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‘FISH & Chips’ takes scientists inside cells to see genes at work
By Sarah Post

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Cleverly called ‘FISH & Chips,’a new technology lets scientists see which genes are switched on or off in their natural environment, the cell nucleus. The technology allows researchers to peer directly into individual cells and see genes being activated. With colorful images representing genes at work, FISH & Chips promises to help reveal how genes interact with a cell's physical environment.

Studying the circumstances in which genes are activated, or expressed, lets scientists relate gene expression patterns to what the cell is doing—or going to do, according to Robert Singer, who led the research at the Albert Einstein College of Medicine in Bronx, New York. The study appears in today's issue of Science.

A single human colon cancer cell nucleus with a pseudo-colored representation of activated genes. View full

Cancers, for instance, start as genetic defects in isolated cells, and the new technology could be used to pinpoint or track genes involved in the changes that lead to tumors. "If we had a way of looking at all cancer-relevant genes, we'd be able to predict what kind of therapies would be useful," observes Singer.

FISH & Chips could prove valuable in many areas of biomedical research. The technology allows researchers to monitor how specific genes—in single cells—turn on or off in response to a drug or changes in the cellular environment. Among the trillions of cells in our body, sometimes it is just one that matters in disease.

‘FISH & Chips is a fusion of genomics and cell biology.’

Looking at cells individually should help researchers discover disease genes that could be singled out and targeted in therapies. This strategy may be useful in examining tissue biopsies, which typically consist of different types of cells—blood vessels and muscle, for instance, or nerve cells and skin.

FISH & Chips is based on an imaging technology called fluorescence in situ hybridization, or FISH. In this technique, a gene's cellular location is determined using molecular 'probes' that bind to genetic material, triggering a fluorescent signal when the gene is active.

FISH, however, shows only whether one gene is on or off and therefore does not provide information about relationships among genes.

The team at Albert Einstein addressed this limitation by developing a method that allows them to observe patterns in how groups of genes are turned on or off. They use probes that are labeled with 'bar codes'—two or three different fluorescent colors—that make different genes easily identifiable.

Because the fluorescent tags light up as genes are activated, only new gene products can be monitored with this method. For this reason, the technology is ideal for observing genes being turned on or off over time, even at low levels of expression.

This precision led researchers to some unexpected results when they tested out the technique. Repeating a well-documented experiment on gene expression, they monitored the expression of eleven genes after giving growth-inducing serum to human skin cells. Surprisingly, some genes were turned on that had not been picked up by researchers using gene chips, or DNA microarrays. These genes were apparently expressed at low levels and essentially slipped under the radar of the microarrays.

"The genes could not be detected within the sensitivity limits of the chip," explains Singer. Gene chips show the total amount of gene products being made, so if very little is being transcribed, it will not appear in the data.

Conceptual diagram of barcoding. View larger

Gene chips are microchips or glass slides arrayed with bits of DNA representing thousands of genes. In the new technology, the 'chip' is not a glass slide or microchip but the cell nucleus. As technologies for studying gene expression, the researchers say, the tools are complimentary.

Gene chips, which have been used to create molecular profiles of tumor cells, require a relatively large amount of DNA. Researchers either combine the genetic material from many cells or take it from a single cell and magnify it many times. The results may gloss over important differences between cells.

With gene chips, researchers have to destroy the cells to obtain the genetic material. "You destroy the very cells you're following," says Singer. "You don't know which cells genes are associated with."

As a plus, however, gene chips show the total amount of gene products present in cells, not just the new material as it is being made. This lets scientists gauge the relative expression of genes much more easily. And microarray technology is powerful enough to monitor essentially an entire genome at once.

"We have no aims to replace microarrays," says Jeffrey Levsky, a member of the research team. "We just want to offer a complementary approach."

In the Science paper, the researchers coined the phrase "cellular genomics" to describe the fusion genomics and cell biology.

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Levsky, J.M. et al. Single-cell gene expression profiling. Science 297, 836-840 (August 2, 2002).

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