods. However, tissue arrays minimize the amount of material and reagents used, and many samples can be processed in parallel, increasing reproducibility.

But even with an automated tissue arrayer, which Beecher Instruments recently brought to market, making tissue arrays is a labor-intensive business: The tissues need to be collected from patients, fixed, and embedded in paraffin. Guided by a microscope, a pathologist then takes tiny core biopsies from these donor blocks, and inserts them into the holes of a microarray paraffin master block. This block is then cut manually into sections, yielding about 200-300 slides.

TARP produces arrays that contain up to 500 spots, each 0.6 mm in diameter. Besides normal human tissues from organs throughout the body, they include samples from brain tumors, melanomas, lymphomas, ovarian cancers, breast cancers, colon cancers, lung cancers, and prostate cancers. Most of these tissues come from the Cooperative Human Tissue Network, an NCI-supported institution that collects cancer tissue samples from about 40 hospitals across the US. In the future, Hewitt said he hopes to offer an even wider selection of tissues. As an alternative to arrays, which use precious patient material, he is also about to launch a chip that carries 58 well-characterized NCI cancer cell lines embedded in agarose.

Moreover, Hewitt provides custom arrays, both for diseases other than cancer such as kidney disease and for clinical cancer studies. But “very few people have really good large collections of material,” he said. Recently, however, he has been consulted more about epidemiological studies. For example, the UK’s National Health Service, he said, is currently planning a large cancer tissue array project involving clinical trials.

Tissue in the Till

At $20 apiece for extramural researchers, TARP arrays are a bargain, but commercial providers also exist. Imgenex is the exclusive North American distributor of tissue arrays manufactured by SuperBioChip Laboratories, a Korean company founded by Woo Ho Kim, a professor of pathology at Seoul National University in Korea, who has access to a large number of patient samples. Imgenex has been selling Kim’s tissue arrays since the fall of 2000 and has seen a seven- to eight-fold increase in sales since then, said Sujay Singh, the company’s president and CEO. This sometimes creates a shortage of arrays, he said, as certain tumor samples get used up.

Each of Imgenex’s slides contains 60 tissues of 2 mm diameter, either normal samples or tumor samples — of the same type, or in combination — from about 20 different cancer types. Moreover, the company provides arrays carrying normal rat and mouse tissues. About half of its customers are from industry, said Singh, although these account for about 70 percent of Imgenex’s tissue array sales. Singh is optimistic about the prospects for his product: “The market will grow if not 10-fold, I would say at least three- to four-fold in the next year,” he predicted.

Another player in the emerging tissue array market is ResGen, a subsidiary of Invitrogen, which has had tissue chips out for less than a year. The company provides arrays with up to 100 different normal human tissue samples of 0.6 mm in diameter obtained from US distributors, as well as arrays with about 50 different mouse tissues. However, adding disease tissue arrays to its program “is a very distinct possbility,” said Matt Baker, ResGen’s antibody group manager. Apart from standard arrays, ResGen also provides custom arrays made from customers’ tissues or ResGen’s tissues according to customer specifications.

 

Manual Steps Drive Scientists Mad

Despite the availability of these commercial products, more and more academic centers, as well as pharmaceutical companies including Merck and Genentech, are producing their own arrays, according to Hewitt.

Still, nobody has figured out how to eliminate the key human step in tissue analysis, the examination by the trained eyes of pathologists or researchers. “I have a [presentation] slide that says ‘Pathologist goes mad, seeks to clone himself’ because of that problem,” said Hewitt. Several companies have been working on image-capturing devices and software that can quantify fluorescence to alleviate the problem to some degree. But even if humans will still have to make the final call, establishing references against which users can compare their data will also be of great importance, said Baker.

Finally, making tissue array data available to the community, and establishing standards for doing so — an issue not unknown to DNA microarray researchers — remains a challenge. Hewitt, who said he spends much of his time on database development, said one solution might be to “just give them the [raw] image and let them interpret it.”

— JK

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